Lexicomp”

Pediatric & Neonatal

We

Dosage Handbook
An Extensive Resource forClinicians
Treating Pediatric and Neonatal Patients

<<
ke4 American Pharmacists Association’
wen’? medication use. Advancing patient care. i
APhA Lexicomp is the official drug reference
for the American Pharmacists Association.

Original Authors:
Carol K. Taketomo, PharmD
Jane H. Hodding, PharmD
Donna M. Kraus, PharmD, FAPhA, FCCP

> Wolters Kluwer

 Use of This Handbook

How do | find information on a drug?

The Pediatric & Neonatal Dosage Handbook has been designed to follow
the format of a dictionary. Trade (brand) and generic drug names are listed
alphabetically, eliminating the need for an alphabetical index. A trade name is
identified by a diamond-like symbol and cross-referenced by page number to
the generic drug monograph. Dictionary-like headings at the top of each page
expedite your search:

What information is included in a drug monograph?

A drug monograph is a listing of fields that combine to form specific information
under a generic drug name. Each drug monograph in this handbook contains up
to 45 key fields of information. Specific fields include pronunciation, use, usual
dosage, dosage forms, administration, extemporaneous preparations, and more.

What type of information is available within the Appendix?

The Appendix offers a compilation of tables, guidelines, and conversion
information which is often helpful when considering patient care. Each edition
of this handbook includes new or updated Appendix sections.

How do | use the Therapeutic Category & Key Word Index?

This index alphabetically organizes therapeutic categories and key words, while
providing a listing of drugs and related topics. The index is fully cross-referenced
by page number to provide quick access to specific drug monographs.

How do | know the information and content in this handbook is reliable?

Since 1978, Lexicomp has been a leader in point-of-care clinical information.
Wolters Kluwer Clinical Drug Information continues to develop Lexicomp
resources that help healthcare providers make more informed decisions, reduce
adverse drug events, and deliver better patient care.

How often is Lexicomp information updated?

The in-house clinical team conducts daily surveillance of numerous medical
publications and websites to obtain information on new drugs, indications,
dosing, warnings and precautions, adverse effects and interactions. Wolters
Kluwer is dedicated to maintaining the depth and relevance of our Lexicomp
information and providing customers with new information as quickly as
possible. While the print publication is updated annually, Lexicomp® Online
(Web-based platform) and Lexicomp® Mobile Apps (smartphone and tablet
applications) are updated daily with new content.

www.wolterskluwerCDI.com
 Lexicomp*
Pediatric & Neonatal
Dosage Handbook
An Extensive Resource for Clinicians
Treating Pediatric and Neonatal Patients

P— A
ke4 American Pharmacists Association’
wo” medication use. Advancing patient care.

_ APhA Lexicomp is the official drug reference

for the American Pharmacists Association

Original Authors:
Carol K. Taketomo, PharmD
Jane H. Hodding, PharmD
Donna M. Kraus, PharmD, FAPhA, FCCP

Wolters Kluwer
“Heo Bo 1 find irefesyenantions ees Wyoui

Pre (Oth

haha hee :
esntins
ube ba a
eae verte dhe,

ne featctet iehacre PMT ARC yh bah

Le oydare lun, extemporaneousprei nie

Now do juse the Frempentic Category & Key Word tnudtox!r

, fee
or wity organizes the TAPAULIC CatestOraes aki Rentive
vad viss and related rapide The iia Pale eras
(ie cr Age quitk atteds Wiapecihc dantmenoerag

ewe? othe ietormarion and content in this hemdhook is rei

Semen ly oer yet poiit-oF edt de HrsSal bev
ghindd« i ye Oreste bo te y
owas
i i Aa W F
iM ; or, y atio 1 CEE © ae ion¥ Hedae ee
.
a wider (Ae Firs aad Cesar
Ae detiver better payer cor ; "

tion Aah Seale idle bitormnation apdtedl? | .

2) ean conderks datly sui arta: ya
aise 1
ii ot MAIO con pining formatior
aera! agin ors, adverse etieitsmapa ; !
‘ ¢
Uh, ML ax
aR PYNSE, the dentin Si
‘or ieee 2
S pthon rer Wah Tht Ovaws
 ° ®
Lexicomp

Pediatric & Neonatal

Dosage Handbook
An Extensive Resource for Clinicians
Treating Pediatric and Neonatal Patients

Original Authors:

Carol K. Taketomo, PharmD

Director of Pharmacy and Nutrition Services
Children's Hospital Los Angeles

Jane Hurlburt Hodding, PharmD

Executive Director, Inpatient Pharmacy Services and
Clinical Nutrition Services
Long Beach Memorial Medical Center and
Miller Children's Hospital

Donna M. Kraus, PharmD, FAPhA, FPPAG, FCCP

Associate Professor of Pharmacy Practice and
Pediatric Clinical Pharmacist
Departments of Pharmacy Practice and Pediatrics,
University of Illinois

Lexicomp®

Pa
x
S&S
APhA
 NOTICE
This data is intended to serve the user as a handy reference and not as a complete drug information resource. It does not
include information on every therapeutic agent available. The publication covers 1,118 commonly used drugs. In addition, it
does not include all potentially relevant information about any particular drug. Instead, it is intended to present important
aspects of drug data in a more concise and accessible format than is typically found in medical literature or product material
supplied by manufacturers. (

The nature of drug information is that it is constantly evolving because of ongoing research and clinical experience and is often
subject to interpretation. While Wolters Kluwer Clinical Drug Information makes reasonable efforts to publish accurate
information, users are advised that the authors, editors, reviewers, contributors, and publishers cannot be responsible for
the continued currency of the information or for any errors, omissions, or the application of this information, or for any
consequences arising therefrom. Therefore, the authors, editors, reviewers, contributors, and publishers shall have no liability
to any person or entity with regard to claims, loss, or damage caused, or alleged to be caused, directly or indirectly, by the use of
information contained herein. Because of the dynamic nature of drug information and the characteristics and needs unique to
individual patients, readers are advised that decisions regarding drug therapy must be based on the independent judgment of
the clinician. Users must regularly consult multiple sources (eg, medical literature and a manufacturer's most current product
information) to remain aware of changing information about a drug and medical practices regarding its use. Therefore, this data
is intended to be used in conjunction with other necessary information and is not intended to be solely relied upon by any user.
The user of this data hereby and forever releases the authors, editors, reviewers, contributors, and publishers of this data from
any and all liability of any kind that might arise out of the use of this data. The authors, editors, reviewers, contributors, and
publishers are not responsible for any inaccurate source materials developed ngthird-parties or for any user misunderstandings
that may arise from the data.
Certain of the authors, editors, reviewers, and contributors have written portions of this book in their individual capacities. The
inclusion of content is not intended to indicate that it has been reviewed or endorsed by any federal or state agency,
pharmaceutical company, or regulatory body.
The publishers have made reasonable efforts to avoid reproducing without permission, any content that may be subject to third-
party copyright claims. Any questions regarding content that may be subject to such claims will be addressed at the first
opportunity.
If you have any suggestions or questions regarding any information presented in this data, please contact our drug information
pharmacists at (855) 633-0577. Book revisions are available at our website at http://www.wolterskluwercdi.com/clinical-notices/
revisions/.
© 2018 Wolters Kluwer Clinical Drug Information, Inc. and its affiliates and/or licensors. All rights reserved
© 1992 to 2017, 1st to 24th Editions, Wolters Kluwer Clinical Drug Information, Inc. and its affiliates and/or licensors. All rights
reserved
Printed in the United States. No part of this publication may be reproduced, stored in a retrieval system, used as a source of
information for transcription into a hospital information system or electronic health or medical record, or transmitted in any form
or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior written permission of the
publisher. Should you or your institution have a need for this information in a format we protect, we have solutions for you.
Please contact our office at the number above.
This manual was produced using LIMS — A complete publishing service of Wolters Kluwer Clinical Drug Information, Inc.

Lexicomp®

ISBN 978-1-59195-374-6 (Domestic Edition)

ISBN 978-1-59195-375-3 (International Edition)

).Wolters Kluwer
 INTRODUCTION

TABLE OF CONTENTS
PUL ccanoncnccand conten seate ct ste teenies epetaner ec eal MMP HE a a la Bs Ah a ani ee ec Pa 2
JAG WYTaW HLS 0Ca RBI RLESS, 2 arena, setonee sah earl eee Bind2 etiam a ih oo bd a eee LP An ea Sr 4
Pte OOM AIA CIMISONUseAeatacsc: es et chica usp erent ele baraac Hpcemtalt stucsmedesntuoal’ -atva hes pysaiquasgustaibiveNaaea east esti ekianuwansd segue eup toby 5
Drug Interactions Editorial Advisory Panel. 20
Editorial Advisory Panel...........c:ccsseeee sicily
PESOAEREIES AOCHITCAEPARLT OLS Ce eas eNews sah gnc vous Seprach dak ada veh oS Samat “Mby Cehtn sb raseSuceinvano bopepeees ob bx Cavan Coarveeds Lan bemetinttens Alege ttsent ext14
BDeseription/of Sections and) Fields‘Used ‘in this' Handbook). 2/82 ee EL a ee I a 15
Definition of Age Group Terminology.
Preventing Prescribing Errors...........ccccccseseesapeescecsseseeseseecereentene h
FDA Name Differentiation Project: The Use of "Tall Man" Letters.......0...cccccccsceccecesecsseseseessecsscessevsseecsesesesessessueseeecesesesseeen sens19
(ol SYRIANS CPALL THRUIN(GAG [2H B]S18(CFS Sa Sat SSE Bp athe ER HPA ai ng RUS aay CARD dcecs Pica SLU (oa gr AA ree tet 23
PEW)BE) 12S csoaca: une donuts osdcocbdasoctico cbaagoLe. ht dastndon oubtolids Oe saubasst. cocuctseepabedaceb socHecc hon dara soepe Seer os cere bere ie ar eap ease 2103
Cardiology / Pulmonary. 2104
Re Oma iarAME OLIN Ssea eee chindo ns canias DSA wes deericimae acme cctinecs ex nclbvorah sn pihhse ny vonduebt epee baer ston nee eA Fe}
Conversion Tables.............0. 2140
Gastroenterology and Nutrition 2143
CLONER I CIDEV CIO DING I at ice tas stra tec rhb oyu tg Wk cy shots Say tncre dy apenaariieysdryanviap adehce eisdoe STAD Sin dk cae a Sead aata'sah Soscedaideny gv sleiress aslente 2180
POG NOUS SENSESOS HAMBLIN OLOGY ers tacatrst Bhs cern ct etwas: cocker Agen can tency boloregsentete Same» WiDyOh vwhicntues erent xe gite daraatnanen tos!taryrts 2182
CAD ORALONY Es Bex cxcuret > den certsrptnscycec 2187
Neonatology... . 2193
NYSYD) AON SSDP Bye aly PERE ERS NE SR SIRE Ra ERE set ae AL en WOO Rt (Se ee RE a en a See 2194
BD NICL5 EER ce eb ae Seance dno nssks ine sGinecn tnd enscnsbasenauuddseesenes sucess teayeentaprpinienoknce diecveneen 2198
Niscellancousinivi 1G) eholveene tet toot Bll 00S 1 TOA sens Nain SUP SETI DA ORS epee) 2199
MibeTAPGUC LCAEGON ea KEV VOL INDEX tense owacht owsbseennvaien etenuuns «enpascliniboVeavmsany « i OWAdDawerseenastitesea Dip néahsunpenboved els deineasnodiys cinndsdes 2227
PREFACE

PREFACE
This twenty-fifth edition of the Pediatric & Neonatal Dosage Handbook is designed to be a practical and convenient guide to the
dosing and usage of medications in neonates, infants, children, and adolescents. The pediatric population is a dynamic group,
with major changes in pharmacokinetics and pharmacodynamics taking place throughout infancy and childhood. Therefore, the
need for the evaluation and establishment of medication dosing regimens in pediatric patients of different ages is great.
Special considerations must be taken into account when dosing medications in pediatric and neonatal patients. Unfortunately,
due to a lack of adequate trials, most medications commonly used in neonates and children do not have FDA approved labeling
for use in pediatric patients. Only 30% of drugs used in children in a 1988 survey carried FDA approval in their labeling.
Seventy-five percent of medications listed in the 1990 Physicians' Desk Reference (PDR) carried some type of precaution or
disclaimer statement for use in children.’ An analysis of the 2009 PDR reported that 56% of products included pediatric labeling.
Another study found that 45% of parenteral medications used in the neonatal intensive care unit are not approved by the FDA
for use in neonates.? Thus, further studies are needed to improve FDA drug labeling for pediatric patients, especially for
neonates (and particularly preterm neonates).°:4
Investigations have also demonstrated the need for further improvement in FDA drug labeling for medications specifically used
in critically ill children. One study. found that 67% of medications used in a pediatric intensive care unit did not have FDA-
approved labeling for use in pediatric patients or only had approval for use in limited age groups.° Of all drugs prescribed in a
pediatric cardiac intensive care unit (CICU), 36% were prescribed "off-label" (ie, the drug did not have an FDA-approved labeled
indication based on the patient's age); 94% of patients received one or more off-label medications; and the frequency of use of
off-label drugs was higher in CICU patients who were younger, and in those with a higher severity of illness.° Considering the
large number of medications without FDA-approved labeling that are used in critically ill neonates and children, further pediatric
studies are clearly warranted to improve FDA drug labeling, and the safe and effective use of medications in these patients.
The FDA Modernization Act of 1997, the Children's Health Act of 2000, the Best Pharmaceuticals for Children Act of 2002, and
the Pediatric Research Equity Act of 2003 have all helped to increase pediatric drug studies. The FDA Amendment Act of 2007,
which was signed into law in September 2007, reauthorizes and amends the Pediatric Research Equity Act and the Best
Pharmaceuticals for Children Act (Title !V and Title V, Public Law 110-85, 110th Congress). The Food and Drug Administration
Safety and Innovation Act of 2012 renews and strengthens the Best Pharmaceuticals for Children Act and the Pediatric
Research Equity Act by making these two laws permanent (and no longer subject to reauthorization every five years).
The FDA Modernization Act of 1997 (Section 111, Public Law 105-115, 105th Congress) encouraged pharmaceutical
companies to conduct pediatric drug studies by allowing 6 months of market exclusivity to certain designated drugs. A list of
drugs, for which additional pediatric information may produce pediatric health care benefits, was required by this law to be
developed by the US Department of Health and Human Services (HHS), with input from the American Academy of Pediatrics,
the Pediatric Pharmacology Research Unit Network,’ and the US Pharmacopoeia. For complete list: http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/DevelopmentResources/ucm077695.htm
The pediatric section of the FDA Modernization Act was renewed by Congress and signed into law January 4, 2002. This new
law, called the Best Pharmaceuticals for Children Act, reauthorized the use of the 6-month patent extension to encourage
pharmaceutical companies to conduct pediatric drug research. This law called for the establishment of an Office of Pediatric
Therapeutics within the FDA and established an FDA Pediatric Pharmacology Advisory Committee and a Pediatric Sub-
committee of the Oncologic Drugs Advisory Committee. It also created a research fund for pediatric studies of drugs that are off
patent, granted a special "priority status" to pediatric labeling changes, required the Department of Health and Human Services
(along with the Institute of Medicine) to conduct a study to assess federally funded pediatric research, and called for the
development of a Final Rule that required drug labeling to include a toll-free number to report adverse events.®
The Best Pharmaceuticals for Children Act was reauthorized, amended, and signed into law in September 2007, as part of the
FDA Amendment Act of 2007.°. This amended law establishes an internal review committee (the Pediatric Review Committee)
within the FDA to review written requests that were issued and the submitted reports from drug manufacturers."° It also requires
manufacturers who were granted a patent extension to revise pediatric labeling in a timely manner; reduces the patent
extension from 6 months to 3 months for drugs with combined gross sales >1 billion dollars; prohibits the extension of market
exclusivity for >9 months; requires manufacturers to explain why a pediatric formulation cannot be developed (when requested
to perform pediatric studies); requires product labeling to include information about pediatric studies whether or not the studies
demonstrate that the drug is safe and effective; requires the government to notify the public of pediatric drug formulations that
were developed and studied and found to be safe and effective, but not introduced into the market within 1 year; and requires
that a report be submitted to congress that assesses the use of patent extensions in making sure that medications used by
pediatric patients are tested and properly labeled."
The 1998 Pediatric Final Rule was an FDA regulation, titled "Regulations Requiring Manufacturers to Assess the Safety and
Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule".’* This important regulation required that
manufacturers conduct pediatric studies for certain new and marketed drugs and biological products. This requirement was
mandatory, and its scope included new drugs (ie, new chemical entities, new dosage forms, new indications, new routes of
administration, and new dosing regimens) and certain marketed drugs (ie, where the drug product offered meaningful -
therapeutic benefit or had substantial use in pediatric patients, AND the absence of pediatric labeling posed a risk). This
FDA regulation became effective April 1, 1999, but studies mandated under this rule were not required to be submitted to the
FDA before December 2, 2000. The 1998 Pediatric Final Rule and the authority of the FDA to require manufacturers to conduct
pediatric studies was challenged with a law suit. In March 2002, the FDA requested a 2-month stay on the lawsuit, so it could
publish a notice and suspend the 1998 Pediatric Final Rule for 2 years. During the 2-year suspension of the Rule, the FDA
planned to study whether the Best Pharmaceuticals for Children Act of 2002 made the 1998 Final Rule unnecessary. After
multiple organizations lobbied Congress and the President, the Secretary of the Department of Health and Human Services
announced in April 2002, that the FDA would continue to defend the Pediatric Final Rule of 1998 in court. However, on October
17, 2002, the US District Court for the District of Columbia barred the FDA from enforcing the Pediatric Final Rule. Fortunately,
Congress passed the Pediatric Research Equity Act of 2003 (Public Law S.650, 108th Congress). This law essentially
reinstates the Pediatric Final Rule and authorizes the FDA to require pharmaceutical manufacturers to conduct pediatric
studies of certain drugs and biological products. It also establishes an FDA Pediatric Advisory Committee. The Pediatric
Research Equity Act was reauthorized, amended, and signed into law in September 2007, as part of the FDA Amendment Act
of 2007.
The Children's Health Act of 2000 was signed into law on October 17, 2000. This important law establishes a Pediatric
Research Initiative (headed by the Director of the NIH) and provides funds to increase support for pediatric clinical research.
The Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law on July 9, 2012.1 The pediatric
provisions of this law renew and strengthen the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. -
FDASIA makes both of these important Acts permanent and thus ensures that pediatric patients will have a permanent place in
drug research and development. This new law requires a pediatric study plan to be submitted earlier by drug manufacturers
subject to the Pediatric Research Equity Act. It also gives the FDA new authority to help ensure that requirements of the
Pediatric Research Equity Act are met in a more timely fashion. These requirements should help increase pediatric drug
development and generate pediatric drug information more quickly. FDASIA also addresses several neonatal concerns. It
requires the Office of Pediatric Therapeutics to include a member with expertise in a pediatric subgroup that is less likely to be
studied under other laws, and specifies that for five years after enactment, this should include an individual with expertise in
neonatology. The Act also specifies that an FDA employee with expertise in neonatology should be a member of the Pediatric
Review Committee. FDASIA also requires Best Pharmaceuticals for Children Act requests for pediatric drug studies to include a
 INTRODUCTION

rationale for not including neonatal studies if none are requested. These requirements should help to increase neonatal drug
information. More information may be found at the following:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase
While these important laws, plus other FDA regulations that required expanded information in the Pediatric Use section of the
prescribing information for all prescription drugs, will help to increase and disseminate pediatric and neonatal drug information,
the practice of off-label prescribing in pediatric patients is a common occurrence. Off-label use is defined by The American
Academy of Pediatrics (AAP) as: "The use of a drug that is not included in the package insert (approved labeling) for that drug
and the purpose of off-label use is to benefit an individual patient". It is important to note that the term "off-label" does not imply
an improper, illegal, contraindicated, or investigational use, nor does it necessarily signify a lack of data or clinical experience.'4
The content included within this handbook serves as a compilation of recommended pediatric and neonatal doses found in the
literature, provides relevant clinical information regarding the use of drugs in all pediatric patients (neonates through
adolescents), and is intended to assist pediatric health care professionals with evidence-based therapeutic decisions.

New in This Edition

This new edition includes 1,121 unique drug monographs and incorporates additions and revisions in a format that we hope the
user will find beneficial. As with each edition, hundreds of drug monographs have been updated and revised, including updates
to many monographs based on new guideline recommendations. Thirty-nine new monographs have been added: Acetohy-
droxamic Acid; Acrivastine and Pseudoephedrine; Alendronate; Aliskiren; Anthralin; Artesunate; Articaine and Epinephrine;
Asenapine; Atropine and Pralidoxime; Bacitracin, Neomycin, Polymyxin B, and Pramoxine; Balanced Salt Solution; Barium;
Benralizurhab; Brompheniramine and Phenylephrine; Brompheniramine, Dextromethorphan, and Phenylephrine; Burosumab-
twza; Cerliponase Alfa; Chlorhexidine Gluconate (Oral); Chlorhexidine Gluconate (Topical); Ciprofloxacin and Fluocinolone;
Demeclocycline; Eslicarbazepine; Fingolimod; Gemtuzumab Ozogamicin; Glycerol Phenylbutyrate; Hemin; Indigotindisulfonate
Sodium; Ipilimumab; Lamivudine and Tenofovir Disoproxil Fumarate; Latanoprost; Magnesium Carbonate; Mivacurium;
Nesiritide; Nilotinib; Nivolumab; Pregabalin; Tezacaftor and lvacaftor; Tisagenlecleucel; Vestronidase Alfa-vjbk; Voretigene
Neparvovec-rzyl.
It is hoped this edition continues to be a valuable and practical source of clinical drug information for the pediatric health care
professional. Suggestions to improve future editions are welcome.
References
Al. Food and Drug Letter, Washington Business Information, Inc. November 23, 1990.

2 Kumar P, Walker JK, Hurt KM, Bennett KM, Grosshans N, Fotis MA. Medication use in the neonatal intensive care unit:
current patterns and off-label use of parenteral medications. J Pediatr. 2008;152:412.
American Academy of Pediatrics, Committee on Drugs. Off-label use of drugs in children. Pediatrics. 2014;133:563-567.
Milne CP, Davis J. The pediatric studies initiative: after 15 years have we reached the limits of the law? Clinical
Therapeutics. 2014:36:156-162.
5. Yang CP, Veltri MA, Anton B, Taster M, Berkowitz ID. Food and Drug Administration approval for medications used in the
pediatric intensive care unit: a continuing conundrum. Pediatr Crit Care Med. 2011;12:e195-e199.
6. Maltz LA, Klugman D, Spaeder MC, Wessel DL. Off-label drug use in a single-center pediatric cardiac intensive care unit.
World J Pediatr Congenital Heart Surg. 2013;4:262-266.
7. _ http://)www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm
Birenbaum D. Pediatric initiatives: a regulatory perspective of the US experience. 2002. Available at http://www.fda.gov/
cder/pediatric/presentation/Ped_Init_2002_ DB/index.htm
9. Establishment of the Pediatric Review Committee, available at http://www.fda.gov/cder/pediatric/Pediatric_Review_Com-
mittee_Establishment%20_Memo.pdf
10. Ref B.S. 1156. The best pharmaceuticals for children amendments of 2007. Available at http://www.washingtonwatch.
com/bills/show/110 SN 1156.html
11. "Department of Health and Human Services, Food and Drug Administration, 21CFR Parts 201, 312, 314, and 601,
regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in
pediatric patients; final rule. Fed Regist. 1998;63(231):66631-66672.
12. Food and Drug Administration Safety and Innovation Act (FDASIA), Title V - Pediatric Drugs and Devices, Public Law
112-144, 112th Congress, July 9, 2012. Available at http://www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-
112publ144.pdf
13. “Pediatric use drug labeling NDA supplements due by December 1996 - FDA final rule; agency establishing pediatric
subcommittee to track implementation. F-D-C Reports - The Pink Sheet. Wallace Werble Jr, Publisher; 1994.
44. American Academy of Pediatrics (AAP). Off-label use of drugs in children. Pediatrics. 2014; 33;563-567. Available at
http://pediatrics.aappublications.org/content/133/3/563.full.pdf+html
ACKNOWLEDGMENTS

ACKNOWLEDGMENTS
Special acknowledgement goes to all Lexicomp staff for their contributions to this handbook.
The original authors wish to thank their families, friends, and colleagues who supported them in their efforts to complete this
handbook.
Special thanks goes to Chris Lomax, PharmD, who played a significant role in bringing. APhA and Lexicomp together.
In addition, Dr Taketomo would like to thank Robert Taketomo, PharmD, MBA for his professional guidance and continued
support, Celeste Ewig, PharmD, BCPS, and the pharmacy staff at Children's Hospital, Los Angeles, for their assistance.
Dr Kraus would like to especially thank Keith A. Rodvold, PharmD, for his ongoing professional and personal support, and the
pediatric and neonatal clinical pharmacists at the Children's Hospital University of Illinois for their assistance.
Dr Hodding would like to thank Glenn Hodding, PharmD; Neepa Rai, PharmD; and the pediatric pharmacists at Miller Children's
Hospital for their continued professional and personal support.
Some of the material contained in this book was a result of pediatric pharmacy contributors throughout the United States and
Canada. Lexicomp has assisted many pediatric medical institutions to develop hospital-specific formulary manuals that contain
clinical drug information as well as dosing. Working with these pediatric clinical pharmacists, pediatric hospital pharmacy and
therapeutics committees, and hospital drug information centers, Lexicomp has developed an evolutionary drug database that
reflects the practice of pediatric pharmacy in these major pediatric institutions.
 INTRODUCTION

NEONATAL EDITORIAL ADVISORY PANEL

William F. Buss, PharmD
Clinical Pharmacist
Neonatal Intensive Care Unit, Indiana University Health, James Whitcomb Riley Hospital for Children

M. Petrea Cober, PharmD, BCNSP

Clinical Pharmacy Coordinator
Neonatal Intensive Care Unit, Children's Hospital of Akron
Assistant Professor of Pharmacy Practice
Northeast Ohio Medical University (NEOMED)

Sherry Luedtke, PharmD

Associate Professor
Department of Pharmacy Practice, Texas Tech University HSC School of Pharmacy

Christopher McPherson, PharmD

Clinical Pharmacist
Neonatal Intensive Care Unit, St. Louis Children's Hospital
Assistant Professor
Department of Pediatrics, Washington University School of Medicine

Charla E. Miller Nowak, RPh, PharmD

Neonatal Clinical Pharmacy Specialist
Wolfson Children's Hospital

Nicole Passerrello, PharmD, BCPPS, BCPS

Senior Clinical Content Specialist
Wolters Kluwer

Amy L. Potts, PharmD, BCPS

Assistant Director
' Department of Pharmacy
PGY1 & PGY2 Residency Program Director
Monroe Carell Jr. Children's Hospital at Vanderbilt

Chasity M. Shelton, PharmD, BCPS, BCNSP

Assistant Professor of Clinical Pharmacy
- Department of Clinical Pharmacy, University of Tennessee Health Science Center
Clinical Pharmacy Specialist
Pediatric Infectious Diseases and Antimicrobial Stewardship, Le Bonheur Children's Hospital
DRUG INTERACTIONS EDITORIAL ADVISORY PANEL

DRUG INTERACTIONS EDITORIAL ADVISORY PANEL

Melody Berg, PharmD, MPH, BCPS-AQ ID, AAHIVP
Senior Clinical Content Specialist
Wolters Kluwer

Kay Burke, PharmD ;

Senior Clinical Content Specialist
Wolters Kluwer

Jamie Hoffman, PharmD, BCPS

Senior Clinical Content Specialist
Wolters Kluwer

Jooran Kim, PharmD

Pharmacotherapy Contributor
Vancouver, Canada
Carrie Nemerovski, PharmD, BCPS, AQ-Cardiology
Senior Clinical Content Specialist
Wolters Kluwer

Sacha R. Pollard, PharmD, BCPS

Pharmacotherapy Contributor
Fort Mill, South Carolina

Steve Sklar, PharmD

Senior Clinical Manager
Wolters Kluwer

Stephen Marc Stout, PharmD, MS, BCPS

Director, Clinical Content
Wolters Kluwer

Daniel S. Streetman, PharmD, MS, RPh

Clinical Manager, Metabolism, Interactions, & Genomics Group
Wolters Kluwer

David M. Weinstein, PhD, RPh

Senior Director, Clinical Content
Wolters Kluwer
 INTRODUCTION

EDITORIAL ADVISORY PANEL

Jane Acton, PharmD Nicole M. Bohm, PharmD, BCPS
Senior Clinical Content Specialist, Drug Files Clinical Specialist, Internal Medicine and Associate Professor
Wolters Kluwer South Carolina College of Pharmacy
Residency Program Director, PGY2 Internal Medicine
Joseph F. Alexander Jr., MD Medical University of South Carolina
Clinical Professor of Internal Medicine
Northeast Ohio Medical University (NEOMED) Peter Bonis, MD
Allergist/Immunologist Chief Medical Officer
Summa Health System Clinical Effectiveness

Roaa Al-Gain, PharmD, BCPS, BCACP Douglas J. Borys, PharmD, DABAT, FAACT
Drug Information Pharmacist and Clinical Pharmacist, Professor in Pharmaceutical Sciences
Anticoagulation Concordia University Wisconsin, School of Pharmacy
King Faisal Specialist Hospital & Research Center
Diedra L. Bragalone, PharmD, MBA, BCOP,
Abdulrazaq Al-Jazairi, PharmD, FCCP, BCPS
BCPS-AQ, Cardiology Senior Clinical Content Specialist
Head, Medical/Critical Care Pharmacy Services and Wolters Kluwer
Clinical Pharmacist, Cardiology
Department of Pharmacy Services, King Faisal Lee Bragg, PharmD
Specialist Hospital & Research Center Senior Clinical Content Specialist
Wolters Kluwer
Nada Al-Qadheeb, PharmD, BCPS,
BCCCP, FCCP, FCCM Leslie A. Briscoe, MSN, PMHNP-BC
Certified Nurse Practitioner - Psychiatry
Clinical Pharmacy Consultant, Critical Care
Louis Stokes Cleveland VA Medical Center, US Department of
Hafer Al-Batin Central Hospital
Veterans Affairs
Aljohara Al-Sakran, PharmD, BCPS
Susan P. Bruce, PharmD, BCPS
Clinical Pharmacy Specialist, Pediatrics
Chair and Associate Professor
King Faisal Specialist Hospital & Research Center
Department of Pharmacy Practice, Northeast Ohio Medical
William Alvarez Jr., BS, PharmD, BCPS University (NEOMED)
Clinical Director, Content Harmonization
Whitney Redding Buckel, PharmD, BCPS
Wolters Kluwer
Clinical Pharmacist
_ Tracy Anderson-Haag, PharmD, BCPS Intermountain Medical Center
Clinical Pharmacy Specialist, Kidney Transplantation
Wendy Moore Bullington, PharmD, BCPS
Hennepin County Medical Center
Clinical Pharmacy Specialist, Pulmonary Medicine and
Christina L. Aquilante, PharmD, FCCP Clinical Coordinator, Internal Medicine
Associate Professor Medical University of South Carolina
Department of Pharmaceutical Sciences
Naomi Burns, BSc (hons), Clin Dip
Co-Director
Medicines. Safety Pharmacist
Center for Translational Pharmacokinetics &
Western Sussex Hospitals NHS Trust (UK)
Pharmacogenomics, University of Colorado Denver
School of Pharmacy William F. Buss, PharmD
Kylie Barnes, PharmD, BCPS Clinical Pharmacist
Neonatal Intensive Care Unit, Indiana University Health,
Clinical Pharmacist
James Whitcomb Riley Hospital for Children
Kansas City Care Clinic
Clinical Assistant Professor Ben Caldwell, RPh
Department of Pharmacy Practice, University of Clinical Content Specialist, Clinical Decision Support Dosing
Missouri Kansas City, School of Pharmacy Content
Elizabeth A. Bartis, RN, MSN, FNP Wolters Kluwer
Family Nurse Practitioner Stacey L. Campbell, PharmD, MPH, BCPS
Charlotte, North Carolina Medical Intensive Care Unit Clinical Pharmacy Specialist
Verna L. Baughman, MD Emory University Hospital
Professor Todd Canada, PharmD, BCNSP, BCCCP, FASHP,
Anesthesiology and Neurosurgery, University of Illinois
FTSHP
Elizabeth J. Beckman, PharmD, BCPS, Clinical Pharmacy Services Manager
BCPPS, BCCCP University of Texas MD Anderson Cancer Center
Clinical Knowledge Management Analyst, Office of the Katie Carls, PharmD, BCPP
Executive Vice President for Health Affairs Clinical Manager, International Content
UK Healthcare Wolters Kluwer
Judith L. Beizer, PharmD, CGP, FASCP, AGSF Corey A. Carter, MD
Clinical Professor Chief of Thoracic Oncology
Department of Clinical Pharmacy Practice, St John's John P. Murtha Cancer Center, Walter Reed National Military
University College of Pharmacy and Health Sciences Medical Center
Emily C. Benefield, PharmD, BCPS, BCPPS Romulo Carvalho
Advanced Clinical Pharmacist — Pediatric Solid Organ Pharmacotherapy Contributor
Transplant Rio de Janeiro, Brazil
Intermountain Healthcare
Jared Cash, PharmD, BCPS
Tarun Bhalla, MD, MBA, FAAP Director, Pharmacy
Pediatric Anesthesiologist Primary Children's Hospital, Intermountain Healthcare
Nationwide Children's Hospital
Larisa H. Cavallari, PharmD, BCPS
Jeffrey R. Bishop, PharmD, MS, BCPP Assistant Professor
Assistant Professor Department of Pharmacy Practice, University of Illinois
Department of Pharmacy Practice, University of Illinois
at Chicago Shawn Chase, PharmD
Clinical Content Specialist, Clinical Decision Support Dosing
Amie Blaszczyk, PharmD, CGP, BCPS, FASCP Content
Associate Professor.and Division Head — Geriatrics Wolters Kluwer
Texas Tech University Health Sciences Center
EDITORIAL ADVISORY PANEL

Ashley H. Chasick, PharmD Emily E. Davies, PharmD, CPE

Clinical Pharmacy Specialist, Oncology/Bone Marrow Clinical Pharmacist
Transplant University Hospital Home Health
Ochsner Medical Center
Lacey Davis, PharmD, BCPS
Angela Clark, PharmD, BCPS Clinical Pharmacist, Hospice, Palliative Care, and Post-Acute
Clinical Pharmacy Specialist, Cardiothoracic Intensive Care
Care Unit and Cardiology Team Lead Aultman Hospital
University of Michigan Health System
Beth Deen, PharmD, BDNSP
M. Petrea Cober, PharmD, BCNSP Senior Pediatric Clinical Pharmacy Specialist
Clinical Pharmacy Coordinator Cook Children's Medical Center
Neonatal Intensive Care Unit, Children's Hospital of Akron
Assistant Professor of Pharmacy Practice Renee K. Dixon, MD
Northeast Ohio Medical University (NEOMED) Attending Physician, Critical and Pulmonary Care
University of Maryland Medical Center, UMMC Midtown
Adam Cochrane, PharmD, BCPS Campus, and Baltimore Veterans Affairs Hospital.
Organ Transplant Clinical Specialist
Inova Fairfax Hospital Kim S. Dufner, PharmD
Adjunct Assistant Professor Clinical Content Specialist
Butler University Wolters Kluwer

Christine M. Cohn, PharmD, BCPS Kelly Dunn, PA-C

Senior Clinical Content Specialist Physician Assistant
Wolters Kluwer Troy Sleep Center-and AAIRS Clinic

Mellaknese Coker, BSN, RN, CAPA, CPN, CRT Ijeoma Julie Eche, MSN, FNP-BC, AOCNP,
Clinical Nurse Manager CPHON, BMT-CN
Sibley Memorial Hospital/Johns Hopkins Medicine Family Nurse Practitioner, Staff Nurse
Beth Israel Deaconess Medical Center, Boston Children's
Michelle Condren, PharmD, BCPPS, AE-C, Hospital
CDE, FPPAG
Professor, Director of Pediatric Research, and Mary Eche, PharmD, BCPS, BCCCP
Director of Pharmacology Clinical Pharmacist II
University of Oklahoma School of Community Beth Israel Deaconess Medical Center
Medicine, Department of Pediatrics
Michael S. Edwards, PharmD, MBA, BCOP
Jessica Connell, RN, BSN Pharmacotherapy Contributor
Pharmacotherapy Contributor Chevy Chase, Maryland
Tifton, Georgia
Vicki L. Ellingrod, PharmD, BCPP
Kim Connell, PharmD Head, Clinical Pharmacogenomics Laboratory and Associate
Pharmacotherapy Contributor Professor
Thomasville, Georgia Department of Psychiatry, Colleges of Pharmacy and
Medicine, University of Michigan 4
Elizabeth Connor, MD
Gynecologic Oncology Fellow Jacqueline Ellis, RN, MSN
Cleveland Clinic Foundation Women's Health Institute Pharmacotherapy Contributor
Twinsburg, Ohio
Ann P. Conrad, ANP-BC, RN, ACRN
Advanced Practice Nurse Marty Eng, PharmD, RPh, BCGP, BCPP, CDP,
Community Hospitalists CADDCT, FASCP
Associate Professor, Department of Pharmacy Practice
Abigail Cook, PharmD, BCPS Cedarville University, School of Pharmacy
Clinical Specialist, Advanced Heart Failure/Heart Transplant
Loyola University Health System Kelley K. Engle, BSPharm
Pharmacotherapy Contributor
Amanda H. Corbett, PharmD, BCPS, Stow, Ohio
FCCP, AAHIVE
Clinical Assistant Professor Christopher Ensor, PharmD, BCPS (AQ-CV)
Eshelman School of Pharmacy, University of North Carolina Clinical Pharmacy Specialist, Thoracic Transplantation
University of Pittsburgh Medical Center
Susan Cornell, PharmD, CDE, FAPhA, FAADE
Associate Professor Jennifer Eshelman, PharmD, BCPPS
Department of Pharmacy Practice Pediatric Heart Institute Clinical Pharmacy Specialist
Assistant Director of Experimental Education Children's Hospital Colorado
Midwestern University, Chicago College of Pharmacy
Erin Fabian, PharmD, RPh, BCPS
Marilyn Cortell, RDH, MS, FAADH Senior Clinical Content Specialist
Associate Professor Wolters Kluwer
New York City College of Technology, City University of
New York
Michael Fahey, BSc, MSc, PhD, MRPharmS
Director
Harold L. Crossley, DDS, MS, PhD Alignment Consulting
Professor Emeritus
Baltimore College of Dental Surgery, University of
Margie Farrar-Simpson
Maryland Baltimore Manager, Ambulatory Case Management
Children's National Medical Center
Melanie W. Cucchi, BS, PharmD, RPh
Elizabeth A. Farrington, PharmD, FCCP, FCCM,
Clinical Manager, Pediatric & Neonatal Content
Wolters Kluwer FPPAG, BCPS
Pharmacist II] - Pediatrics
Judy Cvetinovich, RPh New Hanover Regional Medical Center
Clinical Manager, Clinical Decision Support Dosing Content
Wolters Kluwer J. Emanuel Finet, MD
Staff, Section of Heart Failure and Transplantation Medicine
Mitchell J. Daley, PharmD, FCCM, BCPS Cleveland Clinic
Clinical Pharmacy Specialist — Critical Care
University Medical Center Brackenridge Christine Fitzgerald, PharmD, BCPS
Pharmacotherapy Contributor
Kathryn E. Dane, PharmD, BCPS Valleio, California
Clinical Pharmacy Specialist, Inpatient Anticoagulation
and Hematology Terri Fowler, DNP, APRN, FNP-C
The Johns Hopkins Hospital Assistant Professor
Medical University of South Carolina
 INTRODUCTION

David Frame, PharmD Martin D. Higbee, PharmD

Hematology/Oncology/BMT Clinical Specialist Retired Associate Professor
University of Michigan Medical Center Department of Pharmacy Practice and Science, The
University of Arizona
Kristina M. Frangella, PharmD, BCPS,
CDE, BCACP Jane Hurlburt Hodding, PharmD
Clinical Pharmacy Specialist, Ambulatory Care Executive Director, Inpatient Pharmacy Services and Clinical
Louis Stokes Cleveland Department of Veteran Affairs Nutrition Services
Medical Center Long Beach Memorial Medical Center and Miller Children's
Hospital
Carole W. Fuseck, MSN, RN, ACCNS-AG,
VA-BC Mark T. Holdsworth, PharmD
Associate Professor of Pharmacy & Pediatrics and Pharmacy
Clinical Nurse Specialist, Critical Care
Practice Area Head
Louis Stokes Cleveland Department of Veteran Affairs
College of Pharmacy, The University of New Mexico
Medical Center

Jennifer Gatsos-Walter, PharmD Edward Horn, PharmD, BCPS

Clinical Specialist, Transplant/Cardiothoracic Surgery
Senior Clinical Content Specialist , Clinical Decision
Allegheny General Hospital
Support Dosing Content
Wolters Kluwer Collin A. Hovinga, PharmD, MS, FCCP
Charlés Gaudet, BSN, RN, CCRN Director of Research Support Services
Seton Healthcare Family, Dell Children's Medical Center
Staff Nurse
Clinical Associate Professor of Pharmacy
Tufts Medical Center
UT Austin School of Pharmacy
Laura Gaudet, BDN, RN-BC
Joanna Hudson, PharmD, BCPS, FASN, FCCP,
Staff Nurse
Massachusetts General Hospital FNKF
Clinical Pharmacist, Nephrology
Joyce Generali, RPh, MS, FASHP Methodist University Hospital
Senior Clinical Manager, In-depth Content Professor, Department of Clinical Pharmacy and Department
Wolters Kluwer of Medicine-Division of Nephrology
University of Tennessee Health Science Center
Ann Gentry, PharmD
Medical Writer Makiko Ilwasawa, PharmD, BCPS
Gentry Medical Communications Chief Pharmacist, Drug Information Center
National Cerebral and Cardiovascular Center
Riane Ghamrawi, PharmD, BCPS
Antimicrobial Stewardship Pharmacist Specialist Adam B. Jackson, PharmD, BCPS
West. Chester Hospital Clinical Pharmacy Specialist in Infectious Diseases
Kaiser Permanente
Heather L. Girand, PharmD
Professor of Pharmacy, Pediatrics Anna M. Wodlinger Jackson, PharmD, BCPS-AQ
Pharmacy Practice, Ferris State University College of Cardiology
Pharmacy Pharmacotherapy Contributor
Fort Lauderdale, Florida
Meredith D. Girard, MD, FACP
Medical Staff Douglas L. Jennings, PharmD, AACC, BCPS-AQ
Department of Internal Medicine, Summa Health Systems
Cardiology, FCCP
Assistant Professor Internal Medicine
Clinical Pharmacy Manager, Heart Transplant and Mechanical
Northeast Ohio Medical University (NEOMED)
Circulatory Support
Morton P. Goldman, RPh, PharmD, BCPS, New York Presbyterian Columbia Medical Center
FCCP Sallie Johnson, PharmD, BCPS-AQ Cardiology
Health Care Consultant Clinical Pharmacy Specialist, Cardiology
American Pharmacotherapy, Inc Penn State Milton S. Hershey Medical Center
Julie A. Golembiewski, PharmD Beth Outland Jones, RPh
Clinical Associate Professor and Clinical Pharmacist, Clinical Content Specialist, Clinical Decision Support
Anesthesia/Pain Precautions Team
Colleges of Pharmacy and Medicine, University of Illinois Wolters Kluwer
Jeffrey P. Gonzales, PharmD, BCPS Christine M. Jones, MPA-C
Critical Care Clinical Pharmacy Specialist Clinical Content Specialist, Clinical Decision Support
University of Maryland Medical Center Precautions Team
Wolters Kluwer
John Grabenstein, RPh, PhD, FAPhA
Pharmacotherapy Contributor Michael A. Kahn, DDS
West Point, Pennsylvania Professor and Chairman
Department of Oral and Maxillofacial Pathology, Tufts
Shellee A. Grim, PharmD, MS-CTS, BCPS
University School of Dental Medicine
Senior Clinical Content Specialist
Wolters Kluwer Julie J. Kelsey, PharmD
Clinical Specialist
Tracy Hagemann, PharmD
Women's Health and Family Medicine, Department of
Associate Dean and Professor of Clinical Pharmacy
Pharmacy Services, University of Virginia Health System
University of Tennessee College of Pharmacy
Patricia Kelsey, RPh, CPHIMS
Kat Hall, MPharm, IPresc, PGCertClinEd,
Clinical Content Specialist, Clinical Decision Support Dosing
PGDipGPP, MFRPSII, MRPharmS, FHEA Content
Director of Centre for Inter-Professional Postgraduate Wolters Kluwer
Education and Training
University of Reading Patrick J. Kiel, PharmD, BCPS, BCOP
Clinical Pharmacy Specialist
Steve Hart, MD yg Hematology and Stem Cell Transplant, Indiana University
Director, Clinical Decision Support Precautions Team Simon Cancer Center
Wolters Kluwer
Jooran Kim, PharmD
Eric Henry, PharmD Pharmacotherapy Contributor
Clinical Content Specialist, Drug Files Vancouver, Canada
Wolters Kluwer
Polly E. Kintzel, PharmD, BCPS, BCOP
Clinical Pharmacy Specialist - Oncology
Spectrum Health
EDITORIAL ADVISORY PANEL

Michael Klepser, PharmD, FCCP, FIDP Jennifer Loucks, PharmD, BCPS

Professor of Pharmacy Solid Organ Transplant Clinical Pharmacist
Department of Pharmacy Practice, Ferris State University The University of Kansas Hospital

Shilpa Klocke, PharmD, BCPS Jennifer Fisher Lowe, PharmD, BCOP

Clinical Pharmacy Specialist, Neurology Clinical Oncology Pharmacist
Kaiser Permanente IU Health Simon Cancer-Center

Sandra Knowles, RPh, BScPhm Sherry Luedtke, PharmD

Drug Information Pharmacist Associate Professor
Sunnybrook Health Sciences Centre Department of Pharmacy Practice, Texas Tech University
HSC School of Pharmacy
Omer N. Koc, MD
Staff Physician Viki Lui, BPharm, MPH, MSHP
Hematology and Medical Oncology Department, Lead Education Pharmacist for Pharmacy Department
Cleveland Clinic The Royal Melbourne Hospital

Jill M. Kolesar, PharmD, FCCP, BCPS Shannon N. Lukez, RN, MSN, ANP-BC
Associate Professor Adult Nurse Practitioner - Orthopedics
School of Pharmacy, University of Wisconsin Paul P. Mountaineer Orthopedic Specialists
Carbone Comprehensive Cancer Center
Jordan Lundberg, PharmD, BCOP
Susannah E. Koontz, PharmD, BCOP Clinical Specialist Pharmacist
Principal and Consultant The Arthur G. James Cancer Hospital and Richard J. Solove
Pediatric Hematology/Oncology and Stem Cell Research Institute-at The Ohio State University
Transplantation/Cellular Therapy, Koontz Oncology
Consulting, LLC : Scott Lundy, MD, PhD
Resident Physician
Amy Kramer, PharmD Cleveland Clinic Foundation
Clinical Content Specialist, Clinical Decision Support
Precautions Team Tracy Macaulay, PharmD, AACC, BCPS (AQ-CV)
Wolters Kluwer Clinical Pharmacy Specialist
UKHealthcare Pharmacy Services
Donna M. Kraus, PharmD, FAPhA, FPPAG, FCCP
Associate Professor of Pharmacy Practice and Pediatric Janis MacKichan, PharmD, FAPhA
Clinical Pharmacist Professor Emeritus
Departments of Pharmacy Practice and Pediatrics, University Department of Pharmacy Practice, Northeast Ohio Medical
of Illinois University (NEOMED)

Daniel L. Krinsky, RPh, MS Jason Makii, PharmD, BCPS

Manager, MTM Services Manager, Clinical Services and Residency Program Director,
Giant Eagle Pharmacy PGY-2 Critical Care, Department of Pharmacy Services
Assistant Professor University Hospitals Cleveland Medical Center
Department of Pharmacy Practice, Northeast Ohio Medical
Melissa Makii, PharmD, BCPS
University (NEOMED)
Clinical Pharmacy Specialist
Tim T.Y. Lau, PharmD, ACPR, FCSHP Pediatric Oncology, Rainbow Babies & Children's Hospital
Pharmacotherapeutic Specialist in Infectious Diseases
Marketa Marvanova, PharmD, PhD, BCGP, BCPP
Pharmaceutical Sciences, Vancouver General Hospital
Chair of the Pharmacy Practice Department
Lisiane Leal College of Health Professions, School of Pharmacy, North
Pharmacotherapy Contributor Dakota State University
Porto Alegre, Brazil
Vincent F. Mauro, BS, PharmD, FCCP
Mandy C. Leonard, PharmD, BCPS Professor of Clinical Pharmacy and Adjunct Professor of
System Director, Drug Use Policy and Formulary Medicine
Management Colleges of Pharmacy and Medicine, The University of Toledo
Cleveland Clinic
Shawn Mazur, PharmD
Anthony K. Leung, DO, FACP, FIDSA, FASCP Clinical Pharmacy Manager, Infectious Diseases
Physician New York-Presbyterian/Weill Cornell Medical Center
Department of Medicine Infectious Disease, Summa
Joseph McGraw, PharmD, MPH, PhD, BCPS
Health System
Assistant Professor of Pharmaceutical Science and
Associate Professor of Internal Medicine
Metabolism Laboratory Director
Northeast Ohio Medical University
Concordia University Wisconsin, School of Pharmacy
Jonathan Leung, PharmD, BCPS, BCPP
Neuropsychiatric Clinical Pharmacist
Shawn McKinney, RPh
Mayo Clinic Clinical Manager, Drug Files
Wolters Kluwer
Debbie Lewis, RPh
Clinical Content Specialist, Drug Files
Ann Marie McMullin, MD
Wolters Kluwer
Associate Staff
Emergency Services Institute, Cleveland Clinic
Jeffrey D. Lewis, PharmD, MACM
Dean and Professor
Christopher McPherson, PharmD
Lloyd L. Gregory School of Pharmacy, Palm Beach Clinical Pharmacist
Atlantic University Neonatal Intensive Care Unit, St. Louis Children's Hospital
Assistant Professor
John Lindsley, PharmD, BCPS Department of Pediatrics, Washington University School of
Cardiology Clinical Pharmacy Specialist Medicine
The Johns Hopkins Hospital
Mary Lynn McPherson, PharmD, MA, MDE,
Nicholas A. Link, PharmD, BCOP BCPS, CPE
Clinical Specialist, Oncology Professor and Executive Director, Advanced Post-Graduate
Hillcrest Hospital Education in Palliative Care
University of Maryland
Lisa K. Lohr, PharmD
Oncology Pharmacy Specialist Timothy F. Meiller, DDS, PhD
Masonic Cancer Clinic Professor
Oncology and Diagnostic Sciences, Baltimore College of
Julie Lothamer, RPh Dental Surgery
Clinical Content Specialist, Clinical Decision Support Professor of Oncology
Dosing Content Marlene and Stewart Greenebaum Cancer Center, University
Wolters Kluwer of Maryland Medical System

10
 INTRODUCTION

Micheline Meiners, MSc, PhD Kimberly Novack, PharmD, BCPS

Pharmacotherapy Contributor Clinical Pharmacy Specialist, Cystic Fibrosis and Pharmacy
Lago Norte, Brazil Clinical Coordinator
Nationwide Children's Hospital
Cathy A. Meives, PharmD
Clinical Manager, Core Pharmacology Charla E. Miller Nowak, RPh, PharmD
Wolters Kluwer Neonatal Clinical Pharmacy Specialist
Wolfson Children's Hospital
Megan Menon, PharmD, BCOP
Clinical Pharmacy Specialist
Hye-Won Veronica Oh, PharmD
Roswell Park Cancer Institute
Adjunct Professor and Preceptor
Jenna Meredith, APRN, MSN, NNP-BC Dongguk College of Pharmacy
Neonatal Nurse Practitioner
MetroHealth Medical Center Carlene N. Oliverio, PharmD, BCPS
Clinical Content Specialist
Karin Meyer, RPh, MBA Wolters Kluwer
Clinical Content Specialist, Clinical Decision Support
Dosing Content Neeta O'Mara, PharmD, BCPS
Wolters Kluwer Clinical Pharmacist
Dialysis Clinic
Patty, Milazzo, RPh
Senior Director, Drug Files Tom Palma, MS, RPh, BCPS
Wolters Kluwer Clinical Content Specialist
Wolters Kluwer
Julie Miller, PharmD
Pharmacy Clinical Specialist, Cardiology Ji Hyun Park, PharmD, RPh
Nationwide Children's Hospital
Clinical Pharmacist
Stacy E. Miller, PharmD, BCPS, BCPP KEPCO Medical Center, Hanjeon Hospital, KMC
Senior Clinical Content Specialist
Wolters Kluwer Susie H. Park, PharmD, BCPP
Assistant Professor of Clinical Pharmacy
Katherine Mills, PharmD University of Southern Califormia
Pharmacotherapy Contributor ° -
Bristow, Virginia Nicole Passerrello, PharmD, BCPPS, BCPS
Senior Clinical Content Specialist
Stephanie S. Minich, PharmD, BCOP Wolters Kluwer
Senior Clinical Content Specialist
Wolters Kluwer Neha Patel, PharmD, BCPS
Clinical Specialist, Solid Organ Transplant, Adjunct Facility
Jay M. Mirtallo, MS, RPh, BCNSP, Medical University of South Carolina
FASHP, FASPEN
Professor of Clinical Pharmacy — Director, MS in Brent Pettijohn Sr., RPh
Health System Pharmacy Clinical Content Specialist, Drug Files
Ohio State University Wolters Kluwer

J. Cameron Mitchell, PharmD, BCPS, BCPP Rebecca Pettit, PharmD, MBA, BCPS
Pharmacy Clinical Specialist, Psychiatry Pediatric Pulmonary Clinical Pharmacy Specialist
UNC Hospitals at WakeBrook Riley Hospital for Children, Indiana University Health,
Maggie Monogue, PharmD Department of Pharmacy
Infectious Diseases Clinical Pharmacy Specialist
Hanna Phan, PharmD, FCCP
Texas Health Resources, Fort Worth
Clinical Pharmacy Specialist, Pediatric Pulmonology and
Lauri Moore, RPh, MBA Sleep
Vice President, Content Development Banner University Medical Center, Tucson
Wolters Kluwer
Cameron Phillips, BPharm, MClin Pharm
John M. Moorman, PharmD, BCPS Clinical Pharmacist
Pharmacotherapy Specialist, Endocrinology Flinders Medical Center
Cleveland Clinic Akron General
Jennifer L. Placencia, PharmD
Michael P. Moranville, PharmD, Neonatal Clinical Pharmacy Specialist
BCPS-AQ Cardiology © =~” Texas Children's Hospital
Senior Clinical Content Specialist
Wolters Kluwer Sacha R. Pollard, PharmD, BCPS
Pharmacotherapy Contributor
Kara M. Morris, DDS, MS Fort Mill, South Carolina
Pediatric Dentist
Olentangy Pediatric Dentistry Karen Post, RPh
Clinical Manager, Drug Files
Naoto Nakagawa, PharmD, PhD Wolters Kluwer
Chief Pharmacist
Drug Information Center, Japan Ted Post, MD
Editor-in-Chief
Lynne Nakashima, PharmD Clinical Effectiveness
Professional Practice Leader, Clinical Professor
B.C. Cancer Agency, Vancouver Centre, University of BC Lindsey Pote, PharmD, BCPS
Clinical Pharmacy Specialist, Solid Organ Transplantation
Carrie Nemerovski, PharmD, BCPS, Johns Hopkins Hospital
AQ-Cardiology Amy L. Potts, PharmD, BCPS
Senior Clinical Content Specialist
Assistant Director
Wolters Kluwer
Department of Pharmacy
Elizabeth A. Neuner, PharmD, BCPS PGY1 & PGY2 Residency Program Director
Infectious Diseases Clinical Specialist Monroe Carell Jr. Children's Hospital at Vanderbilt
Cleveland Clinic Erin Powell, PharmD
Kristen Rose Nichols, PharmD, Clinical Content Specialist, Drug Files
Wolters Kluwer
BCPS-AQ ID, BCPPS
Clinical Pharmacist, Pediatric Infectious Diseases Saira Rab, PharmD, BCPS (AQ-ID), AAHIVP
Indiana University Health Riley Hospital for Children Infectious Diseases/HIV Clinical Pharmacist Specialist
Grady Health System

11
EDITORIAL ADVISORY PANEL

Sally Rafie, PharmD, BCPS Amy Skyles, PharmD

Medical Safety Pharmacist Clinical Pharmacist Specialist
UC San Diego Health System University of Michigan Health System

Melissa Ray, PharmD, BCPS, BCPPS Michael Smith, PharmD, BCPS

Clinical Pharmacist III Assistant Professor of Clinical Pharmacy
UnitedHealth Group — Optum Department of Pharmacy Practice and Pharmacy
Administration, University of the Sciences in Philadelphia
Esta Razavi, PharmD, MBA
Clinical Content Specialist, Clinical Decision Support Sarah Smith, RPh, PharmD, BCPS
Precautions Team Clinical Director, Clinical Decision Support Dosing Content
Wolters Kluwer Wolters Kluwer

Brent Reed, BS, PharmD, BCPS-AQ Stephanie Costante Smith, PharmD, BCPS
Cardiology, FAHA Clinical Pharmacist
Clinical Pharmacy Specialist, Heart Transplantation Clinic Hospital of the University of Pennsylvania
University of Maryland Heart Center
Tiffeny T. Smith, PharmD
James Reissig, PharmD, BCPS Clinical Pharmacy Specialist, Infectious
Assistant Director, Clinical Services Diseases/Antimicrobial Stewardship
Cleveland Clinic Akron General UT Southwestern Medical Center

Neil Reynolds, BPharm, MSc Timothy Smith, MD

Senior Pharmacist Pediatric Anesthesiologist
Fiona Stanley Hospital Nationwide Children's Hospital

Vanitra Richards, PharmD Joseph Snoke, RPh, BCPS

Clinical Content Specialist, Clinical Decision Support Director, Core Pharmacology Group
Precautions Teams Wolters Kluwer
Wolters Kluwer
John Speakman, PharmD
Linda Riski-Lindorff, RPh Clinical Content Specialist, Drug Files
Senior Clinical Content Specialist, Drug Files Wolters Kluwer
Wolters Kluwer
Patricia L. Spenard, PharmD
Amy Rybarczyk, PharmD, BCPS Clinical Content Specialist, Clinical Decision Support
Pharmacy Clinical Manager Precautions Team
Wooster Community Hospital Wolters Kluwer

Rikki L. Rychel, PharmD, BCPS, CDE Joni Lombardi Stahura, BS, PharmD, RPh
Clinical Pharmacy Specialist, Ambulatory Care Senior Clinical Content Specialist
Louis Stokes Cleveland Department of Veterans Affairs Wolters Kluwer
Medical Center
Stephen Marc Stout, PharmD, MS, BCPS
Shannon Saldana, PharmD, MS, BCPP Director, Clinical Content
Psychiatry Advanced Clinical Pharmacist Wolters Kluwer
Primary Children's Hospital
Daniel S. Streetman, PharmD, MS, RPh
Reem Santos, BPharm, MSc Clinical Manager, Metabolism, Interactions, & Genomics
Specialist Antimicrobial Pharmacist Group
Cambridge University Hospitals Wolters Kluwer

Cheryl Sargel, PharmD Darcie-Ann Streetman, PharmD, RPh

Advanced Patient Care Pharmacist Senior Clinical Content Specialist
Nationwide Children's Hospital Wolters Kluwer

Kandace M. Schuft, PharmD Carol K. Taketomo, PharmD

Senior Clinical Content Specialist, Clinical Decision Director of Pharmacy and Nutrition Services
Support Pharmacogenomics Content Children's Hospital Los Angeles
Wolters Kluwer
Ken Yu Tan, PharmD, CGP, BCACP, BCPS
Todd P. Semla, MS, PharmD, BCPS, FCCP, Senior Clinical Pharmacist
AGSF Singapore General Hospital
National PBM Clinical Program Manager — Mental Mary Temple-Cooper, PharmD
Health & Geriatrics Pediatric Clinical Research Specialist
Department of Veterans Affairs, Pharmacy Benefits Hillcrest Hospital
Management Services
Associate Professor, Clinical Jennifer Thackray, PharmD, BCPS
Department of Medicine, Psychiatry and Behavioral Health, Pediatric Oncology Clinical Pharmacist
Feinberg School of Medicine, Northwestern University Memorial Sloan-Kettering Cancer Center
Chasity M. Shelton, PharmD, BCPS, BCNSP Christopher Thomas, PharmD
Assistant Professor of Clinical Pharmacy Clinical Pharmacy Specialist, Pediatric CVICU
Department of Clinical Pharmacy, University of Tennessee Riley Hospital for Children, Indiana University Health
Health Science Center
Clinical Pharmacy Specialist Kelan Thomas, PharmD, MS, BCPS, BCPP
Pediatric Infectious Diseases and Antimicrobial Stewardship, Assistant Professor of Pharmacy Practice
Le Bonheur Children's Hospital Touro University California, College of Pharmacy
Clinical Pharmacist
Nicole M. Sifontis, PharmD, FCCP, BCPS St. Helena Hospital Center for Behavioral Health Office
Clinical Professor, Department of Pharmacy Practice and
Clinical Pharmacist, Abdominal Organ Transplant Service Elizabeth A. Tomsik, PharmD, BCPS
Temple University School of Pharmacy Senior Clinical Director, Drug Content
Wolters Kluwer
Pamela J. Sims, PharmD, PhD
Professor Leslye Trachte, PharmD
Department of Pharmaceutical, Social, and Administrative Pharmacotherapy Contributor
Sciences, McWhorter School of Pharmacy, Samford Lawton, Oklahoma
University
Dana Travis, RPh
Grant Sklar, PharmD, BCPS Clinical Content Specialist
Assistant Professor, Department of Pharmacy and Principal Wolters Kluwer
Clinical Pharmacist, General Medicine
National University Hospital of Singapore Heidi Trinkman, PharmD
Pediatric Hematology/Oncology Clinical Pharmacy Specialist
Cook Children's Medical Center

12
 INTRODUCTION

Tanya Uritsky, PharmD, BCPS Regine L. White, PharmD, RPh

Clinical Pharmacy Specialist in Pain and Palliative Care Senior Clinical Content Specialist
Hospital of the University of Pennsylvania Wolters Kluwer

Andriette van Jaarsveld, BPharm, MScMed Ashley Whitley, APRN, FNP-C

Clinical Pharmacy Specialist Family Nurse Practitioner
Mediclinic Southern, Africa (Stellenbosch) USAF GUARD
Amy Van Orman, PharmD, BCPS Greg Wiggers, PharmD, PhD
Senior Clinical Content Specialist Clinical Content Specialist
Wolters Kluwer Wolters Kluwer

Carlos Vidotti Andrea Williams, RPh

Pharmacotherapy Contributor Clinical Content Specialist
Brasilia DF, Brazil Wolters Kluwer

Polly Waggoner, RPh Keetra Williams, BSN, RN

Clinical Director, Drug Files Clinical Supervisor/Manager
Wolters Kluwer Children's National Medical Center

Geoffrey Wall, RPh, PharmD, FCCP, BCPS, CGP Nathan Wirick, PharmD, BCPS
Professar of Clinical Sciences and Associate Professor of Clinical Specialist in Infectious Diseases and Antibiotic
Pharmacy Practice Management i
Drake University Hillcrest Hospital

Sarah Warren, PharmD Adrian Wong, PharmD, BCPS, BCCCP

Senior Clinical Content. Specialist, Clinical Decision Support Senior Pharmacist, Fellow,,Outcomes Research and
Pharmacogenomics Content Pharmacy Informatics
Wolters Kluwer Brigham and Women's Hospital

Kristin Watson, PharmD, BCPS Wende Wood, RPh, BSPharm, BCPP

Associate Professor, Cardiology and Pharmacotherapy Pharmacotherapy Contributor
University of Maryland, School of Pharmacy Toronto, Ontario, Canada
Clinical Pharmacy Specialist, Heart Failure Clinic
Veterans Affairs Medical Center ” Richard L. Wynn,.BSPharm, PhD
Professor of Pharmacology
JoEllen L. Weilnau, PharmD Baltimore College of Dental Surgery, University of Maryland
Clinical Coordinator
Department of Hematology/Oncology/Bone Marrow Sevasti Yeropoli, MD
Transplant, Children's Hospital of Akron OB/GYN
Paragon Obstetrics and Gynecology
David M. Weinstein, PhD, RPh
Senior Director, Clinical Content Jessica Zatroch, DDS
Wolters Kluwer Private Practice Dentist
Willoughby Hills, OH
Cindy Wethington, RPh
Clinical Content Specialist, Clinical Decision Support Roberta Ziccarelli, RPh
Dosing Content Clinical Content Specialist, Drug Files
Wolters Kluwer Wolters Kluwer

13
ABOUT THE ORIGINAL AUTHORS

ABOUT THE ORIGINAL AUTHORS

Carol K. Taketomo, PharmD
Dr Taketomo received her doctorate from the University of Southern California School of Pharmacy. Subsequently, she
completed a clinical pharmacy residency at the University of California Medical Center in San Diego. With over 40 years of
clinical experience at one of the largest pediatric teaching hospitals in the nation, she is an acknowledged expert in the practical
aspects of pediatric drug distribution and clinical pharmacy practice. She currently holds the appointment of Adjunct Assistant
Professor of Pharmacy Practice at the University of Southern California School of Pharmacy.
In her current capacity as Director of Pharmacy and Nutritional Services at Children's Hospital of Los Angeles, Dr Taketomo
plays an active role in the education and training of the medical, pharmacy, and nursing staff. She coordinates the Pharmacy
Department's performance improvement and medication use evaluation programs, maintains the hospital's strict formulary
program, and is the editor of the house staff manual. Her particular interests are strategies to influence physician prescribing
patterns, introducing LEAN concepts into clinical practice and transitions of care, and methods to decrease medication errors in
the pediatric setting. She has been the author of numerous publications and is an active presenter at professional meetings.
She is a consultant for SwissPedDose and a member of ASHP's Standardize for Safety Initiative oral liquid expert panel.
Dr Taketomo is a member of the American Pharmacists Association (APhA), American Society of Health-System Pharmacists
(ASHP), California Society of Hospital Pharmacists (CSHP), and Southern California Pediatric Pharmacy Group.

Jane Hurlburt Hodding, PharmD

Dr Hodding earned a doctorate and completed her pharmacy residency at the University of California School of Pharmacy
(UCSF) in San Francisco. She has held teaching positions as Assistant Clinical Professor of Pharmacy at UCSF as well as
Assistant Clinical Professor of Pharmacy Practice at the University of Southern California in Los Angeles and now holds the
position of Assistant Dean at UCSF School of Pharmacy. Currently, Dr Hodding is the Executive Director, Pharmacy and
Nutritional Services at Long Beach Memorial and Miller Children's & Women's Hospital in Long Beach, California.
Throughout her 40 years of pediatric pharmacy practice, Dr Hodding has actively pursued methods to improve the safety of
medication use in neonates, children, and adolescents. She has actively practiced as a clinical pharmacy specialist in neonatal
intensive care, pediatric intensive care, and pediatric hematology/oncology. Parenteral nutrition is another area of focus. She
has published numerous articles covering neonatal medication administration, aminoglycoside and theophylline clearance in
premature infants, and medication safety in children. ;
Dr Hodding is a member of the American Pharmacists Association (APhA), American Society of Health-System Pharmacists
(ASHP), and California Society of Hospital Pharmacists (CSHP). She is frequently an invited speaker on the topics of
Medication Safety in Children, A Multidisciplinary Approach; Monitoring Drug Therapy in the NICU; Fluid and Electrolyte
Therapy in Children; Drug Therapy Considerations in Children; and Parenteral Nutrition in the Premature Infant.

Donna M. Kraus, PharmD, FAPhA, FPPAG, FCCP

Dr Kraus received her Bachelor of Science in Pharmacy from the University of Illinois at Chicago (UIC). She worked for several
years as a hospital pediatric/obstetric satellite pharmacist before earning her doctorate degree at the UIC. Dr Kraus then
completed a postdoctoral pediatric specialty residency at the University of Texas Health Science Center in San Antonio. She
served as a pediatric intensive care clinical pharmacist for 15 years and for the past 17 years has been an ambulatory care
pediatric clinical pharmacist, specializing in pediatric HIV pharmacotherapy and patient/parent medication adherence. Dr Kraus
has also served as a clinical pharmacist consultant to a pediatric long-term care facility for over 21 years. She currently holds
the appointment of Associate Professor of Pharmacy Practice in both the Departments of Pharmacy Practice and Pediatrics at
the University of Illinois in Chicago.
In her 38 years of active pharmacy experience, Dr Kraus has dealt with pediatric pharmacy issues and pharmacotherapy
problems. She is an active educator and has been a guest lecturer in China, Thailand, and Hong Kong. Dr Kraus has played a
leading role in the advanced training of postgraduate pharmacists and has been the Director of the UIC (ASHP accredited)
Pediatric Residency and Fellowship Program for 28 years. Dr Kraus’ research areas include pediatric drug dosing and
developmental pharmacokinetics and pharmacodynamics. She has published a number of articles on various issues of
pediatric pharmacy and pharmacotherapy.
Dr Kraus has been an active member of numerous professional associations including the American Pharmacists Association
(APhA), American Society of Health-System Pharmacists (ASHP), Illinois Pharmacists Association (IPhA), American College of
Clinical Pharmacy (ACCP), and Illinois College of Clinical Pharmacy (ICCP). She has served as Chairperson of the ASHP
Commission on Therapeutics; member of the Board of Directors of the Pediatric Pharmacy Advocacy Group (PPAG); Member-
at-Large of the Academy of Pharmaceutical Research and Science (APhA); member of the ASHP, Commission on
Credentialing, Design/Writing Group, Educational Outcomes, Goals and Objectives for Postgraduate Year Two (PGY2)
Pediatric Pharmacy Residency Programs (2007); member of the Alliance for Pediatric Quality, Improve First Measures Task
Force; and member of the PPAG Advisory Board. Dr Kraus also served as an Editorial Board member of the American Journal
of Health-System Pharmacy and the Journal of Pediatric Pharmacy Practice. Currently, she serves as an Editorial Board
member of The Journal of Pediatric Pharmacology and Therapeutics. Dr Kraus was recently named by PPAG as the 2013
recipient of the Richard A. Helms Award of Excellence in Pediatric Pharmacy Practice. This award recognizes sustained and
meritorious contributions to PPAG and to pediatric pharmacy practice; and contributions of importance to education, new
knowledge, and outreach. Dr Kraus has been awarded Fellow status by the American Pharmacists Association, the Pediatric
Pharmacy Advocacy Group, and the American College of Clinical Pharmacy. She is the APhA designated author for this
handbook.

14
 INTRODUCTION

DESCRIPTION OF SECTIONS AND FIELDS USED IN

THIS HANDBOOK
The Pediatric & Neonatal Handbook, 25th edition is organized into a drug information section, an appendix, and a
therapeutic category & key word index.

Drug information is presented in a consistent format and provides the following:

Generic Name US adopted name

Pronunciation Phonetic pronunciation guide
Medication Safety Issues In an effort to promote the use of safe medications, this field is intended to highlight possible
sources of medication errors such as sound-alike/look-alike drugs or highly concentrated
formulations which require vigilance on the part of health care professionals. In addition,
medications which have been associated with severe consequences in the event of a medication
error are also identified in this field.
Related Information Cross-references to other pertinent drug information found in the Appendix.
Brand Names: US Trade names (manufacturer-specific) found in the United States. The symbol [DSC] appears
after trade names that have been recently discontinued.
Brand Names: Canada Trade names found in Canada
Therapeutic Category Unique systematic classification of medications
Generic Availability (US) Indicates availability of generic products in the United States
Use Information pertaining to FDA approved indications or other off-label uses of the drug. Labeled
uses will be indicated in parentheses by "FDA-approved in", followed by the specific patient
population. "FDA-approved in all ages" denotes ages day 0 through adult. Uses mentioned at the
end of the section without "FDA-approved" language are unique off-label pediatric uses.
Prescribing and Access Restrictions Provides information on any special requirements regarding the prescribing, obtaining, or
dispensing of drugs, including access restrictions pertaining to drugs with REMS elements and
those drugs with access restrictions that are not REMS-related
Medication Guide Available Identifies drugs that have an FDA-approved Medication Guide
Pregnancy Risk Factor Five categories established by the FDA to indicate the potential of a systemically absorbed drug
for causing risk to the fetus; the FDA is replacing this category system with scientific data and
other information specific to the use of the drug in pregnant women as new drugs and product
labeling on existing drugs are approved
Pregnancy Considerations A summary of human and/or animal information pertinent to or associated with the use of the
drug as it relates to clinical effects on the fetus, newborn, or pregnant woman
Breastfeeding Considerations Information pertinent to or associated with the human use of the drug as it relates to clinical
effects on the nursing infant or postpartum woman
Contraindications Information pertaining to inappropriate use of the drug as dictated by approved labeling
Warnings/Precautions Precautionary considerations, hazardous conditions related to use of the drug, and disease
states or patient populations in which the drug should be cautiously used. Boxed warnings, when
present, are clearly identified and are adapted from the FDA-approved labeling. Consult the
product labeling for the exact black box warning through the manufacturer's or the FDA website.
Warnings: Additional Pediatric Considerations Provides further details for precautionary considerations that are specific to pediatric and
neonatal patients
Adverse Reactions Side effects are grouped by body system and include a listing of the more common and/or
serious side effects. Due to space limitations, every reported side effect is not listed.
Drug Interactions
Metabolism/Transport Effects lf a drug has demonstrated involvement with cytochrome P450 enzymes, or other metabolism or
transport proteins, this field will identify the drug as an inhibitor, inducer, or substrate of the
specific enzyme(s) (eg, CYP1A2 or UGT1A1). CYP450 isoenzymes are identified as substrates
(minor or major), inhibitors (weak, moderate, or strong), and inducers (weak or strong).
Avoid Concomitant Use Designates drug combinations which should not be used concomitantly, due to an unacceptable
risk:benefit assessment. Frequently, the concurrent use of the agents is explicitly prohibited or
contraindicated by the product labeling
Increased Effect/Toxicity Drug combinations that result in an increased or toxic therapeutic effect between the drug listed
in the monograph and other drugs or drug classes
Decreased Effect Drug combinations that result in a decreased therapeutic effect between the drug listed in the
monograph and other drugs or drug classes
Food Interactions Possible important interactions between the drug listed in the monograph and food, alcohol, or
other beverages
Hazardous Drugs Handling Considerations Indicates whether a drug is considered to be hazardous and provides handling reccomendations
for hazardous drugs
Storage/Stability Information regarding storage and stability of commercially available products and products that
have been reconstituted, diluted, or otherwise prepared. Provides the time and conditions for
which a solution or mixture will maintain potency.
Mechanism of Action How the drug works in the body to elicit a response
Pharmacodynamics/Kinetics The magnitude of a drug's effect depends on the drug concentrations at the site of action. The
pharmacodynamics are expressed in terms of onset of action and duration of action.
Pharmacokinetics are expressed in terms of absorption, distribution, protein binding,
metabolism, bioavailability, half-life, time to peak serum concentration, and elimination.
Pharmacodynamics/Kinetics: Additional Provides further details for pharmacodynamic and pharmacokinetic considerations that are
Considerations specific to special populations (eg, pediatric, geriatric, renal or hepatic impairment, race and
gender).
Dosing
Neonatal The amount of the drug to be typically administered during therapy; may also include dosing
information for preterm neonates. Please note that dosages for neonates may be listed by
variable parameters: Postnatal age (PNA) (eg, PNA <7 days), gestational age (GA),
postmenstrual age (PMA), and/or by body weight (eg, 1,200 to 2,000 g or 1.2 to 2 kg). Neonatal-
specific dosing adjustment in renal impairment for select drugs will be provided in this field if
available. Dosing information not from product labeling will have a citation. For additional
information, consult Dosing: Renal Impairment: Pediatric field for suggested renal impairment
adjustment.
Pediatric The amount of the drug to be typically administered during therapy; may include dosing
information for infants, children, and adolescents and other suggest dosing adjustments for
toxicity or concomitant medication(s). Dosing information not from product labeling will have a
citation.
When both fixed-doses and weight-directed doses (eg, milligram per kilogram [mg/kg]) are listed,
the preferred method is the weight-directed. When weight-directed (eg, mg/kg) and maximum
doses are provided, use the weight-directed (mg/kg) dose to calculate the milligram dose for the
patient, but do not exceed the maximum dose listed. Do not exceed adult maximum dosage for
a given indication unless otherwise noted. If using fixed dosing based upon age, special care and
lower doses should be used in children who have a low weight for their age. When ranges of
doses are provided, initiate therapy at the lower end of the range and titrate the dose accordingly,
unless otherwise indicated.

15
DESCRIPTION OF SECTIONS AND FIELDS USED IN THIS HANDBOOK

Renal Impairment: Pediatric For select drugs, the dosage adjustment in renal impairment (dose or interval) is given according
to glomerular filtration rate (GFR) or creatinine clearance (CrCl). Since most studies that
recommend dosing in renal dysfunction are conducted in adult patients, CrCl is usually
expressed in units of mL/minute. However, in order to extrapolate the adult information to the
pediatric population, one must assume that the adults studied were of standard surface area (ie,
1.73 m*). Therefore, although the value of CrCl listed for dosing adjustment in renal impairment
or dosing interval in renal impairment may be expressed in mL/minute, it is assumed to be equal
to the same value in mL/minute/1.73 m*.
To calculate the dose in a pediatric patient with renal dysfunction, first calculate the normal dose
(ie, the dose for a patient without renal dysfunction), then use the guidelines to adjust the dose.
For example, the normal cefazolin dose for a 20 kg child with a severe infection is 100 to
150 mg/kg/day divided every 8 hours. If one selected 150 mg/kg/day divided every 8 hours, the
dose would be 1,000 mg every 8 hours in normal renal function. If CrCl was 40 to 70 mL/minute,
the dose would be 900 mg every 12 hours and if CrCl was 20 to 40 mL/minute, the dose would
be 375 mg every 12 hours and if the CrCl was 5 to 20 mL/minute, the dose would be 300 mg
every 24 hours. Dosing adjustments in renal impairment are adult data, unless otherwise
indicated.
Hepatic Impairment: Pediatric Dosage adjustments and other cautionary information provided for pediatric patients with hepatic
impairment
Usual Infusion Concentrations: Neonatal Information describing the usual concentrations of drugs for continuous infusion administration in
the neonatal population, as appropriate. Concentrations are derived from the literature,
manufacturer recommendation, or organizational recommendations (eg, the Institute for Safe
Medication Practices [ISMP]) and are universally established. Institution-specific standard
concentrations may differ from those listed.
Usual Infusion Concentrations: Pediatric Information describing the usual concentrations of drugs for continuous infusion administration in
pediatric population, as appropriate. Concentrations are derived from the literature,
manufacturer recommendation, or organizational recommendations (eg, the Institute for Safe
Medication Practices [ISMP]) and are universally established. Institution-specific standard
concentrations may differ from those listed.—
Preparation for Administration Provides information regarding the preparation of drug products prior to administration, including
dilution, reconstitution, etc.
Administration Information regarding the recommended final concentration, and rates of administration of
parenteral drugs, or other guidelines and relevant information to properly administer
medications.
Vesicant/Extravasation Risk Indicates whether the drug is considered to be a vesicant and likely to cause significant morbidity
if the infusion infiltrates soft tissues
Monitoring Parameters pack esthtests and patient physical parameters that should be monitored for safety and
efficacy.
Reference Range Therapeutic and toxic serum concentrations listed, including peak and trough levels when
appropriate
Test Interactions Listing of assay interferences when relevant
Additional Information Other data about the drug are offered when appropriate.
Product Availability Provides availability information on products that have been approved by the FDA but are not yet
available for use. Estimates for when a product may be available are included when this
information is known. May also provide any unique or critical drug availability issues.
Controlled Substance Contains controlled substance schedule information as assigned by the United States Drug
Enforcement Administration (DEA) or Canada's Controlled Drugs and Substance Act (CDSA).
CDSA information is only provided for drugs available in Canada and not available in the US.
Dosage Forms Considerations More specific information regarding product concentrations, ingredients, package sizes, amount
of doses per container, and other important details pertaining to various formulations of
medications
Dosage Forms Information with regard to form, strength, and availability of the drug in the United States. Note:
Additional formulation information (eg, excipients, preservatives) is included when available.
Please consult product labeling for further information.
Extemporaneous Preparations Directions for preparing liquid formulations from solid drug products. May include stability
information and references.

Appendix
The appendix offers a compilation of tables, guidelines, and conversion information which can often be helpful when considering
patient care. This section is broken down into various sections for ease of use.

Therapeutic Category & Key Word Index

This index provides a useful listing of an easy-to-use therapeutic classification system. Also listed are controlled substances and
preservative free, sugar free, dye free, and alcohol free medications.

16
 INTRODUCTION

DEFINITION OF AGE GROUP TERMINOLOGY

Information in this database may be listed according to specific age or by age group. The following are definitions of age groups
and age-related terminologies applied within the database. These definitions should be used unless otherwise specified in the
monograph.

Gestational age (GA)? The time from conception until birth. More specifically, gestational age is defined as
the number of weeks from the first day of the mother's last menstrual period (LMP)
until the birth of the baby. Gestational age at birth is assessed by the date of the
LMP and by physical and neuromuscular examination (eg, New Ballard Score).
Postnatal age (PNA)? Chronological age since birth
Postmenstrual age (PMA)? Postmenstrual age is calculated as gestational age plus postnatal age (PMA = GA
+ PNA).
Neonate A full-term newborn 0 to 28 days postnatal age. Some experts may also apply this
terminology to a premature neonate who is >28 days but whose postmenstrual age
(PMA) is $42 to 46 weeks.
Premature neonate” Neonate born at <37 weeks gestational age
Term neonate” Neonate born at 37 weeks 0 days to 41 weeks 6 days (average ~40 weeks)
gestational age
Infant 1 month (>28 days) to 12 months of age
Child/Children 1 to 12 years of age
Adolescent* 13 to 18 years of age
Adult >18 years of age
*Pregnant, postpartum, or lactating adolescent females are considered within adult information unless otherwise specified.
*Engle WA; American Academy of Pediatrics Committee on Fetus and Newborn. Age terminology during the perinatal period. Pediatrics. 2004;114
(5):1362-1364.
Fleischman AR, Oinuma M, Clark SL. Rethinking the definition of 'term pregnancy’. Obstet Gynecol. 2010;116(1):136-139.

17
PREVENTING PRESCRIBING ERRORS

PREVENTING PRESCRIBING ERRORS

Prescribing errors account for the majority of reported medication errors and have prompted health care professionals to focus
on the development of steps to make the prescribing process safer. Prescription legibility has been attributed to a portion of
these errors and legislation has been enacted in several states to address prescription legibility. However, eliminating
handwritten prescriptions and ordering medications through the use of technology [eg, computerized prescriber order entry
(CPOE)] has been the primary recommendation. Whether a prescription is electronic, typed, or hand-printed, additional, safe
practices should be considered for implementation to maximize the safety of the prescribing process. Listed below are
suggestions for safer prescribing:
o Ensure correct patient by using at least 2 patient identifiers on the prescription (eg, full name, birth date, or address).
Review prescription with the patient or patient's caregiver.
< If pediatric patient, document patient's birth date or age and most recent weight. If geriatric patient, document patient's
birth date or age.
© Prevent drug name confusion: For more information, see http://www.ismp.org/tools/confuseddrugnames.pdf.
= Use TALLman lettering (eg, buPROPion, busPlRone, predniSONE, prednisoLONE). For more information, see
http://www. fda.gov/drugs/drugsafety/medicationerrors/default.htm.
- Avoid abbreviated drug names (eg, MSO4, MgSO, MS, HCT, 6MP, MTX), as they may be misinterpreted and
cause error.
= Avoid investigational names for drugs with FDA approval (eg, FK-506, CBDCA).
- Avoid chemical names such as 6-mercaptopurine or 6-thioguanine, as’sixfold overdoses have been given when
these were not recognized as chemical names. The proper names of these drugs are mercaptopurine or
thioguanine.
- Use care when prescribing drugs that look or sound similar (eg, look- alike, sound-alike drugs). Common examples
include: CeleBREX vs CeleXA, hydrOXYzine vs hydrALAZINE, ZyPREXA vs ZyrTEC.
‘ Avoid dangerous, error-prone abbreviations (eg, regardless of letter-case: U, |U, QD, QOD, ug, cc, @). Do not use
apothecary system or symbols. Additionally, text messaging abbreviations (eg, "2Day") should never be used.
- For more information, see http://www.ismp.org/tools/errorproneabbreviations.pdf.
C Always use a leading zero for numbers <1 (0.5 mg is correct and .5 mg is incorrect) and never usé a trailing zero for
whole numbers (2 mg is correct and 2.0 mg is incorrect).
- Always use a space between a number and its units as it is easier to read. There should be no periods after the
abbreviations mg or mL (10 mg is correct and 10mg is incorrect).
a For doses that are 21,000 dosing units, use properly placed commas to prevent 10-fold errors (100,000 units is correct
and 100000 units is incorrect).
© Do not prescribe drug dosage by the type of container in which the drug is available (eg, do not prescribe "1 amp", "2
vials", etc).

= Do not write vague or ambiguous orders which have the potential for misinterpretation by other health care providers.
Examples of vague orders to avoid: "Resume pre-op medications," "give drug per protocol," or "continue home
medications."
O Review each prescription with patient (or patient's caregiver) including the medication name, indication, and directions
for use.
0 Take extra precautions when prescribing high alert drugs (drugs that can cause significant patient harm when prescribed
in error). Common examples of these drugs include: Anticoagulants, chemotherapy, insulins, opioids, and sedatives.
- For more information, see http://www.ismp.org/tools/institutionalhighalert.asp or http://www.ismp.org/communi-
tyRx/tools/ambulatoryhighalert.asp.
To Err ls Human: Building a Safer Health System, Kohn LT, Corrigan JM, Donaldson MS, eds. Washington, D.C.: National Academy Press. 2000.

A Complete Outpatient Prescription’

A complete outpatient prescription can prevent the prescriber, the pharmacist, and/or the patient from making a mistake and can
eliminate the need for further clarification. The complete outpatient prescription should contain:
0 Patient's full name
0 Medication indication
QO Allergies
e Prescriber name and telephone or pager number
© For pediatric patients: Their birth date or age and current weight
© For geriatric patients: Their birth date or age
0 Drug name, dosage form and strength
0 For pediatric patients: Intended daily weight-based dose so that calculations can be checked by the pharmacist (ie, mg/kg/
day or units/kg/day)
0 Number or amount to be dispensed
0 Complete instructions for the patient or caregiver, including the purpose of the medication, directions for use (including
dose), dosing frequency, route of administration, duration of therapy, and number of refills.
-) Dose should be expressed in convenient units of measure.
OG When there are recognized contraindications for a prescribed drug, the prescriber should indicate knowledge of this fact to
the pharmacist (ie, when prescribing a potassium salt for a patient receiving an ACE inhibitor, the prescriber should write
"K serum leveling being monitored").
Upon dispensing of the final product, the pharmacist should ensure that the patient or caregiver can effectively demonstrate the
appropriate administration technique. An appropriate measuring device should be provided or recommended. Household
teaspoons and tablespoons should not be used to measure liquid medications due to their variability and inaccuracies in
measurement; oral medication syringes are recommended.
For additional information, see http://www.ismp.org/Newsletters/acutecare/articles/20020601.asp
‘Levine SR, Cohen MR, Blanchard NR, et al. Guidelines for preventing medication errors in pediatrics. J Pediatr Pharmacol
Ther. 2001;6:426-442.

18
 INTRODUCTION

FDA NAME DIFFERENTIATION PROJECT: THE USE OF

“TALL MAN" LETTERS
Confusion between similar drug names is an important cause of medication errors. For years, The Institute For Safe Medication
Practices (ISMP), has urged generic manufacturers to use a combination of large and small letters as well as bolding (ie,
chlorproMAZINE and chlorproPAMIDE) to help distinguish drugs with look-alike names, especially when they share similar
strengths. Recently the FDA's Division of Generic Drugs began to issue recommendation letters to manufacturers suggesting
this novel way to label their products to help reduce this drug name confusion. Although this project has had marginal success,
the method has successfully eliminated problems with products such as diphenhydrAMINE and dimenhyDRINATE. Hospitals
should also follow suit by making similar changes in their own labels, preprinted order forms, computer screens and printouts,
and drug storage location labels.
Lexi-Comp, Inc. Medical Publishing will use "Tall-Man” letters for the drugs suggested by the FDA or recommended by ISMP.
The following is a list of generic and brand name product names and recommended revisions.

Drug Product Recommended Revision

acetazolamide acetaZOLAMIDE
alprazolam ALPRAZolam
amiloride aMlLoride
amlodipine amLODIPine
aripiprazole ARIPiprazole
atomoxetine atoMOXetine
" atorvastatin atorvaSTATin
Avinza AVINza
azacitidine azaClITIDine
azathioprine azaTHlOprine
bupropion buPROPion
buspirone busPIRone
carbamazepine carBAMazepine
carboplatin CARBOplatin
cefazolin ceFAZolin
cefotetan cefoTEtan
cefoxitin cefOXitin
ceftazidime cefTAZidime
ceftriaxone ceffRIAXone
Celebrex CeleBREX
Celexa CeleXA
chlordiazepoxide chlordiazePOXIDE
chlorpromazine chlorproMAZINE
chlorpropamide chlorproPAMIDE
cisplatin ClSplatin
clobazam cloBAZam
clomiphene clomiPHENE
clomipramine clomiPRAMINE
clonazepam clonazePAM
clonidine cloNIDine
clozapine cloZAPine
cycloserine cycloSERINE
cyclosporine cycloSPORINE
dactinomycin DACTINomycin
daptomycin DAPTOmycin
daunorubicin DAUNOrubicin
Depo-Medrol DEPO-Medrol
diazepam diazePAM
diltiazem dilTIAZem
dimenhydrinate dimenhyDRINATE
diphenhydramine diphenhydrAMINE
dobutamine DOBUTamine
docetaxel DOCEtaxel
dopamine DOPamine
doxorubicin DOXOrubicin
duloxetine DULoxetine
ephedrine ePHEDrine
epinephrine EPINEPHrine
epirubicin epiRUBicin
eribulin eriBULin
fentanyl! fentaNYL
flavoxate flavoxATE
fluoxetine FLUoxetine
fluphenazine fluPHENAZine
fluvoxamine fluvoxaMINE
glipizide glipiZIDE
glyburide glyBURIDE
guaifenesin guaiFENesin
guanfacine guanFACINE

19
 FDA NAME DIFFERENTIATION PROJECT: THE USE OF "TALL MAN" LETTERS

q (continued)
Drug Product Recommended Revision
Humalog HumaLOG
Humulin HumuLIN
hydralazine hydrALAZINE
hydrochlorothiazide hydroCHLOROthiazide
hydrocodone HYDROcodone
hydromorphone HYDROmorphone
hydroxyprogesterone HYDROXYprogesterone
hydroxyzine hydrOXYzine
idarubicin IDArubicin
idarucizumab idaruCIZUmab
infliximab inFLIXimab
Invanz INVanz
isotretinoin !SOtretinoin
Klonopin KlonoPIN
Lamictal LaMmiCtal
Lamisil LamISIL
lamivudine lamiVUDine
lamotrigine lamoTRigine
levetiracetam LevETIRAcetam
levocarnitine levOCARNitine
levofloxacin levoFLOXacin
levoleucovorin LEVOleucovorin
lorazepam LORazepam
medroxyprogesterone medroxyPROGESTERone
metformin metFORMIN
methazolamide " methazolAMIDE
methimazole methIMAzole
methylprednisolone methylPREDNISolone
methyltestosterone methyITESTOSTERone
metolazone metOLazone
metronidazole metroNIDAZOLE
metyrapone metyraPONE
metyrosine metyroSINE
mifepristone miFEPRIStone
misoprostol miSOPROStol
mitomycin mitoMYcin
mitoxantrone MitoXANTRONE
Nexavar NexAVAR
Nexium NexlUM
nicardipine niCARdipine
nifedipine NIFEdipine
nimodipine niMODipine
Novolin NovoLIN
Novolog NovoLOG
olanzapine OLANZapine
oxcarbazepine OXcarbazepine
oxycodone oxyCODONE
Oxycontin OxyCONTIN
oxymorphone oxyMORphone
paclitaxel PACLitaxel
paroxetine PARoxetine
pazopanib PAZOPanib
pemetrexed PEMEtrexed
penicillamine penicillAMINE
pentobarbital PENTobarbital
phenobarbital PHENobarbital
ponatinib PONATinib
pralatrexate PRALAtrexate
prednisolone prednisoLONE
prednisone predniSONE
Prilosec PriLOSEC
Prozac PROzac
quetiapine QUEtiapine
quinidine quiNiDine
quinine quiNINE
rabeprazole RABEprazole
ranitidine raNITIdine
rifampin rifAMPin
rifaximin rifAXIMin
rimantadine riMANTAdine
Risperdal RisperDAL
risperidone risperiDONE
rituximab riTUXimab

20
 INTRODUCTION

(continued)
Drug Product Recommended Revision
romidepsin romiDEPsin
romiplostim romiPLOStim
ropinirole rOPINIRole
Sandimmune sandIMMUNE
Sandostatin SandoSTATIN
saxagliptin SAXagliptin
Seroquel SEROquel
Sinequan SINEquan
sitagliptin S!Tagliptin
Solu-Cortef Solu-CORTEF
Solu-Medrol SOLU-Medrol
sorafenib SORAfenib
sufentanil SUFentanil
sulfadiazine sulfADIAZINE
sulfasalazine sulfaSALAzine
sumatriptan SUMAtriptan
sunitinib SUNItinib
Tegretol TEGretol
tiagabine tiaGABine
tizanidine tiZANidine
‘tolazamide TOLAZamide
tolbutamide TOLBUTamide
tramadol traMADol
trazodone traZODone
Trental TRENtal
valacyclovir valACYclovir
valganciclovir valGANciclovir
vinblastine vinBLAStine
vincristine vinCRIStine
zolmitriptan ZOLMitriptan
Zyprexa ZyPREXA
Zyrtec ZyrTEC
FDA and ISMP lists of look-alike drug names with recommended tall man letter. http://www.ismp.org/tools/tallmanletters.pdf. Accessed January 6, 2011.
Name differentiation project. http:/www.fda.gov/Drugs/DrugSafety/MedicationErrors/ucm164587.htm. Accessed January 6, 2011.
U.S. Pharmacopeia. USP quality review: use caution - avoid confusion. March 2001, No. 76. http://www.usp.org

21
an Sai a aya

(eal a Pye as
a cneemal |
+h EON ‘ i =
iiumiufin
lea
‘nyieetandng + POL leis ot r
nycrecnioraies ° ee
) ego
, Fat
‘ Ds GF
hiydhoncdonas ' :
hydrocsbiptene ae xl te _"
rycen re ate pice eth, Sy h
-hydicyzing - ‘ J
ieryolen at
Weeurtnurread p ABTS:
ete wratd : Peinexf ka
: ee ingLiRiona.
” ry ober ees re
; 5 4) nes Ee i | dihetAAOe Wyant)” : : pe Fee)
Divers
otredinats ve. OD ae WE *8Oteligalte
« ingie Oy
Rusnemin | ; ; WISA * Pik
niche
Loni
ri
VS
sinotricgined ae

inyveracetem
fs
leyvooninvins. i,
i
lefiowaan
‘ I
TeV OOVON

saan pit

thoy,
: 7 _seotacn ey meant Es _
neither
| mathydprictniosbarrs “IG sy yey NEHER
atednyllentonierone ; a ee seine: stage issiisieatal
reaihar cy ve J er
bapewhe
prety
mn Leseale
ee
‘THB SryUNUnEL hesenooe todmeltal
TPa See: pene
POSgh 8 ec oma ae ne
mithaeraciens : preues wav i oT
Aiisenretoe
eitiornyon
miiteriraria
Nexave a o yi
Nexiure PA
carla :
1 Laisa '
:
ann ry

avons oon
Nowalng ’ h ete
clertapins | : a ‘RAT rate
cktatsayepye ~ ; ; i Sainiw ea asia
sopcodone CP Se ggg ae
Onycoriles ‘ ; Ri ret A i an
HOPPIN Mes ee Seite ar
A RA Irae! oe
paniinwes
Bosomenirees ; , eae he Pam ageH: a
fazopanib . ht ; ‘7 i” Peek
peated 2 a
penicdianing |. hea perio
pentobertinal | ; a7 ;
phenokhantyta |
porate
pravinaste
oredsclorme
Decay
Priloseg
Prozac
quetiapine
cqeilyvigainie mr
- putea oi
mibepramle
ALPHABETICAL LISTING OF DRUGS
ABACAVIR

@ 0.9% Sodium Chloride see Sodium Chloride Therefore, in the US, where formula is accessible,
on page 1834 affordable, safe, and sustainable, and the risk of infant
@ A-25 [OTC] see Vitamin A on page 2063 mortality due to diarrhea and respiratory infections is low,
females with HIV infection should completely avoid
@ AA-Clozapine (Can) see CloZAPine on page 500 breastfeeding to decrease the potential transmission of
HIV (HHS [perinatal] 2017).
Abacavir (a BAK a veer) Contraindications Hypersensitivity to abacavir or any
component of the formulation; patients who are positive
Medication Safety Issues for the HLA-B*5701 allele; moderate to severe hepatic
High alert medication: impairment
This medication is in a class the Institute for Safe Warnings/Precautions Abacavir should always be used
Medication Practices (ISMP) includes among its list of as a component of a multidrug regimen. Do not use
drug classes that have a heightened risk of causing abacavir/lamivudine (plus efavirenz or plus atazanavir/
significant patient harm when used in error. ritonavir) in adolescent and adult HIV-1 patients with a
Brand Names: US Ziagen pre-ART HIV RNA >100,000 copies/mL (HHS [adult]
Brand Names: Canada Ziagen 2015). [US Boxed Warning]: Serious and sometimes
Therapeutic Category Antiretroviral Agent; HIV Agents fatal hypersensitivity reactions have occurred.
(Anti-HIV Agents); Nucleoside Reverse Transcriptase Patients who carry the HLA-B*5701 allele are at a
Inhibitor (NRT1) 3. higher risk for a hypersensitivity reaction to abacavir,
Generic Availability (US) Yes although hypersensitivity reactions have occurred in
Use Treatment of HIV-1 infection in combination with other patients who do not carry the HLA-B*57071 allele. All
antiretroviral agents (FDA approved in ages 23 months patients should be screened for the HLA-B*5701 allele
and adults); Note: HIV regimens consisting of three prior to initiating or reinitiation of therapy unless
antiretroviral agents are strongly recommended. patients have. had a previously documented HLA-
Medication Guide Available Yes B*5701 allele assessment. Discontinue abacavir if a
Pregnancy Considerations Abacavir has a high level of hypersensitivity reaction is suspected. Abacavir is
transfer across the human placenta. No increased risk of contraindicated in patients who have the HLA-
overall birth defects has been observed following first B*5701 allele or in patients with a prior hypersensi-
trimester exposure according to data collected by the tivity reaction to abacavir. Reintroduction of any aba-
antiretroviral pregnancy registry. cavir-containing product can result in life-threatening
or fatal hypersensitivity reactions, even in patients
Maternal antiretroviral therapy (ART) may increase the who have no history of hypersensitivity to abacavir
risk of preterm delivery, although available information is therapy. Such reactions can occur within hours. An
conflicting possibly due to variability of maternal factors allergy to abacavir should be documented in the medical
(disease severity; gestational age at initiation of therapy); record of allele-positive patients. Reactions usually occur
however, maternal antiretroviral medication should not be within 9 days of starting abacavir; ~90% occur within 6
withheld due to concerns of preterm birth. Information weeks, although these reactions may occur at any time
related to stillbirth, low birth weight, and small for gesta- during therapy (HHS [adult] 2015). These reactions usu-
tional age infants is limited. Long-term follow-up is recom- ally include signs or symptoms from two or more of the
mended for all infants exposed to antiretroviral following: Fever, skin rash, constitutional symptoms
medications; children who develop significant organ sys- (malaise, fatigue, aches), respiratory symptoms (eg, phar-
tem abnormalities of unknown etiology (particularly of the yngitis, dyspnea, cough), and GI symptoms (eg, abdomi-
CNS or heart) should be evaluated for potential mitochon- nal pain, diarrhea, nausea, vomiting). Other signs and
drial dysfunction. Cases of lactic acidosis and hepatic symptoms include lethargy, headache, myalgia, edema,
steatosis related to mitochondrial toxicity have been abnormal chest x-ray findings, arthralgia and paresthesia.
reported with use of nucleoside reverse transcriptase
Anaphylaxis, liver failure, renal failure, hypotension, adult
inhibitors (NRTIs). These adverse events are similar to
respiratory distress syndrome, respiratory failure, myoly-
other rare but life-threatening syndromes which occur
sis, and death have occurred in association with hyper-
during pregnancy (eg, HELLP syndrome). In general
sensitivity reactions. Physical findings (lymphadenopathy,
nucleoside reverse transcriptase inhibitors are well toler-
mucous membrane lesions, and rash [maculopapular,
ated and the benefits of use generally outweigh poten-
urticarial or variable]) may occur. Erythema multiforme
tial risk.
has also been reported. Laboratory abnormalities (eg,
In general, ART is recommended for all pregnant females elevated liver function tests, elevated creatine phosphoki-
with HIV to keep the viral load below the limit of detection nase, elevated creatinine, and lymphopenia) may occur.
and reduce the risk of perinatal transmission. When HIV is Abacavir should be permanently discontinued if hyper-
diagnosed during pregnancy in a female who has never sensitivity cannot be ruled out, even when other diagno-
received antiretroviral therapy, ART should begin as soon ses are possible and regardless of HLA-B*5701 status.
as possible after diagnosis. Females who become preg- Abacavir SHOULD NOT be restarted because more
nant on a stable ART regimen may continue that regimen severe symptoms may occur within hours, including
if viral suppression is effective, appropriate drug exposure LIFE-THREATENING HYPOTENSION AND DEATH. If
can be achieved, contraindications for use in pregnancy abacavir is restarted following an interruption in therapy
are not present, and the regimen is well tolerated. Mon- not associated with symptoms of a hypersensitivity reac-
itoring during pregnancy is more frequent than in non- tion, carefully evaluate the patient for previously unsus-
pregnant adults; ART should be continued postpartum for pected symptoms of hypersensitivity. Do not restart if
all females living with HIV. hypersensitivity is suspected or cannot be ruled out
regardless of HLA-B*5701 status. If abacavir is restarted,
The Health and Human Services (HHS) Perinatal HIV continually monitor for symptoms of a hypersensitivity
Guidelines consider abacavir in combination with lamivu-
reaction. Make the patient aware that reintroduction
dine to be a preferred NRTI backbone for initial therapy in
should only take place if medical care is readily acces-
antiretroviral-naive pregnant females (do not use in
sible.
females who are positive for the HLA-B*5701 allele). This
backbone is not recommended with atazanavir/ritonavir or [US Boxed Warning]: Lactic acidosis and severe hep-
efavirenz if pretreatment HIV RNA is >100,000 copies/mL. atomegaly with steatosis (sometimes fatal) have
The pharmacokinetics of abacavir are not significantly occurred with antiretroviral nucleoside analogues.
changed by pregnancy and dose adjustment is not Female gender, prior liver disease, obesity, and prolonged
needed for pregnant females. treatment may increase the risk of hepatotoxicity. May be
associated with fat redistribution (eg, buffalo hump,
Health care providers are encouraged to enroll pregnant
peripheral wasting with increased abdominal girth, cush-
females exposed to antiretroviral medications as early in
ingoid appearance). Immune reconstitution syndrome
pregnancy as possible in the Antiretroviral Pregnancy
may develop, resulting in the occurrence of an inflamma-
Registry (1-800-258-4263 or http://www.APRegistry.
tory response to an indolent or residual opportunistic
com). Health care providers caring for HIV-infected
infection during initial HIV treatment or activation of auto-
females and their infants may contact the National Peri-
immune disorders (eg, Graves disease, polymyositis,
natal HIV Hotline (888-448-8765) for clinical consultation
Guillain-Barré syndrome) later in therapy; further evalua-
(HHS [perinatal] 2017).
tion and treatment may be required. Use with caution and
Breastfeeding Considerations
adjust dosage in patients with mild hepatic impairment
Abacavir is present in breast milk.
(contraindicated in moderate to severe impairment).
Abacavir was detected in the serum of an infant following
exposure via breast milk. Use has been associated with an increased risk of myo-
Maternal or infant antiretroviral therapy does not com- cardial infarction (MI) in observational studies; however,
pletely eliminate the risk of postnatal HIV transmission. based on a meta-analysis of 26 randomized trials, the
In addition, multiclass-resistant virus has been detected FDA has concluded there is not an increased risk. Con-
in breastfeeding infants despite maternal therapy. sider using with caution in patients with risks for coronary

24
 ABACAVIR

heart disease and minimizing modifiable risk factors (eg, Mechanism of Action Nucleoside reverse transcriptase
hypertension, hyperlipidemia, diabetes mellitus, and inhibitor. Abacavir is a guanosine analogue which is
smoking) prior to use. Potentially significant drug-drug phosphorylated to carbovir triphosphate which interferes
_interactions may exist, requiring dose or frequency adjust- with HIV viral RNA-dependent DNA polymerase resulting
ment, additional monitoring, and/or selection of alternative in inhibition of viral replication.
therapy. Some dosage forms may contain propylene gly- Pharmacodynamics/Kinetics (Adult data unless
col; large amounts are potentially toxic and have been noted)
associated with hyperosmolality, lactic acidosis, seizures Absorption: Rapid and extensive absorption
and respiratory depression; use caution (AAP, 1997; Zar, Distribution: Vg: 0.86 + 0.15 L/kg
2007). Oral solution contains sorbitol. Use oral solution CSF to plasma AUC ratio: 27% to 33%
with caution in patients who are fructose intolerant; may Protein binding: 50%
experience abdominal discomfort and/or diarrhea with Metabolism: Hepatic via alcohol dehydrogenase and glu-
administration of the oral solution. Some dosage forms curonyl transferase to inactive carboxylate and glucur-
may contain polysorbate 80 (also known as Tweens). onide metabolites; not significantly metabolized by
Hypersensitivity reactions, usually a delayed reaction, cytochrome P450 enzymes; intracellulary metabolized
have been reported following exposure to pharmaceutical to carbovir triphosphate.
products containing polysorbate 80 in certain individuals Bioavailability: Tablet: 83%; Solution and tablet provide
(Isaksson 2002; Lucente 2000; Shelley 1995). Thrombo- comparable AUCs
cytopenia, ascites, pulmonary deterioration, and renal and Half-life elimination (serum):
hepatic failure have been reported in premature neonates Pediatric patients 23 months to $13 years: 1 to 1.5 hours
after receiving parenteral products containing polysorbate (Hughes 1999; Kline 1999)
80 (Alade 1986; CDC 1984). See manufacturer’s labeling. Adults: 1.54 + 0.63 hours
Warnings: Additional Pediatric Considerations May Hepatic impairment (mild): Increases half-life by 58%
cause mild hyperglycemia; more common in pediatric Half-life, intracellular: 12 to 26 hours
patients. Some dosage forms may contain propylene Time to peak: ,
glycol; in neonates large amounts of propylene glycol Pediatric patients 23 months to $13 years: Within 1.5
delivered orally, intravenously (eg, >3,000 mg/day), or hours (Hughes 1999)
topically have been associated with potentially fatal tox- Adults: 0.7 to 1.7 hours
icities which can include metabolic acidosis, seizures, Excretion: Urine: ~83% (1.2% as unchanged drug, 30% as
renal failure, and CNS depression; toxicities have also 5'-carboxylic acid metabolite, 36% as the glucuronide,
been reported in children and adults including hyperos- and 15% as other metabolites); feces (16% total dose)
molality, lactic acidosis, seizures and respiratory depres- Clearance (apparent): Single dose 8 mg/kg (Hughes
sion; use caution (AAP 1997; Shehab 2009). 1999):
Adverse Reactions Pediatric patients 23 months to $13 years: 17.84 mL/
Central nervous system: Abnormal dreams, anxiety, chills, minute/kg
depression, dizziness, fatigue, headache, malaise, Adults: 10.14 mL/minute/kg
migraine, sleep disorder Pharmacodynamics/Kinetics: Additional Consider-
Dermatologic: Skin rash ations
Endocrine & metabolic: Hypertriglyceridemia, increased Hepatic function impairment: In mild hepatic impairment
gamma-glutamyl transferase (Child-Pugh score 5 to 6), AUC increased 89%.
Gastrointestinal: Abdominal pain, diarrhea (increased inci- Dosing
dence with once daily dosing), gastritis, gastrointestinal Pediatric
disease, increased serum amylase, nausea, nausea and HIV-1 infection, treatment: Note: Use in combination
vomiting, pancreatitis, vomiting with other antiretroviral agents:
Hematologic & oncologic: Neutropenia, thrombocytopenia Infants <3 months: Not approved for use; safety, effi-
Hepatic: Increased serum ALT, increased serum AST cacy, and dosage not established
Hypersensitivity: Hypersensitivity reaction (including ana- Infants 23.months, Children, and Adolescents: Oral:
phylaxis and multiorgan failure; excluding subjects carry- Twice-daily dosing:
ing the HLA-B*5701 allele) Weight-directed dosing: Oral solution: 8 mg/kg/dose
Neuromuscular & skeletal: Increased creatine phosphoki- twice daily; maximum dose: 300 mg/dose. Note:
nase, musculoskeletal pain Weight-band dosing may be used in certain
Respiratory: Bronchitis, ENT infection, pneumonia (chil- patients, weighing at least 14 kg; especially rapid
dren), viral respiratory tract infection growing younger children (HHS [pediatric] 2016)
Miscellaneous: Fever Weight-band dosing for patients 214 kg: Tablets
Rare but important or life-threatening: Anemia, erythema (scored 300 mg tablets), oral solution:
multiforme, hepatomegaly, hepatotoxicity, hyperglyce- 14 to <20 kg: 150 mg twice daily
mia, immune reconstitution syndrome, lactic acidosis, 20 to <25 kg: 150 mg in the morning and 300 mg in
leukopenia, liver steatosis, myocardial infarction, pain, the evening
redistribution of body fat, renal disease, Stevens-John- 225 kg: 300 mg twice daily
son syndrome, toxic epidermal necrolysis Once-daily dosing: Note: Efficacy of once daily dos-
Drug Interactions he ae ing has only been demonstrated in patients who
Metabolism/Transport Effects Inhibits MRP2 transitioned from twice daily dosing after 36 weeks
Avoid Concomitant Use There are no known interac- of treatment. Some experts recommend avoiding
tions where it is recommended to avoid concomitant use. once daily therapy for infants and young children
Increased Effect/Toxicity receiving oral solution until viral load has been
Abacavir may increase the levels/effects of: Cabozanti- undetectable and CD4 have been stable for more
nib than 6 months (HHS [pediatric 2016]).
Decreased Effect Weight-directed dosing: Oral solution: 16 mg/kg/
Abacavir may decrease the levels/effects of: Methadone dose once daily; maximum dose: 600 mg/dose.
Note: Weight-band dosing may be used in certain
The levels/effects of Abacavir may be decreased by: patients weighing 214 kg; especially rapid growing
Methadone; Orlistat; Protease Inhibitors younger children (HHS [pediatric] 2016)
Food Interactions Ethanol decreases the elimination of Weight-band dosing for patients 214 kg: Tablets
abacavir and may increase the risk of toxicity. Manage- (scored 300 mg tablets), oral solution:
ment: Avoid ethanol during therapy; if ethanol is con- 14 to <20 kg: 300 mg once daily
sumed during therapy, monitor for signs/symptoms. of 20: to <25 kg: 450 mg once daily
abacavir toxicity. 225 kg: 600 mg once daily
Hazardous Drugs Handling Considerations Renal Impairment: Pediatric There are no dosage
Hazardous agent (NIOSH 2016 [group 2)). adjustments provided in the manufacturer’s labeling;
however, renal is a minor route of elimination.
Use appropriate precautions for receiying, handling,
Hepatic Impairment: Pediatric Moderate to severe
administration, and disposal. Gloves (single) should be
hepatic impairment (Child-Pugh class B or C): All
worn during receiving, unpacking, and placing in storage.
patients: Use is contraindicated
NIOSH recommends single gloving for administration of Administration Oral: May be administered without regard
intact tablets or capsules. NIOSH recommends double to food
gloving, a protective gown, and (if there is a potential for Monitoring Parameters HLA-B*5707 genotype status
vomit or spit up) eye/face protection for administration of prior to initiating therapy or resuming therapy in patients
an oral liquid (NIOSH 2016). Assess risk to determine of unknown HLA-B*5707 status (including patients previ-
appropriate containment strategy (USP-NF 2017). ously tolerating therapy); signs and symptoms of hyper-
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). sensitivity reaction (in all patients, but especially in those
Oral solution may be refrigerated; do not freeze. untested for the HLA-B*5707 allele) >
25
 ABACAVIR

< Note: The absolute CD4 cell count is currently recom-

mended to monitor immune status in children of all ages;
Tablet, Oral:
Ziagen: 300 mg [scored]
CD4 percentage can be used as an alternative in children Generic: 300 mg
<5 years of age. This recommendation is based on the
use of absolute CD4 cell counts in the current pediatric
HIV infection stage classification and as thresholds for
Abacavir and Lamivudine
(a BAK a veer & la MI vyoo deen)
urgency of initiation of antiretroviral treatment (HHS
[pediatric] 2017). Medication Safety Issues '
High alert medication:
Prior to initiation of therapy: Genotypic resistance testing,
This medication is in a class the Institute for Safe
CD4 and viral load (every 3 to 4 months), CBC with
Medication Practices (ISMP) includes among its list of
differential, LFTs, BUN, creatinine, electrolytes, glucose,
drug classes that have a heightened risk of causing
urinalysis (every 6 to 12 months), and assessment of
significant patient harm when used in error.
readiness for adherence with medication regimen. At
Brand Names: US Epzicom
initiation and with any change in treatment regimen:
CBC with differential, electrolytes, calcium, phosphate,
Brand Names: Canada Apo-Abacavir-Lamivudine;
glucose, LFTs, bilirubin, urinalysis (at initiation), BUN, Kivexa; Mylan-Abacavir/Lamivudine; Teva-Abacavir/Lam-
creatinine, albumin, total protein, lipid panel (at initiation), ivudine
CD4, and viral load. After 1 to 2 weeks of therapy: Signs of Therapeutic Category Antiretroviral Agent; HIV Agents
medication toxicity and adherence. After 2 to 4 weeks of (Anti-HIV Agents); Nucleoside Analog Reverse Transcrip-
therapy: CBC with differential, viral load, signs of medi- tase Inhibitor (NRT1)
cation toxicity, and adherence; then every 3 to 4 months: Generic Availability (US) Yes
CBC with differential, electrolytes, glucose, LFTs, bilirubin, Use Treatment of HIV-1 infection in combination with other
BUN, creatinine, CD4, viral load, signs of medication antiretroviral agents (FDA approved in pediatric patients
toxicity, and adherence. Lipid panel and urinalysis every weighing 225 kg and adults); Note: HIV regimens consist-
6 to 12 months. CD4 monitoring frequency may be ing of three antiretroviral agents are strongly recom-
decreased to every 6 to 12 months in children who are mended.
adherent to therapy if the value is well above the threshold Medication Guide Available Yes
for opportunistic infections, viral suppression is sustained, Pregnancy Considerations
and the clinical status is stable for more than 2 to 3 years. The Health and Human Services (HHS) Perinatal HIV
In patients with known or suspected complex drug resist- Guidelines consider abacavir in combination with lamivu-
ance patterns, phenotypic resistance testing (usually in dine to be a preferred nucleoside reverse transcriptase
addition to genotypic resistance testing) should be per- inhibitor (NRTI) backbone for initial use in antiretroviral-
formed (HHS [pediatric] 2017). Monitor for growth and naive pregnant females (do not use in females who are
development, signs of, HlV-specific physical conditions, positive for the HLA-B*5701 allele). This backbone is not
HIV disease progression, opportunistic infections or lactic recommended with atazanavir/ritonavir or efavirenz if pre-
acidosis; serum amylase, serum creatine kinase. treatment HIV RNA is >100,000 copies/mL.
Additional Information The patient Medication Guide, In general, females who become pregnant on a stable
which includes written manufacturer information, should antiretroviral therapy (ART) regimen may continue that
be dispensed to the patient with each new prescription regimen if viral suppression is effective, appropriate drug
and refill; the Warning Card describing the hypersensitivity exposure can be achieved, contraindications for use in
reaction should be given to the patient to carry with them. pregnancy are not present, and the regimen is well
The development of the abacavir hypersensitivity reaction tolerated (HHS [perinatal] 2017).
has been associated with certain HLA genotypes (eg, Refer to individual monographs for additional information.
HLA-B*5701, HLA-DR7, HLA-DQ3) which may help pre- Breastfeeding Considerations Abacavir and lamivu-
dict which patients are at risk for developing the abacavir dine are present in breast milk (HHS [perinatal] 2017).
hypersensitivity reaction (Hetherington 2002; Lucas 2007; See individual agents.
Mallal 2002). Patients who test positive for the HLA- Contraindications
B*57071 allele should have an abacavir allergy recorded Hypersensitivity to abacavir, lamivudine, or any compo-
in their medical record and should not receive abacavir. nent of the formulation; patients who have the HLA-
All patients who receive abacavir (and their caregivers) B*5701 allele; moderate or severe hepatic impairment
should be educated about the risk of abacavir hyper- Canadian labeling: Additional contraindications (not in US
sensitivity reactions (including patients who test negative labeling): Hepatic impairment (regardless of severity)
for the HLA-B*5707 allele, as the risk for the reaction is not Warnings/Precautions
completely eliminated). Approximately 4% of patients who [US Boxed Warning]: Serious and sometimes fatal
test negative for the HLA-B*5707 allele will experience a hypersensitivity reactions have occurred with abaca-
clinically suspected abacavir hypersensitivity reaction vir, a component of abacavir/lamivudine. Patients who
compared to 61% of those who test positive for the carry the HLA-B*5707 allele are at a higher risk for a
HLA-B*5701 allele. hypersensitivity reaction to abacavir, although hyper-
The prevalence of HLA-B*5707 in the United States has sensitivity reactions have occurred in patients who do
been estimated to be 8% in Caucasians, 2.5% in African- not carry the HLA-B*5707 allele. All patients should be
Americans, 2% in Hispanics, 1% in Asians; in the sub- screened for the HLA-B*5707 allele prior to initiating
Saharan Africa it is <1%. Pretherapy identification of HLA- or reinitiation of therapy unless patients have had a
B*5701-positive patients and subsequent avoidance of previously documented HLA-B*5707 allele assess-
abacavir therapy in these patients has been shown to ment. Do not use abacavir and lamivudine (plus efavirenz
significantly reduce the occurrence of abacavir-associated or plus atazanavir/ritonavir) in adolescent and adult HIV-1
hypersensitivity reactions. A familial predisposition to the patients with a pre-ART HIV RNA >100,000 copies/mL
abacavir hypersensitivity reaction has also been reported; (HHS [adult] 2015). Patients testing positive for the pres-
use abacavir with great caution in children of parents who ence of the HLA-B*5707 allele are at an increased risk for
experience a hypersensitivity reaction to abacavir (Peyr- hypersensitivity reactions. Abacavir is contraindicated
iére 2001). in patients who have the HLA-B*5707 allele or in
patients with a prior hypersensitivity reaction to aba-
Reverse transcriptase mutations of K65R, L74V, Y115F, cavir. Reintroduction of any abacavir-containing prod-
and M184V have been associated with abacavir resist- uct can result in life-threatening or fatal
ance; at least 2 to 3 mutations are needed to decrease hypersensitivity reactions, even in patients who have
HIV susceptibility by 10-fold. The presence of a multiple no history of hypersensitivity to abacavir therapy.
number of these abacavir resistance-associated muta- Such reactions can occur within hours. Additionally,
tions, may confer cross-resistance for other nucleoside HLA-B*57071 allele-positive patients (including abacavir
or nucleotide reverse transcriptase inhibitors (eg, didano- treatment naive patients) should have an allergy to aba-
sine, emtricitabine, lamivudine, zalcitabine, or tenofovir). A cavir documented in their medical record (HHS [adult]
progressive decrease in abacavir susceptibility is associ- 2015). Reactions usually occur within 9 days of starting
ated with an increasing number of thymidine analogue abacavir; ~90% occur within 6 weeks Patients exhibiting
mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, symptoms from two or more of the following: Fever, skin
K219E/R/H/Q/N). rash, constitutional symptoms (eg, malaise, fatigue,
Dosage Forms Excipient information presented when aches), respiratory symptoms (eg, pharyngitis, dyspnea,
available (limited, particularly for generics); consult spe- cough), and GI symptoms (eg, abdominal pain, nausea,
cific product labeling. vomiting) should discontinue therapy immediately and
Solution, Oral: seek medical attention. Abacavir/lamivudine should: be
Ziagen: 20 mg/mL (240 mL) [contains methylparaben, permanently discontinued if hypersensitivity cannot be
propylene glycol, propylparaben, saccharin sodium; ruled out, even when other diagnoses are possible and
strawberry-banana flavor] regardless of HLA-B*5707 status. Abacavir/lamivudine
Generic: 20 mg/mL (240 mL) SHOULD NOT be restarted because more severe

26
 ABACAVIR AND LAMIVUDINE

symptoms may occur within hours, including LIFE- Avoid Concomitant Use
THREATENING HYPOTENSION AND DEATH. Fatal Avoid concomitant use of Abacavir and Lamivudine with
hypersensitivity reactions have occurred following the any of the following: Emtricitabine
reintroduction of abacavir in patients whose therapy was Increased Effect/Toxicity
interrupted (ie, interruption in drug supply, temporary Abacavir and Lamivudine may increase the levels/effects
discontinuation while treating other conditions). Reactions of; Cabozantinib; Emtricitabine
occurred within hours. In some cases, signs of hyper-
sensitivity may have been previously present, but attrib- The levels/effects of Abacavir and Lamivudine may be
uted to other medical conditions (eg, acute onset
increased by: Trimethoprim
respiratory diseases, gastroenteritis, reactions to other Decreased Effect
medications). If abacavir/lamivudine is restarted following Abacavir and Lamivudine may decrease the levels/
an interruption in therapy, evaluate the patient for previ- effects of: Methadone
ously unsuspected symptoms of hypersensitivity. Do not The levels/effects of Abacavir and Lamivudine may be
restart if hypersensitivity is suspected or if hypersensitivity decreased by: Methadone; Orlistat; Protease Inhibitors;
cannot be ruled out regardless of HLA-B*5707 status. Sorbitol
[US Boxed Warning]: Severe acute exacerbations of Food Interactions Ethanol decreases the elimination of
abacavir and may increase the risk of toxicity. Manage-
hepatitis B have been reported in patients who are co-
ment: Monitor patients.
infected with hepatitis B virus (HBV) and HIV-1 and
have discontinued lamivudine, which is 1 component
Hazardous Drugs Handling Considerations
of abacavir/lamivudine. Monitor patients closely for sev- Hazardous agent (NIOSH 2016 [group 2)).
eral months following discontinuation of therapy for Abacavir is a hazardous agent. Use appropriate precau-
chronic hepatitis B; clinical exacerbations may occur. tions for receiving, handling, administration, and disposal.
Gloves (single) should be worn during receiving, unpack-
Lactic acidosis and severe hepatomegaly with steatosis,
ing, and placing in storage. NIOSH recommends single
including fatal cases, have been reported with the use of
gloving for administration of intact tablets or capsules
nucleoside analogues and other antiretrovirals. Female
(NIOSH 2016).
gender and obesity may increase the risk for develop-
Storage/Stability Store at 25°C (77°F); excursions per-
ment. Suspend treatment in any patient who develops
mitted to 15°C to 30°C (59°F to 86°F).
clinical or laboratory findings suggestive of lactic acidosis
Mechanism of Action Nucleoside reverse transcriptase
or hepatotoxicity (transaminase elevation may/may not
inhibitor combination.
accompany hepatomegaly and steatosis). Due to fixed
dose of combination product, use is not recommended Abacavir is a guanosine analogue which is phosphory-
with renal impairment (CrCl <50 mL/minute). Patients may lated to carbovir triphosphate which interferes with HIV
develop immune reconstitution syndrome resulting in the viral RNA-dependent DNA polymerase resulting in inhib-
occurrence of an inflammatory response to an indolent or ition of viral replication.
residual opportunistic infection during initial HIV treatment
Lamivudine is a cytosine analog. After lamivudine is
or activation of autoimmune disorders (eg, Graves’ dis-
triphosphorylated, the principle mode of action is inhibition
ease, polymyositis, Guillain-Barré syndrome) later in ther-
of HIV reverse transcription via viral DNA chain termina-
apy; further evaluation and treatment may be required.
tion; inhibits RNA-dependent DNA polymerase activities of
Potentially significant drug-drug interactions may exist,
reverse transcriptase.
requiring dose or frequency adjustment, additional mon-
Pharmacodynamics/Kinetics (Adult data unless
itoring, and/or selection of alternative therapy. Concom-
itant use of other abacavir or lamivudine-containing
noted) One Epzicom tablet is bioequivalent, in the extent
(AUC) of absorption and peak concentration, to two
products with the fixed-dose combination product should
abacavir 300 mg tablets and two lamivudine 150 mg
be avoided. Concomitant use of emiricitabine-containing
tablets; see individual agents.
products should be avoided. Use has been associated
Dosing
with. an increased risk of myocardial infarction (MI) in
observational studies; however, in a meta-analysis of Pediatric Note: Use in combination with other antiretro-
viral agents.
randomized, controlled clinical trials, no excess risk of
HIV-1 infection, treatment:
MI was observed. Available data are inconclusive. Con-
Children and Adolescents weighing <25 kg: Not rec-
sider using with caution in patients with risks for coronary
ommended; product is a fixed-dose combination.
heart disease and minimizing modifiable risk factors (eg,
Children and Adolescents weighing 225 kg: Oral: 1
hypertension, hyperlipidemia, diabetes mellitus, and
tablet daily
smoking) prior to use. Due to fixed dose of combination
Renal Impairment: Pediatric Children and Adoles-
product, use is not recommended with mild hepatic impair-
cents weighing 225 kg: CrCl <50 mL/minute: Use not
ment; use in patients with moderate or severe hepatic
recommended; use individual antiretroviral agents to
impairment is contraindicated. Potentially significant
reduce dosage
drug-drug interactions may exist, requiring dose or fre-
Hepatic Impairment: Pediatric Use is contraindicated;
quency adjustment, additional monitoring, and/or selec-
use individual antiretroviral agents to reduce dosage
tion of alternative therapy.
Administration May be administered without regards to
Warnings: Additional Pediatric: Considerations The
meals.
major clinical toxicity of lamivudine in pediatric patients is
Monitoring Parameters HLA-B*5707 genotype status
pancreatitis; discontinue therapy if clinical signs, symp-
prior to initiating therapy or resuming therapy in patients
toms, or laboratory abnormalities suggestive of pancrea-
of unknown HLA-B*5707 status (including patients previ-
titis occur. Abacavir may cause mild hyperglycemia; more
ously tolerating therapy); signs and symptoms of abacavir
common in pediatric patients.
hypersensitivity reaction (in all patients, but especially in
Adverse Reactions See individual agents as well as those untested for the HLA-B*5707 allele)
other combination products for additional information.
Central nervous system: Abnormal dreams, anxiety, Note: The absolute CD4 cell count is currently, recom-
depression, dizziness, fatigue, headache, insomnia, mended to monitor immune status in children of all ages;
malaise, migraine, vertigo CD4 percentage can be used as an alternative in children
Dermatologic: Skin rash <5 years of age. This recommendation is based on the
Gastrointestinal: Abdominal pain, diarrhea, gastritis use of absolute CD4 cell counts in the current pediatric
Hypersensitivity: Hypersensitivity (including multiorgan HIV infection stage classification and as thresholds for
failure and anaphylaxis; higher incidence in subjects urgency of initiation of antiretroviral treatment (HHS
carrying the HLA-B*57071 allele) [pediatric] 2017).
Miscellaneous: Fever Prior to initiation of therapy: Genotypic resistance testing,
Rare but important or life-threatening: Abnormal breath CD4 and viral load (every 3 to 4 months), CBC with
sounds, alopecia, anemia (including pure red cell aplasia differential, LFTs, BUN, creatinine, electrolytes, glucose,
and severe anemias progressing on therapy), aplastic urinalysis (every 6 to 12 months), hepatitis B screening (if
anemia, erythema multiforme, exacerbation of hepatitis previously demonstrated no immunity to hepatitis B), and
B, hepatitis, hyperglycemia, immune reconstitution syn- assessment of readiness for adherence with medication
drome, increased creatine phosphokinase, lactic acido- regimen. At initiation and with any change in treatment
sis, liver steatosis, lymphadenopathy, myasthenia, regimen: Hepatitis B screening (at change in therapy, in
paresthesia, peripheral neuropathy, redistribution of patients who previously demonstrated no immunity to
body fat, rhabdomyolysis, seizure, splenomegaly, Ste- hepatitis B), CBC with differential, electrolytes, calcium,
vens-Johnson syndrome, stomatitis, weakness, phosphate, glucose, LFTs, bilirubin, urinalysis (at. initia-
wheezing tion), BUN, creatinine, albumin, total protein, lipid panel (at
Drug Interactions initiation), CD4, and viral load. After 1 to 2 weeks of
Metabolism/Transport Effects Refer to individual therapy: Signs of medication toxicity and adherence. After
components. 2 to 4 weeks of therapy: CBC with differential, viral load,

27
 ABACAVIR AND LAMIVUDINE

< signs of medication toxicity, and adherence; then every 3

to 4 months: CBC with differential, electrolytes, glucose,
suppression is effective, appropriate drug exposure can
be achieved, contraindications for use in pregnancy are
LFTs, bilirubin, BUN, creatinine, CD4, viral load, signs of not present, and the regimen is well tolerated (HHS
medication toxicity, and adherence. Every 6 to 12 months: [perinatal] 2017).
Lipid panel and urinalysis. CD4 monitoring frequency may
Refer to individual monographs.
be decreased to every 6 to 12 months in children who are
adherent to therapy if the value is well above the threshold
Breastfeeding Considerations Abacavir, dolutegravir,
for opportunistic infections, viral suppression is sustained,
and lamivudine are present in breast milk. See individual
agents.
and the clinical status is stable for more than 2 to 3 years.
In patients with known or suspected complex drug resist- Contraindications Hypersensitivity to abacavir, dolute-
ance patterns, phenotypic resistance testing (usually in gravir, lamivudine, or any component of the formulation;
addition to genotypic resistance testing) should be per- patients with HLA-B*5707 allele; concomitant dofetilide;
formed (HHS [pediatric] 2017). Monitor for growth and moderate or severe hepatic impairment
development, signs of HIV-specific physical conditions, Warnings/Precautions
HIV disease progression, opportunistic infections, pan- [US Boxed Warning]: Serious hypersensitivity reac-
creatitis, or lactic acidosis; serum creatinine kinase. tions (sometimes fatal) have occurred in patients
Additional Information The development of the abacavir taking abacavir (in Triumeq). Patients who carry the
hypersensitivity reaction has been associated with certain HLA-B*5701 allele are at a higher risk for a hyper-
HLA genotypes (eg, HLA-B*5701, HLA-DR7, HLA-DQ3) sensitivity reaction to abacavir, although hypersensi-
which may help predict which patients are at risk for tivity reactions have occurred in patients who do not
developing the abacavir hypersensitivity reaction (Hether- carry the HLA-B*5707 allele. All patients should be
ington 2002; Lucas 2007; Mallal 2002). Patients who test screened for the HLA-B*5707 allele prior to initiating
positive for the HLA-B*5707 allele should have an abaca- therapy with Triumeq or reinitiation of therapy with
vir allergy recorded in their medical record and should not Triumeq unless patients have had a previously docu-
receive abacavir. All patients who receive abacavir (and mented HLA-B*5701 allele assessment. Discontinue
their caregivers) should be educated about the risk of Triumeq if a hypersensitivity reaction is suspected.
abacavir hypersensitivity reactions (including patients Triumeq is contraindicated in patients who have the
who test negative for the HLA-B*5707 allele, as the risk HLA-B*5707 allele or in patients with a prior hyper-
for the reaction is not completely eliminated). Approxi- sensitivity reaction to abacavir. Reintroduction of
mately 4% of patients who test negative for the HLA- Triumeq or any other abacavir-containing product
B*5707 allele will experience a clinically suspected aba- can result in life-threatening or fatal hypersensitivity
cavir hypersensitivity reaction compared to 61% of those reactions, even in patients who have no history of
who test positive for the HLA-B*5707 allele. hypersensitivity to abacavir therapy. Such reactions
can occur within hours. Additionally, allele-positive
The prevalence of HLA-B*5707 in the United States has patients (including abacavir treatment naive) should have
been estimated to be 8% in Caucasians, 2.5% in African- an allergy to abacavir documented in their medical record.
Americans, 2% in Hispanics, <1% in Asians; in the sub- Reactions usually occur within 9 days of starting abacavir;
Saharan Africa it is 1%. Pretherapy identification of HLA- ~90% occur within 6 weeks (HHS [adult] 2017). These
B*5701-positive patients and subsequent avoidance of reactions usually include signs or symptoms in 2 of the
abacavir therapy in these patients has been shown to following groups: fever, skin rash, Gl symptoms (eg,
significantly reduce the occurrence of abacavir-associated abdominal pain, nausea, vomiting, diarrhea), constitu-
hypersensitivity reactions. A familial predisposition to the tional (eg, generalized malaise, fatigue, achiness), or
abacavir hypersensitivity reaction has been reported; use respiratory symptoms (eg, pharyngitis, dyspnea, cough).
abacavir with great caution in children of parents who Other signs and symptoms include lethargy, headache,
experience a hypersensitivity reaction to abacavir (Peyr- myalgia, edema, abnormal chest x-ray findings, arthralgia
iére 2001). and paresthesia. Anaphylaxis, liver failure, renal failure,
Reverse transcriptase mutations of K65R, L74V, Y115F, hypotension, adult respiratory distress syndrome, respira-
and M184V have been associated with abacavir resist- tory failure, myolysis, and death have occurred in associ-
ance; at least 2 to 3 mutations are needed to decrease ation with hypersensitivity reactions. Physical findings
HIV susceptibility by 10-fold. The presence of a multiple (lymphadenopathy, mucous membrane lesions, and rash
number of these abacavir resistance-associated muta- [maculopapular, urticarial or variable]) may occur. Eryth-
tions, may confer cross-resistance for other nucleoside ema multiforme has also been reported. Laboratory
or nucleotide reverse transcriptase inhibitors (eg, didano- abnormalities (eg, elevated liver function tests, elevated
sine, emtricitabine, lamivudine, zalcitabine, or tenofovir). A creatine phosphokinase, elevated creatinine, and lympho-
progressive decrease in abacavir susceptibility is associ- penia) may occur. Triumeq should be permanently dis-
ated with an increasing number of thymidine analogue continued if hypersensitivity cannot be ruled out, even
mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, when other diagnoses are possible. Following a hyper-
K219E/R/H/Q/N). sensitivity reaction, Triumeq SHOULD NOT be restarted
Dosage Forms Excipient information presented when because more severe symptoms may occur within hours,
available (limited, particularly for generics); consult spe- including LIFE-THREATENING HYPOTENSION AND
cific product labeling. DEATH. If Triumeq is to be restarted following an inter-
Tablet, Oral: ruption in therapy not associated with symptoms of a
Epzicom: Abacavir 600 mg and lamivudine 300 mg [con- hypersensitivity reaction, carefully evaluate the patient
tains fd&c yellow #6 (sunset yellow)] for previously unsuspected symptoms of hypersensitivity.
Generic: Abacavir 600 mg and lamivudine 300 mg Do not restart if hypersensitivity is suspected or cannot be
ruled out regardless of HLA-B*5707 status. If Triumeq is
restarted, continually monitor for symptoms of a hyper-
Abacavir, Dolutegravir, and Lamivudine sensitivity reaction. Make the patient aware that reintro-
(a BAK a veer, doe loo TEG ra vir, & la MI vyoo deen)
duction should only take place if medical care is readily
Medication Safety Issues accessible. Hypersensitivity reactions reported with dolu-
High alert medication: tegravir include rash, constitutional findings, and organ
The Institute for Safe Medication Practices (ISMP) dysfunction (eg, liver injury). Discontinue immediately if
includes this medication among its list of drugs which signs of hypersensitivity (eg, severe rash, rash with fever,
have a heightened risk of causing significant patient malaise, fatigue, muscle/joint aches, blistering or peeling
harm when used in error. of skin, oral blisters/lesions, conjunctivitis, facial edema,
Brand Names: US Triumeq hepatitis, eosinophilia, angioedema or difficulty breathing)
Brand Names: Canada Triumeq occur. Monitor clinical status, liver function tests and
Therapeutic Category Antiretroviral, Integrase Inhibitor initiate supportive therapy as appropriate. If hypersensi-
(Anti-HIV); Antiretroviral, Reverse Transcriptase Inhibitor, tivity occurs, do not reinitiate therapy. Do not restart
Nucleoside (Anti-HIV) Triumeq or any other abacavir or dolutegravir-containing
Generic Availability (US) No product in patients who have stopped Triumeq therapy
due to a hypersensitivity reaction.
Use
Treatment of HIV-1 infection (FDA approved in pediatric Lactic acidosis and severe hepatomegaly with steatosis,
patients weighing 240 kg and adults) including fatal cases, have been reported with nucleoside
Note: Not recommended for use in patients with known or analogues alone or in combination, including abacavir,
clinically suspected integrase strand transfer inhibitor lamivudine and other antiretrovirals. Female gender and
resistance because the dose of dolutegravir is insuffi- obesity may increase the risk for development. Suspend
cient in these subpopulations. treatment in any patient who develops clinical or labora-
Medication Guide Available Yes tory findings suggestive of lactic acidosis or hepatotoxicity
Pregnancy Considerations In general, females who (transaminase elevation may/may not accompany hepa-
become pregnant on a stable antiretroviral therapy tomegaly and steatosis). Pancreatitis has been observed
(ART) regimen may continue that regimen if viral with lamivudine and abacavir. Discontinue use if

28
 ABACAVIR, DOLUTEGRAVIR, AND LAMIVUDINE

pancreatitis is suspected ‘and resume only after pancrea- Drug Interactions

titis has been ruled out. Patients may develop immune Metabolism/Transport Effects Refer to individual
reconstitution syndrome resulting in the occurrence of an components.
inflammatory response to an indolent or residual oppor- Avoid Concomitant Use
tunistic infection during initial HIV treatment or activation Avoid concomitant use of Abacavir, Dolutegravir, and
of autoimmune disorders (eg, Graves disease, polymyo- Lamivudine with any of the following: Dofetilide; Emtrici-
sitis, Guillain-Barré syndrome) later in therapy; further tabine; Fosphenytoin-Phenytoin; Nevirapine; OXcarba-
evaluation and treatment may be required. Use has been zepine; PHENobarbital; Primidone; St John's Wort
associated with an increased risk of MI in observational Increased Effect/Toxicity
studies; however, in meta-analyses of randomized, con- Abacavir, Dolutegravir, and Lamivudine may increase
trolled clinical trials, no excess risk of Ml.was observed. the levels/effects of: Cabozantinib; Dofetilide; Emtricita-
Available data are inconclusive. Consider using with cau- bine; MetFORMIN
tion in patients with risks for coronary heart disease and
minimizing modifiable risk factors (eg, hypertension, The levels/effects of Abacavir, Dolutegravir, and Lam-
hyperlipidemia, diabetes mellitus and smoking) prior to ivudine may be increased by: Trimethoprim
use. HIV and hepatitis B virus (HBV) coinfected patients Decreased Effect
receiving lamivudine-containing antiretroviral regimens Abacavir, Dolutegravir, and Lamivudine may decrease
have developed lamivudine resistant HBV variants. [US the levels/effects of: Methadone
Boxed Warning]: Exacerbation of hepatitis B has been
The levels/effects of Abacavir, Dolutegravir, and Lam-
reported with discontinuation of lamivudine in coin-
ivudine’ may be decreased by: Aluminum Hydroxide;
fected HIV/HBV patients; monitor hepatic function Calcium Salts; CarBAMazepine; Efavirenz; Etravirine;
with clinical and laboratory evaluations for at least
Fosamprenavir; Fosphenytoin-Phenytoin; Iron Salts;
several months after discontinuing Triumeq in coin-
Magnesium Salts; Methadone; Multivitamins/Minerals
fected patients. Antihepatitis B therapy initiation may
(with ADEK, Folate, Iron); Multivitamins/Minerals (with
be warranted, if appropriate.
AE, No Iron); Nevirapine; Orlistat; OXcarbazepine; PHE-
Hepatic. adverse events, including elevated transami- Nobarbital; Primidone; Protease Inhibitors; RifAMPin;
nases, hepatitis, and acute liver failure (sometimes requir- Selenium; Sorbitol; St John's Wort; Sucralfate; Tiprana-
ing liver transplant), have been reported with regimens vir; Zinc Salts
containing dolutegravir. Risk may be increased in patients Food Interactions Ethanol decreases the elimination of
with significant transaminase elevations or hepatitis B or C abacavir and may increase the risk of toxicity. Manage-
prior to treatment; however, hepatotoxicity has been ment: Avoid ethanol intake; closely monitor patients
reported. in patients with no preexisting hepatic disease reporting concurrent ethanol intake.
or other risk factors. In some patients receiving dolute- Hazardous Drugs Handling Considerations
gravir-containing regimens, elevations in transaminases Hazardous agent (NIOSH 2016 [group 2)).
may be concurrent with development. of immune recon-
Abacavir is a hazardous agent. Use appropriate precau-
stitution syndrome or hepatitis B reactivation (especially if
tions for receiving, handling, administration, and disposal.
antihepatitis therapy has been discontinued). Baseline
Gloves (single) should be worn during receiving, unpack-
and periodic laboratory LFT evaluation during therapy is
ing, and placing in storage. NIOSH recommends single
recommended for patients with preexisting risk factors;
also consider LFT monitoring in patients without identifi-
gloving for administration of intact tablets or capsules
able hepatic disease risk. (NIOSH 2016).
Storage/Stability Store at 25°C (77°F); excursions are
Potentially significant drug-drug interactions may exist, permitted between 15°C and 30°C (59°F and 86°F).
requiring dose or frequency adjustment, additional mon- Dispense in original container; protect from moisture.
itoring, and/or selection of alternative therapy. Concom- Mechanism of Action Dolutegravir inhibits HIV integrase
itant use of other abacavir-, lamivudine-, or dolutegravir- by binding to the integrase active site and blocking the
containing products with the fixed-dose combination prod- strand transfer step of retroviral DNA integration. Abacavir
uct should be avoided. Use with caution in combination is converted by cellular enzymes to the active metabolite,
with interferon alfa with or without ribavirin in HIV/HBV carbovir triphosphate (CBV-TP), an analogue of deoxy-
coinfected patients; monitor closely for hepatic decom- guanosine-5'-triphosphate (dGTP). CBV-TP inhibits the
pensation (eg, Child-Pugh score >6), anemia, or neutro- activity of HIV-1 reverse transcriptase (RT) both by com-
penia; dose reduction or discontinuation of interferon and/ peting with the natural substrate dGTP and by its incor-
or ribavirin may be required if toxicity is evident. Triumeq, poration into viral DNA. Intracellularly, lamivudine is
as a fixed-dose combination tablet, should not be used in phosphorylated to its active 5’-triphosphate metabolite,
patients requiring dosage adjustment, including patients lamivudine triphosphate (3TC-TP). The principal mode of
with CrCl <50 mL/minute and patients with mild hepatic action of 3TC-TP is inhibition of reverse transcriptase via
impairment; use is contraindicated in moderate to severe DNA chain termination after incorporation of the nucleo-
hepatic impairment. tide analogue.
Dolutegravir may increase serum creatinine due to inhib- Pharmacodynamics/Kinetics (Adult data unless
ition of tubular secretion of creatinine without affecting noted) Pharmacokinetic studies of Triumeq show no
renal glomerular function- or effective renal plasma flow difference in values when compared to dolutegravir as a
(Gutierrez 2014). Increased serum creatinine occurred single agent given with abacavir and lamivudine as a
within the first 4 weeks of-treatment with dolutegravir combination product. See individual agents.
and remained stable through 144 weeks of treatment. Dosing
Warnings: Additional Pediatric Considerations The Pediatric
major clinical toxicity of lamivudine in pediatric patients is HIV-1 infection, treatment:
pancreatitis; discontinue therapy if clinical signs, symp- Children and Adolescents weighing <40 kg: Not rec-
toms, or laboratory abnormalities suggestive of pancrea- ommended; product is a fixed-dose combination
titis occur. Abacavir may cause mild hyperglycemia; more Children and Adolescents weighing 240 kg: Oral: One
common in pediatric patients. tablet (abacavir 600 mg/dolutegravir 50 mg/lamivu-
Adverse Reactions See individual agents as well as dine 300 mg) once daily
other combination products for additional information. Dosing adjustment for concomitant therapy with
Central nervous system: Depression, drowsiness, fatigue, efavirenz, fosamprenavir/ritonavir, tipranavir/rito-
headache, insomnia, lethargy, nightmares, sleep disor- navir, carbamazepine, or rifampin: Limited data
der, suicidal ideation available: Children and Adolescents weighing 240 kg:
Dermatologic: Pruritus Oral: One tablet once daily, with an additional dolute-
Endocrine & metabolic: Hyperglycemia (2126 mg/dL), gravir 50 mg tablet daily administered 12 hours after
hypertriglyceridemia Triumeq
Gastrointestinal: Abdominal distention, abdominal dis- Renal Impairment: Pediatric
tress, abdominal pain, anorexia, dyspepsia, flatulence, CrCl 250 mL/minute: No dosage adjustment necessary
gastroesophageal reflux disease, increased serum CrCl <50 mL/minute: Use is not recommended (use
lipase (1.5 x ULN), upper abdominal pain, vomiting dose-adjusted individual component drugs)
Hematologic & oncologic: Decreased neutrophils Hepatic Impairment: Pediatric
Hepatic: Hepatitis, increased serum ALT (>2.5 x ULN), Mild impairment (Child-Pugh class A): Use is not recom-
increased serum AST (>2.5 x ULN) mended (use dose-adjusted individual component
Neuromuscular & skeletal: Arthralgia, increased creatine drugs).
phosphokinase (26.0 x ULN), myositis Moderate to severe impairment (Child-Pugh class B or
Renal: Renal insufficiency C): Use is contraindicated.
Miscellaneous: Fever Administration Oral: Administer with or without food.
Rare but important or life-threatening: Abnormal dreams, Administer 2 hours before or 6 hours after cation-contain-
diarrhea, dizziness, hypersensitivity reaction, immune ing antacids or laxatives, sucralfate, oral supplements
reconstitution syndrome, nausea, skin rash containing iron or calcium, or buffered medications. »
29
ABACAVIR, DOLUTEGRAVIR, AND LAMIVUDINE

Alternatively, may be administered with supplements con- present, and the regimen is well tolerated (HHS [perinatal]
taining calcium or iron at the same time if administered 2017).
together with food.
See individual agents.
Monitoring Parameters HLA-B*5701 genotype status
Breastfeeding Considerations Abacavir, lamivudine,
prior to initiating therapy or resuming therapy in patients
and zidovudine are present in breast milk. See individual
of unknown HLA-B*57071 status (including patients previ-
agents.
ously tolerating therapy); signs and symptoms of abacavir
Contraindications ’
hypersensitivity reaction (in all patients, but especially in
Hypersensitivity to abacavir, lamivudine, zidovudine, or
those untested for the HLA-B*57071 allele)
any component of the formulation; patients positive for
Note: The absolute CD4 cell count is currently recom- HLA-B*5701 allele; moderate or severe hepatic impair-
mended to monitor immune status in children of all ages; ment.
CD4 percentage can be used as an alternative in children Canadian labeling: Additional contraindications (not in US
<5 years of age. This recommendation is based on the labeling): Hepatic impairment (regardless of severity of
use of absolute CD4 cell counts in the current pediatric impairment); ANC <750 cells/mm?; hemoglobin
HIV infection stage classification and as thresholds for <7.5 g/dL or 4.65 mmol/L
initiation of antiretroviral treatment (HHS [pediatric] 2016). Warnings/Precautions
[US Boxed Warning]: Serious hypersensitivity reac-
Prior to initiation of therapy: Genotypic resistance testing, tions (sometimes fatal) have occurred in patients
CD4 and viral load (every 3’'to 4 months), CBC with taking abacavir (in Trizivir). Patients who carry the
differential, LFTs, BUN, creatinine, electrolytes, glucose, HLA-B*5701 allele are at a higher risk for a hyper-
urinalysis (every 6 to 12 months), hepatitis B screening (if sensitivity reaction to abacavir, although hypersensi-
previously demonstrated no immunity to hepatitis B), and tivity reactions have occurred in patients who do not
assessment of readiness for adherence with medication carry the HLA-B*5707 allele. All patients should be
regimen. At initiation and with any change in treatment screened for the HLA-B*57071 allele prior to initiating
regimen: Hepatitis B screening (at change in therapy, in therapy with Trizivir or reinitiation of therapy with
patients who previously demonstrated no immunity to Trizivir unless patients have had a previously docu-
hepatitis B), CBC with differential, electrolytes, calcium, mented HLA-B*5707 allele assessment. Discontinue
phosphate, glucose, LFTs, bilirubin, urinalysis (at initia- Trizivir if a hypersensitivity reaction is suspected.
tion), BUN, creatinine, albumin, total protein, lipid panel (at Trizivir is contraindicated in patients who have the
initiation), CD4, and viral load. After 1 to 2 weeks of HLA-B*5701 allele or in patients with a prior hyper-
therapy: Signs of medication toxicity and adherence. After sensitivity reaction to abacavir. Reintroduction of
2 to 4 weeks of therapy: CBC with differential, viral load, Trizivir or any other abacavir-containing product can
signs of medication toxicity, and adherence; then every 3 result in life-threatening or fatal hypersensitivity reac-
to 4 months: CBC with differential, electrolytes, glucose, tions, even in patients who have nohistory of hyper-
LFTs, bilirubin, BUN, creatinine, CD4, viral load, signs of sensitivity to abacavir therapy. Such reactions can
medication toxicity, and adherence. Every 6 to 12 months: occur within hours. Additionally, allele-positive patients
Lipid panel and urinalysis. CD4 monitoring frequency may (including abacavir treatment naive) should have an
be decreased to every 6 to 12 months in children who are allergy to abacavir documented in their medical record.
adherent to therapy if the value is well above the threshold Reactions usually occur within 9 days of starting abacavir;
for opportunistic infections, viral suppression is sustained, ~90% occur within 6 weeks, although these reactions may
and the clinical status is stable for more than 2 to 3 years. occur at any time during therapy (HHS [adult] 2015).
In patients with known or suspected complex drug resist- These reactions usually include signs or symptoms in 2
ance patterns, phenotypic resistance testing (usually in or more of the following groups: fever; rash; gastrointes-
addition to genotypic resistance testing) should be per- tinal (eg, nausea, vomiting, diarrhea, abdominal pain);
formed (HHS [pediatric] 2016). Monitor for growth and constitutional (eg, generalized malaise, fatigue, achiness);
development, signs of HIV-specific physical conditions, respiratory (eg, dyspnea, cough, pharyngitis). Other signs
HIV disease progression, opportunistic infections, hyper- and symptoms. include lethargy, headache, myalgia,
sensitivity, pancreatitis, or lactic acidosis; serum creatinine edema, abnormal chest x-ray findings, arthralgia and
kinase. paresthesia. Anaphylaxis, liver failure, renal failure, hypo-
Dosage Forms Excipient information presented when tension, adult respiratory distress syndrome, respiratory
available (limited, particularly for generics); consult spe- failure, myolysis, and death have occurred in association
cific product labeling. with hypersensitivity reactions. Physical findings (lympha-
Tablet, Oral: denopathy, mucous membrane lesions, and rash [macu-
Triumeq: Abacavir 600 mg, dolutegravir 50 mg, and lopapular, urticarial or variable]) may occur. Erythema
lamivudine 300 mg multiforme has also been reported. Laboratory abnormal-
ities (eg, elevated liver function tests, elevated creatine
@ Abacavir/Dolutegravir/Lamivudine see Abacavir, Dolu- phosphokinase, elevated creatinine, and lymphopenia)
tegravir, and Lamivudine on page 28 may occur. Trizivir should be permanently discontinued if
hypersensitivity cannot be ruled out, even when other
Abacavir, Lamivudine, and Zidovudine diagnoses are possible. Following a hypersensitivity reac-
(a BAK a veer, la MI vyoo deen, & zye DOE vyoo deen) tion, Trizivir SHOULD NOT be restarted because more
severe symptoms may occur within hours, including LIFE-
Medication Safety Issues THREATENING HYPOTENSION AND DEATH. If Trizivir
High alert medication: is to be restarted following an interruption in therapy not
This medication is in a class the Institute for Safe associated with symptoms of a hypersensitivity reaction,
Medication Practices (ISMP) includes among its list of carefully evaluate the patient for previously unsuspected
drug classes that have a heightened risk of causing symptoms of hypersensitivity. Do not restart if hypersensi-
significant patient harm when used in error. tivity is suspected or cannot be ruled out regardless of
Brand Names: US Trizivir HLA-B*5707 status. If Trizivir is restarted, continually
Brand Names: Canada Trizivir monitor for symptoms of a hypersensitivity reaction. Make
Therapeutic Category Antiretroviral Agent; HIV Agents the patient aware that reintroduction should only take
(Anti-HIV Agents); Nucleoside Analog Reverse Transcrip- place if medical care is readily accessible.
tase Inhibitor (NRT1)
[US Boxed Warning]: Lactic acidosis and severe hep-
Generic Availability (US) Yes atomegaly with steatosis, including fatal cases, have
Use Treatment of HIV-1 infection, either alone or in combi- been reported with the use of nucleoside analogues.
nation with other antiretroviral agents (FDA approved in Female gender and obesity may increase the risk for
pediatric patients 240 kg and adults); Note: HIV regimens development. Suspend treatment in any patient who
consisting of three antiretroviral agents are strongly rec- develops clinical or laboratory findings suggestive of lactic
ommended; Note: Data on the use of this triple NRTI acidosis or hepatotoxicity (transaminase elevation may/
combination regimen in patients with baseline viral loads may not accompany hepatomegaly and steatosis). Pan-
>100,000 copies/mL is limited. creatitis has been observed with abacavir, lamivudine and
Medication Guide Available Yes zidovudine; rule out pancreatitis in patients who develop
Pregnancy Considerations signs/symptoms (eg, nausea/vomiting, abdominal pain,
The Health and Human Services (HHS) Perinatal HIV elevated lipase and amylase) during therapy. [US Boxed
Guidelines generally do not recommend this combination Warning]: Zidovudine has been associated with hem-
as initial therapy in antiretroviral-naive pregnant females atologic toxicities (eg, neutropenia, anemia); use with
due to inferior virologic activity. However, females who caution in patients with bone marrow compromise (eg,
become pregnant on this regimen, in absence of other granulocyte count <1,000 cells/mm? or hemoglobin
antiretroviral medications, may continue if viral suppres- <9.5 g/dL). Frequent complete blood counts are recom-
sion is. effective, appropriate drug exposure can be mended in patients with advanced HIV-1 disease. Dosage
achieved, contraindications for use in pregnancy are not interruption may be needed if anemia or neutropenia

30
 ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE

develops. [US Boxed Warnings]: Exacerbation of hep- BCG (\ntravesical); Deferiprone; Dipyrone; Emtricita-
atitis B (including fatalities) has been reported with bine; Stavudine
discontinuation of lamivudine in coinfected HIV/HBV Increased Effect/Toxicity
patients; monitor hepatic function (eg, serum ALT) and Abacavir, Lamivudine, and Zidovudine may increase the
HBV viral DNA closely for several months after discontin- levels/effects of: Amodiaquine; Cabozantinib; CloZA-
uing Trizivir in coinfected patients. Emergence of HBV Pine; Deferiprone; Emtricitabine; Ribavirin (Oral Inhala-
virus variants associated with resistance to lamivudine tion); Ribavirin (Systemic)
have been reported in HIV-1 infected subjects who have
received lamivudine-containing antiretroviral regimens in The levels/effects of Abacavir, Lamivudine, and Zidovu-
the presence of HBV coinfection. [US Boxed Warning]: dine may be increased by: Acemetacin; Acyclovir-Vala-
Prolonged use of zidovudine has been associated cyclovir; Chloramphenicol (Ophthalmic); Clarithromycin;
with symptomatic myopathy and myositis. May cause Dexketoprofen; Dipyrone; DOXOrubicin (Conventional);
loss of subcutaneous fat, especially in the face, limbs, and DOXOrubicin (Liposomal); Fluconazole; Ganciclovir-Val-
buttocks. Lipoatrophy incidence and severity are related to ganciclovir; Interferons; Methadone; Probenecid; Proma-
cumulative exposure and may be only partially reversible; zine; Raltegravir; Tenoxicam; Teriflunomide; Tolvaptan;
improvement may take months to years after switching to Trimethoprim; Valproate Products
a regimen that does not contain zidovudine. Monitor Decreased Effect
patients for signs of lipoatrophy and consider switching Abacavir, Lamivudine, and Zidovudine may decrease the
to a non-zidovudine-containing regimen if lipoatrophy levels/effects of: BCG (Intravesical); Methadone; Stavu-
occurs. Patients may develop immune reconstitution syn- dine
drome resulting in the occurrence of an inflammatory The levels/effects of Abacavir, Lamivudine, and Zidovu-
response to an indolent or residual opportunistic infection dine may be decreased by: Clarithromycin; DOXOrubicin
during initial HIV treatment or activation of autoimmune (Conventional); DOXOrubicin (Liposomal); Methadone;
disorders (eg, Graves disease, polymyositis, Guillain- Orlistat; Protease Inhibitors; Rifamycin Derivatives; Sor-
Barré syndrome) later in therapy; further evaluation and bitol
treatment may be required. Use has been associated with Food Interactions Ethanol decreases the elimination of
an increased risk of MI in observational studies; however, abacavir and may increase the risk of toxicity. Manage-
in a meta-analysis of randomized, controlled clinical trials, ment: Monitor patients.
no excess risk of MI was observed. Available data are
Hazardous Drugs Handling Considerations
inconclusive. Consider using with caution in patients with Hazardous agent (NIOSH 2016 [group 2]).
risks for coronary heart disease and minimizing modifiable
risk factors (eg, hypertension, hyperlipidemia, diabetes Abacavir is a hazardous agent. Use appropriate precau-
mellitus, and smoking) prior to use. Patients with pro- tions for receiving, handling, administration, and disposal.
longed prior nucleoside reverse transcriptase inhibitor Gloves (single) should be worn during receiving, unpack-
(NRTI) exposure or presence of HIV-1 isolates containing ing, and placing in storage. NIOSH recommends single
multiple mutations conferring resistance to NRTIs have gloving for administration of intact tablets or capsules
limited response to abacavir. The potential for cross (NIOSH 2016).
resistance between abacavir and other NRTIs should be Storage/Stability Store at 25°C (77°F); excursions per-
considered when evaluating new regimens in therapy mitted to 15°C to 30°C (59°F to 86°F).
experienced patients.. Potentially significant drug-drug Mechanism of Action The combination of abacavir,
interactions may exist, requiring dose or frequency adjust- lamivudine, and zidovudine is believed to act synergisti-
ment, additional monitoring, and/or selection of alternative cally to inhibit reverse transcriptase via DNA chain termi-
therapy. nation after incorporation of the nucleoside analogue as
well as to delay the emergence of mutations conferring
Trizivir, as a fixed-dose combination tablet, should not be
resistance.
used in pediatric patients <40 kg or those requiring dos-
age adjustment; should not be used in patients with CrCl Pharmacodynamics/Kinetics (Adult data unless
<50 mL/minute. noted) Bioavailability studies of Trizivir® show no differ-
ence in AUC or Crax when compared to abacavir, lam-
Warnings: Additional Pediatric Considerations The
ivudine, and zidovudine given together as individual
major clinical toxicity of lamivudine in pediatric patients is
pancreatitis; discontinue therapy if clinical signs, symp- agents. See individual agents.
toms, or laboratory abnormalities suggestive of pancrea- Dosing
titis occur. Abacavir may cause mild hyperglycemia; more Pediatric
common in pediatric patients. HIV-1 infection, treatment: May use alone or in combi-
Adverse Reactions See individual agents as well as nation with other antiretroviral agents:
other combination products for additional information. Children and Adolescents <40 kg: Not recommended;
Central nervous system: Anxiety, depression, fatigue, product is a fixed-dose combination
headache, malaise Children and Adolescents 240 kg: Oral: 1 tablet twice
Dermatologic: Skin rash daily
Endocrine & metabolic: Increased amylase, increased Renal Impairment: Pediatric
gamma-glutamyl transferase, increased serum triglycer- Pediatric patients 240 kg:
ides, redistribution of body fat ; CrCl 250 mL/minute: No dosage adjustment necessary.
Gastrointestinal: Diarrhea, nausea, nausea and vomiting, CrCl <50 mL/minute: Use not recommended (use indi-
pancreatitis vidual antiretroviral agents to reduce dosage).
Hematologic & oncologic: Neutropenia Hepatic Impairment: Pediatric
Hepatic: Increased serum ALT Mild impairment (Child-Pugh Class A): Use is not rec-
Hypersensitivity: Hypersensitivity (based on abacavir ommended; use individual antiretroviral agents to
component; higher risk in carriers of the HLA-B*5701 reduce dosage.
allele) Moderate to severe impairment (Child-Pugh Class B or
Immunologic: Immune reconstitution syndrome C): Use is contraindicated.
Infection: Viral infection Administration May be administered without regard to
Miscellaneous: Fever and chills meals.
Neuromuscular & skeletal: Increased creatine phospho- Monitoring Parameters HLA-B*5701 genotype status
kinase prior to initiating therapy or resuming therapy in patients
Respiratory: ENT infection of unknown HLA-B*5707 status (including patients previ-
Rare but important or life-threatening: Abdominal pain, ously tolerating therapy); signs and symptoms of abacavir
allergic sensitization (including anaphylaxis), alopecia, hypersensitivity reaction (in all patients, but especially in
anemia, anorexia, aplastic anemia, cardiomyopathy, those untested for the HLA-B*5707 allele)
decreased appetite, dyspepsia, erythema multiforme,
Note: The absolute CD4 cell count is currently recom-
exacerbation of hepatitis B (posttreatment), gynecomas-
mended to monitor immune status in children of all ages;
tia, increased serum bilirubin, increased serum trans-
CD4 percentage can be used as an alternative in children
aminases, insomnia, lactic acidosis, liver steatosis,
<5 years of age. This recommendation is based on the
lymphadenopathy, myalgia, myasthenia, oral mucosa
use of absolute CD4 cell counts in the current pediatric
hyperpigmentation, paresthesia, peripheral neuropathy,
HIV infection stage classification and as thresholds for
rhabdomyolysis, seizure, sleep disorder, splenomegaly,
urgency of initiation of antiretroviral treatment (HHS
Stevens-Johnson syndrome, stomatitis, thrombocytope-
[pediatric] 2017).
nia, urticaria, vasculitis, wheezing
Drug Interactions Prior to initiation of therapy: Genotypic resistance testing,
Metabolism/Trarsport Effects Refer to individual CD4 and viral load (every 3 to 4 months), CBC with
components. differential, LFTs, BUN, creatinine, electrolytes, glucose,
Avoid Concomitant Use urinalysis (every 6 to 12 months), hepatitis B screening (if
Avoid concomitant use of Abacavir, Lamivudine, and previously demonstrated no immunity to hepatitis B), and
Zidovudine with any of the following: Amodiaquine; assessment of readiness for adherence with medication

31
ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE

regimen. At initiation and with any change in treatment

regimen: CBC with differential, electrolytes, calcium, Abatacept (ab a TA sept)
phosphate, glucose, LFTs, bilirubin, urinalysis (at initia-
Medication Safety Issues
tion), BUN, creatinine, albumin, total protein, lipid panel (at
Sound-alike/look-alike issues:
initiation), CD4, and viral load. After 1 to 2 weeks of
Orencia may be confused with Oracea
therapy: Signs of medication toxicity and adherence. After
Brand Names: US Orencia; Orencia ClickJect
2 to 4 weeks of therapy: CBC with differential, viral load,
Brand Names: Canada Orencia :
signs of medication. toxicity and adherence; then every 3
Therapeutic Category Antirheumatic, Disease Modifying
to 4 months: CBC with differential, electrolytes, glucose,
Generic Availability (US) No
LFTs, bilirubin, BUN, creatinine, CD4, viral load, signs of
Use Treatment of moderately- to severely-active polyartic-
medication toxicity, and adherence. Lipid panel and uri- ular juvenile idiopathic arthritis as monotherapy or con-
nalysis every 6 to 12 months. CD4 monitoring frequency comitantly with methotrexate (IV: FDA approved in ages 6
may be decreased to every 6 to 12 months in children who to 17 years; SubQ: FDA approved in ages 2 to 17 years).
are adherent to therapy if the value is well above the Treatment of moderately- to severely-active rheumatoid
threshold for opportunistic infections, viral suppression is arthritis as monotherapy or in combination with other
sustained, and the clinical status is stable for more than 2 DMARDs (IV; SubQ: FDA approved in adults). Treatment
to 3 years. In patients with known or suspected complex of active psoriatic arthritis (PsA) (IV; SubQ: FDA approved
drug resistance patterns, phenotypic resistance testing in adults). Note: Abatacept should not be used in combi-
(usually in addition to genotypic resistance testing) should nation with TNF antagonists or with other biologic rheu-
be performed (HHS [pediatric] 2017). Monitor for growth matoid arthritis drugs, such as anakinra.
and development, signs of HIV-specific physical condi- Pregnancy Considerations Information related to the
tions, HIV disease progression, opportunistic infections, use of abatacept in pregnancy is limited (Kumar 2015).
Until additionaldata are available, it is recommended to
hepatotoxicity, anemia, pancreatitis, or lactic acidosis;
discontinue use and switch to a safer medication prior to
serum creatine kinase
conception unless no other pregnancy compatible medi-
Additional Information The development of the abacavir cation is able to control maternal disease (Gotestam
hypersensitivity reaction has been associated with certain Skorpen 2016).
HLA genotypes (eg, HLA-B*5701, HLA-DR7, HLA-DQ3)
which may help predict which patients are at risk for A pregnancy registry has been established to monitor
developing the abacavir hypersensitivity reaction (Hether- outcomes of women exposed to abatacept during preg-
ington 2002; Lucas 2007; Mallal 2002). Patients who test nancy (1-877-311-8972).
positive for the HLA-B*5707 allele should have an abaca- Breastfeeding Considerations It is not known if abata-
cept is present in human milk. Until information is avail-
vir allergy recorded in their medical record and should not
able, it is recommended to avoid breastfeeding during
receive abacavir. All patients who receive abacavir (and
therapy unless no other compatible medication is able to
their caregivers) should be educated about the risk of control maternal disease. Breastfeeding should not be
abacavir hypersensitivity reactions (including patients discouraged if no other agent is available (Gdtestam
who test negative for the HLA-B*5707 allele, as the risk Skorpen 2016).
for the reaction is not completely eliminated). Approxi- Contraindications
mately 4% of patients who test negative for the HLA- There are no contraindications listed within the manufac-
B*5701 allele will experience a clinically suspected aba- turer's US labeling.
cavir hypersensitivity reaction compared to 61% of those Canadian labeling: Additional contraindications (not in US
who test positive for the HLA-B*5707 allele. labeling): Hypersensitivity to abatacept or any compo-
nent of the formulation; patients with, or at risk of sepsis
The prevalence of HLA-B*5707 in the United States has syndrome (eg, immunocompromised, HIV positive)
been estimated to be 8% in Caucasians, 2.5% in African- Warnings/Precautions Serious and potentially fatal
Americans, 2% in Hispanics, 1% in Asians; in the sub- infections (including tuberculosis and sepsis) have been
Saharan Africa it is <1%. Pretherapy identification of HLA- reported, particularly in patients receiving concomitant
B*5701-positive patients and subsequent avoidance of immunosuppressive therapy. RA patients receiving a con-
abacavir therapy in these patients has been shown to comitant TNF antagonist experienced an even higher rate
significantly reduce the occurrence of abacavir-associated of serious infection. Caution should be exercised when
hypersensitivity reactions. A skin patch test is in develop- considering the use of abatacept in any patient with a
ment for clinical screening purposes; however, only PCR- history of recurrent infections, with conditions that predis-
mediated genotyping methods are currently in clinical pose them to infections, or with chronic, latent, or localized
practice use for documentation of this susceptibility infections. Patients who develop a new infection while
marker. A familial predisposition to the abacavir hyper- undergoing treatment should be monitored closely. If a
sensitivity reaction has been reported; use abacavir with patient develops a serious infection, abatacept should be
discontinued. Screen patients for latent tuberculosis infec-
great caution in children of parents who experience a
tion prior to initiating abatacept; safety in tuberculosis-
hypersensitivity reaction to abacavir (Peyriére 2001).
positive patients has not been established. Treat patients
Reverse transcriptase mutations of K65R, L74V, Y115F, testing positive according to standard therapy prior to
and M184V have been associated with abacavir resist- initiating abatacept. Adult patients receiving abatacept in
ance; at least 2 to 3 mutations are needed to decrease combination with TNF-blocking agents had higher rates of
HIV susceptibility by 10-fold. The presence of a multiple infections (including serious infections) than patients on
number of these abacavir resistance-associated muta-
TNF-blocking agents alone. Potentially significant drug-
drug interactions may exist, requiring dose or frequency
tions may confer cross-resistance for other nucleoside or
adjustment, additional monitoring, and/or selection of
nucleotide reverse transcriptase inhibitors (eg, didano-
alternative therapy. Monitor for signs and symptoms of
sine, emtricitabine, lamivudine, zalcitabine, or tenofovir).
infection when transitioning from TNF-blocking agents to
A progressive decrease in abacavir susceptibility is asso- abatacept. Due to the effect of T-cell inhibition on host
ciated with an increasing number of thymidine analogue defenses, abatacept may affect immune responses
mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, against infections and malignancies; impact on the devel-
K219E/R/H/Q/N). opment and course of malignancies is not fully defined.
Dosage Forms Excipient information presented when
Use caution with chronic obstructive pulmonary disease
available (limited, particularly for generics); consult spe-
(COPD), higher incidences of adverse effects (COPD
cific product labeling.
exacerbation, cough, rhonchi, dyspnea) have been
Tablet, Oral: observed; monitor closely. Rare cases of hypersensitivity,
Trizivir: Abacavir sulfate 300 mg, lamivudine 150 mg, anaphylaxis, or anaphylactoid reactions have been
and zidovudine 300 mg [contains fd&c blue #2 (indi- reported with intravenous administration; may occur with
gotine)] first infusion. Some reactions (hypotension, urticaria,
Generic: Abacavir sulfate 300 mg, lamivudine 150 mg, dyspnea) occurred within 24 hours of infusion. Discon-
and zidovudine 300 mg tinue treatment if anaphylaxis or other serious allergic
reaction occurs; medications for the treatment of hyper-
@ Abacavir/Lamivudine/Zidovudine see Abacavir, Lami- sensitivity reactions should be available for immediate
vudine, and Zidovudine on page 30 use. Patients should be screened for viral hepatitis prior
@ Abacavir Sulfate see Abacavir on page 24 to use; antirheumatic therapy may cause reactivation of
hepatitis B. Patients should be brought up to date with all
@ Abacavir Sulfate and Lamivudine see Abacavir and
immunizations before initiating therapy. Live vaccines
Lamivudine on page 26
should not be given concurrently or within 3 months of
@ Abacavir Sulfate, Dolutegravir, and Lamivudine see discontinuation of therapy; there is no data available
Abacavir, Dolutegravir, and Lamivudine on page 28 concerning secondary transmission of live vaccines in

32
 ABATACEPT

patients receiving therapy. Powder for injection may con- Clearance: 0.22 to 0.23 mL/hour/kg; Children 6 to 17
tain maltose, which may result in falsely-elevated serum years: JIA: 0.4 mL/hour/kg (increases with baseline body
glucose readings on the day of infusion. Higher incidences weight)
of infection and malignancy were observed in the elderly; Dosing
use with caution. Pediatric
Warnings: Additional Pediatric Considerations Juvenile idiopathic arthritis: Note: Dosing varies by
Reactivation of TB has been reported in pediatric patients route of administration (IV or SubQ); use extra pre-
receiving biologic response modifiers (infliximab and eta- caution.
nercept); prior to therapy, patients with no TB risk factors IV: Children and Adolescents 6 to 17 years: Note:
should be screened for latent TB infection (LTBI) with an Dose is based on body weight at each dose admin-
age appropriate test (ie, <5 years of age: tuberculin skin istration. Following the initial |V infusion, repeat IV
test, and 25 years of age: IGRA [interferon gamma release dose at 2 weeks and 4 weeks after the initial
assay]); if any TB risk factors are present or symptoms, infusion, and every 4 weeks thereafter.
both LTBI screening tests should be performed (AAP Patient weight:
{Davies 2016]) <75 kg: 10 mg/kg
Adverse Reactions Note: COPD patients experienced a 75 to 100 kg: 750 mg
higher frequency of COPD-related adverse reactions >100 kg: 1,000 mg
(COPD exacerbation, cough, dyspnea, pneumonia, rhon- SubQ: Children 22 years and Adolescents $17 years:
chi) Note: Administer without an IV loading dose and
Cardiovascular: Hypertension use the following weight-based dosing. The auto-
Central nervous system: Dizziness, headache injector for subcutaneous injection has not been
Dermatologic: Skin rash studied in patients under 18 years of age.
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia,
Patient weight:
nausea 10 to <25 kg: 50 mg once weekly
225 to <50 kg: 87.5 mg once weekly
Genitourinary: Urinary tract infection
250 kg: 125 mg once weekly
Immunologic: Antibody development, immunogenicity
Rheumatoid arthritis: Adolescents 218 years:
Infection: Herpes simplex infection, infection, influenza
IV: Weight-based dosing: Following the initial |V infu-
Local: Injection site reaction
sion (using the weight-based dosing), repeat IV
Neuromuscular & skeletal: Back pain, limb pain
infusion (using the same weight-based dosing) at 2
Respiratory: Bronchitis, cough, nasopharyngitis, pneumo-
weeks and 4 weeks after the initial infusion, and
nia, rhinitis, sinusitis, upper respiratory tract infection
every 4 weeks thereafter.
Miscellaneous: Fever, infusion-related reaction
<60 kg: 500 mg
Rare but. important or life-threatening: Acute lymphocytic
60 to 100 kg: 750 mg
leukemia, anaphylactoid reaction, anaphylaxis, cellulitis, >100 kg: 1,000 mg
diverticulitis, dyspnea, exacerbation of arthritis, exacer- SubQ: 125 mg once weekly. Note: SubQ dosing may
bation of chronic obstructive pulmonary disease, flush- be initiated with or without an IV loading dose.
ing, hypersensitivity reaction, hypotension, joint wear, If initiating with an IV loading dose: Administer the
malignant lymphoma, malignant melanoma, malignant initial IV infusion (using the weight-based dosing),
neoplasm of bile duct, malignant neoplasm of bladder, then administer 125 mg SubQ within 24 hours of
malignant neoplasm of breast, malignant neoplasm of the infusion, followed by 125 mg SubQ once
cervix, malignant neoplasm of kidney, malignant neo- weekly thereafter.
plasm of lung, malignant neoplasm of prostate, malig- If transitioning from IV therapy to SubQ therapy:
nant neoplasm of skin, malignant neoplasm of thyroid, Administer the first SubQ dose instead of the next
malignant neoplasm of uterus, myelodysplastic syn- scheduled IV dose.
drome, ovarian cyst, pruritus, pyelonephritis, rhonchi, Renal Impairment: Pediatric There are no dosage
urticaria, varicella, vasculitis (including cutaneous vascu- adjustments provided in the manufacturer's labeling;
litis and leukocytoclastic vasculitis), wheezing has not been studied.
Drug Interactions Hepatic Impairment: Pediatric There are no dosage
Metabolism/Transport Effects None known. adjustments provided in the manufacturer's labeling; has
Avoid Concomitant Use not been studied.
Avoid concomitant use of Abatacept with any of the Preparation for Administration
following: Anakinra; Anti-TNF Agents; Baricitinib; BCG \V: Prepare abatacept using only the silicone-free dispos-
(Intravesical); Belimumab; Natalizumab; Pimecrolimus; able syringe provided with each vial (for information on
RiTUXimab; Tacrolimus (Topical); Tocilizumab; Tofaciti- obtaining additional silicone-free disposable syringes
nib; Vaccines (Live) contact Bristol-Myers Squibb at 1-800-ORENCIA).
Increased Effect/Toxicity Reconstitute each vial with 10 mL SWFI using the
Abatacept may increase the levels/effects of: Belimu- provided silicone-free disposable syringe (discard solu-
mab; Fingolimod; Leflunomide; Natalizumab; Tofacitinib; tions accidentally reconstituted with siliconized syringe
Vaccines (Live) as they may develop translucent particles) and an 18- to
21-gauge needle. Inject SWFI down the side of the vial to
The levels/effects of Abatacept may be increased by: avoid foaming. Gently rotate to dissolve; do not shake.
Anakinra; Anti-TNF Agents; Baricitinib; Denosumab; The vial should be vented to allow any foam that is
Ocrelizumab; Pimecrolimus; RiTUXimab; Roflumilast; present to dissipate. The reconstituted solution contains
Tacrolimus (Topical); Tocilizumab; Trastuzumab 25 mg/mL abatacept. Further dilute (using a silicone-free
Decreased Effect syringe) in 100 mL NS to a final concentration of
Abatacept may decrease the levels/effects of: BCG <10 mg/mL. Prior to adding abatacept to the 100 mL
(Intravesical); Coccidioides immitis Skin Test; Nivolu- bag, the manufacturer recommends withdrawing a vol-
mab; Pidotimod; Sipuleucel-T; Tertomotide; Vaccines ume of NS equal to the abatacept volume required,
(Inactivated); Vaccines (Live) resulting in a final volume of 100 mL. Mix gently; do
not shake.
The levels/effects of Abatacept may be decreased by:
SubQ: Allow prefilled syringe to reach room temperature
Echinacea
prior to administration by removing from refrigerator 30
Storage/Stability to 60 minutes prior to administration.
Prefilled syringe: Store at 2°C to 8°C (36°F to 46°F); do
Administration
not freeze. Protect from light.
IV: Administer through a 0.2 to 1.2 micron low protein-
Powder for injection: Prior to reconstitution, store at 2°C to binding filter. Infuse over 30 minutes.
8°C (36°F to 46°F); do not freeze. Protect from light. SubQ: Allow prefilled syringe and autoinjector to warm to
After dilution in NS, may be stored for up to 24 hours at room temperature for 30 minutes prior to administration.
room temperature or refrigerated at 2°C to 8°C (36°F to Inject into the front of the thigh (preferred), abdomen
46°F). Must be used within 24 hours of reconstitution. (except for 2-inch area around the navel), or the outer
Mechanism of Action Selective costimulation modulator; area of the upper arms (if administered by a caregiver).
inhibits T-cell (T-lymphocyte) activation by binding to Rotate injection sites (21 inch apart); do not administer
CD80 and CD86 on antigen presenting cells (APC), thus into tender, bruised, red, or hard skin.
blocking the required CD28 interaction between APCs and Monitoring Parameters Monitor improvement of symp-
T cells. Activated T lymphocytes are found in the synovium toms and physical function assessments (eg, joint swel-
of rheumatoid arthritis patients. ling, pain, and tenderness; ESR or C-reactive protein
Pharmacodynamics/Kinetics (Adult data unless level). Latent TB screening prior to initiating therapy;
noted) signs/symptoms of infection (prior to, during, and following
Distribution: Vss: 0.07 L/kg (range: 0.02 to 0.13 L/kg) therapy); CBC with differential; LFTs at baseline; HBV
Bioavailability: SubQ: 78.6% (relative to IV administration) screening prior to initiating signs and symptoms of hyper-
Half-life elimination: RA: 13.1 days (range: 8 to 25 days) sensitivity reaction; signs/symptoms of malignancy

33
 ABATACEPT

q Test Interactions Contains maltose; may result in falsely or injections into the levator scapulae. Risk of aspiration
elevated blood glucose levels with dehydrogenase pyrro- resulting from severe dysphagia is increased in patients
loquinolinequinone or glucose-dye-oxidoreductase testing when swallowing is already compromised, Limiting the
methods on the day of infusion. Glucose monitoring dose injected into the sternocleidomastoid muscle may
methods which utilize glucose dehydrogenase nicotine reduce the occurrence of dysphagia. Use extreme caution
adenine dinucleotide (GDH-NAD), glucose oxidase, or in patients with preexisting respiratory disease; treatment
glucose hexokinase are recommended. of cervical dystonia-using botulinum toxin may weaken
Dosage Forms Excipient information presented when accessory muscles that are necessary for these patients
available (limited, particularly for generics); consult spe- to maintain adequate ventilation. Serious breathing diffi-
cific product labeling. culties, including respiratory failure, have been reported.
Solution Auto-injector, Subcutaneous [preservative free]: Risk of aspiration resulting from severe dysphagia is
Orencia ClickJect: 125 mg/mL (1 mL) increased in patients with decreased respiratory function.
Solution Prefilled Syringe, Subcutaneous [preservative Limiting the dose injected into the sternocleidomastoid
free]: muscle may reduce the occurrence of dysphagia. Use
Orencia: 50 mg/0.4 mL (0.4 mL); 87.5 mg/0.7 mL (0.7 with caution in patients with neuromuscular diseases
mL); 125 mg/mL (1 mL) (eg, myasthenia gravis, Eaton-Lambert syndrome) and
Solution Reconstituted, Intravenous [preservative free]: neuropathic disorders (eg, amyotrophic lateral sclerosis).
Orencia: 250 mg (1 ea)
Hypersensitivity and anaphylactic reactions may occur
@ Abbott-43818 see Leuprolide on page 1191 rarely; immediate treatment (including epinephrine
1 mg/mL) should be available. Higher doses or more
Abbott-Citalopram (Can) see Citalopram on page 461
frequent administration may result in neutralizing antibody
@ ABC see Abacavir on page 24 formation and loss of efficacy. Rarely, arrhythmia and
@ ABCD see Amphotericin B Cholestery! Sulfate Complex myocardial infarction have been reported with use of
on page 133 onabotulinumtoxinA (another botulinum toxin formulation),
@ Abelcet see Amphotericin B (Lipid Complex) sometimes in patients with preexisting cardiovascular
on page 137 disease. Use with caution if there is inflammation or
excessive weakness or atrophy at the proposed injection
@ Abenol (Can) see Acetaminophen on page 37
site(s); use is contraindicated if infection is present. Long-
@ Abilify see ARIPiprazole on page 174 term effects of chronic therapy unknown.
@ Abilify Discmelt [DSC] see ARIPiprazole on page 174
Reduced blinking from injection of the orbicularis muscle
@ Abilify Maintena see ARI|Piprazole on page 174 can lead to corneal exposure and ulceration when treating
@ Abilify Mycite see ARIPiprazole on page 174 blepharospasm. Retrobulbar hemorrhages may occur
@ ABLC see Amphotericin B (Lipid Complex) on page 137 from needle penetration into orbit when treating strabis-
mus; spatial disorientation, double vision, or past-pointing
may occur if one or more extraocular muscles are para-
AbobotulinumtoxinA lyzed. Covering the affected eye may help. Careful testing
(aye bo BOT yoo lin num TOKS in aye) of corneal sensation, avoidance of lower lid injections, and
treatment of epithelial defects are necessary. Use caution
Medication Safety Issues
in patients with angle closure glaucoma.
Other safety concerns:
Botulinum products are not interchangeable; potency Safety in the treatment of hyperhidrosis has not been
differences may exist between the products. established. The possibility of an immune reaction result-
Brand Names: US Dysport; Dysport (Glabellar Lines) ing from an intradermal injection is unknown.
[DSC]
Safety and effectiveness of injection into proximal muscles
Brand Names: Canada Dysport Aesthetic; Dysport Ther-
of the lower limb have not been established in pediatric
apeutic
patients.
Therapeutic Category Neuromuscular Blocker Agent,
Toxin Do not use more frequently than every 3 months for
Generic Availability (US) No temporary reduction in glabellar lines. Patients with
Use Treatment of lower limb spasticity (FDA approved in marked facial asymmetry, ptosis, excessive dermatocha-
pediatric patients 2 to 17 years); treatment of cervical lasis, deep dermal scarring, thick sebaceous skin, or the
dystonia (FDA approved in adults); temporary improve- inability to substantially lessen glabellar lines by physically
ment in the appearance of moderate to severe glabellar spreading them apart were excluded from clinical trials.
lines associated with corrugator and procerus muscle Use with caution in patients with surgical alterations to the
activity (FDA approved in adults <65 years); treatment of facial anatomy or with inflammation at the proposed
upper limb spasticity (to decrease the severity of injection sites. Reduced blinking from injection of the
increased muscle tone in elbow flexors, wrist flexors, orbicularis muscle can lead to corneal exposure and
and finger flexors) (FDA approved in adults) ulceration. Spatial disorientation, double vision, or past
Medication Guide Available Yes pointing may occur if one or more extraocular muscles
Pregnancy Considerations Adverse events have been are paralyzed. Efficacy was not observed in older adults
observed in animal reproduction studies. (265 years) and an increased frequency of ocular adverse
Breastfeeding Considerations It is not known if abobo- events was reported in older adults compared to younger
tulinumtoxinA is present in breast milk. According to the adults.
manufacturer, the decision to continue or discontinue
Product contains albumin and may carry a remote risk for
breastfeeding during therapy should take into account
transmission of viral diseases and variant Creutzfeldt-
the risk of infant exposure, the benefits of breastfeeding
Jakob disease. Product may contain lactose; do not
to the infant, and benefits of treatment to the mother.
administer to patients allergic to cow's milk protein. Botu-
Contraindications Known hypersensitivity (eg, anaphy- linum products (abobotulinumtoxinA, onabotulinumtoxinA,
laxis) to botulinum toxin or any component of the formu- rimabotulinumtoxinB) are not interchangeable; potency
lation, including cow milk protein; infection at the proposed units are specific to each preparation and cannot be
injection site(s)
compared or converted to any other botulinum product.
Warnings/Precautions [US Boxed Warning]: Distant Adverse Reactions
spread of botulinum toxin beyond the site of injection Cervical dystonia:
has been reported; dysphagia and breathing difficul-
Cardiovascular: Decreased heart rate
ties have occurred and may be life threatening; other
Central nervous system: Dizziness, facial paresis,
symptoms reported include asthenia, blurred vision,
fatigue, headache, voice disorder
diplopia, dysarthria, dysphonia, generalized muscle
Endocrine & metabolic: Increased serum glucose
weakness, ptosis, and urinary incontinence which
Gastrointestinal: Dysphagia, xerostomia
may develop within hours or weeks following injec-
Immunologic: Antibody development (binding or neutral-
tion. Risk likely greatest in children treated for spasticity,
izing)
but symptoms can also occur in adults treated for spas-
Infection: Infection
ticity and other conditions. Systemic effects have occurred
Local: Discomfort at injection site, pain at injection site
following use in approved and unapproved uses including
Neuromuscular & skeletal: Amyotrophy, musculoskeletal
lower than the maximum recommended total dose. Imme-
pain, myasthenia
diate medical attention required if respiratory, speech, or
Ophthalmic: Eye disease
swallowing difficulties appear. Dysphagia common when
Respiratory: Dyspnea (onset: ~1 week; duration: ~3
used for cervical dystonia and may persist for several
weeks)
weeks after administration. In severe cases, patients
may require alternative feeding methods (eg, feeding Glabellar lines:
tube). Risk factors include smaller neck muscle mass, Central nervous system: Headache
bilateral injections into the sternocleidomastoid muscle, Dermatologic: Contact dermatitis

34
 ABOBOTULINUMTOXINA

Gastrointestinal: Nausea Pharmacodynamics/Kinetics (Adult data unless

Genitourinary: Hematuria noted)
Immunologic: Antibody development Onset of action: Peak effect: Cervical dystonia: 2 to 4
Infection: Influenza weeks; Upper limb spasticity: 1 week
Local: Discomfort at injection site, injection site reaction, Duration: Cervical dystonia, glabellar lines: 24 months;
pain at injection site, swelling at injection site Lower limb spasticity: 25 % months; Upper limb spastic-
Ophthalmic: Blepharoptosis, eyelid edema ity: 25 months
Respiratory: Bronchitis, cough, nasopharyngitis, phar- Absorption: Not expected to be present in peripheral blood
yngolaryngeal pain, sinusitis, upper respiratory tract at recommended doses following intramuscular (IM)
infection injection
Upper limb spasticity: Dosing
Cardiovascular: Hypertension, syncope Pediatric
Central nervous system: Abnormal gait, convulsions, Note: Potency units are specific to product and assay
depression, dizziness, falling, fatigue, feeling of heavi- method utilized; do not interchange botulinum toxin
ness, headache, hypertonia, hypoesthesia, myasthe- products
nia, seizure (partial) Lower limb spasticity: Note: Individualize dose based
Endocrine & metabolic: Increased serum triglycerides on the following: Patient size, number and location of
Gastrointestinal: Constipation, diarrhea, dysphagia, muscles involved, severity of spasticity, local muscle
nausea weakness, response to prior treatment, and/or adverse
Genitourinary: Urinary tract infection reaction history.
Hematologic & oncologic: Bruise Children 22 years and Adolescents <18 years: IM:
Immunologic Antibody development Individual recommended dose range per muscle per
Infection: Infection, influenza limb:
Local: Injection site reaction Gastrocnemius: 6 to 9 units/kg/dose divided in up to
Neuromuscular & skeletal: Back pain, limb pain, muscu- 4 injections per muscle per limb; a single injection
loskeletal pain, weakness site should not exceed 0.5 mL
Respiratory: Cough, nasopharyngitis Soleus: 4 to 6 units/kg/dose divided in up to 2
Miscellaneous: Accidental injury injections per muscle per limb; a single injection
site should not exceed 0.5 mL
Lower limb spasticity: Total dose range per treatment session: 10 to 15
Cardiovascular: Hypertension (adults), peripheral edema units/kg/dose for each limb up to a maximum dose
(adults) of the lesser of either: Unilateral limb: 15 units/kg/
Central nervous system: Depression (adults), epilepsy, dose; bilateral limbs: 30 units/kg/dose or 1,000
falling (more frequesnt in patients 265 years of age), units/dose
fatigue (adults), headache (adults), insomnia (adults), May repeat therapy at intervals 212 weeks; in clinical
myasthenia, seizure studies, the majority of patients were retreated
Gastrointestinal: Constipation (adults), dysphagia between 16 to 22 weeks; however, some patients
(adults), nausea (children & adolescents), viral gastro- had a longer duration of response.
enteritis (children & adolescents), vomiting (children & Renal Impairment: Pediatric There are no dosage
adolescents) adjustments provided in the manufacturer's labeling;
Hematologic & oncologic: Bruise (adults) however, dosage adjustment unlikely as abobotulinum-
Hepatic: Increased serum ALT (adults) toxinA is not expected to be present in peripheral blood
Immunologic: Antibody development at recommended doses following intramuscular (IM)
Infection: Influenza (children & adolescents), varicella injection.
(children & adolescents) Hepatic Impairment: Pediatric There are no dosage
Neuromuscular & skeletal: Arthralgia (adults), back pain adjustments provided in the manufacturer's labeling;
(adults), bone fracture (adults, wrist), limb pain, weak- however, dosage adjustment unlikely as abobotulinum-
ness (adults) toxinA is not expected to be present in peripheral blood
Otic: Otic infection (children & adolescents) at recommended doses following intramuscular (IM)
Respiratory: Bronchitis (children & adolescents), cough injection.
(children & adolescents), flu-like symptoms (adults), Preparation for Administration IM: Reconstitute with
nasopharyngitis (children & adolescents), oropharyng- preservative-free NS; preparation instructions vary by
eal pain (children & adolescents), pharyngitis (children indication and strength; use appropriate reconstitution
& adolescents), rhinitis (children & adolescents), upper methods. During reconstitution, swirl gently to dissolve;
respiratory tract infection (more common in children & do not shake. Use immediately after reconstitution in the
adolescents), viral respiratory tract infection (children & syringe.
adolescents) Pediatric: Lower limb spasticity: Reconstitute 300-unit vial
Miscellaneous: Fever (children & adolescents) with 1.5 mL of diluent or 500-unit vial with 2.5 mL of
Any indication: Rare but important or life-threatening: diluent; resultant concentration is 20 units per 0.1 mL (or
Anaphylaxis, blurred vision, burning sensation, connec- 200 units/mL). Further dilution may be required to
tive tissue disease (excessive granulation tissue), dip- achieve the final volume for injection.
lopia, dysarthria, dysphagia, erythema, facial paresis, Adult:
hypersensitivity reaction, hypoesthesia, photophobia, Cervical dystonia: Reconstitute 300-unit vial with 0.6 mL
urinary incontinence, xerophthalmia, vertigo of diluent to obtain a concentration of 50 units per 0.1
Drug Interactions mL; reconstitute 500-unit vial with 1 mL of diluent to
Metabolism/Transport Effects None known. obtain a concentration of 50 units per 0.1 mL; alter-
Avoid Concomitant Use There are no known interac- natively, may reconstitute 500-unit vial with 2 mL of
tions where it is recommended to avoid concomitant use. diluent to obtain a concentration of 25 units per 0.1 mL.
Increased Effect/Toxicity Glabellar lines: Reconstitute 300-unit vial with 2.5 mL of
diluent to obtain a concentration of 10 units per 0.08 mL
AbobotulinumtoxinA may increase the levels/effects of:
(12 units per 0.1 mL); alternatively, may reconstitute
Neuromuscular-Blocking Agents; RimabotulinumtoxinB
300-unit vial with 1.5 mL of diluent to obtain a concen-
The levels/effects of AbobotulinumtoxinA may be tration of 10 units per 0.05 mL (20 units per 0.1 mL).
increased by: Aminoglycosides; Anticholinergic Agents; Upper limb spasticity: Reconstitute 300-unit vial with 1.5
OnabotulinumtoxinA mL of diluent to obtain a concentration of 200 units/mL;
Decreased Effect There are no known significant inter- or reconstitute 300-unit vial with 3 mL diluent to obtain
actions involving a decrease in effect. a concentration of 100 units/mL. Reconstitute the 500-
Storage/Stability Store undiluted vials under refrigeration unit vial with 2.5 mL of diluent to obtain a concentration
at 2°C to 8°C (36°F to 46°F). Protect from light- After of 200 units/mL. Alternatively, the. 500-unit vial can be
reconstitution, store vials in original container under refrig- further diluted to obtain a concentration of 100 units/
eration, protect from light, and use within 24 hours (does mL. Using a 5 mL syringe, draw up 2.5 mL of the
not contain preservative); single-use vials. Do not freeze diluent; then draw up 2.5 mL of the reconstituted
after reconstitution. solution. Do not invert; mix gently.
Mechanism of Action AbobotulinumtoxinA (previously Administration
known as botulinum toxin type A) is a neurotoxin produced Pediatric: Lower limb spasticity: IM: Use an appropriately
by Clostridium botulinum, spore-forming anaerobic bacil- sized sterile syringe (eg, 3 mL) and needle to administer
lus, which appears to affect only the presynaptic mem- intramuscularly. Although actual location of the injection
brane of the neurorhuscular junction in humans, where it sites can be determined by palpation, the use of an
prevents calcium-dependent release of acetylcholine and injection guiding technique (eg, electromyography or
produces a state of denervation. Muscle inactivation per- electrical stimulation) is recommended to target the
sists until new fibrils grow from the nerve and form junction injection sites. Do not administer >0.5 mL in any single
plates on new areas of the muscle-cell walls. injection site. >
35
ABOBOTULINUMTOXINA

Adult: 2013). Agents other than acarbose are currently recom-

Cervical dystonia: Use an appropriately sized gauge mended to treat diabetes in pregnant women (ADA
needle to administer intramuscularly. Limiting the dose 2018c).
injected into the sternocleidomastoid muscle may Breastfeeding Considerations It is not known if acar-
reduce the occurrence of dysphagia. Simultaneous bose is present in breast milk.
EMG-guided application may be helpful in locating
active muscle not identified by physical examination Breastfeeding is not-recommended by the manufacturer.
alone. However, <2% of an oral dose of acarbose is absorbed
Glabellar lines: Use a 30-gauge needle to administer systemically in adults, which may limit the amount that
intramuscularly. Apply pressure on the superior medial could distribute into breast milk.
orbital rim, and inject into each of 5 sites (2 injections in Contraindications Hypersensitivity to acarbose or any
each corrugator muscle and 1 in the procerus muscle). component of the formulation; diabetic ketoacidosis; cir-
Ensure injected volume/dose is accurate and where thosis; inflammatory bowel disease, colonic ulceration,
feasible keep to a minimum. Avoid injection near the partial intestinal obstruction, patients predisposed to intes-
levator palpebrae superioris, particularly in patients tinal obstruction; chronic intestinal diseases associated
with larger brow depressor complexes. Medial corru- with marked disorders of digestion or absorption; condi-
gator injections should be at least 1 cm above the bony tions that may deteriorate as a result of increased gas
supraorbital ridge. Do not inject toxin closer than 1 cm formation in the intestine
above the central eyebrow. ~ Warnings/Precautions Treatment-emergent elevations
Upper limb spasticity: Use an appropriately sized sterile of serum transaminases (AST and/or ALT) and hyper-
needle to administer intramuscularly. Although actual bilirubinemia may occur (dose-related). These elevations
location of the injection sites can be determined by were asymptomatic, reversible, more common in females,
palpation, the use of injection guiding technique (eg,
and, in general, were not associated with other evidence
electromyography, electrical stimulation) is recom-
of liver dysfunction. Fulminant hepatitis (may be fatal) has
mended to target the injection sites. No more than 1
been reported. If elevations are observed, a reduction in
mL should generally be administered at any single
dosage or withdrawal of therapy may be indicated, partic-
injection site.
ularly if the elevations persist. Hypoglycemia is unlikely to
Monitoring Parameters Monitor patients closely for
occur with acarbose monotherapy but may occur with
signs/symptoms of systemic toxic effects (possibly occur-
ring 1 day to several weeks after treatment) and thera- combination therapy (eg, sulfonylureas, insulin, metfor-
peutic endpoints based on use. min). In patients taking acarbose, oral glucose (dextrose)
should be used instead of sucrose (cane sugar) in the
Lower limb spasticity: Modified Ashworth Scale; overall treatment of mild-to-moderate hypoglycemia since the
treatment goals include: Improved gait and balance, facil- hydrolysis of sucrose to glucose and fructose is inhibited
itation of patient care, increased comfort with therapy, by acarbose. Use with caution in patients with hepatic
improved tolerance of bracing, and prevention of muscu- impairment. Not recommended in patients with significant
loskeletal complications impairment (serum creatinine >2 mg/dL or CrCl <25 mL/
Dosage Forms Excipient information presented when minute/1.73 m?). It may be necessary to discontinue
available (limited, particularly for generics); consult spe- acarbose and administer insulin if the patient is exposed
cific product labeling. [DSC] = Discontinued product to stress (ie, fever, trauma, infection, surgery). Potentially
Solution Reconstituted, Intramuscular:
significant interactions may exist, requiring dose or fre-
Dysport: 300 units (1 ea); 500 units (1 ea) [contains
quency adjustment, additional monitoring, and/or selec-
albumin human, milk protein]
tion of alternative therapy. Increased intake of sucrose
Dysport (Glabellar Lines): 300 units (1 ea [DSC]) [con-
(cane sugar) and food that contains sucrose during treat-
tains albumin human, milk protein]
ment can lead to GI symptoms (eg, flatulence and bloat-
@ Absorica see |SOtretinoin (Systemic) on page 1135 ing), loose stools, and occasionally diarrhea. If a diabetic
@ Abstral see FentaNYL on page 837 diet is not followed, the GI side effects may be intensified.
If severe symptoms develop in spite of adherence to a
@ ABthrax see Raxibacumab on page 1746
diabetic diet, temporarily or permanently reduce dose.
@ Acanya see Clindamycin and Benzoyl Peroxide Diabetes self-management education (DSME) is essential
on page 476 to maximize the effectiveness of therapy.
Adverse Reactions
Acarbose (Ay car bose) Gastrointestinal: Diarrhea and abdominal pain tend to
return to pretreatment levels over time; frequency and
Medication Safety Issues intensity of flatulence tend to abate with time
Sound-alike/look-alike issues: Hepatic: Increased serum transaminases
Precose may be confused with PreCare Rare but important or life-threatening: Edema, erythema,
High alert medication: hepatic injury, hepatitis, intestinal obstruction, jaundice,
The Institute for Safe Medication Practices (ISMP) pneumatosis cystoides intestinalis, skin rash, thrombo-
includes this medication among its list of drug classes cytopenia, urticaria
which have a heightened risk of causing significant Drug Interactions
patient harm when used in error.
Metabolism/Transport Effects None known.
International issues:
Precose [US, Malaysia] may be confused with Precosa
Avoid Concomitant Use There are no known interac-
brand name for Saccharomyces boulardii (Finland, tions where it is recommended to avoid concomitant use.
Sweden] Increased Effect/Toxicity
Brand Names: US Precose Acarbose may increase the levels/effects of: Hypoglyce-
Brand Names: Canada Glucobay mia-Associated Agents ‘
Therapeutic Category Antidiabetic Agent, Alpha-gluco- The levels/effects of Acarbose may be increased by:
sidase Inhibitor; Antidiabetic Agent, Oral Alpha-Lipoic Acid; Androgens; Guanethidine; Mono-
Generic Availability (US) Yes amine Oxidase Inhibitors; Neomycin; Pegvisomant; Pro-
Use Management of type I! diabetes mellitus (noninsulin- thionamide; Quinolones; Salicylates; Selective Serotonin
dependent, NIDDM) when hyperglycemia cannot be man- Reuptake Inhibitors
aged by diet and exercise alone (FDA approved in adults); Decreased Effect
has also been used for prevention of reactive hypoglyce- Acarbose may decrease the levels/effects of: Digoxin
mia caused by dumping syndrome after Nissen fundopli-
cation The levels/effects of Acarbose may be decreased by:
Pregnancy Risk Factor B Hyperglycemia-Associated Agents; Quinolones; Rito-
Pregnancy Considerations drine; Thiazide and Thiazide-Like Diuretics
Adverse events have not been observed in animal repro- Storage/Stability Store at <25°C (77°F). Protect from
duction studies. Less than 2% of an oral dose of acarbose moisture.
is absorbed systemically, which should limit fetal expo- Mechanism of Action Competitive inhibitor of pancreatic
sure. a-amylase and intestinal brush border a-glucosidases,
In women with diabetes, maternal hyperglycemia can be resulting in delayed hydrolysis of ingested complex carbo-
associated with congenital malformations as well as hydrates and disaccharides and absorption of glucose;
adverse effects in the fetus, neonate, and the mother dose-dependent reduction in postprandial serum insulin
(ACOG 2005; ADA 2018c; Metzger 2007). To prevent and glucose peaks; inhibits the metabolism of sucrose to
adverse outcomes, prior to conception and throughout glucose and fructose
pregnancy, maternal blood glucose and HbA, should be Pharmacodynamics/Kinetics. (Adult data unless
kept as close to target goals as possible but without noted)
causing significant hypoglycemia (ADA 2018c; Blumer Absorption: <2% as active drug; ~35% as metabolites
 ACETAMINOPHEN

Metabolism: Exclusively via Gl tract, principally by intesti- @ Acellular Pertussis see Diphtheria and Tetanus Toxoids,
nal bacteria and digestive enzymes; 13 metabolites Acellular Pertussis, and Poliovirus Vaccine on page 660
identified (major metabolites are sulfate, methyl, and ¢@ Acellular pertussis see Diphtheria and Tetanus Toxoids,
glucuronide conjugates) Acellular Pertussis, Poliovirus and Haemophilus b Con-
Bioavailability: Low systemic bioavailability of parent com- jugate Vaccine on page 662
pound; acts locally in Gl tract
Half-life elimination: ~2 hours @ Acellular Pertussis see Diphtheria and Tetanus Toxoids,
Time to peak: Active drug: ~1 hour and Acellular Pertussis Vaccine on page 664
Excretion: Urine (~34% as inactive metabolites, <2% @ Acellular pertussis see Diphtheria, Tetanus Toxoids,
parent drug and active metabolite); feces (~51% as Acellular Pertussis, Hepatitis B (Recombinant), and Polio-
unabsorbed drug) virus (Inactivated) Vaccine on page 667
Pharmacodynamics/Kinetics: Additional Consider- @ Acephen [OTC] see Acetaminophen on page 37
ations
@ Acerola C 500 [OTC] see Ascorbic Acid on page 186
Renal function impairment: In patients with CrCl <25 mL/
- minute/1.73 m?, the Cmax was ~5 times higher, and the @ Acetadote see Acetylcysteine on page 48
AUC was 6 times larger.
Dosing Acetaminophen a seet a MIN oh fen)
Pediatric Note: Dosage must be individualized on the
basis of effectiveness and tolerance. Medication Safety Issues
Diabetes mellitus, type 2: Children 210 years and Sound-alike/look-alike issues:
Adolescents: Very limited data available: Oral: Initial Acephen may be confused with AcipHex
dose: 25 mg 3 times daily with the first bite of each Acetaminophen may be confused with acetazolamide
main meal; may also initiate at 25 mg once daily with FeverALL may be confused with Fiberall
gradual titration to 25 mg 3 times daily as tolerated; Triaminic Children's Fever Reducer Pain Reliever may
then increase in 25 mg/dose increments in 2 to 4 be confused with Triaminic cough and cold products
week intervals as tolerated. Weight-based maximum Tylenol may be confused with atenolol, timolol, Tylenol
dose: <60 kg: 50 mg/dose, >60 kg: 100 mg/dose. PM, Tylox
Clinical trials in pediatric patients are lacking; dosing
based on expert reported clinical experience; overall Infusion bottles of ropivacaine and IV acetaminophen
dosing is similar to that used in adult patients look similar. Potentially fatal mix-ups have been
(DeFronzo 1999; Jacobson-Dickman 2005; Kliegman reported in which a glass bottle of Naropin was mis-
2016) taken for Ofirmev in perioperative areas.
Dumping syndrome (reactive hypoglycemia) after Other safety concerns:
Nissen fundoplication: Limited data available: Duplicate therapy issues: This product contains acetami-
Infants 24 months and young children who have failed nophen, which may be a component of combination
nutritional manipulations: Oral: Initial dose: 12.5 to products. Do not exceed the maximum recommended
25 mg before each bolus feeding of formula contain- daily dose of acetaminophen.
ing complex carbohydrates. Increase in 12.5 to Infant concentration change: All children’s and infant
25 mg/dose increments until postprandial serum glu- acetaminophen products are available as 160 mg/5
cose stable (>60 mg/dL was used in clinical reports). mL. Some remaining infant concentrated solutions of
Reported dose range: 12.5 to 100 mg/dose. Dosing 80 mg/0.8 mL and 100 mg/mL may still be available on
based on a few small studies (total n=11). Acarbose pharmacy shelves or in patient homes. Check concen-
was well tolerated in most patients; except a few trations closely prior to administering or dispensing and
patients experienced flatulence (De Cunto 2011; Ng verify concentration available to patients prior to rec-
2001; Zung 2003). ommending a dose (November 2011).
Administration Oral: Administer with first bite of each Injection: Reports of 10-fold overdose errors using the
main meal parenteral product have occurred in the U.S. and
Monitoring Parameters Fasting blood glucose; post- Europe; calculation of doses in "mg" and subsequent
prandial glucose, serum creatinine, hemoglobin Aj, (at administration of the dose in "mL" using the commer-
least twice yearly in patients who have stable glycemic cially available concentration of 10 mg/mL contributed
control and are meeting treatment goals; quarterly in to these errors. Expressing doses as mg and mL, as
patients not meeting treatment goals or with therapy well as pharmacy preparation of doses, may decrease
change [ADA 2016]); liver enzymes every 3 months for error potential (Dart, 2012; ISMP, 2012).
the first year of therapy and periodically thereafter International issues:
Reference Range Plasma Blood Glucose and HbA,, Depon [Greece] may be confused with Depen brand
Goals for Diabetes Patients (ADA 2016): Goals should name for penicillamine [US]; Depin brand name for
be individualized based on individual needs/circumstan- nifedipine [India]; Dipen brand name for diltiazem
ces (eg, patients who experience severe hypoglycemia, [Greece]
patients with hypoglycemic unawareness); lower goals Duorol [Spain] may be confused with Diuril brand name
may be reasonable if they can be achieved without for chlorothiazide [US, Canada]
excessive hypoglycemia. Note: Postprandial blood glu- Paralen [Czech Republic] may be confused with Aralen
cose should be measured when there is a discrepancy brand name for chloroquine [US, Mexico]
between preprandial blood glucose concentrations and Related Information
HbA,, values and to help assess glycemia for patients
Acetaminophen Serum Level Nomogram on page 2198
who receive basal/bolus regimens. It is usually drawn 1 to
Oral Medications That Should Not Be Crushed or Altered
2 hours after starting a meal and is considered to be the
on page 2217
"peak."
Infants, Children, and Adolescents: Relative Infant Dose on page 2207
Preprandial glucose: 90 to 130 mg/dL Brand Names: US Acephen [OTC]; Aspirin Free Anacin
Bedtime/overnight glucose: 90 to 150 mg/dL Extra Strength [OTC]; Cetafen Extra [OTC]; Cetafen
HbA,<: <7.5% [OTC]; FeverAll Adult [OTC]; FeverAll Children's [OTC];
Adults, nonpregnant: FeverAll Infants’ [OTC]; FeverAll Junior Strength [OTC];
Preprandial glucose: 80 to 130 mg/dL Little Fevers [OTC]; Mapap Arthritis Pain [OTC]; Mapap
Posiprandial glucose: <180 mg/dL Children's [OTC]; Mapap Extra Strength [OTC]; Mapap
HbA,<: <7% [OTC]; Midol Long Lasting Relief [OTC]; Non-Aspirin Pain
Dosage Forms Excipient information presented when Reliever [OTC]; Nortemp Children's [OTC]; Ofirmev; Pain
available (limited, particularly for generics); consult spe- & Fever Children's [OTC]; Pain Eze [OTC]; Pharbetol
cific product labeling. Extra Strength [OTC]; Pharbetol [OTC]; Q-Pap Children's
Tablet, Oral: 5 [OTC] [DSC]; Q-Pap Extra Strength [OTC] [DSC]; Q-Pap
Precose: 25 mg, 50 mg, 100 mg Infants’ [OTC] [DSC]; Q-Pap [OTC] [DSC]; Silapap Child-
Generic: 25 mg, 50 mg, 100 mg ren's [OTC]; Silapap Infants' [OTC] [DSC]; Triaminic Child-
ren's Fever Reducer Pain Reliever [OTC]; Tylenol 8 HR
@ Accel-Amlodipine (Can) see AmLODIPine on page 120 Arthritis Pain [OTC]; Tylenol 8 HR [OTC] [DSC]; Tylenol
@ Accel-Clarithromycin (Can) see Clarithromycin Children's [OTC]; Tylenol Extra Strength [OTC]; Tylenol
on page 466 Infants' [OTC]; Tylenol Jr. Meltaways [OTC] [DSC]; Tylenol
@ Accell-Citalopram (Can) see Citalopram on page 461 [OTC]; Valorin Extra [OTC]; Valorin [OTC]
@ Accolate see Zafirlukast on page 2080 Brand Names: Canada Abenol; Apo-Acetaminophen;
Atasol; Novo-Gesic; Pediatrix; Tempra; Tylenol
@ AccuNeb see Albuterol on page 72 Therapeutic Category Analgesic, Nonopioid; Antipyretic
@ Accupril! see Quinapril on page 1728 Generic Availability (US) Yes: Excludes extended
@ Accutane see |SOtretinoin (Systemic) on page 1135 release products; injectable formulation
 ACETAMINOPHEN

€ Use exceed the maximum recommended daily dose (>4 g

Oral: daily in adults). In addition, chronic daily dosing may also
Immediate release: result in liver damage in some patients. Limit acetamino-
Oral suspension, chewable tablets: Relief of minor phen dose from all sources (prescription, OTC, combina-
aches and pains due to the common cold, flu, sore tion products) and all routes of administration (IV, oral,
throat, headaches, and toothaches; reduction of fever rectal) to <4 g/day (adults). Use with caution in patients
(All indications: OTC products: FDA approved in with alcoholic liver disease; consuming 23 alcoholic
infants and children <12 years; consult specific prod- drinks/day may increase the risk of liver damage: Use
uct formulations for appropriate age groups) caution in patients with hepatic impairment or active liver
Caplet/tablet: Relief of minor aches and pains due to disease; use of IV formulation is contraindicated in
the common cold, headaches, minor pain of arthritis, patients with severe hepatic impairment or severe active
backache, menstrual cramps, muscle aches, and liver disease.
toothaches (All indications: OTC products: FDA
[Injection: US Boxed Warning]: Take care to avoid
approved in ages 26 years and adults; consult specific
dosing errors with acetaminophen injection, which
product formulation for appropriate age group)
could result in accidental overdose and death; ensure
Extended release: Relief of minor aches and pains due
that the dose in mg is not confused with mL, dosing in
to the common cold, headaches, backache, muscle
patients <50 kg is based on body weight, infusion
aches, menstrual cramps, toothaches, and minor pain
pumps are properly programmed, and total daily dose
of arthritis; reduction of fever (All indications: OTC
of acetaminophen from all sources does not exceed
products: FDA approved in ages 212 or 18 years and
the maximum daily limits.
adults; consult specific product formulations for appro-
priate age groups) Hypersensitivity and anaphylactic reactions have been
Parenteral: Reduction of fever (FDA approved in pediatric reported including life-threatening anaphylaxis; discon-
patients [age not specified] and adults); treatment of mild tinue immediately if symptoms occur. Serious and poten-
to moderate pain (FDA approved in ages 22 years and tially fatal skin reactions, including acute generalized
adults); treatment of moderate to severe pain when exanthematous pustulosis (AGEP), Stevens-Johnson syn-
combined with opioid analgesia (FDA approved in ages drome (SJS), and toxic epidermal necrolysis (TEN), have
22 years and adults) occurred rarely with acetaminophen use. Discontinue
Rectal: Relief of minor aches, pains, and headaches; therapy at the first appearance of skin rash.
reduction of fever (All indications: OTC products: FDA
Benzyl alcohol and derivatives: Some dosage forms may
approved in ages 26 months and adults; consult specific
contain benzyl alcohol and/or sodium benzoate/benzoic
product formulation for appropriate age group); has also
acid; benzoic acid (benzoate) is a metabolite of benzyl
been used for management of postoperative pain
alcohol; large amounts of benzyl! alcohol (299 mg/kg/day)
Pregnancy Considerations Acetaminophen crosses the
have been associated with a potentially fatal toxicity
placenta and can be detected in cord blood, newborn
("gasping syndrome") in neonates; the "gasping syn-
serum, and urine immediately after delivery (Levy 1975;
drome" consists of metabolic acidosis, respiratory dis-
Naga Rani 1989; Wang 1997). An increased risk of
tress, gasping respirations, CNS dysfunction (including
teratogenic effects has not been observed following
convulsions, intracranial hemorrhage), hypotension and
maternal use of acetaminophen during pregnancy. Prena-
cardiovascular collapse (AAP ["Inactive" 1997]; CDC,
tal constriction of the ductus arteriosus has been noted in
1982); some data suggests that benzoate displaces bilir-
case reports following maternal use during the third tri-
ubin from protein binding sites (Ahlfors, 2001); avoid or
mester (Suhag 2008; Wood 2005). The use of acetami-
use dosage forms containing benzy! alcohol and/or benzyl!
nophen in normal doses during pregnancy is not
alcohol derivative with caution in neonates. See manufac-
associated with an increased risk of miscarriage or still
turer's labeling.
birth; however, an increase in fetal death or spontaneous
abortion may be seen following maternal overdose if treat- Polysorbate 80: Some dosage forms may contain poly-
ment is delayed (Li 2003; Rebordosa 2009; Riggs 1989). sorbate 80 (also known as Tweens). Hypersensitivity
Frequent maternal use of acetaminophen during preg- reactions, usually a delayed reaction, have been reported
nancy may be associated with wheezing and asthma in following exposure to pharmaceutical products containing
early childhood (Perzanowki 2010). polysorbate 80 in certain individuals (Isaksson, 2002;
Breastfeeding Considerations Acetaminophen is Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites,
excreted in breast milk (Notarianni 1987). pulmonary deterioration, and renal and hepatic failure
have been reported in premature neonates after receiving
The relative infant dose (RID) of acetaminophen is 3.98%
parenteral products containing polysorbate 80 (Alade,
when calculated using the highest breast milk concentra-
1986; CDC, 1984). See manufacturer’s labeling. Some
tion located and compared to an infant therapeutic dose of
products may contain aspartame which is metabolized to
60 mg/kg/day. In general, breastfeeding is considered
phenylalanine and must be avoided (or used with caution)
acceptable when the RID is <10%; when an RID is
in patients with phenylketonuria.
>25% breastfeeding should generally be avoided (Ander-
son 2016; Ito 2000). Using the highest milk concentration Propylene glycol: Some dosage forms may contain pro-
(15.9 mcg/mL), the estimated daily infant dose via breast pylene glycol; large amounts are potentially toxic and have
milk is 2.385 mg/kg/day. This milk concentration was been associated hyperosmolality, lactic acidosis, seizures,
obtained following a single maternal dose of oral acetami- and respiratory depression; use caution (AAP ["Inactive"
nophen 1,000 rng (Hurden 1980). 1997]; Zar, 2007).
Following a single oral maternal dose of acetaminophen When used for self-medication (OTC), patients should be
650 mg, the half-life of acetaminophen is 1.35 to 3.5 hours instructed to contact healthcare provider if symptoms get
in breast milk (Berlin 1980). Acetaminophen can be worse or new. symptoms appear, redness or swelling is
detected in the urine of nursing infants (Notarianni present in the painful area, fever lasts >3 days (all ages),
1987). Except for a single case report of a rash (Matheson or pain (excluding sore throat) lasts longer than: Adults: 10
1985), adverse reactions have generally not been days, Children and Adolescents: 5 days, Infants: 3 days.
observed in nursing infants (Ito 1993). When treating children with sore throat, if sore throat is
severe, persists for >2 days, or is followed by fever, rash,
Current guidelines note that nonopioid analgesics are
headache, nausea, or vomiting, consult health care pro-
preferred for the treatment of pain in breastfeeding women
vider immediately.
and acetaminophen is one of the preferred nonopioid
agents (Montgomery 2012; Sachs 2013). Acetaminophen Use with caution in patients with chronic malnutrition or
is considered compatible with breastfeeding when used in severe renal impairment; use intravenous formulation with
usual recommended doses (WHO 2002). caution in patients with severe hypovolemia. Use with
Contraindications caution in patients with known G6PD deficiency.
Injection: Hypersensitivity to acetaminophen or any com- Warnings: Additional Pediatric Considerations Pro-
ponent of the formulation; severe hepatic impairment or phylactic use of acetaminophen to reduce fever and
severe active liver disease discomfort associated vaccination is not recommended
OTC labeling: When used for self-medication, do not use by the Advisory Committee on Immunization Practices
with other drug products containing acetaminophen or if (ACIP). Additionally, the ACIP does not recommend pro-
allergic to acetaminophen or any of the inactive ingre- phylactic acetaminophen to reduce risk of febrile seizure
dients in infants and children with or without a history of febrile
Warnings/Precautions [Injection: US Boxed Warning]: seizures. Antipyretics have not been shown to prevent
Acetaminophen has been associated with acute liver febrile seizures (NCIRD/ACIP 2011). One study reported
failure, at times resulting in liver transplant and death. that routine prophylactic administration of acetaminophen
Hepatotoxicity is usually associated with excessive to prevent fever prior to vaccination decreased the
acetaminophen intake and often involves more than immune response of some vaccines; in the trial evaluating
one product that contains acetaminophen. Do not 459 infants (including 226 who received acetaminophen),

38
 ACETAMINOPHEN

antibody geometric mean concentrations (GMCs) for tar- The levels/effects of Acetaminophen may be decreased
geted vaccine immune response markers were lower in by: Barbiturates; CarBAMazepine; Fosphenytoin-Phe-
significantly more infants in the acetaminophen group nytoin
compared with control. Before the booster dose, children Food Interactions Rate of absorption may be decreased
who received prophylactic acetaminophen had lower anti- when given with food. Management: Administer without
body GMCs for all vaccine serotypes than children in the regard to food.
control group; this effect persisted after boosting even in Storage/Stability
the absence of additional acetaminophen doses. The Injection: Store intact vials and bags at 20°C to 25°C (68°F
clinical significance of this reduction in immune response to 77°F); do not refrigerate or freeze. Use within 6 hours
has not been established (Prymula 2009). Antipyretics of penetrating vial/bag or transferring to another con-
may be used to treat fever or discomfort following vacci- tainer. Discard any unused portion.
nation (NCIRD/ACIP 2011). Oral formulations: Store at 20°C to 25°C (68°F to 77°F);
avoid excessive heat (20°C [104°F]). Avoid high humidity
Some dosage forms may contain propylene glycol; in
(chewable tablets).
neonates large amounts of propylene glycol delivered
Suppositories: Store at 2°C to 27°C (25°F to 80°F); do not
orally, intravenously (eg, >3,000 mg/day), or topically
freeze.
have been associated with potentially fatal toxicities which
can include metabolic acidosis, seizures, renal failure, and
Mechanism of Action Although not fully elucidated, the
analgesic effects are believed to be due to activation of
CNS depression; toxicities have also been reported in
descending serotonergic inhibitory pathways in the CNS.
children and adults including hyperosmolality, lactic acido-
Interactions with other nociceptive systems may be
sis, seizures and respiratory depression; use caution
(AAP, 1997; Shehab, 2009). involved as well (Smith 2009). Antipyresis is produced
from inhibition of the hypothalamic heat-regulating center.
Adverse Reactions
Oral, Rectal:
Pharmacodynamics/Kinetics (Adult data unless
Dermatologic: Skin rash noted)
Endocrine & metabolic: Decreased serum bicarbonate, Note: With the exception of half-life, the pharmacokinetic
decreased serum calcium, decreased serum sodium, profile in pediatric patients (0-18 years) is similar to adult
hyperchloremia, hyperuricemia, increased serum patients.
glucose Onset of action:
Genitourinary: Nephrotoxicity (with chronic overdose) Oral: <1 hour
Hematologic & oncologic: Anemia, leukopenia, neutro- IV: Analgesia: 5 to 10 minutes; Antipyretic: Within 30
penia, pancytopenia minutes
Hepatic: Increased serum alkaline phosphatase, Peak effect: IV: Analgesic: 1 hour
increased serum bilirubin — Duration:
IV, Oral: Analgesia: 4 to 6 hours
Hypersensitivity: Hypersensitivity reaction (rare)
Renal: Hyperammonemia, renal disease (analgesic) IV: Antipyretic: 26 hours
IV: Absorption: Primarily absorbed in small intestine (rate of
Cardiovascular: Hypertension, hypotension, peripheral absorption dependent upon gastric emptying); minimal
edema (adults), tachycardia absorption from stomach; varies by dosage form
Central nervous system: Agitation (neonates, infants, Distribution: ~1 L/kg at therapeutic doses
children, and adolescents), anxiety (adults), fatigue Protein binding: 10% to 25% at therapeutic concentra-
(adults), headache (more common in adults), insomnia tions; 8% to 43% at toxic concentrations
(adults), trismus (adults) Metabolism: At normal therapeutic dosages, primarily
Dermatologic: Pruritus (neonates, infants, children, and hepatic metabolism to sulfate and glucuronide conju-
gates, while a small amount is metabolized by CYP2E1
adolescents), skin rash
to a highly reactive intermediate, N-acetyl-p-benzoqui-
Endocrine & metabolic: Hypervolemia, hypoalbuminemia
(neonates, infants, children, and adolescents), hypoka-
none imine (NAPQI), which is conjugated rapidly with
lemia, hypomagnesemia (neonates, infants, children, glutathione and inactivated to nontoxic cysteine and
and adolescents), hypophosphatemia (neonates, mercapturic acid conjugates. At toxic doses (as little as
infants, children, and adolescents) 4 g daily) glutathione conjugation becomes insufficient to
meet the metabolic demand causing an increase in
Gastrointestinal: Abdominal pain, constipation (neo-
nates, infants, children, and adolescents), diarrhea
NAPQI concentrations, which may cause hepatic cell
(neonates, infants, children, and adolescents), nausea
necrosis. Oral administration is subject to first pass
metabolism.
(more common in adults), vomiting (more common in
Half-life elimination: Prolonged following toxic doses
adults)
Neonates: 7 hours (range: 4 to 10 hours)
Genitourinary: Oliguria (neonates, infants, children, and
Infants: ~4 hours (range: 1 to 7 hours)
adolescents)
Children: 3 hours (range: 2 to 5 hours)
Hematologic & oncologic: Anemia
Adolescents: ~3 hours (range: 2 to 4 hours)
Hepatic: Increased serum transaminases
Adults: ~2 hours (range: 2 to 3 hours); may be slightly
Local: Pain at injection site
prolonged in severe renal insufficiency (CrCl <30 mL/
Neuromuscular & skeletal: Limb pain, muscle spasm
Ophthalmic: Periorbital edema.
minute): 2 to 5.3 hours
Time to peak, serum: Oral: Immediate release: 10 to 60
Respiratory: Abnormal breath sounds (adults), atelecta-
minutes (may be delayed in acute overdoses); IV: 15
sis (neonates, infants, children, and adolescents),
minutes
dyspnea (adults), hypoxia, pleural effusion (neonates,
Excretion: Urine (<5% unchanged; 60% to 80% as glucur-
infants, children, and adolescents), pulmonary edema
onide metabolites; 20% to 30% as sulphate metabolites;
(neonates, infants, children, and adolescents), stridor
~8% cysteine and mercapturic acid metabolites)
(adults), wheezing (adults)
Miscellaneous: Fever (neonates, infants, children, and Pharmacodynamics/Kinetics: Additional Consider-
adolescents) ations
Rare but important or life-threatening: Anaphylaxis, hyper- Hepatic function impairment: The half-life may increase 2-
sensitivity reaction fold or more in patients with liver disease.
Drug Interactions Dosing
Metabolism/Transport Effects Substrate of CYP1A2 Neonatal
(minor), CYP2A6 (minor), CYP2C9 (minor), CYP2D6 Fever:
(minor), CYP2E1 (minor), CYP3A4 (minor); Note: Oral: Limited: data available:
Assignment of Major/Minor substrate status based on GA 28 to 32 weeks: 10 to 12 mg/kg/dose every 6 to 8
clinically relevant drug interaction potential hours; maximum: daily dose: 40 mg/kg/day (Anand
Avoid Concomitant Use There are no known interac- 2001; Anand 2002)
tions where it is recommended to avoid concomitant use. GA 33 to 37 weeks or term neonates <10 days: 10 to
Increased Effect/Toxicity 15 mg/kg/dose every 6 hours; maximum daily dose:
60 mg/kg/day (Anand 2001; Anand 2002)
Acetaminophen may increase the levels/effects of:
Busulfan; Dasatinib; Imatinib; Mipomersen; Phenylephr-
Term neonates 210 days: 10 to 15 mg/kg/dose every
4 to 6 hours (Anand 2001; Anand 2002); do not
ine (Systemic); Prilocaine; Sodium Nitrite; SORAfenib;
exceed 5 doses in 24 hours; maximum daily dose:
Vitamin K Antagonists
75 mg/kg/day
The levels/effects of Acetaminophen may be increased IV:
by: Alcohol (Ethyl); Dapsone (Topical); Dasatinib; Flu- GA 28 to <32 weeks: Limited data available: Note:
cloxacillin; |soniazid; MetyraPONE; Nitric Oxide; Probe- Some experts do not recommend the use of IV
necid; SORAfenib; Tetracaine (Topical) acetaminophen in premature neonates <32 weeks
Decreased Effect PMA until pharmacokinetic and pharmacodynamic
Acetaminophen may decrease the levels/effects of: studies have been conducted in this age group (van
LamoTRigine den Anker 2011).

39
 ACETAMINOPHEN

q Loading dose (Allegaert 2007; Bartocci 2007):

20 mg/kg/dose
Tylenol OTC were decreased to 3,000 mg/day and
3,250 mg/day respectively, and the dosing interval for
Maintenance dose (Allegaert 2007; Allegaert 2011; Extra Strength Tylenol OTC was increased. Health care
Bartocci 2007): 10 mg/kg/dose every 12 hours; professionals may still prescribe or recommend the 4 g
some suggest 7.5 mg/kg/dose every 8 hours; max- adult daily maximum to patients 212 years of age (but
imum daily dose: 22.5 mg/kg/day are advised to use their own discretion and clinical
GA 232 weeks: judgment) (McNeil Consumer Healthcare 2014).
Manufacturer's labeling: Note: Oral liquids are available in multiple concentra-
PNA <4 weeks: 12.5 mg/kg/dose every 6 hours; tions (eg, 160 mg/5 mL, 500 mg/5 mL and 500 mg/15
maximum daily dose: 50 mg/kg/day mL); precautions should be taken to verify and avoid
PNA >4 weeks: 15 mg/kg/dose every 6 hours; confusion between the different concentrations; dose
maximum daily dose: 60 mg/kg/day should be clearly presented as "mg"
Alternate dosing: Pain (mild to moderate) or fever: Note: Limit acet-
Loading dose (Allegaert 2007; Bartocci 2007): aminophen dose from all sources (prescription and
20 mg/kg/dose OTC); maximum daily dose of acetaminophen should
Maintenance dose (Allegaert 2007; Allegaert 2011; be limited to <75 mg/kg/day in <5 divided doses and
Bartocci 2007): not to exceed 4,000 mg/day for most products
PMA 32 weeks: 10 mg/kg/dose every 12 hours; although some formulations suggest lower maximum
some suggest 7.5 riig/kg/dose every 8 hours; daily dosing (see dosing information for further detail):
maximum daily dose: 22.5 mg/kg/day Oral: Note: With OTC use, should not exceed recom-
PMA 33 to 36 weeks: 10 mg/kg/dose every 8 mended treatment duration unless directed by
hours; some suggest 7.5 to 10 mg/kg/dose health care provider; for fever: 3 days (all ages);
every 6 hours; maximum daily dose: pain (excluding sore throat): Children 212 years and
40 mg/kg/day Adolescents: 10 days, children: 5 days, or infants: 3
PMA 237 weeks: 10 mg/kg/dose every 6 hours; days; sore throat in children: 2 days
maximum daily dose: 40 mg/kg/day Weight-directed dosing: Infants, Children, and Ado-
Rectal: Limited data available: lescents: 10 to 15 mg/kg/dose every 4 to 6 hours
GA 28 to 32 weeks: 20 mg/kg/dose every 12 hours; as needed (American Pain Society 2008; Kliegman
maximum daily dose: 40 mg/kg/day (Anand 2001; 2011; Sullivan 2011); do not exceed 5 doses in 24
Anand 2002) hours; maximum daily dose: 75 mg/kg/day not to
GA 33 to 37 weeks or term neonates <10 days: exceed 4,000 mg/day
Loading dose: 30 mg/kg; then 15 mg/kg/dose every Fixed dosing:
8 hours; maximum daily dose: 60 mg/kg/day (Anand Oral suspension, chewable tablets: Infants and
2001; Anand 2002) Children <12 years: Consult specific product for-
Term infants 210 days: Loading dose: 30 mg/kg; then mulations for appropriate age groups. See table;
20 mg/kg/dose every 6 to 8 hours (Anand 2001; use of weight to select dose is preferred; if weight
Anand 2002); do not exceed 5 doses in 24 hours; is not available, then use age; doses may be
maximum daily dose: 75 mg/kg/day repeated every 4 hours; maximum: 5 doses/day
Pain: Limited data available:
Acetaminophen Dosing (Oral)
Oral:
GA 28 to 32 weeks: 10 to 12 mg/kg/dose every 6 to 8 Weight (preferred)* Dosage
hours; maximum daily dose: 40 mg/kg/day (Anand (mg)
2001; Anand 2002)
GA 33 to 37 weeks or term neonates <10 days: 10 to 6 to 11 0 to 3 mo 40
15 mg/kg/dose every 6 hours; maximum daily dose: 12 to 17 4 to 11 mo 80
60 mg/kg/day (Anand 2001; Anand 2002)
Term neonates 210 days: 10 to 15 mg/kg/dose every
4 to 6 hours (Anand 2001; Anand 2002); do not
exceed 5 doses in 24 hours; maximum daily dose:
75 mg/kg/day
\V: Efficacy results variable; optimal dose not estab- |27.3t0326 | eoto71 |9to1oy | 400 _|
lished; Note: Some experts do not recommend the 32.7 to 43.2 72 to 95
use of IV acetaminophen in premature neonates <32
AManufacturer’s recommendations are based on weight in
weeks PMA until pharmacokinetic and pharmacody- pounds (OTC labeling); weight in kg listed here is derived
namic studies have been conducted in this age group from pounds and rounded; kg weight listed also is adjusted to
(van den Anker 2011). allow for continuous weight ranges in kg. OTC labeling
instructs consumer to consult with physician for dosing
Loading dose (Allegaert 2007; Bartocci 2007): instructions in infants and children under 2 years of age.
20 mg/kg/dose Immediate release solid dosage formulations:
Maintenance dose (Allegaert 2007; Allegaert 2011; Note: Actual OTC dosing recommendations
Bartocci 2007): may vary by product and/or manufacturer:
PMA 28 to 32 weeks: 10 mg/kg/dose every 12 Children 6 to 11 years: 325 mg every 4 to 6
hours; some suggest 7.5 mg/kg/dose every 8 hours; maximum daily dose: 1,625 mg/day;
hours; maximum daily dose: 22.5 mg/kg/day Note: Do not use more than 5 days unless
PMA 33 to 36 weeks: 10 mg/kg/dose every 8 hours; directed by a physician
some suggest 7.5 to 10 mg/kg/dose every 6 hours; Children 212 years and Adolescents:
maximum daily dose: 40 mg/kg/day Regular strength: 650 mg every 4 to 6 hours;
PMA 237 weeks: 10 mg/kg/dose every 6 hours; maximum daily dose: 3,250 mg/day unless
maximum daily dose: 40 mg/kg/day directed by a physician; under physician
Note: Manufacturer neonatal pharmacokinetic data supervision daily doses $4,000 mg may
suggests that 7.5 mg/kg/dose every 6 hours pro- be used
duces a similar pharmacokinetic exposure as Extra strength: 1,000 mg every 6 hours; max-
standard dosing in children 22 years. imum daily dose: 3,000 mg/day unless
Rectal: directed by a physician; under physician
GA 28 to 32 weeks: 20 mg/kg/dose every 12 hours; supervision daily doses $4,000 mg may
maximum daily dose: 40 mg/kg/day (Anand 2001; be used
Anand 2002) Extended release: Children 212 years and Adoles-
GA 33 to 37 weeks or term neonates <10 days: cents: 1,300 mg every 8 hours; maximum daily
Loading dose: 30 mg/kg; then 15 mg/kg/dose every dose: 3,900 mg/day
8 hours; maximum daily dose: 60 mg/kg/day (Anand IV:
2001; Anand 2002) Infants and Children <2 years:
Term infants 210 days: Loading dose: 30 mg/kg; then Manufacturer’s labeling: Fever: 15 mg/kg/dose
20 mg/kg/dose every 6 to 8 hours (Anand 2001; every 6 hours; maximum daily dose:
Anand 2002); do not exceed 5 doses in 24 hours; 60 mg/kg/day
maximum daily dose: 75 mg/kg/day Alternate dosing: Limited data available: Pain and
Pediatric Note: In 2011, McNeil Consumer Healthcare fever: 7.5 to 15 mg/kg/dose every 6 hours; max-
reduced the maximum daily doses and increased the imum daily dose: 60 mg/kg/day (Wilson-
dosing interval on the labeling of some of their acetami- Smith 2009)
nophen OTC products used in older pediatric patients Children 22 years and Adolescents:
(usually children 212 years and adolescents) and adults <50 kg: 15 mg/kg/dose every 6 hours or
in an attempt to protect consumers from inadvertent 12.5 mg/kg/dose every 4 hours; maximum single
overdoses. For example, the maximum daily dose of dose: 15 mg/kg up to 750 mg; maximum daily
Extra Strength Tylenol OTC and Regular Strength dose: 75 mg/kg/day not to exceed 3,750 mg/day

40
 ACETAMINOPHEN

250 kg: 1,000 mg every 6 hours or 650 mg every 4 administration. Small volume pediatric doses (up to
hours; maximum single dose: 1,000 mg; maxi- 600 mg [60 mL]) may be placed in a syringe.
mum daily dose: 4,000 mg/day Doses of 1,000 mg (250 kg): Insert vented IV set through
Rectal: vial stopper.
Weight-directed dosing: Limited data available: Administration
Infants and Children <12 years: 10 to 20 mg/kg/ Oral: Administer with food to decrease GI upset; shake
dose every 4 to 6 hours as needed; do not exceed drops and suspension well before use; do not crush or
5 doses in 24 hours (Kliegman 2011; Vernon chew extended release products
1979); maximum daily dose: 75 mg/kg/day Parenteral: For IV infusion only. May administer undiluted
Fixed dosing: over 15 minutes. Use within 6 hours of opening vial or
Infants 6 to 11 months: 80 mg every 6 hours; transferring to another container. Discard any unused
maximum daily dose: 320 mg/day portion; single-use vials only.
Infants and Children 12 to 36 months: 80 mg every Rectal: Remove wrapper; insert suppository well up into
4 to 6 hours; maximum daily dose: 400 mg/day the rectum.
Children >3 to 6 years: 120 mg every 4 to 6 hours; Test Interactions Acetaminophen may cause false-pos-
maximum daily dose: 600 mg/day itive urinary 5-hydroxyindoleacetic acid.
Children >6 up to 12 years: 325 mg every 4 to 6 Additional Information 2 mg propacetamol (pro-
hours; maximum daily dose: 1,625 mg/day drug) = 1 mg paracetamol = 1 mg acetaminophen
Children 212 years and Adolescents: 650 mg Acetaminophen (15 mg/kg/dose given orally every 6
every 4 to 6 hours; maximum daily dose: hours for 24 hours) did not relieve the intraoperative or
'* 3,900 mg/day the immediate postoperative pain associated with neo-
Pain; peri-/postoperative management; adjunct to natal circumcision; some benefit was seen 6 hours after
opioid therapy: circumcision (Howard, 1994).
IV: There is currently no scientific evidence to support alter-
Infants and Children <2 years: Limited data avail- nating acetaminophen with ibuprofen in the treatment of
able: 7.5 to 15 mg/kg/dose every 6 hours; max- fever (Mayoral, 2000).
imum daily dose: 60 mg/kg/day (Wilson- Based on recommendations provided by the Food and
Smith, 2009) Drug Administration (FDA), all over-the-counter (OTC)
Children 22 years and Adolescents: pediatric single-ingredient acetaminophen liquid prod-
<50 kg: 15 mg/kg/dose every 6 hours or ucts are now only available as a single concentration
12.5 mg/kg/dose every 4 hours; maximum single of 160 mg/5 mL; the transition began in 2011. The
dose: 15 mg/kg up to 750 mg; maximum daily concentration 80 mg/0.8 mL is no longer available in
dose: 75 mg/kg/day not to exceed 3,750 mg/day the US. The recommended mg/kg dose is unaffected.
250 kg: 1,000 mg every 6 hours or 650 mg every 4 Product Availability Ofirmev 100 mL IV bag formulation:
hours; maximum single dose: 1,000 mg; maxi- FDA approved November 2016; availability anticipated in
mum daily dose: 4,000 mg/day the second quarter of 2017.
Rectal: Limited data available: Children and Adoles- Dosage Forms Excipient information presented when
cents: available (limited, particularly for generics); consult spe-
Loading dose: 40 mg/kg for 1 dose, in most trials, cific product labeling. [DSC] = Discontinued product
the dose was administered postoperatively (Bir- Caplet, oral: 500 mg
mingham 2001; Capici 2008; Hahn 2000; Mire- Cetafen Extra: 500 mg
skandari 2011; Prins 2008; Riad 2007; Viitanen Mapap Extra Strength: 500 mg
2003); a maximum dose of 1,000 mg was most Mapap Extra Strength: 500 mg [scored]
frequently reported. However, in one trial evaluat- Pain Eze: 650 mg
ing 24 older pediatric patients (all patients 225 kg; Tylenol: 325 mg
mean age: ~13 years), the data suggested that a Tylenol Extra Strength: 500 mg
dose of 1,000 mg does not produce therapeutic Caplet, extended release, oral:
serum concentrations (target for study: >10 Mapap Arthritis Pain: 650 mg
mcg/mL) compared to a 40 mg/kg dose (up to Midol Long Lasting Relief: 650 mg
~2,000 mg); the resultant C,,ax was: 7.8 mcg/mL Tylenol 8 HR Arthritis Pain: 650 mg
(1,000 mg dose group) vs 15.9 mcg/mL (40 mg/kg Capsule, oral:
dose group). Note: Therapeutic serum concentra- Mapap Extra Strength: 500 mg
tions for analgesia have not been well-established Tylenol: 325 mg
(Howell 2003). Tylenol Extra Strength: 500 mg
Injection, solution [preservative free]:
Maintenance dose: 20 to 25 mg/kg/dose every 6
hours as needed for 2 to 3 days has been sug-
Ofirmev: 10 mg/mL (100 mL)
Liquid, oral: 1460 mg/5 mL (120 mL, 473 mL); 500 mg/5 mL
gested if further pain control is needed postoper-
(240 mL)
atively; maximum daily dose: 100 mg/kg/day;
Mapap Extra Strength: 500 mg/5 mL (237 mL) [contains
therapy longer than 5 days has not been evaluated
propylene glycol, sodium 9 mg/15 mL, sodium ben-
(Birmingham 2001; Hahn 2000; Prins 2008).
zoate; cherry flavor]
Note: In the majority of trials, suppositories were not
Q-Pap Children's: 160 mg/5 mL (118 mL [DSC], 473. mL
divided due to unequal distribution of drug within
[DSC]) [ethanol free; contains propylene glycol, sodium
suppository; doses were rounded to the nearest
2 mg/5 mL, sodium benzoate; cherry flavor, grape
mg amount using 1 or 2 suppositories of available
flavor]
product strengths.
Silapap Children's: 160 mg/5 mL (118 mL, 237 mL, 473
Renal Impairment: Pediatric mL) [ethanol free, sugar free; contains propylene gly-
IV: Children 22 years and Adolescents: CrCl $30 mL/ col, sodium benzoate; cherry flavor]
minute: Use with caution; consider decreasing daily Tylenol Extra Strength: 500 mg/15 mL (240 mL [DSC})
dose and extending dosing interval [ethanol free; contains propylene glycol, sodium ben-
Oral (Aronoff 2007): zoate; cherry flavor]
Infants, Children, and Adolescents: Solution, oral: 160 mg/5 mL (5 mL, 10 mL, 20 mL);
GFR 210 mL/minute/1.73 m2: No adjustment 325 mg/10.15 mL (10.15 mL); 650 mg/20.3 mL
required (20.3 mL)
GFR <10 mL/minute/1.73 m?: Administer every 8 Pain & Fever Children's: 160 mg/5 mL (118 mL, 473 mL)
hours [ethanol free, sugar free; contains propylene glycol,
Intermittent hemodialysis or peritoneal dialysis: sodium 1 mg/5 mL, sodium benzoate; cherry flavor]
Administer every 8 hours Solution, oral [drops]: 80 mg/0.8 mL (15 mL [DSC})
CRRT: No adjustments necessary . Little Fevers: 80 mg/mL (30 mL [DSC}) [dye free, ethanol
Hepatic Impairment: Pediatric Use with caution. Lim- free, gluten free; contains propylene glycol, sodium
ited, low-dose therapy is usually well-tolerated in hepatic benzoate; berry flavor]
disease/cirrhosis; however, cases of hepatotoxicity at Q-Pap Infants': 80 mg/0.8 mL (15 mL [DSC]) [ethanol
daily acetaminophen dosages <4,000 mg/day have free; contains propylene glycol; fruit flavor]
been reported. Avoid chronic use in hepatic impairment. Silapap Infants': 80 mg/0.8 mL (15 mL [DSC], 30 mL
Preparation for Administration [DSC}) [ethanol free; contains propylene glycol, sodium
Parenteral: Injectable solution may be administered benzoate; cherry flavor]
directly from the vial without further dilution. Use within Suppository, rectal: 120 mg (12s); 325 mg (12s);
6 hours of opening vial or transferring to another con- 650 mg (12s)
tainer. Discard any unused portion; single-use vials only. Acephen: 120 mg (12s, 50s, 100s); 325 mg (6s, 12s,
Doses <1,000 mg (<50 kg): Withdraw appropriate dose 50s, 100s); 650 mg (12s, 50s, 100s)
from vial and transfer to a separate sterile container FeverAll Adults: 650 mg (50s)
(eg, glass bottle, plastic 1V container, syringe) for FeverAll Children's: 120 mg (6s, 50s)

M1
ACETAMINOPHEN

FeverAll Infants': 80 mg (6s, 50s) Use Relief of mild to moderate pain (FDA approved in
FeverAll Junior Strength: 325 mg (6s, 50s) adults)
Suspension, oral: 160 mg/5 mL (5 mL, 10.15 mL, 20.3 mL) Pregnancy Risk Factor C
Mapap Children's: 160 mg/5 mL (118 mL) [ethanol free; Pregnancy Considerations Animal reproduction studies
contains propylene glycol, sodium benzoate; cherry have not been conducted with this combination. [US
flavor] Boxed Warning]: Prolonged use of opioids during
Nortemp Children's: 160 mg/5 mL (118 mL) [ethanol pregnancy can cause neonatal opioid withdrawal syn-
free; contains propylene glycol, sodium benzoate; cot- drome, which may be life-threatening if not recog-
ton candy flavor] nized and treated according to protocols developed
Pain & Fever Children's: 160 mg/5 mL (60 mL) [ethanol by neonatology experts. If opioid use is required for a
free; contains propylene glycol, sodium benzoate; prolonged period in a pregnant woman, advise the
cherry flavor] patient of the risk of neonatal opioid withdrawal syn-
Q-Pap Children's: 160 mg/5 mL (118 mL [DSC}) [ethanol drome and ensure that appropriate treatment will be
free; contains sodium 2 mg/5 mL, sodium benzoate; available. Refer to individual agents.
bubblegum flavor, cherry flavor, grape flavor] Breastfeeding Considerations Acetaminophen and
Tylenol Children's: 160 mg/5 mL (120 mL) [dye free, codeine are present in breast milk. Due to-the potential
ethanol free; contains propylene glycol, sodium ben- for serious adverse reactions in the breastfed infant,
zoate; cherry flavor] breastfeeding is not recommended by the manufacturer.
Tylenol Children's: 160 mg/5:*mL (120 mL) [ethanol free; Refer to individual agents.
contains propylene glycol, sodium 2 mg/5 mL, sodium Contraindications
benzoate; bubblegum flavor] Hypersensitivity (eg, anaphylaxis) to acetaminophen,
Tylenol Children's: 160 mg/5 mL (60 mL, 120 mL) [etha- codeine, or any component of the formulation; pediatric
nol free; contains propylene glycol, sodium 2 mg/5 mL, patients <12 years of age; postoperative management in
sodium benzoate; cherry flavor] pediatric patients <18 years of age who have undergone
Tylenol Children's: 160 mg/5 mL (120 mL) [ethanol-free; tonsillectomy and/or adenoidectomy; significant respira-
contains propylene glycol, sodium 2 mg/5 mL, sodium tory depression; acute or severe bronchial asthma in an
benzoate; grape flavor] unmonitored setting or in the absence of resuscitative
Tylenol Children's: 160 mg/5 mL (120 mL) [ethanol free; equipment; GI obstruction, including paralytic ileus
contains propylene glycol, sodium 2 mg/5 mL, sodium (known or suspected); concurrent use with or within 14
benzoate; strawberry flavor] days following monoamine oxidase inhibitors (MAOIs)
Tylenol Infants': 160 mg/5 mL (60 mL) [ethanol free; therapy.
contains propylene glycol, sodium benzoate; grape Canadian labeling: Additional contraindications (not in US
flavor] labeling): Mechanical GI obstruction (eg, bowel obstruc-
Syrup, oral: tion, strictures) or any disease/condition that affects
Triaminic Children's Fever Reducer Pain Reliever: bowel transit (known or suspected); suspected surgical
160 mg/5 mL (118 mL) [contains benzoic acid, sodium abdomen (eg, acute appendicitis, pancreatitis); severe
6 mg/5 mL; bubblegum flavor] hepatic impairment or severe active liver disease; acute
Triaminic Children's Fever Reducer Pain Reliever: or severe bronchial asthma, chronic obstructive airway
160 mg/5 mL (118 mL) [contains sodium 5 mg/5 mL, disease; status asthmaticus; hypercapnia; cor pulmo-
sodium benzoate; grape flavor] nale; acute alcoholism; delirium tremens; seizure disor-
Tablet, oral: 325 mg, 500 mg der; severe CNS depression; increased cerebrospinal or
Aspirin Free Anacin Extra Strength: 500 mg intracranial pressure; head injury; pregnancy; use during
Cetafen: 325 mg labor and delivery. Some products may contraindicate
Mapap: 325 mg use in patients <18 years (refer to specific product
Mapap Extra Strength: 500 mg labeling).
Non-Aspirin Pain Reliever: 325 mg
Pharbetol: 325 mg Documentation of allergenic cross-reactivity for opioids is
Pharbetol Extra Strength: 500 mg limited. However, because of similarities in chemical
Q-Pap: 325 mg [scored] [DSC] structure and/or pharmacologic actions, the possibility
Q-Pap Extra Strength: 500 mg [scored] [DSC] of cross-sensitivity cannot be ruled out with certainty.
Tylenol: 325 mg Warnings/Precautions [US Boxed Warning]: Life-
Tylenol Extra Strength: 500 mg threatening respiratory depression and death have
Valorin: 325 mg [sugar free] occurred in children who received codeine. Most of
Valorin Extra: 500 mg [sugar free] the reported cases occurred following tonsillectomy
Tablet, chewable, oral: 80 mg and/or adenoidectomy, and many of the children had
Mapap Children's: 80 mg [fruit flavor] evidence of being ultrarapid metabolizers of codeine
Tablet, dispersible, oral: 80 mg, 160 mg due to a CYP2D6 polymorphism. Acetaminophen/
Mapap Children's: 80 mg [bubblegum flavor] [DSC] codeine is contraindicated in pediatric patients <12
Mapap Children's: 80 mg [grape flavor] years of age and pediatric patients <18 years of age
Tylenol Jr. Meltaways: 160 mg [bubblegum flavor] [DSC] following tonsillectomy and/or adenoidectomy. Avoid
Tylenol Jr. Meltaways: 160 mg [grape flavor] [DSC] the use of acetaminophen/codeine in pediatric
patients 12 to 18 years of age who have other risk
factors that may increase their sensitivity to the res-
Acetaminophen and Codeine piratory depressant effects of codeine. Risk factors
(a seet a MIN oh fen & KOE deen)
include conditions associated with hypoventilation, such
Medication Safety Issues as postoperative status, obstructive sleep apnea, obesity,
Sound-alike/look-alike issues: severe pulmonary disease, neuromuscular disease, and
Procet-30 may be confused with Percocet concomitant use of other medications that cause respira-
Tylenol may be confused with atenolol, timolol, Tylox tory depression. Deaths have also occurred in breastfeed-
High alert medication: ing infants after being exposed to high concentrations of
The Institute for Safe Medication Practices (ISMP) morphine because the mothers were ultrarapid metabo-
includes this medication among its list of drug classes lizers. [US Boxed Warning]: Prolonged use during
which have a heightened risk of causing significant pregnancy can cause neonatal opioid withdrawal syn-
patient harm when used in error. drome, which may be life-threatening if not recog-
Other safety concerns: nized and treated according to protocols developed
Duplicate therapy issues: This product contains acetami- by neonatology experts. If opioid use is required for a
nophen, which may be a component of other combina- prolonged period in a pregnant woman, advise the
tion products. Do not exceed the maximum patient of the risk of neonatal opioid withdrawal syn-
recommended daily dose of acetaminophen. drome and ensure that appropriate treatment will be
T3 is an error-prone abbreviation (mistaken as liothyr- available. Signs and symptoms include irritability, hyper-
onine) = activity and abnormal sleep pattern, high pitched cry,
International issues: tremor, vomiting, diarrhea and failure to gain weight.
Codex: Brand name for acetaminophen/codeine [Brazil], Onset, duration, and severity depend on the drug used,
but also the brand name for saccharomyces boulardii duration of use, maternal dose, and rate of drug elimina-
{Italy] tion by the newborn.
Codex [Brazil] may be confused with Cedax brand name Avoid use of codeine in patients with impaired conscious-
for ceftibuten [US and multiple international markets] ness or coma as these patients are susceptible to intra-
Brand Names: US Capital/Codeine [DSC]; Tylenol with cranial effects of CO2 retention. Some products may
Codeine #3; Tylenol with Codeine #4 contain metabisulfite which may cause allergic reactions.
Brand Names: Canada Procet-30 Use caution in patients with two or more copies of the
Therapeutic Category Analgesic, Narcotic variant CYP2D6*2 allele; may have extensive conversion
Generic Availability (US) May be product dependent to morphine and thus increased opioid-mediated effects.

42
 ACETAMINOPHEN AND CODEINE

Avoid the use of codeine in these patients; consider buprenorphine) analgesics may precipitate withdrawal
alternative analgesics such as morphine or a nonopioid symptoms and/or reduced analgesic efficacy in patients
agent (Crews 2012). The occurrence of this phenotype is following prolonged therapy with mu opioid agonists.
seen in 0.5% to 1% of Chinese and Japanese, 0.5% to 1% Abrupt discontinuation following prolonged use may also
of Hispanics, 1% to 10% of Caucasians, 3% of African- lead to withdrawal symptoms. Taper dose gradually when
Americans, and 16% to 28% of North Africans, Ethiopians, discontinuing. Potentially significant drug-drug interactions
and Arabs. may exist, requiring dose or frequency adjustment, addi-
tional monitoring, and/or selection of alternative therapy.
Serious and potentially fatal skin reactions, including
[US Boxed Warning]: Concomitant use of opioids with
acute generalized exanthematous pustulosis (AGEP),
benzodiazepines or other CNS depressants, including
Stevens-Johnson syndrome (SJS), and toxic epidermal
alcohol, may result in profound sedation, respiratory
necrolysis (TEN) have occurred rarely with acetamino-
depression, coma, and death. Reserve concomitant
phen use. Discontinue therapy at the first appearance of
prescribing of acetaminophen/codeine and benzodia-
skin rash or any other sign of hypersensitivity. Limit
zepines or other CNS depressants for use in patients
acetaminophen dose from all sources (prescription,
for whom alternative treatment options are inad-
‘OTC, combination products) to <4 g/day in adults. Do
equate. Limit dosages and durations to the minimum
not use acetaminophen/codeine concomitantly with other
required. Follow patients for signs and symptoms of
acetaminophen-containing products.
respiratory depression and sedation. [US Boxed
[US Boxed Warning]: Acetaminophen has been asso- Warning]: The effects of concomitant use or discon-
ciated with cases of acute liver failure, at times result- tinuation of CYP450 3A4 inducers, 3A4 inhibitors, or
ing in liver transplant and death. Most of the cases of 2D6 inhibitors with codeine are complex. Use of
liver injury are associated with the use of acetamino- CYP450 3A4 inducers, 3A4 inhibitors, or 2D6 inhib-
phen at dosages that exceed 4 g/day, and often itors with acetaminophen/codeine requires careful
involve more than one acetaminophen-containing consideration of the effects on-the parent drug,
product. Risk is increased with alcohol use, preexisting codeine, and the active metabolite, morphine.
liver disease, and intake of more than one source of
acetaminophen-containing medications. Chronic daily Use with caution in cachectic or debilitated patients, or in
dosing in adults has also resulted in liver damage in some morbidly obese patients; adrenal insufficiency (including
patients. Hypersensitivity and anaphylactic reactions have Addison disease); biliary tract impairment (including acute
been reported with acetaminophen use; discontinue pancreatitis); renal or severe hepatic impairment; toxic
immediately if symptoms of allergic or hypersensitivity psychosis; delirium tremens; thyroid disorders; prostatic
reactions occur. Use with caution in patients with hyper- hyperplasia and/or urethral stricture; seizure disorder;
sensitivity reactions to other phenanthrene-derivative head injury, intracranial lesions or increased intracranial
opioid agonists (hydrocodone, hydromorphone, levorpha- pressure. May cause or aggravate constipation; chronic
nol, oxycodone, oxymorphone). Use acetaminophen with use may result in obstructive bowel disease, particularly in
caution in patients with known G6PD deficiency. Use with those with underlying intestinal motility disorders. May
caution in patients with alcoholic liver disease; consuming also be problematic in patients with unstable angina and
23 alcoholic drinks/day may increase the risk of liver patients post-myocardial infarction. Consider preventive
damage. measures (eg, stool softener, increased fiber) to reduce
the potential for constipation. [US Boxed Warning]: Seri-
May cause CNS depression, which may impair physical or ous, life-threatening, or fatal respiratory depression
mental abilities; patients must be cautioned about per- may occur with use. Monitor for respiratory depres-
forming tasks which require mental alertness (eg, operat- sion, especially during initiation of therapy or follow-
ing machinery or driving). [US Boxed Warning]: Use ing a dose increase. Carbon dioxide retention from
exposes patients and other users to the risks of opioid-induced respiratory depression can exacerbate
opioid addiction, abuse, and misuse, which can lead the sedating effects of opioids. Use with caution and
to overdose and death. Assess each patient's risk monitor for respiratory depression in patients with signifi-
prior to prescribing acetaminophen/codeine, and cant chronic obstructive pulmonary disease or cor pulmo-
monitor all patients regularly for the development of nale, and those with a substantially decreased respiratory
these behaviors or conditions. Use with caution in reserve, hypoxia, hypercapnia, or preexisting respiratory
patients with a history of drug abuse or acute alcoholism; depression, particularly when initiating and titrating ther-
potential for drug dependency exists. Other factors asso- apy; critical respiratory depression may occur, even at
ciated with increased risk for misuse include younger age, therapeutic dosages. Consider the use of alternative non-
concomitant depression (major), and psychotropic medi- opioid analgesics in these patients. May obscure diagno-
cation use. Consider offering naloxone prescriptions in sis or clinical course of patients with acute abdominal
patients with factors associated with an increased risk conditions. Use with caution in the elderly; may be more
for overdose, such as history of overdose or substance sensitive to adverse effects, such as respiratory depres-
use disorder, higher opioid dosages (250 morphine milli- sion. Use opioids for chronic pain with caution in this age
gram equivalents/day orally), and concomitant benzodia- group; monitor closely due to an increased potential for
zepine use (Dowell [CDC 2016]). Abuse or misuse of ER risks, including certain risks such as falls/fracture, cogni-
tablets by crushing, chewing, snorting, or injecting the tive impairment, and constipation. Clearance may also be
dissolved product will result-in. the uncontrolled delivery reduced in older adults (with or without renal impairment)
of the oxycodone and can result in overdose and death. resulting in a narrow therapeutic window and increasing
Chronic pain (outside of end-of-life or palliative care, the risk for respiratory depression or overdose (Dowell
active cancer treatment, sickle cell disease, or medica- [CDC 2016)).
tion-assisted treatment for opioid use disorder) in out- [US Boxed Warning]: Accidental ingestion of acetami-
patient setting in adults: Opioids should not be used as nophen/codeine, especially by children, can result in
first-line therapy for chronic pain management (pain >3- a fatal overdose of codeine. [US Boxed Warning]:
month duration or beyond time of normal tissue healing) Ensure accuracy when prescribing, dispensing, and
due to limited short-term benefits, undetermined long-term administering acetaminophen/codeine oral solution
benefits, and association with serious risks (eg, overdose, or suspension. Dosing errors due to confusion
Ml, auto accidents, risk of developing opioid use disorder). between mg and mL and other codeine containing
Preferred management includes nonpharmacologic ther- oral products of different concentrations can result
apy and nonopioid therapy (eg, NSAIDs, acetaminophen, in accidental overdose and death. May cause severe
certain anticonvulsants and antidepressants). If opioid hypotension (including orthostatic hypotension and syn-
therapy is initiated, it should be combined with nonphar- cope); use with caution in patients with hypovolemia,
macologic and nonopioid therapy, as appropriate. Prior to
cardiovascular disease (including acute Ml), or drugs
initiation, Known risks of opioid therapy should be dis- which may exaggerate hypotensive effects (including phe-
cussed and realistic treatment goals for pain/function nothiazines or general anesthetics). Monitor for symptoms
should be established, including consideration for discon-
of hypotension following initiation or dose titration. Avoid
tinuation if benefits do not outweigh risks. Therapy should
use in patients with circulatory shock. Use opioids with
be continued only if clinically meaningful improvement in
caution for chronic pain in patients with mental health
pain/function outweighs risks. Therapy should be initiated
conditions (eg, depression, anxiety disorders, post-trau-
at the lowest effective dosage using immediate-release
matic stress disorder) due to increased risk for opioid use
opioids (instead of extended-release/long-acting opioids).
disorder and overdose; more frequent monitoring is rec-
Risk associated with use increases with higher opioid
ommended (Dowell [CDC 2016]). Use opioids with caution
dosages. Risks and benefits should be re-evaluated when
for chronic pain and titrate dosage cautiously in patients
increasing dosageto 250 morphine milligram equivalents
with risk factors for sleep-disordered breathing, including
(MME)/day orally; dosages 290 MME/day orally should be
HF and obesity. Avoid opioids in patients with moderate to
avoided unless carefully justified (Dowell [CDC 2016)).
severe sleep-disordered breathing (Dowell [CDC 2016)).
Concurrent use of mixed agonist/antagonist (eg, pentazo-
cine, nalbuphine, butorphanol) or partial agonist (eg,
An opioid-containing analgesic regimen should be tailored
to each patient's needs and based upon the type of pain >
43
ACETAMINOPHEN AND CODEINE

being treated (acute versus chronic), the route of admin- Eluxadoline; Flunitrazepam; HYDROcodone; Imatinib;
istration, degree of tolerance for opioids (naive versus Methotrimeprazine; MetyroSINE; Mipomersen; Opioid
chronic user), age, weight, and medical condition. The Analgesics; Orphenadrine; OxyCODONE; Paraldehyde;
optimal analgesic dose varies widely among patients; Perhexiline; Phenylephrine (Systemic); Piribedil; Prami-
doses should be titrated to pain relief/prevention. Opioids pexole; Prilocaine; Ramosetron; ROPINIRole; Rotigo-
decrease bowel motility; monitor for decreased bowel tine; Selective Serotonin Reuptake Inhibitors; Serotonin
motility in postop patients receiving opioids. Use with Modulators; Sodium Nitrite; SORAfenib; Suvorexant;
caution in the perioperative setting; individualize treatment Thalidomide; Vitamin K Antagonists; Zolpidem :
when transitioning from parenteral to oral analgesics.
The levels/effects of Acetaminophen and Codeine may
Some dosage forms may contain propylene glycol; large be increased by: Abiraterone Acetate; Ajmaline; Amphet-
amounts are potentially toxic and have been associated amines; Anticholinergic Agents; Asunaprevir; Brimoni-
hyperosmolality, lactic acidosis, seizures and respiratory dine (Topical); Bromopride; Bromperidol; Cannabis;
depression; use caution (AAP ["Inactive" 1997]; Zar 2007).
Chlormethiazole; Chlorphenesin Carbamate; CNS
Some dosage forms may contain sodium benzoate/ben- Depressants; Cobicistat; CYP3A4 Inhibitors (Strong);
zoic acid; benzoic acid (benzoate) is a metabolite of Dapsone (Topical); Darunavir; Dasatinib; Dimethindene
benzyl alcohol; large amounts of benzyl alcohol (Topical); Dronabinol; Droperidol; Flucloxacillin; |sonia-
(299 mg/kg/day) have been associated with a potentially zid; Kava Kava; Lofexidine; Lumefantrine; Magnesium
fatal toxicity ("gasping syndromé") in neonates; the "gasp- Sulfate; Methotrimeprazine; MetyraPONE; Minocycline;
ing syndrome" consists of metabolic acidosis, respiratory Monoamine Oxidase Inhibitors; Nabilone; Nitric Oxide;
distress, gasping respirations, CNS dysfunction (including Oxomemazine; Panobinostat; Peginterferon Alfa-2b;
convulsions, intracranial hemorrhage), hypotension, and Perampanel; Perhexiline; Probenecid; QuiNINE; Rufina-
cardiovascular collapse (AAP ["Inactive" 1997]; CDC mide; Sodium Oxybate; Somatostatin Analogs; SORA-
1982); some data suggests that benzoate displaces bilir- fenib; Succinylcholine; Tapentadol; Tetracaine (Topical);
ubin from protein binding sites (Ahlfors 2001); avoid or use Tetrahydrocannabinol
dosage forms containing benzyl alcohol derivative with
Decreased Effect
caution in neonates, See manufacturer's labeling.
Acetaminophen and Codeine may decrease the levels/
Warnings: Additional Pediatric Considerations Use
effects of: Diuretics; Gastrointestinal Agents (Prokinetic);
is contraindicated in pediatric patients <12 years of age
Pegvisomant
and for postoperative management in pediatric patients 12
to 18 years of age who have undergone tonsillectomy and/ The levels/effects of Acetaminophen and Codeine may
or adenoidectomy; prior to 2017, acetaminophen/codeine be decreased by: CYP2D6 Inhibitors (Moderate);
was approved for use in children as young as 3 years of CYP2D6 Inhibitors (Strong); CYP3A4 Inducers (Moder-
age. Codeine has also been removed from the WHO List ate); CYP3A4 Inducers (Strong); CYP3A4 Inhibitors
of Essential Medications in Children since 2011. Codeine (Moderate); Nalmefene; Naltrexone; Opioids (Mixed
has been associated with reports of life-threatening or Agonist / Antagonist); Peginterferon Alfa-2b
fatal respiratory depression in children and adolescents;
Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
a review of FDA adverse events data and the literature
protect from light.
includes reports of at least 21 deaths in infants or children
(1965-2015). Multifactorial causes for the respiratory Mechanism of Action
depression have been identified; of primary concern are Acetaminophen: Although not fully elucidated, the analge-
unrecognized ultrarapid metabolizers of CYP2D6 who sic effects are believed to be due to activation of
may have extensive conversion of codeine (prodrug) to descending serotonergic inhibitory pathways in the
morphine and thus increased opioid-mediated effects (ie, CNS. Interactions with other nociceptive systems may
respiratory depression). Other oral opioid and nonopioid be involved as well (Smith 2009). Antipyresis is pro-
analgesics are alternate options depending upon severity duced from inhibition of the hypothalamic heat-regulating
of pain and other patient specific factors (eg, age, route of center.
administration, etc); however, each also has unique ther- Codeine: Binds to opiate receptors in the CNS, causing
apeutic challenges and concerns; refer to individual mono- inhibition of ascending pain pathways, altering the per-
graphs for detailed information. Avoid codeine use in ception of and response to pain; causes cough suppres-
pediatric patient populations in which it is contraindicated; sion by direct central action in the medulla; produces
in rare cases where codeine-containing product is the only generalized CNS depression.
option, consider genotype testing prior to use; use extra Pharmacodynamics/Kinetics (Adult data uniess
precaution; monitor closely for adverse effects (AAP noted) See individual agents.
[Tobias 2016]; Dancel 2017; Gammal 2016; Gold- Dosing
schneider 2017; Poonai 2015).
Pediatric Note: Doses should be titrated to appropriate
Some dosage forms may contain propylene glycol; in analgesic effect:
neonates large amounts of propylene glycol delivered Pain management, mild to moderate: Note: Use is
orally, intravenously (eg, >3,000 mg/day), or topically contraindicated in pediatric patients <12 years of age
have been associated with potentially fatal toxicities which and for postoperative management in pediatric
can include metabolic acidosis, seizures, renal failure, and patients 12 to 18 years of age who have undergone
CNS depression; toxicities have also been reported in tonsillectomy and/or adenoidectomy. Codeine has
children and adults including hyperosmolality, lactic acido- been associated with reports of life-threatening or
sis, seizures and respiratory depression; use caution fatal respiratory depression in children and adoles-
(AAP. 1997; Shehab 2009). cents; multifactorial causes have been identified; of
Adverse Reactions Also see individual agents. primary concern are unrecognized ultrarapid metabo-
Central nervous system: Dizziness, drowsiness, dyspho- lizers of CYP2D6 who may have extensive conversion
ria, euphoria, sedation, serotonin syndrome of codeine (prodrug) to morphine and thus increased
Dermatologic: Pruritus, skin rash
opioid-mediated effects. Avoid codeine use in pedia-
Endocrine & metabolic: Adrenocortical. insufficiency
tric patient populations in which it is contraindicated;
Gastrointestinal: Abdominal pain, constipation, nausea,
in rare cases in which codeine-containing product is
vomiting
the only option, consider genotype testing prior to
Hematologic & oncologic: Agranulocytosis, thrombocyto-
use; use extra precaution; monitor closely for adverse
penia
Hypersensitivity: Hypersensitivity reaction
effects (AAP [Tobias 2016]; Dancel 2017; Gammal
Respiratory: Dyspnea 2016; Goldschneider 2017; Poonai 2015).
Rare but important or life-threatening: Hypogonadism Children and Adolescents: Limited data available in
(Brennan 2013; Debono 2011), respiratory depression ages <12 years and in postoperative tonsillectomy
Drug Interactions and/or adenoidectomy patients: Not a preferred
Metabolism/Transport Effects Refer to individual agent; use only when determined codeine is only
components. option
Avoid Concomitant Use Weight-directed dosing: Dosage for individual com-
Avoid concomitant use of Acetaminophen and Codeine ponents:
with any of the following: Azelastine (Nasal); Bromper- Codeine: Oral: 0.5 to 1 mg/kg/dose every 4 to 6
idol; Eluxadoline; Opioids (Mixed Agonist / Antagonist); hours; maximum dose: 60 mg/dose (APS 2016).
Orphenadrine; Oxomemazine; Paraldehyde; Thalido- Note: Do not use for postoperative tonsillectomy
mide and/or adenoidectomy pain management
Increased Effect/Toxicity Acetaminophen: Oral: 10 to 15 mg/kg/dose every 4
Acetaminophen and Codeine may increase the levels/ to 6 hours; do not exceed 5 doses in 24 hours;
effects of: Alvimopan; Azelastine (Nasal); Blonanserin; maximum daily dose: 75 mg/kg/day not to
Busulfan; Dasatinib; Desmopressin; Diuretics; exceed 4,000 mg/day

44
 ACETAZOLAMIDE

Fixed dosing: Manufacturer's labeling: Oral solution: chlorpropamide [Multiple international markets]; Dobu-
Dosage expressed as mL of formulation containing trex brand name for dobutamine [Multiple international
120 mg acetaminophen and 12 mg codeine per 5 markets]; Trimox brand name for amoxicillin [Brazil];
mL: Zimox brand name for amoxicillin [Italy] and carbidopa/
Children: levodopa [Greece]
3 to 6 years: Oral: 5 mL 3 to 4 times daily as Related Information
needed Oral Medications That Should Not Be Crushed or Altered
7 to 12 years: Oral: 10 mL 3 to 4 times daily as on page 2217
» needed Brand Names: US Diamox Sequels [DSC]
Adolescents: Oral: 15 mL every 4 hours as needed Brand Names: Canada Acetazolam; Diamox
Renal Impairment: Pediatric Children and Adoles- Therapeutic Category Anticonvulsant, Miscellaneous;
cents: There are no specific dosage adjustments pro- Carbonic Anhydrase Inhibitor; Diuretic, Carbonic Anhy-
vided in the manufacturer's labeling; however, clearance drase Inhibitor
may be reduced; active metabolites may accumulate. Generic Availability (US) Yes
_ Use with caution; initiate at lower doses or longer dosing
Use
intervals followed by careful titration. See individual Oral:
monographs for specific adjustments.
Immediate release tablets: Adjunct treatment of edema
Hepatic Impairment: Pediatric Children and Adoles- due to congestive heart failure, drug-induced edema,
cents: There are no dosage adjustments provided in the
centrencephalic epilepsies, chronic simple (open-
manufacturer’s labeling; however, product contains acet-
angle) glaucoma, secondary glaucoma, and preoper-
aminophen; use with caution. Cases of hepatotoxicity at
atively in acute angle-closure glaucoma where delay of
daily acetaminophen dosages <4 g/day have been
surgery is desired (FDA approved in adults); prevention
reported. See individual monographs.
or amelioration of symptoms associated with acute
Administration Oral: Administer with food to decrease Gl mountain sickness (FDA approved in adults); treatment
upset; shake suspension well before use
of metabolic alkalosis
Monitoring Parameters Pain relief, respiratory rate, Extended release capsules (Diamox Sequels): Adjunc-
~ mental status, blood pressure, bowel function; signs of tive treatment of chronic simple (open-angle) glau-
misuse, abuse, and addiction coma, secondary glaucoma, and preoperatively in
Chronic pain (long-term therapy outside of end-of-life or acute angle-closure glaucoma where delay of surgery
palliative care, active cancer treatment, sickle cell dis- is desired (FDA approved in ages 212 years and
ease, or medication-assisted treatment for opioid use adults); prevention or amelioration of symptoms asso-
disorder): Evaluate benefits/risks of opioid therapy within ciated with acute mountain sickness (FDA approved in
1 to 4 weeks of treatment initiation and with dose ages 212 years and adults)
increases. Re-evaluate benefits/risks every 3 months dur- Parenteral: Adjunct treatment of edema due to congestive
ing therapy or more frequently in patients at increased risk heart failure, drug-induced edema, centrencephalic epi-
of overdose or opioid use disorder. Urine drug testing is lepsies, chronic simple (open-angle) glaucoma, secon-
recommended prior to initiation and re-checking should be dary glaucoma, and preoperatively in acute angle-
considered at least yearly (includes controlled prescription closure glaucoma where delay of surgery is desired
medications and illicit drugs of abuse). State prescription (FDA approved in adults); treatment of metabolic alka-
drug monitoring program (PDMP) data should be losis
reviewed by clinicians prior to initiation and periodically Pregnancy Risk Factor C
during therapy (frequency ranging from every prescription Pregnancy Considerations
to every 3 months) (Dowell [CDC 2016)). Adverse events have been observed in animal reproduc-
Test Interactions See individual agents. tion studies. Limited data is available following the use of
Controlled Substance Liquid products: C-V; Tablet: C-Ill acetazolamide in pregnant women for the treatment of
Dosage Forms Excipient information presented when idiopathic intracranial hypertension (Falardeau 2013; Kes-
available (limited, particularly for generics); consult spe- ler 2013).
cific product labeling. [DSC] = Discontinued product Pregnant women exposed to acetazolamide during preg-
Solution, Oral: - nancy for the, treatment of seizure disorders are encour-
Generic: Acetaminophen 120 mg and codeine phos- aged to enroll themselves into the AED Pregnancy
phate 12 mg per 5 mL (5 mL, 12.5 mL, 118 mL, 120 Registry by calling 1-888-233-2334. Additional information
mL [DSC], 473 mL) is available at aedpregnancyregistry.org
Suspension, Oral: Breastfeeding Considerations Acetazolamide is
Capital/Codeine: Acetaminophen 120 mg and codeine present in breast milk. In a case report, low concentrations
phosphate 12 mg per 5 mL (473 mL [DSC)) [fruit punch
of acetazolamide were detected in the breast milk and the
flavor] infant serum following a maternal dose of acetazolamide
Tablet, Oral:
500 mg twice daily. Acetazolamide concentrations in the
Tylenol with Codeine #3: Acetaminophen 300 mg and
breast milk were 1.3 to 2.1 mcg/mL, 1 to 9 hours after the
codeine phosphate 30 mg [contains corn starch,
dose. Acetazolamide concentrations in the infant serum
sodium metabisulfite]
were 0.2 to 0.6 mcg/mL, 2 to 12 hours after nursing.
Tylenol with Codeine #4: Acetaminophen 300 mg and
Maternal plasma concentrations were 5.2 to 6.4 mcg/mL,
codeine phosphate 60 mg [contains corn starch,
1 to 7 hours after the dose. All levels were obtained on
sodium metabisulfite]
days 4 to 5 of therapy, 10 days after delivery (S6derman
Generic: Acetaminophen 300 mg and codeine phos-
1984). Due to the potential for serious adverse reactions in
phate 15 mg, Acetaminophen 300 mg and codeine
the breastfed infant, the manufacturer recommends a
phosphate 30 mg, Acetaminophen 300 mg and
decision be made whether to discontinue breastfeeding
codeine phosphate 60 mg
or to discontinue the drug, taking into account the impor-
Acetaminophen and Hydrocodone see Hydrocodone tance of treatment to the mother.
and Acetaminophen on page 1002 Contraindications
@ Acetaminophen and Oxycodone see Oxycodone and Hypersensitivity to acetazolamide, sulfonamides, or any
component of the formulation; marked hepatic disease or
Acetaminophen on page 1527
insufficiency; decreased sodium and/or potassium lev-
¢@ Acetaminophen, Butalbital, and Caffeine see Butalbi- els; adrenocortical insufficiency; cirrhosis; hyperchlore-
tal, Acetaminophen, and Caffeine on page 329 mic acidosis; severe renal disease or dysfunction; long-
@ Acetaminophen/Codeine see Acetaminophen and term use in noncongestive angle-closure glaucoma
Codeine on page 42 Note: Although the FDA approved product labeling states
@ Acetaminophen/Hydrocodone see Hydrocodone and this medication is contraindicated with other sulfona-
Acetaminophen on page 1002 > mide-containing drug classes, the scientific basis of this
statement has been challenged. See "Warnings/Precau-
@ Acetasol HC see Acetic Acid, Propylene Glycol Diace-
tions" for more detail.
tate, and Hydrocortisone on page 47
Warnings/Precautions Use with caution in patients with
@ Acetazolam (Can) see AcetaZOLAMIDE on page 45 hepatic dysfunction; in cirrhosis, avoid electrolyte and
acid/base imbalances that might lead to hepatic encephal-
AcetaZOLAMIDE (a set a ZOLE a mide) opathy. Use with caution in patients with respiratory
acidosis and diabetes mellitus (may change glucose con-
Medication Safety Issues trol). Use with caution in the elderly; may be more sensi-
Sound-alike/look-aiike issues: tive to side effects. Impairment of mental alertness and/or
Acetazolamide may be confused with acetaminophen physical coordination may occur. Increasing the dose
International issues: does not increase diuresis and may increase the inci-
Diamox {Canada and multiple international markets] may dence of drowsiness and/or paresthesia; often results in
be confused with Diabinese brand name for a reduction of diuresis. Potentially significant drug-drug

45
 ACETAZOLAMIDE

< interactions may exist, requiring dose or frequency adjust-

ment, additional monitoring, and/or selection of alternative
inhibits carbonic anhydrase in central nervous system to
retard abnormal and excessive discharge from CNS neu-
therapy. rons.
Pharmacodynamics/Kinetics (Adult data unless
IM administration is painful because of the alkaline pH of
noted)
the drug; use by this route is not recommended.
Onset of action: Capsule (extended release): 2 hours;
Sulfonamide ("sulfa") allergy: The FDA-approved product Tablet (immediate release): 1 to 1.5 hours; IV: 2 to 10
labeling for many medications containing a sulfonamide minutes :
chemical group includes a broad contraindication in Peak effect: Capsule (extended release): 8 to 18 hours;
patients with a prior allergic reaction to sulfonamides. IV: 15 minutes; Tablet: 2 to 4 hours
There is. a potential for cross-reactivity between members Duration: Inhibition of aqueous humor secretion: Capsule
of a specific class (eg, two antibiotic sulfonamides). How- (extended release): 18 to 24 hours; IV: 4 to 5 hours;
ever, concerns for cross-reactivity have previously Tablet: 8 to 12 hours
extended to all compounds containing the sulfonamide Absorption: Appears to be dose dependent; erratic with
structure (SO2NH2). An expanded understanding of aller- daily doses >10 mg/kg
gic mechanisms indicates cross-reactivity between anti- Distribution: Erythrocytes, kidneys; blood-brain barrier
biotic sulfonamides and nonantibiotic sulfonamides may Protein binding: 95%
not occur or at the very least this potential is extremely low Half-life: 2.4 to 5.8 hours
(Brackett 2004; Johnson 2005; Slatore 2004; Tornero Time to peak, plasma: Capsule (extended release): 3 to 6
2004). In particular, mechanisms of cross-reaction due hours; Tablet: 1 to 4 hours; IV: 15 minutes
to antibody production (anaphylaxis) are unlikely to occur Excretion: Urine (70% to 100% [IV, tablet], 47% [extended
with nonantibiotic sulfonamides. T-cell-mediated (type IV) release capsule] as unchanged drug within 24 hours)
reactions (eg, maculopapular rash) are less well under- Dosing a
stood and it is not possible to completely exclude this Neonatal Metabolic alkalosis: Limited data available;
potential based on current insights. In cases where prior dosing regimens variable: PMA 230 weeks: IV, Oral: 3 to
reactions were severe (Stevens-Johnson syndrome/TEN), 5 mg/kg/dose every 6 to 8 hours, commonly reported
some clinicians choose to avoid exposure to these duration is 3 to 4 doses; most experience in patients with
classes. a PMA 240 weeks using IV administration, dosing shown
Warnings: Additional Pediatric Considerations to significantly lower serum bicarbonate concentrations
Growth retardation has been reported in children receiving (Andrews 2013; Tam 2014); another trial used 5 mg/kg/
chronic therapy (possibly due to chronic acidosis). dose once daily for 3 doses with success in postcardiac
Adverse Reactions Frequency not defined. surgery patients (age range: 8 days to 20 months)
Cardiovascular: Flushing (Moffett 2007)
Central nervous system: Ataxia, confusion, convulsions, Pediatric
depression, dizziness, drowsiness, excitement, fatigue, Altitude illness, acute:
flaccid paralysis, headache, malaise, paresthesia Prevention: Limited data available: Infants, Children,
Dermatologic: Allergic skin reaction, skin photosensitivity, and Adolescents: Oral: Immediate release:
Stevens-Johnson syndrome, toxic epidermal necrolysis, 2.5 mg/kg/dose every 12 hours started either the
urticaria day before (preferred) or on the day of ascent and
Endocrine & metabolic: Electrolyte imbalance, growth may be discontinued after staying at the same
retardation (children), hyperglycemia, hypoglycemia, elevation for 2 to 3 days or if descent initiated;
hypokalemia, hyponatremia, metabolic acidosis maximum dose: 125 mg/dose (Luks 2010). Note:
Gastrointestinal: Decreased appetite, diarrhea, dysgeusia, The International Society for Mountain Medicine
glycosuria, melena, nausea, vomiting does not recommend prophylaxis in children except
Genitourinary: Crystalluria, hematuria in the rare circumstance of unavoidable rapid ascent
Hematologic and oncologic: Agranulocytosis, aplastic or in children with known previous susceptibility to
anemia, leukopenia, thrombocytopenia, thrombocyto- acute mountain sickness (Pollard 2001). Higher
penic purpura doses are effective up to 500 mg, but are also
Hepatic: Abnormal hepatic function tests, cholestatic jaun- associated with increased adverse effects and not
dice, fulminant hepatic necrosis, hepatic insufficiency recommended (Luks 2010).
Hypersensitivity: Anaphylaxis Treatment: Acute mountain sickness (AMS); moder-
Local: Pain at injection site ate: Limited data available: Infants, Children, and
Ophthalmic: Myopia Adolescents: Oral: Immediate release: 2.5 mg/kg/
Otic: Auditory disturbance, tinnitus dose every 8 to 12 hours; maximum dose: 250 mg/
Renal: Polyuria, renal failure dose. Note: With high altitude cerebral edema,
Miscellaneous: Fever dexamethasone is the primary treatment; however,
Drug Interactions acetazolamide may be used adjunctively with the
Metabolism/Transport Effects None known. same treatment dose (Luks 2010; Pollard 2001).
Glaucoma:
Avoid Concomitant Use
Children <12 years: Limited data available: Oral:
Avoid concomitant use of AcetaZOLAMIDE with any of
Immediate release: 10 to 30 mg/kg/day divided
the following: Carbonic Anhydrase Inhibitors; Mecamyl-
every 6 to 8 hours; maximum daily dose:
amine
1,000 mg/day (Portellos 1998; Sabri 2006)
Increased Effect/Toxicity
Children 212 years and Adolescents: Oral:
AcetaZOLAMIDE may increase the Jevels/effects of:
Immediate release: Limited data available: 15 to
Ajmaline; Alpha-/Beta-Agonists (Indirect-Acting); Aman-
30 mg/kg/day in divided doses every 6 to 8 hours;
tadine; Amphetamines; CarBAMazepine; Carbonic
maximum daily dose: 1,000 mg/day
Anhydrase Inhibitors; CycloSPORINE (Systemic); Fle-
Extended release (Diamox sequels):
cainide; Fosphenytoin-Phenytoin; Mecamylamine; Mem-
Manufacturer's labeling: 500 mg twice daily
antine; MetFORMIN; Primidone; QuiNIDine; Sodium
Alternate dosing: Weight-directed dosing: Limited
Bicarbonate; Sodium Phosphates
data available: 15 to 30 mg/kg/day in divided
The levels/effects of AcetaZOLAMIDE may be increased doses twice daily; maximum daily dose:
by: Dexketoprofen; Diacerein; Opioid Analgesics; Sali- 1,000 mg/day (Pagliaro 2002; Sabri 2006)
cylates Edema: Limited data available: Infants, Children, and
Decreased Effect Adolescents: Oral (immediate release), IV: 5 mg/kg/
AcetaZOLAMIDE may decrease the levels/effects of: dose once daily or every other day in the morning
Lithium; Methenamine; Primidone; Trientine (Park 2014)
Epilepsy, short-term management: Limited data
The levels/effects of AcetaZOLAMIDE may be available: Infants, Children, and Adolescents: Oral:
decreased by: Mefloquine; Mianserin; Opioid Analge- Immediate release: Usual range: 4 to 16 mg/kg/day
sics; Orlistat in 3 to 4 divided doses; may titrate; maximum daily
Storage/Stability dose: 30 mg/kg/day or 1,000 mg/day (whichever is
Capsules, tablets: Store at controlled
room temperature. less) (Reiss 1996); Note: Minimal additional benefit
Injection: Store intact vials at 20°C to
25°C (68°F to 77°F). with doses >16 mg/kg/day; extended release cap-
Store reconstituted solutions for 3
days under refriger- sule is not recommended for treatment of epi-
ation at 2°C to 8°C (36°F to 46°F),
or 12 hours at room lepsy
temperature, 20°C to 25°C (68°F to 77°F). Metabolic alkalosis: Limited data available; dosing
Mechanism of Action Reversible inhibition of the regimens variable: Infants, Children, and Adoles-
enzyme carbonic anhydrase resulting in reduction of cents: IV, Oral (immediate release): 5 mg/kg/dose
hydrogen ion secretion at renal tubule and an increased once daily for 3 doses been used in a prospective
renal excretion of sodium, potassium, bicarbonate, and trial of postcardiac surgical patients (age range: 8
water. Decreases production of aqueous humor and days to 20 months) and results showed a significant

46
 ACETIC ACID, PROPYLENE GLYCOL DIACETATE, AND HYDROCORTISONE

decrease in serum bicarbonate concentrations (Mof-

fett 2007). A retrospective trial of 34 pediatric patients Acetic Acid (Otic) (a sce tik as ia)
(mean age: 1.9 years; range: 18 days to 12 years)
reported a mean effective dose of 5.4 mg/kg/dose Medication Safety Issues
every 6 to 8 hours; a trend showed every 6-hour Sound-alike/look-alike issues:
dosing had a higher success rate but not statistically VoSol may be confused with Vexol, VoSol HC
significant (Andrews 2013). In adults, the reported Therapeutic Category Otic Agent, Anti-infective
dosing is 500 mg as a single dose (Marik 1991; Generic Availability (US) Yes
Moviat 2006). Use Otic solution: Treatment of superficial infections of the
Pseudotumor cerebri: Limited data available: external auditory canal (FDA approved in ages 23 years
Children: Oral: Immediate release: Usual reported and adults)
initial dose: 15 to 25 mg/kg/day in 2 to 3 divided Pregnancy Risk Factor C
doses; may increase if needed to a maximum daily Pregnancy Considerations Animal reproduction studies
dose: 100 mg/kg/day or 2,000 mg/day (whichever is have not been conducted.
less); therapy continued until resolution of head- Breastfeeding Considerations Use with caution in
ache, disc swelling, and visual field abnormalities; breastfeeding women.
usually several months (eg, 3 to 9 months) (Dis- Contraindications Hypersensitivity to acetic acid or any
telmaier 2006; Hacifazlioglu 2012; Ko 2010; Per component of the formulation; perforated tympanic mem-
2013; Rangwalla 2007; Soler 1998; Spennato brane
2011; Standridge 2010). Adverse Reactions
Adolescents: Oral: Immediate release: Initial: 500 mg Central nervous system: Localized burning, stinging sen-
twice daily; may increase if needed; maximum daily sation
dose: 4,000 mg/day; usual adult dose range: 1,000 Local: Local irritation
to 4,000 mg/day in 2 to 4 divided doses (Phillips Drug Interactions
2012; Standridge 2010) Metabolism/Transport Effects None known.
_ Renal Impairment: Pediatric There are no dosage Avoid Concomitant Use There are no known interac-
adjustments provided in the manufacturer's labeling; tions where it is recommended to avoid concomitant use.
acetazolamide is contraindicated in severe renal impair-
Increased Effect/Toxicity There are no known signifi-
ment.
cant interactions involving an increase in effect.
Hepatic Impairment: Pediatric All patients: There are
Decreased Effect There are no known significant inter-
no dosage adjustments provided in the manufacturer's
actions involving a decrease in effect.
labeling; however, acetazolamide is contraindicated in
Storage/Stability Store at room temperature at 20°C to
patients with cirrhosis or severe liver impairment.
25°C (68°F to 77°F).
Preparation for Administration Parenteral: Reconsti-
Dosing
tute with at least 5 mL SWFI to provide a solution con-
Pediatric Otitis externa, acute: Children 23 years and
taining not more than 100 mg/mL; maximum
Adolescents: Otic: Insert saturated wick of cotton; keep
concentration: 100 mg/mL
moist 24 hours by adding 3 to 5 drops every 4 to 6 hours;
Administration
remove wick after 24 hours and instill 5 drops 3 to 4
Oral: Administer with food to decrease GI upset; tablet
times daily. Note: In children, 3 to 4 drops may be
may be crushed and suspended in cherry or chocolate
sufficient due to the smaller capacity of the ear canal
syrup to disguise the bitter taste of the drug
Renal Impairment: Pediatric Children 23 years and
Parenteral:
Adolescents: There are no dosing adjustments pro-
IV: Direct IV injection is the preferred parenteral route of
vided in the manufacturer's labeling.
administration. Specific |!V push rates are not provided
in the manufacturer's labeling. Some have recom- Hepatic Impairment: Pediatric Children 23 years and
mended a maximum rate of 500 mg/minute (Gahart Adolescents: There are no dosing adjustments pro-
2014). Additionally, a study in adults to assess cere- vided in the manufacturer's labeling.
brovascular reserve used a rapid IV push of up to 1g Administration Not for internal intake or IV infusion; top-
over $1 minute (Piepgras 1990). ical use or irrigation use only
IM: Not recommended as the drug's alkaline pH makes it Dosage Forms Excipient information presented when
very painful available (limited, particularly for generics); consult spe-
Monitoring Parameters Serum electrolytes, CBC and cific product labeling. [DSC] = Discontinued product
platelet counts; intraocular pressure in glaucoma patients; Solution, Otic:
monitor growth in pediatric patients Generic: 2% (15 mL, 60 mL [DSC])
Test Interactions May cause false-positive results for @ Acetic Acid, Hydrocortisone, and Propylene Glycol
urinary protein with Albustix®, Labstix®, Albutest®, Diacetate see Acetic Acid, Propylene Glycol Diacetate,
Bumintest®; interferes with HPLC theophylline assay and Hydrocortisone on page 47
and serum uric acid levels; may lead to false-negative
aldosterone/renin ratio (ARR) (Funder 2016)
Additional Information Sodium content of 500 mg injec- Acetic Acid, Propylene Glycol Diacetate,
tion: 2.049 mEq and Hydrocortisone
Dosage Forms Excipient information presented when (a SEE tik AS id, PRO pa leen GLY kole dye AS e tate, & hye droe
available (limited, particularly for generics); consult spe- KOR ti sone)
cific product labeling. [DSC] = Discontinued product
Medication Safety Issues
Capsule Extended Release 12 Hour, Oral:
Sound-alike/look-alike issues:
Diamox Sequels: 500 mg [DSC]
VoSol may be confused with Vexol
Generic: 500 mg
Brand Names: US Acetasol HC; VoSolIHC [DSC]
Solution Reconstituted, Injection [preservative free]:
Generic: 500 mg (1 ea) Therapeutic Category Otic Agent, Anti-infective
Tablet, Oral: Generic Availability (US) Yes
Generic: 125 mg, 250 mg Use Treatment of superficial infections of the external
Extemporaneous Preparations A 25 mg/mL oral sus- auditory canal (otitis externa) (FDA approved in ages 23
pension may be made with tablets and either a 1:1 mixture years and adults)
of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora- Contraindications Hypersensitivity to acetic acid, propy-
Sweet® SF and Ora-Plus®. Crush twelve 250 mg tablets lene glycol, hydrocortisone, or any component of the
in a mortar and reduce to a fine powder. Add small formulation; perforated tympanic membrane; herpes sim-
portions of chosen vehicle and mix to a uniform paste; plex; vaccinia, and varicella
mix while adding the vehicle in incremental proportions to Warnings/Precautions Transient stinging or burning may
almost 120 mL; transfer to a calibrated bottle, rinse mortar occur when first used in inflamed ear. Discontinue if
with vehicle, and add quantity of vehicle sufficient to make sensitization or irritation occurs.
120 mL. Label "shake well" and "refrigerate". Stable for 60 Adverse Reactions Otic: Stinging of ear (includes burn-
days (Allen, 1996). When diluted in 120 mL solution of ing sensation; may occasionally occur when first instilled
cherry syrup concentrate diluted 1:4 with simple syrup, NF, into acutely inflamed ear)
it is stable 60 days refrigerated (preferred) or at room Drug Interactions
temperature (Nahata, 2004). Metabolism/Transport Effects Refer to individual
Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopur- components.
inol, Azathioprine, Clonazepam, and Flucytosine in Extemporane- Avoid Concomitant Use
ously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53
(16):1944-9.
Avoid concomitant use of Acetic Acid, Propylene Glycol
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, Sth Diacetate, and Hydrocortisone with any of the following:
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004. Aldesleukin

47
ACETIC ACID, PROPYLENE GLYCOL DIACETATE, AND HYDROCORTISONE

Increased Effect/Toxicity (eg, nausea, vomiting, anorexia) and generalized malaise.

Acetic Acid, Propylene Glycol Diacetate, and Hydrocor- In patients receiving therapy for >2 weeks, monitor hem-
tisone may increase the levels/effects of: Ceritinib; atologic parameters (eg, CBC with reticulocytes) at 3-
Deferasirox; Ritodrine month intervals for the duration of treatment. If the retic-
Decreased Effect ulocyte count exceeds 6%, consider a reduction in the
Acetic Acid, Propylene Glycol Diacetate, and Hydrocor- dosage. Anemia is usually reversible after treatment is
tisone may decrease the levels/effects of: Aldesleukin; discontinued. Use with caution in patients with renal
Corticorelin; Hyaluronidase impairment; close monitoring of renal function is recom-
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). mended and dosage adjustments are recommended. An
Dosing increased incidence of rash has occurred. A nonpruritic,
Pediatric Otitis externa, acute: Children 23 years and macular skin rash has occurred in the upper extremities
Adolescents: Otic: Insert saturated wick of cotton; keep
and on the face of patients on long-term therapy, usually
moist 24 hours by adding 3 to 5 drops every 4 to 6 hours; with concomitant ethanol use. The rash most often occurs
remove wick after 24 hours and instill 5 drops 3 to 4 30 to 45 minutes after ethanol consumption and resolves
times daily. Note: In children, 3 to 4 drops may be spontaneously in 30 to 60 minutes. Patients should limit or
sufficient due to the smaller capacity of the ear canal. avoid alcohol during therapy.
Renal Impairment: Pediatric Children 23 years and Adverse Reactions
Adolescents: There are no dosing adjustments provided Cardiovascular: Deep vein thrombosis (rare), embolism,
in the manufacturer's labeling. flushing, palpitations, phlebitis
Central nervous system: Anxiety, depression, headache,
Hepatic Impairment: Pediatric Children 23 years and
malaise, nervousness
Adolescents: There are no dosing adjustments provided
Dermatologic: Alopecia, macular eruption
in the manufacturer's labeling.
Gastrointestinal: Anorexia, nausea, vomiting
Administration Otic: Not for internal intake; topical use
Hematologic& oncologic: Hemolytic anemia, reticulocy-
only; prior to use, warm suspension by holding bottle in
tosis
hands; shake well before use; patient should lie with
Neuromuscular & skeletal: Tremor
affected ear upward for instillation
Drug Interactions
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
Metabolism/Transport Effects None known.
cific product labeling. [DSC] = Discontinued product Avoid Concomitant Use There are no known interac-
Solution, otic [drops]: Acetic acid 2%, propylene glycol tions where it is recommended to avoid concomitant use.
diacetate 3%, and hydrocortisone 1% (10 mL) Increased Effect/Toxicity
Acetasol HC: Acetic acid 2%, propylene glycol diacetate The levels/effects of Acetohydroxamic Acid may be
3%, and hydrocortisone 1% (10 mL) [contains benze- increased by: Alcohol (Ethyl)
thonium chloride] Decreased Effect There are no known significant inter-
VoSol HC: Acetic acid 2%, propylene glycol diacetate actions involving a decrease in effect.
3%, and hydrocortisone 1% (10 mL [DSC]) [contains Food Interactions Food may decrease absorption of
benzethonium chloride] acetohydroxamic acid. Management: Administer on an
empty stomach, 1 hour before or 2 hours after meals.
Storage/Stability Store between 15°C and 30°C (59°F
Acetohydroxamic Acid and 86°F). Protect from moisture.
(a SEE toe hye droks am ik AS id)
Mechanism of Action Acetohydroxamic acid inhibits
Medication Safety Issues bacterial urease enzymes, decreasing the formation of
Sound-alike/look-alike issues: ammonia in the urine by urea-splitting organisms. A
Lithostat may be confused with Lithobid reduction in urinary ammonia and decreased pH may
Brand Names: US Lithostat increase the activity of some antimicrobial agents.
Brand Names: Canada Lithostat Pharmacodynamics/Kinetics (Adult data unless
Therapeutic Category Urinary Tract Product noted)
Generic Availability (US) No Absorption: Oral: Well absorbed
Half-life elimination: 5-10 hours (increased in patients with
Use Adjunctive therapy in chronic urea-splitting urinary
reduced renal function)
infection (FDA approved in children and adults)
Time to peak: 0.25-1 hour
Pregnancy Risk Factor X
Excretion: Urine (36% to 65% as unchanged drug)
Pregnancy Considerations Adverse effects were
Dosing
observed in animal reproduction studies. Use is contra-
Pediatric Chronic urea-splitting urinary infection;
indicated in pregnant women or women of childbearing
adjunct therapy to decrease urinary ammonia levels
potential who are not using a reliable form of contra-
and alkalinity: Children and Adolescents: Oral: Initial:
ception.
10 mg/kg/day in 2 or 3 divided doses; adjust dose as
Breastfeeding Considerations It is not known if aceto-
needed (higher or lower) for optimum therapeutic effect
hydroxamic acid is excreted in breast milk. Due to the
and minimization of side effects; in adults, usual dose is
potential for serious adverse reactions in the nursing
250 mg/dose (10 to 15 mg/kg/day) and the maximum
infant, a decision should be made whether to discontinue
daily dose: 1,500 mg/day.
nursing or to discontinue the drug, taking into account the
Renal Impairment: Pediatric There are no pediatric
importance of treatment to the mother.
specific recommendations; based on experience in adult
Contraindications Patients whose physical state and
patients, dosing adjustment suggested and for sCr
disease are amenable to definitive surgery and appropri-
>2.5 mg/dL (or CrCl <20 mL/minute), use is contraindi-
ate antimicrobial agents; patients whose urine is infected
cated.
by nonurease-producing organisms; patients whose uri-
Hepatic Impairment: Pediatric There are no dosage
nary infections can be controlled by culture-specific oral
adjustments provided in the manufacturer's labeling.
antimicrobial agents; patients whose renal function is poor
Administration Oral: Administer on an empty stomach, 1
(ie, serum creatinine >2.5 mg/dL and/or creatinine clear-
hour before or 2 hours after meals. Administer 1 hour
ance <20 mL/minute); female patients who do not evi-
dence a satisfactory method of contraception; pregnancy before or 2 hours after taking iron or any product that
contains iron.
Warnings/Precautions Struvite stones, which occur as a
result of urinary tract infections with urea splitting organ-
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
isms, are typically surgically removed. However, in
cific product labeling.
patients who are not candidates for surgical removal or
Tablet, Oral:
in patients at risk for recurrent urinary tract infection with
Lithostat: 250 mg
urease-producing organisms, treatment with acetohy-
droxamic acid may be beneficial (AUA guidelines [Pearle, # Acetoxyl (Can) see Benzoyl Peroxide on page 259
2014]). Acetohydroxamic acid is intended to decrease
@ Acetoxymethylprogesterone see MedroxyPROGES-
urinary ammonia and alkalinity, but it should not be used
TERone on page 1287
in lieu of curative surgical treatment (for patients with
stones) or antimicrobial treatment. Long-term treatment
with acetohydroxamic acid may be warranted to maintain Acetylcysteine (a se teel sis teen)
urease inhibition as long as urea-splitting infection is
present. Experience with acetohydroxamic acid does not Medication Safety Issues
go beyond 7 years. Acetohydroxamic acid may suppress Sound-alike/look-alike issues:
bone marrow function or cause hepatic injury. Close Acetylcysteine may be confused with acetylcholine
monitoring of hematologic and hepatic function is recom- Mucomyst may be confused with Mucinex
mended. Use caution in patients with anemia; has been Related Information
associated with hemolytic anemia (Coombs' negative), Acetaminophen Serum Level Nomogram on page 2198
which may be associated with gastrointestinal distress Brand Names: US Acetadote; Cetylev

48
 ACETYLCYSTEINE

Brand Names: Canada Acetylcysteine Injection; Acetyl- carefully restarted. Treatment for anaphylactoid reac-
cysteine Solution; Mucomyst; Parvolex tions should be immediately available. Use caution in
Therapeutic Category Antidote, Acetaminophen; Muco- patients with asthma or history of bronchospasm as
lytic Agent \ these patients may be at increased risk. Conversely,
Generic Availability (US) Yes; excludes effervescent patients with high acetaminophen concentrations
tablet. (>150 mg/L) may be at a reduced risk for anaphylactoid
Use reactions (Pakravan 2008; Sandilands 2009; War-
Inhalation: Adjunctive therapy in patients with abnormal, ing 2008).
viscid, or inspissated mucous secretions in conditions Acute acetaminophen overdose: Acetylcysteine is indi-
such as chronic bronchopulmonary diseases (chronic cated in patients with a serum acetaminophen concen-
emphysema, emphysema with bronchitis, chronic asth- tration that indicates they are at "possible" risk or greater
matic bronchitis, tuberculosis, bronchiectasis, primary for hepatotoxicity when plotted on the Rumack-Matthew
amyloidosis of the lung); acute pulmonary diseases nomogram. There are several situations where the
(pneumonia, bronchitis, tracheobronchitis); pulmonary nomogram is of limited use. Serum acetaminophen
.complications of cystic fibrosis; tracheostomy care; pul- concentrations obtained <4 hours postingestion are not
monary complications associated with surgery; use dur- reliable, except to document the presence of acetamino-
ing anesthesia; post-traumatic chest conditions; phen (Seifert 2015). Patients presenting late may have
atelectasis due to mucous obstruction; diagnostic bron- undetectable serum concentrations, despite having
chial studies (bronchograms, bronchospirometry, bron- received a toxic dose. The nomogram is less predictive
chial wedge catheterization (All indications: FDA of hepatic injury following an acute overdose with an
approved in pediatric patients [age not specified] and extended release acetaminophen product. The nomo-
adults) gram also does not take into account patients who may
Injection, Oral: Antidote for acetaminophen toxicity to be at higher risk of acetaminophen toxicity (eg, alco-
prevent or lessen hepatic injury after ingestion of a holics, malnourished patients, concurrent use of
potentially hepatotoxic quantity of acetaminophen in CYP2E1 enzyme-inducing agents [eg, isoniazid]).
patients with acute ingestion or from repeated supra- Nevertheless, acetylcysteine should be administered to
therapeutic ingestion (RSTI) (FDA approved in pediatric any patient with signs of hepatotoxicity, even if the serum
patients [age not specified] and adults) acetaminophen concentration is low or undetectable.
Has also been used orally and rectally to treat distal Patients who present >24 hours after an acute ingestion
intestinal obstruction syndrome (previously known as or patients who present following an acute ingestion at
“meconium ileus or its equivalent") an unknown time may be candidates for acetylcysteine
Pregnancy Considerations Adverse events have not therapy; consultation with a poison control center or
been observed in animal reproduction studies. Based on Clinical toxicologist is highly recommended.
limited reports using acetylcysteine to treat acetamino- Repeated supratherapeutic ingestion (RSTI) of acetami-
phen overdose in pregnant women, acetylcysteine has nophen: The Rumack-Matthew nomogram is not
been shown to cross the placenta and may provide designed to be used following RSTls. In general, an
protective concentrations in the fetus. accurate past medical history, including a comprehen-
sive acetaminophen ingestion history, in conjunction with
Acetylcysteine may be used to treat acetaminophen over- AST concentrations and serum acetaminophen concen-
dose in during pregnancy (Wilkes 2005). In general, trations, may give the clinician insight as to the patient's
medications used as antidotes should take into consid- tisk of acetaminophen toxicity. Some experts recom-
eration the health and prognosis of the mother; antidotes mend that acetylcysteine be administered to any patient
should be administered to pregnant women if there is a with "higher than expected" serum acetaminophen con-
clear indication for use and should not be withheld centrations or serum acetaminophen concentration >10
because of fears of teratogenicity (Bailey 2003). mcg/mL, even in the absence of hepatic injury; others
Breastfeeding Considerations It is not known if acetyl- recommend treatment for patients with laboratory evi-
cysteine is excreted in breast milk. According to the dence and/or signs and symptoms of hepatotoxicity
manufacturer, the decision to continue or discontinue (Hendrickson 2006; Jones 2000). Consultation with a
breastfeeding during therapy should take into account poison control center or a clinical toxicologist is highly
the risk of infant exposure, the benefits of breastfeeding recommended.
to the infant, and benefits of treatment to the mother. Adverse Reactions
Based on pharmacokinetics, acetylcysteine should be Intravenous:
nearly completely cleared 30 hours after administration; Cardiovascular: Edema, flushing, tachycardia
breastfeeding women may consider pumping and discard- Dermatologic: Rash, pruritus, urticaria
ing breast milk for 30 hours after administration. Gastrointestinal: Nausea, vomiting
Contraindications Immunologic: Autoimmune disease
Hypersensitivity to acetylcysteine or any component of the Respiratory: Pharyngitis, rhinorrhea, rhonchi, throat
formulation. tightness
Effervescent tablet (Cetylev): There are no contraindica- Miscellaneous: Anaphylactoid reaction
tions listed in the manufacturer's labeling. Rare but important or life-threatening: Anaphylaxis,
Warnings/Precautions angioedema, bronchospasm, chest tightness, cough,
Inhalation: Since increased bronchial secretions may dizziness (Sandilands 2008), dyspnea (Sandilands
' develop after inhalation, percussion, postural drainage, 2008), hypotension, respiratory distress, stridor,
and suctioning should follow. If bronchospasm occurs, wheezing
administer a bronchodilator; discontinue acetylcysteine if
bronchospasm progresses. Oral:
!V: IV administration can cause’ fluid overload, potentially Cardiovascular: Chest tightness, hypotension (Bebarta
resulting in hyponatremia, seizure and death. To avoid 2010; Sandilands 2009)
fluid overload in patients <40 kg and those requiring fluid Dermatologic: Rash (with or without fever), urticaria
restriction, decrease volume of diluent proportionally Gastrointestinal: Gastrointestinal symptoms, nausea,
(see table in dosing section). vomiting
Oral: Oral administration of acetylcysteine may result in Hypersensitivity: Hypersensitivity reaction
nausea and vomiting, which may exacerbate vomiting Respiratory: Bronchitis, bronchospasm
associated with acetaminophen overdose. Therefore, Rare but important or life-threatening: Angioedema
patients at risk of gastrointestinal hemorrhage (eg, (Bebarta 2010), tachycardia (Bebarta 2010)
esophageal varices, peptic ulcer) may experience an Drug Interactions
even higher risk of gastrointestinal hemorrhage during Metabolism/Transport Effects None known.
therapy. Effervescent tablets (Cetylev) contain sodium; Avoid Concomitant Use There are no known interac-
consider acetylcysteine treatment as a source of sodium tions where it is recommended to avoid concomitant use.
in patients who may be sensitive to excess sodium Increased Effect/Toxicity There are no known signifi-
intake (eg, heart failure, hypertension, renal impairment). cant interactions involving an increase in effect.
Anaphylactoid reactions: Acute flushing and erythema Decreased Effect There are no known significant inter-
have been reported; usually occurs within 30 to 60 actions involving a decrease in effect.
minutes and may resolve spontaneously. Serious ana- Storage/Stability
phylactoid reactions (some fatal) have also been Effervescent tablets (Cetylev): Store at 20°C to 25°C
reported and are more commonly associated with IV (68°F to 77°F); excursions permitted to 15°C to 30°C
administration, but may also occur with oral administra- (59°F to 86°F). Protect from moisture. Following disso-
tion (Mroz 1997). When used for acetaminophen over- lution in water, the solution should be used within 2
dose, the incidence is reduced when the initial loading hours.
dose is administered over 60 minutes. The acetylcys- Solution for inhalation/oral administration: Store unopened
teine infusion may be interrupted until treatment of vials at room temperature; once opened, store under
allergic symptoms is initiated; the infusion can then be refrigeration and use within 96 hours. A color change
ACETYLCYSTEINE

may occur in opened vials (light purple) and does not Pediatric
affect the safety or efficacy. Acetaminophen poisoning: Infants, Children, and
Solution for injection (Acetadote): Store intact vials at Adolescents: Only the 72-hour oral and 21-hour IV
20°C to 25°C (68°F to 77°F). Following reconstitution, regimens are FDA approved. Ideally, in patients with
solution is stable for 24 hours at room temperature. A an acute acetaminophen ingestion, treatment should
color change may occur in opened vials (light pink or begin within 8 hours of ingestion or as soon as
purple) and does not affect the safety or efficacy. Discard possible after ingestion. In patients with a suspected
unused portion. acute ingestion where the time of ingestion is
Mechanism of Action unknown, the serum acetaminophen concentration
Acetaminophen overdose: Acetylcysteine acts as a hep- is unobtainable or uninterpretable within 8 hours of
atoprotective agent by restoring hepatic glutathione,
ingestion, the patient presents >8 hours after inges-
serving as a glutathione substitute, and enhancing the
tion, or there is clinical evidence of toxicity, initiate
nontoxic sulfate conjugation of acetaminophen.
treatment immediately and re-evaluate the need for
Mucolytic: Exerts mucolytic action through its free sulf-
acetylcysteine upon receipt of the results (if applica-
hydryl group which opens up the disulfide bonds in the
mucoproteins thus lowering mucous viscosity. ble). In patients who present following repeated
Pharmacodynamics/Kinetics (Adult data unless supratherapeutic ingestions (RSTI) and treatment is
deemed appropriate, acetylcysteine should be initi-
noted)
Onset of action: Inhalation: 5 to 10 minutes ated immediately. Regardless of the treatment regi-
Duration: Inhalation: >1 hour men selected, serum acetaminophen concentrations,
Distribution: Vgss: 0.47 L/kg liver function, and clinical status should be evaluated
Protein binding: 66% to 87% during and prior to the end of the treatment regimen to
Metabolism: Undergoes extensive first pass metabolism determine if treatment discontinuation is appropriate.
to form cysteine and disulfides (N,N-diacetylcysteine and In-patients.who continue to experience symptoms of
N-acetylcysteine); cysteine is further metabolized to form hepatotoxicity or elevated liver function tests at the
glutathione and other metabolites conclusion of a 72-hour oral or 21-hour IV regimen,
Half-life elimination: extending the treatment course may be appropriate;
Reduced acetylcysteine: 2 hours however, when and to which patients additional doses
Total acetylcysteine: Adults: 5.6 hours; Newborns: 11 should be administered is unclear. Possible candi-
hours dates for extended therapy include patients with a
Effervescent tablets: Terminal half-life: 18.1 hours suspected massive overdose, concomitant ingestion
Time to peak, plasma: Oral solution: 1 to 2 hours; Effer- of other substances, or patients with preexisting liver
vescent tablets: 1 to 3.5 hours (median: 2 hours) disease. In patients with persistently elevated acet-
Excretion: Urine (13% to 38%) aminophen concentrations, persistently elevated liver
Dosing function tests, or an elevated INR, additional acetyl-
Neonatal Acetaminophen poisoning: Limited data cysteine should be administered. Typically, an addi-
available in patients <5 kg: Neonatal experience consists tional "third dose" or "third bag" (IV: 100 mg/kg
of several case reports and dosing utilized was based on
[maximum dose: 10 g/dose] infused over 16 hours)
suggested dosing for pediatric patients >5 kg (Aw 1999;
is administered; however, this dose may be inad-
Bucaretchi 2014; de la Pintiere 2003; Isbister 2001;
equate in some patients (Rumack 2012), Consultation
Nevin 2010; Walls 2007); the youngest patient reported
with a poison control center or clinical toxicologist is
to receive acetylcysteine for acetaminophen overdose
was a neonate with GA 27 week, birthweight:
highly recommended to determine optimal patient
750 grams, and PNA 7 days at time of treatment (Brener care.
2013). Consultation with a poison control center or Oral: Effervescent tablet (Cetylev) or solution for oral
clinical toxicologist is highly recommended to determine administration (using injectable/nebulizer formula-
optimal patient care. tion): There is no data for use of the OTC supple-
ment tablets for acetaminophen poisoning. Dosing
Only the 72-hour oral and 21-hour IV regimens are FDA below is based on effervescent tablet (Cetylev) or a
approved. Ideally, in patients with an acute acetamino- solution for oral administration that is prepared from
phen ingestion, treatment should begin within 8 hours of
the solution for oral inhalation: 72-hour regimen:
ingestion or as soon as possible after ingestion. In
Consists of 18 doses; total dose delivered:
patients with a suspected acute ingestion where the time
1,330 mg/kg
of ingestion is unknown, the serum acetaminophen con-
Loading dose: 140 mg/kg; maximum dose: 15
centration is unobtainableor uninterpretable within 8
hours of ingestion, the patient presents >8 hours after g/dose
ingestion, or there is clinical evidence of toxicity, initiate Maintenance dose: 70 mg/kg every 4 hours for 17
treatment immediately and re-evaluate the need for doses; maximum dose: 7.5 g/dose; repeat dose if
acetylcysteine upon receipt of the results (if applicable). emesis occurs within 1 hour of administration;
In patients who present following repeated suprathera- Note: Consultation with a poison control center
peutic ingestions (RSTI) and treatment is deemed appro- or clinical toxicologist is highly recommended when
priate, acetylcysteine should be initiated immediately. considering the discontinuation of oral acetylcys-
Serum acetaminophen concentrations, liver function, teine prior to the conclusion of a full 18-dose
and clinical status should be evaluated during and prior course of therapy.
to the end of the treatment regimen to determine if IV (Acetadote): 21-hour regimen: Consists of 3 doses;
treatment discontinuation is appropriate. Based on expe- total dose delivered: 300 mg/kg
rience in older patients, patients who continue to expe- Loading dose: 150 mg/kg infused over 60 minutes;
rience symptoms of hepatotoxicity or elevated liver maximum dose: 15 g/dose
function tests at the conclusion of a 21-hour IV regimen, Second dose: 50 mg/kg infused over 4 hours; max-
extending the treatment course may be appropriate; imum dose: 5 g/dose
however, when and to which patients additional doses Third dose: 100 mg/kg infused over 16 hours; max-
should be administered is unclear. Possible candidates imum dose: 10 g/dose
for extended therapy include patients with a suspected Respiratory conditions, adjuvant therapy: Note:
massive overdose, concomitant ingestion of other sub-
Patients should receive an aerosolized bronchodilator
stances, or patients with preexisting liver disease. In
10 to 15 minutes prior to acetylcysteine:
patients with persistently elevated acetaminophen con-
Nebulized inhalation:
centrations, persistently elevated liver function tests, or
Face mask, mouth piece, tracheostomy:
an elevated INR, additional acetylcysteine administration
should be considered. Typically, an additional "third Infants: 1 to 2 mL of 20% solution (may be further
dose" or "third bag" (IV: 100 mg/kg infused over 16 diluted with sodium chloride or sterile water for
hours) is administered; however, this dose may be inhalation) or 2 to 4 mL of 10% solution (undi-
inadequate in some patients (Rumack 2012); neonatal luted); administer 3 to 4 times daily
experience describing administration of a "third bag" is Children: 3 to 5 mL of 20% solution (may be further
lacking. Consultation with a poison control center or diluted with sodium chloride or sterile water for
clinical toxicologist recommended. inhalation) or 6 to 10 mL of 10% solution (undi-
luted); administer 3 to 4 times daily
IV (Acetadote): 21-hour regimen: Consists of 3 doses;
Adolescents: 3 to 5 mL of 20% solution (may be
total dose delivered: 300 mg/kg
further diluted with sodium chloride or sterile
Loading dose: 150 mg/kg infused over 60 minutes water for inhalation) or 6 to 10 mL of 10% solution
(undiluted); administer 3 to 4 times daily; usual
Second dose: 50 mg/kg infused over 4 hours
dosing range: 20% solution: 1 to 10 mL or 10%
Third dose: 100 mg/kg infused over 16 hours solution: 2 to 20 mL every 2 to 6 hours

50
 ACETYLCYSTEINE

- Tent, croupette: 10% or 20% solution: Dose must be Osmolarity in

Acetadote Osmolarity in |Osmolarity in
individualized; dose is volume of solution neces- Concentration 12NS D5w Sterile Water
sary to maintain a very heavy mist in tent or for Injection
croupette; in some cases, may require up to 300 7 mg/mL 245 mOsmol/L |343 mOsmol/L 91 mOsmol/L
mL solution/treatment
Direct instillation: Children and Adolescents: 24 mg/mL 466 mOsmol/L |564 mOsmol/L 312 mOsmol/L
Endotracheal: 1 to 2 mL of 10% to 20% solution
every 1 to 4 hours as needed Solution for inhalation: The 20% solution may be diluted
Percutaneous endotracheal catheter: 1 to 2 mL of with sodium chloride or sterile water; the 10% solution
20% or 2 to 4 mL of 10% solution every 1 to 4 may be used undiluted.
hours via syringe attached to catheter Rectal: Dilute the inhalation solution in NS to the desired
Diagnostic bronchogram: Children and Adolescents: final concentration of 4 to 6%; may also be given
Nebulization or endotracheal: 1 to 2 mL of 20% undiluted (Mascarenhas 2003; Perman 1975)
solution or 2 to 4 mL of 10% solution administered 2 Administration
to 3 times prior to procedure Oral: Differs based on use.
Distal intestinal obstruction syndrome (previously Acetaminophen poisoning:
known as meconium ileus equivalent): Limited Effervescent tablets (Cetylev): Use within 2 hours of
data available; dosing regimens variable (polyethy- preparation. If the patient vomits within 1 hour of
lene glycol has become more widely used for this administration, repeat that dose. If the patient is
indication): persistently unable to retain the orally administered
Oral: acetylcysteine, acetylcysteine may be administered
Children <10 years: 30 mL of 10% solution diluted in by nasoduodenal tube.
30 mL juice or soda 3 times/day for 24 hours Solution for oral administration: Administer as a 5%
Children 10 years and Adolescents: 60 mL of 10% solution (see Preparation for Administration); use
solution diluted in 60 mL juice or soda 3 times/day within 1 hour of preparation. If patient vomits within
for 24 hours 1 hour of dose, readminister. Note: The unpleasant
Note: Prior to treatment, administer a phosphosoda odor (sulfur-like) becomes less noticeable as treat-
enema. A clear liquid diet should be used during ment progresses. It is helpful to put the acetylcysteine
the 24-hour acetylcysteine treatment on ice, in a cup with a cover, and drink through a
Rectal enema: Children: Varying dosages; 100 to 300 straw; alternatively, administer via an NG tube.
mL of 4% to 6% solution 2 to 4 times daily; 50 mL of Parenteral: Acetaminophen poisoning: |V (Acetadote):
20% solution 1 to 4 times daily and 5 to 30 mL of Loading dose: Administer lV over 60 minutes
10% to 20% solution 3 to 4 times daily have been
Second dose: Administer IV over 4 hours
used; rectal enemas appear to have less favorable
Third dose: Administer IV over 16 hours
results than oral administration (Mascarenhas
Inhalation solution: May be administered by nebulization
2003). Note: Higher concentrations (10% to 20%)
either undiluted (both 10% and 20%) or diluted in NS
appear to increase fluid in the bowel and lead to
Rectal: Inhalation solution may be given undiluted (10% to
increased incidence of adverse effects (Per-
20%) or diluted to 4% to 6% solution and administer
man 1975)
rectally (Mascarenhas 2003; Perman 1975)
Renal Impairment: Pediatric There are no dosage
Monitoring Parameters
adjustments provided in the manufacturer's labeling.
Acetaminophen poisoning: Monitor patient for the devel-
Hepatic Impairment: Pediatric There are no dosage
opment of anaphylaxis or anaphylactoid reactions; mon-
adjustments provided in the manufacturer's labeling.
itor serum acetaminophen concentrations, AST, ALT,
Preparation for Administration
bilirubin, PT, INR, serum creatinine, BUN, serum glu-
Oral: Acetaminophen poisoning:
cose, hemoglobin, hematocrit, and electrolytes. Assess
Effervescent tablets (Cetylev): Dissolve the effervescent
patient for nausea, vomiting, and skin rash following oral
tablets in the appropriate volume of water based upon
administration. Reassess LFTs for possible hepatotox-
patient weight; use within 2 hours of preparation
icity every 4 to 6 hours. An early elevation in the INR may
1 to <20 kg: Prepare a 50 mg/mL solution by dissolving
be related to acetylcysteine therapy (Schmidt 2002).
two 2.5 g tablets in 100 mL of water; determine
volume for the calculated dose and administer; dis- Acute ingestion: Obtain the first acetaminophen concen-
card any remaining solution tration 4 hours postingestion (or as soon as possible
20 to <60 kg: Dissolve an appropriate number of tablets thereafter); plot on the Rumack-Matthew nomogram. In
(2.5 or 5 g tablets in any combination) to deliver the patients who have ingested an extended release formu-
calculated dose in 150 mL of water lation of acetaminophen or have coingested an agent
260 kg: Dissolve an appropriate number of tablets (2.5 known to delay gastric emptying, obtain a repeat serum
or 5g tablets in any combination) to deliver the acetaminophen measurement 4 to 6 hours following the
calculated dose in 300 mL of water first measurement if the original concentration (taken at 4
Solution for oral administration using the inhalation/ to 8 hours postingestion) when plotted on the Rumack-
injectable solution: Dilute the 20% solution 1:3 with a Matthew nomogram indicated that treatment was not
cola, orange juice,or other soft drink to'prepare a 5% necessary.
solution. Use within 1 hour of preparation. Dosage Forms Excipient information presented when
Parenteral: !V (Acetadote): Acetaminophen poisoning: available (limited, particularly for generics); consult spe-
Note: Volume of diluent based on weight; compatible cific product labeling.
diluents include D5W, 1/2NS, SWFI: Injection, solution [preservative free]: 20% (30 mL)
Patient weight 5 to 20 kg: Dilute dose in the following Acetadote: 20% [200 mg/mL] (30 mL)
volumes of compatible diluents: Solution, for inhalation/oral: 10% [100 mg/mL] (10 mL, 30
Loading dose: 3 mL/kg mL); 20% [200 mg/mL] (10 mL, 30 mL)
Second dose: 7 mL/kg Solution, for inhalation/oral [preservative free]: 10%
Third dose: 14 mL/kg [100 mg/mL] (4 mL, 10 mL, 30 mL); 20% [200 mg/mL]
Patient weight 21 to 40 kg: Dilute dose in the following (4 mL, 10 mL, 30 mL)
volumes of compatible diluents: Tablet Effervescent, Oral:
Loading dose: 100 mL Cetylev: 500 mg, 2.5 g [contains edetate disodium;
Second dose: 250 mL lemon mint flavor]
Third dose: 500 mL
Patient weight: 41 to 100 kg: Dilute dose in the following @ Acetyicysteine Injection (Can) see Acetylcysteine
volumes of compatible diluents. In patients requiring on page 48
fluid restriction, decrease diluent volume by 50%. @ Acetylcysteine Sodium see Acetylcysteine on page 48
Loading dose: 200 mL @ Acetylcysteine Solution (Can) see Acetylcysteine
Second dose: 500 mL - on page 48
Third dose: 1,000 mL
Undiluted injection, solution (Acetadote) is hyperosmolar @ Acetylsalicylic Acid see Aspirin on page 194
(2,600 mOsmol/L); when the diluent volume is @ ACH-Montelukast (Can) see Montelukast on page 1399
decreased for patients <40 kg or requiring fluid restric- @ Achromycin see Tetracycline (Systemic) on page 1925
tion, the osmolarity of the solution may remain higher
@ ACH-Temozolomide (Can) see Temozolomide
than desirable for intravenous infusion. To ensure tol-
on page 1905
erance of the infusion, osmolarity should be adjusted to
a physiologically safe level (eg, 2150 mOsmol/L in @ Aciclovir see Acyclovir (Systemic) on page 53
children). @ Aciclovir see Acyclovir (Topical) on page 57
@ Acid Control (Can) see Famotidine on page 826
® Acidophilus/Bulgaricus see Lactobacillus
on page 1166

51
ACRIVASTINE AND PSEUDOEPHEDRINE

@ Acidoph/L.Bulg/Bif.B/S.Thermop see Lactobacillus Oxatomide; Oxomemazine; Paraldehyde; Potassium

on page 1166 Chloride; Potassium Citrate; Thalidomide; Tiotropium;

perishes Spade areal pcr Increased Effectoxicity Increased risk of hyperten

@ Rela Re Gutcer Ted sey ane Cie 0 ReGen sive crisis when acrivastine and pseudoephedrine are
@ Acid Reducer (Can) see RaNITidine on page 1742 given with MAO inhibitors or sympathomimetics.
Acid Reducer Maximum Strength [OTC] see Famoti- Increased risk of.severe CNS depression when given
dine on page 826 with CNS depressants and ethanol. }
@ Acidulated Phosphate Fluoride see Fluoride Decreased Effect Decreased effect of guanethidine,
on page 886 reserpine, methyldopa, and beta-blockers when given
* Roch RABE fer 1735 in conjunction with acrivastine and pseudoephedrine.
ie oak’ PERS SE RAOe Storage/Stability Store at 15°C to 25°C (59°F to 77°F) in
@ AcipHex Sprinkle see RABEprazole on page 1735 a dry place. Protect from light.
@ Aclovate [DSC] see Alclometasone on page 75 Mechanism of Action Refer to Pseudoephedrine; acri-
Acne-Clear [OTC] see Benzoyl Peroxide on page 259 vastine is an analogue of triprolidine and it is considered to
be relatively less sedating than traditional antihistamines;
@ AcneFree Acne Clearing System [OTC] see Benzoyl
believed to involve competitive blockade of H,-receptor
Peroxide on page 259
sites resulting in the inability of histamine to combine with
AcneFree Severe Clearing Syst [OTC] see Benzoyl its receptor sites and exert its usual effects on target cells
Peroxide on page 259 Pharmacodynamics/Kinetics (Adult data unless
@ Acne Medication [OTC] [DSC] see Benzoyl Peroxide noted)
on page 259 Pseudoephedrine: See Pseudoephedrine.
¢@ Acne Medication 5 [OTC] see Benzoyl Peroxide Acrivastine: ;
on page 259 Absorption: Rapidly absorbed
Distribution: ~0.5-0.8 L/kg
@ Acne Medication 10 [OTC] see Benzoyl Peroxide Protein binding: ~50% primarily to albumin
Ch Paden 2o8 Metabolism: Minimally hepatic
eee Half-life elimination: ~2-4 hours
Acrivastine and Pseudoephedrine Acrivastine propionic acid metabolite (active): ~4 hours
(AK ri vas teen & soo doe e FED rin) Time to peak: ~1.1 hours
Medication Safety Issues pide’
7 .
Urine
7
(84%);
of).
feces (13%)
9

International issues:
Pediatric Seasonal allergic rhinitis: Children 212 years
Benadryl! international brand name for acrivastine and
and Adolescents: Oral: Acrivastine 8 mg/pseudoephe-
pseudoephedrine [Great Britain], but also the brand
drine 60 mg per capsule: One capsule every 4 to 6
name for cetirizine [Great Britain, Phillipines] and sev-
hours; maximum daily dose: 4 doses/24 hours
eral products containing diphenhydramine [U.S., Can-
Renal Impairment: Pediatric Children 212 years and
ada]
Adolescents: Clearance of acrivastine, propionic acid
Brand Names: US Semprex®-D
metabolite (active) and pseudoephedrine is prolonged
Therapeutic Category Antihistamine in mild to severe renal impairment (CrCl <48 mL/minute);
Generic Availability
: (US) No ‘ ; avoid use.
Use Temporary relief of symptoms associated with sea- Hepatic Impairment: Pediatric There are no dosage
sonal Mie rhinitis (FDA approved in ages 212 years adjustments recommended in manufacturer's labeling.
and adults Administration Oral: May take with or without food
Pregnancy Risk Factor B Test Interactions Pseudoephedrine: Interferes with urine
Pregnancy Considerations Teratogenic effects were not detection of amphetamine (false-positive)
observed in animal reproduction studies with this combi-
Dosage Forms Excipient information presented when
nation; therefore, the manufacturer classifies acrivastine/
available (limited, particularly for generics); consult spe-
pseudoephedrine as pregnancy category B. The use of
cific product labeling.
antihistamines for the treatment of rhinitis during preg-
Capsule, Oral:
nancy is generally considered to be safe at recommended Semprex®-D: Acrivastine 8 mg and pseudoephedrine
doses. Information related to the use of acrivastine during
hydrochloride 60 mg
pregnancy is limited; therefore, other agents are preferred.
Also refer to the Pseudoephedrine monograph for addi- @ Act [OTC] see Fluoride on page 886
tional information. @ ACT-D see DACTINomycin on page 558
Breastfeeding Considerations It is not known if acri- ae ;
vastine is excreted into breast milk. According to the #) ACT-Amlodipine (Can) see AmLODIPine onipage”120
manufacturer, the decision to continue or discontinue ACT Citalopram (Can) see Citalopram on page 467
ee ay ri ne a @ ACT Diltiazem CD (Can) see DilTIAZem on page 643
uct should take into account the risk of exposure to the A d
infant and the benefits of treatment to the frather Pseu- o ACT, DildazemiT <Cab)\see, DN izere onimetemeas
doephedrine is excreted into breast milk; refer to the @ Actemra see Tocilizumab on page 1967
Pseudoephedrine monograph for additional information. @ ACT Escitalopram (Can) see Escitalopram on page 769
Contraindications Hypersensitivity to pseudoephedrine, @ ACT Etidronate (Can) see Etidronate on page 798
acrivastine, other alkylamine antihistamines such as chlor-
pheniramine, or any component of the formulation; use MAMET Mabe \Comtgomorin| oppagege 7
with or within 14 days of MAO inhibitors; severe hyper- ® Acthar see Corticotropin on page 517
tension, severe coronary artery disease @ ActHIB see Haemophilus b Conjugate Vaccine
Warnings/Precautions Use with caution in patients >60 on page 972
years of age. Use with caution in patients with high blood Acticlate see Doxycycline on page 695
pressure, ischemic heart disease, diabetes, increased
intraocular pressure, GI or GU obstruction, asthma, thy- # Actidose-Aqua [OTC] see Charcoal, Activated
roid disease, or prostatic hyperplasia. Not recommended on page 413
for use in children. @ Actidose/Sorbitol [OTC] see Charcoal, Activated
Adverse Reactions Also refer to Pseudoephedrine on page 413
monograph. @ Actigall see Ursodiol on page 2020
Central nervous system: Dizziness, drowsiness, head- @ Actinomycin see DACTINomycin on page 558
ache, insomnia, nervousness
Gastrointestinal: Dyspepsia, xerostomia @ Actinomycin D see DACTINomycin on page 558
Genitourinary: Dysmenorrhea @ Actinomycin Cl see DACTINomycin on page 558
Baath yeaa a Ree | @ Actiq see FentaNYL on page 837
are but important or life-threatening: Anaphylaxis, F
angioedema, bronchospasm, erythema multiforme + “Activa oo se sdaee
Drug Interactions @ Activase rt-PA (Can) see Alteplase on page 96
Metabolism/Transport Effects None known. @ Activated Carbon see Charcoal, Activated on page 413
Avoid Concomitant Use @ Activated Charcoal see Charcoal, Activated
Avoid concomitant use of Acrivastine and Pseudoephe- on page 413
drine with any of the following: Aclidinium; Azelastine
(Nasal); Bromperidol: Cimetropium: Eluxadoline: Ergot Activated Dimethicone see Simethicone on page 1825
Derivatives; Glycopyrrolate (Oral Inhalation); loben- @ Activated Ergosterol see Ergocalciferol on page 759
guane| 123; Ipratropium (Oral Inhalation); Levosulpiride; @ Activated Factor XIII see Factor XIIl Concentrate
Monoamine Oxidase Inhibitors; Orphenadrine; (Human) on page 824

52
4 ACYCLOVIR (SYSTEMIC)

@ Activated Methylpolysiloxane see Simethicone number of birth defects with exposure to acyclovir when
on page 1825 compared to those expected in the general population.
@ Activated PCC see Anti-inhibitor Coagulant Complex However, due to the small size of the registry and lack of
(Human) on page 161 long-term data, the manufacturer recommends using dur-
@ Active-Cyclobenzaprine see Cyclobenzaprine ing pregnancy with caution and only when clearly needed.
on page 529 Acyclovir is recommended for the treatment of genital
herpes in pregnant women (CDC [Workowski 2015]).
@ Active Injection D see Dexamethasone (Systemic)
Breastfeeding Considerations Acyclovir is excreted in
on page 598
breast milk. The manufacturer recommends that caution
@ Active-Tramadol see TraMADol on page 1984 be exercised when administering acyclovir to nursing
@ Act Kids [OTC] see Fluoride on page 886 women. Limited data suggest exposure to the nursing
@ ACT Latanoprost (Can) see Latanoprost on page 1184 infant of ~0.3 mg/kg/day following oral administration of
acyclovir to the mother. Acyclovir may be used for the
@ ACT-Moxifloxacin (Can) see Moxifloxacin (Ophthalmic)
treatment of genital herpes in breastfeeding women (CDC
on page 1411
[Workowski 2015]). Breast feeding mothers with herpetic
@ ACT Olanzapine (Can) see OLANZapine on page 1485 lesions near or on the breast should avoid breastfeeding
@ ACT Olanzapine ODT (Can) see OLANZapine (Gartner 2005).
on page 1485 Contraindications Hypersensitivity to acyclovir, valacy-
@ ACT Ondansetron (Can) see Ondansetron clovir, or any component of the formulation
on.page 1502 Warnings/Precautions Neurotoxicity (eg, tremor/myo-
@ ACT Oxycodone CR (Can) see OxyCODONE clonus, confusion, agitation, lethargy, hallucination,
on page 1522 impaired consciousness) has been reported; risk may be
@ ACT Ranitidine (Can) see RaNITldine on page 1742 increased with higher doses and in patients with renal
failure. Monitor patients for signs/symptoms of neurotox-
@ Act Restoring [OTC] see Fluoride on page 886 icity; ensure appropriate dosage reductions in patients
¢@ ACT-Rosuvastatin (Can) see Rosuvastatin with renal impairment (Chowdhury 2016). Use with cau-
on page 1789 tion in immunocompromised patients; thrombotic micro-
@ ACT Temozolomide (Can) see Temozolomide angiopathy has been reported. Use caution in the elderly
on page 1905 or preexisting renal disease (may require dosage mod-
@ Act Total Care [OTC] see Fluoride on page 886 ification). Renal failure (sometimes fatal) has been
reported. Maintain adequate hydration during oral or IV
@ Act Total Care Dry Mouth [OTC] see Fluoride
therapy. Use IV preparation with caution in patients with
on page 886 :
underlying neurologic abnormalities, serious hepatic or
¢ Act Total Care Sensitive [OTC] see Fluoride electrolyte abnormalities, or substantial hypoxia. Ence-
on page 886 phalopathic changes characterized by lethargy, obtunda-
@ Acular see Ketorolac (Ophthalmic) on page 1159 tion, confusion, hallucination, tremors, agitation, seizure,
@ Acular LS see Ketorolac (Ophthalmic) on page 1159 or coma have been observed in patients receiving IV
¢ Acuvail see Ketorolac (Ophthalmic) on page 1159 acyclovir. Acyclovir IV is an irritant (depending on concen-
tration); avoid extravasation. Potentially significant drug-
@ ACV see Acyclovir (Systemic) on page 53 drug interactions may exist, requiring dose or frequency
@ ACV see Acyclovir (Topical) on page 57 adjustment, additional monitoring, and/or selection of
@ Acycloguanosine see Acyclovir (Systemic) on page 53 alternative therapy.
@ Acycloguanosine see Acyclovir (Topical) on page 57 Varicella: For maximum benefit, treatment should begin
within 24 hours of appearance of rash; oral route not
Acyclovir (Systemic) (ay sYE kloe veer) recommended for routine use in otherwise healthy chil-
dren with varicella but may be effective in patients at
Medication Safety Issues increased risk of moderate to severe infection (>12 years
Sound-alike/look-alike issues: of age, chronic cutaneous or pulmonary disorders, long-
Acyclovir may be confused with famciclovir, ganciclovir, term salicylate therapy, corticosteroid therapy).
Retrovir, valacyclovir, valganciclovir Warnings: Additional Pediatric Considerations Acy-
Zovirax may be confused with Doribax, Valtrex, Zithro- clovir can cause intrarenal obstructive nephropathy, inter-
max, Zostrix, Zyloprim, Zyvox stitial nephritis, and tubular necrosis resulting in significant
Related Information renal insufficiency. In one study, 35% (131/373 courses) in
Oral Medications That Should Not Be Crushed or Altered 371 pediatric patients treated with IV acyclovir mostly for
on page 2217 meningoencephalitis were observed to have renal dys-
Brand Names: US: Zovirax function. Renal dysfunction typically occurred within 48
Brand Names: Canada Zovirax hours of initiation and was reversible in most cases after
Therapeutic Category Antiviral Agent, Oral; Antiviral dosage reduction or discontinuation, although in some
Agent, Parenteral instances, return to baseline was not observed. Analysis
Generic Availability (US) Yes of the degree of dysfunction based on percent reduction of
Use estimated GFR (eGFR) showed that of the 373 acyclovir
Parenteral: Treatment of initial and prophylaxis of recur- courses, 22% (81/373) had an eGFR reduction of 25% to
rent mucosal and cutaneous herpes simplex (HSV 1 and 49%, renal injury (defined as a 50% to 75% reduction in
HSV 2) infections in immunocompromised patients (FDA eGFR) in 9.7% (36/373), and renal failure (eGFR reduc-
approved in all ages); treatment of severe initial epi- tion >75%) in 3.8% (14/373). Doses >500 mg/m? were
sodes of herpes genitalis in immunocompetent patients significantly associated with all levels of nephrotoxicity
(FDA approved in ages 212 years and adults); treatment and acyclovir doses >15 mg/kg were significantly associ-
of herpes simplex encephalitis, including neonatal her- ated with a 25% to 49% reduction in eGFR. Statistically
pes simplex virus (FDA approved in all ages); treatment significant risk factors for renal failure identified through
of herpes zoster (shingles) infections in immunocompro- univariate analysis were age >8 years, weight >20 kg, BMI
mised patients (FDA approved in all ages)
>19 kg/m?, and concurrent ceftriaxone with or without
Oral: Treatment of varicella (chickenpox) in immunocom-
gadolinium. Associations of other antibiotics and contrast
petent patients (FDA approved in ages 22 years and
agents were not statistically significant. Monitor renal
adults); treatment of initial episodes and prophylaxis of
function during therapy, particularly for high doses and in
recurrent herpes simplex (HSV 2, genital herpes) and
older pediatric patients (>8 years). Outside of the neonatal
acute treatment of herpes zoster (shingles) (FDA
approved in adults) : period, reduced dosing or use of mg/m? dosing in larger
children may need to be considered; further studies are
Has also been used for treatment of varicella-zoster
infections in healthy, nonpregnant persons >13 years of necessary (Rao 2015).
age, children >12 months of age who have a chronic skin Adverse Reactions
or lung disorder or are receiving long-term aspirin ther- Oral:
apy, and immunocompromised patients; oral therapy has Central nervous system: Headache, malaise
also been used for suppression following parenteral Gastrointestinal: Diarrhea, nausea, vomiting
treatment of neonatal HSV infection Parenteral:
Pregnancy Risk Factor B Dermatologic: Hives, itching, rash
Pregnancy Considerations Teratogenic effects were not Gastrointestinal: Nausea, vomiting
observed in animal reproduction studies. Acyclovir has Hepatic: Liver function tests increased
been shown to cross the human placenta (Henderson Local: Inflammation at injection site, phlebitis
1992). Results from a pregnancy registry, established in Renal: Acute renal failure, BUN increased, creatinine
1984 and closed in 1999, did not find an increase in the increased

53
 ACYCLOVIR (SYSTEMIC)

q All forms: Rare but important or life-threatening: Abdomi-

nal pain, aggression, agitation, anemia, anorexia, ataxia,
PNA 15 to 28 days: IV: 20 mg/kg/dose every 8 hours
Body weight 1 to 2 kg (Bradley 2015):
coma, confusion, consciousness decreased, delirium, PNA s7 days: IV: 20 mg/kg/dose every 12 hours
desquamation, disseminated intravascular coagulopathy PNA 8 to 28 days: IV: 20 mg/kg/dose every 8 hours
(DIC), dizziness, dysarthria, encephalopathy, fatigue, Body weight >2 kg: IV: 20 mg/kg/dose every 8 hours
fever, gastrointestinal distress, hallucinations, hematuria, (AAP [Kimberlin 2013]; Bradley 2015; CDC [Work-
hemolysis, hepatitis, hyperbilirubinemia, hypotension, owski 2015]; Red Book [AAP 2015])
insomnia, jaundice, leukocytoclastic vasculitis, leukocy- HSV, chronic suppression following any HSV infec-
tosis, leukopenia, lymphadenopathy, mental depression, tion:
myalgia, neutrophilia, pain, psychosis, renal failure, renal AAP Recommendation (low dose, 6-month course):
pain, seizure, somnolence, sore throat, thrombocytope- Oral: 300 mg/m2/dose every 8 hours for 6 months;
nia, thrombotic microangiopathy, thrombocytosis, visual begin after completion of a 14- to 21-day course of IV
disturbances therapy dependent upon type of infection (AAP [Kim-
Drug Interactions berlin 2013]; Kimberlin 2011; Red Book [AAP 2015])
Metabolism/Transport Effects Inhibits CYP1A2 Alternate dosing (high-dose, 2-year course) in infants
(weak) with disseminated or CNS infection (Tiffany 2005):
Avoid Concomitant Use Limited data available: Oral: Begin after completion
Avoid concomitant use of Acyclovir (Systemic) with any of a 21-day course of IV therapy; dosing based on a
of the following: Foscarnet;. Varicella Virus Vaccine; prospective trial of 16 consecutive neonates (GA:
Zoster Vaccine (Live/Attenuated) Premature: n=4; term= 12; age at treatment: Neonate:
Increased Effect/Toxicity n=14; PNA >30 days: n=1) following disseminated or
Acyclovir (Systemic) may increase the levels/effects of: CNS infection; pharmacokinetic data were used to
CloZAPine; Mycophenolate; Tenofovir Products; TiIZANi- determine dosing regimen to maintain serum acyclo-
dine; Zidovudine vir concentration above target of 2 mcg/mL; treatment
was continued for 2 years in 14 of 16 patients; results
The levels/effects of Acyclovir (Systemic) may be showed normal neurodevelopmental outcomes in
increased by: Foscarnet; Mycophenolate; Tenofovir 69% and normal motor development in 70%; no
Products untoward effects were reported during the study
Decreased Effect duration.
Acyclovir (Systemic) may decrease the levels/effects of: Initial dosing: Approximate dose: 1,200 to 1,600 mg/
Talimogene Laherparepvec; Varicella Virus Vaccine; m?/dose twice daily
Zoster Vaccine (Live/Attenuated) Preterm neonate: Proportional decrease of full-term
Storage/Stability initial dose
Capsule, oral suspension, tablet: Store at controlled room ~ Full term or near term: 400 mg twice daily
temperature of 15°C to 25°C (59°F to 77°F); protect from Maintenance dosing: In the trial, serum acyclovir
capsule and tablet from moisture. concentrations were evaluated to assess adequacy
Powder for injection: Store undiluted vials at 15°C to 25°C of dosing to maintain serum concentrations above
(59°F to 77°F). Following reconstitution (final concen- the target of 2 to 3 mcg/mL. Samples were collected
tration 50 mg/mL), solution is stable for 12 hours at room 1 hour after a witnessed dose; if the acyclovir serum
temperature. concentration approached or was below the target,
Solution for injection: Store solution at 20°C to 25°C (68°F the dose was increased to the next greater 200 mg
fOoh abs). increment. Serum concentrations were evaluated
Do not refrigerate reconstituted solutions or solutions every 3 months; in order to limit the phlebotomy
diluted for infusion as they may precipitate. Once diluted losses, follow-up serum concentrations were not
for infusion with NS or D5W, use within 24 hours. evaluated outside of routine monitoring.
Mechanism of Action Acyclovir is converted to acyclovir Varicella (chickenpox), treatment: IV: 10 to 15 mg/kg/
monophosphate by virus-specific thymidine kinase then dose every 8 hours for 5 to 10 days; continue for 248
further converted to acyclovir triphosphate by other cellu- hours after the last new lesions have appeared (Ogilvie
lar enzymes. Acyclovir triphosphate inhibits DNA synthe- 1998; Sauerbrei 2007; Smith 2009)
sis and viral replication by competing with Dosing adjustment in renal impairment: IV:
deoxyguanosine triphosphate for viral DNA polymerase >50 mL/minute/1.73 m?: No adjustments necessary
and being incorporated into viral DNA. 25 to 50 mL/minute/1.73 m?: Administer the usual
Pharmacodynamics/Kinetics (Adult data unless recommended dose every 12 hours
noted) 10 to <25 mL/minute/1.73 m?: Administer the usual
Absorption: Oral: Poorly absorbed; absorption improves recommended dose every 24 hours
with multiple small doses compared to one large daily <10 mL/minute/1.73 m?: Administer 50% of the usual
dose (de Miranda 1983) recommended dose every 24 hours (eg, if the usual
Distribution: Widely (eg, brain, kidney, lungs, liver, spleen, recommended dose is 10 mg/kg/dose every 8 hours,
muscle, uterus, vagina, CSF) (de Miranda 1983; Laskin administer 5 mg/kg/dose every 24 hours)
1983); CSF acyclovir concentration is ~50% of plasma Pediatric Note: Obese patients should be dosed using
concentrations. ideal body weight. Parenteral IV doses >15 mg/kg/dose
Vass (Blum 1982; Laskin 1983; Spector 1981): or 500 mg/m? may be associated with an increased risk
Neonates to 3 months of age: 28.8 L/1.73 m? of nephrotoxicity; close monitoring of renal function is
Children 1 to 2 years: 31.6 L/1.73 m? recommended (Rao 2015).
Children 2 to 7 years: 42 L/1.73 m? CMV prophylaxis: Low-risk allogeneic hematopoietic
Adults: 0.8 L/kg (63.6 L) stem cell transplant (HSCT) in seropositive recipient.
Protein binding: 9% to 33% Note: Begin at engraftment and continue to day 100;
Metabolism: Converted by viral enzymes to acyclovir requires close monitoring for CMV reactivation (due to
monophosphate, and further converted to diphosphate weak activity); not for use in patients at high risk for
then triphosphate (active form) by cellular enzymes CMV disease (Tomblyn 2009):
Bioavailability: Oral: 10% to 20% with normal renal func- Oral: \ ,
tion (bioavailability decreases with increased dose) Infants, Children, and Adolescents <40 kg: 600 mg/
Half-life elimination: Terminal: Neonates and Infants <3 m?2/dose 4 times daily; maximum. dose:
months: 3.8 + 1.19 hours; Infants >3 months to Children 800 mg/dose
$12 years: 2:36 + 0.97 hours; Adults: ~2.5 hours (with Children and Adolescents 240 kg: 800 mg 4 times
normal renal function); 20 hours (ESRD) (Gorlitzsky daily
2017); Hemodialysis: ~5 hours IV: Infants, Children, and Adolescents: 500 mg/m?/
Excretion: Urine (62% to 91% as unchanged drug and dose every 8 hours
metabolite) Herpes zoster, acute retinal necrosis, treatment
Pharmacodynamics/Kinetics: Additional Consider- (HIV-exposed/-positive):
ations Initial treatment: IV: Note: Follow up IV therapy with
Renal function impairment: Total body clearance and half- oral acyclovir or valacyclovir maintenance therapy.
life are dependent on renal function. Infants: 10 to 15 mg/kg/dose every 8 hours for 10 to
Dosing 14 days (DHHS [pediatric] 2013)
Neonatal Children: 10 to 15 mg/kg/dose every 8 hours for 10
HSV infection, treatment: Duration: CNS and dissemi- to 14 days (DHHS [pediatric] 2013)
nated infections: At least 21-day treatment duration; Adolescents: 10 to 15 mg/kg/dose every 8 hours for
skin and mucous membrane infections: 14-day treat- 10 to 14 days (DHHS [adult] 2015)
ment duration (Bradley 2015; CDC [Workowski 2015]; Maintenance treatment; begin after 10- to 14-day
AAP [Kimberlin 2013]; Red Book [AAP] 2015): course of IV acyclovir: Oral: Infants and Children:
Body weight <1 kg (Bradley 2015): 20 mg/kg/dose 4 times daily for 4 to 6 weeks (DHHS
PNA $14 days: IV: 20 mg/kg/dose every 12 hours (pediatric] 2013)

54
 ACYCLOVIR (SYSTEMIC)

Herpes zoster (shingles), treatment: of 2 to 3 mcg/mL. Samples were collected 1

Immunocompetent host: hour after a witnessed dose; if the acyclovir
Ambulatory therapy: Oral: Children 212 years and serum concentration approached or was below
Adolescents: 800 mg every 4 hours (5 doses per the target, the dose was increased to the next
day) for 5 to 7 days (Red Book [AAP 2015]) greater 200 mg increment. Maximum dose:
Hospitalized patient: IV: 1,200 mg. Serum concentrations were eval-
Infants: 10 mg/kg/dose every 8 hours for 7 to 10 uated every 3 months; in order to limit the
days (Red Book [AAP 2015]) phlebotomy losses, follow-up serum concentra-
Children and Adolescents: 500 mg/m2/dose every tions were not evaluated outside of routine
8 hours for 7 to 10 days; some experts recom- monitoring.
mend 10 mg/kg/dose every 8 hours (Red Book HSV encephalitis, treatment:
[AAP 2015]) Infants and Children 3 months to <12 years:
Immunocompromised host (non-H/V-exposed/-posi- Non-HIV-exposed/-positive: |V: 10 to 15 mg/kg/dose
tive): IV: Infants, Children, and Adolescents: every 8 hours for 14 to 21 days. Note: Due to
10 mg/kg/dose every 8 hours for 7 to 10 days increased risk of neurotoxicity and nephrotoxicity,
(Red Book [AAP 2015]) higher doses (20 mg/kg) are not recommended
HIV-exposed/-positive: (Red Book [AAP 2015)).
Mild, uncomplicated disease and no or moderate HIV-exposed/-positive: \V: 10 mg/kg/dose every 8
immune suppression: Oral: hours for 21 days; higher doses (up to 20 mg/kg)
Infants and Children: 20 mg/kg/dose 4 times daily may be necessary (DHHS [pediatric] 2013)
for 7 to 10 days; maximum dose: 800 mg/dose; Children 212 years and Adolescents (independent of
consider. longer course if resolution of lesions is HIV status): IV: 10 mg/kg/dose every 8 hours for 14
slow (DHHS [pediatric] 2013) to 21 days (Red Book [AAP 2015)]
Adolescents: 800 mg 5 times daily for 7 to 10 days, HSV genital infection:
longer if lesions resolve slowly (DHHS First infection, mild to moderate:
[adult] 2015) Non-HIV-exposed/-positive:
Severe immune suppression or complicated dis- Children <12 years: Oral: 40 to 80 mg/kg/day
ease; trigeminal nerve involvement, extensive mul- divided in 3 to 4 doses per day for 5 to 10 days;
tidermatomal zoster or extensive cutaneous maximum daily dose: 1,200 mg/day (Bradley
lesions or visceral involvement: IV: 2015; Red Book [AAP 2015])
Infants: 10 mg/kg/dose every 8 hours until resolu- Children and Adolescents 212 years: Oral: 200 mg
tion of cutaneous lesions and visceral disease every 4 hours while awake (5 times daily) or
clearly begins, then convert to oral therapy to 400 mg 3 times daily for 7 to 10 days; treatment
complete a 10- to 14-day total course of therapy can be extended beyond 10 days if healing is not
(DHHS [pediatric] 2013) complete (CDC [Workowski 2015]; Red Book
Children: 10 mg/kg/dose or 500 mg/m2/dose [AAP 2015])
every 8 hours until resolution of cutaneous
HIV-exposed/-positive:
lesions and visceral disease clearly begins, then Children: Oral: 20 mg/kg/dose 3 times daily for 7 to
convert to oral therapy to complete a 10- to 14-
10 days; maximum dose: 400 mg/dose (DHHS
day total course of therapy (DHHS [pedia-
[pediatric] 2013)
tric] 2013)
Adolescents: Oral: 400 mg 3 times daily for 5 to 14
Adolescents: 10 to 15 mg/kg/dose every 8 hours
days (DHHS [adult] 2015)
until clinical improvement is evident, then convert
First infection, severe (independent of HIV status): IV:
to oral therapy to complete a 10- to 14-day total
Children and Adolescents 212 years: 5 mg/kg/dose
course of therapy (DHHS [adult] 2015)
every 8 hours for 5 to 7 days or 5 to 10 mg/kg/dose
HSV neonatal infection, treatment and suppressive
every 8 hours for 2 to 7 days, followed with oral
therapy in very young infants (independent of HIV
therapy to complete at least 10 days of therapy
status):
(CDC [Workowski 2015]; Red Book [AAP 2015])
Treatment (disseminated, CNS, or skin, eye, or mouth
Recurrent infection:
disease): Infants 1 to 3 months: IV: 20 mg/kg/dose
Children <12 years (independent of HIV status):
every 8 hours; treatment duration: For cutaneous
Oral: 20 mg/kg/dose 3 times daily for 5 days;
and mucous membrane infections (skin, eye, or
maximum dose: 400 mg/dose (Bradley 2015;
mouth): 14 days; for CNS or disseminated infection:
DHHS [pediatric] 2013)
21 days (AAP [Kimberlin 2013]; Bradley 2015; CDC
Children and Adolescents 212 years:
[Workowski 2015]; DHHS [pediatric] 2013; Red
Non-HIV-exposed/-positive: Oral: 200 mg every 4
Book [AAP 2015])
Chronic suppressive therapy following any neonatal hours while awake (5 times daily) for 5 days, or
HSV infection: 400 mg 3 times daily for 5 days, or 800 mg twice
AAP Recommendation (low dose, 6-month course): daily for 5 days or 800 mg 3 times daily for 2 days
Infants: Oral: 300 mg/m?/dose every 8 hours for 6 (CDC [Workowski 2015]; Red Book [AAP 2015])
months; begin after completion of a 14- to 21-day- HIV-exposed/-positive: Adolescents: Oral: 400 mg
course of IV therapy dependent-upon type of 3 times daily for 5 to 14 days (DHHS [adult] 2015)
infection (AAP [Kimberlin 2013]; Kimberlin 2011; Suppression, chronic:
Red Book [AAP 2015]) Non-HIV-exposed/-positive:
Alternate dosing (high dose, 2-year course) in Children <12 years: Limited data available: Oral:
infants with disseminated or CNS infection (Tiffany 20 mg/kg/dose twice daily; maximum dose:
2005): Limited data available: Infants and Children 400 mg/dose (Bradley 2015)
<3 years: Oral: Begin after completion of a 21-day Children and Adolescents 212 years: Oral: 400 mg
course of IV therapy; dosing based on a prospec- twice daily; reassess therapy after 12 months
tive trial of 16 consecutive neonates (GA: Prema- (CDC [Workowski 2015]; Red Book [AAP 2015])
ture: n=4; term= 12; age at treatment: Neonate: HIV-exposed/-positive:
n=14; PNA >30 days: n=1) following disseminated Infants and Children: Oral: 20 mg/kg/dose twice
or CNS infection; pharmacokinetic data were used daily; maximum dose: 800 mg/dose (DHHS
to determine dosing regimen to maintain serum [pediatric] 2013)
acyclovir concentration above target of 2 to 3 Adolescents: Oral: 400 mg twice daily (DHHS
mceg/mL; treatment was continued for 2 years in adult] 2015)
14 of 16 patients; results showed normal neuro- HSV gingivostomatitis:
developmental outcomes in 69% and normal motor Non-HIV-exposed/-positive: Primary infection:
development in 70%; no untoward effects were AAP recommendations: Children and Adolescents:
reported during the study duration. i Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days;
Initial dosing: 400 mg twice daily; approximate usual maximum dose: 200 mg/dose, others have
dose: 1,200 to 1,600 mg/m?/dose twice daily reported higher (400 mg/dose) (Bradley 2015; Cer-
Maintenance dosing: Note: Approximate doses for nik 2008; Red Book [AAP. 2015])
patients born at term: Alternate dosing: Infants 210 months, Children, and
Infants 1 to <5 months: 400 mg twice daily Adolescents: Oral: 15 mg/kg/dose five times daily
Infants 5 to <9 months: 600 mg twice daily for 7 days; maximum dose: 200 mg/dose (Amir
Infants and Children 9 to <15 months: 800 mg 1997; Balfour 1999); dosing based on a placebo
twice daily controlled trial in children 1 to 6 years of age (n=72,
Children 15 to 24 months: 1,000 mg twice daily treatment group: n=31); results showed when
Note: In the trial, serum acyclovir concentrations treatment started within 72 hours of symptom
were evaluated to assess adequacy of dosing to onset a shorter duration of symptoms and viral
maintain serum concentrations above the target shedding was observed (Amir 1997) >
55
 ACYCLOVIR (SYSTEMIC)

q HIV-exposed/-positive (DHHS [pediatric] 2013):

Mild, symptomatic: Oral: Infants and Children:
Children and Adolescents 240 kg:
IV: 250 mg/m2/dose every 12 hours
20 mg/kg/dose 4 times daily for 7 to 10 days; Oral: 400 to 800 mg twice daily
maximum dose: 400 mg/dose Prevention of late reactivation: Note: Treatment
Moderate to severe, symptomatic: IV: Infants and during first year after HSCT. f
Children: 5 to 10 mg/kg/dose every 8 hours; switch Infants, Children, and Adolescents <40 kg: Oral: 60
to oral therapy once lesions begin to regress to 90 mg/kg/day in 2 to 3 divided doses; max-
HSV, herpes labialis (cold sore) (HIV-exposed/-pos- imum daily dose: 800 mg twice daily
itive): Treatment: Children and Adolescents 240 kg: Oral: 800 mg
Infants and Children: Oral: 20 mg/kg/dose 4 times twice daily
daily for 5 days; maximum dose: 400 mg/dose Other immunocompromised hosts who are HSV sero-
(DHHS [pediatric] 2013) positive:
Adolescents: Oral: 400 mg 3 times daily for 5 to 10 IV: Infants, Children, and Adolescents: 5 mg/kg/
days (DHHS [adult] 2015) dose every 8 hours during period of risk (Red Book
HSV, herpes labialis (cold sore) recurrent, chronic [AAP 2015])
suppressive therapy: Immunocompetent Children Oral: Children 22 years and Adolescents: 200 mg
and Adolescents: Oral: 10 mg/kg/dose 3 times daily; every 4 hours while awake (5 doses daily) or
maximum daily dose: 1,000 mg/day; reevaluate after 200 mg every 8 hours; administer during periods
12 months (Red Book [AAP 2015]}) of risk (Red Book [AAP 2015])
HSV mucocutaneous infection: Varicella (chickenpox) or Herpes zoster (shingles),
Immunocompetent host: Infants, Children, and Ado- prophylaxis
lescents: Hematopoietic stem cell transplant (HSCT): Prophy-
Treatment (Bradley 2015): laxis of disease reactivation: Note: Continue therapy
|\V: 5 mg/kg/dose every 8 hours for 1 year after HSCT (Tomblyn 2009):
Oral: 20 mg/kg/dose 4 times daily for 5 to 7 days; Infants, Children, and Adolescents <40 kg: Oral: 60
maximum dose: 800 mg/dose to 80 mg/kg/day in 2 to 3 divided doses
Suppression, chronic: Limited data available; no Children and Adolescents 240 kg: Oral: 800 mg
pediatric data; some experts recommend oral twice daily
20 mg/kg/dose 2 to 3 times daily for 6 to 12 HIV-exposed/-positive: Limited data available: Note:
months, then reevaluate need; maximum dose: Consider use if >96 hours postexposure or if VZV-
400 mg/dose (Bradley 2015) immune globulin is not available; begin therapy 7 to
Immunocompromised host: 10 days after exposure; some experts begin therapy
Treatment: at first appearance of rash (DHHS [pediatric] 2013).
IV: Infants and Children: Oral: 20 mg/kg/dose 4 times
Infants and Children: 10 mg/kg/dose every 8 daily for 7 days; maximum dose: 800 mg/dose
hours for 7 to 14 days (Red Book [AAP 2015}) (DHHS [pediatric] 2013)
Adolescents: 5 to 10 mg/kg/dose every 8 hours; Adolescents: Oral: 800 mg 5 times daily for 5 to 7
change to oral therapy after lesions begin to days (DHHS [adult] 2015)
regress (DHHS [adult] 2015; Red Book Other immunocompromised hosts: Infants, Children,
[AAP 2015]) and Adolescents: Oral: 20 mg/kg/dose 4 times daily
Oral: Children 22 years and Adolescents: for 7 days; maximum dose: 800 mg/dose. Note:
1,000 mg/day in 3 to 5 divided doses for 7 to Consider use if VZV-immune globulin or IVIG is not
14 days; some suggest the maximum daily dose available; begin therapy 7 to 10 days after exposure
should not exceed 80 mg/kg/day (Red Book (Red Book [AAP] 2015).
2009; Red Book [AAP 2015]) Varicella (chickenpox), treatment: Begin treatment
Suppression, chronic (cutaneous, ocular) episodes: within the first 24 hours of rash onset:
Infants and Children (HIV-exposed/-positive): Oral: Immunocompetent host:
20 mg/kg/dose twice daily; maximum dose: Ambulatory therapy: Oral: Children 22 years and
800 mg/dose; reassess after 12 months (DHHS Adolescents: 20 mg/kg/dose 4 times daily for 5
[pediatric] 2013) days; maximum daily dose: 3,200 mg/day (Red
Children 12 years of age (non-HIV-exposed/-pos- Book [AAP 2015])
itive): Prevention of ocular episodes: Oral: Hospitalized patient: IV: Infants, Children, and Ado-
400 mg twice daily; reassess at 12 months (Red lescents: 10 mg/kg/dose or 500 mg/m?2/dose every
Book [AAP 2015]) 8 hours for 7 to 14 days (Bradley 2015; Red Book
Adolescents (independent of HIV status): Oral: [AAP 2015]); some experts recommend 15 to
400 mg twice daily; reassess at 12 months 20 mg/kg/dose for severe disseminated or CNS
(DHHS [adult] 2015; Red Book [AAP 2015]) infection (Bradley 2015)
HSV progressive or disseminated infection, treat- Immunocompromised host (non-H/V-exposed/-posi-
ment (immunocompromised host): tive): IV:
Non-HIV-exposed/-positive: Infants, Children, and Infants: 10 mg/kg/dose every 8 hours for 7 to 10
Adolescents: IV: 10 mg/kg/dose every 8 hours for days (Red Book [AAP 2015])
7 to 14 days (Red Book [AAP 2015]) Children and Adolescents: 500 mg/m2/dose every 8
HIV-exposed/-positive: Infants, Children, and Adoles- hours for 7 to 10 days; some experts recommend
cents: IV: 10 mg/kg/dose every 8 hours for 21 days; 10 mg/kg/dose every 8 hours (Red Book
higher doses (up to 20 mg/kg/dose) may be used in [AAP 2015])
children <12 years of age (DHHS [pediatric] 2013; HIV-exposed/-positive:
Red Book [AAP 2015]) Mild, uncomplicated disease and no or moderate
HSV, acute retinal necrosis, treatment (HIV- immune suppression: Oral: ’
exposed/-positive): Children (DHHS [pediatric] Infants and Children: 20 mg/kg/dose 4 times daily
2013): for 7 to 10 days and until no new lesions for 48
Initial treatment: IV: 10 to 15 mg/kg/dose every 8 hours; maximum dose: 800 mg/dose (DHHS
hours for 10 to 14 days. Note: Follow up IV therapy ({pediatric] 2013)
with oral acyclovir or valacyclovir maintenance Adolescents: 800 mg 5 times daily for 5 to 7 days
therapy. (DHHS [adult] 2015)
Maintenance treatment: Begin after 10- to 14-day Severe, complicated disease or severe immune
course of IV acyclovir: Oral: 20 mg/kg/dose 4 times suppression: IV:
daily for 4 to 6 weeks Infants: 10 mg/kg/dose every 8 hours for 7 to 10
HSV prophylaxis; immunocompromised hosts, days and until no new lesions for 48 hours (DHHS
seropositive: [pediatric] 2013)
Hematopoietic stem cell transplant (HSCT) in sero- Children: 10 mg/kg/dose or 500 mg/m?2/dose
positive recipient (Tomblyn 2009): every 8 hours for 7 to 10 days or until no new
Prevention of early reactivation: Note: Begin at lesions for 48 hours (DHHS [pediatric] 2013)
conditioning and continue until engraftment or res- Adolescents: 10 to 15 mg/kg/dose every 8 hours
olution of mucositis; whichever is longer (~30 days for 7 to 10 days; may convert to oral therapy after
post-HSCT) defervescence and if no evidence of visceral
Infants, Children, and Adolescents <40 kg: involvement is evident (DHHS [adult] 2015)
IV: 250 mg/m2/dose every 8 hours or 125 mg/ Renal Impairment: Pediatric
m?/dose every 6 hours; maximum daily dose: Monitor closely for neurotoxicity (Chowdhury 2016).
80 mg/kg/day Infants, Children and Adolescents: IV:
Oral: 60 to 90 mg/kg/day in 2 to 3 divided doses; CrCl >50 mL/minute/1.73 m: No dosage adjustment
maximum dose: 800 mg/dose twice daily necessary

56
 ACYCLOVIR (TOPICAL)

CrCl 25 to 50 mb/minute/1.73 m2: Administer the Use

usual recommended dose every 12 hours Buccal tablet: Treatment of recurrent herpes labialis (cold
CrCl 10 to <25 mL/minute/1.73 m?: Administer the sores) in immunocompetent patients (FDA approved in
usual recommended dose every 24 hours adults)
CrCl <10 mL/minute/1.73 m?: Administer 50% of the Topical (cream): Treatment of recurrent herpes labialis
usual recommended dose every 24 hours (eg, if the (cold sores) in immunocompetent patients (FDA
usual recommended dose is 10 mg/kg/dose every 8 approved in ages 212 years and adults)
hours, then administer 5 mg/kg/dose every 24 Topical (ointment): Management of initial genital herpes
hours) and in limited, nonlife-threatening mucocutaneous HSV
Intermittent hemodialysis (IHD): Dialyzable (60% infections in immunocompromised patients (FDA
reduction following a 6-hour session): 5 mg/kg/dose approved in adults)
every 24 hours; administer after hemodialysis on Pregnancy Risk Factor B
dialysis days (Aronoff 2007) Pregnancy Considerations Teratogenic effects were not
Peritoneal dialysis (PD): 5 mg/kg/dose every 24 observed in animal studies. When administered orally,
hours; no supplemental dose needed (Aronoff 2007) acyclovir crosses the placenta. Refer to the Acyclovir
Continuous renal replacement therapy (CRRT): (Systemic) monograph for details. The amount of acyclovir
10 mg/kg/dose every 12 hours (Aronoff 2007) available systemically following topical application of the
Hepatic Impairment: Pediatric There are no dosage cream or ointment is significantly less in comparison to
adjustments provided in the manufacturer's labeling. oral doses.
Preparation for Administration Parenteral: Reconsti- Breastfeeding Considerations When administered
tute vial for injection to 50 mg/mL with SWFI; do not use orally, acyclovir enters breast milk. Refer to the Acyclovir
bacteriostatic water containing benzyl alcohol or para- (Systemic) monograph for details. The amount of acyclovir
bens. For intravenous infusion, dilute in DSW, D5NS, available systemically following topical application of the
_D51/4NS, D51/2NS, LR, or NS to a final concentration cream or ointment is significantly less in comparison to
$7 mg/mL. In fluid restricted patients, concentrations up oral doses. Nursing mothers with herpetic lesions near or
to 10 mg/mL have been infused; concentrations on the breast should avoid breastfeeding.
>10 mg/mL increase the risk of phlebitis. Contraindications
Administration Buccal tablet: Hypersensitivity to acyclovir, valacyclovir,
Oral: May administer with or without food; shake suspen- milk protein concentrate or any component of the for-
sion well before use. Maintain adequate hydration during mulation
therapy. : Cream, ointment: Hypersensitivity to acyclovir, valacyclo-
Parenteral: Administer by slow IV infusion over at least 1 vir, or any component of the formulation
hour; rapid infusion is associated with nephrotoxicity due Warnings/Precautions
to crystalluria and renal tubular damage and should be Genital herpes: Physical contact should be avoided when
avoided. Maintain adequate hydration during therapy. lesions are present; transmission may also occur in the
Avoid IV push, IM, or SubQ administration. absence of symptoms. Treatment should begin with the
Acyclovir !V is an irritant (depending on concentration); first signs or symptoms. There are no data to support the
avoid extravasation. If extravasation occurs, stop infu- use of acyclovir ointment to prevent transmission of
sion immediately and disconnect (leave cannula/nee- infection to other persons or prevent recurrent infections
dle in place); gently aspirate extravasated solution (do if no signs or symptoms are present.
NOT flush the line); remove needle/cannula; elevate
Herpes labialis: Treatment should begin with the first signs
extremity. Apply dry warm compresses. Intradermal
or symptoms. Cream is for external use only to the lips
hyaluronidase may be considered for refractory cases
and face; do not apply to eye or inside the mouth or nose,
(Reynolds 2014).
or any mucous membranes. Ointment should also not be
Vesicant/Extravasation Risk Irritant at concentrations
used in the eye and be used with caution in immunocom-
>7 mg/mL
promised patients. Cream may be irritating and cause
Monitoring Parameters Urinalysis, BUN, serum creati- contact sensitization. Buccal tablets are applied to the
nine, urine output; liver enzymes, CBC; monitor for neuro-
area of the upper gum above the incisor tooth on the
toxicity and nephrotoxicity when using high dose therapy; same side as the symptoms; do not apply to the inside
neutrophil count at least twice weekly in neonates receiv- of the lip or cheek. Some products may contain milk
ing acyclovir 60 mg/kg/day IV protein concentrate.
Additional Information Sodium content of 1 g: 5.1 mEq Warnings: Additional Pediatric Considerations
Dosage Forms Excipient information presented when Some dosage forms may contain propylene glycol; in
available (limited, particularly for generics); consult spe- neonates large amounts of propylene glycol delivered
cific product labeling. [DSC] = Discontinued product orally, intravenously (eg, >3,000 mg/day), or topically
Capsule, Oral: have been associated with potentially fatal toxicities which
Zovirax: 200 mg [contains fd&c blue #2 (indigotine), can include metabolic acidosis, seizures, renal failure, and
parabens] CNS depression; toxicities have also been reported in
Generic: 200 mg ‘ IE children and adults including hyperosmolality, lactic acido-
Solution, Intravenous, as sodium [strength expressed as sis, seizures, and respiratory depression; use caution
base]: (AAP 1997; Shehab 2009).
Generic: 50 mg/mL (10 mL, 20 mL) Adverse Reactions
Solution Reconstituted, Intravenous, as sodium [strength Central nervous system: Lethargy (buccal tablet)
expressed as base]: Dermatologic: Erythema (buccal tablet), local pain (oint-
Generic: 500 mg (1 ea [DSC]); 1000 mg (1 ea [DSC]) ment; mild; includes transient burning and stinging), skin
Suspension, Oral: rash (buccal tablet)
Zovirax: 200 mg/5 mL (473 mL [DSC]) [contains meth- Gastrointestinal: Aphthous stomatitis (buccal tablet), gin-
ylparaben, propylparaben] gival pain (buccal tablet)
Zovirax: 200 mg/5 mL (473 mL) [contains methylpara- Local: Application site irritation (buccal tablet), application
ben, propylparaben; banana flavor] site reaction (cream; including dry lips, desquamation,
Generic: 200 mg/5 mL (473 mL) dryness of skin, cracked lips, burning skin, pruritus,
Tablet, Oral: flakiness of skin, and stinging on skin)
Zovirax: 400 mg Rare but important or life-threatening: Anaphylaxis,
Zovirax: 800 mg [contains fd&c blue #2 (indigotine)] eczema
Generic: 400 mg, 800 mg Drug Interactions
Metabolism/Transport Effects None known.
Acyclovir (Topical) (ay SYE kloe veer) Avoid Concomitant Use There are no known interac-
tions where it is recommended to avoid concomitant use.
Medication Safety Issues Increased Effect/Toxicity There are no known signifi-
Sound-alike/look-alike issues: cant interactions involving an increase in effect.
Acyclovir may be confused with ganciclovir, Retrovir, Decreased Effect
valacyclovir Acyclovir (Topical) may decrease the levels/effects of:
Zovirax may be confused with Doribax, Valtrex Zithro- Talimogene Laherparepvec
max, Zostrix, Zyloprim, Zyvox Storage/Stability
International issue's: Buccal tablet: Store at 20°C to 25°C (68°F to 77°F);
Opthavir [Mexico] may be confused with Optivar brand excursions permitted between 15°C and 30°C (59°F
name for azelastine [U.S.] and 86°F). Protect from moisture.
Brand Names: US Sitavig; Zovirax Cream: Store at or below 25°C (77°F); excursions permit-
Brand Names: Canada Zovirax ted between 15°C and 30°C (59°F and 86°F).
Therapeutic Category Antiviral Agent, Topical Ointment: Store at controlled room temperature of 20°C to
Generic Availability (US) May be product dependent 25°C (68°F to 77°F) in a dry place. >
57
 ACYCLOVIR (TOPICAL)

q Mechanism of Action Acyclovir is converted to acyclovir

monophosphate by virus-specific thymidine kinase then Acyclovir and Hydrocortisone
further converted to acyclovir triphosphate by other cellu- (ay SYE kloe veer & hye droe KOR ti sone)
lar enzymes. Acyclovir triphosphate inhibits DNA synthe- Brand Names: US Xerese
sis and viral replication by competing with Brand Names: Canada Xerese ‘
deoxyguanosine triphosphate for viral DNA polymerase
Therapeutic Category Antiviral Agent, Topical; Cortico-
and being incorporated into viral DNA. steroid, Topical
Pharmacodynamics/Kinetics (Adult data unless Generic Availability (US) No
noted) Use Early treatment of recurrent herpes labialis (cold
Absorption: Minimal sores) to shorten healing time and to reduce likelihood
Buccal tablet: Single dose application of buccal tablets of ulceration (FDA approved in ages 26 years and adults)
containing 50 mg to the buccal mucosa provided mean Pregnancy Risk Factor B
maximum salivary concentrations 8 hours after tablet Pregnancy Considerations Animal reproduction studies
application. Plasma concentrations were delayed and studies in pregnant women have not been conducted
(undetectable at 5 hours) and subsequently below with Xerese. Systemic exposure of acyclovir and hydro-
antiviral activity concentration (0.018 to 0.055 mcg/mL). cortisone after topical administration is minimal. See indi-
Cream: Plasma concentrations following topical applica- vidual agents.
tion of the cream were below the limit of detection in 5/6 Breastfeeding Considerations Systemic exposure of
male volunteers (<0.01 uM) and 0.014 uM in one acyclovir and hydrocortisone after topical administration
subject. is minimal.-See individual agents.
Ointment: Following application of the ointment to Contraindications
patients with varicella-zoster infection, acyclovir plasma There are no contraindications listed in the manufacturer’s
concentrations were <0.01 to 0.28 mcg/mL in patients US labeling.
with normal renal function and <0.01 to 0.78 mceg/mL in Canadian labeling: Known or suspected history of hyper-
a patient with renal impairment. sensitivity to acyclovir, valacyclovir, hydrocortisone or
Excretion: Urine (Buccal tablet: Primarily renally excreted any component of the cream.
unchanged; Cream: 0.04% of the daily dose; Ointment: Warnings/Precautions Treatment should begin with the
<0.02% to 9.4% of the daily dose) first signs or symptoms. For external use only to the lips
Dosing and around the mouth; do not apply to eye, inside the
Pediatric Herpes labialis (cold sores): Topical cream: mouth or nose, or on the genitals. Contact healthcare
Children 212 years and Adolescents: Apply 5 times/day provider if cold sore does not heal in 2 weeks. Use with
for 4 days caution in immunocompromised patients. Use has been
Renal Impairment: Pediatric There are no dosage associated with local sensitization (irritation). Potentially
adjustments provided in the manufacturer’s labeling; significant interactions may exist, requiring dose or fre-
however, dosage adjustment is unlikely due to low sys- quency adjustment, additional monitoring, and/or selec-
temic absorption. tion of alternative therapy.
Hepatic Impairment: Pediatric There are no dosage Warnings: Additional Pediatric Considerations
adjustments provided in the manufacturer’s labeling; Some dosage forms may contain propylene glycol; in
however, dosage adjustment is unlikely due to low sys- neonates large amounts of propylene glycol delivered
temic absorption. orally, intravenously (eg, >3,000 mg/day), or topically
Administration have been associated with potentially fatal toxicities which
Buccal tablet: Apply within 1 hour after onset of prodro- can include metabolic acidosis, seizures, renal failure, and
mal symptoms and before appearance of any signs of CNS depression; toxicities have also been reported in
lesions. Apply tablet with a dry finger immediately after children and adults including hyperosmolality, lactic acido-
removing it from packaging. Place tablets to the upper sis, seizures, and respiratory depression; use caution
gum just above the incisor tooth (canine fossa) on the (AAP 1997; Shehab 2009).
same side of the mouth as the prodromal symptoms and Adverse Reactions Rare but important or life-threaten-
hold in place with slight pressure over the upper lip for 30 ing: Allergic contact sensitivity, application site reaction,
seconds to ensure adhesion. The rounded side of the burning sensation of skin, contact dermatitis (when
applied under occlusion), dyschromia, erythema, exfolia-
tablet should be placed on the upper gum (for comfort
purposes, does not affect efficacy). Do not crush, chew,
tion of skin, tingling of skin, xeroderma
suck, or swallow. If tablet falls off within the first 6 hours, Drug Interactions
reposition the same tablet immediately or apply a new Metabolism/Transport Effects Refer to individual
tablet. If tablet is swallowed within the first 6 hours, drink components.
a glass of water and apply a new tablet. If tablet falls out Avoid Concomitant Use
or is swallowed after the first 6 hours, do not reapply. Avoid concomitant use of Acyclovir and Hydrocortisone
Patients may eat and drink normally while tablet is in with any of the following: Aldesleukin
place. Avoid gum chewing, brushing teeth, wearing an Increased Effect/Toxicity
upper denture or touching/pressing the tablet after place- Acyclovir and Hydrocortisone may increase the levels/
ment. Rinse mouth gently if teeth need to be cleaned effects of: Ceritinib; Deferasirox; Ritodrine
while the tablet is in place. Drink plenty of liquids in case Decreased Effect
of dry mouth. Acyclovir and Hydrocortisone may decrease the levels/
Topical: Cream or ointment: Apply as early as possible effects of: Aldesleukin; Corticorelin; Hyaluronidase; Tali-
following the onset of prodromal symptoms or when mogene Laherparepvec
lesions appear. Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
Cream: Not for use on the genitals. Ensure the face and/ excursions permitted to 15°C to 30°C (59°Fto 86°F); do
or lips are clean and dry. Not for use in the eye, mouth, not freeze.
or mucous membranes. Wash hands with soap and Mechanism of Action
water prior to application and after application. Apply an Acyclovir: Acyclovir is converted to acyclovir monophos-
amount to sufficiently cover the affected area, including phate by virus-specific thymidine kinase then further con-
verted to acyclovir triphosphate by other cellular enzymes.
the outer margin. Avoid unnecessary rubbing of the
Acyclovir triphosphate inhibits DNA synthesis and viral
affected area. Do not apply other topical products to
replication by competing with deoxyguanosine triphos-
the affected area during therapy.
phate for viral DNA polymerase and being incorporated
Ointment: Use a fingercot or rubber glove when applying
into viral DNA.
ointment to prevent autoinoculation of other body sites
or transmission of infection to other persons. Not for Hydrocortisone: Topical corticosteroids have anti-inflam-
use in the eye. matory, antipruritic, and vasoconstrictive properties.
Dosage Forms Excipient information presented when Pharmacodynamics/Kinetics (Adult data unless
available (limited, particularly for generics); consult spe- noted) See individual agents.
cific product labeling. Dosing
Cream, External: Pediatric Herpes labialis (cold sores): Children 26
Zovirax: 5% (5 g) [contains cetostearyl alcohol, propy- years and Adolescents: Topical: Apply 5 times daily for
lene glycol] 5 days; initiate therapy at first sign of infection (ie, during
Ointment, External: the prodrome or when lesions appear)
Zovirax: 5% (30 g) Renal Impairment: Pediatric There are no dosage
Generic: 5% (5 g, 15 g, 30 g) adjustments provided in the manufacturer's labeling.
Tablet, Buccal: Hepatic Impairment: Pediatric There are no dosage
Sitavig: 50 mg [contains milk protein concentrate] adjustments provided in the manufacturer's labeling.

58
 ADALIMUMAB

Administration Topical: For external use only. Wash decrease exposure to the newborn. In addition, the admin-
hands before and after use. Use sufficient amount to cover istration of live vaccines should be postponed until anti-
the affected area(s), including the outer margin of cold TNF concentrations in the infant are negative (Habal
sore; do not rub affected area nor cover area with a 2012; Mahadeven 2013; Zelinkova 2013).
bandage. Do not bathe or shower for 30 minutes following
Women exposed to adalimumab during pregnancy for the
application. Not for use in the eye, inside the mouth or
treatment of an autoimmune disease (eg, inflammatory
nose, or on the genitals.
bowel disease) may contact the OTIS Autoimmune Dis-
Dosage Forms Excipient information presented when eases Study at 877-311-8972.
available (limited, particularly for generics); consult spe-
Breastfeeding Considerations Low concentrations of
cific product labeling.
adalimumab may be detected in breast milk but are
Cream, topical:
unlikely to be absorbed by a nursing infant. According to
Xerese: Acyclovir 5% and hydrocortisone 1% (5 g)
the manufacturer, the decision to continue or discontinue
@ Acyclovir/Hydrocortisone see Acyclovir and Hydrocor- breastfeeding during therapy should take into account the
tisone on page 58 risk of infant exposure, the benefits of breastfeeding to the
infant, and benefits of treatment to the mother.
@ Acyclovir Sodium see Acyclovir (Systemic) on page 53
Contraindications There are no contraindications listed
@ ACZ885 see Canakinumab on page 352 in the manufacturer's US labeling.
# Aczone see Dapsone (Topical) on page 567 Canadian labeling: Known hypersensitivity to adalimumab
@ Adacel see Diphtheria and Tetanus Toxoids, and Acel- or any component of the formulation; severe infection
lular Pertussis Vaccine on page 664 (eg, sepsis, tuberculosis, opportunistic infection); mod-
erate-to-severe heart failure (NYHA class III/IV)
@ Adacel-Polio (Can) see Diphtheria and Tetanus Toxoids,
Warnings/Precautions [US Boxed Warnings]: Active
Acellular Pertussis, and Poliovirus Vaccine on page 660
tuberculosis (disseminated or extrapulmonary),
@ Adalat XL (Can) see NIFEdipine on page 1449 including reactivation of latent tuberculosis, has been
@ Adalat CC see NIFEdipine on page 1449 reported in patients receiving adalimumab. Evaluate
patients for tuberculosis risk factors and latent tuber-
culosis infection (with a skin test) prior to and during
Adalimumab (a da LIM yoo mab) therapy. Treatment for latent tuberculosis should be
initiated before use. Patients with initial negative
Medication Safety Issues
tuberculin skin tests should receive continued mon-
Sound-alike/look-alike issues:
itoring for tuberculosis during and after treatment.
Adalimumab may be confused with sarilumab.
Consider antituberculosis treatment if an adequate course
Humira may be confused with Humulin, Humalog
of treatment cannot be confirmed in patients with a history
Humira Pen may be confused with HumaPen Memoir
of latent or active tuberculosis or with risk factors despite
(used with HumaLOG)
negative skin test. Some patients who tested negative
Brand Names: US Humira; Humira Pediatric Crohns prior to therapy have developed active infection; tests for
Start; Humira Pen; Humira Pen-Crohns Starter; Humira
latent tuberculosis infection may be falsely negative while
Pen-Psoriasis Starter
on adalimumab therapy. Use with caution in patients who
Brand Names: Canada Humira have traveled to or resided in regions where tuberculosis
Therapeutic Category Antirheumatic, Disease Modify- is endemic. Monitor for signs and symptoms of tuber-
ing; Gastrointestinal Agent, Miscellaneous; Monoclonal culosis in all patients.
Antibody; Tumor Necrosis Factor (TNF) Blocking Agent
Generic Availability (US) No Rare reactivation of hepatitis B (HBV) has occurred in
Use Treatment of moderately to severely active polyartic- chronic carriers of the virus, usually in patients receiving
ular juvenile idiopathic arthritis (JIA) alone or in combina- concomitant immunosuppressants (some have been
tion with methotrexate (Humira: FDA approved in ages 2 fatal); evaluate for HBV prior to initiation in all patients.
to 17 years weighing 210 kg; Amjevita: FDA approved in Monitor during and for several months following discontin-
ages 4 to 17 years weighing 215 kg; Cyltezo: FDA uation of treatment in HBV carriers; interrupt therapy if
approved in ages 4 to 17 years weighing 230 kg); treat- reactivation occurs and treat appropriately with antiviral
ment and maintenance of remission in patients with mod- therapy; if resumption of therapy is deemed necessary,
erately to severely active Crohn disease with inadequate exercise caution and monitor patient closely.
response to conventional treatment or patients who have [US Boxed Warning]: Patients receiving adalimumab
lost response to or are intolerant of infliximab (Humira: are at increased risk for serious infections which may
FDA approved ages 26 years and adults; Amjevita, result in hospitalization and/or fatality; infections usu-
Cyltezo: FDA approved in adults); treatment of moderately ally developed in patients receiving concomitant
to severely active rheumatoid arthritis (RA) alone or in immunosuppressive agents (eg, methotrexate, corti-
combination with methotrexate or other nonbiologic, dis- costeroids) and may present as disseminated (rather
ease-modifying antirheumatic drugs (DMARDs) (Humira, than local) disease. Active tuberculosis (including
Amijevita, Cyltezo: FDA approved in adults); treatment of reactivation of latent tuberculosis), invasive fungal
active psoriatic arthritis alone or in combination with non- (including aspergillosis, blastomycosis, candidiasis,
biologic DMARDs (Humira, Amjevita, Cyltezo: FDA coccidioidomycosis, histoplasmosis, and pneumo-
approved in adults); treatment of active ankylosing spon- cystosis) and bacterial, viral or other opportunistic
dylitis (Humira, Amjevita, Cyltezo: FDA approved in infections (including legionellosis and listeriosis)
adults); treatment of moderate to severe chronic plaque have been reported. Monitor closely for signs/symp-
psoriasis when systemic therapy is required and other toms of infection during and after treatment. Discon-
agents are less appropriate (Humira, Amjevita, Cyltezo: tinue for serious infection or sepsis. Consider risks
FDA approved in adults); treatment and maintenance of versus benefits prior to initiating therapy in patients
remission in patients with moderately to severely active with chronic or recurrent infection. Consider empiric
ulcerative colitis unresponsive to immunosuppressants antifungal therapy in patients who are at risk for
(Humira, Amjevita, Cyltezo: FDA approved in adults); invasive fungal infections who develop severe sys-
treatment of moderate to severe hidradenitis suppurativa temic illness. Caution should be exercised when consid-
(Humira: FDA approved in adults); treatment of noninfec- ering use in the elderly, patients with a history of an
tious intermediate, posterior, and panuveitis (Humira FDA opportunistic infection, patients taking concomitant immu-
approved in adults). Has also been used in children with nosuppressants (eg, corticosteroids, methotrexate), or in
idiopathic or JIA-associated uveitis and chronic uveitis patients with conditions that predispose them to infections
Note: Amjevita (adalimumab-atto) and Cyltezo (adalimu- (eg, advanced or poorly controlled diabetes) or residence/
mab-adbm) are approved as biosimilar agents. Approved travel in areas of endemic tuberculosis or mycoses (blas-
tomycosis, coccidioidomycosis, histoplasmosis), or with
ages and uses may vary (consult product labeling).
latent infections. Do not initiate adalimumab in patients
Medication Guide Available Yes
with an active infection, including clinically important local-
Pregnancy Considerations Adalimumab crosses the
ized infection. Patients who develop a new infection while
placenta and can-be detected in cord blood at birth at
undergoing treatment should be monitored closely. There
concentrations higher than those in the maternal serum. In
is limited experience with patients undergoing surgical
one study of pregnant women with inflammatory bowel
procedures while on therapy; consider long half-life with
disease, adalimumab was found to be measurable in a
planned procedures and monitor closely for infection.
newborn for up to'41 weeks following delivery. Maternal
doses of adalimumab were 40 mg every other week (n=9) [US Boxed Warning]: Lymphoma and other malignan-
or 40 mg weekly (n=1) and the last dose was administered cies (some fatal) have been reported in children and
0.14 to & weeks prior to delivery (median 5.5 weeks) adolescents receiving TNF-blocking agents, including
(Mahadevan 2013). If therapy for inflammatory bowel adalimumab. Half of the malignancies reported in chil-
disease is needed during pregnancy, adalimumab should dren and adolescents were lymphomas (Hodgkin and
be discontinued before 30 weeks gestation in order to non-Hodgkin) while other cases varied and included rare

59
 ADALIMUMAB

. malignancies usually associated with immunosuppression

and malignancies not typically observed in this population.
FDA also reviewed 147 postmarketing reports of leukemia
(including acute myeloid leukemia, chronic lymphocytic
Most patients were receiving concomitant immunosup- leukemia, and chronic myeloid leukemia) in patients (chil-
pressants. [US Boxed Warning]: Hepatosplenic T-cell dren and adults) using TNF-blockers. Average onset time
lymphoma (HSTCL), a rare T-cell lymphoma, has been to development of Jeukemia was within the first 1 to 2
reported (some fatal) primarily in patients with Crohn years of TNF-blocker initiation.
disease or ulcerative colitis treated with adalimumab
Reactivation of TB has been reported in pediatric patients
and who received concomitant azathioprine or mer-
receiving biologic response modifiers (infliximab and eta-
captopurine; reports occurred predominantly in ado-
nercept); prior to therapy, patients with no TB risk factors
lescent and young adult males. The impact of
should be screened for latent TB infection (LTBI) with an
adalimumab on the development and course of malig-
age appropriate test (ie, <5 years of age: tuberculin skin
nancy is not fully defined. Compared to the general
test, and 25 years of age: IGRA [interferon gamma release
population, an increased risk of lymphoma has been noted
assay]); if any TB risk factors are present or symptoms,
in clinical trials; however, rheumatoid arthritis alone has
both LTBI screening tests should be performed (AAP
been previously associated with an increased rate of
lymphoma and leukemia. A higher incidence of nonmela- [Davies 2016])
noma skin cancers was noted in adalimumab-treated Adverse Reactions
patients (0.7/100 patient years), when compared to the Cardiovascular: Atrial fibrillation, cardiac arrest, cardiac
control group (0.2/100 patient years). Rare cases of new- arrhythmia, chest pain, coronary artery disease, deep
onset or exacerbation of demyelinating disorders (eg, vein thrombosis, hypertension, hypertensive encephal-
multiple sclerosis, optic neuritis, peripheral demyelinating opathy, myocardial infarction, palpitations, pericardial
disease, including Guillain-Barré syndrome) have been effusion, pericarditis, peripheral edema, subdural hema-
reported; there is a known association between intermedi- toma, syncope, tachycardia
ate uveitis and central demyelinating disorders. Consider Central nervous system: Confusion, headache, myasthe-
discontinuing use in patients who develop peripheral or nia, paresthesia, torso pain
central nervous system demyelinating disorders during Dermatologic: Cellulitis, erysipelas, skin rash
treatment. Use with caution in patients with preexisting Endocrine & metabolic: Dehydration, hypercholesterole-
or recent onset central or peripheral nervous system mia, hyperlipidemia, ketosis, menstrual disease, para-
demyelinating disorders. thyroid disease
Gastrointestinal: Abdominal pain, cholecystitis, cholelithia-
Worsening and new-onset heart failure (HF) has been sis, diverticulitis, esophagitis, gastrointestinal hemor-
reported; use caution in patients with decreased left rhage, nausea, vomiting
ventricular function. Use caution in patients with HF. Genitourinary: Cystitis, hematuria, pelvic pain, urinary
Patients should be brought up to date with all immuniza- tract infection
tions before initiating therapy. No data are available con- Hematologic & oncologic: Adenoma, agranulocytosis, car-
cerning the effects of adalimumab on vaccination. Live cinoma (including breast, gastrointestinal, skin, urogen-
vaccines should not be given concurrently. No data are ital), malignant lymphoma, malignant melanoma,
available concerning secondary transmission of live vac- paraproteinemia, polycythemia, positive ANA titer
cines in patients receiving adalimumab. Rare cases of Hepatic: Hepatic necrosis, increased serum alkaline phos-
pancytopenia and aplastic anemia have been reported phatase
with TNF-blockers. Patients must be advised to seek Hypersensitivity: Hypersensitivity reaction (more common
medical attention if they develop signs and symptoms in children)
suggestive of blood dyscrasias; discontinue if significant Immunologic: Antibody development (significance
hematologic abnormalities are confirmed. Use with cau- unknown)
tion in patients with a history of significant hematologic Infection: Herpes simplex infection, herpes zoster, infec-
abnormalities. Positive antinuclear antibody titers have tion (children and adolescents), sepsis, serious infection
been detected in patients (with negative baselines) treated (including dental caries, gastroenteritis, rotavirus, vari-
with adalimumab. Rare cases of autoimmune disorder, cella)
including |jupus-like syndrome, have been reported; mon- Local: Injection site reaction
itor and discontinue adalimumab if symptoms develop. Neuromuscular & skeletal: Arthralgia (plaque psoriasis),
May rarely cause hypersensitivity, anaphylaxis, anaphy- arthritis, arthropathy, back pain, bone disease, bone
lactoid reactions, or angioneurotic edema; medications for fracture, increased creatine phosphokinase, limb pain,
the treatment of hypersensitivity reactions should be muscle cramps, myasthenia, osteonecrosis, septic
available for immediate use. Infection and malignancy arthritis, synovitis, tendon disease, tremor
has been reported at a higher incidence in elderly patients Ophthalmic: Cataract
compared to younger adults; use caution in elderly Renal: Nephrolithiasis, pyelonephritis
patients. Potentially significant drug-drug interactions Respiratory: Asthma, bronchospasm, dyspnea, flu-like
may exist, requiring dose or frequency adjustment, addi- symptoms, pharyngitis (juvenile idiopathic arthritis), pleu-
tional monitoring, and/or selection of alternative therapy.
ral effusion, pneumonia, respiratory depression, sinus-
The packaging (needle cover of prefilled syringe and itis, tuberculosis (including reactivation of latent infection;
autoinjector) may contain latex. Some dosage forms disseminated, miliary, lymphatic, peritoneal, and pulmo-
may contain polysorbate 80 (also known as Tweens). nary), upper respiratory tract infection
Hypersensitivity reactions, usually a delayed reaction, Miscellaneous: Abnormal healing, accidental injury, post-
have been reported following exposure to pharmaceutical operative complication (infection)
products containing polysorbate 80 in certain individuals Rare but important or life-threatening: Abscess (limb,
(Isaksson 2002; Lucente 2000; Shelley 1995). Thrombo- perianal), alopecia, anal fissure, anaphylactoid reaction,
cytopenia, ascites, pulmonary deterioration, and renal and anaphylaxis, angioedema, aplastic anemia, appendicitis,
hepatic failure have been reported in premature neonates bacterial infection, basal cell carcinoma, cardiac failure,
after receiving parenteral products containing polysorbate cerebrovascular accident, cervical dysplasia, circulatory
80 (Alade 1986; CDC 1984). See manufacturer's labeling. shock, cytopenia, dermal ulcer, endometrial hyperplasia,
Warnings: Additional Pediatric Considerations Post- erythema multiforme, fixed drug eruption, fulminant
marketing reports of lymphomas and other malignancies necrotizing fasciitis, fungal infection, Guillain-Barré syn-
were primarily in pediatric patients with Crohn disease or drome, hepatic failure, hepatitis B (reactivation), hepa-
ulcerative colitis treated with adalimumab and who tosplenic T-cell lymphomas (children, adolescents, and
received concomitant azathioprine or mercaptopurine; young adults), hepatotoxicity (idiosyncratic) (Chalasani
reports occurred predominantly in adolescent and young 2014), histoplasmosis, hypersensitivity angiitis,
adult males. As compared to the general population, an increased serum transaminases, interstitial pulmonary
increased risk of lymphoma has been noted in clinical disease (eg, pulmonary fibrosis), intestinal obstruction,
trials; however, rheumatoid arthritis has been previously intestinal perforation, leukemia, leukopenia, liver meta-
associated with an increased rate of lymphoma. In an stases, lupus-like syndrome, lymphadenopathy, lympho-
analysis of children and adolescents who had received cytosis, malignant neoplasm of ovary, meningitis (viral),
TNF-blockers (etanercept and infliximab), the FDA identi- Merkel cell carcinoma, multiple sclerosis, mycobacte-
fied 48 cases of malignancy. Of the 48 cases, ~50% were rium avium complex, myositis (children and adoles-
lymphomas (eg, Hodgkin and non-Hodgkin lymphoma). cents), neutropenia, optic neuritis, pancreatitis,
Other malignancies, such as leukemia, melanoma, and pancytopenia, protozoal infection, psoriasis (including
solid organ tumors were reported; malignancies rarely new onset, palmoplantar, pustular, or exacerbation),
seen in children (eg, leiomyosarcoma, hepatic malignan- pulmonary embolism, respiratory failure, sarcoidosis,
cies, and renal cell carcinoma) were also observed. Of septic shock, skin granuloma (annulare; children and
note, most of these cases (88%) were receiving other adolescents), Stevens-Johnson syndrome, streptococ-
immunosuppressive medications (eg, azathioprine and cal pharyngitis (children and adolescents), systemic
methotrexate). The role of TNF-blockers in the develop- lupus erythematosus, testicular neoplasm, thrombocyto-
ment of malignancies in children cannot be excluded. The penia, vasculitis (systemic), viral infection

60
 ADALIMUMAB

Drug Interactions Children 24 years and Adolescents:

Metabolism/Transport Effects None known. 15 kg to <30 kg: Humira, Amjevita: SubQ: 20 mg
Avoid Concomitant Use every other week
Avoid concomitant use of Adalimumab with any of the 230 kg: Humira, Amjevita, Cyltezo: SubQ: 40 mg
following: Abatacept; Anakinra; Baricitinib; BCG (\ntra- every other week
vesical); Belimumab; Canakinumab; Certolizumab Body surface area (BSA)-based dosing: Note: Dosing
Pegol; InFLIXimab; Natalizumab; Pimecrolimus; Rilona- based on trials performed with Humira product.
cept; Tacrolimus (Topical); Tocilizumab; Tofacitinib; Vac- Children 2 to <4 years: SubQ: 24 mg/m?/dose every
cines (Live); Vedolizumab other week; maximum dose: 20 mg/dose (Humira
Increased Effect/Toxicity Canadian product labeling 2018; Kingsbury 2014)
Adalimumab may increase the levels/effects of: Abata- Children and Adolescents 4 to 17 years: SubQ:
cept; Anakinra; Belimumab; Canakinumab; Certolizu- 24 mg/m2/dose every other week; maximum dose:
mab Pegol; Fingolimod; InFLIXimab; Leflunomide; 40 mg/dose (Burgos-Vargas 2015; Humira Cana-
Natalizumab; Rilonacept; Thiopurine Analogs; Tofaciti- dian product labeling 2018; Lovell 2008)
nib; Vaccines (Live); Vedolizumab Ulcerative colitis; moderate to severe, refractory:
Limited data available: Children and Adolescents:
The levels/effects of Adalimumab may be increased by:
SubQ: Initial: 100 mg/m? (maximum dose: 160 mg/
Baricitinib; Denosumab; Ocrelizumab; Pimecrolimus;
dose), then 50 mg/m? (maximum dose: 80 mg/dose)
Roflumilast; Tacrolimus (Topical); Tocilizumab; Trastu-
2 weeks later; then on day 29, begin maintenance
zumab
therapy: 25 mg/m? every other week (maximum dose:
Decreased Effect
40 mg/dose) (Turner 2012). Note: Trials performed
Adalimumab may decrease the levels/effects of: BCG
with Humira product:
(Intravesical); Coccidioides immitis Skin Test; Cyclo-
Uveitis: Limited data available; dosing regimens varia-
SPORINE (Systemic); Nivolumab; Pidotimod; Sipuleu-
ble; Note: Trials performed with Humira product.
cel-T; Tertomotide; Theophylline Derivatives; Vaccines
BSA-directed dosing: Children 24 years and Adoles-
(Inactivated); Vaccines (Live); Warfarin
cents: SubQ: 24 or 40 mg/m? every 2 weeks; max-
The levels/effects of Adalimumab may be decreased by: imum dose 40 mg/dose (Gallagher 2007; Simonini
Echinacea 2011). Dosing based on one prospective trial compar-
Storage/Stability Store at 2°C to 8°C (36°F to 46°F) in ing 24 mg/m2/dose every 2 weeks of adalimumab
original container to protect from light; do not freeze. Do (n=16, ages 6 to 12 years) to infliximab (n=17, ages
not use if frozen even if it has been thawed. Do not store in 5 to 13 years) and on a retrospective trial of biologic
extreme heat or cold. If needed, may be stored at room response modifiers, including five patients who
temperature up to a maximum of 25°C (77°F) for up to 14 received adalimumab at 40 mg/m2/dose every 2
days; discard if not used within 14 days. weeks
Mechanism of Action Adalimumab is a recombinant Weight-directed dosing: Children 22 years and Adoles-
monoclonal antibody that binds to human tumor necrosis cents (Biester 2007; Ramanan 2017; Sen 2012; Tyn-
factor alpha (TNF-alpha), thereby interfering with binding jala 2008):
to TNFa receptor sites and subsequent cytokine-driven <30 kg: SubQ: 20 mg every other week
inflammatory processes. Elevated TNF levels in the syno- 230 kg: SubQ: 40 mg every other week
vial fluid are involved in the pathologic pain and joint Renal Impairment: Pediatric There are no dosage
destruction in immune-mediated arthritis. Adalimumab adjustments provided in the manufacturer's labeling.
decreases signs and symptoms of psoriatic arthritis, rheu- Hepatic Impairment: Pediatric There are no dosage
matoid arthritis, and ankylosing spondylitis. It inhibits adjustments provided in the manufacturer's labeling.
progression of structural damage of rheumatoid and psori-
Administration SubQ: Administer subcutaneously into
atic arthritis. Reduces signs and symptoms and maintains
thigh or lower abdomen (avoid areas within 2 inches of
clinical remission in Crohn disease and ulcerative colitis;
navel); rotate injection sites. May leave at room temper-
reduces epidermal thickness and inflammatory cell infiltra-
ature for ~15 to 30 minutes prior to use; do not remove cap
tion in plaque psoriasis.
or cover while allowing product to reach room temper-
Pharmacodynamics/Kinetics (Adult data unless ature. Do not use if solution is discolored or contains
noted) particulate matter. Do not administer to skin which is
Distribution: Vg: 4.7 to 6 L; Synovial fluid concentrations:
red, tender, bruised, or hard. Needle cap of the prefilled
31% to 96% of serum syringe or needle cover for the adalimumab pen may
Bioavailability: Absolute: 64%
contain latex. Prefilled pens and syringes are available
Half-life elimination: Terminal: ~2 weeks (range: 10 to
for use by patients (self-administration); the Humira vial is
20 days)
intended for institutional use only and does not contain a
Time to peak, serum: SubQ: 131 + 56 hours
preservative; discard unused portion. }
Pharmacodynamics/Kinetics: Additional-Consider-
Monitoring Parameters Monitor improvement of symp-
ations Geriatric: In patients with rheumatoid arthritis
toms and physical function assessments. Latent TB
(RA), there was a trend toward lower clearance with
screening prior to initiating and during therapy; signs/
increasing age in patients 40 to >75 years of age.
symptoms of infection (prior to, during, and following
Dosing
therapy); CBC with differential; signs/symptoms/worsen-
Pediatric Note: Amjevita (adalimumab-atto) and Cyltezo
ing of heart failure; LFTs at baseline; HBV screening prior
(adalimumab-adbm) are approved as biosimilar agents
to initiating (all patients), HBV carriers (during and for
to Humira. Approved ages and uses may vary (consult
several months following therapy); signs and symptoms
product labeling).
of hypersensitivity reaction; symptoms of lupus-like syn-
Crohn disease; moderate to severe; refractory: Chil-
drome; signs/symptoms of malignancy (eg, splenomegaly,
dren 26 years and Adolescents: Humira:
hepatomegaly, abdominal pain, persistent fever, night
17 kg to <40 kg: SubQ: Initial: 80 mg divided into 2
sweats, weight loss), including periodic skin examination.
injections (40 mg each) on day 1, then 40 mg admin-
istered 2 weeks later (day 15); and then on day 29,
Product Availability
begin maintenance dose: 20 mg every other week. Amjevita (adalimumab-atto): FDA approved September
Patients who continue to experience flares after 12 2016; anticipated availability is currently unknown. Amje-
weeks of therapy may benefit from weekly dosing vita is approved as biosimilar to Humira. Consult the
(Dubinsky 2016; Hyams 2012). prescribing information for additional information.
240 kg: SubQ: Initial: 160 mg divided into 4 injections Cyltezo (adalimumab-adbm): FDA approved August 2017;
(40 mg each, administered on one day or as 2 anticipated availability is currently unknown. Cyltezo is
injections per day over 2 consecutive days), then approved as biosimilar to Humira. Information pertaining
80 mg (divided into 2 injections [40 mg each] admin- to this product within the monograph is pending revision.
istered on one day) 2 weeks later (day 15); and then Consult the prescribing information for additional infor-
on day 29 begin maintenance dose: 40 mg every mation.
other week. Patients who continue to experience Dosage Forms Excipient information presented when
flares after 12 weeks of therapy may benefit from available (limited, particularly for generics); consult spe-
weekly dosing: (Dubinsky 2016; Hyams 2012). cific product labeling.
Juvenile idiopathic arthritis (JIA): Pen-injector Kit, Subcutaneous [preservative free]:
Fixed dosing: Humira Pen: 40 mg/0.8 mL (1 ea) [contains polysor-
Children 2 to 4 years: bate 80]
10 kg to <15 kg: Humira: SubQ: 10 mg every Humira Pen-Crohns Starter: 40 mg/0.8 mL (1 ea) [con-
other week tains polysorbate 80]
15 to <30 kg: Humira: SubQ: 20 mg every Humira Pen-Psoriasis Starter: 40 mg/0.8 mL (1 ea)
other week : [contains polysorbate 80]

61
 ADALIMUMAB

< Prefilled Syringe Kit, Subcutaneous [preservative free]:

Humira: 10 mg/0.2 mL (1 ea); 20 mg/0.4 mL (1 ea);
facial edema (gel), skin discoloration, skin rash (cream/
gel), swelling of lips (gel)
40 mg/0.8 mL (1 ea); 10 mg/0.1 mL (1 ea); 20 mg/0.2 Drug Interactions
mL (1 ea); 40 mg/0.4 mL (1 ea) [contains polysor- Metabolism/Transport Effects None known.
bate 80] Avoid Concomitant Use }
Humira Pediatric Crohns Start: 40 mg/0.8 mL (1 ea); Avoid concomitant use of Adapalene with any of the
80 mg/0.8mL & 40 mg/0.4 mL (1 ea) [contains poly- following: Aminolevulinic Acid (Systemic); Multivitamins/
sorbate 80] Fluoride (with ADE); Multivitamins/Minerals (with ADEK,
Folate, Iron); Multivitamins/Minerals (with AE, No Iron)
¢@ Adalimumab-adbm see Adalimumab on page 59
Increased Effect/Toxicity
¢@ Adalimumab-atto see Adalimumab on page 59 Adapalene may increase the levels/effects of: Amino-
@ Adamantanamine Hydrochloride see Amantadine levulinic Acid (Systemic); Aminolevulinic Acid (Topical);
on page 102 Porfimer; Verteporfin

The levels/effects of Adapalene may be increased by:

Adapalene (a DaP a leen) Multivitamins/Fluoride (with ADE); Multivitamins/Miner-
als (with ADEK, Folate, Iron); Multivitamins/Minerals
Brand Names: US Differin; Differin [OTC] (with AE, No Iron)
Brand Names: Canada Differin; Differin XP Decreased Effect There are no known significant inter-
Therapeutic Category Acne Products actions involving a decrease in effect.
Generic Availability (US) Yes Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
Use Treatment of acne vulgaris (Gel 0.3%; Cream, Lotion excursions permitted to 15°C to 30°C (59°F to 86°F); do
0.1%: FDA approved in ages 212 years and adults; OTC: not freeze. Protect from light.
Gel 0.1%: FDA approved in ages 212 years and adults) Lotion: Protect from light and heat; do not refrigerate.
Pregnancy Risk Factor C Mechanism of Action Retinoid-like compound which is a
Pregnancy Considerations Adverse effects were modulator of cellular differentiation, keratinization, and
observed in animal reproduction studies. Retinoids may inflammatory processes, all of which represent important
cause harm when administered during pregnancy. A case features in the pathology of acne vulgaris
report described maternal use of adapalene 1 month prior Pharmacodynamics/Kinetics (Adult data unless
to pregnancy and through 13 weeks' gestation; cerebral
noted)
and ocular malformations were reported in the exposed
Onset of action: 8 to 12 weeks
fetus which resulted in termination of pregnancy (Autret
Absorption: Topical: Minimal; only trace amounts have
1997). In clinical trials, women of childbearing potential
been measured in serum after chronic application
were required to have a negative pregnancy test prior to
Half-life elimination, terminal: 7 to 51 hours (gel)
therapy.
Excretion: Bile
Breastfeeding Considerations It is not known if adapa-
Dosing
lene is present in breast milk. The manufacturer recom-
mends that caution be exercised when administering Pediatric Acne vulgaris, treatment: Children 27 years
adapalene to breastfeeding women. and Adolescents: Limited data available in ages <12
years (Eichenfield 2013): Topical: Apply once daily;
Contraindications Hypersensitivity to adapalene or any
component of the formulation. cream or gel should be applied in the evening (at bed-
Lotion: There are no contraindications listed in the manu- time). Note: During the initial 2 weeks of therapy, it may
facturer's labeling. appear that acne worsens; full effect may take up to 8 to
OTC labeling: When used for self-medication, do not use 12 weeks of therapy.
on damaged skin (cuts, abrasions, eczema, sunburn). Renal Impairment: Pediatric There are no dosage
Documentation of allergenic cross-reactivity for retinoids adjustments provided in the manufacturer's labeling;
is limited. However, because of similarities in chemical however, dosage adjustment unlikely necessary due to
structure and/or pharmacologic actions, the possibility of low systemic absorption.
cross-sensitivity cannot be ruled out with certainty. Hepatic Impairment: Pediatric There are no dosage
Warnings/Precautions Hypersensitivity reactions such adjustments provided in the manufacturer's labeling;
as pruritus, face edema, eyelid edema, and swelling have however, dosage adjustment unlikely necessary due to
been reported. Discontinue use immediately if allergic or low systemic absorption.
anaphylactoid/anaphylactic reactions occur. Use is asso- Administration Topical: For topical external use only.
ciated with increased susceptibility/sensitivity to UV light; Avoid contact with eyes, angles of the nose, lips, and
avoid sunlamps or excessive sunlight exposure. Daily mucous membranes. Do not apply to cuts, abrasions,
sunscreen use and other protective measures are recom- eczematous, or sunburned skin. Shortly after application,
mended. Patients with sunburn should discontinue use a mild transitory sensation of warmth or slight stinging may
until sunburn has healed. For external use only; avoid occur. Moisturizers may be used if necessary; avoid
contact with abraded, broken, eczematous, or sunburned moisturizers containing alpha hydroxy or glycolic acid-
skin, mucous membranes, eyes, lips, and angles of the containing products. Wash hands after application.
nose. Wax depilation is not recommended. Cream/gel: Cleanse affected area with a mild or soapless
cleanser and pat dry; apply a thin film to skin in the
Certain cutaneous signs and symptoms such as eryth-
evening before bedtime; apply enough to cover entire
ema, dryness, scaling, stinging/burning, or pruritus may
affected area.
occur during treatment; these are most likely to occur
Lotion: Apply after washing gently with a mild or soapless
during the first 2 to 4 weeks and will usually lessen with
cleanser and then pat dry; dispense a nickel size amount
continued use. Treatment can increase skin sensitivity to
(3 to 4 pump actuations) to cover entire face.
weather extremes of wind or cold. Concomitant topical
Monitoring Parameters Reduction in lesion size and/or
medications (eg, medicated or abrasive soaps and cleans-
inflammation; reduction in the number of lesions
ers, or cosmetics with a strong drying effect, products with
high concentrations of alcohol, astringents, spices or Dosage Forms Excipient information presented when
limes) should be avoided due to increased skin irritation. available (limited, particularly for generics); consult spe-
Depending on the severity of irritation, use moisturizer, cific product labeling.
reduce the frequency of application or discontinue use. Cream, External:
Warnings: Additional Pediatric Considerations May Differin: 0.1% (45 g)
cause mild hyperglycemia; more common in pediatric Generic: 0.1% (45 g)
patients. Some dosage forms may contain propylene Gel, External:
glycol; in neonates large amounts of propylene glycol Differin: 0.3% (45 g) [contains edetate disodium, meth-
delivered orally, intravenously (eg, >3,000 mg/day), or ylparaben, propylene glycol]
topically have been associated with potentially fatal tox- Differin: 0.1% (15 g, 45 g) [fragrance free, oil free; con-
icities which can include metabolic acidosis, seizures, tains edetate disodium, methylparaben, propylene
renal failure, and CNS depression; toxicities have also glycol]
been reported in children and adults including hyperos- Generic: 0.1% (45 g); 0.3% (45 g)
molality, lactic acidosis, seizures and respiratory depres- Lotion, External:
sion; use caution (AAP 1997; Shehab 2009). Differin: 0.1% (59 mL) [contains methylparaben, propy-
Adverse Reactions lene glycol, propylparaben]
Dermatologic: Burning sensation of skin, desquamation, Generic: 0.1% (59 mL)
erythema, exfoliation of skin, pruritus, skin abnormalities
(discomfort), skin irritation, stinging of the skin, sunburn, Adapalene and Benzoyl Peroxide
xeroderma (a DAP a leen & BEN zoe il peer OKS ide)
Rare but important or life-threatening: Acne flare, angioe-
dema (gel), application site pain (gel), conjunctivitis, Brand Names: US Epiduo; Epiduo Forte
contact dermatitis, dermatitis, eczema, eyelid edema, Brand Names: Canada Tactupump; Tactupump Plus

62
 ADEFOVIR

Therapeutic Category Acne Products; Topical Skin inflammatory processes, all of which represent important
Product; Topical Skin Product, Acne features in the pathology of acne vulgaris.
Generic Availability (US) May be product dependent Pharmacodynamics/Kinetics (Adult data unless
Use Treatment of acne vulgaris (Epiduo: FDA approved in noted)
ages 29 years and adults; Epiduo Forte: FDA approved in Absorption: Via the skin
ages 212 years and adults) Metabolism: Benzoyl peroxide: Converted to benzoic acid
Pregnancy Risk Factor C in skin
Pregnancy Considerations Animal reproduction studies Excretion: Adapalene: Primarily through bile; Benzoyl
have not been conducted with this combination. The peroxide: Urine
Canadian labeling does not recommend use in pregnant Dosing
women and advises contraceptive counseling to women of Pediatric Note: Application of more than recommended
reproductive potential prior to initiating therapy. Refer to amount or more frequent administration does not result
individual monographs. in quicker onset of action and is associated with more
Breastfeeding Considerations It is not known if adapa- irritant effects.
lene or benzoyl peroxide are excreted in breast milk Acne vulgaris:
following topical administration. The manufacturer recom- Epiduo (adapalene 0.1%/benzoy! peroxide 2.5%): Chil-
mends that caution be exercised when administering ad to dren 27 years and Adolescents; limited data in chil-
nursing:women. Also refer to individual monographs. dren <9 years: Topical: Apply a thin film once daily to
Contraindications There are no contraindications listed affected areas of cleansed and dried skin (Eichen-
in the US labeling. field 2013)
Canadian labeling: Hypersensitivity to adapalene, benzoyl Epiduo Forte (adapalene 0.3%/benzoyl peroxide
peroxide, or any component of the formulation; applica- 2.5%): Children 212 years and Adolescents: Topical:
tion to areas of skin affected by eczema or seborrheic Apply a thin film once daily to affected areas of
- dermatitis cleansed and dried skin
Warnings/Precautions Use is associated with increased Renal Impairment: Pediatric There are no dosage
susceptibility/sensitivity to UV light; avoid sunlamps or adjustments provided in manufacturer's labeling; how-
excessive sunlight exposure. Daily sunscreen use and ever, systemic absorption is not extensive making the
other protective measures (eg, hat) are recommended if need for a dose adjustment unlikely.
sun exposure cannot be avoided. Certain cutaneous signs Hepatic Impairment: Pediatric There are no dosage
and symptoms (eg, erythema, dryness, scaling, burning/ adjustments provided in manufacturer's labeling; how-
stinging) may occur during treatment; these are most likely ever, systemic absorption is not extensive making the
to occur during the first 4 weeks and will usually lessen need for a dose adjustment unlikely.
with continued use. Irritant and allergic contact dermatitis Administration Topical: Apply a pea-sized amount for
may occur. Use of moisturizer, decreased use, or discon- each affected area of the face (eg, forehead, chin, each
tinuation may be recommended. Avoid contact with cheek). May also be applied to affected areas of the trunk.
abraded skin, eyes, mucous membranes, and eyes. Do Skin should be clean and dry before applying. For external
not apply to cuts, abrasions, eczematous or sunburned use only; avoid applying to eyes, lips, and mucous mem-
skin. Avoid use of waxing as a depilatory method on branes; not for oral, ophthalmic, or intravaginal use.
treated skin. Avoid concomitant use of other potentially Dosage Forms Excipient information presented when
irritating topical products (medicated or abrasive soaps available (limited, particularly for generics); consult spe-
and cleansers, soaps and cosmetics that have strong cific product labeling.
skin-drying effect and products with high concentrations Gel, topical:
of alcohol, astringents, spices, or limes). May bleach hair Epiduo: Adapalene 0.1% and benzoyl peroxide
or colored fabric. Concomitant use of benzoyl peroxide 2.5% (45 g)
with sulfone products (eg, dapsone, sulfacetamide) may Epiduo Forte: Adapalene 0.3% and benzoyl peroxide
cause temporary discoloration (yellow/orange) of facial 2.5% (45 g, 60g)
hair and skin. Application of products at separate times Generic: Adapalene 0.1% and benzoyl peroxide
during the day or washing off benzoy! peroxide prior to 2.5% (45 g)
application of other products may avoid skin discoloration
(Dubina 2009). Potentially significant drug-drug interac- @ Adapalene/Benzoy! Peroxide see Adapalene and Ben-
tions may exist, requiring dose or frequency adjustment, zoyl Peroxide on page 62
‘additional monitoring, and/or selection of alternative ther- @ ADD 234037 see Lacosamide on page 1163
apy. @ Addamel N see Trace Elements on page 1983
Adverse Reactions Also see individual agents.
Dermatologic: Atopic dermatitis, burning sensation of skin,
Addamel N [DSC] see Trace Elements on page 1983
contact dermatitis, eczema, local dryness, localized @ Addaprin [OTC] see Ibuprofen on page 1034
erythema, skin irritation, stinging sensation of the skin, @ Adderall see Dextroamphetamine and Amphetamine
xeroderma on page 614
Local: Application site irritation, local desquamation
® Adderall XR see Dextroamphetamine and Amphetamine
Rare but important or life-threatening: Constriction of the
on page 614
pharynx, eyelid edema, facial swelling, skin blister
Drug Interactions
Metabolism/Transport Effects None known. Adefovir (a DEF o veer)
Avoid Concomitant Use
Avoid concomitant use of Adapalene and Benzoyl Per- Brand Names: US Hepsera
oxide with any of the following: Aminolevulinic Acid Brand Names: Canada Hepsera
(Systemic); Multivitamins/Fluoride (with ADE); Multivita- Therapeutic Category Antiretroviral Agent, Reverse
mins/Minerals (with ADEK, Folate, Iron); Multivitamins/ Transcriptase Inhibitor (Nucleotide)
Minerals (with AE, No Iron) Generic Availability (US) Yes
Increased Effect/Toxicity Use Treatment of chronic hepatitis B with evidence of
Adapalene and Benzoyl Peroxide may increase the active viral replication and either persistent elevations of
levels/effects of: Aminolevulinic Acid (Systemic); Amino- ALT or AST or histologically active disease (FDA approved
levulinic Acid (Topical); Dapsone (Topical); Porfimer; in ages 212 years and adults)
Verteporfin Pregnancy Risk Factor C
Pregnancy Considerations Adverse events have been
The levels/effects of Adapalene and Benzoyl Peroxide observed in animal reproduction studies.
may be increased by: Multivitamins/Fluoride (with ADE);
Multivitamins/Minerals (with ADEK, Folate, Iron); Multi- Health care providers are encouraged to enroll women
vitamins/Minerals (with AE, No Iron) exposed to adefovir during pregnancy in the Hepsera
Decreased Effect pregnancy registry (800-258-4263).
Adapalene and Benzoyl Peroxide may decrease the Breastfeeding Considerations It is not known if adefo-
levels/effects of: \sotretinoin (Topical) vir is excreted in breast milk. Due to the potential for
Storage/Stability Store at 25°C (77°F); excursions per- serious adverse reactions in the nursing infant, the man-
mitted between 15°C to 30°C (59°F to 86°F). Protect from ufacturer recommends a decision be made whether to
light and heat. wo discontinue nursing or to discontinue the drug, taking into
Mechanism of Action account the importance of treatment to the mother.
Benzoyl peroxide releases free-radical oxygen which oxi- Contraindications Hypersensitivity to adefovir or any
dizes bacterial proteins in the sebaceous follicles component of the formulation
decreasing the number of anaerobic bacteria and Warnings/Precautions [US Boxed Warning]: Use with
decreasing irritating-type free fatty acids. caution in patients with renal dysfunction or in
Adapalene is a retinoid-like compound which is a modu- patients at risk of renal toxicity (including concurrent
lator of cellular differentiation, keratinization, and nephrotoxic agents or NSAIDs). Chronic administration >
63
 ADEFOVIR

| may result in nephrotoxicity. Dosage adjustment is

required in adult patients with renal dysfunction or in
Mechanism of Action Acyclic nucleotide reverse tran-
scriptase inhibitor (adenosine analog) which interferes
patients who develop renal dysfunction during therapy; with HBV viral RNA-dependent DNA polymerase resulting
no data available for use in children 212 years or adoles- in inhibition of viral replication.
cents with renal impairment. Pharmacodynamics/Kinetics (Adult data unless
noted)
Current clinical hepatitis B practice guidelines do not
Note: Pharmacokinetic data reported in pediatric patients
recommend adefovir for initial use in the management of
(12-18 years) similar to reported adult data.
chronic HBV due to high rate of resistance with long-term
Distribution: 0.35 to 0.39 L/kg
use; other antiviral agents with a high barrier to drug
Protein binding: $4%
resistance are preferred (eg, tenofovir or entecavir). In
Metabolism: Prodrug; rapidly converted to adefovir (active
the setting of lamivudine-resistant HBV, adefovir (including
metabolite) in intestine
when combined with lamivudine) is also not a preferred
Bioavailability: 59%
strategy to manage antiviral resistance; consult current
Half-life elimination: 7.5 hours; prolonged in renal
clinical practice guidelines for recommendations (AASLD
impairment
[Terrault 2016]). If used, combination therapy with lamivu-
Time to peak: Median: 1.75 hours (range: 0.58 to 4 hours)
dine should be used to decrease the risk of resistance in
Excretion: Urine (45% as active metabolite within 24
patients with lamivudine-resistant HBV.
hours); Dialysis: ~35% of dose (10 mg) removed during
Calculate creatinine clearance before initiation of therapy. 4 hours hemodialysis session
Consider alternative therapy in patients who do not Pharmacodynamics/Kinetics: Additional Consider-
respond to adefovir monotherapy treatment. [US Boxed ations”
Warning]: May cause the development of HIV resist- Renal function impairment: C,,ax and AUC increased in
ance in patients with unrecognized or untreated HIV those with moderate or severe renal function impairment
infection. Determine HIV status prior to initiating treat- or with end-stage renal disease.
ment with adefovir. [US Boxed Warning]: Fatal cases of Dosing
lactic acidosis and severe hepatomegaly with steato- Pediatric
sis have been reported with the use of nucleoside Hepatitis B infection, chronic: Note: Optimal duration
analogues alone or in combination with other antire- of treatment not established, continuation of therapy for
trovirals. Female gender, obesity, and prolonged treat- at least 12 months after seroconversion has been
ment may increase the risk of hepatotoxicity. Treatment . suggested. Prolonged therapy (up to 4 years) has been
should be discontinued in patients with lactic acidosis or reported to be safe and well-tolerated in pediatric
signs/symptoms of hepatotoxicity (which may occur with- patients (2 to 18 years). Patients not achieving a <2
out marked transaminase elevations). [US Boxed Warn- log decrease in serum HBV DNA after at least 6 months
ing]: Acute exacerbations of hepatitis may occur (in of therapy should either receive additional treatment or
up to 25% of patients) when antihepatitis therapy is be switched to an alternative therapy (AASLD [Terrault
discontinued. Exacerbations typically occur within 12 2016]; Jonas 2012; Lok 2009).
weeks and may be self-limited or resolve upon resuming Children 2 to <7 years: Limited data available; efficacy
treatment; risk may be increased with advanced liver results variable: Oral: 0.3 mg/kg/dose once daily;
disease or cirrhosis. Monitor patients following discontin- maximum dose: 10 mg (Jonas 2008; Jonas 2012)
uation of therapy. Ethanol should be avoided in hepatitis B Children 27 to <12 years: Limited data available; effi-
infection due to potential hepatic toxicity. Do not use cacy results variable: Oral: 0.25 mg/kg/dose once
concurrently with tenofovir (Viread®) or any product con- daily; maximum dose: 10 mg (Jonas 2008;
taining tenofovir (eg, Truvada, Atripla, Complera). Jonas 2012)
Warnings: Additional Pediatric Considerations Effi- Children 212 years and Adolescents: Oral: 10 mg once
cacy in pediatric patients <12 years has not been daily; in HIV-exposed/-positive patients not requiring
reported; in clinical trials of children 2 to 12 years, positive combination antiretroviral therapy or receiving a lam-
responses to adefovir therapy were observed (13% to ivudine- or emtricitabine-containing HIV-suppressive
17% of subjects evaluated); however, findings did not regimen, adefovir may be considered as HBV alter-
reach statistical significance (Jonas 2008). nate therapy (interferon is preferable) (HHS [pedia-
Adverse Reactions tric 2016])
Central nervous system: Headache Renal Impairment: Pediatric Children 212 years and
Dermatologic: Pruritus, skin rash Adolescents: There are no dosage adjustments provided
Endocrine & metabolic: Hypophosphatemia (<2 mg/dL in in the manufacturer's labeling; no data available; con-
pre-/post-liver transplant patients) sider dosage reduction.
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, Administration Oral: May be administered without regard
flatulence, nausea, vomiting to food.
Genitourinary: Hematuria Monitoring Parameters HIV status (prior to initiation of
Hepatic: Hepatitis (exacerbation; within 12 weeks of ade- therapy); serum creatinine (prior to initiation and during
fovir discontinuation) therapy); LFTs for several months following discontinua-
Neuromuscular & skeletal: Back pain, weakness tion of adefovir; HBV DNA (every 3 to 6 months during
Renal: Increased serum creatinine (20.5 mg/dL in com- therapy); HBeAg and anti-HBe; if at risk for renal impair-
pensated liver disease; incidence may be higher in ment, also consider serum phosphate, urinalysis (glucose/
patients with decompensated cirrhosis or in liver trans- protein); bone density for individuals at risk for fracture or
plant recipients), renal failure history of osteopenia (AASLD [Terrault 2016])
Respiratory: Cough, rhinitis Dosage Forms Excipient information presented when
Rare but important or life-threatening: Fanconi's syn- available (limited, particularly for generics); consult spe-
drome, hepatitis, myopathy, nephrotoxicity, osteomala- cific product labeling.
cia, pancreatitis, proximal tubular nephropathy Tablet, Oral, as dipivoxil:
Drug Interactions Hepsera: 10 mg
Metabolism/Transport Effects Substrate of OAT1, Generic: 10 mg
OATS; Inhibits MRP2 @ Adefovir Dipivoxil see Adefovir on page 63
Avoid Concomitant Use
@ Adenocard see Adenosine on page 64
Avoid concomitant use of Adefovir with any of the follow-
ing: Tenofovir Products @ Adenoscan see Adenosine on page 64
Increased Effect/Toxicity
Adefovir may increase the levels/effects of: Cabozanti- Adenosine (a DEN oh seen)
nib; Tenofovir Products
Medication Safety Issues
The levels/effects of Adefovir may be increased by:
High alert medication:
Ataluren; Tenofovir Products; Teriflunomide; Tolvaptan
This medication is in a class the Institute for Safe
Decreased Effect
Medication Practices (ISMP) includes among its list of
Adefovir may decrease the levels/effects of: Tenofovir drug classes that have a heightened risk of causing
Products
significant patient harm when used in error.
The levels/effects of Adefovir may be decreased by: Related Information
Orlistat Adult ACLS Algorithms on page 2108
Food Interactions Food does not have a significant effect Pediatric ALS (PALS) Algorithms on page 2105
on adefovir absorption. Management: Administer without Brand Names: US Adenocard; Adenoscan
regard to meals. Brand Names: Canada Adenocard; Adenosine Injection,
Storage/Stability Store controlled room temperature of USP; PMS-Adenosine
25°C (77°F); excursions permitted between 15°C to 30°C Therapeutic Category Antiarrhythmic Agent, Miscellane-
(59°F to 86°F). ous

64
 ADENOSINE

Generic Availability (US) Yes Adenocard: Transient AV block is expected. Administer

Use as a rapid bolus, either directly into a vein or (if adminis-
Adenocard: Treatment of paroxysmal supraventricular tered into an IV line), as close to the patient as possible
tachycardia (PSVT), including that associated with (followed by saline flush), Dose reduction recommended
accessory bypass tracts (eg, Wolff-Parkinson-White syn- when administered via central line (ACLS, 2010). When
drome) (FDA approved in all ages); Note: When clin- used in PSVT, at the time of conversion to normal sinus
ically advisable, appropriate vagal maneuvers should be rhythm, a variety of new rhythms may appear on the ECG.
attempted prior to adenosine administration; used in Watch for proarrhythmic effects (eg, polymorphic ventric-
PALS algorithms for probable supraventricular tachycar- ular tachycardia) during and shortly after administration/
dia and stable regular monomorphic wide-complex termination of arrhythmia. Benign transient occurrence of
tachycardia as a therapeutic (if arrhythmia supraventric- atrial and ventricular ectopy is common upon termination
_ular) and diagnostic maneuver of arrhythmia. Adenosine does not convert atrial fibrilla-
Adenoscan: Pharmacologic stress agent used in myocar- tion/flutter to normal sinus rhythm; however, may be used
dial perfusion thallium-201 scintigraphy (FDA approved diagnostically in these settings if the underlying rhythm is
in adults) not apparent. Adenosine should not be used in patients
Pregnancy Risk Factor C with Wolff-Parkinson-White (WPW) syndrome and preex-
Pregnancy Considerations Animal reproduction studies cited atrial fibrillation/flutter since ventricular fibrillation
have mot been conducted. Adenosine is an endogenous may result (AHA/ACC/HRS [January, 2014]). Use with
substance and adverse fetal effects would not be antici- extreme caution in heart transplant recipients; adenosine
pated. Adenosine is recommended for the acute treatment may cause prolonged asystole; reduction of initial adeno-
of SVT in pregnant women. The usual recommended sine dose is recommended (ACLS, 2010); considered by
doses may be used, although higher doses may be some to be contraindicated in this setting (Delacrétaz,
needed in some cases (Page [ACC/AHA/HRS 2015)). 2006). Avoid use in irregular or polymorphic wide-complex
- ACLS guidelines suggest use is safe and effective in tachycardias; may cause degeneration to ventricular fibril-
pregnancy (ACLS [Neumar 2010)). lation (ACLS, 2010). When used for PSVT, dosage reduc-
tion recommended when used with concomitant drugs
Breastfeeding Considerations It is not known if adeno-
which potentiate the effects of adenosine (carbamaze-
sine is excreted in breast milk following maternal admin-
pine, dipyridamole)
istration. Adenosine is endogenous in breast milk
(Sugawara 1995). Due to the potentiai for adverse reac- Adenoscan: Hypersensitivity reactions (including dysp-
tions in the nursing infant, the manufacturer recommends nea, pharyngeal edema, erythema, flushing, rash, or chest
a decision be made to interrupt nursing or not administer discomfort) have been reported following Adenoscan
adenosine taking into account the importance of treatment administration. Seizures (new-onset or recurrent) have
to the mother. been reported following Adenoscan administration; risk
Contraindications Hypersensitivity to adenosine or any may be increased with concurrent use of aminophylline.
component of the formulation; second- or third-degree AV Use of any methylxanthine (eg, aminophylline, caffeine,
block, sick sinus syndrome, or symptomatic bradycardia theophylline) is not recommended in patients experiencing
(except in patients with a functioning artificial pacemaker); seizures associated with Adenoscan administration.
known or suspected bronchoconstrictive or bronchospas- Drugs which antagonize adenosine (theophylline [includes
tic lung disease (Adenoscan), asthma (ACLS [Neumar, aminophylline], caffeine) should be withheld for five half-
2010]; Adenoscan prescribing information, 2014) lives prior to adenosine use. Avoid dietary caffeine for at
Warnings/Precautions ECG monitoring required during least 12 hours prior to pharmacologic stress testing (Hen-
use. Equipment for resuscitation and trained personnel zlova, 2006). Withhold dipyridamole-containing medica-
experienced in handling medical emergencies should tions for at least 24 hours prior to pharmacologic stress
always be immediately available. Adenosine decreases testing (Henzlova, 2006).
conduction through the AV node and may produce first-,
Cardiovascular events: Cardiac arrest (fatal and nonfatal),
second-, or third-degree heart block. Patients with preex-
myocardial infarction (MI), cerebrovascular accident (hem-
isting S-A nodal dysfunction may experience prolonged
orrhagic and ischemic), and sustained ventricular tachy-
sinus pauses after adenosine; use caution in patients with
cardia (requiring resuscitation) have occurred following
first-degree AV block or bundle branch block. Use is
Adenoscan use. Avoid use in patients with signs or
contraindicated in patients with high-grade AV block, sinus
symptoms of unstable angina, acute myocardial ischemia,
node dysfunction or symptomatic bradycardia (unless a
or cardiovascular instability due to possible increased risk
functional artificial pacemaker is in place). Rare, pro-
of significant cardiovascular consequences. Appropriate
longed episodes of asystole have been reported, with fatal
measures for resuscitation should be available during use.
outcomes in some cases. Discontinue adenosine in any
In addition, systolic and diastolic pressure increases have
patient who develops persistent or symptomatic high-
been observed with Adenoscan infusion. In most instan-
grade AV block. Use caution in patients receiving other
ces, blood pressure increases resolved spontaneously
drugs which slow AV node conduction (eg, digoxin, vera-
within several minutes; occasionally, hypertension lasted
pamil). Potentially significant-interactions may exist,
for several hours.
requiring dose or frequency adjustment, additional mon-
itoring, and/or selection of alternative therapy. Pulmonary artery hypertension: Acute vasodilator testing
(not an approved use): Use with extreme caution in
There have been reports of atrial fibrillation/flutter after
patients with concomitant heart failure (LV systolic dys-
adenosine administration in patients with PSVT associ-
function with significantly elevated left heart filling pres-
ated with accessory conduction pathways; has also been
sures) or pulmonary veno-occlusive disease/pulmonary
reported in patients with or without a history of atrial capillary hemangiomatosis; significant decompensation
fibrillation undergoing myocardial perfusion imaging with has occurred with other highly selective pulmonary vaso-
adenosine infusion. Adenosine may also produce pro-
dilators resulting in acute pulmonary edema.
found vasodilation with subsequent hypotension. When
Adverse Reactions
used as a bolus dose (PSVT), effects are generally self-
Cardiovascular: Atrioventricular block, cardiac arrhythmia
limiting (due to the short half-life of adenosine). However,
(transient and new arrhythmia after cardioversion; eg,
when used as a continuous infusion (pharmacologic
atrial fibrillation, atrial premature contractions, premature
stress testing), effects may be more pronounced and
ventricular contractions), chest pain, chest pressure (and
persistent, corresponding to continued exposure; discon-
discomfort), depression of ST segment on ECG, hypo-
tinue infusion in patients who develop persistent or symp-
tension, palpitations
tomatic hypotension. Adenosine infusions should be used
Central nervous system: Apprehension, dizziness, head-
with caution in patients with autonomic dysfunction, sten-
ache, nervousness, numbness, paresthesia
otic valvular heart disease, pericarditis, pleural effusion,
Dermatologic: Diaphoresis, facial flushing
carotid stenosis (with cerebrovascular insufficiency), or
Gastrointestinal: Gastrointestinal distress, Nausea
uncorrected hypovolemia. Use caution in elderly patients;
Neuromuscular & skeletal: Neck discomfort (includes
may be at increased risk of hemodynamic effects, brady- throat, jaw), upper extremity discomfort
cardia, and/or AV block. Respiratory: Dyspnea, hyperventilation
Avoid use in patients with bronchoconstriction or broncho- Rare but important or life-threatening: Atrial fibrillation,
spasm (eg, asthma); dyspnea, bronchoconstriction, and blurred vision, bradycardia, bronchospasm, cardiac
respiratory compromise have occurred during use. Per the arrest, increased intracranial pressure, injection site
ACLS guidelines and the manufacturer of Adenoscan, use reaction, myocardial infarction, respiratory arrest, tor-
considered contraindicated in patients with asthma. Use sades de pointes, transient hypertension, ventricular
caution in patients with obstructive lung disease not arrhythmia, ventricular fibrillation, ventricular tachycardia
associated with bronchoconstriction (eg, emphysema, Drug !nteractions
bronchitis). Immediately discontinue therapy if severe Metabolism/Transport Effects None known.
respiratory difficulty is observed. Appropriate measures Avoid Concomitant Use There are no known interac-
for resuscitation should be available during use. tions where it is recommended to avoid concomitant use. >
 ADENOSINE

| Increased Effect/Toxicity
The levels/effects of Adenosine may be increased by:
extremity for 10 to 20 seconds after the NS flush. Note:
Preliminary results in adults suggest adenosine may be
CarBAMazepine; Digoxin; Dipyridamole; Nicotine administered via a central line at lower doses (eg, Adults:
Decreased Effect Initial dose: 3 mg); FDA approved labeling for pediatric
The levels/effects of Adenosine may be decreased by: patients weighing <80 kg states that doses listed may be
Caffeine and Caffeine Containing Products; Theophyl- administered either peripherally or centrally.
line Derivatives Monitoring Parameters Continuous ECG, heart rate,
Storage/Stability Store between 15°C and 30°C (59°F blood pressure, respirations
and 86°F). Do not refrigerate; crystallization may occur Additional Information Not effective in atrial flutter, atrial
(may dissolve by warming to room temperature). fibrillation, or ventricular tachycardia; short duration of
Mechanism of Action action is an advantage as adverse effects are usually
Antiarrhythmic actions: Slows conduction time through rapidly self-limiting; effects may be prolonged in patients
the AV node, interrupting the re-entry pathways through with denervated transplanted hearts.
the AV node, restoring normal sinus rhythm Dosage Forms Excipient information presented when
Myocardial perfusion scintigraphy: Adenosine also available (limited, particularly for generics); consult spe-
causes coronary vasodilation-and increases blood flow cific product labeling.
in normal coronary arteries with little to no increase in Solution, Intravenous:
stenotic coronary arteries; thallium-201 uptake into the Adenocard: 6 mg/2 mL (2 mL); 12 mg/4 mL (4 mL)
stenotic coronary arteries will be less than that of normal Adenoscan: 3 mg/mL (20 mL, 30 mL)
coronary arteries revealing areas of insufficient Generic: 3 mg/mL (20 mL, 30 mL); 6 mg/2 mL (2 mL)
blood flow. Solution, Intravenous [preservative free]:
Pharmacodynamics/Kinetics (Adult data unless Generic: 3 mg/mL (20 mL, 30 mL); 6 mg/2 mL (2 mL);
noted) 12 mg/4 mL (4 mL)
Onset of action: Rapid Solution Prefilled Syringe, Intravenous:
Duration: Very brief Generic: 90 mg/30 mL (30 mL); 60 mg/20 mL (20 mL)
Metabolism: Removed from systemic circulation primarily
by vascular endothelial cells and erythrocytes (by cellular a Adenosine Injection, USP (Can) see Adenosine
uptake); rapidly metabolized intracellularly; phosphory- on page 64
lated by adenosine kinase to adenosine monophosphate Adenosine Phosphate see Adenosine on page 64
(AMP) which is then incorporated into high-energy pool;
ADH see Vasopressin on page 2042
intracellular adenosine is also deaminated by adenosine
deaminase to inosine; inosine can be metabolized to Admelog see Insulin Lispro on page 1096
hypoxanthine, then xanthine and finally to uric acid. Admelog SoloStar see Insulin Lispro on page 1096
Half-life elimination: <10 seconds Adoxa [DSC] see Doxycycline on page 695
Dosing
Adoxa Pak 1/100 [DSC] see Doxycycline on page 695
Neonatal Paroxysmal supraventricular tachycardia:
Adenocard: Rapid IV: Initial dose: 0.05 to 0.1 mg/kg; if Adoxa Pak 1/150 [DSC] see Doxycycline on page 695
not effective within 1 to 2 minutes, increase dose by 0.05 Adoxa Pak 2/100 [DSC] see Doxycycline on page 695
to 0.1 mg/kg increments every 1 to 2 minutes to a
Oo
¢%
eeAdrenaclick [DSC] see EPINEPHrine (Systemic)
e$¢¢
maximum single dose of 0.3 mg/kg or until termination
on page 748
of PSVT
Pediatric Sa Adrenalin see EPINEPHrine (Nasal) on page 752
Paroxysmal supraventricular tachycardia: Adeno- ¢ Adrenalin see EPINEPHrine (Systemic) on page 748
card: ¢ Adrenalin® (Can) see EPINEPHrine (Nasal)
PALS Guidelines: Infants, Children and Adolescents: on page 752
Rapid IV; lO: Initial: 0.1 mg/kg (maximum initial dose:
® Adrenaline see EPINEPHrine (Nasal) on page 752
6 mg/dose); if not effective, increase to 0.2 mg/kg
(maximum dose: 12 mg/dose) (PALS [Klien- Sd Adrenaline see EPINEPHrine (Systemic) on page 748
man 2010]) ¢ Adrenaline Acid Tartrate see EPINEPHrine (Systemic)
Manufacturer's labeling: Rapid IV: on page 748
Infants, Children, and Adolescents <50 kg: Initial
¢ Adrenaline Bitartrate see EPINEPHrine (Systemic)
dose: 0.05 to 0.1 mg/kg via peripheral or central
on page 748
line; maximum initial dose: 6 mg/dose; if not effec-
tive within 1 to 2 minutes, increase dose by 0.05 to ¢ Adrenaline Hydrochloride see EPINEPHrine (Sys-
0.1 mg/kg increments every 1 to 2 minutes to a temic) on page 748
maximum single dose of 0.3 mg/kg or 12 mg, which- ¢ Adrenaline Tartrate see EPINEPHrine (Systemic)
ever is lower or until termination of PSVT on page 748
Children and Adolescents 250 kg: Initial: 6 mg via
e Adrenocorticotropic Hormone see Corticotropin
peripheral line, if not effective within 1 to 2 minutes,
on page 517
12 mg may be given; may repeat 12 mg bolus if
needed. Note: In adults it has been suggested that Sd ADR (error-prone abbreviation) see DOXOrubicin
the initial dose of adenosine should be reduced to (Conventional) on page 692
3 mg if patient is currently receiving carbamazepine Sd Adria see DOXOrubicin (Conventional) on page 692
or dipyridamole, has a transplanted heart, or if
® Adriamycin see DOXOrubicin (Conventional)
adenosine is administered via central line (ACLS
on page 692
2010; Chang 2002).
Renal Impairment: Pediatric There are no dosage ¢ Adriamycin PFS (Can) see DOXOrubicin (Conventional)
adjustments provided in the manufacturer's labeling. on page 692
However, adenosine is not renally eliminated. a4 Adrucil see Fluorouracil (Systemic) on page 889
Hepatic Impairment: Pediatric There are no dosage Adsorbent Charcoal see Charcoal, Activated
adjustments provided in the manufacturer's labeling. on page 413
However, adenosine is not hepatically eliminated.
Advagraf (Can) see Tacrolimus (Systemic)
Preparation for Administration
on page 1892
Parenteral: IV:
Doses 2600 mcg: Give undiluted Advair (Can) see Fluticasone and Salmeterol
Doses <600 mcg: Further dilution of dose may be on page 905
necessary to ensure complete and accurate adminis- Advair Diskus see Fluticasone and Salmeterol
tration; dilution with NS to a final concentration of 300 on page 905
to 1,000 mceg/mL has been used; to prepare a 300
Advair HFA see Fluticasone and Salmeterol
mcg/mL solution, add 3 mg of adenosine (1 mL) to 9
on page 905
mL of NS; to prepare a 1,000 mcg/mL, add 3 mg of
adenosine (1 mL) to 2 mL of NS Advanced Acne Wash [OTC] see Benzoyl Peroxide
Administration Parenteral: For rapid bolus lV use, admin- on page 259
ister over 1 to 2 seconds at peripheral IV site closest to Advanced Allergy Collection see Hydrocortisone (Top-
patient's heart (IV administration into lower extremities ical) on page 1013
may result in therapeutic failure or requirement of higher Advanced Eye Relief™ Dry Eye Environmental [OTC]
doses); follow each bolus with NS flush (infants and see Artificial Tears on page 185
children: 5 to 10 mL; adults: 20 mL); Note: The use of
two syringes (one with adenosine dose and the other with Advanced Eye Relief™ Dry Eye Rejuvenation [OTC]
NS flush) connected to a T-connector or stopcock is see Artificial Tears on page 185
recommended for IV and !.0. administration (PALS Advanced Probiotic [OTC] see Lactobacillus
2010). If given IV peripherally in adults, elevate the on page 1166

66
 AGALSIDASE BETA

@ Advate see Antihemophilic Factor (Recombinant) of childbearing potential are encouraged to enroll in the
on page 154 Fabry registry (www.registrynxt.com or 1-800-745-4447).
@ Advil [OTC] see Ibuprofen on page 1034 Breastfeeding Considerations It is not known if agalsi-
dase beta is excreted in breast milk. The manufacturer
@ Advil (Can) see Ibuprofen on page 1034
recommends that caution be exercised when administer-
@ Advil Cold & Sinus [OTC] see Pseudoephedrine and ing agalsidase beta to nursing women. Nursing mothers
Ibuprofen on page 1714 are encouraged to enroll in the Fabry registry (www.-
@ Advil Cold & Sinus (Can) see Pseudoephedrine and registrynxt.com or 1-800-745-4447).
Ibuprofen on page 1714 Contraindications There are no contraindications listed
@ Advil Cold & Sinus Daytime (Can) see Pseudoephe- within the manufacturer's labeling.
drine and Ibuprofen on page 1714 Warnings/Precautions Life-threatening anaphylactic
@ Advil Junior Strength [OTC] see Ibuprofen and severe allergic reactions have been reported. Reac-
on page 1034 tions may include angioedema, bronchospasm, chest
discomfort, dysphagia, dyspnea, flushing, hypotension,
@ Advil Migraine [OTC] see Ibuprofen on page 1034 nasal congestion, pruritus, rash, and urticaria. Stop infu-
@ Advil Pediatric Drops (Can) see Ibuprofen sion if severe reactions occur; immediate medical support
on page 1034 should be readily available. Use caution when administer-
@ Adyphren see EPINEPHrine (Systemic) on page 748 ing to patients with history of an anaphylactic or severe
allergic reaction. Infusion-related reactions are common,
@ Adyphren Il see EPINEPHrine (Systemic) on page 748
and may be severe (chills, vomiting, hypotension, pares-
@ Adyphren Amp see EPINEPHrine (Systemic) thesia); pretreatment with antipyretics and antihistamines
on page 748 is advised. Decrease infusion rate, temporarily discon-
@ Adyphren Amp Il see EPINEPHrine (Systemic) tinue infusion, and/or administer additional antipyretics,
on page 748 antihistamines, and/or steroids to manage infusion reac-
Adzenys ER see Amphetamine on page 130 tions. Immediate discontinuation of infusion should be
considered for severe reactions. Appropriate medical sup-
Adzenys XR-ODT see Amphetamine on page 130
port for the management of infusion reactions should be
Aerius (Can) see Desloratadine on page 593 readily available. Infusion reactions have occurred despite
Aerius Kids (Can) see Desloratadine on page 593 premedication. Use with caution when readministering to
AeroBid see Flunisolide (Oral Inhalation) on page 879 patients with history of infusion reactions.
oe
Oo
eeeAerospan [DSC] see Flunisolide (Oral Inhalation) Use caution in patients with cardiovascular disease (may
on page 879 have increased risk of complications from infusion reac-
Afeditab CR see NIFEdipine on page 1449 tions; monitor closely). Most patients develop IgG anti-
bodies to agalsidase beta within 3 months from the onset
@ Afentanil HCI see Alfentanil on page 83
of therapy; skin test (IgE) reactivity has been observed.
® Afinitor see Everolimus on page 808 Rechallenge of patients with IgE-mediated reaction or who
@ Afinitor Disperz see Everolimus on page 808 have had a positive skin test may be done with caution. A
@ AFirm 1X [OTC] [DSC] see Vitamin A on page 2063 registry has been created to monitor therapeutic
responses and adverse effects during long-term treat-
@ AFirm 2X [OTC] [DSC] see Vitamin A on page 2063
ment, as well as effects on pregnant and breastfeeding
@ AFirm 3X [OTC] [DSC] see Vitamin A on page 2063 women and their offspring; patients should be encouraged
@ Aflexeryl-MC [OTC] [DSC] see Capsaicin on page 357 to register (www.registrynxt.com or 1-800-745-4447).
@ Afluria see Influenza Virus Vaccine (Inactivated) Adverse Reactions
on page 1073 Cardiovascular: Bradycardia, cardiac arrhythmia, cerebro-
vascular accident, chest discomfort, chest pain, facial
@ Afluria Quadrivalent see Influenza Virus Vaccine (Inac-
edema, flushing, hypertension, hypotension, low cardiac
tivated) on page 1073
output, peripheral edema, tachycardia, ventricular hyper-
@ Afrin 12 Hour [OTC] see Oxymetazoline (Nasal) trophy
on page 1532 Central nervous system: Anxiety, ataxia, burning sensa-
@ Afrin Childrens [OTC] see Phenylephrine (Nasal) tion, chills, depression, dizziness, falling, fatigue, head-
on page 1614 ache, hypoesthesia, pain, paresthesia, procedural pain,
@ Afrin Extra Moisturizing [OTC] [DSC] see Oxymetazo- sensation of cold, vertigo
line (Nasal) on page 1532 Dermatologic: Excoriation, pallor, pruritus, skin rash, ther-
mal injury, urticaria
@ Afrin Menthol Spray [OTC] see Oxymetazoline (Nasal) Gastrointestinal: Abdominal pain, diarrhea, nausea, tooth-
on page 1532 ache, vomiting, xerostomia
@ Afrin Nasal Spray [OTC] see Oxymetazoline (Nasal) Genitourinary: Nephrotic syndrome
on page 1532 : : Hematologic & oncologic: Bruise
@ Afrin NoDrip Extra Moisture [OTC] see Oxymetazoline Hypersensitivity: Anaphylaxis, hypersensitivity reaction
(Nasal) on page 1532 Immunologic: Development of IgG Antibodies
Infection: Fungal infection, localized infection, viral
@ Afrin NoDrip Original [OTC] see Oxymetazoline (Nasal)
on page 1532 infection
Local: Infusion site reaction
@ Afrin NoDrip Sinus [OTC] see Oxymetazoline (Nasal) Neuromuscular & skeletal: Back pain, limb pain, muscle
on page 1532 spasm, myalgia
@ Afrin Saline Nasal Mist [OTC] see Sodium Chloride Otic: Hypoacusis, tinnitus
on page 1834 Renal: Increased serum creatinine
@ Afrin Sinus [OTC] see Oxymetazoline (Nasal) Respiratory: Cough, dyspnea, lower respiratory tract
on page 1532 infection, nasal congestion, pharyngeal edema, pharyng-
itis, respiratory congestion, sinusitis, upper respiratory
@ Afstyla see Antihemophilic Factor (Recombinant)
tract infection, wheezing
on page 154
Miscellaneous: Fever, procedural complications (postpro-
@ Aftertest Topical Pain Relief [OTC] see Benzocaine cedure)
on page 257 Rare but important or life-threatening: Anaphylactic shock,
angioedema (including auricular edema, dysphagia, lip
Agalsidase Beta (aye GAL si days BAY ta) edema, ocular edema, pharyngeal edema, tongue
edema), bronchospasm, cardiac failure, hypersensitivity
Medication Safety Issues angiitis, hypoxia, lymphadenopathy, myocardial infarc-
Sound-alike/look-alike issues: tion, palpitations, pneumonia, renal failure, respiratory
Agalsidase beta may be confused with agalsidase alfa, failure, sepsis
alglucerase, alglucosidase alfa Drug Interactions
Brand Names: US Fabrazyme Metabolism/Transport Effects None known.
Brand Names: Canada Fabrazyme Avoid Concomitant Use
Therapeutic Category Enzyme, a-galactosidase A; Avoid concomitant use of Agalsidase Beta with any of
Fabry's Disease, Treatment Agent the following: Amiodarone; Chloroquine; Gentamicin
Generic Availability (US) No (Systemic)
Use Treatment of Fabry disease (FDA approved in ages 28 Increased Effect/Toxicity There are no known signifi-
years and adults) cant interactions involving an increase in effect.
Pregnancy Risk Factor B Decreased Effect
Pregnancy Considerations Adverse events have not The levels/effects of Agalsidase Beta may be decreased
been observed in animal reproduction studies. Women by: Amiodarone; Chloroquine; Gentamicin (Systemic) »
67
AGALSIDASE BETA

Storage/Stability Store intact vials between 2°C and 8°C Reference Range Normal endogenous activity of alpha-
(36°F and 46°F). Reconstituted solutions and solutions galactosidase A in plasma is approximately 170 nmol/
diluted in NS are stable for 24 hours at 2°C and 8°C hour/mL; in patients with Fabry disease this activity is
(36°F and 46°F). <1.5 nmol/hour/mL
Mechanism of Action Agalsidase beta is a recombinant Normal (goal) globotriasylceramide (GL3) <1.2 ng/micro-
form of the enzyme alpha-galactosidase-A, which is liter
required for the hydrolysis of GL-3 and other glycosphin- Dosage Forms Excipient information presented when
golipids. The compounds may accumulate (over many available (limited, particularly for generics); consult spe-
years) within the tissues of patients with Fabry disease, cific product labeling.
leading to renal and cardiovascular complications. In Solution Reconstituted, Intravenous [preservative free]:
Clinical trials of limited duration, agalsidase been noted Fabrazyme: 5 mg (1 ea); 35 mg (1 ea) [contains mouse
to reduce tissue inclusions of a key sphingolipid (GL-3). It (murine) and/or hamster protein]
is believed that long-term enzyme replacement may
reduce clinical manifestations of renal failure, cardiomy- AG-Citalopram (Can) see Citalopram on page 461
opathy, and stroke. However, the relationship to a reduc- @ AgNO; see Silver Nitrate on page 1823
tion in clinical manifestations has not been established. @ AG-Ondansetron (Can) see Ondansetron on page 1502
Pharmacodynamics/Kinetics (Adult data unless @ AgonEaze see Lidocaine and Prilocaine on page 1220
noted)
@ Agriflu (Can) see Influenza Virus Vaccine (Inactivated)
Distribution: Vass: Children: 247 to 1097 mL/kg; Adults: 81
on page 1073
to 570 mL/kg
Half-life elimination (dose-dependent): Children: 86 to-151 @ Agrylin see Anagrelide on page 147
minutes; Adults: 45 to 119 minutes @ AHA see Acetohydroxamic Acid on page 48
Clearance: Children: 1.1 to 5.8 mL/minute/kg; Adults: 0.8 @ AHF (Human) see Antihemophilic Factor (Human)
to 4.9 mL/minute/kg on page 153
Dosing @ AHF (Human) see Antihemophilic Factor/von Willebrand
Pediatric Factor Complex (Human) on page 158
Fabry Disease: Children 28 years and Adolescents: IV:
@ AHF (Recombinant) see Antihemophilic Factor
1 mg/kg/dose every 2 weeks
(Recombinant) on page 154
Dosing adjustment for toxicity: Children 28 years and
Adolescents: Patients with IgE antibodies or a positive @ A-hydroCort see Hydrocortisone (Systemic)
skin test to agalsidase beta (rechallenge): IV: on page 1009
0.5 mg/kg every 2 weeks at an initial maximum infusion @ A-Hydrocort [DSC] see Hydrocortisone (Systemic)
rate of 0.01 mg/minute; may gradually escalate dose on page 1009
(to maximum of 1 mg/kg every 2 weeks) and/or infusion @ A-hydroCort see Hydrocortisone (Topical) on page 1013
rate (doubling the infusion rate every 30 minutes to a @ AICC see Anti-inhibitor Coagulant Complex (Human)
maximum rate of 0.25 mg/minute) as tolerated. on page 161
Renal Impairment: Pediatric There are no dosage
@ AIGIV see Anthrax Immune Globulin (Human)
adjustments provided in the manufacturer’s labeling.
on page 151 3
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer’s labeling.
@ AirDuo RespiClick see Fluticasone and Salmeterol
on page 905
Preparation for Administration |V: Allow vials and
diluent to reach room temperature prior to reconstitution @ Airomir (Can) see Albuterol on page 72
(~30 minutes). Each 35 mg vial should be reconstituted @ AK-Fluor see Fluorescein on page 885
with 7.2 mL SWFI: reconstitute 5 mg vials with 1.1 mL @ Akne-Mycin [DSC] see Erythromycin (Topical)
SWFI; inject down internal side wall of vial; roll and tilt on page 768
gently; do not shake. Resulting solution contains
@ Akovaz see EPHEDrine (Systemic) on page 747
5 mg/mL. Do not use filter needle to prepare. To make
final infusion solution, add the desired amount of recon- @ AK Pentolate Oph Soln (Can) see Cyclopentolate
stituted solution to NS to make a final volume based on on page 531
patient weight (see table for dilution volumes). Prior to @ AK-Poly-Bac see Bacitracin and Polymyxin B (Ophthal-
adding the volume of agalsidase beta dose to the NS, mic) on page 238
remove an equal volume of NS. Avoid vigorous shaking or ® AK Sulf Liq (Can) see Sulfacetamide (Ophthalmic)
agitation. on page 1875
@ Akten see Lidocaine (Ophthalmic) on page 1215
Recommended Minimum
Volumes for Dilution Akwa Tears [OTC] see Ocular Lubricant on page 1482
@ AL12 [OTC] see Lactic Acid and Ammonium Hydroxide
Minimum Total on page 1165
Patient Weight
Volume
(kg) (mL) @ Ala-Cort see Hydrocortisone (Topical) on page 1013
$35 @ Alagesic LQ see Butalbital, Acetaminophen, and Caf-
35.1 to 70 feine on page 329
70.1 to 100 @ Alahist DM [OTC] [DSC] see Brompheniramine, Dextro-
>100 methorphan, and Phenylephrine on page 297
@ Ala Scalp see Hydrocortisone (Topical) on page 1013
Administration IV: Pretreatment with acetaminophen and @ ala seb [OTC] see Sulfur and Salicylic Acid
an antihistamine is recommended to reduce infusion- on page 1884
related side effects. A 0.2 micron low protein-binding filter @ Alavert [OTC] see Loratadine on page 1247
may be used during administration. Initial infusion not to @ Alavert Allergy and Sinus [OTC] see Loratadine and
exceed 15 mg/hour (0.25 mg/minute); after patient toler- Pseudoephedrine on page 1249
ance to initial infusion rate is established, the infusion rate
@ Alaway [OTC] see Ketotifen (Ophthalmic) on page 1160
may be increased in increments of 3 to 5 mg/hour (0.05 to
0.08 mg/minute) with subsequent infusions. Per the man- @ Alaway Childrens Allergy [OTC] see Ketotifen (Oph-
ufacturer's recommendation: For patients weighing <30 thalmic) on page 1160
kg, the maximum infusion rate should remain at @ Albalon (Can) see Naphazoline (Ophthalmic)
0.25 mg/minute; for patients weighing >30 kg, the admin- on page 1425
istration duration should not be less than 1.5 hours (based
upon individual tolerability). An initial maximum infusion
Albendazole (ai BEN da zole)
rate of 0.01 mg/minute should be used for rechallenge in
patients with IgE antibodies or who have had a positive Medication Safety Issues
skin test to agalsidase beta; may increase infusion rate Sound-alike/look-alike issues:
(doubling the infusion rate every 30 minutes) to a max- Albenza may be confused with Aplenzin, Relenza
imum rate of 0.25 mg/minute as tolerated. International issues:
Monitoring Parameters Vital signs during infusion; infu- Albenza [US] may be confused with Avanza brand name
sion-related reactions; globotriasylceramide (GL3) plasma for mirtazapine [Australia]
levels; improvement in disease symptomatology; develop- Brand Names: US Albenza
ment of IgG or IgE antibodies in patients with suspected Therapeutic Category Anthelmintic
allergic reactions (test available from manufacturer) Generic Availability (US) No

68
 ALBENDAZOLE

Use Treatment of parenchymal neurocysticercosis due to Food Interactions Albendazole serum levels may be
active lesions caused by larval forms of Taenia solium increased if taken with a fatty meal (increases the oral
(pork tapeworm) and treatment of cystic hydatid disease bioavailability by up to 5 times). Management: Should be
of the liver, lung, and peritoneum caused by the larval form administered with a high-fat meal when treating systemic
of Echinococcus granulosus (dog tapeworm) (FDA infections.
approved in pediatric patients (age not specified) and Storage/Stability Store between 20°C and 25°C (68°F to
adults); has also been used in the treatment of Ancylos- HG), F
toma caninum, Ancylostoma duodenale (hookworm),
Mechanism of Action Active metabolite, albendazole
Ascariasis (intestinal roundworm), Baylisascaris procyonis
sulfoxide, causes selective degeneration of cytoplasmic
(raccoon roundworm), Capillariasis, Clonorchis sinensis microtubules in intestinal and tegmental cells of intestinal
(Chinese liver fluke), cutaneous larva migrans, Enterobia- helminths and larvae; glycogen is depleted, glucose
sis (pinworm), Filariasis (Wuchereria Bancroft), Giardiasis, uptake and cholinesterase secretion are impaired, and
Gnathostoma spinigerum, Gongylonema sp: microspori- desecratory substances accumulate intracellulary. ATP
diosis, Necator americanus (hookworm), Oesophagosto- production decreases causing energy depletion, immobi-
mum bifurcum, Opisthorchis viverrini (liver fluke), lization, and worm death.
Strongyloides stercoralis, Trichinellosis (Trichinosis), Tri-
Pharmacodynamics/Kinetics (Adult data unless
chostrongyliasis (hairworm), Trichuris trichiura (whip-
worm), and Toxocariasis (ocular larva migrans, visceral
noted)
larva migrans) Note: In pediatric patients (6-13 years), pharmacokinetic
values were reported to be similar to adult data.
Pregnancy Risk Factor C
Absorption: Poor from the Gl tract; may increase up to 5
Pregnancy Considerations Adverse events were times when administered with a fatty meal
observed in animal reproduction studies. Albendazole
Distribution: Widely distributed throughout the body
should not be used during pregnancy, if at all possible. including urine, bile, liver, cyst wall, cyst fluid, and CSF
- The manufacturer recommends a pregnancy test prior to
Protein binding: 70%
therapy in women of reproductive potential. Women Metabolism: Hepatic; extensive first-pass effect; pathways
should be advised to avoid pregnancy during and for at include rapid sulfoxidation to active metabolite (albenda-
least 1 month following therapy. Discontinue if pregnancy zole sulfoxide [major]), hydrolysis, and oxidation
occurs during treatment. Half-life elimination: 8 to 12 hours (albendazole sulfoxide)
Breastfeeding Considerations Albendazole excretion Time to peak, serum: 2 to 5 hours for the metabolite
into breast milk was studied following a single oral Excretion: Urine (<1% as active metabolite); feces
400 mg dose in breastfeeding: women 2 weeks to 6
Pharmacodynamics/Kinetics: Additional Consider-
months postpartum (n=33). Mean albendazole concentra-
ations
tions 6 hours after the dose were 63.7 + 11.9 ng/mL
Hepatic function impairment: Systemic availability, rate of
(maternal serum) and 31.9 + 9.2 ng/mL (milk). An active
absorption, and the elimination half-life of albendazole
and inactive metabolite was also detected in breast milk
sulfoxide are increased in patients with extrahepatic
(Abdel-tawab, 2009). The manufacturer recommends that
obstruction.
caution be exercised when administering albendazole to
nursing women. Dosing
Contraindications Hypersensitivity to albendazole, ben- Pediatric
zimidazoles, or any component of the formulation Neurocysticercosis (Taenia solium, pork tape-
Warnings/Precautions Reversible elevations in hepatic worm): Children and Adolescents: Note: Patients
enzymes have been reported; patients with abnormal should receive concurrent corticosteroid for the first
LFTs and hepatic echinococcosis are at an increased risk week of albendazole therapy and anticonvulsant ther-
apy as required.
of hepatotoxicity. Discontinue therapy if LFT elevations are
>2 times the upper limit of normal; may consider restarting <60 kg: Oral: 7.5 mg/kg/dose twice daily for 8 to 30
days; maximum dose: 400 mg/dose
treatment with frequent monitoring of LFTs when hepatic
260 kg: Oral: 400 mg twice daily for 8 to 30 days
enzymes return to pretreatment values. Discontinue ther-
Hydatid disease (Echinococcus granulosus, dog
apy if hepatic enzymes are significantly increased. Agra-
tapeworm): Children and Adolescents (WHO 2010):
nulocytosis, aplastic anemia, granulocytopenia,
<60 kg: Oral: 7.5 mg’kg/dose twice daily; maximum
leukopenia, and pancytopenia have occurred leading to
dose: 400 mg/dose; 28-day cycle followed by a 14-
fatalities (rare); use with caution in patients with hepatic
day albendazole-free interval, for a total of 3 cycles
impairment (more susceptible to hematologic toxicity).
260 kg: Oral: 400 mg twice daily; 28-day cycle fol-
Discontinue therapy in all patients who develop clinically
lowed by a 14-day albendazole-free interval, for a
significant decreases in blood cell counts.
total of 3 cycles
Neurocysticercosis: Corticosteroids should be adminis- Ancyclostoma caninum (Eosinophilic enterocoli-
tered before or upon initiation of albendazole therapy to tis): Limited data available: Children and Adoles-
minimize inflammatory reactions and prevent increased cents: Oral: 400 mg as a single dose (Medical Letter
intracranial pressure. Anticonvulsant therapy should be [Parasitic infections 2013})
used concurrently to prevent seizures. If retinal lesions Ancylostoma duodenale or Necator americanus
exist, weigh risk of further retinal damage due to albenda- (hookworms):
zole-induced inflammatory changes to the retinal lesion vs Infants 23 months: Very limited data available: Oral:
benefit of disease treatment. 200 mg as a single dose. Dosing based on two
Adverse Reactions cases (patient #1: age: 12 weeks, weight: 4.2 kg;
Central nervous system: Dizziness, headache (more com- and patient #2: age: 8 months, weight: 5.8 kg) of
“mon in neurocysticercosis), increased intracranial pres- exclusively breastfed infants who showed clinical
sure, meningism, vertigo improvement after single-dose albendazole therapy
Dermatologic: Alopecia (Bhatia 2010)
Gastrointestinal: Abdominal pain, nausea and vomiting Children <2 years: Limited data available: Oral:
Hepatic: Increased liver enzymes (more common in 200 mg as a single dose; may repeat in 3 weeks
(WHO 2010)
hydatid)
Children >2 years and Adolescents: Limited data
Miscellaneous: Fever
available: Oral: 400 mg as a single dose; may
Rare but important or life-threatening: Acute hepatic fail-
repeat in 3 weeks (CDC; Medical Letter [Parasitic
ure, acute renal failure, agranulocytosis, aplastic ane-
infections 2013]; WHO 2010)
mia, erythema multiforme, granulocytopenia, hepatitis,
Ascariasis (intestinal roundworm): Limited data
hypersensitivity reaction, leukopenia, neutropenia,_pan-
available:
cytopenia, skin rash, Stevens-Johnson syndrome,
Children <2 years: Oral: 200 mg as a single dose;
thrombocytopenia, urticaria
may repeat in 3 weeks (WHO 2010)
Drug Interactions Children >2 years and Adolescents: Oral: 400 mg as
Metabolism/Transport Effects Substrate of CYP1A2 a single dose; may repeat in 3 weeks (CDC; Medical
(minor), CYP3A4 (minor); Note: Assignment of Major/ Letter [Parasitic infections 2013]; WHO 2010)
Minor substrate status based on clinically relevant drug Baylisascaris procyonis (raccoon roundworm),
interaction potential postexposure prophylaxis and treatment: Limited
Avoid Concomitant Use There are no known interac- data available: Children and Adolescents: Oral: Fre-
tions where it is recommended to avoid concomitant use. quently reported dose: 40 mg/kg/day (range: 20 to
Increased Effect/Toxicity 50 mg/kg/day) in a single or two divided doses or
The levels/effects of Albendazole may be increased by: 400 mg twice daily. Initiate as soon as possible after
Grapefruit Juice potential exposure (ideally within 3 days) to prevent
Decreased Effect clinical disease in any child at risk (eg, ingestion of
The levels/effects of Albendazole may be decreased by: raccoon stool or contaminated soil). Duration for
CarBAMazepine; PHENobarbital; Phenytoin prophylaxis is at least 10 days. Reported treatment >
69
ALBENDAZOLE

duration is usually 4 weeks (Gavin 2002; Graeff- Renal Impairment: Pediatric There are no dosage
Teixeira 2016; Hajek 2009; Murray 2004; Pai 2007; adjustments provided in the manufacturer’s labeling
Park 2000; Peters 2012). (has not been studied). However, the need for adjust-
Capillariasis: Limited data available: Children and ment not likely since albendazole is primarily eliminated
Adolescents: Oral: 400 mg once daily for at least 10 by hepatic metabolism. ]
days (CDC; Medical Letter [Parasitic infections 2013]; Hepatic Impairment: Pediatric There are no dosage
Sawamura 1999) adjustments provided in the manufacturer’s labeling.
Clonorchis sinensis (Chinese liver fluke): Limited Administration Oral: Administer with food. For patients
data available: Children and Adolescents: Oral: who have difficulty swallowing whole tablets, tablet may
10 mg/kg/dose once daily for 7 days (CDC; Medical be crushed or chewed and swallowed with a drink of
Letter [Parasitic infections 2013] water.
Cutaneous larva migrans (dog and cat hookworm): Monitoring Parameters Monitor liver function tests and
Infants 28 months and Children $10 kg: Very limited CBC at start of each cycle and every 2 weeks during
data available: Oral: 200 mg once daily for 3 days. therapy (more frequent monitoring for patients with liver
Dosing based on four cases (ages 8, 11, 12, and 13 disease), fecal specimens for ova and parasites; preg-
months) of infants who showed clinical improvement nancy test; ophthalmic exam for retinal lesions (patients
after therapy. There was complete resolution of with neurocysticercosis)
infection in two of these infants; one infant had initial Dosage Forms Excipient information presented when
improvement, then recurrence requiring a second available (limited, particularly for generics); consult spe-
course of therapy and eventually alternate therapy, cific product labeling.
and another infant had resolution of symptoms fol- Tablet,-Oral:
lowed by appearance of a similar lesion at a different Albenza: 200 mg [contains saccharin sodium]
location 3 months later, received a second course,
and had rapid resolution of all symptoms @ Albenza see Albendazole on page 68
(Black 2010). @ Albuked 5 see Albumin on page 70
Children weighing >10 kg and Adolescents: Limited @ Albuked 25 see Albumin on page 70
data available: Oral: 400 mg once daily for 3 days
(Medical Letter [Parasitic infections 2013]; WHO
2010); some patients may only need a single dose Albumin (ai BYoo min)
(WHO 2010)
Enterobiasis (pinworm): Limited data available:
Medication Safety Issues
Sound-alike/look-alike issues:
Children <2 years: Oral: 200 mg as a single dose;
Albuminar-25 (albumin) may be confused with Privigen
may repeat in 3 weeks (WHO 2010)
(immune globulin) due to similar packaging
Children >2 years and Adolescents: Oral: 400 mg as
Albutein may be confused with albuterol
a single dose; may repeat in 2 to 3 weeks (Medical
Buminate may be confused with bumetanide
Letter [Parasitic infections 2013]; WHO 2010)
Filariasis (Wuchereria Bancroft); microfilaria, Brand Names: US Albuked 25; Albuked 5; Albumin-ZLB;
Albuminar-25; Albuminar-5; AlbuRx; Albutein; Buminate;
reduction or suppression or community eradica-
Flexbumin; Human Albumin Grifols; Kedbumin; Plasbu-
tion programs: Limited data available. Administer in
min-25; Plasbumin-5
combination with either ivermectin or diethylcarbama-
zine. Note: Does not kill all the adult worms (Medical
Brand Names: Canada Alburex-25; Alburex-5; Albutein
25%; Albutein 5%; Octalbin 25%; Octalbin 5%; Plasbu-
Letter [Parasitic infections 2013]; WHO 2010).
min-25; Plasbumin-5
Children <10 kg: Oral: 200 mg once annually for 5
years Therapeutic Category Blood Product Derivative; Plasma
Volume Expander
Children >10 kg and Adolescents: Oral: 400 mg once
annually for 5 years Generic Availability (US) Yes
Giardiasis (Giardia duodenalis): Limited data avail- Use Treatment of hemolytic anemia of the newborn (FDA
able: Children 22 years and Adolescents: Oral: approved in neonates); treatment of hypovolemia (FDA
10 mg/kg/day once daily for 5 days; maximum dose: approved in pediatric patients [age not specified] and
400 mg/dose or 400 mg once daily for 5 days (Esco- adults); plasma volume expansion and maintenance of
bedo 2016, Medical Letter [Parasitic infections 2013]; cardiac output in the treatment of certain types of shock
Yereli 2004) or impending shock (FDA approved in pediatric patients
Microsporidia infection (except Enterocytozoon sp. {age not specified] and adults); may be useful to treat
and V. corneae): Limited data available: Children and hypoalbuminemia in burn patients, ARDS, severe neph-
Adolescents: Oral: 7.5 mg/kg/dose twice daily; max- rosis, and cardiopulmonary bypass; unless the condition
imum dose: 400 mg/dose (HHS [pediatric 2016]; responsible for hypoproteinemia can be corrected, albu-
Medical Letter [Parasitic infections 2013]) in HIV- min can provide only symptomatic relief or supportive
exposed/-positive, continue until resolution of signs treatment; has also been used for large volume para-
and symptoms and sustained immune reconstitution centesis, nephrotic syndrome, neonatal hypotension,
(>6 months at CDC immunologic category 1 or 2) after and ascites. Note: Safety and efficacy in pediatric patients
based on previously demonstrated clinical experience with
ART initiation (HHS [pediatric 2016])
Strongyloidiasis (Strongyloides stercoralis): Lim- albumin; product specific data may not be available.
ited data available: Pregnancy Risk Factor C
Children <10 kg: Oral: 200 mg once daily for 3 days; Pregnancy Considerations Animal reproduction studies
may repeat course in 3 weeks (WHO 2010) have not been conducted. Available data is insufficient to
Children >10 kg and Adolescents: recommend use of albumin to reduce the risk of ovarian
CDC recommendations: Oral: 400 mg twice daily for hyperstimulation syndrome (ASRM 2016). Use for other
7 days (CDC) indications may be considered in pregnant women when
WHO recommendations: Oral: 400 mg once daily contraindications to nonprotein colloids exist (Liumbruno
for 3 days; may repeat course in 3 weeks 2009).
(WHO 2010) Breastfeeding Considerations Endogenous albumin is
Trichinellosis (Trichinosis): Limited data available: found in breast milk. The manufacturer recommends that
CDC recommendations: Children and Adolescents: caution be exercised when administering albumin to nurs-
Oral: 400 mg twice daily for 8 to 14 days (CDC; ing women.
Medical Letter [Parasitic infections 2013]) Contraindications Hypersensitivity to albumin or any
WHO recommendations: Children >10 kg and Ado- component of the formulation; severe anemia, heart fail-
lescents: Oral: 400 mg once daily for 8 to 14 days ure; patients at risk of volume overload (eg, patients with
(WHO 2010) renal insufficiency, severe anemia, stabilized chronic ane-
Trichuriasis (whipworm): Limited data available: Chil- mia, or heart failure); dilution with sterile water for injection
dren >2 years and Adolescents: Oral: 400 mg once (may cause hemolysis or acute renal failure)
daily for 3 days (Medical Letter [Parasitic infections Warnings/Precautions Severe allergic or anaphylactic
2013]; WHO 2010); mild cases may be treated with a reaction may occur; discontinue immediately and manage
single dose of 200 to 400 mg; may repeat course in 3 appropriately if allergic or anaphylactic reactions are
weeks (WHO 2010) suspected. Cardiac or respiratory failure, renal failure, or
Toxocariasis (ocular larva migrans, visceral larva increasing intracranial pressure can occur; closely monitor
migrans): Limited data available: hemodynamic parameters in all patients. Use with caution
CDC recommendations: Children and Adolescents: in conditions where hypervolemia and its consequences
Oral: 400 mg twice daily for 5 days (CDC; Medical or hemodilution may increase the risk of adverse effects
Letter [Parasitic infections 2013]) (eg, heart failure, pulmonary edema, hypertension, hem-
“WHO recommendation: Children and Adolescents: orrhagic diathesis, esophageal varices). Adjust rate of
Oral: 10 mg/kg/dose once daily for 5 days; maxi- administration per hemodynamic status and solution con-
mum dose: 400 mg/dose (WHO 2010) centration; monitor closely with rapid infusions. Avoid

70
 ALBUMIN

rapid infusions in patients with a history of cardiovascular Dosing

disease (may cause circulatory overload and pulmonary Neonatal Note: Albumin 5% should be used in hypovo-
edema). Discontinue at the first signs of cardiovascular lemic or intravascularly depleted patients; albumin 25%
overload (eg, headache, dyspnea, jugular venous disten- should be used in patients with fluid or sodium restric-
tion, rales, abnormal elevations in systemic or central tions (eg, patients with hypoproteinemia and generalized
venous blood pressure). Monitor blood pressure. All edema, or nephrotic syndrome); use the 25% concen-
tration with extreme caution in neonates, due to risk of
patients should be observed for signs of hypervolemia
intraventricular hemorrhage (from rapid expansion of the
such as pulmonary edema. Large replacement volumes
intravascular volume); infuse slowly. Dose depends on
may result in electrolyte imbalance. Monitor electrolytes condition of patient:
and replace or maintain as indicated. Large replacement Ascites with hypoalbuminemia: 25% albumin: IV: 1 g/
volumes may result in coagulation abnormality. Monitor kg/dose over 2 to 3 hours; may repeat up to 3 times per
and replete with blood constituents if indicated. day until albumin is >2.5 g/dL (Giefer 2011; Sabri 2003)
Hemolytic disease of the newborn: 25% albumin: IV:
Use with caution in patients with hepatic or renal impair-
1 g/kg/dose administer prior to or during plasma
ment because of added protein load. Use with caution in exchange
those patients for whom sodium restriction is necessary; Hypovolemia, plasma volume expansion: 5% albu-
albumin 5% and 25% solutions contain 130 to 160 mEq/L min: IV: 0.5 to 1 g/kg/dose (10 to 20 mL/kg/dose) over
sodium and are considered isotonic with plasma. The 60 minutes (may be administered more rapidly over at
parenteral product may contain aluminum (Kelly, 1989); least 15 to 20 minutes for use in shock) (Cloherty 2012;
toxic aluminum concentrations may be seen with high Kliegman 2007). Note: Normal saline (or blood) are
doses, prolonged use, or renal dysfunction. Premature preferred for volume expansion in the delivery room
neonates are at higher risk due to immature renal function (AHA [Kattwinkel 2010]; AHA [Wyckoff 2015]).
Hypotension: Limited data available: 5% albumin: IV:
‘and aluminum intake from other parenteral sources.
0.5 g/kg/dose (10 mL/kg/dose) over 15 to 20 minutes;
Parenteral aluminum exposure of >4 to 5 mcg/kg/day is
may repeat once if necessary. Dosing from a study
associated with CNS and bone toxicity; tissue loading may
comparing albumin to NS for hypotension in newborns
occur at lower doses (Federal Register, 2002). See man- (<24 hours old); neonates in the albumin treatment
ufacturer’s labeling. Albumin is a product of human group (n=49, GA 30.8 + 4.4 weeks) had a greater
plasma, may potentially contain infectious agents which improvement in blood pressure and were less likely to
could transmit disease. Screening of donors, as well as require subsequent vasopressors compared to the NS
testing and/or inactivation or removal of certain viruses, treatment arm (n=52, GA 30.1 + 4.1 weeks) (Lynch
reduces the risk. Infections thought to be transmitted by 2008) Another study using the same dose, found no
this product should be reported to the manufacturer. Pack- statistically significant difference between neonates
aging may contain natural latex rubber. Patients with receiving albumin (n=21, GA: 25 to 40 weeks) com-
pared to NS (n=20, GA: 25 to 40 weeks) (Oca 2003).
chronic renal insufficiency receiving albumin solution
Pediatric Note: Albumin 5% should be used in hypovo-
may be at risk for accumulation of aluminum and potential
lemic or intravascularly depleted patients; albumin 25%
toxicities (eg, hypercalcemia, vitamin D refractory osteo- should be used in patients with fluid or sodium restric-
dystrophy, anemia, and severe progressive encephalop- tions (eg, patients with hypoproteinemia and generalized
athy). In patients with increased microvascular edema, or nephrotic syndrome). Dose depends on con-
permeability (eg, sepsis, trauma, burn), the translocation dition of patient:
of fluid from the interstitial compartment to the intravas- Ascites with hypoalbuminemia: Limited data avail-
cular compartment may decrease due to increased albu- able: Infants, Children, and Adolescents: 25% albu-
min in the interstitial space. Furthermore, in extreme min: IV: 1 g/kg/dose over 2 to 3 hours; may repeat up
microvascular permeability states, administration of albu- to 3 times per day until albumin is >2.5 g/dL; max-
min (or other colloids) may increase the net flux of fluid imum dose: 25 g/dose (Giefer 2011, Sabri 2003)
Hypovolemia, plasma volume expansion, including
into the interstitial space reducing intravascular volume
hypovolemic shock (SCCM [Dellinger 2013)]):
and precipitating edematous states (eg, pulmonary
Infants, Children, and Adolescents: 5% albumin: IV:
edema) (Roberts, 1998). Do not dilute 5% albumin with 0.5 to 1 g/kg/dose (10 to 20 mL/kg/dose) over 5 to 10
sterile water for injection (may result in hemolysis). minutes. Usual adult dose: 12.5 to 25 g/dose (250 to
Warnings: Additional Pediatric Considerations In 500 mL/dose). May repeat after 30 minutes if
neonates, use the 25% concentration with extreme cau- response is not adequate (Kleigman 2007).
tion due to risk of intraventricular hemorrhage (from rapid Large volume paracentesis: Limited data available:
expansion of the intravascular volume); infuse slowly. Infants, Children, and Adolescents: 5% or 25% albu-
min: IV: 0.5 to 1 g/kg over 1 to 2 hours after para-
Due to the occasional shortage of 5% human albumin, 5% centesis (Giefer 2011, Kramer 2001)
solutions may at times be prepared by diluting 25% human Nephrotic syndrome edema, refractory: Infants,
albumin with NS or with DSW (if sodium load is a concern); Children, and Adolescents: 25% albumin: IV: 0.5 to
however, do not use sterile water to dilute albumin sol- 1 g/kg/dose over 30 to 60 minutes followed by diuretic
utions, as this may result in hypotonic-associated hemol- therapy (Gipson 2009; Kliegman 2011; Robin-
ysis which can be fatal. son 2003)
Adverse Reactions Renal Impairment: Pediatric There are no dosing
adjustments provided in the manufacturer's labeling;
Cardiovascular: Cardiac failure (precipitation), edema,
use with caution.
hypertension, hypotension, tachycardia
Hepatic Impairment: Pediatric There are no dosing
Central nervous system: Chills, headache adjustments provided in the manufacturer's labeling.
Dermatologic: Pruritus, skin rash, urticaria Preparation for Administration If 5% human albumin is
Endocrine & metabolic: Hypervolemia unavailable, it may be prepared by diluting 25% human
Gastrointestinal: Nausea, vomiting albumin with NS or D5W (if sodium load is a concern). Do
Hypersensitivity: Anaphylaxis not use sterile water to dilute albumin solutions, as this
Respiratory: Bronchospasm, pulmonary edema has been associated with hypotonic-associated hemoly-
Miscellaneous: Fever sis.
Drug Interactions Administration
Metabolism/Transport Effects None known. Parenteral: IV: Too rapid infusion may result in vascular
overload. Rate of infusion dependent upon use. In
Avoid Concomitant Use There are no known interac-
emergencies, may administer as rapidly as necessary
tions where it is recommended to avoid concomitant use.
to improve clinical condition. After initial volume replace-
Increased Effect/Toxicity There are no known signifi- ment:
cant interactions involving an increase in effect. 5%: Do not exceed 2 to 4 mL/minute in patients with
Decreased Effect There are no known significant inter- normal plasma volume; 5 to 10 mL/minute in patients
actions involving a decrease in effect. with hypoproteinemia
Storage/Stability Store at <30°C (86°F); do not freeze. 25%: Do not exceed 1 mL/minute in patients with normal
Do not use solution if4t is turbid or contains a deposit; use plasma volume; 2 to 3 mL/minute in patients with
within 4 hours after opening vial; discard unused portion. hypoproteinemia
Product-specific details:
Mechanism of Action Provides increase in intravascular
Albuminar: May administer via the administration set
oncotic pressure and causes mobilization of fluids from provided (in-line 60 micron filter) or via any admin-
interstitial into intravascular space istration set; use of filter is optional; size of filter may
Pharmacodynamics/Kinetics (Adult data unless vary according to institutional policy. Method of filter
noted) Half-life: 15 to 20 days sterilization used by manufacturer includes 0.2 micron >
YA
ALBUMIN

filter; however, aggregates may form under storage, in ages 22 years and adults; Immediate release and
shipping, and handling. Administration via very small extended release tablets: FDA approved in ages 26
filter will not damage product, but will slow flow rate. years and adults). Note: Although an FDA approved
Albutein: May administer via the administration set indication, the use of oral albuterol for management of
provided (in-line 50 micron filter) or via any admin- acute asthma or long-term daily maintenance treatment
istration set; use of filter is optional; size of filter may is not recommended due to long onset of action and risk
vary according to institutional policy. Method of pro- of side effects (GINA 2008; GINA 2012; NAEPP 2007)
duction includes passage through 0.22 micron filter. Oral inhalation:
May administer via filter as small as 0.22 microns. Inhalation aerosol (metered dose inhaler): Treatment or
Buminate: Administer via the administration set pro- prevention of bronchospasm in patients with reversible
vided (in-line 15 micron filter) or via any filtered obstructive airway disease; prevention of exercise-
administration set; use 25 micron filter to ensure induced bronchospasm (All indications: FDA approved
adequate flow rate in ages 24 years and adults)
Plasbumin: May administer with or without an IV filter; Nebulization solution: Treatment of bronchospasm in
filter as small as 0.22 microns may be used patients with reversible obstructive airway disease
Monitoring Parameters Observe for signs of hypervole- (FDA approved in ages 22 years and adults; Proventil:
mia, pulmonary edema, cardiac failure, vital signs, fluid FDA approved in ages 212 years and adults); treatment
status, Hgb, Hct, urine specific gravity of acute attacks of bronchospasm (FDA approved in
Additional Information In certain conditions (eg, hypo- ages 22 years and adults; Proventil: FDA approved in
proteinemia with generalized edema, nephrotic syn- ages 212 years and adults). Note: Approval ages for
drome), doses of albumin may be followed with IV generics may vary; consult prescribing information for
furosemide: 0.5 to 1 mg/kg/dose. details.
Both albumin 5% and 25% contain 130 to 160 mEq/L of Pregnancy Risk Factor C
sodium; albumin 5% is osmotically equivalent to an equal Pregnancy Considerations Adverse events have been
volume of plasma; albumin 25% is osmotically equivalent observed in some animal reproduction studies. Albuterol
to 5 times its volume of plasma. crosses the placenta (Boulton 1997). Congenital anoma-
Dosage Forms Excipient information presented when lies (cleft palate, limb defects) have rarely been reported
available (limited, particularly for generics); consult spe- following maternal use during pregnancy. Multiple medi-
cific product labeling. [DSC] = Discontinued product cations were used in most cases, no specific pattern of
Solution, Intravenous: defects has been reported, and no relationship to albuterol
Albumin-ZLB: 5% (250 mL, 500 mL); 25% (50 mL, has been established. The amount of albuterol available
100 mL) systemically following inhalation is significantly less in
Albuminar-5: 5% (250 mL, 500 mL) comparison to oral doses.
Albuminar-25: 25% (50 mL, 100 mL) Uncontrolled asthma is associated with adverse events on
Albutein: 25% (50 mL, 100 mL)
pregnancy (increased risk of perinatal mortality, pree-
Buminate: 5% (250 mL, 500 mL); 25% (20 mL) clampsia, preterm birth, low birth weight infants). Poorly
Plasbumin-5: 5% (50 mL, 250 mL)
controlled asthma or asthma exacerbations may have a
Plasbumin-25: 25% (20 mL, 50 mL, 100 mL)
greater fetal/maternal risk than what is associated with
Generic: 5% (50 mL [DSC]); 25% (50 mL, 100 mL)
appropriately used asthma medications. Albuterol is the
Solution, Intravenous [preservative free]:
preferred short acting beta-agonist when treatment for
Albuked 5: 5% (250 mL)
asthma is needed during pregnancy (ACOG 2008; GINA
Albuked 25: 25% (50 mL, 100 mL)
2016; NAEPP 2007). If high doses are required during
AlbuRx: 5% (250 mL, 500 mL)
labor and delivery, monitoring of glucose concentrations in
Albutein: 5% (50 mL, 250 mL, 500 mL); 25% (20 mL, 50
the newborn for 24 hours is recommended, especially in
mL, 100 mL)
preterm infants (GINA 2016).
Flexbumin: 5% (250 mL); 25% (50 mL, 100 mL)
Human Albumin Grifols: 25% (50 mL, 100 mL) Albuterol may affect uterine contractility. Maternal pulmo-
Kedbumin: 25% (50 mL, 100 mL) nary edema and other adverse events have been reported
Plasbumin-5: 5% (50 mL, 250 mL) when albuterol was used for tocolysis. Albuterol is not
Plasbumin-25: 25% (20 mL, 50 mL, 100 mL) approved for use as a tocolytic; use caution when needed
Generic: 5% (100 mL, 250 mL, 500 mL); 25% (50 mL, to treat bronchospasm in pregnant women. Use of the
100 mL) injection (Canadian product; not available in the US.) is
@ Albuminar-5 see Albumin on page 70
specifically contraindicated in women during the first or
second trimester who may be at risk of threatened
@ Albuminar-25 see Albumin on page 70 abortion.
@ Albumin (Human) see Albumin on page 70 Breastfeeding Considerations It is not known if albu-
@ Albumin-ZLB see Albumin on page 70 terol is present in breast milk.
The amount of albuterol available systemically following
@ Alburex-5 (Can) see Albumin on page 70
inhalation is significantly less in comparison to oral
@ Alburex-25 (Can) see Albumin on page 70 doses. According to the manufacturer, the decision to
@ AlbuRx see Albumin on page 70 continue or discontinue breastfeeding during therapy
@ Albutein see Albumin on page 70 should take into account the risk of exposure to the
infant and the benefits of treatment to the mother.
@ Albutein 5% (Can) see Albumin on page 70
Women with asthma should be encouraged to breast-
@ Albutein 25% (Can) see Albumin on page 70 feed (GINA 2016). Use of albuterol is generally consid-
ered acceptable in breastfeeding women when used in
Albuterol (al BYOO ter ole) usual doses (WHO 2002).
Contraindications :
Medication Safety Issues Inhalation, Oral: Hypersensitivity to albuterol or any com-
Sound-alike/look-alike issues: ponent of the formulation; severe hypersensitivity to milk
Albuterol may be confused with Albutein, atenolol proteins (dry powder inhalers).
Proventil may be confused with Bentyl, PriLOSEC, Pri- Canadian labeling: Additional contraindications (not in US
nivil labeling):
Salbutamol may be confused with salmeterol Injection: Ventolin: Hypersensitivity to albuterol or any
Ventolin may be confused with phentolamine, Benylin, component of the formulation; tachyarrhythmias; risk of
Vantin abortion during first or second trimester
Related Information Inhalation: Tocolytic use in patients at risk of premature
Oral Medications That Should Not Be Crushed or Altered labor or threatened abortion
on page 2217 Warnings/Precautions Albuterol is a short-acting beta2-
Brand Names: US ProAir HFA; ProAir RespiClick; Pro- agonist (SABA) that should be used as needed for quick
ventil HFA; Ventolin HFA; VoSpire ER [DSC] relief of asthma symptoms. Based on a step-wise treat-
Brand Names: Canada Airomir; Ventolin Diskus; Ventolin ment approach using asthma guidelines, monotherapy
HFA; Ventolin |.V. Infusion; Ventolin Nebules P.F.; Ventolin without concurrent use of a long-term controller medica-
Respirator tion should only be reserved for patients with mild, inter-
Therapeutic Category Adrenergic Agonist Agent; Anti- mittent forms of asthma without the presence of risk
asthmatic; Betazg-Adrenergic Agonist; Bronchodilator; factors (Step 1 and/or exercise-induced) (GINA 2016;
Sympathomimetic NAEPP 2007). Patient must be instructed to seek medical
Generic Availability (US) May be product dependent attention in cases where acute symptoms are not relieved
Use or a previous level of response is diminished. The need to
Oral: Treatment of bronchospasm in patients with rever- increase frequency of use may indicate deterioration of
sible obstructive airway disease (Syrup: FDA approved asthma, and treatment must not be delayed.

72
 ALBUTEROL

Use with caution in patients with cardiovascular disease Respiratory: Bronchitis, bronchospasm (exacerbation of
(arrhythmia, coronary insufficiency, or hypertension, or HF underlying pulmonary disease), cough, dyspnea, epis-
heart failure); beta-agonists may produce ECG changes taxis (children and adolescents 6 to 14 years), exacer-
(flattening of the T wave, prolongation of the QTc interval, bation of asthma, flu-like symptoms, increased bronchial
ST segment depression) and/or cause elevation in blood secretions, laryngitis, nasal congestion, nasopharyngitis,
pressure, heart rate and result in CNS stimulation/excita- oropharyngeal edema, oropharyngeal pain, pharyngitis,
tion. Betaz-agonists may increase risk of arrhythmia, pulmonary disease, respiratory tract disease, rhinitis,
increase serum glucose (and aggravate preexisting dia- sinus headache, sinusitis, throat irritation, upper respira-
betes and ketoacidosis), or decrease serum potassium. In tory tract infection, upper respiratory tract inflammation,
a scientific statement from the American Heart Associa- viral upper respiratory tract infection, wheezing
tion, albuterol has been determined to be an agent that Miscellaneous: Accidental injury, fever
may either cause direct myocardial toxicity or exacerbate Rare but important or life-threatening: Anaphylaxis, atrial
underlying myocardial dysfunction (magnitude: moderate fibrillation, exacerbation of diabetes mellitus, gag reflex,
to major) (AHA [Page 2016]). Use with caution in patients glossitis, hyperglycemia, hypokalemia, hypotension,
with renal impairment. ketoacidosis, lactic acidosis, paradoxical bronchospasm,
Immediate hypersensitivity reactions (urticaria, angioe- peripheral vasodilation, supraventricular tachycardia,
dema, rash, bronchospasm), including anaphylaxis, have tongue ulcer
been reported. Do not exceed recommended dose; seri- Drug Interactions
ous adverse events, including fatalities, have been asso- Metabolism/Transport Effects None known.
ciated with excessive use of inhaled sympathomimetics. Avoid Concomitant Use
Rarely, paradoxical bronchospasm may occur with use of Avoid concomitant use of Albuterol with any of the
inhaled bronchodilating agents (may be fatal); this should following: Beta-Blockers (Nonselective); lobenguane |
be distinguished from inadequate response. All patients 123; Loxapine
~ should utilize a spacer device or valved holding chamber Increased Effect/Toxicity
when using a metered-dose ‘inhaler; in addition, use Albuterol may increase the levels/effects of: Atosiban;
spacer for children <5 years of age and consider adding Doxofylline; Loop Diuretics; Loxapine; QTc-Prolonging
a face mask for infants and children <4 years of age. Agents (Highest Risk); QTc-Prolonging Agents (Moder-
Some dosage forms may contain sodium benzoate/ben- ate Risk); Sympathomimetics; Thiazide and Thiazide-
zoic acid; benzoic acid (benzoate) is a metabolite of Like Diuretics
benzyl alcohol; large amounts of benzyl! alcohol
(299 mg/kg/day) have been associated with a potentially The levels/effects of Albuterol may be increased by:
AtoMOXetine; Cannabinoid-Containing Products;
fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Cocaine (Topical); Guanethidine; Linezolid; MiFEPRI-
ing syndrome" consists of metabolic acidosis, respiratory
distress, gasping respirations, CNS dysfunction (including Stone; Monoamine Oxidase Inhibitors; Tedizolid; Tricy-
convulsions, intracranial hemorrhage), hypotension, and clic Antidepressants
cardiovascular collapse (AAP ["Inactive" 1997]; CDC Decreased Effect
1982); some data suggests that benzoate displaces bilir- Albuterol may decrease the levels/effects of: lobenguane
ubin from protein binding sites (Ahlfors 2001); avoid or use 1123
dosage forms containing benzy! alcohol derivative with The levels/effects of Albuterol may be decreased by:
caution in neonates. See manufacturer's labeling. Powder Beta-Blockers (Beta Selective); Beta-Blockers (Nonse-
for oral inhalation contains lactose; hypersensitivity reac- lective); Betahistine
tions (eg, anaphylaxis, angioedema, pruritus, and rash) Storage/Stability
have been reported in patients with milk protein allergy. Metered-dose inhalers (HFA aerosols): Store at 15°C to
Potentially significant interactions may exist, requiring 25°C (59°F to 77°F). Do not store at temperature >120°F.
dose or frequency adjustment, additional monitoring,
Do not puncture. Do not use or store near heat or open
and/or selection of alternative therapy. flame.
Warnings: Additional Pediatric Considerations Ventolin HFA: Discard when counter reads 000 or 12
CNS stimulation, hyperactivity, and insomnia occur more months after removal from protective pouch, whichever
frequently in younger children than in adults. In children
comes first. Store with mouthpiece down.
receiving oral albuterol therapy, erythema multiforme and
Dry powder inhalers:
Stevens-Johnson syndrome have been reported (rare). ProAir RespiClick: Store between 15°C and 25°C (59°F
Outbreaks of lower respiratory tract colonization and
and 77°F). Avoid exposure to extreme heat, cold, or
infection have been attributed to contaminated multidose humidity. Discard 13 months after opening the foil
albuterol bottle.
pouch, or when the counter displays 0, whichever
Adverse Reactions Incidence of adverse effects is comes first
dependent upon age of patient, dose, and route of admin-
Ventolin Diskus [Canadian product]: Store at <30°C
istration. ; (86°F). Keep in a dry place. Protect from frost and light.
Cardiovascula.: Chest discomfort, chest pain, edema,
Diskus is nonrefillable and should be discarded after all
extrasystoles, flushing, hypertension, palpitations, tachy-
doses have been administered.
cardia
Infusion solution [Canadian product]: Ventolin IV: Store at
Central nervous system: Anxiety, ataxia, depression, diz-
15°C to 30°C (59°F to 86°F). Protect from light. After
ziness, drowsiness, emotional lability, excitement (chil-
dilution, discard unused portion after 24 hours.
dren and adolescents 2 to 14 years), fatigue, headache,
Nebulization solution: Store at 2°C to 25°C (36°F to 77°F).
hyperactivity (children and adolescents 6 to 14 years),
Do not use if solution changes color or becomes cloudy.
insomnia, malaise, migraine, nervousness, pain, rest-
Products packaged in foil should be used within 1 week
lessness, rigors, shakiness (children and adolescents 6
(or according to the manufacturer's recommendations) if
to 14 years), vertigo, voice disorder
removed from foil pouch.
Dermatologic: Diaphoresis, pallor (children 2 to 6 years),
Syrup: Store at 20°C to 25°C (68°F to 77°F).
skin rash, urticaria
Tablet: Store at 20°C to 25°C (68°F to 77°F).
Endocrine & metabolic: Diabetes mellitus, increased
Tablet, extended release: Store at 20°C to 25°C (68°F
serum glucose
Gastrointestinal: Anorexia (children 2 to 6 years), diar- to 77°F)
rhea, dyspepsia, eructation, flatulence, gastroenteritis, Mechanism of Action Relaxes bronchial smooth muscle
gastrointestinal symptoms (children 2 to 6 years), glossi- by action on betaz-receptors with little effect on heart rate
tis, increased appetite (children and adolescents 6 to 14 Pharmacodynamics/Kinetics (Adult data unless
years), nausea, unpleasant taste (inhalation site), viral noted)
gastroenteritis, vomiting, xerostomia Onset of action: Peak effect:
Genitourinary: Difficulty in micturition, urinary tract Nebulization/oral inhalation: 0.5 to 2 hours
infection CFC-propelled albuterol: 10 minutes (peak plasma
Hematologic & oncologic: Decreased hematocrit, concentration)
decreased hemoglobin, decreased white blood cell Inhalation powder: 30 minutes (peak plasma concen-
count, lymphadenopathy tration)
Hepatic: Increased serum ALT, increased serum AST HFA inhalers: 25 minutes (peak plasma concentration);
Hypersensitivity: Hypersensitivity reaction ~56 minutes (peak FEV, effect)
Infection: Cold symptoms, infection Oral: Immediate release: 2 to 3 hours
Local: Application site reaction (HFA inhaler) Duration: Nebulization/oral inhalation: 2 to 6 hours; Oral:
Neuromuscular & skeletal: Back pain, hyperkinesia, leg Immediate release: 4 to 6 hours; extended release
cramps, muscle cramps, musculoskeletal pain, tremor tablets: Up to 12 hours
Ophthalmic: Conjunctivitis (children 2 to 6 years) Protein binding: 10%
Otic: Otalgia, otitis media, ear disease, tinnitus Metabolism: Hepatic to an inactive sulfate

73
ALBUTEROL

Half-life elimination: Inhalation: 3.8 to ~5 hours; Oral: 3.7 Nebulization: Limited data in ages <2 years:
to 5 hours
Excretion: Urine (30% as unchanged drug); feces (<20%) Albuterol Nebulization Dosage
Pharmacodynamics/Kinetics: Additional Consider- 0.5% 0.083%
ations Solution Solution Frequency
(mL) (mL)
Renal function impairment: There was a 67% decline in
Infants and
albuterol clearance in patients with CrCl 7 to 53 mL/ Children <5 y 0.63 to 2.5 mg} 0.13 to 0.5 mL| 0.76 to 3 mL |Every 4 to 6h
minute. Children 25 y
and 4.25to5mg | 0.25to1mlL | 1.5to6mL | Every 4to 8h
Dosing Adolescents
Neonatal
Bronchospasm, treatment:
Bronchodilation: Limited data available: Oral inhala-
Oral inhalation:
tion:
Inhalation, aerosol (metered dose inhaler):
Nebulization: Usual reported dose: 1.25 to 2.5 mg/dose Manufacturer's labeling: Children 24 years and Ado-
(Ballard 2002). In a retrospective report, 16 VLBW lescents: 90 mcg/puff: 1 to 2 puffs every 4 to 6
neonates (mean GA: 26.1 + 1.2 weeks; mean birth- hours
weight: 817 + 211 g) received 1.25 mg/dose every 8 Alternate dosing: Limited data available: Infants,
hours for >2 weeks (Mhanna 2009) Children, and Adolescents: 90 mcg/puff: 4 to 8
Inhalation, aerosol (metered dose inhaler); mechani- puffs every 15 to 20 minutes for 3 doses; then
cally ventilated patients: 90 mcg/spray: 1 to 2 puffs every 1 to 4 hours (Hegenbarth 2008)
administered into the ventilator circuit was the most Nebulization:
frequently reported dose in a survey of 68 neonatal Manufacturer labeling: Children 22 years and Ado-
intensive care units (Ballard 2002); typically used lescents:
every 6 hours (Fok 1998); may consider more fre- 10 to 15 kg: 1.25 mg 3 to 4 times/day
quent use if clinically indicated >15 kg: 2.5 mg 3 to 4 times/day
Hyperkalemia; adjunct therapy: Limited data available: Alternate dosing: Limited data available (Hegen-
Oral inhalation: Nebulization: 0.4 mg (in 2 mL of NS) barth 2008): Infants, Children, and Adolescents:
every 2 hours was administered to premature neonates Intermittent: 0.5% (5 mg/mL) solution: 2.5 mg
(GA: 25 + 1 weeks; PNA: 5 + 1 days) with a birthweight every 20 minutes for 3 doses, then 0.15 to
<2 kg (736 + 89 g) and serum potassium concentration 0.3 mg/kg up to 10 mg every 1 to 4 hours
26 mEq/L in a randomized, placebo controlled, double Continuous (prolonged nebulization): 0.5 mg/kg/
blind study (treatment group: n=8); administration con- hour up to 10 to 15 mg/hour ~
tinued until serum potassium levels were <5 mEq/L or Oral: Note: Not the preferred route for treatment of
maximum of 12 doses were administered; results asthma; inhalation via nebulization or MDI is preferred
showed potassium serum concentrations significantly (GINA 2014; GINA 2014a; NAEPP 2007)
declined in the first 4 hours of albuterol treatment Immediate release formulation (syrup, tablets):
compared to placebo and continued to be lower at 8 Children 2 to 6 years: 0.1 to 0.2 mg/kg/dose 3 times
hours after first dose; mean number doses adminis-
daily; maximum dose: 4 mg
Children 6 to 12 years: 2 mg/dose 3 to 4 times daily
tered was 6 doses (Singh 2002). Note: Albuterol
Adolescents: 2 to 4 mg/dose 3 to 4 times daily
should be not be used as the sole agent for treating
Sustained release formulation (tablets):
severe hyperkalemia, especially in patients with renal
Children 26 years: 0.3 to 0.6 mg/kg/day divided
failure.
twice daily; maximum daily dose: 8 mg/day
Pediatric Adolescents: 4 mg/dose twice daily; may increase to
Asthma, acute exacerbation: Oral inhalation: 8 mg/dose twice daily
Outpatient: Inhalation aeroso/ (metered dose inhaler): Exercise-induced bronchospasm; prevention:
90 mcg/puff: Children and Adolescents: 2 to 6 puffs (NAEPP 2007; Parsons 2013): Oral inhalation:
every 20 minutes (GINA 2014; NAEPP 2007); if good Inhalation, aerosol (metered dose inhaler): Limited data
response after 2 doses then every 3 to 4 hours for 24 available in ages <4 years: 90 mcg/puff:
to 48 hours (NAEPP 2007); Note: GINA guideline Infants and Children <5 years: 1 to 2 puffs 5 to 20
dosing is based on the 100 mcg/puff salbutamol minutes before exercising
product (not available in U.S.) (GINA 2014) Children 25 years and Adolescents: 2 puffs 5 to 20
Emergency care/hospital: minutes before exercising
Inhalation aerosol (metered dose inhaler): 90 mcg/ Hyperkalemia; adjunct therapy: Limited data available:
puff: Infants, Children, and Adolescents: Oral inhalation:
Children: Limited data available in ages <4 years: 4 Nebulization: 10 mg/dose or 0.3 to 0.5 mg/kg/dose
to 8 puffs every 20 minutes for 3 doses then every has been used by some centers and based on experi-
1 to 4 hours (NAEPP 2007) ence that has shown the effective nebulization for
Adolescents: 4 to 8 puffs every 20 minutes for up to hyperkalemia is 4 times more than the bronchodilatory
4 hours then every 1 to 4 hours (NAEPP 2007) dose (Furhman 2011; Weiner 1998; Weisburg 2008).
Nebulization: Note: Albuterol should not be used as the sole agent
Infants and Children: Limited data in ages <2 years: for treating severe hyperkalemia, especially in patients
Intermittent: 0.15 mg/kg (minimum dose: 2.5 mg) with renal failure.
every 20 minutes for 3 doses then 0.15 to Renal Impairment: Pediatric All patients: Use with
0.3 mg/kg not to exceed 10 mg every 1 to 4 hours caution in patients with renal impairment. No dosage
(NAEPP 2007) adjustment required, including patients on hemodialysis,
Continuous: Dosing regimens variable; optimal peritoneal dialysis, or CRRT (Aronoff 2007).
dosage not established: Hepatic Impairment: Pediatric There are no dosage
NIH Guidelines: 0.5 mg/kg/hour (NAEPP 2007) adjustments provided in manufacturer's labeling.
Alternate dosing: Limited data available: Preparation for Administration Solution for nebuliza-
0.3 mg/kg/hour has also been used safely in tion: 0.5% solution: Dilute 0.25 mL (1.25 mg dose) or 0.5
mL (2.5 mg dose) of solution to a total of 3 mL with normal
the treatment of severe status asthmaticus in
saline; also compatible with cromolyn or ipratropium neb-
children (Papo 1993); higher doses of 3 mg/kg/
ulizer solutions
hour + 2.2 mg/kg/hour in children (n=19, mean
Administration
age: 20.7 months + 38 months) resulted in no
Oral inhalation: In infants and children <4 years, a face
cardiotoxicity (Katz 1993)
mask with either the metered dose inhaler or nebulizer is
Adolescents:
recommended (GINA 2014a; NAEPP 2007)
Intermittent: 2.5 to 5 mg every 20 minutes for 3
Inhalation, aerosol (metered dose inhaler): Prime the
doses then 2.5 to 10 mg every 1 to 4 hours as
inhaler (before first use or if it has not been used for
needed more than 2 weeks) by releasing 4 test sprays into the
Continuous: 10 to 15 mg/hour air away from the face (3 test sprays for ProAir HFA);
Asthma, maintenance therapy (nonacute) (NAEPP shake well before use; use spacer for children <5 years
2007): Oral inhalation: of age and consider adding a face mask for infants and
Inhalation, aerosol (metered dose inhaler): \nfants, children <4 years of age. HFA inhalers should be
Children, and Adolescents: Limited data available in cleaned with warm water at least once per week; allow
ages <4 years: 90 mcg/puff: 2 puffs every 4 to 6 hours to air dry completely prior to use.
as needed. Note: Not recommended for long-term Nebulization: Concentrated solutions (20.5%) should be
daily maintenance treatment; regular use exceeding diluted prior to use; adjust nebulizer flow to deliver
2 days/week for symptom control (not prevention of dosage over 5 to 15 minutes; avoid contact of the
exercise-induced bronchospasm) indicates the need dropper tip (multidose bottle) with any surface, includ-
for additional long-term control therapy. ing the nebulizer reservoir and associated ventilator

74
 ALCLOMETASONE

equipment. For continuous nebulization, the total Decreased Effect There are no known significant inter-
amount of fluid delivered is determined by nebulizer actions involving a decrease in effect.
delivery device; usually 25 to 30 mL per 1 hour of Storage/Stability Store at 15°C to 25°C (59°F to 77°F).
nebulization, protocols may vary by institution (Hegen- Mechanism of Action Direct H,-receptor antagonist and
barth 2008). Blow-by administration is not recom- inhibitor of histamine release from mast cells
mended; use a mask device if patient is unable to Pharmacodynamics/Kinetics (Adult data unless
hold mouthpiece in mouth for administration. noted)
Oral: Administer with food; do not crush or chew extended Absorption: Minimal systemic absorption
release tablets j Protein binding: ~40%; Carboxylic acid (metabo-
Monitoring Parameters Serum potassium, oxygen satu- lite): ~60%
ration, heart rate, pulmonary function tests, respiratory Metabolism: Non-CYP450 cytosolic enzymes to the active
rate, use of accessory muscles during respiration, supra- metabolite carboxylic acid
sternal retractions; arterial or capillary blood gases (if Half-life elimination: Carboxylic acid: ~2 hours
patient's condition warrants)
Dosing
Test Interactions Increased renin (S), increased aldoster- Pediatric Allergic conjunctivitis: Children 22 years and
one (S)
Adolescents: Ophthalmic: Instill 1 drop in each eye once
Dosage Forms Considerations ProAir HFA 8.5 g can- daily
isters, ProAir RespiClick 0.65 g inhaler, Proventil HFA
Renal Impairment: Pediatric There are no dosing
6.7 g canisters, and Ventolin HFA 18 g canisters contain
adjustments provided in the manufacturer's labeling.
200 inhalations. Ventolin HFA 8 g canisters contain 60
Hepatic Impairment: Pediatric There are no dosing
inhalations.
adjustments provided in the manufacturer's labeling.
Dosage Forms Excipient information presented when
Administration For topical ophthalmic use only. Contact
available (limited, particularly for generics); consult spe-
lenses should be removed prior to application, and may be
. cific product labeling. [DSC] = Discontinued product
reinserted 10 minutes after administration. Separate
Aerosol Powder Breath Activated, Inhalation:
administration of other ophthalmic agents by 5 minutes.
ProAir RespiClick: 90 mcg/actuation (1 ea) [contains milk
Do not insert contacts if eyes are red. Avoid contaminating
protein]
the applicator tip with affected eye(s).
Aerosol Solution, Inhalation:
ProAir HFA: 90 mcg/actuation (8.5 g) Dosage Forms Excipient information presented when
Proventil HFA: 90 mcg/actuation (6.7 g) available (limited, particularly for generics); consult spe-
Ventolin HFA: 90-meg/actuation (8 g, 18 g) cific product labeling.
Nebulization Solution, Inhalation: Solution, Ophthalmic:
Generic: 0.63 mg/3 mL (3 mL); 0.083% [2.5 mg/3 mL] (3 Lastacaft: 0.25% (3 mL) [contains benzalkonium chlor-
mL); 0.5% [2.5 mg/0.5 mL] (20 mL) ide, edetate disodium]
Nebulization Solution, Inhalation [preservative free]: @ Alcaine [DSC] see Proparacaine on page 1698
Generic: 0.63 mg/3 mL (3 mL); 1.25 mg/3 mL (3 mL);
0.083% [2.5 mg/3 mL] (3 mL); 0.5% [2.5 mg/0.5 mL] @ Alcaine (Can) see Proparacaine on page 1698
(1 ea) @ Alcalak [OTC] [DSC] see Calcium Carbonate
Syrup, Oral: on page 340
Generic: 2 mg/5 mL (473 mL)
Tablet, Oral:
Alclometasone (al kloe MET a sone)
Generic: 2 mg, 4 mg
Tablet Extended Release 12 Hour, Oral: Medication Safety Issues
VoSpire ER: 4 mg [DSC] [contains fd&c blue #1 alumi- Sound-alike/look-alike issues:
num lake, fd&c yellow #10 aluminum lake] Aclovate® may be confused with Accolate®
VoSpire ER: 8 mg [DSC] International issues:
Generic: 4 mg, 8 mg Cloderm: Brand name for alclometasone [Indonesia], but
also brand name for clobetasol [China, India, Malaysia,
@ Albuterol Sulfate see Albuterol on page 72
Singapore, Thailand]; clocortolone [U.S., Canada]; clo-
trimazole [Germany]
Alcaftadine (ai kar ta deen) Related Information
Topical Corticosteroids on page 2114
Brand Names: US Lastacaft
Brand Names: US Aclovate [DSC]
Therapeutic Category Histamine H, Antagonist; Hista-
Therapeutic Category Adrenal Corticosteroid; Anti-
mine H, Antagonist, Second Generation; Mast Cell Stabil-
inflammatory Agent; Corticosteroid, Topical; Glucocorti-
izer
coid
Generic Availability (US) No
Generic Availability (US) Yes
Use Prevention 2f itching associated with allergic conjunc-
Use Treatment of inflammation and pruritic manifestations
tivitis (FDA approved in ages 22 years and adults)
of corticosteroid-responsive dermatosis (low to medium
Pregnancy Risk Factor B
potency topical corticosteroid) (FDA approved in ages 21
Pregnancy Considerations Adverse events were not
year and adults); Note: In pediatric patients, safety and
observed in animal reproduction studies. The amount of
efficacy 23 weeks have not been established.
alcaftadine absorbed systemically following ophthalmic
Pregnancy Risk Factor C
administration is minimal.
Breastfeeding Considerations It is not known if alcaf-
Pregnancy Considerations Adverse events have been
observed with corticosteroids following topical application
tadine is excreted in breast milk. The manufacturer rec-
in animal reproduction studies.
ommends that caution be exercised when administering
alcaftadine to nursing women Systemic bioavailability of topical corticosteroids is varia-
Contraindications Hypersensitivity to alcaftadine or any ble (integrity of skin, use of occlusion, etc) and may be
component of the formulation. further influenced by trimester of pregnancy (Chi 2017). In
Warnings/Precautions Product contains benzalkonium general, the use of topical corticosteroids is not associated
chloride which may be absorbed by soft contact lenses; with a significant risk of adverse pregnancy outcomes.
remove lenses prior to administration and wait 10 minutes However, there may be an increased risk of low birth
before reinserting. Not for the treatment of contact lens weight infants following maternal use of potent or very
irritation; do not wear contact lens if eye is red. For topical potent topical products, especially in high doses. Use of
ophthalmic use only. To avoid eye injury and contamina- mild to moderate potency topical corticosteroids is pre-
tion, do not touch dropper tip to eyelids or any surface. ferred in pregnant women and the use of large amounts or
Adverse Reactions use for prolonged periods of time should be avoided (Chi
Central nervous system: Headache 2016; Chi 2017; Murase 2014). Also avoid areas of high
Ophthalmic: Burning sensation of eyes, eye irritation, eye percutaneous absorption (Chi 2017). The risk of stretch
pruritus, eye redness, stinging of eyes marks may be increased with use of topical corticosteroids
Respiratory: Nasopharyngitis (Murase 2014).
Rare but important or life-threatening: Erythema of eyelid, Breastfeeding Considerations It is not known if suffi-
eye discharge, eyelid edema, hypersensitivity, swelling cient quantities of alclometsone are absorbed following
of eye topical administration to produce detectable amounts in
Drug Interactions breast milk. Systemic corticosteroids are present in breast
Metabolism/Transport Effects None known. milk. Although the manufacturer recommends that caution
Avoid Concomitant Use There are no known interac- be used, topical corticosteroids are generally considered
tions where it is recommended to avoid concomitant use. acceptable for use in breastfeeding women (Butler 2014;
Increased Effect/Toxicity There are no known signifi- WHO 2002). Do not apply topical corticosteroids to nip-
cant interactions involving an increase in. effect. ples; hypertension was noted in a breastfeeding infant »
“1S
ALCLOMETASONE

exposed to a topical corticosteroid while breastfeeding endogenous chemical mediators of inflammation (kinins,
(Butler 2014; Leachman 2006). histamine, liposomal enzymes, prostaglandins) through
Contraindications the induction of phospholipase Ap inhibitory proteins (lip-
Hypersensitivity to alclometasone or any component of ocortins) and sequential inhibition of the release of arach-
the formulation. idonic acid. Alclometasone has low range potency. »
Documentation of allergenic cross-reactivity for cortico- Pharmacodynamics/Kinetics (Adult data unless
steroids is limited. However, because of similarities in noted)
chemical structure and/or pharmacologic actions, the Onset of action: Initial response (Ruthven 1988): Eczema:
possibility of cross-sensitivity cannot be ruled out with 5.3 days; Psoriasis: 6.7 days
certainty. Absorption: Topical: ~3% absorbed systemically after 8
Warnings/Precautions Topical corticosteroids may be hours when applied to intact skin
absorbed percutaneously. Absorption may cause manifes-
Time to peak: Peak response (Ruthven 1988): Eczema:
tations of Cushing syndrome, hyperglycemia, or glycosu-
13.9 days; Psoriasis: 14.8 days
ria. Absorption is increased by the use of occlusive
Dosing
dressings, application to denuded skin, or application to
large surface areas. May cause hypercorticism or sup- Pediatric Steroid-responsive dermatoses: Children
pression of hypothalamic-pituitary-adrenal (HPA) axis, and Adolescents: Topical: Apply thin film to affected area
particularly in younger children or in patients receiving 2 to 3 times daily. Note: Therapy should be discontinued
high doses for prolonged periods. HPA axis suppression when control is achieved; if no improvement is seen
may lead to adrenal crisis. within 2 weeks, reassessment of diagnosis may be
necessary. Do not use for >3 weeks.
Prolonged treatment with corticosteroids has been asso- Renal Impairment: Pediatric There are no dosage
ciated with the development of Kaposi sarcoma (case
adjustments provided in the manufacturer's labeling.
reports); if noted, discontinuation of therapy should be
Hepatic Impairment: Pediatric There are no dosage
considered (Goedert 2002). Prolonged use may result in
adjustments provided in the manufacturer's labeling.
fungal or bacterial superinfection; discontinue if dermato-
logical infection persists despite appropriate antimicrobial Administration Topical: Apply sparingly in a thin film to
therapy. Local sensitization (redness, irritation) may occur; clean, dry skin; rub in lightly; for external use only; avoid
discontinue if sensitization is noted. Allergic contact der- contact with the eyes; generally not for routine use on the
matitis can occur, it is usually diagnosed by failure to heal face, underarms, or groin area (including diapered area).
rather than clinical exacerbation. Do not use on open wounds or weeping lesions. The
treated skin area should not be bandaged or covered
Safety and efficacy for use >3 weeks has not been unless directed by the prescriber. Wash hands thoroughly
established. Children may absorb proportionally larger before and after use.
amounts after topical application and may be more prone
Monitoring Parameters Clinical signs and symptoms of
to systemic effects. HPA axis suppression, intracranial
improvement in condition; assessment of HPA suppres-
hypertension, and Cushing syndrome have been reported
in children receiving topical corticosteroids. Prolonged use sion (eg, ACTH stimulation test, morning plasma cortisol
may affect growth velocity; growth should be routinely test, urinary free cortisol test) if treatment for prolonged
monitored in pediatric patients. Not for the treatment of periods or if HPA axis suppression is suspected; growth in
diaper dermatitis. pediatric patients :
Dosage Forms Excipient information presented when
Avoid use with occlusive dressings. Discontinue use if available (limited, particularly for generics); consult spe-
irritation occurs. If no improvement is seen within 2 weeks, cific product labeling. [DSC] = Discontinued product
reassessment of diagnosis may be necessary. Avoid Cream, External, as dipropionate:
contact with eyes. Generally not for routine use on the Aclovate: 0.05% (15 g [DSC], 60 g [DSC]) [contains
face, underarms, or groin area (including diapered area).
cetearyl alcohol, propylene glycol]
Warnings: Additional Pediatric Considerations The Generic: 0.05% (15 g, 45 g, 60 g)
extent of percutaneous absorption is dependent on sev-
Ointment, External, as dipropionate:
eral factors, including epidermal integrity (intact vs
Generic: 0.05% (15 g, 45g, 60 g)
abraded skin), formulation, age of the patient, prolonged
duration of use, and the use of occlusive dressings. @ Alclometasone Dipropionate see Alclometasone
Percutaneous absorption of topical steroids is increased on page 75
in neonates (especially preterm neonates), infants, and
young children. Infants and small children may be more @ Alcohol, Absolute see Alcohol (Ethyl) on page 76
susceptible to HPA axis suppression, intracranial hyper- @ Alcohol, Dehydrated see Alcohol (Ethyl) on page 76
tension, Cushing syndrome, or other systemic toxicities
due to larger skin surface area to body mass ratio.
Alcohol (Ethyl) (At koe hol, ETH il)
Some dosage forms may contain propylene glycol; in
neonates large amounts of propylene glycol delivered Medication Safety Issues
orally, intravenously (eg, >3,000 mg/day), or topically Sound-alike/look-alike issues:
have been associated with potentially fatal toxicities which Ethanol may be confused with Ethyol, Ethamolin
can include metabolic acidosis, seizures, renal failure, and Brand Names: US Epi-Clenz [OTC]; GelRite [OTC];
CNS depression; toxicities have also been reported in Isagel [OTC]; Lavacol [OTC]; Prevacare [OTC]; Protec-
children and adults including hyperosmolality, lactic acido- TeaV [OTC]; Purell Advanced [OTC]; Purell [OTC]
sis, seizures and respiratory depression; use caution Brand Names: Canada Biobase; Biobase-G
(AAP 1997; Shehab 2009). Therapeutic Category Anti-infective Agent, Topical; Anti-
Adverse Reactions dote, Ethylene Glycol Toxicity; Antidote, Methanol Toxicity;
Central nervous system: Localized burning Fat Occlusion (Central Venous Catheter), Treatment
Dermatologic: Acne vulgaris, allergic dermatitis, atrophic Agent; Neurolytic
striae, erythema, folliculitis, hypopigmentation, local dry-
Generic Availability (US) Yes
ness, miliaria, papular rash, perioral dermatitis, pruritus,
Use
skin atrophy
Endocrine & metabolic: Cushing's syndrome, growth sup- Injection: Therapeutic neurolysis of nerves or ganglia for
pression, HPA-axis suppression the relief of intractable, chronic pain in such conditions
Infection: Secondary infection as inoperable cancer and trigeminal neuralgia (dehy-
Local: Local irritation drated alcohol injection) (FDA approved in adults); epi-
Drug Interactions dural or individual motor nerve injections to control
Metabolism/Transport Effects None known. certain manifestations of cerebral palsy and spastic
Avoid Concomitant Use paraplegia, celiac plexus block to relieve pain of inoper-
Avoid concomitant use of Alclometasone with any of the able upper abdominal cancer, and intra- and subcuta-
following: Aldesleukin neously for relief of intractable pruritis ani (diluted [40%
Increased Effect/Toxicity to 50%] dehydrated alcohol injection: FDA approved in
Alclometasone may increase the levels/effects of: Cer- adults); has also been used as an antidote for the treat-
itinib; Deferasirox; Ritodrine ment of methanol and ethylene glycol intoxication, as a
Decreased Effect lock solution for the prevention and treatment of catheter
Alclometasone may decrease the levels/effects of: Alde- related infections, and for treatment of occluded central
sleukin; Corticorelin; Hyaluronidase venous catheters due to lipid deposition from fat emul-
Storage/Stability Store between 2°C and 30°C (36°F and sion infusion (particularly 3-in-1 admixture)
86°F). Topical: Skin antiseptic (hand sanitizer gels, foams sol-
Mechanism of Action Topical corticosteroids have anti- utions and rubbing ethyl alcohol: FDA approved pediatric
inflammatory, antipruritic, and vasoconstrictive properties. patients [age not specified] and adults)
May depress the formation, release, and activity of Pregnancy Risk Factor C (injection)
 ALCOHOL (ETHYL)

Pregnancy Considerations Animal reproduction studies Dimethindene (Topical); Disulfiram; Eluxadoline; Fliban-
have not been conducted with alcohol injection. Ethanol serin; Flunitrazepam; Gabapentin Enacarbil; GuanFA-
crosses the placenta, enters the fetal circulation, and has CINE; HYDROcodone; Lercanidipine; Levosulpiride;
teratogenic effects in humans (AAP 2000; Barceloux Lormetazepam; Melatonin; Mequitazine; MetFORMIN;
1999). The following withdrawal symptoms have been Methadone; Methylphenidate; MetroNIDAZOLE (Sys-
noted in the neonate following maternal ethanol consump- temic); Mianserin; Mirtazapine; Modafinil; Monoamine
tion during pregnancy: Crying, hyperactivity, irritability, Oxidase Inhibitors; Nefopam; Niclosamide; Nilutamide;
poor suck, tremors, seizures, poor sleeping pattern, Orphenadrine; Oxomemazine; Paraldehyde; Perampa-
hyperphagia, and diaphoresis (Hudak 2014). Fetal alcohol nel; Pipamperone [INT]; Piribedil; Prothionamide; Rilme-
syndrome (FAS) is a term referring to a combination of nidine; Sodium Oxybate; Stiripentol; Sulpiride;
physical, behavioral, and cognitive abnormalities resulting Sulthiame; Suvorexant; Tapentadol; Thalidomide; Tinida-
from ethanol exposure during fetal development. Since a zole; Topiramate; Trabectedin; Zopiclone
“safe" amount of ethanol consumption during pregnancy Increased Effect/Toxicity
has not been determined, the AAP recommends those Alcohol (Ethyl) may increase the levels/effects of: Acet-
women who are pregnant or planning a pregnancy refrain aminophen; Acetohydroxamic Acid; Acitretin; Agomela-
from all ethanol intake (AAP 2000). When used as an tine; Amantadine; Aminophylline; Aspirin; Azelastine
antidote during the second or third trimester, FAS is not (Nasal); Azelastine (Systemic); Bedaquiline; Biperiden;
likely, to occur due to the short treatment period; use Blonanserin; Brivaracetam; Bromocriptine; Buprenor-
during the first trimester is controversial (Barceloux 1999).
phine; BuPROPion; Chlormethiazole; Chlorphenesin
Breastfeeding Considerations Ethanol is excreted in Carbamate; CloBAZam; CycloSERINE; Cysteamine
breast milk in concentrations similar to maternal blood (Systemic); Didanosine; Diethylpropion; Doxylamine;
concentrations (Koren 2002). Milk production may be
Eluxadoline; Ethionamide; Ezogabine; Fesoterodine; Fli-
decreased and adverse events to the nursing infant may
banserin; Flunitrazepam; Fosphenytoin; Gabapentin
. occur (eg, sleep disturbances, impaired motor develop-
Enacarbil; GuanFACINE; HYDROcodone; Indoramin;
ment or postnatal growth) (Sachs 2013). The actual clear-
ISOtretinoin (Systemic); Lercanidipine; Levomilnacipran;
ance of ethanol from breast milk is dependent upon the
Levosulpiride; Lomitapide; Lormetazepam; Mecamyl-
mother's weight and amount of ethanol consumed (Koren
amine; Melatonin; Mequitazine; MetFORMIN; Metha-
2002). Guidelines recommend to avoid drinking com-
done; Methotrimeprazine; Methylphenidate;
pletely, or limit intake to the equivalent of ethanol 0.5 g/
kg/day and waiting 90 to 120 minutes after alcohol inges- MetyroSINE; Mipomersen; Mirtazapine; Monoamine Oxi-
dase Inhibitors; Morniflumate; Nefopam; Niacin; Nicor-
tion before breastfeeding (Reece-Stremtan 2015; Sachs
2013). andil; NIFEdipine; Nonsteroidal Anti-Inflammatory
Contraindications Hypersensitivity to ethyl alcohol or any Agents; Opioid Analgesics; Orphenadrine; OXcarbaze-
component of the formulation; seizure disorder and dia- pine; Oxybutynin; OxyCODONE; Paraldehyde; Phendi-
betic coma; subarachnoid injection of dehydrated alcohol metrazine; Pheniramine; Phentermine; Phenytoin;
in patients receiving anticoagulants; pregnancy (pro- Phosphodiesterase 5 Inhibitors; Piribedil; Pramipexole;
longed use or high doses at term) Propacetamol; Propranolol; Prothionamide; Quinagolide;
Warnings/Precautions Ethyl alcohol is a flammable Rilmenidine; ROPINIRole; Rotigotine; Rufinamide;
liquid and should be kept cool and away from any heat Selective Serotonin Reuptake Inhibitors; Serotonin/Nor-
source. Proper positioning of the patient for neurolytic epinephrine Reuptake Inhibitors; Sodium Oxybate; Sul-
administration is essential to control localization of the piride; Suvorexant; Tacrolimus (Systemic); Tapentadol;
injection of dehydrated alcohol (which is hypobaric) into Thalidomide; Theophylline; Thiazide and Thiazide-Like
the subarachnoid space; avoid extravasation. Not for Diuretics; Topiramate; Trabectedin; TraZODone; Tre-
SubQ administration. Do not administer simultaneously prostinil; Trimethobenzamide; Trospium; Vasodilators
with blood due to the possibility of pseudoagglutination (Organic Nitrates); Zolpidem; Zopiclone
or hemolysis; may potentiate severe hypoprothrombic The levels/effects of Alcohol (Ethyl) may be increased
bleeding. Clinical evaluation and periodic lab determina- by: Amisulpride; Benznidazole; Brimonidine (Topical);
tions, including serum ethanol levels, are necessary to
Bromocriptine; Bromopride; Bromperidol; BuPROPion;
monitor effectiveness, changes in electrolyte concentra-
Cannabis; Cefminox; Cefoperazone; CefoTEtan; Chlor-
tions, and acid-base balance (when used as an antidote).
amphenicol (Systemic); Cisapride; CNS Depressants;
Use with caution in patients with diabetes (ethy! alcohol Dapoxetine; Dimethindene (Topical); Disulfiram; Drona-
may decrease blood sugar), hepatic impairment, patients binol; Droperidol; Efavirenz; Griseofulvin; HydrOXYzine;
with gout, shock, following cranial surgery, and in antici- Kava Kava; Ketoconazole (Systemic); Lofexidine; Mag-
pated postpartum hemorrhage. Monitor blood glucose nesium Sulfate; Methotrimeprazine; MetroNIDAZOLE
closely, particularly in children as treatment of ingestions (Systemic); MetroNIDAZOLE (Topical); Mianserin; Mino-
is associated with hypoglycemia. Avoid extravasation dur- cycline; Molsidomine; Nabilone; Niclosamide; Niluta-
ing !V administration. Ethyl alcohol passes freely into mide; Oxomemazine; Perampanel; Pipamperone [INT];
breast milk at a level approximately equivalent to maternal Stiripentol; Sulfonylureas; Sulthiame; Tacrolimus (Top-
serum level; minimize dermal exposure of ethyl alcohol in ical); Tetrahydrocannabinol; Tinidazole; Trimeprazine;
infants as significant systemic absorption and toxicity can Varenicline; Verapamil
occur. Decreased Effect
When used as a topical antiseptic, improper use may lead Alcohol (Ethyl) may decrease the levels/effects of:
to product contamination. Although infrequent, product Alpha-Lipoic Acid; Armodafinil; Aspirin; Cyproterone;
contamination has been associated with reports of local- Cysteamine (Systemic); Dexlansoprazole; Fospheny-
ized and systemic infections. To reduce the risk of infec- toin; Melatonin; Modafinil; Ombitasvir, Paritaprevir, Rito-
tion, ensure antiseptic products are used according to the navir, and Dasabuvir; Phenytoin; Propranolol; Vitamin K
labeled instructions; avoid diluting products after opening; Antagonists
and apply single-use containers only one time to one The levels/effects of Alcohol (Ethyl) may be decreased
patient and discard any unused solution (FDA Drug Safety
by: Efavirenz
Communication, 2013).
Storage/Stability Store at room temperature; do not use
Adverse Reactions
unless solution is clear and container is intact.
Cardiovascular: Flushing, hypotension, phlebitis
Mechanism of Action When used to treat ethylene glycol
Central nervous system: Agitation, alcohol intoxication,
or methanol toxicity, ethyl alcohol competitively inhibits
brain disease, central nervous system depression,
alcohol dehydrogenase, an enzyme which catalyzes the
coma, disorientation, drowsiness, headache, neuropa-
metabolism of ethylene glycol and methanol to their toxic
thy, sedation, seizure (rare), vertigo
Endocrine & metabolic: Hypoglycemia metabolites. In neurolysis, alcohol will destroy nerves at
Gastrointestinal: Gastric irritation, nausea,-vomiting the site of injection.
Genitourinary: Urinary retention Pharmacodynamics/Kinetics (Adult data unless
Miscellaneous: Tissue damage noted)
Renal: Polyuria Absorption: Oral: Rapid
Drug Interactions Distribution: Vg: 0.6-0.7 L/kg; decreased in women
Metabolism/Transport Effects Induces CYP2E1 Metabolism: Hepatic (90% to 98%) to acetaldehyde or
(weak), UGT1A1 «2 acetate
Avoid Concomitant Use Half-life elimination: Rate: 15-20 mg/dL/hour (range:
Avoid concomitant use of Alcohol (Ethyl) with any of the 10-34 mg/dL/hour); increased in alcoholics
following: Acitretin; Agomelatine; Alpha-Lipoic Acid; Excretion: Kidneys and lungs (~2% unchanged)
Amantadine; Amisulpride; Armodafinil; Azelastine Dosing
(Nasal); Bedaquiline; Benznidazole; Bromopride; Brom- Pediatric
peridol; Cefminox; CycloSERINE; Cysteamine (Sys- Antiseptic: Children and Adolescents: Ethyl rubbing
temic); Dapoxetine; Dexlansoprazole; Didanosine; alcohol: Topical: Apply 1 to 3 times daily as needed

wi
ALCOHOL (ETHYL)

Methanol or ethylene glycol ingestion: Limited data Methanol or ethylene glycol ingestion: Infants, Chil-
available (Barceloux 1999; Barceloux 2002): Infants, dren, and Adolescents: Absolute ethyl alcohol: Dos-
Children, and Adolescents: Note: IV administration is age adjustment for hemodialysis: Maintenance dose:
the preferred route; continue therapy until ethylene IV:
glycol and/or methanol is no longer detected or levels Nondrinker: 169 mg/kg/hour (equivalent to 2.13 mL/
are <20 mg/dL and the patient is asymptomatic and kg/hour using a 10% solution)
metabolic acidosis has been corrected. If ethylene Chronic drinker: 257 mg/kg/hour (equivalent to 3.26
glycol and/or methanol levels are not available in a mL/kg/hour using a 10% solution)
timely manner, continue therapy until the estimated Oral:
time of clearance of ethylene glycol and/or methanol Nondrinker: 169 mg/kg/hour (equivalent to 0.22 mL/
has elapsed and the patient is asymptomatic with a kg/hour using a 98% solution)
Chronic drinker: 257 mg/kg/hour (equivalent to 0.33
normal pH. If patient has coingested ethanol, meas-
mL/kg/hour using a 98% solution)
ure the baseline serum ethanol concentration and
Hepatic Impairment: Pediatric There are no dosage
adjust the ethyl alcohol loading dose based on results
adjustments provided in the manufacturer's labeling.
to achieve a serum ethanol level of ~100 mg/dL.
Preparation for Administration
Absolute ethyl alcohol [98% (196 proof) = 77.4 g
Oral: Ethylene glycol or methanol poisoning: Dilute ethyl
EtOH/dL]:
alcohol (98% ethanol injection solution) to a <20% sol-
IV: Note: Contact the Poison Control Center for
ution with water or juice.
options related to compounding !V ethanol.
Parenteral: IV:
Initial: 600 to 700 mg/kg [equivalent to 7.6 to 8.9 Ethylene glycal or methanol poisoning: Dilute ethyl! alco-
mL/kg using a 10% solution] hol (98% ethanol injection solution) to a 10% solution in
Maintenance (not receiving hemodialysis): Goal of D5W or D10W.
therapy is to maintain serum ethanol levels Occluded central venous catheter/central venous cathe-
>100 mg/dL. ter lock: To prepare 70% solution: Add 0.8 mL SWFI to
Nondrinker: 66 mg/kg/hour [equivalent to 0.83 2 mL ethyl alcohol (98% ethanol injection solution)
mL/kg/hour using a 10% solution] (Cober 2007)
Chronic drinker: 154 mg/kg/hour [equivalent to Administration
1.96 mL/kg/hour using a 10% solution] Oral: Ethylene glycol or methanol poisoning: After diluting
Oral: Note: Solution must be diluted to a <20% ethyl alcohol (98% ethanol injection solution) to <20%
concentration with water orjuice and administered solution, administer hourly by mouth or via nasogastric
orally or via a nasogastric tube. tube. Out-of-hospital management with orally adminis-
Initial: 600 to 700 mg/kg (equivalent to 0.78 to 0.9 tered ethanol is not recommended.
mL/kg using a 98% solution) Parenteral: Not for SubQ administration; IV:
Maintenance (not receiving hemodialysis): Goal of Ethylene glycol or methanol poisoning: After diluting
therapy is to maintain serum ethanol levels ethyl alcoho! (98% ethanol injection solution) to 10%
>100 mg/dL v/v solution, infuse initial dose over 60 minutes; central
Nondrinker: 66 mg/kg/hour (equivalent to 0.09 vein is the preferred route.
mL/kg/hour using a 98% solution) Occluded central venous catheter/central venous cathe-
Chronic drinker: 154 mg/kg/hour (equivalent to ter lock: After diluting ethyl alcohol (98% ethanol injec-
0.20 mL/kg/hour using a 98% solution) tion solution) to 70% solution, instill with a volume equal
Central venous catheter lock: Limited data available: to the internal volume of the catheter; assess patency
Infants, Children, and Adolescents: See institution- at 30 to 60 minutes (or per institutional protocol); may
repeat. Ensure adequate measurement of catheter
based protocol: Dehydrated alcohol injection: IV:
volume to ensure adequate coverage of line and no
Catheter-related blood stream infection (CRBSI):
excess ethanol is administered. Ethanol forms a visual
Prophylaxis: Note: Use suggested in patients with
precipitate with heparin or citrate, flush catheter well
long term catheters with a history of multiple
with normal saline before administration. (Cober 2007;
CRBSI episode (IDSA [O’Grady 2011]); dosing
Cober 2011)
regimens variable: 70% ethanol; instill a volume
Intraneural: Adult: Separate needles should be used for
equal to the internal volume of the catheter once each of multiple injections or sites to prevent residual
daily with a dwell time of 2 to 14 hours; withdraw alcohol deposition at sites not intended for tissue
ethanol at the end of the dwell time (Cober 2011; destruction; inject slowly after determining proper place-
Mouw 2008; Wales 2011). Less frequent dosing (3 ment of needle; since dehydrated alcohol is hypobaric
times per week) for a minimum 4 hour dwell time when compared with spinal fluid, proper positioning of
(Jones 2010) and once weekly dosing with a 2- the patient is essential to control localization of injections
hour dwell time (Pieroni 2013) have also shown to into the subarachnoid space
produce statistically significant reductions in infec- Monitoring Parameters Antidotal therapy: Blood ethanol
tion rate and catheter loss; most study subjects levels (at the end of the loading dose, every 1 to 2 hours
were receiving long-term outpatient cyclic paren- until stabilized, and then every 2 to 4 hours thereafter);
teral nutrition. However, a small case-series blood glucose, electrolytes (including serum magnesium),
observed an increase in infection rate when the arterial pH, blood gases, methanol or ethylene glycoi
frequency of ethanol locks were decreased to less blood levels, heart rate, blood pressure
than daily (eg, twice weekly or once weekly; dwell Reference Range
times not specified) during an ethanol shortage; all Symptoms associated with serum ethanol levels:
patients in this study had tunneled silastic cathe- Nausea and vomiting: Serum level >100 mg/dL
ters (Ralls 2012) Coma: Serum level >300 mg/dL
Treatment: Dosing regimens variable: 70% ethanol; Antidote for methanol/ethylene glycol: Goal range: Blood
instill a volume equal to the internal volume of the ethanol level: 100-150 mg/dL (22-32 mmol/liter)
catheter with a dwell time 4 to 25 hours; some Dosage Forms Excipient information presented when
protocols utilized single dose and others repeated available (limited, particularly for generics); consult spe-
the dose once daily for 3 to 5 days; dosing should cific product labeling.
be repeated for each lumen and used in combina- Aerosol, foam, topical [instant hand sanitizer]:
tion with systemic antimicrobials (Danneberg 2003; Epi-Clenz: 62% (240 mL, 480 mL)
McGrath 2011; Onland 2006; Valentine 2011). For Foam, topical [instant hand sanitizer]:
fungal bloodstream infection, case-reports Purell Advanced: 70% (45 mL, 535 mL, 700 mL,
describe success using once daily with dwell times 1200 mL)
Gel, topical [instant hand sanitizer]:
of 2 to 24 hours for 14 days following the patient's
Epi-Clenz: 70% (45 mL, 120 mL, 480 mL)
first negative blood culture (Blackwood 2011)
Epi-Clenz Plus: 62% (45 mL, 800 mL)
Fat occlusion of central venous catheters: Dehydrated
GelRite: 62% (120 mL, 480 mL, 800 mL, 1000 mL)
alcohol injection: Up to 3 mL of 70% ethanol (max-
Isagel: 60% (59 mL, 118 mL, 621 mL, 800 mL)
imum: 0.55 mL/kg); instill a volume equal to the Prevacare: 60% (120 mL, 240 mL, 960 mL, 1200 mL,
internal volume of the catheter; may repeat if
1500 mL)
patency not restored after 30 to 60 minute dwell ProtecTeaV: 70% (236 mL)
time; if dose repeated, reassess after 4-hour dwell Purell: 62% (15 mL, 30 mL, 59 mL, 60 mL, 120 mL, 236
time (Pennington 1987; Werlin 1995). mL, 240 mL, 250 mL, 360 mL, 500 mL, 800 mL, 1000
Renal Impairment: Pediatric mL, 2000 mL)
There are no dosage adjustments provided in the man- Purell Advanced: 70% (30 mL, 236 mL, 1000 mL,
-ufacturer's labeling. Hemodialysis clearance: 300 to 2000 mL)
400 mL/minute with an ethanol removal rate of Injection, solution [dehydrated, preservative free]: 98% (1
280 mg/minute. mL, 5 mL)

78
 ALDESLEUKIN

Liquid, topical [denatured]: are also associated with CLS. CLS onset is immediately
Lavacol: 70% (473 mL) after treatment initiation. Monitor fluid status and organ
Generic: 70% (480 mL, 3840 mL) perfusion status carefully; consider fluids and/or pressor
Pad, topical [instant hand sanitizer/towelette]: agents to maintain organ perfusion. [US Boxed Warn-
Isagel: 60% (50s, 300s) ing]: Therapy should be restricted to patients with
Purell: 62% (24s, 35s, 40s, 100s, 120s, 175s, 1000s, normal cardiac and pulmonary functions as-defined
4000s) by thallium stress and formal pulmonary function
testing. Extreme caution should be used in patients
with a history of prior cardiac or pulmonary disease
Alcohol (Isopropyl) (At ka hol eye soe PROE pil) and in patients who are fluid-restricted or where edema
Brand Names: US Essentra Wipes 9x9"; Pharmacist may be poorly tolerated. In a scientific statement from the
Choice Alcohol [OTC] American Heart Association, interleukin-2 has been deter-
mined to be an agent that may either cause direct myo-
Therapeutic Category Pharmaceutical Aid
cardial toxicity (rare) or exacerbate underlying myocardial
Generic Availability (US) May be product dependent dysfunction (magnitude: major) (AHA [Page 2016]). With-
Use External antiseptic for the prevention of topical infec- hold treatment for signs of organ hypoperfusion, including
tions associated with burns or minor cuts/scrapes; rubbing
altered mental status, reduced urine output, systolic BP
and massaging as an external stimulant; hand sanitizer; <90 mm Hg or cardiac arrhythmia. Once blood pressure is
preparation of skin prior to injection or surgery normalized, may consider diuretics for excessive weight
Dosage Forms Excipient information presented when gain/edema. Recovery from CLS generally begins soon
available (limited, particularly for generics); consult spe- after treatment cessation. Perform a thorough clinical
cific product labeling. [DSC] = Discontinued product evaluation prior to treatment initiation; exclude patients
Gel, External: with significant cardiac, pulmonary, renal, hepatic, or cen-
Generic: 70% (118 mL [DSC]) tral nervous system impairment from treatment. Patients
-Miscellaneous, External: with. a more favorable performance status prior to treat-
Essentra Wipes 9x9": 70% (30 ea, 270 ea) ment initiation are more likely to respond to aldesleukin
Pad, External: treatment, with a higher response rate and generally lower
Pharmacist Choice Alcohol: 70% (100 ea) toxicity.
@ Aldactazide see Hydrochlorothiazide and Spironolac- [US Boxed Warning]: Should be administered under
tone on page 1001 the supervision of an experienced cancer chemother-
@ Aldactazide 25 (Can) see Hydrochlorothiazide and Spi- apy physician in a facility with cardiopulmonary or
ronolactone on page 1001 intensive specialists and intensive care facilities
available. Adverse effects are frequent and sometimes
Aldactazide 50 (Can) see Hydrochlorothiazide and Spi-
fatal. May exacerbate preexisting or initial presentation of
ronolactone on page 1001
autoimmune diseases and inflammatory disorders; exac-
@ Aldactone see Spironolactone on page 1860 erbation and/or new onset have been reported with alde-
sleukin and interferon alfa combination therapy. Thyroid
Aldesleukin (ai des L0o kin) disease (hypothyroidism, biphasic thyroiditis, and thyro-
toxicosis) may occur; the onset of hypothyroidism is
Medication Safety Issues usually 4 to 17 weeks after treatment initiation; may be
Sound-alike/look-alike issues: reversible upon treatment discontinuation (Hamnvik,
Aldesleukin may be confused with oprelvekin 2011). Patients should be evaluated and treated for CNS
Proleukin may be confused with oprelvekin metastases and have a negative scan prior to treatment;
High alert medication: new neurologic symptoms and lesions have been reported
This medication is in a class the Institute for Safe in patients without preexisting evidence of CNS metasta-
Medication Practices (ISMP) includes among its list of ses (symptoms generally improve upon discontinuation,
drug classes which have a heightened risk of causing however, cases with permanent damage have been
significant patient harm when used in error. reported). Mental status changes (irritability, confusion,
Brand Names: US Proleukin depression) can occur and may indicate bacteremia,
Brand Names: Canada Proleukin sepsis, hypoperfusion, CNS malignancy, or CNS toxicity.
May cause seizure; use with caution in patients with
Therapeutic Category Antineoplastic Agent, Biologic
seizure disorder. Ethanol use may increase CNS adverse
Response Modulator; Antineoplastic Agent, Miscellane-
effects.
ous; Biological Response Modulator
Generic Availability (US) No [US Boxed Warning]: Impaired neutrophil function is
Use Treatment of metastatic renal cell carcinoma and associated with treatment; patients are at risk for
metastatic melanoma (FDA approved in adults); has also disseminated infection (including sepsis and bacterial
been used in the treatment of high-risk neuroblastoma endocarditis), and central line-related gram-positive
Pregnancy Risk Factor C rere infections. Treat preexisting bacterial infection appro-
Pregnancy Considerations Adverse events were priately prior to treatment initiation. Antibiotic prophy-
observed in animal reproduction studies. Use during laxis that has been associated with a reduced
pregnancy only if benefits to the mother outweigh potential incidence of staphylococcal infections in aldesleukin
risk to the fetus. Effective contraception is recommended studies includes the use of oxacillin, nafcillin, cipro-
for fertile males and/or females using this medication. floxacin, or vancomycin. Monitor for signs of infection or
Breastfeeding Considerations It is not known if alde- sepsis during treatment.
sleukin is excreted in breast milk. Due to the potential for [US Boxed Warning]: Withhold treatment for patients
serious adverse reactions in the breastfeeding infant, a developing moderate-to-severe lethargy or somno-
decision should be made to discontinue breastfeeding or lence; continued treatment may result in coma. Stand-
to discontinue the drug, taking into account the importance ard prophylactic supportive care during high-dose
of treatment to the mother. aldesleukin treatment includes acetaminophen to relieve
Contraindications Hypersensitivity to aldesleukin or any constitutional symptoms and an Hz antagonist to reduce
component of the formulation; patients with abnormal the risk of GI ulceration and/or bleeding. May impair renal
thallium stress or pulmonary function tests; patients who or hepatic function; patients must have a serum creatinine
have had an organ allograft. Re-treatment is contra- $1.5 mg/dL prior to treatment. Concomitant nephrotoxic or
indicated in patients who have experienced sustained hepatotoxic agents may increase the risk of renal or
ventricular tachycardia (25 beats), uncontrolled or unre- hepatic toxicity. Potentially significant drug-drug interac-
sponsive cardiac arrhythmias, chest pain with ECG tions may exist, requiring dose or frequency adjustment,
changes consistent with angina or Ml, cardiac tamponade, additional monitoring, and/or selection of alternative ther-
intubation >72 hours, renal failure requiring dialysis for apy. Enhancement of cellular immune function may
>72 hours, coma or toxic psychosis lasting >48 hours, increase the risk of allograft rejection in transplant
repetitive or refractory seizures, bowel ischemia/perfora- patients. An acute array of symptoms resembling alde-
tion, or GI bleeding requiring surgery. sleukin adverse reactions (fever, chills, nausea, rash,
Warnings/Precautions [US Boxed Warning]: Aldesleu- pruritus, diarrhea, hypotension, edema, and oliguria) were
kin therapy has been associated with capillary leak observed within 1 to 4 hours after iodinated contrast media
syndrome (CLS), characterized by vascular tone loss administration, usually when given within 4 weeks after
and extravasation of plasma proteins and fluid into aldesleukin treatment, although has been reported several
extravascular space. CLS results in hypotension and months after aldesleukin treatment. The incidence of
reduced organ perfusion, which may be severe and dyspnea and severe urogenital toxicities is potentially
can result in death. Cardiac arrhythmia, angina, myo- increased in elderly patients. Aldesleukin doses >12 to
cardial infarction, respiratory insufficiency (requiring 15 million units/m? are associated with a moderate emetic
intubation), gastrointestinal bleeding or infarction, potential; antiemetics are recommended to prevent nau-
renal insufficiency, edema and mental status changes sea and vomiting (Dupuis, 2011).

79
ALDESLEUKIN

Adverse Reactions Storage/Stability Store intact vials under refrigeration at

Cardiovascular: Cardiac arrest, cardiac arrhythmia, car- 2°C to 8°C (36°F to 46°F). Protect from light. Plastic
diac disease (includes blood pressure changes, HF and (polyvinyl chloride) bags result in more consistent drug
ECG changes), edema, hypotension, myocardial infarc- delivery and are recommended. According to the manu-
tion, peripheral edema, supraventricular tachycardia, facturer, reconstituted vials and solutions diluted in DSW
tachycardia, vasodilatation, ventricular tachycardia for infusion are stable for 48 hours at room temperature or
Central nervous system: Anxiety, chills, coma, confusion, refrigerated although refrigeration is preferred because
dizziness, drowsiness, malaise, pain, psychosis, stupor they do not contain preservatives. Do not freeze.
Dermatologic: Exfoliative dermatitis, pruritus, skin rash Mechanism of Action Aldesleukin is a human recombi-
Endocrine & metabolic: Acidosis, hypocalcemia, hypo- nant interleukin-2 product which promotes proliferation,
magnesemia, weight gain differentiation, and recruitment of T and B cells, natural
Gastrointestinal: Abdominal pain, anorexia, diarrhea, killer (NK) cells, and thymocytes; causes cytolytic activity
enlargement of abdomen, nausea, stomatitis, vomiting
in a subset of lymphocytes and subsequent interactions
between the immune system and malignant cells; can
Genitourinary: Anuria, oliguria
stimulate lymphokine-activated killer (LAK) cells and
Hematologic & oncologic: Anemia, blood coagulation dis-
tumor-infiltrating lymphocytes (TIL) cells.
order (includes intravascular coagulopathy), leukopenia,
Pharmacodynamics/Kinetics (Adult data unless
thrombocytopenia
Hepatic: Hyperbilirubinemia, increased serum alkaline
noted)
Absorption: Oral: Not absorbed
phosphatase, increased serum AST
Distribution: Primarily into plasma, lymphocytes, lungs,
Immunologic: Antibody development
liver,-kidney; and spleen; Vg: 6.3 to 7.9 L (Whitting-
Infection: Infection, sepsis
‘ton 1993)
Neuromuscular & skeletal: Weakness
Metabolism: Renal (metabolized to amino acids in the
Renal: Acute renal failure, increased serum creatinine cells lining the proximal convoluted tubules of the kidney)
Respiratory: Apnea, cough, dyspnea, pulmonary disease Half-life elimination: IV:
(includes pulmonary congestion, rales, rhonchi), respira- Children: Distribution: 14 + 6 minutes; Elimination: 51 +
tory tract disease (includes acute respiratory distress 11 minutes
syndrome, pulmonary infiltrates, and pulmonary Adults: Distribution: 13 minutes; Terminal: 85 minutes
changes), rhinitis Excretion: Urine (primarily as metabolites)
Miscellaneous: Fever Dosing
Rare but important or life-threatening: Agitation, ailergic Pediatric Note: Dosing and frequency may vary by
interstitial nephritis, anaphylaxis, angioedema, asthma, indication, protocol, and/or treatment phase and hema-
atrial arrhythmia, atrioventricular block, blindness (tran- tologic response; refer to specific protocols. Consider
sient or permanent), bowel infarction, bradycardia, brain premedication with an antipyretic to reduce fever, an
disease, bullous pemphigoid, capillary leak syndrome, Hz antagonist for prophylaxis of gastrointestinal irrita-
cardiomyopathy, cellulitis, cerebral edema, cerebral tion/bleeding, antiemetics, and antidiarrheals; continue
lesion, cerebral vasculitis, cerebrovascular accident, for 12 hours after the last aldesleukin dose. Antibiotic
cholecystitis, colitis, delirium, depression (severe; lead- prophylaxis is recommended to reduce the incidence of
ing to suicide), diabetes mellitus, duodenal ulcer, endo- infection. Aldesleukin doses >12 to 15 million units/m?
carditis, eosinophilia, exacerbation of Crohn's disease, are associated with a moderate emetic potential; antie-
extrapyramidal reaction, gastritis, hematemesis, metics are recommended to prevent nausea and vomit-
hemoptysis, hemorrhage (including cerebral, gastroin- ing (Dupuis 2011):
testinal, retroperitoneal, subarachnoid, subdural), hep- Neuroblastoma: Limited data available: Children and
atic failure, hepatitis, hepatosplenomegaly, Adolescents: IV: 3 million units/m/day continuous infu-
hypertension, hyperthyroidism, hyperuricemia, hyper- sion over 24 hours for 4 consecutive days during week
ventilation, hypothermia, hypoventilation, hypoxia, IgA 1 and 4.5 million units/m?/day continuous infusion over
glomerulonephritis (crescentic), increased blood urea 24 hours for 4 consecutive days during week 2 of
nitrogen, increased nonprotein nitrogen, inflammatory cycles 2 and 4 (regimen also includes isotretinoin,
arthritis, insomnia, intestinal necrosis, intestinal obstruc- dinutuximab [an anti-GD2 antibody], and sargramos-
tion, intestinal perforation, ischemic heart disease, leu- tim) (Yu 2010)
kocytosis, lymphocytopenia, malignant hyperthermia, Dosing adjustment for toxicity: The presented dosing
meningitis, myasthenia gravis (oculo-bulbar), mydriasis, adjustments are based on experience in adult patients.
myocarditis, myopathy, myositis, neuralgia, neuritis, neu-
Refer to specific protocol for management in pediatric
patients if available.
ropathy, neutropenia, optic neuritis, pancreatitis, para-
Adult:
noia, pericardial effusion, pericarditis, peripheral
Withhold or interrupt a dose for toxicity; do not
gangrene, phlebitis, pneumonia, pneumothorax, pulmo-
reduce the dose.
nary edema, pulmonary embolism, renal tubular
Cardiovascular toxicity:
necrosis, respiratory acidosis, respiratory arrest, respi-
Atrial fibrillation, supraventricular tachycardia, or
ratory failure, restricted systemic blood flow, rhabdo-
bradycardia that is persistent, recurrent, or
myolysis, scleroderma, seizure, shock, Stevens- requires treatment: Withhold dose; may resume
Johnson syndrome, syncope, thrombosis, thyroiditis, when asymptomatic with full recovery to normal
tissue necrosis at injection site, tracheoesophageal fis- sinus rhythm.
tula, transient ischemic attacks, urticaria, ventricular Systolic BP <90 mm Hg (with increasing pressor
premature contractions requirements): Withhold dose; may resume treat-
Drug Interactions ment when systolic BP 290 mm Hg and stable or
Metabolism/Transport Effects None known. pressor requirements improve.
Avoid Concomitant Use Any ECG change consistent with Ml, ischemia or
Avoid concomitant use of Aldesleukin with any of the myocarditis (with or without chest pain), or sus-
following: BCG (Intravesical); Bromperidol; Corticoste- pected cardiac ischemia: Withhold dose; may
roids; Deferiprone; Dipyrone resume when asymptomatic, Mi/myocarditis have
Increased Effect/Toxicity been ruled out, suspicion of angina is low, or
Aldesleukin may increase the levels/effects of: Amifos- there is no evidence of ventricular hypokinesia.
tine; Antipsychotic Agents (Second Generation [Atypi- CNS toxicity: Mental status change, including mod-
cal]); Bromperidol; CloZAPine; Deferiprone; erate confusion, agitation, somnolence, delirium,
DULoxetine; lodinated Contrast Agents; Levodopa; or alterations in cognitive function or impaired
Nitroprusside; Pholcodine memory. Withhold dose; may resume when
resolved completely.
The levels/effects of Aldesleukin may be increased by: Dermatologic toxicity: Bullous dermatitis or marked
Alfuzosin; Barbiturates; Benperidol; Blood Pressure worsening of preexisting skin condition: Withhold
Lowering Agents; Brimonidine (Topical); Chlorampheni- dose; may treat with antihistamines or topical
col (Ophthalmic); Diazoxide; Dipyrone; Herbs (Hypoten- products (do not use topical steroids); may resume
sive Properties); Interferons (Alfa); Lormetazepam; with resolution of all signs of bullous dermatitis.
Molsidomine; Naftopidil; Nicergoline; Nicorandil; Obinu- Gastrointestinal: Stool guaiac repeatedly >3 to 4+:
tuzumab; Pentoxifylline; Phosphodiesterase 5 Inhibitors; Withhold dose; may resume with negative stool
Promazine; Prostacyclin Analogues; Quinagolide guaiac.
Decreased Effect Infection: Sepsis syndrome, clinically unstable: With-
Aldesleukin may decrease the levels/effects of: BCG hold- dose; may resume when sepsis syndrome
(Intravesical) has resolved, patient is clinically stable, and infec-
tion is under treatment.
The levels/effects of Aldesleukin may be decreased by: Respiratory toxicity: Oxygen saturation <90%: With-
Bromperidol; Corticosteroids hold dose; may resume when >90%.

80
 ALENDRONATE

Retreatment with aldesleukin is contraindicated Use Treatment of osteoporosis (Binosto, Fosamax: FDA
with the following toxicities: Sustained ventricular approved in postmenopausal females and adult males);
tachycardia (25 beats), uncontrolled or unrespon- prevention of osteoporosis (Fosamax: FDA approved in
sive cardiac arrhythmias, chest pain with ECG postmenopausal females); treatment of Paget disease of
changes consistent with angina or MI, cardiac tam- the bone in patients who are symptomatic, at risk for future
ponade, intubation >72 hours, renal failure requiring complications, or with alkaline phosphatase 22 times the
dialysis for >72 hours, coma or toxic psychosis upper limit of normal (Fosamax: FDA approved in adults);
lasting >48 hours, repetitive or refractory seizures, treatment of glucocorticoid-induced osteoporosis in
bowel ischemia/perforation, or Gl bleeding requiring patients with low bone mineral density who are receiving
surgery a daily dosage 27.5 mg of prednisone (or equivalent)
Preparation for Administration Reconstitute vials with (Fosamax: FDA approved in adults); has also been used
1.2 mL SWFI (preservative free) to a concentration of 18 in the treatment of osteogenesis imperfect and osteopenia
million [18 x 10° units (1.1 mg)]/1 mL; sterile water should in cystic fibrosis, nonambulatory (eg, cerebral palsy), and
be injected towards the side of the vial. Gently swirl; do not rheumatology patients
shake. Further dilute dosage in D5W to a final concen- Medication Guide Available Yes
tration between 0.49 to 1.1 million units/mL (30 to 70 Pregnancy Risk Factor C
mceg/mL); final dilutions <0.49 million units/mL (30 Pregnancy Considerations Adverse events were
meg/mL) or >1.1 million units/mL (70 mcg/mL) have observed in animal reproduction studies. It is not known
shown increased variability in drug stability and bioactivity if bisphosphonates cross the placenta, but fetal exposure
and should be avoided; addition of 0.1% albumin has been is expected (Djokanovic 2008; Stathopoulos 2011).
used to increase stability and decrease the extent of Bisphosphonates are incorporated into the bone matrix
sorption if low final concentrations cannot be avoided. and gradually released over time. The amount available in
Plastic (polyvinyl chloride) bags result in more consistent the systemic circulation varies by dose and duration of
’ drug delivery and are recommended. Filtration may result therapy. Theoretically, there may be a risk of fetal harm
in loss of bioactivity. Avoid bacteriostatic water for injection when pregnancy follows the completion of therapy; how-
and NS for reconstitution or dilution; increased aggrega- ever, available data have not shown that exposure to
tion may occur. bisphosphonates during pregnancy significantly increases
the risk of adverse fetal events (Djokanovic 2008; Levy
For continuous IV infusion, dilute in DSW maintaining the 2009; Stathopoulos 2011). Until additional data is avail-
same final concentration. able, most sources recommend discontinuing bisphosph-
Administration onate therapy in women of reproductive potential as early
Parenteral: Aldesleukin doses >12 to 15 million units/m? as possible prior to a planned pregnancy; use in preme-
are associated with a moderate emetic potential; antie- nopausal women should be reserved for special circum-
metics are recommended to prevent nausea and vomit- stances when rapid bone loss is occurring (Bhalla 2010;
ing (Dupuis 2011) Pereira 2012; Stathopoulos 2011). Because hypocalcemia
IV: Allow solution to reach room temperature prior to has been described following in utero bisphosphonate
administration; infuse over 15 minutes; flush line before exposure, exposed infants should be monitored for hypo-
and after with D5W, particularly if maintenance IV line calcemia after birth (Djokanovic 2008; Stathopoulos
contains sodium chloride. Some protocols infuse as a 2011).
continuous infusion (Legha 1998; Yu 2010). Breastfeeding Considerations It is not known if alendr-
Monitoring Parameters Baseline and periodic: CBC with onate is excreted into breast milk. The manufacturer
differential and platelets, blood chemistries including elec- recommends that caution be exercised when administer-
trolytes, renal and hepatic function tests, and in adults: ing alendronate to nursing women.
chest x-ray; pulmonary function tests and arterial blood Contraindications
gases (baseline), thallium stress test (prior to treatment). Hypersensitivity to alendronate or any component of the
Monitor thyroid function tests (TSH at baseline then every formulation; hypocalcemia; abnormalities of the esoph-
2 to 3 months during aldesleukin treatment [Hamnvik agus (eg, stricture, achalasia) which delay esophageal
2011)). emptying; inability to stand or sit upright for at least 30
minutes; increased risk of aspiration (effervescent tab-
Monitoring during therapy dependent on route; in pediatric
lets; oral solution)
patients receiving continuous infusion, more frequent
Canadian labeling: Additional contraindications (not in the
monitoring may be necessary (refer to specific protocol)
US labeling): Renal insufficiency with creatinine clear-
and should include daily (hourly if hypotensive) vital signs
ance <35 mL/minute
(temperature, pulse, blood pressure, and respiration rate),
Documentation of allergenic cross-reactivity for
weight and fluid intake and output; in a patient with a
bisphosphonates is limited. However, because of sim-
decreased blood pressure (eg, in adults, especially sys-
ilarities in chemical structure and/or pharmacologic
tolic BP <90 mm Hg), cardiac monitoring for rhythm should
actions, the possibility of cross-sensitivity cannot be
be conducted. If an abnormal complex or rhythm is seen,
ruled out with certainty.
an ECG should be performed; vital signs in these hypo-
Warnings/Precautions Use caution in patients with renal
tensive patients should be taken hourly and central
impairment (not recommended for use in patients with
venous pressure (CVP) checked; monitor for change in
CrCl <35 mL/minute); hypocalcemia must be corrected
mental status, and for signs of infection.
before therapy initiation; ensure adequate calcium and
Additional Information 18 x 10° int. units = 1.1 mg vitamin D intake. May cause irritation to upper gastro-
protein intestinal mucosa. Esophagitis, dysphagia, esophageal
Dosage Forms Excipient information presented when ulcers, esophageal erosions, and esophageal stricture
available (limited, particularly for generics); consult spe- (rare) have been reported; risk increases in patients
cific product labeling. unable to comply with dosing instructions. Use with cau-
Solution Reconstituted, Intravenous [preservative free]: tion in patients with dysphagia, esophageal disease, gas-
Proleukin: 22,000,000 units (1 ea) tritis, duodenitis, or ulcers (may worsen underlying
@ Aldomet see Methyldopa on page 1340 condition). Discontinue use if new or worsening symptoms
develop.
@ Aldurazyme see Laronidase on page 1183
Osteonecrosis of the jaw (ONJ), also referred to as
medication-related osteonecrosis of the jaw (MRON4J),
Alendronate (a LEN droe nate) has been reported in patients receiving bisphosphonates.
Known risk factors for MRONJ include invasive dental
Medication Safety Issues
procedures (eg, tooth extraction, dental implants, boney
Sound-alike/look-alike issues:
surgery), cancer diagnosis, concomitant therapy (eg, che-
Alendronate may be confused with risedronate
motherapy, corticosteroids, angiogenesis inhibitors), poor
Fosamax may be confused with Flomax, Fosamax Plus
oral hygiene, ill-fitting dentures, and comorbid disorders
D, fosinopril, Zithromax
(anemia, coagulopathy, infection, preexisting dental or
International issues:
periodontal disease). Risk may increase with increased
Fosamax [US, Canada, and multiple international mar-
duration of bisphosphonate use. According to a position
kets] may be confused with Fisamox brand name for
paper by the American Association of Maxillofacial Sur-
amoxicillin [Australia]
geons (AAOMS), MRONJ has been associated with
Related Information bisphosphonate and other antiresorptive agents (denosu-
Oral Medications That Should Not Be Crushed or Altered mab), and antiangiogenic agents (eg, bevacizumab, suni-
on page 2217 tinib) used for the treatment of osteoporosis or
Brand Names: US Binosto; Fosamax malignancy; risk of MRON4 is significantly higher in can-
Brand Names: Canada Fosamax cer patients receiving antiresorptive therapy compared to
Therapeutic Category Bisphosphonate Derivative
Generic Availability (US) May be product dependent
patients receiving osteoporosis treatment (regardless of
medication used or dosing schedule). MRON4J risk is also >
81
 ALENDRONATE

d increased with intravenous antiresorptive use compared

to the minimal risk associated with oral bisphosphonate
Endocrine & metabolic: Decreased serum calcium (tran-
sient, mild), decreased serum phosphate (transi-
use, although risk appears to increase with oral ent, mild)
bisphosphonates when duration of therapy exceeds 4 Gastrointestinal: Abdominal distension, abdominal pain,
years (AAOMS [Ruggiero 2014]). The manufacturer's acid regurgitation, constipation, diarrhea, dyspepsia,
labeling states that in patients requiring invasive dental dysphagia, esophageal ulcer, flatulence, gastric ulcer
procedures, discontinuing bisphosphonates may reduce (may be severe with complications), gastritis, gastro-
the risk of ONJ and clinical judgment should guide the esophageal reflux disease, melena, nausea
decision. However, the AAOMS suggests there is cur- Neuromuscular & skeletal: Muscle cramps, musculoske-
rently no evidence that interrupting oral bisphosphonate letal pain (includes bone pain, joint pain, and
therapy alters the risk of ONJ following tooth extraction, muscle pain)
and that in patients receiving oral bisphosphonates for <4 Rare but important or life-threatening: Alopecia, choles-
years who have no clinical risk factors, no alternations or teatoma, conjunctivitis, duodenal ulcer (may be severe
delay in any procedure common to oral/maxillofacial sur- with complications), dysgeusia, episcleritis, erythema,
geons, periodontists, and other dental providers is neces- erosive esophagitis, esophageal perforation, esophageal
sary (special considerations apply to patients receiving stenosis, esophageal ulcer, esophagitis, exacerbation of
dental implants). Conversely, in patients receiving oral asthma, femur fracture (low energy fractures, including
bisphosphonates for >4 years or in patients receiving oral subtrochanteric and diaphyseal), hypersensitivity reac-
bisphosphonates for <4 years who have also taken corti- tion (includes angioedema and urticaria), hypocalcemia
costeroids or antiangiogenic medications concomitantly, (symptomatic), joint swelling, malaise, oropharyngeal
the AAOMS recommends considering a 2-month, drug- ulcer, osteonecrosis of the jaw (generally associated with
free period prior to invasive dental procedures (recom- tooth extraction and/or local infection with delayed heal-
mendation based on a theoretical benefit). Patients devel- ing), peripheral edema, scleritis, skin rash (occasionally
oping ONJ during therapy should receive care by an oral with photosensitivity), Stevens-Johnson syndrome, toxic
surgeon (AAOMS [Ruggiero 2014]). According to the epidermal necrolysis, uveitis, vertigo, weakness
manufacturer, discontinuation of the bisphosphonate ther- Drug Interactions
apy should be considered (based on risk/benefit evalua- Metabolism/Transport Effects None known.
tion) in patients who develop ONJ. Avoid Concomitant Use
Atypical femur fractures (AFF) have been reported in Avoid concomitant use of Alendronate with any of the
patients receiving bisphosphonates. The fractures include following: Parathyroid Hormone
subtrochanteric femur (bone just below the hip joint) and Increased Effect/Toxicity
diaphyseal femur (long segment of the thigh bone). Some Alendronate may increase the levels/effects of: Defer-
patients experience prodromal pain weeks or months asirox
before the fracture occurs. It is unclear if bisphosphonate
The levels/effects of Alendronate may be increased by:
therapy is the cause for these fractures; atypical femur
Aminoglycosides; Angiogenesis Inhibitors (Systemic);
fractures have also been reported in patients not taking
Aspirin; Nonsteroidal Anti-Inflammatory Agents
bisphosphonates, and in patients receiving glucocorti-
coids. Patients receiving long-term (>3 to 5 years) Decreased Effect
bisphosphonate therapy may be at an increased risk Alendronate may decrease the levels/effects of: Para-
(Adler 2016; NOF [Cosman 2014]); however, benefits of thyroid Hormone
therapy (when used for osteoporosis) generally outweigh The levels/effects of Alendronate may be decreased by:
absolute risk of AFF within the first 5 years of treatment Antacids; Calcium Salts; Iron Salts; Magnesium Salts;
(Adler 2016). Patients presenting with thigh or groin pain Multivitamins/Minerals (with ADEK, Folate, Iron); Multi-
with a history of receiving bisphosphonates should be vitamins/Minerals (with AE, No Iron); Proton Pump Inhib-
evaluated for femur fracture. Consider interrupting itors
bisphosphonate therapy in patients who develop a femoral Food Interactions All food and beverages interfere with
shaft fracture; assess for fracture in the contralateral limb. absorption. Coadministration with dairy products may
Severe (and occasionally debilitating) bone, joint, and/or decrease alendronate absorption. Beverages (especially
muscle pain have been reported during bisphosphonate orange juice, coffee, and mineral water) and food may
treatment. The onset of pain ranged from a single day to reduce the absorption of alendronate as much as 60%.
several months. Consider discontinuing therapy in Management: Alendronate must be taken first thing in the
patients who experience severe symptoms; symptoms morning and 230 minutes before the first food, beverage
usually resolve upon discontinuation. Some patients expe- (except plain water), or other medication of the day.
rienced recurrence when rechallenged with same drug or Storage/Stability
another bisphosphonate; avoid use in patients with a Oral solution: Store at 25°C (77°F), excursions permitted
history of these symptoms in association with bisphosph- to 15°C to 30°C (59°F to 86°F). Do not freeze.
onate therapy. Tablet (Fosamax): Store at room temperature of 15°C to
30°C (59°F to 86°F). Keep in well-closed container.
Conjunctivitis, uveitis, episcleritis, and scleritis have been
Tablet, effervescent (Binosto): Store at 20°C to 25°C (68°F
reported with alendronate; patients presenting with signs
to 77°F), excursions permitted to 15°C to 30°C (59°F to
of ocular inflammation may require further ophthalmologic
86°F). Protect from moisture. Store in original blister
evaluation. Potentially significant drug-drug interactions
package until use.
may exist, requiring dose or frequency adjustment, addi-
Mechanism of Action A bisphosphonate which inhibits
tional monitoring, and/or selection of alternative therapy.
bone resorption via actions on osteoclasts or on osteo-
Consult drug interactions database for more detailed
clast precursors; decreases the rate of bone resorption,
information. Each effervescent tablet contains 650 mg of
leading to an indirect increase in bone mineral density. In
sodium (NaCl 1650 mg); use with caution in patients
Paget disease, characterized by disordered resorption
following a sodium-restricted diet.
and formation of bone, inhibition of resorption leads to
Warnings: Additional Pediatric Considerations The
an indirect decrease in bone formation; but the newly-
potential adverse effects of bisphosphonate therapy on
formed bone has a more normal architecture.
the immature bones of growing children are concerning
and data to fully describe are insufficient. Animal data has Pharmacodynamics/Kinetics (Adult data unless
shown alendronate (high-dose) inhibits longitudinal bone noted)
growth (Rauch 2004); pediatric patients with osteogenesis Distribution: 28 L (exclusive of bone)
imperfecta (Ol) treated with pamidronate for 4 years Protein binding: ~78%
showed increased height z scores (Zeitlin 2003); pediatric Metabolism: None
growth effects with other bisphosphonates is lacking. Bioavailability: Fasting:
Possible decreased bone remodeling affecting growth or Children 24 years and Adolescents: Mean range: 0.41%
fracture healing may occur with bisphosphonate therapy; to 0.56% (Nakhla 2011; Ward 2005)
a case-report in an adolescent treated with high-dose Adults: 0.6%; reduced up to 60% with coffee or orange
pamidronate described abnormal long-bone modeling juice
(Rauch 2004); a large, placebo-controlled Ol trial Half-life elimination: Exceeds 10 years
(n=109, age range: 4 to 19 years) reported that alendro- Excretion: Urine; feces (as unabsorbed drug)
nate did not interfere with fracture healing (Ward 2011). Pharmacodynamics/Kinetics: Additional Consider-
Rapid and in some cases significant weight gain has been ations
reported with pamidronate therapy in pediatric patients Renal function impairment: Elimination may be reduced.
which may negatively affect rehabilitation in patients with Dosing
O! (Zeitlin 2003). Monitor patients closely. Pediatric
Adverse Reactions Note: Patients should receive supplemental calcium and
Central nervous system: Headache vitamin D if dietary intake is inadequate.
 ALFENTANIL

Osteogenesis imperfecta: Limited data available, Tablet (Fosamax): Must be taken with 6 to 8 oz of plain
dosing regimens and efficacy results variable (Akcay water. The tablet should be swallowed whole; do not
2008; Pizones 2005; Seikaly 2005; Ward 2011): Chil- chew or suck on the tablet.
dren 22 years and Adolescents: Tablet, effervescent (Binosto): Dissolve one tablet in 4 oz
$30 kg: Oral: 5 mg once daily of room temperature plain water only; once efferves-
30 to <40 kg: 5 or 10 mg once daily cence stops, wait 25 minutes and stir the solution for
240 kg: Oral: 10 mg once daily ~10 seconds and then drink
Dosing based on several prospective and retrospec- Monitoring Parameters
tive trials; most smaller studies reported increased Osteogenesis imperfecta: In pediatric trials, serum cal-
bone mineral density (BMD), decreased frequency cium and phosphorus, alkaline phosphatase, urinary
of fractures, alleviation of chronic pain, and in some calcium/creatinine ratio every 3 months; bone mineral
patients increased mobility (Akcay 2008; Pizones density (DEXA) at baseline and periodically with therapy
2005; Seikaly 2005; Unal 2005; Vyskocil 2005). (eg, every 6 to 12 months); annual skeletal survey
The largest trial, a multicenter, randomized, pla- (Akcay 2008; Seikaly 2005)
cebo-controlled trial (n=109 in treatment group, Cystic fibrosis: Based on expert recommendations and in
n=83 completed 2-year follow-up) reported signifi- pediatric trial experience, growth parameters (eg, height,
cant increases in lumbar spine BMD; however, other weight, z-scores, etc) at baseline and periodically with
\efficacy markers including long-bone fracture rate therapy; bone mineral density (lumber; baseline and
and pediatric disability score were no different than every 6 months or annually) (Aris 2005; Bianchi 2013)
placebo (Ward 2011). Osteopenia/Osteoporosis: Bone mineral density, number
Osteopenia associated with cystic fibrosis (CF): and location of fractures, height and weight, pain; serum
Limited data available: Children 25 years and Adoles- calcium and 25(OH)D; alkaline phosphatase, biochem-
cents: Oral: ical markers of bone turnover
$25 kg: 5 mg once daily Paget disease: Alkaline phosphatase; pain; serum cal-
>25 kg: 10 mg once daily cium and 25(OH)D
Dosing based on a randomized, placebo-controlled Test Interactions Bisphosphonates may interfere with
trial of CF patients (n= 128, treatment group: n=65) diagnostic imaging agents such as technetium-99m-
diphosphonate in bone scans.
with low apparent BMD age and inadequate
response to calcium and calcifediol treatment;
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
results showed a significant increase in BMD
cific product labeling.
(16.3% vs 3.1% from baseline); evaluation of effect
Solution, Oral:
on fracture rate not possible due to sample size and
Generic: 70 mg/75 mL (75 mL)
duration (trial duration: 2 years); alendronate
Tablet, Oral:
appeared to be well-tolerated with no notable differ-
Fosamax: 70 mg
ence in adverse effects reported (Bianchi 2013)
Generic: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Osteopenia, nonambulatory patients (eg, cerebral
Tablet Effervescent, Oral:
palsy, muscular dystrophy): Limited data available,
Binosto: 70 mg
efficacy results variable: Note: Due to added com-
plexity of administration requirements (eg, remaining @ Alendronate Sodium see Alendronate on page 81
in an upright position for an extended time) weekly @ Alendronic Acid Monosodium Salt Trihydrate see
dosing is preferred in these patients. Alendronate on page 87
Fixed dosing (Apkon 2008; Houston 2014; Sholas
@ Aler-Dryl [OTC] see DiphenhydrAMINE (Systemic)
2005): Children 26 years and Adolescents: Oral:
on page 652
Usual reported dose: 35 mg once weekly. Dosing
based on experience in 42 patients (age range: 6 to @ Alertec (Can) see Modafinil on page 1391
16 years) from two case series and a retrospective @ Alevazol [OTC] see Clotrimazole (Topical) on page 499
trial. In the retrospective cohort study (n=29 mean @ Aleve [OTC] see Naproxen on page 1426
age: 12 years), treatment showed a non-statistically
@ Aleve (Can) see Naproxen on page 1426
significant trend in Z-score stabilization (Houston
2014). A case series of 10 patients (age range: 6 @ Aleveer [OTC] [DSC] see Capsaicin on page 357
to 16 years) reported fewer fractures after treatment @ Alfenta (Can) see Alfentanil on page 83
started compared to the prior year; alendronate was
reported as being well tolerated; one patient discon-
tinued therapy for hematemesis (also receiving high-
Alfentanil (ai FEN ta nil)
dose ibuprofen therapy) (Sholas 2005). Medication Safety Issues
Weight-directed dosing: Children 23 years and Ado- Sound-alike/look-alike issues:
lescents: Oral: 1 mg/kg/dose once weekly (Paksu Alfentanil may be confused with Anafranil, fentanyl,
2012); if using a solid dosage form, consider dose remifentanil, sufentanil
rounding to the nearest 10 mg (up or down as Alfenta may be confused with Sufenta
appropriate) (Lethaby 2007). Dosing based on a High alert medication:
prospective trial of 26 patients (age range: 3 to 17 The Institute for Safe Medication Practices (ISMP)
years); results showed after one year of treatment, includes this medication among its list of drug classes
increased BMD and decreased alkaline phos- which have a heightened risk of causing significant
phatase. patient harm when used in error.
Osteopenia/Osteoporosis, rheumatology patients Related Information
(eg, JIA, SLE, dermatomyositis): Limited data avail- Opioid Conversion Table on page 2138
able: Children 24 years and Adolescents: Brand Names: Canada Alfenta; Alfentanil Injection, USP
$20 kg: Oral: 5 mg once daily Therapeutic Category Analgesic, Narcotic; General
>20 kg to 30 kg: Oral: 5 or 10 mg once daily Anesthetic
>30 kg: Oral: 10 mg once daily Generic Availability (US) Yes
Dosing based on a prospective trial (multicenter and Use Analgesic adjunct for the maintenance of anesthesia
single center) (Bianchi 2000; Cimaz 2002; Unal with barbiturate/nitrous oxide/oxygen; analgesic with
2006); results from trials showed bone mineral den- nitrous oxide/oxygen in the maintenance of general anes-
sity (BMD) was significantly increased (to normal thesia; analgesic component for monitored anesthesia
values in some patients) after alendronate therapy; care; primary anesthetic for induction of anesthesia in
in some cases, bene turnover markers were general surgery when endotracheal intubation and
reduced without a reduction of inflammatory activity mechanical ventilation are required (All indications: FDA
(underlying rheumatologic disease process) approved in ages 212 years and adults)
Preparation for Administration Tablet, effervescent Pregnancy Considerations Adverse events have been
(Binosto): Dissolve effervescent tablet in 120 mL of room observed in some animal reproduction studies. Alfentanil
temperature plain water (not mineral water or flavored is known to cross the placenta, which may result in severe
water); wait 25 minutes after effervescence stops, then respiratory depression in the newborn (Mattingly 2003).
stir for 10 seconds and administer When used for pain relief during labor, opioids may
Administration Administer first thing in the morning and temporarily affect the heart rate of the fetus (ACOG
230 minutes before the first food, beverage (except plain 2002). Use during labor and immediately prior to labor is
water), or other medication of the day. Do not take with not recommended by the manufacturer.
mineral water or with other beverages. Remain upright (do Breastfeeding Considerations Alfentanil is excreted in
not lie down) for at least 30 minutes and until after first breast milk. Significant concentrations were observed in
food of the day (to reduce esophageal irritation). breast milk following administration of alfentanil 60 mcg/kg
Oral solution: Follow administer of oral solution with at to nine women who underwent postpartum tubal ligation;
least 2 oz of plain water. . concentrations were undetectable after 28 hours. >
83
 ALFENTANIL

q According to the manufacturer, the decision to continue or

discontinue breastfeeding during therapy should take into
psychosis, renal impairment, history of seizure disorders,
and/or thyroid dysfunction.
account the risk of infant exposure, the benefits of breast-
May produce muscular rigidity that involves all skeletal
feeding to the infant, and benefits of treatment to the
muscles, including those of the neck and extremities;
mother. Parenteral opioids used during labor have the
incidence is dose-related. Initial doses up to 20 mcg/kg
potential to interfere with a newborn's natural reflex to
may cause skeletal muscle rigidity, particularly of the
nurse within the first few hours after birth. Breastfeeding
truncal muscles. Doses >130 mcg/kg will consistently
infants exposed to large doses of opioids should be
cause muscle rigidity with an immediate onset. Consider
monitored for apnea and sedation (Montgomery 2012).
the concomitant use of a nondepolarizing skeletal muscle
Contraindications
relaxant to decrease the incidence. Discontinue infusion at
Hypersensitivity (eg, anaphylaxis) to alfentanil or any
least 10 to 15 minutes prior to the end of surgery during
component of the formulation.
general anesthesia; during administration for Monitored
Canadian labeling: Additional contraindication (not in US
Anesthesia Care (MAC), infusions may be continued to
labeling): Suspected surgical abdomen (eg, acute
the end of the procedure.
appendicitis or pancreatitis); mild pain that can be man-
aged with other pain medications; acute or severe bron-
Adverse Reactions
Cardiovascular: Bradycardia, cardiac arrhythmia, chest
chial asthma, chronic obstructive airway, status
asthmaticus; acute respiratory depression, hypercapnia,
wall rigidity, hypertension, hypotension, peripheral vaso-
cor pulmonale; acute alcoholism, delirium tremens, and dilation, tachycardia
Central nervous system: Dizziness, drowsiness, sedation
convulsive disorders; severe CNS depression, increased
cerebrospinal or intracranial pressure and head injury; (postoperative)
concurrent use or use within 14 days of an MAO inhib- Gastrointestinal: Constipation, nausea, vomiting
itor; women who are nursing, pregnant, or during labor Neuromuscular & skeletal: Muscle movements (skeletal)
Ophthalmic: Blurred vision, miosis
and delivery
Documentation of allergenic cross-reactivity for opioids is Respiratory: Apnea, respiratory depression (postoper-
limited. However, because of similarities in chemical ative)
structure and/or pharmacologic actions, the possibility Rare but important or life-threatening: Anaphylaxis, bron-
of cross-sensitivity can not be ruled out with certainty. chospasm, confusion (postoperative), drug dependence,
Warnings/Precautions [US Boxed Warning]: Alfentanil euphoria (postoperative), headache, hypercapnia, lar-
exposes users to the risks of opioid addiction, abuse,
yngospasm, muscle rigidity (neck and extremities), myo-
and misuse, which can lead to overdose and death. clonus, pruritus, shivering, urticaria
Assess each patient’s risk prior to prescribing alfen- Drug Interactions
tanil and monitor all patients regularly for the develop- Metabolism/Transport Effects Substrate of CYP3A4
ment of these behaviors and conditions. Alfentanil (major); Note: Assignment of Major/Minor substrate sta-
should be administered health care providers specifically tus based on clinically relevant drug interaction potential
trained in the use of anesthetic agents and should not be Avoid Concomitant Use
used in diagnostic or therapeutic procedures outside the Avoid concomitant use of Alfentanil with any of the
monitored anesthesia setting; opioid antagonist, resusci- following: Azelastine (Nasal); Bromperidol; Conivaptan;
tative and intubation equipment should be readily avail- Crizotinib; Eluxadoline; Enzalutamide; Fusidic Acid (Sys-
able. Serious, life-threatening, or fatal respiratory temic); Idelalisib; Opioids (Mixed Agonist / Antagonist);
depression, even when used as recommended, may Orphenadrine; Oxomemazine; Paraldehyde; Thalido-
occur. Monitor closely for respiratory depression, espe- mide
cially during initiation or dose escalation. Carbon dioxide Increased Effect/Toxicity
retention from opioid-induced respiratory depression can Alfentanil may increase the levels/effects of: Alvimopan;
exacerbate the sedating effects of opioids. Use with Azelastine (Nasal); Beta-Blockers; Blonanserin; Calcium
caution and monitor for respiratory depression in patients Channel Blockers (Nondihydropyridine); Desmopressin;
with significant chronic obstructive pulmonary disease or Diuretics; Eluxadoline; Flunitrazepam; HYDROcodone;
cor pulmonale, and those with a substantially decreased Methotrimeprazine; MetyroSINE; Opioid Analgesics;
respiratory reserve, hypoxia, hypercapnia, or preexisting Orphenadrine; OxyCODONE; Paraldehyde; Piribedil;
respiratory depression, particularly when initiating and Pramipexole; Propofol; Ramosetron; ROPINIRole; Roti-
titrating therapy. Benzodiazepines or other CNS depres- gotine; Selective Serotonin Reuptake Inhibitors; Seroto-
sants: Concomitant use of opioids with benzodiazepines nin Modulators; Suvorexant; Thalidomide; Zolpidem
or other CNS depressants, including alcohol, may result in
The levels/effects of Alfentanil may be increased by:
hypotension, profound sedation, respiratory depression,
Amphetamines; Anticholinergic Agents; Aprepitant; Bri-
coma, and death. Following the administration of alfenta-
monidine (Topical); Bromopride; Bromperidol; Cannabis;
nil, the dose of other CNS depressant drugs should be
Ceritinib; Chlormethiazole; Chlorphenesin Carbamate;
reduced. CYP3A4 interactions: Use with all CYP3A4
Cimetidine; CNS Depressants; Conivaptan; Crizotinib;
inhibitors may result in an increase in alfentanil plasma
concentrations, which could increase or prolong adverse
CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors
(Strong); DiazePAM; DilTl[AZem; Dimethindene (Top-
drug effects and may cause potentially fatal respiratory
ical); Dronabinol; Droperidol; Erythromycin (Systemic);
depression. In addition, discontinuation of a concomitant
Fluconazole; Fosaprepitant; Fosnetupitant; Fusidic Acid
CYP3A4 inducer may result in increased alfentanil con-
centrations. Monitor patients receiving alfentanil and any (Systemic); Idelalisib; Kava Kava; Lofexidine; Magne-
sium Sulfate; Methotrimeprazine; MiFEPRIStone; Mino-
CYP3A4 inhibitor or inducer. Potentially life-threatening
serotonin syndrome (SS) has occurred with concomitant cycline; Nabilone; Netupitant; Ombitasvir, Paritaprevir,
Ritonavir, and Dasabuvir; Oxomemazine; Palbociclib;
use of alfentanil and serotonergic agents (eg, SSRIs,
SNRIs, triptans, TCAs, 5-HT3 receptor antagonists, mirta-
Perampanel; Rufinamide; Simeprevir; Sodium Oxybate;
zapine, trazodone, tramadol) and agents that impair Stiripentol; Succinylcholine; Tapentadol; pedals Sopdet
metabolism of serotonin (eg, MAO inhibitors). Discontinue nabinol
alfentanil if serotonin syndrome is suspected. Potentially Decreased Effect
significant interactions may exist, requiring dose or fre- Alfentanil may decrease the levels/effects of: Diuretics;
quency adjustment, additional monitoring, and/or selec- Gastrointestinal Agents (Prokinetic); Pegvisomant
tion of alternative therapy. The levels/effects of Alfentanil may be decreased by:
Anaphylaxis reactions may occur. May cause hypoten- Enzalutamide; Nalmefene; Naltrexone; Opioids (Mixed
sion; use with caution in patients with hypovolemia, car- Agonist / Antagonist); Rifamycin Derivatives
diovascular disease (including acute Ml), or drugs which Storage/Stability Store intact vials at 20°C to 25°C (68°F
may exaggerate hypotensive effects (including phenothia- to 77°F). Protect from light.
zines or general anesthetics). Monitor for symptoms of Mechanism of Action Binds with stereospecific recep-
hypotension following initiation or dose titration. Bradycar- tors at many sites within the CNS, increases pain thresh-
dia may occur; use with caution when administering to old, alters pain perception, inhibits ascending pain
patients with bradyarrhythmias. Degree of bradycardia pathways; is an ultra short-acting opioid
may be more pronounced when administered with non- Pharmacodynamics/Kinetics (Adult data unless
vagolytic skeletal muscle relaxants (eg, vecuronium, cis- noted) Note: An early study of continuous infusion
atracurium) or when anticholinergic agents (eg, atropine) suggested nonlinear pharmacokinetics in neonates (Wiest
are not used. Opioids may obscure diagnosis or clinical 1991).
course of patients with acute abdominal conditions. Use Onset of action: Rapid, within 5 minutes
with caution in patients who are morbidly obese, cachectic Duration (dose dependent): 30 to 60 minutes
or debilitated patients and in the elderly. Use with caution Distribution: Vg:
in patients with biliary tract dysfunction (including acute Newborns (premature): 0.5 to 0.6 L/kg (Davis 1988;
pancreatitis), delirium tremens; head injury, intracranial Marlow 1990)
lesions, or elevated intracranial pressure; hepatic impair- Children: 0.163 to 0.4 L/kg (Davis 1989; Meistel-
ment, prostatic hyperplasia and/or urinary stricture, toxic man 1987)

84
 ALGLUCOSIDASE ALFA

Adults: 0.4 to 1 L/kg Renal Impairment: Pediatric There are no dosage

Protein binding: adjustments provided in the manufacturer's labeling;
Neonates: 67% use with caution.
Adults: 88% to 92% Hepatic Impairment: Pediatric There are no dosage
Bound to alpha,-acid glycoprotein adjustments provided in the manufacturer's labeling; use
Metabolism: Hepatic with caution.
Half-life elimination: Preparation for Administration Parenteral:
Newborns (premature): 5.33 to 9 hours (Davis 1988; IV: Dilute prior to administration with NS, D5W, D5NS or
Marlow 1990) LR to a concentration of 25 to 80 mcg/mL
Children: 40 to 63 minutes (Davis 1988; Meistelman Continuous |V infusion: Further dilute in D5W, NS D5NS
1987; Roure 1987) or LR to a concentration of 40 mcg/mL
_ Adults: 90 to 111 minutes Administration Parenteral: IV: Inject slowly over 3 to 5
Excretion: Only 1% of dose is excreted unchanged; urine
minutes or by continuous IV infusion
(major route of elimination of metabolites)
Monitoring Parameters Respiratory rate, blood pres-
Pharmacodynamics/Kinetics: Additional Consider- sure, heart rate, neurological status (for degree of anal-
ations gesia/anesthesia)
Hepatic function impairment: Reduced plasma clearance Controlled Substance C-II
and extended terminal elimination may develop.
Dosage Forms Excipient information presented when
Geriatric: Reduced plasma clearance and extended ter-
available (limited, particularly for generics); consult spe-
minal elimination may develop.
cific product labeling.
Dosing
Solution, Intravenous [preservative free]:
Neonatal |V: Doses should be titrated to appropriate Generic: 1000 mcg/2 mL (2 mL); 2500 mcg/5 mL (5 mL)
effects; wide range of doses is dependent upon desired
degree of analgesia/anesthesia @ Alfentanil Hydrochloride see Alfentanil on page 83
Dose not established; reported range: 9 to 20 mcg/kg/ @ Alfentanil Injection, USP (Can) see Alfentanil
dose; a high percentage of neonates (GA: 30 to 40 on page 83
weeks; PNA <3 days) receiving alfentanil (prior to @ Alfentanyl see Alfentanil on page 83
procedures) at doses of 9 to 15 mcg/kg (mean dose: @ Alglucosidase see Alglucosidase Alfa on page 85
11.7 mcg/kg) developed chest wall rigidity; 9 out of 20
(45%) developed mild or moderate rigidity that did not
affect ventilation, while 4 out of 20 (20%) had severe Alglucosidase Alfa (ai gloo KOSE i dase AL fa)
rigidity interfering with respiration for ~5 to 10 minutes
(Pokela 1992). In a separate study, severe muscle Medication Safety Issues
rigidity developed in five out of eight (63%) neonates Sound-alike/look-alike issues:
(GA: 29 to 36 weeks; PNA 2 to 6 days) following a dose Alglucosidase alfa may be confused with agalsidase alfa,
of 20 mcg/kg (Saarenmaa 1996); use of a skeletal agalsidase beta, alglucerase
muscle relaxant to prevent chest wall rigidity is recom- Brand Names: US Lumizyme; Myozyme [DSC]
mended; however, smaller alfentanil doses may be Brand Names: Canada Myozyme
required in newborns. Therapeutic Category Enzyme
Pediatric Note: Doses should be titrated to appropriate Generic Availability (US) No
effects; wide range of doses is dependent upon desired Use
degree of analgesia/anesthesia Myozyme: Replacement therapy of alpha-glucosidase
Anesthesia: (GAA) for infantile-onset Pompe disease [FDA approved
Children <12 years: in pediatric patients (age not specified)]
Pre-induction, emergence agitation prevention, anal- Lumizyme: Replacement therapy of alpha-glucosidase
gesia in tonsillectomy, or dental procedure patients (GAA) for Pompe disease (FDA approved in pediatrics
undergoing general anesthesia: Limited data avail- patients [age not specified] and adults)
able: IV: 10 to 20 mcg/kg/dose (Annila 1999; Barto- Pregnancy Risk Factor C
lek 2007; Kim 2009; Kwak 2010; Ng 1999; Rahman Pregnancy Considerations
Al-Refai 2007) Adverse events were observed in some animal reproduc-
Procedural analgesia for LP or bone marrow aspira- tion studies. Use of alfa-glucosidase in pregnant women
tion (in addition to propofol): Limited data available: has been reported (Perniconi 2016; Rohman 2016; San-
Intermittent IV: 2 to 3 mcg/kg/dose (total dose: tos 2016; Zagnoli 2013).
mean: 1.4 mcg/kg + 2.4; range: 1.8 to 9.6 mcg/kg)
administered to 20 patients ages 2 to 16 years old A registry has been established for Pompe patients;
(von Heijne 2004) women of childbearing potential are encouraged to enroll
Children 212 years and Adolescents: See table; Note: in the registry (Www.pomperegistry.com or
Base dose on actual body weight.unless >20% above 1-800-745-4447).
ideal body weight, then base dose on lean body Breastfeeding Considerations Endogenous acid alfa-
weight glucosidase can be detected in breast milk; concentra-
tions are lower in women with Pompe disease. Following
an infusion of alglucosidase alfa in one woman with
Alfentanil Dosing Pompe disease, maximum enzyme activity was found in
breast milk 2.5 hours after the dose and was ~0.3% of the
maternal peak plasma value. Activity in breast milk
returned to baseline values within 24 hours after the
(Increments/
Infusion) |(mes/ka) infusion (de Vries, 2011). The manufacturer recommends
that caution be used if administered to breastfeeding
3-5 meg/kg,
Spontaneously women; exposure may be minimized by temporarily
every 5-20
minutes or 8-40
breathing or
assisted ventilation
pumping and discarding breast milk for 24 hours after
0.5-1 mcg/
kg/minute when required. administration.
Incremental
eghed Assisted or
injgetion controlled A registry has been established for, Pompe patients;
5-15 meg/kg ventilation required.
every 5-20 Up to 75 Attenuation of women who are breastfeeding are encouraged to enroll
minutes response to
laryngoscopy and
in the registry (www.pomperegistry.com or
intubation. 1-800-745-4447)
0.5-3 meg/
Assisted or
controlled
Contraindications There are no contraindications listed
Dependent
kg/minute; or n ventilation required. in the manufacturer’s labeling.
Continuous ,
Conti average duration ~ Some attenuation of
infusion
>45 infusion of response to Warnings/Precautions [U.S. Boxed Warning]: Life-
rate: 1-1.5 intubation and
meg/kg/ precede incision, with threatening anaphylactic reactions and severe hyper-
minute intraoperative
stability, sensitivity reactions, some of which were IgE medi-
Assisted or ated, may occur. Severe immune-mediated reactions
controlled
Dependent | ventilation required, (eg, necrotizing skin lesions, nephrotic syndrome
. 0.5-1.5 meg/ on Administer induction secondary to membranous glomerulonephritis, pro-
Anesthetic >45 130-245 kg/minute duration | dose slowly (over 3
induction as or general
anesthetic
ofif
procedure
minutes).
Concentration of
teinuria, inflammatory arthropathy) may occur. Imme-
inhalation agents diate medical support should be readily available.
reduced by 30% to
50% for initial hour. Anaphylactic and severe hypersensitivity reactions may
Monitored 3-5 meg/kg
Sedation,
occur during and up to 3 hours after infusion. Patients who
every 5-20
Anesthesia
Care
3-8 minutes or responsiveness,
spontaneously
develop IgE antibodies to alglucosidase alfa may be at a
0.25-1 meg/
(MAC) kg/minute breathing. higher risk; monitor these patients closely during admin-
istration. Immune-mediated reactions have occurred up to
3 years after initiation of therapy. Monitor urinalysis »
85
 ALGLUCOSIDASE ALFA

4 periodically. Monitor for immune-mediated reaction devel-

opment. Consider testing for IgG titers in patients who
Local: Catheter infection (infants and children), infusion
site reaction, local swelling
develop allergic or immune-mediated reactions; may also Neuromuscular & skeletal: Muscle twitching, musculoske-
test for IgE antibodies or other mediators of anaphylaxis. letal pain, myalgia, stiffness, tremor
Consider risks/benefits of readministration following an Ophthalmic: Blurred vision }
anaphylactic or severe allergic reaction or an immune- Otic: Auditory impairment, otalgia, otitis media (infants and
mediated reaction; some patients have been successfully children)
rechallenged under close clinical supervision; appropriate Renal: Nephrolithiasis
resuscitation measures should be available. Infusion- Respiratory: Bronchiolitis (infants and children), cough
related reactions are common and may occur during and (infants and children), cyanosis, dyspnea, epistaxis,
up to 2 hours after infusion; discontinue immediately for nasopharyngitis (infants and children), pharyngeal
severe hypersensitivity or anaphylactic reaction; mild to edema, pharyngitis (more common in infants and chil-
moderate reactions may be managed by reducing the dren), pneumonia (infants and children), respiratory dis-
infusion rate and/or administering antihistamines and/or tress (infants and children), respiratory failure (infants
antipyretics. Appropriate medical support for the manage- and children), respiratory syncytial virus infection (infants
ment of infusion reactions should be readily available. Use and children), respiratory tract infection, rhinitis (children
caution with subsequent infusions; infusion reactions have and adolescents), rhinorrhea (infants and children),
occurred despite premedication with antihistamines, anti- tachypnea (infants and children), upper respiratory tract
pyretics, and/or corticosteroids. Patients with acute under- infection (more common in infants and children)
lying illness are at greater risk for infusion reactions, Miscellaneous: Fever (infants and children), infusion
including cardiorespiratory failure; monitor closely during related reaction (infants and children)
infusion. Although less common, delayed-onset (within 48 Rare but important or life-threatening: Acute cardiorespir-
hours after administration) infusion reactions have also atory failure, aortic dissection, apnea, bronchospasm,
occurred. The presence of IgG antibodies has been cerebrovascular accident, convulsions, coronary artery
observed within 3 months from the onset of therapy in disease, dehydration, flu-like symptoms, hemothorax,
the majority of patients. High and sustained IgG antibody herniated disk, hyperparathyroidism, hypersensitivity,
titers may result in reduced efficacy of alglucosidase alfa hypervolemia, livedo reticularis, muscle spasm, neph-
(eg, loss of motor function, ventilator dependence, death). rotic syndrome (secondary to membranous glomerulo-
Regularly monitor all patients for development of IgG nephritis), nodal arrhythmia, periorbital edema,
antibodies; consider testing for IgG titers in patients who pneumothorax, pulmonary infection, sepsis, skin
develop hypersensitivity reactions, other immune-medi- necrosis, ventricular premature contractions
ated reactions, or loss of clinical response. Patients with Drug Interactions
reduced clinical response may also be tested for inhibitory Metabolism/Transport Effects None known.
antibody activity. Avoid Concomitant Use There are no known interac-
[U.S. Boxed Warning]: Use caution in patients with tions where it is recommended to avoid concomitant use.
compromised cardiac or respiratory function; risk of Increased Effect/Toxicity There are no known signifi-
acute cardiorespiratory failure secondary to infusion- cant interactions involving an increase in effect.
related reactions or fluid overload may be increased. Decreased Effect There are no known significant inter-
Additional monitoring is warranted in this patient actions involving a decrease in effect.
population. Cardiorespiratory failure has been observed Storage/Stability Store intact vials between 2°C and 8°C
in patients with cardiac hypertrophy up to 72 hours after (36°F and 46°F). Final solutions diluted in NS for infusion
infusion; arrhythmias have also been observed in patients should be used immediately if possible but may be stored
with cardiac hypertrophy. Patients with sepsis may be at for up to 24 hours between 2°C and 8°C (36°F and 46°F);
increased risk for cardiorespiratory failure during infu- do not freeze. Protect from light.
sions. Some dosage forms may contain polysorbate 80 Mechanism of Action Alglucosidase alfa is a recombi-
(also known as Tweens). Hypersensitivity reactions, usu- nant form of the enzyme acid alpha-glucosidase (GAA),
ally a delayed reaction, have been reported following which is required for glycogen cleavage. Due to an
exposure to pharmaceutical products containing polysor- inherited GAA deficiency or absence, glycogen accumu-
bate 80 in certain individuals (Isaksson, 2002; Lucente lates in the tissues of patients with Pompe disease,
2000; Shelley, 1995). Thrombocytopenia, ascites, pulmo- leading to progressive muscle weakness. In infantile-
nary deterioration, and renal and hepatic failure have been onset Pompe disease, glycogen accumulates in cardiac
reported in premature neonates after receiving parenteral and skeletal muscles and hepatic tissue, leading to car-
products containing polysorbate 80 (Alade, 1986; CDC, diomyopathy and respiratory failure. Juvenile- and adult-
1984). See manufacturer’s labeling. Use of general anes- onset Pompe disease are limited to glycogen accumula-
thesia for catheter placement for alglucosidase alfa infu- tion in skeletal muscle, leading to respiratory failure.
sions may be complicated by the presence of cardiac and Alglucosidase alfa binds to mannose-6-phosphate recep-
skeletal (including respiratory) muscle weakness in tors on the cell surface, is internalized, and transported to
patients with Pompe disease; use general anesthesia with lysosomes where it is activated for increased enzymatic
caution. Monitor for development. A registry has been glycogen cleavage.
created to monitor therapeutic responses and adverse Pharmacodynamics/Kinetics (Adult data unless
effects during long-term treatment; patients should be
noted)
encouraged to register (www.pomperegistry.com or
Distribution: V,,: Infants 1 to 7 months: 96 + 16 mL/kg
1-800-745-4447).
Half-life elimination: Infants 1 to 7 months: 2.3 hours;
Adverse Reactions Adults: 2.4 hours
Cardiovascular: Bradycardia (infants and children), chest
Pharmacodynamics/Kinetics: Additional Consider-
discomfort, chest pain, flushing, hypertension (infants
ations
and children), increased blood pressure, oxygen satu-
Antibody formation: Higher mean clearance (50%) was
ration decreased (infants and children), peripheral
observed in patients who tested positive for antibodies to
edema, tachycardia (infants and children)
alglucosidase alfa.
Central nervous system: Agitation (infants and children),
dizziness, drowsiness, fatigue, headache, malaise, pain,
Dosing
pain (postprocedural; more common in infants and chil- Pediatric
dren), paresthesia, rigors (infants and children), vertigo Infantile-onset Pompe disease: Infants 21 month,
Dermatologic: Diaper rash (infants and children), eryth- Children, and Adolescents: Lumizyme, Myozyme: IV:
ema (infants and children), hyperhidrosis, pallor (infants 20 mg/kg every 2 weeks
and children), papular rash, pruritus, skin rash (more Late-onset (noninfantile) Pompe disease: Infants 21
common in infants and children), urticaria month, Children, and Adolescents: Lumizyme: IV:
Endocrine & metabolic: Hypokalemia 20 mg/kg every 2 weeks
Gastrointestinal: Constipation (more common in infants Renal Impairment: Pediatric There are no dosage
and children), diarrhea (more common in infants and adjustments provided in the manufacturer's labeling.
children), dyspepsia, gastroenteritis (more common in Hepatic Impairment: Pediatric There are no dosage
infants and children), gastroesophageal reflux disease adjustments provided in the manufacturer's labeling.
(infants and children), nausea, oral candidiasis (infants Preparation for Administration Visually inspect the
and children), upper abdominal pain (children and ado- powder in the vial for particulate matter prior to reconsti-
lescents), vomiting (more common in infants and tution. After vial reaches room temperature, reconstitute
children) each vial with 10.3 mL SWFI. Inject slowly down internal
Hematologic & oncologic: Anemia (infants and children), side wall of vial (do not inject into powder; avoid foaming).
lymphadenopathy Roll and tilt gently; do not invert, swirl, or shake. Resulting
Hypersensitivity: Anaphylaxis, hypersensitivity reaction solution contains 5 mg/mL. To make final infusion, add the
(infants and children) desired amount of reconstituted solution (based on patient
Immunologic: Development of IgG antibodies (more com- weight) to 50 to 1,000 mL NS (do not use filter needle to
mon in adults; may affect efficacy) prepare) to a final concentration of 0.5 to 4 mg/mL.

86
 ALISKIREN

Remove airspace from infusion bag prior to admixture to angioedema, some cases necessitating hospitalization
minimize particle formation due to sensitivity of drug to air- and intubation has been observed with aliskiren use.
liquid interfaces. Do not shake. Protect from light. Discontinue immediately following the occurrence of ana-
Administration Infuse through a low protein-binding, 0.2 phylaxis or angioedema; do not readminister. Prolonged
micron in-line filter. Do not administer products with visual- frequent monitoring may be required especially if tongue,
ized particulate matter. Infuse over ~4 hours; initiate at glottis, or larynx are involved as they are associated with
1 mg/kg/hour. If tolerated, increase by 2 mg/kg/hour every airway obstruction. Patients with a history of airway sur-
30 minutes to a maximum rate of 7 mg/kg/hour. Decrease gery may have a higher risk of airway obstruction. Early,
rate or temporarily hold for infusion reactions. Monitor vital aggressive, and appropriate management is critical. Dur-
signs prior to each rate increase. Protect from light. ing the initiation of therapy, symptomatic hypotension may
Monitoring Parameters Liver enzymes (baseline and occur, particularly in volume or salt-depleted patients or
periodically; elevation may be due to disease process); with concomitant use of other agents acting on the renin-
vital signs during and following infusion; immune mediated angiotensin-aldosterone system. Prior to initiation, correct
reactions; volume overload; periodic urinalysis hypovolemia or salt depletion, or closely monitor during
The manufacturer recommends monitoring for IgG anti- treatment initiation. If hypotension does occur, this is not a
body formation every 3 months for 2 years, then annu-
contraindication for further use; once blood pressure has
ally. Consider testing if patient develops allergic or other
been stabilized, aliskiren usually can be continued without
suspected immune mediated reaction. No commercial
difficulty. Use in patients with diabetes has demonstrated
tests are available; however, sampling kits can be
an increased incidence of renal impairment, hypotension,
obtained by contacting Genzyme Corporation at
1-800-745-4447. and hyperkalemia; use is contraindicated in patients with
diabetes who are taking an ACE inhibitor or ARB. Poten-
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe- tially significant interactions may exist, requiring dose or
-cific product labeling. [DSC] = Discontinued product frequency adjustment, additional monitoring, and/or selec-
Solution Reconstituted, Intravenous [preservative free]: tion of alternative therapy.
Lumizyme: 50 mg (1 ea) [contains polysorbate 80] Warnings: Additional Pediatric Considerations Pre-
Myozyme: 50 mg (1 ea [DSC]) clinical studies show increased exposure in pediatric
patients compared to adults; use is not recommended in
@ Alinia see Nitazoxanide on page 1455 children <6 years of age and is contraindicated for use in
children <2 years of age.
Aliskiren (a lis KYE ren) Adverse Reactions
Dermatologic: Skin rash
Medication Safety Issues Gastrointestinal: Diarrhea
Sound-alike/look-alike issues: Neuromuscular & skeletal: Increased creatine phosphoki-
Tekturna may be confused with Valturna nase (>300% increase)
Brand Names: US Tekturna Renal: Increased blood urea nitrogen, increased serum
Brand Names: Canada Rasilez creatinine
Therapeutic Category Renin Inhibitor Respiratory: Cough
Generic Availability (US) No Rare but important or life-threatening: Anaphylaxis,
Use Treatment of hypertension (FDA approved in ages 26 decreased hematocrit, decreased hemoglobin, gastro-
years and weighing 220 kg and adults) esophageal reflux disease, hepatic insufficiency, hyper-
Pregnancy Considerations [US Boxed Warning]: kalemia, hyponatremia, increased uric acid, nausea,
Drugs that act on the renin-angiotensin system can rhabdomyolysis, seizure, severe hypotension, Stevens-
cause injury and death to the developing fetus. Dis- Johnson syndrome, tonic-clonic seizures, vomiting
continue as soon as possible once pregnancy is Drug Interactions
detected. The use of drugs which act on the renin- Metabolism/Transport Effects Substrate of CYP3A4
angiotensin system are associated with oligohydramnios. (minor), P-glycoprotein/ABCB1; Note: Assignment of
Oligohydramnios, due to decreased fetal renal function, Major/Minor substrate status based on Clinically relevant
may lead to fetal lung hypoplasia and skeletal malforma- drug interaction potential
tions. Use is also associated with anuria, hypotension, Avoid Concomitant Use
renal failure, skull hypoplasia, and death in the fetus/
Avoid concomitant use of Aliskiren with any of the
neonate. The exposed fetus should be monitored for fetal
following: Bromperidol; CycloSPORINE (Systemic); ltra-
growth, amniotic fluid volume, and organ formation.
conazole
Infants exposed in utero should be monitored for hyper-
kalemia, hypotension, and oliguria. Increased Effect/Toxicity
Breastfeeding Considerations It is not known if aliski- Aliskiren may increase the levels/effects of: Amifostine;
ren is present in breast milk. Due to the potential for Angiotensin || Receptor Blockers; Angiotensin-Convert-
serious adverse reactions in the breastfeeding infant, ing Enzyme Inhibitors; Antipsychotic Agents (Second
breastfeeding is not recommended by the manufacturer. Generation [Atypical]); Bromperidol; DULoxetine; Hypo-
Contraindications tension-Associated Agents; Levodopa; Nitroprusside;
Hypersensitivity to aliskiren or any component of the Pholcodine
formulation; concomitant use with an ACE inhibitor or The levels/effects of Aliskiren may be increased by:
ARB in patients with diabetes; children <2 years of age Alfuzosin; AtorvaSTATin; Barbiturates; Benperidol; Brig-
Canadian labeling: Additional contraindications (not in US atinib; Brimonidine (Topical); Canagliflozin; CycloSPOR-
labeling): History of angioedema with aliskiren, ACE INE (Systemic); Diazoxide; Drospirenone; Heparin;
inhibitors, or ARBs; hereditary or idiopathic angioedema;
Heparins (Low Molecular Weight); Herbs (Hypotensive
pregnancy, breastfeeding; concomitant use with ACE
Properties); Itraconazole; Ketoconazole (Systemic); Lor-
inhibitors or ARBs in patients with GFR <60 mL/minute/
metazepam; Lumacaftor; Molsidomine; Naftopidil; Nicer-
1°73 m2
goline; Nicorandil; Nonsteroidal Anti-Inflammatory
Warnings/Precautions [US Boxed Warning]: Drugs
Agents; Obinutuzumab; Pentoxifylline; P-glycoprotein/
that act on the renin-angiotensin system can cause
ABCB1 Inhibitors; Phosphodiesterase 5 Inhibitors;
injury and death to the developing fetus. Discontinue
as soon as possible once pregnancy is detected. Potassium Salts; Prostacyclin Analogues; Quinagolide;
Changes in renal function, including acute renal failure, Ranolazine; Verapamil
may occur; risk is increased in patients with renal artery Decreased Effect
stenosis, severe heart failure, post-myocardial infarction, Aliskiren may decrease the levels/effects of: Furosemide
volume depletion, or patients receiving ARB, ACEI or The levels/effects of Aliskiren may be decreased by:
NSAIDs. Consider withholding or discontinuing therapy Amphetamines; Brigatinib; Bromperidol; Grapefruit
in patients who develop a clinically significant decrease
Juice; Herbs (Hypertensive Properties); Lumacaftor;
in renal function. Use with caution in patients with renal
Methylphenidate; Nonsteroidal Anti-Inflammatory
impairment; risk of developing acute renal failure and
Agents; P-glycoprotein/ABCB1 Inducers; Yohimbine
hyperkalemia is increased. Avoid concomitant use with
an ACE inhibitor or ARB in patients with CrCl <60 mL/ Food Interactions High-fat meals decrease absorption.
minute. Hyperkalemia may occur; risk increased in Grapefruit juice may decrease the serum concentration of
patients with renal impairment or diabetes, or concomitant aliskiren. Management: Administer at the same time each
use with ACE inhibitors, ARBs, NSAIDs, potassium-spar- day; administer with or without a meal, but consistent
ing diuretics, potassium supplements, and/or potassium- administration with regards to meals is recommended.
containing salts. Anaphylaxis and angioedema have been Avoid concomitant use of aliskiren and grapefruit juice.
reported. Since the effect of aliskiren on bradykinin levels Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
is unknown, the risk of kinin-mediated etiologies of angioe- excursions are permitted to 15°C to 30°C (59°F to 86°F).
dema occurring is also unknown. Use with caution in any Protect from moisture. Dispense blisters in the original
patient with a history of angioedema (of any etiology) as container.
 ALISKIREN

| Mechanism of Action Decreases plasma renin activity

and inhibits conversion of angiotensinogen to angiotensin
@ Allegra 12 Hour (OTC) (Can) see Fexofenadine
on page 854
I. @ Allegra 24 Hour (OTC) (Can) see Fexofenadine
Pharmacodynamics/Kinetics (Adult data unless on page 854
noted) Note: Reported pharmacokinetic data in pediatric @ Allegra Allergy [OTC] see Fexofenadine on page 854
patients 6 to 17 years is similar to that of adults.
Onset of action: Maximum antihypertensive effect: Within @ Allegra Allergy Childrens [OTC] see Fexofenadine
2 weeks on page 854
Absorption: Poor; absorption decreased by high-fat meal. @ Aller-Chior [OTC] see Chlorpheniramine on page 428
Aliskiren is a substrate of P-glycoprotein; concurrent use @ Allerdryl (Can) see DiphenhydrAMINE (Systemic)
of P-glycoprotein inhibitors may increase absorption. on page 652
Metabolism: Extent of metabolism unknown; in vitro stud-
@ Allergy [OTC] see Loratadine on page 1247
ies indicate metabolism via CYP3A4
Bioavailability: ~3% @ Allergy 24-HR [OTC] see Fexofenadine on page 854
Half-life elimination: ~24 hours (range: 16 to 32 hours) @ Allergy Relief [OTC] see DiphenhydrAMINE (Systemic)
Time to peak, plasma: 1 to 3 hours on page 652
Excretion: Urine (~25% of absorbed dose excreted
@ Allergy Relief [OTC] see Loratadine on page 1247
unchanged in urine); feces (unchanged via biliary
excretion) @ Allergy Relief Childrens [OTC] see DiphenhydrAMINE
Pharmacodynamics/Kinetics: Additional Consider- (Systemic) on page 652
ations Geriatric: AUC is increased in patients 265 years. @ Allergy Relief For Kids [OTC] [DSC] see Loratadine
Dosing on page 1247
Pediatric Note: Prior to initiation, correct hypovolemia @ Allergy-Time [OTC] see Chlorpheniramine on page 428
and/or closely monitor volume status in patients on
@ Allerject (Can) see EPINEPHrine (Systemic)
concurrent diuretics during treatment initiation.
on page 748
Hypertension: Children 26 years of age weighing 220
kg and Adolescents: Oral: Oral tablets or pellets (if @ Allernix (Can) see DiphenhydrAMINE (Systemic)
unable to swallow tablets): on page 652
20 kg to 50 kg: Initial: 75 mg once daily; if blood Aller-Relief [OTC] (Can) see Cetirizine (Systemic)
pressure not adequately controlled, may increase to on page 411
150 mg once daily; maximum daily dose: 150 mg/day @ Allevess [OTC] see Capsaicin on page 357
250 kg: Initial: 150 mg once daily; if blood pressure not
adequately controlled, may increase to 300 mg once @ Alloprin (Can) see Allopurinol on page 88
daily; maximum daily dose: 300 mg/day
Renal Impairment: Pediatric Children 26 years and Allopurinol (ai oh PuRE i nole)
Adolescents: Oral:
CrCl] 230 mL/minute: No initial dosage adjustment nec- Medication Safety Issues
essary Sound-alike/look-alike issues:
CrCl <30 mL/minute: There are no dosage adjustments Allopurinol may be confused with Apresoline
provided in the manufacturer's labeling (has not been Zyloprim may be confused with zolpidem, ZORprin,
studied); however, limited data in adults suggests no Zovirax
dosage adjustment is necessary (Vaidyanathan 2007). Brand Names: US Aloprim; Zyloprim
Risk of hyperkalemia is increased and progressive Brand Names: Canada Alloprin; Zyloprim
renal impairment may occur; use with caution, monitor Therapeutic Category Antigout Agent; Uric Acid Low-
serum potassium closely. ering Agent
ESRD (requiring hemodialysis): No dosage adjustment Generic Availability (US) Yes
necessary. Hemodialysis eliminates a minimal fraction;
Use
does not significantly alter overall aliskiren exposure.
Oral: Management of hyperuricemia associated with can-
Risk of hyperkalemia is increased with chronic therapy;
cer treatment for leukemia, lymphoma, or solid tumor
use with extreme caution, monitor serum potassium
malignancies (FDA approved in pediatric patients [age
closely.
not specified] and adults); management of primary or
Hepatic Impairment: Pediatric Children 26 years and
secondary gout (acute attack, tophi, joint destruction,
Adolescents: Oral: No initial dosage adjustment neces-
uric acid lithiasis, and/or nephropathy) (FDA approved
sary
in adults); management of recurrent calcium oxalate
Administration
calculi (with uric acid excretion >800 mg/day in men
Oral: Administer at the same time daily with or without a
and >750 mg/day in women) (FDA approved in adults);
meal, but consistent administration with regards to meals
has also been used for treatment of hyperuricemia
is recommended; high-fat meal reduces absorption.
associated with inborn errors of purine metabolism
Oral pellets: For patients unable to swallow tablets,
(Lesch-Nyhan syndrome) and recurrent calcium oxalate
administer oral pellets by opening the dispensing cap-
calculi associated with glycogen storage disease
sule, emptying the entire contents onto a spoon, swal-
lV: Management of hyperuricemia associated with cancer
lowing, and then following with milk (dairy or soy-
treatment for leukemia, lymphoma, or solid tumor malig-
based) or water immediately without chewing or crush-
ing the pellets. Alternatively, may open the dispensing
nancies who cannot tolerate oral therapy (FDA approved
capsule and mix with 21 teaspoon(s) of only vanilla in children and adults)
pudding (milk or soy-based), vanilla ice cream (milk or Pregnancy Risk Factor C
soy-based), milk (dairy or soy-based), or water; less Pregnancy Considerations Adverse events were
dosing vehicle may be used if desired. Do not swallow observed in some animal reproduction studies. Allopurinol
the capsules or empty the contents of the capsule crosses the placenta (Torrance 2009). An increased risk of
directly into the mouth. Do not chew or crush the adverse fetal events has not been observed (limited data)
capsule. (Hoeltzenbein 2013).
Monitoring Parameters Blood pressure, serum potas- Breastfeeding Considerations Allopurino!l and its
sium, BUN, and serum creatinine (baseline, and periodi- metabolite are excreted into breast milk; the metabolite
cally); volume status (during therapy initiation) was also detected in the serum of the breastfeeding infant
Test Interactions May lead to false-positive or false- (Kamilli 1993). The manufacturer recommends caution be
negative aldosterone/renin ratio (ARR) (Funder 2016) used when administering allopurinol to breastfeeding
Dosage Forms Excipient information presented when women.
available (limited, particularly for generics); consult spe- Contraindications
cific product labeling. Severe hypersensitivity reaction to allopurinol or any
Tablet, Oral: component of the formulation
Tekturna: 150 mg, 300 mg Canadian labeling: Additional contraindications (not in US
labeling): Breastfeeding mothers and children (except
@ Aliskiren Hemifumarate see Aliskiren on page 87 those with cancer therapy-induced hyperuricemia or
@ Alkeran see Melphalan on page 1295 Lesch-Nyhan syndrome)
@ Allclenz [OTC] [DSC] see Sodium Chloride Note: While not an absolute contraindication, the Ameri-
on page 1834 can College of Rheumatology suggests avoiding the use
of allopurinol in patients with the HLA-B*5801 genotype
@ All Day Allergy [OTC] see Cetirizine (Systemic)
due to the increased risk of allopurinol hypersensitivity
on page 411
syndrome (AHS). The guidelines suggest HLA-B*5801
@ All Day Allergy Childrens [OTC] see Cetirizine (Sys- screening in patients with a high incidence of this geno-
temic) on page 411 type; this includes patients of Korean descent who have
@ All Day Relief [OTC] see Naproxen on page 1426 stage 3 or worse chronic kidney disease, as well as
 ALLOPURINOL

patients of Han Chinese or Thai descent regardless of Adverse Reactions

kidney function (ACR [Khanna 2012a]). Dermatologic: Skin rash
Warnings/Precautions Allopurinol has been associated Endocrine & metabolic: Gout (acute)
with hypersensitivity reactions. In some instances, a skin Gastrointestinal: Diarrhea, nausea
rash may be followed by more severe hypersensitivity Hepatic: Increased liver enzymes, increased serum alka-
reactions including exfoliative, urticarial, and purpuric line phosphatase
lesions, Stevens-Johnson syndrome, generalized vasculi- Rare but important or life-threatening: Ageusia, agranulo-
tis, and/or hepatotoxicity (irreversible); some reactions cytosis, alopecia, angioedema, aplastic anemia, cata-
have been fatal (rare). Discontinue at first sign of skin ract, cholestatic jaundice, ecchymoses, eczematoid
rash or other signs indicative of allergic reaction. Consider dermatitis, eosinophilia, exfoliative dermatitis, hepatic
HLA-B*5801 testing in patients at a higher risk for allopur- necrosis, hepatitis, hepatomegaly, hepatotoxicity (idio-
inol hypersensitivity syndrome (eg, Koreans with stage 3 syncratic) (Chalasani, 2014), hyperbilirubinemia, hyper-
or worse CKD and Han Chinese and Thai descent regard- sensitivity reaction, leukocytosis, leukopenia, lichen
less of renal function) prior to initiation of therapy (ACR planus, macular retinitis, myopathy, necrotizing angiitis,
[Khanna 2012a)). nephritis, neuritis, neuropathy, onycholysis, pancreatitis,
purpura, renal failure, skin granuloma (annulare), Ste-
Cases of hepatotoxicity (reversible) have been reported.
vens-Johnson syndrome, thrombocytopenia, toxic epi-
Asymptomatic elevations of serum alkaline phosphatase
dermal necrolysis, toxic pustuloderma, uremia,
or serum transaminases have been observed. Monitor for
vasculitis, vesicobullous dermatitis
signs/symptoms of hepatotoxicity and evaluate liver func-
Drug Interactions
tion if they occur. Periodic liver function tests are recom-
Metabolism/Transport Effects None known.
mended during the early stages of therapy in patients with
preexisting hepatic impairment. Avoid Concomitant Use
Avoid concomitant use of Allopurinol with any of the
Even when normal or subnormal serum uric acid levels following: Didanosine; Pegloticase; Tegafur
have been attained, an increase in acute gout attacks has Increased Effect/Toxicity
been reported during the early stages of allopurinol admin- Allopurinol may increase the levels/effects of: Amoxicil-
istration. When allopurinol is initiated, maintenance colchi- lin; Ampicillin; AzaTHIlOprine; Bacampicillin; Bendamus-
cine doses should generally be administered as tine; CarBAMazepine; Cyclophosphamide;
prophylaxis. Additionally, it is recommended to initiate with CycloSPORINE (Systemic); Didanosine; Doxofylline;
a low allopurinol dose (100 mg daily) and increase at Mercaptopurine; Pegloticase; Theophylline Derivatives;
weekly intervals by 100 mg until a serum uric acid level Vitamin K Antagonists
of 6 mg/dL or less is attained (do not exceed the max-
imum recommended dose of 800 mg/day). In some cases, The levels/effects of Allopurinol may be increased by:
colchicine or anti-inflammatory agents may be required to Angiotensin-Converting Enzyme Inhibitors; Loop Diu-
suppress gouty attacks. After several months of therapy, retics; Thiazide and Thiazide-Like Diuretics
attacks usually decrease in duration and severity. These Decreased Effect
episodes may be due to mobilization of urates from tissue Allopurinol may decrease the levels/effects of: Tegafur
deposits, causing fluctuations in the serum uric acid The levels/effects of Allopurinol may be decreased by:
levels. Even with adequate allopurinol therapy, several Antacids
months may be required to deplete the uric acid pool Storage/Stability
enough to achieve control of the acute attacks. Powder for injection: Store at 20°C to 25°C (68°F to 77°F).
Dose reductions are recommended in patients with renal Following preparation, intravenous solutions in NS or
impairment; monitor closely. Patients with reduced renal D5W should be stored at 20°C to 25°C (68°F to 77°F).
function receiving thiazide diuretics in combination with Do not refrigerate reconstituted and/or diluted product.
allopurinol may .be at increased risk for hypersensitivity Must be administered within 10 hours of solution prepa-
reactions. Some patients with preexisting renal disease or ration.
poor urate clearance have shown a rise in BUN with Tablet: Store at 15°C to 25°C (59°F to 77°F). Store in a dry
allopurinol. Patients with renal impairment should be care- place. Protect from light.
fully monitored during the early stages of allopurinol treat- Mechanism of Action Allopurinol inhibits xanthine oxi-
ment; reduce the dose or withdraw therapy if increased dase, the enzyme responsible for the conversion of hypo-
renal function abnormalities appear and persist. Renal xanthine to xanthine to uric acid. Allopurinol is
failure associated with allopurinol has been observed in metabolized to oxypurinol which is also an inhibitor of
patients with hyperuricemia secondary to neoplastic dis- xanthine oxidase; allopurinol acts on purine catabolism,
eases. Concurrent conditions including multiple myeloma reducing the production of uric acid without disrupting the
and congestive myocardial disease were present among biosynthesis of vital purines.
patients whose renal dysfunction. increased after allopur- Pharmacodynamics/Kinetics (Adult data unless
inol was begun. Renal failure is also frequently associated noted)
with gouty nephropathy and rarely with hypersensitivity Onset of action:
reactions associated with allopurinol. Albuminuria has Gout: Decrease in serum and urine uric acid: 2 to 3 days;
been observed among patients who developed clinical peak effect: 1 week or longer; normal serum urate
gout following chronic glomerulonephritis and chronic levels achieved typically within 1 to 3 weeks
pyelonephritis. Cancer therapy-induced hyperuricemia: Median time to
plasma uric acid control: 27 hours (Cortes 2010)
Concomitant use of allopurinol (at doses of 300 to
Absorption: Oral: 90% from GI tract
600 mg/day) with mercaptopurine or azathioprine will
Distribution: Vss: IV: 0.84 to 0.87 L/kg
require a reduction in the mercaptopurine or azathioprine
Metabolism: Rapidly oxidized to active metabolites, pri-
dose to approximately one-third to one-fourth of the usual
marily oxypurinol
dose. Subsequent dose adjustments may be necessary
Bioavailability: ~49% to 53%
based on therapeutic response and toxicity. Potentially
Half-life elimination: Parent drug: ~1 to 2 hours; Oxy-
significant drug-drug interactions may exist, requiring
purinol: ~15 hours
dose or frequency adjustment, additional monitoring,
Time to peak, plasma: Oral: Allopurinol: 1.5 hours; Oxy-
and/or selection of alternative therapy.
purinol: 4.5 hours
Fluid intake sufficient to yield a daily urinary output of at Excretion: Urine (76% as oxypurinol, 12% as unchanged
least 2 liters and maintenance of a neutral or (preferably) a drug); feces (~20%)
slightly alkaline urine are desirable in order to avoid Dosing
possible formation of xanthine calculi due’ to allopurinol Pediatric
therapy and to help prevent renal urate precipitation in Note: Dosing presenting in multiple formats (mg/m?/
patients receiving concomitant uricosuric agents. Do not dose, mg/m?/day, mg/kg/day, and a fixed mg dose);
use to treat asymptomatic hyperuricemia. Bone marrow take extra precautions to ensure accuracy.
suppression has been reported in patients receiving allo- Hyperuricemia associated with chemotherapy man-
purinol, most of whom received concomitant medications agement: Maintain adequate hydration; begin allo-
with a potential for hematologic toxicity. The onset occurs purinol 1 to 2 days before initiation of induction
between 6 weeks to 6 years after allopurinol initiation. chemotherapy; may continue for 3 to 7 days after
Varying degrees of bone marrow depression, affecting chemotherapy (Coiffier 2008); daily doses >300 mg
one or more cell lines may occur (rare) in patients receiv- should be administered in divided doses:
ing allopurinol alone. May occasionally cause drowsiness; Oral:
patients must be cautioned about performing tasks that Manufacturer's labeling:
require mental ‘alertness (eg, operating machinery or Children <6 years: 150 mg daily
driving). } Children 6 to 10 years: 300 mg daily

89
 ALLOPURINOL

q Children >10 years and Adolescents: 600 to

800 mg daily for 2 to 3 days in 2 to 3 divided
Reference Range
Children and Adolescents:
doses
Alternate dosing: Tumor lysis syndrome; intermedi- Uric Acid Normal Values
ate-risk: Limited data available (Coiffier 2008): Normal Serum
Infants, Children, and Adolescents: Concentration
Weight-directed dosing: 10 mg/kg/day divided
every 8 hours; maximum daily dose: 800 mg/day
1.8 to § mg/dl
4 to 6 years
BSA-directed dosing: 50 to 100 mg/m?/dose every
8 hours; maximum daily dose: 300 mg/m?/day 7 to 9 years
\V: For patients unable to tolerate oral therapy (BSA-
directed dosing):
Manufacturer's labeling: Children and Adolescents:
Initial: 200 mg/m2/day administered once daily or
in equally divided doses at 6-, 8-, or 12-hour
intervals
Alternate dosing: Tumor lysis syndrome; intermedi-
ate-risk: Limited data available: Infants, Children, 12 to 15 years:
Female
and Adolescents: 200 to 400 mg/m2/day in 1 to 3
divided doses; maximum daily dose: 600 mg/day 16 to 19 years
Male
(Coiffier 2008) : Female
Hyperuricemia associated with inborn errors of
Adult:
purine metabolism (Lesch-Nyhan syndrome): Lim- Males: 3.4 to 7 mg/dL or slightly more
ited data available: Oral: Infants, Children, and Ado- Females: 2.4 to 6 mg/dL or slightly more
lescents: Initial: 5 to 10 mg/kg/day; adjust dose to Target: <6 mg/dL
maintain a high-normal serum uric acid concentration In adults, values >7 mg/dL are sometimes arbitrarily
and a urinary uric acid/creatinine ratio <1; reported regarded as hyperuricemia, but there is no sharp line
range: 3.7 to 9.7 mg/kg/day; usual maximum daily between normals on the one hand, and the serum uric
dose: 600 mg/day (Torres 2007; Torres 2007a). acid of those with clinical gout. Normal ranges cannot
Recurrent calcium oxalate renal stones (including be adjusted for purine ingestion, but high purine diet
glycogen storage disease): Limited data available: increases uric acid. Uric acid may be increased with
Oral: Children and Adolescents: 4 to 10 mg/kg/day in body size, exercise, and stress.
divided doses 3 to 4 times daily; maximum daily dose: Dosage Forms Excipient information presented when
300 mg/day (Copelvitch 2012; Santos-Victor- available (limited, particularly for generics); consult spe-
iano 1998) cific product labeling.
Renal Impairment: Pediatric Allopurinol and oxypur- Solution Reconstituted, Intravenous, as sodium [strength
inol are dialyzable. expressed as base]:
Infants, Children, and Adolescents: There are no dosage Generic: 500 mg (1 ea)
adjustments provided in the manufacturer's labeling; Solution Reconstituted, Intravenous, as sodium [strength
however, the following guidelines have been used by expressed as base, preservative free]:
some Clinicians: Aloprim: 500 mg (1 ea)
Management of hyperuricemia associated with Tablet, Oral:
chemotherapy: Oral, IV: Zyloprim: 100 mg, 300 mg [scored]
Aronoff 2007: Generic: 100 mg, 300 mg
CrCl 30 to 50 mL/minute/1.73 m2: Administer 50% Extemporaneous Preparations A 20 mg/mL oral sus-
of normal dose. pension may be made with tablets and either a 1:1 mixture
GFR 10 to 29 mL/minute/1.73 m?: Administer 50% of Ora-Sweet® and Ora-Plus® or a 1:1 mixture of Ora-
of normal dose. Sweet® SF and Ora-Plus® or a 1:4 mixture of cherry
GFR <10 mL/minute/1.73 m?: Administer 30% of syrup concentrate and simple syrup, NF. Crush eight
normal dose. 300 mg tablets in a mortar and reduce to a fine powder.
Intermittent hemodialysis: Administer 30% of nor- Add small portions of chosen vehicle and mix to a uniform
mal dose. paste; mix while adding the vehicle in incremental propor-
Peritoneal dialysis: Administer 30% of nor- tions to almost 120 mL; transfer to a calibrated bottle,
mal dose. rinse mortar with vehicle, and add quantity of vehicle
Continuous renal replacement therapy (CRRT): sufficient to make 120 mL. Label "shake well". Stable for
Administer 50% of normal dose. 60 days refrigerated or at room temperature (Allen 1996;
Coiffier 2008: Dosage reduction of 50% is recom- Nahata 2004).
mended in renal impairment. Allen LV Jr and Erickson MA 3rd, “Stability of Acetazolamide, Allopur-
inol, Azathioprine, Clonazepam, and Flucytosine in Extemporane-
Hepatic Impairment: Pediatric There are no dosage ously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53
adjustments provided in the manufacturer's labeling. (16):1944-9.
Preparation for Administration Parenteral: Reconsti- Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th
tute 500 mg vial with 25 mL SWFI to prepare a 20 mg/mL ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
solution; further dilute with D5W or NS to final concen- @ Allopurinol Sodium see Allopurinol on page 88
tration not to exceed 6 mg/mL
@ All trans Retinoic Acid see Tretinoin (Systemic)
Administration Note: Fluid intake should be sufficient to
on page 1993
yield neutral or slightly alkaline (preferably) urine and a
daily urine output of at least 2 L in adults. @ All-trans Vitamin A Acid see Tretinoin (Systemic)
Oral: Administer after meals with plenty of fluid on page 1993
Parenteral: The rate of infusion is dependent upon the
volume of the infusion; infuse maximum single daily Almotriptan (ai moh TRIP tan)
doses (600 mg/day) over 230 minutes; whenever possi-
ble, therapy should be initiated at 12 to 24 hours Medication Safety Issues
(pediatric patients) or 24 to 48 hours (adults) before Sound-alike/look-alike issues:
the start of chemotherapy known to cause tumor lysis Axert may be confused with Antivert
(including adrenocorticosteroids) (Coiffier 2008). Intra- Brand Names: US Axert
venous daily therapy can be administered as a single Brand Names: Canada Axert; Mylan-Almotriptan; San-
infusion or in equally divided doses at 6-, 8-, or 12-hour doz-Almotriptan
intervals. Therapeutic Category Antimigraine Agent; Serotonin
Monitoring Parameters CBC, serum uric acid levels 5-HT1p Receptor Agonist
every 2 to 5 weeks during dose titration until desired level Generic Availability (US) Yes
is achieved and every 6 months thereafter (ACR guide- Use Acute treatment of migraine with or without aura (FDA
lines [Khanna 2012]), liver function tests (periodically in approved in ages 12 to 17 years and adults); Note: FDA
patients with preexisting hepatic disease), renal function labeled indication in adolescents is for patients with history
(BUN, serum creatinine or creatinine clearance (periodi- of migraine lasting 24 hours when left untreated
cally), prothrombin time [periodically in patients receiving Pregnancy Risk Factor C
warfarin]); consider HLA-B*5801 testing prior to initiation Pregnancy Considerations Adverse events were
of therapy in patients at a higher risk for allopurinol hyper- observed in animal reproduction studies. Information
sensitivity syndrome (ACR guidelines [Khanna 2012)). related to almotriptan use in pregnancy is limited (Kallén,
Monitor hydration status, for signs and symptoms of 2011; Nezvalova-Henriksen, 2010; Nezvalova-Henriksen,
hypersensitivity, hepatotoxicity 2012). Until additional information is available, other

90
 ALMOTRIPTAN

agents are preferred for the initial treatment of migraine in Increased Effect/Toxicity
pregnancy (Da Silva, 2012; MacGregor, 2012; Williams, Almotriptan may increase the levels/effects of: Antipsy-
2012). : chotic Agents; Droxidopa; Ergot Derivatives; Metoclopra-
Breastfeeding Considerations It is not known if almo- mide; Serotonin Modulators; SUMAtriptan; TraMADol
triptan is excreted in breast milk. The manufacturer rec-
ommends that caution be exercised when administering The levels/effects of Almotriptan may be increased by:
almotriptan to nursing women. Antiemetics (SHT3 Antagonists); Antipsychotic Agents;
CYP3A4 Inhibitors (Strong); Dapoxetine; Ergot Deriva-
Contraindications Hypersensitivity to almotriptan or any
tives; Metaxalone; Methylene Blue; Methylphenidate;
component of the formulation; hemiplegic or basilar
Monoamine Oxidase Inhibitors; Opioid Analgesics; Tra-
migraine; known or suspected ischemic heart disease
(eg, angina pectoris, MI, documented silent ischemia,
MADol
coronary artery vasospasm, Prinzmetal's variant angina); Decreased Effect There are no known significant inter-
cerebrovascular syndromes (eg, stroke, transient ische- actions involving a decrease in effect.
mic attacks); peripheral vascular disease (eg, ischemic Storage/Stability Store at 25°C (77°F); excursions per-
bowel disease); uncontrolled hypertension; use within 24 mitted to 15°C to 30°C (59°F to 86°F).
hours of another 5-HT, agonist; use within 24 hours of Mechanism of Action Selective agonist for serotonin
ergotamine derivatives and/or ergotamine-containing (5-HT1g and 5-HT15 receptors) in cranial arteries; causes
medications (eg, dihydroergotamine, ergotamine) vasoconstriction and reduces sterile inflammation associ-
Warnings/Precautions Almotriptan is only indicated for ated with antidromic neuronal transmission correlating
the treatment of acute migraine headache; not indicated with relief of migraine
for migraine prophylaxis, or the treatment of cluster head- Pharmacodynamics/Kinetics (Adult data unless
aches, hemiplegic migraine, or basilar migraine. If a noted) Note: Reported values are similar between ado-
patient does not respond to the first dose, the diagnosis lescent and adult patients (Baldwin 2004).
~ of acute migraine should be reconsidered. Absorption: Well absorbed
Distribution: Vg: ~180 to 200 L
Almotriptan should not be given to patients with docu- Protein binding: ~35%
mented ischemic or vasospastic CAD. Patients with risk Metabolism: Via MAO type A oxidative deamination
factors for CAD (eg, hypertension, hypercholesterolemia, (~27% of dose) and CYP3A4 and 2D6 (~12% of dose)
smoker, obesity, diabetes, strong family history of CAD, to inactive metabolites
menopause, male >40 years of age) should undergo Bioavailability: ~70%
adequate cardiac evaluation prior to administration; if the Half-life elimination: Mean: 3 to 5 hours (Baldwin 2004;
cardiac evaluation is "satisfactory," the first dose of almo- McEnroe 2005)
triptan should be given in the healthcare provider's office Time to peak, plasma: 1 to 3 hours
(consider ECG monitoring). All patients should undergo Excretion: Urine (~75%; ~40% of total dose as unchanged
periodic evaluation of cardiovascular status during treat- drug); feces (~13% of total dose as unchanged drug and
ment. Cardiac events (coronary artery vasospasm, tran- metabolites)
sient ischemia, myocardial infarction, ventricular Pharmacodynamics/Kinetics: Additional Consider-
tachycardia/fibrillation, cardiac arrest, and death), cere-
ations
bral/subarachnoid hemorrhage, stroke, peripheral vascu-
Renal function impairment: Clearance is decreased
lar ischemia, and colonic ischemia have been reported
approximately 65% in those with CrCl 10 to 30 mL/
with 5-HT, agonist administration. Patients who experi-
minute and decreased approximately 40% in those with
ence sensations of chest pain/pressure/tightness or symp-
CrCl 31 to 71 mL/minute. C,,3, increased approximately
toms suggestive of angina following dosing should be
80%.
evaluated for coronary artery disease or Prinzmetal's
Hepatic function impairment: The maximum decrease
angina before receiving additional doses; if dosing is
expected in almotriptan clearance due to hepatic func-
resumed and similar symptoms recur, monitor with ECG.
tion impairment would be 60%.
Significant elevation in blood pressure, including hyper-
Geriatric: A longer terminal half-life (3.7 vs 3.2 h) and a
tensive crisis, has also been reported on rare occasions
25% higher AUC has been observed in elderly patients.
following 5-HT, agonist administration in patients with and
without a history of hypertension.
Dosing
Pediatric
Acute migraine agents (eg, triptans, opioids, ergotamine, Migraine: Children 212 years and Adolescents: Oral:
or a combination of the agents) used for 10 or more days Initial: 6.25 to 12.5 mg in a single dose; if headache
per month may lead to worsening of headaches (medi- returns, may repeat the dose after 2 hours; maximum 2
cation overuse headache); withdrawal treatment may be doses/day; maximum daily dose: 25 mg/day. Note:
necessary in the setting of overuse. Transient and perma- The safety of treating >4 migraines/month has not been
nent blindness and partial vision loss have been reported established.
(rare) with 5-HT, agonist administration. Almotriptan con- Dosage adjustment with concomitant use of an
tains a sulfonyl group which is structurally different from a enzyme inhibitor: Children 212 years and Adoles-
sulfonamide. Cross-reactivity in patients with sulfonamide cents:
allergy has not been evaluated; however, the manufac- Patients receiving a potent CYP3A4 inhibitor: Initial:
turer recommends that caution be exercised in this patient 6.25 mg in a single dose; maximum daily dose:
population. Use with caution in liver or renal dysfunction. 12.5 mg/day
Symptoms of agitation, confusion, hallucinations, hyper- Patients with renal impairment and concomitant use of
reflexia, myoclonus, shivering, and tachycardia (serotonin a potent CYP3A4 inhibitor: Avoid use
syndrome) may occur with concomitant proserotonergic Patients with hepatic impairment and concomitant use
drugs (ie, SSRIs/SNRIs or triptans) or agents which of a potent CYP3A4 inhibitor: Avoid use
reduce almotriptan's metabolism. Concurrent use of sero- Renal Impairment: Pediatric Children 212 years and
tonin precursors (eg, tryptophan) is not recommended. If Adolescents: Severe renal impairment (CrCl <30 mL/
concomitant administration with SSRIs is warranted, mon- minute): Initial: 6.25 mg in a single dose; maximum daily
itor closely, especially at initiation and with dose dose: 12.5 mg/day
increases. Hepatic Impairment: Pediatric Children 212 years and
Adverse Reactions Adolescents: Initial: 6.25 mg in a single dose; maximum
Central nervous system: Dizziness, drowsiness, head- daily dose: 12.5 mg/day
ache Administration Oral: May administer without regard to
Gastrointestinal: Nausea, vomiting, xerostomia meals.
Neuromuscular & skeletal: Paresthesia z Dosage Forms Excipient information presented when
Rare but important or life-threatening: Anaphylactic shock, available (limited, particularly for generics); consult spe-
anaphylaxis, angina pectoris, angioedema, colitis, coro- cific product labeling. [DSC] = Discontinued product
nary artery vasospasm, hemiplegia, hypersensitivity Tablet, Oral, as maleate:
reaction, hypertension, ischemic heart disease, mastal- Axert: 6.25 mg [DSC]
gia, myocardial infarction, neuropathy, seizure, skin rash, Axert: 12.5 mg [contains fd&c blue #2 (indigotine)]
syncope, tachycardia, ventricular fibrillation, ventricular Generic: 6.25 mg, 12.5 mg
tachycardia
Drug Interactions @ Almotriptan Malate see Almotriptan on page 90
Metabolism/Transport Effects Substrate of CYP2D6 @ Alocane Emergency Burn Max Str [OTC] see Lido-
(minor), CYP3A4 (minor); Note: Assignment of Major/ caine (Topical) on page 1215
Minor substrate status based on clinically relevant drug
@ Alocril see Nedocromil (Ophthalmic) on page 1429
interaction potential
Avoid Concomitant Use @ Alodox Convenience [DSC] see Doxycycline
Avoid concomitant use of Almotriptan with any of the on page 695
following: Dapoxetine; Ergot Derivatives; Methylene @ Aloe Vesta Antifungal [OTC] see Miconazole (Topical)
Blue; Monoamine Oxidase Inhibitors; SUMAtriptan on page 1371

94
ALPRAZOLAM

@ Aloe Vesta Clear Antifungal [OTC] see Miconazole In general, breastfeeding is considered acceptable when
(Topical) on page 1371 an RID of a medication is <10% (Anderson 2016; Ito
@ Aloprim see Allopurinol on page 88 2000). However, some sources note breastfeeding should
only be considered if the RID is <5% for psychotropic
@ Aloquin [DSC] see lodoquinol on page 1115
agents (Larsen 2015).
@ Alora see Estradiol (Systemic) on page 779
The RID of alprazolam was calculated using a mean
@ Aloxi see Palonosetron on page 1541 maximum milk concentration of 3.7 ng/mL, providing an
@ Alpha-Galactosidase-A (Recombinant) see Agalsidase estimated daily infant dose via breast milk of 0.555 mcg/
Beta on page 67 kg/day. This milk concentration was obtained following
¢@ Alphagan see Brimonidine (Ophthalmic) on page 290 administration of a single oral dose of alprazolam
@ Alphagan P see Brimonidine (Ophthalmic) on page 290 0.5 mg to eight postpartum females. Peak breast milk
concentrations of alprazolam occurred at ~1 hour and
a-2-interferon see Interferon Alfa-2b on page 1109 the half-life was ~14 hours; metabolites were not detected
@ Alphanate see Antihemophilic Factor/von Willebrand (Oo 1995).
Factor Complex (Human) on page 158
Case reports have noted drowsiness (Ito 1993) or CNS
@ AlphaNine SD see Factor IX (Human) on page 820 depression (Kelly 2012) in infants exposed to alprazolam
@ AlphaTrex [DSC] see Betamethasone (Topical) while breastfeeding. Symptoms of withdrawal were
on page 269 described in an infant following alprazolam exposure in
@ Alph-E [OTC] see Vitamin E (Systemic) on page 2065 utero and Via~-breast milk (Anderson 1989).
@ Alph-E-Mixed [OTC] see Vitamin E (Systemic) Breastfeeding is not recommended by the manufacturer. If
on page 2065 a benzodiazepine is needed in breastfeeding females, use
@ Alph-E-Mixed 1000 [OTC] see Vitamin E (Systemic) of shorter acting agents is preferred (Larsen 2015;
on page 2065 WHO 2002).
Contraindications Hypersensitivity to alprazolam or any
component of the formulation (cross-sensitivity with other
ALPRAZolam (al PRAY zoe lam) benzodiazepines may exist); acute narrow-angle glau-
coma; concurrent use with ketoconazole, itraconazole,
Medication Safety Issues
or other potent CYP3A4 inhibitors.
Sound-alike/look-alike issues:
Canadian labeling: Additional contraindications (not in US
ALPRAZolam may be confused with alprostadil, LOR-
labeling): Myasthenia gravis; severe hepatic insuffi-
azepam, triazolam
ciency; severe respiratory insufficiency; sleep apnea.
Xanax may be confused with Fanapt, Lanoxin, Tenex,
Tylox, Xopenex, Zantac, ZyrTEC Warnings/Precautions [US Boxed warning]: Concom-
Geriatric Patients: High-Risk Medication: itant use of benzodiazepines and opioids may result
Beers Criteria: Alprazolam is identified in the Beers in profound sedation, respiratory depression, coma,
Criteria as a potentially inappropriate medication to be and death. Reserve concomitant prescribing of these
avoided in patients 65 years and older (independent of drugs for use in patients for whom alternative treat-
diagnosis or condition) due to increased risk of ment options are inadequate. Limit dosages and dura-
impaired cognition, delirium, falls, fractures, and motor tions to the minimum required. Follow patients for
vehicle accidents with benzodiazepine use (Beers Cri- signs and symptoms of respiratory depression and
teria [AGS 2015]). sedation.
Related Information Rebound or withdrawal symptoms, including seizures,
Oral Medications That Should Not Be Crushed or Altered may occur following abrupt discontinuation or large
on page 2217 decreases in dose (more common in adult patients receiv-
Brand Names: US ALPRAZolam Intensol; ALPRAZolam ing >4 mg/day or prolonged treatment); the risk of seiz-
XR; Niravam [DSC]; Xanax; Xanax XR ures appears to be greatest 24 to 72 hours following
Brand Names: Canada Apo-Alpraz; Apo-Alpraz TS; discontinuation of therapy. Breakthrough anxiety may
Jamp-Alprazolam; Mylan-Alprazolam; Nat-Alprazolam; occur at the end of dosing interval. Potentially significant
Riva-Alpraz; Teva-Alprazolam; Xanax; Xanax TS interactions may exist, requiring dose or frequency adjust-
Therapeutic Category Antianxiety Agent; Benzodiaze- ment, additional monitoring, and/or selection of alternative
pine therapy. Use with caution in patients receiving concurrent
Generic Availability (US) May be product dependent CYP3A4 inhibitors, moderate or strong CYP3A4 inducers,
Use and major CYP3A4 substrates; consider alternative
Immediate release tablets and oral solution: Treatment of agents that avoid or lessen the potential for CYP-mediated
generalized anxiety disorder (GAD); anxiety associated interactions. Use with caution in renal impairment or
with depression; short-term relief of symptoms of anxi- predisposition to urate nephropathy; has weak uricosuric
ety; treatment of panic disorder, with or without agora- properties. Use with caution in or debilitated patients (use
phobia (All indications: FDA approved in ages 218 years lower starting dose), patients with hepatic disease (includ-
and adults) ing alcoholics) or respiratory disease, or obese patients.
Extended release tablets: Treatment of panic disorder, Cigarette smoking may decrease alprazolam concentra-
with or without agoraphobia (FDA approved in ages tions up to 50%,
218 years and adults)
Causes CNS depression (dose related) which may impair
Oral disintegrating tablets (Niravam): Treatment of gener-
physical and mental capabilities. Patients must be cau-
alized anxiety disorder (GAD) and treatment of panic
tioned about performing tasks that require mental alert-
disorder, with or without agoraphobia (All indications:
ness (eg, operating machinery or driving). Effects with
FDA approved in ages 218 years and adults)
other sedative drugs or ethanol may be potentiated.
Pregnancy Risk Factor D Benzodiazepines have been associated with falls and
Pregnancy Considerations Benzodiazepines have the traumatic injury and should be used with extreme caution
potential to cause harm to the fetus. Alprazolam and its in patients who are at risk of these events.
metabolites cross the human placenta. Teratogenic effects
have been observed with some benzodiazepines; how- Use caution in patients with depression, particularly if
ever, additional studies are needed. The incidence of suicidal risk may be present. Episodes of mania or hypo-
premature birth and low birth weights may be increased mania have occurred in depressed patients treated with
following maternal use of benzodiazepines; hypoglycemia alprazolam. May cause physical or psychological depend-
and respiratory problems in the neonate may occur follow- ence. Acute withdrawal may be precipitated in patients
ing exposure late in pregnancy. Neonatal withdrawal after administration of flumazenil. Tolerance does not
symptoms may occur within days to weeks after birth develop to the anxiolytic effects (Vinkers, 2012). Chronic
and "floppy infant syndrome" (which also includes with- use of this agent may increase the perioperative benzo-
drawal symptoms) has been reported with some benzo- diazepine dose needed to achieve desired effect.
diazepines (Bergman 1992; Iqbal 2002; Wikner 2007).
Benzodiazepines have been associated with anterograde
When treating pregnant females with panic disorder,
amnesia. Paradoxical reactions have been reported with
psychosocial interventions should be considered prior to
benzodiazepines, particularly in adolescent/pediatric or
pharmacotherapy (APA 2009). If a benzodiazepine is
psychiatric patients. Does not have analgesic, antidepres-
needed in pregnancy, agents other than alprazolam are
sant, or antipsychotic properties.
preferred (Larsen 2015).
Adverse Reactions
Breastfeeding Considerations Alprazolam is present in
Cardiovascular: Chest pain, hypotension, palpitations
breast milk.
Central nervous system: Agitation, akathisia, altered men-
The relative infant dose (RID) of alprazolam is 7.9% when tal status, anxiety, ataxia, cognitive dysfunction, confu-
calculated using a mean breast milk concentration and sion, depersonalization, depression, derealization,
compared to a weight-adjusted maternal dose of 0.5 mg. disinhibition, disorientation, disturbance in attention,
 ALPRAZOLAM

dizziness, drowsiness, drug dependence, drug with- a high-fat meal is given 2 hours before dosing. Tmax iS
drawal, dysarthria, dystonia, equilibrium disturbance, decreased 33% when food is given immediately prior to
fatigue, feeling hot, headache, hypersomnia, hypoesthe- dose and increased by 33% when food is given 21 hour
sia, insomnia, irritability, lethargy, malaise, memory after dose. Management: Administer without regard to
impairment, nervousness, nightmares, restlessness, food.
sedation, talkativeness, vertigo Storage/Stability
Dermatologic: Allergic skin reaction, dermatitis, diaphore- Immediate release tablets: Store at 20°C to 25°C (68°F to
sis, pruritus, skin rash TT°F).
Endocrine & metabolic: Change in libido, decreased libido, Extended release tablets: Store at 25°C (77°F); excur-
hot flash, increased libido, menstrual disease, weight sions permitted to 15°C to 30°C (59°F to 86°F).
gain, weight loss Oral concentrate: Store at 20°C to 25°C (68°F to 77°F).
Gastrointestinal: Abdominal pain, anorexia, constipation, Protect from moisture. Discard opened bottle after
decreased appetite, diarrhea, dyspepsia, increased 90 days.
appetite, nausea, sialorrhea, vomiting, xerostomia Orally disintegrating tablet: Store at 20°C to 25°C (68°F to
Genitourinary: Difficulty in micturition, dysmenorrhea, sex- 77°F); excursions permitted to 15°C to 30°C (59°F to
ual disorder, urinary incontinence 86°F). Protect from moisture.
Neuromuscular & skeletal: Arthralgia, back pain, dyskine- Mechanism of Action Binds to stereospecific benzodia-
sia, limb pain, muscle cramps, muscle twitching, myal- zepine receptors on the postsynaptic GABA neuron at
gia, tremor, weakness several sites within the central nervous system, including
Ophthalmic: Blurred vision the limbic system, reticular formation. Enhancement of the
Respiratory: Allergic rhinitis, dyspnea, hyperventilation, inhibitory effect of GABA on neuronal excitability results by
nasal congestion increased neuronal membrane permeability to chloride
Rare but important or life-threatening: Abnormal dreams, ions. This shift in chloride ions results in hyperpolarization
aggressive behavior, amnesia, angioedema, apathy, bra- (a less excitable state) and stabilization. Benzodiazepine
dyphrenia, chest tightness, choking sensation, clumsi- receptors and effects appear to be linked to the GABA-A
ness, cold and clammy skin, diplopia, dysgeusia, receptors. Benzodiazepines do not bind to GABA-B recep-
dysphagia, edema, emotional lability, epistaxis, eupho- tors.
ria, falling, fever, galactorrhea, gastrointestinal disease, Pharmacodynamics/Kinetics (Adult data unless
gynecomastia, hallucination, hangover effect, hepatic noted)
failure, hepatitis, homicidal ideation, hyperprolactinemia, Absorption: Readily absorbed; Extended release: Slower
hypomania, hypotonia, impaired consciousness, impulse relative to immediate release formulation resulting in a
control disorder, increased energy, increased liver concentration that is maintained 5 to 11 hours after
enzymes, increased serum bilirubin, increased thirst, dosing; rate increased following night time dosing (ver-
intoxicated feeling, jaundice, jitteriness, mania, mydria- sus morning dosing)
sis, otalgia, outbursts of anger, paraplegia, peripheral Distribution: Immediate release: Vy: 0.84 to 1.42 L/kg
edema, photophobia, psychomotor retardation, relaxa- (Greenblatt 1993)
tion, rhinorrhea, rigors, seizure, sensation of cold, sinus Protein binding: 80%; primarily to albumin
tachycardia, skin photosensitivity, sleep apnea, sleep Metabolism: Hepatic via CYP3A4; forms two active
talking, Stevens-Johnson syndrome, stupor, suicidal metabolites (4-hydroxyalprazolam and a-hydroxyalpra-
ideation, syncope, tinnitus, urinary frequency, urticaria, zolam [about half as active as alprazolam]) and an
voice disorder inactive metabolite benzophenone metabolite, however,
Drug Interactions the active metabolites are unlikely to contribute to much
Metabolism/Transport Effects Substrate of CYP3A4 of the pharmacologic effects because of their low con-
(major); Note: Assignment of Major/Minor substrate sta- centrations and lesser potencies.
tus based on clinically relevant drug interaction potential; Bioavailability: Immediate release: 84% to 92% (Green-
Inhibits CYP3A4 (weak) blatt 1993); Extended release: 90%
Avoid Concomitant Use Half-life elimination:
Avoid concomitant use of ALPRAZolam with any of the Adults: 11.2 hours (Immediate release range: 6.3 to 26.9
following: Azelastine (Nasal); Bromperidol; Conivaptan; hours; Extended release range: 10.7 to 15.8 hours);
Fusidic Acid (Systemic); Idelalisib; Indinavir; Itracona- Orally-disintegrating tablet: Mean: 12.5 hours (range:
zole; Ketoconazole (Systemic); OLANZapine; Orphena- 7.9 to 19.2 hours) ;
drine; Oxomemazine; Paraldehyde; Pimozide; Sodium Alcoholic liver disease: 19.7 hours (range: 5.8 to 65.3
Oxybate; Thalidomide hours)
Increased Effect/Toxicity Obesity: 21.8 hours (range: 9.9 to 40.4 hours)
ALPRAZolam may increase the levels/effects of: Alcohol Elderly: 16.3 hours (range: 9 to 26.9 hours)
(Ethyl); ARIPiprazole; Azelastine (Nasal); Blonanserin; Time to peak, serum:
Buprenorphine; CloZAPine; CNS Depressants; Dofeti- Immediate release: 1 to 2 hours
Extended release: Adolescents and Adults: ~9 hours,
lide; Flibanserin; Flunitrazepam; HYDROcodone; Lomi-
tapide; Methadone; Methotrimeprazine; MetyroSINE; relatively steady from 4 to 12 hours (Glue 2006);
Mirtazapine; NiMODipine; Opioid Analgesics; Orphena- decreased by 1 hour when administered at bedtime
drine; OxyCODONE; Paraldehyde; Pimozide; Piribedil;
(as compared to morning administration); decreased by
33% when administered with a high-fat meal; increased
Pramipexole; ROPINIRole; Rotigotine; Selective Seroto-
by 33% when administered 21 hour after a high-
nin Reuptake Inhibitors; Sodium Oxybate; Suvorexant;
fat meal
Thalidomide; Zolpidem
Orally-disintegrating tablet: 1.5 to 2 hours; occurs ~15
The levels/effects of ALPRAZolam may be increased by: minutes earlier when administered with water;
Aprepitant; Boceprevir; Brimonidine (Topical); Bromopr- increased to ~4 hours when administered with a high-
ide; Bromperidol; Cannabis; Ceritinib; Chlormethiazole; fat meal
Chlorphenesin Carbamate; Conivaptan; CYP3A4 Inhib- Excretion: Urine (as unchanged drug and metabolites)
itors (Moderate); CYP3A4 Inhibitors (Strong); Dimethin- Pharmacodynamics/Kinetics: Additional Consider-
dene (Topical); Doxylamine; Dronabinol; Droperidol; ations
Erythromycin (Systemic); FluvoxaMINE; Fosaprepitant; Race: Maximal concentrations and half-life are approx-
Fosnetupitant; Fusidic Acid (Systemic); HydrOXYzine; imately 15% and 25% higher in Asians.
Idelalisib; Indinavir; Itraconazole; Kava Kava; Ketocona- Cigarette smoking: Concentrations may be reduced by up
zole (Systemic); Lofexidine; Magnesium Sulfate; Mela- to 50% in smokers.
tonin; Methotrimeprazine; MiFEPRIStone; Minocyeline; Dosing
Nabilone; Netupitant; OLANZapine; Ombitasvir, Paritap- Pediatric Note: Titrate dose to effect; use lowest effec-
revir, and Ritonavir; Ombitasvir, Paritaprevir, Ritonavir, tive dose. The usefulness of this medication should be
and Dasabuvir; Oxomemazine; Palbociclib; Perampanel; periodically reassessed.
Rufinamide; Simeprevir; Stiripentol; Tapentadol; Tedu- Anxiety: <
glutide; Telaprevir; Tetrahydrocannabinol; Trimeprazine Children 27 years and Adolescents <18 years: Lim-
Decreased Effect ited data available: Oral: Immediate release: Initial:
The levels/effects of ALPRAZolam may be decreased 0.005 to 0.02 mg/kg/dose 3 times daily (Kliegman
by: Bosentan; CYP3A4 Inducers (Moderate); CYP3A4 2007); dosing based on a trial in patients 7 to 16
Inducers (Strong); Dabrafenib; Deferasirox; Enzaluta- years of age (n=13), initial doses of 0.005 mg/kg or
mide; Mitotane; Pitolisant; Sarilumab; Siltuximab; St 0.125 mg/dose were given 3 times/day for situa-
John's Wort; Theophylline Derivatives; Tocilizumab; tional anxiety and increments of 0.125 to 0.25 mg/
Yohimbine dose were used to increase doses to maximum of
Food Interactions Alprazolam serum concentration is 0.02 mg/kg/dose or 0.06 mg/kg/day; a range of
unlikely to be increased by grapefruit juice because of 0.375 to 3 mg/day was needed (Pfefferbaum
alprazolam's high oral bioavailability. The Cmax of the 1987). Another study in 17 children (8 to 17 years
extended release formulation is increased by 25% when of age) with overanxious disorder or avoidant

93
 ALPRAZOLAM

4 disorders used initial daily doses of 0.25 mg for

children <40 kg and 0.5 mg for those >40 kg. The
A1 mg/mL oral suspension may be made with tablets and
one of three different vehicles (a 1:1 mixture of Ora-
dose was titrated at 2-day intervals to a maximum of Sweet® and Ora-Plus®, a 1:1 mixture of Ora-Sweet®
0.04 mg/kg/day. Required doses ranged from 0.5 to SF and Ora-Plus®, or a 1:4 mixture of cherry syrup with
3.5 mg/day with a mean of 1.6 mg/day. Based on Simple Syrup, NF). Crush sixty 2 mg tablets in a mortar
Clinical global ratings, alprazolam appeared to be and reduce to a fine powder. Add 40 mL of vehicle and mix
better than placebo; however, this difference was to a uniform paste; mix while adding the vehicle in
not statistically significant (Simeon 1992). incremental proportions to almost 120 mL; transfer to a
Adolescents 218 years: Oral: Immediate release: calibrated bottle, rinse mortar with vehicle, and add a
Initial: 0.25 to 0.5 mg 3 times daily; titrate dose quantity of vehicle sufficient to make 120 mL. Label
upward as needed every 3 to 4 days; usual max- "shake well" and "refrigerate". Stable for 60 days.
imum daily dose: 4 mg/day. Patients requiring doses Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
>4 mg/day should be increased cautiously. Periodic
reassessment and consideration of dosage reduc- @ ALPRAZolam Intensol see ALPRAZolam on page 92
tion is recommended.
@ ALPRAZolam XR see ALPRAZolam on page 92
Panic disorder: Adolescents 218 years: Oral:
Immediate release: Initial: 0.5 mg 3 times daily; titrate
dose upward as needed every 3 to 4 days in incre- Alprostadil (ai pros ta dill)
ments <1 mg/day; mean dose used in controlled
trials: 5 to.6 mg/day; maximum daily dose: 10 mg/ Medication Safety Issues
day (rarely required) Sound-alike/look-alike issues:
Extended release: Initial: 0.5 to 1mg once daily; Alprostadil may be confused with alPRAZolam
titrate dose upward as needed every 3 to 4 days in Prostin VR may be confused with Prostin E2 (dinopro-
increments <1 mg/day; usual dose: 3 to 6 mg/day; stone)
maximum daily dose: 10 mg/day (rarely required) Brand Names: US Caverject; Caverject Impulse; Edex;
Switching from immediate release to extended Muse; Prostin VR
release: Administer the same total daily dose, but Brand Names: Canada Alprostadil Injection USP; Cav-
give once daily; if effect is not adequate, titrate dose erject; Muse Pellet; Prostin VR
as above. Therapeutic Category Prostaglandin
Premenstrual dysphoric disorder: Limited data avail- . Generic Availability (US) May be product dependent
able: Adolescents: Oral: Initial dose: 0.25 mg 3 times Use
daily; titrate as needed. Usual daily dose: 1.25 to Prostin VR Pediatric: Temporary maintenance of patency
2.25 mg/day (Kliegman 2011) of ductus arteriosus in neonates with ductal-dependent
Discontinuation of therapy: Abrupt discontinuation congenital heart disease until surgery can be performed
should be avoided. Daily dose must be gradually (FDA approved in neonates)
decreased no more frequently than every 3 days; Caverject, Caverject Impulse: Diagnosis (adjunct to other
however, some patients may require a slower reduc- diagnostic tests) and treatment of erectile dysfunction
tion. If withdrawal symptoms occur, resume previous (FDA approved in adult males)
dose and discontinue on a less rapid schedule. Edex, Muse: Treatment of erectile dysfunction (FDA
Renal Impairment: Pediatric There are no dosage approved in adult males)
adjustments provided in the manufacturer's labeling. Pregnancy Risk Factor C (Muse)
Administration Oral: Pregnancy Considerations Adverse events have been
Immediate release tablet: Adults: May be administered observed in animal reproduction studies. Alprostadil is not
sublingually if oral administration is not possible; absorp- indicated for use in women. The manufacturer of Muse
tion and onset of effect is comparable to oral adminis- recommends a condom barrier when being used during
tration (Scavone, 1987; Scavone, 1992) sexual intercourse with a pregnant woman.
Extended release tablet: Administer once daily, preferably Breastfeeding Considerations Alprostadil is not indi-
in the morning; do not crush, chew, or break; swallow cated for use in women.
whole Contraindications
Orally disintegrating tablet: Do not remove tablets from Intracavernous: Hypersensitivity to alprostadil or any com-
bottle until right before dose; using dry hands, place ponent of the formulation; conditions predisposing men
tablet on top of tongue. If using one-half of tablet, to priapism (eg, sickle cell anemia or trait, multiple
immediately discard remaining half (half tablet may not myeloma, leukemia); men with anatomical deformation
remain stable). Administration with water is not nec- or fibrotic conditions of the penis (eg, angulation, cav-
essary. ernosal fibrosis, or Peyronie disease); penile implants
Monitoring Parameters CNS and cardiovascular status, IV: There are no contraindications listed in the manufac-
respiratory rate turer's labeling.
Controlled Substance C-IV Transurethral: Hypersensitivity to alprostadil or any com-
Dosage Forms Excipient information presented when ponent of the formulation; urethral stricture, balanitis,
available (limited, particularly for generics); consult spe- severe hypospadias and curvature, and in men with
cific product labeling. [DSC] = Discontinued product acute or chronic urethritis; men who are prone to venous
Concentrate, Oral: thrombosis or who have a hyperviscosity syndrome (eg,
ALPRAZolam Intensol: 1 mg/mL (30 mL) [unflavored sickle cell anemia or trait, thrombocythemia, polycythe-
flavor] mia, multiple myeloma) predisposing them to priapism;
Tablet, Oral: use in men for whom sexual activity is inadvisable;
Xanax: 0.25 mg [scored] sexual intercourse with a pregnant woman unless a
Xanax: 0.5 mg [scored; contains fd&c yellow #6 (sunset condom barrier is being used
yellow)]
Documentation of allergenic cross-reactivity for prosta-
Xanax: 1 mg [scored; contains fd&c blue #2 (indigotine)]
glandins is limited. However, because of similarities in
Xanax: 2 mg [scored]
chemical structure and/or pharmacologic actions, the
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
possibility of cross-sensitivity cannot be ruled out with
Tablet Disintegrating, Oral:
certainty.
Niravam: 0.25 mg [DSC] [scored; orange flavor]
Generic: 0.25 mg, 0.5 mg, 1 mg, 2 mg
Warnings/Precautions Prostin VR Pediatric: Use cau-
tiously in neonates with bleeding tendencies. [US Boxed
Tablet Extended Release 24 Hour, Oral:
Warning]: Apnea may occur in 10% to 12% of neo-
ALPRAZolam XR: 0.5 mg
nates with congenital heart defects, especially in
ALPRAZolam XR: 1 mg [contains fd&c yellow #10 (qui-
those weighing <2 kg at birth. Apnea usually appears
noline yellow)]
ALPRAZolam XR: 2 mg [contains fd&c blue #2 (indi-
during the first hour of drug infusion. When used for
patency of ductus arteriosus infuse for the shortest time
gotine)]
at the lowest dose consistent with good patient care. Use
ALPRAZolam XR: 3 mg [contains fd&c blue #2 (indigo-
for >120 hours has been associated with antral hyper-
tine), fd&c yellow #10 (quinoline yellow)]
plasia and gastric outlet obstruction. Potentially significant
Xanax XR: 0.5 mg
interactions may exist, requiring dose or frequency adjust-
Xanax XR: 1 mg [contains fd&c yellow #10 (quinoline
ment, additional monitoring, and/or selection of alternative
yellow)]
therapy.
Xanax XR: 2 mg [contains fd&c blue #2 (indigotine)]
Xanax XR: 3 mg [contains fd&c blue #2 (indigotine), fd&c Priapism/prolonged erection may occur when used for
yellow #10 (quinoline yellow)] erectile dysfunction; instruct patient to seek immediate
Generic: 0.5 mg, 1 mg, 2 mg, 3 mg medical assistance if an erection persists 24 hours; dis-
Extemporaneous Preparations Note: Commercial oral continue therapy if priapism or prolonged erection occurs
solution is available (Alprazolam Intensol™: 1 mg/mL [dye or if signs of penile fibrosis develop (penile angulation,
free, ethanol free, sugar free; contains propylene glycol]) cavernosal fibrosis, or Peyronie disease). To minimize the

94
 ALPROSTADIL

chances of prolonged erection or priapism, titrate slowly to Avoid Concomitant Use

the lowest effective dose. Use is contraindicated in men Avoid concomitant use of Alprostadil with any of the
who have conditions that predispose them to priapism (eg, following: Phosphodiesterase 5 Inhibitors
sickle cell anemia or trait, multiple myeloma, leukemia). Increased Effect/Toxicity
Underlying causes of erectile dysfunction should be eval- The levels/effects of Alprostadil may be increased by:
uated and treated prior to therapy. Treatment for erectile Phosphodiesterase 5 Inhibitors
dysfunction should not be used in men whom sexual Decreased Effect There are no known significant inter-
activity is inadvisable because of underlying cardiovascu- actions involving a decrease in effect.
lar status. Penile fibrosis may occur when used for erectile
Storage/Stability
dysfunction; discontinue use in men who develop penile
Caverject Impulse: Store unreconstituted product at 20°C
angulation or cavernosal fibrosis. Intracavernous injec-
to 25°C (68°F to 77°F); excursions permitted between
tions can increase peripheral blood levels of alprostadil,
15°C and 30°C (59°F and 86°F). Following reconstitu-
resulting in hypotension. Syncope has also been reported.
tion, store at 2°C to 25°C (36°F to 77°F) and use within
Avoid use in men with known cavernosal venous leakage.
24 hours (do not freeze). Discard any unused solution.
Patients must be cautioned to avoid tasks such as operat-
ing machinery or driving following administration where Caverject powder: Store 20 mcg vials at 20°C to 25°C
injury could result if hypotension or syncope were to occur. (68°F to 77°F). Store 40 mcg vials at 2°C to 8°C (36°F to
46°F) until dispensed. After dispensing, stable for up to 3
Muse: Urethral abrasion resulting in minor bleeding or months at or below 25°C (77°F). Following reconstitu-
spotting may occur from improper administration. tion, all strengths should be stored at or below 25°C
Caverject and Caverject Impulse: A superfine needle is (77°F); do not refrigerate or freeze; use within 24 hours.
used for administration. Needle breakage (a portion of the Edex: Store at 25°C (77°F); excursions are permitted
needle remaining in the penis) has been reported; hospi- between 15°C and 30°C (59°F and 86°F).
. talization and surgical removal may be necessary. Muse: Store at 2°C to 8°C (36°F to 46°F); may be stored
at room temperature (below 30°C [86°F]) for up to 14
Benzyl alcohol and derivatives: Some dosage forms may days. Do not expose to temperatures >30°C (86°F).
contain benzyl alcohol; large amounts of benzy! alcohol Each system is for single use only; discarded after use.
(299 mg/kg/day) have been associated with a potentially Prostin VR Pediatric: Refrigerate at 2°C to 8°C (36°F to
fatal toxicity ("gasping syndrome") in neonates; the "gasp- 46°F). Extended storage information at room temper-
ing syndrome" consists of metabolic acidosis, respiratory ature may be available; contact product manufacturer
distress, gasping respirations, CNS dysfunction (including to obtain current recommendations.
convulsions, intracranial hemorrhage), hypotension, and Mechanism of Action Causes vasodilation by means of
cardiovascular collapse (AAP ["Inactive" 1997]; CDC, direct effect on vascular and ductus arteriosus smooth
1982); some data suggests that benzoate displaces bilir- muscle; relaxes trabecular smooth muscle by dilation of
ubin from protein binding sites (Ahlfors 2001); avoid or use cavernosal arteries when injected along the penile shaft,
dosage forms containing benzy! alcohol with caution in
allowing blood flow to and entrapment in the lacunar
neonates. See manufacturer's labeling.
spaces of the penis (ie, corporeal veno-occlusive mecha-
Warnings: Additional Pediatric Considerations nism)
Alprostadil should not be used in neonates with respiratory
Pharmacodynamics/Kinetics (Adult data unless
distress syndrome; full diagnostic workup should be done
to differentiate between respiratory distress syndrome and noted)
cyanotic heart disease. Cortical proliferation of long bones Onset of action: Erectile dysfunction: 5 to 20 minutes
has been associated with long-term infusions of alprosta- Duration: Ductus arteriosus will begin to close within 1 to 2
dil; most cases of bone changes occurred 4 to 6 weeks hours after drug is stopped; Erectile dysfunction:
after starting alprostadil, but has occurred as early as 9 Intended duration <1 hour
days. In a study of 86 infants awaiting cardiac transplant, Distribution: Insignificant following penile injection
the incidence of hyperostosis was 42% at <30 days of Protein binding, plasma: 81% to albumin
alprostadil infusion, 87% at 30 to 60 days and 100% at Metabolism: IV: ~70% to 80% by oxidation during a single
>60 days. Cortical hyperostosis usually resolves over 6 to pass through the lungs; metabolite (13,14 dihydro-PGE,)
12 months after stopping alprostadil (Kaufman 1996; Woo is active and has been identified in neonates
1994). ; Half-life elimination: 30 seconds to 10 minutes
Adverse Reactions Time to peak:
Intraurethral: Acyanotic congenital heart disease: Usual: 1.5 to 3
Central nervous system: Dizziness, headache, pain hours; Range: 15 minutes to 11 hours.
Genitourinary: Penile pain, testicular pain, urethral Cyanotic congenital heart disease: Usual: ~30 minutes
bleeding (minor), urethral burning, vulvovaginal pruritus Erectile dysfunction: Intracavernosal 30. to 60 minutes;
(female partner) Transurethral: ~16 minutes
Rare but important or life-threatening: Tachycardia Excretion: Primarily urine (90% as metabolites) within 24
Intracavernosal injection: Pies Key ibe hours; feces
Cardiovascular: Hypertension Pharmacodynamics/Kinetics: Additional Consider-
Central nervous system: Dizziness, headache ations Pulmonary disease: May have reduced capacity to
Genitourinary: Penile disease, penile pain, penile rash, clear the drug.
penile swelling, prolonged erection (>4 hours), Peyro- Dosing
nie's disease Neonatal Ductus arteriosus patency, maintenance:
Local: Bruising at injection site, hematoma at injec- Continuous IV infusion: Initial: 0.05 to 0.1 mcg/kg/minute;
tion site once therapeutic response is achieved, reduce rate to
Rare but important or life-threatening: Balanitis, injection lowest effective dosage; with unsatisfactory response,
site hemorrhage, priapism increase rate gradually; usual maintenance: 0.01 to 0.4
Intravenous: mcg/kg/minute; higher doses may be required in patients
Cardiovascular: Bradycardia, cardiac arrest, edema, receiving ECMO support (Stone 2006); apnea may be
flushing, hypertension, hypotension, tachycardia less likely to occur at doses <0.015 mcg/kg/minute
Central nervous system: Dizziness, headache, seizure
(Browning Carmo 2007). Note: Therapeutic response
Endocrine & metabolic: Hypokalemia
is indicated by an increase in systemic blood pressure
Gastrointestinal: Diarrhea
and pH in those with restricted systemic blood flow and
Hematologic & oncologic: Disseminated intravascular
acidosis, or by an increase in oxygenation (pOz) in those
coagulation
with restricted pulmonary blood flow.
Infection: Sepsis i
Local: Local pain (in structures other than the injec- Pediatric Ductus arteriosus patency, maintenance:
tion site) Infants: Continuous IV infusion: Initial: 0.05 to 0.1 mcg/
Neuromuscular & skeletal: Back pain kg/minute; once therapeutic response is achieved,
Respiratory: Apnea, cough, flu-like symptoms, nasal reduce rate to lowest effective dosage; with unsatisfac-
congestion, sinusitis, upper respiratory infection tory response, increase rate gradually; usual mainte-
Miscellaneous: Fever nance: 0.01 to 0.4 mcg/kg/minute. Note: Therapeutic
Rare but important or life-threatening: Anemia, anuria, response is indicated by an increase in systemic blood
bradypnea, cardiac failure, cerebral hemorrhage, gas- pressure and pH in those with restricted systemic blood
troesophageal reflux disease, hematuria, hemorrhage, flow and acidosis, or by an increase in oxygenation (pO2)
hyperbilirubinemia, hyperemia, hyperirritability, hyper- in those with restricted pulmonary blood flow.
kalemia, hypoglycemia, hypothermia, neck hyperexten- Renal Impairment: Pediatric There are no dosage
sion, peritonitis, second degree atrioventricular block, adjustments provided in the manufacturer's labeling.
shock, supraventricular tachycardia, thrombocytope- Hepatic Impairment: Pediatric There are no dosage
nia, ventricular fibrillation adjustments provided in the manufacturer’s labeling.
Drug Interactions Usual Infusion Concentrations: Neonatal IV infu-
Metabolism/Transport Effects None known. sion: 10 mcg/mL
ALPROSTADIL

Usual Infusion Concentrations: Pediatric IV infu- CathFlo Activase: Treatment of occluded central venous
sion: 10 mcg/mL or 20 mcg/mL access devices (catheters) to restore function (FDA
Preparation for Administration Continuous IV infusion: approved in pediatric patients [age not specified] and
Prostin VR Pediatric: Dilute with D5W, D10W, or NS to a adults)
maximum concentration of 20 mcg/mL per the manufac- Pregnancy Considerations Adverse events have ‘been
turer. ISMP and Vermont Oxford Network recommend a observed in animal reproduction studies. The risk of
standard concentration of 10 mcg/mL for neonates (ISMP bleeding may be increased in pregnant women. Outcome
2011). Avoid direct contact of undiluted alprostadil with the information is available following alteplase use in preg-
plastic walls of volumetric infusion chambers because the nancy (Hirano 2013; Leonhardt 2006; Li 2012; Ozkan
drug will interact with the plastic and create a hazy 2013). Currently, most guidelines consider pregnancy to
solution; discard solution and volumetric chamber if this be a relative contraindication for its use (ACCF/AHA
occurs. [O’Gara 2013]; AHA/ASA [Jauch 2013]; Kearon 2012;
Administration Kearon 2016; O'Connor 2010). Alteplase should not be
Continuous IV infusion: Administer into a large vein or withheld from pregnant women in life-threatening situa-
alternatively through an umbilical artery catheter placed tions but should be avoided when safer alternatives are
at the ductal opening. ie available (Bates 2012; Leonhardt 2006; Li 2072).
Breastfeeding Considerations It is not known if alte-
Rate of infusion (mL/hour) = dose (mcg/kg/minute) x
plase is present in breast milk.
weight (kg) x 60 minutes/hour divided by concentration
Contraindications Hypersensitivity to alteplase or any
(mcg/mL)
component-of the formulation
Monitoring Parameters Arterial pressure, respiratory
rate, heart rate, temperature, pO2; monitor for gastric Treatment of STEMI or PE: Active internal bleeding;
obstruction in patients receiving PGE, for longer than history of recent stroke; recent (within 3 months
120 hours; x-rays may be needed to assess cortical [ACCF/AHA: Within 2 months]) intracranial or intraspinal
hyperostosis in patients receiving prolonged PGE, ther- surgery or serious head trauma; presence of intracranial
apy conditions that may increase the risk of bleeding (eg,
Additional Information Other dosage forms of alprosta- intracranial neoplasm, arteriovenous malformation,
dil [Caverject injection, Caverject Impulse injection, Edex aneurysm); known bleeding diathesis; severe uncon-
injection, and Muse Pellet (urethral)] are indicated for the trolled hypertension (ACCF/AHA: Unresponsive to emer-
diagnosis and treatment-of erectile dysfunction in adult gency therapy)
males; see package inserts for further information for this Additional absolute contraindications (ACCF/AHA
use. [O’Gara 2013]; Kearon 2012; Kearon 2016): Active
Dosage Forms Excipient information presented when bleeding (excluding menses); any prior intracranial
available (limited, particularly for generics); consult spe- hemorrhage; suspected aortic dissection; ischemic
cific product labeling. stroke within 3 months except when within 4.5 hours;
Kit, Intracavernosal: significant closed head orfacial trauma within 3 months
Caverject Impulse: 10 mcg [contains benzyl alcohol] with radiographic evidence of bony fracture or brain
Caverject Impulse: 20 mcg injury
Edex: 10 mcg, 20 mcg, 40 mcg
Pellet, Urethral: Treatment of acute ischemic stroke (AIS): Current intra-
Muse: 125 mcg (1 ea, 6 ea); 250 mcg (1 ea, 6 ea); 500 cranial hemorrhage; subarachnoid hemorrhage; active
mcg (1 ea, 6 ea); 1000 mcg (1 ea, 6 ea) internal bleeding; recent (within 3 months) intracranial
Solution, Injection: or intraspinal surgery or serious head trauma; presence
Prostin VR: 500 mcg/mL (1 mL) [contains benzyl! alcohol] of intracranial conditions that may increase the risk of
Generic: 500 meg/mL (1 mL) bleeding (eg, intracranial neoplasm, arteriovenous mal-
Solution Reconstituted, Intracavernosal: formation, aneurysm); known bleeding diathesis; severe
Caverject: 20 mcg (1 ea) uncontrolled hypertension
Caverject: 20 mcg (1 ea); 40 mcg (1 ea) [contains benzyl Additional contraindications (AHA/ASA [Jauch 2013):
alcohol] History of intracranial hemorrhage; suspicion of subar-
achnoid hemorrhage; stroke within 3 months; arterial
@ Alprostadil Alfadex see Alprostadil on page 94 puncture at a noncompressible site in previous 7 days;
@ Alprostadil Injection USP (Can) see Alprostadil uncontrolled hypertension at time of treatment (eg,
on page 94 >185 mm Hg systolic or >110 mm Hg diastolic); multi-
lobar cerebral infarction (hypodensity >1/3 cerebral
@ Alsuma [DSC] see SUMAtriptan on page 1886
hemisphere); known bleeding diathesis including but
@ Altabax see Retapamulin on page 1750 not limited to current use of oral anticoagulants with an
@ Altacaine see Tetracaine (Ophthalmic) on page 1924 INR >1.7 (or PT >15 seconds), current use of direct
@ Altachlore [OTC] see Sodium Chloride on page 1834 thrombin inhibitors or direct factor Xa inhibitors with
elevated sensitive laboratory tests (eg, aPTT, INR,
@ Altafrin see Phenylephrine (Ophthalmic) on page 1615
ECT, TT, or appropriate factor Xa activity assays)
@ Altalube [OTC] see Artificial Tears on page 185 (See "Note"), administration of heparin within 48 hours
@ Altamist Spray [OTC] see Sodium Chloride preceding the onset of stroke with an elevated aPTT
on page 1834 greater than the upper limit of normal, or platelet count
Altarussin [OTC] see GuaiFENesin on page 964 <100,000/mm°.
Note: The AHA/ASA 2013 guidelines do allow the use of
@ Altaryl [OTC] [DSC] see DiphenhydrAMINE (Systemic)
alteplase in patients taking direct thrombin inhibitors
on page 652
(eg, dabigatran) or direct factor Xa inhibitors (eg, rivar-
oxaban) when sensitive laboratory tests (eg, aPTT,
Alteplase (A. te piase) INR, ECT, TT, or appropriate direct factor Xa activity
assays) are normal or the patient has not received a
Medication Safety Issues dose of these agents for >2 days (assuming normal
Sound-alike/look-alike issues: renal function) (Jauch 2013). The AHA/ASA 2016
Activase may be confused with Cathflo Activase, scientific statement states that alteplase is not recom-
TNKase mended in patients who have received LMWH treat-
Alteplase may be confused with Altace ment doses within the previous 24 hours (AHA/ASA
"tPA" abbreviation should not be used when writing [Demaerschalk 2016]).
orders for this medication; has been misread as Additional exclusion criteria within clinical trials:
TNKase (tenecteplase) Presentation <3 hours after initial symptoms (NINDS,
High alert medication: 1995): Time of symptom onset unknown, rapidly
The Institute for Safe Medication Practices (ISMP) improving or minor symptoms, major surgery within
includes this medication (IV) among its list of drugs 2 weeks, GI or urinary tract hemorrhage within 3
which have a heightened risk of causing significant weeks, aggressive treatment required to lower blood
patient harm when used in error. pressure, glucose level <50 or >400 mg/dL, and
Brand Names: US Activase; Cathflo Activase lumbar puncture within 1 week.
Brand Names: Canada Activase rt-PA; Cathflo Activase Note: The AHA/ASA 2016 scientific statement recom-
Therapeutic Category Thrombolytic Agent; Thrombotic mends alteplase use in patients presenting <3 hours
Occlusion (Central Venous Catheter), Treatment Agent after initial symptoms with mild but disabling stroke
Generic Availability (US) No symptoms in the opinion of the treating physician.
Use Alteplase is also reasonable in patients presenting
Activase: Thrombolytic agent used in treatment of acute <3 hours after initial symptoms with moderate-to-
MI, acute ischemic stroke, and acute massive pulmonary severe ischemic stroke who demonstrate early
embolism (All indications: FDA approved in adults) improvement, but remain moderately impaired and

96
 ALTEPLASE

potentially disabled in the examiner's judgment (AHA/ Use with caution in patients with advanced age (eg, >75
ASA [Demaerschalk 2016]). years of age); increased risk of bleeding. In the treatment
Presentation 3 to 4.5 hours after initial symptoms (AHA/ of pulmonary embolism, >75 years of age is considered a
ASA [Jauch 2013]; ECASS-III; Hacke 2008; Powers relative contraindication (Kearon 2012; Kearon 2016). In
2015): Age >80 years, time of symptom onset the treatment of acute ischemic stroke (AIS) (within 3 to
unknown, rapidly improving or minor symptoms, cur- 4.5 hours after symptom onset), alteplase use in patients
rent use of oral anticoagulants regardless of INR, >80 years of age is considered an exclusion criteria (AHA/
glucose level <50 or >400 mg/dL, aggressive intra- ASA [Jauch 2013]; Hacke 2008). However, according to
venous treatment required to lower blood. pressure, the AHA/AHA 2016 scientific statement, alteplase use in
major surgery or severe trauma within 3 months, patients >80 years of age with acute ischemic stroke
baseline National Institutes of Health Stroke Scale presenting within 3 to 4.5 hours after symptom onset is
(NIHSS) score >25 [ie, severe stroke], and history of safe and can be as effective as in younger patients (AHA/
both stroke and diabetes. ASA [Demaerschalk 2016]). Use with caution in patients
Note: The AHA/ASA 2016 scientific statement has receiving oral anticoagulants. According to the AHA/ASA
provided updated evidence on certain patients pre- 2013 guidelines, in the treatment of AIS within 3 hours of
senting in the 3 to 4.5 hour after initial symptoms symptom onset, the current use of oral anticoagulants
window excluded in the aforementioned earlier guide- producing an INR >1.7, direct thrombin inhibitors, or direct
lines, including: patients >80 years (alteplase use in factor Xa inhibitors with elevated sensitive laboratory tests
the 3 to 4.5 hour window can be safe and as effective are contraindications. However, alteplase may be admin-
as in younger patients); patients taking warfarin with istered to patients with AIS having received direct throm-
_an INR <1.7 (alteplase use appears safe and may be bin inhibitors (eg, dabigatran) or direct factor Xa inhibitors
beneficial); patients with a history of both stroke and (eg, rivaroxaban) when sensitive laboratory tests (eg,
diabetes (alteplase use may be as effective as treat- aPTT, INR, platelet count, ECT, TT, or appropriate direct
ment in the 0 to 3 hour window, and may be a factor Xa activity assays) are normal or the patient has not
reasonable option) (AHA/ASA [Demaerschalk 2016]). received a dose of these agents for >2 days (assuming
Warnings/Precautions Internal bleeding (intracranial, normal renal function). When treating AIS 3 to 4.5 hours
retroperitoneal, gastrointestinal, genitourinary, respiratory) after symptom onset, the use of alteplase should be
or external bleeding, especially at arterial and venous avoided with current use of any oral anticoagulant regard-
puncture, sites may occur (may be fatal). The total dose less of INR (AHA/ASA [Jauch 2013]). However, according
should not exceed 90 mg for acute ischemic stroke or to the AHA/ASA 2016 scientific statement, when treating
100 mg for acute myocardial infarction or pulmonary AIS 3 to 4.5 hours after symptom onset, the use of
embolism. Doses 2150 mg associated with significantly alteplase appears safe and may be beneficial for patients
increased risk of intracranial hemorrhage compared to taking warfarin with an INR <1.7 (AHA/AHA [Demaer-
doses $100 mg. Bleeding risk is low. Monitor all potential schalk 2016]). In the treatment of STEMI, adjunctive use
bleeding sites; if serious bleeding occurs, the infusion of of parenteral anticoagulants (eg, enoxaparin, heparin, or
alteplase and any other concurrent anticoagulants (eg, fondaparinux) is recommended to improve vessel patency
heparin) should be stopped and the patient should be and prevent reocclusion and may also contribute to bleed-
treated appropriately. Concurrent heparin anticoagulation ing; monitor for bleeding (ACCF/AHA [O’Gara 2013]).
may contribute to bleeding. In the treatment of acute Alteplase has not been shown to adequately treat under-
ischemic stroke, concurrent use of anticoagulants was lying deep vein thrombosis in patients with PE. Consider
not permitted during the initial 24 hours of the <3 hour the possible risk of re-embolization due to the lysis of
window trial (NINDS 1995). The AHA/ASA does not rec- underlying deep venous thrombi in this setting.
ommend initiation of anticoagulant therapy within 24 hours
of treatment with alteplase (AHA/ASA [Jauch 2013)). In the treatment of AIS, according to the AHA/ASA 2016
Initiation of SubQ heparin ($10,000 units) or equivalent scientific statement, alteplase use is recommended in
doses of low molecular weight heparin for prevention of patients with end-stage renal disease on hemodialysis
DVT during the first 24 hours of the 3 to 4.5 hour window who have a normal aPTT (very limited populations eval-
trial was permitted and did not increase the incidence of uated). Patients with an elevated aPTT may have an
intracerebral hemorrhage (Hacke 2008). Alteplase use is increased risk for hemorrhagic complications (AHA/ASA
not recommended for acute ischemic stroke in patients [Demaerschalk 2016}).
who have received a treatment dose of LMWH within the
Coronary thrombolysis may result in reperfusion arrhyth-
previous 24 hours (AHA/ASA [Demaerschalk 2016]). For
mias (eg, accelerated idioventricular rhythm) (Miller 1986).
acute PE, withhold heparin during the 2-hour infusion
Patients who present within 3 hours of stroke symptom
period. Intramuscular injections and nonessential handling
onset should be treated with alteplase unless contraindi-
of the patient should be avoided. Venipunctures should be
cations exist. A longer time window (3 to 4.5 hours after
performed carefully and only when necessary. Avoid
internal jugular and subclavian venous punctures. If arte- symptom onset) has been shown to be safe and effica-
rial puncture is necessary, use.an_ upper extremity vessel
cious for select individuals who meet ECASS Ill criteria
that can be manually compressed. Avoid aspirin for 24 (AHA/ASA [Demaerschalk 2016]; AHA/ASA [Jauch 2013];
hours following administration of alteplase; administration Hacke 2008; Powers 2015). Treatment of patients with
within 24 hours increases the risk of hemorrhagic trans- minor neurological deficit or with rapidly improving symp-
formation. According to the AHA/ASA 2016 scientific toms is not recommended. Follow standard management
statement, alteplase is recommended for patients taking for STEMI while infusing alteplase.
antiplatelet drug monotherapy or antiplatelet combination Cholesterol embolization has been reported rarely in
therapy (eg, aspirin and clopidogrel) before stroke on the patients treated with thrombolytic agents. Hypersensitivity
basis that the benefit outweighs a possible small reactions (eg, anaphylaxis, urticaria, angioedema) have
increased risk of symptomatic intracerebral hemorrhage been reported; fatal outcome has been reported (rare).
(sICH) (AHA/AHA [Demaerschalk 2016]). Although typically mild and transient, orolingual angioe-
Use may increase risk of thromboembolic events in dema has occurred during and up to 2 hours after alte-
patients with high probability of left heart thrombus (eg, plase infusion in patients treated for acute ischemic stroke
patients with mitral stenosis or atrial fibrillation). For the and acute myocardial infarction; the use of concomitant
following conditions, the risk of bleeding is higher with use ACE inhibitors, female sex and strokes involving the
of thrombolytics and should be weighed against the insular and frontal cortex have been associated with an
benefits of therapy: For PE: Systolic BP >180 mm Hg or increased risk (Foster-Goldman 2013; Lin 2014; Pinho
diastolic BP >110 mm Hg; recent bleeding (nonintracra- 2016). Monitor closely for hypersensitivity reactions during
nial); recent surgery or invasive procedure; ischemic infusion and for several hours after; if signs of hyper-
stroke >3 months previously; anticoagulated (eg, VKA sensitivity occur or angioedema develops, discontinue
therapy); traumatic CPR; pericarditis or-pericardial fluid; the infusion and promptly institute appropriate therapy.
diabetic retinopathy; >75 years of age; low body weight In the treatment of AIS, according to the AHA/ASA 2016
(<60 kg); female; black race (Kearon 2012; Kearon 2016); scientific statement, alteplase use is recommended in
lumbar puncture within 10 days (ASRA [Horlocker 2012]). patients with end-stage renal disease on hemodialysis
For ST-elevation myocardial infarction (STEMI): History of and a normal aPTT (very limited populations evaluated).
chronic, severe, poorly controlled hypertension; significant
Patients with an elevated aPTT may have an increased
hypertension on presentation (systolic BP >180 mm Hg or
risk for hemorrhagic complications (AHA/ASA [Demaer-
diastolic BP >110 mm Hg); history of prior ischemic stroke
schalk 2016)]).
>3 months; dementia; traumatic or prolonged CPR (>10
minutes); major surgery (<3 weeks); recent internal bleed- Cathflo Activase: When used to restore catheter function,
ing (within 2 to 4 weeks); noncompressible vascular use Cathflo cautiously in those patients with known or
punctures; active peptic ulcer; oral anticoagulant therapy suspected catheter infections. Evaluate catheter for other
(ACCF/AHA [O’Gara 2013]); lumbar puncture within 10 causes of dysfunction before use. Avoid excessive pres-
days (ASRA [Horlocker 2012]) : sure when instilling into catheter.

9%
ALTEPLASE

Some dosage forms may contain polysorbate 80 (also hepatic; >50% present in plasma is cleared within 5
known as Tweens). Hypersensitivity reactions, usually a minutes after the infusion is terminated, ~80% cleared
delayed reaction, have been reported following exposure within 10 minutes (Semba 2000)
to pharmaceutical products containing polysorbate 80 in Dosing
certain individuals (Isaksson 2002; Lucente 2000; Shelley Neonatal t
1995). Thrombocytopenia, ascites, pulmonary deteriora- Occluded IV catheter: Intracatheter: Dose listed is per
tion, and renal and hepatic failure have been reported in lumen; for multilumen catheters, treat one lumen at
premature neonates after receiving parenteral products a time; do not infuse into patient; dose should
containing polysorbate 80 (Alade 1986; CDC 1984). See always be aspirated out of catheter after dwell.
manufacturer’s labeling. Manufacturer's labeling: Central venous catheter: Use
Warnings: Additional Pediatric Considerations Sig- a 1 mg/mL concentration; instill a volume equal to
nificant bleeding complications including neonatal |VH and 110% of the internal lumen volume of the catheter;
hemorrhage requiring PRBC transfusion have been do not exceed 2 mg in 2 mL; leave in lumen for up to 2
reported in pediatric patients receiving systemic tPA ther- hours, then aspirate out of catheter; may instill a
apy for thrombolysis (Monagle, 2012; Weiner, 1998). Fail- second dose if catheter remains occluded after 2-hour
ure of thrombolytic agents in-newborns/neonates may dwell time
occur due to the lew plasminogen concentrations (~50%
Alternate dosing:
to 70% of adult levels); supplementing plasminogen (via
Chest guidelines (Monagle 2008): Limited data avail-
administration of fresh frozen plasma) may possibly help.
able: Central venous catheter: 0.5 mg diluted in NS
Adverse Reactions to a-voelume equal to the internal volume of the
Cardiovascular: Intracranial hemorrhage (CVA: More com-
lumen; instill in lumen over 1 to 2 minutes; leave in
mon within 90 days)
lumen for 1 to 2 hours, then aspirate out of catheter;
Cerebrovascular accident (new ischemic stroke in CVA)
flush catheter with NS. Note: The most recent
Dermatologic: Ecchymosis (AMI)
guidelines (2012) continue to recommend alteplase
Gastrointestinal: Gastrointestinal hemorrhage (AMI)
as a treatment. option but specific dosage recom-
Genitourinary: Genitourinary tract hemorrhage (AMI)
mendation is not provided (Monagle 2012).
Hematologic & oncologic: Arterial embolism, major hem-
Soylu, 2010: Limited data available: Central venous
orrhage, pulmonary embolism
catheter: 0.25 to 0.5 mg/mL solution; instill a volume
Infection: Sepsis
Rare but important or life-threatening: Anaphylaxis, to fill the catheter; leave in lumen for up to 2 hours,
angioedema, atrioventricular block, atrioventricular dis- then aspirate out of catheter; dosing described in
sociation, cardiac arrhythmia, cardiac failure, cardiac trial of 18 neonates including four patients with GA
tamponade, cardiogenic shock, cerebral edema, cere- $32 weeks
bral herniation, deep vein thrombosis, embolism, epis- Systemic thrombosis: Note: Dose must be titrated to
taxis, fever, gingival hemorrhage, hypersensitivity effect. No pediatric studies have compared local to
reaction, hypotension, ischemia (recurrent), laryngeal systemic thrombolytic therapy; therefore, there is no
edema, mitral valve insufficiency, myocardial reinfarc- evidence to suggest that local infusions are superior.
tion, myocardial rupture, nausea, pericardial effusion, The pediatric patients' small vessel size may increase
pericarditis, pleural effusion, pulmonary edema, retroper- the chance of local damage to blood vessels and
itoneal hemorrhage, seizure, skin rash, thromboembo- formation of a new thrombus; however, local infusion
lism, urticaria, vomiting may be appropriate for catheter-related thrombosis if
Drug Interactions the catheter is already in place (Monagle 2012). Vari-
Metabolism/Transport Effects None known. ous "low-dose" regimens have been used, both with
Avoid Concomitant Use There are no known interac- local (or regional) and systemic administration.
tions where it is recommended to avoid concomitant use. Standard dose infusion: IV: Note: The optimal dose for
Increased Effect/Toxicity various thrombotic conditions is not established; most
Alteplase may increase the levels/effects of: Anticoagu- published papers consist of case reports and series;
lants; Dabigatran Etexilate; Desirudin; Prostacyclin Ana- few prospective neonatal studies have been con-
logues ducted; dose must be titrated to effect (eg, fibrinogen
>100 to 150 mg/dL). Administration of FFP may be
The levels/effects of Alteplase may be increased by: considered prior to dose infusion. Current Chest
Agents with Antiplatelet Properties; Herbs (Anticoagu- guidelines recommend use only when major vessel
lant/Antiplatelet Properties); Limaprost; Salicylates
occlusion is causing critical compromise of organs or
Decreased Effect limbs in the neonate (Monagle, 2012).
The levels/effects of Alteplase may be decreased by: Chest guidelines (Monagle 2012): Limited data avail-
Aprotinin; Nitroglycerin
able: Usual dose: 0.5 mg/kg/hour for 6 hours;
Storage/Stability reported range: 0.1 to 0.6 mg/kg/hour; some
Activase: Store intact vials at room temperature (not to patients may require longer or shorter duration of
exceed 30°C [86°F]), or under refrigeration at 2°C to 8°C
therapy. Higher doses may be associated with an
(36°F to 46°F); protect from light. Store reconstituted
increased incidence of serious bleeding (Monagle
solution at 2°C to 30°C (36°F to 86°F) and use within 8
2008; Monagle 2012).
hours. Discard any unused solution
Additional reported standard dose regimens:
Cathflo Activase: Store intact vials at 2°C to 8°C (36°F to
No loading dose regimens: Very limited data avail-
46°F); protect from light. Store reconstituted solution at
able: Seven neonates (GA: 24 to 38 weeks) with
2°C to 30°C (36°F to 86°F) and use within 8 hours.
arterial thrombosis received a continuous IV infu-
Discard any unused solution.
Solutions of 0.5 mg/mL, 1 mg/mL, and 2 mg/mL in SWI sion of 0.1 mg/kg/hour initially; infusion rate was
retained 294% of fibrinolytic activity at 48 hours when titrated to maintain fibrinogen levels >100 mg/dL;
stored at 2°C in plastic syringes; these solutions retained dosage increases were made in 0.1 mg/kg/hour
290% of fibrinolytic activity when stored in plastic increments every 6 hours to a maximum of
syringes at -25°C or -70°C for 7 or 14 days, thawed at 0.4 mg/kg/hour; no heparin was used in these
room temperature and then stored at 2°C for 48 hours patients (Weiner, 1998). In case series of three
(Davis 2000). Solutions of 1 mg/mL in SWI were stable neonates (GA: 26 to 36 weeks) with infective
for 22 weeks in plastic syringes when stored at -30°C endocarditis and intracardiac thrombosis, a daily
and for ~1 month in glass vials when stored at -20°C; intermittent infusion of 0.2 mg/kg/hour over 6
bioactivity remained unchanged for 6 months in propy- hours for 5 days was used (Anderson, 2009).
lene containers when stored at -20°C and for 2 weeks in Loading dose regimens: Limited data available;
glass vials when stored at -70°C (Generali 2001). dosage reported varies widely: One trial of 16
Mechanism of Action Initiates local fibrinolysis by bind- neonates used a loading dose of 0.1 mg/kg over
ing to fibrin in a thrombus (clot) and converts entrapped 10 minutes, followed by an intermittent infusion of
plasminogen to plasmin 0.3 mg/kg/hour infusion for 3 hours every 12 to 24
Pharmacodynamics/Kinetics (Adult data unless hours as determined by response and monitoring
noted) parameters; a maximum of 4 additional intermittent
Duration: >50% present in plasma cleared ~5 minutes doses were allowed; heparin was held during
after infusion terminated, ~80% cleared within 10 alteplase infusion (Farnoux, 1998). In another trial,
minutes; fibrinolytic activity persists for up to 1 hour after a loading dose of 0.7 mg/kg bolus over 30 to 60
infusion terminated (Semba 2000) minutes was used followed by continuous IV infu-
Distribution: Vg (initial): Approximates plasma volume sion at an initial rate of 0.2 mg/kg/hour for 1 to 4
Half-life elimination: Initial: 5 minutes days in 13 neonates (GA: 27 to 42 weeks) with
Excretion: Clearance (in patients with acute MI receiving catheter-related thrombosis (used in conjunction
accelerated regimen): Rapidly from circulating plasma with heparin infusion); reported effective range:
(572 + 132 mL/minute) (Tanswell 1992), primarily 0.1 to 0.3 mg/kg/hour (Hartmann 2001).

98
 ALTEPLASE

Low dose infusion: Very limited data available: Initial Additional reported regimens: \V:
dose: IV: 0.02 to 0.03 mg/kg/hour, titrate dose based Wang 2003: Initial: 0.01 to 0.03 mg/kg/hour; usual
on patient response, range reported 0.01 to effective range: 0.015 to 0.03 mg/kg/hour; dura-
0.06 mg/kg/hour; duration of therapy based on tion of therapy based on clinical response; in this
patient response. A trial comparing standard-dose study of 17 pediatric patients (1.5 to 18 years)
and low-dose alteplase in pediatric patients included with acute and chronic thrombus, dosing was
five neonates (four preterm; PNA 1 to 14 days) with titrated to effect up to 0.06 mg/kg/hour in children
acute thrombus in low-dose group; dosing in neo- and adolescents; final effective range: 0.007 to
nates was initiated at 0.03 mg/kg/hour, in three neo- 0.06 mg/kg/hour; administration included sys-
nates receiving systemic therapy, the effective dose temic therapy as well as local infusions directly
was 0.03 mg/kg/hour in one patient and 0.06 mg/kg/ at site of thrombus (n=4); duration of therapy
hour in the other two patients; the remaining two ranged from 4 to 96 hours. A similar dosing range
neonates received local infusions and required a has been reported in pediatric case reports
(Doyle 1992).
higher infusion rate (0.1 mg/kg/hour and
Leary 2010: Initial: 0.03 to 0.06 mg/kg/hour for 12
0.24 mg/kg/hour); duration of therapy ranged from
to 48 hours; doses were titrated as necessary up
48 to 70 hours; complete clot resolution occurred in
to 0.12 mg/kg/hour; dosing from a retrospective
all patients. One preterm neonate with staphylococcal
study of 23 patients (median age: 12 years,
sepsis experienced a subdural bleed at the dose of
range: 6 months to 21.5 years) diagnosed with
0.24 mg/kg/hour (Wang, 2003). One case series of DVT; eight patients required a dose increase to
four neonates and infants (PNA: 25 to 43 days, 2
0.12 mg/kg/hour; overall response rate: 59%,
preterm) with caval thrombosis due to central line with complete clot resolution in 18% and partial
reported using 0.02 to 0.1 mg/kg/hour with mixed resolution in 41%
results; resolution of clot occurred in only two patients Bratincsak 2013: Initial: 0.05 mg/kg/hour for 30
(Anderson 1991). minutes, if no signs of bleeding, rate increased
Pediatric to 0.1 mg/kg/hour; therapy used in 12 children
Occluded IV catheters: Infants, Children, Adoles- with arterial or femoral vascular occlusions follow-
cents: Intracatheter: Dose listed is per lumen; for ing cardiac catheterization
multilumen catheters, treat one jumen at a time; Catheter-directed infusion: Limited data available:
do not infuse into patient; dose should always be Children and Adolescents: Intra-arterial, IV (admin-
aspirated out of catheter after dwell. istered through catheter or via catheter with tip
Manufacturer's labeling: Cathflo Activase: Central placed at anatomic site of clot): 0.025 mg/kg/hour
venous catheter: or 0.5 to 2 mg/hour for 12 to 24 hours (Giglia 2013)
Patients <30 kg: Use a 1 mg/mL concentration; Parapneumonic effusion: Limited data available:
instill a volume equal to 110% of the internal lumen Infants >3 months, Children, and Adolescents: Intra-
volume of the catheter; do not exceed 2 mg in 2 pleural:
mL; may instill a second dose if catheter remains Fixed dose: 4 mg in 40 mL NS, first dose at time of
occluded after 2-hour dwell time chest tube placement with 1-hour dwell time, repeat
Patients 230 kg: 2 mg in 2 mL; may instill second every 24 hours for 3 days (total of 3 doses) (Bradley
2011; St. Peter 2009)
dose if catheter remains occluded after 2-hour
Weight-directed: 0.1 mg/kg (maximum: 3 mg) in 10 to
dwell time
30 mL NS, first dose after chest tube placement,
Chest guidelines (Monagle 2008): Note: The most
0.75- to 1-hour dwell time, repeat every 8 hours for 3
recent guidelines (2012) continue to recommend
days (total of 9 doses) (Bradley 2011; Haw-
alteplase as a treatment option but specific dosage
kins 2004)
recommendation is not provided (Monagle 2012)
Renal Impairment: Pediatric There are no dosage
Central venous catheter: Note: Some institutions
adjustments provided in manufacturer's labeling.
use lower doses (eg, 0.25 mg/0.5 mL) in infants
Hepatic Impairment: Pediatric There are no dosage
1 to <3 months adjustments provided in manufacturer's labeling.
Patients <10 kg: 0.5 mg diluted in NS to a volume Usual Infusion Concentrations: Pediatric IV infu-
equal to the internal volume of the lumen; instill in sion: 0.5 mg/mL or 1 mg/mL
lumen over 1 to 2 minutes; leave in lumen for 1 to Preparation for Administration
2 hours, then aspirate out of catheter, do not Intracatheter: Cathflo Activase: Reconstitute with 2.2 mL
infuse into patient; flush catheter with NS. SWFI; do not reconstitute with bacteriostatic water for
Patients >10 kg: 1 mg in 1 mL of NS; use a volume injection; allow vial to stand undisturbed so large bubbles
equal to the internal volume of the lumen; max- may dissipate; swirl gently, do not shake; complete
imum: 2 mg in 2 mL per lumen; instill in each dissolution occurs within 3 minutes. Final concentration:
lumen over 1 to 2 minutes; leave in lumen for 1 to 1 mg/mL.
2 hours; then aspirate out of catheter, do not IV: Activase: Reconstitute vials with supplied diluent
infuse into patient; flush catheter with NS (SWF); do not reconstitute with bacteriostatic water for
SubQ port: injection; use large bore needle and syringe to recon-
Patients $10 kg: 0.5 mg diluted with NS to 3 mL stitute 50 mg vial (50 mg vial has a vacuum) and accom-
Patients >10 kg: 2 mg diluted with NS to 3 mL panying transfer device to reconstitute 100 mg vial
Systemic thrombosis: Note: Dose must be titrated to (100 mg vial does not contain vacuum); swirl gently, do
effect. No pediatric studies have compared local to not shake; final concentration after reconstitution:
systemic thrombolytic therapy; therefore, there is no 1 mg/mL. Reconstituted solution should be clear or pale
evidence to suggest that local infusions are superior. yellow and transparent with a pH of 5 to 7.3. The
The pediatric patients' small vessel size may increase 1 mg/mL solution may be administered or may be diluted
the chance of local damage to blood vessels and further (immediately before use) with an equal volume of
formation of a new thrombus; however, local infusion NS or D5W to yield a final concentration of 0.5 mg/mL;
may be appropriate for catheter-related thromboses if swirl gently, do not shake; dilutions to concentrations
the catheter is already in place (Monagle 2012). <0.5 mg/mL are not recommended for routine clinical
use; dilutions <0.5 mg/mL using D5W or, SWFI may
Standard dose infusion: Limited data available; opti-
mal dose not established; most published papers
result in a precipitate (Frazin 1990).
consist of case reports; few prospective pediatric
Administration
Parenteral:
studies have been conducted; several studies have
Intracatheter: CathFlo Activase: Instill the appropriate
used the following doses (Levy 1991; Weiner 1998):
dose into the occluded catheter; do not force solution
Infants, Children, and Adolescents: Ghest 2012 and
into catheter; leave in lumen; evaluate catheter function
AHA 2013 recommendations: IV: Usual dose:
(by attempting to aspirate blood) after 30 minutes; if
0.5 mg/kg/hour for 6 hours; range: 0.1 to catheter is functional, aspirate 4 to 5 mL of blood out of
0.6 mg/kg/hour; some patients may require longer catheter in patients 210 kg or 3 mL in patients <10 kg to
or shorter duration of therapy; higher doses may be remove drug and residual clot, then gently flush cath-
associated with an increased incidence of serious eter with NS; if catheter is still occluded, leave alteplase
bleeding (Giglia 2013; Monagle 2008; Mona- in lumen and evaluate catheter function after 120
gle 2012). minutes of dwell time; if catheter is functional, aspirate
Low-dose infusion: Limited data available. Various 4 to 5 mL of blood out of catheter in patients 210 kg or 3
"low-dose" regimens have been used: Infants, Chil- mL in patients <10 kg and gently flush with NS; if
dren, and Adolescents: catheter remains occluded after 120 minutes of dwell
AHA 2013 recommendations: |V: 0.03 to time, a second dose may be instilled by repeating the
0.06 mg/kg/hour for 12 to 48 hours; maximum above administration procedure. Discard any unused
hourly dose: 2 mg/hour (Giglia 2013) solution (solution does not contain preservatives). >
99
ALTEPLASE

IV: Activase: Decreased Effect There are no known significant inter-

Bolus: Bolus dose may be readied using one of the actions involving a decrease in effect.
following methods: 1) Remove bolus dose from recon- Storage/Stability Store at room temperature. Protect
stituted vial using syringe and needle; for 50 mg vial: from excessive heat.
Do not prime syringe with air, insert needle into vial Dosing '
stopper; for 100 mg vial, insert needle away from Pediatric
puncture mark created by transfer device; 2) Remove Skin irritation: Children and Adolescents: Topical:
bolus dose from a port on the infusion line after Soak: Soak the affected area in solution for 15 to 30
priming; 3) Program an infusion pump to deliver the minutes as needed; may repeat 3 times daily or as
bolus at the beginning of the infusion. Administer over directed
1 minute followed by infusion. Wet dressings/compress: Soak a clean, soft cloth in
Infusion: Remaining dose for STEMI, AIS, or total dose solution and apply loosely to affected area for 15 to 30
for acute pulmonary embolism may be administered minutes; may repeat as needed for 4 to 8 hours or as
as follows: Any quantity of drug not to be administered directed
to the patient must be removed from vial(s) prior to Renal Impairment: Pediatric There are no dosage
administration of remaining dose. adjustments provided in the manufacturer’s labeling.
50 mg vial: Use polyvinyl chloride IV bag or glass vial Hepatic Impairment: Pediatric There are no dosage
and infusion set adjustments provided in the manufacturer’s labeling.
100 mg vial: Use same puncture site made by trans- Preparation for Administration
fer device to insert spike end of infusion set and Boro-Packs: Add 473 ml (16 oz) of water to 1 or 2 packs of
infuse from vial powder; shake well to dissolve. Do not strain or filter.
May also be further diluted in NS or D5W if desired. Pedi-Boro: Dissolve 1 to 3 packets in 473 mL (16 oz) of
Intrapleural: Instill dose into chest tube at time of chest cool or warm water; stir or shake until fully dissolved. Do
tube placement and clamp drain. Although the optimum not strain or filter.
dwell time has not been determined, clinical trials more Administration Topical: Keep away from eyes; for exter-
often have used either a 45 minute (Hawkins 2004) or 1 nal use only. Discard solution after each use.
hour (Rahman 2011; St. Peter 2009) dwell time; after
When used as a compress or wet dressing, soak a clean
dwell period, release clamp and connect chest tube to
soft cloth in the solution. Apply cloth loosely to. affected
continuous suction.
area for 15 to 30 minutes. Do not occlude dressing to
Monitoring Parameters
prevent evaporation. Do not allow dressing to dry out.
Systemic use: Blood pressure; CBC, reticulocyte, platelet
Dosage Forms Excipient information presented when
count; fibrinogen level, plasminogen, fibrin/fibrinogen
available (limited, particularly for generics); consult spe-
degradation products, PT, PTT, signs of bleeding
cific product labeling.
Intracatheter use: Catheter function (by attempting to
Packet, External:
aspirate blood); signs of sepsis, GI bleeding, bleeding
Boro-Packs: Aluminum sulfate 49% and calcium acetate
at injection site, and venous thrombosis 51% per packet (14 ea, 100 ea)
Test Interactions Altered results of coagulation and fibri- Pedi-Boro Soak: Aluminum sulfate tetradecahydrate
nolytic activity tests 1191 mg and calcium acetate monohydrate 839 mg
Additional Information Activase and CathFlo Activase per packet (12 ea, 100 ea)
also contain L-arginine and phosphoric acid (for pH adjust- Generic: Aluminum sulfate tetradecahydrate 1347 mg
ment). Advantages of alteplase include: Low immunoge- and calcium acetate monohydrate 952 mg per packet
nicity, short half-life, direct activation of plasminogen, and (1 ea, 12 ea)
a strong and specific affinity for fibrin. Solution, External:
Dosage Forms Excipient information presented when Generic: (480 mL)
available (limited, particularly for generics); consult spe-
cific product labeling.
Solution Reconstituted, Injection: Aluminum Hydroxide
(a LOO mi num hye DROKS ide)
Cathflo Activase: 2 mg (1 ea) [contains polysorbate 80]
Solution Reconstituted, Intravenous: Brand Names: US DermaMed [OTC]
Activase: 50 mg (1 ea); 100 mg (1 ea) Brand Names: Canada Amphojel; Basaljel
@ Alteplase Recombinant see Alteplase on page 96 Therapeutic Category Antacid; Antidote; Gastrointesti-
nal Agent, Gastric or Duodenal Ulcer Treatment; Protec-
@ Alteplase, Tissue Plasminogen Activator, Recombi- tant, Topical
nant see Alteplase on page 96 Generic Availability (US) May be product dependent
@ Altoprev see Lovastatin on page 1255 Use
Oral: Relief of heartburn, acid indigestion and sour stom-
Aluminum Acetate (a LOO mi num AS e tate) ach (OTC product: FDA approved in adults); has also
been used to reduce phosphate absorption in hyper-
Brand Names: US Boro-Packs [OTC]; Pedi-Boro Soak phosphatemia associated with chronic renal failure
[OTC] Topical: Temporary protection and relief of discomfort from
Therapeutic Category Topical Skin Product chafed and abraded skin, minor cuts, scrapes, minor
Generic Availability (US) Yes burns, and other skin irritations (OTC product: FDA
approved in adults)
Use Temporary relief of minor skin irritations due to poison
ivy, poison oak, poison sumac, insect bites, and athlete’s Pregnancy Considerations Most aluminum-containing
foot (FDA approved in pediatric patients [age not speci- antacids are considered acceptable for treating heartburn
fied] and adults); rashes caused by soaps, detergents, of pregnancy, as well as aspiration prophylaxis during
labor (Richter [ACG 2007]).
cosmetics, or jewelry (FDA approved in pediatric patients
[age not specified] and adults). Note: Approved ages and Breastfeeding Considerations Aluminum is endoge-
uses for products may vary; consult labeling for specific nous to breast milk (Chao 2014; Fanni 2014). Information
information. specific to the quantification of aluminum in breast milk
following the administration of aluminum hydroxide-con-
Pregnancy Considerations Animal reproduction studies
taining antacids in breastfeeding females has not been
have not been conducted. The amount of aluminum
located.
acetate available systemically following topical application
is unknown. Aluminum hydroxide is considered compatible with breast-
Breastfeeding Considerations It is not known if topi- feeding when used in usual recommended doses; monitor
cally administered aluminum acetate is excreted in breast the breastfeeding infant for adverse effects (WHO 2002).
milk. Warnings/Precautions Oral: Hypophosphatemia may
Warnings/Precautions For external use only; do not occur with prolonged administration or large doses; alu-
cover the treated area with plastic or other material to minum intoxication and osteomalacia may occur in
prevent evaporation. Avoid contact with eyes. Discontinue patients with uremia. Use with caution in patients with
use if irritation occurs, condition worsens, or if symptoms HF, renal failure, edema, cirrhosis, and low sodium diets,
persist more than 7 days; consult health care provider if and patients who have recently suffered gastrointestinal
irritation or sensitivity increases. hemorrhage; uremic patients not receiving dialysis may
Adverse Reactions Local: Local irritation develop osteomalacia and osteoporosis due to phosphate
Drug Interactions depletion.
Metabolism/Transport Effects None known. Elderly may be predisposed to constipation and fecal
Avoid Concomitant Use There are no known interac- impaction. Careful evaluation of possible drug interactions
tions where it is recommended to avoid concomitant use. must be done. When used as an antacid in ulcer treat-
Increased Effect/Toxicity There are no known signifi- ment, consider buffer capacity (mEq/mL) to calcu-
cant interactions involving an increase in effect. late dose.

100
 ALUMINUM HYDROXIDE AND MAGNESIUM HYDROXIDE

Topical: Not for application over deep wounds, puncture Children and Adolescents: Oral: Liquid (320 mg/5
wounds, infected areas, or lacerations. When used for self mL): Dose should be individualized; dose dependent
medication (OTC use), consult with healthcare provider if upon phosphate intake/absorption and dialysis
needed for >7 days clearance; therefore, a specific dose range is not
Warnings: Additional Pediatric Considerations Sys- available. Mean phosphorous binding power:
temic absorption of aluminum has been reported in infants 22.3 mg phosphorous/5mL of aluminum hydroxide
receiving both short-term and long-term antacid therapy; (KDOQI 2005).
use with caution; consider monitoring serum aluminum Renal Impairment: Pediatric There are no dosage
concentrations to monitor for toxicity (Tsou 1991; Wood- adjustments provided in the manufacturer's labeling;
ard-Knight 1992). Avoid long-term use of aluminum con- aluminum may accumulate in renal impairment and
taining phosphate binders in patients with CKD stages 3 to cause toxicity.
5 due to risk of aluminum related bone disease and Hepatic Impairment: Pediatric There are no dosage
encephalopathy (KDIGO 2009; KDOQI [Uhlig 2010}). adjustments provided in the manufacturer's labeling.
Adverse Reactions Administration
Gastrointestinal: Constipation, fecal discoloration (white Oral: Shake suspension well before use; dose should be
speckles), fecal impaction, nausea, stomach cramps, followed with water
vomiting Antacid: Administer after meals and at bedtime
To decrease phosphorus: Administer with meals
Endocrine & metabolic: Hypomagnesemia, hypophospha-
Topical: For external use only; avoid contact with eyes
temia
Monitoring Parameters GI complaints, stool frequency;
Drug Interactions
calcium and phosphorus levels periodically when patient
Metabolism/Transport Effects None known. is on chronic therapy; in patients with chronic kidney
Avoid Concomitant Use disease, serum phosphate, and serum aluminum concen-
Avoid concomitant use of Aluminum Hydroxide with any trations
of the following: Deferasirox; QuiNINE; Raltegravir; Vita- Reference Range
min D Analogs Aluminum: Baseline serum aluminum level <20 mcg/L
Increased Effect/Toxicity (KDOQI 2005)
Aluminum Hydroxide may increase the levels/effects of: Corrected total serum calcium: Children, Adolescents, and
Amphetamines; Dexmethylphenidate; Methylphenidate Adults: CKD stages 2 to 5D: Maintain normal ranges;
preferably on the lower end for stage 5 (KDIGO 2009;
The levels/effects of Aluminum Hydroxide may be
KDOQI 2005)
increased by: Ascorbic Acid; Calcium Polystyrene Sulfo-
Phosphorus (KDIGO 2009):
nate; Citric Acid Derivatives; Multivitamins/Fluoride (with
CKD stages 3 to 5: Maintain normal ranges
ADE); Multivitamins/Minerals (with ADEK, Folate, Iron);
CKD stage 5D: Lower elevated phosphorus levels
Multivitamins/Minerals (with AE, No Iron); Sodium Poly-
toward the normal range
styrene Sulfonate; Vitamin D Analogs
Dosage Forms Excipient information presented when
Decreased Effect available (limited, particularly for generics); consult spe-
Aluminum Hydroxide may decrease the levels/effects of: cific product labeling.
Acalabrutinib; Allopurinol; Antipsychotic Agents (Pheno- Ointment, External:
thiazines); Atazanavir; Bictegravir; Bisacodyl; Bismuth DermaMed: (113 g)
Subcitrate; Bisphosphonate Derivatives; Bosutinib; Suspension, Oral:
Bromperidol; Captopril; Cefditoren; Cefpodoxime; Cefur- Generic: 320 mg/5 mL (473 mL)
oxime; Chenodiol; Chloroquine; Cholic Acid; Corticoste-
roids (Oral); Cysteamine (Systemic); Dabigatran
Etexilate; Dasatinib; Deferasirox; Deferiprone; Delavir- Aluminum Hydroxide and Magnesium
dine; Diacerein; Dolutegravir; Eltrombopag; Elvitegravir; Hydroxide
Erlotinib; Ethambutol; Fexofenadine; Fosinopril; Gaba- (a LOO mi num hye DROKS ide & mag NEE zhum hye DROK side)
pentin; Gefitinib; Hyoscyamine; Iron Salts; Itraconazole;
Brand Names: US Mag-Al [OTC]
Ketoconazole (Systemic); Lanthanum; Ledipasvir; Levo-
thyroxine; Mequitazine; Mesalamine; Methenamine; Mul-
Brand Names: Canada Diovol; Diovol Ex; Gelusil Extra
Strength; Mylanta
tivitamins/Fluoride (with ADE); Mycophenolate;
Neratinib; Nilotinib; PAZOPanib; Penicill[AMINE; Phos-
Therapeutic Category Antacid; Gastrointestinal Agent,
Gastric or Duodenal Ulcer Treatment
phate Supplements; Potassium Phosphate; QuiNINE;
Generic Availability (US) No
Quinolones; Raltegravir; Rilpivirine; Riociguat; Rosuvas-
Use Symptomatic relief of hyperacidity associated with the
tatin; Sotalol; Strontium Ranelate; Sulpiride; Tetracy-
diagnosis of peptic ulcer, gastritis, peptic esophagitis,
clines; Trientine; Ursodiol; Velpatasvir
gastric hyperacidity, or hiatal hernia (OTC product: FDA
Storage/Stability Store at controlled room temperature.
approved in ages 212 years and adults)
Avoid freezing.
Pregnancy Considerations Most aluminum- and mag-
Mechanism of Action As an antacid, aluminum hydrox- nesium-containing antacids are considered low risk during
ide neutralizes hydrochloride in the stomach to form Al pregnancy (Mahadevan 2006).
(Cl)3 salt + HzO, resulting in increased gastric pH and Breastfeeding Considerations Most aluminum- and
inhibition of pepsin activity (Weberg 1998). As an agent for magnesium-containing antacids are considered low risk
the short term treatment of hyperphosphatemia (off-label in nursing women (Mahadevan 2006).
use), aluminum hydroxide binds phosphate in the gastro- Contraindications OTC labeling: When used for self-
intestinal tract preventing absorption of phosphate medication, do not use if you have renal impairment
(Schucker 2005). Warnings/Precautions Prolonged antacid therapy may
Pharmacodynamics/Kinetics (Adult data unless result in hypophosphatemia; aluminum in antacid may
noted) . form insoluble complexes with phosphate leading to
Duration: Dependent on gastric emptying time: Fasting decreased phosphate absorption in the Gl tract. Rarely,
state: 20 to 60 minutes; One hour after meals: Up to 3 severe hypophosphatemia can lead to anorexia, muscle
hours weakness, malaise, and osteomalacia. Use with caution in
Excretion: Urine (normal renal function): 17% to 30%; patients with renal impairment; avoid use in severe renal
combines with dietary phosphate in the intestine and is impairment; hypermagnesemia or aluminum. intoxication
excreted in the feces may occur in severe renal impairment, particularly with
Dosing prolonged use. Aluminum intoxication may lead to osteo-
Pediatric 8 : malacia or dialysis encephalopathy. Potentially significant
Antacid: Note: Chronic antacid therapy not recom- interactions may exist, requiring dose or frequency adjust-
mended for management of GERD in pediatric ment, additional monitoring, and/or selection of alternative
patients; if antacid therapy required, consider combi- therapy. Some dosage forms may contain propylene gly-
nation product of magnesium/aluminum hydroxide col; large amounts are potentially toxic and have been
(AAP [Lightdale 2013]; NASPGHAN/ESPGHAN [Van- associated hyperosmolality, lactic acidosis, seizures and
denplas 2009]) respiratory depression; use caution (AAP 1997; Zar 2007).
Children and Adolescents: Limited data available: Self-medication (OTC use): When used for self-medica-
Oral: (Liquid 320 mg/5 mL): 5 to 15 mL (320 to tion, patients should be instructed to consult their health-
960 mg) every 6 hours (Nelson 1996) care prescriber prior to using if they are on a magnesium
Hyperphosphatemia associated with chronic renal and/or sodium restricted diet. Do not take the maximum
failure: Note: The use of aluminum hydroxide should dose for >14 days.
be reserved for serum phosphorus levels >7 mg/dL Warnings: Additional Pediatric Considerations
and limited to a single short-term use (4 to 6 weeks) Some dosage forms may contain propylene glycol; in
given the toxicities associated with long-term use neonates large amounts of propylene glycol delivered
(KDOQI 2005). orally, intravenously (eg, >3,000 mg/day), or topically >
101
 ALUMINUM HYDROXIDE AND MAGNESIUM HYDROXIDE

4 have been associated with potentially fatal toxicities which

can include metabolic acidosis, seizures, renal failure, and
Administration Oral: Shake well before use; administer 1
to 2 hours after meals (Orenstein 1988)
CNS depression; toxicities have also been reported in Monitoring Parameters GI! complaints, stool frequency;
children and adults including hyperosmolality, lactic acido- serum phosphate concentrations in patients on hemodial-
sis, seizures and respiratory depression; use caution ysis receiving chronic aluminum-containing antacid ther-
(AAP 1997; Shehab 2009). apy; serum electrolytes in patients with renal impairment
receiving magnesium-containing antacids
Absorption of aluminum has been reported in infants
receiving both short-term and long-term antacid therapy; Dosage Forms Excipient information presented when
use with caution; consider monitoring serum aluminum available (limited, particularly for generics); consult spe-
concentrations to monitor for toxicity (Tsou 1991; Wood- cific product labeling.
ard-Knight 1992) Liquid, oral:
Mag-Al: Aluminum hydroxide 200 mg and magnesium
Adverse Reactions
hydroxide 200 mg per 5 mL (30 mL) [dye free, ethanol
Central nervous system: Calcium or chalky taste
free, sugar free; contains propylene glycol, sodium
Endocrine & metabolic: Hypermagnesemia (rare), hypo-
phosphatemia (rare) 4 mg/5 mL; peppermint flavor]
Gastrointestinal: Abdominal cramps, constipation, fecal @ Aluminum Sucrose Sulfate, Basic see Sucralfate
discoloration (white speckles), fecal impaction, nausea, on page 1870
vomiting
@ Aluminum Sulfate and Calcium Acetate see Aluminum
Drug Interactions
Acetate on page 100
Metabolism/Transport Effects None known.
Avoid Concomitant Use @ Aluminum Sulfate Tetradecahydrate and Calcium
Avoid concomitant use of Aluminum Hydroxide and Acetate see Aluminum Acetate on page 100
Magnesium Hydroxide with any of the following: Calcium ¢@ Alupent see Metaproterenol on page 1318
Polystyrene Sulfonate; Deferasirox; MiSOPROStol; Qui- @ Alvesco see Ciclesonide (Oral Inhalation) on page 4417
NINE; Raltegravir; Sodium Polystyrene Sulfonate; Vita-
min D Analogs
Increased Effect/Toxicity Amantadine (a Man ta deen)
Aluminum Hydroxide and Magnesium Hydroxide may
Medication Safety Issues
increase the levels/effects of: Amphetamines; Calcium
Sound-alike/look-alike issues:
Channel Blockers; Calcium Polystyrene Sulfonate; Dex- —
Amantadine may be confused with amiodarone, raNITI-
methylphenidate; Gabapentin; Methylphenidate; MiSO-
dine, riMANTAdine
PROStol; Neuromuscular-Blocking Agents;
Symmetrel may be confused with Synthroid
Penicill[AMINE; QuiNIDine; Sodium Polystyrene Sulfo-
nate Brand Names: US Gocovri; Osmolex ER
Therapeutic Category Anti-Parkinson's Agent (Dopa-
The levels/effects of Aluminum Hydroxide and Magne- mine Agonist); Antiviral Agent; Antiviral Agent, Adaman-
sium Hydroxide may be increased by: Ascorbic Acid; tane
Calcium Channel Blockers; Citric Acid Derivatives; Multi- Generic Availability (US) May be product dependent
vitamins/Fluoride (with ADE); Multivitamins/Minerals Use Prophylaxis and treatment of influenza A viral infection
(with ADEK, Folate, Iron); Multivitamins/Minerals (with (FDA approved in ages 21 year and adults); Note: Due to
AE, No Iron); Vitamin D Analogs high resistance rates, amantadine is no longer recom-
Decreased Effect mended by the CDC for the treatment or prophylaxis of
Aluminum Hydroxide and Magnesium Hydroxide may influenza A (CDC, 2011); symptomatic and adjunct treat-
decrease the levels/effects of: Acalabrutinib; Allopurinol; ment of parkinsonism; treatment of drug-induced extrap-
Alpha-Lipoic Acid; Antipsychotic Agents (Phenothia- yramidal reactions (FDA approved in adults); has also
zines); Atazanavir; Bictegravir; Bisacodyl; Bismuth Sub- been used for attention-deficit/hyperactivity disorder
citrate; Bisphosphonate Derivatives; Bosutinib; (ADHD), autism, fatigue associated with multiple sclero-
Bromperidol; Captopril; Cefditoren; Cefpodoxime; Cefur- sis, and in post-traumatic brain injury for behavior and
oxime; Chenodiol; Chloroquine; Cholic Acid; Corticoste- cognition
roids (Oral); Cysteamine (Systemic); Dabigatran Pregnancy Risk Factor C
Etexilate; Dasatinib; Deferasirox; Deferiprone; Delavir-
Pregnancy Considerations
dine; Diacerein; Dolutegravir; Eltrombopag; Elvitegravir;
Adverse events have been observed in animal reproduc-
Erlotinib; Ethambutol; Fexofenadine; Fosinopril; Gaba-
tion studies and teratogenic events have been observed in
pentin; Gefitinib; Hyoscyamine; Iron Salts; Itraconazole;
humans (case reports) (Seier 2017).
Ketoconazole (Systemic); Lanthanum; Ledipasvir; Levo-
thyroxine; Mequitazine; Mesalamine; Methenamine; Mul- When treatment for Parkinson disease is needed, agents
tivitamins/Fluoride (with ADE); Mycophenolate; other than amantadine are recommended in pregnant
Neratinib; Nilotinib; PAZOPanib; Penicill[AMINE; Phos- women (Seier 2017).
phate Supplements; Potassium Phosphate; QuiNINE;
Untreated influenza infection is associated with an
Quinolones; Raltegravir; Rilpivirine; Riociguat; Rosuvas-
tatin; Sotalol; Strontium Ranelate; Sulpiride; Tetracy-
increased risk of adverse events to the fetus and an
clines; Trientine; Ursodiol; Velpatasvir
increased risk of complications or death to the mother.
Other agents are currently recommended for the treat-
The levels/effects of Aluminum Hydroxide and Magne- ment or prophylaxis influenza in pregnant women and
sium Hydroxide may be decreased by: Alpha-Lipoic women up to2 weeks postpartum. Appropriate antiviral
Acid; Trientine agents are currently recommended as an adjunct to
Storage/Stability Store at room temperature; avoid freez- vaccination and should not be used as a substitute for
ing. vaccination in pregnant women (CDC 2011; CDC 2014).
Pharmacodynamics/Kinetics (Adult data unless Breastfeeding Considerations Amantadine is present
noted) Duration: Dependent on gastric emptying time: in breast milk. Amantadine may alter breast milk produc-
Fasting state: 20-60 minutes; 1 hour after meals: May tion or excretion. According to the manufacturer, the
be up to 3 hours decision to breastfeed during therapy should consider
Dosing the risk of infant exposure, the benefits of breastfeeding
Pediatric to the infant, and benefits of treatment to the mother.
Note: Chronic antacid therapy not recommended for Contraindications Hypersensitivity to amantadine or any
management of GERD in pediatric patients (AAP component of the formulation; end-stage renal disease
(Lightdale 2013]; Vandenplas 2009). (CrCl <15 mL/minute/1.73 m?) (extended release only).
Antacid: Aluminum hydroxide 200 mg and magnesium Warnings/Precautions May cause CNS depression,
hydroxide 200 mg per 5 mL: which may impair physical or mental abilities; patients
Children <12 years: Limited data available: Short- must be cautioned about performing tasks that require
term therapy only: Oral: 0.5 to 1 mL/kg/dose after mental alertness (eg, operating machinery or driving).
meals and at bedtime; maximum dose: 20 mL/dose Patients taking amantadine for Parkinson disease have
(Orenstein 1988) reported falling asleep while engaged in activities of daily
Children 212 years and Adolescents: Oral: 10 to 20 living, sometimes without warning. Patients with a con-
mL 4 times daily; maximum daily dose: 80 mL per 24 comitant sleep disorder may be at a greater risk. There is
hours insufficient information that dose reduction will eliminate
Renal Impairment: Pediatric There are no dosage episodes of falling asleep or daytime somnolence. There
adjustments provided in the manufacturer's labeling; have been reports of suicidal ideation/attempt and depres-
aluminum and/or magnesium may accumulate in renal sion in patients with and without a history of psychiatric
impairment. illness. Rarely, reversible elevations in transaminases
Hepatic Impairment: Pediatric There are no dosage have been reported. Use with caution in patients with
adjustments provided in the manufacturer's labeling. hepatic impairment, a history of recurrent eczematoid

102
 AMANTADINE

dermatitis, seizures, and in those receiving CNS stimulant creatinine, keratitis, leukocytosis, leukopenia, mania,
drugs; reduce dose in renal impairment. Use of the mydriasis, neuroleptic malignant syndrome (associated
extended-release product is contraindicated in end-stage with dosage reduction or abrupt withdrawal of amanta-
renal disease (CrCl <15 mL/minute/1.73 m2). A symptom dine), neutropenia, oculogyric crisis, optic nerve palsy,
complex resembling neuroleptic malignant syndrome (ele- paresthesia, pathological gambling, pruritus, psychosis,
vated temperature, muscular rigidity, altered conscious- pulmonary edema, seizure, skin photosensitivity, skin
ness, and autonomic instability) with no other obvious rash, slurred speech, stupor, tachycardia, tachypnea,
cause has been reported in association with rapid dose
tremor, urinary retention, visual disturbance (including
reduction, withdrawal of, or changed in drugs that
punctate subepithelial or other corneal opacity),
increased central dopaminergic dose. Abrupt discontinua-
weakness
tion of amantadine may cause agitation, anxiety, delirium,
delusions, depression, hallucinations, paranoia, parkinso-
Drug Interactions
nian crisis, slurred speech, or stupor. Visual and auditory Metabolism/Transport Effects Substrate of OCT2
hallucinations, delusions, illusions, and paranoia were Avoid Concomitant Use
reported in clinical trials; monitor for the occurrence of Avoid concomitant use of Amantadine with any of the
these symptoms especially at initiation and after dose following: Alcohol (Ethyl); Amisulpride; Sulpiride
increases; use is not recommended in patients with pre- Increased Effect/Toxicity
existing psychotic disorders. Upon discontinuation of Amantadine may increase the levels/effects of: Anticho-
amantadine therapy, gradually taper dose. Elderly patients linergic Agents; BuPROPion; Glycopyrrolate (Systemic);
may be more susceptible to the CNS effects (using 2 Memantine; Trimethoprim
divided daily doses of immediate-release products may
minimize this effect); may require dosage reductions. Use The levels/effects of Amantadine may be increased by:
with caution in patients with heart failure, peripheral Alcohol (Ethyl); Alkalinizing Agents; BuPROPion; Car-
_ edema, or orthostatic hypotension; dizziness, syncope, bonic Anhydrase Inhibitors; Methylphenidate; Propiver-
orthostatic hypotension, presyncope, postural dizziness, ine; Trimethoprim
and hypotension have been reported in clinical trials; Decreased Effect
dosage reduction may be required. Avoid in untreated Amantadine may decrease the levels/effects of: Ami-
angle closure glaucoma. Potentially significant interac- sulpride; Antipsychotic Agents (First Generation [Typi-
tions may exist, requiring dose or frequency adjustment, cal]); Influenza Virus Vaccine (Live/Attenuated)
additional monitoring, and/or selection of alternative ther-
apy. The levels/effects of Amantadine may be decreased by:
Amisulpride; Antipsychotic Agents (First Generation
Dopamine agonists have been associated with compul-
[Typical]); Antipsychotic Agents (Second Generation
sive behaviors and/or loss of impulse control, which has
manifested as pathological gambling, libido increases
[Atypical]); Bromopride; Metoclopramide; Sulpiride; Uri-
(hypersexuality), urges to spend money, and/or binge nary Acidifying Agents
eating. Causality has not been established, and contro- Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
versy exists as to whether this phenomenon is related to excursions permitted to 15°C to 30°C (59°F to 86°F).
the underlying disease, prior behaviors/addictions, and/or Protect immediate-release capsules from moisture.
drug therapy. Dose reduction or discontinuation of therapy Mechanism of Action
has been reported to reverse these behaviors in some, but Antiviral:
not all cases. Risk for melanoma development is The mechanism of amantadine’s antiviral activity has not
increased in Parkinson disease patients; drug causation been fully elucidated. It appears to primarily prevent the
or factors contributing to risk have not been established. release of infectious viral nucleic acid into the host cell
Patients should be monitored closely and periodic skin by interfering with the transmembrane domain of the
examinations should be performed. Tolerance has also viral M2 protein. Amantadine is also known to prevent
been reported with long-term use (Zubenko 1984). viral assembly during replication. Amantadine inhibits
Due to increased resistance, the ACIP has recommended the replication of influenza A virus isolates from each of
that rimantadine and amantadine no longer be used for the subtypes (ie, H1N1, H2N2 and H3N2), but has very
the treatment or prophylaxis of influenza A in the United little or no activity against influenza B virus isolates.
States until susceptibility has been re-established; consult Parkinson disease:
current guidelines (CDC 2011). The exact mechanism of amantadine in the treatment of
Some dosage forms may contain propylene glycol; large Parkinson disease and drug-induced extrapyramidal
amounts are potentially toxic and have been associated symptoms is not known. Data from early animal studies
hyperosmolality, lactic acidosis, seizures, and respiratory suggest that amantadine may have direct and indirect
depression; use caution (AAP 1997; Zar 2007). effects on dopamine neurons; however, recent studies
Adverse Reactions have demonstrated that amantadine is a weak, non-
Cardiovascular: Livedo reticularis (may be more common competitive NMDA receptor antagonist. Although
in women), orthostatic hypotension (maybe more com- amantadine has not been shown to possess direct
mon in men), peripheral edema, presyncope, syncope anticholinergic activity, clinically, it exhibits anticholiner-
Central nervous system: Abnormal dreams (may be more gic-like side effects (dry mouth, urinary retention, and
common in women), agitation, anxiety, apathy, ataxia constipation).
(may be more common in men and adults 265 years Pharmacodynamics/Kinetics (Adult data unless
old), confusion, delusions, depression, dizziness, drows- noted)
iness, dyschromia, dystonia, falling, fatigue, hallucina-
Onset of action: Antidyskinetic: Within 48 hours
tion, headache, illusion, insomnia, irritability,
Absorption: Well absorbed
nervousness, paranoia, suicidal ideation
Distribution: Vg: Normal: 3 to 8 L/kg; Renal failure: 5.1 +
Gastrointestinal: Anorexia, constipation, decreased appe-
tite, diarrhea, nausea (may be more common in women), 0.2 L/kg (Aoki 1988)
vomiting, xerostomia (may be more common in women) Protein binding: Normal renal function: ~67%; Hemodial-
Genitourinary: Benign prostatic hypertrophy, urinary tract ysis: ~59% (Aoki 1988)
infection Metabolism: Not appreciable; small amounts of an acetyl
Hematologic & oncologic: Bruise metabolite identified
Neuromuscular & skeletal: Joint swelling, muscle spasm Bioavailability: Immediate release: 86% to 94%
Ophthalmic: Blurred vision, cataract (may be more com- (Aoki 1988)
mon in women), xerophthalmia Half-life elimination: Normal renal function: 16 + 6 hours (9
Respiratory: Cough, dry nose to 31 hours); Healthy, older (260 years) males: 29 hours
Rare but important or life-threatening): Abnormal gait, (range: 20 to 41 hours) (Aoki 1988); End-stage renal
abnormality in thinking, acute respiratory tract failure, disease: 8 days
aggressive behavior, agranulocytosis, amnesia, anaphy- Time to peak, plasma: Extended-release capsule: 12
laxis, cardiac arrhythmia (including malignant arrhyth- hours (mean; range: 6 to 20 hours); extended-release
mias), cardiac failure, coma, corneal edema, tablet: 7.5 hours (median; range: 5.5 to 12 hours);
decreased libido, decreased visual acuity, delirium, dia-
immediate release: 2 to 4 hours
phoresis, dysphagia, dyspnea, eczema, edema, EEG
Excretion: Urine (80% to 90% unchanged) by glomerular
pattern changes, euphoria, fever, hyperkinesia, hyper-
filtration and tubular secretion
sensitivity reaction, hypertension, hypertonia, hypokine-
sia, hypotension, impulse control disorder, increased Pharmacodynamics/Kinetics: Additional Consider-
blood urea nitrogen, increased creatine phosphokinase, ations
increased gamma-glutamyl transferase, increased lac- Renal function impairment: Elimination half-life is
tate dehydrogenase, increased libido, increased serum increased 2- to 3-fold or greater when CrCl is less than
alkaline phosphatase, increased serum ALT, increased 40 mL/minute/1.73 m?.
serum AST, increased serum bilirubin, increased serum Geriatric: Clearance is reduced
AMANTADINE

Dosing Adolescents 216 years: Initial: 100 mg twice daily for

Pediatric 14 days; on Week 3 increase to 150 mg twice daily;
Attention-deficit/hyperactivity disorder (ADHD): may further increase to 200 mg twice daily on Week
Limited data available: Oral: Children 25 years and 4 if needed; dosing based on a multicenter, double-
Adolescents: Initial: 50 mg/day; titrate up at 4-7 day blind, placebo-controlled trial of 184 patients (age
intervals in 50 mg increments to effect; reported range: 16-65 years; treatment group, n=87) which
range: 50-150 mg/day in divided doses 1-3 times showed 4 weeks of amantadine therapy initiated at
daily (morning, noon, and 4 PM); maximum daily dose 4-16 weeks postinjury increased the rate of func-
(weight-dependent): <30 kg: 100 mg/day; 230 kg: tional recovery (Giacino, 2012).
150 mg/day (Donfrancecso, 2007; King, 2001; Administration Oral: May be taken without regard to
Mohammadi, 2010); dosing based on two small food. For regimens with multiple daily dosing, timing of
open-label trials (n=24, n=20; age range: 5-14 years) doses may vary based upon patient tolerance (eg, if
which suggested improvements in symptoms and insomnia develops, administer evening dose several
ADHD outcome scores; a comparison trial with meth- hours before bedtime) and use [for ADHD, administer
ylphenidate (n=40) did not detect differences in effi- morning and noon; if thrice daily dosing, last dose should
cacy between the treatment groups (Mohammadi, be given around 4 PM (Mohammadi, 2010)].
2010). Monitoring Parameters Renal function; mental status,
Autism (hyperactivity, irritability): Limited data avail- monitor for signs of neurotoxicity; periodic skin exam for
able: Oral: Children 25 years and Adolescents: Initial: melanoma, blood pressure
2.5 mg/kg/dose once daily for 1 week, then increase Test Interactions May interfere with urine detection of
to 2.5 mg/kg/dose twice daily; maximum daily dose: amphetamines/methamphetamines (false-positive).
200 mg/day; dosing based on short-term (4-week) Product Availability Osmolex ER tablets: FDA approved
double-blind, placebo-controlled trial of 39 pediatric February 2018; anticipated availability is currently
patients (treatment group, n=19) which showed unknown. Information pertaining to this product within
improvement in clinician-rated behavioral and hyper- the monograph is pending revision. Consult the prescrib-
activity ratings (King, 2001a). ing information for additional information.
Influenza A treatment/prophylaxis: Oral: Note: Due Dosage Forms Excipient information presented when
to issues of resistance, amantadine is no longer available (limited, particularly for generics); consult spe-
recommended for the treatment or prophylaxis of cific product labeling.
influenza A. Please refer to the current ACIP recom- Capsule, Oral, as hydrochloride:
mendations. The following is based on the manufac- Generic: 100 mg
turer's labeling and ACIP recommendations: Capsule Extended Release 24 Hour, Oral, as hydrochlor-
Influenza A treatment: ide [strength expressed as base]:
1-9 years: 5 mg/kg/day in 2 divided doses (manu- Gocovri: 68.5 mg, 137 mg
Syrup, Oral, as hydrochloride:
facturer's labeling: 4.4-8.8 mg/kg/day); maximum
Generic: 50 mg/5 mL (10 mL, 473 mL)
daily dose: 150 mg/day
Tablet, Oral, as hydrochloride:
210 years and <40 kg: 5 mg/kg/day in 2 divided
Generic: 100 mg
doses (CDC, 2011)
Tablet Extended Release 24 Hour, Oral, as hydrochloride
210 years and 240 kg: 100 mg twice daily
[strength expressed as base]:
(CDC, 2011)
Osmolex ER: 129 mg [contains fd&c yellow #10 (quino-
Note: Initiate within 24-48 hours after onset of
line yellow), fd&c yellow #6 (sunset yellow)]
symptoms; continue for 24-48 hours after symp-
Osmolex ER: 193 mg [contains fd&c blue #2 (indigotine),
tom resolution (duration of therapy is generally
fd&c red #40, fd&c yellow #10 (quinoline yellow), fd&c
3-5 days)
yellow #6 (sunset yellow)]
Influenza A prophylaxis: Refer to "Influenza A treat-
Osmolex ER: 258 mg [contains brilliant blue fef (fd&c
ment" dosing
blue #1), fd&c red #40, fd&c yellow #10 (quinoline
Note: Continue prophylaxis throughout the peak
yellow), fd&c yellow #6 (sunset yellow)]
influenza activity in the community or throughout
the entire influenza season in patients who cannot @ Amantadine Hydrochloride see Amantadine
be vaccinated. Development of immunity following on page 102
vaccination takes ~2 weeks; amantadine therapy @ Ambien see Zolpidem on page 2095
should be considered for high-risk patients from
@ Ambien CR see Zolpidem on page 2095
the time of vaccination until immunity has devel-
oped. For ages <9 years receiving influenza vac- AmBisome see Amphotericin B (Liposomal)
cine for the first time, amantadine prophylaxis on page 140
should continue for 6 weeks (4 weeks after the @ AmeriDerm PeriShield [OTC] see Zinc Oxide
first dose and 2 weeks after the second dose). on page 2088
Multiple sclerosis-associated lassitude (fatigue): @ A-Methapred see MethyIPREDNISolone on page 1350
Limited data available (Pohl, 2007): Oral:
# Amethocaine Hydrochloride see Tetracaine (Ophthal-
<10 years or weight <40 kg: 2.5 mg/kg/dose twice
mic) on page 1924
daily; maximum daily dose: 150 mg/day
210 years and weight 240 kg: 100 mg twice daily, may ¢@ Amethocaine Hydrochloride see Tetracaine (Systemic)
titrate dose to clinical response; maximum daily on page 1923
dose: 400 mg/day Amethocaine Hydrochloride see Tetracaine (Topical)
Traumatic brain injury (TBI): Limited data available: on page 1924
Oral: @ Amethopterin see Methotrexate on page 1333
Children 26 years and Adolescents <16 years:
4-6 mg/kg/day in 2 divided doses; maximum daily @ Ametop (Can) see Tetracaine (Topical) on page 1924
dose (age or weight dependent): If <10 years or <40 @ AMG103 see Blinatumomab on page 282
kg: 150 mg/day; if 210 years or 240 kg: 200 mg/day @ AMG-162 see Denosumab on page 588
(Beers, 2005; McMahon, 2009). While total daily @ Amicar see Aminocaproic Acid on page 110
dose similar in trials, the reported dosing
approaches and efficacy results are variable (eg, @ Amidate see Etomidate on page 807
timing of therapy initiation, duration of study, out-
come measures) (Williams, 2007). In an open-label, Amifostine (am i Fos teen)
case-controlled trial of 27 pediatric patients with TBI
within the last 24 months prior to enrollment (n=17 Medication Safety Issues
amantadine treatment, n=10 controls), patients Sound-alike/look-alike issues:
received 5 mg/kg/day for entire study period of 12 Ethyol may be confused with ethanol
weeks; results showed improvement in behavior Brand Names: US Ethyol
(parental report) and a subset analysis suggested Brand Names: Canada Ethyol
therapy more effective on cognition for those with Therapeutic Category Antidote, Cisplatin; Cytoprotective
more recent injury (Beers, 2005). In a double-blind, Agent
placebo-controlled crossover trial of seven pediatric Generic Availability (US) Yes
patients (mean age: 12.7 years) with TBI within last Use Reduction of cumulative renal toxicity associated with
12 weeks prior to enrollment, therapy was initiated at repeated administration of cisplatin in patients with
4 mg/kg/day up to 300 mg/day for 1 week, and advanced ovarian cancer (FDA approved in adults);
increased to 6 mg/kg/day up to 400 mg/day for reduction of moderate to severe xerostomia from radiation
Weeks 2 and 3 of the study duration; improved treatment of the head and neck where the radiation port
consciousness observed during treatment period of includes a substantial portion of the parotid glands (FDA
study (McMahon, 2009; Vargus-Adams, 2010). approved in adults); has also been used as a

104
 AMIFOSTINE

cytoprotective agent to selectively protect normal tissues of esophagitis due to chemotherapy in patients with non-
against toxicity due to cytotoxic chemotherapy. Note: The small cell lung cancer. Additionally, amifostine may be
Clinical data do not suggest the efficacy of cisplatin-based considered to decrease the incidence of acute and late
chemotherapy or radiation therapy for the approved indi- xerostomia in patients undergoing radiation therapy alone
cations is altered by amifostine. Data on the effects of (for head and neck cancer); however, the guidelines do
amifostine on the efficacy of chemotherapy or radiother- not support the use of amifostine in patients with head and
apy in other settings is limited. Do not administer amifos- neck cancer receiving concurrent platinum-based chemo-
tine in other settings where chemotherapy can produce a therapy.
significant survival benefit or cure, or in patients receiving Adverse Reactions
definitive radiotherapy, unless within the context of a Cardiovascular: Bradycardia, chest pain, extrasystoles,
clinical study. flushing, hypotension (more common in ovarian cancer;
Pregnancy Considerations Adverse events have been generally transient), ischemic heart disease, tachycardia
‘observed in animal reproduction studies. Central nervous system: Chills, dizziness, drowsiness,
Breastfeeding Considerations It is not known if amifos- malaise, sensation of cold
tine is present in breast milk. Due to the potential for Dermatologic: Erythema multiforme, skin rash
adverse reactions in the breastfed infant, the manufac- Endocrine & metabolic: Hypocalcemia (head and neck
turer recommends discontinuing breastfeeding during cancer; clinically significant)
amifostine treatment. Gastrointestinal: Diarrhea, hiccups, nausea and vomiting
Contraindications Hypersensitivity to amifostine, amino- (more common in ovarian cancer), severe nausea and
thiol compounds, or any component of the formulation vomiting (more common in ovarian cancer)
Hypersensitivity: Anaphylaxis
Warnings/Precautions Hypotension may occur during or
Local: Injection site reaction (includes bruising at injection
shortly after infusion. Short term (reversible) syncope (loss
site, erythema at injection site, inflammation at injection
of consciousness) has been rarely reported. Patients who
site, injection site pruritus, pain at injection site, rash at
are hypotensive or dehydrated should not receive amifos-
injection site, swelling at injection site, urticaria at injec-
tine. Interrupt antihypertensive therapy for 24 hours before
tion site)
treatment; patients who cannot safely stop their antihy-
Ophthalmic: Blurred vision, diplopia
pertensives 24 hours before should not receive amifos-
Respiratory: Apnea, dyspnea, hypoxia, sneezing
tine. Adequately hydrate prior to treatment and keep in a
Miscellaneous: Fever
supine position during infusion. Monitor blood pressure
<1%, postmarketing, and/or case reports: Anaphylactoid
every 5 minutes during the infusion. If hypotension requir-
reaction, atrial fibrillation, atrial flutter, cardiac arrhyth-
ing interruption of therapy occurs, patients should be
mia, DRESS syndrome, hypersensitivity reaction
placed in the Trendelenburg position and given an infusion
(includes chest discomfort, laryngeal edema, pruritus,
of normal saline using a separate IV line; subsequent
rigors, urticaria), myocardial infarction, renal failure, seiz-
infusions may require a dose reduction. Infusions >15
ure, Stevens-Johnson syndrome, supraventricular tachy-
minutes are associated with a higher incidence of adverse
cardia, syncope, toxic epidermal necrolysis, transient
effects. Use caution in patients with cardiovascular and
hypertension
cerebrovascular disease and any other patients in whom
the adverse effects of hypotension may have serious
Drug Interactions
adverse events. Metabolism/Transport Effects None known.
Avoid Concomitant Use
Serious cutaneous reactions (some fatal), including eryth- Avoid concomitant use of Amifostine with any of the
ema multiforme, Stevens-Johnson syndrome, toxic epi- following: Bromperidol
dermal necrolysis, toxicoderma, exfoliative dermatitis, Increased Effect/Toxicity
and drug reaction with biopsy-proven eosinophilia and Amifostine may increase the levels/effects of: Antipsy-
system symptoms (DRESS) have been reported with chotic Agents (Second Generation [Atypical]); Bromper-
amifostine. May be delayed, developing up to weeks after idol; DULoxetine; Pholcodine
treatment initiation. Cutaneous reactions have been
reported more frequently when used as a radioprotectant. The levels/effects of Amifostine may be increased by:
Evaluate for dermatologic reactions prior to each dose, Alfuzosin; Barbiturates; Benperidol; Blood Pressure
during therapy and after treatment discontinuation. Dis- Lowering Agents; Brimonidine (Topical); Diazoxide;
continue treatment for severe/serious cutaneous reactions Herbs (Hypotensive Properties); Lormetazepam; Molsi-
or mucosal lesions which appear outside of the radiation domine; Naftopidil; Nicergoline; Nicorandil; Obinutuzu-
port and for bullous, edematous or erythematous lesions mab; Pentoxifylline; Phosphodiesterase 5 Inhibitors;
on the palms or soles. Prostacyclin Analogues; Quinagolide
Decreased Effect
Amifostine doses >300 mg/m? are associated with a The levels/effects of Amifostine may be decreased by:
moderate emetic potential (Dupuis 2011). It is recom- Bromperidol
mended that antiemetic medication, including dexametha- Storage/Stability Store intact vials at 20°C to 25°C (68°F
sone 20 mg IV and a serotonin 5-HT3 receptor antagonist to 77°F). Reconstituted solutions (500 mg/10 mL) and
be administered prior to and in conjunction with amifos- solutions diluted in NS (in polyvinyl! chloride [PVC] bags)
tine. Rare hypersensitivity reactions, including anaphy- for infusion are chemically stable for up to 5 hours at room
laxis and allergic reaction, have been reported; temperature (~25°C [~77°F]) or up to 24 hours under
discontinue if severe acute allergic reaction occurs; do refrigeration (2°C to 8°C [36°F to 46°F)).
not rechallenge. Medications for the treatment of hyper- Mechanism of Action Amifostine is a prodrug that is
sensitivity reactions should be available. dephosphorylated by alkaline phosphatase in tissues to
a pharmacologically-active free thiol metabolite. The free
Reports of clinically-relevant hypocalcemia are rare, but
serum calcium levels should be monitored in patients at thiol is available to bind to, and detoxify, reactive metab-
olites of cisplatin; and can also act as a scavenger of free
risk of hypocalcemia, such as those with nephrotic syn-
drome; may require calcium supplementation. According radicals that may be generated (by cisplatin or radiation
to the manufacturer, amifostine should not be used (in therapy) in tissues.
patients receiving chemotherapy for malignancies other Pharmacodynamics/Kinetics (Adult data unless
than ovarian cancer) where chemotherapy is expected to noted)
provide significant survival benefit or in patients receiving Metabolism: Hepatic dephosphorylation to two metabo-
definitive radiotherapy, unless within the context of a lites (active-free thiol and disulfide)
Clinical trial. The American Society of Clinical Oncology Half-life elimination: Children: 9.3 minutes (Fouladi 2001);
(ASCO) has published guidelines for the use of protec- Adults: ~8 minutes
tants for chemotherapy and radiation (Hensley 2009). Excretion: Urine (minimal; as amifostine and metabolites)
According to the ASCO guidelines, amifostine may be Dosing
considered for prevention of nephrotoxicity in patients Pediatric Refer to individual protocols.
receiving cisplatin-based therapy. While amifostine may Cytoprotective agent against cisplatin or high-dose
be considered to reduce the incidence of grade 3 or 4 alkylating agents: Limited data available: Efficacy
neutropenia associated with chemotherapy, the guidelines results variable:
suggest that alternative strategies (eg, growth factors) Gastrointestinal and hematologic toxicity reduction:
may be utilized in this situation. The guidelines recom- Infants, Children, and Adolescents: IV: 740 mg/m?/
mend against the use of amifostine to reduce the inci- dose once daily prior to cytotoxic chemotherapy. In a
dence of thrombocytopenia associated with study of patients (n=11, age range: 2.5 months to 17
chemotherapy or radiation therapy. Data is insufficient to years) receiving the same combination chemother-
recommend amifostine for prevention of neurotoxicity or apy at the same doses (including cisplatin or high-
ototoxicity associated with platinum-based chemotherapy, dose alkylating agent) with or without amifostine,
for prevention of neurotoxicity associated with paclitaxel, patients who received amifostine had significantly
for prevention of radiation therapy-induced mucositis reduced incidences of mucositis and gastrointestinal
associated with head and neck cancer, or for prevention toxicities and a significantly reduced requirement for

105
 AMIFOSTINE

q erythrocyte transfusions. However, there was no

difference in the number of platelet transfusions Amikacin (ami KAY sin)
required (Cetingtil 2009). In another study in osteo-
sarcoma patients treated with cisplatin or carbopla- Medication Safety Issues
tin as part of combination chemotherapy, there was Sound-alike/look-alike issues:
a reduction in neutrophil and leukocyte toxicity in Amikacin may be confused with Amicar, anakinra .
patients who received amifostine (n=17) compared Amikin may be confused with Amicar, Kineret
to those who did not (n=19); however, amifostine did Brand Names: Canada Amikacin Sulfate Injection, USP;
not protect against platelet effects (Petrilli 2002). Amikin
Other studies have not shown protection against Therapeutic Category Antibiotic, Aminoglycoside
myelosuppression (Adamson 1995; Bern- Generic Availability (US) Yes
stein 2006). Use Treatment of serious infections (bone and respiratory
Nephrotoxicity reduction: Children and Adolescents: infections, endocarditis, and septicemia) due to organisms
IV: 740 mg/m2/dose given immediately prior to cis- resistant to gentamicin and tobramycin, including Pseudo-
platin. In a small study of intracavitary cisplatin monas, Klebsiella, Enterobacter, Serratia, Proteus, and
therapy for solid tumors,.three patients (ages: 2 to Providencia species, and E. coli (FDA approved in all
6 years) received amifostine. Of these patients, only ages); has also been used for documented infection of
one experienced persistent renal dysfunction (Kat- susceptible mycobacterial organisms
zenstein 2010). Pregnancy Risk Factor D
Reduction of platinum-induced hearing loss: Children Pregnancy Considerations Adverse events were not
and Adolescents 3 to 20 years: IV: 600 mg/m?/dose observed in the initial animal reproduction studies. Ami-
given immediately prior to and 3 hours into cisplatin kacin crosses the placenta and produces detectable con-
administration has been shown to reduce cisplatin- centrations in the fetus. Aminoglycosides may cause fetal
induced hearing loss in patients with average-risk harm if administered to a pregnant woman. There are
medulloblastoma. Amifostine did not protect against several reports of total irreversible bilateral congenital
hearing loss in patients with high-risk medulloblas- deafness in children whose mothers received another
toma (Fouladi 2008; Gurney 2014). Other studies aminoglycoside (streptomycin) during pregnancy.
using a single dose of 740 mg/m? or 825 mg/m? Although serious side effects to the fetus/infant have not
immediately prior to cisplatin did not prevent ototox- been reported following maternal use of all aminoglyco-
icity (Katzenstein 2009; Marina 2005; Petrilli 2002). sides, a potential for harm exists.
Xerostomia, moderate to severe from radiation of
the head and neck, reduction: Limited data avail- Due to pregnancy-induced physiologic changes, some
able: Children 27 years and Adolescents: SubQ: pharmacokinetic parameters of amikacin may be altered
200 mg once daily given 30 minutes prior to standard (Bernard 1977).
fraction radiation therapy. Dosing based on a small Breastfeeding Considerations Amikacin is excreted
pilot study in pediatric patients who received subcuta- into breast milk (trace amounts) (Matsuda 1984). Due to
neous amifostine (n=5, age range: 7 to 15 years) fora the potential for serious adverse reactions in the nursing
total of 129 injections. No grade 3 or 4 mucosal or skin infant, the manufacturer recommends a decision be made
reactions occurred (Anacak 2007). whether to discontinue nursing or to discontinue the drug,
Dosing adjustment for toxicity: The presented dosing taking into account the importance of treatment to the
adjustments are based on experience in adult patients; mother. As a class, aminoglycosides are expected to be
specific recommendations for pediatric patients are poorly distributed into breast milk, limiting systemic expo-
limited. Refer to specific protocol for management in sure to a nursing infant. In general, modification of bowel
pediatric patients if available. flora may occur with any antibiotic exposure (Chung
Adult: Dermatologic toxicity: 2002).
Rash involving lips or mucosa (of unknown etiology Contraindications Hypersensitivity to amikacin, other
outside of radiation port) and for bullous, edematous aminoglycosides, or any component of the formulation
or erythematous lesions on hands, feet, or trunk: Warnings/Precautions [US Boxed Warning]: Amikacin
Withhold treatment and obtain dermatologic consul- may cause neurotoxicity, nephrotoxicity, and/or neu-
tation; reinitiate only after careful evaluation. romuscular blockade and respiratory paralysis; usual
Severe/serious cutaneous reaction associated with risk factors include preexisting renal impairment, concom-
fever (or other constitutional symptoms) or severe itant neuro-/nephrotoxic medications, advanced age and
acute allergic reaction: Discontinue treatment per- dehydration. Dose and/or frequency of administration
manently. must be monitored and modified in patients with renal
Renal Impairment: Pediatric There are no dosage impairment. Drug should be discontinued if signs of oto-
adjustments provided in the manufacturer's labeling. toxicity, nephrotoxicity, or hypersensitivity occur. Ototox-
Hepatic Impairment: Pediatric There are no dosage icity is proportional to the amount of drug given and the
adjustments provided in the manufacturer's labeling. duration of treatment. Tinnitus or vertigo may be indica-
Preparation for Administration Parenteral: tions of vestibular injury and impending bilateral irrever-
IV: Reconstitute 500 mg vials with 9.7 mL of NS to a sible damage. Renal damage is usually reversible.
concentration of 50 mg/mL; dose must be further diluted Irreversible deafness, renal failure, and death due to
with NS to a final concentration of 5 to 40 mg/mL. neuromuscular blockade have been reported following
SubQ: Reconstitute with 2.5 mL NS or SWF. use of aminoglycosides as surgical irrigation; rapid sys-
Administration Parenteral: IV: Administer amifostine temic absorption occurs with topical application (except to
doses 2600 mg/m? as an IV intermittent infusion over 15 the urinary bladder). Use with caution in patients with renal
minutes since the 15-minute infusion is better tolerated insufficiency, neuromuscular disorders (including myas-
than a more prolonged infusion. Administer 200 mg/m? thenia gravis or parkinsonism), preexisting vertigo, hear-
dose as a 3-minute infusion. Patients should be kept in ing loss, tinnitus, or hypocalcemia. Prolonged use may
supine position during infusion and amifostine should be result in fungal or bacterial superinfection, including C.
interrupted if the blood pressure decreases significantly difficile-associated diarrhea (CDAD) and pseudomembra-
from baseline or if the patient develops symptoms related nous colitis; CDAD has been observed >2 months post-
to decreased cerebral or cardiovascular perfusion. antibiotic treatment. Potentially significant drug-drug
Patients experiencing decreased blood pressure should interactions may exist, requiring dose or frequency adjust-
receive a rapid infusion of NS and be kept supine or ment, additional monitoring, and/or selection of alternative
placed in the Trendelenburg position. Amifostine can be therapy. [US Boxed Warning]: Avoid concomitant or
restarted if the blood pressure returns to the baseline sequential use of other neurotoxic and/or nephrotoxic
level. drugs (eg, bacitracin, cisplatin, amphotericin B, paro-
Monitoring Parameters Baseline blood pressure fol- momycin, polymyxin B, colistin, vancomycin, other
lowed by a blood pressure reading every 5 minutes during aminoglycosides) and concomitant use with potent
the infusion and after administration if clinically indicated; diuretics (eg, ethacrynic acid, furosemide) since diu-
monitor electrolytes, urinalysis, serum calcium, serum retics themselves may cause ototoxicity and may
magnesium; monitor | & O; evaluate for cutaneous reac- enhance aminoglycoside toxicity. Cross-sensitivity to
tions prior to each dose other aminoglycosides may occur. May contain sulfites
Dosage Forms Excipient information presented when which may cause allergic-type reactions (including ana-
available (limited, particularly for generics); consult spe- phylaxis) as well as life-threatening or less severe asth-
cific product labeling. [DSC] = Discontinued product matic episodes in certain individuals.
Solution Reconstituted, Intravenous: Warnings: Additional Pediatric Considerations Use
Ethyol: 500 mg (1 ea) with caution in pediatric patients on extracorporeal mem-
Generic: 500 mg (1 ea [DSC]) brane oxygenation (ECMO); pharmacokinetics of amino-
Solution Reconstituted, Intravenous [preservative free]: glycosides may be altered; dosage adjustment and close
Generic: 500 mg (1 ea [DSC]) monitoring necessary.

106
 AMIKACIN

Adverse Reactions PNA 215 days: 15 mg/kg/dose every 24 hours

Central nervous system: Neurotoxicity Gestational age 30 to 34 weeks, PNA <60 days:
Genitourinary: Nephrotoxicity 15 mg/kg/dose every 24 hours
Otic: Auditory ototoxicity, vestibular ototoxicity Gestational age 235 weeks:
Rare but important or life-threatening: Dyspnea, eosino- PNA <7 days: 15 mg/kg/dose every 24 hours
philia, hypersensitivity reaction PNA 28 days: 17.5 mg/kg/dose every 24 hours
Drug Interactions Weight-directed dosing (Red Book (AAP 2015}): IM, IV:
Metabolism/Transport Effects None known. Body weight <1 kg:
Avoid Concomitant Use PNA s14 days: 15 mg/kg/dose every 48 hours
Avoid concomitant use of Amikacin with any of the PNA 15 to 28 days: 15 mg/kg/dose every 24 hours
following: Ataluren; BCG (Intravesical); Cholera Vaccine; Body weight 1 to 2 kg:
-Foscarnet; Mannitol (Systemic); Mecamylamine; PNA <7 days: 15 mg/kg/dose every 48 hours
Methoxyflurane PNA 8 to 28 days: 15 mg/kg/dose every 24 hours
Increased Effect/Toxicity Body weight >2 kg:
Amikacin may increase the levels/effects of: Abobotuli- PNA <7 days: 15 mg/kg/dose every 24 hours
numtoxinA; Bisphosphonate Derivatives; CARBOplatin; PNA 8 to 28 days: 17.5 mg/kg/dose every 24 hours
Colistimethate; CycloSPORINE (Systemic); Mecamyl- Meningitis: |V: Note: Use smaller doses and longer
amine; Methoxyflurane; Neuromuscular-Blocking intervals for neonates <2 kg (Tunkel 2004):
Agents; OnabotulinumtoxinA; RimabotulinumtoxinB; PNA s7 days and 22 kg: 15 to 20 mg/kg/day divided
Tenofovir Products every 12 hours
PNA >7 days and 22 kg: 30 mg/kg/day divided every 8
The levels/effects of Amikacin may be increased by: hours
Amphotericin B; Arbekacin; Ataluren; Capreomycin; Dosing adjustment’ in renal impairment: Consider
Cefazedone; Cephalosporins (2nd Generation); Cepha- single-dose administration with serum concentration
losporins (3rd Generation); Cephalosporins (4th Gener- monitoring in patients with urine output <1 mL/kg/hour
ation); Cephalothin; Cephradine; ClSplatin; Foscarnet; or serum creatinine >1.3 mg/dL rather than scheduled
Loop Diuretics; Mannitol (Systemic); Nonsteroidal Anti- dosing.
Inflammatory Agents; Oxatomide; Tenofovir Products; Pediatric
Vancomycin Note: Individualization is critical because of the low
Decreased Effect ; therapeutic index. Dosage should be based on an
Amikacin may decrease the levels/effects of: BCG (Intra- estimate of ideal body weight. In morbidly obese chil-
vesical); BCG Vaccine (Immunization); Cholera Vaccine; dren and adolescents, dosage requirement may best
Distigmine; Lactobacillus and Estriol; Sodium. Picosul- be estimated using a dosing weight of IBW + 0.4
fate; Typhoid Vaccine (TBW - IBW). Initial dosing recommendation pre-
sented; dosage should be individualized based upon
The levels/effects of Amikacin may be decreased by:
serum concentration monitoring. Initial and periodic
Penicillins
plasma drug concentrations (eg, peak and trough with
Storage/Stability Store intact vials at 20°C to 25°C (68°F
conventional dosing, post dose level at a prespecified
to 77°F). Following admixture at concentrations of 0.25 to
time with extended-interval dosing) should be deter-
5 mg/mL in DSW, NS, D51/4NS, D51/2NS, LR, Normosol M
mined, particularly in critically ill patients with serious
in D5W, Normosol R in D5, Plasma-Lyte 56 in D5 or
infections or in disease states known to significantly
Plasma-Lyte 148 in D5W, amikacin is stable for 24 hours
alter aminoglycoside pharmacokinetics (eg, cystic fib-
at room temperature, 60 days at 4°C (39°F), or 30 days at
rosis, burns, or major surgery).
-15°C (5°F). Previously refrigerated or thawed frozen
General dosing, severe, susceptible infections:
solutions are stable for 24 hours when stored at 25°C
Infants, Children, and Adolescents:
(77°F).
IM, IV: 15 to 22.5 mg/kg/day divided every 8 hours or
Mechanism of Action Inhibits protein synthesis in sus- 15 to 20 mg/kg/dose every 24 hours (Red Book
ceptible bacteria by binding to 30S ribosomal subunits [AAP 2015]);
Pharmacodynamics/Kinetics (Adult data unless CNS infections:
noted) Meningitis (Tunkel 2004):
Absorption: Infants and Children: IV: 20 to 30 mg/kg/day divided
IM: Rapid every 8 hours
Oral: Poorly absorbed Adolescents: IV: 15 mg/kg/day divided every 8
Distribution: Vg: 0.25 L/kg (Vozeh 1988); primarily into hours
extracellular fluid (highly hydrophilic); poor penetration VP-shunt infection, ventriculitis: Limited data avail-
into the blood-brain barrier even when meninges are able: Intraventricular/intrathecal (use a preserva-
inflamed; Vg is increased in neonates and patients with tive-free preparation): Infants, Children, and
edema, ascites, fluid overload; Vg is decreased in Adolescents: 5 to 50 mg/day; usual dose:
patients with dehydration : 3 - 30 mg/day
Relative diffusion of antimicrobial agents from blood into Cystic fibrosis, pulmonary infection: Infants, Chil-
CSF: Good only with inflammation (exceeds dren, and Adolescents:
usual MICs) Traditional dosing: IV, IM: 10 mg/kg/dose every 8
CSF:blood level ratio: Infants: Normal meninges: 10% to hours (Wallace 1993)
20%; Inflamed meninges: up to 50% Extended-interval dosing: IV: 30 mg/kg/dose every 24
Protein-binding: 0% to 11% hours (Flume 2009); Note: The CF Foundation
Half-life elimination (renal function and age dependent): recommends extended-interval dosing as preferred
Infants: Low birth weight (1 to 3 days): 7 to 9 hours; Full- over traditional dosing.
term >7 days: 4 to 5 hours (Howard 1975) Endocarditis, treatment: Children and Adolescents:
Children: 1.6 to 2.5 hours IV: 15 mg/kg/day divided every 8 to 12 hours; use in
Adolescents: 1.5 + 1 hour combination with other antibiotics dependent upon
Adults: Normal renal function: ~2 hours; Anuria/end- organism and source of infection (ie, valve-type)
stage renal disease: 17 to 150 hours (Aronoff 2007) (AHA [Baltimore 2015])
Time to peak, serum: IM: 60 minutes; IV: Within 30 Intra-abdominal infection, complicated: Infants,
minutes following a 30-minute infusion Children, and Adolescents: IV: 15 to 22.5 mg/kg/day
Excretion: Urine (94% to 98% unchanged) divided every 8 to 24 hours (Solomkin 2010)
Pharmacodynamics/Kinetics: Additional Consider- Mycobacterium, avium complex infection (MAC),
ations Renal function impairment: Clearance is treatment: HIV-exposed/-positive:
decreased in renal impairment. Infants and Children: IV: 15 to 30 mg/kg/day divided
Dosing es every 12 to 24 hours as part of a multiple drug
Neonatal Note: Dosing strategies may vary by institution regimen; maximum daily dose: 1,500 mg/day
as a wide variety of dosing regimens have been studied (HHS [Ol pediatric 2013))
(Allegaert 2006; Allegaert 2008; Labaune 2001; Sherwin Adolescents: IV: 10 to 15 mg/kg/dose every 24 hours
2009). Dosage should be based on actual weight unless as part of a multiple drug regimen; maximum daily
the patient has hydrops fetalis. Note: Consider prolon- dose: 1,500 mg/day (HHS [O! adult 2016]; HHS [Ol
gation of dosing interval when coadministered with ibu- pediatric 2013])
profen or indomethacin or in neonates with history of the Tuberculosis, drug-resistant:
following: Birth depression, birth hypoxia/asphyxia, or Infants, Children, and Adolescents $14 years:
cyanotic congenital heart disease. Non-HIV-exposed/-positive:
General dosing; susceptible infection: Once-daily regimen: IM, IV: 15 to 20 mg/kg/dose
Age-directed dosing (Bradley 2016): IM, IV: once daily as part of a multiple drug regimen
Gestational age <30 weeks: (ATS/CDC/IDSA [Nahid 2016]); current guide-
PNA s14 days: 15 mg/kg/dose every:48 hours lines do not provide a maximum daily dose; for »
107
 AMIKACIN

q HIV-exposed/-positive pediatric patients, a max-

imum daily dose of 1,000 mg/day has been sug-
With conventional dosing, typically obtain serum concen-
tration after the third dose; exceptions for earlier monitor-
gested for similar mg/kg doses (HHS [Ol ing may include neonates or patients with rapidly
pediatric 2013]) changing renal function. With extended-interval dosing,
Twice-weekly regimen: IM, IV: 25 to 30 mg/kg/ usually obtain serum concentration after first, second, or
dose administered twice weekly as part of a third dose.
multiple drug regimen; dosing based on experi- Not all infants and children who receive aminoglycosides
ence in adult patients and pediatric pharmacoki- require monitoring of serum aminoglycoside concentra-
netic considerations (ATS/CDC/IDSA [Nahid tions. Indications for use of aminoglycoside serum con-
2016]); current guidelines do not provide a max- centration monitoring include:
imum daily dose; for HIV-exposed/-positive ¢ Treatment course >5 days
pediatric patients, a maximum daily dose of * Patients with decreased or changing renal function
1,000 mg/day has been suggested for similar ¢ Patients with poor therapeutic response
mg/kg doses (HHS [OI pediatric 2013}) * Neonates and Infants <3 months of age ~
HIV-exposed/-positive: IM, IV: 15 to 30 mg/kg/dose * Atypical body constituency (obesity, expanded extrac-
once daily as part of-a multiple drug regimen; ellular fluid volume)
maximum daily dose: 1,000 mg/day (HHS [Ol * Clinical need for higher doses or shorter intervals (eg,
pediatric 2013]) cystic fibrosis, burns, endocarditis, meningitis, critically
Adolescents 215 years: Independent of HIV status: ill patients, relatively resistant organisms)
Once-daily regimen: IM, IV: 15 mg/kg/dose once ¢ Patients on hemodialysis or chronic ambulatory peri-
daily as part of a multiple drug regimen (ATS/ toneal dialysis
CDC/IDSA [Nahid 2016]; HHS [Ol adult 2016}); * Signs of nephrotoxicity or ototoxicity
current guidelines do not provide a maximum daily * Concomitant use of other nephrotoxic agents
dose; for HIV-exposed/-positive pediatric patients, Reference Range Therapeutic levels:
a maximum daily dose of 1,000 mg/day has been Peak:
suggested for similar mg/kg doses (HHS [Ol pedia- Life-threatening infections: 25 to 40 mcg/mL
tric 2013]) Serious infections: 20 to 25 mcg/mL
Three-times-weekly regimen: IM, IV: 25 mg/kg/dose Urinary tract infections: 15 to 20 mcg/mL
3 times weekly (ATS/CDC/IDSA [Nahid 2016]; Trough: <8 mceg/mL; the American Thoracic Society (ATS)
HHS [Ol] adult 2016]). Current guidelines do not recommends trough levels of <4 to 5 mcg/mL for patients
provide a maximum dose; for HIV-exposed/-pos- with hospital-acquired pneumonia
itive pediatric patients, a maximum daily dose of Timing of serum samples: Draw peak 30 minutes after
1,000 mg/day has been suggested for similar completion of 30-minute infusion or at 1 hour following
mg/kg doses (HHS [Ol pediatric 2013)). initiation of infusion or IM injection; draw trough within 30
Peritonitis (CAPD): Infants, Children, and Adoles- minutes prior to next dose; aminoglycoside levels meas-
cents: Intraperitoneal: Continuous: Loading dose: ured from blood taken from Silastic central catheters can
25 mg per liter of dialysate; maintenance dose: sometimes give falsely elevated readings
12 mg per liter (Warady 2012) Test Interactions Some penicillin derivatives may accel-
Renal Impairment: Pediatric erate the degradation of aminoglycosides in vitro, leading
Infants, Children, and Adolescents: IM, IV: to a potential underestimation of aminoglycoside serum
The following adjustments have been recommended concentration.
(Aronoff 2007); Note: Renally adjusted dose recom- Dosage Forms Excipient information presented when
mendations are based on doses of 5 to 7.5 mg/kg/ available (limited, particularly for generics); consult spe-
dose every 8 hours: cific product labeling.
GFR >50 mL/minute/1.73 m?: No adjustment Solution, Injection, as sulfate:
required Generic: 500 mg/2 mL (2 mL); 1 g/4 mL (4 mL)
GFR 30 to 50 mL/minute/1.73 m?: Administer every Solution, Injection, as sulfate [preservative free]:
12 to 18 hours Generic: 500 mg/2 mL (2 mL); 1 g/4 mL (4 mL)
GFR 10 to 29 mL/minute/1.73 m?: Administer every @ Amikacin Sulfate see Amikacin on page 106
18 to 24 hours
@ Amikacin Sulfate Injection, USP (Can) see Amikacin
GFR <10,mL/minute/1.73 m?: Administer every 48 to
on page 106
72 hours
Intermittent hemodialysis: 5 mg/kg/dose; redose as @ Amikin (Can) see Amikacin on page 106
indicated by serum concentrations
Peritoneal dialysis (PD): 5 mg/kg/dose; redose as AMILoride (a mit oh ride)
indicated by serum concentrations
Continuous renal replacement therapy (CRRT): Medication Safety Issues
7.5 mg/kg/dose every 12 hours, monitor serum Sound-alike/look-alike issues:
concentrations AMlLoride may be confused with amiodarone, amLODI-
Preparation for Administration Parenteral: IV intermit- Pine, inamrinone
tert infusion: Dilute in a compatible solution (eg, NS, Geriatric Patients: High-Risk Medication:
D5W) to a final concentration of 0.25 to 5 mg/mL per the Beers Criteria: Diuretics are identified in the Beers Cri-
manufacturer; concentrations as high as 10 mg/mL have teria as potentially inappropriate medications to be
been reported (Murray 2014). used with caution in patients 65 years and older due
Administration to the potential to cause or exacerbate syndrome of
Parenteral: Administer around-the-clock to promote less inappropriate antidiuretic hormone secretion (SIADH)
variation in peak and trough serum levels. or hyponatremia; monitor sodium concentration closely
IM: Administer undiluted into a large muscle mass. Slower when initiating or adjusting the dose in older adults
absorption and lower peak concentrations, probably due (Beers Criteria [AGS 2015)).
to poor circulation in the atrophic muscle, may occur Brand Names: Canada Midamor
following IM injection; in paralyzed patients, suggest IV Therapeutic Category Antihypertensive Agent; Diuretic,
route Potassium Sparing
Intermittent IV infusion: Infuse over 30 to 60 minutes; in Generic Availability (US) Yes
infants infusion over 1 to 2 hours is recommended by the Use Counteracts potassium loss induced by other diuretics
manufacturer. in the treatment of hypertension or heart failure; usually
Some penicillins (eg, carbenicillin, ticarcillin, and pipera- used in conjunction with more potent diuretics, such as
cillin) have been shown to inactivate aminoglycosides in thiazides or loop diuretics (FDA approved in adults); has
vitro. This has been observed to a greater extent with also been used for management of edema and congenital
tobramycin and gentamicin, while amikacin has shown nephrogenic diabetes insipidus
greater stability against inactivation. Concurrent use of Pregnancy Risk Factor B
these agents may pose a risk of reduced antibacterial Pregnancy Considerations Adverse events were not
efficacy in vivo, particularly in the setting of profound observed in animal reproduction studies.
renal impairment; however, definitive clinical evidence is Breastfeeding Considerations It is not known if ami-
lacking. If combination penicillin‘aminoglycoside therapy loride is present in breast milk. Due to the potential for
is desired in a patient with renal dysfunction, separation serious adverse reactions in the breastfeeding infant, a
of doses (if feasible), and routine monitoring of amino- decision should be made to discontinue breastfeeding or
glycoside levels, CBC, and clinical response should be to discontinue the drug, taking into account the importance
considered. of treatment to the mother.
Monitoring Parameters Urinalysis, urine output, BUN, Contraindications Hypersensitivity to amiloride or any
serum creatinine, peak and trough serum amikacin con- component of the formulation; presence of elevated serum
centrations; be alert to ototoxicity potassium levels (>5.5 mEq/L); if patient is receiving other

108
 AMILORIDE

potassium-conserving agents (eg, spironolactone, triam- Decreased Effect

terene) or potassium supplementation (medicine, potas- AMlLoride may decrease the levels/effects of: Cardiac
sium-containing salt substitutes, potassium-rich diet) Glycosides; QuiNIDine
except in severe and/or refractory cases of hypokalemia;
anuria; acute or chronic renal insufficiency; evidence of The levels/effects of AMiLoride may be decreased by:
diabetic nephropathy. Patients with evidence of renal Amphetamines; Brigatinib; Bromperidol; Herbs (Hyper-
impairment (blood urea nitrogen [BUN] >30 mg/dL or tensive Properties); Methylphenidate; Nonsteroidal Anti-
serum creatinine >1.5 mg/dL) or diabetes mellitus should Inflammatory Agents; Opioid Analgesics; Yohimbine
not receive amiloride without close, frequent monitoring of Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
serum electrolytes and renal function.
Avoid freezing or excessive heat. Protect from moisture.
Warnings/Precautions [US Boxed Warning]: Hyper-
Mechanism of Action Blocks epithelial sodium channels
kalemia (serum potassium levels >5.5 mEq/L) may
occur, which can be fatal if not corrected; patients at
in the late distal convoluted tubule (DCT), and collecting
higher risk include those with renal impairment, dia- duct which inhibits sodium reabsorption from the lumen.
betes, and the elderly. Serum potassium levels must This effectively reduces intracellular sodium, decreasing
be monitored at frequent intervals especially when the function of Na+/K+ATPase, leading to potassium
therapy is initiated, when dosages are changed or retention and decreased calcium, magnesium, and hydro-
with any illness that may cause renal dysfunction. gen excretion. As sodium uptake capacity in the DCT/
Risk of hyperkalemia may be increased when used con- collecting duct is limited, the natriuretic, diuretic, and
comitantly with other medications that may increase antihypertensive effects are generally considered weak.
potassium (eg, angiotensin agents). Signs/symptoms of Pharmacodynamics/Kinetics (Adult data unless
hyperkalemia include paresthesias, muscle weakness,
noted) :
fatigue, flaccid paralysis of limbs, bradycardia, shock,
-and ECG abnormalities. If hyperkalemia occurs, discon- Onset of action: Within 2 hours; Peak effect: 6 to 10 hours
tinue amiloride immediately and manage hyperkalemia as Duration: ~24 hours
clinically appropriate. May decrease sodium and chloride Absorption: 30% to 90% (Macfie 1981)
and increase BUN, especially with concomitant diuretic Distribution: Vg: 350 to 380 L (Macfie 1981)
therapy; close medical supervision and dose evaluation Protein binding: Minimal (Macfie 1981)
are required. Watch for and correct electrolyte disturban- Metabolism: Does not undergo hepatic metabolism
ces; adjust dose to avoid dehydration. Half-life elimination: Normal renal function: 6 to 9 hours;
In cirrhosis, avoid electrolyte and’ acid/base imbalances Renal impairment (CrCl <50 mL/minute): 21 to 144 hours
that might lead to hepatic encephalopathy. If possible, (George 1980)
avoid use in patients with diabetes mellitus; if cannot be Time to peak, serum: 3 to 4 hours
avoided, use with extreme caution and monitor electro- Excretion: Urine (~50%; as unchanged drug);
lytes and renal function closely. Discontinue amiloride at feces (~40%)
least 3 days prior to glucose tolerance testing. Use with Dosing
caution in patients who are at risk for metabolic or respi- Pediatric
ratory acidosis (eg, cardiopulmonary disease, poorly con- Hypertension: Limited data available: Children and
trolled diabetes); monitor acid base balance frequently.
Adolescents: Oral: Initial: 0.4 to 0.625 mg/kg/dose
Amiloride is primarily eliminated renally; patients with
once daily; maximum daily dose: 20 mg/day (NHBPEP
renal impairment are at greater risk for toxicities. Avoid
use of diuretics for treatment of elevated blood pressure in 2004; NHLBI 2011)
patients with primary adrenal insufficiency (Addison dis- Edema: Limited data available: Children and Adoles-
ease). Adjustment of glucocorticoid/mineralocorticoid ther- cents: Oral: 0.625 mg/kg/day divided every 12 to 24
apy and/or use of other antihypertensive agents is hours; maximum daily dose: 20 mg/day (Van der
preferred to treat hypertension (Bornstein 2016; Vorst 2006)
Inder 2015). Nephrogenic diabetes insipidus, congenital: Limited
Potentially significant drug-drug interactions may exist, data available: Infants, Children, and Adolescents:
requiring dose or frequency adjustment, additional mon- Oral: 0.3 mg/kg/day in divided doses 3 times daily or
itoring, and/or selection of alternative therapy. 20 mg/1.73 m2/day in combination with hydrochloro-
Adverse Reactions thiazide; dosing based on a retrospective descriptive
Central nervous system: Dizziness, fatigue, headache analysis (n=30, age range: 1 month to 40 years), two
Endocrine & metabolic: Dehydration, gynecomastia, pediatric case series (n=4 and n=5), and a case report.
hyperchloremic metabolic acidosis, hyperkalemia, hypo- (Kirchlechner 1999; Kliegman 2016; Knoers 1990;
natremia Uyeki 1993; Van Lieburg 1999)
Gastrointestinal: Abdominal pain, change in appetite, con- Hepatic Impairment: Pediatric There are no dosage
stipation, diarrhea, gas pain, nausea, vomiting
adjustments provided in the manufacturer's labeling; use
Genitourinary: Impotence ‘ om f
with caution.
Neuromuscular & skeletal: Muscle cramps, weakness
Respiratory: Cough, dyspnea Administration Oral: Administer with food or milk
Rare but important or life-threatening: Bladder spasm, Monitoring Parameters Serum potassium, sodium, cre-
cardiac arrhythmia, chest pain, dysuria, gastrointestinal atinine, BUN, blood pressure, fluid balance
hemorrhage, increased intraocular pressure, jaundice, Test Interactions May lead to false-negative aldosterone/
orthostatic hypotension, palpitations, polyuria renin ratio (ARR) (Funder 2016)
Drug Interactions Dosage Forms Excipient information presented when
Metabolism/Transport Effects Substrate of OCT2 available (limited, particularly for generics); consult spe-
Avoid Concomitant Use cific product labeling.
Avoid concomitant use of AMILoride with any of the Tablet, Oral, as hydrochloride:
following: Bromperidol; CycloSPORINE (Systemic); Spi-
Generic: 5 mg
ronolactone; Tacrolimus (Systemic)
Extemporaneous Preparations A 1 mg/mL oral sus-
Increased Effect/Toxicity
AMlLoride may increase the levels/effects of: Amifostine; pension may be made with tablets. Crush ten 5 mg tablets
Ammonium Chloride; Angiotensin-Converting Enzyme in a mortar and reduce to a fine powder. Add small
Inhibitors; Antipsychotic Agents (Second Generation proportions up to 20 mL of Glycerin BP or Glycerin, USP
[Atypical]); Bromperidol; Cardiac Glycosides; Cyclo- and mix to uniform paste; mix while adding sterile water in
SPORINE (Systemic); Dofetilide; DULoxetine; Hypoten- incremental proportions to almost 50 mL; transfer to a
sion-Associated Agents; Levodopa; Nitroprusside; calibrated bottle, rinse mortar with sterile water, and add
Pholcodine; Sodium Phosphates; Spironolactone; Tacro- quantity of sterile water sufficient to make 50 mL. Label
limus (Systemic) "shake well" and "refrigerate". Stable for 21 days.
The levels/effects of AMiLoride may be increased by: Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
Alfuzosin; Angiotensin || Receptor Blockers; Barbitu-
rates; Benperidol; Brigatinib; Brimonidine (Topical); @ Amiloride HCI see AMiLoride on page 108
BuPROPion; Canagliflozin; Diacerein; Diazoxide; Dro-
spirenone; Eplerenone; Heparin; Heparins (Low Molec- @ Amiloride Hydrochloride see AMILoride on page 108
ular Weight); Herbs (Hypotensive Properties); @ 2-Amino-6-Mercaptopurine see Thioguanine
Lormetazepam; Molsidomine; Naftopidil; Nicergoline; on page 1937
Nicorandil; Nonsteroidal Anti-Inflammatory Agents; Obi-
@ 2-Amino-6-Methoxypurine Arabinoside see Nelara-
nutuzumab; Opioid Analgesics; Pentoxifylline; Phospho-
diesterase 5 Inhibitors; Potassium Salts; Prostacyclin bine on page 1430
Analogues; Quinagolide; Tolvaptan @ Aminobenzylpenicillin see Ampicillin on page 142

109
AMINOCAPROIC ACID

Drug Interactions
Aminocaproic Acid (a mee noe ka PROE ik AS id) Metabolism/Transport Effects None known.
Avoid Concomitant Use
Medication Safety Issues
Avoid concomitant use of Aminocaproic Acid with any of
Sound-alike/look-alike issues:
the following: Anti-inhibitor Coagulant Complex
Amicar may be confused with amikacin, Amikin
(Human); Factor IX Complex (Human) [(Factors II, IX, X)]
International issues:
Amicar [US] may be confused with Omacor brand name Increased Effect/Toxicity
for Omega-3-Acid Ethyl Esters [multiple international Aminocaproic Acid may increase the levels/effects of:
markets] Anti-inhibitor Coagulant Complex (Human); Factor IX
Brand Names: US Amicar Complex (Human) [(Factors Il, IX, X)]
Therapeutic Category Hemostatic Agent The levels/effects of Aminocaproic Acid may be
Generic Availability (US) Yes increased by: Tretinoin (Systemic) ’
Use To enhance hemostasis when fibrinolysis contributes Decreased Effect There are no known significant inter-
to bleeding (causes may include cardiac surgery, hema- actions involving a decrease in effect.
tologic disorders, neoplastic disorders, abruptio placen- Storage/Stability Store intact vials, tablets, and syrup at
tae, hepatic cirrhosis, and urinary fibrinolysis) (FDA 15°C to 30°C (59°F to 86°F). Do not freeze injection or
approved in adults); has also been used for traumatic syrup. Solutions diluted for IV use in D5W or NS to
hyphema, prevention of perioperative bleeding, refractory concentrations of 10-100 mg/mL are stable at 4°C
hematuria, and. prevention of bleeding associated with
(39°F) and_23°C (73°F) for 7 days (Zhang, 1997).
ECMO in high-risk patients
Mechanism of Action Binds competitively to plasmino-
Pregnancy Risk Factor C :
gen; blocking the binding of plasminogen to fibrin and the
Pregnancy Considerations Animal reproduction studies
subsequent conversion to plasmin, resulting in inhibition of
have not been conducted.
fibrin degradation (fibrinolysis).
Breastfeeding Considerations It is not known if amino-
Pharmacodynamics/Kinetics (Adult data unless
caproic acid is excreted in breast milk. The manufacturer
recommends that caution be exercised when administer- noted)
ing aminocaproic acid to nursing women Onset of action: ~1 to 72 hours
Contraindications Disseminated intravascular coagula- Distribution: Widely through intravascular and extravascu-
tion (without heparin); evidence of an active intravascular lar compartments; Vg: Oral: 23 L; IV: 30 L
clotting process Metabolism: Minimally hepatic
Warnings/Precautions Avoid rapid !V administration Bioavailability: Oral: 100%
(may induce hypotension, bradycardia, or arrhythmia); Half-life elimination: 1 to 2 hours
rapid injection of undiluted solution is not recommended. Time to peak: Oral: 1.2 + 0.45 hours
Use with caution in patients with renal disease; amino- Excretion: Urine (65% as unchanged drug, 11% as metab-
caproic acid may accumulate in patients with decreased olite)
renal function. Intrarenal obstruction may occur secondary Dosing
to glomerular capillary thrombosis or clots in the renal Neonatal
pelvis and ureters. Do not use in hematuria of upper Prevention of bleeding associated with extracorpor-
urinary tract origin unless possible benefits outweigh risks. eal membrane oxygenation (ECMO), high-bleeding
Do not administer without a definite diagnosis of labora- risk patients: Limited data available: IV: 100 mg/kg
tory findings indicative of hyperfibrinolysis. Inhibition of prior to or immediately after cannulation, followed by
fibrinolysis may promote clotting or thrombosis; more 25-30 mg/kg/hour for up to 72 hours; target activated
likely due to the presence of DIC. Skeletal muscle weak- clotting time (ACT) range during therapy of 180-200
ness ranging from mild myalgias and fatigue to severe seconds has been used (Downard, 2003; Horwitz,
myopathy with rhabdomyolysis and acute renal failure has 1998; Wilson, 1993); variable results; patients requiring
been reported with prolonged use. Monitor CPK; discon- surgery just prior to or while on ECMO seem to benefit
tinue treatment with a rise in CPK. Do not administer with most
factor IX complex concentrates or anti-inhibitor coagulant Prevention of perioperative bleeding associated with
complexes; may increase risk for thrombosis. cardiac surgery: Limited data available: IV: 75 mg/kg
Benzyl alcohol and derivatives: Some dosage forms may administered at the beginning and end of cardiopulmo-
contain benzyl alcohol; large amounts of benzyl alcohol nary bypass, along with 75 mg/100 mL added to the
(299 mg/kg/day) have been associated with a potentially priming fluid for cardiopulmonary bypass (Martin, 2011)
fatal toxicity ("gasping syndrome") in neonates; the "gasp- Pediatric
ing syndrome" consists of metabolic acidosis, respiratory Control of hemorrhage (oral, epistaxis, menorrha-
distress, gasping respirations, CNS dysfunction (including gia) in hemophilic patients, adjunct treatment:
convulsions, intracranial hemorrhage), hypotension and Limited data available: Infants, Children, and Adoles-
cardiovascular collapse (AAP ["Inactive" 1997]; CDC, cents: Oral: 50-100 mg/kg/dose every 6 hours; max-
1982); some data suggests that benzoate displaces bilir- imum daily dose: 24 g/day (Acharya, 2011)
ubin from protein binding sites (Ahlfors, 2001); avoid or Control of mucosal bleeding in thrombocytopenia/
use dosage forms containing benzyl alcohol with caution platelet dysfunction: Limited data available: Infants,
in neonates. See manufacturer’s labeling. Children, and Adolescents: Oral, IV: 50-100 mg/kg/
Adverse Reactions dose every 6 hours; maximum daily dose: 24 g/day
Cardiovascular: Arrhythmia, bradycardia, edema, hypo- (Bussel, 2011; Lipton, 2011)
tension, intracranial hypertension, peripheral ischemia, Hematuria (gross; upper tract), refractory: Limited
syncope, thrombosis data available: Children 211 years and Adolescents:
Central nervous system: Confusion, delirium, dizziness, Oral: 100 mg/kg/dose every 6 hours; continue for 2
fatigue, hallucinations, headache, malaise, seizure, days beyond resolution of hematuria; dosing based
stroke
on case series (n=4) which showed hematuria reso-
Dermatologic: Rash, pruritus lution within 2-7 days; risks and benefits must be
Gastrointestinal: Abdominal pain, anorexia, cramps, diar-
weighed prior to use (Kaye, 2010)
rhea, Gl irritation, nausea, vomiting
Prevention of bleeding associated with dental pro-
Genitourinary: Dry ejaculation
cedures in hemophilic patients: Limited. data avail-
Hematologic: Agranulocytosis, bleeding time increased,
able: Infants, Children, and Adolescents: Oral:
leukopenia, thrombocytopenia
50-100 mg/kg/dose every 6 hours; maximum daily
Loeal: Injection site necrosis, injection site pain, injection
dose: 24 g/day; used in conjunction with DDAVP or
site reactions
Neuromuscular & skeletal: CPK increased, myalgia, myo- factor replacement therapy; continue for up to 7 days
sitis, myopathy, rhabdomyolysis (rare), weakness or until mucosal healing is complete (Acharya, 2011)
Ophthalmic: Vision decreased, watery eyes Prevention of bleeding associated with extracor-
Otic: Tinnitus poreal membrane oxygenation (ECMO), high-
Renal: BUN increased, intrarenal obstruction (glomerular bleeding risk patients: Limited data available:
capillary thrombosis), myoglobinuria (rare), renal fail- Infants, Children, and Adolescents: IV: 100 mg/kg
ure (rare) prior to or immediately after cannulation, followed by
Respiratory: Dyspnea, nasal congestion, pulmonary 25-30 mg/kg/hour for up to 72 hours; target activated
embolism clotting time (ACT) range during therapy of 180-200
Miscellaneous: Allergic reaction, anaphylactoid reaction, seconds has been used (Downard, 2003; Horwitz,
anaphylaxis 1998; Wilson, 1993); variable results; patients requir-
Rare but important or life-threatening: Hepatic lesion, ing surgery just prior to or while on ECMO seem to
hyperkalemia, myocardial lesion benefit most

110
 AMINOPHYLLINE

Prevention of perioperative bleeding associated Use Treatment of symptoms and reversible airflow obstruc-
with cardiac surgery: Limited data available: tion associated with asthma, COPD, or other chronic lung
Infants and Children <2 years: Dosing regimens var- diseases [FDA approved in pediatric patients (age not
iable: IV: In the largest trial (n=120, all patients <20 specified) and adults]; has also been used for treatment
kg), a dose of 75 mg/kg was administered at the of apnea of prematurity and to increase diaphragmatic
beginning and end of cardiopulmonary bypass contractility
(CPB), and 75 mg/100 mL was added to the CPB Pregnancy Risk Factor C
priming fluid (Martin, 2011a). Another study group in Pregnancy Considerations Adverse events were
two separate trials (n=110, age range: 2 months to observed in some animal reproduction studies. Theophyl-
14 years) used a 100 mg/kg dose after induction, line crosses the placenta. Refer to Theophylline mono-
graph for additional information.
during CPB pump priming, and when weaning CPB
(over 3 hours) for a total of three doses (Chauhan, Breastfeeding Considerations Theophylline is present
in breast milk. Refer to Theophylline monograph for addi-
2000; Chauhan, 2004).
tional information.
Children 22 years and Adolescents: IV: 100 mg/kg
Contraindications
after induction, during CPB pump priming, and when
Hypersensitivity to aminophylline, theophylline, ethylene-
weaning CPB (over 3 hours) for a total of 3 doses; diamine, or any component of the formulation.
regimen used in two separate trials (n=110, age Canadian labeling: Additional contraindications (not in US
range: 2 months to 14 years) (Chauhan, 2000; labeling): Coronary artery disease where cardiac stim-
Chauhan, 2004) ulation might prove harmful; peptic ulcer disease.
Prevention of perioperative bleeding associated Warnings/Precautions Severe and potentially fatal the-
with spinal surgery (eg, idiopathic scoliosis): Lim- ophylline toxicity may occur if reduced theophylline clear-
ited data available: Children 211 years and Adoles- ance occurs. Theophylline clearance may be decreased in
cents: IV: 100 mg/kg (maximum dose: 5 g) patients with acute pulmonary edema, heart failure, cor
administered over 15-20 minutes after induction, fol- pulmonale, fever (2102°F for 224 hours or lesser temper-
lowed by a continuous IV infusion of 10 mg/kg/hour ature elevations for longer periods), hepatic disease,
for the remainder of the surgery; discontinued at time acute hepatitis, cirrhosis, hypothyroidism, sepsis with
of wound closure (Florentino-Pineda, 2001; Floren- multiorgan failure, shock, neonates (term and premature),
tino-Pineda, 2004) infants <3 months of age with decreased renal function,
Traumatic hyphema: Limited data available: Infants, infants <1 year, elderly >60 years, and patients following
Children, and Adolescents: Oral: 50-100 mg/kg/dose cessation of smoking. Consider benefits versus risks and
the need for more intensive monitoring in these patients;
every 4 hours for 5 days; maximum daily dose: 30 g/
reduced infusion rate required. If a patient develops signs
day (Brandt, 2001; Crouch, 1999; Teboul, 1995)
and symptoms of theophylline toxicity (eg, nausea or
Renal Impairment: Pediatric There are no dosage persistent, repetitive vomiting), a serum theophylline level
adjustments are provided in the manufacturer's labeling,
should be measured immediately and subsequent doses
but aminocaproic acid may accumulate in patients with withheld. Use with caution in patients with cardiac arrhyth-
decreased renal function; use with caution. mias (excluding bradyarrhythmias); use may exacerbate
Hepatic Impairment: Pediatric There are no dosage arrhythmias. Use with caution in patients with hepatic
adjustments are provided in the manufacturer's labeling impairment (eg, cirrhosis, acute hepatitis, cholestasis);
(has not been studied). risk of severe and potentially fatal theophylline toxicity is
Preparation for Administration Parenteral: Dilute IV increased. Theophylline clearance is decreased 250% or
solution in D5W, NS, or LR to a maximum concentration more in these patients. Dose reduction and frequent
of 20 mg/mL. monitoring of serum theophylline concentrations are
Administration required. Use with caution in patients with active peptic
Oral: May, administer without regard to food ulcer disease or seizure disorders; use may exacerbate
Parenteral: Do not administer undiluted; rapid IV injection these conditions.
(IVP) of undiluted solution is not recommended due to Use extreme caution in the elderly; these patients are at
possible hypotension, bradycardia, and arrhythmia. greater risk of serious theophylline toxicity Select dose
Intermittent IV infusion: After further dilution, administer with caution and with frequent monitoring of concentra-
over 15 to 60 minutes (rate dependent upon use). tions (especially <1 year); rate of clearance is highly
Continuous IV infusion: Must further dilute prior to admin- variable in these patients. Do not increase dose in
istration. response to acute exacerbation of symptoms unless
Monitoring Parameters Fibrinogen, fibrin split products, steady state serum theophylline concentration is <10
serum creatinine kinase (long-term therapy); serum potas- mceg/mL. As the rate of theophylline clearance may be
dose-dependent, an increase in dose based upon a sub-
sium, BUN, creatinine
therapeutic serum concentration measurement should be
Reference Range Therapeutic concentration: >130
limited to ~25% increase of the previous infusion rate or
meg/mL (concentration necessary for inhibition of fibrinol- daily dose. Vesicant; ensure proper catheter or needle
ysis) position prior to and during infusion; avoid extravasation.
Dosage Forms Excipient information presented when Potentially significant interactions may exist, requiring
available (limited, particularly for generics); consult spe- dose or frequency adjustment, additional monitoring,
cific product labeling. [DSC] = Discontinued product and/or selection of alternative therapy.
Solution, Intravenous: Adverse Reactions Adverse events observed at thera-
Generic: 250 mg/mL (20 mL) peutic serum levels:
Solution, Oral: Central nervous system: Headache, insomnia, irritability,
Amicar: 25% (236.5 mL) [contains edetate disodium, restlessness, seizure
methylparaben, propylparaben, saccharin sodium; Dermatologic: Allergic skin reaction, exfoliative dermatitis
raspberry flavor] Gastrointestinal: Diarrhea, nausea, vomiting
Syrup, Oral: Genitourinary: Diuresis (transient)
Amicar: 25% (473 mL [DSC]) Neuromuscular & skeletal: Tremor
Generic: 25% (237 mL [DSC], 473 mL [DSC}) Drug Interactions
Tablet, Oral: Metabolism/Transport Effects Substrate of CYP1A2
Amicar: 500 mg [scored] (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1
Amicar: 1000 mg [DSC] (minor), CYP3A4 (minor); Note: Assignment of Major/
Minor substrate status based on clinically relevant drug
Amicar: 1000 mg [scored] -
interaction potential
Generic: 500 mg [DSC], 1000 mg [DSC]
Avoid Concomitant Use
Avoid concomitant use of Aminophylline with any of the
Aminophylline (am in oF Fi lin) following: Acebrophylline; Doxofylline; lobenguane | 123;
Riociguat
Medication Safety Issues Increased Effect/Toxicity
Sound-alike/look-alike issues: Aminophylline may increase the levels/effects of: Dox-
Aminophylline may be confused with amitriptyline, ampi- ofylline; Formoterol; Indacaterol; lohexol; lomeprol; lopa-
cillin js midol; Olodaterol; Pancuronium; Riociguat;
Related Information Sympathomimetics
Theophylline on page 1933 The levels/effects of Aminophylline may be increased by:
Brand Names: Canada Aminophylline Injection Abiraterone Acetate; Acebrophylline; Alcohol (Ethyl);
Therapeutic Category Antiasthmatic; Bronchodilator; Allopurinol; Antithyroid Agents; AtoMOXetine; BuPRO-
Respiratory Stimulant; Theophylline Derivative Pion; Cannabinoid-Containing Products; Cimetidine;
Generic Availability (US) Yes Cocaine (Topical); CYP1A2 Inhibitors (Moderate);
AMINOPHYLLINE

Deferasirox; Disulfiram; Estrogen Derivatives; Febuxo- Excretion: Theophylline: Urine (~50% as unchanged drug
stat; Fluconazole; FluvoxaMINE; Guanethidine; Interfer- [Neonates]; ~10% as unchanged drug [Infants >3
ons; Isoniazid; Linezolid; Macrolide Antibiotics; months, Adolescents, and Adults])
Methotrexate; Mexiletine; Obeticholic Acid; Pefloxacin; Pharmacodynamics/Kinetics: Additional Consider-
Peginterferon Alfa-2b; Pentoxifylline; Propafenone; Qui- ations
NINE; Quinolones; Tedizolid; Thiabendazole; Ticlopi- Renal function impairment: Clearance is decreased in
dine; Vemurafenib; Zafirlukast; Zileuton infants <3 months with decreased renal function.
Decreased Effect Hepatic function impairment: Clearance is decreased by
Aminophylline may decrease the levels/effects of: 250% in patients with hepatic impairment (eg, cirrhosis,
Adenosine; Benzodiazepines; CarBAMazepine; Fosphe- acute hepatitis, cholestasis).
nytoin; lobenguane | 123; Lithium; Pancuronium; Phe- Pediatric: Clearance is very low in neonates and reaches
nytoin; Regadenoson; Thiopental; Zafirlukast max values by 1 year of age, remains relatively constant
until about 9 years of age, and then slowly decreases by
The levels/effects of Aminophylline may be decreased
approximately 50% to adult values at about 16 years of
by: Adalimumab; Barbiturates; Beta-Blockers (Beta1
age. Renal excretion of unchanged theophylline in neo-
Selective); Beta-Blockers (Nonselective); Cannabis;
nates amounts to about 50% of the dose, compared to
CarBAMazepine; CYP1A2 Inducers (Moderate); Cypro- about 10% in children older than three months and in
terone; Fosphenytoin; Isoproterenol; Phenytoin; Pro-
adults.
tease Inhibitors; Sulfinpyrazone; Teriflunomide; Thyroid
Geriatric: Clearance is decreased by an average of 30% in
Products
patients >60 years.
Food Interactions Gender: Significant reduction in theophylline clearance
Ethanol: Ethanol may decrease theophylline clearance. has been reported in women on the 20th day of the
Management: Avoid or limit ethanol. menstrual cycle and during the third trimester of preg-
Food: Theophylline clearance is increased and half-life nancy.
decreased by low carbohydrate/high protein diets, Smoking: Clearance is increased by smoking (ie, mari-
parenteral nutrition, and daily consumption of charcoal- juana or tobacco) by ~50% in young adult and ~80% in
broiled beef; a high carbohydrate/low protein diet can elderly tobacco smokers. Cessation of smoking for 1
decrease the clearance and prolong the half-life of week causes a reduction in theophylline clearance
theophylline. Management: Avoid extremes of dietary by ~40%.
protein and carbohydrate intake. Dosing
Storage/Stability Store at 20°C to 25°C (68°F to 77°F) in Neonatal Note: All dosages expressed as aminophylline;
original carton. Protect from light. Do not use if discolored dose should be individualized based on serum concen-
or if crystals are present. trations. Due to longer half-life than older patients, the
Mechanism of Action Theophylline has two distinct time to achieve steady-state serum concentration is
actions; smooth muscle relaxation (ie, bronchodilation) prolonged in neonates (see theophylline half-life); obtain
and suppression of the response of the airways to stimuli serum theophylline concentration after 48 to 72 hours of
(ie, non-bronchodilator prophylactic effects). Bronchodila- therapy (usually 72 hours in neonates); repeat values
tion is mediated by inhibition of two isoenzymes, phos- should be obtained 3 days after each change in dosage
phodiesterase (PDE III and, to a lesser extent, PDE IV) or weekly if on a stabilized dosage. If renal function
while non-bronchodilation effects are mediated through decreased, consider dose reduction and additional mon-
other molecular mechanisms. Theophylline increases the itoring.
force of contraction of diaphragmatic muscles through Apnea of prematurity: IV:
enhancement of calcium uptake through adenosine-medi- Manufacturer's labeling:
ated channels. Loading dose: 5.7 mg/kg/dose
Pharmacodynamics/Kinetics (Adult data unless Maintenance:
noted) PNA $24 days: 1.27 mg/kg/dose every 12 hours to
Theophylline: achieve a target concentration of 7.5 mcg/mL
Distribution: Theophylline: ~0.45 L/kg based on ideal body PNA >24 days: 1.9 mg/kg/dose every 12 hours to
weight; distributes poorly into body fat; Vy may increase achieve a target concentration of 7.5 mcg/mL
in premature neonates, hepatic cirrhosis, acidemia Alternate dosing:
(uncorrected), elderly, and third trimester of pregnancy. Loading dose: 5 to 8 mg/kg/dose; in a prospective
Protein binding: Theophylline: ~40%, primarily to albumin; randomized controlled trial of 61 neonates (birth
decreased in neonates (due to a greater percentage of weight: <1,500 g), a loading dose of 8 mg/kg/dose
fetal albumin), hepatic cirrhosis, acidemia (uncorrected), achieved targeted theophylline serum concentra-
elderly, third trimester of pregnancy. tions in more patients compared to a loading dose
Metabolism: Theophylline: Hepatic via demethylation of 6 mg/kg/dose (Hochwald 2002)
(CYP 1A2) and hydroxylation (CYP 2E1 and 3A4); forms Maintenance: Initial: 2 to 6 mg/kg/day divided every 8
active metabolites (caffeine and 3-methylxanthine) to 12 hours (Bhatt-Mehta 2003; Hochwald 2002);
Half-life elimination: Theophylline: Highly variable and increased dosages may be indicated as liver metab-
dependent upon age, hepatic function, cardiac function, olism increases; monitor serum concentrations to
lung disease, and smoking history determine appropriate dosages
Premature infants, postnatal age 3 to 15 days: 30 hours Dosing adjustment in renal impairment: Dose reduc-
(range: 17 to 43 hours) tion and frequent monitoring of serum theophylline
Premature infants, postnatal age 25 to 57 days: 20 hours concentrations are required in neonates with
(range: 9.4 to 30.6 hours) decreased renal function; 50% of dose is excreted
Term infants, postnatal age 1 to 2 days: 25.7 hours unchanged in the urine of neonates.
(range: 25 to 26.5 hours) Pediatric Note: All dosages expressed as aminophyl-
Term infants, postnatal age 3 to 30 weeks: 11 hours line; use ideal body weight to calculate dose; adjust
(range: 6 to 29 hours) dose based on steady-state serum concentrations.
Children 1 to 4 years: 3.4 hours (range: 1.2 to 5.6 hours) Obstructive airway disease, acute symptoms:
Children and Adolescents 6 to 17 years: 3.7 hours Infants, Children, and Adolescents: Note: Not recom-
(range: 1.5 to 5.9 hours) mended for the treatment of asthma exacerbations
Adults 218 years to <60 years (asthma, nonsmoking, (GINA 2016; NAEPP 2007).
otherwise healthy): 8.7 hours (range: 6.1 to 12.8 hours) Loading dose: \V:
Elderly >60 years (nonsmoking, healthy): 9.8 hours Patients not currently receiving aminophylline or
(range: 1.6 to 18 hours) theophylline: 5.7 mg/kg/dose
Clearance: Certain conditions may significantly alter theo- Patients currently receiving aminophylline or theo-
phylline clearance; severe and potentially fatal theophyl- phylline: A loading dose is not recommended with-
line toxicity may occur if reduced theophylline clearance out first obtaining a serum theophylline
occurs. concentration in patients who have received amino-
Decreased theophylline clearance: Neonates and phylline or theophylline within the past 24 hours. The
infants; elderly >60 years; acute pulmonary edema, loading dose should be calculated as follows:
cor pulmonale; fever (2102°F for 224 hours or lesser Dose = (C desired — C measured) (V4)
temperature elevations for longer periods); heart fail- C desired = desired serum theophylline concen-
ure; hepatic impairment (eg, cirrhosis, acute hepatitis, tration
cholestasis); hypothyroidism; patients following cessa- C measured = measured serum theophylline con-
tion of smoking; sepsis with multiple organ failure; centration
shock; third trimester of pregnancy. Maintenance dose: Continuous IV infusion: Note: Dos-
Increased theophylline clearance: Hyperthyroidism; ing presented is to achieve a target concentration of
cystic fibrosis; smoking (ie, marijuana or tobacco). 10 mcg/mL. Lower initial doses may be required in
Time to peak, serum: Within 30 minutes patients with reduced theophylline clearance. Dosage

112
 AMIODARONE

should be adjusted according to serum concentration Guidelines for Drawing Theophylline Serum
measurements during the first 12- to 24-hour period. Concentrations
Infants 4 to 6 weeks: 1.9 mg/kg/dose every 12 hours
Infants 6 to 52 weeks: Dose (mg/kg/hour) = [(0.008 X When to Obtain Sample“
age in weeks) + 0.21] divided by 0.79 30 min after end of 30-min
Children 1 to <9 years: 1.01 mg/kg/hour
Children 9 to <12 years: 0.89 mg/kg/hour A F A 12 to 24 h after initiation of
Adolescents 12 to <16 years (otherwise healthy, non-
smokers): 0.63 mg/kg/hour; maximum dose: The time to achieve steady-state serum concentration is prolonged in
patients with longer half-lives (eg, infants and adults with cardiac or liver
1,139 mg/day unless serum concentrations indicate failure; see theophylline half-life). In these patients, serum theophylline
need for larger dose concentrations should be drawn after 48 to 72 hours of therapy; may
need to obtain concentrations prior to steady-state to assess the
Adolescents 12 to <16 years (cigarette or marijuana patient's current progress or evaluate potential toxicity.
smokers): 0.89 mg/kg/hour
Adolescents 216 years (otherwise healthy, non- Test Interactions Plasma glucose, uric acid, free fatty
smokers): 0.51 mg/kg/hour; maximum dose: acids, total cholesterol, HDL, HDL/LDL ratio, and urinary
1,139 mg/day unless serum concentrations indicate free cortisol excretion may be increased by theophylline.
need for larger dose Theophylline may decrease triiodothyronine.
Cardiac decompensation, cor pulmonale, hepatic dys- Additional Information Theophylline dose is 79% of
function, sepsis with multiorgan failure, shock: aminophylline dose.
Infants, Children, and Adolescents: Initial: Each mg/kg of theophylline administered as a bolus will
0.25 mg/kg/hour; maximum dose: 507 mg/day increase the serum theophylline concentration by an
unless serum concentrations indicate need for larger average of 2 mcg/mL.
dose. Dosage Forms Excipient information presented when
Dosage adjustment based on serum theophylline available (limited, particularly for generics); consult spe-
concentrations: Infants, Children, and Adolescents: cific product labeling.
Note: Recheck serum theophylline concentrations in Solution, Intravenous, as dihydrate:
12 hours (ages 1 month to <16 years) or 24 hours Generic: 25 mg/mL (10 mL, 20 mL)
(ages 216 years) after IV dose; adjust dose based on
the following serum concentration results: @ Aminophylline Injection (Can) see Aminophylline
<9.9 mcg/mL: If tolerated, but symptoms remain, on page 1171
increase dose by ~25%. Recheck serum theophylline @ 5-Aminosalicylic Acid see Mesalamine on page 1313
concentrations.
10 to 14.9 mcg/mL: Maintain dosage if tolerated and Amiodarone (a MEE oh da rone)
symptoms controlled. Recheck serum concentrations
at 24-hour intervals. If symptoms not controlled, con- Medication Safety Issues
sider additional medications for management. Sound-alike/look-alike issues:
15 to 19.9 mcg/mL: Consider 10% dose reduction to Amiodarone may be confused with amantadine, aMILor-
improve safety margin even if dose is tolerated. ide, inamrinone
20 to 24.9 mcg/mL: Decrease dose by ~25%. Recheck Cordarone may be confused with Cardura, Cordran
serum concentrations. High alert medication:
25 to 30 mcg/mL: Stop infusion for 12 hours (ages 1 The Institute for Safe Medication Practices (ISMP)
month to <16 years) or 24 hours (ages 216 years) and includes this medication (IV formulation) among its list
decrease subsequent doses by at least 25%. of drugs which have a heightened risk of causing
Recheck serum concentrations. significant patient harm when used in error.
>30 mcg/mL: Stop dosing and treat overdose; if Geriatric Patients: High-Risk Medication:
resumed, decrease subsequent doses by at least Beers Criteria: Amiodarone is identified in the Beers
50%. Recheck serum concentrations. Criteria as a potentially inappropriate medication to be
Renal Impairment: Pediatric avoided in patients 65 years and older as first-line
Infants 1 to 3 months: There are no specific dosage therapy for atrial fibrillation (unless patient has concom-
itant heart failure or substantial left ventricular hyper-
adjustments provided in the manufacturer’s labeling;
trophy) due to increased toxicities compared to other
consider dose reduction and frequent monitoring of
antiarrhythmics used in atrial fibrillation (Beers Criteria
serum theophylline concentrations.
[AGS 2015}).
Infants >3 months, Children, and Adolescents: No
International Issues:
adjustment necessary.
Amyben [brand name for amiodarone (Great Britain)]
Hepatic Impairment: Pediatric Infants, Children, and may be confused with Ambien [US, Argentina, Israel]
Adolescents: Initial: 0.25 mg/kg/hour; maximum dose: Related Information
507 mg/day unless serum concentrations indicate need
Adult ACLS Algorithms on page 2108
for larger dose. Use with caution and monitor serum
Pediatric ALS (PALS) Algorithms on page 2105
theophylline concentrations frequently.
Brand Names: US Cordarone [DSC]; Nexterone; Pacer-
Usual Infusion Concentrations: Pediatric IV infu- one
sion: 1 mg/mL
Brand Names: Canada Cordarone
Preparation for Administration Parenteral: May admin- Therapeutic Category Antiarrhythmic Agent, Class III
ister undiluted at 25 mg/mL (Klaus 1989) or may further
Generic Availability (US) Yes
dilute to a concentration of 21 mg/mL.
Use
Administration Parenteral: For !V administration only; IM
Oral: Management of life-threatening recurrent ventricular
use is not recommended; IM administration causes arrhythmias [eg, recurrent ventricular fibrillation (VF) or
intense pain. Loading doses should be administered over recurrent hemodynamically unstable ventricular tachy-
30 minutes; doses may be further diluted and infused over cardia (VT)] unresponsive to other therapy or in patients
20 to 30 minutes; maximum rate of infusion: 0.36 mg/kg/ intolerant to other therapy (FDA approved in adults)
minute and should not exceed 25 mg/minute IV: Initiation of management and prophylaxis of frequently
Vesicant; ensure proper needle or catheter placement recurrent VF and hemodynamically unstable VT unre-
prior to and during IV infusion. Avoid extravasation. If sponsive to other therapy; VF and VT in patients requir-
extravasation occurs, stop infusion immediately and dis- ing amiodarone who are not able to take oral therapy (All
connect (leave needle/cannula in place); gently aspirate indications: FDA approved in adults)
Note: Also has been used to treat supraventricular
extravasated solution (do NOT flush the line); initiate
arrhythmias unresponsive to other therapy. Amiodarone
hyaluronidase antidote; remove needle/cannula; apply
is recommended in the PALS guidelines for SVT (unre-
dry cold compresses (Hurst 2004; Reynolds 2014); ele-
sponsive to vagal maneuvers and adenosine). It is
vate extremity.
recommended in both the PALS and ACLS guidelines
Vesicant/Extravasation Risk Vesicant for cardiac arrest with pulseless VT or VF (unresponsive
Monitoring Parameters Serum theophylline concentra- to defibrillation, CPR, and vasopressor administration)
tions, heart rate, respiratory rate, number and severity of and control of hemodynamically-stable monomorphic VT
apnea spells (when used for apnea of prematurity); arterial or wide-complex tachycardia of uncertain origin. The
or capillary blood gases (if applicable); pulmonary function drug is also recommended in the ACLS guidelines for
tests. Monitor infusion site. re-entry SVT (unresponsive to vagal maneuvers and
Reference Range Therapeutic concentrations: adenosine); control of rapid ventricular rate due to con-
Asthma: 5 to 15 mcg/mL duction via an accessory pathway in pre-excited atrial
Apnea of prematurity: 6 to 12 mcg/mL; goal concentration arrhythmias; control of stable narrow-complex tachycar-
is reduced due to decreased protein binding and higher dia; and control of polymorphic VT with a normal QT
free fraction interval.

113
 AMIODARONE

€ Medication Guide Available Yes incidence, but pulmonary toxicity has been reported in
Pregnancy Considerations Adverse events have been patients treated with low doses. The lowest effective dose
observed in some animal reproduction studies. Amiodar- should be used as appropriate for the acuity/severity of the
one crosses the placenta (~10% to 50%) and may cause arrhythmia being treated. [US Boxed Warning (tablet)]:
fetal harm when administered to a pregnant woman. Liver toxicity is common, but usually mild with evi-
Reported risks include neonatal bradycardia, QT prolon- dence of only increased liver enzymes; severe liver
gation, and periodic ventricular extrasystoles; neonatal toxicity can occur and has been fatal in a few cases.
hypothyroidism (with or without goiter); neonatal hyper- Hepatic enzyme levels are frequently elevated in patients
thyroxinemia; neurodevelopmental abnormalities inde- exposed to amiodarone; most cases are asymptomatic. If
pendent of thyroid function; jerk nystagmus with increases >3x ULN (or 22x baseline in patients with
synchronous head titubation; fetal growth retardation; preexisting elevations), consider dose reduction or dis-
and/or premature birth. Oral or IV amiodarone should be continuation. Monitor hepatic enzymes regularly in
used in pregnant women only to treat arrhythmias refrac- patients on relatively high maintenance doses. Elevated
tory to other treatments or when other treatments are bilirubin levels have been reported have been reported in
contraindicated (Page [ACC/AHA/HRS 2015]; ESG/ patients administered IV amiodarone.
AEPC/DGesGM/ESC 2011). [US Boxed Warning (tablet)]: Amiodarone can exacer-
Breastfeeding Considerations Amiodarone and its bate arrhythmias, by making them more difficult to
active metabolite are excreted in breast milk. Breastfeed- tolerate or reverse; other types of arrhythmias have
ing may lead to significant infant exposure and potential occurred, including significant heart block, sinus bradycar-
toxicity. Due to the long half-life, amiodarone may be dia, new ventricular fibrillation, incessant ventricular tachy-
present in breast milk for several days following discontin- cardia, increased resistance to cardioversion, and
uation of maternal therapy (Hall 2003). The manufacturer polymorphic ventricular tachycardia associated with QTc
recommends that breastfeeding be discontinued if treat- prolongation (torsades de pointes [TdP]). Risk may be
ment is needed. increased with concomitant use of other antiarrhythmic
Contraindications agents or drugs that prolong the QTc interval. Proarrhyth-
Hypersensitivity to amiodarone, iodine, or any component mic effects may be prolonged. Amiodarone should not be
of the formulation; severe sinus-node dysfunction caus- used in patients with Wolff-Parkinson-White (WPW) syn-
ing marked sinus bradycardia; second- and third-degree drome and preexcited atrial fibrillation/flutter since ven-
heart block (except in patients with a functioning artificial tricular fibrillation may result (AHA/ACC/HRS
pacemaker); bradycardia causing syncope (except in [January 2014)).
patients with a functioning artificial pacemaker); cardio-
genic shock Monitor pacing or defibrillation thresholds in patients with
Note: The FDA-approved product labeling states amio- implantable cardiac devices (eg, pacemakers, defibrilla-
darone is contraindicated in patients with iodine hyper- tors). May cause hyper- or hypothyroidism; hyperthyroid-
sensitivity. This does not include most patients with ism may result in thyrotoxicosis (including fatalities) and/or
allergic reactions to shellfish or contrast media, which the possibility of arrhythmia breakthrough or aggravation.
are usually not due to iodine itself (Beall 2007, Brouse If any new signs of arrhythmia appear, consider the
2005, Lakshmanadoss 2012). However, exercise caution possibility of hyperthyroidism. Hypothyroidism (sometimes
in patients with severe allergies to shellfish or contrast severe) may be primary or subsequent to resolution of
media (Brouse 2005). preceding amiodarone-induced hyperthyroidism; myxe-
Canadian labeling (oral formulation): Additional contra- dema (may be fatal) has been reported. If hyper- or
indications (not in US labeling): Evidence of hepatitis; hypothyroidism occurs, reduce dose or discontinue amio-
pulmonary interstitial abnormalities; thyroid dysfunction darone. Thyroid nodules and/or thyroid cancer have also
Warnings/Precautions Note: Although the US Boxed been reported. Use caution in patients with thyroid dis-
Warnings pertain to the tablet prescribing information, ease; thyroid function should be monitored prior to treat-
these effects may also be seen with intravenous admin- ment and periodically thereafter, particularly in the elderly
istration depending on duration of use. and in patients with underlying thyroid dysfunction. In
acute myocardial infarction, beta-blocker therapy should
[US Boxed Warning (tablet)]: Only indicated for still be initiated even though concomitant amiodarone
patients with life-threatening arrhythmias because of therapy provides beta-blockade.
risk of substantial toxicity. Alternative therapies
should be tried first before using amiodarone.
Regular ophthalmic examination (including slit lamp and
Patients should be hospitalized when amiodarone is fundoscopy) is recommended. May cause optic neuro-
pathy and/or optic neuritis resulting in visual impairment
initiated. The 2015 ACLS guidelines recommend the
consideration of IV amiodarone as the preferred antiar-
(peripheral vision loss, changes in acuity) at any time
rhythmic for the treatment of pulseless VT/VF unrespon- during therapy; permanent blindness has occurred. If
symptoms of optic neuropathy and/or optic neuritis occur,
sive to CPR, defibrillation, and vasopressor therapy (AHA
prompt ophthalmic evaluation is recommended. If diag-
[Link 2015]). In patients with. non-life-threatening arrhyth-
mias (eg, atrial fibrillation), amiodarone should be used
nosis of optic neuropathy and/or optic neuritis is con-
firmed, reevaluate amiodarone therapy. Corneal
only if the use of other antiarrhythmics has proven inef-
microdeposits occur in a majority of adults and may cause
fective or are contraindicated.
visual disturbances in up to 10% of patients (blurred
[US Boxed Warning (tablet)]: Pulmonary toxicity vision, halos); asymptomatic microdeposits may be rever-
(hypersensitivity pneumonitis or interstitial/alveolar sible and are not generally considered a reason to dis-
pneumonitis and abnormal diffusion capacity without continue treatment. Corneal refractive laser surgery is
symptoms) may occur. Reports of acute-onset pulmo- generally contraindicated in amiodarone users (from man-
nary injury (pulmonary infiltrates and/or mass on X-ray, ufacturers of surgical devices).
pulmonary alveolar hemorrhage, pleural effusion, pulmo-
Peripheral neuropathy has been reported rarely with
nary fibrosis, bronchospasm, wheezing, fever, dyspnea,
chronic administration; may resolve when amiodarone is
cough, hemoptysis, hypoxia) have occurred; some cases
discontinued, but resolution may be slow and incomplete.
have progressed to respiratory failure and/or death. Fatal-
ities due to pulmonary toxicity occur in ~10% of cases; Amiodarone is a potent inhibitor of CYP enzymes and
most fatalities due to sudden cardiac death occurred when transport proteins (including p-glycoprotein), which may
amiodarone was discontinued; rule out other causes of lead to increased serum concentrations/toxicity of a num-
respiratory impairment before discontinuing amiodarone ber of medications. Particular caution must be used when
in patients with life-threatening arrhythmias; use extreme a drug with QTc-prolonging potential relies on metabolism
caution if dose is decreased or discontinued. If hyper- via these enzymes, since the effect of elevated concen-
sensitivity pneumonitis occurs, discontinue amiodarone trations may be additive with the effect of amiodarone.
and institute steroid therapy; if interstitial/alveolar pneu- Carefully assess risk:benefit of coadministration of other
monitis occurs, institute steroid therapy and reduce amio- drugs which may prolong QTc interval. Additional poten-
darone dose or preferably, discontinue. Some cases of tially significant interactions may exist, requiring dose or
interstitial/alveolar pneumonitis may resolve following dos- frequency adjustment, additional monitoring, and/or selec-
age reduction and steroid therapy; rechallenge at a lower tion of alternative therapy. Patients may still be at risk for
dose has not resulted in return of interstitial/alveolar amiodarone-related adverse reactions or drug interactions
pneumonitis in some patients; however, in some patients after the drug has been discontinued. The pharmacoki-
the pulmonary lesions have not been reversible. Educate netics are complex (due to prolonged duration of action
patients about monitoring for symptoms (eg, nonproduc- and half-life) and difficult to predict. Correct electrolyte
tive cough, dyspnea, pleuritic pain, hemoptysis, wheezing, disturbances, especially hypokalemia, hypomagnesemia,
weight loss, fever, malaise). Evaluate new respiratory or hypocalcemia, prior to use and throughout therapy. Use
symptoms; preexisting pulmonary disease does not caution when initiating amiodarone in patients on warfarin.
increase risk of developing pulmonary toxicity, but if Cases of increased INR with or without bleeding have
pulmonary toxicity develops then the prognosis is worse. occurred in patients treated with warfarin; monitor INR
Use of lower doses may be associated with a decreased closely after initiating amiodarone in these patients.

114
 AMIODARONE

May cause hypotension and bradycardia (infusion-rate dehydrogenase, increased serum alkaline phosphatase,
related). May cause life-threatening or fatal cutaneous increased serum creatinine, infusion site reaction
reactions, including Stevens-Johnson syndrome and toxic (including cellulitis, edema, erythema, extravasation pos-
epidermal necrolysis (TEN). If symptoms or signs (eg, sibly leading to venous/infusion site necrosis, granu-
progressive skin rash often with blisters or mucosal loma, hypoesthesia, induration, inflammation,
lesions) occur, immediately discontinue. During long-term intravascular amiodarone deposition/mass, pain, phlebi-
treatment, a blue-gray discoloration of exposed skin may tis, pigment changes, pruritus, skin sloughing, thrombo-
occur; risk increased in patients with fair complexion or phlebitis, thrombosis, urticaria), interstitial pneumonitis,
excessive sun exposure; may be related to cumulative jaundice, lupus-like syndrome, malignant neoplasm of
dose and duration of therapy. There has been limited skin, malignant neoplasm of thyroid, mass (pulmonary),
experience in patients receiving IV amiodarone for >3 muscle spasm, myasthenia, myopathy, myxedema
weeks. Some dosage forms may contain polysorbate 80 (including myxedema coma), neutropenia, optic neuro-
(also known as Tweens). Hypersensitivity reactions, usu- pathy, pancytopenia, pleural effusion, pleurisy, pruritus,
ally a delayed reaction, have been reported following pseudotumor cerebri, pulmonary alveolar hemorrhage,
exposure to pharmaceutical products containing polysor- pulmonary infiltrates, respiratory distress syndrome, res-
bate 80 in certain individuals (Isaksson, 2002; Lucente piratory failure, rhabdomyolysis, SIADH, sinoatrial arrest,
2000; Shelley 1995). Thrombocytopenia, ascites, pulmo- skin carcinoma, skin granuloma, skin rash, spontaneous
nary deterioration, and renal and hepatic failure have been ecchymoses, thyroid nodule, thyrotoxicosis, toxic epider-
reported in premature neonates after receiving parenteral mal necrolysis, urticaria, vasculitis, ventricular premature
products containing polysorbate 80 (Alade 1986; CDC contractions, visual field defect, wheezing, xerostomia
1984). See manufacturer's labeling. Drug Interactions
_ Use caution and close perioperative monitoring in surgical Metabolism/Transport Effects Substrate of CYP1A2
patients; may enhance myocardial depressant and con- (minor), CYP2C19 (minor), CYP2C8 (major), CYP2D6
duction effects of halogenated inhalational anesthetics; (minor), CYP3A4 (major), P-glycoprotein/ABCB1; Note:
adult respiratory distress syndrome (ARDS) has been Assignment of Major/Minor substrate status based on
reported postoperatively (fatal in rare cases). Hypotension Clinically relevant drug interaction potential; Inhibits
upon discontinuation of cardiopulmonary bypass during CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak),
open-heart surgery have been reported (rare); relationship OCT2, P-glycoprotein/ABCB1
to amiodarone is unknown. Commercially-prepared pre- Avoid Concomitant Use
mixed infusion contains the excipient cyclodextrin (sulfo- Avoid concomitant use of Amiodarone with any of the
butyl ether beta-cyclodextrin), which may accumulate in following: Agalsidase Alfa; Agalsidase Beta; Amifampri-
patients with renal insufficiency, although the clinical sig- dine; Aminolevulinic Acid (Systemic); Antiarrhythmic
nificance of this finding is uncertain (Luke 2010). May be a Agents (Class la); Azithromycin (Systemic); Bromperi-
vesicant; ensure proper needle or catheter placement dol; Ceritinib; Conivaptan; Daclatasvir; Fingolimod; Fusi-
prior to infusion; avoid extravasation. dic Acid (Systemic); Grapefruit Juice;
Adverse Reactions Hydroxychloroquine; Idelalisib; Indinavir; Lofepramine;
Cardiovascular: Asystole, atrial fibrillation, atrioventricular Lopinavir; Macimorelin; MiFEPRIStone; Mizolastine;
block, bradycardia, cardiac arrest, cardiac arrhythmia, Nelfinavir; PAZOPanib; Pimozide; Probucol; Promazine;
cardiac failure, cardiogenic shock, edema, exacerbation Propafenone; QTc-Prolonging Agents (Highest Risk);
of cardiac arrhythmia, flushing, hypotension (more com- QTc-Prolonging Agents (Moderate Risk); Ritonavir;
mon in intravenous; refractory in rare cases), nodal Saquinavir; Silodosin; Sofosbuvir; Tipranavir; Topotecan;
arrhythmia, prolonged Q-T interval on ECG (associated VinCRIStine (Liposomal); Vinflunine
with worsening arrhythmia), sinus bradycardia, sinus
Increased Effect/Toxicity
node dysfunction, torsades de pointes, ventricular fibril-
Amiodarone may increase the levels/effects of: Afatinib;
lation, ventricular tachycardia
Amifostine; Aminolevulinic Acid (Systemic); Aminolevu-
Central nervous system: Abnormal gait, altered sense of
linic Acid (Topical); Antiarrhythmic Agents (Class la);
smell, ataxia, dizziness (more common in oral), fatigue,
Antipsychotic Agents (Second Generation [Atypical]);
headache, insomnia, involuntary body movements,
AtorvaSTATin; Beta-Blockers; Betrixaban; Bilastine; Bra-
malaise, paresthesia, peripheral neuropathy, sleep dis-
dycardia-Causing Agents; Brentuximab Vedotin; Brom-
order
peridol; Cardiac Glycosides; Celiprolol; Ceritinib;
Dermatologic: Skin photosensitivity, solar dermatitis, Ste-
vens-Johnson syndrome Colchicine; CycloSPORINE (Systemic); Dabigatran
Endocrine & metabolic: Decreased libido, hyperthyroid- Etexilate; DOXOrubicin (Conventional); DULoxetine;
ism, hypothyroidism, phospholipidemia (pulmonary Edoxaban; Everolimus; Flecainide; Flibanserin; Fosphe-
phospholipidosis; more common in oral) nytoin; Hypotension-Associated Agents; Lacosamide;
Gastrointestinal: Abdominal pain, altered salivation, ano- Levodopa; Lidocaine (Systemic); Lidocaine (Topical);
rexia, constipation, diarrhea, dysgeusia, nausea (more Lomitapide; Loratadine; Lovastatin; Mipomersen; Nalde-
common in oral), vomiting (more common in oral) medine; Naloxegol; NiMODipine; Nitroprusside; PAZO-
Hematologic & oncologic: Blood coagulation disorder, Panib; Perhexiline; P-glycoprotein/ABCB1 Substrates;
thrombocytopenia Phenytoin; Pholcodine; Pimozide; Porfimer; Propafe-
Hepatic: Abnormal hepatic function tests, hepatic disease, none; Prucalopride; QTc-Prolonging Agents (Highest
increased serum ALT, increased serum AST Risk); Red Yeast Rice; RifAXIMin; Silodosin; Simvasta-
Neuromuscular & skeletal: Tremor tin; TiZANidine; Topotecan; Venetoclax; Verteporfin; Vin-
Ophthalmic: Blurred vision (more common in oral), corneal CRIStine (Liposomal); Vitamin K Antagonists
deposits, dry eye syndrome, optic neuritis, photophobia,
The levels/effects of Amiodarone may be increased by:
visual disturbance, visual halos around lights
Abiraterone Acetate; Amifampridine; Aprepitant; Ataza-
Renal: Renal insufficiency
navir; Azithromycin (Systemic); Barbiturates; Blood
Respiratory: Adult respiratory distress syndrome, hyper-
Pressure Lowering Agents; Boceprevir; Bretylium; Bri-
sensitivity pneumonitis, pneumonitis, pneumonitis
monidine (Topical); Buprenorphine; Calcium Channel
(alveolar), pulmonary edema, pulmonary fibrosis (more
Blockers (Nondihydropyridine); Cimetidine; Cobicistat;
common in oral), pulmonary toxicity (more common
Conivaptan; Cyclophosphamide; CYP2C8 Inhibitors
in oral)
(Moderate); CYP2C8 Inhibitors (Strong); CYP3A4 Inhib-
Miscellaneous: Fever
Rare but important or life-threatening: Acute pancreatitis, itors (Moderate); CYP3A4 Inhibitors (Strong); Daclatas-
vir; Darunavir; Deferasirox; Diazoxide; Fingolimod;
acute renal failure, agranulocytosis, alopecia, anaphy-
lactic shock, anaphylactoid reaction, anaphylaxis, FLUoxetine; Fosamprenavir; Fosaprepitant; Fosnetupi-
angioedema, aplastic anemia, back pain, blue-gray skin tant; Fosphenytoin; Fusidic Acid (Systemic); Grapefruit
pigmentation, bronchiolitis obliterans organizing pneu- Juice; Herbs (Hypotensive Properties); Hydroxychloro-
monia, bronchospasm, bullous dermatitis, cardiac con- quine; Idelalisib; Indapamide; Indinavir; Lidocaine (Top-
duction disturbance (including bundle branch block, ical); Lofepramine; Lopinavir; Lormetazepam;
infra-HIS block, and antegrade conduction via an acces- Macimorelin; MiFEPRIStone; Mizolastine; Molsidomine;
sory pathway), cholestasis, cholestatic hepatitis, confu- Naftopidil; Nelfinavir; Netupitant; Nicergoline; Nicorandil;
sion, cough, delirium, demyelinating disease Obinutuzumab; Ombitasvir, Paritaprevir, and Ritonavir;
(polyneuropathy), disorientation, DRESS syndrome, Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir; Pal-
drug-induced Parkinson disease, dyspnea, eczema, bociclib; Pefloxacin; Pentoxifylline; P-glycoprotein/
eosinophilic pneumonitis, epididymitis, epithelial kerat- ABCB1 Inhibitors; Phosphodiesterase 5 Inhibitors; Pro-
opathy (vortex, Chan 2015), erythema multiforme, exfo- bucol; Promazine; Prostacyclin Analogues; QTc-Pro-
liative dermatitis, fever, granulocytosis, hallucination, longing Agents (Indeterminate Risk and Risk
hemolytic anemia, hemoptysis, hepatic cirrhosis, hepatic Modifying); QTc-Prolonging Agents (Moderate Risk);
failure, hepatitis, hepatotoxicity (idiosyncratic) (Chala- Quinagolide; Ritonavir; Ruxolitinib; Saquinavir; Simepre-
sani 2014), hypoesthesia, hypotension, hypoxia, impo- vir; Sofosbuvir; Stiripentol; Telaprevir; Teneligliptin;
tence, increased intracranial pressure, increased lactate Tipranavir; Tofacitinib; Vinflunine; Xipamide

115
 AMIODARONE

| Decreased Effect
Amiodarone may decrease the levels/effects of: Agalsi-
Dosing
Neonatal
dase Alfa; Agalsidase Beta; Clopidogrel; Sodium lodide Supraventricular,tachycardia: Limited data available:
1131; Thyroid Products Oral: Loading dose: 10 to 20 mg/kg/day in 2 divided
doses for 7 to 10 days; dosage should then be reduced
The levels/effects of Amiodarone may be decreased by: to 5 to 10 mg/kg/day once daily and continued for 2 to 7
Bile Acid Sequestrants; Bosentan; Bromperidol; months; dosing based on a study of 50 infants (<9
CYP3A4 Inducers (Moderate); CYP3A4 Inducers months of age) and neonates (as young as 1 day of
(Strong); Dabrafenib; Deferasirox; Enzalutamide; Etra- life); Note: Patients who received a higher loading dose
virine; Fosphenytoin; Grapefruit Juice; Mitotane; Orlistat; (20 mg/kg/day) were more likely to have a prolongation
Phenytoin; Pitolisant; RifAMPin; Sarilumab; Siltuximab; of the corrected QT interval (Etheridge 2001).
St John's Wort; Tocilizumab Tachyarrhythmia, including junctional ectopic tachy-
Food Interactions Food increases the rate and extent of cardia (JET), paroxysmal supraventricular tachy-
absorption of amiodarone. Grapefruit juice increases bio- cardia (PSVT): Limited data available; the following
availability of oral amiodarone by 50% and decreases the dosing is based on studies that included neonates,
conversion of amiodarone to N-DEA (active metabolite); infants, and children.
altered effects are possible. Management: Take consis- Loading dose: IV: 5 mg/kg given over 60 minutes;
tently with regard to meals; grapefruit juice should be Note: Most studies used bolus infusion time of 60
avoided during therapy. minutesto avoid hypotension; may repeat initial load-
Storage/Stability ing dose to.a maximum total initial load: 10 mg/kg; do
Tablets: Store at 20°C to 25°C (68°F to 77°F); protect from not exceed total daily bolus of 15 mg/kg/day (Ether-
light. idge 2001; Figa 1994; Haas 2008; Raja 1994;
Injection: Store undiluted vials and premixed solutions Soult 1995).
(Nexterone) at 20°C to 25°C (68°F to 77°F); excursions Continuous IV infusion (if needed): Note: Reported
are permitted between 15°C and 30°C (59°F and 86°F). dosing units for regimens are variable (mcg/kg/minute
Protect from light during storage; protect from excessive and mg/kg/day); use caution to ensure appropriate
heat. There is no need to protect solutions from light dose and dosing units are used; taper infusion as
during administration. When vial contents are admixed in soon as Clinically possible and switch to oral therapy
D5W to a final concentration of 1-6 mg/mL, amiodarone ~ if necessary.
is stable for 24 hours in glass or polyolefin bottles and for Dosing based on mcg/kg/minute: Initial: 5 meg/kg/
2 hours in polyvinyl chloride (PVC) bags; do not use minute; increase incrementally as clinically needed;
evacuated glass containers as buffer may cause precip- usual required dose: 10 mcg/kg/minute; range: 5 to
itation. Nexterone is available as premixed solutions. 15 mcg/kg/minute (Figa 1994; Kovacikova 2009;
Although amiodarone adsorbs to PVC tubing, all clinical Lane 2010)
Dosing based on mg/kg/day: Initial: 10 mg/kg/day;
studies used PVC tubing and the recommended doses
increase incrementally as clinically needed; range:
account for adsorption; in adults, PVC tubing is recom-
10 to 20 mg/kg/day (Haas 2008; Lane 2010; Raja
mended. Discard any unused portions of premixed sol-
1994; Soult 1995)
utions.
Pediatric
Mechanism of Action Class III antiarrhythmic agent
Perfusing tachycardias: Infants, Children, and Ado-
which inhibits adrenergic stimulation (alpha- and beta-
lescents: IV, 1.0.: Loading dose: 5 mg/kg (maximum:
blocking properties), affects sodium, potassium, and cal-
300 mg/dose) over 20 to 60 minutes; may repeat
cium channels, prolongs the action potential and refrac-
twice up to maximum total dose of 15 mg/kg during
tory period in myocardial tissue; decreases AV conduction acute treatment (PALS [Kleinman 2010])
and sinus node function Shock refractory VF or pulseless VT: Infants, Chil-
Pharmacodynamics/Kinetics (Adult data unless dren, and Adolescents: IV, !.0.: 5 mg/kg (maximum:
noted) 300 mg/dose) rapid bolus; may repeat twice up to a
Onset of action: Oral: 2 days to 3 weeks; IV: (electro- maximum total dose of 15 mg/kg during acute treat-
physiologic effects) within hours; Antiarrhythmic effects: ment (PALS [de Caen 2015]; PALS [Kleinman 2010})
2 to 3 days to 1 to 3 weeks; mean onset of effect may be Tachyarrhythmia, including junctional ectopic
shorter in children vs adults and in patients receiving IV tachycardia (JET), paroxysmal supraventricular
loading doses tachycardia (PSVT): Limited data available: Infants,
Peak effect: 1 week to 5 months Children, and Adolescents:
Duration after discontinuing therapy: Variable, 2 weeks to Oral: Loading dose: 10 to 15 mg/kg/day in 1 to 2
months: Children: less than a few weeks; Adults: Several divided doses/day for 4 to 14 days or until adequate
months control of arrhythmia or prominent adverse effects
Note: Duration after discontinuation may be shorter in occur; dosage should then be reduced to 5 mg/kg/
children than adults day given once daily for several weeks; if arrhythmia
Absorption: Oral: Slow and variable does not recur, reduce to lowest effective dosage
Distribution: possible; usual daily minimal dose: 2.5 mg/kg/day;
IV: Rapid redistribution with a decrease to 10% of peak maintenance doses may be given for 5 of 7
values within 30 to 45 minutes after completion of days/week
infusion Note: For infants, some have suggested BSA-
IV single dose: Vgs,: Mean range: 40 to 84 L/kg directed dosing: Loading dose: 600 to 800 mg/
Oral: Vg: 66 L/kg (range: 18 to 148 L/kg) 1.73 m2/day in 1 to 2 divided doses (equivalent
Protein binding: >96% to 347 to 462 mg/m?/day); maintenance dose: 200
Metabolism: Hepatic via CYP2C8 and 3A4 to active N- to 400 mg/1.73 m?/day once daily (equivalent to
desethylamiodarone metabolite; possible enterohepatic 116 to 231 mg/m2/day) (Bucknall 1986; Coumel
recirculation 1980; Coumel 1983; Paul 1994)
Bioavailability: Oral: ~50% (range: 35% to 65%) Note: Prolongation of the corrected QT interval was
Half-life elimination: Note: Half-life is shortened in children more likely in infants <9 months of age who
vs adults received higher loading doses (20 mg/kg/day vs
Amiodarone: 10 mg/kg/day in 2 divided doses) (n=50; mean
age: 1 + 1.5 months) (Etheridge 2001)
Single dose: 58 days (range: 15 to 142 days)
IV: Loading dose: 5 mg/kg (maximum: 300 mg/dose)
Oral chronic therapy: Mean range: 40 to 55 days
given over 60 minutes; Note: Most studies used
(range: 26 to 107 days)
bolus infusion time of 60 minutes to avoid hypoten-
IV single dose: Mean range: 9 to 36 days
sion; may repeat initial loading dose to a maximum
N-desethylamiodarone (active metabolite):
total initial load: 10 mg/kg; do not exceed total daily
Single dose: 36 days (range: 14 to 75 days)
bolus of 15 mg/kg/day (Etheridge 2001; Figa 1994;
Oral chronic therapy: 61 days
Haas 2008; Raja 1994; Soult 1995)
IV single dose: Mean range: 9 to 30 days Note: Dividing the 5 mg/kg loading dose into
Time to peak, serum: Oral: 3 to 7 hours 1 mg/kg aliquots (each administered over 5 to 10
Excretion: Feces; urine (<1% as unchanged drug) minutes) has been used; an additional 1 to
Pharmacodynamics/Kinetics: Additional Consider- 5 mg/kg loading dose was given in the same
ations manner, if needed, after 30 minutes (Perry 1996)
Hepatic function impairment: After a single dose of amio- Continuous IV infusion (if needed); Note: Reported
darone injection in cirrhotic patients, C,pax was signifi- dosing units for regimens are variable (mcg/kg/
cantly lower and average concentration values were minute and mg/kg/day); use caution to ensure
seen for desethylamiodarone, but mean amiodarone appropriate dose and dosing units are used; taper
levels were unchanged. infusion as soon as Clinically possible and switch to
Geriatric: Clearance is lower and half-life is increased. oral therapy if necessary.

116
 AMITRIPTYLINE

Dosing based on meg/kg/minute: Initial: 5 meg/kg/ Neonates: Administer loading dose over 60 minutes;
minute; increase incrementally as clinically may be followed by continuous infusion (Figa 1994;
needed; usual required dose: 10 mcg/kg/minute; Haas 2008; Raja 1994)
range: 5 to 15 mcg/kg/minute; maximum daily Infants, Children, and Adolescents: Administer loading
dose: 2200 mg/day (Figa 1994; Kovacikova dose over 20 to 60 minutes (PALS [Kleinman 2010));
2009; Lane 2010) may be followed by continuous IV infusion
Dosing based on mg/kg/day: Initial: 10 mg/kg/day; Vesicant/Extravasation Risk May be a vesicant.
increase incrementally as clinically needed; range: Monitoring Parameters Heart rate and rhythm, blood
10 to 20 mg/kg/day; maximum daily dose: pressure, ECG, chest x-ray, pulmonary function tests,
2,200 mg/day (Lane 2010; Perry 1996; Raja thyroid function tests; serum glucose, electrolytes (espe-
1994; Soult 1995) cially potassium and magnesium), triglycerides, liver
Usual Infusion Concentrations: Pediatric Note: Pre- enzymes; ophthalmologic exams including fundoscopy
and slit-lamp examinations, physical signs and symptoms
mixed solutions available.
of thyroid dysfunction (lethargy, edema of hands and feet,
IV infusion: 1.8 mg/mL
weight gain or loss), and pulmonary toxicity (dyspnea,
Preparation for Administration IV: Perfusing arrhyth-
cough; oxygen saturation, blood gases). Monitor pacing
mias: Information based on adult data: Injection must be or defibrillation thresholds in patients with implantable
diluted before IV use. Maximum concentration for IV cardiac devices (eg, pacemakers, defibrillators) at initia-
infusion: 6 mg/mL. Increased phlebitis may occur with tion of therapy and periodically during treatment. Monitor
peripheral infusions >3 mg/mL in D5W, and concentra- infusion site.
tions $2.5 mg/mL may be less irritating. Solutions that will Reference Range Therapeutic: Chronic oral dosing: 1 to
infuse for >2 hours must be prepared in a non-PVC 2.5 mg/L (SI: 2 to 4 micromoles/L) (parent); desethyl|
-container (eg, glass or polyolefin). metabolite (active) is present in equal concentration to
Infants, Children, and Adolescents: No data available parent drug; serum concentrations may not be of great
regarding concentration for infusion; consider adult con- value for predicting toxicity and efficacy; toxicity may occur
centrations when diluting; commercially prepared pre- even at therapeutic concentrations
mixed solutions in concentrations of 1.5 mg/mL and Dosage Forms Considerations Vials for injection con-
1.8 mg/mL are available. tain benzyl alcohol which has been associated with "gasp-
Adults: Usual dilutions: First loading infusion: 150 mg in ing syndrome" in neonates. Commercially-prepared
100 mL D5W (1.5 mg/mL); then 900 mg in 500 mL DSW premixed solutions do not contain benzyl alcohol.
(1.8 mg/mL) to deliver rest of dose ; Dosage Forms Excipient information presented when
Administration available (limited, particularly for generics); consult spe-
Oral: Administer at same time in relation to meals; do not cific product labeling. [DSC] = Discontinued product
administer with grapefruit juice. In adults, may administer Solution, Intravenous, as hydrochloride:
in divided doses with meals if GI upset occurs or if taking Nexterone: 150 mg/100 mL in Dextrose (100 mL);
large daily dose. 360 mg/200 mL in Dextrose (200 mL)
IV: Adjust administration rate to patient's clinical condition Generic: 150 mg/3 mL (3 mL); 450 mg/9 mL (9 mL);
and urgency; give slowly to patients who have a pulse
900 mg/18 mL (18 mL); 1000 mg/500 mL in Dextrose
5% (500 mL [DSC]); 150 mg/100 mL in Dextrose 5%
(ie, perfusing arrhythmia). With perfusing arrhythmias
(100 mL); 450 mg/250 mL in Dextrose 5% (250 mL);
(eg, atrial fibrillation, stable ventricular tachycardia), do
750 mg/500 mL in Dextrose 5% (500 mL [DSC], 515
not exceed recommended IV concentrations or rates of
mL); 900 mg/500 mL in Dextrose 5% (500 mL)
infusion listed below (severe hepatic toxicity may occur). Tablet, Oral, as hydrochloride:
Slow the infusion rate if hypotension or bradycardia Cordarone: 200 mg [DSC] [scored]
develops. Pacerone: 100 mg
May be a vesicant; ensure proper needle or catheter Pacerone: 200 mg [scored; contains fd&c red #40, fd&c
placement prior to and during IV infusion. Avoid extrav- yellow #6 (sunset yellow)]
asation. If extravasation occurs, stop infusion immedi- Pacerone: 400 mg [scored; contains fd&c yellow #10
ately and disconnect (leave needle/cannula in place); aluminum lake]
gently aspirate extravasated solution (do NOT flush the Generic: 100 mg, 200 mg, 400 mg
line); initiate hyaluronidase antidote for refractory Extemporaneous Preparations
cases; remove needle/cannula; apply dry warm com- 5 mg/mL Oral Suspension (ASHP Standard Concen-
presses (Reynolds 2014); elevate extremity. tration) (ASHP 2017)
Pulseless VT or VF: A 5 mg/mL oral suspension may be made with tablets and
Infants, Children, and Adolescents: Administer via either a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1
rapid IV bolus; adult data in this setting suggest mixture of Ora-Sweet SF and Ora-Plus adjusted to a pH
administration of undiluted drug may be preferred between 6-7 using a sodium bicarbonate solution (5 g/
(Dager 2006; Skrifvars 2004). Note: PALS guidelines 100 mL of distilled water). Crush five 200 mg tablets in a
(Kleinman 2010) do not specify dilution of bolus dose mortar and reduce to a fine powder. Add small portions
and The Handbook of Emergency Cardiovascular of the chosen vehicle and mix to a uniform paste; mix
Care (Hazinski 2015) and the ACLS guidelines do while adding the vehicle in incremental proportions to
not make any specific recommendations regarding almost 200 mL; transfer to a calibrated bottle, rinse
dilution of amiodarone in this setting. mortar with vehicle, and add quantity of vehicle sufficient
Adults: May be administered rapidly and undiluted. to make 200 mL. Label "shake well" and "protect from
light." Stable for 42 days at room temperature or 91 days
Note: The Handbook of Emergency Cardiovascular
refrigerated (preferred) (Nahata 1999; Nahata 2014).
Care (Hazinski 2015) and the 2010 ACLS guidelines Nahata MC, Morosco RS, Hipple TF. Stability of amiodarone in extem-
do not make any specific recommendations regarding poraneous oral suspensions prepared from commercially available
dilution of amiodarone in this setting; however, in this vehicles. Journal of Pediatric Pharmacy Practice. 1999;4(4):186-189.
setting, administering undiluted is preferred (Dager Nahata MC and Pai VB. Pediatric Drug Formulations. 6th ed. Cincin-
nati, OH: Harvey Whitney Books Co; 2014.
2006; Skrifvars 2004).
Perfusing arrhythmias: Information based on adult @ Amiodarone HCI see Amiodarone on page 113
data: Injection must be diluted before IV use. Adminis- @ Amiodarone Hydrochloride see Amiodarone
ter via central venous catheter, if possible; increased on page 113
phlebitis may occur with peripheral infusions >3 mg/mL
in D5W; the use of a central venous catheter with
concentrations >2 mg/mL for infusions >1 hour is rec- Amitriptyline (a mee TRIP ti leen)
ommended. An in-line filter has been recommended
Medication Safety Issues
during administration for continuous infusions to reduce
Sound-alike/look-alike issues:
the incidence of phlebitis. Must be infused via volumet-
Amitriptyline may be confused with aminophylline, imipr-
ric infusion device; drop size of IV solution may be
amine, nortriptyline
reduced and underdosage may occur if drop counter- Elavil may be confused with Aldoril, Eldepryl, enalapril,
infusion sets are used. PVC tubing is recommended for Equanil, Plavix
administration regardless of infusion duration. Incom- Elavil may be confused with Elavil OTC (an over-the-
patible with heparin; flush with saline prior to and counter sleep aid containing melatonin, valerian root,
following infusion. Note: IV administration at lower flow and vitamins).
rates (potentially associated with use in pediatrics) and Geriatric Patients: High-Risk Medication:
higher concentrations than recommended may result in Beers Criteria: Amitriptyline (alone or in combination) is
leaching of plasticizers (DEHP) from intravenous tub- identified in the Beers Criteria as a potentially inappro-
ing. DEHP may adversely affect male reproductive tract priate medication to be avoided in patients 65 years
development. Alternative means of dosing and admin- and older (independent of diagnosis or condition) due
istration (1 mg/kg aliquots) may need to be considered. to its strong anticholinergic properties and potential for

117
 AMITRIPTYLINE

q sedation and orthostatic hypotension. Because of their

association with falls and fractures, tricyclic antidepres-
plasma and urine of breastfeeding infants (Yoshida
1997). It should be noted that actual milk concentrations
sants (TCAs) are to be avoided in patients 65 years and of tricyclic antidepressants are generally related to mater-
older with a history of falls or fractures. In addition, use nal serum concentration and vary by fat content of breast
TCAs with caution due to their potential to cause or milk; the level of detection varies greatly by assay method
exacerbate syndrome of inappropriate antidiuretic hor- (Yoshida 1997).
mone secretion (SIADH) or hyponatremia; monitor
Most sources have not reported adverse events in infants
sodium closely with initiation or dosage adjustments
exposed to amitriptyline via breast milk (Fortinguerra
in older adults (Beers Criteria [AGS 2015)).
2009; Larsen 2015; Yoshida 1997). However, in a case
Pharmacy Quality Alliance (PQA): Amitriptyline (alone or
report, severe sedation with associated poor feeding was
in combination) is identified as a high-risk medication in
observed in a breastfed infant (~15 days old) following the
patients 65 years and older on the PQA’s, Use of High-
initiation of amitriptyline 10 mg/day in the mother. Symp-
Risk Medications in the Elderly (HRM) performance
toms in the infant decreased within 24 hours and resolved
measure, a safety measure used by the Centers for
within 48 hours after the maternal dose was discontinued.
Medicare and Medicaid Services (CMS) for Medicare
Once amitriptyline was reinitiated in the mother, symptoms
plans.
in the infant returned (Uguz 2017).
Related Information
Relative Infant Dose on page 2207 Infants of mothers using psychotropic medications should
Brand Names: US Elavil [DSC] be monitored daily for changes in sleep, feeding patterns,
Brand Names: Canada Apo-Amitriptyline; Bio-Amitripty- and behavior (Bauer 2013) as well as infant growth and
line; Elavil; Levate; Novo-Triptyn; PMS-Amitriptyline neurodevelopment (Sriraman 2015).
Therapeutic Category Antidepressant, Tricyclic (Tertiary Tricyclic antidepressants are not the preferred therapy for
Amine); Antimigraine Agent
depression in breastfeeding women. However, if a TCA is
Generic Availability (US) Yes needed, amitriptyline is one of the agents with information
Use Treatment of depression (FDA approved in ages 212 available (Larsen 2015). A woman already stabilized on a
years and adults); has also been used as adjunct therapy TCA during pregnancy may continue that medication while
for chronic pain management, and migraine prophylaxis breastfeeding (Sriraman 2015). Migraine prophylaxis
Medication Guide Available Yes should be avoided in women who are breastfeeding; if
Pregnancy Risk Factor C needed, amitriptyline may be used if other agents are
Pregnancy Considerations Adverse events have been ineffective or contraindicated (Pringsheim 2012). The
observed in some animal reproduction studies. Amitripty- WHO considers amitriptyline to be compatible with breast-
line crosses the human placenta; CNS effects, limb feeding in doses $150 mg/day (WHO 2002). Due to the
deformities, and developmental delay have been noted potential for serious adverse reactions in the breastfed
in case reports (causal relationship not established). infant, the manufacturer recommends a decision be made
Tricyclic antidepressants may be associated with irritabil- whether to discontinue breastfeeding or to discontinue the
ity, jitteriness, and convulsions (rare) in the neonate drug, taking into account the importance of treatment to
(Yonkers 2009). Crying, constipation, problems with uri- the mother.
nating, and nausea may also occur in neonates exposed Contraindications
during pregnancy (Larsen 2015). Hypersensitivity to amitriptyline or any component of the
The ACOG recommends that therapy for depression formulation; coadministration with or within 14 days of
during pregnancy be individualized; treatment should MAOls; coadministration with cisapride; acute recovery
incorporate the clinical expertise of the mental health phase following myocardial infarction
clinician, obstetrician, primary health care provider, and Canadian labeling: Additional contraindications (not in the
pediatrician (ACOG 2008). According to the American US labeling): Severe liver impairment; acute heart failure
Psychiatric Association (APA), the risks of medication Documentation of allergenic cross-reactivity for tricyclic
treatment should be weighed against other treatment antidepressants jis limited. However, because of similar-
options and untreated depression. For women who dis- ities in chemical structure and/or pharmacologic actions,
continue antidepressant medications during pregnancy the possibility of cross-sensitivity cannot be ruled out with
and who may be at high risk for postpartum depression, certainty.
the medications can be restarted following delivery (APA Warnings/Precautions [US Boxed Warning]: Antide-
2010). Treatment algorithms have been developed by the pressants increase the risk of suicidal thinking and
ACOG and the APA for the management of depression in behavior in children, adolescents, and young adults
women prior to conception and during pregnancy (Yonkers (18 to 24 years of age) with major depressive disorder
2009). Tricyclic antidepressants are not the preferred (MDD) and other psychiatric disorders; consider risk
therapy for depression in pregnant women but may be prior to prescribing. Short-term studies did not show an
helpful when agitation is also present. If a TCA is needed, increased risk in patients >24 years of age and showed a
amitriptyline one of the preferred agents. Maternal serum
decreased risk in patients 265 years. Closely monitor for
concentrations should be monitored during pregnancy clinical worsening, suicidality, or unusual changes in
(Larsen 2015; Yonkers 2009). Although not a first-line behavior, particularly during the initial 1-2 months of
agent, amitriptyline may be used for the treatment of therapy or during periods of dosage adjustments
post-traumatic stress disorder in pregnant women (Ban- (increases or decreases); the patient's family or caregiver
delow 2008). Migraine prophylaxis should be avoided should be instructed to closely observe the patient and
during pregnancy; if needed, amitriptyline may be used if communicate condition with health care provider. A med-
other agents are ineffective or contraindicated (Pring-
ication guide should be dispensed with each prescription.
sheim 2012). Amitriptyline is not FDA approved for use in children.
Pregnant women exposed to antidepressants during preg-
The possibility of a suicide attempt is inherent in major
nancy are encouraged to enroll in the National Pregnancy
depression and may persist until remission occurs. Wor-
Registry for Antidepressants (NPRAD). Women 18 to 45
sening depression and severe abrupt suicidality that are
years of age or their health care providers may contact the
not part of the presenting symptoms may require discon-
registry by calling 844-405-6185. Enrollment should be
tinuation or modification of drug therapy. The patient's
done as early in pregnancy as possible.
family or caregiver should be alerted to monitor patients
Breastfeeding Considerations Amitriptyline and the for the emergence of suicidality and associated behaviors
metabolite nortriptyline are present in breast milk (Bader (such as agitation, irritability, hostility, impulsivity, and
1980).
hypomania) and notify healthcare provider.
The relative infant dose (RID) of amitriptyline is 1.2%
May precipitate a shift to mania or hypomania in patients
when calculated using the highest breast milk concentra-
with bipolar disorder. Patients presenting with depressive
tion located and compared to a weight-adjusted maternal
symptoms should be screened for bipolar disorder. Ami-
dose of 175 mg/day. In general, breastfeeding is consid-
triptyline is not FDA approved for bipolar depression.
ered acceptable when the RID is <10% (Anderson 2016;
Ito 2000). Using the highest milk concentration (197 ng/ The degree of sedation, anticholinergic effects, orthosta-
mL), the estimated daily infant dose via breast milk is sis, and conduction abnormalities are high relative to other
0.03 mg/kg/day. This milk concentration was obtained antidepressants. Heart block may be precipitated in
following maternal administration of oral amitriptyline patients with preexisting conduction system disease and
175 mg/day for ~28 days (Yoshida 1997). In a review use is relatively contraindicated in patients with conduc-
article which included six mother/infant pairs, following tion abnormalities. In a scientific statement from the
maternal use of amitriptyline 75 to 175 mg/day, the esti- American Heart Association, amitriptyline has been deter-
mated exposure to the breastfeeding infant was calculated mined to be an agent that may exacerbate underlying
as 0.2% to 1.9% of the weight-adjusted maternal dose myocardial dysfunction (magnitude: moderate) (AHA
(additional detail not provided) (Fortinguerra 2009). Very [Page 2016]). May cause CNS depression, which may
small amounts of amitriptyline can be detected in the impair physical or mental abilities; patients must be

118
 AMITRIPTYLINE

cautioned about performing tasks that require mental Neuromuscular & skeletal: Lupus-like syndrome, tremor,
alertness (eg, operating machinery or driving). Use with weakness
caution in patients with a history of cardiovascular disease Ophthalmic: Accommodation disturbance, blurred vision,
(including previous MI, stroke, tachycardia, or conduction increased intraocular pressure, mydriasis
abnormalities). Use with caution in patients with urinary Otic: Tinnitus
retention, benign prostatic hyperplasia, increased intra- Rare but important or life-threatening: Angle-closure glau-
ocular pressure (IOP), narrow-angle glaucoma, xerosto- coma, neuroleptic malignant syndrome (rare; Stevens,
mia, visual problems, constipation, or a history of bowel 2008), serotonin syndrome (rare)
obstruction. Drug Interactions
Metabolism/Transport Effects Substrate of CYP1A2
TCAs may rarely cause bone marrow suppression; mon-
(minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9
itor for any signs of infection and obtain CBC if symptoms
(minor), CYP2D6 (major), CYP3A4 (minor); Note:
(eg, fever, sore throat) evident. May alter glucose control - Assignment of Major/Minor substrate status based on
use with caution in patients with diabetes. Recommended clinically relevant drug interaction potential
by the manufacturer to discontinue prior to elective sur- Avoid Concomitant Use
gery; risks exist for drug interactions with anesthesia and
Avoid concomitant use of Amitriptyline with any of the
for cardiac arrhythmias. However, definitive drug interac- following: Aclidinium; Azelastine (Nasal); Bromopride;
tions have not been widely reported in the literature and Bromperidol; Cimetropium; Cisapride; Dapoxetine; Dro-
continuation of tricyclic antidepressants is generally rec- nedarone; Eluxadoline; Glycopyrrolate (Oral Inhalation);
ommended as long as precautions are taken to reduce the lobenguane | 123; Ipratropium (Oral Inhalation); Levo-
significance of any adverse events that may occur (Pass, sulpiride; Linezolid; Methylene Blue; Monoamine Oxi-
2004). May lower seizure threshold - use caution in dase Inhibitors; Orphenadrine; Oxatomide;
patients with a previous seizure disorder or condition Oxomemazine; Paraldehyde; Potassium Chloride;
predisposing to seizures such as brain damage, alcohol- Potassium Citrate; Thalidomide; Tiotropium; Umeclidi-
ism, or concurrent therapy with other drugs which lower nium
the seizure threshold. May increase the risks associated Increased Effect/Toxicity
with electroconvulsive therapy. Bone fractures have been Amitriptyline may increase the levels/effects of: Abobo-
associated with antidepressant treatment. Consider the tulinumtoxinA; Alcohol (Ethyl); Alpha-/Beta-Agonists
possibility of a fragility fracture if an antidepressant-treated (Direct-Acting); Alpha1-Agonists; Amphetamines; Anti-
patient presents with unexplained bone pain, point tender- cholinergic Agents; Antipsychotic Agents; Aspirin; Aze-
ness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012). lastine (Nasal); Beta2-Agonists; Blonanserin;
Use with caution in patients with hepatic or renal dysfunc- Buprenorphine; Cimetropium; Cisapride; Citalopram;
tion. May cause mild pupillary dilation which in susceptible CNS Depressants; Desmopressin; Dronedarone; Elux-
individuals can lead to an episode of narrow-angle glau- adoline; Escitalopram; Fluconazole; Flunitrazepam; Glu-
coma. Consider evaluating patients who have not had an cagon; Glycopyrrolate (Oral Inhalation); HYDROcodone;
iridectomy for narrow-angle glaucoma risk factors. Ther- lohexol; lomeprol; lopamidol; Methotrimeprazine; Meth-
apy is relatively contraindicated in patients with sympto- ylene Blue; MetyroSINE; Mirabegron; Mirtazapine; Nic-
matic hypotension. orandil; Nonsteroidal Anti-Inflammatory Agents (COX-2
Selective); Nonsteroidal Anti-Inflammatory Agents (Non-
Abrupt discontinuation or interruption of antidepressant
selective); OnabotulinumtoxinA; Opioid Analgesics;
therapy has been associated with a discontinuation syn-
Orphenadrine; OxyCODONE; Paraldehyde; Perhexiline;
drome. Symptoms arising may vary with antidepressant
Piribedil; Potassium Chloride; Potassium Citrate; Prami-
however commonly include nausea, vomiting, diarrhea,
pexole; QTc-Prolonging Agents (Highest Risk); QTc-Pro-
headaches, light-headedness, dizziness, diminished
longing Agents (Moderate Risk); QuiNIDine;
appetite, sweating, chills, tremors, paresthesias, fatigue,
Ramosetron; RimabotulinumtoxinB; ROPINIRole; Roti-
somnolence, and sleep disturbances (eg, vivid dreams,
gotine; Selective Serotonin Reuptake Inhibitors; Seroto-
insomnia). Greater risks for developing a discontinuation
nin Modulators; Sodium Phosphates; Sulfonylureas;
syndrome have been associated with antidepressants
Suvorexant; Thalidomide; Thiazide and Thiazide-Like
with shorter half-lives, longer durations of treatment, and
Diuretics; Tiotropium; Vitamin K Antagonists; Yohimbine;
abrupt discontinuation. For antidepressants of short or
Zolpidem
intermediate half-lives, symptoms may emerge within 2-5
days after treatment discontinuation and last 7-14 days The levels/effects of Amitriptyline may be increased by:
(APA, 2010; Fava, 2006; Haddad, 2001; Shelton, 2001; Abiraterone Acetate; Aclidinium; Altretamine; Amanta-
Warner, 2006). C dine; Amezinium; Amifampridine; Antiemetics (5HT3
Adverse Reactions Anticholinergic effects may be pro- Antagonists); Antipsychotic Agents; Asunaprevir; Brimo-
nounced; moderate to marked sedation can occur (toler- nidine (Topical); Bromopride; Bromperidol; BuPROPion;
ance to these effects usually occurs). Cannabis; Chloral Betaine; Chlormethiazole; Chlorphe-
Cardiovascular: Atrioventricular-conduction disturbance, nesin Carbamate; Cimetidine; Cinacalcet; Citalopram;
cardiac arrhythmia, cardiomyopathy (rare), cerebrovas- Cobicistat; CYP2D6 Inhibitors (Moderate); CYP2D6
cular accident, ECG changes (nonspecific), edema, Inhibitors (Strong); Dapoxetine; Darunavir; Dexmethyl-
facial edema, heart block, hypertension, myocardial phenidate; Dimethindene (Topical); Doxylamine; Drona-
infarction, orthostatic hypotension, palpitations, syncope, binol; Droperidol; DULoxetine; Escitalopram;
tachycardia Fluconazole; FLUoxetine; FluvoxaMINE; HydrOXYzine;
Central nervous system: Anxiety, ataxia, cognitive dys- Imatinib; Ipratropium (Oral Inhalation); Kava Kava; Line-
function, coma, confusion, delusions, disorientation, diz- zolid; Lithium; Magnesium Sulfate; Metaxalone; Metho-
ziness, drowsiness, drug withdrawal (nausea, headache, trimeprazine; Methylene Blue; Methylphenidate;
malaise, irritability, restlessness, dream and sleep dis- Metoclopramide; MetyroSINE; Mianserin; MiFEPRI-
Stone; Minocycline; Monoamine Oxidase Inhibitors;
turbance, mania [rare], and hypomania [rare]), dysarth-
Nabilone; Oxatomide; Oxomemazine; Panobinostat;
ria, EEG pattern changes, excitement, extrapyramidal
PARoxetine; Peginterferon Alfa-2b; Perampanel; Per-
reaction (including abnormal involuntary movements
hexiline; Pramlintide; Protease Inhibitors; QuiNIDine;
and tardive dyskinesia), fatigue, hallucination, headache,
Rufinamide; Sertraline; Sodium Oxybate; Tapentadol;
hyperpyrexia, insomnia, lack of concentration, night-
Tedizolid; Terbinafine (Systemic); Tetrahydrocannabinol;
mares, numbness, paresthesia, peripheral neuropathy,
Thyroid Products; Topiramate; Trimeprazine; Umeclidi-
restlessness, sedation, seizure, tingling of extremities
nium; Valproate Products
Dermatologic: Allergic skin rash, alopecia, diaphoresis,
Decreased Effect
~ skin photosensitivity, urticaria 5
Amitriptyline may decrease the levels/effects of: Acetyl-
Endocrine & metabolic: Altered serum glucose, decreased
cholinesterase Inhibitors; Alpha1-Agonists; Alpha2-Ago-
libido, galactorrhea, gynecomastia, increased libido,
nists; Alpha2-Agonists (Ophthalmic); Amifampridine;
SIADH, weight gain, weight loss
Gastrointestinal Agents (Prokinetic); Guanethidine;
Gastrointestinal: Ageusia, anorexia, constipation, diar-
lobenguane | 123; Itopride; Levosulpiride; Nitroglycerin;
rhea, melanoglossia, nausea, paralytic ileus, parotid
Pitolisant; Secretin
gland enlargement, stomatitis, unpleasant taste, vomit-
ing, xerostomia The levels/effects of Amitriptyline may be decreased by:
Genitourinary: Breast hypertrophy, impotence, testicular Acetylcholinesterase Inhibitors; Amifampridine; Barbitu-
swelling, urinary frequency, urinary retention, urinary rates; CarBAMazepine; Peginterferon Alfa-2b; St
tract dilation John's Wort
Hematologic & oncologic: Bone marrow depression Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
(including agranulocytosis, leukopenia, and thrombocy- Protect from light.
topenia), eosinophilia, purpura Mechanism of Action Increases the synaptic concen-
Hepatic: Hepatic failure, hepatitis (rare; including altered tration of serotonin and/or norepinephrine in the central
liver function and jaundice) ; nervous system by inhibition of their reuptake by the
Hypersensitivity: Tongue edema presynaptic neuronal membrane pump.
AMITRIPTYLINE

Pharmacodynamics/Kinetics (Adult data unless If intolerable withdrawal symptoms occur following a

noted) dose reduction, consider resuming the previously
Onset of action: Individual responses may vary; however, prescribed dose and/or decrease dose at a more
4 to 8 weeks of treatment are needed before determining gradual rate (APA 2010; Bauer 2002; Haddad 2001;
if a patient with depression is partially or non-responsive; NCCMH 2010; Schatzberg 2006; Shelton 2001;
similarly 8 to 12 weeks are required for an adequate Warner 2006).
migraine prophylaxis trial (APA, 2010; Pringsheim, MAO inhibitor recommendations:
2012); desired therapeutic effect (for analgesia) may Switching to or from an MAO inhibitor antidepressant:
take as long as 1 to 3 weeks. Allow 14 days to elapse between discontinuing an
Absorption: Rapid, well absorbed MAO inhibitor intended to treat depression and
Distribution: Vg: ~18 to 22 L/kg (Schulz, 1985) initiation of amitriptyline.
Protein binding: >90% Allow 14 days to elapse between discontinuing
Metabolism: Rapid; hepatic N to demethylation to nortrip- amitriptyline and initiation of an MAO inhibitor
tyline (active), hydroxy derivatives and conjugated deriv- intended to treat depression.
atives Use with reversible MAO inhibitors (such as linezolid
Bioavailability: ~43% to 46% (Schulz, 1985) or IV methylene blue):
Half-life elimination: ~13 to 36 hours (Schulz, 1985) Do not initiate amitriptyline in patients receiving line-
Time to peak, serum: ~2 to 5 hours (Schulz, 1985) zolid or IV methylene blue; consider other inter-
Excretion: Urine (glucuronide or sulfate conjugate metab- ventions. for psychiatric condition.
olites; 18% as unchanged drug); Feces (small amounts) If urgent treatment with linezolid or IV methylene
Special Populations: Elderly: May have increased plasma blue is required in a patient already receiving
levels (Schulz, 1985) amitriptyline and potential benefits outweigh poten-
Pharmacodynamics/Kinetics: Additional Consider- tial risks, discontinue amitriptyline promptly and
ations Geriatric: May have increased plasma levels and administer linezolid or IV methylene blue. Monitor
prolonged half-life (Schulz, 1985) for serotonin syndrome for 2 weeks or until 24
Dosing hours after the last dose of linezolid or IV methyl-
Pediatric ene blue, whichever comes first. May resume
Chronic pain management: Limited data available: amitriptyline 24 hours after the last dose of linezolid
Children and Adolescents: Oral: Initial: 0.1 mg/kg at or IV methylene blue
bedtime, may advance as tolerated over 2 to 3 weeks
Renal Impairment: Pediatric Children 212 years and
to 0.5 to 2 mg/kg at bedtime (APS 2008; Freidrichs-
Adolescents: There are no dosage adjustments provided
dorf 2007; Kliegman 2011)
in manufacturer's labeling; however, renally eliminated;
Depressive disorders: Note: Controlled clinical trials
use with caution.
have not shown tricyclic antidepressants to be supe-
rior to placebo for the treatment of depression in Hepatic Impairment: Pediatric Children 212 years and
children and adolescents; not recommended as first- Adolescents: There are no dosage adjustments provided
line medication; may be beneficial for patients with in manufacturer's labeling; however, hepatically metab-
comorbid conditions (Biramaher 2007; Dopheide olized; use with caution.
2006; Wagner 2005) Administration Oral: May administer with food to
Children 9 to <12 years: Limited data available: Oral: decrease Gl upset
Initial: 1 mg/kg/day in 3 divided doses; after 3 days, Monitoring Parameters Heart rate, blood pressure, men-
dose may be increased to 1.5 mg/kg/day in 3 div- tal status, weight. Monitor patient periodically for symptom
ided doses (Kashani 1984; Kliegman 2007); dosing resolution; monitor for worsening depression, suicidality,
was reported in a small pilot study (n=9) and associated behaviors (especially at the beginning of
(Kashani 1984) therapy or when doses are increased or decreased).
Children 212 years and Adolescents: Reference Range Note: Plasma levels do not always
Manufacturer's labeling: Usual initial dosage: 10 mg correlate with clinical effectiveness
three times daily and 20 mg at bedtime. In general, Therapeutic:
lower doses are recommended compared to Amitriptyline plus nortriptyline (active metabolite):
adults; maximum daily dose: 200 mg/day (Klieg- 100-250 ng/mL (SI: 360 to 900 nmol/L)
man 2007) Nortriptyline 50 to 150 ng/mL (SI: 190 to 570 nmol/L)
Alternate dosing: Usual range: 30 to 100 mg at Toxic: >500 ng/mL (SI: >1,800 nmol/L)
bedtime or in divided doses twice daily; maximum Dosage Forms Excipient information presented when
daily dose: 200 mg/day (Kliegman 2007; Nelson available (limited, particularly for generics); consult spe-
1996). In adults, therapy is initiated with 25 to cific product labeling. [DSC] = Discontinued product
50 mg daily single dose at bedtime or in divided Tablet, Oral, as hydrochloride:
doses (APA 2010; Bauer 2013). Elavil: 25 mg [DSC] [contains fd&c blue #2 aluminum
Migraine prophylaxis: Limited data available (Her-
lake, fd&c yellow #10 aluminum lake]
shey 2000; Lewis 2004): Older children and Adoles-
Generic: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg
cents: Oral: Initial: 0.25 mg/kg/day, given at bedtime;
increase dose by 0.25 mg/kg/day every 2 weeks to @ Amitriptyline Hydrochloride see Amitriptyline
1 mg/kg/day. Reported dosing range: 0.2 to on page 117
1.7 mg/kg/day (Hershey 2000). Dosing based on a
@ Amjevita see Adalimumab on page 59
large open-label trial in 192 children (mean age 12 +3
years) with >3 headaches/month (61% with migraine, @ AmLactin [OTC] see Lactic Acid and Ammonium
8% with migraine with aura, and 10% with tension- Hydroxide on page 1165
type headaches) used an initial dose of 0.25 mg/kg/
day given before bedtime; doses were increased AmLODIPine (am Loe di peen)
every 2 weeks by 0.25 mg/kg/day to a final dose of
1 mg/kg/day; patients also used appropriate abortive Medication Safety Issues
medications and lifestyle adjustments; at initial reeval- Sound-alike/look-alike issues:
uation (mean: 67 days after initiation of therapy), the AmLODIPine may be confused with aMlLoride
mean number of headaches per month significantly Norvasc may be confused with Navane, Norvir, Vascor
decreased from 17.1 to 9.2; the mean duration of International issues:
headaches decreased from 11.5 to 6.3 hours; con- Norvasc [U.S., Canada, and multiple international mar-
tinued improvement was observed at follow-up visits; kets] may be confused with Vascor brand name for
minimal adverse effects were reported. Note: Mean imidapril [Philippines] and simvastatin [Malaysia, Sin-
final dose was 0.99 + 0.23 mg/kg; range:
gapore, and Thailand]
0.16-1.7 mg/kg/day; ECGs were obtained on children
Brand Names: US Norvasc
receiving >1 mg/kg/day or in those describing a car-
diac side effect (Hershey 2000). Brand Names: Canada Accel-Amlodipine; ACT-Amlodi-
Discontinuation of therapy: Upon discontinuation of pine; Amlodipine-Odan; Apo-Amlodipine; Auro-Amlodi-
antidepressant therapy, gradually taper the dose to pine; Bio-Amlodipine; Dom-Amlodipine; GD-Amlodipine;
minimize the incidence of withdrawal symptoms and JAMP-Amlodipine; Mar-Amlodipine; Mint-Amlodipine;
allow for the detection of reemerging symptoms. Mylan-Amlodipine; Norvasc; PHL-Amlodipine; PMS-Amlo-
Evidence supporting ideal taper rates is limited. APA dipine; Q-Amlodipine; RAN-Amlodipine; ratio-Amlodipine;
and NICE guidelines suggest tapering therapy over at Riva-Amlodipine; Sandoz Amlodipine; Septa-Amlodipine;
_ least several weeks with consideration to the half-life Teva-Amlodipine
of the antidepressant; antidepressants with a shorter Therapeutic Category Antianginal Agent; Antihyperten-
half-life may need to be tapered more conservatively. sive Agent; Calcium Channel Blocker; Calcium Channel
In addition for long-term treated patients, WFSBP Blocker, Dihydropyridine
guidelines recommend tapering over 4 to 6 months. Generic Availability (US) Yes

120
 AMLODIPINE

Use Treatment of hypertension (FDA approved in ages 26 osteoarthritis, pancreatitis, paresthesia, peripheral ische-
years and adults); chronic stable angina (FDA approved in mia, peripheral neuropathy, phototoxicity, purpura, rig-
adults); vasospastic (Prinzmetal's) angina (FDA approved ors, tachycardia, thrombocytopenia, tremor, vasculitis,
in adults); angiographically documented CAD [to decrease ventricular tachycardia, weight gain
risk of hospitalization (due to angina) and coronary revas- Drug Interactions
cularization procedure] (FDA approved in sacl) Metabolism/Transport Effects Substrate of CYP3A4
Pregnancy Considerations (major); Note: Assignment of Major/Minor substrate sta-
Amlodipine crosses the placenta. Cord blood concentra- tus based on clinically relevant drug interaction potential;
tions were approximately one-third of maternal serum at Inhibits BCRP/ABCG2, CYP3A4 (weak)
delivery, and concentrations in the newborn were below Avoid Concomitant Use
the limit of quantification (<0.1 ng/mL) when measured in Avoid concomitant use of AmLOD/Pine with any of the
eight infants within 48 hours of delivery (Morgan 2017). following: Bromperidol; Conivaptan; Fusidic Acid (Sys-
Information related to the use of amlodipine in pregnancy temic); Idelalisib; Pimozide
is limited (Ahn 2007; Nahapetian 2008; Vigil-De Gracia Increased Effect/Toxicity
2014; Yu 2015). Due to pregnancy induced pharmacologic AmLODIPine may increase the levels/effects of: Amifos-
changes, amlodipine pharmacokinetics may be altered tine; Antipsychotic Agents (Second Generation [Atypi-
immediately postpartum; large individual patient variability cal]); ARIPiprazole; Atosiban; Bromperidol; Calcium
was observed (Naito 2015b). Channel Blockers (Nondihydropyridine); CycloSPORINE
(Systemic); Dofetilide; DULoxetine; Flibanserin; Fosphe-
Untreated chronic maternal hypertension is associated
nytoin; Hypotension-Associated Agents; Levodopa;
with adverse events in the fetus, infant, and mother. If
Lomitapide; Lovastatin; Magnesium Salts; Neuromuscu-
treatment for hypertension during pregnancy is needed,
lar-Blocking Agents (Nondepolarizing); NiMODipine;
. agents other than amlodipine are preferred (ACOG 2013).
Nitroprusside; Phenytoin; Pholcodine; Pimozide; QuiNl-
Breastfeeding Considerations Amlodipine is present in
Dine; Simvastatin; Tacrolimus (Systemic)
breast milk.
The levels/effects of AnLODIPine may be increased by:
The relative infant dose (RID) of amlodipine is 4.18%
Alfuzosin; Alpha1-Blockers; Antifungal Agents (Azole
(interquartile range 3.12% to 7.25%) when calculated
Derivatives, Systemic); Antihepaciviral Combination
using a median breast milk concentration and compared
Products; Aprepitant; Barbiturates; Benperidol; Brigati-
to a weight adjusted maternal dose of 6.01 mg +
nib; Brimonidine (Topical); Calcium Channel Blockers
2.31 mg/day. In general, breastfeeding is considered
(Nondihydropyridine); Ceritinib; Conivaptan; Cyclo-
acceptable when the RID is <10%; when an RID is
SPORINE (Systemic); CYP3A4 Inhibitors (Moderate);
>25% breastfeeding should generally be avoided (Ander- CYP3A4 Inhibitors (Strong); Dapoxetine; Diazoxide; Flu-
son 2016; Ito 2000). Using a median predose milk con-
conazole; Fosaprepitant; Fosnetupitant; Fusidic Acid
centration (11.5 ng/mL; IQR 9.84 to 18 ng/mL), authors of
(Systemic); Herbs (Hypotensive Properties); Idelalisib;
a study calculated the estimated daily infant dose via Lormetazepam; Macrolide Antibiotics; Magnesium Salts;
breast milk to be 4.17 mcg/kg/day (IQR 3.05 to 6.32 MiFEPRIStone; Molsidomine; Naftopidil; Netupitant; Nic-
mcg/kg/day). This milk concentration was obtained follow- ergoline; Nicorandil; Obinutuzumab; Palbociclib; Pentox-
ing maternal administration of amlodipine at a median ifylline; Phosphodiesterase 5 Inhibitors; Prostacyclin
daily dose of 6.01 mg + 2.31 mg; the women (n=31) were Analogues; Quinagolide; QuiNIDine; Simeprevir; Stiri-
~3 weeks postpartum and sampling occurred prior to a pentol
dose and ~10 days after treatment initiation. The max-
Decreased Effect
imum RID calculated was 15.2%. Adverse events were
AmLOD!IPine may decrease the levels/effects of: Clopi-
not observed in the breastfed infants (Naito 2015a).
dogrel; QuiNIDine
Contraindications
Hypersensitivity to amlodipine or any component of the The levels/effects of AnLODIPine may be decreased by:
formulation Amphetamines; Barbiturates; Bosentan; Brigatinib;
Canadian labeling: Additional contraindications (not in US Bromperidol; Calcium Salts; CarBAMazepine; CYP3A4
labeling): Hypersensitivity to other dihydropyridines; Inducers (Moderate); CYP3A4 Inducers (Strong); Dab-
severe hypotension (SBP <90 mm Hg); breastfeeding rafenib; Deferasirox; Efavirenz; Enzalutamide; Herbs
Warnings/Precautions Increased angina and/or MI has (Hypertensive Properties); Melatonin; Methylphenidate;
occurred with initiation or dosage titration of calcium Mitotane; Phenytoin; Pitolisant; Rifamycin Derivatives;
channel blockers. Symptomatic hypotension can occur; Sarilumab; Siltuximab; St John's Wort; Tocilizumab;
acute hypotension upon initiation is unlikely due to the Yohimbine
gradual onset of action. Blood pressure must be lowered Food Interactions Grapefruit juice may modestly
at a rate appropriate for the patient's clinical condition. increase amlodipine levels. Management: Monitor closely
Use caution in severe aortic stenosis and/or hypertrophic with concurrent use.
cardiomyopathy with outflow tract obstruction. With the Storage/Stability Store at 15°C to 30°C (59°F to 86°F).
exception of amlodipine, calcium channel blockers should Mechanism of Action Inhibits calcium ion from entering
be avoided whenever possible in patients with heart failure the "slow channels" or select voltage-sensitive areas of
with reduced ejection fraction (HFrEF). Amlodipine may vascular smooth muscle and myocardium during depola-
be used for the treatment of hypertension or ischemic rization, producing a relaxation of coronary vascular
heart disease in patients with HFrEF, but has no effect smooth muscle and coronary vasodilation; increases myo-
on functional status or mortality (ACCF/AHA [Yancy cardial oxygen delivery in patients with vasospastic
2013]). Use caution in patients with hepatic impairment; angina. Amlodipine directly acts on vascular smooth
may require lower starting dose; titrate slowly with severe muscle to produce peripheral arterial vasodilation reduc-
hepatic impairment. The most common side effect is ing peripheral vascular resistance and blood pressure.
peripheral edema; occurs within 2 to 3 weeks of starting Pharmacodynamics/Kinetics (Adult data unless
therapy. Reflex tachycardia may occur with use. Peak noted)
antihypertensive effect is delayed; dosage titration should Onset of action: Antihypertensive effect: Significant reduc-
occur after 7 to 14 days on a given dose. Initiate at a lower tions in blood pressure at 24 to 48 hours after first dose;
dose in the elderly. slight increase in heart rate within 10 hours of admin-
Adverse Reactions istration may reflect some vasodilating activity (Donnelly
Cardiovascular: Flushing (more common in females), 1993)
palpitations, peripheral edema (more common in Duration: Antihypertensive effect: At least 24 hours (Don-
females) nelly 1993); has been shown to extend to at least 72
Central nervous system: Dizziness, drowsiness, fatichie, hours when discontinued after 6 to 7 weeks of therapy
male sexual disorder (Biston 1999)
Dermatologic: Pruritus, skin rash Absorption: Well absorbed (Meredith 1992)
Gastrointestinal: Abdominal pain, nausea Distribution: Mean V4:
Neuromuscular & skeletal: Muscle cramps, weakness Children >6 years: Similar to adults on a mg per kg basis;
Respiratory: Dyspnea, pulmonary edema Note: Weight-adjusted Vg in younger children (<6
Rare but important or life-threatening: Acute interstitial years of age) may be greater than in older children
nephritis (Ejaz 2000), anorexia, atrial fibrillation, brady- (Flynn 2006)
cardia, cholestasis, conjunctivitis, depression, diarrhea, Adults: 21 L/kg (Scholz 1997)
difficulty in micturition, diplopia, dysphagia, epistaxis, Protein binding: ~93%
erythema multiforme, exfoliative dermatitis, extrapyrami- Metabolism: Hepatic (~90%) to inactive metabolites
dal reaction, eye pain, female sexual disorder, gingival Bioavailability: 64% to 90%
hyperplasia, gynecomastia, hepatitis, hot flash, hyper- Half-life elimination: Terminal (biphasic): 30 to 50 hours;
glycemia, hypersensitivity angiitis, hypersensitivity reac- increased with hepatic dysfunction
tion, hypoesthesia, increased serum transaminases, Time to peak, plasma: 6 to 12 hours
increased thirst, insomnia, leukopenia, maculopapular Excretion: Urine (10% of total dose as unchanged drug,
rash, myalgia, nocturia, orthostatic hypotension, 60% of total dose as metabolites)
 AMLODIPINE

q Clearance: May be decreased in patients with hepatic

insufficiency or moderate to severe heart failure; Ammonium Chloride (a MoE nee um KLOR ide)
weight-adjusted clearance in children >6 years of age
is similar to adults; Note: Weight-adjusted clearance in Therapeutic Category Metabolic Alkalosis Agent;, Uri-
younger children (<6 years of age) may be greater than nary Acidifying Agent
in older children (Flynn 2006) Generic Availability (US) Yes
Pharmacodynamics/Kinetics: Additional Consider- Use Treatment of hypochloremia or metabolic alkalosis
ations (FDA approved in adults)
Hepatic function impairment: AUC may increase ~40% to Pregnancy Risk Factor C
60%. Pregnancy Considerations Animal reproduction studies
Geriatric: AUC may increase ~40% to 60%. have not been conducted.
Moderate to severe heart failure: AUC may increase Contraindications Severe hepatic or renal dysfunction;
~40% to 60%. should not be administered when metabolic alkalosis due
Dosing to vomiting of hydrochloric acid is accompanied by loss of
Pediatric sodium (excretion of sodium bicarbonate in the urine)
Hypertension: Oral: Warnings/Precautions Monitor closely for signs and
Children 1 to 5 years: Limited data available: Note: A symptoms of ammonia toxicity, including pallor, diaphore-
population pharmacokinetic study found that chil- sis, altered breathing, bradycardia, arrhythmias, retching,
dren <6 years of age had weight-adjusted clearance twitching, seizure, and coma.
and Vg of amlodipine that were significantly greater May result in increased ammonia concentrations leading
than children 26 years of age. This may suggest the
to worsened encephalopathy (Adrogue 1998); use is
need for higher mg/kg/day doses in younger children
contraindicated in severe hepatic impairment. May result
(<6 years of age); however, the study included only
in increased urea formation resulting in exacerbation of
a small number of younger children (n=11) (Flynn
uremic symptoms (Devlin 2014); use is contraindicated in
2006). One retrospective pediatric study (n=55) that
severe renal impairment. Use caution in patients with
included only eight patients 1-6 years of age used
primary respiratory acidosis or pulmonary insufficiency.
initial doses of 0.05-0.1 mg/kg/day; doses were
Adverse Reactions
titrated upwards as needed; mean required dose
Central nervous system: Coma (with rapid infusion [Devlin
was significantly higher in patients 1-6 years of
2014]), confusion (with rapid infusion [Devlin 2014]),
age (0.3 + 0.16 mg/kg/day) compared to older chil-
seizure (with rapid infusion [Devlin 2014])
dren (6 to 12 years: 0.16 + 0.12 mg/kg/day; 12 to 20
Endocrine & metabolic: Hypervolemia (from large volume
years: 0.14 + 0.1 mg/kg/day) (Flynn 2000a).
diluent)
Children and Adolescents 6 to 17 years: 2.5 to 5 mg
Local: Extravasation, injection site infection, injection site
once daily; doses >5 mg daily have not been fully
phlebitis, pain at injection site, venous thrombosis at
studied. In a randomized, placebo-controlled trial of
injection site
amlodipine in children (n=268; mean age: 12.1
Miscellaneous: Fever
years; range: 6 to 16 years), a significant reduction
in systolic blood pressure (compared to placebo)
Drug Interactions
was observed in both the 2.5 mg once daily and Metabolism/Transport Effects None known.
the 5 mg once daily amlodipine groups. The authors Avoid Concomitant Use There are no known interac-
recommend an initial dose of 0.06 mg/kg/day with a tions where it is recommended to avoid concomitant use.
maximum dose of 0.34 mg/kg/day (not to exceed Increased Effect/Toxicity
10 mg/day) (Flynn 2004). Ammonium Chloride may increase the levels/effects of:
Renal Impairment: Pediatric Children 26 years and ChlorproPAMIDE; Salicylates
Adolescents: No dosage adjustment necessary (Doyle The levels/effects of Ammonium Chloride may be
1989; Kungys 2003). increased by: Potassium-Sparing Diuretics
Hepatic Impairment: Pediatric There are no pediatric- Decreased Effect
specific recommendations; based on experience in adult Ammonium Chloride may decrease the levels/effects of:
patients, dosing adjustment and slow titration suggested. Alpha-/Beta-Agonists (Indirect-Acting); Amantadine;
Administration Oral: May be administered without regard Amphetamines; Mecamylamine
to food. Storage/Stability Store intact vials at 20°C to 25°C (68°F
Monitoring Parameters Blood pressure, heart rate, liver to 77°F). Solution may crystallize if exposed to low tem-
enzymes peratures. If crystals are observed, warm vial to room
Test Interactions May lead to false-negative aldosterone/ temperature in a water bath prior to use.
renin ratio (ARR) (Funder 2016). Mechanism of Action Increases acidity by increasing
Dosage Forms Considerations AmLOD!Pine Bes+Syr- free hydrogen ion concentration
Spend SF oral suspension is available as a compounding Pharmacodynamics/Kinetics (Adult data unless
kit. Refer to manufacturer's labeling for compounding noted)
instructions.
Metabolism: Hepatic; forms urea and hydrochloric acid
Dosage Forms Excipient information presented when Excretion: Urine
available (limited, particularly for generics); consult spe- Dosing
cific product labeling.
Pediatric
Tablet, Oral:
Metabolic alkalosis: Limited data available: Infants,
Norvasc: 2.5 mg, 5 mg, 10 mg
Children, and Adolescents:
Generic: 2.5 mg, 5 mg, 10 mg
Note: Ammonium chloride is an alternative treatment
Extemporaneous Preparations A 1 mg/mL oral sus-
and use generally replaced by other acidic sources
pension may be made with tablets and either a 1:1 mixture
(eg, hydrochloric acid, arginine) (Adrogué 1998;
of simple syrup and 1% methylcellulose or a 1:1 mixture of
Sierra 2018); should be used only after sodium and
Ora-Plus® and Ora-Sweet®. Crush fifty 5 mg tablets in a
potassium chloride supplementation has been opti-
mortar and reduce to a fine powder. Add small portions of
mized. The following equations represent different
the chosen vehicle and mix to a uniform paste; mix while
methods of chloride or alkalosis correction utilizing
adding the vehicle in incremental proportions to almost
either the serum Cl, the serum HCO3, or the base
250 mL; transfer to a calibrated bottle, rinse mortar with
excess. These equations will yield different require-
vehicle, and add quantity of vehicle sufficient to make 250
ments of ammonium chloride (Devlin 2014; Martin
mL. Label "shake well" and "refrigerate". Stable for 56
1982; Nelson 1996): Initially, administer 1/2 to 2/3 of
days at room temperature or 91 days refrigerated.
the calculated dose, and then re-evaluate.
Nahata MC, Morosco RS, and Hipple TF, "Stability of Amlodipine
Besylate in Two Liquid Dosage Forms," J Am Pharm Assoc (Wash) IV:
1999, 39(3):375-7. Dosing of mEq NH,CI via the chloride-deficit method
(hypochloremia):
@ AmLODIPine Bes+SyrSpend SF see AmLODIPine mEq NH,Cl = 0.2 L/kg x wt in kg x [103 - serum
on page 120 Cl] mEq/L
@ Amlodipine Besylate see AmLOD!Pine on page 120 Dosing of mEq NH4Cl via the bicarbonate-excess
@ Amlodipine-Odan (Can) see AmLOD!|Pine on page 120 method (refractory hypochloremic metabolic alkalo-
Sis):
@ Ammens® Original Medicated [OTC] see Zinc Oxide
mEq NH,Cl = 0.5 L/kg x wt in kg x [serum HCO; -
on page 2088
24] mEq/L
# Ammens® Shower Fresh [OTC] see Zinc Oxide Dosing of mEg NH*CI via the base excess method:
on page 2088 mEq NH,Cl = 0.3 L/kg x wt in kg x base
@ Ammonapse see Sodium Phenylbutyrate on page 1843 excess (mEq/L)

122
 AMOBARBITAL

Oral (using injectable formulation): Very limited data Contraindications Hypersensitivity to barbiturates or any
available: Infants and Children: Initial: Calculate dose component of the formulation; history of manifest or latent
using the applicable equation (see previous) and porphyria; marked liver function impairment; marked res-
titrate dose based on response; in some cases may piratory disease in which dyspnea or obstruction is evi-
need to administer up to 4 times daily; due to potential dent.
bioavailability differences between oral and IV routes Warnings/Precautions Tolerance to hypnotic effect can
of administration, higher oral doses than calculated occur; do not use for >2 weeks to.treat insomnia. Potential
may be necessary; monitor laboratory parameters for drug dependency exists, abrupt cessation may precip-
closely. Dosing based on a case-series of 3 patients itate withdrawal, including status epilepticus in epileptic
(ages: 6 weeks, 2 months, and 3 years); resolution of patients. Do not administer to patients in acute or chronic
metabolic alkalosis was reported in 2 of the patients pain. Use caution in elderly, debilitated, renally impaired,
within 4 to 8 days of therapy; total weight-based dose or pediatric patients. May cause paradoxical responses,
required for resolution: 10.7 mEq/kg total and 18 including agitation and hyperactivity, particularly in acute
mEq/kg total; no adverse effects from oral/NG-tube pain and pediatric patients. Use with caution in patients
administration were reported (Mathew 2012). with hepatic impairment, decreased dosage may be
Renal Impairment: Pediatric needed; contraindicated in severe impairment. Do not
Mild-to-moderate impairment: There are no dosage administer to patients showing premonitory signs of hep-
adjustments provided in the manufacturer’s labeling; atic coma. Use with caution in patients with depression or
use with caution. suicidal tendencies, or in patients with a history of drug
Severe impairment: Use is contraindicated. abuse or acute alcoholism. Tolerance, psychological and
Hepatic Impairment: Pediatric physical dependence may occur with prolonged use. Use
Mild-to-moderate impairment: There are no dosage with caution in patients with borderline hypoadrenal func-
adjustments provided in the manufacturer’s labeling; tion; even if it is of pituitary or of primary adrenal origin.
use with caution. Systemic effects of exogenous and endogenous cortico-
Severe impairment: Use is contraindicated. steroids may be diminished by amobarbital. Use with
Preparation for Administration Parenteral: IV: Dilute caution in patients with respiratory disease; may cause
prior to use to usual concentration of 0.2 mEq/mL; max- respiratory depression.
imum concentration: 0.4 mEq/mL
Administration Parenteral: !V: Must be diluted prior to May cause CNS depression, which may impair physical or
administration; administer by slow intravenous infusion to mental abilities. Patients must be cautioned about per-
avoid local irritation and adverse effects. Infuse over 3 forming tasks which require mental alertness (eg, operat-
hours; maximum rate of infusion: 1 mEq/kg/hour; in adults ing machinery or driving). Use of this agent as a hypnotic
rate of infusion should not exceed 5 mL/minute. in the elderly is not recommended. Abrupt cessation may
Monitoring Parameters Serum electrolytes, acid/base precipitate withdrawal, including delirium and convulsions
status, serum ammonia, signs/symptoms of ammonia (some fatal); withdraw gradually.
toxicity Rapid lV administration may cause respiratory depression,
Dosage Forms Excipient information presented when apnea, laryngospasm, or vasodilation with a fall in blood
available (limited, particularly for generics); consult spe-
pressure; avoid perivascular extravasation or intra-arterial
cific product labeling.
injection; discontinue if patient complains of pain in the
Injection, solution: Ammonium 5 mEq/mL and chloride 5 limb. Restrict use of IV administration to conditions in
mEq/mL (20 mL) [equivalent to ammonium chloride
which other routes are not feasible, if patient is uncon-
267.5 mg/mL]
scious (eg, cerebral hemorrhage, eclampsia, or status
@ Ammonium Hydroxide and Lactic Acid see Lactic Acid epilepticus) or patient resists (eg, delirium), or because
and Ammonium Hydroxide on page 1165 prompt action is imperative. Solution for injection is highly
alkaline and extravasation may cause local tissue damage
@ Ammonium Lactate see Lactic Acid and Ammonium
with subsequent necrosis. Potentially significant interac-
Hydroxide on page 1165
tions may exist, requiring dose or frequency adjustment,
# Ammonul see Sodium Phenylacetate and Sodium Ben- additional monitoring, and/or selection of alternative
zoate on page 1841 therapy.
® AMN107 see Nilotinib on page 1452 Warnings: Additional Pediatric Considerations Neo-
Amnesteem see |SOtretinoin (Systemic) on page 1135 nates may experience withdrawal symptoms with chronic
maternal use; monitor for closely. In pediatric patients,
barbiturates may produce paradoxical excitement.
Amobarbital (am oh BAR bi tal) Adverse Reactions Reported as barbiturate use (not
Medication Safety Issues specifically amobarbital).
Geriatric Patients: High-Risk Medication:—- Cardiovascular: Bradycardia, hypotension, syncope
Beers Criteria: Amobarbital is identified in the Beers Central nervous system: Abnormality in thinking, agitation,
Criteria as a potentially inappropriate medication to be anxiety, ataxia, central nervous system depression, con-
avoided in patients 65 years and older (independent of fusion, dizziness, drowsiness, hallucination, headache,
diagnosis or condition) due to its high rate of physical insomnia, nervousness, nightmares, psychiatric dis-
dependence, tolerance to sleep benefits, and turbance
increased risk of overdose at low dosages (Beers Gastrointestinal: Constipation, nausea, vomiting
Criteria [AGS 2015)). Hematologic & oncologic: Megaloblastic anemia (following
Pharmacy Quality Alliance (PQA): Amobarbital is identi- chronic phenobarbital use)
fied as a high-risk medication in patients 65 years and Hepatic: Hepatic injury
older on the PQA’s, Use of High-Risk Medications in Hypersensitivity: Hypersensitivity reaction (including
the Elderly (HRM) performance measure, a safety angioedema, skin rash, and exfoliative dermatitis)
measure used by the Centers for Medicare and Med- Local: Injection site reaction
icaid Services (CMS) for Medicare plans. Neuromuscular & skeletal: Hyperkinesia
Brand Names: US Amytal Sodium Respiratory: Apnea, atelectasis (postoperative), hypoven-
Therapeutic Category Anticonvulsant, Barbiturate; Bar- tilation
biturate; General Anesthetic; Hypnotic; Sedative Miscellaneous: Fever
Generic Availability (US) No vs Drug Interactions
Use Hypnotic in short-term treatment of insomnia; to Metabolism/Transport Effects None known.
reduce anxiety and provide sedation preoperatively Avoid Concomitant Use
(FDA approved in ages 26 years and adults); has also Avoid concomitant use of Amobarbital with any of the
been used for the intracarotid amobarbital procedure following: Azelastine (Nasal); Bromperidol; Hemin;
(Wada test) Methoxyflurane; Mianserin; Orphenadrine; Oxomema-
Pregnancy Risk Factor D zine; Paraldehyde; Somatostatin Acetate; Thalidomide;
Pregnancy Considerations Barbiturates cross the pla- Ulipristal; Voriconazole
centa and distribute in fetal tissue. Teratogenic effects Increased Effect/Toxicity
have been reported with 1st trimester exposure. Exposure Amobarbital may increase the levels/effects of: Alcohol
during the 3rd trimester may lead to symptoms of acute (Ethyl); Azelastine (Nasal); Blonanserin; Blood Pressure
withdrawal foilowing delivery; symptoms may be delayed Lowering Agents; Buprenorphine; CNS Depressants;
up to 14 days. Flunitrazepam; HYDROcodone; Methotrimeprazine;
Breastfeeding Considerations Small amounts of barbi- Methoxyflurane; MetyroSINE; Mirtazapine; Opioid Anal-
turates are excreted in breast milk; information specific for gesics; Orphenadrine; OxyCODONE; Paraldehyde; Pir-
amobarbital is not available. The manufacturer recom- ibedil; Pramipexole; ROPINIRole; Rotigotine; Selective
mends that caution be used if administered to a breast- Serotonin Reuptake Inhibitors; Suvorexant; Thalidomide;
feeding woman. Thiazide and Thiazide-Like Diuretics; Zolpidem

123
 AMOBARBITAL

| The levels/effects of Amobarbital may be increased by:

Brimonidine (Topical); Bromopride; Bromperidol; Canna-
Administration
Parenteral: Following reconstitution, dose must be admin-
bis; Chloramphenicol (Systemic); Chlormethiazole; istered within 30 minutes.
Chlorphenesin Carbamate; Dimethindene (Topical); IM: Administer deeply into a large muscle. Do not use
Doxylamine; Dronabinol; Droperidol; Felbamate; more than 5 mL at any single site (may cause tissue
HydrOXYzine; Kava Kava; Lofexidine; Magnesium Sul- damage)
fate; Methotrimeprazine; Mianserin; Minocycline; Nabi- \V: Use only when IM administration is not feasible.
lone; Oxomemazine; Perampanel; Primidone; Administer by slow IV injection (maximum rate:
Rufinamide; Sodium Oxybate; Somatostatin Acetate; 50 mg/minute in adults)
Tapentadol; Tetrahydrocannabinol; Trimeprazine; Val- Monitoring Parameters Vital signs should be monitored
proate Products during injection and for several hours after administration.
Decreased Effect If using IV, monitor patency of IV access; extravasation
Amobarbital may decrease the levels/effects of: Beta- may cause local tissue damage. Monitor hematologic,
Blockers; Calcium Channel Blockers; Chloramphenicol renal, and hepatic function with prolonged therapy.
(Systemic); CycloSPORINE (Systemic); Doxycycline; Reference Range
Estrogen Derivatives (Contraceptive); Felbamate; Gri- Therapeutic: 1-5 meg/mL (SI: 4-22 mol/L)
seofulvin; Hemin; LamoTRigine; Methoxyflurane; Mian- Toxic: >10 meg/mL (SI: >44 umol/L)
Lethal: >50 mcg/mL
serin; Progestins (Contraceptive); Propacetamol;
Teniposide; Theophylline Derivatives; Tricyclic Antide- Controlled Substance C-II
pressants; Ulipristal; Valproate Products; Vitamin K Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
Antagonists; Voriconazole
cific product labeling.
The levels/effects of Amobarbital may be decreased by: Solution Reconstituted, Injection, as sodium:
Mianserin; Multivitamins/Minerals (with ADEK, Folate, Amytal Sodium: 500 mg (1 ea)
Iron); Pyridoxine; Rifamycin Derivatives
@ Amobarbital Sodium see Amobarbital on page 123
Storage/Stability Store intact vials at 15°C to 30°C (59°F
to 86°F). Following reconstitution, solution should be used
within 30 minutes. Amoxicillin (a moks isit in)
Mechanism of Action An intermediate-acting barbitu-
tate; barbiturates depress the sensory cortex, decrease Medication Safety Issues
motor activity, and alter cerebellar function producing Sound-alike/look-alike issues:
drowsiness, sedation, and hypnosis. Amoxicillin may be confused with amoxapine, Augmentin
Amoxil may be confused with amoxapine
Pharmacodynamics/Kinetics (Adult data unless
International issues:
noted)
Fisamox [Australia] may be confused with Fosamax
Onset of action: Rapid, within minutes
brand name for alendronate [US, Canada, and multiple
Duration of action: Variable
international markets] and Vigamox brand name for
Metabolism: Primarily hepatic via microsomal enzymes moxifloxacin [US, Canada, and multiple international
Half-life elimination: 16 to 40 hours (mean: 25 hours) markets]
Time to peak: Maximum effect: Hours Limoxin [Mexico] may be confused with Lanoxin brand
Excretion: Urine (as metabolites, negligible amounts name for digoxin [US, Canada, and multiple interna-
excreted unchanged in urine); feces (metabolites) tional markets]; Lincocin brand name for lincomycin
Dosing (US, Canada, and multiple international markets]
Pediatric Note: Dosage should be individualized with Zimox: Brand name for amoxicillin [Italy], but also the
consideration of patient's age, weight, and medical con- brand name for carbidopa/levodopa [Greece]
dition. Use of amobarbital as a sedative and as a Zimox [Italy] may be confused with Diamox which is the
hypnotic for the treatment of insomnia and as a hypnotic brand name for acetazolamide [Canada and multiple
for preoperative sedation has been replaced by newer international markets]
agents. Related Information
Hypnotic (eg, preoperative sedation): Children 26 Oral Medications That Should Not Be Crushed or Altered
years and Adolescents: IM (preferred), !V: Usual on page 2217
recommendation (Limited data available): 2 to Brand Names: US Moxatag
3 mg/kg/dose; maximum dose: 500 mg/dose; dosing Brand Names: Canada Novamoxin; Pro-Amox-250; Pro-
based on generally recognized expert recommenda- Amox-500
tions; published pediatric trial data is lacking (Nelson Therapeutic Category Antibiotic, Penicillin
1996). The manufacturer describes the ordinary dose Generic Availability (US) Yes
range in children 6 to 12 years as 65 to 500 mg and Use
specific dosing recommendations based on patient Immediate release preparations (oral suspension, chew-
size are not available; however, in several instances, able tablets, tablets, and capsules): Treatment of infec-
this may exceed expert weight-based recommenda- tions of ear, nose, skin, and soft tissue; genitourinary
tions; if using manufacturer dosing, initiate therapy at tract; or upper or lower respiratory tract due to suscep-
the lower end of the range and titrate the dose tible (beta-lactamase negative) organisms (FDA
accordingly. approved in all ages); combination therapy of Helico-
Intracarotid amobarbital procedure (Wada test): Lim- bacter pylori (FDA approved in adults); has also been
ited data available; dosing regimens variable: Chil- used for the treatment of Lyme disease, prophylaxis of
dren 26 years and Adolescents: Intra-arterial: 75 to bacterial endocarditis, prophylaxis in sickle cell or
125 mg/dose; typically administered through femo- asplenic patients, prophylaxis of peritonitis in patients
ral arterial catheter; consult institution specific pro- undergoing dental treatment or treatment of exit-site or
tocols (Acharay 1997; Burns 2009; Hinz 1994; Kim tunnel infections in patients with peritoneal dialysis cath-
2007; Szabo 1993) eters, urinary tract infection prophylaxis, and postexpo-
Renal Impairment: Pediatric There are no dosage sure prophylaxis and treatment of anthrax
adjustments provided in the manufacturer's labeling; Extended release tablet (Moxatag): Treatment of tonsillitis
dosing should be reduced; specific recommendations and/or pharyngitis secondary to Streptococcus pyo-
genes (FDA approved in ages 212 years and adults)
not available.
Note: Although FDA approved for the treatment of acute
Hepatic Impairment: Pediatric There are no dosage
uncomplicated anogenital and urethral gonorrhea in men
adjustments provided in the manufacturer's labeling;
and women, clinical practice guidelines do not recom-
dosing should be reduced; specific recommendations mend amoxicillin for treatment of gonorrhea due to
not available; drug is contraindicated in patients with resistance (CDC [Workowski 2015])
marked hepatic impairment; avoid use in patients with Pregnancy Risk Factor B
premonitory signs of hepatic coma.
Pregnancy Considerations Adverse events have not
Preparation for Administration been observed in animal reproduction studies. Amoxicillin
Parenteral: Following reconstitution, dose must be admin- crosses the placenta (Muller 2009). Maternal use of
istered within 30 minutes. amoxicillin has generally not resulted in an increased risk
IM: Reconstitute with 2.5 mL of SWFI to make a 20% of adverse fetal effects; however, a possible association
solution. Rotate vial to dissolve, do not shake. Do not with cleft lip with cleft palate has been observed in some
use unless a clear solution forms within 5 minutes. studies (more data is needed) (Lin 2012; Puhdé 2007).
IV: Reconstitute with 5 mL of SWFI to make a 10% IV Amoxicillin may be used for the management of Bacillus
‘solution; if other concentrations are necessary see anthracis in pregnant women when penicillin susceptibility
manufacturer's labeling for detailed instructions. Rotate is documented (Meaney-Delman 2014). Amoxicillin is an
vial to dissolve, do not shake. Do not use unless a clear alternative antibiotic for the treatment of chlamydial infec-
solution forms within 5 minutes. tions in pregnancy (CDC [Workowski 2015]). Amoxicillin

124
 AMOXICILLIN

can also be used in the management of preterm prema- of children receiving amoxicillin and is a generalized dull,
ture rupture of membranes and in certain situations prior red, maculopapular rash, generally appearing 3 to 14 days
to vaginal delivery in women at high risk for endocarditis after the start of therapy. It normally begins on the trunk
(ACOG 120 2011; ACOG 139 2013). and spreads over most of the body. It may be most intense
at pressure areas, elbows, and knees. A high percentage
Due to pregnancy-induced physiologic changes, some
(43% to 100%) of patients with infectious mononucleosis
pharmacokinetic parameters of amoxicillin may be altered
have developed rash during therapy; amoxéicillin-class
(Andrew 2007). Oral ampicillin-class antibiotics are poorly
antibiotics are not recommended in these patients.
absorbed during labor.
Adverse Reactions
Breastfeeding Considerations Amoxicillin is excreted
Cardiovascular: Hypersensitivity angiitis
in breast milk (Kafetzis 1981).
Central nervous system: Agitation, anxiety, behavioral
The relative infant dose (RID) of amoxicillin is 0.15% to changes, confusion, dizziness, headache, hyperactivity
0.54% when calculated using the highest average breast (reversible), insomnia, seizure
milk concentration located: and compared to an infant Dermatologic: Acute generalized exanthematous pustulo-
therapeutic dose of 25 to 90 mg/kg/day. In general, sis, erythematous maculopapular rash, erythema multi-
breastfeeding is considered acceptable when the RID is forme, exfoliative dermatitis, Stevens-Johnson
<10%} when an RID is >25% breastfeeding should gen- syndrome, toxic epidermal necrolysis, urticaria
erally be avoided (Anderson 2016; Ito 2000). Using the Gastrointestinal: Dental discoloration (brown, yellow, or
highest average milk concentration (0.9 mcg/mL), the gray; rare), diarrhea, hemorrhagic colitis, melanoglossia,
estimated daily infant dose via breast milk is mucocutaneous candidiasis, nausea, pseudomembra-
0.135 mg/kg/day. This milk concentration was obtained nous colitis, vomiting
following maternal administration of a single oral dose of Genitourinary: Crystalluria
-amoxicillin 1,000 mg (Kafetzis 1981). Hematologic & oncologic: Agranulocytosis, anemia, eosi-
nophilia, hemolytic anemia, leukopenia,thrombocytope-
Self-limiting diarrhea, rash, and somnolence have been nia, thrombocytopenia purpura
reported in nursing infants exposed to amoxicillin (Benya- Hepatic: Cholestatic hepatitis, cholestatic jaundice, hep-
mini 2005; Goldstein 2009; Ito 1993); the manufacturer atitis (acute cytolytic), increased serum ALT, increased
warns of the potential for allergic sensitization in the infant. serum AST
In general, antibiotics that are present in breast milk may Hypersensitivity: Anaphylaxis
cause nondose-related modification of bowel flora. Mon- Immunologic: Serum sickness-like reaction
itor infants for GI disturbances, such as thrush or diarrhea Drug Interactions
(WHO 2002). Metabolism/Transport Effects None known.
Although the manufacturer recommends that caution be Avoid Concomitant Use
exercised when administering amoxicillin to breastfeeding Avoid concomitant use of Amoxicillin with any of the
women, amoxicillin is considered compatible with breast- following: BCG (Intravesical); Cholera Vaccine
feeding when used in usual recommended doses (WHO Increased Effect/Toxicity
2002). Amoxicillin has been recommended to treat masti- Amoxicillin may increase the levels/effects of: Methotrex-
tis in breastfeeding women when penicillin susceptibility is ate; Vitamin K Antagonists
documented (WHO 2000) and also for the management of
The levels/effects of Amoxicillin may be increased by:
Bacillus anthracis (Meaney-Delman 2014).
Acemetacin; Allopurinol; Probenecid
Contraindications
Decreased Effect
Serious hypersensitivity to amoxicillin (eg, anaphylaxis,
Amoxicillin may decrease the levels/effects of: BCG
Stevens-Johnson syndrome) or to other beta-lactams,
(Intravesical); BCG Vaccine (Immunization); Cholera
or any component of the formulation
Vaccine; Lactobacillus and Estriol; Mycophenolate;
Canadian labeling: Additional contraindications (not in US
Sodium Picosulfate; Typhoid Vaccine
labeling): Infectious mononucleosis (Suspected or con-
firmed) The levels/effects of Amoxicillin may be decreased by:
Warnings/Precautions In patients with renal impairment, Tetracyclines
doses and/or frequency of administration should be modi- Storage/Stability Store at room temperature. Reconsti-
fied in response to the degree of renal impairment; dosage tuted oral suspension remains stable for 14 days at room
adjustment recommended in patients with GFR <30 mL/ temperature or refrigerated (refrigeration preferred). Unit-
minute. Avoid extended release 775 mg tablet and imme- dose antibiotic oral syringes are stable at room temper-
diate release 875 mg tablet in patients with GFR <30 mL/ ature for at least 72 hours (Tu 1988).
minute or patients requiring hemodialysis. A high percent- Mechanism of Action Inhibits bacterial cell wall syn-
age of patients with infectious mononucleosis develop an thesis by binding to one or more of the penicillin-binding
erythematous rash during amoxicillin therapy; avoid use in proteins (PBPs) which in turn inhibits the final transpepti-
these patients. Serious and occasionally severe or fatal dation step of peptidoglycan synthesis in bacterial cell
hypersensitivity (anaphylactic) reactions have been walls, thus inhibiting cell wall biosynthesis. Bacteria even-
reported in patients on penicillin therapy, including amox- tually lyse due to ongoing activity of cell wall autolytic
icillin, especially with a history of beta-lactam hypersensi- enzymes (autolysins and murein hydrolases) while cell
tivity (including severe reactions with cephalosporins) and/ wall assembly is arrested.
or a history of sensitivity to multiple allergens. Prolonged Pharmacodynamics/Kinetics (Adult data unless
use may result in fungal or bacterial superinfection, includ- noted)
ing C. difficile-associated diarrhea (CDAD) and pseudo- Absorption: Oral:
membranous colitis; CDAD has been observed >2 months Immediate-release: Rapid with or without food
postantibiotic treatment. Potentially significant interactions Extended-release: Rate of absorption is slower com-
may exist, requiring dose or frequency adjustment, addi- pared to immediate-release formulations; food
tional monitoring, and/or selection of alternative therapy. decreases the rate but not extent of absorption
Distribution: Readily into liver, lungs, prostate, muscle,
Chewable tablets may contain phenylalanine; see manu-
middle ear effusions, maxillary sinus secretions, bone,
facturer’s labeling.
gallbladder, bile, and into ascitic and synovial fluids; poor
Benzyl alcohol and derivatives: Some dosage forms may CSF penetration (except when meninges are inflamed)
contain sodium benzoate/benzoic acid; benzoic acid (ben- Protein binding: ~20%
zoate) is a metabolite of benzyl alcohol; large amounts of Half-life elimination: Adults: Immediate-release: 61.3
benzyl alcohol (299 mg/kg/day) have been associated minutes; Extended-release: 90 minutes
with a potentially fatal toxicity ("gasping syndrome") in Time to peak: Capsule, oral suspension: 1 to 2 hours;
neonates; the "gasping syndrome" consists of metabolic Chewable tablet: 1 hour; Extended-release: 3.1 hours
acidosis, respiratory distress, gasping respirations, CNS Excretion: Urine (60% as unchanged drug) lower in neo-
dysfunction (including convulsions, intracranial hemor- nates
rhage), hypotension, and cardiovascular collapse (AAP Dosing
["Inactive" 1997]; CDC 1982); some data suggests that Neonatal Note: All neonatal dosing recommendations
benzoate displaces bilirubin from protein binding sites based on immediate release product formulations (ie,
(Ahlfors 2001); avoid or use dosage forms containing oral suspension).
benzyl alcohol derivative with caution in neonates. See General dosing, susceptible infection: Oral: 20 to
manufacturer’s labeling. 30 mg/kg/day in divided doses every 12 hours
Warnings: Additional Pediatric Considerations Otitis media, acute (AOM), Group A or B streptococ-
Epstein-Barr virus infection (infectious mononucleosis), cus: Oral stepdown therapy after IV/IM penicillin or
acute lymphocytic leukemia, or cytomegalovirus infection ampicillin: Oral: 30 to 40 mg/kg/day in divided doses
increases risk for amoxicillin-induced maculopapular rash. every 8 hours (Bradley 2015)
Appearance of a rash should be carefully evaluated to UTI, prophylaxis (hydronephrosis, vesicoureteral
differentiate a nonallergic amoxicillin rash from a hyper- reflux): Oral: 10 to 15 mg/kg once daily (Belarmino
sensitivity reaction. Amoxicillin rash occurs in 5% to 10% 2006; Greenbaum 2006; Mattoo 2007)

125
AMOXICILLIN

Pediatric Pneumonia, community-acquired: Infants 23

Note: Unless otherwise specified, all pediatric dosing months, Children, and Adolescents (IDSA [Bradley
recommendations based on immediate release product 2011]):
formulations (oral suspension, chewable tablet, tablet, Empiric therapy for presumed bacterial pneumonia:
and capsule). Oral: 90 mg/kg/day in divided doses every 12 hours;
General dosing, susceptible infection: maximum daily dose: 4,000 mg/day
Mild to moderate infection: Group A Streptococcus, mild infection or step-down
Infants $3 months: Oral: 25 to 50 mg/kg/day in therapy: Oral: 50 to 75 mg/kg/day in divided doses
divided doses every 8 hours (Red Book [AAP every 12 hours; maximum daily dose: 4,000 mg/day
2015]). Note: Manufacturer's labeling recom- Haemophilus influenzae, mild infection or step-down
mends a maximum daily dose of 30 mg/kg/day therapy: Oral: 75 to 100 mg/kg/day in divided doses
divided into 2 doses per day for this age group. every 8 hours; maximum daily dose: 4,000 mg/day
Infants >3 months, Children, and Adolescents: Streptococcus pneumonia (penicillin MIC <2
AAP recommendations (Red Book [AAP 2015)): meg/mL); mild infection or step-down therapy: Oral:
Oral: 25 to 50 mg/kg/day in divided doses every 90 mg/kg/day in divided doses every 12 hours or
8 hours; maximum dose: 500 mg/dose 45 mg/kg/day in divided doses every 8 hours; max-
Manufacturer's labeling: Oral: 20 to 40 mg/kg/day imum daily dose: 4,000 mg/day
in divided doses every 8 hours (maximum dose: Pneumococcal infection prophylaxis for anatomic
500 mg/dose) or 25 to 45 mg/kg/day in divided or functional asplenia [eg, sickle cell disease
doses every 12 hours (maximum dose: (SCD)] (Price 2007; Red Book [AAP 2015)):
875 mg/dose) Before 2 months of age (or as soon as SCD is
Severe infection (as step-down therapy): Infants, Chil- diagnosed or asplenia occurs) through 5 years of
dren, and Adolescents: Oral: 80 to 100 mg/kg/day in age: Oral: 20 mg/kg/day in divided doses every 12
divided doses every 8 hours; maximum dose: hours; maximum dose: 250 mg/dose
500 mg/dose for most indications (Red Book Children 26 years and Adolescents: Oral: 250 mg
[AAP 2015]) every 12 hours; Note: The decision to discontinue
Anthrax: penicillin prophylaxis after 5 years of age in children
who have not experienced invasive pneumococcal
Cutaneous, without systemic involvement: Infants,
infection and have received recommended pneumo-
Children, and Adolescents: Oral: 75 mg/kg/day in 3
coccal immunizations is patient and clinician
divided doses. Maximum dose: 1,000 mg/dose.
dependent.
Duration of therapy: 7 to 10 days for naturally
Rhinosinusitis, acute bacterial; uncomplicated:
acquired infection, up to 60 days for biological
Note: AAP guidelines recommend amoxicillin as
weapon-related exposure (AAP [Bradley 2014)).
first-line empiric therapy for pediatric patients 1 to
Inhalational, postexposure prophylaxis: Infants, Chil-
18 years with uncomplicated cases and where resist-
dren, and Adolescents: Oral: 75 mg/kg/day in div-
ance is not suspected; however, the IDSA guidelines
ided doses every 8 hours for 60 days after exposure;
consider amoxicillin/clavulanate as the preferred ther-
maximum dose: 1,000 mg/dose (AAP [Brad-
apy (IDSA [Chow 2012]; AAP [Wald 2013)):
ley 2014)).
Low dose: Children 22 years and Adolescents: Oral:
Catheter (peritoneal dialysis), exit-site or tunnel
45 mg/kg/day in divided doses every 12 hours;
infection: Infants, Children, and Adolescents: Oral:
Note: Only use for uncomplicated, mild to moderate
10 to 20 mg/kg once daily; maximum dose: 1,000 mg/
infections in children who do not attend daycare and
dose (ISPD [Warady 2012])
who have not received antibiotics within the last
Endocarditis, prophylaxis: Note: AHA guidelines
month (AAP [Wald 2013]).
(Baltimore 2015) limit the use of prophylactic anti-
High dose (use reserved for select patients; see
biotics to patients at the highest risk for infective
Note): Children 22 years and Adolescents: Oral:
endocarditis (IE) or adverse outcomes (eg, prosthetic 80 to 90 mg/kg/day in divided doses every 12 hours;
heart valves, patients with previous IE, unrepaired
maximum dose: 2,000 mg/dose; Note: Should only
cyanotic congenital heart disease, repaired congenital use for mild to moderate infections in children who
heart disease with prosthetic material or device during do not attend daycare and who have not received
first 6 months after procedure, repaired congenital
antibiotics within the last month and live in commun-
heart disease with residual defects at the site or ities with a high prevalence of nonsusceptible S.
adjacent to site of prosthetic patch or device, heart pneumoniae resistance (AAP [Wald 2013]).
transplant recipients with cardiac valvulopathy): Tonsillopharyngitis; Group A streptococcal infec-
Dental or oral procedures or respiratory tract proce- tion, treatment and primary prevention of rheu-
dures (eg, tonsillectomy, adenoidectomy): \nfants, matic fever:
Children, and Adolescents: Oral: 50 mg/kg 30 to Immediate release (oral suspension, chewable tab-
60 minutes before procedure; maximum dose: lets, tablets, capsules): Children and Adolescents 3
2,000 mg/dose (AHA [Wilson 2007]) to 18 years: Oral: 50 mg/kg once daily or 25 mg/kg
H. pylori eradication: Children and Adolescents: Oral: twice daily for 10 days; maximum daily dose:
50 mg/kg/day in 2 divided doses for 10 to 14 days. 1,000 mg/day (AHA [Gerber 2009]; IDSA [Shul-
Note: Duration dependent on regimen used; maxi- man 2012])
mum daily dose: 2,000 mg/day. Administer in combi- Extended release tablets: Children 212 years, and
nation with a proton pump inhibitor or bismuth Adolescents: Oral: 775 mg once daily for 10 days;
subsalicylate and at least one other antibiotic (clari- Note: Patient must be able to swallow tablet whole.
thromycin and/or metronidazole) (NASPGHAN/ UTI, prophylaxis (hydronephrosis, vesicoureteral
ESPGHAN [Koletzko 2011)). reflux): Infants <2 months: Oral: 10 to 15 mg/kg once
Lyme disease: Infants, Children, and Adolescents: daily; some suggest administration in the evening
Oral: 50 mg/kg/day in divided doses every 8 hours; (drug resides in bladder longer); Note: Due to resist-
maximum dose: 500 mg/dose (Halperin 2007; IDSA ance, amoxicillin should not be used for prophylaxis
[Wormser 2006]) after 2 months of age (Belarmino 2006; Greenbaum
Otitis media, acute (AOM): Infants 22 months and 2006; Mattoo 2007).
Children: Oral: 80 to 90 mg/kg/day in divided doses Renal Impairment: Pediatric
every 12 hours; variable duration of therapy, if <2 There are no dosage adjustments provided in the
years of age or severe symptoms (any age): 10-day manufacturer's labeling; however, the following guide-
course; if 2 to 5 years of age with mild to moderate lines have been used by some clinicians (Aronoff
symptoms: 7-day course; 26 years of age with mild to 2007): Oral:
moderate symptoms: 5- to 7-day course; some Immediate release: Infants, Children, and Adoles-
experts recommend initiating with 90 mg/kg/day cents:
(AAP. [Lieberthal 2013]; Red Book [AAP 2015]); a Mild to moderate infection: Dosing based on 25 to
maximum dose is not provided in the Guidelines for 50 mg/kg/day divided every 8 hours:
The Diagnosis and Management of Acute Otitis Media GFR >30 mL/minute/1.73 m?: No adjustment
(AAP [Lieberthal 2013]); however, some experts sug- required
gest a maximum daily dose of 4,000 mg/day for high- GFR 10 to 29 mL/minute/1.73 m?: 8 to 20 mg/kg/
dose amoxicillin therapy (Bradley 2015). dose every 12 hours
Peritonitis (peritoneal dialysis), prophylaxis for GFR <10 mL/minute/1.73 m?: 8 to 20 mg/kg/dose
patients requiring invasive dental procedures: every 24 hours
Infants, Children, and Adolescents: Oral: 50 mg/kg Hemodialysis: Moderately dialyzable (20% to
administered 30 to 60 minutes before dental proce- 50%); ~30% removed by 3-hour hemodialysis: 8
dure; maximum dose: 2,000 mg/dose (ISPD to 20 mg/kg/dose every 24 hours; give after
[Warady 2012]) dialysis

126
 AMOXICILLIN AND CLAVULANATE

Peritoneal dialysis: 8 to 20 mg/kg/dose every 24 sensitivity; however, use is not recommended in the
hours management of preterm premature rupture of mem-
Severe infection (high dose): Dosing based on 80 to branes. Oral ampicillin-class antibiotics are poorly
90 mg/kg/day divided every 12 hours: absorbed during labor.
GFR >30 mL/minute/1.73 m?: No adjustment Breastfeeding Considerations Amoxicillin is excreted
required in breast milk following administration amoxicillin/clavula-
GFR 10 to 29 mL/minute/1.73 m?: 20 mg/kg/dose nate (Weber 1984).
every 12 hours; do not use the 875 mg tablet
GFR <10 mL/minute/1.73 m?: 20 mg/kg/dose The relative infant dose (RID) of amoxicillin following
every 24 hours; do not use the 875 mg tablet administration of amoxicillin/clavulanate is 0.02% to
Hemodialysis: Moderately dialyzable (20% to 0.07% when calculated using the highest average breast
50%); ~30% removed by 3-hour hemodialysis: milk concentration located and compared to an infant
20 mg/kg/dose every 24 hours; give after dialysis therapeutic dose of 25 to 90 mg/kg/day. In general,
Peritoneal dialysis: 20 mg/kg/dose every 24 hours breastfeeding is considered acceptable when the RID is
Extended release: Children 212 years and Adoles- <10%; when an RID is >25% breastfeeding should gen-
cents: CrCl <30 mL/minute: Not recommended erally be avoided (Anderson 2016; Ito 2000). Using the
Hepatic Impairment: Pediatric There are no dosage highest average milk concentration (0.12 mcg/mL), the
adjustments provided in the manufacturer's labeling. estimated daily infant dose via breast milk is
Preparation for Administration Oral: Immediate 0.018 mg/kg/day. This milk concentration was obtained 4
release: Reconstitute powder for oral suspension with to 6 hours following maternal administration of oral amox-
appropriate amount of water as specified on the bottle. icillin/clavulanate 250 mg/125 mg (Takase 1982).
Shake vigorously until suspended.
Constipation, diarrhea, restlessness, and rash have been
Administration Oral:
Immediate release: May be administered on an empty or reported in breastfeeding infants exposed to amoxicillin
full stomach; may be mixed with formula, milk, cold drink, and clavulanate; reversible elevations in AST and ALT
or juice; administer dose immediately after mixing; shake have been noted in one infant (Benyamini 2005). The
suspension well before use. manufacturer warns of the potential for allergic sensitiza-
Extended release: Take within 1 hour of finishing a meal; tion in the infant. In general, antibiotics that are present in
do not chew or crush tablet. breast milk may cause nondose-related modification of
Monitoring Parameters With prolonged therapy, monitor bowel flora. Monitor infants for GI disturbances, such as
renal, hepatic, and hematologic function periodically; thrush and diarrhea (WHO 2002).
observe for change in bowel frequency; monitor for signs Although the manufacturer recommends that caution be
of anaphylaxis during first dose exercised when administering amoxicillin and clavulanate
Test Interactions to breastfeeding women, amoxicillin/clavulanate is consid-
May interfere with urinary glucose tests (Benedict's sol- ered compatible with breastfeeding when used in usual
ution, Clinitest, Fehling’s Solution).
recommended doses (WHO 2002).
Some penicillin derivatives may accelerate the degrada-
Contraindications
tion of aminoglycosides in vitro, leading to a potential
Hypersensitivity to amoxicillin, clavulanic acid, other beta-
underestimation of aminoglycoside serum concentration.
lactam antibacterial drugs (eg, penicillins, cephalospor-
Dosage Forms Excipient information presented when
ins), or any component of the formulation; history of
available (limited, particularly for generics); consult spe-
cholestatic jaundice or hepatic dysfunction with amox-
cific product labeling. [DSC] = Discontinued product
Capsule, Oral:
icillin/clavulanate potassium therapy
Generic: 250 mg, 500 mg Augmentin XR: Additional contraindications: Severe renal
Suspension Reconstituted, Oral: impairment (creatinine clearance <30 mL/minute) and
Generic: 125 mg/5 mL (80 mL, 100 mL, 150 mL); hemodialysis patients
200 mg/5 mL (50 mL, 75 mL, 100 mL); 250 mg/5 mL Canadian labeling: Additional contraindications (not in US
(80 mL, 100 mL, 150 mL); 400 mg/5 mL (50 mL, 75 mL, labeling): Suspected or confirmed mononucleosis
100 mL) Warnings/Precautions Hypersensitivity reactions,
Tablet, Oral: including anaphylaxis (some fatal), have been reported.
Generic: 500 mg, 875 mg Prolonged use may result in fungal or bacterial super-
Tablet Chewable, Oral:
infection, including C. difficile-associated diarrhea (CDAD)
Generic: 125 mg, 250 mg
and pseudomembranous colitis; CDAD has been
Tablet Extended Release 24 Hour, Oral:
observed >2 months postantibiotic treatment. Although
Moxatag: 775 mg [contains cremophor el, fd&c blue #2
rarely fatal, hepatic dysfunction (eg, cholestatic jaundice,
aluminum lake]
hepatitis) has been reported. Patients at highest risk
Generic: 775 mg [DSC]
include those with serious underlying disease or concom-
itant medications. Hepatic toxicity is usually reversible.
Amoxicillin and Clavulanate Monitor liver function tests at regular intervals in patients
(a moks i SIL in & klav yoo LAN ate) with hepatic impairment. High percentage of patients with
infectious mononucleosis have developed rash during
Medication Safety Issues
Sound-alike/look-alike issues: therapy; ampicillin class antibiotics not recommended in
Augmentin may be confused with amoxicillin, Azulfidine these patients. Incidence of diarrhea is higher than with
Related Information amoxicillin alone. Due to differing content of clavulanic
acid, not all formulations are interchangeable; use of an
Oral Medications That Should Not Be Crushed or Altered
on page 2217 inappropriate product for a specific dosage could result in
either diarrhea (which may be severe) or subtherapeutic
Brand Names: US Augmentin; Augmentin ES-600; Aug-
mentin XR clavulanic acid concentrations leading to decreased clin-
Brand Names: Canada Amoxi-Clav; Apo-Amoxi-Clav;
ical efficacy. Low incidence of cross-allergy with cepha-
Clavulin; Novo-Clavamoxin; ratio-Aclavulanate losporins exists. Monitor renal, hepatic, and hematopoietic
Therapeutic Category Antibiotic, Beta-lactam and Beta- function if therapy extends beyond approved duration
lactamase Combination; Antibiotic, Penicillin times. Some products contain phenylalanine. Potentially
Generic Availability (US) Yes : significant drug-drug interactions may exist, requiring
dose or frequency adjustment, additional monitoring,
Use Infections caused by susceptible organisms involving
the lower respiratory tract, otitis media, sinusitis, skin and and/or selection of alternative therapy.
skin structure, and urinary tract; spectrum same as amox- Warnings: Additional Pediatric Considerations
icillin in addition to beta-lactamase producing M. catar- Epstein-Barr virus infection (infectious mononucleosis),
rhalis, H. influenzae, N. gonorrhoeae, and S. aureus acute lymphocytic leukemia, or cytomegalovirus infection
(excluding MRSA) (FDA approved in all ages) increase risk for penicillin-induced maculopapular rash.
Pregnancy Risk Factor B Appearance of a rash should be carefully evaluated to
Pregnancy Considerations Adverse events have not differentiate a nonallergic ampicillin rash from a hyper-
been observed in animal reproduction studies. Both amox- sensitivity reaction; rash occurs in 5% to 10% of children
icillin and clavulanic acid cross the placenta. Maternal use and is a generalized dull red, maculopapular rash, gen-
of amoxicillin/clavulanate has generally not resulted in an erally appearing 3 to 14 days after the start of therapy. It
increased risk of birth defects. A possible increased risk of normally begins on the trunk and spreads over most of the
necrotizing enterocolitis in neonates or bowel disorders in body. It may be most intense at pressure areas, elbows,
children exposed’to amoxicillin/clavulanate in utero has and knees. A high percentage (43% to 100%) of patients
been observed. In women with acute infections during with infectious mononucleosis have developed rash dur-
pregnancy, amoxicillin/clavulanate may be given if an ing therapy; ampicillin-class antibiotics are not recom-
antibiotic is required and appropriate based on bacterial mended in these patients.

say
 AMOXICILLIN AND CLAVULANATE

€ Adverse Reactions General dosing, susceptible infection: Oral:

Dermatologic: Diaper rash, skin rash, urticaria Infants <3 months: 30 mg amoxicillin/kg/day divided
Gastrointestinal: Abdominal distress, diarrhea, loose every 12 hours using the 125 mg/5 mL oral suspen-
stools, nausea, vomiting sion only /
Genitourinary: Vaginitis Infants 23 months, Children, and Adolescents:
Infection: Candidiasis, vaginal mycosis Mild to moderate infection:
Rare but important or life-threatening: Cholestatic jaun- Patients weighing <40 kg: Immediate release for-
dice, flatulence, headache, hepatic insufficiency, hepati- mulations:
tis, hepatotoxicity (idiosyncratic) (Chalasani, 2014), Twice daily dosing: 25 mg amoxéicillin/kg/day in
increased liver enzymes, increased serum alkaline phos- divided doses twice daily using the 200 mg/5
phatase, prolonged prothrombin time, thrombocythemia, mL or 400 mg/5 mL oral suspension or the
vasculitis (hypersensitivity) 200 mg or 400 mg chewable tablets; maximum
Additional adverse reactions seen with ampicillin-class single dose: 500 mg amoxicillin
antibiotics: Acute generalized exanthematous pustulo- Three times daily dosing: 20 mg amoxicillin/kg/
sis, agitation, agranulocytosis, anaphylaxis, anemia, day in divided doses 3 times daily using the
angioedema, anxiety, behavioral changes, confusion, 125 mg/5 mL or 250 mg/5 mL oral suspension;
convulsions, crystalluria, dental discoloration, dizziness, maximum single dose: 500 mg amoxicillin
dyspepsia, enterocolitis, eosinophilia, erythema multi- Patients weighing 240 kg: Immediate release for-
forme, exfoliative dermatitis, gastritis, glossitis, hematu- mulations:
ria, hemolytic anemia, hemorrhagic colitis, hyperactivity, Twice.daily dosing: 500 mg amoxicillin every 12
immune thrombocytopenia, increased serum bilirubin,
hours using 500 mg tablet; or if difficulty swal-
lowing, the 125 mg/5 mL or 250 mg/5mL oral
increased serum transaminases, insomnia, interstitial
suspension may be used
nephritis, leukopenia, melanoglossia, mucocutaneous
Three times daily dosing: 250 mg amoxicillin
candidiasis, pruritus, pseudomembranous colitis, serum
every 8 hours using the 250 mg tablet
sickness-like reaction, Stevens-Johnson syndrome, sto-
More severe infection:
matitis, thrombocytopenia, toxic epidermal necrolysis
Patients weighing <40 kg: /mmediate release for-
Drug Interactions
mulations:
Metabolism/Transport Effects None known. Twice daily dosing: 45 mg amoxicillin/kg/day in
Avoid Concomitant Use divided doses twice daily using the 200 mg/5
Avoid concomitant use of Amoxicillin and Clavulanate mL or 400 mg/5 mL oral suspension or the
with any of the following: BCG (Intravesical); Cholera 200 mg or 400 mg chewable tablets; maximum
Vaccine single dose: 875 mg amoxicillin
Increased Effect/Toxicity Three times daily dosing: 40 mg amoxicillin/kg/
Amoxicillin and Clavulanate may increase the levels/ day in divided doses 3 times daily using the
effects of: Methotrexate; Vitamin K Antagonists 125 mg/5 mL or 250 mg/5 mL oral suspension;
The levels/effects of Amoxicillin and Clavulanate may be maximum single dose: 500 mg amoxicillin
increased by: Acemetacin; Allopurinol; Probenecid Patients weighing 240 kg:
Decreased Effect Immediate release formulations:
Twice daily dosing: 875 mg amoxicillin every 12
Amoxicillin and Clavulanate may decrease the levels/
hours using the 875 mg tablet, or if difficulty
effects of: BCG (Intravesical); BCG Vaccine (Immuniza-
swallowing, the 200 mg/5 mL or the 400 mg/5
tion); Cholera Vaccine; Lactobacillus and Estriol; Myco-
mL oral suspension may be used
phenolate; Sodium Picosulfate; Typhoid Vaccine
Three times daily dosing: 500 mg amoxicillin
The levels/effects of Amoxicillin and Clavulanate may be every 8 hours using the 500 mg tablet, or if
decreased by: Tetracyclines difficulty swallowing, the 125 mg/5 mL or
Storage/Stability 250 mg/S5mL oral suspension may be used
Powder for oral suspension: Store dry powder at or below. Extended release tablet: 2,000 mg amoxicillin
25°C (77°F). Reconstituted oral suspension should be every 12 hours.
kept in refrigerator. Discard unused suspension after 10 Otitis media, acute: Infants 23 months and Children:
days (consult manufacturer's labeling for specific recom- Oral: 90 mg amoxicillin/kg/day divided every 12 hours
mendations). Unit-dose antibiotic oral syringes are stable for up to 10 days using the 600 mg/5 mL oral sus-
under refrigeration for 24 hours (Tu 1988). pension only in children with severe illness, who have
Tablet: Store at or below 25°C (77°F). Dispense in original received amoxicillin in the past 30 days, who have
container. treatment failure at 48 to 72 hours on first-line therapy,
Mechanism of Action Clavulanic acid binds and inhibits and when coverage for B-lactamase positive H. influ-
beta-lactamases that inactivate amoxicillin resulting in enzae and M. catarrhalis is needed. Variable duration
amoxicillin having an expanded spectrum of activity. of therapy; the manufacturer suggests 10-day course
Amoxicillin inhibits bacterial cell wall synthesis by binding in all patients, however new data suggests a shorter-
to one or more of the penicillin-binding proteins (PBPs) course in some cases: If <2 years of age or severe
which in turn inhibits the final transpeptidation step of symptoms (any age): 10-day course; if 2 to 5 years of
peptidoglycan synthesis in bacterial cell walls, thus inhibit- age with mild to moderate symptoms: 7-day course; if
ing cell wall biosynthesis. Bacteria eventually lyse due to 26 years of age with mild to moderate symptoms: 5- to
ongoing activity of cell wall autolytic enzymes (autolysins 7-day course (AAP [Lieberthal 2013]). Note: Per the
manufacturer, the 600 mg/5 mL formulation should
and murein hydrolases) while cell wall assembly is
arrested.
only be used for patients weighing <40 kg.
Pneumonia, community-acquired: Infants 23
Pharmacodynamics/Kinetics (Adult data unless
months, Children, and Adolescents: Oral:
noted) Amoxicillin pharmacokinetics are not affected by
Manufacturer's labeling:
clavulanic acid.
Patients weighing <40 kg: Immediate release for-
Amoxicillin: See individual Amoxicillin monograph.
mulations:
Clavulanic acid:
Twice daily dosing: 45 mg amoxicillin/kg/day in
Protein binding: ~25% divided doses twice daily using the 200 mg/5
Half-life elimination: 1 hour mL or 400 mg/5 mL oral suspension or the
Time to peak: 1.5 hours 200 mg or 400 mg chewable tablets; maximum
Excretion: Urine (25% to 40% as unchanged drug) single dose: 875 mg amoxicillin
Dosing Three times daily dosing: 40 mg amoxicillin/kg/day _
Neonatal Note: Dosing based on amoxicillin component; in divided doses 3 times daily using the 125 mg/5
dose and frequency are product specific; not all products mL or 250 mg/5 mL oral suspension; maximum
are interchangeable, using a product with the incorrect single dose: 500 mg amoxicillin
amoxicillin:clavulanate ratio could result in subtherapeu- Patients weighing 240 kg:
tic clavulanate concentrations or severe diarrhea. Immediate release formulations:
General dosing, susceptible infection: Oral: 30 mg Twice daily dosing: 875 mg amoxicillin every 12
amoxicillin/kg/day divided every 12 hours using the hours using the 875 mg tablet or if difficulty
125 mg/5 mL suspension only swallowing, the 200 mg/5 mL or the 400 mg/5
Pediatric mL oral suspension may be used
Note: Dosing based on amoxicillin component; dose and Three times daily dosing: 500 mg amoxicillin
frequency are product specific; not all products are every 8 hours using the 500 mg tablet or if
interchangeable; using a product with the incorrect difficulty swallowing, the 125 mg/5 mL or
amoxicillin:clavulanate ratio could result in subthera- 250 mg/S5mL oral suspension may be used
peutic clavulanic acid concentrations or severe diar- Extended release tablet: 2,000 mg amoxicillin
rhea. every 12 hours

128
 AMOXICILLIN AND CLAVULANATE

Alternate dosing: IDSA guidelines; beta-lactamase CrCl 10 to 29 mL/minute/1.73 m?: 20 mg amoxicillin/

positive H. influenzae strains (Bradley 2011): /mme- kg/dose every 12 hours; do not use the 875 mg
diate release formulations: tablet
Standard dose: 45 mg amoxicillin/kg/day in divided CrCl <10 mL/minute/1.73 m?: 20 mg amoxicillin/kg/
doses 3 times daily using the 125 mg/5 mL or dose every 24 hours; do not use the 875 mg tablet
250 mg/5 mL oral suspension formulation; if Hemodialysis: 20 mg amoxéicillin/kg/dose every 24
patient >40 kg, may also use 500 mg tablet; max- hours; give after dialysis; do not use the 875 mg
imum single dose: 500 mg amoxicillin tablet
High dose: 90 mg amoxicillin/kg/day in divided Peritoneal dialysis: 20 mg amoxicillin/kg/dose every
doses 2 times daily using the 600 mg/5 mL oral 24 hours; do not use the 875 mg tablet
suspension formulation. A wider dosing range of
Hepatic Impairment: Pediatric There are no dosage
80 to 100 mg/kg/day divided every 8 hours has
adjustments provided in the manufacturer's labeling; use
also been used (Bradley 2002). Note: Per the
with caution. Use contraindicated in patients with a
manufacturer, the 600 mg/5 mL formulation should
history of amoxicillin and clavulanate-associated hepatic
only be used for patients weighing <40 kg.
dysfunction.
Rhinosinusitis, acute bacterial: Oral:
AAP recommendations (Wald 2013): Children and Preparation for Administration Reconstitute powder
Adolescents: High-dose: 80 to 90 mg amoxicillin/ for oral suspension with appropriate amount of water as
kg/day divided every 12 hours, maximum dose: specified on the bottle. Shake vigorously until suspended.
2,000 mg/dose; use the 600 mg/5 mL oral suspen- Administration Oral: Can be given without regard to
sion; treatment duration variable: 10 to 28 days, meals. Administer at the start of a meal to decrease the
some have suggested discontinuation of therapy 7 frequency or severity of Gl side effects; may mix with milk,
days after resolution of signs and symptoms of formula, or juice; shake suspension well before use
infection. Note: Recommended for patients with Monitoring Parameters With prolonged therapy, monitor
any of the following: Moderate to severe infection, renal, hepatic, and hematologic function periodically; mon-
age <2 years, childcare attendance, or recent anti- itor for signs of anaphylaxis during first dose
biotic treatment. Per the manufacturer, the 600 mg/5 Test Interactions
mL formulation should only be used for patients May interfere with urinary glucose tests using cupric
weighing <40 kg. , sulfate (Benedict's solution, Clinitest, Fehling's solution).
IDSA recommendations (Chow 2012): Children and Glucose tests based on enzymatic glucose oxidase
Adolescents: reactions (eg, Clinistix) are recommended.
Patients weighing <40 kg: Ampicillin may transiently interfere with plasma concen-
Standard dose: Immediate release formulations: trations of total conjugated estriol, estriol-glucuronide,
45 mg amoxicillin/kg/day divided every 12 hours
conjugated estrone and estradiol in pregnant women.
for 10 to 14 days using the 200 mg/5 mL or
Additional Information Products may not be inter-
400 mg/5 mL oral suspension, or the 200 mg
changeable. Both the 250 mg and 500 mg tablets contain
and 400 mg chewable tablets formulations only
the same amount of clavulanic acid; two 250 mg tablets
High dose (use reserved for select patients; see
Note): /mmediate release formulations: 90 mg are not equivalent to one 500 mg tablet. Additionally, four
amoxicillin/kg/day divided every 12 hours for 10 250 mg tablets or two 500 mg tablets are not equivalent to
to 14 days, using the 600 mg/5 mL oral suspen- a single 1,000 mg extended release tablet. Based upon
sion only; Note: Use recommended in the follow- usual dosing in pediatric patients <40 kg, typical "TID"
ing: Areas with high endemic rates of penicillin- regimens provide 5 to 10 mg/kg/day of clavulanate and
nonsusceptible S. pneumonia, patients with "BID" regimens 3.4 to 6.4 mg/kg/day.
severe infections, daycare attendance, age <2
Some penicillins (eg, carbenicillin, ticarcillin, piperacillin)
years, recent hospitalization, antibiotic use within
have been shown to inactivate aminoglycosides in vitro.
the past month, patients who are immunocom-
This has been observed to a greater extent with tobramy-
promised or if initial therapy fails (second-line
cin and gentamicin, while amikacin. has shown greater
therapy)
stability against inactivation. Concurrent use of these
Skin and soft tissue infections, impetigo: Infants 23
agents may pose a risk of reduced antibacterial efficacy
months, Children, and Adolescents: Oral: 25 mg
amoxicillin/kg/day in divided doses twice daily using in vivo, particularly in the setting of profound renal impair-
the 200 mg/5 mL or 400 mg/5 mL oral suspension or ment. However, definitive clinical evidence is lacking. If
the 200 mg or 400 mg chewable tablets; maximum combination penicillin/aminoglycoside therapy is desired
single dose: 875 mg amoxicillin/dose (IDSA [Ste- in a patient with renal dysfunction, separation of doses (if
vens 2014]) : feasible) and routine monitoring of aminoglycoside levels,
Streptococci, group A; chronic carrier treatment: CBC, and clinical response should be considered.
Infants 23 months, Children, and Adolescents: Oral: Dosage Forms Excipient information presented when
40 mg amoxicillin/kg/day in divided doses every 8 available (limited, particularly for generics); consult spe-
hours for 10 days using the 125 mg/5 mL or cific product labeling. [DSC] = Discontinued product
250 mg/5 mL oral suspension or if patient weighs Powder for suspension, oral:
240 kg, the 500 mg tablet; maximum single dose: Augmentin:
500 mg amoxicillin (Shulman 2012) 125: Amoxicillin 125 mg and clavulanate potassium
Urinary tract infections: Infants and Children 2 to 24 31.25 mg per 5 mL (75 mL, 100 mL, 150 mL) [con-
months: Oral: 20 to 40 mg amoxicillin/kg/day in div- tains potassium 0.16 mEq/5 mL; banana flavor]
ided doses 3 times daily using the 125 mg/5 mL or 200: Amoxicillin 200 mg and clavulanate potassium
250 mg/5 mL oral suspension; maximum single dose: 28.5 mg per 5 mL (50 mL, 75 mL, 100 mL) [contains
500 mg amoxicillin (AAP 2011) phenylalanine 7 mg/5 mL and potassium 0.14 mEq/5
Renal Impairment: Pediatric mL; orange flavor] [DSC]
Infants, Children, and Adolescents: There are no dos- 250: Amoxicillin 250 mg and clavulanate potassium
age adjustments provided in the manufacturer's label- 62.5 mg per 5 mL (75 mL, 100 mL, 150 mL) [contains
ing; however, the following guidelines have been used potassium 0.32 mEq/5 mL; orange flavor]
by some clinicians (Aronoff 2007): Oral: 400: Amoxicillin 400 mg and clavulanate potassium
Mild to moderate infection: Dosing based on 20 to
57 mg per 5 mL (50 mL, 75 mL, 100 mL) [contains
40 mg amoxicillin/kg/day divided every 8 hours or 25
phenylalanine 7 mg/5 mL and potassium 0.29 mEq/5
to 45 mg amoxicillin/kg/day divided every 12 hours:
mL; orange flavor] [DSC]
GFR >30 mL/minute/1.73 m?: No adjustment
Augmentin ES-600:
required
600: Amoxicillin 600 mg and clavulanate potassium
GFR 10 to 29 mL/minute/1.73 m?: 8 to 20 mg
amoxicillin/kg/dose every 12 hours 42.9 mg per 5 mL (75 mL, 125 mL, 200 mL) [contains
GFR <10 mL/minute/1.73 m2: 8 to 20 mg amoxicillin/ phenylalanine 7 mg/5 mL, potassium 0.23 mEq/5 mL;
kg/dose every 24 hours strawberry cream flavor]
Hemodialysis: 8 to 20 mg amoxicillin/kg/dose every Generic: 200: Amoxicillin 200 mg and clavulanate potas-
24 hours; give after dialysis sium 28.5 mg per 5 mL (50 mL, 75 mL, 100 mL); 250:
Peritoneal dialysis: 8 to 20 mg amoxicillin/kg/dose Amoxicillin 250 mg and clavulanate potassium
every 24 hours 62.5 mg per 5 mL (75 mL, 100 mL, 150 mL); 400:
Severe infection (high dose): Dosing based on 80 to Amoxicillin 400 mg and clavulanate potassium 57 mg
90 mg amoxicillin/kg/day divided every 12 hours: per 5 mL (50 mL, 75 mL, 100 mL); 600: Amoxicillin
CrCl >30 mL/minute/1.73 m?: No.adjustment 600 mg and clavulanate potassium 42.9 mg per 5 mL
required (75 mL, 125 mL, 200 mL)

129
 AMOXICILLIN AND CLAVULANATE

< Tablet, oral:

Augmentin:
maternal dose when evaluating the literature for both
amphetamine and dextroamphetamine.
250: Amoxicillin 250 mg and clavulanate potassium
The RID of amphetamine was calculated using a, milk
125 mg [contains potassium 0.63 mEq/tablet] [DSC]
concentration of 138 ng/mL, providing an estimated daily
500: Amoxicillin 500 mg and clavulanate potassium
infant dose via breast milk of 0.021 mg/kg/day. This milk
125 mg [contains potassium 0.63 mEq/tablet]
concentration was obtained 42 days after delivery, follow-
875: Amoxicillin 875 mg and clavulanate potassium
ing maternal administration of amphetamine 20 mg/day in
125 mg [contains potassium 0.63 mEq/tablet]
4 divided doses for the treatment of narcolepsy throughout
Generic: 250: Amoxicillin 250 mg and clavulanate potas-
pregnancy and continuing postpartum. Milk concentra-
sium 125 mg; 500: Amoxicillin 500 mg and clavula-
tions were higher than those in the maternal plasma.
nate potassium 125 mg; 875: Amoxicillin 875 mg and
Amphetamine was also detected in the urine of the
clavulanate potassium 125 mg
breastfeeding infant (Steiner 1984).
Tablet, chewable, oral:
Generic: 200: Amoxicillin 200 mg and clavulanate potas- In case reports, growth and development were normal in
sium 28.5 mg [contains phenylalanine]; 400: Amox- two infants exposed to amphetamine via breast milk
icillin 400 mg and clavulanate potassium 57 mg following chronic maternal use for narcolepsy. One infant
[contains phenylalanine] was followed for 10 months and the other for 24 months;
Tablet, extended release, oral: long-term neurodevelopment has not been evaluated
Augmentin XR: 1000: Amoxicillin 1000 mg and clavula- (Ohman 2015; Steiner 1984). The majority of human data
nate acid 62.5 mg [contains potassium 12.6 mg (0.32 are based on illicit amphetamine/methamphetamine expo-
mEq) and sodium 29.3 mg (1.27 mEq) per tablet; sure and not from therapeutic maternal use (Golub 2005).
packaged in either a 7-day or 10-day package] Increased irritability, agitation, and crying have been
Generic: 1000: Amoxicillin 1000 mg and clavulanate acid reported in breastfed infants. As a class, amphetamines
62.5 mg may also decrease milk supply (ACOG 2011). Breastfeed-
ing is not recommended (AAP 2012).
@ Amoxicillin and Clavulanate Potassium see Amoxicil- Contraindications :
lin and Clavulanate on page 127 Immediate release: Hypersensitivity or idiosyncrasy to
@ Amoxicillin and Clavulanic Acid see Amoxicillin and amphetamine, other sympathomimetic amines, or any
Clavulanate on page 127 component of the formulation; advanced arteriosclerosis;
@ Amoxicillin-Clavulanate see Amoxicillin and Clavula- symptomatic cardiovascular disease; moderate to
nate on page 127 severe hypertension; hyperthyroidism; agitated states;
history of drug abuse; use during or within 14 days
@ Amoxicillin/Clavulanate K see Amoxicillin and Clavula-
following MAO inhibitor.
nate on page 127
Extended release: Hypersensitivity to amphetamine or
@ Amoxicillin/Potassium Clav see Amoxicillin and Clav- any component of the formulation, anaphylactic reac-
ulanate on page 127 tions and angioedema have been reported; use during
@ Amoxicillin Trinydrate see Amoxicillin on page 124 or within 14 days following MAO inhibitor (including
Amoxi-Clav (Can) see Amoxicillin and Clavulanate linezolid or intravenous methylene blue).
on page 127 Documentation of allergenic cross-reactivity for amphet-
amines is limited. However, because of similarities in
@ Amoxil see Amoxicillin on page 124
chemical structure and/or pharmacologic actions, the
@ Amoxycillin see Amoxicillin on page 124 possibility of cross-sensitivity cannot be ruled out with
@ Amoxycillin and Clavulanate Potassium see Amoxicil- certainty.
lin and Clavulanate on page 127 Warnings/Precautions [US Boxed Warning]: Potential
@ Amoxycillin and Clavulanic Acid see Amoxicillin and for drug abuse and dependency exists; prolonged use
Clavulanate on page 127 may lead to drug dependency and must be avoided.
Assess the risk for abuse prior to prescribing, and
@ Amphadase see Hyaluronidase on page 996 monitor for signs of abuse and dependence while on
therapy. Consider the possibility of patients obtaining
Amphetamine (am FET ameen) amphetamines for non-therapeutic use or distribution
to others; prescribe sparingly. Use of immediate-
Brand Names: US Adzenys ER; Adzenys XR-ODT; release formulation is contraindicated in patients with
Dyanavel XR; Evekeo history of drug abuse. Write prescriptions for the smallest
Therapeutic Category Stimulant quantity consistent with good patient care to minimize
Generic Availability (US) No possibility of overdose.
Use {US Boxed Warning]: Misuse may cause serious car-
Immediate release tablet (Evekeo): Treatment of ADHD diovascular events including sudden death. Adverse
(FDA approved in ages 23 years through adolescence); effects have been reported at usual doses in patients with |
narcolepsy (FDA approved in ages 26 years and. adults); preexisting structural cardiac abnormalities or other seri-
exogenous obesity (FDA approved in ages 212 years ous heart problems (sudden death in children and adoles-
and adults) cents; sudden death, stroke, and MI in adults). These
Extended release suspension (Dyanavel XR): Treatment products should be avoided in the patients with known
of attention-deficit/hyperactivity disorder (ADHD) (FDA serious structural cardiac abnormalities, cardiomyopathy,
approved in ages 6 to 17 years) serious heart rhythm abnormalities, coronary artery dis-
Medication Guide Available Yes ease, or other serious cardiac problems that could
Pregnancy Risk Factor C increase the risk of sudden death that these conditions
Pregnancy Considerations Adverse effects have been alone carry. Patients should be carefully evaluated for
observed in animal reproduction studies. Information cardiac disease prior to initiation of therapy. Patients
related to use of amphetamine in pregnancy is limited who develop symptoms such as exertional chest pain,
(Maurovich-Horvat 2012). The majority of human data unexplained syncope, or other symptoms suggestive of
are based on illicit anphetamine/methamphetamine expo- cardiac disease during treatment should undergo a
sure and not from therapeutic maternal use (Golub 2005). prompt cardiac evaluation. Hypertension and tachycardia
Use of amphetamines during pregnancy may lead to an may occur; monitor blood pressure and heart rate in all
increased risk of premature birth and low birth weight; patients. May impair the ability to engage in potentially
newborns may experience symptoms of withdrawal. hazardous activities; patients must be cautioned about
Behavioral problems may also occur later in childhood performing tasks that require mental alertness (eg, oper-
(LaGasse 2012). Newborns should be monitored for agi- ating machinery or driving).
tation, irritability, excessive drowsiness, or feeding difficul-
ties Cases of intestinal necrosis, including some deaths, have
Breastfeeding Considerations Amphetamine is present been reported with the concomitant use of sodium poly-
in breast milk. styrene sulfonate and sorbitol, two of the inactive ingre-
dients in Adzenys ER. In these cases, patients were
The relative infant dose (RID) of amphetamine is 7.24% administered sodium polystyrene sulfonate at doses
when calculated using the highest breast milk concentra- greater than 200 times the amount present in Adzenys
tion located and compared to a weight-adjusted maternal ER, however no absolute safe levels for the interaction of
dose of 20 mg/day. sodium polystyrene sulfonate and sorbitol have been
established.
In general, breastfeeding is considered acceptable when
the RID of a medication is <10% (Anderson 2016; Ito Stimulants are associated with peripheral vasculopathy,
2000). However some sources note breastfeeding should including Raynaud phenomenon; signs/symptoms are
only be considered if the RID is <5% for psychotropic usually mild and intermittent, and generally improve with
agents (Larsen 2015). The manufacturer reports relative dose reduction or discontinuation. Digital ulceration and/or
infant doses of 2% to 13.8% of the weight-adjusted soft tissue breakdown have been observed rarely; monitor

130
 AMPHETAMINE

for digital changes during therapy and seek further eval- medications compared to 10 of 564 (1.8%) children who
uation (eg, rheumatology) if necessary (Syed 2008). Diffi- died suddenly. While the authors of this study conclude
culty in accommodation and blurred vision has been there may be an association between stimulant use and
reported with the use of stimulants. Use with caution in sudden death in children, there were a number of limi-
patients with hypertension and other cardiovascular con- tations to the study and the FDA cannot conclude this
ditions that might be exacerbated by increases in blood information impacts the overall risk:benefit profile of these
pressure or heart rate (eg, preexisting hypertension, heart medications (Gould 2009). In a large retrospective cohort
failure, recent MI, ventricular arrhythmia). Use of immedi- study involving 1,200,438 children and young adults (aged
ate-release formulation is contraindicated in patients with 2 to 24 years), none of the currently available stimulant
advanced arteriosclerosis, moderate to severe hyperten- medications or atomoxetine were shown to increase the
sion, or symptomatic cardiovascular disease. Use with risk of serious cardiovascular events (ie, acute MI, sudden
caution in patients with preexisting psychosis or bipolar cardiac death, or stroke) in current (adjusted hazard ratio:
disorder; may exacerbate symptoms of behavior and 0.75; 95% Cl: 0.31 to 1.85) or former (adjusted hazard
thought disorder or induce mixed/manic episode, respec- ratio: 1.03; 95% Cl: 0.57 to 1.89) users compared to
tively. Screen patients with comorbid depressive symp- nonusers, It should be noted that due to the upper limit
toms prior to initiating treatment to determine if they are at of the 95% Cl, the study could not rule out a doubling of
risk for bipolar disorder, including a family history of the risk, albeit low (Cooper 2011).
suicide, bipolar disorder, and depression. May be associ-
Stimulant medications may increase blood pressure (aver-
ated with aggressive behavior or hostility (causal relation-
age increase: 2 to 4 mm Hg) and heart rate (average
ship not established); monitor for development or
worsening of these behaviors. New-onset psychosis or increase: 3 to 6 bpm); some patients may experience
mania may also occur with stimulant use; consider dis- greater increases.
- continuing therapy if hallucinations, delusional thinking, or Long-term effects in pediatric patients have not been
mania occurs. Limited information exists regarding determined. Use of stimulants in children has been asso-
amphetamine use in seizure disorder (Cortese 2013). ciated with growth suppression; monitor growth; treatment
Use with caution in patients with a history of seizure interruption may be needed. Appetite suppression may
disorder; may lower seizure threshold leading to new occur; monitor weight during therapy, particularly in chil-
onset or breakthrough seizure activity. Use with caution dren. Evaluation of the effect of stimulants on growth in
in patients with Tourette syndrome or other tic disorders. ADHD diagnosed children <12 years receiving treatment
Stimulants may exacerbate tics (motor and phonic) and for at least 3 years with stimulants has shown decreased
Tourette syndrome; however, evidence demonstrating height and weight changes over time compared to age
increased tics is limited. Evaluate for tics and Tourette matched control; height: 4.7 to 5.5 cm/year compared to
syndrome prior to therapy initiation (AACAP [Murphy 6.3 cm/year and 2.1 to 3.3 kg/year compared to 4.4 kg/
2013}; Pliszka 2007). Potentially significant drug-drug year (Poulton 2016). In pediatric patients 8 to 17 years
interactions may exist, requiring dose or frequency adjust- actively treated with stimulants, significant reductions in
ment, additional monitoring, and/or selection of alternative total femoral, femoral neck, and lumbar bone mineral
therapy. Potentially life-threatening serotonin syndrome density (BMD) were observed compared to matched
(SS) may occur when amphetamine is used in combina- unmedicated cohorts; also reported were significantly
tion with other serotonergic agents (eg, selective serotonin more subjects in the stimulant-treated group with BMD
reuptake inhibitors, serotonin norepinephrine reuptake measurements in the osteopenic range compared to
inhibitors, triptans, tricyclic antidepressants, fentanyl, lith- matched cohorts (38.3% to 21.6%) (Howard 2015). A
ium, tramadol, buspirone, St. John's wort, tryptophan), longitudinal cohort-controlled trial reported no different in
agents that impair metabolism of serotonin (eg, mono- peak height velocity and final adult height in subjects with
amine oxidase inhibitors) or CYP2D6 inhibitors that impair ADHD and/or treated with stimulants (Harstad 2014).
metabolism of amphetamine. Concomitant use with mono- Adverse Reactions As reported in children and adults
amine oxidase inhibitors is contraindicated. If concomitant unless otherwise noted.
use of amphetamine with serotonergic drugs or CYP2D6 Cardiovascular: Increased blood pressure, palpitations,
inhibitors is indicated, initiate amphetamine at a low dose Raynaud's phenomenon, tachycardia
and monitor patient closely for signs and symptoms of SS. Central nervous system: Dizziness, dysphoria, euphoria,
Discontinue treatment (and any concomitant serotonergic exacerbation of Gilles de la Tourette's syndrome, head-
agent) immediately if signs/symptoms arise. Angioedema ache, insomnia, overstimulation, psychosis, restless-
and anaphylactic reactions have been reported in patients ness, tics (including exacerbation), vocal tics
with hypersensitivity reactions. (exacerbation)
Appetite suppression may occur in children; monitor Dermatologic: Urticaria
weight during therapy. Use of stimulants has been asso- Endocrine & metabolic: Change in libido, growth suppres-
ciated with weight loss and slowing of growth rate; monitor sion (children), weight loss (children)
growth rate and weight during treatment. Treatment inter- Gastrointestinal: Anorexia, constipation, diarrhea, dysgeu-
ruption may be necessary in patients who are not increas- sia, gastrointestinal disease, upper abdominal pain,
ing in height or gaining weight as expected. vomiting, xerostomia
Genitourinary: Erectile dysfunction (frequent or prolonged
Abrupt discontinuation following high doses or for pro- erections), impotence
longed periods may result in symptoms for withdrawal. Neuromuscular & skeletal: Dyskinesia, rhabdomyolysis,
Warnings: Additional Pediatric Considerations Seri- tremor
ous cardiovascular events, including sudden death, may Respiratory: Allergic rhinitis, epistaxis
occur in patients with preexisting structural cardiac abnor- Rare but important or life-threatening: Mania, peripheral
malities or other serious heart problems. Sudden, death vascular disease
has been reported in children and adolescents; sudden Drug Interactions
death, stroke, and MI have been reported in adults. Avoid Metabolism/Transport Effects Substrate of CYP2D6
the use of amphetamines in patients with known serious (minor); Note: Assignment of Major/Minor substrate sta-
structural cardiac abnormalities, cardiomyopathy, serious tus based on clinically relevant drug interaction potential
heart rhythm abnormalities, coronary artery disease, or Avoid Concomitant Use
other serious cardiac problems that could place patients at Avoid concomitant use of Amphetamine with any of the
an increased risk to the sympathomimetic effects of following: Acebrophylline; lobenguane | 123; Monoamine
amphetamines. Patients should be carefully evaluated Oxidase Inhibitors
for cardiac disease prior to initiation of therapy..The Increased Effect/Toxicity
American Heart Association recommends that all children Amphetamine may increase the levels/effects of: Dox-
diagnosed with ADHD who may be candidates for medi- ofylline; lohexol; lomeprol; lopamidol; Opioid Analgesics;
cation, such as amphetamine, should have a thorough Sympathomimetics
cardiovascular assessment prior to initiation of therapy.
This assessment should include a combination of medical The levels/effects of Amphetamine may be increased by:
history, family history, and physical examination focusing Acebrophylline; Alkalinizing Agents; Antacids; AtoMOX-
on cardiovascular disease risk factors. An ECG is not etine; BuPROPion; Cannabinoid-Containing Products;
mandatory but should be considered. If a child displays Carbonic Anhydrase Inhibitors; Cocaine (Topical);
symptoms of cardiovascular disease, including chest pain, CYP2D6 Inhibitors (Moderate); CYP2D6 Inhibitors
dyspnea, or fainting, parents should seek immediate (Strong); Guanethidine; Linezolid; Monoamine Oxidase
medical care for the child. In a recent retrospective study Inhibitors; Proton Pump Inhibitors; Tedizolid; Tricyclic
on the possible association between stimulant medication Antidepressants
use and sudden death in children, 564 previously healthy Decreased Effect
children who died suddenly in motor vehicle accidents Amphetamine may. decrease the levels/effects of: Anti-
were compared to a group of 564 previously healthy histamines; Antihypertensive Agents; Ethosuximide;
children who died suddenly. Two of the 564 (0.4%) chil- lobenguane | 123; loflupane | 123; PHENobarbital; Phe-
dren in motor vehicle accidents were taking stimulant nytoin
AMPHETAMINE

The levels/effects of Amphetamine may be decreased Children 26 years and Adolescents: Oral: Initial:
by: Ammonium Chloride; Antipsychotic Agents; Ascorbic 5 mg once or twice daily; increase daily dose in
Acid; Gastrointestinal Acidifying Agents; Lithium; Meth- 5 mg increments at weekly intervals until optimal
enamine; Multivitamins/Fluoride (with ADE); Multivita- response is obtained; first doses should be given
mins/Minerals (with ADEK, Folate, Iron); Multivitamins/ at awakening; additional daily doses (1 to 2 doses)
Minerals (with AE, No Iron); Urinary Acidifying Agents may be necessary and should be separated by 4 to
Food Interactions Amphetamine serum levels may be 6 hour intervals. Only in rare cases will it be
reduced if taken with acidic food, juices, or vitamin C. necessary to exceed 40 mg daily.
Management: Monitor response when taken concurrently. Extended release suspension: Children 26 years and
Storage/Stability Store at 20°C to 25°C (68°F to 77°F); Adolescents: Oral: Initial: 2.5 or 5 mg once daily in
excursions permitted from 15°C to 30°C (59°F to 86°F). the morning; may increase in 2.5 to 10 mg/day
Store orally disintegrating tablet blister packages in travel increments every 4 to 7 days until optimal response
case provided. is obtained; maximum daily dose: 20 mg/day
Mechanism of Action Amphetamines are noncatechol- Note: Do not substitute extended release formula-
amine sympathomimetic amines that promote release of tion for other amphetamine products on a mg-per-
catecholamines (primarily dopamine and norepinephrine) mg basis since base composition and pharmaco-
from their storage sites in the presynaptic nerve terminals. kinetic profiles are not similar. If switching from
A less significant-mechanism may include their ability to other amphetamine products, discontinue that
block the reuptake of catecholamines by competitive treatment, and titrate as per the recommended
inhibition. The anorexigenic effect is probably secondary dosing schedule.
to the CNS-stimulating effect; the site of action is probably Exogenous obesity: Immediate release tablet: Chil-
the hypothalamic feeding center. dren 212 years and Adolescents: Oral: Initial: 5 to
Pharmacodynamics/Kinetics (Adult data unless 10 mg once daily; titrate in 5 to 10 mg increments (at
noted) a minimum of weekly intervals); maximum daily dose:
Note: Alkaline urine pH will result in reduced renal elim- 30 mg/day in divided doses
ination of amphetamine and acidic urine pH will result in Narcolepsy: Immediate release tablet:
increased renal elimination. Decreased renal elimination Children 6 to 12 years: Oral: Initial: 5 mg.once daily;
in the context of alkaline urine pH may be more pro- increase daily dose in 5 mg increments at weekly
nounced when renal elimination is already decreased. intervals until optimal responseis obtained; first
Duration of action: Adzenys XR-ODT: 10 to 12 hours; doses should be given at awakening; additional daily
Evekeo: 4 to 6 hours (Jain 2017) doses (5 or 10 mg) may be necessary and should be
Absorption: Oral: Evekeo: Rapid (de la Torre 2004) separated by 4 to 6 hour intervals; usual daily
Distribution: Oral: Evekeo: Vg: 3 to 4 L/kg (de la dosage range: 5 to 60 mg daily in divided doses
Torre 2004) Children 212 years and Adolescents: Oral: Initial:
Protein binding: Oral: Evekeo: 16% (de la Torre 2004) 10 mg once daily; increase daily dose in 10 mg
Metabolism: Hepatic via oxidation, deamination, and increments at weekly intervals until optimal
CYP2D6 response is obtained; first doses should be given
Bioavailability: Oral: at awakening; additional daily doses (5 or 10 mg)
Dyanavel XR: 106% of d-amphetamine and 111% for |-
may be necessary and should be separated by 4 to
amphetamine (relative to equivalent dose of immedi-
6 hour intervals; usual daily dosage range: 5 to
ate-release mixed amphetamine salts)
60 mg daily in divided doses
Evekeo: Good (de la Torre 2004)
Renal Impairment: Pediatric There are no dosage
Half-life elimination: Oral:
adjustments provided in the manufacturer's labeling;
Adzenys ER:
use with caution; elimination may be decreased with
Children 6 to 12 years: d-amphetamine 12.7 hours
renal impairment.
(mean) and l-amphetamine 15.3 hours (mean)
Adults: d-amphetamine 11.4 hours (mean) and |- Hepatic Impairment: Pediatric There are no dosage
amphetamine 14.1 hours (mean) adjustments provided in the manufacturer's labeling; use
Adzenys XR-ODT: with caution; elimination may be decreased with hepatic
Children 6 to 12 years: d-amphetamine 9 to 10 hours impairment.
(mean) and l-amphetamine 10 to 11 hours (mean) Administration Administer with or without food; for short-
Adults: d-amphetamine 11 hours (mean) and |-amphet- term adjunct treatment of exogenous obesity, administer
amine 14 hours (mean) 30 to 60 minutes before meals. For ADHD and narcolepsy,
Dyanavel XR: administer the first dose on awakening; administer addi-
Children: d-amphetamine 10.43 + 2.01 hours and I- tional doses at intervals of 4 to 6 hours. Avoid late evening
amphetamine 12.14 + 3.15 hours dosing. Shake suspension well before administration.
Adults: d-amphetamine 12.36 + 2.95 hours and I- Monitoring Parameters CNS activity, blood pressure,
amphetamine 15.12 + 4.4 hours pulse; height, weight, growth parameters; appetite;
Evekeo: 12 hours (de la Torre 2004) signs/symptoms of misuse, abuse, addiction, tolerance
Time to peak, serum: Oral: or dependence; behavioral changes; signs of peripheral
Adzenys ER: d-amphetamine and l-amphetamine: 5 vasculopathy (eg, digital changes)
hours (median) with or without food
ADHD: Evaluate patients for cardiac disease prior to
Adzenys XR-ODT: Median time d-amphetamine 5 hours
(7 hours with food) and |-amphetamine ~5.25 hours initiation of therapy with thorough medical history, family
(7.75 hours with food) history, and physical exam; consider ECG; perform ECG
Dyanavel XR: and echocardiogram if findings suggest cardiac disease;
Children: Median time d-amphetamine 3.9 hours and |- promptly conduct cardiac evaluation in patients who
amphetamine 4.5 hours develop chest pain, unexplained syncope, or any other
Adults: 4 (2 to 7) hours symptom of cardiac disease during treatment. Monitor
Evekeo: Within 4 hours (de la Torre 2004) CNS activity, blood pressure, heart rate, sleep, appetite,
Excretion: Urine (30% to 40% unchanged; ~50% as abnormal movements, height, weight, BMI, growth in
metabolites) children. Patients should be reevaluated at appropriate
Pharmacodynamics/Kinetics: Additional Consider- intervals to assess continued need of the medication.
ations Observe for signs/symptoms of aggression or hostility, or
Body weight: Systemic exposure and maximum concen- depression. Monitor for visual disturbances.
tration of d- and l-amphetamine decrease as body weight Test Interactions Amphetamines may elevate plasma
increases; volume of distribution, clearance, and half-life corticosteroid levels; may interfere with urinary steroid
increase as body weight increases. determinations.
Dosing Additional Information
Pediatric Evekeo contains d-amphetamine and |-amphetamine in a
Note: Individualize and titrate to lowest effect dose. 1:1 ratio.
Attention-deficit/hyperactivity disorder: Dyanavel XR contains d-amphetamine and |-amphet-
Immediate release tablet: amine in a 3.2:1 ratio.
Children 3 to 5 years: Oral: Initial: 2.5 mg once daily; Treatment of ADHD should include "drug holidays" or
increase daily dose in 2.5 mg increments at weekly periodic discontinuation of medication in order to assess
intervals until optimal response is obtained; first the patient's requirements, decrease tolerance, and limit
dose should be given at awakening; additional suppression of linear growth and weight. Medications
daily doses (1 to 2 doses) may be necessary and used to treat ADHD should be part of a total treatment
should be separated by 4 to 6 hour intervals. program that may include other components, such as
Maximum dose not specified; in children 26 years, psychological, educational, and social measures.
daily doses >40 mg/day are rarely necessary. Controlled Substance C-II

132
 AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX

Dosage Forms Excipient information presented when Warnings: Additional Pediatric Considerations
available (limited, particularly for generics); consult spe- In a multicenter study of pediatric patients (<16 years of
cific product labeling. age), amphotericin B cholestyrel sulfate complex (ABCD)
Suspension Extended Release, Oral: use had a significantly lower incidence of renal toxicity
Adzenys ER: 1.25:mg/mL (450 mL) [contains fd&c yel- (12%; 3/25 patients) than amphotericin B deoxycholate
low #6 (sunset yellow), methylparaben, polyethylene (52%; 11/21 patients).
glycol, propylene glycol, propylparaben; orange flavor] Adverse Reactions Amphotericin B colloidal dispersion
Suspension Extended Release, Oral, as base: has an improved therapeutic index compared to conven-
Dyanavel XR: 2.5 mg/mL (464 mL) [contains methylpar- tional amphotericin B, and has been used safely in
aben, polysorbate 80, propylparaben] patients with amphotericin B-related nephrotoxicity; how-
Tablet, Oral, as sulfate: ever, continued decline of renal function has occurred in
Evekeo: 5 mg [scored] some patients.
Evekeo: 10 mg [scored; contains. brilliant blue fcf (fd&c
blue #1)] Cardiovascular: Chest pain, facial edema, hypertension,
Tablet Extended Release Disintegrating, Oral, as base: hypotension, tachycardia
Adzenys XR-ODT: 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, Central nervous system: Abnormality in thinking, chills,
15.7 'mg, 18.8 mg drowsiness, headache, insomnia
Dermatologic: Diaphoresis, pruritus, skin rash
@ Amphetamine and Dextroamphetamine see Dextro- Endocrine & metabolic: Hyperglycemia, hypocalcemia,
amphetamine and Amphetamine on page 614 hypokalemia, hypomagnesemia, hypophosphatemia
@ Amphetamine Sulfate see Amphetamine on page 130 Gastrointestinal: Abdominal pain, diarrhea, enlargement
of abdomen, hematemesis, nausea, stomatitis, vomiting,
@ Amphet Asp/Amphet/D-Amphet see Dextroamphet-
xerostomia
amine and Amphetamine on page 614
Hematologic & oncologic: Anemia, hemorrhage, thrombo-
# Amphojel (Can) see Aluminum Hydroxide on page 100 cytopenia
@ Amphotec [DSC] see Amphotericin B Cholesteryl Sul- Hepatic: Abnormal hepatic function tests, hyperbilirubine-
fate Complex on page 133 mia, increased serum alkaline phosphatase, jaundice
Miscellaneous: Fever
Neuromuscular & skeletal: Back pain, muscle rigidity,
Amphotericin B Cholesteryl Sulfate tremor
Complex Renal: Increased serum creatinine
(am foe TER i sin bee kole LES te ril SUL fate KOM plecks) Respiratory: Dyspnea, epistaxis, hypoxia, increased
Medication Safety Issues cough, rhinitis
High alert medication: Rare but important or life-threatening: Acidosis, atrial
The Institute for Safe Medication Practices (ISMP) arrhythmia, cardiac arrest, cardiac failure, gastrointesti-
nal hemorrhage, hepatic failure, injection site reaction,
includes this medication among its list of drugs which
have a heightened risk of causing significant patient oliguria, pain at injection site, pleural effusion, renal
harm when used in error. failure, seizure, syncope, ventricular arrhythmia
Other safety concerns: Drug Interactions
Lipid-based amphotericin formulations (Amphotec) may Metabolism/Transport Effects None known.
be confused with conventional formulations (Amphocin, Avoid Concomitant Use
Fungizone) Avoid concomitant use of Amphotericin B Cholesteryl
Large overdoses have occurred when conventional for- Sulfate Complex with any of the following: Bromperidol;
mulations were dispensed inadvertently for lipid-based Foscarnet; Methoxyflurane; Saccharomyces boulardii
products. Single daily doses of conventional amphoter- Increased Effect/Toxicity
icin formulation never exceed 1.5 mg/kg. Amphotericin B Cholesteryl Sulfate Complex may
Brand Names: US Amphotec [DSC] increase the levels/effects of: Amifostine; Aminoglyco-
Therapeutic Category Antifungal Agent, Parenteral sides; Antipsychotic Agents (Second Generation [Atyp-
Generic Availability (US) No ical]); Bromperidol; Cardiac Glycosides; Colistimethate;
Use Treatment of invasive aspergillosis in patients who CycloSPORINE (Systemic); DULoxetine; Flucytosine;
have failed amphotericin B deoxycholate treatment, or Hypotension-Associated Agents; Levodopa; Nitroprus-
who have renal impairment or unacceptable toxicity which side; Pholcodine; Sodium Stibogluconate
precludes treatment with amphotericin B deoxycholate in The levels/effects of Amphotericin B Cholesteryl Sulfate
effective doses (FDA approved in pediatric patients [age Complex may be increased by: Alfuzosin; Barbiturates;
not specified] and adults); has also been used for treat- Benperidol; Blood Pressure Lowering Agents; Brimoni-
ment of candidiasis, coccidiodomycosis, and histoplasmo- dine (Topical); Corticosteroids (Orally Inhaled); Cortico-
sis steroids (Systemic); Diazoxide; Dronabinol; Foscarnet;
Pregnancy Risk Factor B Ganciclovir-Valganciclovir; Herbs (Hypotensive Proper-
Pregnancy Considerations Adverse events were not ties); Lormetazepam; Methoxyflurane; Molsidomine;
observed in animal reproduction studies. Amphotericin Naftopidil; Nicergoline; Nicorandil; Obinutuzumab; Pen-
crosses the placenta and enters the fetal circulation. toxifylline; Phosphodiesterase 5 Inhibitors; Prostacyclin
Amphotericin B is recommended for the treatment of Analogues; Quinagolide
serious systemic fungal diseases in pregnant women; Decreased Effect
refer to current guidelines (IDSA [Pappas 2016]; King Amphotericin B Cholesteryl Sulfate Complex may
1998; Pilmis 2015). decrease the levels/effects of: Saccharomyces boulardii
Breastfeeding Considerations It is not known if ampho-
tericin is excreted into breast milk. Due to its poor oral The levels/effects of Amphotericin B Cholesteryl Sulfate
absorption, systemic exposure to the nursing infant is Complex may be decreased by: Antifungal Agents
expected to be decreased; however, because of the (Azole Derivatives, Systemic); Bromperidol
potential for toxicity, breastfeeding is not recommended Storage/Stability Store intact vials at 15°C to 30°C (59°F
by the manufacturer (Mactal-Haaf 2001). to 86°F). After reconstitution, the solution should be
Contraindications Hypersensitivity to amphotericin B or refrigerated at 2°C to 8°C (36°F to 46°F) and used within
any component of the formulation (unless the benefits 24 hours. Concentrations of 0.1-2 mg/mL in D5W are
outweigh the possible risk to the patient) stable for 24 hours at 2°C to 8°C (36°F to 46°F).
Warnings/Precautions Anaphylaxis has been reported Mechanism of Action Binds to ergosterol. altering cell
with amphotericin B-containing drugs. If severe respiratory membrane permeability in susceptible fungi and causing
distress occurs, the infusion should be immediately dis- leakage of cell components with subsequent cell death.
continued; the patient should not receive further infusions. Proposed mechanism suggests that amphotericin causes
During the initial dosing, the drug should be administered an oxidation-dependent stimulation of macrophages
under close clinical observation. Acute infusion reactions, (Lyman, 1992).
sometimes severe, may occur 1-3 hours after starting Pharmacodynamics/Kinetics (Adult data unless
infusion. These reactions are usually more common with noted)
the first few doses and generally diminish with subsequent Distribution: Vg: Total volume increases with higher doses,
doses, Pretreatment with antihistamines/corticosteroids reflects increasing uptake by tissues (with 4 mg/kg/day =
and/or decreasing the rate of infusion can be used to 4 L/kg); predominantly distributed in the liver; concen-
manage reactions. Avoid rapid infusion. In a scientific trations in kidneys and other tissues are lower than
statement from the American Heart Association, ampho- observed with conventional amphotericin B (Walsh
tericin has been determined to be an agent that may 2008)
cause direct myocardial toxicity (magnitude: moderate/ Half-life elimination: ~28 hours; prolonged with higher
major) (AHA [Page 2016)]). doses
 AMPHOTERICIN B CHOLESTERYL SULFATE COMPLEX

q Dosing Hepatic Impairment: Pediatric

Neonatal Note: Amphotec has been discontinued in the Mild to moderate impairment: There are no dosage
US for more than 1 year. adjustments provided in manufacturer's labeling; how-
ever, no pharmacokinetic changes. were noted in
Medication errors, including deaths, have resulted patients with mild to moderate impairment.
from confusion between lipid-based forms of Severe impairment: There are no dosage adjustments
amphotericin (Abelcet, Amphotec, AmBisome) and provided in the manufacturer's labeling (has not been
conventional amphotericin B for injection. Lipid-
studied).
based and conventional formulations are not inter-
Preparation for Administration Parenteral: IV: Recon-
changeable and have different dosing recommenda-
stitute 50 mg and 100 mg vials with 10 mL and 20 mL of
tions. Overdoses have occurred when conventional
SWFI, respectively; resultant concentration: 5 mg/mL.
formulations were dispensed inadvertently for lipid-
Shake the vial gently by hand until all solid particles have
based products.
dissolved. Further dilute amphotericin B colloidal disper-
Note: In neonates, lipid formulations of amphotericin sion with D5W to a final concentration of ~0.6 mg/mL
have poorer penetration into the central nervous system, (range: 0.16 to 0.83 mg/mL).
kidneys, urinary tract, and eyes than conventional Administration Parenteral: |V: Do not filter or use an
amphotericin and are not preferred in most cases (IDSA inline filter for administration. Flush line with D5W prior
[Pappas 2016]; Red Book [AAP 2015]; Turkova 2011). to and following infusion.
Candidiasis, invasive: Limited data available: IV: 3 to
Initially infuse “diluted solution at 1 mg/kg/hour. Rate of
5 mg/kg/dose once daily; treatment should continue for
infusion may be increased with subsequent doses as
at least 2 weeks after the first negative blood culture
patient tolerance allows (minimum infusion time: 2 hours).
and signs and symptoms have resolved (IDSA [Pap-
If utilizing test dose as recommended by the manufac-
pas 2016])
turer's labeling, infuse over 15 to 30 minutes.
Pediatric Note: Amphotec has been discontinued in the
US for more than 1 year.
Monitoring Parameters Liver function tests, electrolytes,
BUN, Cr, vital signs, CBC, | & O, prothrombin time, signs
Medication errors, including deaths, have resulted of hypokalemia (muscle weakness, cramping, drowsiness,
from confusion between lipid-based forms of ECG changes)
amphotericin (Abelcet, Amphotec, AmBisome) and Additional Information The lipid portion of amphotericin
conventional amphotericin B for injection. Lipid- B cholesteryl sulfate complex formulation does not contain
based and conventional formulations are not inter- phospholipids; for patients receiving parenteral nutrition,
changeable and have different dosing recommenda- adjustment to the amount of lipids should not be needed
tions. Overdoses have occurred when conventional (Sacks 1997).
formulations were dispensed inadvertently for lipid- Product Availability Amphotec has been discontinued in
based products. the US for more than 1 year.
Note: Premedication for patients who experience fever, Dosage Forms Excipient information presented when
chills, hypotension, nausea, or other nonanaphylactic available (limited, particularly for generics); consult spe-
infusion-related immediate reactions may. be given 30 cific product labeling. [DSC] = Discontinued product
to 60 minutes prior to drug administration: NSAIDs (with Suspension Reconstituted, Intravenous:
or without diphenhydramine) or acetaminophen with Amphotec: 50 mg (1 ea [DSC]); 100 mg (1 ea [DSC}])
diphenhydramine or hydrocortisone may be given [contains edetate disodium, hydrochloric acid, lactose,
(Paterson 2008); if patient experiences rigors during sodium cholesteryl sulfate, tromethamine]
infusion, meperidine may be administered. The manu-
@ Amphotericin B Colloidal Dispersion see Amphotericin
facturer’s labeling advises a test dose be administered B Cholesteryl Sulfate Complex on page 133
immediately preceding the first dose when a new course
of treatment occurs. A small amount of drug (eg, 10 mL
of final preparation containing between 1.6 and 8.3 mg Amphotericin B (Conventional)
of drug) should be infused over 15 to 30 minutes and (am foe TER i sin bee con VEN sha nal)
patient should be carefully observed for the next 30
Medication Safety Issues
minutes.
High alert medication:
Aspergillosis, treatment:
The Institute for Safe Medication Practices (ISMP)
Invasive: Infants, Children, and Adolescents: IV:
includes this medication among its list of drugs which
Usual dose range: 3 to 4 mg/kg/dose once daily;
have a heightened risk of causing significant patient
doses as high as 7.5 mg/kg/dose have been
harm when used in error.
described in open label studies (Sandler 2000)
Other safety concerns:
Endocarditis: Children and Adolescents: IV: 3 to
Conventional amphotericin formulations (Amphocin, |
5 mg/kg/dose once daily with or without flucytosine
Fungizone) may be confused with lipid-based formula-
(AHA [Baltimore 2015])
tions (AmBisome, Abelcet, Amphotec).
Candidiasis, treatment: Infants, Children, and Ado-
Large overdoses have occurred when conventional for-
lescents:
mulations were dispensed inadvertently for lipid-based
Invasive: IV: 3 to 5 mg/kg/dose once daily (IDSA
products. Single daily doses of conventional amphoter-
[Pappas 2016])
icin formulation never exceed 1.5 mg/kg.
Endocarditis: Infants, Children, and Adolescents: IV: 3
to 5 mg/kg/dose once daily with or without flucyto-
Brand Names: Canada Fungizone
sine (AHA [Baltimore 2015]; IDSA [Pappas 2016]) Therapeutic Category Antifungal Agent, Systemic; Anti-
Esophageal (HIV-exposed/-positive): Adolescents: IV: fungal Agent, Topical ’
3 to 4 mg/kg/dose once daily for 14 to 21 days (HHS Generic Availability (US) Yes
[Ol adult 2016}) Use Treatment of progressive, potentially life-threatening
Coccidiodomycosis, disseminated (non-CNS) or susceptible fungal infections (FDA approved in pediatric
diffuse pulmonary disease: HIV-exposed/-infected: patients [age not specified] and adults); has also been
Infants and Children: lV: 5 mg/kg/dose once daily until used for fungal peritonitis, irrigant for bladder fungal
clinical improvement; dose may be increased as infections, used in fungal infection in patients with bone
high as 10 mg/kg/dose once daily for life-threatening marrow transplantation, and chemoprophylaxis (low-dose
infection (HHS [Ol pediatric 2013]) IV)
Adolescents: IV: 3 to 5 mg/kg/dose once daily until Pregnancy Risk Factor B
clinical improvement, then change to fluconazole or Pregnancy Considerations Adverse events were not ©
itraconazole (HHS [Ol adult 2016]) observed in animal reproduction studies. Amphotericin
Histoplasmosis, disseminated disease (moderately crosses the placenta and enters the fetal circulation.
severe to severe): HIV-exposed/-positive: Adoles- Amphotericin B is recommended for the treatment of
cents: IV: 3 mg/kg/dose once daily for at least 2 week serious systemic fungal diseases in pregnant women.
induction, followed by oral itraconazole (HHS [Ol Refer to current guidelines (IDSA [Pappas 2016]; King
adult 2016]) 1998; Pilmis 2015).
Renal Impairment: Pediatric Breastfeeding Considerations It is not known if ampho-
Mild to moderate impairment: There are no dosage tericin is excreted into breast milk. Due to its poor oral
adjustments provided in manufacturer's labeling; how- absorption, systemic exposure to the nursing infant is
ever, no pharmacokinetic changes were noted in expected to be decreased; however, because of the
patients with mild to moderate impairment. potential for toxicity, breastfeeding is not recommended
Severe impairment: There are no dosage adjustments by the manufacturer (Mactal-Haaf 2001).
provided in the manufacturer's labeling (has not been Contraindications Hypersensitivity to amphotericin or
studied). any component of the formulation

134
 AMPHOTERICIN B (CONVENTIONAL)

Warnings/Precautions Anaphylaxis has been reported Drug Interactions

with amphotericin B-containing drugs. During the initial Metabolism/Transport Effects None known.
dosing, the drug should be administered under close Avoid Concomitant Use
clinical observation. May cause nephrotoxicity; usual risk Avoid concomitant use of Amphotericin B (Conventional)
factors include underlying renal disease, concomitant with any of the following: Bromperidol; Foscarnet;
nephrotoxic medications and daily and/or cumulative dose Methoxyflurane; Saccharomyces boulardii
of amphotericin. Avoid use with other nephrotoxic drugs; Increased Effect/Toxicity
drug-induced renal toxicity usually improves with interrupt- Amphotericin B (Conventional) may increase the levels/
ing therapy, decreasing dosage, or increasing dosing effects of: Amifostine; Aminoglycosides; Antipsychotic
interval. However permanent impairment may occur, Agents (Second Generation [Atypical]); Bromperidol;
especially in patients receiving large cumulative dose Cardiac Glycosides; Colistimethate; CycloSPORINE
(eg, >5 g) and in those also receiving other nephrotoxic (Systemic); DULoxetine; Flucytosine; Hypotension-
drugs. Hydration and sodium repletion prior to adminis- Associated Agents; Levodopa; Nitroprusside; Pholco-
tration may reduce the risk of developing nephrotoxicity. dine; Sodium Stibogluconate
Frequent monitoring of renal function is recommended. The levels/effects of Amphotericin B (Conventional) may
Acute reactions (eg, fever, shaking chills, hypotension, be increased by: Alfuzosin; Barbiturates; Benperidol;
anorexia, nausea, vomiting, headache, tachypnea) are Blood Pressure Lowering Agents; Brimonidine (Topical);
most common 1 to 3 hours after starting the infusion Corticosteroids (Orally Inhaled); Corticosteroids (Sys-
and diminish with continued therapy. Avoid rapid infusion temic); Diazoxide; Dronabinol; Foscarnet; Ganciclovir-
to prevent hypotension, hypokalemia, arrhythmias, and Valganciclovir; Herbs (Hypotensive Properties); Lorme-
shock. If therapy is stopped for >7 days, restart at the tazepam; Methoxyflurane; Molsidomine; Naftopidil; Nic-
lowest dose recommended and increase gradually. Leu- ergoline; Nicorandil; Obinutuzumab; Pentoxifylline;
koencephalopathy has been reported following adminis- Phosphodiesterase 5 Inhibitors; Prostacyclin Analogues;
tration of amphotericin. Total body irradiation has been Quinagolide
reported to be a possible predisposition. In a scientific Decreased Effect
statement from the American Heart Association, ampho- Amphotericin B (Conventional) may decrease the levels/
tericin has been determined to be an agent that may effects of: Saccharomyces boulardii
cause direct myocardial toxicity (magnitude: moderate/ The levels/effects of Amphotericin B (Conventional) may
major) (AHA [Page 2016)]). be decreased by: Antifungal Agents (Azole Derivatives,
[US Boxed Warning]: Should be used primarily for Systemic); Bromperidol
treatment of progressive, potentially life-threatening Storage/Stability Store intact vials under refrigeration.
fungal infections, not noninvasive forms of infection. Protect from light. Reconstituted vials are stable, pro-
tected from light, for 24 hours at room temperature and
[US Boxed warning]: Verify the product name and
1 week when refrigerated. Parenteral admixtures in DSW
dosage if dose exceeds 1.5 mg/kg.
are stable, protected from light, for 24 hours at room
Warnings: Additional Pediatric Considerations May temperature and 2 days under refrigeration. Short-term
premedicate patients who experience mild adverse reac- exposure (<24 hours) to light during IV infusion does not
tions with acetaminophen and diphenhydramine 30 appreciably affect potency.
minutes prior to the amphotericin B infusion; meperidine Mechanism of Action Binds to ergosterol altering cell
and ibuprofen may help to reduce fevers and chills; hydro- membrane permeability in susceptible fungi and causing
cortisone can be added to the infusion solution to reduce leakage of cell components with subsequent cell death.
febrile and other systemic reactions. If therapy is stopped Proposed mechanism suggests that amphotericin causes
for >7 days, restart at the lowest. dose recommended and an oxidation-dependent stimulation of macrophages
increase gradually. Administer by slow IV infusion; rapid (Lyman 1992).
infusion has been associated with hypotension, hypoka- Pharmacodynamics/Kinetics (Adult data unless
lemia, arrhythmias, and shock. Avoid extravasation; may noted)
cause chemical irritation; monitor infusion site; heparin 1 Absorption: Poor oral absorption
unit/1 mL of infusion solution can be added to reduce Distribution: Minimal amounts enter the aqueous humor,
phlebitis. Use caution with intraperitoneal administration; bile, pericardial fluid, pleural fluid, and synovial fluid
use associated with irritation to the peritoneum and CNS penetration:
abdominal pain; not routinely used unless intolerance to Preterm neonates (GA: 27.4 + 5 weeks): High inter-
other therapies (ISPD [Warady 2000b)). patient variability; 40% to 90% of serum concentra-
Adverse Reactions tions (Baley 1990)
Systemic: Adults: Poor (inflamed or noninflamed meninges)
Cardiovascular: Flushing, hypertension, hypotension Vq: Pediatric patients (0 to 18 years): Highly variable;
Central nervous system: Arachnoiditis, chills, delirium, reported range: 0.38 to 3.99 L/kg (Benson 1989;
headache (less frequent with |.T.), malaise, neuralgia Koren 1988)
(lumbar; especially with intrathecal therapy), pain (less Protein binding, plasma: 90%
Half-life elimination:
frequent with I.T.), paresthesia (especially with intra-
Premature neonates (GA: 27.4 + 5 weeks): 14.8 hours
thecal therapy)
(range: 5 to 82 hours) (Baley 1990)
Endocrine & metabolic: Hypokalemia, hypomagnesemia
Infants and Children (4 months to 14 years); 18.1 + 6.6
Gastrointestinal: Anorexia, diarrhea, epigastric pain,
hours (range: 11.9 to 40.3 hours) (Benson 1989)
heartburn, nausea (less frequent with |.T.), stomach Adults: Biphasic: Initial: 15 to 48 hours; Terminal:
cramps, vomiting (less frequent with I.T.) 15 days
Genitourinary: Urinary retention Time to peak: Within 1 hour following a 4- to 6-hour dose
Hematologic & oncologic: Anemia (normochromic-nor- Excretion: Urine (2% to 5% as biologically active form);
mocytic), leukocytosis ~40% eliminated over a 7-day period and may be
Local: Pain at injection site (with or without phlebitis or detected in urine for at least 7 weeks after discontinued
thrombophlebitis [incidence may increase with periph- use
eral infusion of admixtures]) Clearance (Benson, 1989):
Renal: Renal function abnormality (including azotemia, Infants and Children (8 months to 9 years): 0.57 + 0.152
renal tubular acidosis, nephrocalcinosis [>0.1 mg/mL]), mL/minute/kg
renal insufficiency z Y Children and Adolescents (10 to 14 years): 0.24 + 0.02
Respiratory: Tachypnea mL/minute/kg
Miscellaneous: Fever = Dosing
Rare but important or life-threatening: Acute hepatic Neonatal Medication errors, including deaths, have
failure, agranulocytosis, anuria, blood coagulation dis- resulted from confusion between lipid-based forms
order, bone marrow depression, bronchospasm, car- of amphotericin (Abelcet, Amphotec, AmBisome)
diac arrest, cardiac arrhythmia, cardiac failure, and conventional amphotericin B for injection; con-
convulsions, diplopia, dyspnea, eosinophilia, exfoliation ventional amphotericin B for injection doses should
of skin, hearing loss, hemorrhagic gastroenteritis, hep- not exceed 1.5 mg/kg/day. Although the manufacturer's
atitis, hypersensitivity pneumonitis, increased liver labeling suggests a dose escalation approach; most
enzymes, jaundice, leukoencephalopathy, leukopenia, expert recommendations initiate therapy at the target
maculopapular rash, melena, nephrogenic diabetes dose (Bradley 2016; Red Book [AAP 2015)).
insipidus, oliguria, peripheral neuropathy, pruritus, pul- General dosing, susceptible infections:
monary edema, renal failure, renal tubular acidosis, IV: 1 mg/kg/dose once daily (Bradley 2016; Red Book
shock, Stevens-Johnson syndrome, thrombocytopenia, [AAP] 2015; Turkova 2011); rapidly progressing or
tinnitus, toxic epidermal necrolysis, ventricular fibrilla- severe disease may require higher doses up to
tion, vertigo (transient), visual disturbance, wheezing 1.5 mg/kg/day for the short-term. Once therapy has >
135
 AMPHOTERICIN B (CONVENTIONAL)

4 been established, amphotericin B can be adminis-

tered on an every-other-day basis at 1 to 1.5 mg/kg/
fluconazole-resistant Candida species (C. glabrata,
C. krusei) (IDSA [Pappas 2016])
dose Note: Maintaining a sodium intake of >4 mEq/ Aspergillosis: ;
kg/day in premature neonates may reduce amphoter- Prophylaxis, immunocompromised: Limited data
icin B-associated nephrotoxicity (Turcu 2009) available: Infants, Children, and Adolescents: Intra-
Irrigation, bladder: Limited data available: 50 meg/mL nasal: 7 mg amphotericin B in 7 mL sterile water
solution, administered as either a continuous irrigation was placed in a De Vilbiss atomizer and the aero-
or as an intermittent irrigation 3 times per day with a solized solution was instilled intranasally to each
dwell time of 60 to 90 minutes; dosing based on two nostril 4 times daily delivering an average of 5 mg
case reports in neonates [PNA at treatment: 3 weeks; amphotericin/day to reduce the frequency of inva-
3 months (PCA: 42 weeks)] (Ku 2004; Martinez- sive aspergillosis in neutropenic patients (Jeff-
Pajares 2010) ery 1991)
Intrathecal, intraventricular, or intracisternal (preferably Endocarditis: Children and Adolescents: IV: 1 mg/kg/
into the lateral ventricles through a cisternal Ommaya dose once daily with or without flucytosine (AHA
reservoir): Limited data available; some dosing based [Baltimore 2015})
on experience in older pediatric patients: 0.01 to Blastomycosis (independent of HIV status), moder-
1 mg; frequency varies widely in the literature; admin-
ately severe to severe disease: Infants, Children,
istration has been reported as daily, every other day,
and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily
and even twice weekly (Chiou 1994; Murphy 2000;
as initial therapy for 1 to 2 weeks, followed with oral
IDSA [Pappas 2016]; Red Book [AAP 2015])
itraconazole for a total of 12 months (IDSA [Chap-
Blastomycosis, treatment: IV: 1 mg/kg/dose once daily
man 2008})
(IDSA [Chapman 2008])
Candidiasis; treatment:
Candidiasis:
Invasive, treatment: IV: 1 mg/kg/dose once daily; treat- Invasive: Infants, Children, and Adolescents; IV: 0.5
ment should continue for at least 2 weeks after the to 1 mg/kg/dose once daily; duration of therapy
first negative blood culture and signs and symptoms dependent upon severity and site of infection (IDSA
have resolved (IDSA [Pappas 2016]) [Pappas 2016])
CNS infection: IV: 1 mg/kg/dose once daily; may add Endocarditis: Children and Adolescents: IV: 1 mg/kg/
flucytosine -if there is no clinical response (IDSA dose once daily with or without flucytosine. (AHA
[Pappas 2016}]) [Baltimore 2015])
Urinary tract infections, asymptomatic (high-risk Esophageal:
patients); treatment: IV: 1 mg/kg/dose once daily Non-HIV-exposed/-positive: Infants, Children, and
(IDSA [Pappas 2016]) Adolescents: IV: 0.3 to 0.7 mg/kg/dose once daily;
Urologic procedures; prophylaxis in patients with can- consider step down to an oral antifungal once
diduria: IV: 0.3 to 0.6 mg/kg/dose once daily for patient is able to tolerate oral intake. In flucona-
several days before and after procedure (IDSA [Pap- zole-refractory disease, continue amphotericin B
pas 2016]) for 21 days (IDSA [Pappas 2016])
Pediatric Medication errors, including deaths, have HIV-exposed/-positive:
resulted from confusion between lipid-based forms Infants and Children: IV: 0.3 to 0.7 mg/kg/dose
of amphotericin (Abelcet, Amphotec, AmBisome) once daily (HHS [Ol pediatric 2013])
and conventional amphotericin B for injection; con- Adolescents: IV: 0.6 mg/kg/dose once daily for 14
ventional amphotericin B for injection doses should to 21 days (HHS [Ol adult 2016])
not exceed 1.5 mg/kg/day Oropharyngeal, fluconazole-refractory:
Note: Premedication: For patients who experience Non-HIV-exposed/-positive: Infants, Children, and
infusion-related immediate reactions, premedicate with Adolescents: IV: 0.3 mg/kg/dose once daily (IDSA
the following drugs 30 to 60 minutes prior to drug [Pappas 2016])
administration: NSAID (with or without diphenhydramine) HIV-exposed/-positive:
or acetaminophen with diphenhydramine or hydrocorti- Infants and Children: IV: 0.3 to 0.5 mg/kg/dose
sone. If the patient experiences rigors during the infu- once daily (HHS [Ol pediatric 2013])
sion, meperidine may be administered. Adolescent: IV: 0.6 mg/kg/dose once daily for 14 to
Test dose: Infants, Children, and Adolescents: IV: 21 days (HHS [Ol adult 2016])
0.1 mg/kg/dose to a maximum of 1 mg; infuse over Urinary tract infections (IDSA [Pappas 2016)}):
20 to 60 minutes; an alternative method to the Prophylaxis, urologic procedures in patients with
0.1 mg/kg test dose is to initiate therapy with candiduria: Infants, Children, and Adolescents:
0.25 mg/kg amphotericin administered over 6 hours; IV: 0.3 to 0.6 mg/kg/dose once daily for several
frequent observation of the patient and assessment of days before and after procedure
vital signs during the first several hours of the infusion Treatment:
is recommended; many clinicians believe a test dose Cystitis: Infants, Children, and Adolescents: IV:
is unnecessary Asymptomatic (high-risk patients): 1 mg/kg/dose
General dosing, susceptible infections: once daily
IV: Infants, Children, and Adolescents: Symptomatic (C. krusei or fluconazole-resistant
Initial: 0.25 to 0.5 mg/kg/dose once daily; gradually C. glabrata): 0.3 to 0.6 mg/kg/dose once daily
increase daily, usually in 0.25 mg/kg increments for 1 to 7 days
until the desired daily dose is reached (maximum Pyelonephritis: Infants, Children, and Adoles-
daily dose: 1.5 mg/kg/day); in critically ill patients, cents: IV: 0.3 to 0.6 mg/kg/dose once daily
more rapid dosage acceleration may be warranted for 1 to 7 days; depending on organism, con-
(eg, 20.5 mg/kg daily dose increase); others have sider addition of flucytosine
initiated at target dose for life-threatening infection Coccidioidomycosis:
(HHS [Ol pediatric 2013]) Non-HIV-exposed/-positive (IDSA [Galgiani 2005)]):
Maintenance dose: 0.25 to 1 mg/kg/dose once daily;
Infants, Children, and Adolescents:
rapidly progressing disease may require short-term
Disseminated (non-CNS) disease: IV 0.5 to
use of doses up to 1.5 mg/kg/day; once therapy
1.5 mg/kg/dose every day or every other day; with
has been established, amphotericin B may be
or without concomitant azole antifungal; duration
administered on an every-other-day basis at 1 to
determined by clinical response
1.5 mg/kg/dose in some cases
CNS disease: Intrathecal: 0.1 to 1.5 mg/dose; fre-
Intrathecal, intraventricular, or intracisternal (prefera-
bly into the lateral ventricles through a cisternal quency ranging from daily to weekly (with or with-
Ommaya reservoir): Limited data available; dose out concomitant azole therapy); initiate at a low
variable: Infants, Children, and Adolescents: 0.01 dose and increase until intolerance is noted (eg,
to 1.mg; frequency varies widely in the literature; severe vomiting, exhaustion, or transient dose-
administration has been reported as daily, every related mental status changes); duration deter-
other day and even twice weekly (Chiou 1994; IDSA mined by clinical response
[Pappas 2016]; Murphy 2000; Red Book Pulmonary disease, diffuse: IV 0.5 to 1.5 mg/kg/
[AAP 2015]) dose every day or every other day for several
Irrigation, bladder: Infants, Children, and Adolescents: weeks, followed by an oral azole antifungal for a
Limited data available: 50 mcg/mL solution, admin- total length of therapy 212 months
istered as either a continuous irrigation or as an HIV-exposed/-positive: Disseminated (non-CNS) dis-
intermittent irrigation 3 times daily with a dwell time ease, diffuse pulmonary disease; severely ill:
of 60 to 90 minutes (Fisher 2011; Gubbins 1999); Infants and Children: IV: 0.5 to 1 mg/kg/dose once
some experts have also recommended daily admin- daily until clinical improvement; minimum of sev-
istration for 5 days for the treatment of cystitis due to eral weeks of therapy (HHS [Ol pediatric 2013))

136
 AMPHOTERICIN B (LIPID COMPLEX)

Adolescents: IV: 0.7 to 1 mg/kg/dose once daily until benzyl alcohol, sodium chloride, or other electrolyte
clinical improvement, then initiate triazole therapy solutions may cause precipitation. Further dilute with
(eg, fluconazole or itraconazole) (HHS [Ol D5W, D10W, up to D2Z0W (Wiest 1991); final concen-
adult 2016]) tration should not exceed 0.1 mg/mL for peripheral
Cryptococcal disease: administration. In patients unable to tolerate a large fluid
CNS disease: volume, amphotericin B at a final concentration not to
Non-HIV-exposed/-positive: Infant, Children, and exceed 0.25 mg/mL in DSW or D10W may be adminis-
Adolescents: IV: 0.7 to 1 mg/kg/dose once daily tered through a central venous catheter (Kintzel 1992).
plus flucytosine; Note: Minimum 2- to 4-week Protect from light.
induction, followed by consolidation and chronic Intrathecal: Dilute dose in 0.5 to 2 mL of D5W; use only
suppressive therapy; may increase amphotericin preservative-free ingredients (Klaus 1989)
dose to 1.5 mg/kg/day if flucytosine is not tolerated Irrigation solution (bladder): Further dilute reconstituted
(IDSA [Perfect 2010]) solution in sterile water to a final concentration of 50
HIV-exposed/-positive: mceg/mL (Fisher 2011; Gubbins 1999; IDSA [Pappas
Infants and Children: IV: 1 mg/kg/dose once daily 2016]; Ku 2004; Martinez-Pajares 2010).
plus flucytosine or fluconazole; Note: Minimum 2- Intranasal: Dilute 7 mg amphotericin B in 7 mL sterile
‘week induction, followed by consolidation and water and place in a De Vilbiss atomizer (Jeffrey 1991)
chronic suppressive therapy; a longer duration Administration
of induction therapy may be necessary if CSF is IV: Administer by IV infusion over 2 to 6 hours; an in-line
not negative or lack of clinical improvement; may filter (>1 micron mean pore diameter) may be used for
increase amphotericin dose to 1.5 mg/kg/day administration (Kintzel 1992). For a patient who experi-
alone or in combination with fluconazole if flucy- ences chills, fever, hypotension, nausea, or other non-
tosine is not tolerated (HHS [OI pediatric 2013)) anaphylactic infusion-related reactions, premedicate
Adolescents: IV: 0.7 to 1 mg/kg/dose once daily with the following drugs 30 to 60 minutes prior to drug
with or without flucytosine or fluconazole; Note: administration: A nonsteroidal (eg, ibuprofen) + diphen-
Minimum 2-week induction, followed by consol- hydramine or acetaminophen with diphenhydramine or
idation and chronic suppressive therapy (HHS [Ol hydrocortisone. If the patient experiences rigors during
adult 2016]) the infusion, meperidine may be administered. Bolus
Disseminated (non-CNS disease) or severe pulmo- infusion of normal saline immediately preceding, or
nary disease: Independent of HIV status: |nfants, immediately preceding and following amphotericin B
Children, and Adolescents: IV: 0.7 to 1 mg/kg/dose may reduce drug-induced nephrotoxicity. Risk of neph-
once daily with or without flucytosine; duration of rotoxicity increases with amphotericin B doses
therapy depends on the site and severity of the >1 mg/kg/day.
infection and clinical response (HHS [Ol adult Irrigation solution (bladder): Administer as a continuous
2016]; HHS [Ol pediatric 2013]; IDSA [Per- irrigation or intermittently with a dwell time of 60 to 90
fect 2010]) minutes (Fisher 2011; Gubbins 1999; Ku 2004; Martinez-
Histoplasmosis: Pajares 2010).
Non-HIV-exposed/-positive: Severe disseminated Intranasal: Administer intranasally via a De Vilbiss atom-
(non-CNS) or pulmonary disease: Infants, Children, izer (Jeffrey 1991)
and Adolescents: IV: 0.7 to 1 mg/kg/dose once daily; Monitoring Parameters Renal function (monitor fre-
Note: Minimum 1- to 2-week induction, followed by quently during therapy: Every other day during dose
consolidation therapy (IDSA [Wheat 2007]) increases and at least weekly, thereafter), electrolytes
HIV-exposed/-positive: CNS or severe disseminated (especially potassium and magnesium), liver function
disease: Infants and Children: IV: 0.7 to 1 mg/kg/ tests, PT/PTT, CBC; monitor input and output; monitor
dose once daily, followed by consolidation therapy for signs of hypokalemia (muscle weakness, cramping,
(HHS [OI pediatric 2013]) drowsiness, ECG changes, etc); blood pressure, temper-
Duration of induction: ature, pulse, respiration, IV site
Severe or moderately severe pulmonary disease: 1 Dosage Forms Excipient information presented when
to 2 week minimum available (limited, particularly for generics); consult spe-
Disseminated or clinical improvement delayed: 22 cific product labeling.
weeks Solution Reconstituted, Injection, as desoxycholate:
CNS involvement: 4 to 6 weeks Generic: 50 mg (1 ea)
Leishmaniasis, visceral (HIV-exposed/-positive): Extemporaneous Preparations Intravitreal/intracam-
Adolescents: IV: 0.5 to 1 mg/kg/dose once daily for eral injection: Add 10 mL SWFI to a 50 mg vial; withdraw
a total cumulative dose of 1,500 to 2,000 mg (HHS 1 mL of solution and further dilute with 4 mL SWFI for a
[Ol adult 2016]) concentration of 1 mg/mL. Remove 1 mL of 1 mg/mL
Peritonitis (CAPD): Limited data available: Note: solution and further dilute with 9 mL SWFI to achieve a
Amphotericin B has demonstrated poor peritoneal final concentration of 0.1 mg/mL. A volume of 0.1 mL of
penetration when given systemically and intraperito- the 0.1 mg/mL solution will contain 10 mcg of amphoter-
neal administration is associated with abdominal pain icin. Withdraw dose into a 1 mL syringe for immediate
and peritoneal irritation; other agents may be pre- administration (stability data are not available) (Kaushik
ferred (ISPD [Warady 2012]). 2001).
Intraperitoneal, dialysate: Infants, Children, and Ado- Pt S, Ram J, Brar GS, Jain AK, Chakraborti A, Gupta A. Intra-
lescents: 1 to 4 mg per liter of dialysate has been cameral amphotericin B: initial experience in severe keratomycosis.
used in pediatric patients based on case reports and Cornea. 2001;20(7):715-719.
retrospective reviews (Hogg 1982; Kravitz 1986;
@ Amphotericin B Deoxycholate see Amphotericin B
Raaijmakers 2007; Warady 2000a); lower doses of
0.5 to 3 mg per liter of dialysate has been reported in
(Conventional) on page 134
adults (with or without concomitant systemic ampho- @ Amphotericin B Desoxycholate see Amphotericin B
tericin B therapy); abdominal pain has been asso- (Conventional) on page 134
ciated with doses 22 mg per liter of dialysate
(Bastani 1986; Johnson 1985). Amphotericin B (Lipid Complex)
IV: Infants, Children, and Adolescents: 1 mg/kg/dose (am foe TER i sin bee LIP id KOM pleks)
once daily (ISPD [Warady 2000b])
Sporotrichosis, severe infection (IDSA [Kauffman Medication Safety Issues
2007]): Children and Adolescents: 0.7 mg/kg/dose High alert medication:
once daily; followed by oral itraconazole after a favor- The Institute for Safe Medication Practices (ISMP)
able response is seen with amphotericin initial therapy includes this medication among its list of drugs which
Renal Impairment: Pediatric have a heightened risk of causing significant patient
Infants, Children, and Adolescents: harm when used in error.
If renal dysfunction is due to the drug, the daily total can Other safety concerns:
be decreased by 50% or the dose can be given every Lipid-based amphotericin formulations (Abelcet) may be
other day. IV therapy may take several months. confused with conventional formulations (Fungizone) or
Renal replacement therapy: Poorly dialyzed; no sup- with other lipid-based amphotericin formulations
plemental dose or dosage adjustment necessary, (amphotericin B liposomal [AmBisome]; amphotericin
including patients on intermittent hemodialysis B cholesteryl sulfate complex [Amphotec])
or CRRT. Large overdoses have occurred when conventional for-
Hepatic Impairment: Pediatric There are no dosage mulations were dispensed inadvertently for lipid-based
adjustments provided in the manufacturer's labeling. products. Single daily doses of conventional amphoter-
Preparation for Administration icin formulation never exceed 1.5 mg/kg.
lV: Add 10 mL of preservative-free SWFI to each vial of Brand Names: US Abelcet
amphotericin B; do not use bacteriostatic water; Brand Names: Canada Abelcet

137
 AMPHOTERICIN B (LIPID COMPLEX)

€ Therapeutic Category Antifungal Agent, Systemic Increased Effect/Toxicity

Generic Availability (US) No Amphotericin B (Lipid Complex) may increase the levels/
Use Treatment of invasive fungal infections in patients who effects of: Amifostine; Aminoglycosides; Antipsychotic
are refractory to or intolerant of conventional amphotericin Agents (Second Generation [Atypical]); Bromperidol:
B therapy (FDA approved in children and adults) Cardiac Glycosides; Colistimethate; CycloSPORINE
Pregnancy Risk Factor B (Systemic); DULoxetine; Flucytosine; Hypotension-
Associated Agents; Levodopa; Nitroprusside; Pholco-
Pregnancy Considerations Adverse events were not
dine; Sodium Stibogluconate
observed in animal reproduction studies. Amphotericin
crosses the placenta and enters the fetal circulation. The levels/effects of Amphotericin B (Lipid Complex)
Amphotericin B is recommended for the treatment of may be increased by: Alfuzosin; Barbiturates; Benper-
serious, systemic fungal diseases in pregnant women, idol; Blood Pressure Lowering Agents; Brimonidine (Top-
refer to current guidelines (IDSA [Pappas 2016]; King ical); Corticosteroids (Orally Inhaled); Corticosteroids
1998; Pilmus 2015). : (Systemic); Diazoxide; Dronabinol; Foscarnet; Ganciclo-
Breastfeeding Considerations It is not known if ampho- vir-Valganciclovir; Herbs (Hypotensive Properties); Lor-
tericin is excreted into breast milk. Due to its poor oral metazepam; Methoxyflurane; Molsidomine; Naftopidil;
absorption, systemic exposure to the nursing infant is Nicergoline; Nicorandil; Obinutuzumab; Pentoxifylline;
expected to be decreased; however, because of the Phosphodiesterase 5 Inhibitors; Prostacyclin Analogues;
potential for toxicity, breastfeeding is not recommended Quinagotide
by the manufacturer (Mactal-Haaf 2001). Decreased Effect
Contraindications Hypersensitivity to amphotericin or Amphotericin B (Lipid Complex) may decrease the lev-
any component of the formulation els/effects of: Saccharomyces boulardii
Warnings/Precautions Anaphylaxis has been reported The levels/effects of Amphotericin B. (Lipid Complex)
with amphotericin B-containing drugs. If severe respiratory may be decreased by: Antifungal Agents (Azole Deriva-
distress occurs, the infusion should be immediately dis- tives, Systemic); Bromperidol
continued. During the initial dosing, the drug should be Storage/Stability Intact vials should be stored at 2°C to
administered under close clinical observation. Acute reac- 8°C (35°F to 46°F); do not freeze. Protect intact vials from
tions (including fever and chills) may occur 1-2 hours after - exposure to light. Solutions in DSW for infusion are stable
starting an intravenous infusion. These reactions are for 48 hours under refrigeration and for an additional 6
usually more common with the first few doses and gen- hours at room temperature.
erally diminish with subsequent doses. Infusion has been Mechanism of Action Binds to ergosterol altering cell
rarely associated with hypotension, bronchospasm, membrane permeability in susceptible fungi and causing
arrhythmias, and shock. Acute pulmonary toxicity has leakage of cell components with subsequent cell death.
been reported in patients receiving leukocyte transfusions Proposed mechanism suggests that amphotericin causes
and amphotericin B; amphotericin B lipid complex and an oxidation-dependent stimulation of macrophages.
concurrent leukocyte transfusions are not recommended. Pharmacodynamics/Kinetics (Adult data unless
Concurrent use with antineoplastic agents may enhance noted) Note: Exhibits nonlinear kinetics; volume of dis-
the potential for renal toxicity, bronchospasm or hypoten- tribution and clearance from blood increases with increas-
sion; use with caution. Concurrent use of amphotericin B ing dose.
with other nephrotoxic drugs may enhance the potential Distribution: High tissue concentration found in the liver,
for drug-induced renal toxicity. In a scientific statement spleen, and lung; Vg: Increases with higher doses (likely
from the American Heart Association, amphotericin has reflects increased uptake by tissues); 131 L/kg with
been determined to be an agent that may cause direct 5 mg/kg/day
myocardial toxicity (magnitude: moderate/major) (AHA Half-life elimination: 173 hours following multiple doses
[Page 2016)]). Excretion: 0.9% of dose excreted in urine over 24 hours;
Adverse Reactions Nephrotoxicity and infusion-related effects of hepatic and renal-impairment on drug disposi-
hyperpyrexia, rigor, and chilling are reduced relative to tion are unknown
amphotericin deoxycholate. Dosing
Cardiovascular: Cardiac arrest, chest pain, hypertension, Neonatal Medication errors, including deaths, have
hypotension resulted from confusion between lipid-based forms
Central nervous system: Chills, headache, pain of amphotericin (Abelcet, Amphotec, AmBisome)
Dermatologic: Skin rash and conventional amphotericin B for injection.
Endocrine & metabolic: Hypokalemia Lipid-based and conventional formulations are not inter-
Gastrointestinal: Abdominal pain, diarrhea, gastrointesti- changeable and have different dosing recommenda-
nal hemorrhage, nausea, vomiting tions. Overdoses have occurred when conventional
Hematologic & oncologic: Anemia, leukopenia, thrombo- formulations were dispensed inadvertently for lipid- .
cytopenia based products.
Hepatic: Hyperbilirubinemia Note: In neonates, lipid formulations of amphotericin
Infection: Infection, sepsis have poorer penetration into the central nervous system,
Renal: Increased serum creatinine, renal failure kidneys, urinary tract, and eyes than conventional
Respiratory: Dyspnea, respiratory failure, respiratory tract amphotericin and are not preferred in most cases (IDSA
disease [Pappas 2016]; Red Book [AAP 2015]; Turkova 2011).
Miscellaneous: Fever, multi-organ failure
Rare but important or life-threatening: Acute hepatic fail- Candidiasis, invasive: Limited data available: IV: 3 to
ure, anaphylactoid reaction, anuria, asthma, blood coag- 5 mg/kg/dose once daily; treatment should continue for
at least 2 weeks after the first negative blood culture
ulation disorder, brain disease, bronchospasm, cardiac
and signs and symptoms have resolved (IDSA [Pappas
arrhythmia, cardiomyopathy, cerebrovascular accident,
2016]); a pharmacokinetic study reported use in neo-
cholangitis, cholecystitis, deafness, dysuria, eosino-
nates with GA ranging from 24 to 41 weeks and weight
philia, erythema multiforme, exfoliative dermatitis,
ranging from 0.48 to 4.9 kg (Wiurthwein 2005)
extrapyramidal reaction, hearing loss, hematologic dis-
Pediatric Medication errors, including deaths, have
ease, hemoptysis, hepatic sinusoidal obstruction syn-
resulted from confusion between lipid-based forms
drome (formerly known as hepatic veno-occlusive
of amphotericin (Abelcet, Amphotec, AmBisome)
disease), hepatitis, hepatomegaly, hepatotoxicity, hyper-
and conventional amphotericin B for injection.
calcemia, hyperkalemia, hypersensitivity reaction, hypo-
Lipid-based and conventional formulations are not inter-
calcemia, hypomagnesemia, increased blood urea
changeable and have different dosing recommenda-
nitrogen, increased serum transaminases, injection site
tions. Overdoses have occurred when conventional
reaction, jaundice, leukocytosis, myasthenia, myocardial
formulations were dispensed inadvertently for lipid-
infarction, oliguria, peripheral neuropathy, pleural effu- based products.
sion, pulmonary edema, pulmonary embolism, renal Note: For patients who experience nonanaphylactic
insufficiency, renal tubular acidosis, seizure, shock, infusion-related immediate reactions, premedicate with
tachycardia, thrombophlebitis, ventricular fibrillation, ver- the following drugs 30 to 60 minutes prior to drug
tigo (transient), visual impairment administration: NSAID (with or without diphenhydr-
Drug Interactions amine) or acetaminophen with diphenhydramine or
Metabolism/Transport Effects None known. hydrocortisone. If the patient experiences rigors during
Avoid Concomitant Use the infusion, meperidine may be administered.
Avoid concomitant use of Amphotericin B (Lipid Com- General dosing, susceptible infections: Infants,
plex) with any of the following: Bromperidol; Foscarnet; Children, and Adolescents: IV: 5 mg/kg/dose once
Methoxyflurane; Saccharomyces boulardii daily

138
 AMPHOTERICIN B (LIPID COMPLEX)

Aspergillosis, treatment: HIV-exposed/-positive: IV: Induction therapy:

Invasive: Infants, Children, and Adolescents: IV: 5 mg/kg/dose once daily with flucytosine for at
5 mg/kg/dose once daily; duration of treatment least 2 weeks, followed by fluconazole for con-
depends on site of infection, extent of disease, and solidation therapy (HHS [Ol adult 2016]; IDSA
level of immunosuppression (IDSA [Walsh 2008]) {Perfect 2010]). Note: If flucytosine is not given
Endocarditis: Children and Adolescents: IV: 3 to due to intolerance, duration of amphotericin B
5 mg/kg/dose once daily with or without flucytosine lipid complex therapy should be 4 to 6 weeks
(AHA [Baltimore 2015]) (IDSA [Perfect 2010)).
Blastomycosis, invasive: Infants, Children, and Ado- Transplant patients: Induction therapy: IV:
lescents: IV: 3 to 5 mg/kg/dose once daily for initial 5 mg/kg/dose once daily (with flucytosine) for at
therapy usually for 1 to 2 weeks, if CNS infection 4 to least 2 weeks followed by oral fluconazole. Note:
6 weeks may be needed; follow with oral itraconazole If flucytosine is not given, duration of therapy
for a total of 12 months (IDSA [Chapman 2008]) should be 4 to 6 weeks (IDSA [Perfect 2010)).
Candidiasis, treatment: Histoplasmosis:
Invasive (Independent of HIV status): Infants, Chil- Non-HIV-exposed/-positive: Disseminated (non-CNS)
dren, and Adolescents: IV: 3 to 5 mg/kg/dose once or pulmonary disease: \Infants, Children, and Ado-
daily (IDSA [Pappas 2016]); Note: In HIV-exposed/- lescents: IV: 5 mg/kg/dose once daily for 1 to 2
positive patients, doses at the higher end of the
weeks followed by oral itraconazole for a total of
range may be considered (5 mg/kg/day) (HHS [Ol
12 weeks; conventional amphotericin B typically
pediatric 2013)).
preferred (IDSA [Wheat 2007])
Endocarditis: Infants, Children, and Adolescents: IV: 3
HIV-exposed/-positive: Disseminated disease (mod-
to 5 mg/kg/dose once daily with or without flucyto-
erately severe to severe): Adolescents: IV:
sine (AHA [Baltimore 2015]; IDSA [Pappas 2016])
3 mg/kg/dose once daily for at least 2-week induc-
Esophageal: HIV-exposed/-positive: Adolescents: IV:
tion, followed by oral itraconazole (HHS [Ol
3 to 4 mg/kg/dose once daily for 14 to 21 days (HHS
[Ol adult 2016]) adult 2016])
Coccidioidomycosis, invasive: Leishmaniasis, visceral (HIV-exposed/-positive)
Non-HIV-exposed/-infected: (HHS [OI adult 2016}):
Disseminated infection, nonpulmonary: \nfants, Chil- Treatment: Adolescents: IV: 2 to 4 mg/kg/dose once
dren, and Adolescents: IV: 2 to 5 mg/kg/dose once daily or an interrupted schedule of 4 mg/kg/dose on
daily with or without concomitant azole antifungal days 1 to 5, and on days 10, 17, 24, 31, and 38 to
therapy (IDSA [Galgiani 2005]) achieve a total dose of 20 to 60 mg/kg
Pulmonary infection, diffuse: Infants, Children, and Chronic maintenance: Adolescents: IV: 3 mg/kg/dose
Adolescents: IV: 2 to 5 mg/kg/dose once daily for every 21 days; Note: Use reserved for patients with
several weeks, followed by an oral azole antifungal visceral infection and CD4 count <200 cells/mm*
for a total length of therapy 212 months (IDSA Sporotrichosis infection (IDSA [Kauffman 2007]):
[Galgiani 2005]) Adolescents:
HIV-exposed/-infected: Non-CNS infection, severe Meningeal: IV: 5 mg/kg/dose once daily for 4 to 6
(ie, diffuse pulmonary or severely ill with extrathora- weeks, followed by oral itraconazole
cic, disseminated disease): Pulmonary, osteoarticular, and disseminated: IV: 3 to
Infants and Children: IV: 5 mg/kg/dose once daily 5 mg/kg/dose once daily, followed by oral itracona-
until clinical improvement; dose may be increased zole after a favorable response is seen with ampho-
to as high as 10 mg/kg/dose once daily for life- tericin initial therapy
threatening infection (HHS [Ol pediatric 2013]) Renal Impairment: Pediatric
Adolescents: IV: 3 to 5 mg/kg/dose once daily until Infants, Children, and Adolescents:
clinical improvement, then switch to fluconazole or Manufacturer's recommendations: There are no dos-
itraconazole (HHS [O! adult 2016]) age adjustments provided in manufacturer's labeling
Cryptococcosis: (has not been studied).
Disseminated (non-CNS or severe pulmonary Alternate recommendations: The following adjustments
disease): have been recommended (Aronoff 2007):
Infants and Children (independent of HIV status): IV: Hemodialysis: No supplemental dosage necessary
5 mg/kg/dose once daily; for severe infection in Peritoneal dialysis: No supplemental dosage nec-
HIV-exposed/-infected patients, may consider the essary
addition of flucytosine (HHS [Ol pediatric 2013]; Continuous renal replacement therapy (CRRT): No
IDSA [Perfect 2010]) supplemental dosage necessary
Adolescents:
Hepatic Impairment: Pediatric There are no dosage
Non-HIV-exposed: IV:-5.mg/kg/dose once daily
adjustments provided in manufacturer's labeling (has not
(with flucytosine) for 24 weeks may be used for
been studied).
severe pulmonary cryptococcosis or for crypto-
Preparation for Administration Parenteral: IV: Shake
coccemia with evidence of high fungal burden,
the vial gently until there is no evidence of any yellow
followed by oral fluconazole. Note: If flucytosine
sediment at the bottom. Withdraw the appropriate dose
is not given or treatment is interrupted, consider
prolonging induction therapy for an additional 2 from the vial using an 18-gauge needle. Remove the 18-
weeks (IDSA [Perfect 2010]). gauge needle and attach the provided 5-micron filter
HIV-exposed/-positive: IV: Induction therapy: needle to filter, and dilute the dose with D5W to a final
5 mg/kg/dose once daily with flucytosine for at concentration of 1 mg/mL. Limited data suggests D10W
least 2 weeks, followed by oral fluconazole or and D15W may also be used for dilution (data on file
itraconazole (HHS [Ol adult 2016)). [Sigma-Tau Pharmaceuticals 2014]). Each filter needle
Meningitis: may be used to filter up to four 100 mg vials. A final
Infants and Children: concentration of 2 mg/mL may be used for pediatric
Non-HIV-exposed/-positive: IV: 5 mg/kg/dose once patients and patients with cardiovascular disease.
daily with or without oral flucytosine for a mini- Do not dilute with saline solutions or mix with other
mum 2-week induction; combination with flucyto-
drugs or electrolytes - compatibility has not been estab-
sine is the preferred treatment (IDSA
lished
[Perfect 2010]) a
Administration Parenteral: IV: Prior to administration,
HIV-exposed/-positive: IV: 5 mg/kg/dose once
amphotericin B lipid complex 5 mg/mL concentrated sus-
daily plus flucytosine or fluconazole; Note: Mini-
pension must be diluted. Flush line with D5W prior to
mum 2-week induction, followed by consolidation
and chronic suppressive therapy; a longer dura-
infusion. Gently shake the IV container of diluted drug to
tion of induction therapy may be necessary if CSF insure that contents are thoroughly mixed then administer
is not negative or lack of clinical improvement at a rate of 2.5 mg/kg/hour (over 2 hours). The manufac-
(HHS [Ol pediatric 2013]) turer recommends that an in-line filter should not be used
Adolescents: during administration of amphotericin B lipid complex. If
Non-HIV-exposed/-positive; nontransplant infusion time exceeds 2 hours, mix the contents by gently
patients: IV: Induction therapy: 5 mg/kg/dose rotating the infusion bag every 2 hours.
once daily (with flucytosine) for 24 weeks fol- Monitoring Parameters BUN, serum creatinine, liver
lowed by oral fluconazole; should be used as an function tests, serum electrolytes (especially potassium
alternative to conventional amphotericin B in and magnesium), CBC; vital signs, | & O
patients) with renal concerns. Note: If flucytosine Additional Information The lipid portion of amphotericin
is not given or treatment is interrupted, consider B lipid complex formulation contains 0.045 kcal per 5 mg;
prolonging induction therapy for an additional 2 for patients receiving parenteral nutrition, adjustment to
weeks (IDSA [Perfect 2010]). the amount of lipids may be necessary (Sacks 1997). »
139
AMPHOTERICIN B (LIPID COMPLEX)

Dosage Forms Excipient information presented when hypernatremia, hyperphosphatemia, hypervolemia,

available (limited, particularly for generics); consult spe- hypocalcemia, hypokalemia, hypomagnesemia, hypona-
cific product labeling. tremia, hypophosphatemia, increased lactate dehydro-
Suspension, Intravenous: genase, increased nonprotein nitrogen }
Abelcet: 5 mg/mL (20 mL) Gastrointestinal: Abdominal pain, anorexia, aphthous sto-
matitis, constipation, diarrhea, dyspepsia, dysphagia,
enlargement of abdomen, eructation, fecal incontinence,
Amphotericin B (Liposomal) flatulence, gastrointestinal hemorrhage, gingival hemor-
(am foe TER i sin bee lye po SO mal)
rhage, hematemesis, hemorrhoids, hiccups, increased
Medication Safety Issues serum amylase, intestinal obstruction, mucositis, nau-
High alert medication: sea, rectal disease, stomatitis, vomiting, xerostomia
The Institute for Safe Medication Practices (ISMP) Genitourinary: Dysuria, hematuria, nephrotoxicity, toxic
includes this medication among its list of drugs which nephrosis, urinary incontence, vaginal hemorrhage
have a heightened risk of causing significant patient Hematologic & oncologic: Anemia, blood coagulation dis-
harm when used in error. order, bruise, decreased prothrombin time, hemophthal-
Sound-alike/look-alike issues: mos, hemorrhage, hypoproteinemia, increased
AmBisome may be confused with Ambisolm, Ambisom prothrombin time, leukopenia, oral hemorrhage, pete-
Other safety concerns: chia, purpura, thrombocytopenia
Lipid-based amphotericin formulations (AmBisome) may Hepatic: Abnermal hepatic function tests (not specified),
be confused with conventional formulations (Amphocin, hepatic injury, hepatic sinusoidal obstruction syndrome
Fungizone) or with other lipid-based amphotericin for- (formerly known as hepatic veno-occlusive disease),
mulations (Abelcet, Amphotec) hepatomegaly, hyperbilirubinemia, increased serum
Large overdoses have occurred when conventional for- alkaline phosphatase, increased serum ALT, increased
mulations were dispensed inadvertently for lipid-based serum AST
products. Single daily doses of conventional amphoter- Hypersensitivity: Delayed hypersensitivity, hypersensitivity
icin formulation never exceed 1.5 mg/kg. reaction, transfusion reaction ;
Brand Names: US AmBisome Immunologic: Graft versus host disease
Brand Names: Canada AmBisome Infection: Infection, herpes simplex infection, sepsis
Therapeutic Category Antifungal Agent, Systemic Local: Inflammation at injection site
Generic Availability (US) No Neuromuscular & skeletal: Arthralgia, back pain, myalgia,
Use Empirical therapy for presumed fungal infection in neck pain, ostealgia, tremor, weakness
febrile, neutropenic patients; treatment of patients with Ophthalmic: Conjunctivitis, dry eyes
Aspergillus species, Candida species, and/or Cryptococ- Renal: Acute renal failure, increased blood urea nitrogen,
cus species infections refractory to amphotericin B des- increased serum creatinine, renal failure, renal function
oxycholate (conventional amphotericin), or in patients abnormality
where renal impairment or unacceptable toxicity precludes Respiratory: Asthma, atelectasis, cough, dry nose, dysp-
the use of amphotericin B desoxycholate; treatment of nea, epistaxis, flu-like symptoms, hemoptysis, hyper-
cryptococcal meningitis in HIV-infected patients; treatment
ventilation, hypoxia, pharyngitis, pleural effusion,
of visceral leishmaniasis (all indications: FDA approved in
pneumonia, pulmonary disease, pulmonary edema, res-
ages 21 month and adults); has also been used for treat-
piratory alkalosis, respiratory failure, respiratory insuffi-
ment of systemic Histoplasmosis infection, blastomycosis,
ciency, rhinitis, sinusitis
coccidioidomycosis, and Sporotrichosis
Miscellaneous: Infusion related reactions (fever, chills,
Pregnancy Risk Factor B
vomiting, nausea, dyspnea, tachycardia, hypertension,
Pregnancy Considerations Adverse events were not
vasodilation, hypotension, hyperventilation, hypoxia),
observed in animal reproduction studies. Amphotericin
procedural complication
crosses the placenta and enters the fetal circulation.
Rare but important or life-threatening: Agranulocytosis,
Amphotericin B is recommended for the treatment of
angioedema, cyanosis, hemorrhagic cystitis, hypoventi-
serious systemic fungal diseases in pregnant women;
lation, rhabdomyolysis
refer to current guidelines (IDSA [Pappas 2016]; King
1998; Pilmus 2015). Drug Interactions
Breastfeeding Considerations It is not known if ampho- Metabolism/Transport Effects None known.
tericin is excreted into breast milk. Due to its poor oral Avoid Concomitant Use
absorption, systemic exposure to the nursing infant is Avoid concomitant use of Amphotericin B (Liposomal)
expected to be decreased; however, because of the with any of the following: Bromperidol; Foscarnet;
potential for toxicity, breastfeeding is not recommended Methoxyflurane; Saccharomyces boulardii
by the manufacturer (Mactal-Haaf 2001). Increased Effect/Toxicity
Contraindications Hypersensitivity to amphotericin B Amphotericin B (Liposomal) may increase the levels/
deoxycholate or any component of the formulation effects of: Amifostine; Aminoglycosides; Antipsychotic
Warnings/Precautions Anaphylaxis has been reported Agents (Second Generation [Atypical]); Bromperidol;
with amphotericin B-containing drugs; facilities for cardio- Cardiac Glycosides; Colistimethate; CycloSPORINE
pulmonary resuscitation should be available during admin- (Systemic); DULoxetine; Flucytosine; Hypotension-
istration. Acute infusion reactions (including fever and Associated Agents; Levodopa; Nitroprusside; Pholco-
chills) may occur 1 to 3 hours after starting infusions; dine; Sodium Stibogluconate j
reactions are more common with the first few doses and
generally diminish with subsequent doses. Immediately The levels/effects of Amphotericin B (Liposomal) may be
discontinue infusion if a severe anaphylactic reaction increased by: Alfuzosin; Barbiturates; Benperidol; Blood
occurs; the patient should not receive further infusions. Pressure Lowering Agents; Brimonidine (Topical); Corti-
Acute pulmonary toxicity has been reported in patients costeroids (Orally Inhaled); Corticosteroids (Systemic);
receiving simultaneous leukocyte transfusions and Diazoxide; Dronabinol; Foscarnet; Ganciclovir-Valganci-
amphotericin B. Potentially significant interactions may clovir,; Herbs (Hypotensive Properties); Lormetazepam;
exist, requiring dose or frequency adjustment, additional Methoxyflurane; Molsidomine; Naftopidil; Nicergoline;
monitoring, and/or selection of alternative therapy. Nicorandil; Obinutuzumab; Pentoxifylline; Phosphodies-
Adverse Reactions Nephrotoxicity and infusion-related terase 5 Inhibitors; Prostacyclin Analogues; Quinagolide
hyperpyrexia, rigor, and chilling are reduced relative to Decreased Effect
amphotericin deoxycholate. Amphotericin B (Liposomal) may decrease the levels/
Cardiovascular: Atrial fibrillation, bradycardia, cardiac effects of: Saccharomyces boulardii 1
arrest, cardiac arrhythmia, cardiomegaly, chest pain,
The levels/effects of Amphotericin B (Liposomal) may be
edema, facial edema, flushing, heart valve disease,
decreased by: Antifungal Agents (Azole Derivatives,
hypertension, hypotension, localized phlebitis, ortho-
static hypotension, peripheral edema, tachycardia, vas-
Systemic); Bromperidol
cular disorder, vasodilatation Storage/Stability Store intact vials at <25°C (S77°F).
Central nervous system: Abnormality in thinking, agitation, Reconstituted vials are stable at 2°C to 8°C (36°F to
anxiety, chills, coma, confusion, depression, dizziness, 46°F) for 24 hours. Do not freeze. Begin infusion within
drowsiness, dysesthesia, dystonia, hallucination, head- 6 hours of dilution with D5W. Extended storage informa-
ache, insomnia, malaise, nervousness, pain, paresthe- tion may be available; contact product manufacturer to
sia, rigors, seizure obtain current recommendations.
Dermatologic: Alopecia, cellulitis, dermal ulcer, dermato- Mechanism of Action Binds to ergosterol altering cell
Jogical reaction, diaphoresis, maculopapular rash, pruri- membrane permeability in susceptible fungi and causing
tus, skin discoloration, skin rash, urticaria, leakage of cell components with subsequent cell death.
vesiculobullous dermatitis, xeroderma Proposed mechanism suggests that amphotericin causes
Endocrine & metabolic: Acidosis, hyperchloremia, hyper- an oxidation-dependent stimulation of macrophages
glycemia, hyperkalemia, hypermagnesemia, (Lyman 1992).

140
 AMPHOTERICIN B (LIPOSOMAL)

Pharmacodynamics/Kinetics (Adult data unless Esophageal: HIV-exposed/-positive: Adolescents: IV:

noted) 3 to 4 mg/kg/dose once daily for 14 to 21 days (HHS
Note: Exhibits nonlinear kinetics (greater than propor- [Ol adult 2016))
tional increase in serum concentration with an increase Coccidioidomycosis, invasive:
in dose) Non-HIV-exposed/-positive:
Distribution: Vg: 0.1 to 0.16 L/kg Disseminated infection, nonpulmonary: Infants, Chil-
Half-life elimination: 7 to 10 hours (followinga single 24- dren, and Adolescents: IV: 2 to 5 mg/kg/dose once
hour dosing interval); Terminal half to life: 100 to 153 daily with or without concomitant azole antifungal
hours (following multiple dosing up to 49 days) (IDSA [Galgiani 2005))
Dosing Pulmonary infection, diffuse: Infants, Children, and
Neonatal Medication errors, including deaths, have Adolescents: IV: 2 to 5 mg/kg/dose once daily for
resulted from confusion between lipid-based forms several weeks, followed by an oral azole antifungal
of amphotericin (Abelcet, Amphotec, AmBisome) for a total length of therapy 212 months (IDSA
and conventional amphotericin B for injection. [Galgiani 2005])
Lipid-based and conventional formulations are not inter- HIV-exposed/-positive: Non-CNS infection, severe (ie,
changeable and have different dosing recommenda- diffuse pulmonary or severely ill with extrathoracic,
tions. Overdoses have occurred when conventional disseminated disease):
formulations were dispensed inadvertently for lipid- Infants and Children: IV: 5 mg/kg/dose once daily
until clinical improvement (minimum of several
based products.
weeks of therapy), then initiate triazole therapy
Note: In neonates, lipid formulations of amphotericin (eg, fluconazole or itraconazole); dose may be
have poorer penetration into the central nervous system, increased to as high as 10 mg/kg/dose once daily
kidneys, urinary tract, and eyes than conventional for life-threatening infection (HHS [O! pedia-
amphotericin and are not preferred in most cases (IDSA tric 2016))
[Pappas 2016]; Red Book [AAP 2015]; Turkova 2011). Adolescents: IV: 3 to 5 mg/kg/dose once daily until
Clinical improvement, then switch to fluconazole or
Candidiasis, invasive (non-CNS): Limited data avail-
itraconazole (HHS [Ol adult 2016])
able: IV: 3 to 5 mg/kg/dose once daily (Cetin 2005;
Cryptococcosis, invasive:
IDSA [Pappas 2016]; Juster-Reicher 2003; Queiroz-
Disseminated cryptococcosis (non-CNS or severe
Telles 2008); treatment should continue for at least 2
pulmonary disease):
weeks after the first negative blood culture and signs Infants and Children (independent of HIV status): IV:
and symptoms have resolved (IDSA [Pappas 2016)]); 3 to 5 mg/kg/dose once daily with oral flucytosine;
doses as high as 7 mg/kg/dose once daily have been if flucytosine unavailable or not tolerated, may
used (Juster-Reicher 2003); another report describes a administer alone or in combination with high-dose
dose escalation approach with dosing initiated with fluconazole in HIV-exposed/-positive patients
1 mg/kg/dose on day 1 and increased by 1 mg/kg/dose (HHS [Ol pediatric 2016]; IDSA [Perfect 2010])
once daily to a maximum of 5 mg/kg/dose once daily Adolescents:
(preterm neonate: n=40; term neonate: n=4) (Scar- Non-HIV-exposed/-positive: IV: 3 to 4 mg/kg/dose
cella 1998) once daily for at least 14 days; may consider
Candidiasis, CNS infection: IV: 5 mg/kg/dose once addition of oral flucytosine (IDSA [Perfect 2010])
daily; may add flucytosine if there is no clinical HIV-exposed/-positive: IV: 3 to 4 mg/kg/dose once
response (IDSA [Pappas 2016]) daily with or without flucytosine or fluconazole
Pediatric Medication errors, including deaths, have (HHS [Ol adult 2016])
resulted from confusion between lipid-based forms Meningitis:
of amphotericin (Abelcet, Amphotec, AmBisome) Non-HIV-exposed/-positive: Infants, Children, and
and conventional amphotericin B for injection. Adolescents: IV: 5 mg/kg/dose once daily with
Lipid-based and conventional formulations are not inter- flucytosine (IDSA [Perfect 2010])
changeable and have different dosing recommenda- HIV-exposed/-positive:
tions. Overdoses have occurred when conventional Manufacturer’s labeling: Infants, Children, and
formulations were dispensed inadvertently for lipid- Adolescents: IV: 6 mg/kg/dose once daily
based products. Alternate dosing:
Infants and Children: IV: 6 mg/kg/dose once daily
Note: Premedication: For patients who experience non-
with or without oral flucytosine or high dose
anaphylactic infusion-related immediate reactions, pre-
fluconazole for a minimum 2-week induction;
medicate with the following drugs 30 to 60 minutes prior
Note: Minimum 2-week induction, followed by
to drug administration: NSAID (with or without diphen-
consolidation and chronic suppressive therapy;
hydramine) or acetaminophen with diphenhydramine
a longer duration of induction therapy may be
or hydrocortisone. If the patient experiences rigors
necessary if CSF is not negative or lack of
during the infusion, meperidine may be administered.
Clinical improvement (HHS [OI pediatric 2016])
General dosing: Adolescents: IV: 3 to 4 mg/kg/dose once daily
Empiric therapy: Infants, Children, and Adolescents:
with or without oral flucytosine or fluconazole
IV: 3 mg/kg/dose once daily (HHS, [Ol adult 2016]); doses up to 6 mg/kg/
Treatment, susceptible systemic infection: Infants, dose have been reported for treatment of
Children, and Adolescents: IV: 3 to 5 mg/kg/dose meningoencephalitis and may be considered
once daily for treatment failure or high fungal burden dis-
Aspergillosis, treatment: ease (IDSA [Perfect 2010])
Invasive: Infants, Children, and Adolescents: IV: 3 to Febrile neutropenia, empiric therapy: Infants, Chil-
5 mg/kg/dose once daily (IDSA [Patterson 2016]) dren, and Adolescents: IV: 3 mg/kg/dose once daily
Endocarditis: Children and Adolescents: IV: 3 to (Caselli 2012; IDSA [Patterson 2016])
5 mg/kg/dose once daily with or without flucytosine Histoplasmosis:
(AHA [Baltimore 2015]) Non-HIV-exposed/-positive: Acute pulmonary disease
Blastomycosis, invasive: Infants, Children, and Ado- or disseminated (non-CNS): Infants, Children, and
lescents: IV: 3 to 5-mg/kg/dose once daily for initial Adolescents: IV: 3 mg/kg/dose once daily for 1 to 2
therapy, if CNS infection 4 to 6 weeks may be needed; weeks followed by oral itraconazole for a total of 12
followed by oral itraconazole for a total of 12 months weeks; conventional amphotericin B typically pre-
(IDSA [Chapman 2008]) ferred (IDSA [Wheat 2007])
Candidiasis, treatment: HIV-exposed/-positive:
Invasive (Independent of HIV status): Infant, Children, Disseminated infection (non-CNS disease):
and Adolescents: IV: 3 to 5 mg/kg/dose once daily Infants and Children: IV: 3 to 5 mg/kg/dose once
(Filioti 2007; IDSA [Pappas 2016]); Note: In HIV- daily for at least 2 weeks for induction; if itraco-
exposed/-positive patients, doses at the higher end nazole not tolerated for consolidation therapy,
of the range may be considered (5 mg/kg/day) (HHS may continue for 4 to 6 weeks (HHS [Ol pediatric
[Ol pediatric 2016)). 2016])
CNS infection: Infants, Children, and Adolescents: IV: Adolescents: |V: 3 mg/kg/dose once daily for at
5 mg/kg/dose once daily with or without flucytosine least 2 weeks for induction (HHS [Ol adult 2016])
(IDSA [Pappas 2016]) CNS disease: Infants, Children, and Adolescents:
Endocarditis; Infants, Children, and Adolescents: IV: 3 IV: 5 mg/kg/dose once daily for 4 to 6 weeks for
to 5 mg/kg/dose once daily with or without flucyto- induction, followed by consolidation therapy (HHS
sine (AHA [Baltimore 2015}; IDSA [Pappas 2016]) [Ol adult 2016]; HHS [Ol pediatric 2016]) >
141
AMPHOTERICIN B (LIPOSOMAL)

Leishmaniasis: phosphatidylcholine, sodium succinate hexahydrate,

Visceral infection, treatment: sucrose, tocopherol, dl-alpha]
Immunocompetent patients: Infants, Children, and
Adolescents: IV: Initial: 3 mg/kg/dose once daily on
@ Amphotericin B Liposome see Amphotericin B (Lip-
days 1 to 5 and 3 mg/kg/dose on days 14 and 21. osomal) on page 140
Note: Repeat course may be given to patients who
do not achieve parasitic clearance. Ampicillin (am pi sit in)
Immunocompromised patients: Infants, Children,
and Adolescents: IV: Initial: 4 mg/kg/dose once Medication Safety Issues
daily on days 1 to 5 and 4 mg/kg/dose on days Sound-alike/look-alike issues:
10, 17, 24, 31, 38 Ampicillin may be confused with aminophylline
HIV-exposed/-positive: Brand Names: Canada Ampicillin for Injection
Treatment: Adolescents: IV: 2 to 4 mg/kg/dose Therapeutic Category Antibiotic, Penicillin
once daily or an interrupted schedule of Generic Availability (US) Yes
4 mg/kg/dose on days 1 to 5, and on days 10, Use Treatment of susceptible respiratory, gastrointestinal,
17, 24, 31, and 38 to achieve a total dose of 20 and urinary tract infections; bacterial meningitis, septice-
to 60 mg/kg (HHS [O! adult 2016]) mia, and endocarditis [FDA approved in pediatric patients
Chronic maintenance therapy: Adolescents: IV: (age not specified) and adults]; susceptible organisms
4 mg/kg/dose every 2 to 4 weeks; Note: Use may include streptococci, pneumococci, enterococci, non-
reserved for patients with visceral infection and penicillinase-producing staphylococci, Listeria, meningo-
CD4 count <200 cells/mm? (HHS [Ol adult 2016]) cocci; some strains of H. influenzae, P. mirabilis,
Cutaneous infection, treatment; HIV-exposed/-posi-
Salmonella, Shigella, E. coli, Enterobacter, and Klebsiella;
tive: Adolescents: IV: 2 to 4 mg/kg/dose once daily has also been used as empiric therapy for neonatal sepsis
for 10 days or an interrupted schedule of 4 mg/kg/
or meningitis, endocarditis prophylaxis, prophylaxis of
dose on days 1 to 5, and on days 10, 17, 24, 31, and
peritonitis in patients with peritoneal dialysis catheters
38 to achieve a total dose of 20 to 60 mg/kg (HHS undergoing invasive dental procedures, and treatment of
[Ol adult 2016])
exit site or tunnel infections in patients with peritoneal
Sporotrichosis infection (IDSA [Kauffman 2007)):
dialysis catheters
Disseminated, pulmonary or osteoarticular disease:
Pregnancy Risk Factor B
Adolescents: IV: 3 to 5 mg/kg/dose once daily, fol-
Pregnancy Considerations Adverse events have not
lowed by oral itraconazole after a favorable
response is seen with amphotericin initial therapy
been observed in animal reproduction studies. Ampicillin
Meningeal: Adolescents: IV: 5 mg/kg/dose once daily crosses the placenta, providing detectable concentrations
for 4 to 6 weeks, followed by oral itraconazole in the cord serum and amniotic fluid (Bolognese 1968;
Fisher 1967; MacAulay 1966). Maternal use of ampicillin
Renal Impairment: Pediatric There are no dosage
has generally not resulted in an increased risk of birth
adjustments provided in the manufacturer's labeling.
defects (Aselton 1985; Czeizel 2001b; Heinonen 1977;
End-stage renal disease (ESRD) on intermittent hemo-
dialysis (IHD) (administer after hemodialysis on dialysis Jick 1981; Puhd 2007). Ampicillin is recommended for
days): Poorly dialyzed. use in pregnant women for the management of preterm
prelabor rupture of membranes (PROM) and for the pre-
Hepatic Impairment: Pediatric There are no dosage
vention of early-onset group B streptococcal (GBS) dis-
adjustments provided in the manufacturer's labeling (has
not been studied).
ease in newborns. Ampicillin may also be used in certain
situations prior to vaginal delivery in women at high risk for
Preparation for Administration Parenteral: IV: Recon-
stitute with 12 mL SWFI to a’concentration of 4mg/mL; do endocarditis (ACOG 120 2011; ACOG 188 2018; ACOG
not reconstitute with saline or add saline to the reconsti-
485 2011; CDC [RR-10] 2010).
tuted solution or mix with other drugs; use of any solution The volume of distribution of ampicillin is increased during
other than those recommended, or the presence of a pregnancy and the half-life is decreased. As a result,
bacteriostatic agent in the solution, may cause precipita- serum concentrations in pregnant patients are approxi-
tion. Shake vigorously for at least 30 seconds, until mately 50% of those in nonpregnant patients receiving the
dispersed into a translucent yellow suspension; a 5- same dose. Higher doses may be needed during preg-
micron filter should be on the syringe used to inject the nancy. Although oral absorption is not altered during
reconstituted product from the vial into the diluent. AmBi- pregnancy, oral ampicillin is poorly absorbed during labor
some may be diluted with D5W, to a final concentration of (Philipson 1977; Philipson 1978; Wasz-Hockert 1970).
1 to 2 mg/mL; in infants and small children, a lower Breastfeeding Considerations Ampicillin is present in
concentration of 0.2 to 0.5 mg/mL may be used to provide breast milk. The manufacturer recommends that caution
sufficient volume for infusion. Stability in D10W, D20W, or be exercised when administering ampicillin to breastfeed-
D25W has also been reported. ing women. Due to the low concentrations in human milk,
Administration Parenteral: IV: Do not use in-line filter less minimal toxicity would be expected in the breastfed infant.
than 1 micron to administer AmBisome. Flush line with Nondose-related effects could include modification of
D5W prior to infusion; infusion of diluted AmBisome bowel flora and allergic sensitization.
should start within 6 hours of preparation; infuse over 2 Contraindications Hypersensitivity (eg, anaphylaxis) to
hours; infusion time may be reduced to 1 hour in patients ampicillin, any component of the formulation, or other
who tolerate the treatment. If the patient experiences penicillins; infections caused by penicillinase-producing
discomfort during infusion, the duration of infusion may
organisms
be increased. Discontinue if severe respiratory distress
Warnings/Precautions Dosage adjustment may be nec-
occurs.
essary in patients with renal impairment. Serious and
For a patient who experiences chills, fever, hypotension, occasionally severe or fatal hypersensitivity (anaphylac-
nausea, or other nonanaphylactic infusion-related reac- toid) reactions have been reported in patients on penicillin
tions, premedicate with the following drugs, 30 to 60 therapy, especially with a history of beta-lactam hyper-
minutes prior to drug administration: A nonsteroidal (eg, sensitivity, history of sensitivity to multiple allergens, or
ibuprofen,) + diphenhydramine or acetaminophen with previous IgE-mediated reactions (eg, anaphylaxis,
diphenhydramine or hydrocortisone. If the patient experi- angioedema, urticaria). Serious anaphylactoid reactions
ences rigors during the infusion, meperidine may be require emergency treatment and airway management.
administered. Appropriate treatments must be readily available. Use with
Monitoring Parameters BUN, serum creatinine, liver caution in asthmatic patients. Appearance of any rash
function tests, serum electrolytes (particularly magnesium should be carefully evaluated to differentiate a nonallergic
and potassium), CBC, vital signs, | & O; monitor for signs ampicillin rash from a hypersensitivity reaction. High per-
of hypokalemia (muscle weakness, cramping, drowsiness, centage of patients with infectious mononucleosis have
ECG changes) developed rash during therapy with ampicillin; ampicillin-
Test Interactions Falsely-elevated serum phosphate may class antibiotics not recommended in these patients This
occur when using the PHOSm assay. rash (generalized maculopapular and pruritic) usually
Additional Information The lipid portion of amphotericin appears 7 to 10 days after initiation and usually resolves
B (liposomal) formulation contains 0.27 kcal per 5 mg; for within a week of discontinuation. It is not known whether
patients receiving parenteral nutrition, adjustment to the these patients are truly allergic to ampicillin. Ampicillin
amount of lipids may be necessary (Sacks 1997). rash occurs in 5% to 10% of children receiving ampicillin
Dosage Forms Excipient information presented when and is a generalized dull red, maculopapular rash, gen-
available (limited, particularly for generics); consult spe- erally appearing 3 to 14 days after the start of therapy. It
cific product labeling. normally begins on the trunk and spreads over most of the
Suspension Reconstituted, Intravenous: body. It may be most intense at pressure areas, elbows,
AmBisome: 50 mg (1 ea) [contains cholesterol, dis- and knees. Prolonged use may result in fungal or bacterial
tearoyl phosphatidylglycerol, hydrogenated soy superinfection, including Clostridium difficile-associated

142
 AMPICILLIN

diarrhea (CDAD) and pseudomembranous colitis; CDAD Dosing

has been observed >2 months postantibiotic treatment. Neonatal
Adverse Reactions General dosing, susceptible infection:
Central nervous system: Brain disease (penicillin-
Weight-directed dosing (Bradley 2016; Red Book [AAP
induced), glossalgia, seizure, sore mouth
2015]): IM, IV:
Dermatologic: Erythema multiforme, exfoliative dermatitis,
skin rash, urticaria
Body Postnatal
Note: Appearance of a rash should be carefully eval- Weight Age Dose
uated to differentiate (if possible) nonallergic ampicillin 50 mg/kg/dose every 12 hours
rash from hypersensitivity reaction. Incidence is higher 50 to 75 mg/kg/dose every 12
8 to 14 days
in patients with viral infection, Salmonella infection, hours
lymphocytic leukemia, or patients that have hyperur- 75 mg/kg/dose every 12 hours
icemia. 15 to 28 days or
Gastrointestinal: Diarrhea, enterocolitis, glossitis, melano-
50 mg/kg/dose every 8 hours
glossia, nausea, oral candidiasis, pseudomembranous
50 mg/kg/dose every 12 hours
colitis, stomatitis, vomiting
75 mg/kg/dose every 12 hours
Hematologic & oncologic: Agranulocytosis, anemia, eosi- 1 to
2 kg
8 to 28 days or
nophilia, hemolytic anemia, immune thrombocytopenia,
leukopenia 50 mg/kg/dose every 8 hours
Hepatic: Increased serum AST <7 days 50 mg/kg/dose every 8 hours
Hypersensitivity: Anaphylaxis 8 to 28 days 50 mg/kg/dose every 6 to 8 hours
Immunologic: Serum sickness-like reaction 29 to 60 days 50 mg/kg/dose every 6 hours
Renal: Interstitial nephritis (rare)
Respiratory: Stridor Age-directed dosing (Tremoulet 2014): IM, IV:
Miscellaneous: Fever
Rare but important or life-threatening: Dysgeusia Gestational Postnatal
Age Age
(Syed 2016)
<7 days 50 mg/kg/dose every 12 hours
Drug Interactions ;
8 to 28 days 75 mg/kg/dose every 12 hours
Metabolism/Transport Effects None known.
>34 weeks $28 days 50 mg/kg/dose every 8 hours
Avoid Concomitant Use
Avoid concomitant use of Ampicillin with any of the Group B streptococcal bacteremia (presumed or
following: BCG (Intravesical); Cholera Vaccine proven) (Red Book [AAP 2015]): Note: Treatment of
Increased Effect/Toxicity bacteremia without a defined focus should be for at
Ampicillin may increase the levels/effects of: Methotrex- least 10 days: IM, IV:
ate; Vitamin K Antagonists
Body Postnatal
The levels/effects of Ampicillin may be increased by: Weight Age
Acemetacin; Allopurinol; Probenecid
Decreased Effect 15 to 28 days 50 mg/kg/dose every 8 hours
Ampicillin may decrease the levels/effects of: Atenolol;
<7 days 100 mg/kg/dose every 12 hours
BCG (Intravesical); BCG Vaccine (Immunization); Chol-
8 to 28 days 50 mg/kg/dose every 8 hours
era Vaccine; Lactobacillus and Estriol; Mycophenolate;
100 mg/kg/dose every 12 hours
Sodium Picosulfate; Typhoid Vaccine
8 to 28 days 50 mg/kg/dose every 6 hours
The levels/effects of Ampicillin may be decreased by:
Group B streptococcal meningitis: IV:
Chloroquine; Lanthanum; Tetracyclines
PNA <7 days: 200 to 300 mg/kg/day divided every 8
Food Interactions Food decreases ampicillin absorption
rate; may decrease ampicillin serum concentration. Man- hours or 300 mg/kg/day divided every 6 hours have
agement: Take at equal intervals around-the-clock, pref- been suggested; continue for at least 14 days if
erably on an empty stomach (30 minutes before or 2 hours uncomplicated; (Bradley 2016; Red Book [AAP
after meals). Maintain adequate hydration, unless 2015]; IDSA [Tunkel 2004])
instructed to restrict fluid intake. PNA >7 days: 300 mg/kg/day divided every 6 hours for
Storage/Stability at least 14 days if uncomplicated (Bradley 2016; Red
Oral: Book [AAP 2015]; IDSA [Tunkel 2004])
Capsules; Store at 20°C to 25°C (68°F to 77°F). Surgical prophylaxis: !V: 50 mg/kg as a single dose
Oral suspension: Store dry powder at 20°C to 25°C
(Red Book [AAP 2015])
(68°F to 77°F). Once reconstituted, oral suspension is
stable for 14 days under refrigeration. Pediatric
IV: General dosing, susceptible infection (Red Book
Store intact vials at 20°C to 25°C (68°F to 77°F). [AAP 2015]): Infants, Children, and Adolescents:
Solutions for IM or direct IV should be used within 1 hour. Mild to moderate infection:
Stability of parenteral admixture in NS at 25°C (77°F) is 8 Oral: 50 to 100 mg/kg/day divided every 6 hours;
hours (concentrations up to 30 mg/mL) and at 4°C maximum daily dose: 4,000 mg/day
(39°F) is 24 hours (concentration of 30 mg/mL) or 48 IM, IV: 100 to 150 mg/kg/day divided every 6 hours;
hours (concentrations up to 20 mg/mL). Protect from
maximum daily dose: 4,000 mg/day
freezing.
Severe infection: IM, IV: 200 to 400 mg/kg/day div-
Mechanism of Action Inhibits bacterial cell wall syn-
thesis by binding to one or more of the penicillin-binding ided every 6 hours; maximum daily dose: 12 g/day
proteins (PBPs) which in turn inhibits the final transpepti- Community-acquired pneumonia (CAP) (IDSA/PIDS
dation step of peptidoglycan synthesis in bacterial cell (Bradley 2011]): Infants >3 months, Children, and
walls, thus inhibiting cell wall biosynthesis, Bacteria even- Adolescents: Note: May consider addition of vanco-
tually lyse due to ongoing activity of cell wall autolytic mycin or clindamycin to empiric therapy if community-
enzymes (autolysins and murein hydrolases) while cell acquired MRSA suspected. In children 25 years, a
wall assembly is arrested. ; macrolide antibiotic should be added if atypical pneu-
Pharmacodynamics/Kinetics (Adult data unless
monia cannot be ruled out.
noted)
Empiric treatment or S. pneumoniae (MICs for pen-
Absorption: Oral: 50%
Distribution: Into bile; penetration into CSF occurs with icillin $2 mcg/mL) or H. influenzae (beta-lactamase
inflamed meninges only negative) in fully immunized patients: IV: 150 to
Protein binding: Neonates: 10%; Adults: 15% to 18% 200 mg/kg/day divided every 6 hours
Half-life elimination: Group A Streptococcus: \V: 200 mg/kg/day divided
Neonates: i every 6 hours
PNA 2 to 7 days: 4 hours S. pneumoniae (MICs for penicillin 24 mcg/mL): IV:
PNA 8 to 14 days: 2.8 hours 300 to 400 mg/kg/day divided every 6 hours
PNA 15 to 30 days: 1.7 hours
Endocarditis:
Children and Adults: 1 to 1.8 hours (Bergan 1978)
Treatment: Children and Adolescents: IV: 200 to
Anuric patients: 8 to 20 hours
Time to peak serum concentration: Oral: Within 1 to 2 300 mg/kg/day divided every 4 to 6 hours; maximum
hours ; ’ daily dose: 12 g/day; use in combination with other
Excretion: Urine (~90%, unchanged within 24 hours); antibiotics for at least 4 weeks; some organisms
feces may require longer duration (AHA [Baltimore 2015]) >

143
 AMPICILLIN

. Prophylaxis: Note: AHA guidelines (Baltimore 2015)

limit the use of prophylactic antibiotics to patients at
Some penicillins (eg, carbenicillin, ticarcillin, and pipera-
cillin) have been shown to inactivate aminoglycosides in
the highest risk for infective endocarditis (IE) or vitro. This has been observed to a greater extent with
adverse outcomes (eg, prosthetic heart valves, tobramycin and gentamicin, while amikacin has shown
patients with previous IE, unrepaired cyanotic con- greater stability against inactivation. Concurrent use of
genital heart disease, repaired congenital heart dis- these agents may pose a risk of reduced antibacterial
ease with prosthetic material or device during first 6 efficacy in vivo, particularly in the setting of profound
months after procedure, repaired congenital heart renal impairment; however, definitive clinical evidence is
disease with residual defects at the site or adjacent lacking. If combination penicillin/aminoglycoside therapy
to site of prosthetic patch or device, and heart trans- is desired in a patient with renal dysfunction, separation
plant recipients with cardiac valvulopathy): of doses (if feasible), and routine monitoring of amino-
Dental or oral procedures or respiratory tract proce- glycoside levels, CBC, and clinical response should be
dures (eg, tonsillectomy, adenoidectomy): Infants, considered.
Children, and Adolescents: IV, IM: 50 mg/kg within Monitoring Parameters With prolonged therapy, monitor
30 to 60 minutes before procedure; maximum renal, hepatic, and hematologic function periodically;
dose: 2,000 mg/dose. Intramuscular (IM) injections observe for change in bowel frequency; observe for signs
should be avoided in patients who are receiving of anaphylaxis with first dose
anticoagulant therapy. In these circumstances, Test Interactions May interfere with urinary glucose tests
orally administered regimens should be used using cupric-sulfate (Benedict's solution, Clinitest®)
whenever possible. Intravenously (IV) adminis- Some penicillin derivatives may accelerate the degrada-
tered antibiotics should be used for patients who
tion of aminoglycosides in vitro, leading to a potential
are unable to tolerate or absorb oral medications underestimation of aminoglycoside serum concentration.
(Wilson 2007).
Additional Information Sodium content: Oral suspen-
Intra-abdominal infection, complicated: Infants,
sion (250 mg/5 mL, 5 mL): 10 mg (0.4 mEq); parenteral
Children, and Adolescents: IV: 200 mg/kg/day divided (1 g): 66.7 mg (3 mEq) :
every 6 hours; maximum single dose: 2,000 mg; max-
Dosage Forms Excipient information presented when
imize doses if undrained abdominal abscesses (IDSA available (limited, particularly for generics); consult spe-
[Solomkin 2010]) cific product labeling. [DSC] = Discontinued product
Meningitis: Infants, Children, and Adolescents: IV: 200
Capsule, Oral: i
to 400 mg/kg/day divided every 6 hours; maximum Generic: 250 mg [DSC], 500 mg
daily dose: 12 g/day (Red Book [AAP 2015]; IDSA Solution Reconstituted, Injection, as sodium [strength
[Tunkel 2004]) expressed as base]:
Peritonitis (CAPD): Limited data available: Infants, Generic: 125 mg (1 ea); 250 mg (1 ea); 500 mg (1 ea);
Children, and Adolescents: Intraperitoneal: 125 mg 1g (1 ea); 2 g (1 ea); 10 g (1 ea)
per liter of dialysate for 2 weeks (ISPD Solution Reconstituted, Injection, as sodium [strength
[Warady 2012]) expressed as base, preservative free]:
Surgical prophylaxis: Infants, Children, and Adoles- Generic: 250 mg (1 ea); 500 mg (1 ea)
cents: IV: 50 mg/kg 30 to 60 minutes prior to proce- Solution Reconstituted, Intravenous, as sodium [strength
dure; may repeat in 2 hours if lengthy procedure or expressed as base]:
excessive blood loss; maximum single dose: Generic: 1 g (1 ea); 2 g (1 ea); 10 g (1 ea)
2,000 mg (ASHP/IDSA [Bratzler 2013]; Red Book Solution Reconstituted, Intravenous, as sodium [strength
[AAP 2015]) expressed as base, preservative free]:
Renal Impairment: Pediatric Generic: 10 g (1 ea [DSC])
Infants, Children, and Adolescents: There are no dos- Suspension Reconstituted, Oral:
age adjustments provided in the manufacturer’s label- Generic: 125 mg/5 mL (100 mL [DSC], 200 mL [DSC));
ing; however, the following adjustments have been 250 mg/5 mL (100 mL [DSC], 200 mL [DSC])
recommended (Aronoff 2007). Note: Renally adjusted
dose recommendations are based on IM, IV doses of
100 to 200 mg/kg/day divided every 6 hours: IM, IV: Ampicillin and Sulbactam
GFR 30 to 50 mL/minute/1.73 m?: 35 to 50 mg/kg/
(am pi SIL in & SUL bak tam)
dose every 6 hours Brand Names: US Unasyn
GFR 10 to 29 mL/minute/1.73 m?: 35 to 50 mg/kg/ Therapeutic Category Antibiotic, Beta-lactam and Beta-
dose every 8 to 12 hours lactamase Combination; Antibiotic, Penicillin
GFR <10 mL/minute/1.73 m?: 35 to 50 mg/kg/dose Generic Availability (US) Yes
every 12 hours Use Treatment of susceptible bacterial infections involved
Intermittent hemodialysis: 35 to 50 mg/kg/dose every with skin and skin structure (FDA approved in ages 21
12 hours year and adults); treatment of susceptible bacterial intra- .
Peritoneal dialysis (PD): 35 to 50 mg/kg/dose every abdominal infections and gynecological infections (FDA
12 hours approved in adults)
Continuous renal replacement therapy (CRRT): 35 to Pregnancy Risk Factor B
50 mg/kg/dose every 6 hours
Pregnancy Considerations Adverse events have not
Hepatic Impairment: Pediatric There are no dosage been observed in animal reproduction studies. Both ampi-
adjustments provided in the manufacturer’s labeling. cillin and sulbactam cross the placenta. Maternal use of
Preparation for Administration penicillins has generally not resulted in an increased risk
Oral: Reconstitute powder for oral suspension with appro- of birth defects. When used during pregnancy, pharmaco-
priate amount of water as specified on the bottle. Shake kinetic changes have been observed with ampicillin alone
vigorously until suspended. (refer to the Ampicillin monograph for details). Ampicillin/
Parenteral: sulbactam may be considered for prophylactic use prior to
IM: Reconstitute vial with SWFI to a final concentration of cesarean delivery (consult current guidelines).
125 to 250 mg/mL (see manufacturer's labeling for Breastfeeding Considerations Ampicillin and sulbac-
specific details). tam are both excreted into breast milk in low concentra-
IV: tions. The manufacturer recommends that caution be
IV push: Reconstitute vial with SWF (see manufactur- used if administering to lactating women. Nondose-related
er's labeling for specific details). effects could include modification of bowel flora and
Intermittent IV infusion: Concentration should not allergic sensitization of the infant. The maternal dose of |
exceed 30 mg/mL due to concentration-dependent sulbactam does not need altered in the postpartum period.
stability restrictions. Also refer to the Ampicillin monograph.
Administration Contraindications Hypersensitivity (eg, anaphylaxis or
Oral: Administer around-the-clock to promote less varia- Stevens-Johnson syndrome) to ampicillin, sulbactam, or
tion in peak and trough serum levels. Administer on an to other beta-lactam antibacterial drugs (eg, penicillins,
empty stomach (ie, 1 hour prior to or 2 hours after meals) cephalosporins), or any component of the formulations;
to increase total absorption; shake suspension well history of cholestatic jaundice or hepatic dysfunction
before using associated with ampicillin/sulbactam
Parenteral: Warnings/Precautions Dosage adjustment may be nec-
IM: Inject deep IM into a large muscle mass essary in patients with renal impairment. Serious and
IV: occasionally severe or fatal hypersensitivity (anaphylactic)
IV push: Doses $500 mg should be administered over reactions have been reported in patients on penicillin
3 to 5 minutes; doses >500 mg should be adminis- therapy, especially with a history of beta-lactam hyper-
tered over 10 to 15 minutes; rapid administration has sensitivity, history of sensitivity to multiple allergens.
been associated with seizures. Patients with a history of penicillin hypersensitivity have
Intermittent IV infusion: Infuse over 10 to 15 minutes experienced severe reactions when treated with

144
 AMPICILLIN AND SULBACTAM

cephalosporins. Before initiating therapy, carefully inves- Pharmacodynamics/Kinetics (Adult data unless
tigate previous penicillin, cephalosporin, or other allergen noted)
hypersensitivity. If an allergic reaction occurs, discontinue Ampicillin: See Ampicillin monograph.
and institute appropriate therapy. Hepatitis and cholestatic Sulbactam:
jaundice have been reported (including fatalities). Toxicity Distribution: Widely distributed to bile, blister, and tissue
is usually reversible. Monitor hepatic function at regular fluids; poor penetration into CSF with uninflamed
intervals in patients with hepatic impairment. High per- meninges; higher concentrations attained with inflamed
centage of patients with infectious mononucleosis have meninges; Vg (Nahata 1999):
developed rash during therapy with ampicillin; ampicillin- Children 1 to 12 years: ~0.35 L/kg
class antibacterials are not recommended in these Adults: 0.25 L/kg
patients. Appearance of a rash should be carefully eval- Protein binding: 38%
uated to differentiate a nonallergic ampicillin rash from a Half-life elimination: Children 1 to 12 years (normal renal
hypersensitivity reaction. Prolonged use may result in function): Mean range: ~0.7 to 0.9 hours (Nahata
fungal or bacterial superinfection, including C. difficile- 1999); Adults (normal renal function): 1 to 1.3 hours;
associated diarrhea (CDAD) and pseudomembranous Note: Elimination kinetics of both ampicillin and sul-
colitis, CDAD has been observed >2 months postantibiotic bactam are similarly affected in patients with renal
treatment. impairment, therefore, the blood concentration ratio is
Adverse Reactions Also see Ampicillin. expected to remain constant regardless of renal
Cardiovascular: Phlebitis, thrombophlebitis function.
Dermatologic: Skin rash Excretion: Urine (~75% to 85% as unchanged drug)
Gastrointestinal: Diarrhea within 8 hours ‘
Local: Pain at injection site (IM/IV) Dosing
Rare but important or life-threatening: Abdominal disten-
Neonatal Note: Unasyn (ampicillin/sulbactam) is a com-
tion, abdominal pain, acute generalized exanthematous
bination product formulated in a 2:1 ratio (eg, each 3 g
pustulosis, agranulocytosis, anaphylactic shock, ana-
vial contains 2 g of ampicillin and 1g of sulbactam);
phylaxis, anemia, angioedema, basophilia, candidiasis,
review dosing units carefully. Dosage recommendations
casts in urine (hyaline), chest pain, chills, cholestasis,
are expressed as mg of the ampicillin component.
cholestatic hepatitis, cholestatic jaundice, Clostridium
Susceptible infection (non-CNS), treatment: IV:
difficile associated diarrhea, constriction of the pharynx,
Premature neonate: 100 mg ampicillin/kg/day divided
convulsions, decreased hematocrit, decreased hemoglo-
every 12 hours; dosing based on a pharmacokinetic
bin, decreased neutrophils, decreased red blood cells,
analysis of 15 premature neonates using a 1:1 for-
decreased serum albumin, decreased serum total pro-
tein, dermatitis, dizziness, drowsiness, dyspepsia, dysp- mulation of ampicillin to sulbactam (GA $28 weeks:
nea, dysuria, edema, eosinophilia, epistaxis, erythema,
n=6; GA >28 weeks: n=9) (Sutton 1986)
erythema multiforme, erythrocyturia, exfoliative dermati- Full-term neonate: 100 mg ampicillin/kg/day divided
tis, facial swelling, fatigue, flatulence, gastritis, glossitis, every 8 hours for <8 days was used in 108 neonates
hairy tongue, headache, hemolytic anemia, hepatic (GA 237 weeks) (Manzoni 2009)
insufficiency, hepatitis, hyperbilirubinemia, hypersensitiv- Pediatric Note: Unasyn (ampicillin/sulbactam) is a com-
ity reaction, immune thrombocytopenia, increased blood bination product formulated in a 2:1 ratio (eg, each 3 g
urea nitrogen, increased lactate dehydrogenase, vial contains 2 g of ampicillin and 1g of sulbactam);
increased liver enzymes, increased monocytes, review dosing units carefully. Dosage recommendations
increased serum alkaline phosphatase, increased serum are expressed as either mg of the ampicillin component
ALT, increased serum AST, increased serum creatinine, or as total grams of the ampicillin/sulbactam combi-
injection site reaction, interstitial nephritis, jaundice, leu- nation within the dosing field; review dosing units in
kopenia, lymphocytopenia, lymphocytosis (abnormal), each indication carefully.
malaise, melena, mucous membrane bleeding, nausea, General dosing, susceptible infection: Infants, Chil-
positive direct Coombs test, pruritus, pseudomembra- dren, and Adolescents:
nous colitis, sedation, Stevens-Johnson syndrome, sto- Mild to moderate infection: IV: 100 to 200 mg ampicillin/
matitis, substernal pain, thrombocythemia, kg/day divided every 6 hours; maximum dose:
thrombocytopenia, toxic epidermal necrolysis, urinary 1,000 mg ampicillin/dose (Red Book [AAP 2015]);
retention, urticaria, vomiting may also be administered IM (Bradley 2016)
Drug Interactions Severe infection: IV: 200 mg ampicillin/kg/day divided
Metabolism/Transport Effects None known. every 6 hours; maximum dose: 2,000 mg ampicillin/
Avoid Concomitant Use dose (Red Book [AAP 2015])
Avoid concomitant use of Ampicillin and Sulbactam with Endocarditis, treatment: Children and Adolescents: IV:
any of the following: BCG (Intravesical); Cholera Vaccine 200 to 300 mg ampicillin/kg/day divided every 4 to 6
Increased Effect/Toxicity ees : hours; maximum dose: 2,000 mg ampicillin/dose; may
Ampicillin and Sulbactam may increase the levels/effects use in combination with gentamicin, vancomycin, and/
of: Methotrexate; Vitamin K Antagonists or rifampin (optional; dependent upon organism) for at
least 4 to 6 weeks; some organisms may require longer
The levels/effects of Ampicillin and Sulbactam may be duration (AHA [Baltimore 2015])
increased by: Acemetacin; Allopurinol; Probenecid Intra-abdominal infection, complicated: Infants, Chil-
Decreased Effect dren, and Adolescents: IV: 200 mg ampicillin/kg/day
Ampicillin and Sulbactam may decrease the levels/ divided every 6 hours; Note: Due to high rates of E.
effects of: Atenolol; BCG (Intravesical); BCG Vaccine coli resistance, not recommended for the treatment of
(Immunization); Cholera Vaccine; Lactobacillus and community-acquired intra-abdominal infections (IDSA
Estriol; Mycophenolate; Sodium Picosulfate; Typhoid [Solomkin 2010])
Vaccine Pelvic inflammatory disease: Adolescents: IV: 3 g
The levels/effects of Ampicillin and Sulbactam may be ampicillin/sulbactam every 6 hours with doxycycline
decreased by: Chloroquine; Lanthanum; Tetracyclines (CDC [Workowski 2015])
Storage/Stability Rhinosinusitis, severe infection requiring hospital-
Prior to reconstitution, store at 20°C to 25°C (68°F to ization: Children and Adolescents: IV: 200 to 400 mg
“tae, ampicillin/kg/day divided every 6 hours for 10 to 14
IM: Concentration of 375 mg/mL (250 mg ampicillin/ days; maximum dose: 2,000 mg ampicillin/dose (IDSA
125 mg sulbactam) should be used within 1 hour after [Chow 2012])
reconstitution. Skin and skin structure infection: Children and Ado-
Intermittent IV infusion: Solutions made in NS are stable lescents: IV: 200 mg ampicillin/kg/day divided every 6
up to 72 hours when refrigerated whereas dextrose hours for up to 14 days; maximum dose: 2,000 mg
solutions (same concentration) are stable for only 4 ampicillin/dose
hours. For stability related to specific concentrations Surgical prophylaxis: Children and Adolescents: IV:
and temperatures, see prescribing information. 50 mg ampicillin/kg/dose within 60 minutes prior to
Mechanism of Action Inhibits bacterial cell wall syn- procedure; may repeat in 2 hours if lengthy procedure
thesis by binding to one or more of the penicillin-binding or excessive blood loss; maximum dose: 2,000 mg
proteins (PBPs) which ‘in turn inhibits the final transpepti- ampicillin/dose (Bratzler 2013)
dation step of peptidoglycan synthesis in bacterial cell Renal Impairment: Pediatric
walls, thus inhibiting cell wall biosynthesis. Bacteria even- Children and Adolescents: IV:
tually lyse due to ongoing activity of cell wall autolytic CrCl 230 mL/minute/1.73 m?: No dosage adjustment
enzymes (autolysins and murein hydrolases) while cell required.
wall assembly is arrested. The addition of sulbactam, a CrCl 15 to 29 mL/minute/1.73 m?: Administer every 12
beta-lactamase inhibitor, to ampicillin extends the spec- hours.
trum of ampicillin to include some beta-lactamase-produc- CrCl 5 to 14 mL/minute/1.73 m2: Administer every 24 ,
ing organisms. hours.

145
 AMPICILLIN AND SULBACTAM

4 Hepatic Impairment: Pediatric There are no dosage

adjustments provided in the manufacturer's labeling.
recommends that caution be exercised when administer-
ing amyl nitrite to nursing women.
Preparation for Administration Contraindications ” (
IM: Reconstitute with SWFI or lidocaine (0.5% or 2%) to a Glaucoma; recent head trauma or cerebral hemorrhage;
final concentration of 375 mg/mL of Unasyn (ie, pregnancy
250 mg/mL of ampicillin and 125 mg/mL of sulbactam). For cyanide poisoning: Concurrent carbon monoxide poi-
Administer within 1 hour of preparation. soning
IV: Use within several hours after preparation. Reconsti- Warnings/Precautions Use with caution in patients with
tute with SWEFI. Further dilute with a compatible solution; increased intracranial pressure, low systolic blood pres-
sodium chloride 0.9% (NS) is the diluent of choice for IV sure, and coronary artery disease. Transient episodes of
piggyback use; final concentration should not exceed dizziness, weakness, syncope, and cerebral ischemia
45 mg/mL Unasyn (30 mg/mL of ampicillin and secondary to postural hypotension may occur. Use with
15 mg/mL of sulbactam) caution in patients with increased intracranial pressure;
Administration Parenteral: use is contraindicated in patient with recent head trauma
IM: Administer by deep IM injection. Administer within 1 or cerebral hemorrhage. Use with extreme caution or
hour of preparation. avoid in patients with severe aortic stenosis; may reduce
IV: Administered by slow IV injection over 10 to 15 minutes coronary perfusion resulting in ischemia; considered by
or by intermittent IV infusion over 15 to 30 minutes some to be a contraindication (Reagan 2005).
Some penicillins (eg, carbenicillin, ticarcillin, and pipera- Amyl-nitrite may cause methemoglobin formation and
cillin) have been shown to inactivate aminoglycosides in severe hypotension; serious adverse effects may occur
vitro. This has been observed to a greater extent with at doses less than the recommended therapeutic dose.
tobramycin and gentamicin, while amikacin has shown
Monitor for adequate perfusion and oxygenation; ensure
greater stability against inactivation. Concomitant use of
patient is euvolemic.. Use with caution in patients where
these agents may pose a risk of reduced antibacterial
the diagnosis of cyanide poisoning is uncertain, patients
efficacy in vivo, particularly in the setting of profound renal
with preexisting diminished oxygen or cardiovascular
impairment; however, definitive clinical evidence is lack-
reserve (eg, smoke inhalation victims, anemia, substantial
ing. If combination penicillin/aminoglycoside therapy is
blood loss, and cardiac or respiratory compromise), in
desired in a patient with renal dysfunction, separation of
patients at greater risk for developing methemoglobinemia
doses (if feasible), and routine monitoring of aminoglyco-
side concentrations, CBC, and clinical response should be
(eg, congenital methemoglobin reductase deficiency), and
considered. in patients who may be susceptible to injury from vaso-
Monitoring Parameters With prolonged therapy, monitor dilation. The use of hydroxocobalamin is recommended in
hematologic, renal, and hepatic function; observe for these patients. Use with caution with concomitant medi-
change in bowel frequency; monitor for signs of anaphy- cations known to cause methemoglobinemia (eg, nitro-
laxis during first dose. In patients with preexisting hepatic glycerin, phenazopyridine). Collection of pretreatment
impairment, monitor hepatic function at regular intervals. blood cyanide concentrations does not preclude admin-
Test Interactions May interfere with urinary glucose tests istration and should not delay administration in the emer-
using cupric sulfate (Benedict's solution, Fehling’s solu- gency management of highly suspected or confirmed
tion, or Clinitest®). cyanide toxicity. Pretreatment levels may be useful as
postinfusion levels may be inaccurate. Treatment of cya-
Some penicillin derivatives may accelerate the degrada- nide poisoning should include external decontamination
tion of aminoglycosides in vitro, leading to a potential and supportive therapy. Monitor patients for return of
underestimation of aminoglycoside serum concentration. symptoms for 24 to 48 hours; repeat treatment should
Dosage Forms Excipient information presented when be administered if symptoms return. Fire victims and
available (limited, particularly for generics); consult spe- patients with cyanide poisoning related to smoke inhala-
cific product labeling. tion may present with both cyanide and carbon monoxide
Injection, powder for reconstitution: 1.5 g: Ampicillin 1 g poisoning. !n these patients, the induction of methemoglo-
and sulbactam 0.5 g; 3 g: Ampicillin 2 g and sulbactam binemia (due to amyl nitrite, sodium nitrite) is contra-
1g; 15 g: Ampicillin 10 g and sulbactam 5 g indicated until carbon monoxide levels return to normal
Unasyn:
due to the risk of tissue hypoxia. Methemoglobinemia
1.5 g: Ampicillin 1g and sulbactam 0.5 g [contains
decreases the oxygen carrying capacity of hemoglobin
sodium 115 mg (5 mEq)/1.5 g)]
and the presence of carbon monoxide prevents hemoglo-
3 g: Ampicillin 2 g and sulbactam 1 g [contains sodium
bin from releasing oxygen to the tissues. In this scenario,
115 mg (5 mEq)/1.5 g)}
sodium thiosulfate may be used alone to promote the
15 g: Ampicillin 10 g and sulbactam 5 g [bulk package;
clearance of cyanide. Hydroxocobalamin, however,
contains sodium 115 mg (5 mEq)/1.5 g)]
should be considered to avoid the nitrite-related problems
@ Ampicillin for Injection (Can) see Ampicillin and because sodium thiosulfate has a slow onset of
on page 142 action. Consider consultation with a poison control center
@ Ampicillin Sodium see Ampicillin on page 142 at 1-800-222-1222.
@ Ampicillin Sodium/Sulbactam Na see Ampicillin and Methemoglobin reductase, which is responsible for con-
Sulbactam on page 144 verting methemoglobin back to hemoglobin, has reduced
@ Ampicillin Trinydrate see Ampicillin on page 142 activity in pediatric patients. In addition, infants and young
children have some proportion of fetal hemoglobin which
@ Amrix see Cyclobenzaprine on page 529
forms methemoglobin more readily than adult hemoglobin.
@ Amylase, Lipase, and Protease see Pancrelipase Therefore, pediatric patients (eg, neonates and infants <6
on page 1545 months) are more susceptible to excessive nitrite-induced
methemoglobinemia. Nitrites should be avoided in preg-
Amy! Nitrite (am il NyE trite) nant patients due to fetal hemoglobin's susceptibility to
oxidative stress. Hydroxocobalamin will circumvent this
Therapeutic Category Antidote, Cyanide; Vasodilator, problem and may be a more effective and rapid alter-
Coronary native.
Generic Availability (US) Yes Adverse Reactions
Use Treatment of angina pectoris (FDA approved in Cardiovascular: Cerebral ischemia, facial flushing, hypo-
adults); has also been used as an adjunct treatment of tension, orthostatic hypotension, shock, syncope, tachy-
cyanide toxicity cardia, vasodilatation
Note: Although included as an FDA-approved use in the Central nervous system: Dizziness, headache, increased
manufacturer’s prescribing information, the use of amyl intracranial pressure, restlessness
nitrite for patients experiencing angina pectoris has fallen Dermatologic: Dermatitis, diaphoresis, pallor, skin irritation
out of favor. Newer nitrate compounds are more easily Gastrointestinal: Fecal incontinence, nausea, vomiting
administered. Genitourinary: Urinary incontinence
Pregnancy Risk Factor C Hematologic & oncologic: Hemolytic anemia, methemo-
Pregnancy Considerations Animal reproduction studies globinemia
have not been conducted. Because amyl nitrite signifi- Neuromuscular & skeletal: Weakness
cantly decreases systemic blood pressure and therefore Ophthalmic: Eye irritation, increased intraocular pressure
blood flow to the fetus, use is contraindicated in pregnancy Drug Interactions
(per manufacturer). In addition, fetal hemoglobin may be Metabolism/Transport Effects None known.
more susceptible methemoglobin conversion (Valenzuela, Avoid Concomitant Use
1986). Avoid concomitant use of Amyl Nitrite with any of the
Breastfeeding Considerations It is not known if amyl following: Bromperidol; Phosphodiesterase 5 Inhibitors;
nitrite is excreted in breast milk. The manufacturer Riociguat
 ANAGRELIDE

Increased Effect/Toxicity
Amyl Nitrite may increase the levels/effects of: Amifos- Anagrelide (an AG gre lide)
tine; Antipsychotic Agents (Second Generation [Atypi-
cal]); Bromperidol; DULoxetine; Hypotension- Medication Safety Issues
Associated Agents; Levodopa; Nitroprusside; Pholco- Sound-alike/look-alike issues:
dine; Prilocaine; Riociguat; Sodium Nitrite Anagrelide may be confused with anastrozole
Brand Names: US Agrylin
The levels/effects of Amyl Nitrite may be increased by: Brand Names: Canada Agrylin
Alfuzosin; Barbiturates; Benperidol; Blood Pressure
Therapeutic Category Antiplatelet Agent; Phosphodies-
Lowering Agents; Brimonidine (Topical); Dapsone (Top-
terase Enzyme Inhibitor; Phosphodiestrerase-3 Enzyme
ical); Diazoxide; Herbs (Hypotensive Properties); Lorme-
Inhibitor
tazepam; Molsidomine; Naftopidil; Nicergoline;
Nicorandil; Nitric Oxide; Obinutuzumab; Pentoxifylline; Generic Availability (US) Yes
Phosphodiesterase 5 Inhibitors; Prostacyclin Analogues; Use Treatment of thrombocythemia secondary to myelo-
Quinagolide; Tetracaine (Topical) proliferative disorders to decrease elevated platelet count
Decreased Effect and the associated risk of thrombosis and ameliorate
The levels/effects of Amy! Nitrite may be decreased by: symptoms including thrombo-hemorrhagic events (FDA
Bromperidol approved in ages >6 years and adults)
Storage/Stability Store in a cool place at 2°C to 8°C Pregnancy Risk Factor C
(36°F to 46°F). Protect from light. Contents are flammable; Pregnancy Considerations Adverse events were
protect from open flame or spark. observed in some animal reproduction studies. Data
Mechanism of Action Relaxes vascular smooth muscle; regarding use of anagrelide during pregnancy is limited.
decreases venous ratios and arterial blood pressure; The manufacturer recommends effective contraception in
reduces left ventricular work; decreases myocardial Oz women of childbearing potential.
consumption. When used for cyanide poisoning, amyl Breastfeeding Considerations It is not known if ana-
nitrite promotes the formation of methemoglobin which grelide is present in breast milk. Due to the potential for
competes with cytochrome oxidase for the cyanide ion. serious adverse reactions in the breastfed infant, a deci-
Cyanide combines with methemoglobin to form cyanome- sion should be made whether to discontinue breastfeeding
themoglobin, thereby freeing the cytochrome oxidase and or to discontinue the drug, taking into account the impor-
allowing aerobic metabolism to continue. tance of treatment to the mother.
Pharmacodynamics/Kinetics (Adult data unless Contraindications There are no contraindications listed
noted) in the manufacturer’s labeling.
Onset of action: Angina: Within 30 seconds Warnings/Precautions Major hemorrhagic events have
Duration: Angina: 3-15 minutes; Pharmacologic provoca- occurred when used concomitantly with aspirin. Monitor
tion of latent left ventricular outflow tract (LVOT) gradient closely for bleeding, particularly when used concurrently
in hypertrophic cardiomyopathy (RCM): ~30 seconds with other agents known to increase bleeding risk (eg,
(Reagan, 2005)
anticoagulants, NSAIDs, antiplatelet agents, other phos-
Absorption: Inhalation: Readily absorbed through respira-
phodiesterase 3 (PDE3) inhibitors, and selective serotonin
tory tract
reuptake inhibitors). Ventricular tachycardia and torsades
Metabolism: In the liver to form inorganic nitrates (less
de pointes have been reported. As with other PDE3
potent)
inhibitors, anagrelide may cause vasodilation, tachycar-
Half-life elimination: Amy nitrite: <1 hour; Methemoglobin:
dia, palpitations and heart failure. PDE3 inhibitors are
1 hour
associated with decreased survival (compared to placebo)
Excretion:Urine (~33%)
Dosing in patients with class III or IV heart failure. In a scientific
statement from the American Heart Association, anagre-
Pediatric Cyanide toxicity: Infants, Children, and Ado-
lescents: Inhalation: 0.3 mL ampul crushed into a gauze lide has been determined to be an agent that may cause
pad and placed in front of the patient’s mouth (or direct myocardial toxicity (magnitude: major) (AHA [Page
endotracheal tube if patient is intubated) to inhale over 2016]). Dose-related increases in heart rate and mean
15 to 30 seconds; repeat every minute until sodium QTc interval have been observed in a clinical trial. The
nitrite can be administered. Note: Must separate admin- maximum change in mean heart rate was ~8 beats per
istrations by at least 30 seconds to allow for adequate minute (bpm) at a dose of 0.5 mg and ~29 bpm with a
oxygenation; each ampul will last for ~3 minutes. Amyl 2.5 mg dose. The maximum mean change in QTc | (indi-
nitrite is a temporary intervention that should only be vidual subject correlation) from placebo was 7 ms and 13
used prehospital or if intravenous access cannot be ms with doses of 0.5 mg and 2.5 mg, respectively. Use is
obtained or until 1V hydroxycobalamin or the sodium not recommended in patients with hypokalemia, congen-
nitrite and sodium thiosulfate infusions are ready for ital long QT syndrome, a known history of acquired QTc
administration (ATSDR 2001; Holstege 2015). prolongation, or when using concomitant therapy which
Administration Administer nasally via inhalation. The may prolong the QTc interval. Hypotension accompanied
patient should be lying down during administration. Crush by dizziness may occur, particularly with higher doses.
the ampul in a gauze pad and place in front of patient's Use with caution in patients with cardiovascular disease
mouth (or endotracheal tube if intubated) and allow patient (eg, heart failure, bradyarrhythmias, electrolyte abnormal-
to inhale for 15 to 30 seconds; repeat every minute until ities); consider periodic ECGs; benefits should outweigh
sodium nitrite can be administered. One ampul lasts for ~3 risks. Pretreatment cardiovascular evaluation (including
minutes. ECG) and careful monitoring during treatment is recom-
Monitoring Parameters Monitor blood pressure and mended. Pulmonary hypertension has been reported;
heart rate during therapy evaluate patients for signs and symptoms of underlying
Cyanide toxicity: Monitor for at least 24 to 48 hours after cardiopulmonary disease prior to initiating and during
administration; hemoglobin/hematocrit; co-oximetry; therapy. Interstitial lung disease (including allergic alveo-
serum lactate levels; venous-arterial PO2 gradient; litis, eosinophilic pneumonia, and interstitial pneumonitis)
serum methemoglobin and oxyhemoglobin. Pretreat- has been associated with use; onset is from 1 week to
ment cyanide levels may be useful diagnostically. - several years, usually presenting with progressive dysp-
Reference Range Symptoms associated with blood cya- nea with lung infiltrations; symptoms usually improve after
nide levels: discontinuation. Use caution in patients with mild to mod-
Flushing and tachycardia: 0.5 to 1 mceg/mL erate hepatic dysfunction; dosage reduction and careful
Obtundation: 1 to 2.5 mcg/mL monitoring are required for moderate hepatic impairment;
Coma and respiratory depression: >2.5 mcg/mL use has not been studied in patients with severe impair-
Death: >3 mcg/mL
ment. Hepatic impairment increases anagrelide exposure
Dosage Forms Excipient information presented when
and may increase the risk of QTe prolongation. Monitor
available (limited, particularly for generics), consult spe-
liver function prior to and during treatment. Renal abnor-
cific product labeling.
malities (including renal failure) have been observed with
Liquid, for inhalation: USP: 85% to 103% (0.3 mL)
anagrelide use; may be associated with preexisting renal
@ Amylobarbitone see Amobarbital on page 123 impairment, although dosage adjustment due to renal
@ Amytal Sodium see Amobarbital on page 123 insufficiency was not required; monitor closely in patients
with renal insufficiency. Potentially significant drug-drug
@ Anacaine see Benzocaine on page 257
interactions may exist, requiring dose or frequency adjust-
@ Anadrol-50 see Oxymetholone on page 1534 ment, additional monitoring, and/or selection of alternative
@ Anafranil see ClomiPRAMINE on page 485 therapy.

147
ANAGRELIDE

Adverse Reactions Half-life elimination: Anagrelide: 1.5 hours, similar data

Cardiovascular: Angina pectoris, atrial fibrillation, cardiac reported in pediatric_patients 7-14 years; 3-hydroxy
arrhythmia, cardiac failure, cardiomegaly, cardiomyop- anagrelide: 2.5 hours f
athy, cerebrovascular accident, chest pain, complete Time to peak, serum: 1 hour, similar data reported in
atrioventricular block, decreased diastolic pressure pediatric patients 7-14 years
(pediatric patients), edema, hypertension, increased Excretion: Urine (<1% as unchanged drug)
heart rate (pediatric patients), myocardial infarction, Pharmacodynamics/Kinetics: Additional Consider-
orthostatic hypotension, palpitations, pericardial effu- ations
sion, peripheral edema, syncope, systolic hypotension Hepatic function impairment: AUC increased 8-fold with
(pediatric patients), tachycardia, vasodilatation moderate hepatic function impairment.
Central nervous system: Amnesia, chills, confusion, Geriatric: AUC and C,,ax of anagrelide were 36% and 61%
depression, dizziness, drowsiness, fatigue (pediatric higher, respectively, in fasting elderly patients with
patients), headache, insomnia, malaise, migraine, nerv- essential thrombocythemia compared to fasting adult
ousness, pain, paresthesia patients, but the AUC and C,,2x of the active metabolite,
Dermatologic: Alopecia, pruritus, skin rash 3-hydroxy anagrelide, were 37% and 42% lower, respec-
Gastrointestinal: Abdominal pain, anorexia, constipation, tively, in the elderly patient population.
diarrhea, dyspepsia, flatulence, gastritis, gastrointestinal Dosing
hemorrhage, nausea, pancreatitis, vomiting Pediatric
Hematologic & oncologic: Anemia, bruise, hemorrhage, Essential thrombocythemia: Very limited data avail-
thrombocytopenia --able; several small case series: Children 26 years and
Hepatic: Increased liver enzymes Adolescents: Oral: Initial: 0.5 mg 2-3 times daily;
Neuromuscular & skeletal: Arthralgia, back pain, muscle increase at weekly intervals in 0.5 mg increments until
cramps (pediatric patients), myalgia, weakness platelet count begins to decrease; usual reported
Ophthalmic: Diplopia, visual field defect maintenance dose range: 1-2.5 mg/day; maximum
Otic: Tinnitus daily dose: 10 mg/day (per manufacturer) although
Renal: Hematuria, renal failure the maximum reported dose for essential thrombocy-
Respiratory: Cough, dyspnea, epistaxis, flu-like symptoms, themia: 4 mg/day; once platelet count normalizes,
pleural effusion, pneumonia, pulmonary fibrosis, pulmo- further adjust dose to lowest effective dose; in some
nary hypertension, pulmonary infiltrates cases, discontinuation of therapy has been accom-
Miscellaneous: Fever plished (Chintagumpala, 1995; Lackner, 1998; Lack-
Rare but important or life-threatening: Eosinophilic pneu- ner, 2006); Note: Essential thrombocytopenia is also
monitis, hepatotoxicity, hypersensitivity pneumonitis,
considered a type myeloproliferative disorder.
Secondary thrombocythemia (associated with mye-
interstitial nephritis, interstitial pneumonitis, leukocytosis,
loproliferative disorders): Children >6 years and
prolonged Q-T interval on ECG, skin photosensitivity
Adolescents: Oral: Initial: 0.5 mg once daily; usual
(pediatric patients), torsades de pointes, ventricular
range: 0.5 mg 1-4 times daily; median maintenance
tachycardia
daily dose: Patient age 7-11 years: 1.75 mg/day;
Drug Interactions
patient age: 11-14 years: 2 mg; Note: Maintain initial
Metabolism/Transport Effects None known. dose for 21 week, then adjust to the lowest effective
Avoid Concomitant Use dose to reduce and maintain platelet count
Avoid concomitant use of Anagrelide with any of the <600,000/mm? ideally to the normal range; the dose
following: Amifampridine; Cilostazol; Enoximone; must not be increased by >0.5 mg per day in any 1
Hydroxychloroquine; Macimorelin; MiFEPRIStone; Milri- week; maximum single dose: 2.5 mg; maximum daily
none; Mizolastine; Probucol; Promazine; QTc-Prolonging dose: 10 mg/day
Agents (Highest Risk); QTc-Prolonging Agents (Moder- Renal Impairment: Pediatric Children and Adoles-
ate Risk); Urokinase; Vinflunine cents: No adjustment required in renal insufficiency;
Increased Effect/Toxicity monitor closely.
Anagrelide may increase the levels/effects of: Agents Administration May be administered without regard to
with Antiplatelet Properties; Anticoagulants; Apixaban; food.
Cephalothin; Cilostazol; Collagenase (Systemic); Dabi- Monitoring Parameters Platelet count (every 2 days
gatran Etexilate; Deoxycholic Acid; Edoxaban; Ibritumo- during the first week of treatment and at least weekly until
mab Tiuxetan; Milrinone; Obinutuzumab; QTc- the maintenance dose is reached; continue to monitor
Prolonging Agents (Highest Risk); Riociguat; Rivaroxa- after cessation of treatment); CBC with differential (mon-
ban; Salicylates; Thrombolytic Agents; Urokinase itor closely during first 2 weeks of treatment), liver function
(ALT and AST; baseline and during treatment), BUN, and
The levels/effects of Anagrelide may be increased by:
serum creatinine (monitor closely during first weeks of
Amifampridine; Bilastine; Buprenorphine; Enoximone;
treatment); serum electrolytes; blood pressure; heart rate;
FLUoxetine; Glucosamine; Herbs (Anticoagulant/Anti-
cardiovascular exam including ECG (pretreatment; mon-
platelet Properties); Hydroxychloroquine; Ibrutinib; Inda-
itor during therapy), signs/symptoms of interstitial lung
pamide; Limaprost; Macimorelin; MiFEPRIStone;
disease. Monitor for thrombosis or bleeding.
Mizolastine; Multivitamins/Fluoride (with ADE); Multivita-
Dosage Forms Excipient information presented when
mins/Minerals (with ADEK, Folate, Iron); Multivitamins/
available (limited, particularly for generics); consult spe-
Minerals (with AE, No Iron); Omega-3 Fatty Acids;
cific product labeling. /}
Pefloxacin; Pentosan Polysulfate Sodium; Pentoxifylline;
Capsule, Oral:
Probucol; Promazine; Prostacyclin Analogues; QTc-Pro-
Agrylin: 0.5 mg
longing Agents (Indeterminate Risk and Risk Modifying);
Generic: 0.5 mg, 1 mg
QTc-Prolonging Agents (Moderate Risk); Teneligliptin;
Tipranavir; Vinflunine; Vitamin E (Systemic); Xipamide @ Anagrelide Hydrochloride see Anagrelide on page 147
Decreased Effect There are no known significant inter-
actions involving a decrease in effect.
Storage/Stability Store at 25°C (77°F); excursions per-
Anakinra (ana KIN ra)
mitted to 15°C to 30°C (59°F to 86°F). Protect from light. Medication Safety Issues
Mechanism of Action Anagrelide appears to inhibit cyclic Sound-alike/look-alike issues:
nucleotide phosphodiesterase and the release of arach- Anakinra may be confused with amikacin, Ampyra
idonic acid from phospholipase, possibly by inhibiting Kineret may be confused with Amikin
phospholipase Ap. It also causes a dose-related reduction High alert medication:
in platelet production, which results from decreased meg- This medication is in a class the Institute for Safe
akaryocyte hypermaturation (disrupts the postmitotic Medication Practices (ISMP) includes among its list of
phase of maturation). drug classes that have a heightened risk of causing
Pharmacodynamics/Kinetics (Adult data unless significant patient harm when used in error.
noted) Brand Names: US Kineret
Note: In pediatric patients 7-14 years; data has shown a Brand Names: Canada Kineret
decreased maximum serum concentration (48%) and Therapeutic Category Antirheumatic, Disease Modify-
AUC (55%) compared to adults when normalized to dose ing; Interleukin-1 Receptor Antagonist
and bodyweight. Generic Availability (US) No
Onset of action: Initial: Within 7 to 14 days; complete Use Treatment of neonatal-onset multisystem inflammatory
response (platelets <600,000/mm‘): 4 to 12 weeks disease (NOMID), also known as chronic infantile neuro-
Duration: 6 to 24 hours; upon discontinuation, platelet logical cutaneous and articular syndrome (CINCA), which
count begins to rise within 4 days : is a cryopyrin-associated periodic syndrome (CAPS) [FDA
Metabolism: Hepatic, partially via CYP1A2; to two major approved in pediatric patients (age not specified) and
metabolites, RL603 and 3-hydroxy anagrelide adults]; treatment of moderately to severely active rheu-
Bioavailability: Food has no clinically significant effect matoid arthritis in patients who have failed one or more

148
 ANAKINRA

disease-modifying antirheumatic drugs (DMARDs); may containing polysorbate 80 (Alade 1986; CDC 1984). See
be used alone or in combination with DMARDs that are manufacturer's labeling.
not tumor necrosis factor (TNF)-blocking agents (eg, Warnings: Additional Pediatric Considerations
etanercept, adalimumab) (FDA approved in ages 218 Reactivation of TB has been reported in pediatric patients
years and adults); has also been used for reducing signs receiving biologic response modifiers (infliximab and eta-
and symptoms of systemic juvenile idiopathic arthritic nercept); prior to therapy, patients with no TB risk factors
(SJIA) and polyarticular-course juvenile idiopathic arthritis should be screened for latent TB infection (LTBI) with an
(JIA); management of patients with Kawasaki disease age appropriate test (ie, <5 years of age: tuberculin skin
refractory to intravenous immunoglobulin (IVIG); treat- test, and 25 years of age: IGRA [interferon gamma release
ment of Familial Mediterranean Fever assay]); if any TB risk factors are present or symptoms,
Pregnancy Risk Factor B both LTBI screening tests should be performed (AAP
Pregnancy Considerations Adverse events have not (Davies 2016])
been observed in animal reproduction studies. Adverse Reactions
Information related to the use of anakinra during preg- Central nervous system: Headache
nancy is limited (Makol 2011; Ostensen 2011). Specific Dermatologic: Skin rash (NOMID)
guidelines for use in pregnancy are not available (Saag Endocrine & metabolic: Hypercholesterolemia (RA)
[ACR] 2008); use should not be continued during preg- Gastrointestinal: Diarrhea (RA), nausea (RA), vomiting
nancy until more data is available (Makol 2011; Osten- (NOMID)
sen 2011). Hematologic & oncologic: Change in platelet count (RA;
decreased), decreased white blood cell count (RA),
Women exposed to anakinra during pregnancy may con- eosinophilia (RA) ;
tact the Organization of Teratology Information Services Immunologic: Antibody development (more common in
(OTIS), Rheumatoid Arthritis and Pregnancy Study at RA; no correlation of antibody development and adverse
1-877-311-8972. effects)
Breastfeeding Considerations It is not known if ana- Infection: Infection (more common in RA; including cellu-
kinra is excreted in breast milk. The manufacturer recom- litis, pneumonia, and bone and joint infections)
mends that caution be exercised when administering Local: Injection site reaction (RA and NOMID)
anakinra to nursing women. Endogenous interleukin-1 Neuromuscular & skeletal: Arthralgia (NOMID)
receptor antagonist can be found in breast milk (Buescher Respiratory: Nasopharyngitis (NOMID), upper respiratory
1996). Until additional information is available, use should tract infection (NOMID)
be avoided in nursing women (Makol 2011). Miscellaneous: Fever
Contraindications Hypersensitivity to E. coli-derived pro- Rare but important or life-threatening: Hepatitis (noninfec-
teins, anakinra, or any component of the formulation tious), hypersensitivity reaction (including anaphylaxis,
Warnings/Precautions Anakinra is associated with an angioedema, pruritus, skin rash, urticaria), increased
increased risk of serious infections in rheumatoid arthritis serum transaminases, metastases (malignant lym-
studies. Do not initiate in patients with an active infection. phoma, malignant melanoma), opportunistic infection,
If a patient receiving anakinra for rheumatoid arthritis thrombocytopenia (including severe)
develops a serious infection, therapy should be discon- Drug Interactions
tinued; if a patient receiving anakinra for neonatal-onset Metabolism/Transport Effects None known.
multisystem inflammatory disease (NOMID) develop a Avoid Concomitant Use
serious infection, the risk of a NOMID flare should be
Avoid concomitant use of Anakinra with any of the
weighed against the risks associated with continued treat-
following: Abatacept; Anti-TNF Agents; Baricitinib; BCG
ment. Safety and efficacy have not been evaluated in (Intravesical); Canakinumab; Natalizumab; Pimecroli-
immunosuppressed patients or patients with chronic infec-
mus; Tacrolimus (Topical); Tofacitinib; Vaccines (Live)
tions; the impact.on active or chronic infections has not
Increased Effect/Toxicity
been determined. Immunosuppressive therapy (including
Anakinra may increase the levels/effects of: Abatacept;
anakinra) may lead to reactivation of latent tuberculosis or
Canakinumab; Fingolimod; Leflunomide; Natalizumab;
other atypical or opportunistic infections; test patients for
Tofacitinib; Vaccines (Live)
latent TB prior to initiation, and treat latent TB infection
prior to use. The levels/effects of Anakinra may be increased by: Anti-
TNF Agents; Baricitinib; Denosumab; Ocrelizumab;
A decrease in neutrophil count may occur during treat-
Pimecrolimus; Roflumilast; Tacrolimus (Topical); Trastu-
ment; assess neutrophil count at baseline, monthly for 3
zumab
months, then every 3 months for up to 1 year; in a limited
number of patients with NOMID, neutropenia resolved Decreased Effect
over time with continued anakinra administration. May Anakinra may decrease the levels/effects of: BCG (Intra-
affect defenses against malignancies;_impact on the vesical); Coccidioides immitis Skin Test; Nivolumab;
development and course of malignancies is not fully Pidotimod; Sipuleucel-T; Tertomotide; Vaccines (Inacti-
defined; as compared to the general population, an vated); Vaccines (Live)
increased risk of lymphoma has been noted in clinical The levels/effects of Anakinra may be decreased by:
trials; however, rheumatoid arthritis has been previously Echinacea
associated with an increased rate of lymphoma. Storage/Stability Store in refrigerator at 2°C to 8°C (36°F
Potentially significant drug-drug interactions may exist, to 46°F); do not freeze. Do not shake. Protect from light.
requiring dose or frequency adjustment, additional mon- Discard any unused portion.
itoring, and/or selection of alternative therapy. Use is not Mechanism of Action Antagonist of the interleukin-1 (IL-
recommended in combination with tumor necrosis factor 1) receptor. Endogenous IL-1 is induced by inflammatory
antagonists. Patients should be brought up to date with all stimuli and mediates a variety of immunological
immunizations before initiating therapy; live vaccines responses, including degradation of cartilage (loss of
should not be given concurrently; there is no data avail- proteoglycans) and stimulation of bone resorption.
able concerning the effects of therapy on vaccination or Pharmacodynamics/Kinetics (Adult data unless
secondary transmission of live vaccines in patients receiv- noted)
ing therapy. Hypersensitivity reactions, including anaphy- Bioavailability: SubQ: 95%
lactic reactions and angioedema have been reported; Half-life elimination: Terminal: 4 to 6 hours; Severe renal
discontinue use if severe hypersensitivity occurs. Injection impairment (CrCl <30 mL/minute): ~7 hours; ESRD: 9.7
site reactions commonly occur (within first 4 weeks of hours (Yang 2003)
therapy) and are generally mild with a duration of 14 to Time to peak: SubQ: 3 to 7 hours
28 days. Use caution in patients with renal impairment; Pharmacodynamics/Kinetics: Additional Consider-
extended dosing intervals (every other day) are recom- ations
mended for severe renal insufficiency (CrCl <30 mL/ Renal function impairment: Mean plasma clearance in
minute) and ESRD. Use with caution in patients with patients with mild (CrCl 50 to 80 mL/minute), moderate
asthma; may have increased risk of serious infection. (CrCl 30 to 49 mL/minute), severe (CrCl <30 mL/minute),
Use caution in the elderly due to the potential for higher and end-stage renal disease (ESRD) was decreased by
risk of infections. s 16%, 50%, 70%, and 75%, respectively.
Some dosage forms may contain polysorbate 80 (also Dosing
known as Tweens). Hypersensitivity reactions, usually a Pediatric
delayed reaction, have been reported following exposure Familial Mediterranean Fever; colchicine-resistant:
to pharmaceutical products containing polysorbate 80 in Very limited data available: Children 22 years and
certain individuals (Isaksson 2002; Lucente 2000; Shelley Adolescents: SubQ: 2 mg/kg/dose once daily; dose,
1995). Thrombocytopenia, ascites, pulmonary deteriora- frequency, and duration of therapy were adjusted as
tion, and renal and hepatic failure have been reported in needed based on clinical response, usual reported
premature neonates after receiving parenteral products duration: 4 to 8 months; some patients may require a >
149
ANAKINRA

longer duration. Patients continued to receive con- Juvenile idiopathic arthritis: Additional monitoring: CBC
comitant colchicine (Eroglu 2015). with differential and platelets, C-reactive protein, ESR,
Juvenile idiopathic arthritis (JIA): Limited data avail- ferritin, and LDH [baseline, at follow-up visits (1 to 2
able: weeks; 1, 2, 6, and 9 months)] and with any treatment
Systemic-onset JIA (SOUJIA): Children and Adoles- change (DeWitt 2012)
cents: SubQ: Initial: 1 to 2 mg/kg/dose once daily; Additional Information Anakinra is produced by
maximum initial dose: 100 mg; if no response, may recombinant DNA/E. coli technology.
titrate typically at 2-week intervals by doubling dose Dosage Forms Excipient information presented when
up to 4 mg/kg/dose once daily; maximum dose: available (limited, particularly for generics); consult spe-
200 mg (Dewitt 2012; Gattorno 2006; Hedrich cific product labeling.
2012; Irigoyen 2006; Lequerré 2008; Nigrovi 2011; Solution Prefilled Syringe, Subcutaneous [preservative
Quartier 2011) free]:
Polyarticular course JIA: Children 22 years and Ado- Kineret: 100 mg/0.67 mL (0.67 mL) [contains disodium
lescents: SubQ: 1 mg/kg once daily; maximum edta, polysorbate 80]
dose: 100 mg (llowite 2009; Reiff 2005)
¢@ Anapen (Can) see EPINEPHrine (Systemic)
Kawasaki disease, refractory to IVIG: Very limited
on page 748
data available; reported dosing highly variable: Infants
>2 months and young children (eg, <4 years): SubQ: @ Anapen Junior (Can) see EPINEPHrine (Systemic)
1 to 6 mg/kg/day in 1 to 2 divided doses; dosing on page 748
based on case-reports and expert recommendation @ Anaprox (Can) see Naproxen on page 1426
as an alternate therapeutic option; a case report in a @ Anaprox DS [DSC] see Naproxen on page 1426
2-year old reported a dose of 1 mg/kg/dose once
@ Anaprox DS (Can) see Naproxen on page 1426
daily; another case report in a 3-year old reported a
dose of 2 mg/kg/dose once daily for 14 days; a higher @ Anascorp see Centruroides Immune F(ab’)2 (Equine)
dosing regimen was described in an 11-week old who on page 407
had therapy initiated at 3 mg/kg/dose twice daily and @ Anaspaz see Hyoscyamine on page 1030
further increased to 3 mg/kg/dose three times daily @ Anastia see Lidocaine (Topical) on page 1215
due to continued worsening clinical presentation; after
@ Anavip see Crotalidae Immune F(ab')2 (Equine) .
clinical improvement and corticosteroid taper begun
on page 525
the anakinra dose was decreased to 4 mg/kg/dose
twice daily (AHA [McCrindle 2017]; Cohen 2012; @ Anbesol [OTC] see Benzocaine on page 257
Sanchez-Manubens 2017; Shafferman 2014) @ Anbesol® Baby (Can) see Benzocaine on page 257
Neonatal-onset multisystem inflammatory disease @ Anbesol Cold Sore Therapy [OTC] see Benzocaine
(NOMID) or chronic infantile neurological, cuta- on page 257
neous, and articular syndrome (CINCA) [cryo-
Anbesol JR [OTC] [DSC] see Benzocaine on page 257
pyrin-associated periodic syndromes (CAPS)]:
Infants, Children, and Adolescents: SubQ: Initial: 1 @ Anbesol Maximum Strength [OTC] see Benzocaine
to 2 mg/kg/day in 1 to 2 divided doses; adjust dose in on page 257
0.5 to 1 mg/kg increments as needed to control @ Ancef see CeFAZolin on page 380
inflammation; usual maintenance dose: 3 to @ Anchoic Acid see Azelaic Acid on page 226
4 mg/kg/day; maximum daily dose: 8 mg/kg/day.
@ Ancobon see Flucytosine on page 872
Note: Once-daily administration is preferred; how-
ever, the dose may also be divided and administered @ Andriol (Can) see Testosterone on page 1916
twice daily. ¢@ Androderm see Testosterone on page 1916
Rheumatoid arthritis: Adolescents 218 years: SubQ: @ AndroGel see Testosterone on page 1916
100 mg once daily; administer at approximately the
same time each day
AndroGel Pump see Testosterone on page 1916
Renal Impairment: Pediatric @ Androxy see Fluoxymesterone on page 895
CrCl 230 mL/minute: No dosage adjustment necessary @ Androxy [DSC] see Fluoxymesterone on page 895
CrCl <30 mL/minute: @ AneCream [OTC] see Lidocaine (Topical) on page 1215
NOMID: \nfants, Children, and Adolescents:
Decrease frequency of administration to every other @ AneCream5 [OTC] see Lidocaine (Topical)
on page 1215
day
Rheumatoid arthritis: Adolescents 218 years: Con- @ Anectine see Succinylcholine on page 1868
sider 100 mg every other day @ Anesthesia S/I-40 see Propofol on page 1698
ESRD: <2.5% of the dose is removed by hemodialysis @ Anesthesia S/I-40A see Propofol on page 1698
or CAPD:
NOMID: \nfants, Children, and Adolescents:
@ Anesthesia S/I-40H see Propofol on page 1698
Decrease frequency of administration to every other @ Anesthesia S/I-40S see Propofol on page 1698
day @ Anesthesia S/I-60 see Propofol on page 1698
Rheumatoid arthritis: Adolescents 218 years: 100 mg @ Aneurine Hydrochloride see Thiamine on page 1936
every other day
@ Anexate (Can) see Flumazenil on page 877
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer's labeling (has @ Anhydrous Glucose see Dextrose on page 620
not been studied). @ Anodyne LPT see Lidocaine and Prilocaine
Administration SubQ: Rotate injection sites; inject into on page 1220
outer area of upper arms, abdomen (do not use within 2 @ Ansamycin see Rifabutin on page 1759
inches of belly button), front of middle thighs, or upper
@ Antacid [OTC] see Calcium Carbonate on page 340
outer buttocks; injection should be given at least 1 inch
away from previous injection site; do not administer into @ Antacid Calcium [OTC] see Calcium Carbonate
tender, swollen, bruised, red, or hard skin or skin with on page 340
scars or stretch marks. Allow solution to warm to room @ Antacid Calcium Extra Strength [OTC] see Calcium
temperature prior to use (30 minutes). Do not shake. Carbonate on page 340
Provided in single-use, preservative-free syringes with @ Antacid Extra Strength [OTC] see Caicium Carbonate
27-gauge needles; discard any unused portion. on page 340
Monitoring Parameters Monitor improvement of symp-
@ Anthim see Obiltoxaximab on page 1478
toms and physical function assessments. Latent TB
screenings prior to initiating and during therapy; signs/ ¢@ Anthraforte (Can) see Anthralin on page 150
symptoms of infection (prior to, during, and following
therapy); CBC with differential (baseline, then monthly Anthralin (AN thra iin)
for 3 months, then every 3 months for a period up to 1
year); serum creatinine; LFTs at baseline; HBV screening Brand Names: US_ Dritho-Creme HP; Zithranol; Zithra-
prior to initiating (HBV carriers should also be screened nol-RR [DSC]
during and for several months following therapy); signs Brand Names: Canada Anthraforte; Anthranol; Anthras-
and symptoms of hypersensitivity reaction; symptoms of calp; Micanol
malignancy (eg, splenomegaly, hepatomegaly, abdominal Therapeutic Category Antipsoriatic Agent; Keratolytic
pain, persistent fever, night sweats, weight loss); periodic Agent
skin examination Generic Availability (US) No
 ANTHRAX IMMUNE GLOBULIN (HUMAN)

Use Treatment of scalp psoriasis (shampoo: FDA approved Use Treatment of inhalational anthrax in combination with
in ages 212 years and adults); treatment of chronic or appropriate antibacterial drugs (FDA approved in pediatric
quiescent psoriasis (cream 1%, 1.2%: FDA approved in patients [age not specified] and adults)
adults) Note: Effectiveness is based solely on efficacy studies
Pregnancy Risk Factor C conducted in animal models of inhalational anthrax.
Pregnancy Considerations Animal reproduction studies Anthrax immune globulin (human) (AIGIV) does not have
have not been conducted. 4 direct antibacterial activity, does not cross the blood-
Breastfeeding Considerations It is not known if anthra- brain barrier, and does not prevent or treat meningitis.
lin is excreted in breast milk. Due to the potential for There have been no studies in the pediatric, geriatric, or
serious adverse reactions in the nursing infant, a decision obese populations.
should be made whether to discontinue nursing or to Pregnancy Considerations Human data are not avail-
discontinue the drug, taking into account the importance able related to the use of anthrax immune globulin in
of treatment to the mother. pregnancy. However, anthrax immune globulin is
Contraindications Hypersensitivity to anthralin or any expected to cross the placenta. Anthrax infection is asso-
component of the formulation; acute psoriasis (acutely or ciated with maternal and fetal death. Criteria for treating
actively inflamed psoriatic eruptions) pregnant and postpartum women should be the same as
Warnings/Precautions If redness is observed, reduce nonpregnant women unless other contraindications exist.
frequency of dosage or discontinue application; avoid Dosing of anthrax immune globulin in pregnancy should
eye contact; should generally not be applied to opposing also follow the same weight-based dosing schedule
skin surfaces that may rub or touch (eg, skin folds of the (Meaney-Delman, 2014).
groin, axilla, and breasts) and high strengths should not be Breastfeeding Considerations Human data are not
used on these sites; do not apply to genitalia. Use caution available related to the use of anthrax immune globulin
in patients having extensive and prolonged applications. in breastfeeding women. However, anthrax immune glob-
May stain skin, hair, fingernails (temporary), or fabrics ulin is expected to enter breast milk. Criteria for treating
(may be permanent). breastfeeding women should be the same as nonlactating
Adverse Reactions women unless other contraindications exist (Meaney-Del-
Dermatologic: Allergic contact sensitivity, erythema, hair man, 2014).
discoloration (temporary), nail discoloration (temporary), Contraindications History of anaphylaxis or prior severe
skin discoloration (temporary) systemic reaction associated with the parenteral admin-
Miscellaneous: Transient irritation (uninvolved skin) istration of anthrax immune globulin, other human immune
Drug Interactions globulin preparations, or any component of the formula-
tion; IgA-deficient patients with antibodies against IgA and
Metabolism/Transport Effects None known.
a history of IgA hypersensitivity
Avoid Concomitant Use There are no known interac-
Warnings/Precautions [US Boxed Warning]: Throm-
tions where it is recommended to avoid concomitant use.
bosis may occur with immune globulin products even
Increased Effect/Toxicity Long-term use of topical
in the absence of risk factors for thrombosis. For
corticosteroids may destabilize psoriasis and withdrawal
patients at risk of thrombosis (eg, advanced age,
may also give rise to a "rebound" phenomenon. Allow an
impaired cardiac output, prolonged immobilization,
interval of at least 1 week between the discontinuance of
hypercoagulable conditions, history of venous or
topical corticosteroids and the commencement of ther-
arterial thrombosis, use of estrogens, indwelling cen-
apy.
tral vascular catheters, hyperviscosity, and cardiovas-
Decreased Effect There are no known significant inter-
cular risk factors), administer at the minimum infusion
actions involving a decrease in effect.
rate practicable. Ensure adequate hydration before
Storage/Stability Store at controlled room temperature of administration. Monitor for signs and symptoms of
15°C to 30°C (59°F to 86°F); avoid excessive heat. thrombosis and assess blood viscosity in patients at
Mechanism of Action Reduction of the mitotic rate and risk for hyperviscosity such as those with cryoglobu-
proliferation of epidermal cells in psoriasis by inhibiting lins, fasting chylomicronemia/severe hypertriglyceri-
synthesis of nucleic protein from inhibition of DNA syn- demia, or monoclonal gammopathies. Hypersensitivity
thesis to affected areas and anaphylactic reactions can occur; monitor all patients
Dosing for acute allergic reactions during and following infusion.
Pediatric Scalp psoriasis: Children >12 years and Administration should occur in a setting where appropriate
Adolescents: Topical: Shampoo: Rub shampoo onto treatment for hypersensitivity, anaphylaxis, or shock can
wet scalp, lather and leave on scalp for 3 to 5 minutes; be administered. Discontinue treatment in patients who
rinse thoroughly; apply 3 to 4 times weekly develop a severe hypersensitivity reaction. Patients with
Renal Impairment: Pediatric There are no dosage known antibodies to IgA or a history of IgA hypersensitivity
adjustments provided in the manufacturer’s labeling. are at a greater risk of developing severe hypersensitivity;
Hepatic Impairment: Pediatric There are no dosage use in these patients is contraindicated. Aseptic meningitis
adjustments provided in the manufacturer’s labeling. syndrome (AMS) has been reported with immune globulin
Administration Topical: May apply using latex gloves to administration; may occur with high doses (>2 g/kg).
prevent staining of fingers Syndrome usually appears within several hours to 2 days
Cream: Adults: Apply directly to plaques; rub in gently but following treatment; usually resolves within several days
thoroughly; avoid application to unaffected skin. Petro- after product is discontinued. Conduct a detailed neuro-
leum jelly may be used around the edges of plaques, in logical examination and CSF studies in patients exhibiting
body folds, or skin creases to prevent irritation of unaf- signs and symptoms of AMS (eg, severe headache,
fected skin. nuchal rigidity, drowsiness, fever, photophobia, painful
Shampoo: When applying to scalp, part hair in 1-inch eye movements, nausea, vomiting) to rule out other
segments to reach plaques. Remove by washing after causes of meningitis, particularly anthrax meningitis. Intra-
conclusion of prescribed contact period. When rinsing, venous immune globulin products have been associated
take care to avoid contact with eyes. Immediately clean with antiglobulin hemolysis (acute or delayed); monitor for
tub or shower to prevent staining. Dry off using old towel signs of hemolytic anemia. Cases of hemolysis-related
(stains on fabric may be permanent). renal dysfunction/failure or disseminated intravascular
Dosage Forms Excipient information presented when coagulation (DIC) have been reported. Risk factors asso-
available (limited, particularly for generics); consult spe- ciated with hemolysis include high doses (>2 g/kg) given
cific product labeling. [DSC] = Discontinued product either as a single administration or divided over several
Cream, External: S days, underlying associated inflammatory conditions, and
Dritho-Creme HP: 1% (50 g) [contains methylparaben] non-O blood type (FDA, 2012). Monitor for signs and
Zithranol-RR: 1.2% (45 g [DSC}) [contains brilliant blue symptoms of hemolysis and consider laboratory monitor-
fef (fd&c blue #1)] i ing (eg, hemoglobin and hematocrit prior to initiation, 36 to
Shampoo, External: 96 hours postinfusion, and 7 to 10 days postinfusion) in
Zithranol: 1% (85 g) [contains brilliant blue fcf (fd&c higher risk patients.
blue #1)] Monitor for transfusion-related acute lung injury (TRALI);
@ Anthranol (Can) see Anthralin on page 150 noncardiogenic pulmonary edema has been reported with
immune globulin use. TRALI is characterized by severe
@ Anthrascalp (Can) see Anthralin on page 150
respiratory distress, pulmonary edema, hypoxemia, and
@ Anthrasil see Anthrax Immune Globulin (Human) fever in the presence of normal left ventricular function.
on page 151 Usually occurs within 1 to 6 hours after infusion. Acute
renal dysfunction, acute renal failure, osmotic nephrop-
athy, acute tubular necrosis, and proximal tubular nephr-
Anthrax Immune Globulin (Human) opathy can rarely occur with immune globulin !V products
(AN thraks i MYUN GLOB yoo lin YU man)
and has been associated with fatalities; more likely with
Therapeutic Category Antidote; Blood Product Deriva- products stabilized with sucrose (which does not include
tive; Immune Globulin anthrax immune globulin). Use with caution in any patient
 ANTHRAX IMMUNE GLOBULIN (HUMAN)

q with preexisting renal dysfunction and patients at risk of

renal dysfunction (eg, elderly, diabetes mellitus, volume
Infants, Children, and Adolescents <17 years: IV:
<10 kg: 1 vial (~60 units)
depletion, sepsis, paraproteinemia, and nephrotoxic med- 10 to <18 kg: 2 vials (~120 units) i
ications). In patients at risk of renal dysfunction, ensure 18 to <25 kg: 3 vials (~180 units)
adequate hydration prior to administration; the rate of 25 to <35 kg: 4 vials (~240 units)
infusion should be minimized. Monitor renal function prior 35 to <50 kg: 5 vials (~300 units)
to infusion and periodically thereafter; discontinue if renal 50 to <60 kg: 6 vials (~360 units)
function deteriorates. Patients should be monitored for 260 kg: 7 vials (~420 units)
adverse events which may be related to the rate of Adolescents 217 years: IV: 7 vials (~420 units)
infusion (eg, fever, chills, nausea, vomiting, headache) Maintenance: Consider repeat dosing in patients expe-
during and after the infusion; follow closely the recom- riencing substantial hemorrhage, patients with signifi-
mended infusion rates. Potentially significant drug-drug cant compartmental fluid losses, and in patients
interactions may exist, requiring dose or frequency adjust- whose own immune response may be impaired or
ment, additional monitoring, and/or selection of alternative delayed. The interval between doses should take into
therapy. account the magnitude of ongoing blood and fluid
losses and the clinical status of the patient. Repeat
Anthrax immune globulin is a product of human plasma; dosing has not been evaluated in humans.
may potentially contain infectious agents which could Renal Impairment: Pediatric There are no dosage
transmit disease, including unknown or emerging viruses adjustmentsprovided in the manufacturer's labeling;
and other pathogens. Screening of donors, as well as use with caution; administer at the minimum rate of
testing and/or inactivation or removal of certain viruses, infusion practical; monitor closely.
reduces the risk. Infections thought to be transmitted by Hepatic Impairment: Pediatric There are no dosage
this product should be reported to the manufacturer. adjustments provided in the manufacturer's labeling.
[US Boxed Warning]: Some products may contain Preparation for Administration Thaw frozen vials either
maltose, which may result in falsely elevated blood by placing at room temperature for 1 hour followed by a
glucose readings with some point-of-care blood glu- 37°C water bath or by placing in a refrigerator until thawed
cose testings systems (for example those based on (approximately 14 hours at 2°C to 8°C); do not thaw ina
the GDH-PQQ or glucose-dye-oxidoreductase meth- ~ microwave oven. Do not refreeze vials. Bring to room
ods) which may result in inappropriate administration temperature prior to infusion. Do not shake; avoid foam-
of insulin and subsequent hypoglycemia. Blood glu- ing. Inspect vials to ensure product is fully thawed and free
cose should be measured by a glucose-specific from discoloration and particulate matter. Do not use
method (eg, monitor and test strips). solutions that are cloudy, turbid, or have particulates.
Gently swirl vials to ensure uniformity. Requires no further
Some dosage forms may contain polysorbate 80 (also dilution. Does not contain preservatives; use immediately.
known as Tweens). Hypersensitivity reactions, usually a Administration For IV infusion only. Use of an in-line filter
delayed reaction, have been reported following exposure is optional.
to pharmaceutical products containing polysorbate 80 in Infusion rate: If adverse reactions occur (eg, flushing,
certain individuals (Isaksson 2002; Lucente 2000; Shelley headache, nausea, changes in heart rate or blood
1995). Thrombocytopenia, ascites, pulmonary deteriora- pressure), slow the rate of infusion or temporarily stop
tion, and renal and hepatic failure have been reported in the infusion.
premature neonates after receiving parenteral products Infants, Children, and Adolescents <17 years: Initiate
containing polysorbate 80 (Alade 1986; CDC 1984). See infusion at 0.01 mL/kg/minute (maximum initial rate:
manufacturer’s labeling. 0.5 mL/minute) for 30 minutes; may increase the
Adverse Reactions infusion rate by 0.02 mL/kg/minute (maximum rate
Cardiovascular: Cardiac arrest, edema, hypotension, increase: 1 mL/minute) every 30 minutes as tolerated.
peripheral edema Maximum infusion rate: 0.04 mL/kg/minute or 2 mL/
Central nervous system: Headache (dose dependent) minute, whichever is less.
Endocrine & metabolic: Glycosuria (dose related), hyper- Adolescents 217 years and Adults: Initiate infusion at 0.5
kalemia, metabolic acidosis mL/minute for 30 minutes; may increase the infusion
Gastrointestinal: Nausea rate by 1 mL/minute every 30 minutes as tolerated.
Hematologic & oncologic: Blood coagulation disorder Maximum infusion rate: 2 mL/minute
Hepatic: Ascites Monitoring Parameters Renal function (BUN and serum
Local: Pain at injection site, swelling at injection site creatinine) before initial infusion and at appropriate inter-
Renal: Renal insufficiency vals thereafter; urine output periodically; baseline blood
Respiratory: Acute respiratory distress, pleural effusion, viscosity in patients at risk for hyperviscosity; signs and
pulmonary edema symptoms of hemolysis (hemoglobin and hematocrit prior
Drug Interactions to initiation, 36 to 96 hours postinfusion, and 7 to 10 days
Metabolism/Transport Effects None known. postinfusion in patients at high risk), aseptic meningitis
Avoid Concomitant Use There are no known interac- syndrome, hypersensitivity reactions, infusion-related
tions where it is recommended to avoid concomitant use. reactions, and transfusion-related acute lung injury
Increased Effect/Toxicity Test Interactions Contains maltose; falsely elevated
The levels/effects of Anthrax Immune Globulin (Human) blood glucose levels may occur when glucose monitoring
may be increased by: Estrogen Derivatives
devices and test strips utilizing the glucose dehydrogen-
ase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-
Decreased Effect
oxidoreductase based methods are used. Glucose mon-
Anthrax Immune Globulin (Human) may decrease the
itoring devices and test strips which utilize the glucose-
levels/effects of: Vaccines (Live)
specific method are recommended. Urinalysis after
Storage/Stability Store frozen at <-15°C (s5°F) until anthrax immune globulin administration may result in
required for use. Do not refreeze, reuse, or save for future
transiently elevated glucose; testing should be repeated
use. Discard any partially used vials. to determine if action is warranted.
Mechanism of Action Antibodies obtained from pooled
human plasma of individuals immunized with the anthrax Passively transferred antibodies may yield false-positive
vaccine provide passive immunity and neutralizes the serologic testing results; may yield false-positive direct
anthrax toxin by binding to protective antigen (PA) to and indirect Coombs’ test.
prevent PA-mediated cellular entry of anthrax edema Product Availability Anthrasil: FDA approved March
factor and lethal factor. 2015; availability is limited to the US Strategic National
Pharmacodynamics/Kinetics (Adult data unless Stockpile
noted) @ Anti-D Immunoglobulin see Rh,(D) Immune Globulin
Distribution: Vg: 5.7 to 6.8L on page 1751
Half-life elimination: 24 to 28 days
Time to peak: ~2.5 to 4 hours @ Anti-CD20 Monoclonal Antibody see RiTUXimab
Dosing on page 1779
Pediatric Note: Must be administered in combination @ Anti-Dandruff [OTC] see Selenium Sulfide
with appropriate antimicrobial therapy. on page 1812
Anthrax (inhalational exposure); treatment: @ Anti-Diarrheal [OTC] see Loperamide on page 1241
Initial dose: Select initial dose based on clinical @ Antidigoxin Fab Fragments, Ovine see Digoxin
severity. Dose may be doubled for severe cases in Immune Fab on page 640
patients >5 kg. Single doses >840 units (14 vials)
@ Antidiuretic Hormone see Vasopressin on page 2042
have not been evaluated in humans. Without sub-
stantially delaying administration, consider therapeu- @ Antifungal [OTC] see Miconazole (Topical)
tic thoracentesis and/or abdominal paracentesis prior on page 1371
to or concurrently with administration. @ Anti-Fungal [OTC] see Tolnaftate on page 1971
 ANTIHEMOPHILIC FACTOR (HUMAN)

Adverse Reactions Rare but important or life-threaten-

Antihemophilic Factor (Human) ing: Acute hemolytic anemia, anaphylaxis (rare), blurred
(an tee hee moe FIL ik FAK tor HYU man) vision, chest tightness, chills, drowsiness, fever, head-
ache, hemorrhagic diathesis, hypersensitivity reaction
Medication Safety Issues
(rare), increased factor VIII inhibitors, increased serum
Sound-alike/look-alike issues:
fibrinogen, jitteriness, lethargy, nausea, pain at injection
Factor VIII may be confused with Factor XIII
site, stomach discomfort, tingling sensation, urticaria,
Other safety concerns:
vasomotor symptoms (with rapid infusion), vomiting
Confusion may occur due to the omitting of "Factor VIII"
Drug Interactions
from some product labeling. Review product contents
carefully prior to dispensing any antihemophilic factor.
Metabolism/Transport Effects None known.
Brand Names: US Hemofil M; Koate; Koate-DVI; Mono-
Avoid Concomitant Use There are no known interac-
tions where it is recommended to avoid concomitant use.
clate-P
Brand Names: Canada Hemofil M Increased Effect/Toxicity
The levels/effects of Antihemophilic Factor (Human) may
Therapeutic Category Antihemophilic Agent; Blood
be increased by: Emicizumab-kxwh
Product Derivative
Decreased Effect There are no known significant inter-
Generic Availability (US) No
actions involving a decrease in effect.
Use Prevention and treatment of hemorrhagic episodes in
Storage/Stability Store under refrigeration, 2°C to 8°C
patients with hemophilia A (classical hemophilia); perio-
(36°F to 46°F); do not freeze. Use within 3 hours of
perative management of patients with hemophilia A; can
reconstitution. Do not refrigerate after reconstitution, pre-
provide therapeutic effects in patients with acquired factor
cipitation may occur. ’
Vill inhibitors <10 Bethesda units/mL Hemofil M: May also be stored at room temperature not
Pregnancy Risk Factor C d to exceed 30°C (86°F).
Pregnancy Considerations Animal reproduction studies Koate; Monoclate-P: May also be stored at 25°C (77°F)
have not been conducted. Parvovirus B19 or hepatitis A, for $6 months. Store in original package to protect from
which may be present in plasma-derived products, may light.
affect a pregnant woman more seriously than nonpreg- Mechanism of Action Protein (factor VIII) in normal
nant women. ; plasma which is necessary for clot formation and main-
Breastfeeding Considerations It is not known if anti- tenance of hemostasis; activates factor X in conjunction
hemophilic factor (human) is present in breast milk. with activated factor IX; activated factor X converts pro-
According to the manufacturer, the decision to continue thrombin to thrombin, which converts fibrinogen to fibrin,
or discontinue breastfeeding during therapy should take and with factor XIII forms a stable clot
into account the risk of infant exposure, the benefits of Pharmacodynamics/Kinetics (Adult data unless
breastfeeding to the infant, and benefits of treatment to the noted)
mother. Distribution: Does not readily cross the placenta
Contraindications Hypersensitivity (eg, anaphylaxis) to Half-life elimination: Mean: 14.8 to 17.5 hours
antihemophilic factor (human) or any component of the Dosing
formulation; hypersensitivity to mouse proteins (Hemofil M Pediatric Note: Individualize dosage based on coagu-
and Monoclate-P only). lation studies performed prior to and during treatment at
Warnings/Precautions The development of factor VIII regular intervals:
antibodies has been reported with antihemophilic factors;
monitor for signs of formation of antibodies to factor VIII. Hemophilia A: Children and Adolescents: IV: For every 1
Suspect factor VIII antibodies if the plasma factor VIII level international unit per kg body weight of AHF (human)
does not increase as expected or if bleeding is not administered, factor VIII level should increase by 2%;
controlled after administration. Hypersensitivity reactions calculated dosage should be adjusted to the actual
(including anaphylaxis) may occur; discontinue immedi- vial size
ately if hypersensitivity symptoms occur and administer Formula to calculate dosage required, based on
appropriate treatment. Product of human plasma; may desired increase in factor VIII (% of normal) (Note:
potentially contain infectious agents which could transmit This formula assumes that the patient's baseline AHF
disease. Screening of donors, as well as testing and/or level is <1%): Units required = Body weight (kg) x 0.5
inactivation or removal of certain viruses, reduces the risk. x desired increase in factor VIII (units/dL or % of
Infections thought to be transmitted by this product should normal)
be reported to the manufacturer. Hepatitis A and B vacci- Hospitalized patients: 20-50 units/kg/dose; may be
nation is recommended for all patients receiving plasma higher for special circumstances. Dose can be given
derivatives. Products vary by preparation method; final every 12-24 hours and more frequently in special
formulations contain human-albumin. Hemofil M and circumstances.
Monoclate-P contain trace amounts of mouse protein; Hemophilia A with high titer of inhibitor antibody: 50-75
use. is contraindicated in patients with hypersensitivity to units/kg/hour has been given
mouse protein. Some dosage forms may contain poly- General dosing guidelines (consult individual product
sorbate 80 (also known as Tweens). Hypersensitivity labeling for specific dosage recommendations): Chil-
reactions, usually a delayed reaction, have been reported dren and Adolescents: IV:
following exposure to pharmaceutical products containing Minor hemorrhage (required peak postinfusion AHF
polysorbate 80 in certain individuals (Isaksson 2002; level: 20% to 40%): 10-20 units/kg; repeat every
Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, 12-24 hours for 1-3 days until bleeding is resolved
pulmonary deterioration, and renal and hepatic failure or healing achieved; mild superficial or early hemor-
have been reported in premature neonates after receiving rhages may respond to a single dose
parenteral products containing polysorbate 80 (Alade Moderate hemorrhage (required peak postinfusion AHF
1986; CDC 1984). See manufacturer's labeling. Some level: 30% to 60%): 15-30 units/kg; repeat every
products may contain naturally occurring von Willebrand 12-24 hours for 23 days until pain and disability are
factor for stabilization; however, efficacy has not been resolved
established for the treatment of von Willebrand disease. Alternatively (to achieve peak postinfusion AHF level:
Dosage requirements will vary in patients with factor VIII 50%) Initial: 25 units/kg; maintenance: 10-15 units/
inhibitors; optimal treatment should be determined by kg every 8-12 hours
Clinical response. Frequencyof use is determined by the Severe/life-threatening hemorrhage (required peak
severity of the disorder or bleeding pattern. postinfusion AHF level: 60% to 100%): 30-50 units/
Warnings: Additional Pediatric Considerations For- kg; repeat every 8-24 hours until threat is resolved
mation of factor VIII inhibitors (neutralizing antibodies to Alternatively (to achieve peak postinfusion AHF level:
AHF human) may occur; reported incidence is 3% to 52%; 80% to 100%): 40-50 units/kg; maintenance: 20-25
an increase of inhibitor antibody concentration is seen at 2 units/kg every 8-12 hours
to 7 days, with peak concentrations at 1 to 3 weeks after Minor surgery (required peak postinfusion AHF level:
therapy; children <5 years of age are at greatest risk; Range 30% to 80%): 15-40 units/kg; dose is highly
higher doses of AHF may be needed if antibody is dependent upon procedure and specific product rec-
present; if antibody concentration is >10 Bethesda units/ ommendations; for some procedures, a single dose
mL, patients may not respond to larger doses and alter- plus oral antifibrinolytic therapy within 1 hour is suffi-
native treatment modalities may be needed; monitor cient; in other procedures, may repeat dose every
patients appropriately. Allergic-type hypersensitivity reac- 12-24 hours as needed
tions, including anaphylaxis, may occur; discontinue ther- Major surgery (required peak pre- and postsurgery
apy immediately if/urticaria, hives, hypotension, tightness AHF level: 80% to 100%): 40-50 units/kg; repeat
of the chest, wheezing, dyspnea, faintness, or anaphylaxis every 8-24 hours depending on state of healing
develop; emergency treatment and resuscitative meas- Prophylaxis: May also be given on a regular schedule
ures (eg, epinephrine, oxygen) may be needed. to prevent bleeding >
153
ANTIHEMOPHILIC FACTOR (HUMAN)

Renal Impairment: Pediatric There are no dosage

adjustments provided in the manufacturer's labeling. Antihemophilic Factor ldpenaedbifeas st.
Hepatic Impairment: Pediatric There are no dosage (an tee hee moe FIL ik-FAK tor ree KOM be nant)
adjustments provided in the manufacturer's labeling. Medication Safety Issues
Preparation for Administration Parenteral: If refriger- Sound-alike/look-alike issues:
ated, the dried concentrate and diluent should be warmed Factor Vill may be confused with Factor XIII
to room temperature before reconstitution; see individual Other safety concerns:
product labeling for specific reconstitution guidelines. Confusion may occur due to the omitting of "Factor VIII"
Gently swirl or rotate vial after adding diluent; do not from some product labeling. Review product contents
shake vigorously (Note: For Koate-DVI: Swirl vigorously carefully prior to dispensing any antihemophilic factor.
without creating excessive foaming); use filter needle Brand Names: US Advate; Afstyla; Helixate FS; Kogen-
provided by manufacturer to draw product into syringe; ate FS; Kogenate FS Bio-Set; Kovaltry; Novoeight; Nuwiq;
use one filter needle per vial; do not refrigerate after Recombinate; Xyntha; Xyntha Solofuse
reconstitution (precipitation may occur); administer within Brand Names: Canada Advate; Afstyla; Helixate FS;
3 hours after reconstitution; Note: Use plastic syringes, Kogenate FS; Kovaltry; Nuwig; Xyntha; Xyntha Solofuse;
since AHF may stick to the surface of glass syringes. Zonovate
Administration Parenteral: lV administration only. Admin- Therapeutic Category Antihemophilic Agent
ister through a separate line, do not mix with drugs or Generic Availability (US) No
other IV fluids. Maximum rate of administration is product Use Note: Antihemophilic Factor (Recombinant) is not
dependent: ji indicated for the treatment of von Willebrand disease.
Hemofil M: 10 mL/minute
Advate: Prevention and control of hemorrhagic episodes
Monoclate-P: 2 mL/minute
in patients with hemophilia A; perioperative management
Koate-DVI: Total dose may be given over 5 to 10 minutes;
of patients with hemophilia A; routine prophylaxis to pre-
adjust administration rate based on patient response
vent or reduce the frequency of bleeding episodes in
Monitoring Parameters Bleeding; heart rate and blood
patients with hemophilia A (All indications: FDA approved
pressure (before and during !V administration); AHF levels
in ages 0-16 years and adults)
prior to and during treatment; monitor for development of -
inhibitor antibodies by clinical observation (eg, inadequate Helixate FS, Kogenate FS: Prevention and control of
control of bleeding with adequate doses) and laboratory hemorrhagic episodes in patients with hemophilia A; peri-
tests (eg, inhibitor level, Bethesda assay). In patients with operative management of patients with hemophilia A;
blood groups A, B, or AB who receive large or frequent routine prophylaxis to reduce the frequency of bleeding
doses, monitor Hct, direct Coombs' test, and signs of episodes and reduce the risk of joint damage in children
intravascular hemolysis with hemophilia A with no preexisting joint damage (All
Reference Range indications: FDA approved in ages 0-16 years)
Plasma antihemophilic factor level: Recombinate: Prevention and control of hemorrhagic epi-
Normal range: 50% to 150% sodes in patients with hemophilia A (FDA approved in all
Level to prevent spontaneous hemorrhage: 5% ages); perioperative management of patients with hemo-
Required peak postinfusion AHF activity in blood (as % of philia A (FDA approved in all ages)
normal or units/dL plasma):
Early hemarthrosis, muscle bleed, or oral bleed: 20% Xyntha: Prevention and control of hemorrhagic episodes
to 40%
in patients with hemophilia A (FDA approved in ages 212
years and adults); perioperative management of patients
More extensive hemarthrosis, muscle bleed, or hema-
with hemophilia A (FDA approved in ages 212 years and
toma: 30% to 60%
adults)
Life-threatening bleeds (such as head injury, throat
bleed, severe abdominal pain): 80% to 100% Has also been used in patients with acquired factor VIII
Minor surgery, including tooth extraction: 60% to 80% inhibitors <10 Bethesda units/mL
Major surgery: 80% to 100% (pre- and postoperative) Pregnancy Risk Factor C
Additional Information One unit of AHF is equal to the Pregnancy Considerations Animal reproduction studies
factor VIII activity present in 1 mL of normal human have not been conducted. Factor VIII concentrations may
plasma. If bleeding is not controlled with adequate dose, increase in pregnant women with coagulation disorders.
test for the presence of factor VIII inhibitor; larger doses of Pregnant women should have clotting factors monitored,
AHF may be therapeutic with inhibitor titers <10 Bethesda particularly at 28 and 34 weeks gestation and prior to
units/mL; it may not be possible or practical to control invasive procedures. Prophylaxis may be needed if con-
bleeding if inhibitor titers >10 Bethesda units/mL (due to centrations are <50 units/mL at term and treatment should
the very large AHF doses required); other treatments [eg, continue for 3 to 5 days postpartum depending on route of
antihemophilic factor (porcine), factor IX complex concen- delivery. Because parvovirus infection may cause hydrops
trates, recombinant factor Vila, or anti-inhibitor coagulant fetalis or fetal death, a recombinant product is preferred if
complex] may be needed in patients with inhibitor titers prophylaxis or treatment is needed. The neonate may also
>10 Bethesda units/mL. be at an increased risk of bleeding following delivery and
Dosage Forms Considerations Strengths expressed should be tested for the coagulation disorder (Kadir 2009;
with approximate values. Consult individual vial labels Lee 2006). /
for exact potency within each vial. Breastfeeding Considerations It is not known if anti-
Dosage Forms Excipient information presented when hemophilic factor (recombinant) is present in breast milk.
According to the manufacturer, the decision to continue or
available (limited, particularly for generics); consult spe-
discontinue breastfeeding during therapy should take into
cific product labeling. [DSC] = Discontinued product
account the risk of infant exposure, the benefits of breast-
Kit, Intravenous:
feeding to the infant, and benefits of treatment to the
Monoclate-P: ~250 units [DSC], ~1000 units, ~1500
mother.
units [contains mouse (murine) and/or hamster protein]
Contraindications Hypersensitivity (eg, anaphylaxis) to
Solution Reconstituted, Intravenous:
antihemophilic factor, mouse or hamster protein (Advate,
Koate: ~250 units (1 ea); ~500 units (1 ea); ~1000 units
Afstyla, Helixate FS, Kogenate FS, Kovaltry, Novoeight,
(1 ea) [contains albumin human, polyethylene glycol,
Recombinate, Xyntha, Zonovate [Canadian product}),
polysorbate 80]
bovine protein (Recombinate only), or any component of
Solution Reconstituted, Intravenous [preservative free]: the formulation.
Hemofil M:,~250 units (1 ea) [contains albumin human,
Warnings/Precautions Monitor for signs of formation of ~
mouse (murine) and/or hamster protein, polyethylene
antibodies to factor VIII; may occur at any time but more
glycol] common in young children with severe hemophilia. Sus-
Hemofil M: ~250 units (1 ea [DSC]) [contains mouse pect factor VIII antibodies if the plasma factor VIII level
(murine) and/or hamster protein, polyethylene glycol] does not increase as expected or if bleeding is not
Hemofil M: ~500 units (1 ea) [contains albumin human, controlled after administration. The dosage requirement
mouse (murine) and/or hamster protein, polyethylene will vary in patients with factor VIII inhibitors; optimal
glycol] treatment should be determined by clinical response.
Hemofil M: ~500 units (1 ea [DSC]) [contains mouse Allergic hypersensitivity reactions (including anaphylaxis)
(murine) and/or hamster protein, polyethylene glycol] may occur; discontinue if hypersensitivity symptoms occur
Hemofil M: ~1000 units (1 ea); ~1700 units (1 ea) and administer appropriate treatment. Products vary by
+. [contains albumin human, mouse (murine) and/or ham- preparation method. Recombinate is stabilized using
ster protein, polyethylene glycol] human albumin. Some products are stabilized with or
Koate-DVI: ~250 units (1 ea); ~500 units (1 ea); ~1000 may contain sucrose. Some products may contain trace
units (1 ea) [contains albumin human, polyethylene amounts of mouse or hamster protein. Some dosage
glycol, polysorbate 80] forms may contain polysorbate 80 (also known as

154
 ANTIHEMOPHILIC FACTOR (RECOMBINANT)

Tweens). Hypersensitivity reactions, usually a delayed Nuwig: May also be stored at room temperature (not to
reaction, have been reported following exposure to phar- exceed 25°C [77°F]) up to 3 months; do not return to
maceutical products containing polysorbate 80 in certain refrigerator. Store in original package to protect from
individuals (Isaksson 2002; Lucente 2000; Shelley 1995). light. Use within 3 hours of reconstitution.
Thrombocytopenia, ascites, pulmonary deterioration, and Recombinate: May also be stored at room temperature,
renal and hepatic failure have been reported in premature not to exceed 30°C (86°F). Use within 3 hours of recon-
neonates after receiving parenteral products containing stitution.
polysorbate 80 (Alade 1986; CDC 1984). See manufac- Xyntha: May also be stored at room temperature (not to
turer’s labeling. Recombinate may contain mouse, ham- exceed 25°C [77°F]) up to 3 months; after room temper-
ster or bovine protein. Some products contain von ature storage, product may be returned to the refriger-
Willebrand factor for stabilization; however, efficacy has ator until the expiration date; however, do not store at
not been established for the treatment of von Willebrand’s room temperature and return to refrigerator temperature
disease. more than once. Avoid prolonged exposure to light
Warnings: Additional Pediatric Considerations during storage. Use within 3 hours of reconstitution.
Allergic-type hypersensitivity reactions including anaphy- Xyntha Solofuse: May also be stored at room temperature
laxis may occur; discontinue therapy immediately if urti- not to exceed 25°C [77°F]) up to 3 months; do not return
caria, hives, hypotension, tightness of the chest, to refrigerator; after 3 months at room temperature, must
wheezing, or anaphylaxis develop; emergency treatment use immediately or discard. Use within 3 hours of recon-
and resuscitative measures (eg, epinephrine, oxygen) stitution.
may be needed. Clinical response to antihemophilic factor Mechanism of Action Factor VIII replacement, neces-
administration may vary; dosage must be individualized sary for clot formation and maintenance of hemostasis. It
based on coagulation studies (performed prior to treat- activates factor X in conjunction with activated factor |X;
ment and at regular intervals during treatment) and clinical activated factor X converts prothrombin to thrombin, which
response. lf bleeding is not controlled with the recom- converts fibrinogen to fibrin, and with factor XIII forms a
mended dose, determine plasma level of factor VIII and stable clot.
follow with a sufficient dose to achieve satisfactory clinical Pharmacodynamics/Kinetics (Adult data unless
response. If plasma levels of factor VIII fail to increase as noted)
expected or bleeding continues, suspect the presence of Distribution: Vs: ~0.4 to 0.85 dL/kg
an inhibitor; test as appropriate. Formation of factor VIII Half-life elimination:
inhibitors (neutralizing antibodies to AHF recombinant) Advate: Children <12 years: 8.7 to 11.2 hours; Adoles-
may occur at any time, but is more common in young cents and Adults: 12 hours
children with severe hemophilia during the first years of Afstyla: Children <12 years: 10.2 to 10.4 hours; Children
therapy, or in patients at any age who received little prior 212 years and Adolescents: 14.3 hours; Adults: 14.2
therapy with factor VIII; monitor patients appropriately. hours
Adverse Reactions Helixate FS, Kogenate FS: Children: 10.7 hours; Adults:
Cardiovascular: Chest discomfort, palpitations, sinus 13.7 to 14.6 hours
tachycardia Kovaltry: Children <12 years: ~12 hours; Children 212
Central nervous system: Chills, dizziness, headache, years, Adolescents, and Adults: ~14 hours
insomnia, pain, procedural pain Novoeight: Children <12 years: 7.7 to 10 hours; Adoles-
Dermatologic: Allergic dermatitis, pruritus, skin rash, urti- cents and Adults: 11 to 12 hours
caria Nuwiq: Children <12 years: 11.9 to 13.1 hours; Adoles-
Gastrointestinal: Abdominal distress, abdominal pain, cents and Adults: 17.1 hours
diarrhea, dyspepsia, nausea, vomiting Recombinate: Adults: 14.6 + 4.9 hours
Hematologic & oncologic: Increased factor VIII inhibitors, Xyntha, Xyntha Solofuse: Children and Adolescents: 6.9
lymphadenopathy to 8.3 hours; Adults: 11 to 17 hours
Hepatic: Increased liver enzymes (including in patients Dosing
previously exposed to factor VIII products) Neonatal
Hypersensitivity: Hypersensitivity reaction Individualize dosage based on coagulation studies
Local: Catheter infection, injection site reaction performed prior to treatment and at regular inter-
Neuromuscular & skeletal: Arthralgia, back pain (more vals during treatment; for every 1 international unit
common in children), weakness per kg body weight of rAHF administered, factor VIII
Otic: Otic infection level should increase by 2% (or 2 units/dL); calculated
Respiratory: Cough, nasal congestion, nasopharyngitis, dosage should be adjusted to the actual vial size
pharyngolaryngeal pain, rhinorrhea, upper respiratory Control or prevention of bleeding in patients with
tract infection factor VIII deficiency (hemophilia A): IV: Dosage is
Miscellaneous: Fever (including in patients previously expressed in units of factor VIII activity (ie, international
exposed to factor VIII products),-limb injury units) and must be individualized based on formulation,
Rare but important or life-threatening: Anorexia, catheter severity of factor VIII deficiency, extent and location of
complication (venous catheter access), cold extremities, bleed, and clinical situation of patient.
cyanosis, epistaxis, facial flushing, feeling hot, hema- Formula for units required to raise blood level:
toma, hypotension, limb pain, loss of consciousness, Number of Factor VIII Units required = body weight (in
maculopapular rash, malaise, myalgia, paresthesia, kg) x 0.5 units/kg per units/dL x desired factor VIII
tachycardia, tremor, vasodilatation level increase (units/dL or %)
Drug Interactions For example, for a desired 100% level in a 3 kg
Metabolism/Transport Effects None known. patient who has an actual level of 20%: Number of
Avoid Concomitant Use There are no known interac- Factor VIII Units needed = 3 kg x 80% x 0.5 units/kg
tions where it is recommended to avoid concomitant use. per units/dL = 120 units
Increased Effect/Toxicity Manufacturer's labeling: Advate, Helixate FS, Kogenate
The levels/effects of Antihemophilic Factor (Recombi- FS, Recombinate: Desired Factor VIII level, dosing
nant) may be increased by: Emicizumab-kxwh interval, and duration based on hemorrhage type: IV:
Decreased Effect There are no known significant inter- Minor hemorrhage (early joint hemorrhage, mild
actions involving a decrease in effect. muscle or oral bleed): 10-20 units/kg/dose
Storage/Stability Prior to reconstitution, store refrigerated Desired factor VIII levels (% or units/dL): 20-40
at 2°C to 8°C (36°F to 46°F); do not freeze. Do not Frequency of dosing: Every 8-24 hours
refrigerate after reconstitution. Duration of treatment: 1-3 days until bleeding is
Advate: May also be stored at room temperature (not to resolved or healing achieved; mild, superficial, or
exceed 30°C [86°F]) up to 6 months; donot return to early hemorrhages may respond to a single dose
refrigerator. Use within 3 hours of reconstitution. Moderate hemorrhage (intramuscular bleed, hema-
Afstyla: May also be stored at room temperature (not to toma, moderate bleeding into oral cavity, definite joint
exceed 25°C [77°F]) up to 3 months; do not return to bleed, and known trauma): 15-30 units/kg/dose
refrigerator. Store in original package to protect from Desired factor VIII levels (% or units/dL): 30-60
light. Use within 4 hours of reconstitution. Frequency of dosing: Every 8-24 hours
Helixate FS, Kogenate FS, Kovaltry: May also be stored at Duration of treatment: 23 days until bleeding, pain,
room temperature (not to exceed 25°C [77°F]) up to 12 and disability are resolved or healing is achieved
months; do not return to refrigerator. Protect from Severe/life-threatening hemorrhage (Gl, intracranial,
extreme exposure to light during storage. Use within 3 intra-abdominal, intrathoracic bleeding, retroperito-
hours of reconstitution. neal, retropharyngeal, illiopsoas, CNS bleeding or
Novoeight: May also be stored at room temperature (not to head trauma, fractures):
exceed 30°C [86°F]) up to 12 months; do not return to Helixate FS, Kogenate FS: Initial: 40-50 units/kg;
refrigerator; after 12 months at room temperature, use maintenance: 20-25 units/kg/dose
immediately or discard. Store in original package to Desired factor VIII levels (% or units/dL): 80-100
protect from light. Use within 4 hours of reconstitution. Frequency of dosing: Every 8-12 hours a
155
 ANTIHEMOPHILIC FACTOR (RECOMBINANT)

q Duration of treatment: Until bleeding is resolved

(duration not specified)
Duration of treatment: 1-3 days until bleeding is
resolved or healing achieved; mild, superficial, or
Advate, Recombinate: 30-50 units/kg/dose early hemorrhages may respond to a single dose
Desired factor VIII levels (% or units/dL): 60-100 Moderate hemorrhage (intramuscular bleed, hema-
Frequency of dosing: Every 6-12 hours (Advate) or toma, moderate bleeding into oral cavity, definite
every 8-24 hours (Recombinate) joint bleed, and known trauma): 15-30 units/
Duration of treatment: Until bleeding is resolved kg/dose
(duration not specified) Desired factor VIII levels (% or units/dL): 30-60
Perioperative management: IV: Frequency of dosing: Every 8-24 hours (Advate: <6
Minor surgery (including dental extractions): years old) or every 12-24 hours (Advate: 26
Advate: 30-50 units/kg as bolus infusion beginning years old; Helixate FS; Kogenate FS; Xyntha)
within 1 hour prior to surgery; for dental procedures, Duration of treatment: 23 days until bleeding, pain,
adjunctive therapy may be considered and disability are resolved or healing is achieved
Desired factor VIII levels (% or units/dL): 60-100 Severe/life-threatening hemorrhage (GI, intracranial,
Frequency of dosing: Every 12-24 hours as needed intra-abdominal, intrathoracic bleeding, retroperito-
to control bleeding neal, retropharyngeal, illiopsoas, CNS bleeding or
Duration of treatment: Until bleeding is resolved head trauma, fractures):
(duration not specified) Helixate FS, Kogenate FS: Initial: 40-50 units/kg;
Helixate FS, Kogenate FS: 15-30 units/kg/dose maintenance: 20-25 units/kg/dose ;
Desired factor VIII levels (% or units/dL): 30-60 Desired factor VIII levels (% or units/dL): 80-100
Frequency of dosing: Every 12-24 hours Frequency of dosing: Every 8-12 hours
Duration of treatment: Until bleeding is resolved Duration of treatment: Until bleeding is resolved
(duration not specified) (duration not specified)
Recombinate: Advate, Recombinate, Xyntha: 30-50 units/kg/dose
Desired factor VIII levels (% or units/dL): 60-80 Desired factor VIII levels (% or units/dL): 60-100
Frequency of dosing: Single dose plus oral antifibri- Frequency of dosing: Every 6-12 hours (Advate:
nolytic therapy within 1 hour is sufficient for most <6 years old) or 8-24 hours (Advate: 26 years
cases old; Recombinate; Xyntha)
Major surgery (tonsillectomy, hernia repair, intracranial, Duration of treatment: Until bleeding is resolved
intra-abdominal, or intrathoracic surgery; joint (duration not specified) : :
replacement, trauma): Alternative dosing: Note: The following recommenda-
Advate: 40-60 units/kg/dose tions reflect guideline recommendations for general
Desired factor VIII levels (% or units/dL): Pre- and dosing requirements; may vary from those found
postoperative levels: 80-120; verify 100% activity within prescribing information or practitioner prefer-
has been achieved prior to surgery ence:
Frequency of dosing: Every 6-24 hours as needed IV: Infants, Children, and Adolescents: Desired fac-
tor VIII level to maintain and duration based on site
Duration of treatment: Based on desired level and
of hemorrhage/clinical situation (when no signifi-
state of healing
cant resource constraints exist) [WFH guidelines
Helixate FS, Kogenate FS: 50 units/kg/dose
(Srivastava, 2013)]. Note: Factor VIII level may
Desired factor VIII levels (% or units/dL): Pre- and
either be expressed as units/dL or as %. Dosing
postoperative levels: 100; verify 100% activity has
frequency most commonly corresponds to the half-
been achieved prior to surgery
life of factor VIII but should be determined based
Frequency of dosing: Every 6-12 hours as needed
on an assessment of factor VIII levels before the
Duration of treatment: Until healing is complete
next dose.
(~10-14 days)
Joint: 40-60 units/dL for 1-2 days; may be longer if
Recombinate:
response is inadequate
Desired factor VIII levels (% or units/dL): Pre- and
Superficial muscle (no neurovascular compro-
postoerative: 80-100
mise): 40-60 units/dL for 2-3 days, sometimes
Frequency of dosing: Every 8-24 hours depending
longer if response is inadequate
on state of healing
lliopsoas and deep muscle with neurovascular
Routine prophylaxis: IV:
injury, or substantial blood loss: Initial: 80-100
Advate: 20-40 units/kg/dose every other day (3-4 times
units/dL for 1-2 days; Maintenance: 30-60 units/
weekly). Alternatively, an every-third-day dosing regi-
dL for 3-5 days, sometimes longer as secondary
men may be used to target factor VIII trough levels
prophylaxis during physiotherapy
of 21%
CNS/head: Initial: 80-100 units/dL for 1-7 days;
Helixate FS, Kogenate FS: Note: For use in patients
Maintenance: 50 units/dL for 8-21 days
with no preexisting joint damage: 25 units/kg/dose Throat and neck: Initial: 80-100 units/dL for 1-7
given every other day.
days; Maintenance: 50 units/dL for 8-14 days
Pediatric Gastrointestinal: Initial: 80-100 units/dL for 7-14
Individualize dosage based on coagulation studies days; Maintenance: 50 units/dL (duration not
performed prior to treatment and at regular inter- specified)
vals during treatment; for every 1 international unit Renal: 50 units/dL for 3-5 days
per kg body weight of rAHF administered, factor VIII Deep laceration: 50 units/dL for 5-7 days
level should increase by 2% (or 2 units/dL); calculated Continuous IV infusion: Infants, Children, and Ado-
dosage should be adjusted to the actual vial size lescents: Limited data available: Note: For patients
Control or prevention of bleeding in patients with who require prolonged periods of treatment (eg,
factor VIll deficiency (hemophilia A): IV: Infants, intracranial hemorrhage or surgery) to avoid peaks
Children, and Adolescents: Dosage is expressed in and troughs associated with intermittent infusions
units of factor VIII activity (ie, international units) and [Batorova, 2002; Poon, 2012; WFH guidelines
must be individualized based on formulation, severity (Srivastava, 2013)]:
of factor VIII deficiency, extent and location of bleed, Following initial bolus to achieve the desired factor
and clinical situation of patient. VIII level: Initial dosing: 2-4 units/kg/hour; adjust
Formula for units required to raise blood level: dose based on frequent factor VIIl assays and
Number of Factor VIII Units required = body weight calculation of factor VIII clearance at steady-state
(in kg) x 0.5 units/kg per units/dL x desired VIII using the following equations:
level increase (units/dL or %) Factor Vill clearance (mL/kg/hour) = (current
For example, for a desired 100% level in a 25 kg infusion rate in units/kg/hour) / (plasma Factor
patient who has an actual level of 20%: Number level in units/mL)
of Factor VIII Units needed = 25 kg x 80% x 0.5 New infusion rate (units/kg/hour) = (factor VIII
units/kg per units/dL = 1000 units clearance in mL/kg/hour) x (desired plasma
Manufacturer's labeling: Advate, Helixate FS, Kogen- level in units/mL)
ate FS, Recombinate, Xyntha: Desired factor VIII Perioperative management: IV: Infants, Children, and
level, dosing interval, and duration based on hem- Adolescents:
orrhage type: IV: Manufacturer's labeling: Desired factor VIII level, dos-
Minor hemorrhage (early joint hemorrhage, mild ing interval, and duration based on surgery type:
muscle or oral bleed): 10-20 units/kg/dose Minor surgery (including dental extractions):
Desired factor VIII levels (% or units/dL): 20-40 Advate: 30-50 units/kg as bolus infusion beginning
Frequency of dosing: Every 8-24 hours (Advate: <6 within 1 hour prior to surgery; for dental proce-
years old) or every 12-24 hours (Advate: 26 dures, adjunctive therapy may be considered
years old; Helixate FS; Kogentae FS; Xyntha) Desired factor VIII levels (% or units/dL): 60-100

156
 ANTIHEMOPHILIC FACTOR (RECOMBINANT)

Frequency of dosing: Every 12-24 hours as Alternative dosing: 15-30 units/kg/dose 3 times
needed to control bleeding weekly (WFH guidelines [Srivastava, 2013] [Utrecht
Duration of treatment: Until bleeding is resolved protocol]) or 25-40 units/kg/dose 3 times weekly
(duration not specified) (WFH guidelines [Srivastava, 2013] [Malm6 proto-
Helixate FS, Kogenate FS, Xyntha: 15-30 units/kg/ col]) or 25-50 units/kg/dose administered 3 times
dose; for dental procedures, a single dose plus weekly or every other day (National Hemophilia
oral antifibrinolytic therapy within 1 hour may be Foundation, MASAC recommendation, 2007); opti-
sufficient mum regimen has yet to be defined.
Desired factor VIII levels (% or units/dL): 30-60 Preparation for Administration Parenteral: IV: If refri-
Frequency of dosing: Every 12-24 hours gerated, the dried concentrate and diluent should be
Duration of treatment: 3-4 days or until bleeding warmed to room temperature before reconstitution; see
is resolved individual product labeling for specific reconstitution
Recombinate: guidelines. Gently agitate or rotate vial after adding
Desired factor VIII levels (% or units/dL): 60-80 diluent, do not shake vigorously. Use filter needle provided
Frequency of dosing: Single dose plus oral anti- by manufacturer to draw product into syringe (all products
_, fibrinolytic therapy within 1 hour is sufficient for except Xyntha); do not refrigerate after reconstitution;
most cases administer within 3 hours after reconstitution; Note: Use
Major surgery (tonsillectomy, hernia repair, intracra- plastic syringes, since rAHF may stick to the surface of
nial, intra-abdominal or intrahtoracic surgery; joint glass syringes.
replacement, trauma): Administration Parenteral: IV administration only; use
Advate: 40-60. units/kg/dose administration sets/tubing provided by manufacturer (if
Desired factor VIII levels (% or units/dL): Pre- and provided). Adjust administration rate based on patient
postoperative levels: 80-120; verify 100% activ- response.
ity has been achieved prior to surgery Advate: Infuse over <5 minutes; maximum infusion rate:
Frequency of dosing: Every 6-24 hours (<6 years 10 mL/minute
old) or every 8-24 hours (26 years old) as Helixate FS, Kogenate FS: Infuse over 1 to 15 minutes;
needed based on patient tolerability; use sterile administration
Duration of treatment: Based on desired level and set provided by manufacturer.
state of healing Recombinate:
Helixate FS, Kogenate FS: 50 units/kg/dose Reconstitution with 5 mL of SWFI: Infuse at a maximum
Desired factor VIII levels (% or units/dL): Pre- and rate of 5 mL/minute
postoperative levels: 100; verify 100% activity Reconstitution with 10 mL of SWEFI: Infuse at a maximum
rate of 10 mL/minute
has been achieved prior to surgery
Xyntha, Xyntha Solufuse: Infuse over several minutes;
Frequency of dosing: Every 6-12 hours as
adjust based on patient comfort. Do not admix or admin-
needed
ister in same tubing as other medications.
Duration of treatment: Until healing is complete
WFH recommendations: Infuse slowly with maximum rate
(~10-14 days)
determined by age: Young children: 100 units/minute;
Recombinate: 40-50 units/kg/dose
Adults: 3 mL/minute; may also administer as a continu-
Desired factor VIII levels (% or units/dL): Pre- and
ous infusion in select patients (WFH guidelines [Srivas-
postoperative: 80-100
tava 2013)).
Frequency of dosing: Every 8-24 hours
Monitoring Parameters Bleeding; heart rate and blood
Duration of treatment: Based on state of healing
pressure (before and during IV administration); factor VIII
Xyntha: Children 212 years and Adolescents:
levels prior to and during treatment; monitor for the devel-
Desired factor VIII levels (% or units/dL): 60-100
opment of inhibitor antibodies by clinical observations (eg,
Frequency of dosing: Every 8-24 hours
inadequate control of bleeding with adequate doses) and
Duration of treatment: Until bleeding is resolved
laboratory tests (eg, inhibitor level, Bethesda assay)
and wound healing is achieved
Reference Range
Alternative dosing: Note: The following recommenda-
Classification of hemophilia; normal is defined as 1 unit/
tions reflect guideline recommendations for general
mL of factor VIII
dosing requirements; may vary from those found
Severe: Factor level <1% of normal
within prescribing information or practitioner prefer-
Moderate: Factor level 1% to 5% of normal
ence: Mild: Factor level >5% to <40% of normal
IV: Desired factor VIII level to maintain and duration
Additional Information One unit of rAHF is equal to the
based on site of hemorrhage/clinical situation
factor VIII activity present in 1 mL of fresh pooled human
(when no significant resource constraints exist)
plasma. If bleeding is not controlled with adequate dose,
[WFH guidelines (Srivastava, 2013)]. Note: Factor test for the presence of factor VIII inhibitor; larger doses of
VIII level may either be expressed as units/dL or as rAHF may be therapeutic with inhibitor titers <10 Bethesda
%. Dosing frequency most commonly corresponds units/mL; it may not be possible or practical to control
to the half-life of factor VIIl but should be deter- bleeding if inhibitor titers >10 Bethesda units/mL (due to
mined based on an assessment of factor VIII levels the very large rAHF doses required); other treatments [eg,
before the next dose. antihemophilic factor (porcine), factor IX complex concen-
Surgery (major): trates, recombinant factor Vila, or anti-inhibitor coagulant
Preop:. 80-100 units/dL complex] may be needed in patients with inhibitor titers
Postop: 60-80 units/dL for 1-3 days; then 40-60 >10 Bethesda units/mL
units/dL for 4-6 days; then 30-50 units/dL for Dosage Forms Considerations Strengths expressed
7-14 days with approximate values. Consult individual vial labels
Surgery (minor): for exact potency within each vial.
Preop: 50-80 units/dL Dosage Forms Excipient information presented when
Postop: 30-80 units/dL for 1-5 days depending on available (limited, particularly for generics); consult spe-
procedure type cific product labeling. [DSC] = Discontinued product
Continuous IV infusion: Infants, Children, and Ado- Kit, Intravenous:
lescents: Limited data available: Initial: 25-50 units/ Kogenate FS: 250 units, 500 units, 1000 units [contains
kg prior to surgery, followed by continuous infusion mouse (murine) and/or hamster protein]
at a rate of 3-5 units/kg/hour; regimen based on Kit, Intravenous [preservative free]:
two studies evaluating use in pediatric surgery Afstyla: 250 units, 500 units, 1000 units, 1500 units,
patients (age range: 0.9-17 years); rate was 2000 units, 2500 units, 3000 units [contains polysor-
adjusted and additional boluses given as needed bate 80]
to maintain desired factor VIIl level (Batorova, Helixate FS: 250 units, 500 units, 1000 units, 2000 units,
2012; Dingli, 2002) 3000 units [contains polysorbate 80]
Routine prophylaxis: IV: Infants, Children, and Ado- Kogenate FS: 2000 units, 3000 units [contains mouse
lescents: be (murine) and/or hamster protein]
Manufacturer's labeling: Kogenate FS Bio-Set: 250 units [DSC], 500 units [DSC],
Advate: 20-40 units/kg/dose every other day (3-4 1000 units, 2000 units, 3000 units [contains mouse
times weekly), Alternatively, an-every-third-day (murine) and/or hamster protein]
dosing regimen may be used to target factor VIII Nuwiq;: 250 units, 500 units, 1000 units, 2000 units, 2500
trough levels of 21% units, 3000 units, 4000 units
Helixate FS; Kogenate FS: Note: For use in patients Xyntha: 250 units, 500 units, 1000 units, 2000 units
with no preexisting joint damage: 25 units/kg/dose [albumin free; contains mouse (murine) and/or hamster
given every other day protein, polysorbate 80]

157
ANTIHEMOPHILIC FACTOR (RECOMBINANT)

Xyntha Solofuse: 250 units, 500 units, 1000 units, 2000 Alphanate, Humate-P: The manufacturer recommends
units, 3000 units [albumin free; contains mouse (mur- that caution be exercised when administering antihemo-
ine) and/or hamster protein, polysorbate 80] philic factor/von Willebrand factor (human) to breastfeed-
Solution Reconstituted, Intravenous: ing women. :
Kovaltry: 250 units (1 ea); 500 units (1 ea); 1000 units (1 Alphanate, Wilate: According to the manufacturer, the
ea); 2000 units (1 ea); 3000 units (1 ea) [contains decision to continue or discontinue breastfeeding during
mouse (murine) and/or hamster protein, polysor- therapy should take into account the risk of exposure to
bate 80] the infant and the benefits of treatment to the mother.
Solution Reconstituted, Intravenous [preservative free]: Contraindications. Hypersensitivity reaction, including
Advate: 250 units (1 ea); 500 units (1 ea); 1000 units (1 anaphylactic or severe systemic reaction to antihemophilic
ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units (1 factor or von Willebrand factor or any component of the
ea); 4000 units (1 ea) [albumin free; contains polysor- formulation; hypersensitivity to human plasma derived
bate 80] products (Wilate only).
Novoeight: 250 units (1 ea); 500 units (1 ea); 1000 units Warnings/Precautions Thromboembolic events have
(1 ea); 1500 units (1 ea); 2000 units (1 ea); 3000 units been reported; especially in patients with known risk
(1 ea) [contains mouse (murine) and/or hamster pro- factors for thrombosis. Risk of thromboembolic events
tein, polysorbate 80] may be increased in female patients, patients with endog-
Nuwiq: 250 units (1 ea); 500 units (1 ea); 1000 units (1 enous high concentrations of factor VIII, and in patients
ea); 2000 units (1 ea); 2500 units (1 ea); 3000 units (1 who receive continued treatment resulting in an excessive
ea); 4000 units (1 ea) rise-in factor VIII activity; monitor concentrations of von
Recombinate: 220-400 units (1 ea); 401-800 units (1 ea); Willebrand factor and factor VIII closely. Use with caution
801-1240 units (1 ea); 1241-1800 units (1 ea); and consider antithrombotic measures when treating
1801-2400 units (1 ea) [contains albumin human, poly- patients with von Willebrand disease that are at an
ethylene glycol, polysorbate 80] increased risk for thrombosis. Rapid administration may
result in vasomotor reactions; do not exceed administra-
@ Antihemophilic Factor (Recombinant), Single Chain tion rate recommendations. Hypersensitivity or allergic
see Antihemophilic Factor (Recombinant) on page 154 reactions have been observed, including anaphylaxis
and shock (with or without fever). Monitor patients closely
during infusion; if allergic symptoms occur, discontinue
Antihemophilic Factor/von Willebrand administration and initiate treatment immediately. Patients
Factor Complex (Human) experiencing anaphylactic reactions should be evaluated
(an tee hee moe FIL ik FAK tor von WILL le brand FAK tor KOM plex for the presence of inhibitors. Risk of viral transmission is
HYU man) not totally eradicated. Because antihemophilic factor is
Medication Safety Issues prepared from pooled plasma, it may contain the causa-
Sound-alike/look-alike issues: tive agent of viral hepatitis and other viral diseases (eg,
Factor VIIl may be confused with Factor XIII the variant Creutzfeldt-Jakob disease [vCJD] and theoret-
ically the Creutzfeldt-Jakob disease [CJD]). Screening of
Brand Names: US Alphanate; Humate-P; Wilate
donors, as well as testing and/or inactivation or removal of
Brand Names: Canada Humate-P; Wilate
certain viruses, reduces the risk. Infections thought to be
Therapeutic Category Antihemophilic Agent; Blood transmitted by this product should be reported to the
Product Derivative manufacturer. Hepatitis A and B vaccination is recom-
Generic Availability (US) No mended for all patients receiving plasma derivatives.
Use Neutralizing antibodies (inhibitors) may develop to factor
Hemophilia A (Factor VIII deficiency): VIIl or von Willebrand factor, particularly in patients with
Alphanate: Prevention and treatment of hemorrhagic type 3 (severe) von Willebrand disease. Patients who
episodes in hemophilia A (classic hemophilia) (FDA develop antibodies against von Willebrand factor will not
approved in ages 27 years and adults) have an effective clinical response to therapy and infu-
Humate-P: Prevention and treatment of hemorrhagic sions may result in anaphylactic reactions; these patients
episodes in hemophilia A (classic hemophilia) (FDA should be managed by an experienced physician and
approved in adults) alternatives to therapy should be considered. Any patient
von Willebrand disease (VWD): who has an inadequate response to therapy or a severe
Alphanate: Prophylaxis for surgical and/or invasive pro- adverse reaction should be evaluated for the presence of —
cedures in patients with VWD when desmopressin is inhibitors. Dosage requirements will vary in patients with
either ineffective or contraindicated [FDA approved in factor VIII inhibitors; optimal treatment should be deter-
ages 27 years and adults]. Note: Not indicated for mined by the extent of bleeding, presence of inhibitors,
patients with severe VWD undergoing major surgery. and clinical response. Frequency of use is determined by
Humate-P: Treatment of spontaneous and trauma- the severity of the disorder or bleeding pattern. Products
induced hemorrhagic episodes and prevention of vary by preparation method; some final formulations may .
excessive bleeding during and after surgery in patients contain human albumin.
with mild to moderate and severe VWD where the use
Some dosage forms may contain polysorbate 80 (also
of desmopressin is suspected or known to be inad-
known as Tweens). Hypersensitivity reactions, usually a
equate (FDA approved in ages 21 month and adults).
delayed reaction, have been reported following exposure
Note: Not indicated for the prophylaxis of spontaneous
to pharmaceutical products containing polysorbate 80 in
bleeding episodes.
certain individuals (Isaksson 2002; Lucente 2000; Shelley
Wilate: On demand treatment and control of bleeding
1995). Thrombocytopenia, ascites, pulmonary deteriora-
episodes in patients with VWD (FDA approved in ages
tion, and renal and hepatic failure have been reported in
25 years and adults); perioperative management of
premature neonates after receiving parenteral products
bleeding in patients with VWD (FDA approved in
containing polysorbate 80 (Alade 1986; CDC 1984). See
all ages)
manufacturer’s labeling.
Pregnancy Risk Factor C
Pregnancy Considerations Animal reproduction studies Alphanate and Humate-P contain trace amounts of blood
have not been conducted. Parvovirus B19 or hepatitis A, groups A and B isohemagglutinins; use caution when
which may be present in plasma-derived products, may large or frequently repeated doses are given to individuals
affect a pregnant woman more seriously than nonpreg- with blood groups A, B, and AB. Monitor patients for signs
nant women. of intravascular hemolysis and falling hematocrit; discon-
tinue therapy and consider administration of serologically
Women with von Willebrand disease have an increased compatible type O red blood cells if progressive hemolytic
risk of bleeding associated with invasive gynecologic anemia occurs.
procedures and delivery. The risk of miscarriage is also Warnings: Additional Pediatric Considerations For-
increased (NHLBI 2007; Pacheco 2010). Pregnant women mation of factor VIII inhibitors (neutralizing antibodies to
with von Willebrand disease or hemophilia may have a AHF human) may occur, particularly in patients with Type
transient increase in factor VII| during the second and third 3 (severe) von Willebrand factor; reported overall inci-
trimesters. Close monitoring is needed and therapy is dence is 3% to 52%; an increase of inhibitor antibody
recommended if levels are <50 units/dL prior to delivery concentration is seen at 2 to 7 days, with peak concen-
(Pacheco 2010; Srivastava 2013). If otherwise indicated, trations at 1 to 3 weeks after therapy; children <5 years of
therapy with von Willebrand factor concentrates should be age may also be at greatest risk. Patients who develop
used. Bleeding associated with postpartum hemorrhage is antibodies (usually antibody concentration >10 Bethesda
increased and may be delayed; women should be moni- units/mL) against von Willebrand factor will not have an
tored after delivery for at least 2 weeks (Pacheco 2010). effective clinical response to therapy and infusions may
Breastfeeding Considerations It is not known if anti- result in anaphylactic reactions; these patients should be
hemophilic factor/von Willebrand factor (human) is managed by an experienced physician and alternatives to
excreted in breast milk. therapy should be considered. Any patient who has an

158
 ANTIHEMOPHILIC FACTOR/VON WILLEBRAND FACTOR COMPLEX (HUMAN)

inadequate response to therapy or a severe adverse status of patient. Titrate the dose as needed based on
reaction should be evaluated for the presence of inhib- clinical response; whenever possible, perform serial
itors. FVIII activity assays to assess clinical response.
Adverse Reactions Hemorrhage, treatment: Infants, Children, and Adoles-
Cardiovascular: Chest pain, facial edema, orthostatic cents: IV: Note: Factor VIII concentrations may either
hypotension, peripheral edema, phlebitis, pulmonary be expressed as units/dL or as %. Dosing frequency
embolism (large doses), subdural hematoma, thrombo- most commonly corresponds to the half-life of factor
phlebitis, vasodilatation VIIl but should be determined based on an assessment
Central nervous system: Cerebral hemorrhage, chills, of factor VIII levels before the next dose. Guidelines do
dizziness, drowsiness, fatigue, headache, insomnia, not specify a preferred agent; see product specific
pain, paresthesia information for approved ages and uses.
Dermatologic: Diaphoresis, pruritus, skin rash, urticaria General dosing recommendations: The following rec-
Endocrine & metabolic: Hypermenorrhea ommendations reflect general dosing requirements;
Gastrointestinal: Constipation, gastrointestinal hemor- may vary from those found within prescribing informa-
rhage, nausea (postoperative), sore throat, vomiting tion or practitioner preference (WFH [Srivas-
Genitourinary: Urinary retention, urinary tract infection tav 2013)).
Hematologic & oncologic: Hemorrhage (30%; postopera- In general, administration of 1 unit/kg of factor VIII will
tive), anemia, decreased hematocrit (moderate), increase circulating factor VIII concentrations by ~2
increased factor VIII inhibitors units/dL (or 2%); calculated dosage should be
Hepatic: Increased serum ALT adjusted to the actual vial size.
Hypersensitivity: Anaphylaxis, hypersensitivity reaction Formula to calculate dosage required is based on
Infection: Infection, parvovirus B19 seroconversion (not desired increase in factor VIII (% of normal); Note:
-. accompanied by clinical signs of disease), sepsis This formula assumes that the patient's baseline
Local: Pain at injection site AHF level is <1%:
Neuromuscular & skeletal: Arthralgia, back pain, limb pain Dose (units) = Body weight (kg) x 0.5 x desired
Renal: Pyelonephritis factor VIII increase (units/dL or % of normal)
Respiratory: Cough, pharyngitis, respiratory distress
Miscellaneous: Fever, postoperative pain Desired Factor Vill Concentration to Maintain and
Rare but important or life-threatening: Antibody develop- Duration Based on Site of Hemorrhage/Clinical
ment (neutralizing), cardiorespiratory arrest, hemolysis, Situation (when no significant resource constraints
hypervolemia, parotid gland enlargement, seizure, exist) (WFH [Srivastava 2013])
shock, tachycardia, thromboembolic complications,
venous thrombosis (femoral) 40 to 60 units/dL for 1 to 2 days, may be
Drug Interactions Joint longer if response is inadequate
Metabolism/Transport Effects None known. Superficial
muscle (no 40 to 60 units/dL for 2 to 3 days, sometimes
Avoid Concomitant Use There are no known interac- neurovascular longer if response is inadequate
tions where it is recommended to avoid concomitant use. compromise)
Increased Effect/Toxicity lliopsoas and
The levels/effects of Antihemophilic Factor/von Wille- deep muscle with Initial: 80 to: 100 units/dL for 1 to 2 days
brand Factor Complex (Human) may be increased by: neurovascular Maintenance: 30 to 60 units/dL for 3 to 5
Emicizumab-kxwh injury, or days, sometimes longer as secondary
substantial blood prophylaxis during physiotherapy
Decreased Effect There are no known significant inter- loss
actions involving a decrease in effect. Initial: 80 to 100 units/dL for 1 to 7 days
Storage/Stability Products are stable for three years, up CNS/head Maintenance: 50 units/dL for 8 to 21 days
to the expiration date printed on the label. For single use; Initial: 80 to 100 units/dL for 1 to 7 days
discard any unused contents in vial. dice bancipeck Maintenance: 50 units/dL for 8 to 14 days
Alphanate: Store intact vials at <25°C (<77°F); do not Initial: 80 to 100 units/dL for 7 to 14 days
freeze. May store reconstituted solution at room temper- Gastrointestinal Maintenance: 50 units/dL (duration not
ature (S30°C). Use within 3 hours of reconstitution; do specified)
not refrigerate after reconstitution. Renal 50 units/dL for 3 to 5 days
Humate-P: Store intact vials at <25°C (S77°F); do not Deep laceration 50 units/dL for 5 to 7 days
freeze. Once reconstituted, do not refrigerate and use
within 3 hours.
Wilate: Store intact vials under refrigeration at 2°C to 8°C Preoperative: 80 to 100 units/dL
(36°F to 46°F); do not freeze. Store in original container
Surgery (major): |Postoperative: 60 to 80 units/dL for postop
to protect from light. Intact vials may also be stored at days 1 to 3, then 40 to 60 units/dL for postop
room temperature (not to exceed 25°C [77°F]) for <6 days 4 to 6, then 30 to 50 units/dL for postop
months. Once stored at room temperature, do not return Jp _| days 7 to 14
to the refrigerator. Following reconstitution, use solution
Preoperative: 50 to 80 units/dL
immediately. Surgery (minor):
Mechanism of Action Factor VII| and von Willebrand Postoperative: 30 to 80 units/dL for 1 to 5
days depending on procedure type
factor (VWF), obtained from pooled human plasma, are
used to replace endogenous factor VIII and VWF in Product-specific dosing: Alphanate: Children 27 years
patients with hemophilia or von Willebrand disease. Factor and Adolescents: IV: Note: In general, administration
Vill in conjunction with activated factor IX, activates factor of Alphanate FVIII:C 1 unit/kg will increase the plasma
X which converts prothrombin to thrombin and fibrinogen FVIII:C activity by ~2 units/dL (or 2% of normal), as
to fibrin. VWF promotes platelet aggregation and adhesion demonstrated by the following formulas:
to damaged vascular endothelium and acts as a stabilizing Dosage (units) based on desired increase in factor
carrier protein for factor VIll. (Circulating levels of func- VIII (units/dL or % normal):
tional VWF are measured as ristocetin cofactor activity Dosage (units) = Body Weight (kg) x 0.5 (units/kg per
[VWF:RCo)). units/dL) x desired factor VIII increase (units/dL or %
Pharmacodynamics/Kinetics (Adult data unless normal)
noted) Minor hemorrhage (large bruises; significant cuts or
Onset: Shortening of bleeding time: Immediate scrapes; uncomplicated joint hemorrhage): FVIII:C
Maximum effect: 1 to 2 hours = 15 units/kg/dose twice daily to achieve FVIII:C con-
Duration: von Willebrand disease: Shortening of bleeding centration 30% of normal. Continue until hemor-
time: <6 hours postinfusion; presence of VWF multimers rhage stops and healing has been achieved (1 to
detected in the plasma: 224 hours (Alphanate) 2 days).
Distribution: Vass: VWF:RCo: Humate: 29 to 290 mL/kg; Moderate hemorrhage (nose, mouth, and gum
Wilate: 15 to 160 mL/kg bleeds; dental extractions; hematuria): FVII:C 25
Half-life elimination: units/kg/dose twice daily to achieve FVIII:C concen-
Factor VII| coagulant activity (FVII:C): Range: 8 to 28 tration 50% of normal. Continue treatment until
hours in patients with hemophilia A healing has been achieved (2 to 7 days, on
VWEF:RCo: Range ‘(in patients with von Willebrand dis- average).
ease): Alphanate: 4 to 16 hours; Humate: 3 to 34 hours; Major hemorrhage (joint hemorrhage; muscle hemor-
Wilate: 6 to 49 hours rhage; major trauma; hematuria; intracranial and
Dosing intraperitoneal bleeding): FVIII:C 40 to 50 units/kg/
Pediatric dose twice daily to achieve FVII|:C concentrations
Hemophilia A (Factor VIlIl deficiency): Note: Dosage 80% to 100% of normal for at least 3 to 5 days;
and duration of treatment must be individualized based followed by FVIII:C 25 units/kg/dose twice daily to
on the severity of factor VIII deficiency, extent and maintain FVIII:C concentrations at 50% of normal
location of bleeding, presence of inhibitors and clinical until healing has been achieved. Major hemorrhages >
159
 ANTIHEMOPHILIC FACTOR/VON WILLEBRAND FACTOR COMPLEX (HUMAN)

q may require treatment for up to 10 days. Intracranial

hemorrhage may require prophylactic therapy for up
Major hemorrhage:
Loading dose: VWF:RCo 40 to 60 units/kg
to 6 months. Maintenance dose: VWF:RCo 20 to 40 units/kg/
Surgery: dose every 12 to 24 hours for 5 to 7 days, keeping
Preoperative: FVIII:C 40 to 50 units/kg to achieve the nadir of VWF:RCo and FVIII activity >50%
FVIII:C concentrations 80% to 100% of normal Prophylaxis, surgical/procedural:
Postoperative: FVIII:C 30 to 50 units/kg/dose twice Alphanate: Children 27 years and Adolescents: IV:
daily to maintain FVIIl:C concentrations at 60% to Minor surgery/bleeding:
100% of normal for the next 7 to 10. days or until Preoperative/preprocedure dose: VWF:RCo 75
healing has been achieved. units/kg as a single dose 1 hour prior to surgery
Prophylaxis, primary: Limited data available; multiple to achieve a target FVIII:C activity level of 40 to 50
protocols exist; optimum regimen has yet to be defined: units/dL .
Infants, Children, and Adolescents: IV: Maintenance dose: VWF:RCo 50 to 75 units/kg/
Utrecht protocol: 15 to 30 units/kg/dose 3 times weekly dose every 8 to 12 hours as Clinically needed to
(WFH [Srivastava 2013]) maintain FVIII:C activity level of 40 to 50 units/dL
Malm6 protocol: 25 to 40 units/kg/dose 3 times weekly for 1 to 3 days; do not exceed FVIII:C activity level
(WFH [Srivastava 2013]) of 150 units/dL
MASAC recommendations: 25-to 50 units/kg/dose 3 Major surgery/bleeding (excluding Type 3 VWD):
times weekly or every other day (National Hemophilia Preoperative/preprocedure dose: VWF:RCo 75
Foundation, MASAC recommendation 2007) units/kg as a single dose 1 hour prior to surgery
von Willebrand disease (VWD), treatment: Dosage is to achieve a target FVIII:C activity level of 100
expressed in international units of von Willebrand units/dL
factor: Ristocetin cofactor (VWF:RCo): Dose must be Maintenance dose: VWF:RCo 50 to 75 units/kg/
individualized based on type of VWD, extent and location dose every 8-to 12 hours as clinically needed to
of bleeding, clinical status of patient, and coagulation maintain FVIII:C activity level of 100 units/dL for 3
studies performed prior to and at regular intervals during to 7 days; do not exceed FVIIi:C activity level of
treatment. For major bleeds where repeated dosing is 150 units/dL
required, monitor and maintain the FVIII plasma concen- Humate-P: Infants, Children, and Adolescents: IV:
tration as described for the treatment of hemophilia A. Emergency surgery: VWF:RCo 50 to 60 units/kg to
Products are not identical and should not be used achieve a target VWF:RCo peak plasma concen-
interchangeably (NHLBI 2007). tration of 100 units/dL; monitor trough coagulation
Hemorrhage, treatment: Product-specific dosing: factor levels for subsequent doses
Humate P: \nfants, Children, and Adolescents: IV: Nonemergent surgical management:
Note: In general, administration of 1 unit/kg of factor Loading dose: Calculate based on patient's baseline
Vill would be expected to raise circulating VWF:RCo and target VWF:RCo and IVR. The IVR (in vivo
~5 units/dL recovery) ideally should be assessed prior to sur-
General dosing: VWF:RCo 40 to 80 units/kg/dose gery (eg, previous course of Humate P). If the
every 8 to 12 hours; adjust based on extent and calculated IVR is not available, assume IVR to be
location of hemorrhage 2 units/dL per unit/kg of VWF:RCo administered.
Dosing based on Von Willebrand type and hemor-
Loading dose (units) = (Target peak VWF:RCo
rhage severity:
[units/dL] - Baseline VWF:RCo [units/dL]) x
Type 1, mild VWD (baseline VWF:RCo activity typ-
weight (kg) / IVR (units/dL per units/kg)
ically >30%): Minor hemorrhage (if desmopressin
Note: Target peak VWF:RCo plasma concenira-
is not appropriate) or major hemorrhage (eg,
tions are dependent on surgery type (see below).
severe or refractory epistaxis, Gl bleeding, CNS
Procedure specific target VWF:RCo and FVIII:C
trauma, traumatic hemorrhage):
plasma concentrations and minimum durations:
Loading dose: VWF:RCo 40 to 60 units/kg
Oral surgery (extraction of $2 nonmolar teeth with
Maintenance dose: VWF:RCo 40 to 50 units/kg/
no bony involvement):
dose every 8 to 12 hours for 3 days, maintain
Loading dose: Calculate the loading dose to
VWEF:RCo nadir >50%; follow with VWF:RCo 40
achieve a target peak plasma VWF:RCo con-
to 50 units/kg/dose once daily for up to 7 days
centration of 50 to 60 units/dL and target peak
Type 1, moderate or severe VWD (baseline VWF:
plasma FVIII:C concentration of 40 to 50 units/
RCo activity typically <30%):
dL; administer 1 to 2 hours prior to surgery.
Minor hemorrhage (eg, epistaxis, oral bleeding,
Repeat doses may be required to attain target
menorrhagia): VWF:RCo 40 to 50 units/kg/dose
concentrations.
for 1 to 2 doses
Major hemorrhage (eg, severe or refractory epis-
Maintenance: One-half loading dose every 8
taxis, Gl bleeding, CNS trauma, hemarthrosis, hours as needed to maintain trough VWF:RCo
traumatic hemorrhage): concentration 230 units/dL up to 3 days post-
Loading dose: VWF:RCo 50 to 75 units/kg surgery and trough FVIII:C concentration >30
Maintenance dose: VWF:RCo 40 to 60 units/kg/ units/dL after day 3. Patients with shorter half-
dose every 8 to 12 hours for 3 days; maintain lives may require dosing every 6 hours; may
VWE:RCo nadir >50%; follow with VWF:RCo 40 lengthen the dosing interval to every 12 hours
to 60 units/kg/dose once daily for up to 7 days as appropriate based on pharmacokinetic data.
Types 2 (all variants) and 3 VWD: Administer at least one maintenance dose. Do
Minor hemorrhage (eg, epistaxis, oral bleeding, not exceed VWF:RCo or FVIII:C trough concen-
menorrhagia): VWF:RCo 40 to 50 units/kg/dose tration of 100 units/dL. j
for 1 to 2 doses Minor surgery:
Major hemorrhage (eg, severe or refractory epis- Loading dose: Calculate the loading dose to
taxis, Gl bleeding, CNS trauma, hemarthrosis, achieve a target peak plasma VWF:RCo con-
traumatic hemorrhage): centration of 50 to 60 units/dL and target peak
Loading dose: VWF:RCo 60 to 80 units/kg plasma FVIII:C concentration of 40 to 50 units/
Maintenance dose: VWF:RCo 40 to 60 units/kg/ dL; administer 1 to 2 hours prior to surgery.
dose every 8 to 12 hours for 3 days, maintain Repeat doses may be required to attain target
VWE:RCo nadir >50%; follow with 40 to 60 concentrations.
units/kg/dose once daily for up to 7 days Maintenance: One-half loading dose every 8
Wilate: Children 25 years and Adolescents: IV: Note: hours for at least 48 hours to maintain trough
Patients with Type 3 VWD and those with GI bleeding VWEF:RCo concentration 230 units/dL up to 3
may require higher doses. In general, administration days postsurgery and trough FVIII:C concentra-
of VWF:RCo 1 unit/kg will increase the plasma VWF tion >30 units/dL after day 3. Patients with
activity by ~2 units/dL (or 2% of normal), as demon- shorter half-lives may require dosing every 6
strated by the following formulas: hours; may lengthen the dosing interval to every
Dosage (units) based on desired factor VWF:RCo 12 hours as appropriate based on pharmacoki-
increase (units/dL or % normal) netic data. Do not exceed VWF:RCo or FVIII:C
Dosage (units) = Body weight (kg) x 0.5 (units/kg per trough concentration of 100 units/dL.
units/dL) x desired VWF:RCo increase (units/dL or Major surgery/Oral surgery (extraction of >2 teeth
% normal) or >1 impacted wisdom tooth):
Minor hemorrhage: Loading dose: Calculate the loading dose to
Loading dose: VWF:RCo 20 to 40 units/kg achieve a target peak plasma VWF:RCo con-
Maintenance dose: VWF:RCo 20 to 30 units/kg/ centration of 100 units/dL and target peak
dose every 12 to 24 hours for <3 days, keeping plasma FVIII:C concentration of 80 to 100
the nadir of VWF:RCo and FVIII activity >30% units/dL; administer 1 to 2 hours prior to surgery.

160
 ANTI-INHIBITOR COAGULANT COMPLEX (HUMAN)

Repeat doses may be required to attain target Additional Information One unit of AHF is equal to the
concentrations. factor VIII activity present in 1 mL of normal human
Maintenance: One-half loading dose every 8 plasma. If bleeding is not controlled with adequate dose,
hours for at least 72 hours to maintain both test for the presence of factor VIII inhibitor; larger doses of
trough VWF:RCo and FVIII:C concentrations AHF may be therapeutic with inhibitor titers <10 Bethesda
>50 units/dL up to 3 days postsurgery and >30 units/mL; it may not be possible or practical to control
units/dL after day 3. Patients with’ shorter half- bleeding if inhibitor titers >10 Bethesda units/mL (due to
lives may require dosing every 6 hours; may the very large AHF doses required); other treatments [eg,
lengthen the dosing interval to every 12 hours antihemophilic factor (porcine), factor IX complex concen-
as appropriate based on pharmacokinetic data. trates, recombinant factor Vila, or anti-inhibitor coagulant
Do not exceed VWF:RCo or FVIII:C trough complex] may be needed in patients with inhibitor titers
concentration of 100 units/dL. >10 Bethesda units/mL.
Wilate: Infants, Children, and Adolescents:
General dosing recommendations: The in vivo recov- Exact potency varies among products and between lots of
ery (IVR) should be calculated and baseline plasma the same product; each vial contains the exact labeled
VWEF:RGCo activity should be assessed in all patients amount of VWF activity, as measured with the Ristocetin
prior to surgery. The loading dose may then be cofactor activity (VWF:RCo), and factor VIII (FVIII) activity
calculated using the IVR. If the calculated IVR is and should be consulted prior to use. However, the
not available, assume IVR to be 2 units/dL per unit/ average ratio between VWF:RCo and FVIII among avail-
kg of VWF:RCo administered. If the calculated IVR able products is:
is >2.5, assume IVR to be 2.5 units/dL per units/kg Alphanate: Average ratio not provided by manufacturer
of VWF:RCo administered. The formulas to calcu- or in available literature
late the loading dose is as follows: Humate-P: Average ratio of VWF:RCo to FVIII is 2.4:1
Loading dose (units) = [(Target peak VWF:RCo Wilate: Average ratio of VWF:RCo to FVIII is ~1:1
[units/dL] - Baseline VWF:RCo [units/dL]) x weight Formula to calculate specific in vivo recovery (IVR) is as
(kg)] / IVR (units/dL per units/kg) follows:
Procedure specific dosing and target VWF:RCo IVR (units/dL per units/kg of VWF:RCo administered) =
concentrations:
[Plasma VWF:RCo 30 minutes after infusion (units/dL)] —
Minor surgery (including tooth extraction):
[Plasma VWF:RCo at baseline (units/dL)] / Dose
Loading dose: VWF:RCo 30 to 60 units/kg adminis-
(units /kg)
tered within 3 hours prior to surgery, to achieve
Dosage Forms Considerations Strengths expressed
VWEFE:RCo peak concentration 50% of normal
with approximate values. Consult individual vial labels
Maintenance: VWF:RCo 15.to 30 units/kg/dose (or
for exact potency within each vial.
one-half the loading dose) every 12 to 24 hours to
maintain VWF:RCo trough concentrations >30% of Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
normal until wound healing is achieved, for up to 3
cific product labeling. [DSC] = Discontinued product
days. Do not exceed FVIII:C activity concentrations
of 250%. Injection, powder for reconstitution [human derived]:
Major surgery: Alphanate:
Loading dose: VWF:RCo 40 to 60 units/kg adminis- 250 units [Factor VIIl and VWF:RCo ratio varies by lot;
tered within 3 hours prior to surgery to achieve contains albumin and polysorbate 80; packaged with
VWEF:RCo peak concentration 100% of normal. diluent]
Maintenance: VWF:RCo 20 to 40 units/kg/dose (or 500 units [Factor VIIl and VWF:RCo ratio varies by lot;
one-half the loading dose) every 12 hours for the contains albumin and polysorbate 80; packaged with
first 24 hours after the start of surgery to maintain diluent]
VWEF:RCo trough concentrations >50% of normal; 1000 units [Factor VII] and VWF:RCo ratio varies by lot;
then may adjust to. every 12 to 24 hours to maintain contains albumin and polysorbate 80; packaged with
VWEF:RCo trough concentrations >50% of normal diluent]
and continue until wound healing is achieved, up to 1500 units [Factor VII] and VWF:RCo ratio varies by lot;
6 days or more. Do not exceed FVIII:C activity contains albumin and polysorbate 80; packaged with
concentration of 250%. diluent]
Renal Impairment: Pediatric There are no dosage 2000 units [Factor VII] and VWF:RCo ratio varies by lot;
adjustments provided in the manufacturer’s labeling. contains albumin and polysorbate 80; packaged with
Hepatic Impairment: Pediatric There are no dosage diluent]
adjustments provided in the manufacturer's labeling. Humate-P:
Preparation: for Administration Parenteral: IV: If refri- FVIIl 250 units and VWF:RCo 600 units [contains
gerated, the dried concentrate~and diluent should be albumin; packaged with diluent] [DSC]
warmed to room temperature before reconstitution; see FVIIl 500 units and VWF:RCo 1200 units [contains
product labeling for specific reconstitution guidelines. albumin; packaged with diluent]
Gently swirl or rotate vial after adding diluent; do not FVIII 1000 units and VWF:RCo 2400 units [contains
shake vigorously. For Alphanate or Humate-P, use the albumin; packaged with diluent]
provided filter transfer set to withdraw solution from vial; Wilate:
remove filter spike prior to administration. For Wilate, use FVII 500 units and VWF:RCo 500 units [contains
the provided Mix2Vial transfer device to reconstitute. Use polysorbate 80 (in diluent); packaged with diluent]
plastic syringes; AHF may stick to the surface of glass FVIIl 1000 units and VWF:RCo 1000 units [contains
syringes. For single use; discard any unused contents in polysorbate 80 (in diluent); packaged with diluent]
vial. ¢ Antihemophilic Factor/Vwf see Antihemophilic Factor/
Administration von Willebrand Factor Complex (Human) on page 158
Parenteral: |V: Administer through a separate line, do not
mix with drugs or other IV fluids. Vasomotor reactions @ Anti-Hist Allergy [OTC] see DiphenhydrAMINE (Sys-
may result from rapid administration. temic) on page 652
Alphanate: Infuse slowly; maximum rate: 10 mL/minute
Humate-P: Infuse slowly; maximum rate: 4 mL/minute Anti-inhibitor Coagulant Complex
Wilate: Infuse slowly at a rate of 2 to 4 mL/minute;
reduce the rate or interrupt administration in patients
(Human)
(an TEE in HI bi tor coe AG yoo lant KOM pleks HYU man)
who experience a marked increase in pulse rate.
Monitoring Parameters Signs and symptoms of intra- Brand Names: US FEIBA
vascular hemolysis or bleeding; heart rate and blood Brand Names: Canada FEIBA NF
pressure (before and during !V administration); hyper- Therapeutic Category Antihemophilic Agent; Blood
sensitivity reactions during the infusion. AHF concentra- Product Derivative
tions prior to and during treatment; in patients with Generic Availability (US) No
circulating inhibitors, the inhibitor concentration should Use Control and prevention of bleeding episodes, perioper-
be monitored; hematocrit; VWE activity (circulating con- ative bleeding management, and routine prophylaxis to
centrations of functional VWF are measured as ristocetin prevent or reduce the frequency of bleeding episodes in
cofactor activity [VWF:RCo]). In surgical patients, monitor patients with hemophilia A or B with inhibitors [All indica-
VWF:RCo at baseline and after surgery, trough VWF:RCo tions: FDA approved in infants (>28 days of life), children,
and FVIII:C at least daily.
adolescents, and adults]
Reference Range Hemophilia: Classification of hemo-
philia; normal is defined as 1 unit/mL of factor VIII:C Note: Not indicated for the treatment of bleeding resulting
Severe: Factor level <1% of normal : from coagulation factor deficiencies in the absence of
Moderate: Factor level 1% to 5% of normal inhibitors to factor VIII or factor IX.
Mild: Factor level >5% to 30% of normal Pregnancy Risk Factor C

161
 ANTI-INHIBITOR COAGULANT COMPLEX (HUMAN)

é Pregnancy Considerations Animal reproduction studies Decreased Effect There are no known significant inter-
have not been conducted. actions involving a decrease in effect.
Breastfeeding Considerations It is not known if anti- Storage/Stability Store intact vials at $<25°C (77°F); store
inhibitor coagulant complex is present in breast milk. The in the original package to protect from light: Do not freeze.
manufacturer recommends that caution be exercised Following reconstitution, do not refrigerate and administer
when administering anti-inhibitor coagulant complex to within 3 hours.
breastfeeding women. Mechanism of Action Multiple interactions of the com-
Contraindications Known anaphylactic or severe hyper- ponents in anti-inhibitor coagulant complex restore the
sensitivity to anti-inhibitor coagulant complex or any com- impaired thrombin generation of hemophilia patients with
ponent of the formulation, including factors of the kinin inhibitors. In vitro, anti-inhibitor coagulant complex short-
generating system; disseminated intravascular coagula- ens the activated partial thromboplastin time of plasma
tion (DIC); acute thrombosis or embolism (including myo- containing factor VIII inhibitor. ;
cardial infarction) Pharmacodynamics/Kinetics (Adult data unless
Warnings/Precautions Hypersensitivity and allergic noted)
reactions (including severe and systemic reactions [eg, Onset: Peak thrombin generation: Within 15 to 30 minutes
anaphylaxis with urticaria and angioedema, broncho- (Varadi 2003)
spasm, circulatory shock]) have been observed following Duration: 8 to 12 hours (based on thrombin generation)
administration. Discontinue immediately with signs/symp- (Varadi 2003)
toms of severe hypersensitivity reactions and provide Half-life elimination: 4 to 7 hours (based on thrombin
appropriate supportive care. Infusion reactions (eg, chills, generation) (Varadi 2003)
pyrexia, hypertension) have been reported. [US Boxed Dosing
Warning]: Thromboembolic events (including venous Pediatric Note: Anti-inhibitor coagulant complex
thrombosis, pulmonary embolism, MI, and stroke) (Human) contains mainly nonactivated therapeutic levels
have been reported following administration of anti- of factors Il, IX, and X and mainly activated factor VII.
inhibitor coagulant complex, particularly with admin- Dosage is expressed in units of factor VIII inhibitor
istration of high doses and/or in patients with throm- bypassing activity and is dependent upon the severity
botic risk factors. Monitor patients receiving anti- and location of bleeding, type and level of inhibitors, and
inhibitor coagulant complex for signs and symptoms whether the patient has a history of an anamnestic
of thromboembolic events, especially if more than 200 increase in antihemophilic inhibitor levels following use
units/kg/day is administered. Use with caution in patients of preparations containing antihemophilic factor. Maxi-
with disseminated intravascular coagulation [DIC], mum dose should only be exceeded if bleeding severity
warrants; monitor closely for DIC, coronary ischemia
advanced atherosclerotic disease, crush injury, septice-
and/or signs and symptoms of other thromboembolic
mia, or concomitant treatment with factor Vila. Weigh the
events.
potential benefit of treatment against the potential risk of
Control and prevention of bleeding episodes:
these thromboembolic events. Monitor patients receiving
Infants, Children, and Adolescents: Note: Dosage will
>100 units/kg for the development of DIC, acute coronary
vary with the bleeding site and severity.
ischemia, and signs/symptoms of other thromboembolic
Joint hemorrhage: \V: 50 to 100 -units/kg/dose every
events. If clinical signs/symptoms occur, discontinue use.
12 hours until pain and acute disabilities are
Potentially significant drug-drug interactions may exist,
improved; maximum daily dose: 200 units/kg/day
requiring dose or frequency adjustment, additional mon-
Mucous membrane bleeding: |V: 50 to 100 units/kg/
itoring, and/or selection of alternative therapy.
dose every 6 hours for at least one day or until
Not indicated for the treatment of bleeding episodes bleeding is resolved; maximum daily dose: 200
resulting from coagulation: factor deficiencies in the units/kg/day
absence of inhibitors to factor VIIIl or factor IX. Use of Soft tissue hemorrhage (eg, retroperitoneal bleeding):
antifibrinolytics within ~6 to 12 hours after the adminis- IV: 100 units/kg/dose every 12 hours until resolution
tration of anti-inhibitor coagulant complex is not recom- of bleed; maximum daily dose: 200 units/kg/day
mended. Product contains minute amounts of factor VIII, Other severe hemorrhages (eg, CNS bleeds): \V: 100
which may cause an anamnestic response; anamnestic units/kg/dose every 6 to 12 hours until resolution of
rises were not associated with reduced efficacy. Product bleed; maximum daily dose: 200 units/kg/day
of human plasma; may potentially contain infectious Perioperative management: Infants, Children, and
agents that could transmit disease. During the manufac- Adolescents:
turing process, screening of donors, as well as testing Preoperative: \V: 50 to 100 units/kg (single dose)
and/or inactivation or removal of certain viruses, reduces administered immediately prior to surgery
the risk. Infections thought to be transmitted by this Postoperative: |V: 50 to 100 units/kg/dose every 6 to
product should be reported to the manufacturer and/or 12 hours until resolution of bleed and healing is
to FDA MedWatch. Patients with signs/symptoms of infec- achieved; maximum daily dose: 200 units/kg/day
Routine prophylaxis: Infants, Children, and Adoles-
tion (eg, fever, chills, drowsiness) should be encouraged
cents: IV: 85 units/kg/dose every other day
to consult a health care provider.
Adverse Reactions Renal Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer’s labeling.
Cardiovascular: Cerebrovascular accident (embolic/
Hepatic Impairment: Pediatric There are no dosage
thrombotic stroke), chest discomfort, chest pain,
adjustments provided in the manufacturer's labeling.
decreased blood pressure, flushing, hypertension, hypo-
tension, myocardial infarction, pulmonary embolism,
Preparation for Administration IV: If refrigerated, allow
the vials of anti-inhibitor coagulant complex (concentrate)
tachycardia, thromboembolism, thrombosis (arterial
and SWFI (diluent) to reach room temperature. Recon-
thrombosis, venous thrombosis)
stitute with provided SWFI. Swirl to gently dissolve pow-
Central nervous system: Chills, dizziness, drowsiness,
der; do not shake. Do not refrigerate after reconstitution.
headache, hypoesthesia (including facial), malaise, par-
Administration IV: For IV injection or infusion only; max-
esthesia
imum infusion rate: 2 units/kg/minute. Following reconsti-
Dermatologic: Pruritus, skin rash, urticaria
tution, complete infusion use within 3 hours.
Gastrointestinal: Abdominal distress, diarrhea, dysgeusia,
Monitoring Parameters Monitor for control of bleeding;
nausea, vomiting
signs and symptoms of DIC (blood pressure changes,
Hematologic & oncologic: Disseminated intravascular
. pulse rate changes, chest pain/cough, fibrinogen, platelet
coagulation
count, fibrin-fibrinogen degradation products, significantly-
Hypersensitivity: Angioedema, hypersensitivity reaction
prolonged thrombin time, PT, or partial thromboplastin
(including anaphylaxis)
time), acute coronary ischemia and other thromboembolic
Immunologic: Antibody development (anamnestic events; hemoglobin and hematocrit; hypotension; have
response) epinephrine ready to treat hypersensitivity reactions.
Local: Pain at injection site Note: Tests used to monitor hemostatic efficacy, such as
Miscellaneous: Fever aPTT and TEG, are not useful for monitoring responses
Respiratory: Bronchospasm, cough, dyspnea, wheezing with anti-inhibitor coagulant complex (Hoffman 2012).
Drug Interactions Dosing to normalize these values may result in DIC.
Metabolism/Transport Effects None known. Additional Information One unit of activity is defined as
Avoid Concomitant Use that amount of anti-inhibitor coagulant complex that short-
Avoid concomitant use of Anti-inhibitor Coagulant Com- ens the activated partial thromboplastin time (aPTT) of a
plex (Human) with any of the following: Antifibrinolytic high titer factor VIII inhibitor reference plasma to 50% of
Agents the blank value.
Increased Effect/Toxicity Dosage Forms Considerations
The levels/effects of Anti-inhibitor Coagulant Complex FEIBA strengths expressed in terms of Factor VIII inhibitor
(Human) may be increased by: Antifibrinolytic Agents; bypassing activity with nominal strength values. Consult
Emicizumab-kxwh individual vial labels for exact potency within each vial.

162
 ANTITHYMOCYTE GLOBULIN (EQUINE)

Dosage Forms Excipient information presented when prior to administration of the initial ATG dose. A positive
available (limited, particularly for generics); consult spe- skin test is suggestive of an increased risk for systemic
cific product labeling. allergic reactions with an infusion, although anaphylaxis
Solution Reconstituted, Intravenous [preservative free]: may occur in patients who display negative skin tests. If
FEIBA: 500 units (1 ea); 1000 units (1 ea); 2500 units ATG treatment is deemed appropriate following a positive
(1 ea) skin test, the first infusion should be administered in a
controlled environment with intensive life support immedi-
@ Anti-ltch [OTC] see DiphenhydrAMINE (Topical)
ately available. Also observe for signs/symptoms of aller-
on page 656
gic reactions during repeat courses of administration. Skin
@ Anti-itch Maximum Strength [OTC] see Diphenhydr- testing is not predictive for later development of serum
AMINE (Topical) on page 656 sickness.
@ Anti-Itch Maximum Strength [OTC] see Hydrocortisone
Thrombocytopenia may-occur; may require platelets
(Topical) on page 1073
transfusion support. Discontinue if severe and unremitting
@ Anti-PD-1 Human Monoclonal Antibody MDX-1106 thrombocytopenia and/or leukopenia occur in solid organ
see Nivolumab on page 1464 transplant patients. Clinically significant hemolysis has
@ Anti-PD-1 Monoclonal Antibody MK-3475 see Pembro- been reported (rarely); severe and unremitting hemolysis
lizumab on page 1577 may require treatment discontinuation; chest, flank or
@ Anti-PD-L1 Monoclonal Antibody MSB0010718C see back pain may indicate hemolysis. Abnormal hepatic
Avelumab on page 219 function tests have been observed in patients with aplastic
anemia and other hematologic disorders receiving ATG.
|® Antiseptic Skin Cleanser [OTC] see Chlorhexidine
ATG is an immunosuppressant; monitor closely for signs
Gluconate (Topical) on page 421
of infection. An increased incidence of cytomegalovirus
@ Anti-Tac Monoclonal Antibody see Daclizumab (CMV) infection has been reported in studies. Administer
on page 555 via central line due to chemical phlebitis that may occur
with a peripheral vein. Dose must be administered over at
Antithymocyte Globulin (Equine) least 4 hours. Patient may need to be pretreated with an
(an te THY moe site GLOB yu lin, E kwine) antipyretic, antihistamine, and/or corticosteroid. Intrader-
mal skin testing is recommended prior to first-dose admin-
Medication Safety Issues istration. Product of equine and human plasma; may have
Sound-alike/look-alike issues: a risk of transmitting disease, including a theoretical risk of
Antithymocyte globulin equine (Atgam) may be confused Creutzfeldt-Jakob disease (CJD). Product potency and
with antithymocyte globulin rabbit (Thymoglobulin) activity may vary from lot to lot. Potentially significant
Atgam may be confused with Ativan drug-drug interactions may exist, requiring dose or fre-
Brand Names: US Atgam quency adjustment, additional monitoring, and/or selec-
Brand Names: Canada Atgam tion of alternative therapy. Live viral vaccines may not
Therapeutic Category Immune Globulin; Immunosup- replicate and antibody response may be reduced if admin-
pressant Agent; Polyclonal Antibody istered during ATG treatment. Patients should not be
Generic Availability (US) No immunized with attenuated live viral vaccines prior to
Use Treatment of acute renal allograft rejection in trans- planned ATG treatment, during, and after treatment.
plant patients (FDA approved in pediatric patients [age not Adverse Reactions
specified] and adults); treatment of moderate to severe Cardiovascular: Bradycardia, cardiac disease, cardiac fail-
aplastic anemia in patients not considered suitable candi- ure, chest pain, edema, hypertension, hypotension, myo-
dates for bone marrow transplantation (FDA approved in carditis, phlebitis, thrombophlebitis
pediatric patients [age not specified] and adults); has also Central nervous system: Agitation, brain disease (viral),
been used in treatment of acute graft-vs-host disease burning sensation (burning of soles and burning of
following allogeneic stem cell transplantation palms), chills, dizziness, encephalitis, generalized ache,
Limitations of use: The usefulness of antithymocyte glob- headache, lethargy, seizure
ulin (equine) has not be demonstrated in patients with Dermatologic: Dermatological reaction (wheal/flare), dia-
aplastic anemia who. are suitable candidates for trans- phoresis, night sweats, pruritus, skin rash, urticaria
plantation or in aplastic anemia secondary to neoplastic Gastrointestinal: Diarrhea, nausea, stomatitis, vomiting
disease, storage disease, myelofibrosis, Fanconi syn- Genitourinary: Proteinuria
drome, or in patients with known prior treatment with Hematologic & oncologic: Leukopenia, lymphadenopathy,
myelotoxic agents or radiation therapy. thrombocytopenia
Pregnancy Considerations Hepatic: Abnormal hepatic function tests, hepatospleno-
Adverse events were observed in some animal reproduc- megaly
tion studies. Woman eo Hypersensitivity: Anaphylaxis, serum sickness
Infection: Viral infection
The Transplant Pregnancy Registry International (TPR) is Local: Injection site reaction (pain, redness, swelling)
a registry that follows pregnancies that occur in maternal Neuromuscular & skeletal: Arthralgia, back pain, joint stiff-
transplant recipients or those fathered by male transplant
ness, myalgia
recipients. The TPR encourages reporting of pregnancies
Ophthalmic: Periorbital edema
following solid organ transplant by contacting them at Renal: Renal function test abnormality
1-877-955-6877 or https://www.transplantpregnancy-
Respiratory: Dyspnea, pleural effusion, respiratory dis-
registry.org.
tress
Breastfeeding Considerations It is not known if antith- Miscellaneous: Fever
ymocyte globulin (equine) is excreted into breast milk. Due
Rare but important or life-threatening: Abdominal pain,
to the potential for serious adverse reactions in the nursing
acute renal failure, anaphylactoid reaction, anemia,
infant, the manufacturer recommends a decision be made
apnea, confusion, cough, deep vein thrombosis, disori-
to discontinue nursing or to discontinue the drug, taking
entation, dizziness, eosinophilia, epigastric pain, epis-
into account the importance of treatment to the mother.
taxis, erythema, flank pain, gastrointestinal
Contraindications History of systemic reaction (eg, ana-
hemorrhage, gastrointestinal perforation, granulocytope-
phylactic reaction) to prior administration of antithymocyte
nia, hemolysis, hemolytic anemia, herpes simplex infec-
globulin or any other equine gamma globulin preparation
tion (reactivation), hiccups, hyperglycemia, infection,
Warnings/Precautions [US Boxed Warning]: Antithy-
involuntary body movements, laryngospasm, malaise,
mocyte globulins may cause anaphylaxis when
muscle rigidity, neutropenia, pancytopenia, paresthesia,
injected intravenously. Although antithymocyte glob-
pulmonary edema, pure red cell aplasia, renal artery
ulin (equine) is processed to reduce the level of anti-
thrombosis, sore mouth, sore throat, tachycardia, throm-
bodies that will react to non-T cells, health care
bosis of vein (iliac), toxic epidermal necrolysis, tremor,
providers should be prepared for the potential risk
vasculitis, viral hepatitis, weakness, wound dehiscence
of anaphylaxis and monitor for signs/symptoms dur-
ing infusion. Hypersensitivity and anaphylactic reactions Drug Interactions
may occur; discontinue for symptoms of anaphylaxis; Metabolism/Transport Effects None known.
immediate treatment (including epinephrine 1 mg/mL) Avoid Concomitant Use
should be available. Systemic reaction (rash, dyspnea, Avoid concomitant use of Antithymocyte Globulin
hypotension, tachycardia, or anaphylaxis) precludes fur- (Equine) with any of the following: BCG (\ntravesical);
ther administration of antithymocyte globulin (equine; Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac-
ATG). Respiratory distress, hypotension, or pain (chest, cines (Live)
flank, or back) may indicate an anaphylactoid/anaphylac- Increased Effect/Toxicity
tic reaction. Serious immune-mediated reactions have Antithymocyte Globulin (Equine) may increase the lev-
been reported (rare), including anaphylaxis, infusion reac- els/effects of: Baricitinib; Belatacept; Fingolimod; Leflu-
tions, and serum sickness. Skin testing is recommended nomide; Natalizumab; Tofacitinib; Vaccines (Live)
ANTITHYMOCYTE GLOBULIN (EQUINE)

The levels/effects of Antithymocyte Globulin (Equine) central vein. Any severe systemic reaction to the skin test,
may be increased by: Denosumab; Ocrelizumab; Pime- such as generalized rash, tachycardia, dyspnea, hypoten-
crolimus; Roflumilast; Tacrolimus (Topical); Trastuzumab sion, or anaphylaxis, should preclude further therapy.
Decreased Effect Epinephrine and resuscitative equipment should be
Antithymocyte Globulin (Equine) may decrease the lev- nearby. Patient may need to be pretreated with an anti-
els/effects of: BCG (\ntravesical); Coccidioides immitis pyretic, antihistamine, and/or corticosteroid. Mild itching
Skin Test; Nivolumab; Pidotimod; Sipuleucel-T; Tertomo- and erythema can be treated with antihistamines.
tide; Vaccines (Inactivated); Vaccines (Live) Monitoring Parameters Lymphocyte profile; CBC with
differential and platelet count, vital signs during adminis-
The levels/effects of Antithymocyte Globulin (Equine) tration, liver enzymes, renal function test; hypersensitivity
may be decreased by: Echinacea reaction; signs and symptoms of infection
Storage/Stability Store ampules at 2°C to 8°C (36°F to Dosage Forms Excipient information presented when
46°F). Do not freeze. Do not shake. Solutions diluted for available (limited, particularly for generics); consult spe-
infusion NS, D5‘/4NS, or D51/2NS to a concentration of up cific product labeling.
to 4 mg/mL are stable for 24 hours (including infusion Injectable, Intravenous:
time) under refrigeration. Allow infusion solution to reach Atgam: 50 mg/mL (5 mL) [thimerosal free]
room temperature prior to administration.
Mechanism of Action Immunosuppressant involved in @ Anti-Thymocyte Globulin (Equine) see Antithymocyte
the elimination of antigen-reactive T lymphocytes (killer Globulin (Equine) on page 163
cells) in peripheral blood or alteration in the function of T-
lymphocytes, which are involved in humoral immunity and
partly in cell-mediated immunity; induces complete or
Antithymocyte Globulin (Rabbit)
(an te THY moe site GLOB yu lin RAB bit)
partial hematologic response in aplastic anemia
Pharmacodynamics/Kinetics (Adult data unless Medication Safety Issues
noted) Sound-alike/look-alike issues:
Distribution: Poor into lymphoid tissues; binds to circulat- Antithymocyte globulin rabbit (Thymoglobulin) may be
ing lymphocytes, granulocytes, platelets, bone marrow confused with antithymocyte globulin equine (Atgam)
cells Brand Names: US Thymoglobulin
Half-life elimination: 5.7 + 3 days Brand Names: Canada Thymoglobulin
Excretion: Urine (~1%) Therapeutic Category Immunosuppressant Agent
Dosing Generic Availability (US) No
Pediatric Use Prophylaxis for and treatment of acute rejection of
Test dose: While a skin test is recommended prior to renal transplant; used in conjunction with concomitant
administration of the initial dose, anaphylaxis may still immunosuppression (FDA approved in pediatric patients
occur in patients who display a negative skin test. [age not specified] and adults); has also been used for
Consider testing initially with an epicutaneous prick of treatment of aplastic anemia; prevention and/or treatment
undiluted antithymocyte globulin (ATG); if no wheal in of acute rejection after bone marrow, heart/lung, liver,
10 minutes, then use 0.02 mL intradermally of a intestinal, or multivisceral transplantation in conjunction
1 mg/mL dilution of ATG in normal saline along with a with other immunosuppressive agents
separate saline control of 0.02 mL; observe in 10 Pregnancy Considerations
minutes. A positive skin reaction consists of a wheal Animal reproduction studies have not been conducted.
with the initial prick test (undiluted) or 23 mm in diam- Females of reproductive potential should use effective
eter larger than the saline control with the diluted intra- contraception during and for at least 3 months following
dermal test. A positive skin test is suggestive of an treatment.
increased risk for systemic allergic reactions with an
infusion, although anaphylaxis may occur in patients The Transplant Pregnancy Registry International (TPR) is
who display negative skin tests. If ATG treatment is a registry that follows pregnancies that occur in maternal
deemed appropriate following a positive skin test, the transplant recipients or those fathered by male transplant
first infusion should be administered in a controlled recipients. The TPR encourages reporting of pregnancies
environment with intensive life support immediately following solid organ transplant by contacting them at
available. A systemic reaction precludes further admin- 1-877-955-6877 or https://www.transplantpregnancy-
istration of the drug. Note: Consider premedication with registry.org.
an antihistamine, corticosteroids, and/or an antipyretic. Breastfeeding Considerations This product has not
Aplastic anemia, moderate to severe when no HLA- been evaluated in breastfeeding women and it is not
matched sibling donor: known if antithymocyte globulin (rabbit) is present in
Manufacturer's labeling: Children and Adolescents: breast milk. Because other immunoglobulins are present
IV: 10 to 20 mg/kg/dose once daily for 8 to 14 days; in breast milk, the manufacturer recommends that breast-
then if needed, may administer every other day up to feeding be discontinued during antithymocyte globulin
a total of 21 doses in 28 days (rabbit) therapy.
Alternate dosing (in combination with cyclosporine): Contraindications
Limited data available: Children 22 years and Ado- Hypersensitivity (allergy or anaphylaxis) to rabbit proteins
lescents: |V: 40 mg/kg/dose once daily for 4 days or any component of the formulation; active acute or
(Afable 2011; Rosenfeld 1995; Scheinberg 2009; chronic infection which contraindicate additional immu-
Scheinberg 2011) nosuppression
Renal transplantation rejection, treatment: Children Documentation of allergenic cross-reactivity for drugs in
and Adolescents: IV: 10 to 15 mg/kg/dose once daily this class is limited. However, because of similarities in
for 14 days, then if needed, may administer every chemical structure and/or pharmacologic actions, the
other day up to a total of 21 doses in 28 days possibility of cross-sensitivity cannot be ruled out with
Acute graft-versus-host disease, steroid-resistant, certainty.
treatment: Limited data available: Children and Ado- Warnings/Precautions [US Boxed Warning]: Should
lescents: IV: 30 mg/kg/dose every other day for 6 only be used by physicians experienced in immuno-
doses (MacMillan 2007) or 15 mg/kg/dose twice daily suppressive therapy in transplantation. Maintenance
for 10 doses (MacMillan 2002) immunosuppression may require dosage reduction. Med-
Renal Impairment: Pediatric There are no dosage ical surveillance is required during the infusion. Should be
adjustments provided in the manufacturer's labeling. administered in combination with other immunosuppres-
Hepatic Impairment: Pediatric There are no dosage sants. Antithymocyte globulin (ATG) (rabbit) is available
adjustments provided in the manufacturer’s labeling. (based on region) in different product formulations, ATG-
Thymoglobulin and ATG-Fresenius; the dosing differs
Preparation for Administration IV: Dilute into inverted
bottle of sterile vehicle to ensure that undiluted lympho-
among the formulations. Dosing of antithymocyte globulin
(rabbit) also differs from dosing of other antithymocyte
cyte immune globulin does not contact air. Gently rotate or
globulin products (eg, ATG [equine]); protein compositions
swirl to mix; do not shake. Final concentration should be
and concentrations are different. Use caution to ensure
<4 mg/mL. May be diluted in NS, D5%/4NS, D51/72NS (do
dose prescribed is intended for product being adminis-
not use D5W; low salt concentrations may result in
tered. Initial dose must be administered over at least 6
precipitation).
hours into a high flow vein. Reducing the infusion rate
Administration |V: Infuse dose over at least 4 hours
(and prolonging the administration time) may minimize
through a 0.2 to 1 micron in-line filter. May need to slow
infusion reactions. May pretreat with an antipyretic, anti-
rate of infusion if patient experiences fever or chills during
histamine, and/or corticosteroid.
infusion (Rosenfeld 1995). Allow solution to reach room
temperature prior to infusion. Infusion must be completed Hypersensitivity and fatal anaphylactic reactions have
with 24 hours of preparation. May cause vein irritation been reported. Stop infusion immediately if anaphylactic
(chemical phlebitis) if administered peripherally; infuse reaction occurs. Immediate treatment (including subcuta-
into a vascular shunt, arterial venous fistula, or high-flow neous epinephrine and corticosteroids) should be

164
 ANTITHYMOCYTE GLOBULIN (RABBIT)

available during infusion for management of hypersensi- Mechanism of Action Antithymocyte globulin (rabbit) is a
tivity. Release of cytokines by activated monocytes and polyclonal antibody which appears to cause immunosup-
lymphocytes may lead to cytokine release syndrome pression by acting on T-cell surface antigens and deplet-
(CRS) during infusion; may cause serious cardiopulmo- ing CD4 lymphocytes
nary events (sometimes fatal). Rapid infusion rates have Pharmacodynamics/Kinetics (Adult data unless
been associated with CRS (case reports). Other infusion noted) ‘
reaction symptoms, including flu-like symptoms (fever, Onset of action (T-cell depletion): Within 24 hours (Har-
chills, nausea, muscle/joint pain) may also occur. Local dinger 2006)
infusion site reactions (pain, swelling, skin redness) have Duration: Lymphopenia may persist for up to 1 year
been reported. (Hardinger 2006)
Severe infections (bacterial, fungal, viral and/or protozoal) Half-life elimination: 2 to 3 days
may develop following concomitant use of immunosup- Dosing
pressants with antithymocyte globulin. Reactivation of Pediatric
infections (particularly CMV) and sepsis have been Note: Premedicate with corticosteroids, acetaminophen,
reported. Appropriate antiviral, antibacterial, antiprotozoal, and/or an antihistamine 1 hour prior to infusion to
and/or antifungal prophylaxis is recommended. Monitor reduce the incidence and severity of infusion-related
closely for infection. Immunosuppressants, including reactions. Administer antifungal and antibacterial pro-
antithymocyte globulins may increase the incidence of phylaxis therapy if clinically indicated. For use in solid
malignancies, including lymphoma, post-transplant lym- organ transplantation (ie, kidney), antiviral prophylaxis
phoproliferative disease (PTLD) or other malignancies; is recommended in patients who are CMV-seropositive
may be fatal. Reversible leukopenia, neutropenia, throm- at the time of transplant and for CMV-seronegative
bocytopenia, and lymphopenia may occur. Monitor blood patients scheduled to receive a kidney from a CMV-
counts; leukopenia or thrombocytopenia may require dos- seropositive donor.
age adjustment. Antithymocyte globulin (rabbit) has been Aplastic anemia; refractory: Limited data available:
associated with increased adverse effects when used for Children and Adolescents: IV: 3.5 mg/kg/day once
induction in liver transplantation and should be used daily for 5 days in combination with cyclosporine (Di
cautiously in this population (Boillot 2009). Patients should Bona 1999; Scheinberg 2006; Takahashi 2013);
not be immunized with attenuated live viral vaccines Note: Consistent with observations in adult patients,
during or shortly after treatment; safety of immunization rabbit-antithymocyte globulin is less effective than
following therapy has not been studied. Potentially signifi- horse-antithymocyte globulin when either combined
cant drug-drug interactions may exist, requiring dose or with cyclosporine in children and adolescents for
frequency adjustment, additional monitoring, and/or selec- initial treatment of severe aplastic anemia (Marsh
tion of alternative therapy. 2009; Scheinberg 2011; Yoshimi 2013)
Adverse Reactions Hematopoietic stem cell transplant; graft-versus-
Cardiovascular: Chest pain, edema, hypertension, hypo- host disease (GVHD) prevention: Limited data
tension, peripheral edema, tachycardia available; regimens and protocols variable; refer to
Central nervous system: Anxiety, chills, headache, insom- institutional protocols: Infants, Children, and Adoles-
nia, malaise, pain cents: IV: Usual reported TOTAL dose range: 4.5 to
Dermatologic: Acne vulgaris, diaphoresis, pruritus, 15 mg/kg total divided into 3 to 5 once daily doses
skin rash administered pretransplant; usual regimen is 3 to 4
Endocrine & metabolic: Acidosis, hyperkalemia, hypoka-
doses on consecutive days in combination with che-
lemia, hypophosphatemia
motherapy or radiation (Admiraal 2015; Aversa 2005;
Gastrointestinal: Abdominal pain, anorexia, constipation,
Horn 2006; Kang 2016; Locatelli 2017; Soni 2014;
diarrhea, dyspepsia, gastritis, intestinal candidiasis, nau-
Willemsen 2015). In adolescents 216 years, a lower
sea, vomiting
total dose and timing approach has been successfully
Hematologic & oncologic: Anemia, leukocytosis, leukope-
used: IV: 0.5 mg/kg/day 2 days before transplanta-
nia, malignant neoplasm, thrombocytopenia
tion, 2 mg/kg/day 1 day before transplantation, and
Hypersensitivity: Serum sickness
2 mg/kg/day 1 day after transplantation (total dose:
Infection: Cytomegalovirus disease, herpes simplex infec-
4.5 mg/kg; in addition to standard GVHD prophylaxis)
tion, infection, sepsis
Neuromuscular & skeletal: Arthralgia, back pain, myalgia,
(Walker 2016)
weakness Solid organ transplantation: Note: Doses and timing
Respiratory: Dyspnea, increased cough, pulmonary may vary; refer to institutional specific protocols:
disease Kidney transplantation: \nfant, Children, and Adoles-
Miscellaneous: Drug overdose, fever cents:
Rare but important or life-threatening: Anaphylaxis, blood Induction, prophylaxis: IV: 1.5 mg/kg/dose once
coagulation disorder, cytokine release syndrome, daily for 4 to 10 doses initiated at time of transplant
decreased oxygen saturation, increased liver enzymes, prior to reperfusion of donor kidney; during variable
infusion-related reaction, lymphadenopathy, lymphopro- and dependent on other immunosuppressive regi-
liferative disorder (posttransplant), malignant lymphoma, mens (Khositseth 2005; Li 2010)
proteinuria, solid tumor Acute rejection, treatment: IV: 1.5 mg/kg/dose once
Drug Interactions daily for 7 to 14 days
Metabolism/Transport Effects None known. Heart/lung transplantation: Limited data available:
Avoid Concomitant Use Infant, Children, and Adolescents:
Avoid concomitant use of Antithymocyte Globulin (Rab- Induction, prophylaxis: Reported range: IV: 1 to
bit) with any of the following: BCG (Intravesical); Natali- 2 mg/kg/dose once daily infused over 12 hours
zumab; Pimecrolimus; Tacrolimus (Topical); Vaccines for 5 days; dose dependent on baseline platelet
(Live) count; in trials the following doses were used
Increased Effect/Toxicity based on platelet count (Di Filippo 2003):
Antithymocyte Globulin (Rabbit) may increase the levels/ >150,000/mm‘: IV: 2 mg/kg/dose
effects of: Baricitinib; Belatacept; Fingolimod; Lefluno- 100,000 to 150,000/mmé®: IV: 1.5 mg/kg/dose
mide; Natalizumab; Tofacitinib; Vaccines (Live) 50,000 to <100,000/mm‘: IV: 1 mg/kg/dose
Acute rejection, treatment: IV: 2 mg/kg/dose once
The levels/effects of Antithymocyte Globulin (Rabbit) daily for 5 days (Di Filippo 2003)
may be increased by: Denosumab; Ocrelizumab; Pime- Liver, intestinal, or multivisceral transplant: Limited
crolimus; Roflumilast; Tacrolimus (Topical); Trastuzumab data available: Infants, Children, and Adolescents:
Decreased Effect i Induction, prophylaxis: |V: Total dose of 5 mg/kg
Antithymocyte Globulin (Rabbit) may decrease the lev- divided into separate pre- and post-op doses: 2
els/effects of: BCG (Intravesical); Coccidioides immitis to 3 mg/kg over 6 to 8 hours before allograft
Skin Test; Nivolumab; Pidotimod; Sipuleucel-T; Tertomo- reperfusion, followed by the remainder 2 to
tide; Vaccines (Inactivated); Vaccines (Live) 3 mg/kg over 6 to 8 hours post-operative; used in
The levels/effects of Antithymocyte Globulin (Rabbit) combination with other immunosuppressives
may be decreased by: Echinacea (Bond 2005; Reyes 2005)
Storage/Stability Store intact vial at 2°C to 8°C (36°F to Rejection: 1.5 mg/kg/dose once daily; duration var-
46°F); do not freeze. Protect from light. Reconstituted iable (usually at least 4 to 5 days) based upon
product is stable for up to 24 hours at room temperature; biopsy results (Schmitt 2010; Thangarajah 2013)
however, the prodict contains no preservative and room Renal Impairment: Pediatric There are no dosage
temperature storage is not recommended; the manufac- adjustments provided in the manufacturer's labeling.
turer recommends use immediately after reconstitution Hepatic Impairment: Pediatric There are no dosage
and preparation for infusion in DSW or NS. adjustments provided in the manufacturer's labeling. >
 ANTITHYMOCYTE GLOBULIN (RABBIT)

| Preparation for Administration Parenteral: Allow vials antivenom should be considered early in the course of
to reach room temperature, then reconstitute each vial an envenomation and in patients experiencing local,
with 5 mL SWFI. Rotate vial gently until dissolved; result- regional, or systemic effects refractory to opioids and/or
ing concentration is 5 mg/mL of thymoglobulin. Further benzodiazepines (Brown, 2013). y
dilute dose to a final concentration of 0.5 mg/mL (eg, Breastfeeding Considerations It is not known if anti-
one vial [25 mg] in 50 mL saline or dextrose); in adults, venin (Latrodectus mactans) is excreted in breast milk.
total volume is usually 50 to 500 mL depending on total The manufacturer recommends that caution be exercised
number of vials needed per dose. Mix by gently inverting
when administering antivenin (Latrodectus mactans) to
infusion bag once or twice.
nursing women.
Administration Parenteral: Administer by slow IV infusion
over 6 to 12 hours for the preconditioning/induction dose Warnings/Precautions Carefully review allergies and
or over 6 hours for the initial acute rejection treatment history of exposure to products containing horse serum.
dose; infuse over 4 hours for subsequent doses if first History of atopic sensitivity to horses may increase risk of
dose tolerated. Administer through an in-line filter with immediate sensitivity reactions. Use with caution in
pore size of 0.22 microns via Central line or high flow vein. patients with asthma, hay fever, or urticaria; fatal anaphy-
Premedication with corticosteroids, acetaminophen, and/ laxis has been reported in patients with a history of
or an antihistamine may reduce infusion-related reactions. asthma. All patients require close monitoring in a setting
Monitoring Parameters Platelet count, CBC with differ- where resuscitation can be performed. Allergic reactions
ential, lymphocyte count, vital signs during infusion occur less-frequently than described in initial studies
Test Interactions Potential interference with rabbit anti- (Clark, 2001; Offerman, 2011). One retrospective study
body-based immunoassays and with cross-match or reviewed 163 cases of black widow spider envenomation;
panel-reactive antibody cytotoxicity assays. Has not been 58 patients received antivenin therapy and only 1 case of
shown to interfere with routine clinical laboratory tests anaphylaxis occurred (Clark, 1992). The risk of reaction
which do not use immunoglobulins.
appears to be greatest with bolus administration of undi-
Dosage Forms Excipient information presented when
luted antivenin (Clark, 2001). A skin or conjunctival test
available (limited, particularly for generics); consult spe-
cific product labeling.
may be performed prior to use; however, the utility of skin
Solution Reconstituted, Intravenous: and conjunctival tests to accurately identify patients at risk
Thymoglobulin: 25 mg (1 ea) [contains glycine, mannitol, of early (anaphylactic) or late (serum sickness) hyper-
sodium chloride] sensitivity reactions to horse-derived antivenins has been
questioned (WHO, 2005). Normal horse serum (1:10
@ Antithymocyte Immunoglobulin see Antithymocyte dilution) is included for sensitivity testing. The absence
Globulin (Equine) on page 163 of a skin or conjunctival hypersensitivity reaction does not
@ Antithymocyte Immunoglobulin see Antithymocyte exclude the possibility of anaphylaxis or hypersensitivity
Globulin (Rabbit) on page 164 following antivenin administration. The false-negative rate
@ Antitoxin see Botulism Antitoxin, Heptavalent for skin testing is 10% with similar agents. Conversely,
on page 287 hypersensitivity is not an absolute contraindication in a
Antitumor Necrosis Factor Alpha (Human) see Adali- significantly envenomated patient. A desensitization pro-
mumab on page 59 tocol is available if sensitivity tests are mildly or question-
¢ Anti-VEGF Monoclonal Antibody see Bevacizumab ably positive to reduce risk of immediate severe
on page 273 hypersensitivity reaction. According to the manufacturer,
@ Anti-VEGF rhuMAb see Bevacizumab on page 273 desensitization should be performed when antivenin
administration would be lifesaving; however, the risk of
@ Antivenin see Antivenin (Latrodectus mactans)
anaphylaxis should be weighed against the risks associ-
on page 166
ated with delayed antivenin administration (Rojnuckarin,
Sa Antivenin see Centruroides Immune F(ab’)2 (Equine)
2009). Due to'an increased risk for complications of
on page 407
envenomation, the administration of antivenin may be
o4 Antivenin see Crotalidae Immune F(ab'). (Equine) the preferred initial therapy in patients >60 years of age.
on page 525 Delayed serum sickness, albeit uncommon, may occur 1
@ Antivenin see Crotalidae Polyvalent Immune Fab to 2 weeks following administration, especially when large
(Ovine) on page 526 doses are used (Clark, 2001). Some products may contain
@ Antivenin Black Widow Spider see Antivenin (Latro- thimerosal.
dectus mactans) on page 166 Adverse Reactions
@ Antivenin (Centruroides) Immune F(ab’)2 (Equine) see Dermatologic: Skin rash (rare; associated with hypersen-
Centruroides Immune F(ab’)2 (Equine) on page 407 sitivity reaction)
@ Antivenin (Crotalidae) Immune F(ab’)2 (Equine) see Hypersensitivity: Anaphylaxis, hypersensitivity reaction,
Crotalidae Immune F(ab')2 (Equine) on page 525 serum sickness
Sa Antivenin (Crotalidae) Polyvalent, FAB (Ovine) see Neuromuscular & skeletal: Muscle cramps
Crotalidae Polyvalent Immune Fab (Ovine) on page 526 Drug Interactions
Metabolism/Transport Effects None known.
Avoid Concomitant Use There are no known interac-
Antivenin (Latrodectus mactans)
(an tee VEN in lak tro DUK tus MAK tans) tions where it is recommended to avoid concomitant use.
Increased Effect/Toxicity There are no known signifi-
Therapeutic Category Antivenin cant interactions involving an increase in effect.
Generic Availability (US) Yes Decreased Effect There are no known significant inter-
Use Treatment of patients with symptoms (eg, cramping, actions involving a decrease in effect.
intractable pain, weaknesss, tremor, restless, anxious,
Storage/Stability Refrigerate at 2°C to 8°C (36°F to
convulsions, delirium, cold skin) refractory to supportive
46°F). Do not freeze.
measures due to Latrodectus mactans (black widow spi-
der) envenomation (FDA approved in children and adults); Mechanism of Action Neutralizes the venom of Latro-
has also been used for treatment of patients with symp- dectus mactans (black widow spiders), but may also be
toms (eg, cramping, intractable pain, hypertension) refrac- effective following envenomation by other Latrodectus
tory to supportive measures due to other Latrodectus spp species (including L. bishopi, L. geometricus, L. hesperus,
(including L. bishopi, L. geometricus, L. hesperus, and L. and L. variolus) (Clark, 2001; Isbister, 2003).
variolus) envenomation; Note: The morbidity associated Pharmacodynamics/Kinetics (Adult data unless
with Latrodectus envenomation is high, but mortality is noted) Onset of action: Within 30 minutes; symptoms of
low; therefore, the antivenin should not be used unless envenomation usually subside after 1-3 hours
necessary. Dosing
Pregnancy Risk Factor C Pediatric
Pregnancy Considerations Animal reproduction studies Note: The initial dose of antivenin should be adminis-
have not been conducted. Use during pregnancy (second
tered as soon as possible for prompt relief of symp-
and third trimester) has been described in case reports; all
patients delivered healthy infants (Handel, 1994; Russell,
toms. Delayed antivenin administration may still be
1979; Sherman, 2000). In general, medications used as effective in treating patients with prolonged or refrac-
antidotes should take into consideration the health and tory symptoms resulting from black widow spider bites;
prognosis of the mother; antidotes should be administered a case report describes use of antivenin administration
to pregnant women if there is a clear indication for use and up to 90 hours after bite (O'Malley 1999); however,
should not be withheld because of fears of teratogenicity delayed administration may decrease effectiveness
(Bailey, 2003). Treatment of a pregnant patient with (Edberg 2009).

166
 ANTIVENIN (LATRODECTUS MACTANS)

Sensitivity testing: Infants, Children, and Adoles- conjunctival sac; a positive reaction, if present, will
cents: Skin testing may identify allergic individuals, generally occur within 10 minutes.
but the lack ofan initial reaction does not eliminate the Antivenin for desensitization: SubQ: Administer the anti-
possibility of a hypersensitivity reaction; therefore, venin solution (See Dosing: Pediatric for appropriate
always be prepared to treat an unanticipated hyper- concentration) via subQ injection. Allow 15 to 30 minutes
sensitivity reaction. Intradermal skin test or conjunc- between injections; proceed with the next dose only if a
tival test may be performed prior to antivenin reaction has NOT occurred following the previous dose.
administration: If a reaction occurs, apply a tourniquet proximal to the
Skin test: Intradermal: Up to 0.02 mL of a 1:10 dilution injection site and administer epinephrine (1 mg/mL con-
of normal horse serum (provided in kit) in NS; centration) SubQ or IV proximal to the tourniquet or into
evaluate after 10 minutes against a control test another extremity. Wait at least 30 minutes prior to
(intradermal injection of 0.02 mL NS). Note: Positive continuing the desensitization procedure. If no reaction
reaction consists of an urticarial wheal surrounded occurred after administration of 0.5 mL of antivenin
by a zone of erythema. (undiluted), then may consider administering dose at
Conjunctival test: Instill 1 drop of 1:100 dilution of 15 minute intervals.
normal horse serum into conjunctival sac; a positive Monitoring Parameters Vital signs; hypersensitivity
reaction is indicated by itching of the eye and/or reactions; serum sickness (for 2 to 3 weeks following
reddening of conjunctiva, usually occurring within administration); worsening of symptoms due to enveno-
10 minutes mation
Desensitization: \Infants, Children, and Adolescents: Additional Information The venom of the black widow
In separate vials or syringes, prepare 1:10 and 1:100 spider is a neurotoxin that causes release of a presynaptic
dilutions of antivenin in NS: neurotransmitter. Within 1 hour of the bite, the clinical
SubQ: Inject 0.1 mL, followed by 0.2 mL and 0.5 mL of effects of black widow spider envenomation (BWSE)
a 1:100 dilution at 15- to 30-minute intervals. During include sharp pain, muscle spasm, weakness, tremor,
desensitization procedure, proceed with the next severe abdominal pain with rigidity, hypertension, respira-
dose only if a reaction has not occurred following tory distress, diaphoresis, and facial swelling. Priapism
the previous dose. Repeat procedure with a 1:10 has been reported in pediatric patients following BWSE
dilution of antivenin; and then with undiluted anti- (Hoover 2004; Quan 2009).
venin. If no reaction has occurred following admin- Dosage Forms Excipient information presented when
istration of 0.5 mL of undiluted antivenin, continue available (limited, particularly for generics); consult spe-
the dose at 15-minute intervals until the entire dose cific product labeling.
has been administered. Kit, Injection:
If a reaction occurs, apply a tourniquet proximal to Generic: 6000 Antivenin units
the injection site and administer epinephrine
(1 mg/mL) SubQ or IV proximal to the tourniquet Sd Antivenin Scorpion see Centruroides Immune F(ab’).
or into another extremity. Wait at least 30 minutes, (Equine) on page 407
then administer another antivenin injection at the ¢ Antivenom see Antivenin (Latrodectus mactans)
previous dilution which did not evoke a reaction. on page 166
Latrodectus mactans (black widow spider) enveno- Sa Antivenom see Centruroides Immune F(ab’)s (Equine)
mation; other Latrodectus spp envenomation on page 407
(Clark 2001): Infants, Children, and Adolescents:
.4 Antivenom see Crotalidae Immune F(ab’). (Equine)
Limited data in infants (Monte 2011; Nordt 2012):
Limited data available for some types of envenoma- on page 525
tions. Note: If a positive reaction to a skin or con- Sa Antivenom see Crotalidae Polyvalent Immune Fab
junctival test occurs and antivenin therapy is (Ovine) on page 526
necessary, pretreat the patient with intravenous Sd Antivenom Black Widow Spider see Antivenin (Latro-
diphenhydramine and an H2-blocker while having a dectus mactans) on page 166
syringe of epinephrine (1 mg/mL) at the bedside: Sd Antivenom (Centruroides) Immune F(ab’). (Equine)
Infants and Children <12 years: IM; IV (preferred): see Centruroides Immune F(ab’)2 (Equine) on page 407
One vial (2.5 mL); a second dose may be needed in
Sd Antivenom (Crotalidae) Immune F(ab’)2 (Equine) see
some cases; more than 1 to 2 vials are rarely
required Crotalidae Immune F(ab’) (Equine) on page 525
Children 212 years and Adolescents: IM, IV: One vial Sd Antivenom (Crotalidae) Polyvalent, FAB (Ovine) see
(2.5 mL); a second dose may be needed in some Crotalidae Polyvalent Immune Fab (Ovine) on page 526
cases; more than 1 to 2 vials are rarely required ® Antivenom Scorpion see Centruroides Immune F(ab’)2
Renal, Impairment: Pediatric There are no dosage (Equine) on page 407
adjustments provided in manufacturer's labeling. Antivert see Meclizine on page 1285
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in manufacturer’s labeling. Antizol see Fomepizole on page 913
Preparation for Administration Parenteral: Reconsti- Anucort-HC see Hydrocortisone (Topical) on page 1013
tute antivenin powder with 2.5 mL of SWFI; do not mix Anu-Med [OTC] see Phenylephrine (Topical)
antivenin powder with the vial of horse serum which is on page 1615
supplied for sensitivity testing. With needle still in rubber
Anusol-HC see Hydrocortisone (Topical) on page 1013
stopper, shake vial to dissolve. Excessive agitation or
shaking of the reconstituted vial may cause foaming, Anuzinc (Can) see Zinc Sulfate on page 2089
which may lead to denaturation of the antivenin. When Anzemet see Dolasetron on page 679
reconstituted, solution can range from a light straw to a APAP (abbreviation is not recommended) see Acet-
dark tea color. aminophen on page 37
IV: Further dilute in 10 to 50 mL NS. Note: IV is the
aPCC see Anti-inhibitor Coagulant Complex (Human)
preferred route in severe cases with shock or in children
on page 167
<12 years of age.
Administration ¢ AP-Hist DM [OTC] see Brompheniramine, Dextrome-
Antivenin for treatment: thorphan, and Phenylephrine on page 297
IM: Administer antivenin into the anterolateral thigh. ¢ Apidra see Insulin Glulisine on page 1094
Apply tourniquet proximal to the injection site if an 6 Apidra SoloStar see Insulin Glulisine on page 1094
adverse reaction occurs.
¢ Aplenzin see BuPROPion on page 320
IV: Infuse antivenin over 15 to 30 minutes (Clark 2001).
IV administration preferred in severe cases, with shock, SO Apo-Abacavir-Lamivudine (Can) see Abacavir and
or in children <12 years of age. There appears to be no Lamivudine on page 26
clinical difference in efficacy between the IM and IV SJ Apo-Acetaminophen (Can) see Acetaminophen
route of administration (Isbister 2008). If an immediate on page 37
hypersensitivity reaction occurs, immediately interrupt o Apo-Alpraz (Can) see ALPRAZolam on page 92
antivenin infusion and provide appropriate supportive
therapy. If administration of antivenin can be resumed Sd Apo-Alpraz TS (Can) see ALPRAZolam on page 92
after control of the reaction, reinitiate at a slower ¢ Apo-Amitriptyline (Can) see Amitriptyline on page 117
infusion rate. ¢ Apo-Amlodipine (Can) see AmLOD!IPine on page 120
Horse serum for sensitivity testing: e Apo-Amoxi-Clav (Can) see Amoxicillin and Clavulanate
Intradermal: Inject the horse serum test solution into (not
on page 127
under) the skin; evaluate after 10 minutes against a
control test (intradermal injection of NS). e Apo-Atomoxetine (Can) see AtoMOXetine on page 203
Ophthalmic: Instill the horse serum test solution (appro- ¢ Apo-Beclomethasone (Can) see Beclomethasone
priate dilution: Pediatric: 1:100; Adult: 1:10) into the (Nasal) on page 250

167
APREPITANT

2 Apo-Bisacodyl [OTC] (Can) see Bisacodyl on page 277 ¢ Apo-Montelukast (Can) see Montelukast on page 1399
o Apo-Cal (Can) see Calcium Carbonate on page 340 Sa Apo-Nevirapine XR (Can) see Nevirapine on page 1442
Sd Apo-Carvedilol (Can) see Carvedilol on page 373 Sf Apo-Nizatidine (Can) see Nizatidine on page 1468
¢ Apo-Cefaclor (Can) see Cefaclor on page 378 5 Apo-Oflox (Can) see Ofloxacin (Systemic)
® Apo-Cefadroxil (Can) see Cefadroxil on page 379 on page 1482
e Apo-Cefprozil (Can) see Cefprozil on page 393 Sd Apo-Ofloxacin (Can) see Ofloxacin (Ophthalmic)
on page 1483
¢ Apo-Cefuroxime (Can) see Cefuroxime on page 402
e Apo-Olanzapine (Can) see OLANZapine on page 1485
¢ Apo-Cephalex (Can) see Cephalexin on page 408
¢ Apo-Olanzapine ODT (Can) see OLANZapine
¢ Apo-Cetirizine [OTC] (Can) see Cetirizine (Systemic)
on page 1485
on page 4117
¢ Apo-Omeprazole (Can) see Omeprazole on page 1493
oa Apo-Chlorthalidone (Can) see Chlorthalidone
on page 432 Sd Apo-Ondansetron (Can) see Ondansetron
on page 1502
Apo-Ciclopirox (Can) see Giscpios on page 443
4 Apo-Oxaprozin (Can) see Oxaprozin on page 1515
Apo-Cimetidine (Can) see Cimetidine on page 446
¢ Apo-Oxycodone CR (Can) see OxyCODONE
Apo-Citalopram (Can) see Citalopram on page 4617 on page 1522
¢
¢¢¢
Apo-Clarithromycin (Can) see Clarithromycin ® APOP [DSC] see Sulfacetamide (Topical) on page 1875
on page 466
¢ Apo-Pen VK (Can) see Penicillin V Potassium
Apo-Clarithromycin XL (Can) see Clarithromycin on page 1587
on page 466
e Apo-Piroxicam (Can) see Piroxicam (Systemic)
Apo-Clindamycin (Can) see Clindamycin (Systemic) on page 1632
on page 471
Apo-Prednisone (Can) see PredniSONE on page 1672
Apo-Clobazam (Can) see CloBAZam on page 478
Apo-Primidone (Can) see Primidone on page 1679
Apo-Clomipramine (Can) see ClomiPRAMINE
on page 485 Apo-Procainamide (Can) see Procainamide
on page 1682
Apo-Cromolyn Nasal Spray [OTC] (Can) see Cromolyn
(Nasal) on page 523 Apo-Propranolol (Can) see Propranolol on page 1702

Apo-Cyclobenzaprine (Can) see Cyclobenzaprine Apo-Quinidine (Can) see QuiNIDine on page 1730
on page 529 Apo-Ranitidine (Can) see RaNITldine on page 1742
Apo-Cyclosporine (Can) see CycloSPORINE (Sys- @ Apo-Rosuvastatin
¢¢¢ (Can) see Rosuvastatin
temic) on page 538 on page 1789
Apo-Diazepam (Can) see DiazePAM on page 622 Apo-Sotalol (Can) see Sotalol on page 1856
Apo-Diltiaz (Can) see DilTIAZem on page 643 Apo-Sulfasalazine (Can) see SulfaSALAzine
on page 1882
Apo-Diltiaz CD (Can) see DilTIAZem on page 643
¢ Apo-Sulin (Can) see Sulindac on page 1884
Apo-Diltiaz SR (Can) see DilTIAZem on page 643
S4 Apo-Terazosin (Can) see Terazosin on page 1912
Apo-Diltiaz TZ (Can) see DilT|AZem on page 643
Sd Apo-Terbinafine (Can) see Terbinafine (Systemic)
Apo-Dimenhydrinate [OTC] (Can) see DimenhyDRI-
on page 1913
NATE on page 646
Sa Apo-Tetra (Can) see Tetracycline (Systemic)
Apo-Docusate Calcium [OTC] (Can) see Docusate
on page 1925
on page 677
¢ Apo-Timop (Can) see Timolol (Ophthalmic)
Apo-Docusate Sodium [OTC] (Can) see Docusate
on page 1953
on page 677
* Apo-Travoprost Z (Can) see Travoprost on page 1990
Apo-Doxazosin (Can) see Doxazosin on page 687
a Apo-Trazodone (Can) see TraZODone on page 1991
Apo-Doxy (Can) see Doxycycline on page 695
Sa Apo-Trazodone D (Can) see TraZODone on page 1991
Apo-Doxy Tabs (Can) see Doxycycline on page 695
S4 Apo-Valganciclovir (Can) see ValGANciclovir
Apo-Entecavir (Can) see Entecavir on page 745
on page 2024
Apo-Escitalopram (Can) see Escitalopram on page 769
e Apo-Voriconazole (Can) see Voriconazole
Apo-Esomeprazole (Can) see Esomeprazole on page 2067
on page 776
® APPG see Penicillin G Procaine on page 1586
Apo-Famciclovir (Can) see Famciclovir on page 825
¢ Apprilon (Can) see Doxycycline on page 695
Apo-Famotidine (Can) see Famotidine on page 826
Apo-Flecainide (Can) see Flecainide on page 865
Aprepitant (ap RE pi tant)
oo
Sa
@
eee
¢ Apo-Flunisolide® (Can) see Flunisolide (Nasal)
¢e¢¢
So
e$¢¢
on page 878 Medication Safety Issues
Apo-Flurazepam (Can) see Flurazepam on page 897 Sound-alike/look-alike issues:
Aprepitant may be confused with fosaprepitant, fosnetu-
Apo-Folic (Can) see Folic Acid on page 912
pitant, netupitant, rolapitant
Apo-Furosemide (Can) see Furosemide on page 929 Aprepitant IV (Cinvanti) may be confused with fosapre-
@ Apo-Hydromorphone
¢e¢¢ (Can) see HYDROmorphone pitant IV (Emend for injection)
on page 1017 Emend (aprepitant) oral capsule/suspension formula-
Sd Apo-Hydroxyzine (Can) see HydrOXYzine tions may be confused with Emend for injection (fosap-
on page 1028 repitant)
Related Information
4 Apo-lpravent Solution (Can) see Ipratropium (Oral
Oral Medications That Should Not Be Crushed or Altered
Inhalation) on page 1122
on page 2217
Sd Apo-Ipravent Sterules (Can) see Ipratropium (Oral Inha- Brand Names: US Cinvanti; Emend; Emend Tri-Pack
lation) on page 1122 Brand Names: Canada Emend
¢ Apo-Ketoconazole (Can) see Ketoconazole (Systemic) Therapeutic Category Antiemetic; Substance P/Neuro-
on page 1152 kinin 1 Receptor Antagonist
o Apo-Ketorolac Ophthalmic (Can) see Ketorolac (Oph- Generic Availability (US) May be product dependent
thalmic) on page 1159 Use Prevention of acute and delayed nausea and vomiting
Sd Apo-Lactulose (Can) see Lactulose on page 1167 associated with initial and repeat courses of moderate and
highly emetogenic cancer chemotherapy (MEC & HEC) (in
° Apo-Lamotrigine (Can) see LamoTRigine
combination with other antiemetic agents) (oral suspen-
on page 1174 sion: FDA approved in ages 26 months and adults, cap-
Apo-Latanoprost (Can) see Latanoprost on page 1184 sules: FDA approved in ages 212 years and adults);
Apo-Linezolid (Can) see Linezolid on page 1225 prevention of postoperative nausea and vomiting (PONV)
(capsules: FDA approved in adults)
Apo-Loperamide (Can) see Loperamide on page 1241
Pregnancy Considerations Adverse events were not
Apo-Loratadine (Can) see Loratadine on page 1247 observed in animal reproduction studies. The injection
¢
e$e¢¢¢
Apo-Mometasone (Can) see Mometasone (Nasal) formulation contains ethanol; use should be avoided in
on page 1392 females who are pregnant.

168
 APREPITANT

Efficacy of hormonal contraceptive may be reduced during myalgia, neutropenic enterocolitis, oily skin, perforated
and for 28 days following the last aprepitant dose; alter- duodenal ulcer, pollakiuria, polyuria, polydipsia, post
native or additional effective methods of contraception nasal drip, skin lesion, skin photosensitivity, sneezing,
should be used both during treatment with fosaprepitant staphylococcal infection, Stevens-Johnson syndrome,
or aprepitant and for at least 1 month following the last stomatitis, throat irritation, tinnitus, toxic epidermal nec-
fosaprepitant/aprepitant dose. rolysis, weight gain
Breastfeeding Considerations It is not known if apre- Drug Interactions
pitant is present in breast milk. According to the manu- Metabolism/Transport Effects Substrate of CYP1A2
facturer, the decision to breastfeed during therapy should (minor), CYP2C19 (minor), CYP3A4 (major); Note:
consider the risk of infant exposure, the benefits of Assignment of Major/Minor substrate status based on
breastfeeding to the infant, and benefits of treatment to clinically relevant drug interaction potential; Inhibits
the mother. The injection formulation contains ethanol. CYP3A4 (moderate); Induces CYP2C9 (weak)
Contraindications Avoid Concomitant Use
Hypersensitivity to aprepitant or any component of the Avoid concomitant use of Aprepitant with any of the
formulation; concurrent use with pimozide following: Astemizole; Asunaprevir; Bosutinib; Budeso-
Canadian labeling: Additional contraindications (not in the nide (Systemic); Cisapride; Cobimetinib; Conivaptan;
US labeling): Concurrent use with astemizole, cisapride, CYP3A4 Inducers (Strong); CYP3A4 Inhibitors (Moder-
or terfenadine. ate); CYP3A4 Inhibitors (Strong); Domperidone; Fliban-
Warnings/Precautions Potentially significant drug-drug serin; Fusidic Acid (Systemic); Idelalisib; Ivabradine;
interactions may exist, requiring dose or frequency adjust- Lomitapide; Naloxegol; Neratinib; Pimozide; Simeprevir;
ment, additional monitoring, and/or selection of alternative Terfenadine; Ulipristal |°
therapy. Use caution with severe hepatic impairment
Increased Effect/Toxicity
(Child-Pugh class C); has not been studied. A clinically
Aprepitant may increase the levels/effects of: Abemaci-
significant decrease in INR or prothrombin time (PT) may
clib; Acalabrutinib; AmLODIPine; Apixaban; ARIPipra-
occur with concurrent warfarin therapy; monitor INR/PT for
zole; Astemizole; Asunaprevir; Avanafil;
2 weeks (particularly at 7 to 10 days) following aprepitant
Benzhydrocodone; Blonanserin; Bosentan; Bosutinib;
administration in each chemotherapy cycle. Hypersensi-
Brexpiprazole; Bromocriptine; Budesonide (Systemic);
tivity reactions, including anaphylactic reactions have
Budesonide (Topical); Cannabis; Cilostazol; Cisapride;
been reported with fosaprepitant or oral aprepitant. Symp-
Cobimetinib; Colchicine; Corticosteroids (Systemic);
toms have included flushing, erythema, dyspnea, hypo-
CYP3A4 Substrates (High risk with Inhibitors); Dapox-
tension and syncope. Monitor for hypersensitivity reaction
etine; Deflazacort; Dofetilide; Domperidone; DOXOrubi-
during and following infusion; if a reaction occurs, discon-
cin (Conventional); Dronabinol; Eletriptan; Eliglustat;
tinue infusion and manage appropriately. Do not re-initiate
Eplerenone; Estrogen Derivatives; Everolimus; Fen-
aprepitant IV if hypersensitivity symptoms occur during the
initial infusion. For prevention of chemotherapy-induced taNYL; Flibanserin; GuanFACINE; Halofantrine;
nausea and vomiting, use is not recommended in pediatric HYDROcodone; Ibrutinib; lfosfamide; lvabradine; lvacaf-
patients weighing <6 kg. Not approved for prevention of tor; Lomitapide; Lurasidone; Manidipine; Mirodenafil;
postoperative nausea and vomiting in children. The IV Naldemedine; Nalfurafine; Naloxegol; Neratinib; NiMO-
aprepitant formulation is an emulsion which also contains Dipine; Olaparib; OxyCODONE; Pimecrolimus; Pimo-
the excipients alcohol, egg lecithin, soybean oil, and zide; Propafenone; Ranolazine; Rupatadine;
sucrose. Ruxolitinib; Salmeterol; SAXagliptin; Sildenafil; Simepre-
Adverse Reactions Adverse reactions may be reported vir; Sirolimus; Sonidegib; Suvorexant; Tamsulosin; Ter-
in combination with other antiemetic agents. As reported fenadine; Tetrahydrocannabinol; Tezacaftor; Ticagrelor;
for highly emetogenic cancer chemotherapy or moderately Tolvaptan; Trabectedin; Udenafil; Ulipristal; Venetoclax;
emetogenic cancer chemotherapy, unless otherwise noted Vilazodone; Vindesine; Zopiclone; Zuclopenthixol
as reported for postoperative nausea and vomiting The levels/effects of Aprepitant may be increased by:
(PONV). Ceritinib; Conivaptan; CYP3A4 Inhibitors (Moderate);
Cardiovascular: Bradycardia (PONV), flushing, hypoten- CYP3A4 Inhibitors (Strong); Fosaprepitant; Fusidic Acid
sion (PONV), palpitations, peripheral edema, syn- (Systemic); Idelalisib; Palbociclib; Stiripentol
cope (PONV)
Decreased Effect
Central nervous system: Abnormal behavior (children &
Aprepitant may decrease the levels/effects of: Codeine;
adolescents), agitation (children & adolescents), anxiety,
Estrogen Derivatives (Contraceptive); PARoxetine; Pro-
dizziness, fatigue (more common in adults), headache
gestins (Contraceptive); TOLBUTamide; Warfarin
(children & adolescents), hypoesthesia (PONV), hypo-
thermia (PONV), malaise, peripheral neuropathy The levels/effects of Aprepitant may be decreased by:
Dermatologic: Alopecia, hyperhidrosis, pruritus, skin rash, Bosentan; CYP3A4 Inducers (Moderate); CYP3A4
urticaria 1 BB Z Inducers (Strong); Dabrafenib; Deferasirox; PARoxetine;
Endocrine & metabolic: Decreased serum albumin Pitolisant; Sarilumab; Siltuximab; St John's Wort; Tocili-
(PONV), decreased serum potassium (PONV), zumab
decreased serum sodium, dehydration, hot flash, hypo- Food Interactions Aprepitant serum concentration may
kalemia, hypovolemia (PONV), increased serum glucose be increased when taken with grapefruit juice. Manage-
(PONV), weight loss ment: Avoid concurrent use.
Gastrointestinal: Abdominal pain, constipation (PONV), Storage/Stability
decreased appetite, diarrhea, dyspepsia, dysgeusia, Injection: Store intact vials at 2°C to 8°C (36°F to 46°F); do
eructation, flatulence, gastritis, gastroesophageal reflux not freeze. Vials may remain at room temperature for up
disease, hiccups, nausea, vomiting, xerostomia to 60 days. When stored at ambient room temperature,
Genitourinary: Proteinuria solutions diluted for infusion in NS are stable for 6 hours
Hematologic & oncologic: Anemia, decreased hemoglobin and solutions diluted for infusion in DSW are stable for 12
(children & adolescents), decreased white blood cell
hours.
count, febrile neutropenia, hematoma (PONV), neutro-
Capsules: Store at room temperature of 20°C to 25°C
penia (more common in children & adolescents), throm-
(68°F to 77°F).
bocytopenia
Oral suspension: Store unopened pouch at 20°C to 25°C
Hepatic: Increased serum alkaline phosphatase,
(68°F to 77°F); excursions permitted between 15°C to
increased serum ALT, increased serum AST, increased
30°C (59°F to 86°F). Store in. the original container. Do
serum bilirubin (PONV) _ #
not open pouch until ready to use. Once prepared, if
Infection: Candidiasis, postoperative infection (PONV)
suspension is not used immediately, store refrigerated
Local: Induration at injection site, inflammation at injection
(between [2°C to 8°C/36°F to 46°F]) for up to 72 hours.
site, infusion site reaction ;
When ready to use, the mixture may be kept at room
Neuromuscular & skeletal: Musculoskeletal pain,
temperature (between [20°C to 25°C/68°F to 77°F]) for
weakness
Renal: Increased blood urea nitrogen up to 3 hours.
Respiratory: Cough, dyspnea, hypoxia (PONV), orophar- Mechanism of Action Aprepitant prevents acute and
yngeal pain, pharyngitis, respiratory depression (PONV) delayed vomiting by inhibiting the substance P/neurokinin
Miscellaneous: Wound dehiscence (PONV) 1 (NK) receptor; augments the antiemetic activity of
Rare but important or life-threatening: Abdominal disten- 5-HT3 receptor antagonists and corticosteroids to inhibit
tion, abnormal dreams, abnormal gait, acne vulgaris, acute and delayed phases of chemotherapy-induced eme-
anaphylaxis, angioedema, anxiety, cardiac disease, sis.
chest discomfort, chills, cognitive dysfunction, conjuncti- Pharmacodynamics/Kinetics (Adult data unless
vitis, decreased neutrophils, disorientation, drowsiness, noted)
dysfunction, dySuria, edema, epigastric distress, eupho- Distribution: Vg: IV, Oral: ~70 L; crosses the blood-brain
ria, hematuria, hyperglycemia, hypersensitivity reaction, barrier
hyponatremia, increased thirst, lethargy, muscle cramps, Protein binding: IV: >99%; Oral: >95%
 APREPITANT

q Metabolism: Extensively hepatic via CYP3A4 (major);

CYP1A2 and CYP2C19 (minor); forms 7 metabolites
dose is not to be administered immediately, then the oral
syringe may be kept under refrigeration for up to 72 hours.
(weakly active) Administration Oral:
Bioavailability: ~60% to 65% CINV: May be administered without regard to food, 1 hour
Half-life elimination: Terminal: IV, Oral: ~9 to 13 hours prior to chemotherapy or in the morning (ie, if no chemo-
Time to peak, plasma: Pediatric: Capsule: ~4 hours; therapy is administered on days 2 and 3)
Suspension ~6 hours; Adults: 40 mg: ~3 hours; Capsule: Swallow whole
125 mg followed by 80 mg for 2 days: ~4 hours Oral suspension: Remove cap from oral syringe. Slowly
Excretion: Primarily via metabolism administer suspension along the inner cheek.
Pharmacodynamics/Kinetics: Additional Consider- PONV: Adults: Administer capsule whole within 3 hours
ations prior to induction of anesthesia; follow health care pro-
Renal function impairment: Following a single oral apre- vider instructions about food/drink restrictions prior to
pitant 240 mg dose in patients with severe renal impair- surgery.
ment (CrCl <30 mL/minute) and end stage renal disease Dosage Forms Excipient information presented when
requiring hemodialysis, the AUC of total aprepitant available (limited, particularly for generics); consult spe-
(unbound and protein bound) decreased by 21% and cific product labeling.
Cmax decreased by 32% compared with healthy subjects. Capsule, Oral:
In patients with ESRD undergoing hemodialysis, the Emend: 40 mg, 80 mg, 125.mg
AUC of total aprepitant decreased by 42% and Cmax Emend.Tri-Rack: 80 mg & 125 mg
decreased by 32%. Hemodialysis conducted 4 or 48 Generic: 40 mg, 80 mg, 125 mg, 80 mg & 125 mg
hours after aprepitant dosing had no significant impact Emulsion, Intravenous:
on aprepitant pharmacokinetics. Cinvanti: 130 mg/18 mL (18 mL) [contains alcohol, usp,
Dosing egg phospholipids (egg lecithin), soybean oil]
Pediatric Suspension Reconstituted, Oral:
Note: Concentration of oral suspension may vary (com- Emend: 125 mg (1 ea)
mercially available or extemporaneous compounded); Extemporaneous Preparations A suspension for oral
use caution. administration is commercially available.
Chemotherapy-induced nausea and vomiting . A 20 mg/mL oral aprepitant suspension may be prepared
(CINV), prevention; highly and moderately emeto- with capsules and a 1:1 combination of Ora-Sweet and
genic chemotherapy: Note: Use in combination with Ora-Plus (or Ora-Blend). Empty the contents of four
5-HT3 antagonist antiemetic with or without dexame- 125 mg capsules into a mortar and reduce to a fine
thasone (refer to specific protocols or guidelines powder (process will take 10-15 minutes). Add small
[eg, POGO)). portions of vehicle and mix to a uniform paste. Add
Infants 26 months weighing at least 6 kg, and Chil- sufficient vehicle to form a liquid; transfer to a graduated
dren <12 years weighing <30 kg: Oral: Oral suspen- cylinder, rinse mortar with vehicle, and add quantity of
sion: 3 mg/kg (maximum dose: 125 mg/dose) 1 hour vehicle sufficient to make 25 mL. Label "shake well" and
prior to chemotherapy on day 1, then 2 mg/kg "refrigerate". Stable for 90 days refrigerated.
Dupuis LL, Lingertat-Walsh K, and Walker SE, "Stability of an Extem-
(maximum dose: 80 mg/dose) once daily on days
poraneous Oral Liquid Aprepitant Formulation," Support Care Can-
2 and 3 cer, 2009, 17(6):701-6.
Children <12 years weighing at least 30 kg, Children
212 years, and Adolescents: Oral: Capsules, Oral @ Apresoline see HydrALAZINE on page 997
suspension: 125 mg 1 hour prior to chemotherapy @ Apriso see Mesalamine on page 1313
on day 1, followed by 80 mg once daily on days 2 @ Aprodine [OTC] see Triprolidine and Pseudoephedrine
and 3
on page 2012
Dose rounding for commercially available oral sus-
pension (25 mg/mL): @ Aptensio XR see Methylphenidate on page 1343
If calculated dose is <25 mg, may round dose to @ Aptiom see Eslicarbazepine on page 772
nearest 2.5 mg (0.1 mL) @ Aptivus see Tipranavir on page 1956
If calculated dose is >25 mg, may round dose to
@ Aquacort (Can) see Hydrocortisone (Topical)
nearest 5 mg (0.2 mL)
on page 1013
Renal Impairment: Pediatric
All patients: @ AquaMEPHYTON (Can) see Phytonadione
Mild, moderate, or severe impairment: No dosage on page 1622
adjustment necessary. @ Aquanil HC [OTC] see Hydrocortisone (Topical)
Dialysis-dependent end-stage renal disease (ESRD): on page 1013
No dosage adjustment necessary. @ Aquasol A see Vitamin A on page 2063
Hepatic Impairment: Pediatric
@ Aqueous Crystalline Penicillin G see Penicillin G
All patients:
(Parenteral/Aqueous) on page 1583
Mild to moderate impairment (Child-Pugh class A or B):
No dosage adjustment necessary. @ Aqueous Procaine Penicillin G see Penicillin G Pro-
Severe impairment (Child-Pugh class C): Use with caine on page 1586
caution; no data available; may require additional @ Aqueous Selenium [OTC] see Selenium on page 18117
monitoring for adverse reactions @ Aqueous Vitamin D [OTC] see Cholecalciferol
Preparation for Administration on page 434
Oral Suspension: Suspension kit (aprepitant 25 mg/mL):
@ Aqueous Vitamin E [OTC] see Vitamin E (Systemic)
Kit contains a 1 mL and a 5 mL oral syringe, one syringe
on page 2065
cap, one mixing cup, and the aprepitant 125 mg pouch.
Fill mixing cup with room temperature drinking water; @ Ara-C see Cytarabine (Conventional) on page 549
using the 5 mL oral syringe, measure 4.6 mL of water @ Arabinosylcytosine see Cytarabine (Conventional)
from the mixing cup and discard unused water from cup. on page 549
Make sure the oral syringe contains no air and add the 4.6 @ Aralen [DSC] see Chloroquine on page 424
mL of water back to the empty cup. Shake content of
@ Aralen (Can) see Chloroquine on page 424
aprepitant pouch to bottom of pouch and pour entire
contents of pouch into mixing cup, add lid and snap shut. @ Aranesp (Can) see Darbepoetin Alfa on page 570
Mix suspension by gently swirling 20 times, then gently @ Aranesp (Albumin Free) see Darbepoetin Alfa
invert cup 5 times (to avoid foaming, do not shake vigo- on page 570
rously). The resulting 25 mg/mL suspension will be cloudy @ Arbinoxa [DSC] see Carbinoxamine on page 366
pink to light pink. If clumps are present, repeat mixing by
@ Arcalyst see Rilonacept on page 1766
gently swirling 20 times and gently inverting 5 times. If
foam is present, wait for foam to disappear. @ Aredia (Can) see Pamidronate on page 1542

Measure calculated dose using the appropriate sized oral

syringe: Use 1 mL syringe if dose is <1 mL ($25 mg) and Argatroban (ar GA troh ban)
round to the nearest 0.1 mL (2.5 mg), and use the 5 mL
oral syringe if dose is >1 mL (>25 mg) and round dose to
Medication Safety Issues
Sound-alike/look-alike issues:
the nearest 0.2 mL (5 mg) (see Dosing: Pediatric). Make
sure all air is removed from oral syringe and that it Argatroban may be confused with Aggrastat, Orgaran
High alert medication:
contains the prescribed dose. Place cap on syringe until
it clicks. The Institute for Safe Medication Practices (ISMP)
includes this medication among its list of drugs which
Discard mixing cup and any suspension remaining in cup. have a heightened risk of causing significant patient
Dose may be kept at room temperature for up to 3 hours. If harm when used in error.

170
 ARGATROBAN

Therapeutic Category Anticoagulant, Thrombin Inhibitor Desirudin; lbritumomab Tiuxetan; Nintedanib; Obinutu-
Generic Availability (US) Yes zumab; Omacetaxine; Rivaroxaban; Vitamin K Antago-
Use Prophylaxis or treatment of thrombosis in patients with nists
heparin-induced thrombocytopenia (HIT) (FDA approved The levels/effects of Argatroban may be increased by:
in adults); anticoagulant for percutaneous coronary inter- Agents with Antiplatelet Properties; Apixaban; Bromper-
vention (PCI) in patients who have or are at risk for idol; Dabigatran Etexilate; Dasatinib; Edoxaban; Hemin;
thrombosis-associated HIT (FDA approved in adults). Herbs (Anticoagulant/Antiplatelet Properties); Ibrutinib;
Has also been used in pediatric patients with HIT requiring
Limaprost; MiFEPRIStone; Nonsteroidal Anti-Inflamma-
anticoagulation (eg, procedural anticoagulation including tory Agents; Omega-3 Fatty Acids; Pentosan Polysulfate
cardiac catheterization, extracorporeal membrane oxy-
Sodium; Prostacyclin Analogues; Salicylates; Sugam-
genation [ECMO], and hemodialysis/hemofiltration) madex; Sulodexide; Thrombolytic Agents; Tibolone;
Pregnancy Considerations Information related to arga- Tipranavir; Urokinase; Vitamin’ E (Systemic); Vorapaxar
troban in pregnancy is limited. Use of parenteral direct Decreased Effect
thrombin inhibitors in pregnancy should be limited to those The levels/effects of Argatroban may be decreased by:
women who have severe allergic reactions to heparin, Estrogen Derivatives; Oritavancin; Progestins; Telavan-
including heparin-induced thrombocytopenia, and who cin
cannot receive danaparoid (Guyatt 2012). Storage/Stability
Breastfeeding Considerations It is not known if arga- Vials, 2.5 mL (100 mg/mL) concentrate: Prior to use, store
troban is present in breast milk. According to the manu- vial in original carton at 20°C to 25°C (68°F to 77°F);
facturer, the decision to continue or discontinue excursions permitted to 15°C to 30°C (59°F to 86°F). Do
breastfeeding during therapy should take into account not freeze. Protect from light. The prepared solution,
the risk of infant exposure, the benefits of breastfeeding diluted in D5W, LR, or NS, is stable for 24 hours at
to the infant, and benefits of treatment to the mother. 20°C to 25°C (68°F to 77°F) in ambient indoor light. Do
Contraindications Hypersensitivity to argatroban or any not expose prepared solutions to direct sunlight. Pre-
component of the formulation; major bleeding pared solutions that are protected from light and kept at
Warnings/Precautions The most common complication 20°C to 25°C (68°F to 77°F) or under refrigeration at 2°C
is bleeding and can occur at any site in the body. Use to 8°C (36°F to 46°F) are stable for up to 96 hours.
extreme caution in patients with hematologic conditions Premixed vials (50 mL or 125 mL) and single-use bags for
associated with increased bleeding (eg, congenital or infusion (1 mg/mL): Store at 20°C to 25°C (68°F to
acquired bleeding disorders, Gl lesions); recent puncture 77°F). Do not refrigerate or freeze. Protect from light.
of large vessels or organ biopsy; spinal anesthesia or Mechanism of Action A direct, highly-selective thrombin
immediately following lumbar puncture; recent CVA, inhibitor. Reversibly binds to the active thrombin site of
stroke, intracerebral surgery, or other neuraxial procedure; free and clot-associated thrombin. Inhibits fibrin formation;
severe hypertension; renal impairment; recent major sur- activation of coagulation factors V, VIII, and XIII; activation
gery; recent major bleeding (intracranial, Gl, intraocular, or of protein C; and platelet aggregation.
pulmonary). Monitor for signs and symptoms of bleeding. Pharmacodynamics/Kinetics (Adult data unless
Airway, skin, and generalized hypersensitivity reactions noted)
have been reported. Use caution in critically-ill patients;
Onset of action: Immediate
reduced clearance may require dosage reduction. Use Distribution: 174 mL/kg
with caution in patients with hepatic impairment; dosage
Protein binding: Albumin: 20%; alpha,-acid glycopro-
reduction necessary; may require >4 hours to achieve full tein: 34%
reversal of anticoagulant effects. Avoid use during PCI in Metabolism: Hepatic via hydroxylation and aromatization
patients with clinically significant hepatic impairment or (major route). Metabolism via CYP3A4/5 (minor route) to
elevations of ALT/AST 23 times ULN (has not been four metabolites. Unchanged argatroban is the major
studied). Potentially significant interactions may exist, plasma component. Plasma concentration of metabolite
requiring dose or frequency adjustment, additional mon- M1 is 0% to 20% of the parent drug and is three- to five-
itoring, and/or selection of alternative therapy. fold weaker.
Warnings: Additional Pediatric Considerations The Half-life elimination: 39 to 51 minutes; Hepatic impairment:
appropriate goals of anticoagulation and duration of treat- 181 minutes
ment in pediatric patients have not been established. In Time to peak: Steady-state: 1 to 3 hours
pediatric trials, hypokalemia and abdominal pain were Excretion: Feces (~65%; 14% unchanged); urine (~22%;
reported (Young, 2007). 16% unchanged); low quantities of metabolites M2-4 in
Adverse Reactions As with all anticoagulants, bleeding urine
is the major adverse effect of argatroban. Hemorrhage Clearance:
may occur at virtually any site. Risk is dependent on Pediatric patients (seriously ill): 0.16 L/kg/hour; 50%
multiple variables, including the intensity of anticoagula- lower than healthy adults
tion and patient susceptibility. mie Pediatric patients (seriously ill with elevated bilirubin
Cardiovascular: Angina pectoris, bradycardia, cardiac due to hepatic impairment or cardiac complications;
arrest, chest pain (PCI related), coronary occlusion, n=4): 0.03 L/kg/hour; 80% lower than pediatric
hypotension, ischemic heart disease, myocardial infarc- patients with normal bilirubin
tion (PCI), thrombosis, vasodilation, ventricular tachy- Adult: 0.31 L/kg/hour (5.1 mL/kg/minute); hepatic
cardia impairment: 1.9 mL/kg/minute
Central nervous system: Headache, intracranial hemor- Dosing
rhage, pain Pediatric
Dermatologic: Dermatological reaction (bullous erup- Heparin-induced thrombocytopenia: Limited data
tion, rash) available: Infants and Children $16 years: Note: Titra-
Gastrointestinal: Abdominal pain, diarrhea, gastrointesti- tion of maintenance dose must consider multiple
nal hemorrhage, nausea, vomiting factors including current argatroban dose, current
Genitourinary: Genitourinary tract hemorrhage (including aPTT, target aPTT, and clinical status of the patient.
hematuria) For specific uses, required maintenance dose is
Hematologic & oncologic: Brachial bleeding, decreased highly variable between patients. During the course
hematocrit, decreased hemoglobin, groin bleeding, of treatment, patient's dosing requirements may
minor hemorrhage (CABG related) change as clinical status changes; critically ill patients
Neuromuscular & skeletal: Back pain (PCI related) and patients with hepatic dysfunction require lower
Respiratory: Cough, dyspnea, hemoptysis dose; frequent dosage adjustments may be required
Miscellaneous: Fever in critical patients to maintain desired anticoagulant
Rare but important or life-threatening: Aortic valve steno- activity (Alsoufi 2004; Boshkov 2006; Keegan 2009).
sis, bleeding at injection site (or access site; minor), If argatroban therapy is used concurrently with or
hypersensitivity reaction, local hemorrhage (limb and following FFP or a thrombolytic, some centers
below-the-knee stump), pulmonary edema, retroperito- decrease dose by half (Alsoufi 2004).
neal bleeding Continuous IV infusion:
Drug Interactions Initial dose: 0.75 mcg/kg/minute (Madabushi 2011)
Metabolism/Transpert Effects None known. Maintenance dose: Measure aPTT after 2 hours;
Avoid Concomitant:-Use adjust dose until the steady-state aPTT is 1.5 to
Avoid concomitant use of Argatroban with any of the 3 times the initial baseline value, not exceeding
following: Apixaban; Dabigatran Etexilate; Edoxaban; 100 seconds; adjust in increments of 0.1 to 0.25
Hemin; MiFEPRIStone; Omacetaxine; Rivaroxaban; mcg/kg/minute for normal hepatic function; reduce
Urokinase; Vorapaxar dose in hepatic impairment.
Increased Effect/Toxicity Note: A lower initial infusion rate may be needed in
Argatroban may increase the levels/effects of: Collage- other pediatric patients with reduced clearance of
nase (Systemic); Deferasirox; Deoxycholic Acid; argatroban (eg, patients with heart failure, multiple >
171
ARGATROBAN

organ system failure, severe anasarca, postcar- continuous IV infusion at an initial rate 5-15 mcg/kg/
diac surgery or hepatic impairment). This precau- minute; one case series adjusted the continuous infu-
tion is based on adult studies of patients with these sion dose to maintain target ACT >300 seconds (n=4).
disease states who had reduced argatroban Note: Data is limited to an open-labeled study of a
clearance. mixed population that included six pediatric cardiac
Conversion to oral anticoagulant: Because there catheterization patients and case reports/series (n=4
may be a combined effect on the INR when arga- patients) [Alsoufi, 2004; GlaxoSmithKline Result Sum-
troban is combined with warfarin, loading doses of mary, 2007 (manufacturer unpublished data); Young,
warfarin should not be used. Warfarin therapy 2007]. Further studies are required before these doses
should be started at the expected daily dose. Once can be recommended.
combined INR on warfarin and argatroban is >4, ECMO: Dose not established; data is limited to an open-
stop argatroban. Repeat INR measurement in 4 to labeled study of a mixed population that included one
6 hours; if INR is below therapeutic level, argatro- infant on ECMO, published and submitted abstracts,
ban therapy may be restarted. Repeat procedure and case reports/series (n=16 patients) [Alsoufi, 2004;
daily until desired INR on warfarin alone is GlaxoSmithKline Result Summary, 2007 (manufacturer
obtained. Another option is to use factor X levels unpublished data); Hursting, 2006; Potter, 2007;
to monitor the effect of warfarin anticoagulation. Tcheng, 2004]. Further studies are required before
When factor X level is <0.3, warfarin is considered these doses can be recommended.
therapeutic and at which time argatroban can be The reported argatroban doses used to prime the
discontinued (Alsoufi 2004; Boshkov 2006). ECMO-circuit have varied widely; more recent reports
Renal Impairment: Pediatric “utilize an ECMO priming dose between 30-50 mcg
Mild to severe-impairment: All patients: No dosage based upon patient's clinical status and ACT, followed
adjustment necessary. by a continuous IV infusion at an initial rate of 0.5-2
Dialysis: Dialyzable, ~20% removed over 4 hours dur- mcg/kg/minute; continuous infusion doses were
ing hemodialysis (NCS/SCCM [Frontera 2016}); adjusted to maintain target ACT of at least 200 sec-
removal during hemodialysis and continuous venove- onds; reported ACT target ranges varied from
nous hemofiltration did not alter clinical efficacy when 160-300 seconds or aPTT 2 times initial baseline
used for anticoagulation in renal replacement therapy value. Dosing requirements ranging from 0.1-24
(Tang 2005) mcg/kg/minute have been reported. If patient not
Hepatic Impairment: Pediatric previously anticoagulated on heparin prior to starting
Decreased clearance is seen with hepatic impairment; argatroban, an initial bolus dose may be required.
dose should be reduced. Hemodialysis/Hemofiltration: Dose not established;
Infants, Children, and Adolescents $16 years: Heparin- clinical data limited to case series/reports (Alsoufi,
induced thrombocytopenia; IV continuous infusion: 2004; Hursting, 2006; Young, 2007). Further studies
Initial dose: 0.2 mcg/kg/minute (Young 2011) are required before these doses can be recommended.
Maintenance dose: Measure aPTT after 2 hours; The following doses have been used in limited reports:
adjust dose until the steady-state aPTT is 1.5 to 3 IV continuous infusion: Initial dose: 0.5-2 mcg/kg/
times the initial baseline value, not exceeding 100 minute; infusions were adjusted to maintain target
seconds; adjust in increments of <0.05 mcg/kg/ ACT at least >160 seconds or aPTT >50 seconds;
minute. when reported, ACT target ranges were 160-200
Usual Infusion Concentrations: Pediatric Note: Pre- seconds and aPTT 50-75 seconds. Reported dosing
mixed solutions available. requirements were 0.1-2 mcg/kg/minute. If patient not
IV infusion: 1000 mcg/mL previously anticoagulated on heparin prior to starting
Preparation for Administration lV: argatroban, an initial bolus dose may be required;
Vials for injection, 2.5 mL (1400 mg/mL) concentrate: Dilute initial bolus doses of 65 mcg/kg and 250 mcg/kg have
to a final concentration of 1 mg/mL. Solution may be each been reported.
mixed with NS, D5W, or LR. Do not mix with other Dosage Forms Excipient information presented when
medications prior to dilution. Mix by repeated inversion available (limited, particularly for generics); consult spe-
for 1 minute. A slight but brief haziness may occur upon cific product labeling.
mixing; use of diluent at room temperature is recom- Solution, Intravenous:
mended. Generic: 125 mg/125 mL (125 mL); 250 mg/250 mL (250
Premixed vials for infusion, 50 mL or 125 mL (1 mg/mL): mL); 250 mg/2.5 mL (2.5 mL)
No further dilution is required. Solution, Intravenous [preservative free]:
Generic: 50 mg/50 mL (50 mL); 250 mg/2.5 mL (2.5 mL)
Administration lV: For lV use only. For HIT, administer by
continuous IV infusion. For PCI, administer by IV infusion
and bolus dose over 3 to 5 minutes through a large bore Arginine ar ji neen)
intravenous line.
Monitoring Parameters HIT: Obtain baseline aPTT prior Medication Safety Issues
to start of therapy. Check aPTT 2 hours after start of Administration issues:
therapy and any dosage adjustment. Monitor hemoglobin, The Food and Drug Administration (FDA) has identified
hematocrit, platelets, signs and symptoms of bleeding. several cases of fatal arginine overdose in children and
Test Interactions Argatroban may elevate PT/INR levels has recommended that healthcare professionals
in the absence of warfarin. If warfarin is started, initial PT/ always recheck dosing calculations prior to administra-
INR goals while on argatroban may require modification. tion of arginine. Doses used in children should not
The American College of Chest Physicians suggests exceed usual adult doses.
monitoring chromogenic factor X assay when transitioning Brand Names: US R-Gene 10
from argatroban to warfarin (Garcia, 2012) or overlapping Therapeutic Category Diagnostic Agent, Growth Hor-
administration of warfarin for a minimum of 5 days until mone Function; Metabolic Alkalosis Agent; Urea Cycle
INR is within target range; recheck INR after anticoagulant Disorder (UCD) Treatment Agent
effect of argatroban has dissipated (Guyatt, 2012). Factor Generic Availability (US) No
Xa levels <45% have been associated with INR values >2 Use Diagnostic agent in pituitary function test (stimulant for
after the effects of argatroban have been eliminated the release of growth hormone) (FDA approved in pedia-
(Arpino, 2005). tric patients [age not specified] and adults); has also been
Additional Information Molecular weight: 526.66; arga- used for management of severe, uncompensated, meta-
troban is a synthetic anticoagulant (direct thrombin inhib- bolic alkalosis (pH 27.55) after optimizing therapy with
itor) derived from L-arginine. Increases in aPTT, ACT, PT, sodium or potassium chloride supplements treatment;
INR, and TT occur in a dose-dependent fashion with prevention of necrotizing enterocolitis in neonates; and
increasing doses of argatroban. Adult studies have estab- for treatment/prevention of hyperammonemia associated
lished the use of aPTT for patients with HIT and ACT for with urea cycle disorders
patients with PCI procedures. Therapeutic ranges for PT, Pregnancy Considerations Teratogenic effects were not
INR, and TT have not been identified. observed in animal studies; however, the manufacturer
does not recommend use of arginine during pregnancy.
A reversal agent to argatroban is not available. Should life-
Breastfeeding Considerations Amino acids are present
threatening bleeding occur, discontinue argatroban imme-
in breast milk, the amount following arginine administra-
diately, obtain an aPTT and other coagulation tests, and
tion is not known.
provide symptomatic and supportive care.
Contraindications Hypersensitivity to arginine or any
Infants and Children <16 years: Doses reported in the component of the formulation
literature for infants and children with HIT for procedural Warnings/Precautions Fatal overdose of arginine in
, anticoagulation: pediatric patients has been reported. Exercise extreme
Cardiac Catheterization: Dose not established; the caution when infusing arginine into children. Overdosage
following doses have been used in limited reports: of arginine in children can also result in hyperchloremic
Initial IV bolus dose: 150-250 mcg/kg, followed by metabolic acidosis, cerebral edema, or possibly death.

172
 ARGININE

Severe reactions, including anaphylaxis, have been Weight-directed dosing:

reported; if hypersensitivity occurs, discontinue and insti- Argininosuccinic acid lyase (ASL) or argininosuccinic
tute supportive treatment measures. Arginine metabolism acid synthetase (ASS, Citrullinemia) deficiency: \V:
results in excretion of nitrogen-containing products. Use Loading dose: 600 mg/kg followed by a continuous
with caution in patients with renal impairment; decreased IV infusion of 600 mg/kg/day (Ah Mew 2017; Bat-
excretion may result in an increased amino acid or nitro- shaw 2001; NORD 2012; Summar 2001; UCD Con-
gen burden. Use with caution in patients with electrolyte ference group 2001)
imbalance due to chloride content of product. Carbamyl phosphate synthetase (CPS), ornithine
Irritant with vesicant-like properties. Due to the hyper- transcarbamylase (OTC) or N-acetylglutamate syn-
tonicity of the IV solution, administer via IV infusion only thetase (NAGS) deficiency: |V: Loading dose:
with a patent catheter placed within a patent vein. Extrav- 200 mg/kg followed by a continuous IV infusion of
asation has resulted in burn-like reactions and skin 200 mg/kg/day (Ah Mew 2017; Batshaw 2001;
necrosis requiring surgical intervention. Excessive rates NORD 2012; Summar 2001)
of infusion (eg, <30 minutes) may result in local irritation, Comatose patients: IV: Loading dose: 600 mg/kg
flushing, nausea, or vomiting. followed by a continuous IV infusion of
Warnings: Additional Pediatric Considerations In 250 mg/kg/day (UCD Conference group 2001)
neonates, infants, and children overdosage has resulted Noncomatose patients: IV: Loading dose:
in hyperchloremic metabolic acidosis, cerebral edema, or 200 mg/kg followed by a continuous IV infusion
possibly death; each 1 mEq chloride delivers 1 mEq of 200 mg/kg/day (Batshaw 2001; NORD 2012)
hydrogen; monitor acid base balance closely, particularly Unconfirmed/pending diagnosis: \V: Loading dose:
in neonates. Arginine hydrochloride is metabolized to 600 mg/kg followed ,by a continuous IV infusion of
nitrogen-containing products for excretion; the temporary 600 mg/kg/day (NORD 2012; Summar 2001). If ASS
effect of a high nitrogen load on the kidneys should be and ASL are excluded as diagnostic possibilities,
evaluated. Accumulation of excess arginine may result in reduce dose to 200 mg/kg/day.
an overproduction of nitric oxide, leading to vasodilation BSA-directed dosing:
and hypotension (Summar 2001). Argininosuccinic acid lyase (ASL) or argininosuccinic
acid synthetase (ASS, citrullinemia) deficiency: IV:
Oral products available in the US are often marketed as Loading dose: 12 g/m? followed by a continuous IV
dietary supplements. When using these products, patients infusion of 12 g/m2/day (Batshaw 2001; Brusi-
should take care to ensure that they are receiving phar-
low 1996)
maceutical grade supplements of L-arginine and verify the
Carbamyl phosphate synthetase (CPS) or ornithine
formulation (free base vs arginine HCl). The National Urea
transcarbamylase (OTC) deficiency: IV: Loading
Cycle Disorders Foundation cautions against using oral
dose: 4 g/m? followed by a continuous IV infusion
dietary supplements of arginine HCL (National Urea
of 4 g/m?/day (Batshaw 2001; Brusilow 1996)
Cycles Disorder Foundation).
Urea cycle disorders, chronic therapy: Limited data
Adverse Reactions
available: Note: Dose should be individualized based
Cardiovascular: Flushing (with rapid IV infusion), venous
on patient response; doses may need to be increased
irritation
by ~50% as part of a sick-day routine (Berry 2001).
Central nervous system: Headache, numbness
Note: Dosing based on arginine-free base powder
Gastrointestinal: Nausea, vomiting
product:
Rare but important or life-threatening: Anaphylaxis, burn-
Argininosuccinic acid lyase (ASL) or argininosuccinic
ing sensation of skin (due to extravasation), cerebral
edema, hematuria, hyperkalemia, hypersensitivity reac- acid synthetase (ASS, citrullinemia) deficiency (Bat-
tion, injection site reaction, lethargy, loss of conscious-
shaw 2001; Berry 2001; Brusilow 1996; NORD 2012;
ness, oral paresthesia, skin necrosis (due to
Summar 2001):
extravasation) Weight-directed dosing: Oral: 400 to 700 mg/kg/day
Drug Interactions in 3 to 4 divided doses
BSA-directed dosing: Oral: 8.8 to 15.4 g/m?/day in 3
Metabolism/Transport Effects None known.
to 4 divided doses
Avoid Concomitant Use There are no known interac-
Carbamyl phosphate synthetase (CPS), ornithine
tions where it is recommended to avoid concomitant use.
transcarbamylase (OTC) or N-acetylglutamate syn-
Increased Effect/Toxicity There are no known signifi-
thetase (NAGS) deficiency: Note: Citrulline may be
cant interactions involving an increase in effect.
preferred for some patients (Batshaw, 2001; Brusilow
Decreased Effect There are no known significant inter-
1996; NORD 2012):
actions involving a decrease in effect.
Weight-directed dosing: Oral: 170 mg/kg/day in 3 to 4
Storage/Stability Store at 25°C (77°F). Do not use if
divided doses
frozen. Once the vial has been punctured, may store for
BSA-directed dosing: Oral: 3.8 g/m?/day in 3 to 4
up to 4 hours at 25°C (77°F) (including-infusion time) or 24
divided doses
hours at 2°C to 8°C.
Necrotizing enterocolitis (NEC), prevention: Limited
Mechanism of Action Stimulates pituitary release of
data available: Oral, |V: 261 mg/kg/day added to
growth hormone and prolactin through origins in the
enteral or parenteral nutrition beginning on day of life
hypothalamus; patients with impaired pituitary function
2 to 5 and continued for 28 consecutive days. Dosing
have lower or no increase in plasma concentrations of
growth hormone after administration of arginine. In based on a single-center, prospective, double-blind,
patients with urea cycle disorders, the formation of argi- randomized, placebo-controlled trial of neonates
nine is prohibited; therefore, exogenous administration of (Treatment group: n=75, GA: <32 weeks; birth weight:
arginine is required. <1,250 g) in Canada. Arginine supplementation
Pharmacodynamics/Kinetics (Adult data unless decreased the NEC incidence when compared to pla-
cebo (6.7% vs 27%) (Amin 2002; Shah 2007). Note:
noted)
Absorption: Oral: Well absorbed The only commercial product available in the US is
Distribution: Vg: ~33 L/kg following a 30 g IV dose arginine HCl injection and it is not known whether the
Metabolism: Extensively metabolized in the liver and hydrochloride salt was used in the Canadian study.
intestines (Cynober 2007) Increased administration of HCI in this patient popula-
Bioavailability: Oral: ~68% tion could result in hyperchloremic metabolic acidosis.
Half-life, elimination: 42 + 2 minutes following a 30 g IV Pediatric
dose; exhibits nonlinear, dose-dependent elimination Pituitary function test: Note: Dosing based on argi-
(Tangphao 1999) nine hydrochloride product: Infants, Children, and
Time to peak, serum: Oral: ~2 hours; IV: 22 to 30 minutes Adolescents: IV: 0.5 g/kg over 30 minutes; maximum
(Bode-Boger 1998; Tangphao 1999) dose: 30 g dose
Excretion: Urine (16% during the first 90 minutes; biphasic Metabolic alkalosis: Limited data available: Infants,
elimination) (Tangphao 1999) Children, and Adolescents: IV: Note: Arginine hydro-
Dosing chloride is an alternative treatment for uncompensated
Neonatal metabolic alkalosis after sodium chloride and potas-
Hyperammonemia, acute (urea cycle disorders): Lim- sium chloride supplementation have been optimized; it
ited data available: Note: Administered concomitantly should not be used as initial therapy for chloride
with sodium benzoate and sodium phenylacetate. Dos- supplementation. Each 1g of arginine hydrochloride
age based on specific enzyme deficiency; therapy provides 4.75 mEq chloride. Note: Dosing based on
should continue until ammonia levels are in normal arginine hydrochloride product.
range. Do not! repeat loading dose unless severe Arginine hydrochloride dose (mEq) = 0.5 x weight (kg) x
disorder or receiving dialysis; if used, minimum 6 hour [HCO3 - 24] where HCO3 = the patient's serum
interval between loading doses (Summar 2001). Note: bicarbonate concentration in mEq/L (Martin 1982);
Dosing based on arginine hydrochloride product. give 1/2 to 2/3 of calculated dose and reevaluate. >
173
 ARGININE

< To correct hypochloremia: Arginine hydrochloride dose

(mEq) = 0.2 x weight (kg) x [103 - Cr] where CI = the
Irritant with vesicant-like properties; ensure proper nee-
dle or catheter placement prior to and during IV infu-
patient's serum chloride concentration in mEq/L (Mar- sion. Avoid extravasation. Some recommend infusion
tin 1982); give 1/2 to 2/3 of calculated dose and through central access only (Ah Mew 2017;'UCD
reevaluate. conference group 2001). If extravasation occurs, stop
Hyperammonemia, acute (urea cycle disorders): Lim- infusion immediately and disconnect (leave needle/
ited data available: Infants, Children, and Adolescents: cannula in place); gently aspirate extravasated solution
Note: Administered concomitantly with sodium ben- (do NOT flush the line); initiate hyaluronidase antidote;
zoate and sodium phenylacetate. Dosage based on remove needle/cannula; elevate extremity. Apply dry
specific enzyme deficiency; therapy should continue cold compresses (Reynolds 2014).
until ammonia levels are in normal range. If patient Oral, powder: Arginine-free base: Take with meals and
already receiving arginine therapy, consider either a space doses evenly throughout the day.
reduction in the loading dose or possible elimination Vesicant/Extravasation Risk Irritant with vesicant-like
(Batshaw 2001); if a loading dose is used, it should not properties
be repeated (NORD 2012). Note: Dosing based on
Monitoring Parameters Acid-base status (arterial or
arginine hydrochloride product.
capillary blood gases), serum electrolytes, BUN, glucose,
Weight-directed dosing:
plasma growth hormone concentrations (when evaluating
Argininosuccinic acid lyase (ASL) or argininosuccinic
growth hormone reserve), plasma ammonia and amino
acid synthetase (ASS, citrullinemia) deficiency: \V:
acids (when-treating urea cycle disorders), infusion site
Loading dose: 600 mg/kg followed by a continuous
IV infusion of 600 mg/kg/day (Ah Mew 2017; Bat- Reference Range
shaw 2001; NORD 2012). Pituitary function test: If intact pituitary function, human
Carbamy! phosphate synthetase (CPS), ornithine growth hormone levels should rise after arginine admin-
transcarbamylase (OTC) or N-acetylglutamate syn- istration to 10-30 ng/mL (control range: 0-6 ng/mL)
thetase (NAGS) deficiency: |V: Loading dose: Urea cycle disorders: Goal arginine: 50 to 200 ymol/L
200 mg/kg followed by a continuous IV infusion of (Leonard 2002)
200 mg/kg/day (Ah Mew 2017; Batshaw 2001; Additional Information When treating urea cycle disor-
NORD 2012). ders, sodium bicarbonate use may be necessary to neu-
Unconfirmed/pending diagnosis: \V: Loading dose: . tralize the acidifying effects of arginine HCl (UCD
600 mg/kg followed by a continuous IV infusion of conference group 2001).
600 mg/kg/day (NORD 2012). If ASS and ASL are
Equivalents (Haberle 2012):
excluded as diagnostic possibilities, reduce dose to
100 mg arginine free base = 0.574 mmols
200 mg/kg/day.
100 mg arginine HCL = 0.475 mmol
BSA-directed dosing:
Argininosuccinic acid lyase (ASL) or argininosuccinic Dosage Forms Considerations R-Gene 10 contains
acid synthetase (ASS, citrullinemia) deficiency: \V: chloride 47.5 mEq per 100 mL
Loading dose: 12 g/m? followed by a continuous IV Dosage Forms Excipient information presented when
infusion of 12 g/m?/day (Ah Mew 2017; Batshaw available (limited, particularly for generics); consult spe-
2001; Brusilow 1996) cific product labeling.
Carbamyl phosphate synthetase (CPS) or ornithine Solution, Intravenous, as hydrochloride [preservative
transcarbamylase (OTC) disorder: \V: Loading dose: free]:
4 g/m? followed by a continuous |V infusion of 4 g/ R-Gene 10: 10% (300 mL)
m2/day (Ah Mew 2017; Batshaw 2001; Brusi-
@ Arginine HCI see Arginine on page 172
low 1996)
Urea cycle disorders, chronic therapy; Limited data @ Arginine Hydrochloride see Arginine on page 172
available: Infants, Children, and Adolescents: Note: @ 8-Arginine Vasopressin see Vasopressin on page 2042
Dose should be individualized based on patient
@ Aridol [DSC] see Mannitol (Oral Inhalation)
response; doses may need to be increased by ~50%
on page 1273
as part of a sick-day routine (Berry 2001): Note:
Dosing based on arginine-free base powder prod-
uct: ARIPiprazole (ay ri PIP ray zole)
Argininosuccinic acid lyase (ASL) or argininosuccinic
acid synthetase (ASS, citrullinemia) deficiency (Bat- Medication Safety Issues
shaw 2001; Berry 2001; Brusilow 1996; NORD 2012): Sound-alike/look-alike issues:
Weight-directed dosing: Oral: 400 to 700 mg/kg/day Abilify may be confused with Ambien
in 3 to 4 divided doses ARIPiprazole may be confused with proton pump inhib-
BSA-directed dosing: Oral: 8.8 to 15.4 g/m?/day in 3 itors (dexlansoprazole, esomeprazole, lansoprazole,
to 4 divided doses omeprazole, pantoprazole, RABEprazole)
Carbamy! phosphate synthetase (CPS), ornithine Geriatric Patients: High-Risk Medication:
transcarbamylase (OTC) or N-acetylglutamate syn- Beers Criteria: Antipsychotics are identified in the Beers
thetase (NAGS) deficiency: Note: Citrulline may be Criteria as potentially inappropriate medications to be
preferred for some patients (Batshaw, 2001; Brusilow avoided in patients 65 years and older with dementia
1996; NORD 2012): due to an increased risk of mortality, cerebrovascular
Weight-directed dosing: Oral: 170 mg/kg/day in 3 to 4 accidents (stroke), and a greater rate of cognitive
divided doses decline with use; avoid antipsychotics for behavioral
BSA-directed dosing: Oral: 3.8 g/m?/day in 3 to 4 problems associated with dementia or delirium unless
divided doses alternative nonpharmacologic therapies have failed
Renal Impairment: Pediatric There are no dosage and patient may harm self or others. Use may be
adjustments provided in the manufacturer's labeling; appropriate in geriatric patients with schizophrenia,
use with caution; use may lead to life-threatening hyper- bipolar disorder, or for short-term use as an antiemetic
kalemia. during chemotherapy. In addition, antipsychotics
Hepatic Impairment: Pediatric There are no dosage should be used with caution in older adults due to their
adjustments provided in the manufacturer's labeling; use potential to cause or exacerbate syndrome of inappro-
with caution; use may lead to life-threatening hyper- priate antidiuretic hormone secretion (SIADH) or hypo-
kalemia. natremia; monitor sodium closely with initiation or
Preparation for Administration lV: Hyperammonemia, dosage adjustments in older adults (Beers Criteria
acute (urea cycle disorders): A combination infusion may [AGS 2015]).
be prepared by adding arginine hydrochloride, sodium
Other safety issues:
benzoate, and sodium phenylacetate to 25 to 35 mL/kg
There are two formulations available for intramuscular
of DiOW (Ammonul prescribing information 2016; Sum-
administration: Abilify is an immediate release short-
mar 2001; UCD Conference group 2001).
acting formulation and Abilify Maintena is an extended-
Administration
release formulation. These products are not inter-
IV: Arginine hydrochloride:
changeable.
Pituitary function test: Administer undiluted over 30
Related Information
minutes. For doses <30 g (<300 mL), the manufacturer
recommends transferring the dose to a separate con- Relative Infant Dose on page 2207
tainer prior to administration. Brand Names: US Abilify; Abilify Discmelt [DSC]; Abilify
Hyperammonemia, acute (urea cycle disorders): May Maintena
- administer in combination with sodium benzoate and Brand Names: Canada Abilify; Abilify Maintena
sodium phenylacetate injection; central line preferred. Therapeutic Category Second Generation (Atypical)
Administer loading dose over 90 to 120 minutes (Ah Antipsychotic
Mew 2017; UCD conference group 2001). Generic Availability (US) May be product dependent

174
 ARIPIPRAZOLE

Use for the first month of exposure for symptoms, such as

Oral: Acute and maintenance treatment of schizophrenia appetite changes, insomnia, irritability, or lethargy
(FDA approved in ages 213 years and adults); acute (Uguz 2016).
treatment of bipolar disorder (with acute manic or mixed
The manufacturer recommends a decision be made
episodes) (FDA approved in ages 210 years and adults);
whether to discontinue nursing or to discontinue the drug,
adjunctive therapy (to lithium or valproate) for acute
taking into account the importance of treatment to the
treatment of bipolar disorder (with acute manic or mixed
mother. The manufacturer of the extended-release injec-
episodes) (FDA approved in ages 210 years and adults);
tion recommends the development and health benefits of
treatment of irritability associated with autistic disorder
breastfeeding be considered along with the mother’s
(including symptoms of aggression, deliberate self-inju-
clinical need for therapy and any potential adverse effects
rious behavior, temper tantrums, quickly changing
on the breastfed infant from aripiprazole or from the
moods) (FDA approved in ages 6 to 17 years); treatment
underlying maternal condition. Until additional information
of Tourette's disorder (FDA approved in ages 6 to 18
is available, use of agents other than aripiprazole in
years); adjunctive treatment (to antidepressants) of
breastfeeding women is preferred (Pacchiarotti 2016;
major depressive disorder (FDA approved in adults).
Uguz 2016).
Has also been used in children and adolescents for
Contraindications Hypersensitivity (eg, anaphylaxis, pru-
treatment of ADHD, conduct disorders, and irritability
ritus, urticaria) to aripiprazole or any component of the
associated with other pervasive developmental disor-
formulation.
ders.
Injection: Warnings/Precautions [US Boxed Warning]: Elderly
Immediate release: Abilify: Acute treatment of agitation patients with dementia-related psychosis treated with
associated with schizophrenia or bipolar disorder antipsychotics are at an increased risk of death com-
(manic or mixed) (FDA approved in adults) pared to placebo. Most deaths appeared to be either
Extended release: Abilify Maintena: Treatment of schiz- cardiovascular (eg, heart failure, sudden death) or infec-
ophrenia (FDA approved in adults) tious (eg, pneumonia) in nature. Use with caution in
patients with Lewy body dementia or Parkinson disease
Medication Guide Available Yes
dementia due to greater risk of adverse effects, increased
Pregnancy Risk Factor C
sensitivity to extrapyramidal effects, and association with
Pregnancy Considerations Adverse events have been
irreversible cognitive decompensation or death (APA
observed in animal reproduction studies. Aripiprazole
[Reus 2016]). Aripiprazole is not approved for the
crosses the placenta; aripiprazole and dehydro-aripipra-
treatment of dementia-related psychosis.
zole can be detected in the cord blood at delivery (Nguyen
2011; Watanabe 2011). Antipsychotic use during the third [US Boxed Warning]: Antidepressants increase the
trimester of pregnancy has a risk for abnormal muscle risk of suicidal thinking and -behavior in children,
movements (extrapyramidal symptoms [EPS]) and/or adolescents, and young adults (18 to 24 years of
withdrawal symptoms in newborns following delivery. age) with major depressive disorder (MDD) and other
Symptoms in the newborn may include agitation, feeding psychiatric disorders; consider risk prior to prescribing.
disorder, hypertonia, hypotonia, respiratory distress, som- The possibility of a suicide attempt is inherent in major
nolence, and tremor; these effects may be self-limiting or depression and may persist until remission occurs.
require hospitalization. Patients treated with antidepressants should be observed
for clinical worsening and suicidality, especially during the
Treatment algorithms have been developed by the ACOG
initial few months of a course of drug therapy, or at times
and the APA for the management of depression in women
of dose changes, either increases or decreases. Prescrip-
prior to conception and during pregnancy (Yonkers 2009).
tions should be written for the smallest quantity consistent
The ACOG recommends that therapy during pregnancy
with good patient care. The patient's family or caregiver
be individualized; treatment with psychiatric medications
should be alerted to monitor patients for the emergence of
during pregnancy should incorporate the clinical expertise
suicidality and associated behaviors; patients should be
of the mental health clinician, obstetrician, primary health
instructed to notify their healthcare provider if any of these
care provider, and pediatrician. Safety data related to
symptoms or worsening depression or psychosis occur.
atypical antipsychotics during pregnancy is limited, as
such, routine use is not recommended. However, if a Leukopenia, neutropenia, and agranulocytosis (some-
woman is inadvertently exposed to an atypical antipsy- times fatal) have been reported in clinical trials and
chotic while pregnant, continuing therapy may be prefera- postmarketing reports with antipsychotic use; presence
ble to switching to an agent that the fetus has not yet been of risk factors (eg, preexisting low WBC/ANC or history
exposed to; consider risk:benefit (ACOG 2008). If treat- of drug-induced leuko-/neutropenia) should prompt peri-
ment is needed in a woman planning a pregnancy or if odic blood count assessment. Discontinue therapy at first
treatment is initiated during pregnancy, use of an agent signs of blood dyscrasias or if absolute neutrophil count
other than aripiprazole is preferred (Larsen 2015). <1,000/mm°.
Health care providers are encouragedto enroll women A medication guide concerning the use of antidepressants
exposed to aripiprazole during pregnancy in the National should be dispensed with each prescription. Aripiprazole
Pregnancy Registry for Atypical Antipsychotics is not FDA approved for adjunctive treatment of depres-
(866-961-2388 or http://www.womensmentalhealth.org/ sion in children.
Clinical-and-research-programs/pregnancyregistry/).
May cause extrapyramidal symptoms (EPS), including
Breastfeeding Considerations Aripiprazole and dehy-
pseudoparkinsonism, acute dystonic reactions, akathisia,
droaripiprazole are present in breast milk. (Nordeng 2014)
and tardive dyskinesia (risk of these reactions is very low
The relative infant dose (RID) of aripiprazole is 8.3% when relative to typical/conventional antipsychotics, frequencies
calculated using the highest mean breast milk concen- reported are similar to placebo). Risk of dystonia (and
tration located and compared to a weight-adjusted mater- probably other EPS) may be greater with increased doses,
nal dose of 10 mg/day. use of conventional antipsychotics, males, and younger
patients. Factors associated with greater vulnerability to
In general, breastfeeding is considered acceptable when
tardive dyskinesia include older in age, female gender
the RID of a medication is <10% (Anderson 2016; Ito
combined with postmenopausal status, Parkinson dis-
2000). However, some sources note breastfeeding should
ease, pseudoparkinsonism symptoms, affective disorders
only be considered if the RID is <5% for psychotropic
(particularly major depressive disorder), concurrent med-
agents (Larsen 2015).
ical diseases such as diabetes, previous brain damage,
The RID of aripiprazole was-calculated using a mean milk alcoholism, poor treatment response, and use of high
concentration of 56 ng/mL (aripiprazole) and 8.8 ng/mL doses of antipsychotics (APA [Lehman 2004]; Soares-
(dehydroaripiprazole), providing an estimated daily infant Weiser 2007). Consider therapy discontinuation with
dose via breast milk of 47 mcg/day. This milk concen- signs/symptoms of tardive dyskinesia. May be associated
tration was obtained following maternal administration of with neuroleptic malignant syndrome (NMS).
aripiprazole 10 mg/day during pregnancy and while
May cause CNS depression, which may impair physical or
breastfeeding. Milk samples were obtained at 8 and 10
mental abilities; patients must be cautioned about per-
weeks' postpartum. The RID was calculated by the
forming tasks that require mental alertness (eg, operating
authors of the study using the actual maternal weight.
machinery, driving). May cause orthostatic hypotension
Peak milk concentrations appeared ~3 hours after the
(although reported rates are similar to placebo); use
dose, but remained relatively constant throughout the
caution in patients at risk of this effect or those who would
dosing interval (Nordeng 2014).
not tolerate transient hypotensive episodes (cerebrovas-
Although reports of aripiprazole use in breastfeeding cular disease, cardiovascular disease, or other medica-
women are limited, lactation failure has been observed tions which may predispose). May increase the risk for
in some cases (Lutz 2010; Mendhekar 2006; Nordeng falls due to somnolence, orthostatic hypotension and
2014). In general, infants exposed to second generation motor or sensory instability. Complete fall risk assess-
antipsychotics via breast milk should be monitored weekly ments at baseline and periodically during treatment in >
175
 ARIPIPRAZOLE

4 patients with diseases or on medications that may also

increase fall risk. Has been associated with compulsive
and aripiprazole: 4.4 kg (8.1%) compared to the control
cohort: 0.2 kg (0.65%).
behaviors and/or loss of impulse control, which has man-
Hyperglycemia has been reported with aripiprazole; in
ifested as pathological gambling, uncontrolled sexual
analysis of pediatric trials (patients 6 to.18 years, diag-
urges, uncontrolled spending, binge or compulsive eating,
nosis including schizophrenia, autistic disorder, bipolar
and/or other intense urges. Patients with prior history of
disorder, and Tourette's disorder), the mean change in
impulse control issues may be at increased risk. Dose
fasting glucose was not observed to be significantly differ-
reduction or discontinuation of therapy has been reported
ent than placebo-treated patients (median exposure
to reverse these behaviors in most, but not all, cases
range: 43 to 57 days). However, with longer exposure
(Gaboriau 2014; Moore 2014; Smith 2011).
(mean: 17.2 months), an increased risk for the develop-
Use caution in patients with Parkinson disease; antipsy- ment of type 2 diabetes mellitus (DM) was observed in
chotics may aggravate motor disturbances (APA [Lehman pediatric patients 10 to 18 years receiving second-gen-
2004; APA [Reus 2016]). Use with caution in patients with eration antipsychotics (SGA); for patients initiated on
predisposition to seizures or severe cardiac disease. May SGA: 0.4% incidence with mean exposure at time type 2
alter cardiac conduction; life-threatening arrhythmias have DM diagnosed: 13.5 months; for SGA noniniators
occurred with therapeutic doses of antipsychotics. Anti- (patients receiving another agent prior to SGA initiation):
psychotic use has been associated with esophageal dys- 0.2% incidence with mean exposure at time of type 2 DM
motility and aspiration; risk increases with age. Use with diagnosed: 14.6 months. Amongst specific SGA’s, the risk
caution in patients at risk for aspiration pneumonia (eg, was highest-for aripiprazole (p=0.001) followed by zipra-
Alzheimer dementia), particularly in patients >75 years sidoné (p=0.06) compared to risperidone as the reference
(Herzig 2017; Maddalena 2004). May alter temperature group but not quetiapine or olanzapine (Rubin 2015).
regulation. Potentially significant interactions may exist, Increases in metabolic indices (eg, serum cholesterol,
requiring dose or frequency adjustment, additional mon- triglycerides) were also reported; however, these changes
itoring, and/or selection of alternative therapy. were not significant in patients receiving aripiprazole
(Correll 2009); additionally, in clinical trials, lipid changes
Atypical antipsychotics have been associated with meta-
bolic changes including loss of glucose control, lipid
observed with aripiprazole monotherapy in pediatric
changes, and weight gain (>7% of baseline weight) (risk patients were similar to those observed with placebo.
profile varies with product). Development of hyperglyce- . Biannual monitoring of cardiometabolic indices after the
mia in some cases, may be extreme and associated with first 3 months of therapy is suggested (Correll 2009).
ketoacidosis, hyperosmolar coma, or death. Reports of Children and adolescents may experience a higher fre-
hyperglycemia with aripiprazole therapy have been few quency of some adverse effects than adults, including
and specific risk associated with this agent is not known. EPS (20% vs 5%), fatigue (17% vs 8%), and somnolence
Use caution in patients with diabetes or other disorders of (23% vs 6%).
glucose regulation; monitor for worsening of glucose con-
trol. Patients with risk factors for diabetes (eg, obesity or Pediatric psychiatric disorders are frequently serious men-
family history) should have a baseline fasting blood sugar tal disorders which present with variable symptoms that do
(FBS) and periodic assessment of glucose regulation. not always match adult diagnostic criteria. Conduct a
thorough diagnostic evaluation and carefully consider
Tablets may contain lactose; avoid use in patients with risks of psychotropic medication before initiation in pedia-
galactose intolerance or glucose-galactose malab- tric patients with schizophrenia, bipolar disorder, or irrita-
sorption. bility associated with autistic disorder. Medication therapy
The ability of aripiprazole tablets with sensor to improve for pediatric patients with these disorders is indicated as
patient compliance or modify aripiprazole dosage has not part of a total treatment program that frequently includes
been established. The use’ of aripiprazole tablets with educational, psychological, and social interventions.
sensor to track drug ingestion in "real time" or during an Long-term usefulness of aripiprazole should be periodi-
emergency is not recommended because detection may cally re-evaluated in patients receiving the drug for
be delayed or not occur. extended periods of time.

Orally disintegrating tablets may contain phenylalanine. Some dosage forms may contain propylene glycol; in
neonates large amounts of propylene glycol delivered
There are two formulations available for intramuscular orally, intravenously (eg, >3,000 mg/day), or topically
administration: Abilify is an immediate-release short-act- have been associated with potentially fatal toxicities which
ing formulation and Abilify Maintena is an extended- can include metabolic acidosis, seizures, renal failure, and
release formulation. These products are not inter- CNS depression; toxicities have also been reported in
changeable. children and adults including hyperosmolality, lactic acido-
When discontinuing antipsychotic therapy, the American sis, seizures and respiratory depression; use caution
Psychiatric Association (APA), Canadian Psychiatric (AAP, 1997; Shehab, 2009).
Association (CPA), and World Federation of Societies of Adverse Reactions
Biological Psychiatry (WFSBP) guidelines recommend Cardiovascular: Orthostatic hypotension, peripheral
gradually tapering antipsychotics to avoid physical with- edema, tachycardia
drawal symptoms, including anorexia, anxiety, diaphore- Central nervous system: Agitation (more common in oral),
sis, diarrhea, dizziness, dyskinesia, headache, myalgia, akathisia (more common in adults), anxiety (more com-
nausea, paresthesia, restlessness, tremulousness and mon in oral), ataxia, dizziness, drooling, drowsiness
vomiting (APA [Lehman 2004]; CPA [Addington 2005]; (more common in children and adolescents), dystonia,
Lambert 2007; WFSBP [Hasan 2012]). The risk of with- extrapyramidal reaction (more common in children and
drawal symptoms is highest following abrupt discontinua- adolescents), fatigue (more common in children and
tion of highly anticholinergic or dopaminergic adolescents), headache (more common in adults),
antipsychotics (Cerovecki 2013). Additional factors such hypersomnia, insomnia (less common in injection), irri-
as duration of antipsychotic exposure, the indication for tability, lethargy, pain, restlessness, sedation (more com-
use, medication half-life and risk for relapse should be mon in children and adolescents)
considered. In schizophrenia, there is no reliable indicator Dermatologic: Skin rash
to differentiate the minority who will not from the majority Endocrine & metabolic: Decreased HDL cholesterol (more
who will relapse with drug discontinuation. However, common in adults), increased LDL cholesterol, increased
studies in which the medication of well-stabilized patients serum cholesterol (more common in injection), increased
were discontinued indicate that 75% of patients relapse serum glucose (more common in adults), increased
within 6 to 24 months. Indefinite maintenance antipsy- serum triglycerides (more common in injection), weight
chotic medication is generally recommended, and espe- gain (more common in children and adolescents),
cially for patients who have had multiple prior episodes or weight loss
two episodes within 5 years (APA [Lehman 2004)). Gastrointestinal: Abdominal distress, anorexia, constipa-
Warnings: Additional Pediatric Considerations Ari- tion, decreased appetite, diarrhea, dyspepsia, gastric
piprazole may cause a higher than normal weight gain in distress, increased appetite, nausea, sialorrhea, stom-
children and adolescents; monitor growth (including ach discomfort, toothache, upper abdominal pain, vomit-
weight, height, BMI, and waist circumference) in pediatric ing (more common in oral), xerostomia
patients receiving aripiprazole; compare weight gain to Genitourinary: Dysmenorrhea, urinary incontinence
standard growth curves. Note: A prospective, nonrandom- Hematologic & oncologic: Neutropenia
ized cohort study followed 338 antipsychotic naive pedia- Local: Application site rash (Mycite patch), injection site
tric patients (age: 4 to 19 years) for a median of 10.8 reaction (injection; including erythema, induration,
weeks (range: 10.5 to 11.2 weeks) and reported the inflammation, hemorrhage, pruritus, swelling, rash), pain
following significant mean increases in weight in kg (and at injection site
% change from baseline): Olanzapine: 8.5 kg (15.2%), Neuromuscular & skeletal: Arthralgia, back pain, dyskine-
quetiapine: 6.1 kg (10.4%), risperidone: 5.3 kg (10.4%), sia, limb pain, muscle cramps, muscle rigidity, muscle

176
 ARIPIPRAZOLE

spasm, musculoskeletal pain, myalgia, stiffness, tremor, HydrOXYzine; Idelalisib; Imatinib; Kava Kava; Lithium;
weakness Lofexidine; Magnesium Sulfate; Methadone; Methotri-
Ophthalmic: Blurred vision meprazine; Methylphenidate; Metoclopramide; Metyro-
Respiratory: Aspiration pneumonia, cough, dyspnea, epis- SINE; MiFEPRIStone; Minocycline; Nabilone;
taxis, nasal congestion, nasopharyngitis, pharyngolar- Netupitant; Oxomemazine; Palbociclib; Panobinostat;
yngeal pain, upper respiratory tract infection PARoxetine; Peginterferon Alfa-2b; Perampanel; Per-
Miscellaneous: Fever : hexiline; Ritonavir; Rufinamide; Serotonin Modulators;
Rare but important or life-threatening: Abnormal bilirubin Sertraline; Simeprevir; Sodium Oxybate; Stiripentol;
levels, abnormal gait, abnormal hepatic function tests, Tapentadol; Tetrahydrocannabinol; Trimeprazine
aggressive behavior, agranulocytosis, akinesia, alope- Decreased Effect
cia, altered serum glucose, amenorrhea, anaphylaxis, ARI/Piprazole may decrease the levels/effects of:
angina pectoris, angioedema, anorgasmia, atrial fibrilla-
Amphetamines; Antidiabetic Agents; Anti-Parkinson
tion, atrial flutter, atrioventricular block, bradycardia,
Agents (Dopamine Agonist); Guanethidine; Haloperidol;
bradykinesia, bruxism, cardiac arrhythmia, catatonia,
Piribedil; Quinagolide
cerebrovascular accident, change in libido, chest dis-
comfort, chest pain, choreoathetosis, cogwheel rigidity, The levels/effects of ARIPiprazole may be decreased by:
decreased serum cholesterol, decreased serum trigly- Armodafinil; Bosentan; CYP3A4 Inducers (Moderate);
cerides, delayed ejaculation, delirium, depression, dia- CYP3A4 Inducers (Strong); Dabrafenib; Deferasirox;
betes mellitus, diabetic ketoacidosis, diplopia, disruption Enzalutamide; Lithium; Mitotane; Peginterferon Alfa-2b;
of body temperature regulation, drug-induced Parkinson Piribedil; Pitolisant; Sarilumab; Siltuximab; St John's
disease, dysgeusia, dysphagia, dystonia (oromandibu- Wort; Tocilizumab
lar), edema, elevated glycosylated hemoglobin, erectile Food Interactions Ingestion with a high-fat meal delays
_ dysfunction, esophagitis, extrasystoles, eyelid edema, time to peak plasma level. Management: Administer with-
facial edema, falling, gastroesophageal reflux disease, out regard to meals.
glycosuria, gynecomastia, heatstroke, hepatic failure,
Storage/Stability
hepatitis, hepatotoxicity, hirsutism, homicidal ideation,
Injection, powder (extended release):
hostility, hyperglycemia, hyperhidrosis, hyperinsulinism,
Prefilled syringe: Store below 30°C (86°F). Do not
hyperlipidemia, hypersensitivity reaction, hypertension,
freeze. Protect from light and store in original package.
hypertonia, hypoglycemia, hypokalemia, hypokinesia,
hyponatremia, hypothermia, hypotonia, impulse control
Vial for reconstitution: Store unused vials at 25°C (77°F);
disorder (including pathologic gambling and hypersex- excursions permitted to 15°C to 30°C (59°F to 86°F). If
uality), increased blood urea nitrogen, increased crea- the suspension is not administered immediately after
tinine clearance, increased creatine phosphokinase, reconstitution, store at room temperature in the vial (do
increased gamma-glutamyl transferase, increased lac- not store in a syringe).
tate dehydrogenase, increased liver enzymes, increased Injection, solution (immediate release): Store at 25°C
serum bilirubin, increased serum prolactin, inhibition of (77°F); excursions permitted to 15°C to 30°C (59°F to
prolactin secretion, intentional injury, ischemic heart dis- 86°F). Protect from light. Retain in carton until time
ease, jaundice, joint stiffness, laryngospasm, leukope- of use.
nia, mastalgia, memory impairment, menstrual disease, Oral solution and tablets: Store at 20°C to 25°C (68°F to
mobility disorder, muscle twitching, myasthenia, myocar- 77°F); excursions permitted to 15°C to 30°C (59°F to
dial infarction, myoclonus, neuroleptic malignant syn- 86°F). Use oral solution within 6 months after opening.
drome, nocturia, obesity,, oculogyric crisis, Do not store in conditions where tablets are exposed to
oropharyngeal spasm, palpitations, pancreatitis, panic humid conditions.
attack, photophobia, photopsia, pollakiuria, polydipsia, Mycite Patch: Store at 15°C to 30°C (59°F to 86°F); 15%
polyuria, presyncope, priapism, prolonged Q-T interval to 93% relative humidity.
on ECG, pruritus, psychosis, rhabdomyolysis, seizure Mechanism of Action Aripiprazole is a quinolinone anti-
(including injection), skin photosensitivity, sleep apnea psychotic which exhibits high affinity for Dz, D3, 5-HT44,
syndrome (obstructive) (Health Canada, August 16, and 5-HT2, receptors; moderate affinity for D4, 5-HTac,
2016; Shirani 2011), sleep talking, somnambulism, 5-HT7, alpha, adrenergic, and H, receptors. It also pos-
speech disturbance, suicidal ideation, suicidal tenden- sesses moderate affinity for the serotonin reuptake trans-
cies, supraventricular tachycardia, swollen tongue, syn- porter; has no affinity for muscarinic (cholinergic)
cope, tardive dyskinesia, thrombocytopenia, tics, tongue receptors. Aripiprazole functions as a partial agonist at
spasm, tonic-clonic seizures, torsades de pointes, tran- the Dz and 5-HT,, receptors, and as an antagonist at the
sient ischemic attacks, trismus, uncontrolled diabetes
5-HT2, receptor (de Bartolomeis 2015).
mellitus, urinary retention, urticaria, venous throm-
Pharmacodynamics/Kinetics (Adult data unless
boembolism, ventricular tachycardia
noted) Note: In pediatric patients 10 to 17 years of
Drug Interactions
age, the pharmacokinetic parameters of aripiprazole and
Metabolism/Transport Effects Substrate of CYP2D6
dehydro-aripiprazole have been shown to be similar to
(major), CYP3A4 (major); Note: Assignment of Major/
adult values when adjusted for weight.
Minor substrate status based on clinically relevant drug
interaction potential Onset of action: Initial: 1 to 3 weeks
Avoid Concomitant Use Absorption:
Avoid concomitant use of ARIPiprazole with any of the IM: Extended-release: Slow, prolonged
following: Amisulpride; Azelastine (Nasal); Bromopride; Oral: Well absorbed.
Bromperidol; Conivaptan; Fusidic Acid (Systemic); Ide- Distribution: Vg: 4.9 L/kg
lalisib; Metoclopramide; Orphenadrine; Oxomemazine; Protein binding: 299%, primarily to albumin
Paraldehyde; Piribedil; Sulpiride; Thalidomide Metabolism: Hepatic dehydrogenation, hydroxylation and
Increased Effect/Toxicity N-dealkylation via CYP2D6, CYP3A4 (dehydro-aripipra-
ARIPiprazole may increase the levels/effects of: Alcohol zole metabolite has affinity for D2 receptors similar to the
(Ethyl); Amisulpride; Azelastine (Nasal); Blonanserin; parent drug and represents 40% of the parent drug
Buprenorphine; CNS Depressants; DULoxetine; Fluni- exposure in plasma) (Sheehan 2010)
trazepam; FLUoxetine; Haloperidol; HYDROcodone; Bioavailability: IM: 100%; Tablet: 87%; Note: Orally dis-
lohexol; lomeprol; lopamidol; Mequitazine; Methadone; integrating tablets are bioequivalent to tablets; oral sol-
Methotrimeprazine; Methylphenidate; MetyroSINE; Mir- ution to tablet ratio of geometric mean for peak
tazapine; Opioid Analgesics; Orphenadrine; OxyCO- concentration is 122% and for AUC is 114%.
DONE; Paraldehyde; PARoxetine; Perhexiline; QTc- Half-life elimination: Aripiprazole: 75 hours; dehydro-aripi-
Prolonging Agents (Highest Risk); QTc-Prolonging prazole: 94 hours; IM, extended release (terminal): ~30
Agents (Moderate Risk); Ritonavir; Selective Serotonin to 47 days (dose-dependent)
Reuptake Inhibitors; Serotonin Modulators; Sulpiride; CYP2D6 poor metabolizers: Aripiprazole: 146 hours
Suvorexant; Thalidomide; Zolpidem Time to peak, plasma:
IM:
The levels/effects of ARIPiprazole may be increased by:
Abiraterone Acetate; Acetylcholinesterase Inhibitors Immediate release: 1 to 3 hours
(Central); Aprepitant; Asunaprevir,; Blood Pressure Low- Extended release (after multiple doses): 4 days (deltoid
ering Agents; Brimonidine (Topical); Bromopride; Brom- administration); 5 to 7 days (gluteal administration)
peridol; Cannabis; Ceritinib; Chlormethiazole; Tablet: 3 to 5 hours
Chlorphenesin Carbamate; Conivaptan; CYP2D6 Inhib- With high-fat meal: Aripiprazole: Delayed by 3 hours;
itors (Moderate); CYP2D6 Inhibitors (Strong); CYP2D6 dehydro-aripiprazole: Delayed by 12 hours
Inhibitors (Weak); CYP3A4 Inhibitors (Moderate); Excretion: Feces (55%, ~18% of the total dose as
CYP3A4 Inhibitors (Strong); CYP3A4 Inhibitors (Weak); unchanged drug; 37% of the total dose as changed
Dimethindene (Topical); Doxylamine; Dronabinol; Dro- drug); urine (25%, <1% of the total dose as unchanged
peridol; DULoxetine; FLUoxetine; Fosaprepitant; Fosne- drug; 25% of the total dose as changed drug) (Shee-
tupitant; Fusidic Acid (Systemic); Haloperidol; han 2010)

177
ARIPIPRAZOLE

Pharmacodynamics/Kinetics: Additional Consider- An open-labeled, ‘pilot study (n=25; mean age: 8.6
ations years; range: 5 to 17 years) reported an 88%
Renal function impairment: In severe renal impairment response with a mean final dose of 7.8 mg/day
(CrCl <30 mL/minute), Crax increased by 36% (aripipra- (range: 2.5 to 15 mg/day) (Stigler 2009). A retro-
zole) and 53% (dehydro-aripiprazole), but AUC was 15% spective, noncontrolled, open-label study of 34 PDD
lower for aripiprazole and 7% higher for dehydro-aripi- patients (mean age: 10.2 years; range: 4 to 15
prazole. years) included 10 patients with autistic disorder
Hepatic function impairment: AUC increased by 31% in and 24 patients with PDD-NOS reported a mean
mild hepatic impairment and by 8% in moderate impair- final dose: 8.1 + 4.9 mg/day and an overall response
ment, and decreased by 20% in severe impairment. rate of 32.4% (29.2% in patients with PDD-NOS)
Geriatric: In patients 265 years of age who were adminis- (Masi 2009). In a retrospective chart review of
tered a single oral dose, clearance was 20% lower than children and adolescents with developmental dis-
that observed in younger patients. ability and a wide range of psychiatric disorders
Gender: Cmax and AUC are 30% to 40% higher in women (n=32; age: 5 to 19 years), a mean starting dose
than in men. z of aripiprazole of 7.1 + 0.32 mg/day and a mean
CYP 2D6 metabolizers: 60% higher exposure to aripipra- maintenance dose of 10.55 + 6.9 mg/day was used;
zole and active metabolites in poor CYP 2D6 metabo- a response rate of 56% was reported for the overall
lizers compared to extensive metabolizers population. However, a study population subset
(Sheehan 2010). analysis in patients with mental retardation (n=18)
Dosing ' showed..a lower response rate in patients with
mental retardation with PDD-NOS (38%) than in
Pediatric Note: Oral solution may be substituted for the
patients with mental retardation without PDD-NOS
oral tablet on a mg-per-mg basis, up to 25 mg. Patients
(100%) (Valicenti-McDermott 2006).
receiving 30 mg tablets should be given 25 mg oral
Schizophrenia: Adolescents 13 to 17 years: Oral:
solution. Orally disintegrating tablets (Abilify Discmelt)
Initial: 2 mg daily for 2 days, followed by 5 mg daily
are bioequivalent to the immediate release tablets (Abil-
for 2 days with a further increase to target dose of
ify). Immediate release and extended release parenteral
10 mg daily; subsequent dose increases may be
products are not interchangeable.
made in 5 mg increments up to a maximum daily
Attention-deficit/hyperactivity disorder (ADHD):
dose of 30 mg/day. Note: 30 mg/day was not found
Limited data available: Children 28 years and Adoles-
to be more effective than the 10 mg/day dose.
cents: Oral: Initial: 2.5 mg/day; may increase on a
Tourette syndrome, tic disorders: Children 26 years
weekly basis by 2.5 mg/day increments as tolerated;
and Adolescents: Oral:
maximum daily dose: 10 mg/day; dosing based on an
Patient weight <50 kg: Initial: 2 mg daily for 2 days,
open-label, pilot study (n=23, age: 8 to 12 years)
then increase to target dose of 5 mg/day; in patients
which reported significant improvement in ADHD out-
not achieving optimal control, dose may be further
come scores without an impact on cognitive meas-
titrated at weekly intervals up to 10 mg/day
ures (positive or negative); mean final dose: 6.7 + Patient weight 250 kg: Initial: 2 mg daily for 2 days,
2.4 mg/day (Findling 2008). Other aripiprazole pub- then increase to 5 mg/day for 5 days, then increase
lished reports in pediatric and adolescent patients in
to target dose of 10 mg/day on day 8 of therapy; in
which ADHD is a comorbid diagnosis within the study
patients not achieving optimal control, dose may be
population exist; however, effectiveness in ADHD was
further titrated at weekly intervals in 5 mg/day incre-
not a reported primary outcome measure (Bastiaens
ments up to 20 mg/day
2009; Budman 2008; Findling 2009; Murphy 2009; Discontinuation of therapy: Children and Adolescents:
Valicenti-McDermott 2006). American Academy of Child and Adolescent Psychiatry
Autism; treatment of associated irritiability (includ- (AACAP), American Psychiatric Association (APA),
ing aggression, deliberate self-injurious behavior, Canadian Psychiatric Association (CPA), National Insti-
temper tantrums, and quickly changing moods): tute for Health and Care Excellence (NICE), and World
Children and Adolescents 6 to 17 years: Oral: Initial: Federation of Societies of Biological Psychiatry
2 mg daily for 7 days, followed by 5 mg daily; sub- (WFSBP) guidelines recommend gradually tapering
sequent dose increases may be made in 5 mg incre- antipsychotics to avoid withdrawal symptoms and min-
ments every 27 days, up to a maximum daily dose of imize the risk of relapse (AACAP [McClellan 2007];
15 mg/day APA [Lehman 2004]; Cerovecki 2013; CPA 2005; NICE
Bipolar | disorder (acute manic or mixed episodes): 2013; WFSBP [Hasan 2012]); risk for withdrawal symp-
Children and Adolescents 10 to 17 years: Oral: Initial: toms may be highest with highly anticholinergic or
2 mg daily for 2 days, followed by 5 mg daily for 2 dopaminergic antipsychotics (Cerovecki 2013). When
days with a further increase to target dose of 10 mg stopping antipsychotic therapy in patients with schizo-
daily; subsequent dose increases may be made in phrenia, the CPA guidelines recommend a gradual
5 mg increments, up to a maximum daily dose of taper over 6 to 24 months and the APA guidelines
30 mg/day. Note: The safety of doses >30 mg/day recommend reducing the dose by 10% each month
has not been evaluated. (APA [Lehman 2004]; CPA 2005). Continuing antipar-
Conduct disorder (CD); aggression: Limited data kinsonism agents for a brief period after discontinuation
available: Children 26 years and Adolescents: Oral: may prevent withdrawal symptoms (Cerovecki 2013).
Initial: Patient weight <25 kg: 1 mg/day; 25 to 50 kg: When switching antipsychotics, three strategies have
2 mg/day; 51 to 70 kg: 5 mg/day; >70 kg: 10 mg/day; been suggested: Cross titration (gradually discontinu-
may titrate after 2 weeks to clinical effectiveness; ing the first antipsychotic while gradually increasing the
maximum daily dose: 15 mg/day. Dosing based on new antipsychotic), overlap and taper (maintaining the
an open-label, prospective study (n=23; age: 6 to 17 dose of the first antipsychotic while gradually increas-
years) which evaluated pharmacokinetics and effec- ing the new antipsychotic, then tapering the first anti-
tiveness in patients with a primary diagnosis of CD psychotic), and abrupt change (abruptly discontinuing
(with or without comorbid ADHD); results showed the first antipsychotic and either increasing the new
improvement in CD symptom scores with only minor antipsychotic gradually or starting it at a treatment
improvements in cognition (Findling 2009). dose). Evidence supporting ideal switch strategies
Pervasive Developmental Disorder Not Otherwise and taper rates is limited and results are conflicting
Specified (PDD-NOS) or Asperger Disorder; treat- (Cerovecki 2013; Remington 2005).
ment of associated irritability (aggression, self- Dosage adjustment with concurrent CYP450 inducer
injury, tantrums): Limited data available: Children or inhibitor therapy:
24 years and Adolescents: Oral: Oral: Children and Adolescents:
Preschool age: Initial dose: 1.25 mg/day with titration CYP3A4 inducers (eg, carbamazepine, rifampin): Ari-
every 25 days in 1.25 mg/day increments as toler- piprazole dose should be doubled over 1 to 2 weeks;
ated or clinically indicated (Masi 2009) dose should be subsequently reduced if concurrent
Prepubertal children: Initial dose: 1.25 to 2.5 mg/day inducer agent discontinued.
with titration every 3 to 5 days in 1.25 to 2.5 mg/day Strong CYP3A4 inhibitors (eg, ketoconazole): Aripi-
increments as tolerated or clinically indicated; max- prazole dose should be reduced to 50% of the usual
imum daily dose: 15 mg/day (Masi 2009; Sti- dose, and proportionally increased upon discontinu-
gler 2009) ation of the inhibitor agent.
Adolescents: Initial dose: 2.5 to 5 mg/day with titration CYP2D6 inhibitors (eg, fluoxetine, paroxetine): Aripi-
every 5 days in 2.5 to 5 mg/day increments as prazole dose should be reduced to 50% of the usual
tolerated or clinically indicated; doses >5 mg/day dose, and proportionally increased upon discontinu-
were divided twice daily; if sleep disorder was ation of the inhibitor agent. Note: When aripiprazole
reported, the dose was given in morning and/or at is administered as adjunctive therapy to patients
lunchtime (Masi 2009); maximum daily dose: 15 mg/ with MDD, the dose should not be adjusted, follow
day (Stigler 2009) usual dosing recommendations.

178
 ARSENIC TRIOXIDE

CYP3A4 and CYP2D6 inhibitors: Aripiprazole dose Solution, Oral:

should be reduced to 25% of the usual dose. In Abilify: 1 mg/mL (150 mL [DSC]) [contains methylpara-
patients receiving inhibitors of differing (eg, moder- ben, propylene glycol, propylparaben]
ate 3A4/strong 2D6) or same (eg, moderate 3A4/ Generic: 1 mg/mL (150 mL)
moderate 2D6) potencies (excluding concurrent Suspension Reconstituted ER, Intramuscular:
strong inhibitors), further dosage adjustments can Abilify Maintena: 300 mg (1 ea); 400 mg (1 ea)
be made to achieve the desired clinical response. In Tablet, Oral:
patients receiving strong CYP3A4 and 2D6 inhib- Abilify: 2.mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg [con-
itors, aripiprazole dose is proportionally increased tains corn starch, fd&c blue #2 aluminum lake]
upon discontinuation of one or both inhibitor agents. Generic: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
Dosage adjustment based on CYP2D6 metabolizer Tablet Disintegrating, Oral:
status: Abilify Discmelt: 10 mg [DSC], 15 mg [DSC] [contains
Oral: Children and Adolescents: Aripiprazole dose aspartame, fd&c blue #2 aluminum lake]
should be reduced to 50% of the usual dose in Generic: 10 mg, 15 mg
CYP2D6 poor metabolizers and to 25% of the usual @ Aristospan (Can) see Triamcinolone (Systemic)
dose in poor metabolizers receiving a concurrent on page 1997
strong CYP3A4 inhibitor; subsequently adjust dose
@ Aristospan Intra-Articular [DSC] see Triamcinolone
for favorable clinical response.
(Systemic) on page 1997
Renal Impairment: Pediatric No dosage adjustment
@ ArmonAir RespiClick see Fluticasone (Oral Inhalation)
required.
on page 907 .
Hepatic Impairment: Pediatric No dosage adjustment
required. @ ArmonAir RespiClick 55 see Fluticasone (Oral Inhala-
Preparation for Administration Injection, powder for tion) on page 901
reconstitution: Reconstitute using 1.5 mL sterile water @ ArmonAir RespiClick 113 see Fluticasone (Oral Inhala-
for injection (SWF) (provided) for the 300 mg vial or 1.9 tion) on page 901
mL SWFI (provided) for the 400 mg vial to a final concen- @ ArmonAir RespiClick 232 see Fluticasone (Oral Inhala-
tration of 200 mg/mL; residual SWFI should be discarded tion) on page 901
after reconstitution. Shake vigorously for 30 seconds or
@ Armour Thyroid see Thyroid, Desiccated on page 1946
until the suspension-is uniform; the resulting suspension
will be milky white and opaque. If the suspension is\not @ Arnuity Ellipta see Fluticasone (Oral Inhalation)
on page 901
administered immediately after reconstitution, shake vig-
orously for 60 seconds prior to administration. ® Arranon see Nelarabine on page 1430
Administration @ Arsenic (Ill) Oxide see Arsenic Trioxide on page 179
Oral (all dosage forms): May be administered with or
without food.
Arsenic Trioxide (ar se nik tri OKS id)
Orally-disintegrating tablet: Do not remove tablet from
blister pack until ready to administer; do not push tablet Medication Safety Issues
through foil (tablet may become damaged); peel back High alert medication:
foil to expose tablet; use dry hands to remove tablet This medication is in a class the Institute for Safe
and place immediately on tongue. Tablet dissolves Medication Practices (ISMP) includes among its list of
rapidly in saliva and may be swallowed without liquid; drug classes which have a heightened risk of causing
if needed, tablet can be taken with liquid. Do not split significant patient harm when used in error.
tablet. Administration issues:
Injection: For IM use only; do not administer SubQ or IV; Multiple concentrations: Arsenic trioxide is available in
Note: Immediate release and extended release paren- different concentrations; verify concentration prior to
teral products are not interchangeable. admixture to assure appropriate dose preparation.
Immediate release (Abilify): Inject slowly into deep Brand Names: US Trisenox
muscle mass Brand Names: Canada Trisenox
Extended release (Abilify Maintena): Inject slowly into Therapeutic Category Antineoplastic Agent, Miscellane-
deltoid or gluteal muscle using the provided 1.5 inch ous
(38 mm) needle for nonobese patients or the provided 2 Generic Availability (US) No
inch (50 mm) needle for obese patients. Do not mas- Use Remission induction and consolidation in patients with
sage muscle after administration. Rotate injection sites relapsed or refractory acute promyelocytic leukemia (APL)
between the two gluteal muscles. Administer monthly characterized by t(15;17) translocation or PML/RAR-alpha
(doses should be separated by 226 days). gene expression (FDA approved in ages 24 years and
Monitoring Parameters Vital signs; CBC with differential; adults); has also been used in the initial treatment of APL
fasting lipid profile and fasting blood glucose/Hb Aj. (prior Pregnancy Considerations Based on the mechanism of
to treatment, at 3 months, then annually); weight, growth, action and findings in animal reproduction studies, arsenic
BMI, and waist circumference (especially in children), may cause fetal harm if administered during pregnancy.
personal/family history of diabetes, blood pressure, men- Arsenic crosses the human placenta. In studies of women
tal status, abnormal involuntary movement scale (AIMS), exposed to high levels of arsenic from drinking water, cord
extrapyramidal symptoms (EPS). Weight should be blood levels were similar to maternal serum levels. Dime-
assessed prior to treatment, at 4 weeks, 8 weeks, 12 thylarsinic acid (DMA) was the form of arsenic found in the
weeks, and then at quarterly intervals. Consider titrating fetus. An increased risk of low birth weight and still births
to a different antipsychotic agent for a weight gain 25% of were observed in women who ingested high levels of
the initial weight. Monitor patient periodically for symptom dietary arsenic. Verify pregnancy status in females of
resolution; monitor for worsening depression, suicidality, reproductive potential prior to initiating therapy. Females
and associated behaviors (especially at the beginning of of reproductive potential should use effective contracep-
therapy or when doses are increased or decreased) tion during treatment and for 6 months after the final
arsenic trioxide dose. Males with female partners of
Product Availability
reproductive potential should use effective contraception
Abilify immediate-release injection (9.75 mg/1.3 mL) has
during treatment and for 3 months after the final arsenic
been discontinued in the US for more than 1 year.
trioxide dose. An international consensus panel has pub-
Abilify Mycite: FDA approved November 2017; availability
lished guidelines for the management of hematologic
anticipated in 2018. Information pertaining to this product
malignancies during pregnancy; arsenic trioxide is terato-
within the monograph is pending revision. Abilify Mycite
genic and should not be used throughout pregnancy
is a drug-device combination product comprised of ari- (Lishner 2016). Arsenic trioxide may impair fertility in
piprazole tablets embedded with an Ingestible Event males of reproductive potential (based on findings in
Marker (IEM) sensor intended to track drug ingestion. animal studies).
Consult the prescribing information for additional infor- Breastfeeding Considerations Arsenic is naturally
mation. found in breast milk; concentrations range from 0.2 to 6
Dosage Forms Considerations Oral solution contains mcg/kg. In studies of women exposed to high levels of
fructose 200 mg and sucrose 400 mg per mL. arsenic from drinking water, breast milk concentrations
Dosage Forms Excipient information presented when were low (~3.1 mcg/kg) and did not correlate with mater-
available (limited, particularly for generics); consult spe- nal serum levels. The possible effect of maternal arsenic
cific product labeling. [DSC] = Discontinued product trioxide therapy on breast milk concentrations is not
Prefilled Syringe, |Intramuscular: known. Due to the potential for serious adverse reactions
Abilify Maintena: 300 mg (1 ea); 400 mg (1 ea) in the breastfed infant, the manufacturer recommends
Solution, Intramuscular: discontinuing breastfeeding during therapy and for 2
Abilify: 9.75 mg/1.3 mL (1.3 mL [DSC]) weeks after the final arsenic trioxide dose.

179
 ARSENIC TRIOXIDE

q Contraindications potential; antiemetics are recommended to prevent nau-

Hypersensitivity to arsenic or any component of the for- sea and vomiting (Dupuis 2011). Potentially significant
mulation drug-drug interactions may exist, requiring dose or fre-
Canadian labeling: Additional contraindications (not in the quency adjustment, additional monitoring, and/or selec-
US labeling): Pregnancy; breastfeeding tion of alternative therapy. Arsenic trioxide is available in
Warnings/Precautions [US Boxed Warnings]: Arsenic different concentrations; verify concentration prior to
trioxide may cause QTc interval prolongation, atrio- admixture to assure appropriate dose preparation.
ventricular block, and a torsades de pointes-type Adverse Reactions >10%:
ventricular arrhythmia, which may be fatal. Prior to Cardiovascular: Atrial arrhythmia, chest pain, ECG abnor-
treatment initiation, assess the QTc interval (by ECG), mality (non-QT prolongation), edema, facial edema,
correct preexisting electrolyte abnormalities, and con- flushing, hypertension, hypotension, palpitations, pro-
sider discontinuing medications known to prolong longed Q-T interval on ECG (>500 msec), tachycardia,
QTc interval. Do not administer arsenic trioxide to torsades de pointes
patients with ventricular arrhythmia or prolonged Central nervous system: Agitation, anxiety, coma, confu-
QTcF. In newly diagnosed low-risk APL studies, some sion, depression, dizziness, drowsiness, fatigue, head-
patients who received arsenic trioxide in combination with ache, insomnia, pain, paresthesia, rigors, seizure
tretinoin experienced QTc prolongation >450 msec (for
Dermatologic: Dermatitis, diaphoresis, erythema, hyper-
males) and >460 msec (for females) throughout treatment
pigmentation, night sweats, pallor, pruritus, skin lesion,
cycles. In studies for relapsed or refractory APL, over one-
urticaria,.xeroderma
third of patients who received arsenic trioxide (as mono-
Endocrine & metabolic: Acidosis, hyperglycemia, hyper-
therapy) had at least one ECG with a QTc interval_>500
kalemia, hypocalcemia, hypoglycemia, hypokalemia,
msec. Prolonged QTc has been observed between 1 and
hypomagnesemia, intermenstrual bleeding, weight gain,
5 weeks after start of arsenic trioxide treatment, and
usually resolved by 8 weeks after treatment. There are weight loss
no data on the effect of arsenic trioxide on the QTc interval Gastrointestinal: Abdominal distension, abdominal pain,
during the infusion. The risk of torsades de pointes is abdominal tenderness, anorexia, bloody diarrhea, con-
related to the extent of QTc prolongation, concurrent use stipation, decreased appetite, diarrhea, dyspepsia, fecal
of QTc prolonging medications, a history of torsade des incontinence, gastrointestinal hemorrhage, loose stools,
pointes, preexisting QTc interval prolongation, heart fail- _ nausea, oral bullae, oral candidiasis, sore throat, vomit-
ure, concurrent potassium-wasting diuretics, or other con- ing, xerostomia
ditions associated with hypokalemia or hypomagnesemia. Genitourinary: Oliguria, urinary incontinence, vaginal
The risk may be increased when arsenic trioxide is coad- hemorrhage
ministered with medications associated with electrolyte Hematologic & oncologic: Anemia, APL differentiation
abnormalities (eg, diuretics or amphotericin B). If it is not syndrome, bruise, disseminated intravascular coagula-
possible to discontinue concomitant medications associ- tion, febrile neutropenia, hemorrhage, hyperleukocyto-
ated with QTc prolongation, perform cardiac monitoring sis, leukocytosis, lymphadenopathy, neutropenia,
frequently. Maintain serum potassium >4 mEq/L and petechia, thrombocytopenia
magnesium >1.8 mg/dL during treatment. Monitor ECG Hepatic: Increased serum ALT, increased serum AST
weekly (more frequently in clinically unstable patients). If Hypersensitivity: Hypersensitivity reaction
QTc >500 msec develops, immediately withhold arsenic Infection: Bacterial infection, herpes simplex infection,
trioxide treatment and any medication known to prolong herpes zoster, sepsis.
the QTc interval and correct electrolyte abnormalities; Local: Erythema at injection site, local skin exfoliation,
when the QTc normalizes, resume arsenic trioxide at a pain at injection site, swelling at injection site
reduced dose. Neuromuscular & skeletal: Arthralgia, back pain, limb
[US Boxed Warning]: Patients with acute promyelo- pain, myalgia, neck pain, ostealgia, tremor, weakness
cytic leukemia (APL) treated with arsenic trioxide Ophthalmic: Blurred vision, eye irritation, eye redness
have experienced symptoms of differentiation syn- (with pain), eyelid edema, xerophthalmia
drome (may be fatal if not treated). Symptoms may Otic: Otalgia, tinnitus
include fever (unexplained), dyspnea, acute respira- Renal: Renal failure, renal insufficiency
tory distress, hypoxia, pulmonary infiltrates, pleural Respiratory: Abnormal breath sounds (decreased), cough,
or pericardial effusions, weight gain or peripheral dyspnea, epistaxis, hemoptysis, hypoxia, nasopharyng-
edema, hypotension, and renal, hepatic, or multiorgan itis, pleural effusion, post nasal drip, rales, rhonchi,
dysfunction, occurring with or without leukocytosis. If sinusitis, tachypnea, upper respiratory tract infection,
differentiation syndrome is suspected, immediately wheezing
initiate high-dose corticosteroid therapy and hemody- Miscellaneous: Fever
namic monitoring until signs/symptoms resolve. May Rare but important or life-threatening: Atrioventricular
require temporary discontinuation of arsenic trioxide. block, bone marrow necrosis, cardiac failure, deafness,
The onset of differentiation syndrome has occurred as heart block, increased gamma-glutamyl! transferase,
early as day 1 of induction to as late as the second month malignant melanoma, pancytopenia, paresis, peripheral
of induction therapy. Prophylaxis with prednisone is rec- neuropathy, rhabdomyolysis, squamous cell carcinoma,
ommended when arsenic trioxide is used in combination toxic epidermal necrolysis, ventricular premature con-
with tretinoin. At the first signs of differentiation syndrome, tractions, ventricular tachycardia
interrupt arsenic trioxide and administer dexamethasone Drug Interactions
10 mg IV twice daily; continue high-dose corticosteroids
Metabolism/Transport Effects None known.
until signs/symptoms have abated for at least 3 days. In
newly diagnosed low-risk APL studies, patients treated
Avoid Concomitant Use
with arsenic trioxide in combination with tretinoin experi- Avoid concomitant use of Arsenic Trioxide with any of the
enced elevated AST, alkaline phosphatase, and/or serum following: Amifampridine; BCG (Intravesical); Bromper-
bilirubin which usually resolved with temporary discontin- idol; Deferiprone; Dipyrone; Hydroxychloroquine; Maci-
uation of arsenic trioxide and/or tretinoin. Monitor liver morelin; MiFEPRIStone; Mizolastine; Probucol;
function tests at least 2 to 3 times a week during arsenic Promazine; QTc-Prolonging Agents (Highest Risk);
trioxide treatment and continue monitoring until toxicity QTc-Prolonging Agents (Moderate Risk); Vinflunine
recovers. Withhold arsenic trioxide treatment and/or treti- Increased Effect/Toxicity
noin if AST, alkaline phosphatase and/or serum bilirubin Arsenic Trioxide may increase the levels/effects of:
elevations >5 times the upper limit of normal occur. Long- Amifostine; Antipsychotic Agents (Second Generation
term hepatic abnormalities may occur in patients with APL [Atypical]); Bromperidol; Deferiprone; DULoxetine;
treated with arsenic trioxide in combination with tretinoin. Hypotension-Associated Agents; Levodopa; Nitroprus-
Mild hepatic dysfunction and hepatic steatosis have been side; Pholcodine; QTc-Prolonging Agents (Highest Risk)
observed at a median of 7 years (range: up to 14 years)
following arsenic trioxide and tretinoin combination ther- The levels/effects of Arsenic Trioxide may be increased
apy. Use with caution in patients with hepatic impairment; by: Amifampridine; Barbiturates; Bilastine; Blood Pres-
in patients with severe hepatic impairment, monitor closely sure Lowering Agents; Brimonidine (Topical); Buprenor-
for toxicity. Use with caution in patients with severe renal phine; Chloramphenicol (Ophthalmic); Diazoxide;
impairment (dose reduction may be warranted); systemic Dipyrone; FLUoxetine; Herbs (Hypotensive Properties);
exposure may be higher; monitor closely for toxicities. Hydroxychloroquine; Indapamide; Lormetazepam; Maci-
Arsenic trioxide has not been studied in dialysis patients. morelin; MiFEPRIStone; Mizolastine; Molsidomine; Naf-
Monitor electrolytes, CBC with differential, and coagula- topidil; Nicergoline; Nicorandil; Obinutuzumab;
tion parameters at least twice a week during induction and Pefloxacin; Pentoxifylline; Phosphodiesterase 5 Inhibi-
weekly during consolidation; more frequently if clinically tors; Probucol; Promazine; Prostacyclin Analogues;
indicated. Arsenic trioxide is a human carcinogen; monitor QTc-Prolonging Agents (Indeterminate Risk and Risk
for the development of second primary malignancies. Modifying); QTc-Prolonging Agents (Moderate Risk);
Arsenic trioxide is associated with a moderate emetic Quinagolide; Teneligliptin; Vinflunine; Xipamide

180
 ARTEMETHER AND LUMEFANTRINE

Decreased Effect adolescents 214 years; however, age was not an

Arsenic Trioxide may decrease the levels/effects of: exclusion criteria in clinical trial
Antidiabetic Agents; BCG (Intravesical) Induction (beginning 10 days after initiation of treti-
noin): IV: 0.15 mg/kg/day until bone marrow remis-
The levels/effects of Arsenic Trioxide may be decreased sion; maximum induction: 75 doses
by: Bromperidol Consolidation: IV: 0.15 mg/kg/day Monday through
Hazardous Drugs Handling Considerations Friday for 4 weeks every 8 weeks for 4 cycles
Hazardous agent (NIOSH 2016 [group 1)). (weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28)
Use appropriate precautions for receiving, handling, In combination with tretinoin, idarubicin, and predni-
administration, and disposal. Gloves (single) should be sone (APML4 protocol) (lland 2012): Children >1
worn during receiving, unpacking, and placing in storage. year and Adolescents:
Induction: IV: 0.15 mg/kg/day over 2 hours on days
NIOSH recommends double gloving, a protective gown, 9 to 36 (in combination with tretinoin and idaru-
ventilated engineering controls (a class II biological safety bicin)
cabinet or a compounding aseptic containment isolator), Consolidation: lV: 0.15 mg/kg/day on days 1 to 28 of
and closed system transfer devices (CSTDs) for prepara- consolidation cycle 1 (in combination with treti-
tion. Double gloving, a gown, and (if dosage form allows) noin); 0.15 mg/kg/day on days 1 to 5, 8 to 12, 15
CSTDs are required during administration (NIOSH 2016). to 19, 22 to 26, and 29 to 33 of consolidation cycle
Storage/Stability Store intact vials/ampules at 20°C to 2 (in combination with tretinoin); 2 cycles total
25°C (68°F to 77°F); excursions permitted to 15°C to 30°C Acute promyelocytic leukemia (APL), relapsed or
(59°F to 86°F); do not freeze. Following dilution in DSW or refractory: Children 24 years and Adolescents:
NS, solutions diluted for infusion are stable for 24 hours at Induction: IV: 0.15 mg/kg/day; administer daily until
room temperature or 48 hours when refrigerated: bone marrow remission; maximum induction: 60
Mechanism of Action Arsenic trioxide induces apoptosis doses
in APL cells via morphological changes and DNA frag- Consolidation: IV: 0.15 mg/kg/day starting 3 to 6
mentation; also damages or degrades the fusion protein weeks after completion of induction therapy; max-
promyelocytic leukemia (PML)-retinoic acid receptor imum consolidation: 25 doses over a period of up to
(RAR) alpha 5 weeks
Pharmacodynamics/Kinetics. (Adult data unless Renal Impairment: Pediatric
noted) Children, Adolescents:
Distribution: Vgss: Arsenious acid (As!"'): 562 L; widely Mild to moderate impairment (CrCl 230 mL/minute):
distributed throughout body tissues; dependent on body There are no dosage adjustments provided in the
weight and increases as body weight increases; orally manufacturer's labeling.
administered arsenic trioxide distributes into the CNS Severe renal impairment (CrCl <30 mL/minute): Use
Metabolism: Arsenic trioxide is immediately hydrolyzed to with caution (systemic exposure to metabolites may
the active form, arsenious acid (As'"') which is methy- be higher); may require dosage reduction; monitor
lated (hepatically) to the less active pentavalent metab- closely for toxicity.
olites, monomethylarsonic acid (MMAY) and Dialysis patients: There are no dosage adjustments
dimethylarsinic acid (DMA’) by methyltransferases; As!" provided in the manufacturer's labeling (has not been
is also oxidized to the minor metabolite, arsenic
studied).
acid (AsY) Hepatic Impairment: Pediatric Children, Adolescents:
Half-life elimination: As'"': 10 to 14 hours; MMAY: ~32 There are no dosage adjustments provided in the man-
ufacturer's labeling; use with caution. Patients with
hours; DMA’: ~72 hours
severe impairment (Child-Pugh class C) should be moni-
Time to peak: As''!: At the end of infusion (2 hours); MMAY
and DMAVY; ~10 to 24 hours
tored closely for toxicity.
Excretion: Urine (MMAY, DMAY, and ~15% of a dose as Preparation for Administration Dilute in 100 to 250 mL
D5W or NS. Discard unused portion of ampul.
unchanged As!"')
Pharmacodynamics/Kinetics: Additional Consider- Administration Do not mix with other medications. Infuse
over 1 to 2 hours. If acute vasomotor reactions occur, may
ations
infuse over a maximum of 4 hours. Does not require
Renal function impairment: Results from a pharmacoki-
administration via a central venous catheter.
netic study in patients with advanced malignancies
Vesicant/Extravasation Risk May be an irritant
showed that mean AUC for As!" was ~48% higher in
Monitoring Parameters Baseline then weekly 12-lead
patients with several renal impairment (CrCl <30 mL/
ECG; monitor electrolytes, CBC with differential, and
minute) than in patients with normal renal function (CrCl
coagulation at baseline then at least twice weekly during
>80 mL/minute). Systemic exposure to metabolites
induction and at least weekly during consolidation; more
MMAVY and DMAY may also be increased in patients with
frequent monitoring may be necessary in unstable
renal impairment. Sas ers
patients
Hepatic function impairment: A small pharmacokinetic
Dosage Forms Excipient information presented when
study in patients with hepatocellular carcinoma showed
available (limited, particularly for generics); consult spe-
that the mean dose-normalized AUC and C,,x values
cific product labeling. [DSC] = Discontinued product
were 40% and 70% higher, respectively, in a patient with
Solution, Intravenous:
severe hepatic impairment (Child-Pugh class C) versus
Trisenox: 10 mg/10 mL (10 mL [DSC])
patients with normal hepatic function. Additionally, the
Solution, Intravenous [preservative free]:
mean dose-normalized trough plasma levels for metab-
Trisenox: 12 mg/6 mL (6 mL)
olites MMAY and DMAY were 2.2-fold and 4.7-fold higher,
respectively, than levels in patients with normal hepatic @ Artane see Trihexyphenidyl on page 2008
function. @ Artemether and Benflumetol see Artemether and
Dosing Lumefantrine on page 181
Pediatric
Note: Arsenic trioxide is associated with a moderate
emetic potential; antiemetics are recommended to pre- Artemether and Lumefantrine
vent nausea and vomiting (Dupuis 2011) (ar TEM e ther & loo me FAN treen)
Acute promyelocytic leukemia (APL), initial treat- Brand Names: US Coartem
ment: Limited data available: Therapeutic Category Antimalarial Agent
Single-agent (Mathews 2006): Children and Adoles-
Generic Availability (US) No
cents: Dosing based on experience available for
Use Treatment of acute, uncomplicated malaria infections
children 23 years; however, age was not an exclu-
due to Plasmodium falciparum, including malaria in geo-
sion criteria in clinical trial
graphical regions where chloroquine resistance has been
Induction: IV: 0.15 mg/kg/day (maximum dose:
reported [FDA approved in children 22 months (and at
10 mg/dose); administer daily until bone marrow
least 5 kg) and adults]
remission; maximum induction: 60 doses
Pregnancy Risk Factor C
Consolidation: !V: 0.15 mg/kg/day (maximum dose:
Pregnancy Considerations Safety data from an obser-
10 mg/dose) for 4 weeks, starting 4 weeks after
vational pregnancy study included 500 pregnant women
completion of induction therapy
exposed to artemether/lumefantrine and did not show an
Maintenance: IV: 0.15 mg/kg/dose (maximum dose:
increase in adverse outcomes or teratogenic effects over
10 mg/dose) administered 10 days per month for 6
background rate. Approximately one-third of these
months, starting 4 weeks after completion of con-
patients were in the third trimester.
solidation therapy
In: combination with tretinoin and gemtuzumab in high- Malaria infection in pregnant women may be more severe
risk APL (Ravandi 2009): Children and Adolescents:
Dosing based on experience available for
than in nonpregnant women. Infection may increase the
risk of adverse pregnancy outcomes, including >
181
 ARTEMETHER AND LUMEFANTRINE

q miscarriage, premature delivery, low birth weight, congen-

ital infection, or perinatal death (CDC July 2013). Arte-
Halofantrine;
morelin;
Hydroxychloroquine;
MiFEPRIStone; Mizolastine;
Lumefantrine;
Probucol;
Maci-
Proma-
mether/lumefantrine may be used to treat uncomplicated zine; QTc-Prolonging Agents (Highest Risk); QTc-
malaria during the second and third trimesters. Arte- Prolonging Agents (Moderate Risk); St John's Wort;
mether/lumefantrine also may be used as an alternative Vinflunine
treatment during the first trimester when preferred agents Increased Effect/Toxicity
are not available. Dosing is the same as nonpregnant Artemether and Lumefantrine may increase the levels/
patients (Ballard [CDC] 2018). effects of: Antimalarial Agents; Antipsychotic Agents
Artemether may reduce the effectiveness of hormonal (Phenothiazines); CYP2D6 Substrates (High risk with
contraceptives. An additional nonhormonal method of Inhibitors); Dapsone (Systemic); Dapsone (Topical);
birth control should be used during therapy. Etravirine; Halofantrine; Lumefantrine; QTc-Prolonging
Breastfeeding Considerations It is not known if arte- Agents (Highest Risk)
mether or lumefantrine are present in breast milk. Accord- The levels/effects of Artemether and Lumefantrine may
ing to the manufacturer, the decision to continue or be increased by: Amifampridine; Antimalarial Agents;
discontinue breastfeeding during therapy should take into Artemether; Bilastine; Buprenorphine; CYP3A4_ Inhibi-
account the risk of exposure to the infant and the benefits
tors (Strong); Dapsone (Systemic); Etravirine; FLUoxe-
of treatment to the mother. The CDC does not recommend
tine; Grapefruit Juice; Hydroxychloroquine; Indapamide;
use of this combination when breastfeeding infants weigh-
Macimorelin; MiFEPRIStone; Mizolastine; Pefloxacin;
ing <5 kg (CDC Yellow Book 2017).
Probucol; Rromazine; QTc-Prolonging Agents (Indeter-
Contraindications Hypersensitivity to artemether, lume-
~-minate Risk and Risk Modifying); QTc-Prolonging Agents
fantrine, or any component of the formulation; concurrent
use with strong CYP3A4 inducers (eg, rifampin, carbama- (Moderate Risk); Teneligliptin; Vinflunine; Xipamide
zepine, phenytoin, St John’s wort) Decreased Effect
Warnings/Precautions Use associated with prolonging Artemether and Lumefantrine may decrease the levels/
the QT interval; avoid use in patients at risk for QT effects of: Estrogen Derivatives (Contraceptive); NiMO-
prolongation, including patients with a history of long QT Dipine; Progestins (Contraceptive) _
syndrome, family history of congenital QT prolongation or The levels/effects of Artemether and Lumefantrine may
sudden death, symptomatic arrhythmias, clinically rele- be decreased by: Bosentan; CYP3A4 Inducers (Moder-
vant bradycardia, severe heart disease, known hypokale- ate); CYP3A4 Inducers (Strong); Dabrafenib; Defera-
mia, hypomagnesemia or concurrent administration of
sirox; Etravirine; Nevirapine; Pitolisant; Sarilumab;
antiarrhythmics (eg, Class la or III), drugs metabolized
Siltuximab; St John's Wort; Tocilizumab
by CYP2D6 known to have cardiac effects (eg, flecainide,
Food Interactions Absorption of artemether and lumefan-
tricyclic antidepressants), or other drugs known to prolong
trine is increased in the presence of food. The bioavail-
the QT interval (eg, antipsychotics, antidepressants, mac-
rolides, fluoroquinolones, triazole antifungals, or cisapr- ability of artemether increases two- to threefold and
ide). ECG monitoring is advised if concomitant use of lumefantrine increases 16-fold (particularly a high-fat
agents that prolong the QT interval is medically required. meal). Administration with grapefruit juice may result in
In addition, do not use halofantrine (not available in the increased concentrations of artemether and/or lumefan-
US) and artemether/lumefantrine within 1 month of one trine and potentiate QT prolongation. Management:
another due to the potential additive effects on the QT Administer with a full meal for maximal absorption. Avoid
interval. After discontinuation of artemether/lumefantrine, grapefruit juice.
drugs that prolong the QT interval, including quinidine and Storage/Stability Store at 25°C (77°F); excursions per-
quinine, should be used with caution. Other potentially mitted to 15°C to 30°C (59°F to 86°F).
significant drug-drug interactions may exist, requiring Mechanism of Action A coformulation of artemether and
dose or frequency adjustment, additional monitoring, lumefantrine with activity against Plasmodium falciparum.
and/or selection of alternative therapy. Artemether and major metabolite dihydroartemisinin
(DHA) are rapid schizontocides with activity attributed to
Not indicated for the treatment of severe or complicated
malaria or for the prevention of malaria. In the event of the endoperoxide moiety common to each substance.
disease reappearance after a quiescent period, patients Artemether inhibits an essential calcium adenosine tri-
should be treated with a different antimalarial drug. Use phosphatase. The exact mechanism of lumefantrine is
caution in patients with severe hepatic or renal unknown, but it may inhibit the formation of B-hematin
impairment. by complexing with hemin. Both artemether and lumefan-
Adverse Reactions trine inhibit nucleic acid and protein synthesis. Artemether
Cardiovascular: Palpitation (adults) rapidly reduces parasite biomass and lumefantrine elimi-
Central nervous system: Chills (more common in adults), nates residual parasites.
dizziness (more common in adults), fatigue (more Pharmacodynamics/Kinetics (Adult data unless
common in adults), fever, headache (more common noted)
in adults), insomnia (adults), malaise (adults), sleep Absorption: Artemether: Rapid; Lumefantrine: Initial
disorder (adults), vertigo (adults) absorption at 2 hours; enhanced with food
Dermatologic: Pruritus (adults), skin rash Protein binding: Artemether: 95%; Dihydroartemisinin
Gastrointestinal: Abdominal pain, anorexia (more com- (DHA): 47% to 76%; Lumefantrine: 99.7%
mon in adults), diarrhea, nausea (more common in Metabolism:
adults), vomiting Artemether is hepatically metabolized to an active
Hematologic & oncologic: Anemia metabolite, dihydroartemisinin (DHA), catalyzed pre-
Hepatic: Hepatomegaly, increased serum AST dominately by CYP3A4/5 and to a lesser extent by
Infection: Malaria, plasmodium falciparum (exacerbation: CYP2B6, CYP2C9 and CYP2C19. The artemether/
children) DHA AUC ratio is 1.2 after 1 dose and 0.3 after 6
Neuromuscular & skeletal: Arthralgia (more common in doses which may indicate autoinduction.
adults), myalgia (more common in adults), weakness Lumefantrine is hepatically metabolized to desbutyl-
(more common in adults) lumefantrine by CYP3A4.
Respiratory: Cough (more common in children), naso-
Bioavailability: Absorption of artemether and lumefantrine
pharyngitis, rhinitis
is increased in the presence of food. The bioavailability
Miscellaneous: Fever
of artemether increases two- to threefold and lumefan-
Rare but important or life-threatening: Abnormal gait,
trine increases 16-fold (particularly a high-fat meal).
abnormal lymphocytes, abscess, agitation, asthma,
Half-life elimination: Artemether: 1-2 hours; DHA: 2 hours;
ataxia, back pain, bullous dermatitis, conjunctivitis,
decreased hematocirt, decreased platelet count, Lumefantrine: 72-144 hours
decreased white blood cell count, dysphagia, emotional Time to peak, plasma: Artemether: ~2 hours; Lumefan-
lability, eosinophilia, fine motor control disorder, hema- trine: ~6-8 hours
turia, hemolytic anemia (delayed), hyper-reflexia, hypo- Dosing
esthesia, hypokalemia, impetigo, leukocytosis, Pediatric
nystagmus, oral herpes, otic infection, peptic ulcer, Malaria, uncomplicated (due to P. falciparum, includ-
pneumonia, proteinuria, tinnitus, tremor, upper respira- ing chloroquine resistant P. falciparum): Note: Not
tory tract infection, urinary tract infection, urticaria for treatment of severe or complicated Plasmodium
Drug Interactions falciparum malaria or prevention of malaria.
Metabolism/Transport Effects Refer to individual Infants 22 months, Children, and Adolescents: Oral
components. (artemether 20 mg / lumefantrine 120 mg per tablet):
Avoid Concomitant Use 5 kg to <15 kg: One tablet at hour 0 and at hour 8. on
Avoid concomitant use of Artemether and Lumefantrine the first day and then one tablet twice daily (in the
with any of the following: Amifampridine; Antimalarial morning and evening) on days 2 and 3 (total of 6
Agents; Artemether; CYP3A4 Inducers (Strong); tablets per treatment course)

182
 ARTESUNATE

15 kg to <25 kg: Two tablets at hour 0 and at hour 8 pregnant women may be more severe than in nonpreg-
on the first day and then two tablets twice daily (in nant women. Because P. falciparum malaria can cause
the morning and evening) on days 2 and 3 (total of maternal death, congenital malaria, and fetal loss, preg-
12 tablets per treatment course) nant women traveling to malaria-endemic areas must use
25 kg to <35 kg: Three tablets at hour 0 and at hour personal protection against mosquito bites. Artesunate is
8 on the first day and then three tablets twice daily recommended for the treatment of severe malaria in
(in the morning and evening) on day 2 and 3 (total pregnant women (Kovacs 2015).
of 18 tablets per treatment course) — Breastfeeding Considerations Low concentrations of
235 kg: Four tablets at hour 0 and at hour 8 on the the active metabolite of artesunate (dihydroartemisinin)
first day and then four tablets twice daily (in the can be detected in breast milk. Adverse events in the
morning and evening) on days 2 and 3 (total of 24 nursing infant would not be expected.
tablets per treatment course) Contraindications Hypersensitivity to artesunate or any
Renal Impairment: Pediatric Dosage adjustments are component of the formulation (Hess, 2010)
not recommended in mild or moderate impairment. Use Warnings/Precautions Postartemisinin delayed hemoly-
caution in severe impairment (has not been studied). sis (PADH), characterized by a decrease in hemoglobin
Hepatic Impairment: Pediatric Dosage adjustments due to hemolysis, may occur 1 to 3 weeks after artesunate
are nat recommended in mild or moderate impairment. administration; patients with high parasitemia may be at
Use caution in severe impairment (has not been greater risk. Hemolysis is thought to be caused by delayed
studied). and synchronous clearance of once-infected erythrocytes
Administration Administer with a full meal for best (pitted cells), which continue to circulate after artesunate
absorption. For infants, children, and patients unable to treatment. Hemoglobin levels usually decline in the sec-
swallow tablets: Crush tablet and mix with 5 to 10 mL of ond and third weeks after artesunate administration (Jaur-
water in a clean container; administer; rinse container with eguiberry 2014). Acute kidney injury may be associated
water and administer remaining contents. The crushed with PADH (Plewes 2015). Monitor hemoglobin and renal
mixture should be followed with food/milk, infant formula, function for 1 month after artesunate administration for the
pudding, porridge, or broth if possible. Repeat dose if development of PADH (CDC [Paczkowsi 2014], Plewes
vomiting occurs within 2 hours of administration; for 2015).
persistent vomiting, explore alternative therapy.
Severe allergic reactions have been reported with oral
Monitoring Parameters Monitor for adequate food con-
administration of artesunate (Leonardi 2001); monitor for
sumption (to ensure absorption and efficacy); ECG mon-
signs of hypersensitivity and discontinue treatment in
itoring is advised if concomitant use of other agents that
patients who develop severe hypersensitivity reactions
prolong the QT interval is medically required or patients
(eg, angioedema, dyspnea, erythema, anaphylaxis). QT
with significant hypokalemia or hypomagnesemia
prolongation has been reported with other artemisinin
Dosage Forms Excipient information presented when
derivatives (eg, artemether); however, one report sug-
available (limited, particularly for generics); consult spe- gests that the mean QTc interval was unaffected by
cific product labeling.
artesunate (Maude 2009).
Tablet:
Adverse Reactions
Coartem: Artemether 20 mg and lumefantrine 120 mg
Cardiovascular: Hypotension
@ Artemether/Lumefantrine see Artemether and Lume- Central nervous system: Anxiety, ataxia, dizziness, head-
fantrine on page 181 ache, hyperreflexia, metallic taste, restlessness, slurred
speech
@ Artemisinin Derivative see Artesunate on page 183
Dermatologic: Erythema, pruritus, skin rash, urticaria
Endocrine & metabolic: Hypoglycemia
Artesunate (ar TES 00 nate) Gastrointestinal: Anorexia, diarrhea, nausea, vomiting
Hematologic & oncologic: Anemia, hemolysis, neutrope-
Therapeutic Category Antimalarial Agent; Artemisinin nia, reticulocytopenia
Derivative Hepatic: Increased serum ALT
Use Treatment of severe malaria cause by Plasmodium Hypersensitivity: Angioedema, hypersensitivity reaction
falciparum Neuromuscular & skeletal: Tremor
Prescribing and Access Restrictions Renal: Increased blood urea nitrogen
Investigational agent — not approved for use in the US Respiratory: Dyspnea
Drug Interactions
Artesunate is available in the U.S. for IV use in patients
with malaria through an Investigational New Drug (IND) Metabolism/Transport Effects Substrate of CYP2A6
protocol. To obtain artesunate via the IND protocol, clini- (major); Note: Assignment of Major/Minor substrate sta-
cians must contact the Centers for Disease Control (CDC) tus based on clinically relevant drug interaction potential
Malaria Hotline at 770-488-7788 (business hours) or Avoid Concomitant Use
770-488-7100 (nonbusiness hours) and request to speak Avoid concomitant use of Artesunate with any of the
with a CDC Malaria Branch clinician. Additional informa- following: Artemether; Lumefantrine
tion from the CDC is available at https://www.cdc.gov/ Increased Effect/Toxicity
laboratory/drugservice/formulary.html. Artesunate may increase the levels/effects of: Antipsy-
chotic Agents (Phenothiazines); Dapsone (Systemic);
Eligibility criteria under the IND protocol include (Callender Dapsone (Topical); Lumefantrine; Primaquine
2011; Hess 2010):
- Patients must have malaria: Confirmation by micro- The levels/effects of Artesunate may be increased by:
scopy or undetermined but strong clinical suspicion of Artemether; Dapsone (Systemic); Nevirapine
Plasmodium falciparum or other Plasmodium spp. Decreased Effect
infection The levels/effects of Artesunate may be decreased by:
- Patients must require parenteral therapy: Unable to Nevirapine; Ritonavir
take oral medications, high-density parasitemia (eg, Storage/Stability Store intact vials below 30°C. Protect
>5%), or diagnosis of severe malaria (eg, seizures, from light. Reconstituted solutions are stable below 30°C
shock, hemoglobin <7 g/dL, disseminated intravascular for 1 hour following reconstitution.
coagulation, or acute respiratory distress syn- Mechanism of Action Artesunate, a semisynthetic deriv-
drome [ARDS)). ative of artemisinin, is a prodrug which is converted to
- IV artesunate must be the preferred treatment: IV dihydroartemisinin (DHA). DHA is an antimalarial agent
artesunate is at least as readily available as IV quini- active against all of the erythrocytic stages of the parasite
dine or the patient has experienced quinidine failure including gametocytes; inhibits parasite metabolism and
(eg, parasitemia >10% baseline after 48 hours of enhances the clearance of infected erythrocytes.
quinidine therapy), quinidine intolerance (eg, persistent
Antiparasitic activity is hypothesized to involve cleavage of
hypotension, QRS prolongation >50% of baseline or
the Fe?*of endoperoxide bridge, thereby producing free
QTc interval prolongation >25% of baseline), or contra-
radicals and damaging parasite proteins. DHA may also
indications to quinidine (eg, allergy, left bundle branch
inhibit calcium adenosine triphosphatase (cATP) of the
block, myasthenia gravis, digoxin toxicity).
sarcoplasmic endoplasmic reticulum and impair parasite
For medical access; to |V artesunate in Canada, please protein folding.
refer to special access information on the Public Health Pharmacodynamics/Kinetics (Adult data unless
Agency of Canada website, http://www.phac-aspc.gc.ca/ noted)
tmp-pmvy/quinine/. Distribution: Vgss5: Adults infected with severe malaria:
Pregnancy Considerations Adverse events have been Artesunate: 15.2 L/kg (range: 2.2 to 39 L/kg); Dihydroar-
observed in some animal reproduction studies. Studies in temisinin (DHA): 1.9 L/kg (range: 0.8 to 11.5 L/kg) (New-
pregnant women have not revealed an increased risk of ton 2006)
congenital abnormalities in newborns (Kovacs 2015, Protein binding: Dihydroartemisinin (DHA): 93%
McGready 1998, McGready 2008). Malaria infection in (WHO 2015)
 ARTESUNATE

& Metabolism: Artesunate (prodrug) is rapidly hydrolyzed by dental procedures may resume breastfeeding once they
plasma esterases to an active metabolite, dihydroarte- are awake and stable (Montgomery 2012).
misinin (DHA). DHA undergoes hepatic metabolism via Contraindications
CYP2B6, CYP2C19, and CYP3A4 to inactive metabo- Sulfite hypersensitivity. '
lites (Hess 2010). Documentation of allergenic cross-reactivity for local
Half-life elimination: Artesunate: Adults infected with anesthetics is limited. However, because of similarities
severe malaria: 0.22 hours (range: 0.08 to 0.61 hours); in chemical structure and/or pharmacologic actions, the
Dihydroartemisinin (DHA): 0.34 hours (range: 0.14 to possibility of cross-sensitivity cannot be ruled out with
0.87 hours) (Newton 2006) certainty.
Time to peak: Dihydroartemisinin (DHA): Adults infected Canadian labeling: Additional contraindications (not in US
with severe malaria: Within 15 minutes (Newton 2006) labeling): Allergies to dental anesthetics; patients with
Excretion: Urine (as DHA-glucuronide) (WHO 2015) sepsis near the proposed injection site, severe shock,
Dosing paroxysmal tachycardia, frequent arrhythmia, neurolog-
Pediatric ical disease, or severe hypertension.
Malaria (severe), treatment: Limited data available: Warnings/Precautions Systemic toxicity may occur. Sys-
Infants, Children, and Adolescents: temic absorption of local anesthetics may produce cardi-
Patient weight <20 kg: IM, IV: 3 mg/kg/dose initially, ovascular and/or CNS effects. Toxic blood concentrations
followed by 3 mg/kg/dose at 12 hours, 24 hours, and of local anesthetics depress cardiac conduction and excit-
ability, which may lead to AV block, ventricular arrhyth-
48 hours after the initial dose for a total of 4 doses
mias, and cardiac arrest (sometimes resulting in death). In
over a period of 3 days. Transition to oral therapy at
addition, myocardial contractility is depressed and periph-
least 4 hours after the last dose of artesunate
eral vasodilation occurs, leading to decreased cardiac
(WHO 2015).
output and arterial blood pressure. Restlessness, anxiety,
Patient weight 220 kg: IM, IV: 2.4 mg/kg/dose initially,
tinnitus, dizziness, blurred vision, tremors, depression, or
followed by 2.4 mg/kg/dose at 12 hours, 24 hours,
drowsiness may be early warning signs of CNS toxicity.
and 48 hours after the initial dose for a total of 4doses
Small doses of local anesthetics injected into dental
over a period of 3 days. Transition to oral therapy at
blocks may produce adverse reactions similar to systemic
least 4 hours after the last dose of artesunate
toxicity, including confusion, convulsions, respiratory
(WHO 2015). depression and/or respiratory arrest, and cardiovascular
Note: Longer treatment duration may be required in ° stimulation or depression; these reactions may be due to
severely-ill patients or in patients unable to transition intra-arterial injection of the local anesthetic with retro-
to oral therapy; an additional 4 days has been grade flow to the cerebral circulation. Constantly monitor
reported (Hess 2010; Rosenthal 2008). cardiovascular and respiratory vital signs and patient's
Renal Impairment: Pediatric Infants, Children, and state of consciousness carefully following each injection.
Adolescents: No dosage adjustment necessary (Rosen- Epinephrine may cause local toxicity, including ischemic
thal 2008); use with caution (WHO 2015). injury or necrosis. Local anesthetics containing a vaso-
Hepatic Impairment: Pediatric Infants, Children, and constrictor may cause methemoglobinemia, especially in
Adolescents: No dosage adjustment necessary (Rosen- combination with methemoglobin-inducing agents. Do not
thal 2008); use with caution (WHO 2015). use in patients with congenital or idiopathic methemoglo-
Preparation for Administration Reconstitute vial with binemia, or in patients who are receiving treatment with
11 mL of phosphate buffer diluent (provided), gently swirl methemoglobin-inducing agents. Use with caution in
for 5 to 6 minutes to mix; resultant concentration is patients with impaired cardiovascular function, including
10 mg/mL (CDC 2014). patients with heart block. Use local anesthetics containing
Administration a vasoconstrictor with caution in patients with vascular
IM: Administer by |M injection into the anterior thigh (WHO disease; patients with peripheral vascular disease or
2015). hypertensive vascular disease may exhibit exaggerated
IV: Administer IV over 1 to 2 minutes through a 0.8-micron vasoconstrictor response, possibly resulting in ischemic
hydrophilic polyethersulfone filter (CDC 2014; injury or necrosis. Dosages should be reduced for patients
Hess 2010). with cardiac disease. Use with caution in patients with
Monitoring Parameters Signs and symptoms of hyper- severe hepatic disease (has not been studied).
sensitivity reactions; hemoglobin and renal function 1 Administer reduced dosages, commensurate with age and
month after therapy for postartemisinin delayed hemolysis physical condition to pediatric, elderly, debilitated and/or
(PADH) acutely-ill patients. Avoid intravascular injection; acciden-
Dosage Forms Excipient information presented when tal intravascular injection may be associated with convul-
available (limited, particularly for generics); consult spe- sions, followed by CNS or cardiorespiratory depression
cific product labeling. and coma, progressing ultimately to respiratory arrest.
Solution Reconstituted, Injection: 110 mg [phosphate buf- Aspiration should be performed prior to administration;
fer solution provided as diluent] the needle must be repositioned until no return of blood
can be elicited by aspiration; however, absence of blood in
@ Artesunic Acid see Artesunate on page 183 the syringe does not guarantee that intravascular injection
@ Articadent see Articaine and Epinephrine on page 184 has been avoided. To avoid serious adverse effects and
high plasma levels, use the lowest dosage resulting in
effective anesthesia. Repeated doses may cause signifi-
Articaine and Epinephrine cant increases in blood levels due to the possibility of
(AR ti kane & ep i NEF rin)
accumulation of the drug or its metabolites. Dosage rec-
Brand Names: US Articadent; Orabloc; Septocaine with ommendations should not be exceeded. Health care
Epinephrine 1:100,000; Septocaine with Epinephrine providers should be well trained in diagnosis and manage-
1:200,000; Zorcaine ment of emergencies that may arise from the use of these
Brand Names: Canada Astracaine with Epinephrine agents. Resuscitative equipment, oxygen, and other
1:200,000; Astracaine with Epinephrine forte 1:100,000; resuscitative drugs should be available for immediate
Karticaine; Karticaine Forte; Orabloc 1:100,000; Orabloc use. May contain sodium metabisulfite, which may cause
1:200,000; Posicaine N; Posicaine SP; Septanest N; allergic-type reactions (including anaphylactic symptoms,
Septanest SP; Ultracaine DS; Ultracaine DS Forte; Zor- and life-threatening or less severe asthmatic episodes) in
caine certain susceptible patients. The overall prevalence of the
Therapeutic Category Local Anesthetic sulfite sensitivity in the general population is unknown,
and is seen more frequently in asthmatic than in non-
Generic Availability (US) No
asthmatic persons. Potentially significant interactions
Use Local, infiltrative, or conductive anesthesia in both
may exist, requiring dose or frequency adjustment, addi-
simple and complex dental procedures (FDA approved
tional monitoring, and/or selection of alternative therapy.
in ages 24 years and adults)
Adverse Reactions Adverse reactions are characteristic
Pregnancy Risk Factor C of those associated with other amide-type local anes-
Pregnancy Considerations Adverse events have been thetics; adverse reactions to this group of drugs may also
observed in some animal reproduction studies using this result from excessive plasma levels which may be due to
combination. Articaine crosses the placenta (Strasser overdosage, unintentional intravascular injection, or slow
1977). metabolic degradation. :
Breastfeeding Considerations It is not known if arti- Cardiovascular: Cardiac arrhythmia, cardiac insufficiency,
caine or epinephrine are excreted in breast milk. The facial edema
manufacturer recommends that caution be exercised Central nervous system: Headache, pain, paresthesia,
when administering articaine/epinephrine to breastfeeding seizure
women; consideration may be given to pumping and Gastrointestinal: Gingivitis
discarding milk for 4 hours after the last dose. In general, Hypersensitivity: Hypersensitivity reaction
women administered single dose local anesthesia for Local: Injection site reaction

184
 ARTIFICIAL TEARS

Respiratory: Asthma Dosing presented in variable unit (mg/kg, mg, mL/kg,

Miscellaneous: Tissue necrosis and mL); use extra precaution to verify dosing units.
Rare but important or life-threatening: Abdominal pain, Children 24 years and Adolescents <16 years: Sub-
accidental injury, arthralgia, back pain, constipation, mucosal infiltration and/or nerve block: Articaine 4%/
dermatological disease, diarrhea, dizziness, drowsiness, epinephrine: Injection:
dysgeusia, dysmenorrhea, dyspepsia, ecchymoses, Simple procedures: Reported range: 0.76 to
edema, facial paralysis, gingival hemorrhage, glossitis, 5.65 mg/kg of articaine; maximum articaine dose:
hemorrhage, hyperesthesia, increased thirst, lympha- 7 mg/kg (0.175 mL/kg of 4% solution)
denopathy, malaise, methemoglobinemia, migraine, Complex procedures: 0.37 to 7 mg/kg of articaine;
myalgia, nausea, neck pain, nervousness, neuropathy, maximum articaine dose: 7 mg/kg (0.175 mL/kg of
oral mucosa ulcer, osteomyelitis, otalgia, pharyngitis, 4% solution)
pruritus, rhinitis, sialorrhea, stomatitis, syncope, tachy- Adolescents 217 years: Submucosal infiltration and/or
cardia, tongue edema, vomiting, weakness, xerostomia nerve block: Articaine 4%/epinephrine: Injection:
Drug Interactions Infiltration: 0.5 to 2.5 mL (total articaine dose: 20 to
Metabolism/Transport Effects Refer to individual 100 mg); not to exceed 7 mg/kg (0.175 mL/kg of 4%
components, solution) of articaine
Avoid Concomitant Use Nerve block: 0.5 to 3.4 mL (total articaine dose: 20 to
Avoid concomitant use of Articaine and Epinephrine with 136 mg); not to exceed 7 mg/kg (0.175 mL/kg of 4%
any of the following: Blonanserin; Bromperidol; Bupiva- solution) of articaine
caine (Liposomal); Ergot Derivatives; lobenguane | 123; Oral surgery: 1 to 5.1 mL (total articaine dose: 40 to
Lurasidone 204 mg); not to exceed 7 mg/kg (0.175 mL/kg of 4%
Increased Effect/Toxicity solution) of articaine
' Articaine and Epinephrine may increase the levels/ Renal Impairment: Pediatric There are no dosage
effects of: Bupivacaine (Liposomal); Doxofylline; Lurasi- adjustments provided in the manufacturer's labeling
done; Neuromuscular-Blocking Agents; Sympathomi- (has not been studied).
metics Hepatic Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer’s labeling (has
The levels/effects of Articaine and Epinephrine may be not been studied). Use with caution in patients with
increased by: AtoMOXetine; Beta-Blockers (Nonselec- severe hepatic disease.
tive); Cannabinoid-Containing Products; Chloroprocaine; Administration Dental: For submucosal infiltration and/or
Cocaine (Topical); COMT Inhibitors; Ergot Derivatives; nerve block injection. Avoid intravascular injection. Aspi-
Guanethidine; Hyaluronidase; Inhalational Anesthetics; rate the syringe after tissue penetration and before injec-
Linezolid; Monoamine Oxidase Inhibitors; Serotonin/Nor- tion to minimize chance of direct vascular injection.
epinephrine Reuptake Inhibitors; Tedizolid; Tricyclic Anti- Monitoring Parameters Vital signs, state of conscious-
depressants ness, signs of CNS toxicity (lightheadedness, dizziness,
Decreased Effect tinnitus, restlessness, tremors, twitching, drowsiness, cir-
Articaine and Epinephrine may decrease the levels/ cumoral paresthesia)
effects of: Antidiabetic Agents; Benzylpenicilloy! Polyly- Dosage Forms
sine; lobenguane | 123; Technetium Tc 99m Tilmanocept Excipient information presented when available (limited,
The levels/effects of Articaine and Epinephrine may be particularly for generics); consult specific product label-
decreased by: Alpha1-Blockers; Benperidol; Beta-Block- ing.
ers (Betai Selective); Beta-Blockers (with Alpha-Block- Injection, solution [for dental use]:
ing Properties); Blonanserin; Bromperidol; CloZAPine; Articadent: Articaine hydrochloride 4% [40 mg/mL] and
Promethazine; Spironolactone epinephrine 1:100,000 (1.7 mL) [contains sodium
Storage/Stability Store at 25°C (77°F) with brief excur- metabisulfite]
sions permitted to 15°C to 30°C (59°F to 86°F). Protect Articadent: Articaine hydrochloride 4% [40 mg/mL] and
from light. Do not freeze. epinephrine 1:200,000 (1.7 mL) [contains sodium
Mechanism of Action metabisulfite]
Articaine: Blocks both the initiation and conduction of Orabloc: Articaine hydrochloride 4% [40 mg/mL] and
nerve impulses by increasing the threshold for electrical epinephrine 1:100,000 (1.8 mL) [contains sodium
excitation in the nerve, slowing the propagation of the metabisulfite]
nerve impulse, and reducing the rate of rise of the action Orabloc: Articaine hydrochloride 4% [40 mg/mL] and
potential. epinephrine 1:200,000 (1.8 mL) [contains sodium
Epinephrine: Increases the duration of action of articaine metabisulfite]
by causing vasoconstriction (via alpha effects) which Septocaine with epinephrine 1:100,000: Articaine hydro-
slows the vascular absorption of articaine. chloride 4% [40 mg/mL] and epinephrine 1:100,000
Pharmacodynamics/Kinetics (Adult data unless (1.7 mL) [contains sodium metabisulfite]
Septocaine with epinephrine 1:200,000: Articaine hydro-
noted) Also refer to the Epinephrine (Systemic) mono-
chloride 4% [40 mg/mL] and epinephrine 1:200,000
graph.
(1.7 mL) [contains sodium metabisulfite]
Onset of action: 1 to 9 minutes
Zorcaine: Articaine hydrochloride 4% [40 mg/mL] and
Duration: Complete anesthesia: ~1 hour (infiltration); ~2
epinephrine 1:100,000 (1.7 mL) [contains sodium
hours (nerve block)
metabisulfite]
Distribution: Articaine: ~60% to 80%, bound to albumin
and gamma globulins
Metabolism: Articaine: Hepatic via plasma carboxyester- Artificial Tears (ar ti FISH il tears)
ase to articainic acid (inactive)
Half-life elimination: Articaine/epinephrine: 43.8 to 44.4 Medication Safety Issues
minutes Sound-alike/look-alike issues:
Time to peak, plasma: Articaine: ~25 minutes (single lsopto® Tears may be confused with lsoptin®
dose); 48 minutes (3 doses) Brand Names: US Advanced Eye Relief™ Dry Eye
Excretion: Urine (primarily as metabolites) Environmental [OTC]; Advanced Eye Relief™ Dry Eye
Dosing Rejuvenation [OTC]; Altalube [OTC]; Bion Tears [OTC]
Pediatric [DSC]; GenTeal Tears Mild [OTC]; GenTeal Tears Moder-
Dental anesthesia: Note: The provided dosages are ate [OTC]; GenTeal Tears Night-Time [OTC]; GenTeal
guides only; other dosages may be necessary; how- Tears PF [OTC]; GoodSense Lubricant Eye Drops
ever, do not exceed maximum recommended dose. [OTC]; HypoTears [OTC]; LiquiTears [OTC]; LubriFresh
The actual volumes to be used depend upon a number P.M. [OTC]; Murine Tears® [OTC]; Natural Balance Tears
of factors, such as type and extent of surgical proce- [OTC]; Natures Tears [OTC]; Puralube [OTC]; Soothe®
dure, depth of anesthesia, degree of muscular relaxa- Hydration [OTC]; Soothe® [OTC]; Systane Balance
tion, and condition of the patient. In all cases, the [OTC]; Systane Nighttime [OTC]; Systane Preservative
smallest dose that will produce the desired result Free [OTC]; Systane [OTC]; Systane® Ultra [OTC]; Tears
should be used. Two concentrations of epinephrine Again® [OTC]; Tears Naturale PM [OTC]; Tears Naturale®
(1:100,000 or 1:200,00) with 4% articaine are available; Free [OTC]; Tears Naturale® || [OTC] [DSC]; Viva-Drops®
when more pronounced hemostasis or improved visu- [OTC]
alization of the surgical field are required, epinephrine Brand Names: Canada Teardrops®
1:100,000 may be used; in clinical trials of pediatric Therapeutic Category Ophthalmic Agent, Miscellaneous
patients 4 to 16 years of age, the.1:100,000 was also Generic Availability (US) Yes
used; in adults, the manufacturer recommends epi- Use Ophthalmic lubricant; for temporary relief of burning
nephrine 1:200,000 for most routine dental procedures. and eye irritation due to dry eyes; protectant against
Dosages should be reduced for patients with cardiac further irritation (OTC: FDA approved in adults; refer to
disease and acutely ill and/or debilitated patients. product-specific information regarding FDA approval in >
185
ARTIFICIAL TEARS

pediatric patients); has also been used for symptomatic GenTeal Tears Night-Time: Petrolatum 94% and mineral
treatment of dry eye associated with conjunctivitis, ble- oil 3% (3.5 g)
pharitis, and keratitis Puralube: Petrolatum 85% and mineral oil 15% (3.5 g)
Warnings/Precautions Ophthalmic solutions may con- Tears Naturale PM: Petrolatum 94% and mineral oil 3%
tain benzalkonium chloride which may be absorbed by (3.5 g) [contains lanolin]
contact lenses. Remove contact lenses before using. Ointment, ophthalmic [preservative free]:
Some dosage forms may contain polysorbate 80 (also LubriFresh P.M.: Petrolatum 83% and mineral oil
known as Tweens). Hypersensitivity reactions, usually a 15% (3.5 g)
delayed reaction, have been reported following exposure Systane Nighttime: Petrolatum 94% and mineral oil
to pharmaceutical products containing polysorbate 80 in 3% (3.5 g)
certain individuals (Isaksson, 2002; Lucente 2000; Shel- Solution, ophthalmic:
ley, 1995). Thrombocytopenia, ascites, pulmonary deteri- Advanced Eye Relief™ Dry Eye Environmental: Glycerin
oration, and renal and hepatic failure have been reported 1% (15 mL) [contains benzalkonium chloride]
in premature neonates after receiving parenteral products Advanced Eye Relief™ Dry Eye Rejuvenation: Glycerin
containing polysorbate 80 (Alade, 1986; CDC, 1984). See 0.3% and propylene glycol 1% (30 mL) [contains
manufacturer's labeling. Preservative free formulations benzalkonium chloride]
are preferred in patients with severe dry eye or patients GentTeal Tears Mild: Dextran 70 0.1%, and hydroxy-
on multiple eye drops for chronic disease. Once opened, propyl methylcellulose 2910 0.3% (15 mL)
single use containers should be discarded; do not reuse. GenTeal—Tears Moderate: Dextran 70 0.1%, glycerin
When used for self-medication (OTC), stop use and 0.2%, and hydroxypropyl methylcellulose 2910 0.3%
contact healthcare provider if changes in vision, eye pain, (15 mL)
continued redness or irritation occur, or if the condition HypoTears: Polyvinyl alcohol 1% and polyethylene glycol
worsens or persists for more than 72 hours. To avoid 400 1% (30 mL) [contains benzalkonium chloride]
contamination, do not touch tip of container to any surface. LiquiTears: Polyvinyl alcohol 1.4% (15 mL) [contains
Replace cap after using. Do not use if solution is cloudy or benzalkonium chloride, edetate disodium]
changes color. Murine Tears®: Polyvinyl alcohol 0.5% and povidone
Warnings: Additional Pediatric Considerations 0.6% (15 mL) [contains benzalkonium chloride]
Some dosage forms may contain propylene glycol; in Natural Balance Tears: Dextran 70 0.1% and hydroxy-
neonates large amounts of propylene glycol delivered - propyl methylcellulose 2910 0.3% (15 mL) [contains
orally, intravenously (eg, >3,000 mg/day), or topically benzalkonium chloride, edetate disodium]
have been associated with potentially fatal toxicities which Natures Tears: Dextran 70 0.1% and hydroxypropyl
can include metabolic acidosis, seizures, renal failure, and methylcellulose 2910 0.3% (15 mL) [contains benzal-
CNS depression; toxicities have also been reported in konium chloride, edetate disodium]
children and adults including hyperosmolality, lactic acido- Soothe® Hydration: Povidone 1.25% (15 mL)
sis, seizures, and respiratory depression; use caution Systane Balance: Propylene glycol 0.6% (10 mL)
(AAP 1997; Shehab 2009). Systane® Ultra: Polyethylene glycol 400 0.4% and pro-
Adverse Reactions Ophthalmic: Blurred vision, crusting pylene glycol 0.3% (5 mL, 10 mL)
of eyelid, stinging of eyes (mild) Systane®: Polyethylene glycol 400 0.4% and propylene
Drug Interactions glycol 0.3% (5 mL, 15 mL, 30 mL)
Metabolism/Transport Effects None known. Tears Again®: Polyvinyl alcohol 1.4% (15 mL, 30 mL)
Avoid Concomitant Use There are no known interac- [contains benzalkonium chloride]
tions where it is recommended to avoid concomitant use. Tears Naturale® II: Dextran 70 0.1% and hydroxypropyl
Increased Effect/Toxicity There are no known signifi- methylcellulose 2910 0.3% (15 mL [DSC])
cant interactions involving an increase in effect. Solution, ophthalmic [preservative free]:
Decreased Effect There are no known significant inter- Bion Tears: Dextran 70 0.1% and hydroxypropyl methyl-
actions involving a decrease in effect. cellulose 2910 0.3% per 0.4 mL (28s [DSC])
Storage/Stability Store at room temperature. GenTeal Tears’ Mild: Dextran 70 0.1%, and hydroxy-
Mechanism of Action Products contain demulcents (ie, propyl methylcellulose 2910 0.3% (36s)
cellulose derivatives, dextran 70, gelatin, polyols, polyvi- GenTeal Tears PF: Dextran 70 0.1% and Hydroxypropyl
nal alcohol, or povidone); usually a water-soluble polymer, methylcellulose 2910 0.3% (36s)
applied topically to the eye to protect and lubricate GoodSense Lubricant Eye Drops: Polyethylene glycol
mucous membrane surfaces and relieve dryness and 400 0.4% and propylene glycol 0.3% (30s)
irritation Soothe®: Glycerin 0.6% and propylene glycol 0.6% per
Dosing 0.6 mL (28s)
Neonatal Note: Numerous products available, containing Systane Preservative Free: Polyethylene glycol
variable ingredients; ensure products containing propy- 400 0.4% and propylene glycol 0.3% per 0.4 mL
lene glycol or benzoate derivatives are NOT used in (28s, 30s)
neonatal population; consult product specific labeling. Tears Naturale® Free: Dextran 70 0.1% and hydroxy-
Ocular dryness/irritation or dry eye associated with propyl methylcellulose 2910 0.3% per 0.5 mL
ocular inflammation: Limited data available (Cogen (36s, 60s)
2011; Craiglow 2013; Harvey 2010; Sethuraman 1997): Viva-Drops®: Polysorbate 80 1% (0.5 mL, 10 mL)
Ophthalmic: Preservative-free dosage form:
Gel, Solution: 1 drop into eye(s) as needed to relieve @ Artiss see Fibrin Sealant on page 856
symptoms
Ointment: Apply small amount to inside of the eyelid(s) @ Arymo ER see Morphine (Systemic) on page 1400
one or more times daily @ Arze-Ject-A [DSC] see Triamcinolone (Systemic)
Pediatric on page 1997
Ocular dryness/irritation: Infants, Children, and Ado- @ AsO; see Arsenic Trioxide on page 179
lescents: Ophthalmic: @ ASA see Aspirin on page 194
Gel; Solution: 1 to 2 drops into eye(s) as needed to
relieve symptoms @ 5-ASA see Mesalamine on page 1313
Ointment: Apply small amount (~1/4 inch) to inside of @ Asacol see Mesalamine on page 1313
the eyelid(s) one or more times daily @ Asacol 800 (Can) see Mesalamine on page 1313
Dry eye associated with ocular inflammation (eg,
@ Asacol HD see Mesalamine on page 1313
blepharitis, conjunctivitis, keratitis): Limited data
available: Infants, Children, and Adolescents: Oph- @ Asaphen (Can) see Aspirin on page 194
thalmic 1 to 2 drops into eye(s) at least twice daily @ Asaphen E.C. (Can) see Aspirin on page 194
or as needed to relieve symptoms (Sethuraman 2009) @ Ascocid [OTC] see Ascorbic Acid on page 186
Administration Wash hands thoroughly before adminis-
@ Ascocid-ISO-pH [OTC] see Ascorbic Acid on page 186
tration; do not touch tip of container to the eye or any
surface; replace cap after use. Some products should not @ Ascor see Ascorbic Acid on page 186
be used with contact lenses; consult specific product @ Ascor L 500 (Can) see Ascorbic Acid on page 186
information. @ Ascorbate Sodium see Ascorbic Acid on page 186
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
cific product labeling. [DSC] = Discontinued product Ascorbic Acid (a skor bik As id)
Gel, ophthalmic:
Systane: Polyethylene glycol 400 0.4% and propylene Medication Safety Issues
glycol 0.3% (10 mL, 15 mL) International issues:
Ointment, ophthalmic: Rubex [Ireland] may be confused with Brivex brand
Altalube: Petrolatum 85% and mineral oil 15% (3.5 g) name for brivudine [Switzerland]
 ASCORBIC ACID

Rubex: Brand name for ascorbic acid [Ireland], but also have been associated with potentially fatal toxicities which
the brand name for doxorubicin [Brazil] can include metabolic acidosis, seizures, renal failure, and
Brand Names: US Acerola C 500 [OTC]; Asco-Tabs- CNS depression; toxicities have also been reported in
1000 [OTC]; Ascocid [OTC]; Ascocid-ISO-pH [OTC]; children and adults including hyperosmolality, lactic acido-
Ascor; BProtected Vitamin C [OTC]; C-500 [OTC]; C-Time sis, seizures and respiratory depression; use caution
[OTC]; Cemill SR [OTC]; Cemill [OTC]; Chew-C [OTC]; (AAP, 1997; Shehab, 2009).
Fruit C 500 [OTC]; Fruit C [OTC]; Fruity C [OTC]; Mega-C/ Adverse Reactions —
A Plus [DSC]; Ortho-CS 250 [DSC]; Vita-C [OTC]; Endocrine & metabolic: Hyperoxaluria (with large doses)
VitaChew Vit C Citrus Burst [OTC] Rare but important or life-threatening: Dizziness, fatigue,
Brand Names: Canada Ascor L 500; Vitamin C flank pain, headache
Therapeutic Category Nutritional Supplement; Urinary Drug Interactions
Acidifying Agent; Vitamin, Water Soluble Metabolism/Transport Effects None known.
Generic Availability (US) May be product dependent Avoid Concomitant Use There are no known interac-
Use tions where it is recommended to avoid concomitant use.
Oral: Dietary supplement of Vitamin C (OTC: FDA Increased Effect/Toxicity
approved in adults); has also been used for urinary Ascorbic Acid may increase the levels/effects of: Alumi-
acidification © num Hydroxide; Deferoxamine; Estrogen Derivatives
Parenteral: Prevention and treatment of scurvy (All indi- Decreased Effect
cations: FDA approved in adults) Ascorbic Acid may decrease the levels/effects of:
Pregnancy Risk Factor C Amphetamines; Bortezomib; CycloSPORINE (Systemic)
Pregnancy Considerations Animal reproduction studies
| have not been conducted. Maternal plasma concentra- The levels/effects of Ascorbic Acid may be decreased
tions of ascorbic acid decrease as pregnancy progresses by: Copper
due to hemodilution and increased transfer to the fetus. Storage/Stability
Some pregnant women (eg, smokers) may require sup- Injection: Store under refrigeration at 2°C to 8°C (36°F to
plementation greater than the RDA (IOM 2000). 46°F); protect from light. Use within 4 hours of vial entry;
Breastfeeding Considerations Ascorbic acid is present discard remaining portion.
in breast milk; regulatory mechanisms. prevent concen- Oral: Store at room temperature.
trations from exceeding a required amount (IOM 2000). Mechanism of Action Ascorbic acid is an essential water
According to the manufacturer, the decision to breastfeed soluble vitamin that acts as a cofactor and antioxidant.
during therapy should take into account the risk of infant Ascorbic acid is an electron donor used for collagen
exposure, the benefits of breastfeeding to the infant, and hydroxylation, carnitine biosynthesis, and hormone/amino
benefits of treatment to the mother. acid biosynthesis. It is required for connective tissue syn-
Contraindications There are no contraindications listed thesis as well as iron absorption and storage (IOM 2000).
in the manufacturer's labeling. Pharmacodynamics/Kinetics (Adult data unless
Warnings/Precautions Acidification of the urine by noted)
ascorbic acid may cause precipitation of cysteine, urate Onset of action: Reversal of scurvy symptoms: 2 days to 3
or oxalate stones. Acute and chronic oxalate nephropathy weeks
has been reported with prolonged administration of high IV Absorption: Oral: Readily absorbed in the intestine; an
doses. Patients with renal disease including renal impair- active process thought to be saturable and dose depend-
ment, history of oxalate kidney stones, elderly patients ent (30 to 180 mg/day: 70% to 90%; >1,000 mg/day:
and pediatric patients <2 years of age may be at increased <50%) (IOM 2000)
risk. Monitor renal function in patients at increased risk. Bioavailability: Oral: For doses up to 200 mg, nearly
Discontinue in patients who develop oxalate nephropathy. 100%; declines with increasing doses with ~33% for a
Patients with diabetes mellitus should not take excessive single dose of 1250 mg (Schwedhelm 2003)
doses for extended periods of time. Hemolysis has been Distribution: Pituitary and adrenal glands, leukocytes, eye
reported in patients with glucose-6-phosphatase dehydro- tissues and humors, and brain; lower concentrations in
genase (G6PD) deficiency and the risk for severe hemol- the plasma and saliva (l1OM 2000)
ysis may be increased during ascorbic acid therapy. Dose Metabolism: Reversibly oxidized to dehydroascorbic acid
reductions may be necessary along with appropriate (DHA); both ascorbic acid and DHA are active. Unab-
monitoring (eg, hemoglobin, blood counts). Discontinue sorbed ascorbic acid is degraded in the intestine
treatment if hemolysis is suspected. Use with caution in (IOM 2000)
patients with hemochromatosis; excess ascorbic acid Half-life elimination: 10 hours (Schwedhelm 2003). Bio-
intake may increase the risk of adverse events (IOM logical half-life: 8 to 40 days (IOM 2000)
2000). Use with caution in patients with renal impairment Excretion: Urine (with high serum concentrations) (IOM
or patients prone to recurrent renal calculi; may have 2000); there is an individual specific renal threshold for
increased risk of developing acute or chronic oxalate ascorbic acid; when blood levels are high, ascorbic acid
nephropathy. ; l
is excreted in urine, whereas when the levels are sub-
Aluminum: The parenteral product may contain aluminum; threshold (doses up to 80 mg/day) very little if any
toxic aluminum concentrations may be seen with high ascorbic acid is excreted into urine
doses, prolonged use, or renal dysfunction. Premature Dosing
neonates are at higher risk due to immature renal function Neonatal
and aluminum intake from other parenteral sources. Adequate Intake (Al): Oral: 40 mg daily (~6 mg/kg/day)
Parenteral aluminum exposure of >4 to 5 mcg/kg/day is Parenteral nutrition, maintenance requirement
associated with CNS and bone toxicity; tissue loading may (Vanek, 2012): IV:
occur at lower doses (Federal Register 2002). See man- Preterm: 15-25 mg/kg/day
ufacturer's labeling. Avoid rapid IV injection; may cause Term: 80 mg daily
temporary faintness or dizziness. Some products may Pediatric
contain sodium; use with caution in sodium restricted Adequate Intake (Al):
patients. Use with caution in the elderly; may be at 1-6 months: 40 mg daily (~6 mg/kg/day)
increased risk for oxalate nephropathy. Use with caution 7-12 months: 50 mg daily (~6 mg/kg/day)
in the children <2 years of age; may be at increased risk Recommended daily allowance (RDA):
for oxalate nephropathy due to immature kidney function. 1-3 years: 15 mg daily
Benzyl alcohol and derivatives: Some dosage forms may 4-8 years: 25 mg daily
contain sodium benzoate/benzoic acid; benzoic acid (ben- 9-13 years: 45 mg daily
zoate) is a metabolite of benzyl alcohol; large amounts of 14-18 years: Males: 75 mg daily, females: 65 mg daily
benzyl alcohol (299 mg/kg/day) have been associated Parenteral nutrition, maintenance requirement
with a potentially fatal toxicity ("gasping syndrome") in (Vanek, 2012): IV:
neonates; the "gasping syndrome" consists of metabolic Infants: 15-25 mg/kg/day; maximum daily dose:
acidosis, respiratory distress, gasping respirations, CNS 80 mg/day
dysfunction (including convulsions, intracranial hemor- Children and Adolescents: 80 mg daily
thage), hypotension, and cardiovascular collapse (AAP Scurvy: Infants, Children, and Adolescents: Oral, IM,
["Inactive" 1997]; CDC 1982); some data suggests that IV, SubQ: Initial: 100 mg/dose 3 times daily for 1week
benzoate displaces bilirubin from protein binding sites (300 mg/day) followed by 100 mg once daily until
(Ahlfors 2001); avoid or use dosage forms containing normalization of tissue saturation, usually 1-3 months
benzyl alcohol derivative with caution in neonates. See (AAP, 2009; Weinstein, 2001)
manufacturer's labeling. Renal Impairment: Pediatric
Warnings: Additional Pediatric Considerations Mild to severe impairment: All Patients: There are no
Some dosage forms may contain propylene glycol; in dosage adjustments provided in the manufacturer's
neonates large amounts of propylene glycol delivered labeling. Use with caution in patients with renal impair-
orally, intravenously (eg, >3,000 mg/day), or topically ment or patients prone to recurrent renal calculi; may &

187
ASCORBIC ACID

have increased risk of developing acute or chronic Generic: 500 mg

oxalate nephropathy. Tablet Extended Release, Oral:
ESRD (requiring hemodialysis): Children and Adoles- Cemill: 500 mg
cents: IV, Oral: The KDOQI guidelines for nutrition in Cemill SR: 1000 mg f
children recommend combined dietary and supplement Generic: 500 mg, 1000 mg, 1500 mg
intake should not greatly exceed the age-appropriate Wafer, Oral [preservative free]:
dietary reference intake; use caution in providing sup- Acerola C 500: 500 mg (50 ea) [corn free, no artificial
plementation (KDOQI 2008). color(s), no artificial flavor(s), wheat free, yeast free;
Hepatic Impairment: Pediatric There are no dosage contains acerola (malpighia glabra)]
adjustments provided in the manufacturer's labeling.
Based on the pharmacokinetics of ascorbic acid, a @ Ascorbic Acid/Ascorbate Sodium see Ascorbic Acid
water-soluble vitamin, a dosage adjustment does not on page 186
seem necessary. @ Asco-Tabs-1000 [OTC] see Ascorbic Acid on page 186
Preparation for Administration Parenteral: Prior to IV
@ Ascriptin Maximum Strength [OTC] see Aspirin
administration, dilute in a large volume parenteral solution
on page 194
(eg, NS, glucose). Note: Pressure may develop in the vial
during storage. @ Ascriptin Regular Strength [OTC] see Aspirin
Administration on page 194
Oral: May be administered without regard to meals
Parenteral: Use only in circumstances when the oral route Asenapiné \@a sEN a peen)
is not possible; IM preferred parenteral route due to
improved utilization; for |V use dilute and infuse over at Medication Safety Issues
least 10 minutes; rapid infusion may cause dizziness Geriatric Patients: High-Risk Medication:
Reference Range Beers Criteria: Antipsychotics are identified in the Beers
Normal levels: 10-20 mcg/mL Criteria as potentially inappropriate medications to be
Scurvy: <1-1.5 mcg/mL avoided in patients 65 years and older with dementia
Test Interactions due to an increased risk of mortality, cerebrovascular
False-negative stool occult blood 48 to 72 hours after accidents (stroke), and a greater rate of cognitive
ascorbic acid ingestion. decline with use; avoid antipsychotics for behavioral
May interfere with laboratory tests based on oxidation-_ problems associated with dementia or delirium unless
reduction reactions (eg, blood and urine glucose testing,
alternative nonpharmacologic therapies have failed
nitrite and bilirubin levels, leucocyte count). If possible,
and patient may harm self or others. Use may be
laboratory tests based on oxidation-reduction reactions
appropriate in geriatric patients with schizophrenia,
should be delayed until 24 hours after dose.
bipolar disorder, or for short-term use as an antiemetic
Additional Information Sodium content of 1 g: ~5 mEq
during chemotherapy. In addition, antipsychotics
Dosage Forms Excipient information presented when
should be used with caution in older adults due to their
available (limited, particularly for generics); consult spe-
potential to cause or exacerbate syndrome of inappro-
cific product labeling. [DSC] = Discontinued product
priate antidiuretic hormone secretion (SIADH) or hypo-
Capsule Extended Release, Oral:
C-Time: 500 mg natremia; monitor sodium closely with initiation or
Generic: 500 mg dosage adjustments in older adults (Beers Criteria
Capsule Extended Release, Oral [preservative free]: [AGS 2015)).
Generic: 500 mg Related Information
Crystals, Oral: Oral Medications That Should Not Be Crushed or Altered
Vita-C: (120 g, 480 g) [animal products free, gelatin free, on page 2217
gluten free, lactose free, no artificial color(s), no artifi- Brand Names: US Saphris
cial flavor(s), starch free, sugar free, yeast free] Brand Names: Canada Saphris
Liquid, Oral: Therapeutic Category Antimanic Agent; Second Gener-
BProtected Vitamin C: 500 mg/5 mL (236 mL) [contains ation (Atypical) Antipsychotic
propylene glycol, saccharin sodium, sodium benzoate; Generic Availability (US) No
citrus flavor]
Use Treatment of acute manic or mixed episodes associ-
Generic: 500 mg/5 mL (118 mL, 473 mL)
ated with bipolar | disorder as monotherapy (FDA
Powder, Oral:
approved in ages 210 years and adults) or as adjunctive
Ascocid: (227 g)
treatment with lithium or valproate (FDA approved in
Generic: (113 g, 120 g, 480 g)
adults) and maintenance treatment as monotherapy
Powder Effervescent, Oral:
Ascocid-ISO-pH: (150 g) [corn free, rye free, wheat free] (FDA approved in adults); treatment of schizophrenia
Solution, Injection:
(FDA approved in adults)
Generic: 500 mg/mL (50 mL) Pregnancy Considerations Antipsychotic use during the
Solution, Injection [preservative free]: third trimester of pregnancy has a risk for abnormal
Mega-C/A Plus: 500 mg/mL (50 mL [DSC}) muscle movements (extrapyramidal symptoms [EPS])
Generic: 500 mg/mL (50 mL) and/or withdrawal symptoms in newborns following deliv-
Solution, Intravenous [preservative free]: ery. Symptoms in the newborn may include agitation,
Ascor: 500 mg/mL (50 mL) [contains edetate disodium] feeding disorder, hypertonia, hypotonia, respiratory dis-
Solution, Injection, as sodium ascorbate [preservative tress, somnolence, and tremor; these effects may be
free]: self-limiting or require hospitalization; monitoring of the
Ortho-CS 250: 250 mg/mL (100 mL [DSC]) [contains neonate is recommended. Asenapine may cause hyper-
edetate disodium, water, sterile} prolactinemia, which may decrease reproductive function
Generic: 250 mg/mL (30 mL [DSC)) in both males and females.
Syrup, Oral:
Generic: 500 mg/5 mL (118 mL [DSC], 473 mL [DSC}) The ACOG recommends that therapy during pregnancy
Tablet, Oral: be individualized; treatment with psychiatric medications
Asco-Tabs-1000: 1000 mg [color free, starch free, during pregnancy should incorporate the clinical expertise
sugar free] of the mental health clinician, obstetrician, primary health-
Generic: 100 mg, 250 mg, 500 mg, 1000 mg care provider, and pediatrician. Safety data related to
Tablet, Oral [preservative free]: atypical antipsychotics during pregnancy is limited and
Generic: 250 mg, 500 mg routine use is not recommended. However, if a woman
Tablet Chewable, Oral: is inadvertently exposed to an atypical antipsychotic while
Chew-C: 500 mg pregnant, continuing therapy may be preferable to switch-
Fruit C 500: 500 mg [animal products free, gelatin free, ing to a typical antipsychotic that the fetus has not yet
gluten free, kosher certified, lactose free, no artificial been exposed to; consider risk:benefit (ACOG 2008).
color(s), no artificial flavor(s), starch free, sugar free,
yeast free] Healthcare providers are encouraged to enroll women
Fruit C: 100 mg [animal products free, gelatin free, 18-45 years of age exposed to asenapine during preg-
gluten free, lactose free, no artificial color(s), no artifi- nancy in the Atypical Antipsychotics Pregnancy Registry
cial flavor(s), starch free, sugar free, yeast free] (866-961-2388 or http://www.womensmentalhealth.org/
Fruity C: 250 mg pregnancyregistry).
VitaChew Vit C Citrus Burst: 125 mg Breastfeeding Considerations It is not known if asena-
Generic: 100 mg, 250 mg, 500 mg pine is excreted into breast milk. According to the manu-
Tablet Chewable, Oral [preservative free]: facturer, the decision to breastfeed during therapy should
C-500: 500 mg [animal products free, gluten free, soy take into account the risk of exposure to the infant and the
free, starch free, yeast free] benefits of treatment to the mother.

188
 ASENAPINE

Contraindications Severe hepatic impairment (Child- previous brain damage, alcoholism, poor treatment
Pugh class C); hypersensitivity to asenapine or any com- response, and use of high doses of antipsychotics (APA
ponent of the formulation (eg, anaphylaxis, angioedema, [Lehman 2004]; Soares-Weiser 2007). Use may be asso-
hypotension, tachycardia, swollen tongue, dyspnea, ciated with of neuroleptic malignant syndrome (NMS);
wheezing, rash) monitor for mental status changes, fever, muscle rigidity
Warnings/Precautions [US Boxed Warning]: Elderly and/or autonomic instability. NMS can recur. Following
patients with dementia-related psychosis treated with recovery from NMS, reintroduction of drug therapy should
atypical antipsychotics are at an increased risk of be carefully considered; if an antipsychotic agent is
death. Most deaths appeared to be either cardiovascular resumed, monitor closely for NMS. Atypical antipsychotics
(eg, heart failure, sudden death) or infectious (eg, pneu-
have been associated with development of hyperglyce-
monia) in nature. Use with caution in patients with Lewy
mia; in some cases may be extreme and associated with
body dementia or Parkinson disease dementia due to
ketoacidosis, hyperosmolar coma, or death. All patients
greater risk of adverse effects, increased sensitivity to
extrapyramidal effects, and association with irreversible should be monitored for symptoms of hyperglycemia (eg,
cognitive decompensation or death. (APA [Reus 2016)). polydipsia, polyuria, polyphagia, weakness). Use with
Asenapine is not approved for the treatment of dementia- caution in patients with diabetes or other disorders of
related psychosis. glucose regulation; monitor for worsening of glucose con-
trol. Patients with risk factors for diabetes (eg, obesity or
Pharmacokinetic studies showed a decrease in clearance family history) should have a baseline fasting blood sugar
in older adults (65 to 85 years of age) with psychosis
(FBS) and periodic assessment of glucose regulation.
compared to younger adults; increased risk of adverse
effects and orthostasis may occur. Pediatric patients may Dyslipidemia has been reported with atypical antipsy-
be more sensitive to dystonia with initial dosing and when chotics; risk profile may differ between agents. !n clinical
the recommended dosing escalation schedule is not fol- trials, the incidence of hypertriglyceridemia observed with
lowed. asenapine was greater than that observed with placebo,
Leukopenia, neutropenia, and agranulocytosis (some- while total cholesterol elevations were similar. Significant
times fatal) have been reported in clinical trials and weight gain has been observed with antipsychotic therapy;
postmarketing reports with antipsychotic use; presence incidence varies with product. Monitor waist circumfer-
of risk factors (eg, preexisting low WBC or history of ence and BMI. Anaphylaxis and hypersensitivity reactions
drug-induced leuko/neutropenia) should have a periodic (eg, angioedema, hypotension, tachycardia, swollen
complete blood count performed frequently during the first tongue, dyspnea, wheezing, and rash) have been
few months of therapy. Discontinue therapy at first signs of reported; some cases have occurred after a single dose.
blood dyscrasias or if absolute neutrophil count
<1,000/mm*°. The possibility of a suicide attempt is inherent in psychotic
illness or bipolar disorder; use caution in high-risk patients
May cause CNS depression, which may impair physical or during initiation of therapy. Prescriptions should be written
mental abilities; patients must be cautioned about per- for the smallest quantity consistent with good patient care.
forming tasks that require mental alertness (eg, operating Potentially significant drug-drug interactions may exist,
machinery or driving). Use with caution in patients at risk
requiring dose or frequency adjustment, additional mon-
of seizures or conditions that potentially lower the seizure
itoring, and/or selection of alternative therapy.
threshold (eg, Alzheimer dementia). Elderly patients may
be at increased risk of seizures due to an increased When discontinuing antipsychotic therapy, the American
prevalence of predisposing factors. Use is contraindicated Psychiatric Association (APA), Canadian Psychiatric
in patients with severe hepatic impairment (Child-Pugh Association (CPA), and World Federation of Societies of
class C); increased drug concentrations may occur. Anti- Biological Psychiatry (WFSBP) guidelines recommend
psychotic use has been associated with esophageal dys- gradually tapering antipsychotics to avoid physical with-
motility and aspiration; risk increases with age. Use with drawal symptoms, including anorexia, anxiety, diaphore-
caution in patients at risk for aspiration pneumonia (eg,
sis, diarrhea, dizziness, dyskinesia, headache, myalgia,
Alzheimer disease), particularly in patients >75 years
nausea, paresthesia, restlessness, tremulousness, and
(Herzig 2017; Maddalena 2004). May increase prolactin
levels; clinical significance of hyperprolactinemia in vomiting (APA [Lehman 2004]; CPA [Addington 2005];
patients with breast cancer or other prolactin-dependent Lambert 2007; WFSBP [Hasan 2012]). The risk of with-
tumors is unknown. Impaired core body temperature reg- drawal symptoms is highest following abrupt discontinua-
ulation may occur; caution with strenuous exercise, heat tion of highly anti-cholinergic or dopaminergic
exposure, dehydration, and concomitant medication pos- antipsychotics (Cerovecki 2013). Additional factors such
sessing anticholinergic effects (Kerwin 2004; Kwok 2005; as duration of antipsychotic exposure, the indication for
Martinez 2002). May increase the risk for falls due to use, medication half-life, and risk for relapse should be
somnolence, orthostatic hypotension and motor or sen- considered. In schizophrenia, there is no reliable indicator
sory instability. Complete fall risk assessments at baseline to differentiate the minority who will not from the majority
and periodically during treatment in patients with dis- who will relapse with drug discontinuation. However,
eases, conditions, or on medications that may increase studies in which the medication of well-stabilized patients
fall risk. were discontinued indicate that 75% of patients relapse
Use with caution in patients with cardiovascular diseases within 6 to 24 months. Indefinite maintenance antipsy-
(eg, heart failure, history of myocardial infarction or ische- chotic medication is generally recommended, and espe-
mia, cerebrovascular disease, conduction abnormalities). cially for patients who have had multiple prior episodes or
May cause orthostatic hypotension and syncope; use with 2 episodes within 5 years (APA [Lehman 2004)).
caution in patients at risk of this effect (eg, concurrent Warnings: Additional Pediatric Considerations Use
medication use which may predispose to hypotension/ with caution in children and adolescents; elevated prolac-
bradycardia or presence of dehydration or hypovolemia) tin levels have been observed; long-term effects on growth
or in those who would not tolerate transient hypotensive or sexual maturation have not been evaluated. Similar to
episodes. Use caution with history of cerebrovascular or adult experience, the American Academy of Child and
cardiovascular disease (MI, heart failure, conduction Adolescent Psychiatry (AACAP) guidelines recommend
abnormalities, or ischemic disease). May result in QTc gradually tapering antipsychotics to avoid withdrawal
prolongation. Risk may be increased by conditions or
symptoms and minimize the risk of relapse (AACAP
concomitant medications which cause bradycardia, hypo-
[McClellan 2007)).
kalemia, and/or hypomagnesemia. Avoid use in combina-
tion with QTc-prolonging drugs and in patients with Adverse Reactions
congenital long QT syndrome or patients with history of Cardiovascular: Hypertension (adults), peripheral edema
cardiac arrhythmia, (adults), prolonged Q-T interval on ECG, syncope, tachy-
cardia
May cause extrapyramidal symptoms (EPS), including Central nervous system: Agitation (adults), akathisia
pseudoparkinsonism, acute dystonic reactions, akathisia, (more common in adults; dose-related), anxiety (adults),
and tardive dyskinesia (risk of these reactions is generally
bipolar mood disorder (exacerbation; adults), dizziness,
much lower relative to typical/conventional antipsychotics;
drowsiness (more common in children and adolescents),
frequencies reported are similar to placebo). Risk of
drug-induced Parkinson disease (children and adoles-
dystonia (and probably other EPS) may be greater with
increased doses, use of conventional antipsychotics, cents), dystonia, extrapyramidal reaction, fatigue, head-
males, and younger patients. Factors associated with ache (children and adolescents), hyperinsulinism
greater vulnerability to tardive dyskinesia include older in (children and adolescents), insomnia (more common in
age, female gender combined with postmenopausal sta- adults), irritability, mania (adults), outbursts of anger
tus, Parkinson disease, pseudoparkinsonism symptoms, (children and adolescents), suicidal ideation (children
affective disorders (particularly major depressive disor- and adolescents)
der), concurrent medical diseases such as diabetes, Dermatologic: Skin rash (children and adolescents)

189
 ASENAPINE

4 Endocrine & metabolic: Decreased HDL

dehydration (children and adolescents), increased
cholesterol, Mechanism of Action. Asenapine is a dibenzo-oxepino
pyrrole atypical antipsychotic with mixed serotonin-dopa-
serum cholesterol (adults), increased serum glucose mine antagonist activity. It exhibits high affinity for 5-HT4,,
(more common in adults), increased serum prolactin, 5-HT1ig, 5-HT2,, 5-HT 28, 5-HT2c, 5-HT5.7, Dy-4, H, and,
increased serum triglycerides (more common in adults), alpha,- and alphaz-adrenergic receptors; moderate affinity
weight gain (more common in adults) for Hz receptors. Asenapine has no significant affinity for
Gastrointestinal: Abdominal distress (adults), abdominal muscarinic receptors. The binding affinity to the D2 recep-
pain, constipation (adults), dysgeusia, dyspepsia tor is 19 times lower than the 5-HT2, affinity (Weber
(adults), glossalgia (children and adolescents), 2009). The addition of serotonin antagonism to dopamine
increased appetite, nausea, oral hypoesthesia, oral par- antagonism (classic neuroleptic mechanism) is thought to
esthesia, sialorrhea (adults), toothache (adults), vomit- improve negative symptoms of psychoses and reduce the
ing, xerostomia (adults) incidence of extrapyramidal side effects as compared to
Genitourinary: Dysmenorrhea (children and adolescents) typical antipsychotics (Huttunen 1995).
Hepatic: Increased serum ALT, increased serum AST Pharmacodynamics/Kinetics (Adult data unless
(children and adolescents), increased serum transami- noted)
nases (adults) Absorption: Rapid
Neuromuscular & skeletal: Arthralgia (adults), increased Distribution: Vg: ~20 to 25 L/kg
creatine phosphokinase (adults), myalgia (children and Protein binding: 95% (including albumin and a4-acid gly-
adolescents), strain (children and adolescents) coprotein)
Respiratory: Dyspnea, nasal congestion (children and Metabolism:Hepatic via CYP1A2 oxidation and UGT1A4
adolescents), nasopharyngitis (adults), oropharyngeal glucuronidation
pain (children and_adolescents) Bioavailability: Sublingual: 35%; decreased if swallowed
Miscellaneous: Fever (<2%); decreased if administered with food or liquid
Rare but important or life-threatening: Accommodation Half-life elimination: Terminal: ~24 hours
disturbance, anaphylaxis, anemia, angioedema, applica- Time to peak, plasma: 0.5 to 1.5 hours
tion site reaction (including blisters, inflammation, peel- Excretion: Urine (~50%); feces (~40%)
ing, oral ulcers, sloughing), blurred vision, bundle branch Pharmacodynamics/Kinetics: Additional Consider-
block (temporary), choking sensation, diabetes mellitus, ations
diplopia, dysarthria, dyslipidemia, dysphagia, falling, Hepatic function impairment: Severe hepatic impairment
gastroesophageal reflux disease, hyperglycemia, hyper- (Child-Pugh class C) exposure was 7 times higher than
sensitivity reaction, hyponatremia, hypotension, leuko- in healthy patients.
penia, neuroleptic malignant syndrome, neutropenia, Geriatric: Clearance is decreased, increasing exposure by
seizure, skin photosensitivity, tardive dyskinesia, throm- 30% to 40%.
bocytopenia, tongue edema, urinary incontinence, Dosing
wheezing Pediatric Bipolar disorder: A cute manic or mixed
Drug Interactions episode; monotherapy: Children 210 years and Ado-
Metabolism/Transport Effects Substrate of CYP1A2 lescents $17 years: Sublingual: Initial: 2.5 mg twice
(major), CYP2D6 (minor), CYP3A4 (minor); Note: daily; may titrate after 3 days to 5 mg twice daily, then
Assignment of Major/Minor substrate status based on after an additional 3 days to 10 mg twice daily based on
clinically relevant drug interaction potential; Inhibits tolerability; recommended daily dose range: 5 to
CYP2D6 (weak) 20 mg/day in two divided doses; maximum dose:
Avoid Concomitant Use 10 mg twice daily (20 mg/day).
Avoid concomitant use of Asenapine with any of the Renal Impairment: Pediatric
following: Amifampridine; Amisulpride; Azelastine Children 210 years and Adolescents:
(Nasal); Bromopride; Bromperidol; Hydroxychloroquine; Mild to severe impairment: No dosage adjustment
Macimorelin; Metoclopramide; MiFEPRIStone; Mizolas- necessary; asenapine exposure was similar to sub-
tine; Orphenadrine; Oxomemazine; Paraldehyde; Piribe- jects with normal renal function; the effect of metab-
dil; Probucol; Promazine; QTc-Prolonging Agents olite exposure with renal impairment has not been
(Highest Risk); QTc-Prolonging Agents (Moderate Risk); studied.
Sulpiride; Thalidomide; Vinflunine Dialysis: Has not been studied; use with caution.
Increased Effect/Toxicity Hepatic Impairment: Pediatric
Asenapine may increase the levels/effects of: Alcohol Children 210 years and Adolescents:
(Ethyl); Amisulpride; Azelastine (Nasal); Blonanserin; Mild to moderate hepatic impairment: No dosage
Buprenorphine; CNS Depressants; Flunitrazepam; adjustment necessary.
HYDROcodone; lohexol; lomeprol; lopamidol; Methotri- Severe hepatic impairment: Use is contraindicated.
meprazine; Methylphenidate; MetyroSINE; Opioid Anal- Administration Sublingual: Tablets should be placed
gesics; Orphenadrine; OxyCODONE; Paraldehyde; under the tongue and allowed to completely dissolve. Do
PARoxetine; Perhexiline; QTc-Prolonging Agents (High- not split, crush, chew, or swallow. Avoid eating or drinking
est Risk); Selective Serotonin Reuptake Inhibitors; Sero- for at least 10 minutes after administration.
tonin Modulators; Sulpiride; Suvorexant; Thalidomide; Monitoring Parameters Mental status; vital signs (as
Zolpidem clinically indicated); blood pressure and pulse (baseline;
The levels/effects of Asenapine may be increased by: repeat 3 months after antipsychotic initiation, then yearly);
Abiraterone Acetate; Acetylcholinesterase Inhibitors weight, height, BMI, waist circumference (baseline; repeat
(Central); Amifampridine; Bilastine; Blood Pressure Low- at 4, 8, and 12 weeks after initiating or changing therapy,
ering Agents; Brimonidine (Topical); Bromopride; Brom- then quarterly; consider switching to a different antipsy-
peridol; BuPROPion; Cannabis; Chlormethiazole; chotic for a weight gain more than 5% of initial weight
Chlorphenesin Carbamate; CYP1A2 Inhibitors (Moder- [ADA 2004]); CBC (as clinically indicated; monitor fre-
ate); Deferasirox; Dimethindene (Topical); Doxylamine; quently during the first few months of therapy in patients
Dronabinol; FLUoxetine; FluvoxaMINE; Hydroxychloro- with preexisting low WBC or history of drug-induced
quine; Indapamide; Kava Kava; Macimorelin; Magne- leukopenia/neutropenia); electrolytes and liver function
sium Sulfate; Methotrimeprazine; Methylphenidate; (annually and as clinically indicated); personal and family
Metoclopramide; MetyroSINE; MiFEPRIStone; Minocy- history of obesity, diabetes, dyslipidemia, hypertension, or
cline; Mizolastine; Nabilone; Obeticholic Acid; Oxome- cardiovascular disease (baseline; repeat annually); fasting
mazine; PARoxetine; Pefloxacin; Peginterferon Alfa-2b; plasma glucose level/HbA,, (baseline; repeat 3 months
Perampanel; Probucol; Promazine; QTc-Prolonging after starting antipsychotic, then yearly); fasting lipid panel
Agents (Indeterminate Risk and Risk Modifying); QTc- (baseline; repeat 3 months after initiation of antipsychotic;
Prolonging Agents (Moderate Risk); Rufinamide; Sero- if low-density lipoprotein level is normal, repeat at 2- to 5-
tonin Modulators; Sodium Oxybate; Tapentadol; Teneli- year intervals or more frequently if clinical indicated [ADA
gliptin; Tetrahydrocannabinol; Trimeprazine; Vinflunine; 2004]); prolactin level (baseline [NICE 2014]); changes in
Xipamide menstruation and development of galactorrhea (yearly);
Decreased Effect abnormal involuntary movements or parkinsonian signs
Asenapine may decrease the levels/effects of: Amphet-
(baseline; repeat weekly until dose stabilized for at least 2
amines; Antidiabetic Agents; Anti-Parkinson Agents
weeks after introduction and for 2 weeks after any sig-
(Dopamine Agonist); Guanethidine; Piribedil; Quinago-
nificant dose increase); tardive dyskinesia (every 12
months; high-risk patients every 6 months); ocular exami-
lide
nation (yearly in patients older than 40 years; every 2
The levels/effects of Asenapine may be decreased by: years in younger patients) (ADA 2004; APA [Lehman
Cannabis; CYP1A2 Inducers (Moderate); Cyproterone; 2004]; Marder 2004; NICE 2014).
‘ Piribedil; Teriflunomide Dosage Forms Excipient information presented when
Storage/Stability Store at 20°C to 25°C (68°F to 77°F); available (limited, particularly for generics); consult spe-
excursions permitted to 15°C to 30°C (59°F to 86°F). cific product labeling. [DSC] = Discontinued product
 ASFOTASE ALFA

Tablet Sublingual, Sublingual: injection site (more common in juvenile-onset HPP; also
Saphris: 2.5 mg [black cherry flavor] in perinatal/infantile-onset HPP), induration at injection
Saphris: 5 mg [DSC] site, injection site reaction (including rash, nodule, pap-
Saphris: 5 mg [black cherry flavor] ule, inflammation, hemorrhage, hematoma, calcification,
Saphris: 10 mg [DSC] mass; scar, cellulitis, or not otherwise defined), itching at
Saphris: 10 mg [black cherry flavor] injection site (more common in juvenile-onset HPP; also
in perinatal/infantile-onset HPP), pain at injection site
@ Asenapine Maleate see Asenapine on page 188
(more common in juvenile-onset HPP; also in perinatal/
infantile-onset HPP), skin discoloration at injection site
Asfotase Alfa (Az fo tase AL fa) (including macules: More common in juvenile-onset
HPP; also in perinatal/infantile-onset HPP), swelling at
Brand Names: US Strensiq injection site (more common in juvenile-onset HPP; also
Brand Names: Canada Strensiq in perinatal/infantile-onset HPP), tenderness at injection
Therapeutic Category Enzyme site (more common in juvenile-onset HPP; also in peri-
-Generic Availability (US) No natal/infantile-onset HPP)
Use Treatment of perinatal/infantile- and juvenile-onset Rare but important or life-threatening: Chronic active
hypophosphatasia (HPP) (FDA approved in all ages) hepatitis, hypocalcemia, nephrolithiasis, pyridoxine defi-
Pregnancy Considerations Adverse events have not ciency
been observed in animal reproduction studies. Drug Interactions
Breastfeeding Considerations It is not known if asfo- Metabolism/Transport Effects None known.
tase alfa is excreted in breast milk. According to the Avoid Concomitant Use There are no known interac-
, manufacturer, the decision to continue or discontinue tions where it is recommended to avoid concomitant use.
breastfeeding during therapy should take into account Increased Effect/Toxicity There are no known signifi-
the risk of exposure, the benefits of breastfeeding to the cant interactions involving an increase in effect.
infant, and the benefits of treatment to the mother. Decreased Effect There are no known significant inter-
Contraindications actions involving a decrease in effect.
There are no contraindications listed in the manufacturer’s Storage/Stability Store refrigerated at 2°C to 8°C (36°F to
labeling. 46°F) in original carton and protect from light. Once
Canadian labeling: Additional contraindications (not in US removed from refrigerator, administer within 1 hour. Do
labeling): Hypersensitivity to asfotase alfa or any com- not freeze or shake. Discard any unused product.
ponent of the formulation. Mechanism of Action Asfotase alfa is a human recombi-
Warnings/Precautions Hypersensitivity reactions, nant tissue-nonspecific alkaline phosphatase-Fc-deca-
including anaphylaxis, have been reported; symptoms aspartate fusion protein with enzymatic activity that pro-
consistent with anaphylaxis, including difficulty breathing, motes bone mineralization in patients with hypophospha-
choking sensation, nausea, periorbital edema, and dizzi- tasia.
ness, have been reported. Reactions may occur within Pharmacodynamics/Kinetics (Adult data unless
minutes after administration or in patients on treatment for noted)
>1 year. Other hypersensitivity reactions (eg, vomiting, Onset of action: Reduction in plasma tissue-nonspecific
fever, headache, flushing, irritability, chills, skin erythema, alkaline phosphatase (TNSALP): After 6 to 12 weeks of
rash, pruritus, oral hypoesthesia) have also been
treatment
reported. If a severe hypersensitivity reaction occurs,
Bioavailability: Age range: 1 day to 66 years: Subcuta-
discontinue treatment and initiate appropriate medical
neous: 60.2%
treatment. If the decision is made to re-administer, monitor
Half-life elimination: ~5 days (based on data from 38
patients for a reoccurrence of signs and symptoms of a
patients, ages undefined); in 60 patients aged 1 day to
severe hypersensitivity reaction. Localized lipodystrophy,
66 years (n=45 pediatric patients): ~2.3 days
including lipoatrophy and lipohypertrophy, has been
Time to peak serum concentration:
reported at injection sites after several months. Ensure
Infants and Children <5 years: ~15 hours (range: 0 to
proper injection technique and rotate injection sites.
32.2 hours)
Ectopic calcification of the eye, including the cornea and
Children >5 to 12 years: ~21 hours (range: 12 to 32.2
conjunctiva, and the kidneys (nephrocalcinosis) have
hours)
been reported; there is insufficient information to deter-
mine if these events were consistent with the disease
Dosing
(patients with hypophosphatasia are at increased risk for Neonatal Note: Round patient weight to the nearest kg
developing ectopic calcifications) or due to asfotase alfa. when determining dose. Do not administer the 80 mg/0.8
No visual changes or changes in renal function were mL concentration vial to neonates; systemic exposure is
reported resulting from the occurrence of ectopic calcifi- less than what is achieved with lower concentration vials.
cations. Eye exams and renal ultrasounds are recom- Perinatal/infantile-onset hypophosphatasia (HPP):
mended at baseline and periodically-during treatment. SubQ: 6 mg/kg/week. administered as either 2 mg/kg/
The presence of antibodies has been reported in 78% of dose 3 times weekly or 1 mg/kg/dose 6 times weekly;
treated patients in clinical trials. Approximately 45% of may increase dose up to 9 mg/kg/week administered
these patients showed the presence of neutralizing anti- as 3 mg/kg/dose 3 times weekly; in clinical trials, dose
bodies. Formation of anti-drug antibody results in a increases were considered after at least 4 weeks of
reduced systemic exposure of asfotase alfa. High serum therapy (Whyte 2012; Whyte 2016); maximum total
ALP levels are expected and reflect circulating asfotase weekly dose: 9 mg/kg/week. Note: In trials, lack of
alfa; serum ALP measurements should not be used to efficacy (clinical response) may be defined as no
make clinical decisions during asfotase alfa treatment. improvement in respiratory status, growth, or radio-
Warnings: Additional Pediatric Considerations Cra- graphic findings. Injection site reactions may limit the
niosynostosis associated with increased intracranial pres- tolerability of the-6 times-per-week regimen.
sure in some cases and worsening of preexisting Pediatric
craniosynostosis has been reported in clinical trials in Note: Round patient weight to the nearest kg when
patients <5 years of age; causality with asfotase alfa has determining dose. Do not administer the 80 mg/0.8
not been established due to insufficient data; craniosynos- mL concentration vial to pediatric patients weighing
tosis is frequently reported (61.3%) in patient with hypo- <40 kg; exposure is less than what is achieved with
phosphatasia as manifestation of the condition. Monitor lower concentration vials.
(eg, fundoscopy) patients <5 years of age periodically Perinatal/infantile-onset hypophosphatasia (HPP):
(Stensiq prescribing information [European Medicines Infants, Children, and Adolescents: SubQ: 6 mg/kg/
Agency] 2015). week administered as either 2 mg/kg/dose 3 times
Adverse Reactions | i weekly or 1 mg/kg/dose 6 times weekly; may increase
Endocrine & metabolic: Ectopic calcification (includes dose up to 9 mg/kg/week administered as 3 mg/kg/
calcification of the cornea, conjunctiva, and kidneys; dose 3 times weekly; in clinical trials, dose increases
juvenile-onset HPP; perinatal/infantile-onset HPP), lip- were considered after at least 4 weeks of therapy
odystrophy (Whyte 2012; Whyte 2016); maximum total weekly
Hypersensitivity: Hypersensitivity reaction dose: 9 mg/kg/week. Note: Lack of clinical response
Immunologic: Immunogenicity (positive for antidrug anti- may be defined as no improvement in respiratory
bodies; neutralizing; Presence of antidrug antibodies status, growth, or radiographic findings. Injection site
resulted in reduced systemic exposure of asfotase alfa) reactions may limit the tolerability of the 6-times-per-
~ Local: Atrophy at injection site (more common in juvenile- week regimen.
onset HPP; also in perinatal/infantile-onset HPP), bruis- Juvenile-onset hypophosphatasia (HPP): Children
ing at injection site (more common in juvenile-onset and Adolescents: SubQ: 6 mg/kg/week administered
HPP; also in perinatal/infantile-onset HPP), erythema as either 2 mg/kg/dose 3 times weekly or 1 mg/kg/
at injection site (more common in juvenile-onset HPP; dose 6 times weekly. Injection site reactions may limit
also in perinatal/infantile-onset HPP), hypertrophy at the tolerability of the 6-times-per-week regimen.

191
ASFOTASE ALFA

Renal Impairment: Pediatric There are no dosage taking into account the importance of treatment to the
adjustments provided in the manufacturer's labeling. mother.
Hepatic Impairment: Pediatric There are no dosage Contraindications
adjustments provided in the manufacturer’s labeling. History of serious*hypersensitivity reactions, including
Administration SubQ: For subcutaneous administration anaphylaxis to asparaginase (Erwinia) or any component
only in the abdominal area, thigh, or deltoid. Administer of the formulation; history of serious pancreatitis, serious
within 1 hour upon removal from refrigerator. Rotate the thrombosis, or serious hemorrhagic events with prior
injection sites to reduce the risk of lipodystrophy. Do not asparaginase treatment
administer injections in areas that are reddened, inflamed, Canadian labeling: Additional contraindications (not in the
or swollen. Solution is clear, slightly opalescent or opales- US labeling): Women who are or may become pregnant
cent, colorless to slightly yellow; few small translucent or
Warnings/Precautions Serious hypersensitivity reac-
white particles may be present; discard vial(s) not con-
tions (grade 3 and 4), including anaphylaxis, have
sistent with this appearance. Administer with 1 mL syringe
occurred in 5% of patients in clinical trials. Immediate
with 1/2-inch needle (25 to 29 gauge). For doses >1 mL,
split the volume equally between 2 syringes, and admin- treatment for hypersensitivity reactions should be avail-
ister 2 injections using separate injection sites. able during treatment; discontinue for serious hypersensi-
Note: In pediatric patients <40 kg, do not use the 80 mg/ tivity reactions (and administer appropriate treatment).
0.8 mL vial; systemic exposure of asfotase alfa achieved Pancreatitis has been reported in 5% of patients in clinical
with this higher concentration (80 mg/0.8 mL) is lower trials; promptly evaluate with symptoms suggestive of
than that achieved with the other vial strengths which
pancreatitis. For mild pancreatitis, withhold treatment until
have a lower concentration. A lower exposure may not
signs and symptoms subside and amylase levels return to
be adequate for this subgroup of patients.
normal; may resume after resolution. Discontinue for
Monitoring Parameters Hypersensitivity reaction; signs
severe or hemorrhagic pancreatitis characterized by
and symptoms of ophthalmic and renal ectopic calcifica-
tions and for changes in vision or renal function; periodic
abdominal pain >72 hours and amylase 22 x ULN. Further
evaluations for craniosynostosis (fundoscopy) in patients use is contraindicated if severe pancreatitis is diagnosed.
<5 years of age Serious thrombotic events, including sagittal sinus throm-
Test Interactions Asfotase alfa interferes with alkaline bosis and pulmonary embolism, have been reported with
phosphatase (ALP)-conjugated test systems (commonly asparaginase formulations. Decreases in fibrinogen, pro-
used to measure hormones, bacterial antigens, and anti-
tein C activity, protein S activity, and antithrombin III have
bodies) rendering erroneous test results. Alternative labo- been noted following a 2-week treatment course adminis-
ratory assays that do not utilize ALP-conjugate technology
tered intramuscularly. Discontinue for hemorrhagic or
are recommended in patients receiving asfotase alfa.
thrombotic events; may resume treatment after resolution
Dosage Forms Excipient information presented when
(contraindicated with history of serious thrombosis or
available (limited, particularly for generics); consult spe-
cific product labeling.
hemorrhagic event with prior asparaginase treatment).
Solution, Subcutaneous [preservative free]: In clinical trials, 4% of patients experienced’ glucose
Strensig: 18 mg/0.45 mL (0.45 mL); 28 mg/0.7 mL (0.7 intolerance; may be irreversible; monitor glucose levels
mL); 40 mg/mL (1 mL); 80 mg/0.8 mL (0.8 mL) [con- (baseline and periodic) during treatment; may require
tains mouse (murine) and/or hamster protein] insulin administration.
@ Asmanex 7 Metered Doses see Mometasone (Oral Do not interchange Erwinia asparaginase for E. coli
Inhalation) on page 1394 asparaginase or pegaspargase; ensure the proper formu-
@ Asmanex 14 Metered Doses see Mometasone (Oral lation, route of administration, and dose prior to admin-
Inhalation) on page 1394 istration.
@ Asmanex 30 Metered Doses see Mometasone (Oral Adverse Reactions
Inhalation) on page 1394 Hypersensitivity: Hypersensitivity reaction (includes ana-
@ Asmanex 60 Metered Doses see Mometasone (Oral phylaxis, urticaria)
Inhalation) on page 1394 Cardiovascular: Thrombosis (includes pulmonary embo-
@ Asmanex 120 Metered Doses see Mometasone (Oral lism and cerebrovascular accident)
Inhalation) on page 1394 Endocrine & metabolic: Abnormal transaminase,
decreased glucose tolerance, hyperglycemia (IV: more
@ Asmanex HFA see Mometasone (Oral Inhalation)
common)
on page 1394
Gastrointestinal: Abdominal pain, diarrhea, mucositis,
Asmanex Twisthaler (Can) see Mometasone (Oral Inha- nausea (IV: more common), pancreatitis, vomiting (IV:
lation) on page 1394
more common)
Local: Injection site reaction
Asparaginase (Erwinia) Miscellaneous: Fever
(a SPEAR a ji nase er WIN i ah) Rare but important or life-threatening: Acute renal failure, ©
anorexia, bone marrow depression (rare), changes in
Medication Safety Issues
Sound-alike/look-alike issues: serum lipids, disseminated intravascular coagulation,
Asparaginase (Erwinia) may be confused with asparagi- hemorrhage, hepatomegaly, hyperammonemia, hyper-
nase (E. coli), pegaspargase bilirubinemia, malabsorption syndrome, seizure, transi-
Erwinaze may be confused with Elaprase, Elspar, ent ischemic attacks, weight loss
Oncaspar Drug Interactions
High alert medication: Metabolism/Transport Effects None known.
This medication is in a class the Institute for Safe Avoid Concomitant Use There are no known interac-
Medication Practices (ISMP) includes among its list of tions where it is recommended to avoid concomitant use.
drug classes which have a heightened risk of causing Increased Effect/Toxicity
significant patient harm when used in error. Asparaginase (Erwinia) may increase the levels/effects
Brand Names: US Erwinaze of: Dexamethasone (Systemic)
Brand Names: Canada Erwinase Decreased Effect There are no known significant inter-
Therapeutic Category Antineoplastic Agent, Enzyme; actions involving a decrease in effect.
Antineoplastic Agent, Miscellaneous Storage/Stability Store intact vials refrigerated at 2°C to
Generic Availability (US) No 8°C (36°F to 46°F). Protect from light. Within 15 minutes of
Use Treatment (in combination with other chemotherapy reconstitution, withdraw appropriate volume for dose into~
agents) of acute lymphoblastic leukemia (ALL) in patients
a polypropylene syringe. Do not freeze or refrigerate
with hypersensitivity to E. coli-derived asparaginase (FDA
reconstituted solution; discard if not administered within
approved in ages 21 year and adults)
4 hours.
Prescribing and Access Restrictions For order infor-
mation contact 877-625-2566 or visit http://erwinaze.com/
Mechanism of Action Asparaginase catalyzes the dea-
healthcare-professionals/order-erwinaze/ midation of asparagine to aspartic acid and ammonia,
Pregnancy Risk Factor C reducing circulating levels of asparagine. Leukemia cells
Pregnancy Considerations Adverse events were lack asparagine synthetase and are unable to synthesize
observed in animal reproduction studies. asparagine. Asparaginase reduces the exogenous aspar-
Breastfeeding Considerations It is not known if aspar- agine source for the leukemic cells, resulting in cytotoxicity
_aginase Erwinia chrysanthemi is excreted in breast milk. specific to leukemic cells.
Due to the potential for serious adverse reactions in the Pharmacodynamics/Kinetics (Adult data unless
nursing infant, the manufacturer recommends a decision noted) Half-life elimination: IM: ~16 hours (Asselin
be made to discontinue nursing or to discontinue the drug, 1993; Avramis 2005); IV: ~7.5 hours
 ASPARAGINASE (ERWINIA)

Dosing therapy is stable or completed. Do not withhold

Pediatric Note: If administering IV, consider monitoring therapy for abnormal laboratory findings without
nadir serum asparaginase activity (NSAA) levels; if clinical correlate.
desired levels are not achieved, change to IM admin- Hemorrhage: If grade 2 bleeding in conjunction with
istration. hypofibrinogenemia occurs, withhold therapy until
Acute lymphoblastic leukemia (ALL): Children and bleeding <grade 1. Do not withhold therapy for
Adolescents: abnormal laboratory findings without clinical corre-
As a substitute for pegaspargase: IM, |V: 25,000 units/ late. For grade 3 or 4 bleeding, withhold therapy
m?/dose 3 times weekly (Mon, Wed, Fri) for 6 doses until bleeding <grade 1 and until acute toxicity and
for each planned pegaspargase dose clinical signs resolve and coagulant replacement
As a substitute for asparaginase (E. coli): IM, IV: therapy is stable or completed.
. 25,000 units/m?/dose for each scheduled asparagi- Renal Impairment: Pediatric All patients: There are no
nase (E. coli) dose dosage adjustments provided in the manufacturer's
Dosage adjustment for toxicity: labeling.
Manufacturer's labeling: Children and Adolescents: Hepatic Impairment: Pediatric
Hemorrhagic or thrombotic event: Discontinue treat- There are no dosage adjustments provided in the man-
ment; may resume treatment upon symptom reso- ufacturer's labeling; however, the following adjustments
lution. have been recommended for other asparaginase prod-
Pancreatitis: ucts for hepatotoxicity during treatment (Stock 2011):
Mild pancreatitis: Withhold treatment until signs and Older Adolescents:
symptoms subside and amylase returns to normal; ALT/AST >3 to 5 times ULN: Continue therapy.
may resume after resolution. ALT/AST >5 to 20 times ULN: Delay next dose until
Severe or hemorrhagic pancreatitis (abdominal pain transaminases <3 times ULN.
>72 hours and amylase 22 x ULN): Discontinue ALT/AST >20 times ULN: Discontinue therapy if takes
treatment; further use is contraindicated. longer than 1 week for transaminases to return to <3
Serious hypersensitivity: Discontinue treatment. times ULN.
The following adjustments have also been recom- Direct bilirubin <3 mg/dL: Continue therapy.
mended for asparaginase products (Stock 2011): Direct bilirubin 3.1 to 5 mg/dL: Hold asparaginase and
Older Adolescents: resume when direct bilirubin <2 mg/dL; consider
Hyperammonemia-related fatigue: Continue therapy switching to alternate asparaginase product.
for grade 2 toxicity. If grade 3 toxicity occurs, reduce Direct bilirubin >5 mg/dL: Discontinue asparaginase;
dose by 25%; resume full dose when toxicity <grade do not substitute other asparaginase products; do
2 (make up for missed doses). If grade 4 toxicity not make up for missed doses.
occurs, reduce dose by 50%; resume full dose when
Preparation for Administration Parenteral: Reconsti-
toxicity <grade 2 (make up for missed doses).
tute each vial with 1 mL of preservative-free NS to obtain
Hyperglycemia: Continue therapy for uncomplicated
a concentration of 10,000 units/mL, or with 2 mL preser-
hyperglycemia. If hyperglycemia requires insulin
vative-free NS to obtain a concentration of 5,000 units/mL.
therapy, hold asparaginase (and any concomitant
Gently direct the NS down the wall of the vial (do not inject
corticosteroids) until blood glucose controlled;
forcefully into or onto the powder). Dissolve by gently
resume dosing at prior dose level. For life-threat-
swirling or mixing; do not shake or invert the vial. Result-
ening hyperglycemia or toxicity requiring urgent
ing reconstituted solution should be clear and colorless
intervention, hold asparaginase (and corticoste-
and free of visible particles or protein aggregates. Within
roids) until blood glucose is controlled with insulin;
15 minutes of reconstitution, withdraw appropriate volume
resume asparaginase and do not make up for
for dose into a polypropylene syringe. If administering
missed doses.
intravenously, slowly inject the appropriate volume of
Hypersensitivity reactions: May continue dosing for
urticaria without bronchospasm, hypotension, reconstituted solution into 100 mL of NS; do not shake
edema, or need for parenteral intervention. If wheez-
or squeeze the bag. Administer within 4 hours of recon-
ing or other symptomatic bronchospasm with or stitution.
without urticaria, angioedema, hypotension, and/or Additional special preparation instructions may be
life-threatening hypersensitivity reactions occur, dis- required for select Asparaginase (Erwinia) batches.
continue asparaginase. Asparaginase (Erwinia) vials from certain US batches
Hypertriglyceridemia: \f serum triglyceride level should only be administered intramuscularly.
<1,000 mg/dL, continue asparaginase but monitor Refer to the following for batch-specific information: Erwi-
closely for pancreatitis. If triglyceride level naze [US product]: http://erwinazesupply.com/product-
>1,000 mg/dL, hold asparaginase and monitor; updates/
resume therapy at prior dose level after triglyceride Administration Parenteral: Note: Vials from certain
level returns to baseline. batches should only be administered intramuscularly or
Pancreatitis: require the use of a 0.2 micron filter if administered intra-
Asymptomatic amylase or lipase >3 times ULN venously. Refer to the following for batch-specific informa-
(chemical pancreatitis) or radiologic abnormalities tion: http://erwinazesupply.com/product-updates/
only: Continue asparaginase and monitor levels IM: The volume of each single injection site should be
closely. limited to 2 mL; use multiple injection sites for volumes
Symptomatic amylase or lipase >3 times ULN: Hold >2 mL.
asparaginase until enzyme levels stabilize or are IV: Infuse over 1 or 2 hours; do not infuse other medi-
declining. cations through the same IV line; some product lots may
Symptomatic pancreatitis or clinical pancreatitis require use of a 0.2 micron filter; refer to manufacturer
(abdominal pain with amylase or lipase >3 times for batch-specific information. Note: Some product lots
ULN for >3 days and/or development of pancreatic not for IV administration; refer to manufacturer for batch-
pseudocyst): Permanently discontinue aspara- specific information.
ginase. Monitoring Parameters CBC with differential, amylase,
Thrombosis and bleeding, CNS: liver enzymes, blood glucose (baseline and periodically
Thrombosis: Continue therapy for abnormal labora- during treatment), coagulation parameters, for |V admin-
tory findings without a clinical correlate. If grade 3 istration, consider monitoring nadir serum asparaginase
toxicity occurs, discontinue therapy; if CNS signs/ activity (NSAA) levels. Monitor for symptoms of hyper-
symptoms are fully resolved and further asparagi- sensitivity; symptoms of pancreatitis, thrombosis, or hem-
nase doses are required, may resume therapy at a orrhage
lower dose and/or longer intervals between doses. Dosage Forms Excipient information presented when
Discontinue therapy for grade 4 toxicity. available (limited, particularly for generics); consult spe-
Hemorrhage: Discontinue therapy; do not withhold cific product labeling.
therapy for abnormal laboratory findings without a Solution Reconstituted, Intramuscular:
clinical correlate. If grade 3 toxicity occurs, discon- Erwinaze: 10,000 units (1 ea)
tinue therapy; if CNS signs/symptoms are fully
resolved and further asparaginase doses are @ Asparaginase Erwinia chrysanthemi see Asparagi-
required, may’ fesume therapy at a lower dose nase (Erwinia) on page 192
and/or longer intervals between doses. Discon- @ Aspart Insulin see Insulin Aspart on page 1081
tinue therapy for grade 4 toxicity. @ Aspart Insulin and Insulin Aspart Protamine see Insu-
Thrombosis and bleeding, non-CNS: lin Aspart Protamine and Insulin Aspart on page 1083
Thrombosis: Continue therapy for abnormal labora-
tory findings without a clinical correlate. If grade 3 @ Aspart Insulin and Insulin Degludec see Insulin Deglu-
or 4 toxicity occurs, withhold therapy until acute dec and Insulin Aspart on page 1088
toxicity and clinical signs resolve and anticoagulant @ Aspercin [OTC] see Aspirin on page 194

193
ASPIRIN

to SLE) (ACCP [Bates 2012]; Carp 2004; Tincani 2003).

ASDirin As pir in) Low-dose aspirin to prevent thrombosis may also be used
during the second, and third trimesters in women, with
Medication Safety Issues prosthetic valves (mechanical or bioprosthetic), The use
Sound-alike/look-alike issues: of warfarin is recommended, along with low-dose aspirin,
Aspirin may be confused with Afrin in those with mechanical prosthetic valves (AHA/ACC
Ascriptin may be confused with Aricept {Nishimura 2014]). Low-dose aspirin may also be used
Ecotrin may be confused with Edecrin, Epogen after the first trimester in women with low-risk conditions
Halfprin may be confused with Haltran requiring antiplatelet therapy (AHA/ASA [Kernan 2014]).
ZORprin may be confused with Zyloprim When needed in doses required for the management of
International issues: pain, agents other than aspirin are preferred in pregnant
Cartia [multiple international markets] may be confused women and use in the third trimester is not recommended
with Cartia XT brand name for dilTlAZem [US] (Kallén 2016; Shah 2015).
Geriatric Patients: High-Risk Medication: Breastfeeding Considerations
Beers Criteria: Aspirin, when used chronically at doses Salicylic acid is present in breast milk following maternal
more than 325 mg, is identified in the Beers Criteria as use of aspirin (Bailey 1982; Findlay 1981; Jamali 1981).
a potentially inappropriate medication to be avoided in The relative infant dose (RID) of aspirin is 8% when
patients 65 years and older (unless alternative agents calculated using the highest breast milk concentration
ineffective and patient can receive concomitant gastro- located and compared to an infant therapeutic dose of
protective agent) due to increased risk of GI bleeding 90 mg/kg/day.
and peptic ulcer disease in older adults in high risk In general, breastfeeding is considered acceptable when
category (eg, older than 75 years of age or receiving the RID is <10% (Anderson 2016; Ito 2000).
concomitant oral/parenteral corticosteroids, anticoagu- The RID of aspirin was calculated using a milk concen-
lants, or antiplatelet agents). In addition, when aspirin is tration of 48.1 mcg/mL, providing an estimated daily
used for the primary prevention of cardiac events, it infant dose via breast milk of 7.2 mg/kg/day. This milk
should be used with caution in older adults 80 years concentration was obtained following maternal adminis-
and older due to a lack of evidence of benefit versus tration of aspirin 1,500 mg as a single dose (Jamali
risk (Beers Criteria [AGS 2015)). 1981). The reported time to peak milk concentration is
Related Information variable (2 to 9 hours), milk concentrations decline
Oral Medications That Should Not Be Crushed or Altered slowly, and do not correlate strongly to maternal serum
on page 2217 concentration (Bailey 1982; Bar-Oz 2003; Findlay 1981;
Brand Names: US Ascriptin Maximum Strength [OTC]; Jamali 1981). Salicylate is measurable in the serum
Ascriptin Regular Strength [OTC]; Aspercin [OTC]; Aspir- (Unsworth 1987) and urine (Clark 1981) of breastfed
low [OTC]; Aspirtab [OTC]; Bayer Aspirin Extra Strength infants following maternal use of oral aspirin. Higher
[OTC]; Bayer Aspirin Regimen Adult Low Strength [OTC]; salicylate concentrations may be present in breast milk
Bayer Aspirin Regimen Children's [OTC]; Bayer Aspirin following multiple maternal doses. In addition, salicylate
Regimen Regular Strength [OTC]; Bayer Genuine Aspirin concentrations may be higher than reported as metabo-
[OTC]; Bayer Plus Extra Strength [OTC]; Bayer Women's lite concentrations of salicylic acid were not evaluated in
Low Dose Aspirin [OTC]; Buffasal [OTC]; Bufferin Extra most studies; the longer elimination half-life in infants
Strength [OTC]; Bufferin [OTC]; Buffinol [OTC]; Durlaza; compared to adults should also be considered (Bar-Oz
Ecotrin Arthritis Strength [OTC]; Ecotrin Low Strength 2003; Spigset 2000).
[OTC]; Ecotrin [OTC]; Halfprin [OTC] [DSC]; St Joseph Metabolic acidosis was reported in a 16-day old breastfed
Adult Aspirin [OTC]; Tri-Buffered Aspirin [OTC] full-term infant following maternal doses of aspirin 3.9 g/
Brand Names: Canada Asaphen; Asaphen E.C.; Entro- day (Clark 1981). Thrombocytopenic purpura was also
phen; Novasen; Praxis ASA EC 81 Mg Daily Dose; Pro- reported in one infant following salicylate exposure via
AAS EC-80 breast milk (Spigset 2000). There were no cases of
Therapeutic Category Analgesic, Nonopioid; Anti-inflam- diarrhea, drowsiness, or irritability noted in breastfed
matory Agent; Antiplatelet Agent; Antipyretic; Nonsteroidal infants in the study which included 15 mother-infant pairs
Anti-inflammatory Drug (NSAID), Oral; Salicylate following aspirin exposure (dose, duration, and relation-
Generic Availability (US) May be product dependent ship to breastfeeding not provided) (Ito 1993).
Use Breastfeeding is not recommended by the manufacturer.
Immediate release: Treatment of mild to moderate pain, When a nonopioid analgesic is needed in postpartum
inflammation, and fever (OTC: All products: FDA women who wish to breastfeed, agents other than
approved in adults; refer to product-specific information aspirin are preferred (Montgomery 2012). The WHO
regarding FDA approval in pediatric patients, most prod- considers occasional doses of aspirin to be compatible
ucts FDA approved in ages 212 years), has also been with breastfeeding, but recommends to avoid long-term
used for adjunctive treatment of Kawasaki disease; therapy and consider monitoring the infant for adverse
prevention of vascular mortality during suspected acute effects (hemolysis, prolonged bleeding, metabolic acido-
Ml; prevention of recurrent Ml; prevention of MI in sis) (WHO 2002). Other sources suggest avoiding
patients with angina; prevention of recurrent stroke and aspirin while breastfeeding due to the theoretical risk of
mortality following TIA or stroke; management of rheu- Reye syndrome (Bar-Oz 2003; Spigset 2000). When
matoid arthritis, and rheumatic fever; adjunctive therapy used for vascular indications, breastfeeding may be
in revascularization procedures (coronary artery bypass continued during low-dose aspirin therapy (ACCP [Bates
graft, percutaneous transluminal coronary angioplasty, 2012]; AHA/ASA [Kernan 2014]; WHO 2002).
carotid endarterectomy) Contraindications
Extended release: Reduce the risk of death and MI in Hypersensitivity to NSAIDs; patients with asthma, rhinitis,
patients with chronic coronary artery disease (eg, history and nasal polyps; use in children or teenagers for viral
of Ml, unstable angina, or chronic stable angina); reduce infections, with or without fever. :
the risk of death and recurrent stroke in patients who Documentation of allergenic cross-reactivity for salicylates
have had an ischemic stroke or transient ischemic attack is limited. However, because of similarities in chemical
(TIA) (All indications: FDA approved in adults). Note: Do structure and/or pharmacologic actions, the possibility of
not use extended release capsules in situations for cross-sensitivity cannot be ruled out with certainty.
which a rapid onset of action is required (such as acute Warnings/Precautions Use with caution in patients with
treatment of MI or before percutaneous coronary inter- platelet and bleeding disorders, renal dysfunction, dehy-
vention); use immediate release formulations instead. dration, or erosive gastritis. Avoid use in patients with
Pregnancy Considerations Salicylates have been noted active peptic ulcer disease. Heavy ethanol use (>3
to cross the placenta and enter fetal circulation. Adverse drinks/day) can increase bleeding risks. When using high
effects reported in the fetus include mortality, intrauterine dosages (eg, analgesic or anti-inflammatory uses), use
growth retardation, salicylate intoxication, bleeding abnor- with caution and monitor renal function or consider the use —
malities, and neonatal acidosis. Use of aspirin close to of an alternative analgesic/anti-inflammatory agent (NKF
delivery may cause premature closure of the ductus {Henrich 1996]; Whelton 2000). Low-dose aspirin (eg, 75
arteriosus. Adverse effects reported in the mother include to 162 mg daily) may be safely used in patients with any
anemia, hemorrhage, prolonged gestation, and prolonged degree of renal impairment (KDOQI 2005; KDOQI 2007).
labor (Ostensen 1998). Avoid use in severe hepatic failure. Low-dose aspirin for
cardioprotective effects is associated with a two- to four-
Low-dose aspirin may be used to prevent preeclampsia in
fold increase in UGI events (eg, symptomatic or compli-
women with a history of early-onset preeclampsia and
cated ulcers); risks of these events increase with
preterm delivery (<34 0/7 weeks), or preeclampsia in 21
increasing aspirin dose; during the chronic phase of
prior to pregnancy (ACOG 2013). Treatment is started
aspirin dosing, doses >81 mg are not recommended
after 12 weeks' gestation in women at risk for preeclamp-
unless indicated (Bhatt 2008).
sia (ACCP [Bates 2012]; LeFevre 2014). Low-dose aspirin
is used to treat complications resulting from antiphospho- Discontinue use if tinnitus or impaired hearing occurs.
lipid syndrome in pregnancy (either primary or secondary Caution in mild-to-moderate renal failure (only at high

194
 ASPIRIN

dosages). Patients with sensitivity to tartrazine dyes, nasal Hematologic & oncologic: Anemia, blood coagulation dis-
polyps, and asthma may have an increased risk of salicy- order, disseminated intravascular coagulation, hemolytic
late sensitivity..In the treatment of acute ischemic stroke, anemia, hemorrhage, iron deficiency anemia, prolonged
avoid aspirin for 24 hours following administration of prothrombin time, thrombocytopenia
alteplase; administration within 24 hours increases the Hepatic: Hepatitis (reversible), hepatotoxicity, increased
risk of hemorrhagic transformation (Jauch 2013). Concur- serum transaminases
rent use of aspirin and clopidogrel is not recommended for Hypersensitivity; Anaphylaxis, angioedema
secondary prevention of ischemic stroke or TIA in patients Neuromuscular & skeletal: Acetabular bone destruction,
unable to take oral anticoagulants due to hemorrhagic risk rhabdomyolysis, weakness
(Furie 2011). Aspirin should be avoided (if possible) in Otic: Hearing loss, tinnitus
surgical patients for 1 to 2 weeks prior to elective surgery, Renal: Increased blood urea nitrogen, increased serum
to, reduce the risk of excessive bleeding. In patients with creatinine, interstitial nephritis, renal failure (including
cardiac stents or who have recently (within the previous 14 cases caused by rhabdomyolysis), renal insufficiency,
days) undergone balloon angioplasty that have not com- renal papillary necrosis
pleted their full course of antiplatelet therapy (eg, dual Respiratory: Asthma, bronchospasm, dyspnea, hyperven-
antiplatelet therapy), antiplatelet therapy should be con- tilation, laryngeal edema, noncardiogenic pulmonary
tinued and elective surgery should be delayed until course edema, respiratory alkalosis, tachypnea
of antiplatelet therapy is complete; patient specific situa- Miscellaneous: Low birth weight
tions should be discussed with cardiologist (ACC/AHA Rare but important or life-threatening: Anorectal stenosis
[Fleisher 2014]; ACC/AHA [Levine 2016]; AHA/ACC/ (suppository), atrial fibrillation (toxicity), cardiac conduc-
SCAI/ACS/ADA [Grines 2007)). tion disturbance (toxicity), cerebral infarction (ischemic),
cholestatic jaundice, colitis, colonic ulceration, coronary
When used for self-medication (OTC labeling): Children
artery vasospasm, delirium, esophageal obstruction,
and teenagers who have or are recovering from chick-
esophagitis (with esophageal ulcer), hematoma (esoph-
enpox or flu-like symptoms should not use this product.
ageal), macular degeneration (age-related) (Li 2014),
Changes in behavior (along with nausea and vomiting)
periorbital edema, rhinosinusitis
may be an early sign of Reye's syndrome; patients should
be instructed to contact their healthcare provider if these
Drug Interactions
occur. Metabolism/Transport Effects Substrate of CYP2C9
(minor); Note: Assignment of Major/Minor substrate sta-
Some dosage forms may contain polysorbate 80 (also tus based on clinically relevant drug interaction potential
known as Tweens). Hypersensitivity reactions, usually a Avoid Concomitant Use
delayed reaction, have been reported following exposure Avoid concomitant use of Aspirin with any of the follow-
to pharmaceutical products containing polysorbate 80 in ing: Dexibuprofen; Dexketoprofen; Floctafenine; Influ-
certain individuals (Isaksson 2002; Lucente 2000; Shelley enza Virus Vaccine (Live/Attenuated); Ketorolac
1995). Thrombocytopenia, ascites, pulmonary deteriora- (Nasal); Ketorolac (Systemic); Macimorelin; Omacetax-
tion, and renal and hepatic failure have been reported in ine; Sulfinpyrazone; Urokinase
premature neonates after receiving parenteral products Increased Effect/Toxicity
containing polysorbate 80 (Alade 1986; CDC 1984). See Aspirin may increase the levels/effects of: Agents with
manufacturer's labeling. Antiplatelet Properties; Ajmaline; Alendronate; Angioten-
Aspirin resistance is defined as measurable, persistent sin-Converting Enzyme Inhibitors; Anticoagulants; Apix-
platelet activation that occurs in patients prescribed a aban; Blood Glucose Lowering Agents; Carbonic
therapeutic dose of aspirin. Clinical aspirin resistance, Anhydrase Inhibitors; Carisoprodol; Cephalothin; Colla-
the recurrence of some vascular event despite a regular genase (Systemic); Corticosteroids (Systemic); Dabiga-
therapeutic dose of aspirin, is considered aspirin treat- tran Etexilate; Deoxycholic Acid; Dexibuprofen;
ment failure. Estimates of biochemical aspirin resistance Dexketoprofen; Edoxaban; Heparin; Ibritumomab. Tiux-
range from 5.5% to 60% depending on the population etan; Methotrexate; Nicorandil; Nonsteroidal Anti-Inflam-
studied and the assays used (Gasparyan 2008). Patients matory Agents (COX-2 Selective); Obinutuzumab;
with aspirin resistance may have a higher risk of cardio- Omacetaxine; PRALAtrexate; Rivaroxaban; Salicylates;
vascular events compared to those who are aspirin sensi- Talniflumate; Thiopental; Thrombolytic Agents; Ticagre-
tive (Gum 2003). lor; Urokinase; Valproate Products; Varicella Virus-Con-
Warnings: Additional Pediatric Considerations Do taining Vaccines; Vitamin K Antagonists
not use aspirin in pediatric patients <18 years of age (APS The levels/effects of Aspirin may be increased by:
2016) who have or who are recovering from chickenpox or Agents with Antiplatelet Properties; Alcohol (Ethyl);
flu symptoms (due to the association with Reye syn- Ammonium Chloride; Calcium Channel Blockers (Non-
drome); when using aspirin, changes in behavior (along dihydropyridine); Dasatinib; Felbinac; Floctafenine;
with nausea and vomiting) may be an early sign of Reye Ginkgo Biloba; Glucosamine; Herbs (Anticoagulant/Anti-
syndrome; instruct patients and caregivers to contact their platelet Properties); Ibrutinib; Influenza Virus Vaccine
health care provider if these symptoms. occur;-patients (Live/Attenuated); Ketorolac (Nasal); Ketorolac (Sys-
should be kept current on their influenza and varicella temic); Limaprost; Loop Diuretics; Multivitamins/Fluoride
immunizations. Although Reye syndrome has been (with ADE); Multivitamins/Minerals (with ADEK, Folate,
observed in patients receiving prolonged, high-dose Iron); Multivitamins/Minerals (with AE, No Iron); Non-
aspirin therapy after Kawasaki disease presentation; it steroidal Anti-Inflammatory Agents (Nonselective);
has not been observed in pediatric patients receiving Omega-3 Fatty Acids; Pentosan Polysulfate Sodium;
low (antiplatelet) dosing regimens. Patients with Kawasaki Pentoxifylline; Potassium Phosphate; Prostacyclin Ana-
disease and presenting with influenza or viral illness logues; Selective Serotonin Reuptake Inhibitors; Seroto-
should not receive aspirin; acetaminophen is suggested nin/Norepinephrine Reuptake Inhibitors; Tipranavir;
as an antipyretic in these patients, and an alternate Tricyclic Antidepressants (Tertiary Amine); Vitamin E
antiplatelet agent is suggested for a minimum of 2 weeks (Systemic)
(AHA [McCrindle 2017]). Decreased Effect
Adverse Reactions As with all drugs which may affect Aspirin may decrease the levels/effects of: Angiotensin-
hemostasis, bleeding is associated with aspirin. Hemor- Converting Enzyme Inhibitors; Benzbromarone; Cariso-
rhage may occur at virtually any site. Risk is dependent on prodol; Dexketoprofen; Hyaluronidase; Lesinurad; Loop
multiple variables including dosage, concurrent use of Diuretics; Macimorelin; Multivitamins/Fluoride (with
multiple agents which alter hemostasis, and patient sus- ADE); Multivitamins/Minerals (with ADEK, Folate, Iron);
ceptibility. Many adverse effects of aspirin are dose Multivitamins/Minerals (with AE, No Iron); Nonsteroidal
related, and are extremely rare at low dosages. Other Anti-Inflammatory Agents (Nonselective); Probenecid;
serious reactions are idiosyncratic, related to allergy or Sulfinpyrazone; Ticagrelor; Tiludronate
individual sensitivity.
Cardiovascular: Cardiac arrhythmia, edema, hypotension, The levels/effects of Aspirin may be decreased by:
tachycardia Alcohol (Ethyl); Corticosteroids (Systemic); Dexibupro-
Central nervous system: Agitation, cerebral edema, coma, fen; Dexketoprofen; Floctafenine; Ketorolac (Nasal);
confusion, dizziness, fatigue, headache, hyperthermia, Ketorolac (Systemic); Nonsteroidal Anti-Inflammatory
insomnia, lethargy, nervousness, Reye's syndrome Agents (Nonselective); Sucroferric Oxyhydroxide
Dermatologic: Skin rash, urticaria Food Interactions Food may decrease the rate but not
Endocrine & metabolic: Acidosis, dehydration, hypergly- the extent of oral absorption. Benedictine liqueur, prunes,
cemia, hyperkalemia, hypernatremia (buffered forms), raisins, tea, and gherkins have a potential to cause
hypoglycemia (children) salicylate accumulation. Fresh fruits containing vitamin C
Gastrointestinal: Duodenal ulcer, dyspepsia, epigastric may displace drug from binding sites, resulting in
distress, gastritis, gastrointestinal erosion, gastrointesti- increased urinary excretion of aspirin. Curry powder,
nal ulcer, heartburn, nausea, stomach pain, vomiting paprika, licorice; may cause salicylate accumulation.
Genitourinary: Postpartum hemorrhage, prolonged gesta- These foods contain 6 mg salicylate/100 g. An ordinary
tion, prolonged labor, proteinuria, stillborn infant American diet contains 10-200 mg/day of salicylate. >
195
ASPIRIN

Management: Administer with food or large volume of Anti-inflammatory: Limited data available: Infants,
water or milk to minimize GI upset. Limit curry powder, Children, and Adolescents: Oral: Initial: 60 to
paprika, licorice. 90 mg/kg/day in divided doses; usual maintenance:
Storage/Stability Store oral dosage forms (caplets, tab- 80 to 100 mg/kg/day divided every 6 to 8 hours;
lets, capsules) at room temperature; protect from mois- monitor serum concentrations (Levy 1978)
ture; see product-specific labeling for details. Keep Antiplatelet effects: Limited data available: Infants,
suppositories in refrigerator; do not freeze. Hydrolysis of Children, and Adolescents: Oral: Adequate pediatric
aspirin occurs upon exposure to water or moist air, result- studies have not been performed; pediatric dosage is
ing in salicylate and acetate, which possess a vinegar-like derived from adult studies. Usual adult maximum daily
odor. Do not use if a strong odor is present. dose for antiplatelet effects is 325 mg/day.
Mechanism of Action Irreversibly inhibits cyclooxyge- Acute ischemic stroke (AIS):
nase-1 and 2 (COX-1 and 2) enzymes, via acetylation, Noncardioembolic: 1 to 5 mg/kg/dose once daily for
which results in decreased formation of prostaglandin 22 years; patients with recurrent AlS or TIAs
precursors; irreversibly inhibits formation of prostaglandin should be transitioned to clopidogrel, LMWH, or
warfarin (ACCP [Monagle 2012])
derivative, thromboxane Ag:,-via acetylation of platelet
Secondary to Moyamoya and non-Moyamoya vas-
cyclooxygenase, thus inhibiting platelet aggregation; has
antipyretic, analgesic, and anti-inflammatory properties culopathy: 1 to 5 mg/kg/dose once daily; Note: In
non-Moyamoya vasculopathy, continue aspirin for
Pharmacodynamics/Kinetics (Adult data unless
3 months, with subsequent use guided by repeat
noted) cerebrovascular imaging (ACCP [Monagle 2012]).
Onset: Immediate release: Platelet inhibition: Within 1
Prosthetic heart valve:
hour (nonenteric-coated), Onset of enteric-coated aspirin Bioprosthetic aortic valve (with normal sinus
expected to be delayed (Eikelboom 2012). Note: Chew- rhythm): 1 to 5 mg/kg/dose once daily for 3 months
ing nonenteric-coated or enteric-coated tablets results in (AHA [Giglia 2013]; ACCP [Guyatt 2012]; ACCP
inhibition of platelet aggregation within 20 minutes; [Monagle 2012])
therefore, nonenteric-coated tablets should be chewed Mechanical aortic and/or mitral valve: 1 to 5 mg/kg/
in settings where a more rapid onset is required (eg, dose once daily combined with vitamin K antago-
acute Ml) and enteric-coated tablets may be chewed nist (eg, warfarin) is recommended as first-line
when a rapid effect is required and immediate release antithrombotic therapy (ACCP [Guyatt 2012];
nonenteric-coated tablets are not available (Eikelboom ACCP [Monagle 2012]). Alternative regimens: 6
2012; Feldman 1999; Sai 2011). to 20 mg/kg/dose once daily in combination with
Duration: Immediate release: 4 to 6 hours; however, dipyridamole (Bradley 1985; el Makhlouf 1987;
platelet inhibitory effects last the lifetime of the platelet LeBlanc 1993; Serra 1987; Solymar 1991)
(~10 days) due to its irreversible inhibition of platelet Shunts: Blalock-Taussig; Glenn; postoperative; pri-
COX-1 (Eikelboom 2012). mary prophylaxis: 1 to 5 mg/kg/dose once daily
Absorption: Immediate release: Rapidly absorbed in stom- (ACCP [Monagle 2012]; AHA [Giglia 2013])
ach and upper intestine (Eikelboom 2012); Extended- Norwood, Fontan surgery, postoperative; primary pro-
release capsule: Rate of absorption is dependent upon phylaxis: 1 to 5 mg/kg/dose once daily (ACCP
food, alcohol, and gastric pH. [Monagle 2012]; AHA [Giglia 2013])
Distribution: Vg: 10 L; readily into most body fluids and Transcatheter Atrial Septal Defect (ASD) or Ventricu-
tissues; hydrolyzed to salicylate (active) by esterases in lar Septal Defect (VSD) devices, postprocedure
the GI mucosa, red blood cells, synovial fluid and blood prophylaxis: 1 to 5 mg/kg/dose once daily starting
Protein binding: Concentration dependent; as salicylate one to several days prior to implantation and con-
concentration increases, protein binding decreases: tinued for at least 6 months. For older children and
~90% to 94% (to albumin) at concentrations <80 mcg/mL adolescents, after device closure of ASD, an addi-
(Rosenberg 1981; Juurlink 2015); ~30% with concen- tional anticoagulant may be given with aspirin for 3
trations seen in overdose (Juurlink 2015). to 6 months, but the aspirin should continue for at
Metabolism: Hydrolyzed to salicylate (active) by esterases least 6 months (AHA [Giglia 2013]).
in GI mucosa, red blood cells, synovial fluid, and blood; Ventricular assist device (VAD) placement: 1 to
metabolism of salicylate occurs primarily by hepatic 5 mg/kg/dose once daily initiated within 72 hours
conjugation; metabolic pathways are saturable of VAD placement; should be used with heparin
Bioavailability: Immediate release: 50% to 75% reaches (initiated between 8 to 48 hours following implanta-
systemic circulation tion) and with or without dipyridamole (ACCP [Mona-
Half-life elimination: Parent drug: Plasma concentration: gle 2012])
15 to 20 minutes; Salicylates (dose dependent): 3 hours Kawasaki disease: Limited data available; optimal
at lower doses (300 to 600 mg), 5 to 6 hours (after 1 g), dose not established: Note: Patients with Kawasaki
10 hours with higher doses disease and presenting with influenza or viral illness
Time to peak, serum: Immediate release: ~1 to 2 hours should not receive aspirin; acetaminophen is sug-
(nonenteric-coated), 3 to 4 hours (enteric-coated) (Eikel- gested as an antipyretic in these patients and an |
boom 2012); Extended-release capsule: ~2 hours. Note: alternate antiplatelet agent suggested for a minimum
Chewing nonenteric-coated tablets results in a time to of 2 weeks (AHA [McCrindle 2017]).
peak concentration of 20 minutes (Feldman 1999). Infants, Children, and Adolescents: Oral:
Chewing enteric-coated tablets results in a time to peak Initial therapy (acute phase): Recommended dosing
concentration of 2 hours (Sai 2011). regimens vary. Use in combination with IV immune
Excretion: Urine (75% as salicyluric acid, 10% as sali- globulin (within first 10 days of symptom onset) and
cylic acid) corticosteroids in some cases.
High dose: 80 to 100 mg/kg/day divided every 6
Dosing
hours for up to 14 days until fever resolves for at
Neonatal Antiplatelet effects; p ostoperative congen-
least 48 to 72 hours (AAP [Red Book 2015];
ital heart repair or recurrent arterial ischemic stroke:
ACCP [Monagle 2012]; AHA [Giglia 2013]; AHA
Limited data available: Full-term neonate: Oral:
{McCrindle 2017])
Adequate neonatal studies have not been performed;
Moderate dose: 30 to 50 mg/kg/day divided every
neonatal dosage is derived from clinical experience
6 hours for up to 14 days until fever resolves for
and is not well established; suggested doses: 1 to
at least 48 to 72 hours (AHA [McCrindle 2017])
5 mg/kg/dose once daily (ACCP [Monagle 2012]). Doses Subsequent therapy (low-dose; antiplatelet effects):
are typically rounded to a convenient amount (eg, 1/4 of 3 to 5 mg/kg/day once daily; reported dosing
81 mg tablet) range: 1 to 5 mg/kg/day; initiate after fever
Pediatric resolves for at least 48 to 72 hours (or after 14
Note: Doses are typically rounded to a convenient days). In patients without coronary artery abnor-
amount (eg, 1/4 of 81 mg tablet): malities, administer the lower dose for 6 to 8
Analgesic: Oral, rectal: Note: Do not use aspirin in weeks. In patients with coronary artery abnormal-
pediatric patients <18 years who have or who are ities, low-dose aspirin should be continued indef-
recovering from chickenpox or flu symptoms (eg, viral initely (in addition to therapy with warfarin) (AAP
illness) due to the association with Reye syndrome [Red Book 2015]; ACCP [Monagle 2012]; AHA
(APS 2016): [Giglia 2013]; AHA [McCrindle 2017]).
Infants, Children, and Adolescents weighing <50 kg: Rheumatic fever: Limited data available: Infants, Chil-
Limited data available: 10 to 15 mg/kg/dose every 4 dren, and Adolescents: Oral: Initial: 100 mg/kg/day
to 6 hours; maximum daily dose: 90 mg/kg/day or divided into 4 to 5 doses; if response inadequate, may
4,000 mg/day whichever is less (APS 2016) increase dose to 125 mg/kg/day; continue for 2
Children 212 years and Adolescents weighing 250 kg: weeks; then decrease dose to 60 to 70 mg/kg/day
325 to 650 mg every 4 to 6 hours; maximum daily in divided doses for an additional 3 to 6 weeks (WHO
dose: 4,000 mg/day Guidelines 2004)

196
 ATAZANAVIR

Migratory polyarthritis, with carditis without cardiome- Bayer Women's Low Dose Aspirin: 81 mg [contains
galy or congestive heart failure: \nitial: 100 mg/kg/ elemental calcium 300 mg]
day in 4 divided doses for 3 to 5 days, followed by Caplet, oral [buffered]:
75 mg/kg/day in 4 divided doses for 4 weeks Ascriptin Maximum Strength: 500 mg [contains alumi-
Carditis and cardiomegaly or congestive heart failure: num hydroxide, calcium carbonate, magnesium
At the beginning of the tapering of the prednisone hydroxide] [DSC]
dose, aspirin should be started at 75 mg/kg/day in 4 Bayer Plus Extra Strength: 500 mg [contains calcium
divided doses for 6 weeks i carbonate]
Renal Impairment: Pediatric Caplet, enteric coated, oral:
Infants, Children, and Adolescents: There are no rec- Bayer Aspirin Regimen Regular Strength: 325 mg
ommendations in the manufacturer's labeling; how- Capsule Extended Release, oral:
“ever, the following adjustments have been Durlaza: 162.5 mg
recommended (Aronoff 2007): Suppository, rectal: 300 mg (12s); 600 mg (12s)
GFR 210 mL/minute/1.73 m?: No dosage adjustment Tablet, oral: 325 mg
necessary. Aspercin: 325 mg
GFR <10 mL/minute/1.73 m?: Avoid use. Aspirtab: 325 mg
Intermittent hemodialysis: Dialyzable: 50% to 100%; Bayer Genuine Aspirin: 325 mg
administer daily dose after dialysis session. Tablet, oral [buffered]: 325 mg
Peritoneal dialysis: Avoid use. Ascriptin Regular Strength: 325 mg [contains aluminum
CRRT: No. dosage adjustment necessary; monitor hydroxide, calcium carbonate, magnesium hydroxide]
serum concentrations.
Buffasal: 325 mg [contains magnesium oxide]
Hepatic Impairment: Pediatric All ages: Avoid use in Bufferin: 325 mg [contains calcium carbonate, magne-
_ severe liver disease. sium carbonate, magnesium oxide]
Administration Bufferin Extra Strength: 500 mg [contains calcium car-
Oral:
bonate, magnesium carbonate, magnesium oxide]
Immediate release: Administer with water, food, or milk
Buffinol: 324 mg [sugar free; contains magnesium oxide]
to decrease Gl upset. Do not crush or chew enteric
Tri-Buffered Aspirin: 325 mg [contains calcium carbo-
coated tablets; these preparations should be swal-
nate, magnesium carbonate, magnesium oxide]
lowed whole. For acute myocardial infarction, have
Tablet, chewable, oral: 81 mg
patient chew immediate release tablet.
Bayer Aspirin Regimen Children's: 81 mg [cherry flavor]
Extended release capsules: Do not cut, crush, or chew.
Bayer Aspirin Regimen Children's: 81 mg [orange flavor]
Administer with a full glass of water at the same time
St Joseph Adult Aspirin: 81 mg
each day. Do not administer 2 hours before or 1 hour
Tablet, enteric coated, oral: 81 mg, 325 mg, 650 mg
after alcohol consumption.
Aspir-low: 81 mg
Rectal: Remove suppository from plastic packet and insert
into rectum as far as possible. Bayer Aspirin Regimen Adult Low Strength: 81 mg
Monitoring Parameters CBC, iron studies, ferritin, stools Ecotrin: 325 mg
for occult blood, and renal function tests with prolonged
Ecotrin Arthritis Strength: 500 mg
therapy. Serum salicylate concentration with chronic use; Ecotrin Low Strength: 81 mg
may not be necessary in Kawasaki disease; Note: Halfprin: 81 mg [DSC]
Decreased aspirin absorption and increased salicylate St Joseph Adult Aspirin: 81 mg
clearance has been observed in children with acute @ Aspirin and Oxycodone see Oxycodone and Aspirin
Kawasaki disease; these patients rarely achieve thera- on page 1529
peutic serum salicylate concentrations; thus, monitoring
of serum salicylate concentrations is not necessary in @ Aspirin Free Anacin Extra Strength [OTC] see Acet-
most of these children. aminophen on page 37
Reference Range ® Aspir-low [OTC] see Aspirin on page 194
Timing of serum samples: Peak concentrations usually ® Aspirtab [OTC] see Aspirin on page 194
occur 2 hours after normal doses but may occur 6 to
@ Astagraf XL see Tacrolimus (Systemic) on page 1892
24 hours after acute toxic ingestion.
Salicylate serum concentrations correlate with the phar- @ Astelin (Can) see Azelastine (Nasal) on page 227
macological actions and adverse effects observed. See Astepro see Azelastine (Nasal) on page 227
table. @ Astero see Lidocaine (Topical) on page 1215
Serum Salicylate: Clinical Correlations @ Asthmanefrin Refill [OTC] see EPINEPHrine (Oral Inha-
lation) on page 752
Serum
Salicylate Adverse Effects / @ Asthmanefrin Starter Kit [OTC] [DSC] see EPINEPHr-
Desired Effects Nitonication
Concentration ine (Oral Inhalation) on page 752
(meg/mL)
@ Astracaine with Epinephrine 1:200,000 (Can) see Arti-
Antiplatelet Gl intolerance and
Antipyresis bleeding, caine and Epinephrine on page 184
~100 Analgesia hypersensitivity, @ Astracaine with Epinephrine forte 1:100,000 (Can) see
hemostatic defects
Articaine and Epinephrine on page 184
150 to 300 Anti-inflammatory Mild salicylism @ Atacand see Candesartan on page 353
Nausea/vomiting, @ Atarax (Can) see HydrOXYzine on page 1028
hyperventilation,
Treatment of salicylism, flushing, @ Atasol (Can) see Acetaminophen on page 37
250 to 400 | rheumatic fever sweating, thirst,
headache, diarrhea, and
tachycardia Atazanavir (at a za NA veer)
Respiratory alkalosis,
hemorrhage, Medication Safety Issues
excitement, confusion, High alert medication:
asterixis, pulmonary
edema, convulsions, This medication is in a class the Institute for Safe
>400 to 500 tetany, metabolic Medication Practices (ISMP) includes among its list of
acidosis, fever, coma,— drug classes that have a heightened risk of causing
cardiovascular collapse,
renal and respiratory significant patient harm when used in error.
failure Brand Names: US Reyataz
Brand Names: Canada Reyataz
Test Interactions False-negative results for glucose oxi- Therapeutic Category Antiretroviral Agent; HIV Agents
dase urinary glucose tests (Clinistix); false-positives using (Anti-HIV Agents); Protease Inhibitor
the cupric sulfate method (Clinitest); also, interferes with Generic Availability (US) May be product dependent
Gerhardt test, VMA determination; 5-HIAA, xylose toler- Use Treatment of HIV-1 infection in combination with other
ance test and T3 and T,4; may lead to false-positive antiretroviral agents (Oral powder: FDA approved in ages
aldosterone/renin ratio (ARR) (Funder 2016) 23 months weighing at least 5 kg; Oral capsule: FDA
Dosage Forms Excipient information presented when approved in ages 26 years weighing 215 kg and adults).
available (limited, particularly for generics); consult spe- Note: HIV regimens consisting of three antiretroviral
cific product labeling. [DSC] = Discontinued product agents are strongly recommended; low-dose ritonavir
Caplet, oral: 500 mg (booster dose) is recommended in combination with ata-
Bayer Aspirin Extra Strength: 500 mg zanavir in all patients <13 years of age and in antiretro-
Bayer Genuine Aspirin: 325 mg viral-experienced patients with prior virologic failure. >
197
 ATAZANAVIR

4 Pregnancy Considerations which prolong AV conduction (dosage adjustment required

Atazanavir has a low level of transfer across the human with some agents); rare cases of second-degree AV block
placenta with cord blood concentrations reported as 13% have been reported. May cause or exacerbate preexisting
to 21% of maternal serum concentrations at delivery. An hepatic dysfunction; use caution in patients with, trans-
increased risk of teratogenic effects has not been aminase elevations prior to therapy or underlying hepatic
observed based on information collected by the antiretro- disease, such as hepatitis B or C or cirrhosis; monitor
viral pregnancy registry. Maternal antiretroviral therapy closely at baseline and during treatment. Not recom-
(ART) may increase the risk of preterm delivery, although mended in patients with severe hepatic impairment. In
available information is conflicting possibly due to varia- combination with ritonavir, is not recommended in patients
bility of maternal factors (disease severity; gestational age with any degree of hepatic impairment.
at initiation of therapy); however, maternal antiretroviral
medication should not be withheld due to concerns of Asymptomatic elevations in bilirubin (unconjugated) occur
preterm birth. Information related to stillbirth, low birth commonly during therapy and are reversible upon dis-
weight, and small for gestational age infants is limited. continuation of treatment. Consider alternative therapy if
Long-term follow-up is recommended for all infants jaundice or scleral icterus associated with bilirubin eleva-
exposed to antiretroviral medications; children who tions present cosmetic concerns. Evaluate alternative
develop significant organ system abnormalities of etiologies if transaminase elevations also occur (dose
unknown etiology (particularly of the CNS or heart) should reduction is not recommended because long-term efficacy
be evaluated for potential mitochondrial dysfunction. has not been established).
Hyperglycemia, new onset of diabetes mellitus, or diabetic
Cases of néphrolithiasis and cholelithiasis have been
ketoacidosis have been reported with Pls; it is not clear if
reported in postmarketing surveillance, some associated
pregnancy increases this risk. Hyperbilirubinemia or hypo-
with complications and/or requiring hospitalization. Con-
glycemia may occur in neonates following in utero expo-
sider temporary or permanent discontinuation of therapy if
sure to atazanavir, although data are conflicting (monitor).
symptoms develop. Cases of chronic kidney disease,
The Health and Human Services (HHS) Perinatal HIV including granulomatous interstitial nephritis, have been
Guidelines recommend atazanavir as a preferred Pl as reported in postmarketing surveillance; consider alterna-
initial therapy in antiretroviral-naive pregnant females tive therapy in patients at high risk for renal impairment or
when combined with low-dose ritonavir boosting. Ataza- with preexisting renal disease, Renal laboratory testing
navir is not recommended in treatment-experienced preg- (serum creatinine, estimated CrCl, and urinalysis with
nant females taking both H2-receptor blockers and microscopic examination) should be performed prior to
tenofovir disoproxil fumarate. Pharmacokinetic studies initiation and throughout treatment. Not recommended
suggest that standard dosing during pregnancy may pro- for use in treatment-experienced patients with ESRD on
vide decreased plasma concentrations and some experts hemodialysis. Consider therapy discontinuation in patients
recommend increased doses during the second and third with progressive kidney disease.
trimesters. However, the manufacturer notes that dose
adjustment is not required unless using concomitant H2- Protease inhibitors have been associated with a variety of
receptor blockers or tenofovir disoproxil fumarate in anti- hypersensitivity events (some severe), including rash,
retroviral-experienced pregnant females. Therapeutic anaphylaxis (rare), angioedema, bronchospasm, eryth-
drug monitoring may be useful. ema multiforme, Stevens-Johnson syndrome (rare) and/
or toxic skin eruptions (including DRESS [drug rash,
In general, ART is recommended for all pregnant females eosinophilia and systemic symptoms] syndrome). It is
with HIV to keep the viral load below the limit of detection
generally recommended to discontinue treatment if severe
and reduce the risk of perinatal transmission. When HIV is
rash or moderate symptoms accompanied by other sys-
diagnosed during pregnancy in a female who has never
temic symptoms occur.
received antiretroviral therapy, ART should begin as soon
as possible after diagnosis. Females who become preg- Use with caution in patients with hemophilia A or B;
nant on a stable ART regimen may continue that regimen increased bleeding during protease inhibitor therapy has
if viral suppression is effective, appropriate drug exposure been reported. Changes in glucose tolerance, hypergly-
can be achieved, contraindications for use in pregnancy cemia, exacerbation of diabetes, DKA, and new-onset
are not present, and the regimen is well tolerated. Mon- diabetes mellitus have been reported in patients receiving
itoring during pregnancy is more frequent than in non- protease inhibitors. May be associated with fat redistrib-
pregnant adults; ART should be continued postpartum for ution/accumulation (central obesity, buffalo hump, periph-
all females living with HIV. eral wasting, facial wasting, breast enlargement,
Health care providers are encouraged to enroll pregnant cushingoid appearance). Immune reconstitution syndrome
females exposed to antiretroviral medications as early in may develop resulting in the occurrence of an inflamma-
pregnancy as possible in the Antiretroviral Pregnancy tory response to an indolent or residual opportunistic
Registry (1-800-258-4263 or http://www.APRegistry. infection during initial HIV treatment or activation of auto-
com). Health care providers caring for HIV-infected immune disorders (eg, Graves disease, polymyositis,
females and their infants may contact the National Peri- Guillain-Barré syndrome) later in therapy; further evalua-
natal HIV Hotline (888-448-8765) for clinical consultation tion and treatment may be required. Oral powder contains
(HHS [perinatal] 2017). phenylalanine; avoid or use with caution in patients with
Breastfeeding Considerations phenylketonuria. Oral powder is not recommended for use
Atazanavir is present in breast milk; concentrations are in children <5 kg. Do not use in children <3 months of age
reported to be 13% of those in the maternal plasma. due to potential for kernicterus. Potentially significant
drug-drug interactions may exist, requiring dose or fre-
Maternal or infant antiretroviral therapy does not com- quency adjustment, additional monitoring, and/or selec-
pletely eliminate the risk of postnatal HIV transmission.
tion of alternative therapy. Do not use atazanavir/ritonavir
In addition, multiclass-resistant virus has been detected in
plus abacavir/lamivudine in adolescent and adult HIV-1
breastfeeding infants despite maternal therapy. Therefore,
patients with a pre-ART HIV RNA >100,000 copies/mL
in the US, where formula is accessible, affordable, safe,
(HHS [adult] 2016).
and sustainable, and the risk of infant mortality due to
diarrhea and respiratory infections is low, females with HIV Warnings: Additional Pediatric Considerations Skin
infection should completely avoid breastfeeding to rash may occur with atazanavir use, usually mild to
decrease the potential transmission of HIV (HHS [perina- moderate; maculopapular; reported incidence lower in
tal] 2017). pediatric patients (14% Grade 2 to 4) than adults (21%
Contraindications all grades); median onset: 7.3 weeks; treatment may be
Hypersensitivity (eg, Stevens-Johnson syndrome, eryth- continued if rash is mild to moderate (rash may resolve;
ema multiforme, toxic skin eruptions) to atazanavir or median duration: 1.4 weeks); discontinue therapy in cases
any component of the formulation; concurrent therapy of severe rash. May cause cough; reported incidence in
with alfuzosin, cisapride, elbasvir/grazoprevir, glecapre- pediatric patients: 21%. May cause fever; higher incidence
Vir/pibrentasvir, ergot derivatives (dihydroergotamine, observed in pediatric patients compared to adults (19% vs
ergonovine, ergotamine, methylergonovine), indinavir, 2%).
irinotecan, lovastatin, lurasidone (when atazanavir is Adverse Reactions Includes data from both treatment-
coadministered with ritonavir), midazolam (oral), nevir- naive and treatment-experienced patients. Unless other-
apine, pimozide, rifampin, sildenafil (when used for wise specified, frequency of adverse events is as reported
pulmonary artery hypertension [eg, Revatio]), simvasta- in adults receiving combination antiretroviral therapy.
tin, St. John's wort, or triazolam Cardiovascular: First degree atrioventricular block, sec-
Canadian labeling: Additional contraindications (not in US ond degree atrioventricular block, peripheral edema
labeling): Concomitant use of quinidine Central nervous system: Depression, dizziness, headache
Warnings/Precautions Atazanavir may prolong PR inter- (more common in children), insomnia, peripheral neuro-
val; ECG monitoring should be considered in patients with pathy
preexisting conduction abnormalities or with medications Dermatologic: Skin rash (more common in adults)

198
 ATAZANAVIR

Endocrine & metabolic: Hyperglycemia, hypoglycemia Fostamatinib; Gefitinib; Glecaprevir and Pibrentasvir;
(children), increased amylase (adults), increased serum Grazoprevir; GuanFACINE; Halofantrine; HYDROco-
cholesterol (2240 mg/dL), increased serum triglycerides done; Ibrutinib; lloperidone; Imatinib; Imidafenacin; Indi-
Gastrointestinal: Abdominal pain, diarrhea (more common navir; lrinotecan Products; Isavuconazonium Sulfate;
in children), increased serum lipase (adults), nausea, lvabradine; lvacaftor; Ixabepilone; Lacosamide; Lapati-
vomiting (more common in children) nib; Lercanidipine; Levobupivacaine; Levomilnacipran;
Hematologic & oncologic: Decreased hemoglobin, Lomitapide; Lovastatin; Lumefantrine; Lurasidone; Maci-
decreased neutrophils, decreased platelet count tentan; Manidipine; Maraviroc; Meperidine; Methyl-
Hepatic: Increased serum ALT (children and adults; more PREDNISolone; Midazolam; Midostaurin;
common in adult patients co-infected with hepatitis B MiFEPRIStone; Minoxidil (Systemic); Mirodenafil; Nalde-
and/or C), increased serum AST (more common in medine; Nalfurafine; Naloxegol; Nefazodone; Neratinib;
patients co-infected with hepatitis B and/or C), increased Nevirapine; Nilotinib; NiMODipine; Nisoldipine; Olaparib;
serum bilirubin (children and adults), jaundice Ombitasvir, Paritaprevir, and Ritonavir; Ombitasvir, Par-
Neuromuscular & skeletal: Increased creatine phosphoki- itaprevir, Ritonavir, and Dasabuvir; Ospemifene; Oxy-
nase, limb pain (children), myalgia butynin; OxyCODONE; PACLitaxel (Conventional);
Respiratory: Cough (children), nasal congestion (chil- Palbociclib; Panobinostat; Parecoxib; Paricalcitol; PAZO-
dren), oropharyngeal pain (children), rhinorrhea (chil- Panib; Pimavanserin; Pimecrolimus; Pimozide; Pipera-
dren), wheezing (children) quine; Pitavastatin; PONATinib; Pranlukast;
Miscellaneous: Fever (more common in children) Praziquantel; PrednisoLONE (Systemic); PredniSONE;
Rare but important or life-threatening: Alopecia, angioe- Progestins (Contraceptive); Propafenone; Protease
dema, arthralgia, cholecystitis, cholelithiasis, cholesta- Inhibitors; QUEtiapine; QuiNIDine; Radotinib; Ramel-
sis, chronic renal failure, complete atrioventricular block teon; Ranolazine; Reboxetine; Red Yeast Rice; Regor-
(rare), diabetes mellitus, DRESS syndrome, edema, afenib; Repaglinide; Retapamulin; Ribociclib; Rifabutin;
erythema multiforme, granulomatous interstitial nephri- Rilpivirine; Riociguat; RomiDEPsin; Rosiglitazone; Rosu-
tis, hepatic abnormality, immune reconstitution syn- vastatin; Rupatadine; Ruxolitinib; Salmeterol; Saquina-
drome, interstitial nephritis, left bundle branch block, vir; SAXagliptin; Sildenafil; Silodosin; Simeprevir;
maculopapular rash, nephrolithiasis, pancreatitis, prolon- Simvastatin; Sirolimus; Sonidegib; SORAfenib; SUFen-
gation P-R interval on ECG, prolonged Q-T interval on tanil; Suvorexant; Tacrolimus (Systemic); Tacrolimus
ECG, pruritus, Stevens-Johnson syndrome, torsades de (Topical); Tadalafil; Tamsulosin; Tasimelteon; Temsiroli-
pointes ; mus; Tenofovir Disoproxil Fumarate; Terfenadine; Tetra-
Drug Interactions hydrocannabinol; Tezacaftor; Ticagrelor; Tofacitinib;
Metabolism/Transport Effects Substrate of CYP3A4 Tolterodine; Tolvaptan; Topotecan; Toremifene; Trabec-
(major); Note: Assignment of Major/Minor substrate sta- tedin; TraMADol; TraZODone; Triazolam; Tricyclic Anti-
tus based on clinically relevant drug interaction potential; depressants; Udenafil; Ulipristal; Valbenazine;
Inhibits BCRP/ABCG2, CYP3A4 (strong), OATP1B1/ Vardenafil; Vemurafenib; Venetoclax; Vilazodone; Vin-
SLCO1B1, UGT1A1 CRIStine (Liposomal); Vindesine; Vinflunine; Vinorel-
Avoid Concomitant Use bine; Vorapaxar; Voriconazole; Voxilaprevir; Warfarin;
Avoid concomitant use of Atazanavir with any of the Zolpidem; Zopiclone; Zuclopenthixol
following: Acalabrutinib; Ado-Trastuzumab Emtansine; The levels/effects of Atazanavir may be increased by:
Alfuzosin; Aprepitant; Astemizole;, Asunaprevir; Avanafil; Clarithromycin; Conivaptan; CycloSPORINE (Systemic);
Axitinib; Barnidipine; Belinostat; Blonanserin; Bosutinib; CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors
Bromocriptine; Budesonide (Systemic); Buprenorphine; (Strong); Dapsone (Systemic); Delavirdine; Enfuvirtide;
Ceritinib; Cisapride; Cobimetinib; Conivaptan; Crizotinib; Fosnetupitant; Fusidic Acid (Systemic); Idelalisib; Indi-
Dabrafenib; Dapoxetine; Domperidone; Dronedarone; navir; MIFEPRIStone; Netupitant; Posaconazole; Saqui-
Eletriptan; Eplerenone; Ergot Derivatives; Everolimus; navir; Simeprevir; Stiripentol; Telaprevir; Vilanterol
Flibanserin; Fluticasone (Nasal); Fusidic Acid (Sys- Decreased Effect
temic); Glecaprevir and Pibrentasvir; Grazoprevir; Hal- Atazanavir may decrease the levels/effects of: Abacavir;
ofantrine; Ibrutinib; Idelalisib; Indinavir; Irinotecan Antidiabetic Agents; Boceprevir; Clarithromycin; Delavir-
Products; Isavuconazonium Sulfate; lvabradine; Lapati- dine; Didanosine; Disulfiram; Doxercalciferol; Estrogen
nib; Lercanidipine; Lomitapide; Lovastatin; Macitentan; Derivatives (Contraceptive); Ifosfamide; LamoTRigine;
Midazolam; Naloxegol; Neratinib; Nevirapine; NiMODi- Meperidine; Prasugrel; Telaprevir; Theophylline Deriva-
pine; Nisoldipine; Ombitasvir, Paritaprevir, and Ritonavir; tives; Ticagrelor; Valproate Products; Voriconazole; Zido-
PACLitaxel (Conventional); Palbociclib; PAZOPanib; vudine
Pimozide; Radotinib; Ranolazine; Red Yeast Rice;
Regorafenib; Repaglinide; RifAMPin; Rupatadine; Sal- The levels/effects of Atazanavir may be decreased by:
meterol; Saquinavir; Silodosin; Simeprevir; Simvastatin; Antacids; Boceprevir; Bosentan; Buprenorphine; CarBA-
Sonidegib; St John's Wort; Suvorexant; Tamsulosin; Mazepine; CYP3A4 Inducers (Moderate); CYP3A4
Terfenadine; Ticagrelor; Tipranavir; Tolvaptan; Toremi- Inducers (Strong); Deferasirox; Didanosine; Efavirenz;
fene; Trabectedin; Triazolam; Udenafil; Ulipristal; Vemur- Enzalutamide; Etravirine; Garlic; Histamine H2 Receptor
afenib; VinCRIStine (Liposomal); Vinflunine; Vorapaxar; Antagonists; Minocycline; Mitotane; Nevirapine; Orlistat;
Voriconazole; Voxilaprevir Pitolisant; Proton Pump Inhibitors; RifAMPin; Sarilumab;
Increased Effect/Toxicity Siltuximab; St John's Wort; Tenofovir Disoproxil Fuma-
Atazanavir may increase the levels/effects of: Abemaci- rate; Tipranavir; Tocilizumab; Voriconazole
clib; Acalabrutinib; Ado-Trastuzumab Emtansine; Alfuzo- Food Interactions Bioavailability of atazanavir increased
sin; Alitretinoin (Systemic); Almotriptan; Alosetron; when taken with food. Management: Administer with food.
ALPRAZolam; Amiodarone; AmLODIPine; Apixaban; Storage/Stability
Aprepitant; AR!IPiprazole; ARIPiprazole Lauroxil; Astemi- Capsules: Store at 25°C (77°F); excursions are permitted
zole; Asunaprevir; AtorvaSTATin; Avanafil; Axitinib; Bar- between 15°C and 30°C (59°F and 86°F).
nidipine; Bedaquiline; Belinostat; Benperidol; Oral powder: Store below 30°C (86°F). Store oral powder
Benzhydrocodone; Bictegravir; Blonanserin; Bortezo- in the original packet and do not open until ready to use.
mib; Bosentan; Bosutinib; Brentuximab Vedotin; Brexpi- Once the oral powder is mixed with food or beverage, it
prazole; Brigatinib; Brinzolamide; Bromocriptine; may be kept at 20°C to 30°C (68°F to 86°F) for up to 1
Budesonide (Nasal); Budesonide (Oral Inhalation); hour prior to administration.
Budesonide (Systemic); Budesonide (Topical); Bupre- Mechanism of Action Binds to the site of HIV-1 protease
norphine; BusPIRone; Cabazitaxel; Cabozantinib; Calci- activity and inhibits cleavage of viral Gag-Pol polyprotein
fediol; Calcium Channel Blockers (Nondihydropyridine); precursors into individual functional proteins required for
Cannabidiol; Cannabis; CarBAMazepine; Cariprazine; infectious HIV. This results in the formation of immature,
Ceritinib; Cilostazol; Cisapride; Clarithromycin; CloZA- noninfectious viral particles.
Pine; Cobimetinib; Codeine; Colchicine; Conivaptan; Pharmacodynamics/Kinetics (Adult data unless
Copanlisib; Corticosteroids (Orally Inhaled); Corticoste- noted)
roids (Systemic); Crizotinib; Cyclophosphamide; Cyclo- Absorption: Rapid; enhanced with food
SPORINE (Systemic); CYP3A4 Substrates (High risk Distribution: CSF: Plasma concentration ratio (range):
with Inhibitors); Dabrafenib; Daclatasvir; Dapoxetine; 0.0021 to 0.0226
Dasatinib; Deflazacort; Delamanid; Dexamethasone Protein binding: 86%; binds to both alpha,-acid glycopro-
(Ophthalmic); DOCEtaxel; Dofetilide; Domperidone; tein and albumin (similar affinity)
DOXOrubicin (Conventional); Dronabinol; Dronedarone; Metabolism: Hepatic, primarily by cytochrome P450 iso-
Drospirenone; Dutasteride; Eletriptan; Eliglustat; Eluxa- enzyme CYP3A; also undergoes biliary elimination;
doline; Elvitegravir; Enfuvirtide; Eplerenone; Ergot Deriv- major biotransformation pathways include mono-oxy-
atives; Erlotinib;, Estazolam; Estrogen Derivatives; genation and deoxygenation; minor pathways for parent
Eszopiclone; Etizolam; Etravirine; Everolimus; Evoglip- drug or metabolites include glucuronidation, N-dealkyla-
tin; FentaNYL; Fesoterodine; Flibanserin; Fluticasone tion, hydrolysis and oxygenation with dehydrogenation; 2
(Nasal); Fluticasone (Oral Inhalation); Fluvastatin; minor inactive metabolites have been identified p>
199
ATAZANAVIR

Half-life elimination: Unboosted therapy: 7 to 8 hours; Antiretroviral-experienced patients: Infants 23

Boosted therapy (with ritonavir): 9 to 18 hours; 12 hours months, Children, and Adolescents: Daily dose of
in patients with hepatic impairment atazanavir plus ritonavir given simultaneously with,
Time to peak, plasma: 2 to 3 hours or at least 10 hours after, the H2-receptor antagonist;
Excretion: Feces (79%, 20% of total dose as unchanged dosage of H2-receptor antagonist must be limited to
drug); urine (13%, 7% of total dose as unchanged drug) the equivalent of a 20 mg dose of famotidine twice
Pharmacodynamics/Kinetics: Additional Consider- daily in adults
ations Coadministration with proton pump inhibitor:
Renal function impairment: The mean Cnax Was 9% lower, Antiretroviral-naive patients: Infants 23 months, Chil-
dren, and Adolescents: Daily dose of atazanavir
AUC was 19% higher, and Crin was 96% higher in
plus ritonavir given 12 hours after the proton pump
subjects with severe renal impairment not undergoing
inhibitor; dosage of proton pump inhibitor must be
hemodialysis.
limited to the equivalent of a 20 mg dose of ome-
Dosing
prazole/day in adults
Pediatric
Antiretroviral-experienced patients: Concurrent use
HIV-1 infection, treatment: Use in combination with
not recommended
other antiretroviral agents. Note: Oral capsules and Coadministration with efavirenz: Adolescents 218
oral powder are not interchangeable. In adult studies, years:
the bioavailability of oral capsules was higher than that Antiretroviral-naive patient: Atazanavir 400 mg plus
of oral powder. ritonavir 100 mg given with efavirenz 600 mg (all
Ritonavir-boosted regimen (preferred regimen): Antire- once daily but administered at different times; ata-
troviral-naive and experienced patients: zanavir and ritonavir with food and efavirenz on an
Oral powder: Infants 23 months, Children, and Ado- empty stomach)
lescents: Oral: Antiretroviral-experienced patients: Concurrent use
5 to <15 kg: Atazanavir 200 mg (4 packets) plus not recommended due to decreased atazanavir
ritonavir 80 mg once daily. In antiretroviral-naive exposure
patients weighing 5 to <10 kg unable to tolerate Coadministration with tenofovir disoproxil fumarate:
this dose, may use atazanavir 150 mg (3 packets) Adolescents 218 years:
plus ritonavir 80 mg once daily with close HIV viral Antiretroviral-naive patients: Atazanavir 300 mg plus
load monitoring. ritonavir 100 mg given with tenofovir disoproxil
15 to <25 kg: Atazanavir 250 mg (5 packets) plus fumarate 300 mg (all as a single daily dose)
ritonavir 80 mg once daily Antiretroviral-experienced patients: Atazanavir
225 kg (who cannot swallow a capsule): Atazanavir 300 mg plus ritonavir 100 mg given with tenofovir
300 mg (6 packets) plus ritonavir 100 mg once disoproxil fumarate 300 mg (all as a single daily
daily dose); if Hz antagonist coadministered (not to
Oral capsule: Note: Some experts recommend exceed equivalent daily dose of <40 mg famotidine),
switching to the capsule formulation for any child increase atazanavir to 400 mg (plus ritonavir
215 kg (regardless of age) who can swallow a 100 mg) once daily
capsule whole (HHS [pediatric] 2017). Renal Impairment: Pediatric
Children 26 years and Adolescents <18 years Mild to severe impairment: Infants 23 months, Children,
weighing 215 kg: Oral: and Adolescents: No dosage adjustment necessary
15 kg to <35 kg: Atazanavir 200 mg plus ritonavir End-stage renal disease receiving hemodialysis: Not
100 mg once daily appreciably removed during hemodialysis. Only 2.1%
235 kg: Atazanavir 300 mg plus ritonavir 100 mg of the dose was removed during a 4-hour dialysis
once daily session; however, mean AUC, peak, and trough
Adolescents 218 years: Oral: Atazanavir 300 mg serum concentrations were 25% to 43% lower (versus
once daily plus ritonavir 100 mg or cobicistat adults with normal renal function) when atazanavir
150 mg once daily was administered either prior to, or after hemodialy-
Ritonavir unboosted regimen: Note: Ritonavir-boosted sis; mechanism of the decrease is not currently
atazanavir dosing regimen is preferred; guidelines do known.
not recommend unboosted regimens (HHS [pediatric] Antiretroviral-naive patients: Adolescents 218 years:
2017). Oral powder should not be used for unboosted Atazanavir 300 mg plus ritonavir 100 mg once daily
regimens. Antiretroviral-experienced patients: Use not recom-
Antiretroviral-naive patients: Oral capsule: Adoles- mended
cents weighing 240 kg who are not able to tolerate Hepatic Impairment: Pediatric
ritonavir: Oral: Atazanavir: Antiretroviral-naive patients: Adolescents
13 to <18 years: Atazanavir 620 mg/m?/dose once 218 years:
daily (without ritonavir); closely monitor plasma Mild impairment (Child-Pugh class A): Atazanavir
concentrations to ensure adequate concentrations
400 mg once daily
Moderate impairment (Child-Pugh class B): Atazana-
are achieved (HHS [pediatric] 2017). Note: Data
vir 300 mg once daily
indicates that higher atazanavir dosing (ie, higher
Severe impairment (Child-Pugh Class C): Use not
on a mg/kg or mg/m? basis than predicted by adult
recommended
dosing guidelines) may be needed when atazana-
Note: Patients with underlying hepatitis B or C or
vir is used without ritonavir boosting in children and
those with marked elevations in transaminases prior
adolescents (HHS [pediatric] 2017). Do not use
to treatment may be at increased risk of hepatic
unboosted atazanavir regimen if patient is receiv-
decompensation or further increases in transami-
ing concomitant tenofovir, H2-receptor blockers, or
nases with atazanavir therapy (monitor patients
proton pump inhibitors.
closely).
Adolescents 218 years: Atazanavir 400 mg once Atazanavir and ritonavir: Mild to severe impairment:
daily Use is not recommended (has not been studied).
Dosing adjustments for concomitant therapy: Preparation for Administration
Coadministration with didanosine buffered or enteric- Oral powder: It is preferable to mix oral powder with food,
coated formulations: Infants 23 months, Children, and such as applesauce or yogurt; may also be mixed with a
Adolescents: Administer atazanavir 2 hours before or beverage (eg, milk, infant formula, water) for infants who
1 hour after didanosine buffered or enteric-coated can drink from a cup.
formulations Determine the number of packets (3, 4, 5, or 6 packets)
Coadministration with H2-receptor antagonists: needed. Prior to mixing, tap packet to settle the powder.
Antiretroviral-naive patients: Infants 23 months, Chil- Mix with a small amount (at least one tablespoon) of soft
dren, and Adolescents: Daily dose of atazanavir food (preferred [eg, applesauce, yogurt]) or 230 mL
plus ritonavir given simultaneously with, or at least beverage (milk or water) for cup administration or 10
10 hours after, the H2-receptor antagonist; dosage of mL infant formula for oral syringe administration. Must be
H2-receptor antagonist must be limited to the equiv- administered within 1 hour of preparation.
alent of 40 mg dose of famotidine twice daily in Administration Oral: Administer with food to enhance
adults absorption. Administer atazanavir 2 hours before or 1 hour
Patients unable to tolerate ritonavir: Adolescents after didanosine buffered formulations, didanosine enteric-
218 years: Atazanavir 400 mg once daily given at coated capsules, other buffered medications, or antacids.
least 2 hours before or at least 10 hours after an Ha Administer atazanavir (with ritonavir) simultaneously with,
antagonist; dosage of H2-receptor antagonist must or at least 10 hours after, H2-receptor antagonists; admin-
be limited to the equivalent daily dose of <40 mg ister atazanavir (without ritonavir) at least 2 hours before
famotidine (single dose: $20 mg) or at least 10 hours after H2-receptor antagonist.

200
 ATENOLOL

Administer atazanavir (with ritonavir) 12 hours after proton Packet, Oral, as sulfate:
pump inhibitor. Reyataz: 50 mg (30 ea) [contains aspartame; orange-
Additional formulation. specific information: vanilla flavor]
Oral capsules: Swallow capsules whole, do not open.
Oral powder: @ Atazanavir Sulfate see Atazanavir on page 197
Mixing with food: Using a spoon, mix the recommended
number of oral powder packets with a minimum of one Atenolol (a TEN oh Iole)
tablespoon of food (such as applesauce Or yogurt) in
asmall container. Feed the mixture to the patient. Add Medication Safety Issues
an additional one tablespoon of food to the container, Sound-alike/look-alike issues:
mix, and feed the patient the residual mixture. Atenolol may be confused with albuterol, Altenol, timolol,
Mixing with a beverage such as milk or water in a small Tylenol
drinking cup: Using a spoon, mix the recommended Tenormin may be confused with Imuran, Norpramin,
number of oral powder packets with a minimum of 30 thiamine, Trovan
mL of the beverage in a drinking cup. Have the patient Brand Names: US Tenormin
drink the mixture. Add an additional 15 mL more of Brand Names: Canada Tenormin
beverage to the cup, mix, and have the patient drink Therapeutic Category Antianginal Agent; Antihyperten-
the residual mixture. If water is used, food should also sive Agent; Beta-Adrenergic Blocker
be taken at the same time. Generic Availability (US) Yes
Mixing with liquid infant formula using an oral dosing Use Treatment of hypertension, alone or in combination
syringe and a small medicine cup: Using a spoon, mix with other agents (FDA approved in adults); management
the recommended number of oral powder packets of angina pectoris (FDA: approved in adults); post-MI
with 10 mL of prepared liquid infant formula in the patients (to reduce cardiovascular mortality) (FDA
medicine cup. Draw up the full amount of the mixture approved in adults); has also been used for management
into an oral syringe and administer into either right or of arrhythmias, infantile hemangioma, and thyrotoxicosis
left inner cheek of infant. Pour another 10 mL of Pregnancy Risk Factor D
formula into the medicine cup to rinse off remaining Pregnancy Considerations
oral powder in cup. Draw up residual mixture into the Atenolol crosses the placenta and is found in cord blood.
syringe and administer into either right or left inner Maternal use of atenolol may cause harm to the fetus.
cheek of infant. Administration of atazanavir and Adverse events, such as bradycardia, hypoglycemia and
infant formula using an infant bottle is not recom- reduced birth weight, have been observed following in
mended because full dose may not be delivered. utero exposure to atenolol. Adequate facilities for monitor-
Administer the entire dosage of oral powder (mixed in ing infants at birth is generally recommended. The mater-
the food or beverage) within 1 hour of preparation nal pharmacokinetic parameters of atenolol during the
(may leave the mixture at room temperature during second and third trimesters are within the ranges reported
this 1 hour period). Ensure that the patient eats or in nonpregnant patients (Hebert 2005).
drinks all the food or beverage that contains the
Untreated chronic maternal hypertension and preeclamp-
powder. Additional food may be given after consump-
sia are associated with adverse events in the fetus, infant,
tion of the entire mixture. Administer ritonavir imme-
and mother (ACOG 2015; Magee 2014). Although beta-
diately following oral powder administration.
blockers may be used when treatment of hypertension in
Monitoring Parameters Note: The absolute CD4 cell pregnancy is indicated, agents other than atenolol are
count is. currently recommended to monitor immune status preferred (ACOG 2013; Magee 2014; Regitz-Zagro-
in children of all ages; CD4 percentage can be used as an sek 2011).
alternative in children <5 years of age. This recommen- Breastfeeding Considerations Atenolol is present in
dation is based on the use of absolute CD4 cell counts in breast milk. Bradycardia has been observed in some
the current pediatric HIV infection stage classification and breastfeeding infants and neonates may also be at risk
as thresholds for urgency of initiation of antiretroviral for hypoglycemia. Adverse events may be more likely in
treatment (HHS [pediatric] 2017). premature infants or infants with impaired renal function.
Prior to initiation of therapy: Genotypic resistance testing, The manufacturer recommends that caution be used if
CD4 and viral load (every 3 to 4 months if not started on administering atenolol to a breastfeeding woman.
antiretroviral therapy), CBC with differential, LFTs, BUN, Contraindications
creatinine, electrolytes, glucose, urinalysis, and assess- Hypersensitivity to atenolol or any component of the
ment of readiness for adherence with medication regimen. formulation; sinus bradycardia; sinus node dysfunction;
heart block greater than first-degree (except in patients
At initiation and with any change in treatment regimen: with a functioning artificial pacemaker); cardiogenic
CBC with differential, electrolytes, calcium, phosphate, shock; uncompensated cardiac failure
glucose, LFTs, bilirubin, urinalysis (at initiation), BUN, Canadian labeling: Additional contraindications (not in US
creatinine, glucose (at initiation), albumin, total protein, labeling): Bradycardia (regardless of origin); cor pulmo-
lipid panel (at initiation), CD4, and viral load. nale; hypotension; severe peripheral arterial disorders;
After 1 to 2 weeks of therapy: Signs of medication toxicity anesthesia with agents that produce myocardial depres-
sion; Pheochromocytoma (in the absence of alpha-
and adherence.
blockade); metabolic acidosis
After 2 to 4 weeks of therapy: CBC with differential, viral Warnings/Precautions Consider preexisting conditions
load, signs of medication toxicity, and adherence such as sick sinus syndrome before initiating. Administer
cautiously in compensated heart failure and monitor for a
Every 3 to 4 months: CBC with differential, electrolytes,
worsening of the condition (efficacy of atenolol in heart
glucose, LFTs, bilirubin, BUN, creatinine, CD4, viral load,
failure has not been established). [US Boxed Warning]:
signs of medication toxicity, and adherence.
Beta-blocker therapy should not be withdrawn
Every 6 to 12 months: Lipid panel, glucose, and urinalysis. abruptly (particularly in patients with CAD), but grad-
CD4 monitoring frequency may be decreased to every 6 to ually tapered to avoid acute tachycardia, hyperten-
12 months in children who are adherent to therapy if the sion, and/or ischemia. Beta-blockers without alpha1-
value is well above the threshold for opportunistic infec- adrenergic receptor blocking activity should be avoided
tions, viral suppression is sustained, and the clinical status in patients with Prinzmetal variant angina (Mayer, 1998).
is stable for more than 2 to 3 years. Chronic beta-blocker therapy should not be routinely with-
drawn prior to major surgery. Beta-blockers should be
In patients with known or suspected complex drug resist- avoided in patients with bronchospastic disease (asthma).
ance patterns, phenotypic resistance testing (usually in Atenolol, with B, selectivity, has been used cautiously in
addition to genotypic resistance testing) should be per- bronchospastic disease with close monitoring. May pre-
formed (HHS [pediatric] 2017). Monitor for growth and cipitate or aggravate symptoms of arterial insufficiency in
development, signs of HIV-specific physical conditions, patients with PVD and Raynaud disease; use with caution
HIV disease progression, opportunistic infections or pan- and monitor for progression of arterial obstruction. Use
creatitis. cautiously in patients with diabetes - may mask hypogly-
Reference Range Target plasma trough concentration: cemic symptoms. May mask signs of hyperthyroidism (eg,
2,000:+ 1,000 ng/mL (AHS [pediatric] 2017) tachycardia); use caution if hyperthyroidism is suspected,
Dosage Forms Excipient information presented when abrupt withdrawal may precipitate thyroid storm. Altera-
available (limited, particularly for generics); consult spe- tions in thyroid function tests may be observed. Use
cific product labeling. cautiously in the renally impaired (dosage adjustment
Capsule, Oral, as sulfate: required). Caution in myasthenia gravis or psychiatric
Reyataz: 150 mg, 200 mg, 300 mg [contains fd&c blue disease (may cause CNS depression). Bradycardia may
#2 (indigotine)) be observed more frequently in elderly patients (>65 years
Generic: 150 mg, 200 mg, 300 mg of age); dosage reductions may be necessary. Adequate »
201
 ATENOLOL

q alpha-blockade is required prior to use of any beta-blocker

for patients with untreated pheochromocytoma. May
Children and Adolescents 5 to 16 years of age: Mean:
4.6 hours; range: 3.5 to 7 hours; Patients >10 years of
induce or exacerbate psoriasis. Use caution with history age may have longer half-life (>5 hours) compared to
of severe anaphylaxis to allergens; patients taking beta- children 5 to 10-years of age (<5 hours) (Buck 1989)
blockers may become more sensitive to repeated chal- Adults: Normal renal function: 6 to 7 hours, prolonged
lenges. Treatment of anaphylaxis (eg, epinephrine) in with renal impairment; End-stage renal disease
patients taking beta-blockers may be ineffective or pro- (ESRD): 15 to 35 hours
mote undesirable effects. Potentially significant interac- Time to peak, plasma: Oral: 2 to 4 hours
tions may exist, requiring dose or frequency adjustment, Excretion: Feces (50%); urine (40% as unchanged drug)
additional monitoring, and/or selection of alternative ther- Pharmacodynamics/Kinetics: Additional Consider-
apy. ations
Adverse Reactions Renal function impairment: Elimination is closely related to
Cardiovascular: Bradycardia (persistent), cardiac failure, glomerular filtration rate. Significant accumulation occurs
chest pain, cold extremities, complete atrioventricular when CrCl falls below 35 mL/minute per 1.73 m?.
block, edema, hypotension, Raynaud's phenomenon, Geriatric: Total clearance is about 50% lower than in
second degree atrioventricular block younger subjects. Half-life is markedly longer in elderly
Central nervous system: Confusion, decreased mental patients.
acuity, depression, dizziness, fatigue, headache, insom- Dosing
nia, lethargy, nightmares Pediatric
Gastrointestinal: Constipation, diarrhea, nausea Note: Dosage should be individualized based on patient
Genitourinary: Impotence response.
Rare but important-or life-threatening: Alopecia, dyspnea Arrhythmias: Limited data available: Infants, Children,
(especially with large doses), hallucination, increased and Adolescents: Oral:
liver enzymes, lupus-like syndrome, Peyronie's disease, Long QT syndrome: Usual range: 0.5 to 1 mg/kg/day
positive ANA titer, psoriasiform eruption, psychosis, either once daily or in divided doses every 12 hours
thrombocytopenia, wheezing (Kliegman, 2011). In a retrospective trial (n=57;
Drug Interactions mean age: 9 + 6 years) that titrated atenolol to
achieve a maximum heart rate less than 150 bpm
Metabolism/Transport Effects None known.
(Holter monitor and exercise treadmill), higher doses
Avoid Concomitant Use
were reported; mean effective dose: 1.4 +
Avoid concomitant use of Atenolol with any of the follow-
0.5 mg/kg/day in 2 divided doses (Moltedo, 2011)
ing: Bromperidol; Ceritinib; Floctafenine; Methacholine;
Supraventricular tachycardia: Usual range: 0.3 to
Rivastigmine 1 mg/kg/day either once daily or in divided doses
Increased Effect/Toxicity every 12 hours (Kliegman, 2011, Mehta, 1996; Trip-
Atenolol may increase the levels/effects of: Alphat- pel, 1989). In two separate trials, titration of the dose
Blockers; Alpha2-Agonists; Amifostine; Antipsychotic to >1.4 mg/kg/day did not show additional treatment
Agents (Second Generation [Atypical]); Bradycardia- successes and potentially increased the risk of
Causing Agents; Bromperidol; Bupivacaine; Cardiac Gly- adverse effects (Mehta, 1996; Trippel, 1989).
cosides; Ceritinib; Cholinergic Agonists; Disopyramide; Hemangioma, infantile: Limited data available: Infants
DULoxetine; Ergot Derivatives; Fingolimod; Grass Pollen and Children <2 years: Oral: 1 mg/kg/dose once daily
Allergen Extract (5 Grass Extract); Hypotension-Associ- for 6 months; dosing based on a randomized, con-
ated Agents; Insulins; lvabradine; Lacosamide; Levo- trolled noninferiority trial compared to propranolol
dopa; Lidocaine (Systemic); Lidocaine (Topical); (n=23 total, atenolol treatment group: n=13); atenolol
Mepivacaine; Methacholine; Midodrine; Nitroprusside; was found to be as effective as propranolol; no
Pholcodine; Sulfonylureas significant adverse effects were reported in either
group (Abarzua-Araya, 2014)
The levels/effects of Atenolol may be increased by:
Hypertension: Children and Adolescents: Oral: Initial:
Acetylcholinesterase Inhibitors; Alfuzosin; Alpha2-Ago-
0.5 to 1 mg/kg/day either once daily or divided in
nists; Amiodarone; Barbiturates; Benperidol; Bretylium;
doses twice daily; titrate dose to effect; usual range:
Brigatinib; Brimonidine (Topical); Calcium Channel
0.5 to 1.5 mg/kg/day; maximum daily dose: 2 mg/kg/
Blockers (Nondihydropyridine); Diazoxide; Dipyridamole; day not to exceed 100 mg/day (NHBPEP, 2004;
Disopyramide; Dronedarone; Floctafenine; Glycopyrro- NLHBI, 2011)
late (Systemic); Herbs (Hypotensive Properties); Lorme- Thyrotoxicosis: Limited data available: Children and
tazepam; Methoxyflurane; Molsidomine; Naftopidil; Adolescents: Oral: 1 to 2 mg/kg once daily; may
Nicergoline; Nicorandil; NIFEdipine; Obinutuzumab; increase to twice daily if needed; maximum dose:
Opioids (Anilidopiperidine); Pentoxifylline; Phosphodies- 100 mg/dose (Bahn 2011; Kliegman 2011)
terase 5 Inhibitors; Prostacyclin Analogues; Quinagolide; Renal Impairment: Pediatric
Regorafenib; Reserpine; Rivastigmine; Ruxolitinib; Terli- Children and Adolescents: There are no dosage adjust-
pressin; Tofacitinib ments provided in the manufacturer's labeling; how-
Decreased Effect ever, the following guidelines have been used
Atenolol may decrease the levels/effects of: Beta2-Ago- (Aronoff, 2007): Note: Renally adjusted dose recom-
nists; EPINEPHrine (Nasal); EPINEPHrine (Oral Inhala- mendations are based on doses of 0.8 to 1.5 mg/kg/
tion); Epinephrine (Racemic); EPINEPHrine (Systemic); day:
Theophylline Derivatives GFR >50 mL/minute/1.73 m?: No dosage adjustment
The levels/effects of Atenolol may be decreased by: necessary
Amphetamines; Ampicillin; Bacampicillin; Brigatinib; CrC! 30 to 50 mL/minute/1.73 m?: Maximum dose:
1 mg/kg/dose every 24 hours; maximum daily dose:
Bromperidol; Herbs (Hypertensive Properties); Methyl-
50 mg/day P
phenidate; Nonsteroidal Anti-inflammatory Agents;
CrCl <30 mL/minute/1.73 m?: Maximum dose:
Yohimbine
1 mg/kg/dose every 48 hours
Food Interactions Atenolol serum concentrations may be
Intermittent hemodialysis: Moderately dialyzable
decreased if taken with food. Management: Administer
(20% to 50%); maximum dose: 1 mg/kg/dose every
without regard to meals.
48 hours; give after hemodialysis
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). Peritoneal dialysis: Maximum dose: 1 mg/kg/dose
Mechanism of Action Competitively blocks response to every 48 hours
beta-adrenergic stimulation, selectively blocks beta,- Continuous renal replacement therapy: Maximum
receptors with little or no effect on betaz-receptors except dose: 1 mg/kg/dose every 24 hours
at high doses Hepatic Impairment: Pediatric There are no dosage
Pharmacodynamics/Kinetics (Adult data unless adjustments provided in the manufacturer's labeling;
noted) however, atenolol undergoes minimal hepatic metabo-
Onset of action: Beta-blocking effect: Onset: Oral: <1 lism.
hour; Peak effect: Oral: 2 to 4 hours Administration Oral: May be administered without regard
Duration: Normal renal function: Beta-blocking effect: 12 to food
to 24 hours; Antihypertensive effect: Oral: 24 hours Monitoring Parameters Blood pressure, heart rate,
Absorption: Oral: Rapid, incomplete (~50%) ECG, fluid intake and output, daily weight, respiratory rate
Distribution: Low lipophilicity; does not cross blood-brain Test Interactions Increased glucose; decreased HDL;
barrier may lead to false-positive aldosterone/renin ratio (ARR)
Protein binding: 6% to 16% (Funder 2016)
Metabolism: Limited hepatic Additional Information Limited data suggests that ate-
Half-life elimination: Beta: nolol may have a shorter half-life and faster clearance in
Newborns (<24 hours of age) born to mothers receiving patients with Marfan syndrome. Higher doses (2 mg/kg/
atenolol: Mean: 16 hours; up to 35 hours (Rubin 1983) day divided every 12 hours) have been used in patients
 ATOMOXETINE

with Marfan syndrome (6 to 22 years of age) to decrease hostility or aggressive behaviors have been associated
aortic root growth rate and prevent aortic dissection or with atomoxetine, particularly with the initiation of therapy.
rupture; further studies are needed (Reed, 1993). Treatment-emergent psychotic or manic symptoms (eg,
Dosage Forms Considerations Atenolol+SyrSpend SF hallucinations, delusional thinking, mania) may occur in
PH4 oral suspension is available as a compounding kit. children and adolescents without a prior history of psy-
Refer to manufacturer's labeling for compounding instruc- chotic illness or mania; consider discontinuation of treat-
tions. ment if symptoms occur. Use caution in patients with
Dosage Forms Excipient information presented when comorbid bipolar disorder; therapy may induce mixed/
available (limited, particularly for generics); consult spe- manic episode. Atomoxetine is not approved for major
cific product labeling. depressive disorder. Patients presenting with depressive
Tablet, Oral: symptoms should be screened for bipolar disorder. Rec-
Tenormin: 25 mg, 50 mg, 100 mg ommended to be used as part of a comprehensive treat-
Generic: 25 mg, 50 mg, 100 mg ment program for attention deficit disorders. Atomoxetine
Extemporaneous Preparations 2 mg/mL Oral Sus- does not worsen anxiety in patients with existing anxiety
pension (ASHP Standard Concentration) (ASHP 2017) disorders or tics related to Tourette's disorder.

A 2 mg/mL oral suspension may be made with tablets. Use caution with hepatic disease (dosage adjustments
Crush four 50 mg tablets in a mortar and reduce to a fine necessary in moderate and severe hepatic impairment).
powder. Add a small amount of glycerin and mix to a Use may be associated with rare but severe hepatotox-
uniform paste. Mix while adding Ora-Sweet SF vehicle in icity, including hepatic failure; discontinue and do not
incremental proportions to almost 100 mL; transfer to a restart if signs or symptoms of hepatotoxic reaction (eg,
calibrated amber bottle, rinse mortar with vehicle, and add jaundice, pruritus, flu-like symptoms, dark urine, right
quantity of vehicle sufficient to make 100 mL. Label upper quadrant tenderness) or laboratory evidence of liver
"shake well". Stable for 90 days at room temperature. disease are noted. Use caution in patients who are poor
Nahata MC and Pai VB. Pediatric Drug Formulations. 6th ed. Cincin- metabolizers of CYP2D6 metabolized drugs ("poor metab-
nati, OH: Harvey Whitney Books Co; 2014. olizers"), bioavailability increases; dosage adjustments
Patel D, Doshi DH, Desai A. Short-term stability of atenolol in oral liquid are recommended in patients known to be CYP2D6 poor
formulations. Int J Pharm Compd. 1997;1(6):437-439. metabolizers. In clinical trials, at therapeutic doses, atom-
@ Atenolol+SyrSpend SF PH4 see Atenolol on page 201 oxetine consistently did not prolong the QT/QTc interval;
however, one placebo-controlled study in healthy CYP2D6
@ ATG see Antithymocyte Globulin (Equine) on page 163 poor metabolizers demonstrated a statistically significant
@ Atgam see Antithymocyte Globulin (Equine) increase in QTc with increasing atomoxetine concentra-
on page 163 tions (Loghin 2012; Martinez-Raga 2013). Case reports
@ Athletes Foot Spray [OTC] see Tolnaftate suggest that atomoxetine overdose may increase the QT
on page 1971 interval; however, this occurred when atomoxetine was
Ativan see LORazepam on page 1250 combined with other agents known to have QT prolonga-
tion potential or inhibit CYP2D6 (Barker 2004; Sawant
@ Atlizumab see Tocilizumab on page 1967 2004). Atomoxetine, at high concentrations ex vivo, has
@ ATNAA see Atropine and Pralidoxime on page 216 demonstrated hERG channel block (Scherer 2009).
@ ATO see Arsenic Trioxide on page 179 Orthostasis can occur; use caution in patients predis-
posed to hypotension or those with abrupt changes in
AtoMOXetine (AT oh mox e teen) heart rate or blood pressure. Atomoxetine has been
associated with serious cardiovascular events including
Medication Safety Issues sudden death in patients with preexisting structural car-
Sound-alike/look-alike issues: diac abnormalities or other serious heart problems (sud-
AtoMOXetine may be confused with atorvaSTATin den death in children and adolescents; sudden death,
Related Information stroke, and MI in adults). Atomoxetine should be avoided
Oral Medications That Should Not Be Crushed or Altered in patients with known serious structural cardiac abnor-
on page 2217 malities, cardiomyopathy, serious heart rhythm abnormal-
Brand Names: US Strattera ities, or other serious cardiac problems that could increase
Brand Names: Canada Apo-Atomoxetine; DOM-Atom- the risk of sudden death that these conditions alone carry.
oxetine; Mylan-Atomoxetine; PMS-Atomoxetine; RIVA- Patients should be carefully evaluated for cardiac disease
Atomoxetine; Sandoz-Atomoxetine; Strattera; Teva-Atom-
prior to initiation of therapy. Perform a prompt cardiac
oxetine evaluation in patients who develop symptoms of exertional
chest pain, unexplained syncope, or other symptoms
Therapeutic Category Norepinephrine Reuptake Inhib-
suggestive of cardiac disease during treatment. May
itor, Selective
cause increased heart rate or blood pressure; use caution
Generic Availability (US) Yes
with hypertension or other cardiovascular or cerebrovas-
Use Treatment of attention-deficit/nyperactivity disorder
cular disease; CYP2D6 poor metabolizers may experi-
(ADHD) (FDA approved in ages 26 years and adults)
ence greater increases in blood pressure and heart rate
Medication Guide Available Yes effects. Use caution in patients with a history of urinary
Pregnancy Risk Factor C retention or bladder outlet obstruction; may cause urinary
Pregnancy Considerations Adverse events have been retention/hesitancy; use caution in patients with history of
observed in animal reproduction studies. Information urinary retention or bladder outlet obstruction. Prolonged
related to atomoxetine use in pregnancy is limited; appro- and painful erections (priapism), sometimes requiring sur-
priate contraception is recommended for sexually active gical intervention, have been reported with stimulant and
women of childbearing potential (Heiligenstein, 2003). atomoxetine use in pediatric and adult patients. Priapism
Breastfeeding Considerations It is not known if atom- has been reported to develop after some time on the drug,
oxetine is excreted in breast milk. The manufacturer often subsequent to an increase in dose and also during a
recommends that caution be exercised when administer- period of drug withdrawal (drug holidays or discontinua-
ing atomoxetine to nursing women. tion). Patients with certain hematological dyscrasias (eg,
Contraindications Hypersensitivity to atomoxetine or any sickle cell disease), malignancies, perineal trauma, or
component of the formulation; use with or within 14 days concomitant use of alcohol, illicit drugs, or other medica-
of MAO inhibitors; narrow-angle glaucoma; current or past tions associated with priapism may be at increased risk.
history of pheochromocytoma; severe cardiac or vascular Patients who develop abnormally sustained or frequent
disorders in which the condition would be expected to and painful erections should discontinue therapy and seek
deteriorate with clinically important increases in blood immediate medical attention. An emergent urological con-
pressure (eg, 15 to 20 mm Hg) or heart rate (eg, 20 sultation should be obtained in severe cases. Use has
beats/minute). been associated with different dosage forms and prod-
ucts; it is not known if rechallenge with a different for-
Canadian labeling: Additional contraindications (not in
mulation will risk recurrence. Avoidance of stimulants and
U.S. labeling): Symptomatic cardiovascular diseases,
atomoxetine may be preferred in patients with severe
moderate-to-severe hypertension; advanced arterioscle-
cases that were slow to resolve and/or required detumes-
rosis; uncontrolled hyperthyroidism
cence (Eiland, 2014). Allergic reactions (including anaphy-
Warnings/Precautions [US Boxed Warning]: Use cau- lactic reactions, angioneurotic edema, urticaria, and rash)
tion in pediatric patiehts; may be an increased risk of
may occur (rare).
suicidal ideation. Closely monitor for clinical worsening,
suicidality, or unusual changes in behavior; especially Growth in pediatric patients should be monitored during
during the initial few months of a course of drug therapy, treatment. Height and weight gain may be reduced during
or at times of dose changes, either increases or the first 9 to 12 months of treatment, but should recover by
decreases. The family or caregiver should be instructed 3 years of therapy.
to closely observe’the patient and communicate condition Warnings: Additional Pediatric Considerations Seri-
with healthcare provider. New or worsening symptoms of ous cardiovascular events, including sudden death, may >
 ATOMOXETINE

4 occur in patients with preexisting structural cardiac abnor-

malities or other serious heart problems. Sudden death
Central nervous system: Abnormal dreams,
anxiety, chills, depression, disturbed sleep, dizziness,
agitation,

has been reported in children and adolescents; sudden drowsiness, emotional lability, fatigue, headache (chil-
death, stroke, and MI have been reported in adults. Avoid dren and adolescénts), hostility (children and adoles-
the use of atomoxetine in patients with known serious cents), insomnia, irritability, jitteriness, paresthesia
structural cardiac abnormalities, cardiomyopathy, serious (adults; postmarketing observation in children), restless-
heart rhythm abnormalities, coronary artery disease, or ness, sensation of cold
other serious cardiac problems that could place patients at Dermatologic: Excoriation, hyperhidrosis, pruritus, skin
an increased risk to the noradrenergic effects of atom- rash, urticaria
oxetine. Patients should be carefully evaluated for cardiac Endocrine & metabolic: Decreased libido, hot flash,
disease prior to initiation of therapy. The American Heart increased thirst, menstrual disease, weight loss
Association recommends that all children diagnosed with Gastrointestinal: Abdominal pain, anorexia, constipation,
ADHD who may be candidates for medication, such as decreased appetite, dysgeusia, dyspepsia, flatulence,
atomoxetine, should have a thorough cardiovascular nausea, vomiting, xerostomia
assessment prior to initiation of therapy. This assessment Genitourinary: Dysmenorrhea, dysuria, ejaculatory disor-
should include a combination of medical history, family der, erectile dysfunction, orgasm abnormal, pollakiuria,
history, and physical examination focusing on cardiovas- prostatitis, testicular pain, urinary frequency, urinary
cular disease risk factors. An ECG is not mandatory but retention
should be considered. If a child displays symptoms of Neuromuscular & skeletal: Muscle spasm, tremor,
cardiovascular disease, including chest pain, dyspnea, weakness
or fainting, parents should seek immediate medical care Ophthalmic: Blurred vision, conjunctivitis, mydriasis
for the child. In a-recent retrospective study on the Respiratory: Pharyngolaryngeal pain
possible association between stimulant medication use Miscellaneous: Therapeutic response unexpected
and sudden death in children, 564 previously healthy Rare but important or life-threatening: Alopecia, cerebro-
children who died suddenly in motor vehicle accidents vascular accident, delusions, growth suppression (chil-
were compared to a group of 564 previously healthy dren), hallucination, hepatotoxicity, hypersensitivity
children who died suddenly. Two of the 564 (0.4%) chil- reaction, hypomania, impulsivity, mania, myocardial
dren in motor vehicle accidents were taking stimulant infarction, panic attack, pelvic pain, priapism, Raynaud's
medications compared to 10 of 564 (1.8%) children who phenomenon, rhabdomyolysis, seizure (including
died suddenly. While the authors of this study conclude patients with no prior history or known risk factors for
there may be an association between stimulant use and seizure), severe hepatic disease, suicidal ideation, tics
sudden death in children, there were a number of limi- Drug Interactions
tations to the study and the FDA cannot conclude this Metabolism/Transport Effects Substrate of
information impacts the overall risk:benefit profile of these CYP2C19 (minor), CYP2D6 (major); Note: Assignment
medications (Gould 2009). In a large retrospective cohort of Major/Minor substrate status based on clinically rele-
study involving 1,200,438 children and young adults (aged vant drug interaction potential
2 to 24 years), none of the currently available stimulant Avoid Concomitant Use
medications or atomoxetine were shown to increase the Avoid concomitant use of AtoMOXetine with any of the
risk of serious cardiovascular events (ie, acute MI, sudden
following: |\obenguane | 123; Monoamine Oxidase Inhib-
cardiac death, or stroke) in current (adjusted hazard ratio: itors
0.75; 95% Cl: 0.31 to 1.85) or former (adjusted hazard
Increased Effect/Toxicity
ratio: 1.03; 95% Cl: 0.57 to 1.89) users compared to
AtoMOXetine may increase the levels/effects of: Beta2-
nonusers. It should be noted that due to the upper limit
Agonists; Perhexiline; QTc-Prolonging Agents (Highest
of the 95% Cl, the study could not rule out a doubling of
Risk); QTc-Prolonging Agents (Moderate Risk); Sympa-
the risk, albeit low (Cooper 2011).
thomimetics
May cause significant increases in blood pressure and
The levels/effects of AtoMOXetine may be increased by:
heart rate; in pediatric clinical trials, incidences of max-
Abiraterone Acetate; Asunaprevir; Cobicistat; CYP2D6
imum increases in SBP, DBP, and HR compared to
Inhibitors (Moderate); CYP2D6 Inhibitors (Strong); Dar-
placebo were as follows: SBP (220 mm Hg): 12.5% vs
unavir; Imatinib; MiIFEPRIStone; Monoamine Oxidase
8.7%; DBP (215 mm Hg): 21.5% vs 14.1%; and HR (220
Inhibitors; Panobinostat; Peginterferon Alfa-2b; Per-
bpm): 23.4% vs 11.5%; monitor blood pressure and pulse
hexiline
at baseline, with dosage increases, and periodically during
therapy. Use caution in patients with underlying medical
Decreased Effect
conditions which may be exacerbated by increases in AtoMOXetine may decrease the levels/effects of: loben-
blood pressure and/or heart rate, including hypertension,
guane | 123
tachycardia, or other cardiovascular or cerebrovascular The levels/effects of AtoMOXetine may be decreased by:
conditions; use is contraindicated in patients with severe Peginterferon Alfa-2b
cardiovascular disorders who may experience clinical Storage/Stability Store at 25°C (77°F); excursions are
deterioration of condition with clinical increases in blood permitted between 15°C and 30°C (59°F and 86°F).
pressure or heart rate. Mechanism of Action Selectively inhibits the reuptake of
In pediatric patients, suppression of growth (height and norepinephrine (Ki 4.5 nM) with little to no activity at the
weight) has been reported during the initial 9 to 12 months other neuronal reuptake pumps or receptor sites.
of therapy and has been shown to recover to normative Pharmacodynamics/Kinetics (Adult data unless
values by 3 years of therapy; this growth pattern has been noted) Note: The pharmacokinetics in pediatric patients
observed to be independent of pubertal status and 26 years of age have been shown to be similar to those of
patient’s metabolic profile (ie, poor or extensive metabo- adult patients. -
lizer); growth should be monitored during treatment. Eval- Duration of action: Up to 24 hours (Jain 2017)
uation of the effect of stimulants on growth in ADHD Absorption: Rapid
diagnosed children <12 years receiving treatment for at Distribution: Vg: IV: 0.85 L/kg
least 3 years with stimulants has shown decreased height Protein binding: 98%, primarily albumin
and weight changes over time compared to age matched Metabolism: Hepatic, via CYP2D6 and CYP2C19; forms
control; height: 4.7 to 5.5 cm/year compared to 6.3 cm/ metabolites (4-hydroxyatomoxetine, active, equipotent to
year and 2.1 to 3.3 kg/year compared to 4.4 kg/year atomoxetine; N-desmethylatomoxetine, limited activity);
(Poulton 2016). In pediatric patients 8 to 17 years actively Note: CYP2D6 poor metabolizers have atomoxetine
treated with stimulants, significant reductions in total fem- AUCs that are ~10-fold higher and peak concentrations
oral, femoral neck, and lumbar bone mineral density that are ~fivefold greater than extensive metabolizers; 4-
(BMD) were observed compared to matched unmedicated hyroxyatomoxetine plasma concentrations are very low
cohorts; also reported were significantly more subjects in (extensive metabolizers: 1% of atomoxetine concentra-
the stimulant-treated group with BMD measurements in tions; poor metabolizers: 0.1% of atomoxetine concen-
the osteopenic range compared to matched cohorts trations
(38.3% to 21.6%) (Howard 2015). A longitudinal cohort- Bioavailability: 63% in extensive metabolizers; 94% in
controlled trial reported no different in peak height velocity poor metabolizers
and final adult height in subjects with ADHD and/or treated Half-life elimination: Atomoxetine: 5 hours (up to 24 hours
with stimulants (Harstad 2014). in poor metabolizers); Active metabolites: 4-hydroxyato-
Adverse Reactions Some adverse reactions may be moxetine: 6-8 hours; N-desmethylatomoxetine: 6-8
increased in "poor metabolizers" (CYP2D6). hours (34-40 hours in poor metabolizers)
Cardiovascular: Cold extremities, flushing, increased dia- Time to peak, plasma: 1-2 hours; delayed 3 hours by high-
stolic blood pressure (215 mm Hg), orthostatic hypoten- fat meal
sion, palpitations, prolonged Q-T interval on ECG, Excretion: Urine (80%, as conjugated 4-hydroxy metabo-
syncope, systolic hypertension, tachycardia lite; <3% is excreted unchanged); feces (17%)

204
 ATORVASTATIN

Pharmacodynamics/Kinetics: Additional Consider- Dosage Forms Excipient information presented when

ations available (limited, particularly for generics); consult spe-
Renal function impairment: Extensive metabolizers with cific product labeling.
ESRD had higher systemic exposure (approximately a Capsule, Oral:
65% increase), but there was no difference when expo- Strattera: 10 mg, 18 mg
sure was corrected for mg/kg dose. Strattera: 25 mg [contains fd&c blue #2 (indigotine)]
Hepatic function impairment: AUC is increased in exten- Strattera: 40 mg, 60 mg, 80 mg [contains corn starch,
sive metabolizers with moderate or severe hepatic fd&c blue #2 (indigotine)]
impairment. Strattera: 100 mg [contains fd&c blue #2 (indigotine)]
Dosing Generic: 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg,
Pediatric Attention-deficit/hyperactivity disorder: 100 mg
Children 26 years and Adolescents, weighing <70 kg:
Oral: Initial: 0.5 mg/kg/day; increase after a minimum of @ Atomoxetine Hydrochloride see AtoMOXetine
3 days to ~1.2 mg/kg/day; may administer once daily in on page 203
the morning or divide into 2 doses and administer in the
morning and late afternoon/early evening; maximum AtorvaSTATin (a TORE va sta tin)
daily dose: 1.4 mg/kg/day or 100 mg/day, whichever
is less. Note: Doses >1.2 mg/kg/day have not been Medication Safety Issues
shown to provide additional benefit. Sound-alike/look-alike issues:
Dosage adjustment with concurrent strong CYP2D6 AtorvaSTATin may be confused with atoMOxXetine, lov-
inhibitors (eg, paroxetine, fluoxetine, quinidine) use astatin, nystatin, pitavastatin, pravastatin, rosuvastatin,
or patients known to be CYP2D6 poor metabolizers: simvastatin :
Oral: Initial: 0.5 mg/kg/day for 4 weeks; increase dose Lipitor may be confused with labetalol, Levatol, lisinopril,
to 1.2 mg/kg/day only if clinically needed and the Loniten, Lopid, Mevacor, Zocor, ZyrTEC
initial dose is well tolerated; do not exceed Related Information
1.2 mg/kg/day Oral Medications That Should Not Be Crushed or Altered
Children 26 years and Adolescents, weighing >70 kg: on page 2217
Oral: Initial: 40 mg daily; increase after a minimum of 3 Brand Names: US Lipitor
days to ~80 mg daily; may administer once daily in the Brand Names: Canada Lipitor
morning or divide into 2 doses and administer in Therapeutic Category Antilipemic Agent; HMG-CoA
morning and late afternoon/early evening. After an Reductase Inhibitor
additional 2-4 weeks, may increase (if needed) to Generic Availability (US) Yes
maximum daily dose: 100 mg/day.
Use
Dosage adjustment with concurrent strong CYP2D6
Adjunct to dietary therapy in pediatric patients with hetero-
inhibitors (eg, paroxetine, fluoxetine, quinidine) use
zygous familial hypercholesterolemia if LDL-C remains
or patients known to be CYP2D6 poor metabolizers:
2190 mg/dL, if 2160 mg/dL with family history of prema-
Oral: Initial: 40 mg daily for 4 weeks; increase dose to
ture CHD or presence of 22 cardiovascular risk factors
80 mg daily only if clinically needed and the initial
(FDA approved in boys and postmenarchal girls 10 to 17
dose is well tolerated; do not exceed 80 mg daily
years); adjunct to dietary therapy to decrease elevated
Renal Impairment: Pediatric Children 26 years and
serum total and LDL-C, apolipoprotein B (apo-B), and
Adolescents: No dosage adjustments are recom-
triglyceride levels, and to increase HDL-C in patients
mended.
with primary hypercholesterolemia (heterozygous fami-
Hepatic Impairment: Pediatric
lial and nonfamilial) and mixed dyslipidemia (Fredrickson
Children 26 years and Adolescents:
types Ila and Ilb) (FDA approved in adults); adjunct
Moderate hepatic impairment (Child-Pugh class B):
treatment of homozygous familial hypercholesterolemia
Administer 50% of normal dose
(FDA approved in adults); treatment of isolated hyper-
Severe hepatic impairment (Child-Pugh class C):
triglyceridemia (Fredrickson type IV); treatment of pri-
Administer 25% of normal dose
mary dysbetalipoproteinemia (Fredrickson Type III) (FDA
Administration Oral: May be administered without regard
approved in adults)
to food. Do not crush, chew, or open capsule; swallow
Primary prevention of cardiovascular disease in high risk
whole with water or other liquids. Note: Atomoxetine is an
patients (FDA approved in adults). Has also been used
ocular irritant; if capsule is opened accidently and contents
in prevention of graft coronary artery disease in heart
come into contact with eye, flush eye immediately with
transplant patients.
water and obtain medical advice; wash hands and any
potentially contaminated surface as soon as possible. Pregnancy Risk Factor X
Monitoring Parameters Family members and caregivers Pregnancy Considerations
need to monitor patient daily for emergence. of irritability, Studies in animals and pregnant women have shown
agitation, unusual changes in behavior, and suicide idea- evidence of fetal abnormalities and use is contraindicated
tion. Pediatric patients should be monitored closely for in women who are or may become pregnant. There are
suicidality, clinical worsening, or unusual changes in reports of congenital anomalies following maternal use of
behavior, especially during the initial few months of ther- HMG-CoA reductase inhibitors in pregnancy; however,
apy or at times of dose changes. Appearance of symp- maternal disease, differences in specific agents used,
toms needs to be immediately reported to healthcare and the low rates of exposure limit the interpretation of
provider. the available data (Godfrey 2012; Lecarpentier 2012).
Cholesterol biosynthesis may be important in fetal devel-
Evaluate for cardiac disease prior to initiation of therapy opment; serum cholesterol and triglycerides increase nor-
with thorough medical history, family history, and physical mally during pregnancy. The discontinuation of lipid
exam; consider ECG; perform ECG and echocardiogram if lowering medications temporarily during pregnancy is
findings suggest cardiac disease; promptly conduct car- not expected to have significant impact on the long term
diac evaluation in patients who develop chest pain, unex- outcomes of primary hypercholesterolemia treatment.
plained syncope, or any other symptom of cardiac disease
during treatment. Monitor body weight, BMI, height and Because they are potentially teratogenic, the ADA Diabe-
growth rate (in children); CNS activity; blood pressure and tes guidelines recommends avoiding use of HMG-CoA
heart rate and rhythm (baseline, following dose increases, reductase inhibitors in sexually active women of child-
and periodically during treatment); liver enzymes—in bearing age who are not using reliable contraception
patients with symptoms of liver dysfunction; sleep, appe- (ADA 2018b). If treatment of dyslipidemias is needed in
tite, abnormal movements. Patients should be re-eval- pregnant women or in women of reproductive age, other
uated at appropriate intervals to assess continued need agents are preferred (Berglund 2012; Stone 2013). The
of the medication. Monitor for new psychotic symptoms, manufacturer recommends administration to women of
appearance or worsening of aggressive behavior, or hos- childbearing potential only when conception is highly
tility. unlikely and patients have been informed of potential
Additional Information Atomoxetine hydrochloride is the hazards.
R(-) isomer. Therapy may be discontinued without being Breastfeeding Considerations It is not known if ator-
tapered. Total daily doSes >150 mg/day and single doses vastatin is excreted in breast milk. Due to the potential for
>120 mg/dose have not been systematically evaluated. serious adverse reactions in a nursing infant, use while
Medications used to treat ADHD should be part of a total breastfeeding is contraindicated by the manufacturer.
treatment program that may include other components Contraindications Hypersensitivity to atorvastatin or any
such as psychological, educational, and social measures. component of the formulation; active liver disease; unex-
If used for an extended period of time, long-term useful- plained persistent elevations of serum transaminases;
ness of atomoxetine should be periodically re-evaluated pregnancy or women who may become pregnant; breast-
for the individual patient. feeding
ATORVASTATIN

Warnings/Precautions Secondary causes of hyperlipi- Genitourinary: Urine abnormality (white blood cells pos-
demia should be ruled out prior to therapy. Drug therapy itive in urine), urinary tract infection
should be only one component of multiple risk factor Hepatic: Abnormal hepatic function tests, hepatitis,
intervention in patients at significantly increased risk for increased serum alkaline phosphatase, increased serum
atherosclerotic vascular disease due to hypercholestero- transaminases
lemia. In patients with CHD or multiple risk factors for Neuromuscular & skeletal: Arthralgia, increased creatine
CHD, initiate therapy simultaneously with diet. Rhabdo- phosphokinase, joint swelling, limb pain, muscle fatigue,
myolysis with acute renal failure secondary to myoglobi- muscle spasm, myalgia, musculoskeletal pain, neck pain
nuria and/or myopathy has been reported; patients should Ophthalmic: Blurred vision
be monitored closely. This risk is dose-related and is Otic: Tinnitus
increased with concurrent use of strong CYP3A¢4 inhibitors Respiratory: Epistaxis, nasopharyngitis, pharyngolaryng-
(eg, clarithromycin, itraconazole, protease inhibitors), eal pain
cyclosporine, fibric acid derivatives (eg, gemfibrozil), or Miscellaneous: Fever
niacin (doses 21 g/day); if concurrent use is warranted, Rare but important or life-threatening: Abdominal pain,
consider lower starting and maintenance doses of ator- alopecia, amnesia (reversible), anaphylaxis, anemia,
vastatin. Use caution in patients with inadequately treated angioedema, anorexia, back pain, bullous rash, chest
hypothyroidism, and those taking other drugs associated pain, cognitive dysfunction (reversible), confusion (rever-
with myopathy (eg, colchicine); these patients are predis- sible), cystitis (interstitial; Huang 2015), depression, diz-
posed to myopathy. Uncomplicated myalgia immune- ziness, dysgeusia, elevated glycosylated hemoglobin
mediated necrotizing myopathy (IMNM) associated with (HbA;<), erythema multiforme, fatigue, gynecomastia,
HMG-CoA reductase inhibitors use has also been hepatic failure, hypoesthesia, increased serum glucose,
reported. Patients should be instructed to report unex- interstitial pulmonary disease, jaundice, memory impair-
plained muscle pain, tenderness, weakness, or brown ment (reversible), myopathy, myositis, pancreatitis, par-
urine, particularly if accompanied by malaise or fever. esthesia, peripheral edema, peripheral neuropathy,
Discontinue therapy if markedly elevated CPK levels pruritus, rhabdomyolysis, rupture of tendon, Stevens-
occur or myopathy is diagnosed/suspected. Johnson syndrome, thrombocytopenia, toxic epidermal
Persistent elevations in serum transaminases have been necrolysis, vomiting, weight gain
reported; upon dose reduction, drug interruption, or dis- Drug Interactions
continuation, transaminase levels returned to or near Metabolism/Transport Effects Substrate of CYP3A4
pretreatment levels. Postmarketing reports of fatal and (major), OATP1B1/SLCO1B1, P-glycoprotein/ABCB1;
nonfatal hepatic failure have been reported and are rare. Note: Assignment of Major/Minor substrate status based
If serious hepatotoxicity with clinical symptoms and/or on clinically relevant drug interaction potential
hyperbilirubinemia or jaundice occurs during treatment, Avoid Concomitant Use
interrupt therapy promptly. If an alternate etiology is not Avoid concomitant use of AtorvaSTATin with any of the
identified, do not restart atorvastatin. Liver enzyme tests following: Antihepaciviral Combination Products; Coni-
should be obtained at baseline and as clinically indicated vaptan; CycloSPORINE (Systemic); Fusidic Acid (Sys-
and if signs/symptoms of liver injury occur. Ethanol may temic); Gemfibrozil; Glecaprevir and Pibrentasvir;
enhance the potential of adverse hepatic effects; instruct Idelalisib; PAZOPanib; Posaconazole; Red Yeast Rice;
patients to avoid excessive ethanol consumption. Telaprevir; Tipranavir
Increases in HbA,, and fasting blood glucose have been Increased Effect/Toxicity
reported. Use with caution in patients who consume large AtorvaSTATin may increase the levels/effects of: Aliski-
amounts of ethanol or have a history of liver disease; use ren; Cimetidine; DAPTOmycin; Digoxin; DilTlAZem;
is contraindicated in patients with active liver disease or Ketoconazole (Systemic); Midazolam; PAZOPanib;
unexplained persistent elevations of serum transami- Repaglinide; Spironolactone; Trabectedin; Verapamil
nases. Use with caution in patients with renal impairment
and the elderly; these patients are predisposed to myo- The levels/effects of AtorvaSTATin may be increased by:
pathy. Acipimox; Amiodarone; Antihepaciviral Combination
Products; Aprepitant; Asunaprevir; Azithromycin (Sys-
Patients with recent stroke or TIA receiving long-term temic); Bezafibrate; Boceprevir; Ceritinib; Ciprofibrate;
therapy with high-dose (ie, 80 mg/day) atorvastatin may Clarithromycin; Cobicistat; Colchicine; Conivaptan;
be at increased risk for hemorrhagic stroke (SPARCL CycloSPORINE (Systemic); CYP3A4 Inhibitors (Moder-
Investigators 2006). A subsequent post-hoc analysis dem- ate); CYP3A4 Inhibitors (Strong); Cyproterone; Dacla-
onstrated that patients with lacunar or hemorrhagic stroke tasvir; Danazol; DilTlAZem; Dronedarone; Elbasvir;
may be at higher risk of hemorrhagic stroke; however, this Eltrombopag; Erythromycin (Systemic); Fenofibrate and
finding was determined to be hypothesis generating. The Derivatives; Fluconazole; Fosaprepitant; Fosnetupitant;
overall benefit of treatment with atorvastatin (ie, reduced Fusidic Acid (Systemic); Gemfibrozil; Glecaprevir and
risk of stroke and cardiovascular events) in this population Pibrentasvir; Grapefruit Juice; Grazoprevir; Idelalisib;
seems to outweigh the increased risk of hemorrhagic Itraconazole; Ketoconazole (Systemic); Letermovir;
stroke if one truly exists (Goldstein 2008). The manufac- MiFEPRI|Stone; Netupitant; Niacin; Niacinamide; Palbo-
turer recommends temporary discontinuation for elective ciclib; P-glycoprotein/ABCB1 Inhibitors; Posaconazole;
major surgery, acute medical or surgical conditions, or in
Protease Inhibitors; QuiNINE; Raltegravir; Ranolazine;
any patient experiencing an acute, serious condition sug-
Red Yeast Rice; Rupatadine; Simeprevir; Stiripentol;
gestive of a myopathy or having a risk factor predisposing
Telaprevir; Telithromycin; Teriflunomide; Ticagrelor;
to the development of renal failure secondary to rhabdo-
Tipranavir; Tolvaptan; Velpatasvir; Verapamil; Voricona-
myolysis (eg, sepsis, hypotension, trauma, uncontrolled
zole; Voxilaprevir
seizures, severe metabolic, endocrine, or electrolyte dis-
Decreased Effect
orders). Based on current research and clinical guidelines,
AtorvaSTATin may decrease the levels/effects of: Dabi-
HMG-CoA reductase inhibitors should be continued in the
perioperative period for noncardiac and cardiac surgery gatran Etexilate; Lanthanum
(ACC/AHA [Fleisher 2014]; ACC/AHA [Hillis 2011]). Peri- The levels/effects of AtorvaSTATin may be decreased
operative discontinuation of statin therapy is associated by: Bexarotene (Systemic); Bosentan; CYP3A4 Inducers
with an increased risk of cardiac morbidity and mortality. (Moderate); CYP3A4 Inducers (Strong); Dabrafenib;
Perioperative discontinuation of statin therapy is associ- Deferasirox; Efavirenz; Enzalutamide; Etravirine; Fos-
ated with an increased risk of cardiac morbidity and phenytoin; Mitotane; Phenytoin; Pitolisant; Rifamycin
mortality. Potentially significant interactions may exist, Derivatives; Sarilumab; Siltuximab; St John's Wort; Toci-
requiring dose or frequency adjustment, additional mon- lizumab
itoring, and/or selection of alternative therapy. Consult Food Interactions Atorvastatin serum concentrations
drug interactions database for more detailed information. may be increased by grapefruit juice. Management: Avoid
Some dosage forms may contain polysorbate 80 (also concurrent intake of large quantities of grapefruit juice (>1
known as Tweens). Hypersensitivity reactions, usually a quart/day).
delayed reaction, have been reported following exposure Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
to pharmaceutical products containing polysorbate 80 in Mechanism of Action Inhibitor of 3-hydroxy-3-methylglu-
certain individuals (Isaksson 2002; Lucente 2000; Shel- taryl coenzyme A (HMG-CoA) reductase, the rate-limiting
ley 1995). enzyme in cholesterol synthesis (reduces the production
Adverse Reactions of mevalonic acid from HMG-CoA); this then results in a
Cardiovascular: Hemorrhagic stroke compensatory increase in the expression of LDL receptors
Central nervous system: Insomnia, malaise, myasthenia, on hepatocyte membranes and a stimulation of LDL
nightmares catabolism. In addition to the ability of HMG-CoA reduc-
Dermatologic: Urticaria tase inhibitors to decrease levels of high-sensitivity C-
Endocrine & metabolic: Diabetes mellitus, hyperglycemia reactive protein (hsCRP), they also possess pleiotropic
Gastrointestinal: Abdominal distress, cholestasis, diar- properties including improved endothelial function,
rhea, dyspepsia, eructation, flatulence, nausea reduced inflammation at the site of the coronary plaque,

206
 ATORVASTATIN

inhibition of platelet aggregation, and anticoagulant effects Dosage adjustment for atorvastatin with concomi-
(de Denus 2002; Ray 2005). tant medications: There are no recommendations in
Pharmacodynamics/Kinetics (Adult data unless the manufacturer's labeling for patients <18 years. In
noted) adolescents 218 years, the following have been sug-
Onset of action: Initial changes: 3 to 5 days; Maximal gested:
reduction in plasma cholesterol and triglycerides: 2 to 4 Boceprevir, nelfinavir: Use lowest effective atorvastatin
weeks; LDL reduction: 10 mg/day: 39% (for each dou- dose; maximum daily dose: 40 mg/day
bling of this dose, LDL is lowered approximately 6%) Clarithromycin, itraconazole, fosamprenavir, ritonavir
Absorption: Oral: Rapidly absorbed; extensive first-pass (plus darunavir, fosamprenavir, or saquinavir): Use
metabolism in Gl mucosa and liver lowest effective atorvastatin dose; maximum daily
Distribution: Vg: ~381 L dose: 20 mg/day
Protein binding: 298% Dosing adjustment for toxicity: Muscle symptoms
Metabolism: Hepatic via CYP3A4; forms active ortho- and (potential myopathy): Children 210 years and Adoles-
parahydroxylated derivatives and an inactive beta-oxida- cents: Discontinue use until symptoms can be eval-
tion product; plasma concentrations are elevated in uated; check CPK level; based on experience in adult
patients, with chronic alcoholic liver disease and Childs- patients, also evaluate patient for conditions that may
Pugh class A and B liver disease increase the risk for muscle symptoms (eg, hypothyr-
Bioavailability: ~14% (parent drug); ~30% (parent drug oidism, reduced renal or hepatic function, rheumato-
and equipotent metabolites) logic disorders such as polymyalgia rheumatica, steroid
Half-life elimination: Parent drug: ~14 hours; Equipotent myopathy, vitamin D deficiency, or primary muscle
! metabolites: 20 to 30 hours diseases). Upon resolution (symptoms and any asso-
Time to peak, serum: 1 to 2 hours ciated CPK abnormalities), resume the original or con-
Excretion: Bile (following hepatic and/or extra-hepatic sider a lower dose of atorvastatin and retitrate. If
metabolism; does not appear to undergo enterohepatic muscle symptoms recur, discontinue atorvastatin use.
recirculation); urine (<2% as unchanged drug) After muscle symptom resolution, may then reinitiate a
Pharmacodynamics/Kinetics: Additional Consider- different statin at an initial low dose; gradually increase
ations if tolerated. Based on experience in adult patients, if
Hepatic function impairment: C,,a, and AUC are each 4- muscle symptoms or elevated CPK persists for 2
fold greater in patients with Child-Pugh class A disease; months in the absence of continued statin use, con-
Cmax and AUC are ~16-fold and 11-fold increased, sider other causes of muscle symptoms. If determined
respectively, in patients with Child-Pugh class B disease. to be due to another condition aside from statin use,
- Geriatric: Plasma concentrations are higher (~40% for may resume statin therapy at the original dose (NHLBI
Cmax and 30% for AUC). 2011; Stone 2013)
Gender: Plasma concentrations in women differ from Renal Impairment: Pediatric
those in men (~20% higher for Cmax and 10% lower Children 210 years and Adolescents: Because atorvas-
for AUC) tatin does not undergo significant renal excretion, dose
Dosing modification is not necessary.
Pediatric Dosage should be individualized according to Dialysis: Due to the high protein binding, atorvastatin is
the baseline LDL-C level, the recommended goal of not expected to be cleared by dialysis (has not been
therapy, and patient response; adjustments should be studied).
made at intervals of 4 weeks. Hepatic Impairment: Pediatric Children 210 years and
Heterozygous familial and nonfamilial hypercholes- Adolescents: Contraindicated in active liver disease or in
terolemia: patients with unexplained persistent elevations of serum
Note: Begin treatment if after adequate trial (6 to 12 transaminases.
months) of intensive lifestyle modification emphasiz- Administration Oral: May be taken without regard to
ing body weight normalization and diet, the following meals or time of day. Swallow whole; do not break, crush,
are present (AACE [Jellinger 2017]): or chew.
LDL-C 2190 mg/dL or Monitoring Parameters
LDL-C remains 2160 mg/dL and 2 or more cardiovas- Pediatric patients: Baseline: ALT, AST, and CPK; fasting
cular risk factors: family history of premature athero- lipid panel (FLP) and repeat ALT and AST should be
sclerotic cardiovascular disease (<55 years of age); checked after 4 weeks of therapy; if no myopathy
overweight; obesity; or other elements of insulin symptoms or laboratory abnormalities, then monitor
resistance syndrome or FLP, ALT, and AST every 3 to 4 months during the first
LDL-C 2130 mg/dL and diabetes mellitus (Daniels year and then every 6 months thereafter (NHLBI 2011)
2008; NHLBI 2011) i Adults:
Children 6 to 10 years of age (Tanner stage |): Limited 2013 ACC/AHA Blood Cholesterol Guideline recommen-
data available: Oral: Initial: 5 mg once daily; if target dations (Stone 2013):
LDL-C not achieved after 4 weeks, may increase Lipid panel (total cholesterol, HDL, LDL, triglycer-
incrementally by doubling dose (10 mg/day, ides): Baseline lipid panel; fasting lipid profile within 4
20 mg/day) at monthly intervals until target LDL-C; to 12 weeks after initiation or dose adjustment and
usual maximum daily dose: 40 mg/day; however, in every 3 to 12 months (as clinically indicated) there-
some cases doses up to 80 mg/day have been used; after. If 2 consecutive LDL levels are <40 mg/dL,
dosing based on a long-term trial (3 years) of 272 consider decreasing the dose.
patients (age range: 6 to 15 years); doses of Hepatic transaminase levels: Baseline measurement
80 mg/day were used in 12 patients <10 years of of hepatic transaminase levels (ie, ALT); measure
age; over the 3 year study duration, similar efficacy hepatic function if symptoms suggest hepatotoxicity
was observed without growth or maturation impair- (eg, unusual fatigue or weakness, loss of appetite,
ment (Langslet 2016). abdominal pain, dark-colored urine or yellowing of
Children and Adolescents 10 to 17 years: Oral: Initial: skin or sclera) during therapy.
10 mg once daily; if target LDL-C not achieved after 4 CPK: CPK should not be routinely measured. Baseline
weeks, may increase incrementally by doubling dose CPK measurement is reasonable for some individuals
(20 mg/day, 40 mg/day) at monthly intervals until (eg, family history of statin intolerance or muscle
target LDL-C up to a maximum daily dose: 80 mg/ disease, clinical presentation, concomitant drug ther-
day (Langslet 2016) apy that may increase risk of myopathy). May meas-
Hyperlipidemia: Limited data available: Children and ure CPK in any patient with symptoms suggestive of
Adolescents 10 to 17 years (males and postmenarchal myopathy (pain, tenderness, stiffness, cramping,
females): Oral: Initial: 10 mg once daily; if LDL-C target weakness, or generalized fatigue).
not achieved after 1 to 3 months, may increase to meet Evaluate for new-onset diabetes mellitus during ther-
target LDL-C; in pediatric patients with heterozygous apy; if diabetes develops, continue statin therapy and
familial hypercholestefolemia, a maximum titrated dose encourage adherence to a heart-healthy diet, physical
based upon LDL response: 80 mg/day was used activity, a healthy body weight, and tobacco ces-
(Langslet 2016; McCrindle 2007; NHLBI 2011) sation.
Prevention of graft coronary artery disease: Limited If patient develops a confusional state or memory
data available: Children and Adolescents: Oral: impairment, may evaluate patient for nonstatin
0.2 mg/kg/day rounded to nearest 2.5 mg increment; causes (eg, exposure to other drugs), systemic and
not to exceed age-appropriate doses (Chin 2002; neuropsychiatric causes, and the possibility of
Chin 2008) adverse effects associated with statin therapy. >
207
 ATORVASTATIN

4 Manufacturer recommendation: Liver enzyme tests at

baseline and repeated when clinically indicated. Meas-
Respiratory: Bronchospasm, cough, dyspnea, flu-like
symptoms, rhinitis, sinusitis
ure CPK when myopathy is being considered or may Miscellaneous: Fever
measure CPK periodically in high risk patients (eg, Rare but important or life-threatening: Acute renal failure,
drug-drug interaction). Upon initiation or titration, lipid angioedema, constriction of the pharynx, corneal dis-
panel should be analyzed within 2 to 4 weeks. ease (vortex keratopathy), desquamation, erythema mul-
Dosage Forms Excipient information presented when tiforme, hepatic failure (rare), hepatitis (rare),
available (limited, particularly for generics); consult spe- hypersensitivity reaction, methemoglobinemia, pancrea- —
cific product labeling. titis, Stevens-Johnson syndrome, thrombocytopenia,
Tablet, Oral: urticaria
Lipitor: 10 mg, 20 mg, 40 mg, 80 mg Drug Interactions
Generic: 10 mg, 20 mg, 40 mg, 80 mg Metabolism/Transport Effects None known.
¢@ Atorvastatin Calcium see AtorvaSTATin on page 205
Avoid Concomitant Use
Avoid concomitant use of Atovaquone with any of the
following: Rifamycin Derivatives
Atovaquone (a TOE va kwone) Increased Effect/Toxicity
Atovaquone may increase the levels/effects of: Etopo-
Brand Names: US Mepron side; Etoposide Phosphate
Brand Names: Canada Mepron Decreased Effect
Therapeutic Category Antiprotozoal Atovaquoné may decrease the levels/effects of: Indinavir
Generic Availability (US) Yes
Use Prevention of Pneumocystis jirovecii pneumonia The levels/effects of Atovaquone may be decreased by:
(PCP) and second-line treatment of mild to moderate Efavirenz; Metoclopramide; Rifamycin Derivatives; Rito-
PCP in patients intolerant of trimethoprim/sulfamethoxa- navir; Tetracycline (Systemic)
zole (TMP/SMX) (All indications: FDA approved in ages Food Interactions Ingestion with a fatty meal increases
213 years and adults) absorption. Management: Administer with food, preferably
Pregnancy Risk Factor C high-fat meals (peanuts or ice cream).
Pregnancy Considerations Adverse events were Storage/Stability Store at 15°C to 25°C (59°F to 77°F).
observed in animal reproduction studies. Diagnosis and Do not freeze.
treatment of Pneumocystis jirovecii pneumonia (PCP) in Mechanism of Action Inhibits electron transport in mito-
pregnant women is the same as in nonpregnant women; chondria resulting in the inhibition of key metabolic —
however, information specific to the use of atovaquone in enzymes responsible for the synthesis of nucleic acids —
pregnancy is limited (HHS [O! adult 2015)). and ATP
Breastfeeding Considerations It is not known if atova- Pharmacodynamics/Kinetics (Adult data unless
quone is excreted in breast milk. The manufacturer rec- noted)
ommends that caution be exercised when administering Absorption:
atovaquone to nursing women. Infants and Children <2 years of age: Decreased
Contraindications Hypersensitivity to atovaquone or any absorption
component of the formulation Adults: Oral suspension: Absorption is enhanced 1.4-fold
Warnings/Precautions Hypersensitivity reactions (eg, with food; decreased absorption with single doses
angioedema, bronchospasm, throat tightness, urticaria) exceeding 750 mg
have occurred. When used for Pneumocystis jirovecii Distribution: Vgsg: 0.6 + 0.17 L/kg; CSF concentration is
pneumonia (PCP) treatment, has only been indicated in <1% of the plasma concentration
mild to moderate PCP; not.studied for use in severe PCP; Protein binding: >99%
atovaquone has less adverse effects than trimethoprim- Metabolism: Undergoes enterohepatic recirculation
sulfamethoxazole ([TMP-SMZ], the treatment of choice for Bioavailability: Suspension (administered with food): 47%
mild to moderate PCP), although atovaquone is less + 15%
effective than TMP-SMZ (HHS [OI adult 2015]). Use with Half-life elimination:
caution in elderly patients. Absorption may be decreased Children (4 months to 12 years): 60 hours (range: 31 to
in patients who have diarrhea or vomiting; monitor closely 163 hours)
and consider use of an antiemetic; if severe, consider use Adults: 2.9 days
of an alternative antiprotozoal. Consider parenteral ther- Adults with AIDS: 2.2 days
apy with alternative agents in patients who have difficulty Time to peak, serum: Dual peak serum concentrations at 1
taking atovaquone with food; gastrointestinal disorders to 8 hours and at 24 to 96 hours after dose due to
may limit absorption of oral medications; may not achieve enterohepatic cycling
adequate plasma levels. Use with caution in patients with Excretion: Feces (>94% as unchanged drug); urine (<1%)
severe hepatic impairment; monitor closely; rare cases of Dosing
cholestatic hepatitis, elevated liver function tests, and fatal Pediatric
liver failure have been reported. Potentially significant Pneumocystis jirovecii pneumonia (PCP) (HIV-
drug-drug interactions may exist, requiring dose or fre- exposed/-positive) (HHS [adult Ol! 2017, pediatric
quency adjustment, additional monitoring, and/or selec- Ol 2016]): Limited data available in ages <13 years:
tion of alternative therapy. Prophylaxis; primary or secondary:
Benzyl alcohol and derivatives: Some dosage forms may Infants and Children: Oral:
contain benzyl alcohol; large amounts of benzyl alcohol 1 to 3 months: 30 mg/kg/day once daily
(299 mg/kg/day) have been associated with a potentially 4 to 24 months: 45 mg/kg/day once daily
fatal toxicity ("gasping syndrome") in neonates; the "gasp- >24 months: 30 mg/kg/day once daily; maximum
ing syndrome" consists of metabolic acidosis, respiratory daily dose: 1,500 mg/day
distress, gasping respirations, CNS dysfunction (including Adolescents: Oral: 1,500 mg once daily
convulsions, intracranial hemorrhage), hypotension and Treatment; mild to moderate infection: Treatment
cardiovascular collapse (AAP ["Inactive" 1997]; CDC duration: 21 days
1982); some data suggests that benzoate displaces bilir- Infants and Children: Oral:
ubin from protein binding sites (Ahlfors 2001); avoid or use 1 to 3 months: 30 to 40 mg/kg/day divided once or
dosage forms containing benzy! alcohol with caution in twice daily
neonates. See manufacturer's labeling. 4 to 24 months: 45 mg/kg/day divided once or
Adverse Reactions twice daily
Cardiovascular: Hypotension >24 months: 30 to 40 mg/kg/day divided once or -
Central nervous system: Anxiety, depression, dizziness, twice daily; maximum daily dose: 1,500 mg/day
headache, insomnia, pain Adolescent: Oral: 750 mg twice daily
Dermatologic: Diaphoresis, pruritus, skin rash Toxoplasmosis (toxoplasma gondii); encephalitis
Endocrine & metabolic: Hyperglycemia, hypoglycemia, (HIV-exposed/-positive) (HHS [adult Ol 2017, pedia-
hyponatremia, increased amylase tric Ol 2016]): Limited data available:
Gastrointestinal: Abdominal pain, anorexia, constipation, Primary prophylaxis:
diarrhea, dysgeusia, dyspepsia, nausea, oral candidia- Infants and Children: Oral:
sis, vomiting 1 to 3 months: 30 mg/kg/day once daily
Hematologic & oncologic: Anemia, neutropenia 4 to 24 months: 45 mg/kg/day once daily; with or
Hepatic: Increased liver enzymes without pyrimethamine/leucovorin
. Infection: Infection >24 months: 30 mg/kg/day once daily; maximum
Neuromuscular & skeletal: Myalgia, weakness daily dose: 1,500 mg/day
Renal: Increased blood urea nitrogen, increased serum Adolescents: Oral: 1,500 mg once daily; with or
creatinine without pyrimethamine/leucovorin
 ATOVAQUONE AND PROGUANIL

Treatment (encephalitis): Adolescents: Oral: prophylaxis with this agent should be treated with alter-
1,500 mg twice daily for at least 6 weeks (longer if native agent(s). Absorption of atovaquone may be
extensive disease or incomplete response); use in decreased in patients who have diarrhea or vomiting;
combination with pyrimethamine/leucovorin or sulfa- monitor closely and consider use of an antiemetic. If
diazine is preferred severe, consider use of an alternative antimalarial.
Secondary prophylaxis/chronic maintenance therapy Increased transaminase levels and hepatitis have been
(suppressive): reported with prophylactic use; single case report of
Infants and Children: Oral: hepatic failure requiring transplantation documented.
1 to 3 months: 30 mg/kg/day once daily with leu- Monitor closely and use caution in patients with existing
covorin hepatic impairment. Elevations in AST/ALT may persist for
4 to 24 months: 45 mg/kg/day once daily; with or up to 4 weeks following treatment (Looareesuwan, 1999).
without pyrimethamine/leucovorin Administer with caution to patients with preexisting renal
>24 months: 30 mg/kg/day once daily; maximum disease. May use with caution for treatment of malaria
daily dose: 1,500 mg/day; with leucovorin treatment in patients with severe renal impairment (CrCl
Adolescents: Oral: 750 to 1,500 mg twice daily; use <30 mL/minute) if benefit outweighs risk. Contraindicated
in combination with pyrimethamine/leucovorin or for prophylactic use in severe renal impairment due to the
sulfadiazine is preferred risk of pancytopenia in patients with severe renal impair-
Babesiosis: Limited data available (IDSA [Wormser ment treated with proguanil. Treatment failures have been
2006)): reported in patients >100 kg (case reports); follow-up
Infants and Children: Oral: 40 mg/kg/day divided monitoring is recommended (Durand, 2008).
twice daily; maximum daily dose: 1,500 mg/day with Adverse Reactions The following adverse reactions
azithromycin for 7 to 10 days were reported in patients being treated for malaria. When
Adolescents: Oral: 750 mg twice daily for 7 to 10 days used for prophylaxis, reactions are similar to those seen
with azithromycin with placebo.
Renal Impairment: Pediatric Adolescents 213 years:
Central nervous system: Dizziness, headache
There are no dosage adjustments provided in the man-
Dermatologic: Pruritus (children)
ufacturer’s labeling (has not been studied). However,
Gastrointestinal: Abdominal pain, anorexia, diarrhea, nau-
atovaquone is not appreciably renally excreted.
sea, vomiting
Hepatic Impairment: Pediatric Adolescents 213 Hepatic: Increased serum ALT (increased liver function
years: There are no dosage adjustments provided in test values typically normalized after ~4 weeks),
the manufacturer’s labeling (has not been studied). increased serum AST (increased liver function test val-
Atovaquone undergoes enterohepatic cycling and pri- ues typically normalized after ~4 weeks)
marily hepatic excretion. Use caution in patients with Neuromuscular & skeletal: Weakness
severe impairment; monitor closely. Rare but important or life-threatening: Anaphylaxis (rare),
Administration Oral: Must administer with food or a high- anemia (rare), angioedema, cholestasis, erythema multi-
fat meal. Shake suspension gently before use. Once forme (rare), hallucination, hepatic failure (case report),
opened, a foil pouch can be emptied on a dosing spoon, hepatitis (rare), neutropenia, pancytopenia (with severe
in a cup, or directly into the mouth. renal impairment), psychotic reaction (rare), seizure
Monitoring Parameters CBC with differential, liver (rare), skin photosensitivity, skin rash, Stevens-Johnson
enzymes, bilirubin, serum electrolytes (Na), SCr, serum syndrome (rare), stomatitis, urticaria, vasculitis (rare)
amylase Drug Interactions
Dosage Forms Excipient information presented when Metabolism/Transport Effects None known.
available (limited, particularly for generics); consult spe- Avoid Concomitant Use
cific product labeling. Avoid concomitant use of Atovaquone and Proguanil
Suspension, Oral: with any of the following: Artemether; Lumefantrine;
Mepron: 750 mg/5 mL (5 mL, 210 mL) [contains benzyl Rifamycin Derivatives
alcohol: citrus flavor]
Increased Effect/Toxicity
Generic: 750 mg/5 mL (210 mL) Atovaquone and Proguanil may increase the levels/
effects of: Antipsychotic Agents (Phenothiazines); Dap-
Atovaquone and Proguanil sone (Systemic); Dapsone (Topical); Etoposide; Etopo-
(a TOE va kwone & pro GWA nil) side Phosphate; Lumefantrine; Warfarin

Medication Safety Issues The levels/effects of Atovaquone and Proguanil may be

Sound-alike/look-alike issues: increased by: Artemether; Dapsone (Systemic); Pyri-
Malarone may be confused with mefloquine methamine
Brand Names: US Malarone® Decreased Effect
Brand Names: Canada Malarone; Malarone Pediatric Atovaquone and Proguanil may decrease the levels/
Therapeutic Category Antimalarial Agent effects of: Indinavir; Typhoid Vaccine
Generic Availability (US) Yes The levels/effects of Atovaquone and Proguanil may be
Use Prevention (FDA approved in pediatric patients >11 kg decreased by: Antihepaciviral Combination Products;
and adults) or treatment (FDA approved in pediatric Efavirenz; Ethinyl Estradiol; Metoclopramide; Rifamycin
patients 25 kg and adults) of acute, uncomplicated P. Derivatives; Ritonavir; Tetracycline (Systemic)
falciparum malaria, including chloroquine-resistant P. fal- Food Interactions Atovaquone taken with dietary fat
ciparum significantly increases the rate and extent of absorption;
Pregnancy Risk Factor C AUC is increased 2-3 times and C,,ax is increased 5 times
Pregnancy Considerations Adverse events were not as compared to administration during a fasted state.
observed with the combination of atovaquone/proguanil Management: Administer with food or milk-based drink
in animal reproduction studies. The pharmacokinetics of at the same time each day.
atovaquone and proguanil may be altered during preg- Storage/Stability Store at 25°C (77°F); excursions per-
nancy (Wilby 2011). Malaria infection in pregnant women mitted to 15°C to 30°C (59°F to 86°F).
may be more severe than in nonpregnant women. Mechanism of Action
Because P. falciparum malaria can cause maternal death Atovaquone: Selectively inhibits parasite mitochondrial
and fetal loss, pregnant women traveling to malaria- electron transport.
endemic areas must use personal protection against Proguanil: The metabolite cycloguanil inhibits dihydrofo-
mosquito bites. Atovaquone/proguanil may be used as late reductase, disrupting deoxythymidylate synthesis.
an alternative treatment of malaria in pregnant women; Together, atovaquone/cycloguanil affect the erythrocytic
consult current CDC guidelines (CDC 2013).. and exoerythrocytic stages of development.
Breastfeeding Considerations Small quantities of pro- Pharmacodynamics/Kinetics (Adult data unless
guanil are found in breast milk. This combination is not noted)
recommended if nursing infants <5 kg (safety data is Absorption:
limited concerning therapeutic use in infants <5 kg) (Bog- Atovaquone: The rate and extent of absorption is
gild 2007). increased when administered with dietary fat.
Contraindications Hypersensitivity to atovaquone, pro- Proguanil: Extensive
guanil, or any component of the formulation; prophylactic Distribution: Vg:
use in severe renal impairment (CrCl <30 mL/minute) Atovaquone: Children and Adults: ~8.8 L/kg
Warnings/Precautions Not indicated for cerebral malaria Proguanil: Children >15 years and Adults and 31-110 kg:
or other severe manifestations of complicated malaria. 1617-2502 L; Pediatric patients <15 years and 11-56
Delayed cases of P. falciparum malaria may occur after kg: 462-966 L; concentrated in erythrocytes
stopping prophylaxis; travelers returning from endemic Protein binding:
areas who develop febrile illnesses should be evaluated Atovaquone: >99%
for malaria. Recrudescent infections or infections following Proguanil: 75%

209
 ATOVAQUONE AND PROGUANIL

4 Metabolism: Proguanil: Hepatic to active metabolites,

cycloguanil (via CYP2C19) and 4-chlorophenylbiguanide
outweigh the risks. No dosage adjustment required in
mild to moderate renal impairment.
Bioavailability: Atovaquone/proguanil: 23% when admin- Hepatic Impairment: Pediatric No dosage adjustment
istered with food required in mild to moderate hepatic impairment. No data
Half-life elimination:
available for use in severe hepatic impairment.
Atovaquone: 2-3 days (adults), 1-2 days (children)
Proguanil: 12-21 hours Administration Administer with food or milk at the same
Excretion: time each day. If vomiting occurs within 30 minutes of
Atovaquone: Feces (>94% as unchanged drug); administration, repeat the dose. Tablets are not palatable
urine (<0.6%) if chewed due to bitter taste. For children who have
Proguanil: Urine (40% to 60%) difficulty swallowing tablets, tablets may be crushed and
Pharmacodynamics/Kinetics: Additional Consider- mixed with condensed milk just prior to administration.
ations Dosage Forms Excipient information presented when
Renal function impairment: In patients with moderate renal
available (limited, particularly for generics); consult spe-
impairment (CrCl 30-50 mL/minute), mean oral clear-
ance for proguanil was reduced by ~35% compared with cific product labeling.
patients with normal renal function CrCl >80 mL/minute). Tablet, Oral:
In patients with severe renal impairment (CrCl <30 mL/ Malarone: Atovaquone 250 mg and proguanil hydro-
minute), atovaquone C,,2. and AUC are reduced, but the chloride 100 mg
elimination half-lives for proguanil and cycloguanil are Generic: Atovaquone 250 mg and proguanil hydrochlor-
prolonged, with corresponding increases in AUC, result- ide 100 mg
ing in the potentialof drug accumulation and toxicity with
Tablet, Oral [pediatric]:
repeated dosing.
Malarone: Atovaquone 62.5 mg and proguanil hydro-
Hepatic function impairment: Atovaquone elimination half-
life was increased in patients with moderate hepatic chloride 25 mg
impairment. Proguanil AUC, Cmax, and elimination half- Generic: Atovaquone 62.5 mg and proguanil hydrochlor-
life were increased and cycloguanil (metabolite) AUC ide 25 mg ;
and Cra, were decreased and elimination half-life was
increased in patients with mild hepatic impairment. Pro- . @ Atovaquone and Proguanil Hydrochloride see Atova-
guanil AUC and C,,a. were increased in patients with quone and Proguanil on page 209
moderate hepatic impairment. The pharmacokinetics of @ Atovaquone/Proguanil HCI see Atovaquone and Pro-
atovaquone, proguanil, and cycloguanil have not been guanil on page 209
studied in patients with severe hepatic impairment.
Geriatric: AUC was increased, Tmax was longer, and @ ATRA see Tretinoin (Systemic) on page 1993
elimination half-life was longer in elderly subjects (~15
hours) compared to younger subjects (~8 hours). Atracurium (a tra KYOO ree um)
Dosing
Pediatric Medication Safety Issues
Note: Tablets are available in different strengths (pedia- High alert medication:
tric and adult tablets) and both may be used in pediatric The Institute for Safe Medication Practices (ISMP)
patients depending upon patient weight; use extra
includes this medication among its list of drugs which
precaution
Malaria; prevention (Yellow Book [CDC 2018)}): have a heightened risk of causing significant patient
Infants, Children, and Adolescents: Begin 1 to 2 days harm when used in error.
prior to entering a malaria-endemic area, continue Other safety concerns:
throughout the stay and for 7 days after leaving area: United States Pharmacopeia (USP) 2006: The Interdis-
Oral: ciplinary Safe Medication Use Expert Committee of the
5 to 8 kg: Pediatric tablet (62.5 mg atovaquone/25 mg USP has recommended the following:
proguanil per tablet): 31.25 mg atovaquone/12.5 mg
- Hospitals, clinics, and other practice sites should
proguanil (1/2 tablet) once daily
institute special safeguards in the storage, labeling,
>8 to 10 kg: Pediatric tablet (62.5 mg atovaquone/
25 mg proguanil per tablet): 46.88 mg atovaquone/ and use of these agents and should include these
18.75 mg proguanil (3/4 tablet) once daily safeguards in staff orientation and competency train-
>10 to 20 kg: Pediatric tablet (62.5 mg atovaquone/ ing.
25 mg proguanil per tablet): 62.5 mg atovaquone/ - Healthcare professionals should be on high alert
25 mg proguanil (1 tablet) once daily (especially vigilant) whenever a neuromuscular-block-
>20 to 30 kg: Pediatric tablet (62.5 mg atovaquone/ ing agent (NMBA) is stocked, ordered, prepared, or
25 mg proguanil per tablet): 125 mg atovaquone/
administered.
50 mg proguanil (2 tablets) once daily
>30 to 40 kg: Pediatric tablet (62.5 mg atovaquone/ Brand Names: Canada Atracurium Besylate Injection
25 mg proguanil per tablet): 187.5 mg atovaquone/ Therapeutic Category Neuromuscular Blocker Agent,
75 mg proguanil (3 tablets) once daily Nondepolarizing; Skeletal Muscle Relaxant, Paralytic
>40 kg: Adult tablet (250 mg atovaquone/100 mg Generic Availability (US) Yes
proguanil per tablet): 250 mg atovaquone/100 mg Use Adjunct to general anesthesia, to facilitate endotra-
proguanil (1 tablet) once daily
cheal intubation, and to provide skeletal muscle relaxation
Malaria; treatment, uncomplicated P. falciparum or
during surgery or mechanical ventilation (FDA approved in
P. vivax (CDC 2013): Infants, Children, and Adoles-
cents: Oral: ages 21 month and adults)
5 to 8 kg: Pediatric tablet (62.5 mg atovaquone/25 mg Note: Atracurium does not relieve pain or produce
proguanil per tablet): 125 mg atovaquone/50 mg
sedation.
proguanil (2 tablets) once daily for 3 doses
9 to 10 kg: Pediatric tablet (62.5 mg atovaquone/ Pregnancy Risk Factor C
25 mg proguanil per tablet): 187.5 mg atovaquone/ Pregnancy Considerations Adverse events were
75 mg proguanil (3 tablets) once daily for 3 doses observed in animal reproduction studies. Small amounts
11 to 20 kg: Adult tablet (250 mg atovaquone/100 mg of atracurium have been shown to cross the placenta
proguanil per tablet): 250 mg atovaquone/100 mg when given to women during cesarean section.
proguanil (1 tablet) once daily for 3 doses
Breastfeeding Considerations It is not known if atracu-
21 to 30 kg: Adult tablet (250 mg atovaquone/100 mg
rium is present in breast milk. The manufacturer recom-
proguanil per tablet): 500 mg atovaquone/proguanil/
200 mg proguanil (2 tablets) once daily for 3 doses mends that caution be exercised when administering
31 to 40 kg: Adult tablet (250 mg atovaquone/100 mg atracurium to breastfeeding women.
proguanil per tablet): 750 mg atovaquone/300 mg Contraindications
proguanil (3 tablets) once daily for 3 doses Hypersensitivity to atracurium or any component of the
>40 kg: Adult tablet (250 mg atovaquone/100 mg formulation; known hypersensitivity to benzyl alcohol
proguanil per tablet): 1,000 mg atovaquone/ (multiple dose vials)
400 mg proguanil (4 tablets) once daily for 3 doses
Documentation of allergenic cross-reactivity for neuro-
Renal Impairment: Pediatric All patients: Should not
.be used as prophylaxis in severe renal impairment (CrCl muscular blockers is limited. However, because of sim-
<30 mL/minute) (Yellow Book [CDC 2018]}). For treat- ilarities in chemical structure and/or pharmacologic
ment of malaria, alternative regimens should be used in actions, the possibility of cross-sensitivity cannot be
patients with CrCl <30 mL/minute unless benefits ruled out with certainty.

210
 ATRACURIUM

Warnings/Precautions Severe anaphylactic reactions dextrose 5% in water, or 5% dextrose in sodium chloride

have been reported with atracurium use; some life-threat- 0.9% are stable for up to 24 hours at room temperature or
ening and fatal. Appropriate emergency treatment (includ- under refrigeration.
ing epinephrine 1 mg/mL) should be immediately Mechanism of Action Blocks neural transmission at the
available during use. Reduce initial dosage and inject myoneural junction by binding with cholinergic receptor
slowly (over 1 to 2 minutes) in patients in whom substan- sites
tial histamine release would be potentially hazardous (eg, Pharmacodynamics/Kinetics (Adult data unless
patients with clinically important cardiovascular disease). noted)
Cross-sensitivity with other neuromuscular-blocking Onset of action (dose dependent): 2 to 3 minutes; Peak
agents may occur; use extreme caution in patients with effect: 3 to 5 minutes
previous anaphylactic reactions. Maintenance of an Duration: Recovery begins in 20 to 35 minutes following
adequate airway and respiratory support is critical. All initial dose of 0.4 to 0.5 mg/kg under balanced anes-
patients should receive eye care including liberal use of thesia; recovery to 95% of control takes 60 to 70
lubricating drops, gel, or ointment, and eyelids should minutes; hypothermia may prolong the duration of action
remain closed during continuous neuromuscular blockade Distribution: Vg:
to protect against damage to the cornea (ulceration and Infants: 0.21 L/kg
drying). Certain clinical conditions may result in potentia- Children: 0.13 L/kg
tion or antagonism of neuromuscular blockade: Adults: 0.1 L/kg
Antagonism (decreased paralysis): Respiratory alkalo- Metabolism: Undergoes ester hydrolysis and Hofmann
sis, hypercalcemia, demyelinating lesions, peripheral elimination (nonbiologic process independent of renal,
neuropathies, denervation, and muscle trauma hepatic, or enzymatic function); metabolites have no
Potentiation (increased paralysis): Electrolyte abnormal- neuromuscular blocking) properties; laudanosine, a prod-
ities (eg, severe hypocalcemia, severe hypokalemia, uct of Hofmann elimination, is a CNS stimulant and can
~ hypermagnesemia), neuromuscular diseases, meta- accumulate with prolonged use. Laudanosine is hepati-
bolic acidosis, respiratory acidosis, Eaton-Lambert syn- cally metabolized.
drome and myasthenia gravis Half-life elimination:
Resistance may occur in burn patients (220% of total body Infants: 20 minutes
surface area), usually several days after the injury, and Children: 17 minutes
may persist for several months after wound healing. Adults: Biphasic: Initial (distribution): 2 minutes; Termi-
Resistance may occur in patients who are immobilized. nal: 20 minutes
Use caution in the elderly. Bradycardia may be more Excretion: Urine (<5%)
common with atracurium than with other neuromuscular- Clearance:
blocking agents since it has no clinically-significant effects Infants: 7.9 mL/kg/minute
on heart rate to counteract the bradycardia produced by Children: 6.8 mL/kg/minute
anesthetics. Should be administered by adequately Adults: 5.3 mL/kg/minute
trained individuals familiar with its use. Potentially signifi- Dosing
cant drug-drug interactions may exist, requiring dose or Neonatal Paralysis/skeletal muscle relaxation: IV:
frequency adjustment, additional monitoring, and/or selec- 0.25 to 0.4 mg/kg initially followed by maintenance
tion of alternative therapy. doses of 0.25 mg/kg as needed to maintain neuromus-
cular blockade or a continuous IV infusion 6.7 mcg/kg/
Benzyl alcohol and derivatives: Some dosage forms may minute (0.4 mg/kg/hour) (Clarkson 2001; Kalli 1988);
contain: benzyl alcohol; large amounts of benzyl alcohol Note: Higher intermittent doses (eg, 0.5 mg/kg) have
(299 mg/kg/day) have been associated with a potentially been associated with toxicity and fatal outcomes in
fatal toxicity ("gasping syndrome") in neonates; the "gasp- premature neonates (Clarkson 2001)
ing syndrome" consists of metabolic acidosis, respiratory Pediatric
distress, gasping respirations, CNS dysfunction (including Note: Dose to effect; doses must be individualized due
convulsions, intracranial hemorrhage), hypotension and to interpatient variability. Dosing in obese patients
cardiovascular collapse (AAP ["Inactive" 1997]; CDC should be calculated using ideal body weight (Playfor
1982); some data suggests that benzoate displaces bilir- 2007):
ubin from protein binding sites (Ahlfors 2001); avoid or use Adjunct to surgical anesthesia (neuromuscular
dosage forms containing benzyl alcohol with caution in blockade): Note: Maintenance doses in infants and
neonates. See manufacturer's labeling. children may need to be administered with slightly
Adverse Reactions Adverse reactions are mild, rare, and greater frequency compared to adults.
generally suggestive of histamine release. Initial:
Cardiovascular: Flushing Infants and Children <2 years: IV: 0.3 to 0.4 mg/kg,
Rare but important or life-threatening: Bradycardia, bron- additional doses of 0.3 to 0.4 mg/kg may be
chospasm, dyspnea, erythema, hypersensitivity reac- repeated as needed to maintain neuromuscular
tion, hypotension, increased. bronchial secretions, blockade
injection site reaction, laryngospasm, pruritus, seizure, Children 22 years and Adolescents: IV: 0.4 to
tachycardia, urticaria, wheezing 0.5 mg/kg once followed by 0.08 to 0.1 mg/kg 20
Drug Interactions to 45 minutes after initial dose to maintain neuro-
Metabolism/Transport Effects None known. muscular block; repeat dose at 15- to 25-minute
Avoid Concomitant Use intervals as needed
Avoid concomitant use of Atracurium with any of the Maintenance infusion for continued surgical relaxation
following: QuiNINE during extended surgical procedures:
Increased Effect/Toxicity Infants and Children <2 years: Continuous IV infu-
Atracurium may increase the levels/effects of: Cardiac sion: 6 to 14 mcg/kg/minute (0.4 to 0.8 mg/kg/
Glycosides; Corticosteroids (Systemic); Onabotulinum- hour) (Goudsouzian 1986; Goudsouzian 1988)
toxinA; RimabotulinumtoxinB Children 22 years and Adolescents: Continuous IV
infusion: Initial: 9 to 10 meg/kg/minute (0.54 to
The levels/effects of Atracurium may be increased by: 0.6 mg/kg/hour) at initial signs of recovery from
AbobotulinumtoxinA; Aminoglycosides; Bacitracin (Sys- bolus dose; block is usually maintained by a rate of
temic); Bromperidol; Calcium Channel Blockers; Capreo-
5 to 9 meg/kg/minute (0.3 to 0.54 mg/kg/hour);
mycin; Clindamycin (Topical); Colistimethate;
range: 2 to 15 mcg/kg/minute (0.1 to
CycloSPORINE (Systemic); Fosphenytoin-Phenytoin;
0.9 mg/kg/hour)
Inhalational Anesthetics; Ketorolac (Nasal); Ketorolac
ICU paralysis (eg, facilitate mechanical ventilation)
(Systemic); Lincosamide Antibiotics; Lithium; Local
in selected adequately sedated patients: Infants,
Anesthetics; Loop Diuretics; Magnesium Salts; Minocy-
Children, and Adolescents: IV: Initial bolus: 0.3 to
cline; Pholcodine; Polymyxin B; Procainamide; QuiNl-
0.6 mg/kg, followed by continuous IV infusion of 5 to
Dine; QuiNINE; Spironolactone; Tetracyclines; Thiazide
28 meg/kg/minute (0.3 to 1.7 mg/kg/hour) (Martin
and Thiazide-Like Diuretics; Trimebutine; Vancomycin
1999; Playfor 2007)
Decreased Effect Renal Impairment: Pediatric Infants, Children, and
Atracurium may decrease the levels/effects of: Amifam-
Adolescents: No dosage adjustment necessary.
pridine
Hepatic Impairment: Pediatric Infants, Children, and
The levels/effects of Atracurium may be decreased by: Adolescents: No dosage adjustment necessary.
Acetylcholinesterase Inhibitors; Amifampridine; CarBA- Preparation for Administration Parenteral: For contin-
Mazepine; Fosphenytoin-Phenytoin; Loop Diuretics uous IV infusion, dilute in DSW, NS or DsNS to a maximum
Storage/Stability Store intact vials at 2°C to 8°C (36°F to concentration of 0.5 mg/mL. Atracurium should not be
46°F). Do not freeze. Upon removal from refrigeration to mixed with alkaline solutions.
room temperature) storage conditions (25°C/77°F), use Administration Parenteral: May be administered undi-

®
within 14 days even if re-refrigerated. Dilutions of luted as a bolus injection; do not administer IM due to
0.2 mg/mL or 0.5 mg/mL in 0.9% sodium chloride, tissue irritation. For continuous IV infusions, further dilute

211
ATRACURIUM

and administer via an infusion pump; use infusion solu- caution in patients with autonomic neuropathy, hyperthyr-
tions within 24 hours of preparation. oidism, renal or hepatic impairment, myocardial ischemia,
Monitoring Parameters Muscle twitch response to heart failure, tachyarrhythmias (including sinus tachycar-
peripheral nerve stimulation, heart rate, blood pressure, dia), hypertension,“and hiatal hernia associated with reflux
assisted ventilation status esophagitis. Treatment-related blood pressure increases
Dosage Forms Excipient information presented when and tachycardia may lead to ischemia, precipitate an MI,
available (limited, particularly for generics); consult spe- or increase arrhythmogenic potential. In heart transplant
cific product labeling. recipients, atropine will likely be ineffective in treatment of
Solution, Intravenous, as besylate: bradycardia due to lack of vagal innervation of the trans-
Generic: 50 mg/5 mL (5 mL); 100 mg/10 mL (10 mL) planted heart; cholinergic reinnervation may occur over
Solution, Intravenous, as besylate [preservative free]: time (years), so atropine may be used cautiously; how-
Generic: 50 mg/5 mL (5 mL) ever, some may experience paradoxical slowing of the
heart rate and high-degree AV block upon administration
@ Atracurium Besylate see Atracurium on page 210 (ACLS 2010; Bernheim 2004).
@ Atracurium Besylate Injection (Can) see Atracurium
on page 210 Use may lead to complete urinary retention in patients with
prostatic hypertrophy. Avoid use if possible in patients with
@ Atralin see Tretinoin (Topical) on page 1996 obstructive uropathy or in. other conditions resulting in
@ Atrapro Dermal Spray see Sodium Chloride urinary retention. Use may cause thickening of bronchial
on page 1834 secretions.and formation of viscid plugs in patients with
@ Atriance (Can) see Nelarabine on page 1430 chronic lung disease. Use with extreme caution when
@ Atripla see Efavirenz, Emtricitabine, and Tenofovir Dis- used to treat side effects of acetylcholinesterase inhibition
oproxil Fumarate on page 714 or avoid; may precipitate a myasthenic crisis. Anaphylaxis
may occur. Use may precipitate acute glaucoma.
@ AtroPen see Atropine (Systemic) on page 212
Avoid relying on atropine for effective treatment of type II
second-degree or third-degree AV block (with or without a
Atropine (Systemic) (A troe peen) new wide QRS complex). Asystole or bradycardic pulse-
Medication Safety Issues less electrical activity (PEA): Although no evidence exists
Geriatric Patients: High-Risk Medication: for significant detrimental effects, routine use is unlikely to
Beers Criteria: Atropine is identified in the Beers Criteria have a therapeutic benefit and is no longer recommended
as a potentially inappropriate medication to be avoided (ACLS 2010).
in patients 65 years and older (independent of diag- Anticholinesterase poisoning: Atropine reverses the mus-
nosis or condition) due to its highly anticholinergic carinic but not the nicotinic effects associated with anti-
properties and uncertain effectiveness as an antispas- cholinesterase toxicity. Clinical symptoms consistent with
modic (Beers Criteria [AGS 2015]). highly-suspected organophosphate or carbamate insecti-
Brand Names: US AtroPen cides or nerve agent poisoning should be treated with
Therapeutic Category Antiasthmatic; Anticholinergic antidote immediately; administration should not be
Agent; Antidote, Organophosphate Poisoning; Antispas- delayed for confirmatory laboratory tests. Signs of atropi-
modic Agent, Gastrointestinal; Bronchodilator nization include flushing, mydriasis, tachycardia, and dry-
Generic Availability (US) May be product dependent ness of the mouth or nose. Monitor effects closely when
Use administering subsequent injections as necessary. The
Parenteral: presence of these effects is not indicative of the success
Auto-injector: Antidote for anticholinesterase poisoning of therapy; inappropriate use of mydriasis as an indicator
(carbamate insecticides, nerve agents, organophos- of successful treatment has resulted in atropine toxicity.
phate insecticides, muscarinic poisoning) (FDA Reversal of bronchial secretions is the preferred indicator
approved in all ages) of success. Adjunct treatment with a cholinesterase reac-
Injection: Preoperative medication to inhibit salivation tivator (eg, pralidoxime) may be required in patients with
and secretions; treatment of symptomatic sinus brady- toxicity secondary to organophosphorus insecticides or
cardia, AV block (nodal level) adjuvant use with anti- nerve agents. Treatment should always include proper
cholinesterases (eg, edrophonium, neostigmine) to evacuation and decontamination procedures; medical per-
decrease their side effects during reversal of neuro- sonnel should protect themselves from inadvertent con-
muscular blockade [All indications: FDA approved in tamination. Antidotal administration is intended only for
pediatric patients (age not specified) and adults]; Note: initial management; definitive and more extensive medical
Use is no longer recommended in the management of care is required following administration. Individuals
asystole or pulseless electrical activity (PEA) should not rely solely on antidote for treatment, as other
(ACLS 2010) supportive measures (eg, artificial respiration) may still be
Prescribing and Access Restrictions The AtroPen required.
formulation is available for use primarily by the Depart-
ment of Defense. Children may be more sensitive to the anticholinergic
Pregnancy Risk Factor B/C (manufacturer specific) effects of atropine; use with caution in children with spastic
Pregnancy Considerations Adverse events were not paralysis.
observed in animal reproduction studies (studies not con- Some dosage forms may contain benzyl! alcohol and/or
ducted by all manufacturers). Atropine has been found to sodium benzoate/benzoic acid; benzoic acid (benzoate) is
cross the human placenta (Kanto 1981). In general, med- a metabolite of benzyl alcohol; large amounts of benzyl
ications used as antidotes should take into consideration alcohol (299 mg/kg/day) have been associated with a
the health and prognosis of the mother; antidotes should potentially fatal toxicity ("gasping syndrome") in neonates;
be administered to pregnant women if there is a clear the "gasping syndrome" consists of metabolic acidosis,
indication for use and should not be withheld because of respiratory distress, gasping respirations, CNS dysfunc-
fears of teratogenicity (Bailey 2003). Medications used for tion (including convulsions, intracranial hemorrhage),
the treatment of cardiac arrest in pregnancy are the same hypotension, and cardiovascular collapse (AAP ["Inactive"
as in the non-pregnant woman. Doses and indications 1997]; CDC 1982); some data suggest that benzoate
should follow current Advanced Cardiovascular Life Sup- displaces bilirubin from protein binding sites (Ahlfors
port guidelines. Appropriate medications should not be 2001); avoid or use dosage forms containing benzyl
withheld due to concerns of fetal teratogenicity (Jeejeeb- alcohol and/or benzyl alcohol derivative with caution in
hoy [AHA] 2015). neonates. See manufacturer's labeling.
Breastfeeding Considerations Trace amounts of atro-
pine are present in breast milk. Atropine may suppress Potentially significant drug-drug interactions may exist,
lactation or cause adverse events in the breastfeeding requiring dose or frequency adjustment, additional mon-
infant (data is conflicting). The manufacturer recommends itoring, and/or selection of alternative therapy. Consult
that caution be exercised when administering atropine to drug interactions database for more detailed information.
breastfeeding women. Warnings: Additional Pediatric Considerations Sev-
Contraindications There are no contraindications listed eral reports in the literature have described neonates
in the manufacturer's labeling. developing central anticholinergic syndrome after receiv-
Warnings/Precautions Heat prostration may occur in the ing atropine for bradycardia at doses of 0.1 mg, the
presence of high environmental temperatures. Psychosis minimum dose that has been described for preventing
may occur in sensitive individuals or following use of paradoxical bradycardia. When evaluated based on
excessive doses. Use may convert partial organic pyloric weight, this dose exceeded 0.02 mg/kg in all cases (Gillick
stenosis into complete obstruction. Avoid use in patients 1974; Prakash 2017; Rizzi 2004); some literature has
with paralytic ileus, intestinal atony of the elderly or recommended against using a minimum dose in patients
debilitated patient, severe ulcerative colitis, and toxic <5 kg to prevent overdose (Barrington 2011; Prakash
megacolon complicating ulcerative colitis. Use with 2017).

212
 ATROPINE (SYSTEMIC)

Adverse Reactions Severity and frequency of adverse Decreased Effect

reactions are dose related. Atropine (Systemic) may decrease the levels/effects of:
Cardiovascular: Asystole, atrial arrhythmia, atrial fibrilla- Acetyicholinesterase Inhibitors; Amifampridine; Gastro-
tion, atrioventricular dissociation (transient), bigeminy, intestinal Agents (Prokinetic); Itopride; Levosulpiride;
bradycardia, chest pain, decreased blood pressure, Macimorelin; Nitroglycerin; Secretin
ECG changes (prolonged P wave, shortened PR seg-
The levels/effects of Atropine (Systemic) may be
ment, R on T phenomenon, shortened RT duration,
decreased by: Acetylcholinesterase Inhibitors; Amifam-
prolonged QT interval, widening of QRS Complex, flat-
pridine
tened T wave, repolarization abnormalities, ST segment
Storage/Stability Store injection at room temperature;
elevation, retrograde conduction), ectopic beats (atrial),
avoid freezing. After initial use of multiple-dose vial, dis-
extrasystoles (nodal, ventricular, superventricular), flush-
card within 24 hours. In addition, AtroPen should be
ing, increased blood pressure, left heart failure, myocar-
protected from light. Preparation of bulk atropine solution
dial infarction, nodal arrhythmia (no P wave on ECG),
for mass chemical terrorism at a concentration of 1 mg/mL
palpitations, sinus tachycardia, supraventricular tachy-
is stable for 72 hours at 4°C to 8°C (39°F to 46°F); 20°C to
cardia (including junctional tachycardia), tachycardia,
25°C (68°F to 77°F); 32°C to 36°C (90°F to 97°F) (Dix
trigeminy, ventricular arrhythmia (including flutter), ven-
2003).
tricular fibrillation, ventricular flutter, ventricular prema-
Mechanism of Action Blocks the action of acetylcholine
ture contractions, ventricular tachycardia, weak pulse (or
at parasympathetic sites in smooth muscle, secretory
impalpable peripheral pulses)
glands, and the CNS; increases cardiac output, dries
Central nervous system: Abnormal electroencephalogram
secretions. Atropine reverses the muscarinic effects of
(runs of alpha waves, increase in photic stimulation, and
cholinergic poisoning due to agents with acetylcholines-
signs of drowsiness), agitation (children), amnesia, anxi-
terase inhibitor activity by acting as a competitive antag-
~ety, ataxia, behavioral changes, coma, confusion,
onist of acetylcholine at muscarinic receptors. The primary
decreased deep tendon reflex, delirium, dizziness,
goal in cholinergic poisonings is reversal of bronchorrhea
drowsiness, dysarthria, dysmetria, emotional disturb-
and bronchoconstriction. Atropine has no effect on the
ance, excitement, feeling hot, hallucination (visual or nicotinic receptors responsible for muscle weakness, fas-
aural), headache, hyperpyrexia, hyperreflexia, hyperto- ciculations, and paralysis.
nia, insomnia, intoxicated feeling, irritability (children), Pharmacodynamics/Kinetics (Adult data unless
lack of concentration, lethargy (children), mania, myo-
noted)
clonus, neurologic abnormality, nocturnal enuresis, opis-
Onset of action:
thotonus, paranoia, positive Babinski sign, restlessness,
Inhibition of salivation: IM: Within 30 minutes; maximum
seizure (generally tonic-clonic), stupor, vertigo effect: 30 to 60 minutes (Mirakhur 1980; Volz-
Dermatologic: Anhidrosis, cold skin, dermatitis, dry and Zang 1995)
hot skin, erythematous rash, hyperhidrosis, macular Increased heart rate:
eruption, maculopapular rash, papular rash, scarlatini- IM: Within 15 to 30 minutes (Kentala 1990; Volz-Zang
form rash, skin rash 1995); maximum effect: 45 to 60 minutes (Mirakhur
Endocrine & metabolic: Dehydration, hyperglycemia, 1980; Volz-Zang 1995)
hypoglycemia, hypokalemia, hyponatremia, increased IV: Immediate; maximum effect: 0.7 to 4 minutes (Lon-
thirst, loss of libido nerholm 1975; Santini 1999)
Gastrointestinal: Abdominal and bladder distension, Duration: Inhibition of salivation: IM: <4 hours (Mirakhur
abdominal pain, constipation, delayed gastric emptying, 1980; Volz-Zang 1995)
diminished bowel sounds, dry mucous membranes, dys- Absorption: Rapid and well absorbed from all dosage
phagia, malabsorption, nausea, oral lesion, paralytic forms :
ileus, salivation, vomiting, xerostomia Distribution: Widely throughout the body; crosses blood-
Genitourinary: Difficulty in micturition, impotence, urinary brain barrier
hesitancy, urinary retention, urinary urgency Protein binding: 14% to 44%
Hematologic & oncologic: Abnormal erythrocytes Metabolism: Hepatic via enzymatic hydrolysis
(increased), decreased hemoglobin, increased hemoglo- Half-life elimination: Children <2 years: 6.9 + 3 hours;
bin, leukocytosis, petechiae Children >2 years: 2.5 + 1.2 hours; Adults: 3 + 0.9 hours;
Hypersensitivity: Hypersensitivity reaction Elderly 65 to 75 years of age: 10 + 7.3 hours
Local: Injection site reaction Time to peak: IM: 30 minutes; IM autoinjector: 3 minutes
Neuromuscular & skeletal: Laryngospasm, muscle twitch- Excretion: Urine (13% to 50% as unchanged drug and
ing, weakness metabolites)
Ophthalmic: Abnormal eye movements (cyclophoria and Dosing
heterophoria), angle-closure glaucoma (acute), blephar- Neonatal
itis, blindness, blurred vision, conjunctivitis, crusted of Bradycardia: Note: Neonatal resuscitation guidelines
eyelid, cycloplegia, decreased accommodation, do not include atropine for the treatment of bradycardia
decreased visual acuity, dry eye syndrome, eye irritation, (Kattwinkel 2010).
keratoconjunctivitis sicca, lacrimation, mydriasis, photo- IV, Intraosseous: 0.02 mg/kg/dose; may repeat once in
phobia, strabismus 3 to 5 minutes; reserve use for patients unresponsive
Renal: Increased blood urea nitrogen to improved oxygenation/ventilation and epinephrine
Respiratory: Bradypnea, changes in respiration (labored (Eichenwald 2017); use of aminimum dose of 0.1 mg
respiration), cyanosis, dyspnea, laryngitis, pulmonary in patients <5 kg will result in dosages >0.02 mg/kg; in
edema, respiratory failure, stridor (inspiratory), some cases toxicity and even death have been
tachypnea reported (Barrington 2011; Gillick 1974; Kumar
Miscellaneous: Failure to thrive, fever (secondary to 2015; Rizzi 2004).
decreased sweat gland activity), swelling (children) Endotracheal: 0.04 to 0.06 mg/kg/dose; immediately
Drug Interactions follow with 1 mL of NS; may repeat once if needed
Metabolism/Transport Effects None known. (Eichenwald 2017)
Avoid Concomitant Use Intubation, premedication (preferred vagolytic): IV,
Avoid concomitant use of Atropine (Systemic) with any of IM: 0.02 mg/kg/dose; a minimum dose of 0.1 mg/dose
the following: Aclidinium; Cimetropium; Eluxadoline; Gly- is not recommended (AAP [Kumar 2010]; Barrington
copyrrolate (Oral Inhalation); Ipratropium (Oral Inhala- 2011; Eichenwald 2017).
tion); Levosulpiride; Macimorelin; Oxatomide; Potassium Organophosphate or carbamate insecticide or nerve
Chloride; Potassium Citrate; Tiotropium; Umeclidinium agent poisoning: Note: If exposure is known or
Increased Effect/Toxicity suspected, antidotal therapy should be given as soon
Atropine (Systemic) may increase the levels/effects of: as symptoms appear; do not wait for confirmation. The
AbobotulinumtoxinA; Amezinium; Anticholinergic dose of atropine required varies considerably with the
Agents; Cannabinoid-Containing Products; Cime- severity of poisoning. The total amount of atropine used
tropium; Eluxadoline; EPHEDrine (Systemic); Glucagon; for carbamate poisoning is usually less than with orga-
Glycopyrrolate (Oral Inhalation); Mirabegron; Onabotuli- nophosphate insecticide or nerve agent poisoning.
numtoxinA; Opioid: Analgesics; Potassium Chloride; Severely poisoned patients may exhibit significant tol-
Potassium Citrate; Ramosetron; RimabotulinumtoxinB;
erance to atropine; 22 times the suggested doses may
Ritodrine; Thiazide and Thiazide-Like Diuretics; Tio-
be needed. Titrate to pulmonary status (decreased
bronchial secretions); consider administration of atro-
tropium; Topiramate
pine via continuous IV infusion in patients requiring
The levels/effects of Atropine (Systemic) may be large doses of atropine. Once patient is stable for a
increased by: Aclidinium; Amantadine; Chloral Betaine; period of time, the dose/dosing frequency may be
Ipratropium (Oral Inhalation); Mianserin;. Oxatomide; decreased. Pralidoxime is a component of the manage-
Pramlintide; Umeclidinium ment of organophosphate insecticide and nerve agent >

213
 ATROPINE (SYSTEMIC)

4 toxicity; refer to pralidoxime for the specific route

and dose.
suspected, antidotal therapy should be given as soon
as symptoms appear; do not wait for confirmation. The
IV, IM: Initial: 0.05 to 0.1 mg/kg; repeat every 5 to 15 dose of atropine required varies considerably with the
minutes as needed, doubling the dose if previous severity of poisoning. The total amount of atropine,used
dose did not induce atropinization (AAP [Roberts for carbamate poisoning is usually less than with orga-
2012]; Roberts 2013; Rotenberg 2003). Maintain atro- nophosphate insecticide or nerve agent poisoning.
pinization by administering repeat doses as needed Severely poisoned patients may exhibit significant tol-
for 22 to 12 hours based on recurrence of symptoms erance to atropine; 22 times the suggested doses may
(Roberts 2013). be needed. Titrate to pulmonary status (decreased
Continuous IV infusion: Following atropinization, bronchial secretions); consider administration of atro-
administer 10% to 20% of the total loading dose pine via continuous IV infusion in patients requiring
required to induce atropinization as a continuous IV large doses of atropine. Once patient is stable for a
infusion per hour; adjust as needed to maintain period of time, the dose/dosing frequency may be
adequate atropinization without atropine toxicity decreased. Pralidoxime is a component of the manage-
(Eddleston 2004; Roberts 2007). ment of organophosphate insecticide and nerve agent
IM: AtroPen: 0.25 mg (yellow pen): toxicity; refer to pralidoxime for the specific route
Mild symptoms (22 mild symptoms): Administer one and dose.
0.25 mg (yellow pen) dose as soon as an exposure Infants and Children:
is known or-strongly suspected. If severe symptoms IV, IM: Initial: 0.05 to 0.1 mg/kg; repeat every 5 to 15
develop after the first dose, 2 additional doses minutes-as needed, doubling the dose if previous
should be repeated in rapid succession 10 minutes dose does not induce atropinization (AAP [Roberts
after the first dose; do not administer more than 3 2012]; Hegenbarth 2008; Roberts 2013; Rotenberg
doses. If profound anticholinergic effects occur in 2003). Maintain atropinization by administering
the absence of excessive bronchial secretions, fur- repeat doses as needed for 22 to 12 hours based
ther doses of atropine should be withheld. Mild on recurrence of symptoms (Roberts 2013).
symptoms of insecticide or nerve agent poisoning, Continuous IV infusion: Following atropinization,
as provided by manufacturer in the AtroPen product administer 10% to 20% of the total loading dose
labeling to guide therapy, include: Blurred vision, required to induce atropinization as a continuous
bradycardia, breathing difficulties, chest tightness, IV infusion per hour; adjust as needed to maintain
coughing, drooling, miosis, muscular twitching, nau- adequate atropinization without atropine toxicity
sea, runny nose, salivation increased, stomach (Eddleston 2004; Roberts 2007)
cramps, tachycardia, teary eyes, tremor, vomiting, Adolescents:
or wheezing. IV, IM: Initial: 1 to 3 mg/dose; repeat every 3 to 5
Severe symptoms (21 severe symptom): Immediately minutes as needed, doubling the dose if previous
administer three 0.25 mg (yellow pen) doses. dose does not induce atropinization. Maintain atro-
Severe symptoms of insecticide or nerve agent pinization by administering repeat doses as needed
poisoning, as provided by manufacturer in the for 22 to 12 hours based on recurrence of symptoms
AtroPen product labeling to guide therapy, include: (Roberts 2013).
Breathing difficulties (severe), confused/strange Continuous IV infusion: Following atropinization,
behavior, defecation (involuntary), muscular twitch- administer 10% to 20% of the total loading dose
ing/generalized weakness (severe), respiratory required to induce atropinization as a continuous
secretions (severe), seizure, unconsciousness, uri- IV infusion per hour; adjust as needed to maintain
nation (involuntary); Note: Neonates and infants adequate atropinization without atropine toxicity
may become drowsy or unconscious with muscle (Eddleston 2004; Roberts 2007; Roberts 2013)
floppiness as opposed to muscle twitching. IM (AtroPen): Number of doses dependent upon
Endotracheal: Increase the dose by 2 to 3 times the symptom severity:
usual IV dose. Mix with 3 to 5 mL of normal saline and Weight-directed dosing:
administer. Flush with 3 to 5 mL of NS and follow with <7 kg (<15 Ib): 0.25 mg/dose (yellow pen)
5 assisted manual ventilations (Rotenberg 2003) 7 to 18 kg (15 to 40 Ib): 0.5 mg/dose (blue pen)
Pediatric >18 to 41 kg (>40 to 90 Ib): 1 mg/dose (dark
Bradycardia: Infants, Children, and Adolescents: red pen)
IV, Intraosseous: 0.02 mg/kg/dose; minimum dose: >41 kg (>90 Ib): 2 mg/dose (green pen)
0.1 mg/dose, maximum dose: 0.5 mg/dose; may Mild symptoms (22 mild symptoms): Administer the
repeat once in 5 minutes; reserve use for those weight-directed dose listed above as soon as an
patients unresponsive to improved oxygenation and exposure is known or strongly suspected. If
epinephrine (PALS [Kleinman 2010]); some have severe symptoms develop after the first dose, 2
suggested the minimum dose should not be used in additional doses should be repeated in rapid
patients <5 kg (Barrington 2011; Prakash 2017). succession 10 minutes after the first dose; do
Endotracheal: 0.04 to 0.06 mg/kg/dose; may repeat not administer more than 3 doses. If profound
once if needed (PALS [Kleinman 2010]) anticholinergic effects occur in the absence of
Inhibit salivation and secretions (preanesthesia): |M, excessive bronchial secretions, further doses of
IV, SubQ: Administer dose 30 to 60 minutes preoper- atropine should be withheld. Mild symptoms of
atively then every 4 to 6 hours as needed: insecticide or nerve agent poisoning, as provided
Weight-directed dosing (Nelson 1996): by manufacturer in the AtroPen product labeling
Infants weighing <5 kg: 0.02 mg/kg/dose; use of a to guide therapy, include: Blurred vision, brady-
fixed minimum dosage of 0.1 mg will result in dos- cardia, breathing difficulties, chest tightness,
ages >0.02 mg/kg; there is no documented mini- coughing, drooling, miosis, muscular twitching,
mum dosage in this age group nausea, runny nose, salivation increased, stom-
Infants weighing 25 kg, Children, and Adolescents: ach cramps, tachycardia, teary eyes, tremor,
0.01 to 0.02 mg/kg/dose; maximum single dose: vomiting, or wheezing.
0.4 mg; minimum dose: 0.1 mg Severe symptoms (21 severe symptom): |mmedi-
Fixed dosing: Infants, Children, and Adolescents: ately administer three weight-directed doses in
3 to 7 kg (7 to 16 Ib): 0.1 mg rapid succession. Severe symptoms of insecti-
>7 to 11 kg (17 to 24 Ib): 0.15 mg cide or nerve agent poisoning, as provided by
>11 to 18 kg (>24 to 40 Ib): 0.2 mg manufacturer in the AtroPen product labeling to
>18 to 29 kg (>40 to 65 Ib):): 0.3 mg guide therapy, include: Breathing difficulties
>29 to 41 kg (>65 to 90 Ib):): 0.4 mg (severe), confused/strange behavior, defecation
>41 kg (>90 Ib): 0.4 to 0.6 mg (involuntary), muscular twitching/generalized
Intubation; emergent (premedication): Note: Routine weakness (severe), respiratory secretions
use not recommended for preintubation in infants and (severe), seizure, unconsciousness, urination
children; atropine may be considered in situations with (involuntary); Note: Infants may become drowsy
a high-risk of bradycardia (eg, succinylcholine use) or unconscious with muscle floppiness as
(PALS [de Caen 2015]) or septic shock (Brierley opposed to muscle twitching.
2009). Infants and Children: IV: 0.02 mg/kg/dose with Endotracheal: Increase the dose by 2 to 3 times the
no minimum dose; maximum dose: 0.5 mg/dose (PALS usual IV dose. Mix with 3 to 5 mL of normal saline
[de Caen 2015]). and administer. Flush with 3 to 5 mL of NS and
Muscarine-containing mushroom poisoning: Limited follow with 5 assisted manual ventilations (Roten-
data available: Infants, Children, and Adolescents: IV: berg 2003).
. 0.02 mg/kg/dose; minimum dose: 0.1 mg. Titrate and Renal Impairment: Pediatric There are no dosage
repeat as needed (Goldfrank 2015) adjustments provided in the manufacturer's labeling.
Organophosphate or carbamate insecticide or nerve Hepatic Impairment: Pediatric There are no dosage
agent poisoning: Note: If exposure is known or adjustments provided in the manufacturer's labeling.
 ATROPINE (OPHTHALMIC)

Preparation for Administration Parenteral: Mass tract (FDA approved in pediatric patients [age not speci-
chemical terrorism: Preparation of bulk atropine solu- fied] and adults)
tion: Add atropine sulfate powder to 100 mL NS in poly- Pregnancy Considerations Atropine crosses the pla-
vinyl chloride bags to yield a final concentration of centa following systemic maternal use (Shutt 1979). Atro-
1 mg/mL (Dix 2003). pine is systemically available following ophthalmic
Administration administration. If ophthalmic agents are needed during
Endotracheal: Administer and flush with 1 to 5 mL NS or pregnancy, the minimum effective dose should be used
SWFI based on patient size, followed by 5 manual in combination with punctual occlusion to decrease poten-
ventilations. Absorption may be greater with sterile tial exposure to the fetus (Samples 1988).
water. Stop compressions (if using for cardiac arrest), Breastfeeding Considerations It is not known if atro-
spray the drug quickly down the tube. Follow immedi- pine is excreted in breast milk following ophthalmic admin-
ately with several quick insufflations and continue chest istration; however, systemic absorption occurs. According
compressions. to the manufacturer, the decision to continue or discon-
Parenteral: tinue breastfeeding during therapy should take into
IV: Administer undiluted by rapid IV injection; slow account the risk of infant exposure, the benefits of breast-
injection may result in paradoxical bradycardia feeding to the infant, and benefits of treatment to the
IM: AtroPen: Administer to the outer thigh. Firmly grasp mother.
the autoinjector with the green tip (0.5 mg, 1 mg, and Contraindications Hypersensitivity to atropine or any
2 mg autoinjector) or black tip (0.25 mg autoinjector) component of the formulation; primary glaucoma or
pointed down; remove the yellow safety release tendency toward narrow anterior chamber angle glau-
(0.5 mg, 1 mg, and 2 mg autoinjector) or gray safety coma (ointment only).
| release (0.25 autoinjector). Firmly jab the green tip at a Documentation of allergenic cross-reactivity for anticholi-
-90° angle against the outer thigh; may be administered nergic agents is limited. However, because of similarities
through clothing as long as pockets at the injection site in chemical structure and/or pharmacologic actions, the
are empty. In thin patients or patients <6.8 kg (15 Ib), possibility of cross-sensitivity cannot be ruled out with
bunch up the thigh prior to injection. Hold the auto- certainty.
injector in place for 10 seconds following the injection; Warnings/Precautions Elevated blood pressure may
remove the autoinjector and massage the injection site. occur due to systemic absorption following conjunctival
After administration, the needle will be visible; if the instillation. Photophobia/blurred vision may last up to 2
needle is not visible; repeat the above steps with more weeks due to pupil unresponsiveness and cycloplegia.
pressure. After use, bend the needle against a hard Use with caution in patients with brain damage, Down
surface (needle does not retract) to avoid accidental syndrome, or spastic paralysis; these patients are partic-
injury. ularly susceptible to CNS disturbances and cardiopulmo-
“Monitoring Parameters Heart rate, blood pressure, nary and GI toxicity from systemic absorption of atropine.
pulse, mental status; intravenous administration requires
To avoid precipitating angle closure glaucoma, an estima-
a cardiac monitor
tion of the depth of the anterior chamber angle should be
Organophosphate or carbamate insecticide or nerve made prior to use. Some products may contain benzalko-
agent poisoning: Heart rate, blood pressure, respiratory nium chloride which may be absorbed by soft contact
status, oxygenation secretions. Maintain atropinization lenses. Potentially significant interactions may exist,
with repeated dosing as indicated by clinical status. requiring dose or frequency adjustment, additional mon-
Crackles in lung bases, or continuation of cholinergic itoring, and/or selection of alternative therapy.
signs, may be signs of inadequate dosing. Pulmonary Adverse Reactions Severity and frequency of adverse
improvement may not parallel other signs of atropiniza- reactions are dose related.
tion. Monitor for signs and symptoms of atropine toxicity Cardiovascular: Delirium, flushing, hypotension, increased
(eg, fever, muscle fasciculations, delirium); if toxicity blood pressure
occurs, discontinue atropine and monitor closely. Central nervous system: Irritability, restlessness
Dermatologic: Contact dermatitis, xeroderma
Consult individual institutional policies and procedures. Gastrointestinal: Xerostomia
Dosage Forms Excipient information presented when Ophthalmic: Blurred vision, decreased lacrimation, eye
available (limited, particularly for generics); consult spe- irritation, eyelid edema, eye pain, papillary conjunctivitis,
cific product labeling. [DSC] = Discontinued product photophobia, stinging of eyes, superficial keratitis
Solution, Injection, as sulfate: Respiratory: Dry throat, respiratory depression
Generic: 0.4 mg/mL (1 mL [DSC]); 1 mg/mL (1 mL); Drug Interactions
8 mg/20 mL (20 mL) Metabolism/Transport Effects None known.
Solution, Injection, as sulfate [preservative free]:
Avoid Concomitant Use
Generic: 0.4 mg/0.5 mL (0.5 mL [DSC]); 0.4 mg/mL (1 Avoid concomitant use of Atropine (Ophthalmic) with any
mL); 1 mg/mL (1 mL) ree of the following: Aclidinium; Cimetropium; Eluxadoline;
Solution Auto-injector, Intramuscular, as sulfate: Glycopyrrolate (Oral Inhalation); Ipratropium (Oral Inha-
AtroPen: 0.25 mg/0.3 mL (0.3 mL) [pyrogen free] lation); Levosulpiride; Monoamine Oxidase Inhibitors;
AtroPen: 0.5 mg/0.7 mL (0.7 mL); 1 mg/0.7 mL (0.7 mL); Oxatomide; Potassium Chloride; Potassium Citrate; Tio-
2 mg/0.7 mL (0.7 mL) [pyrogen free; contains phenol] tropium; Umeclidinium
Solution Prefilled Syringe, Injection, as sulfate:
Increased Effect/Toxicity
Generic: 0.25 mg/5 mL (5 mL); 0.5 mg/5 mL (5 mL);
Atropine (Ophthalmic) may increase the levels/effects of:
1 mg/10 mL (10 mL)
AbobotulinumtoxinA; Anticholinergic Agents; Cannabi-
Solution Prefilled Syringe, Intravenous, as sulfate:
noid-Containing Products; Cimetropium; Eluxadoline;
Generic: 2 mg/5 mL (5 mL); 0.8 mg/2 mL (2 mL); 1 mg/
Glucagon; Glycopyrrolate (Oral Inhalation); Mirabegron;
2.5 mL (2.5 mL)
OnabotulinumtoxinA; Opioid Analgesics; Potassium
Chloride; Potassium Citrate; Ramosetron; Rimabotuli-
Atropine (Ophthalmic) (a troe peen) numtoxinB; Thiazide and Thiazide-Like Diuretics; Tio-
tropium; Topiramate
Medication Safety Issues
International issues: The levels/effects of Atropine (Ophthalmic) may be
increased by: Aclidinium; Amantadine; Chloral Betaine;
Atropt [Australia and New Zealand] may be confused
with Azopt brand name for brinzolamide [US, Canada, Ipratropium (Oral Inhalation); Mianserin; Monoamine
Oxidase Inhibitors; Oxatomide; Pramlintide; Umecli-
and multiple international markets] 4
dinium
Brand Names: US Atropine-Care [DSC]; lsopto Atropine
[DSC] D Decreased Effect
Atropine (Ophthalmic) may decrease the levels/effects
Brand Names: Canada Dioptic's Atropine Solution; |so-
of: Acetylcholinesterase Inhibitors; Amifampridine; Gas-
pto Atropine
trointestinal Agents (Prokinetic); Itopride; Levosulpiride;
Therapeutic Category Anticholinergic Agent, Ophthal-
Nitroglycerin; Secretin
mic; Ophthalmic Agent, Mydriatic
Generic Availability (US) Yes The levels/effects of Atropine (Ophthalmic) may be
Use ‘ decreased by: Acetylcholinesterase Inhibitors; Amifam-
Ophthalmic solution: Produce mydriasis and cycloplegia; pridine
produce papillary dilation for cycloplegic refraction, Storage/Stability
penalization of healthy eye in the treatment of amblyopia Solution: Store at 2°C to 25°C (36°F to 77°F).
(All indications: FDA approved in ages 23 months and Ointment: Store at 15°C to 25°C (59°F to 77°F).
adults) Mechanism of Action Blocks the action of acetylcholine
Ophthalmic ointment: Produce mydriasis and cycloplegia; that induces mydriasis and allows the radial pupillary
produce papillary dilation for cycloplegic refraction, pap- dilator muscle to contract resulting in dilation of the pupil;
illary dilation in inflammatory conditions of iris or uveal induces cycloplegia by paralysis of the ciliary muscle. >
 ATROPINE (OPHTHALMIC)

4 Pharmacodynamics/Kinetics (Adult data unless Duodote is only available for use by trained emergency
noted) medical services personnel to treat civilians. Distribution
Onset of action: Ophthalmic solution: Within minutes; is limited to directly from manufacturer (Meridian Medical
maximum effect: within hours Technologies, Inc) to emergency medical service organ-
Duration: Multiple days izations or their suppliers.
Absorption: Well absorbed from all dosage forms Pregnancy Risk Factor C
Metabolism: Hepatic via enzymatic hydrolysis Pregnancy Considerations Reproduction studies have
Bioavailability: Ophthalmic solution: 64% + 29% (range: not been conducted with this combination. Also refer to
19% to 95%) individual agents. The risk:benefit ratio must be consid-
Half-life elimination: 2.5 + 0.8 hours ered in pregnant patients who have been exposed to a
Time to peak: 28 + 27 minutes (range: 3 to 60 minutes) nerve agent such as sarin. While adequate studies have
Excretion: Urine (13% to 50% as unchanged drug and not been conducted, survival of the mother may be
metabolites) dependent upon administering atropine and pralidoxime.
Dosing Breastfeeding Considerations See individual agents.
Pediatric * Contraindications No contraindications exist in the treat-
Amblyopia, healthy eye penalization: Solution (1%): ment of life-threatening organophosphate insecticide or
Infants 23 months and Children <3 years: Ophthalmic: nerve agent poisoning
Instill 1 drop once daily to healthy eye Warnings/Precautions Clinical symptoms consistent
Children 23 years and Adolescents: Ophthalmic: Sol- with highly-suspected organophosphate insecticide or
ution (1%): Instill 1 drop once daily to healthy eye; nerve agent. poisoning should be treated with antidote
dose may be repeated up to twice daily if needed immediately; administration should not be delayed for
Mydriasis, cycloplegia: confirmatory laboratory tests. Treatment should always
Solution (1%): include proper evacuation and decontamination proce-
Infants 23 months and Children <3 years: Ophthal- dures; medical personnel should protect themselves from
mic: Instill 1 drop 40 minutes prior to intended inadvertent contamination. Antidotal administration is
maximal dilation time; maximum dose: 1 drop per intended only for initial management; definitive and more
eye per day extensive medical care is required following administra-
Children 23 years and Adolescents: Ophthalmic: tion. Individuals should not rely solely on antidote for
Instill 1 drop 40 minutes prior to intended maximal treatment, as other supportive measures (eg, artificial
dilation time; may repeat up to twice daily as respiration) may still be required. Continued administra-
needed tion of additional doses in asymptomatic patients may
Ointment: Infants, Children, and Adolescents: Oph- result in atropine toxicity. Signs of atropinization (eg,
thalmic: Apply a small amount in the conjunctival sac flushing, mydriasis, tachycardia, dryness of mouth or
1 to 2 times daily nose) may occur earlier than expected with use of a
Inflammatory conditions of iris and uveal tract: combination product as compared to atropine alone.
Infants, Children, and Adolescents: Ophthalmic: Oint- Monitor effects closely when administering subsequent
ment: Apply a small amount in the conjunctival sac 1 injections as necessary. The presence of these effects
to 2 times daily are not indicative of the success of therapy. Reversal of
bronchial secretions is the preferred indicator of success.
Renal Impairment: Pediatric There are no dosage
Atropine may inhibit sweating and possibly lead to heat-
adjustments provided in the manufacturer's labeling.
related injury or hyperthermia in patients exposed to warm
Hepatic Impairment: Pediatric There are no dosage
environments or exercise. Only when symptoms of poi-
adjustments provided in the manufacturer's labeling.
soning are not severe, use caution in patients with heart
Administration Ophthalmic: Wash hands prior to use. disease, arrhythmias (eg, atrial flutter), severe CAD, or
Solution: Instill solution into conjunctival sac of affected history of recent MI due to treatment-related blood pres-
eye(s); Avoid contact of bottle tip with eye or skin; apply sure increases and tachycardia. Cardiovascular effects
gentle pressure to lacrimal sac during and immediately may lead to ischemia, precipitate a MI or increase arrhyth-
following instillation (1 minute) or instruct patient to mogenic potential. Use caution when symptoms of poison-
gently close eyelid after administration, to decrease ing are not severe in patients with chronic lung disease,
systemic absorption of ophthalmic drops (Urtti 1993; myasthenia gravis, narrow-angle glaucoma, pyloric steno-
Zimmerman 1982) sis, or prostatic hyperplasia. Administration may lead to
Ointment: Place a small amount of ointment into the inspiration of bronchial secretions, formation of dangerous
conjunctival sac of the affected eye(s) viscid plugs or precipitate myasthenic crisis, acute glau-
Monitoring Parameters Heart rate, blood pressure coma, complete pyloric obstruction, or urinary retention in
Dosage Forms Excipient information presented when patients at risk. Use caution in renal impairment; pralidox-
available (limited, particularly for generics); consult spe- ime is excreted renally and the effects of atropine may be
cific product labeling. [DSC] = Discontinued product prolonged in severe renal impairment. Use with caution in
Ointment, Ophthalmic, as sulfate: patients with hepatic impairment; effects of atropine may
Generic: 1% (3.5 g) be prolonged in severe hepatic impairment. Children and
Solution, Ophthalmic, as sulfate: elderly patients may be more sensitive to the anticholiner-
Atropine-Care: 1% (2 mL [DSC], 5 mL [DSC], 15 mL gic effects of atropine. Some dosage forms may contain
[DSC]) [contains benzalkonium chloride, edetate sodium benzoate/benzoic acid; benzoic acid (benzoate) is
disodium] a metabolite of benzyl alcohol; large amounts of benzyl
lsopto Atropine: 1% (5 mL [DSC], 15 mL [DSC]) alcohol (299 mg/kg/day) have been associated with a
Generic: 1% (2 mL, 5 mL, 15 mL) potentially fatal toxicity ("gasping syndrome") in neonates;
the "gasping syndrome" consists of metabolic acidosis,
@ Atropine and Diphenoxylate see Diphenoxylate and
respiratory distress, gasping respirations, CNS dysfunc-
Atropine on page 656
tion (including convulsions, intracranial hemorrhage),
hypotension, and cardiovascular collapse (AAP ["Inactive"
Atropine and Pralidoxime 1997]; CDC 1982); some data suggests that benzoate
(A troe peen & pra li DOKS eem) displaces bilirubin from protein binding sites (Ahlfors
2001); avoid or use dosage forms containing benzyl
Brand Names: US ATNAA; Duodote alcohol derivative with caution in neonates. See manufac-
Therapeutic Category Anticholinergic Agent; Antidote turer's labeling. Potentially significant drug-drug interac-
Generic Availability (US) No tions may exist, requiring dose or frequency adjustment,
Use additional monitoring, and/or selection of alternative ther-
DuoDote: Treatment of poisoning by organophosphate apy.
nerve agents (eg, tabun, sarin, soman) or organophos- Warnings: Additional Pediatric Considerations CNS
phate insecticides for use by trained emergency medical effects (eg, restlessness, tremor, fatigue, locomotor diffi-
services personnel (FDA approved in pediatric patients culties, delirium, hallucinations) are often seen earlier and
weighing >41 kg and adults) at lower doses in pediatric patients compared to adults.
ATNAA: Treatment of poisoning in patients who have been Adverse Reactions
exposed to organophosphate nerve agents (eg, tabun, Reactions reported with Duodote. Also see individual
sarin, soman) that have acetylcholinesterase-inhibiting agents.
activity for self- or buddy-administration by military per- Cardiovascular: Transient increase of blood pressure
sonnel (FDA approved in adults) (usually occurring 15 minutes after administration and
Prescribing and Access Restrictions returning to baseline 4 hours post-dose)
ATNAA (Antidote Treatment-Nerve Agent Auto-Injector) is Central nervous system: Hypertonia (at injection site; mild-
_only available for use by US Armed Forces military to-moderate)
personnel. Information on distribution is available at Local: Pain at injection site (mild-to-moderate)
Defense Services Supply Center-Philadelphia at Drug Interactions
215-737-2341. Metabolism/Transport Effects None known.

216
 ATROPINE AND PRALIDOXIME

Avoid Concomitant Use Symptoms of organophosphate insecticide or nerve

Avoid concomitant use of Atropine and Pralidoxime with agent poisoning, as provided by manufacturer in the
any of the following: Aclidinium; Cimetropium; Eluxado- DuoDote product labeling to guide therapy:
line; Glycopyrrolate (Oral Inhalation); Ipratropium (Oral Mild symptoms: Airway secretions increased,
Inhalation); Levosulpiride; Macimorelin; Oxatomide; blurred vision, bradycardia, breathing difficulties,
Potassium Chloride; Potassium Citrate; Tiotropium; chest tightness, drooling, miosis, nausea, vomiting,
Umeclidinium runny nose, salivation, stomach cramps (acute
Increased Effect/Toxicity onset), tachycardia, teary eyes, tremors/muscular
Atropine and Pralidoxime may increase the levels/effects twitching, wheezing/coughing
of: AbobotulinumtoxinA; Amezinium; Anticholinergic Severe symptoms: Breathing difficulties (severe),
Agents; Cannabinoid-Containing Products; Cime- confused/strange behavior, convulsions, copious
tropium; Eluxadoline; EPHEDrine (Systemic); Glucagon; secretions from lung or airway, involuntary urina-
Glycopyrrolate (Oral Inhalation); Mirabegron; Onabotuli- tion/defecation, muscular twitching/generalized
numtoxinA; Opioid Analgesics; Potassium Chloride; weakness (severe), unconsciousness
Potassium Citrate; Ramosetron; RimabotulinumtoxinB; Renal Impairment: Pediatric Use caution in renal
Ritodrine; Thiazide and Thiazide-Like Diuretics; Tio- impairment; pralidoxime is renally eliminated, patients
tropium; Topiramate with severe renal impairment may require less frequent
dosing following the initial dose.
The levels/effects of Atropine and Pralidoxime may be
Hepatic Impairment: Pediatric There are no specific
increased by: Aclidinium; Amantadine; Chloral Betaine;
dosage adjustments provided in manufacturer's labeling;
Ipratropium (Oral Inhalation); Mianserin; Oxatomide;
patients with severe hepatic impairment may require less
Pramlintide; Umeclidinium
frequent dosing following the initial dose.
Decreased Effect
Administration IM:
Atropine and Pralidoxime may decrease the levels/
DuoDote: Administer IM into the mid-lateral thigh. Hold the
effects of: Acetylcholinesterase Inhibitors; Amifampri-
device firmly at the center with the green tip (needle end)
dine; Gastrointestinal Agents (Prokinetic); ltopride; Lev-
pointing down; remove the gray safety release with the
osulpiride; Macimorelin; Nitroglycerin; Secretin
other hand; do not touch the green tip at any time. The
The levels/effects of Atropine and Pralidoxime may be device is now ready for administration into the mid-lateral
decreased by: Acetylcholinesterase Inhibitors; Amifam- thigh; removal of clothing is not necessary, but pockets
pridine should be empty. If patient does not have a lot of fat at
Storage/Stability the injection site, bunch up thigh tissue for a thicker
Store at 25°C (77°F); excursions permitted to 15°C to injection area. Firmly push the green tip against the
30°C (59°F to 86°F); avoid freezing. Protect from light. mid-lateral thigh. Hold firmly in place until auto-injector
Note: As of May 2014, for certain lots of DuoDote, the US triggers and continue to hold for 10 seconds after the
Food and Drug Administration (FDA) has granted device has triggered. The needle does not retract; after
extended expiration dating for up to 3 years beyond administration, the needle should be visible; if the needle
the manufacturer's labeled expiration dating. Further is not visible, repeat the above steps. After use, bend the
information may be found at http://www.fda.gov/drugs/ needle against a hard surface to avoid accidental injury.
drugsafety/ucm376367.htm?source=govdelivery&utm_- ATNAA: Administer IM in the lateral thigh muscle or
medium=email&utm_source=govdelivery. buttocks. The first dose may be self-administered; sub-
Mechanism of Action sequent doses must be administered by a buddy.
Atropine: Functions as a competitive antagonist of acetyl- Remove the gray safety cap from the back end; place
choline at muscarinic receptors in the peripheral and the front end on the outer thigh or buttocks and push
central nervous system, thus reducing the symptoms of hard to activate the injector. Hold firmly in place for 10
parasympathetic overstimulation resulting from excess seconds. After use, bend the needle into a hook shape
acetylcholine caused by organophosphate insecticide or against a hard surface.
nerve agent poisoning. The parasympatholytic action of Monitoring Parameters Respiratory status, ABGs, pulse
atropine decreases oral and respiratory secretions, oximeter; body temperature (especially in warm climates);
relieves airway constriction, and attenuates the bradycar- blood pressure (peak effect occurs ~15 minutes after
dia induced by organophosphate insecticides and nerve administration); symptoms of poisoning
agents. Antagonizes acetylcholine accumulation at respi- Reference Range Direct measurement of RBC acetylcho-
ratory center and may reduce centrally-mediated respira- linesterase activity provides a measure of degree of
tory paralysis. toxicity, although symptoms may not correlate with degree
of inactivation unless activity reduced to <50%. Sequential
Pralidoxime: An oxime which functions by way of nucleo-
measurement (if rapidly available) may help to determine
philic attack on the ester site of the acetylcholinesterase
the effectiveness of oxime therapy. Plasma (or pseudo)
enzyme which has been deactivated by phosphorylation.
cholinesterase activity is more easily performed, but does
Displacement of the phosphoryl group-allows-_reactivation
not correlate well with the severity and should not be used
of acetylcholinesterase’s hydrolytic activity, thus permitting
to guide therapy.
renewed catalysis of accumulated acetylcholine. Destruc-
tion of accumulated acetylcholine allows for restoration of
Additional Information Evacuation and decontamination
procedures should be undertaken as soon as possible.
normal functioning at neuromuscular junctions and relief
Medical personnel need to protect themselves from acci-
from respiratory muscle paralysis.
dental exposure. Primary prophylaxis against organo-
Pharmacodynamics/Kinetics (Adult data unless
phosphate nerve agents should always consist of
noted) See individual agents.
appropriate protective garments and masks. Organophos-
Dosing phate agents are well absorbed through skin, lungs, and
Pediatric Gl tract. They are usually described as having a petroleum
Organophosphate insecticide or nerve agent poison- or garlic like odor. Once absorbed, organophosphate
ing: Note: If exposure is known or suspected, antidotal agents bind to acetylcholinesterase (also known as RBC
therapy should be given immediately as soon as symp- acetylcholinesterases) and inactivate the enzyme. Acetyl-
toms appear (critical to administer immediately in case cholinesterases catalyze the hydrolysis of acetylcholine to
of soman exposure since its adverse effects develop choline and acetic acid; therefore, once inactivated excess
within minutes). Only health care providers who have acetylcholine accumulates.
had adequate training in the recognition and treatment
of nerve agent or insecticide intoxication should admin- Clinical symptoms of toxicity are associated with choliner-
ister. gic excess and involve the autonomic nervous system,
Children and Adolescents weighing >41 kg: DuoDote CNS, and neuromuscular junction. Clinical features of
(atropine 2.1 mg/pralidoxime 600 mg per autoinjec- acute cholinergic toxicity include bradycardia, miosis, lac-
tor): rimation, salivation, bronchorrhea, bronchospasm, emesis
Mild symptoms (22 mild symptoms): IM: 1 injection and diarrhea. At times, mydriasis and tachycardia may be
(wait 10 to 15 minutes for effect); if after 10 to 15 observed. 100% oxygen and fluid resuscitation are impor-
minutes no severe symptoms emerge, no further tant initial steps in management. Onset and duration of
injections are indicated; if any severe symptoms clinical features consistent with poisoning vary depending
emerge at any point following initial injection, repeat on agent and route of exposure; therefore, every effort
dose by giving 2 additional injections in rapid’ suc- should be made to identify poisoning agent. In addition,
cession. Transport to medical care facility. time interval to "aging" process (irreversible binding
Severe symptoms (21 severe symptom): IM: 3 injec- between organophosphates and acetylcholinesterase)
tions in rapid succession. Transport to medical care vary depending on nerve agent. Once "aging" has
facility. occurred, oxime therapy (eg, pralidoxime) is ineffective,
Maximum cumulative dose: 3 injections unless med- thus making timing of antidote administration critical,
ical care support (eg, hospital, respiratory support) is particularly in the case of soman exposure where "aging"
available process occurs within minutes of exposure.

217
ATROPINE AND PRALIDOXIME

Dosage Forms Excipient information presented when proteinuria and hematuria. Use with caution in patients
available (limited, particularly for generics); consult spe- with renal impairment; may increase risk and/or symptoms
cific product labeling. of gold toxicity and toxicity may be more difficult to detect.
Injection, solution: Therapy should be. discontinued promptly if proteinuria or
ATNAA, Duodote: Atropine 2.1 mg/0.7 mL and pralidox- microscopic hematuria develops. :
ime chloride 600 mg/2 mL [contains benzyl alcohol;
[US Boxed Warning]: Use is only indicated in select
prefilled autoinjector]
patients with active rheumatoid arthritis.
@ Atropine and Pralidoxime Chloride see Atropine and
[US Boxed Warning]: Physicians should be experi-
Pralidoxime on page 216
enced with chrysotherapy and should be familiar with
of Atropine-Care [DSC] see Atropine (Ophthalmic) the toxicity and benefits of therapy.
on page 215
[US Boxed Warning]: Laboratory monitoring should
Sd Atropine, Hyoscyamine, Phenobarbital, and Scopol-
be reviewed prior to each new prescription. The pos-
amine see Hyoscyamine, Atropine, Scopolamine, and
sibility of adverse reactions should be discussed with
Phenobarbital on page 1032_
patients prior to starting therapy and patients should
Sa Atropine Sulfate see Atropine (Ophthalmic) be advised to promptly report any symptoms indicat-
on page 215 ing toxicity. Disease states should be stable prior to
Sa Atropine Sulfate see Atropine (Systemic) on page 212 initiating therapy. May be associated with the development
A Atrovent [DSC] see Ipratropium (Nasal) on page 1121 of cholestatic jaundice (rare). Use with caution in patients
Sa Atrovent (Can) see Ipratropium (Nasal) on page
with hepatic impairment; may increase risk and/or symp-
1121
toms of gold toxicity and toxicity may be more difficult to
Sa Atrovent HFA see Ipratropium (Oral Inhalation) detect. Use may be associated with rare reactions, includ-
on page 1122 ing gold bronchitis, interstitial pneumonitis and interstitial
@ ATV see Atazanavir on page 197 fibrosis; monitor closely.
# Augmentin see Amoxicillin and Clavulanate Benzyl alcohol and derivatives: Some dosage forms may
on page 127 contain benzyl alcohol; large amounts of benzyl alcohol
@ Augmentin ES-600 see Amoxicillin and Clavulanate (299 mg/kg/day) have been associated with a potentially
on page 127 fatal toxicity ("gasping syndrome") in neonates; the "gasp-
@ Augmentin XR see Amoxicillin and Clavulanate ing syndrome" consists of metabolic acidosis, respiratory
on page 127 distress, gasping respirations, CNS dysfunction (including
convulsions, intracranial hemorrhage), hypotension and
cardiovascular collapse (AAP ["Inactive" 1997]; CDC
Auranofin (au RANE ob fin) 1982); some data suggests that benzoate displaces bilir-
Medication Safety Issues ubin from protein binding sites (Ahlfors 2001); avoid or use
Sound-alike/look-alike issues: dosage forms containing benzy! alcohol with caution in
Ridaura may be confused with Cardura neonates. See manufacturer’s labeling.
Brand Names: US Ridaura Warnings: Additional Pediatric Considerations In
Brand Names: Canada Ridaura pediatric trials, diarrhea was the most common adverse
Therapeutic Category Gold Compound effect (Giannini 1990).
Generic Availability (US) No Adverse Reactions
Dermatologic: Alopecia, pruritus, skin rash, urticaria
Use Management of active stage of classic or definite
Gastrointestinal: Abdominal pain, anorexia, constipation,
rheumatoid arthritis in patients who do not respond to or
diarrhea, dysgeusia, dyspepsia, flatulence, glossitis,
tolerate other agents (FDA approved in adults)
loose stools, nausea, stomatitis, vomiting
Pregnancy Risk Factor C
Genitourinary: Hematuria, proteinuria
Pregnancy Considerations Adverse events were
Hematologic and oncologic: Anemia, eosinophilia, leuko-
observed in animal reproduction studies.
penia, thrombocytopenia
Breastfeeding Considerations Injectable gold salts
Hepatic: Increased serum transaminases
have been detected in breast milk. Breastfeeding is not
Ophthalmic: Conjunctivitis
recommended by the manufacturer.
Rare but important or life-threatening: Agranulocytosis,
Contraindications History of gold-induced disorders,
aplastic anemia, angioedema, bronchitis (gold), corneal
including anaphylactic reactions, bone marrow aplasia,
deposits, dysphagia, exfoliative dermatitis (other gold
severe hematologic disorders, exfoliative dermatitis,
compounds), fever, gastrointestinal hemorrhage, gingivi-
necrotizing enterocolitis, or pulmonary fibrosis.
tis, hepatotoxicity, interstitial pneumonitis, jaundice, met-
Warnings/Precautions [US Boxed Warning]: Signs of
allic taste, melena, neutropenia, pancytopenia,
gold toxicity include pruritus, rash, and stomatitis.
Pruritus and metallic taste may occur before dermatitis peripheral neuropathy, pure red cell aplasia, ulcerative
and oral mucous membrane reactions, respectively, and
enterocolitis
should be considered warning signs. Stomatitis may be Drug Interactions
manifested by shallow ulcers on the buccal membranes, Metabolism/Transport Effects None known.
on border of tongue, and on palate or in the pharynx; Avoid Concomitant Use There are no known interac-
sometimes diffuse glossitis or gingivitis develops. Gold tions where it is recommended to avoid concomitant use.
dermatitis may be aggravated by sunlight exposure or Increased Effect/Toxicity There are no known signifi-
an actinic rash may develop. Use with caution in patients cant interactions involving an increase in effect.
with skin rash; may increase risk and/or symptoms of gold Decreased Effect There are no known significant inter-
toxicity and toxicity may be more difficult to detect. actions involving a decrease in effect.
Storage/Stability Store at 15°C to 30°C (59°F to 86°F).
[US Boxed Warning]: Signs of gold toxicity include
Protect from light.
persistent diarrhea/loose stools as well as nausea,
vomiting, anorexia, abdominal cramps, and ulcerative
Mechanism of Action The exact mechanism of action of
enterocolitis (rare). Diarrhea may be managed with a dose gold is unknown; gold salts decrease cellular proliferation,
reduction. Use with caution in patients with inflammatory reduce antibody and cytokine release, and inhibit collage-
bowel disease; may increase risk and/or symptoms of gold nase action (Doan 2005). ;
toxicity and toxicity may be more difficult to detect. Monitor Pharmacodynamics/Kinetics (Adult data unless
patients for Gl. bleeding. noted)
Note: Due to rapid metabolism, the pharmacokinetics of
[US Boxed Warning]: Signs of gold toxicity include auranofin are based on gold concentrations, not aurano-
hematologic depression (decreased hemoglobin, leu- fin.
kocytes (WBC <4,000/mm°), granulocytes Onset of action: Delayed; therapeutic response may not
(<1,500/mm’), or platelets (<150,000/mm°). Use with be seen for 3-4 months after start of therapy, as long as 6
caution in patients with bone marrow depression; may months in some patients
increase risk and/or symptoms of gold toxicity and toxicity Duration: Prolonged
may be more difficult to detect. Therapy should be dis-
Absorption: Oral: ~25% gold in dose is absorbed
continued if signs and symptoms (eg, purpura, ecchymo-
Protein binding: 60%
ses, petechiae) of thrombocytopenia develop or if platelet
Metabolism: Rapid; intact auranofin not detectable in the
count falls to <100,000/mm5; therapy should not be reini-
blood
tiated until thrombocytopenia resolves and if thrombocy-
Half-life elimination (single or multiple dose dependent):
topenia was not caused by the gold therapy.
21 to 31 days
[US Boxed Warning]: Signs of gold toxicity include Time to peak, serum: ~2 hours (Blocka 1986)
proteinuria and hematuria. Renal toxicity ranges from Excretion: Urine (~60% of absorbed gold); remainder in
mild proteinuria to nephrotic syndrome or glomerulitis with feces

218
 AVELUMAB

Dosing @ Avelox ABC Pack [DSC] see Moxifloxacin (Systemic)

Pediatric Juvenile idiopathic arthritis: Limited data on page 1408
available: Note: Reserve for patients intolerant to or @ Avelox I.V. (Can) see Moxifloxacin (Systemic)
unresponsive to other therapies. Children 218 months on page 1408
and Adolescents <17 years: Oral: Initial: 0.1 to
0.15 mg/kg/day in 1 to 2 divided doses; usual mainte-
nance: 0.15 mg/kg/day in 1 to 2 divided doses; max- Avelumab (a VEL ue mab)
imum daily dose: 0.2 mg/kg/day or 9 mg/day. Note:
Medication Safety Issues
With current market availability, may not be able to
Sound-alike/look-alike issues
replicate the exact dosing used in trials; in trials, doses
Avelumab may be confused with atezolizumab, durvalu-
were rounded to nearest whole mg using 1 mg tablet (no
mab, nivolumab
longer available) (Brewer 1983; Giannini 1990; Giannini
High alert medication
1991; Marcolongo 1988).
This medication is in a class the Institute for Safe
Renal Impairment: Pediatric There are no pediatric-
Medication Practices (ISMP) includes among its list of
specific recommendations; based on experience in adult drug classes which have a heightened risk of causing
patients, dosing adjustment suggested. significant patient harm when used in error.
Hepatic Impairment: Pediatric There are no dosage Brand Names: US Bavencio
adjustments provided in the manufacturer's labeling.
Brand Names: Canada Bavencio
Administration Take with or without food; some centers
Therapeutic Category Antineoplastic Agent, Anti-PD-L1
have recommended to administer with food if it causes Gl
Monoclonal Antibody; Antineoplastic Agent, Monoclonal
upset.
Antibody
, Monitoring Parameters Baseline and periodic (at least Generic Availability (US) No
monthly): CBC with differential, platelet count, urinalysis
Use Treatment of metastatic Merkel cell carcinoma (MCC)
for protein; baseline renal and liver function tests; skin and
(FDA approved in ages 212 years and adults)
oral mucosa examinations; specific questioning for symp-
Medication Guide Available Yes
toms of pruritus, rash, stomatitis, or metallic taste
Pregnancy Considerations Immunoglobulins are known
Reference Range Gold: Normal: 0 to 0.1 mcg/mL (SI: 0 to
to cross the placenta and fetal exposure to avelumab is
0.0064 micromoles/L); Therapeutic: 1 to 3 mcg/mL (SI:
expected. Based on the mechanism of action, avelumab
0.06 to 0.18 micromoles/L); Urine <0.1 mcg/24 hours
may cause fetal harm. Immune-mediated fetal rejection
Dosage Forms Excipient information presented when
causing increased abortion or stillbirth was observed in
available (limited, particularly for generics); consult spe-
animal reproduction studies. Women of reproductive
cific product labeling.
potential should use effective contraception during ther-
Capsule, Oral:
apy and for at least 1 month after treatment is complete.
Ridaura: 3 mg [contains brilliant blue fcf (fd&c blue #1),
Breastfeeding Considerations It is not known if avelu-
fd&c red #40, fd&c yellow #6 (sunset yellow)]
mab is present in breast milk. According to the manufac-
@ Auraphene-B [OTC] see Carbamide Peroxide turer, lactating women should not breastfeed during
on page 365 therapy and for at least 1 month after treatment is com-
plete.
@ Auro-Amlodipine (Can) see AmLODIPine on page 120
Contraindications There are no contraindications listed
@ Auro-Carvedilol (Can) see Carvedilol on page 373 in the US manufacturer's labeling.
@ Auro-Cefixime (Can) see Cefixime on page 386 Canadian labeling: Hypersensitivity to avelumab or. any
@ Auro-Cefprozil (Can) see Cefprozil on page 393 component of the formulation.
Warnings/Precautions Adrenal insufficiency may occur.
@ Auro-Cefuroxime (Can) see Cefuroxime on page 402
The median time to onset was 2.5 months (range: 1 day to
@ Auro-Citalopram (Can) see Citalopram on page 461 8 months). In clinical studies, all patients received cortico-
@ Auro-Clindamycin (Can) see Clindamycin (Systemic) steroid therapy for adrenal insufficiency; in patients who
on page 471 received high-dose corticosteroids, the median duration of
@ Auro-Cyclobenzaprine (Can) see Cyclobenzaprine high-dose systemic corticosteroid therapy was 1 day
(range: 1 day to 24 days). Monitor for signs/symptoms of
on page 529
adrenal insufficiency both during and after treatment.
@ Auro-Entecavir (Can) see Entecavir on page 745 Administer corticosteroids as appropriate. Withhold ave-
@ Auro-Lamotrigine (Can) see LamoTRigine lumab for severe (grade 3) or life-threatening (grade 4)
on page 1174 toxicity. Type 1 diabetes mellitus has occurred (including
@ Auro-Montelukast (Can) see Montelukast diabetic ketoacidosis). Monitor closely for hyperglycemia
on page 1399 and other signs/symptoms of diabetes. Insulin or other
anti-hyperglycemic therapy may be required; if severe
@ Auro-Montelukast Chewable Tablets (Can) see Mon-
hyperglycemia is observed, administer antihyperglyce-
telukast on page 1399
mics or insulin and withhold avelumab treatment until
@ Auro-Moxifloxacin (Can) see Moxifloxacin (Systemic) glucose control has been accomplished. Immune-medi-
on page 1408 ated hyperthyroidism, hypothyroidism, and thyroiditis have
@ Auro-Nevirapine (Can) see Nevirapine on page 1442 occurred; and may develop at any time during avelumab
treatment. The median onset for immune-mediated thyroid
@ Auro-Olanzapine ODT (Can) see OLANZapine
disorders was 2.8 months (range: 2 weeks to 13 months).
on page 1485
Monitor for changes in thyroid function (at baseline, peri-
@ Auro-Omeprazole (Can) see Omeprazole on page 1493 odically during treatment, and as clinically indicated) and
@ Auro-Terbinafine (Can) see Terbinafine (Systemic) for signs/symptoms of thyroid disorders. Administer med-
on page 1913 ical management for hyperthyroidism as appropriate; may
¢@ Autologous CART-19 TCR:4-1BB cells see Tisagenle- require treatment interruption and/or permanent discontin-
cleucel on page 1958 uation. Manage hypothyroidism with replacement therapy.
Immune-mediated thyroid disorders may require treat-
@ Auvi-Q see EPINEPHrine (Systemic) on page 748
ment interruption.
@ Ava-Cefprozil (Can) see Cefprozil on page 393
Immune-mediated pneumonitis has been observed,
@ Ava-Clindamycin (Can) see Clindamycin (Systemic)
including fatal cases. The median time to development
on page 471 was 2.5 months (range: 3 days to 11 months) and the
@ Ava-Cyclobenzaprine (Can) see Cyclobenzaprine median duration was 7 weeks (range: 4 days to over 4
on page 529 months). Pneumonitis was managed with systemic corti-
@ Ava-Famciclovir (Can) see Famciclovir on page 825 costeroids; the median duration of initial corticosteroid
therapy was 8 days (range: 1 day to 2.3 months) followed
@ Avage see Tazarotene on page 1902
by a corticosteroid taper. Pneumonitis resolved in approx-
@ Avakine see InFLIXimab on page 1070 imately half of the affected patients. May require treatment
@ Avamys (Can) see Fluticasone (Nasal) on page 899 interruption, corticosteroid therapy (prednisone initial dose
@ Avandia see Rosiglitazone on page 1787 of 1 to 2 mg/kg/day [or equivalent] followed by a taper, for
grade 2 or higher pneumonitis), and/or permanent dis-
@ Avapro see Irbesartan,on page 1124 continuation. Monitor for signs and symptoms of pneumo-
\ @ Avastin see Bevacizumab on page 273 nitis; if pneumonitis is suspected, evaluate with
@ Avaxim (Can) see Hepatitis A Vaccine on page 984 radiographic imaging; administer systemic corticosteroids
for grade 2 or higher pneumonitis. Immune-mediated
@ Avaxim-Pediatric (Can) see Hepatitis A Vaccine
nephritis has occurred. Grade 2 or higher nephritis should
on page 984
be managed with systemic corticosteroids (prednisone
@ Aveed see Testosterone on page 1916 initial dose of 1 to 2 mg/kg/day [or equivalent], followed
@ Avelox see Moxifloxacin (Systemic) on page 1408 by a taper). Monitor serum creatinine at baseline and >
219
 AVELUMAB

4 periodically during therapy. May require treatment inter-

ruption, systemic corticosteroids (for grade 2 or higher
Renal: Acute
renal failure
renal failure, increased serum creatinine,

toxicity), and/or permanent discontinuation. Respiratory: Cough,-dyspnea, pneumonitis (immune-

mediated) : i
Immune-mediated colitis has occurred. The median time
Miscellaneous: Infusion-related reaction
to onset of colitis was 2.1 months (range: 2 days to 11
months) and the median duration was 6 weeks (range: 1 Rare but important or life-threatening: Adrenocortical
day to over 14 months). In many patients, colitis was insufficiency (immune-mediated), arthritis (immune-
managed with high-dose systemic corticosteroids for a mediated), erythema multiforme (immune-mediated),
median duration of 19 days (range: 1 day to 2.3 months), exfoliative dermatitis (immune-mediated), Guillain-Barré
followed by a corticosteroid taper. More than two-thirds of syndrome (immune-mediated), hepatitis (immune-medi-
patients with colitis experienced resolution. May require ated), hyperthyroidism (immune-mediated), myocarditis
treatment interruption, systemic corticosteroid therapy, (immune-mediated), myositis (immune-mediated), neph-
and/or permanent discontinuation. Monitor for signs and ritis (immune-mediated), pemphigoid (immune-medi-
symptoms of colitis; administer systemic corticosteroids ated), pituitary insufficiency (immune-mediated),
(prednisone initial dose of 1 to 2 mg/kg/day [or equivalent] psoriasis (immune-mediated), sepsis (systemic inflam-
followed by a taper) for grade 2 or higher colitis. Immune- matory response; immune-mediated), thyroiditis
mediated hepatitis has occurred, including fatal cases. (immune-mediated), type 1 diabetes mellitus (immune-
The median onset for hepatitis was 3.2 months (range: 7 mediated), uveitis (immune-mediated)
days to 15 months); the median duration was 2.5 months Drug Interactions
(range: 1 day to over 7 months). Hepatitis resolved in Metabolism/Transport Effects None known.
approximately half of the patients. Administer corticoste- Avoid Concomitant Use
roids (prednisone initial dose of 1 to 2 mg/kg/day [or Avoid concomitant use of Avelumab with any of the
equivalent] followed by a taper for grade 2 or higher following: Belimumab
hepatitis), and withhold or discontinue therapy based on
Increased Effect/Toxicity
the severity of liver enzyme elevations. Systemic cortico-
Avelumab may increase the levels/effects of: Belimumab
steroids were used to manage immune-mediated hepati-
tis; the median duration of high-dose corticosteroid
Decreased Effect There are no known significant inter-
therapy was 14 days (range: 1 day to 2.5 months). Monitor actions involving a decrease in effect.
for liver function changes. May require treatment interrup- Storage/Stability Store intact vials at 2°C to 8°C (36°F to
tion, systemic corticosteroids (for grade 2 or higher tox- 46°F); do not freeze. Protect vials from light (store in
icity), and/or permanent discontinuation. original packaging)..Do not shake. Solutions diluted for
infusion should be protected from light and may be stored
Other clinically relevant immune-mediated disorders have at room temperature for up to 4 hours or refrigerated at
been observed rarely with avelumab use and may affect 2°C to 8°C (36°F to 46°F) for no more than 24 hours from
any organ system (may be fatal), including myocarditis, the time of dilution. Do not freeze or shake diluted
myositis, psoriasis, arthritis, exfoliative dermatitis, eryth-
solution. If refrigerated, allow to reach room temperature
ema multiforme, pemphigoid, hypopituitarism, uveitis,
prior to administration.
Guillain-Barré syndrome, and systemic inflammatory
Mechanism of Action Avelumab is a fully human mono-
response. May occur during treatment or following dis-
clonal antibody that binds to programmed death ligand 1
continuation. Other immune-mediated disorders have
been observed with other similar medications (same (PD-L1) to selectively prevent the interaction between the
class), including bullous dermatitis, Stevens Johnson syn- programmed cell death-1 (PD-1) and B7.1 receptors,
drome/toxic epidermal necrolysis, pancreatitis, rhabdo- while still allowing interaction between PD-L2 and PD-1
myolysis, myasthenia gravis, histiocytic necrotizing (Kaufman 2016). PD-L1 is an immune check point protein
lymphadenitis, demyelination, vasculitis, hemolytic ane- expressed on tumor cells and tumor infiltrating cells and
mia, hypophysitis, iritis, and encephalitis. If an immune- down regulates anti-tumor t-cell function by binding to PD-
mediated adverse event is suspected, evaluate appropri- 1 and B7.1; blocking PD-1 and B7.1 interactions restores
ately to confirm or exclude other causes; based on antitumor t-cell function (Fehrenbacher 2016, Rosenberg
severity of reaction, withhold treatment and administer 2016).
systemic corticosteroids and (if appropriate) hormone Pharmacodynamics/Kinetics (Adult data unless
replacement therapy. Upon resolution to grade O or 1, noted)
initiate corticosteroid taper. When reaction remains at Distribution: Vass: 4.72 L (10 mg/kg dose)
grade 1 or less during taper may reinitiate avelumab. Half-life elimination: 6.1 days
Discontinue permanently for severe grade 3 immune- Excretion: Total systemic clearance was 0.59 L/day in
mediated adverse event that is recurrent or for life-threat- patients receiving a 10 mg/kg dose.
ening reactions. Dosing
Infusion-related reactions (including severe and life- Pediatric Note: Prior to first 4 infusions, premedicate
threatening cases) have occurred. Prior to the initial four with an antihistamine and acetaminophen; for subse-
infusions, premedicate with an antihistamine and acetami- quent infusions, consider premedication based on clin-
nophen. Monitor for signs/symptoms of a reaction (eg, ical judgment and a history of and/or severity of infusion-
pyrexia, chills, wheezing, flushing, hypotension, dyspnea, related reactions with previous infusions.
back pain, abdominal pain, urticaria). Some infusion- Merkel cell carcinoma, metastatic: Children 212 years
related reactions occurred after completion of the infusion. and Adolescents: IV: 10 mg/kg/dose once every 2
Interrupt or slow the rate of infusion for mild or moderate weeks until disease progression or unacceptable tox-
infusion-related reactions. Stop infusion and permanently icity
discontinue for severe (grade 3) or life-threatening (grade Dosing adjustment for toxicity: Children 212 years
4) infusion-related reactions. Potentially significant inter- and Adolescents:
actions may exist, requiring dose or frequency adjustment, Endocrinopathies:
additional monitoring, and/or selection of alternative ther- Adrenal insufficiency, grade 3 or 4: Withhold treat-
apy. Consult drug interactions database for more detailed ment; administer corticosteroids as appropriate.
information. Resume avelumab treatment if symptoms improve
Adverse Reactions to grade 0 or 1 after corticosteroid taper.
Cardiovascular: Hypertension, pericardial effusion, periph- Hyperglycemia, grade 3 or 4: Withhold treatment. May
eral edema
require insulin or other anti-hyperglycemic treat-
Central nervous system: Dizziness, fatigue, headache
ment. Resume avelumab once metabolic control
Dermatologic: Cellulitis, pruritus, skin rash
has been achieved.
Endocrine & metabolic: Hyperglycemia, hyponatremia,
Hyperthyroidism or hypothyroidism, grade 3 or 4:
hypothyroidism (immune-mediated), increased amylase,
Withhold treatment. Initiate medical management
increased gamma-glutamyl transferase, weight loss
Gastrointestinal: Abdominal pain, colitis (immune-medi- for hyperthyroidism; manage hypothyroidism with
ated), constipation, decreased appetite, diarrhea, hormone replacement therapy.
increased serum lipase, intestinal obstruction, nausea, Other endocrinopathies, grade 3 or 4: Withhold treat-
vomiting ment; administer corticosteroids as appropriate.
Genitourinary: Urinary tract infection Resume avelumab treatment if symptoms improve
Hematologic & oncologic: Anemia, lymphocytopenia, neu- to grade 0 or 1 after corticosteroid taper.
tropenia, thrombocytopenia Gastrointestinal toxicity:
Hepatic: Increased serum alkaline phosphatase, Diarrhea or colitis, grade 2 or 3: Withhold treatment.
increased serum ALT, increased serum AST, increased Administer high-dose systemic corticosteroids (pre-
serum bilirubin dnisone initial dose of 1 to 2 mg/kg daily or equiv-
Immunologic: Antibody development alent) followed by a corticosteroid taper. May
Neuromuscular & skeletal: Arthralgia, musculoskeletal resume avelumab treatment if symptoms improve
pain, weakness to grade 0 or 1 after corticosteroid taper.

220
 AZACITIDINE

Diarrhea or colitis, grade 4 or recurrent grade 3: avoid foaming or excessive shearing. Discard unused
Discontinue permanently. Administer high-dose sys- portion of the vial.
temic corticosteroids (prednisone initial dose of 1 to Administration IV: Infuse over 60 minutes through a 0.2
2 mg/kg daily or equivalent) followed by a cortico- micron sterile, nonpyrogenic, low-protein binding inline
steroid taper. filter. Do not infuse other medications through the: same
Infusion-related reaction: infusion line.
Grade 1 or 2: Interrupt or slow the rate of infusion. Monitoring Parameters Liver (AST, ALT, and total bilir-
Grade 3 or 4; Permanently discontinue. ubin), renal, and thyroid function tests (at baseline, peri-
Pulmonary toxicities; odically during treatment and as clinically indicated); blood
Pneumonitis, grade 2: Withhold treatment. Administer glucose; signs/symptoms of colitis, thyroid disorders,
high-dose systemic corticosteroids (prednisone ini- pneumonitis, adrenal insufficiency, hepatitis, hyperglyce-
tial dose of 1 to 2 mg/kg daily or equivalent) followed mia, monitor for infusion reactions.
by a corticosteroid taper. May resume avelumab Dosage Forms Excipient information presented when
treatment if symptoms improve to grade 0 or 1 after available (limited, particularly for generics); consult spe-
corticosteroid taper. cific product labeling.
Pneumonitis, grade 3 or 4, or recurrent grade 2: Solution, Intravenous [preservative free]:
Discontinue permanently. Administer high-dose sys- Bavencio: 200 mg/10 mL (10 mL)
temic corticosteroids (prednisone initial dose of 1 to
2 mg/kg daily or equivalent) followed by a cortico- @ Aventyl (Can) see Nortriptyline on page 1472
steroid taper. @ AverTeaX [OTC] see Benzyl Alcohol on page 262
Other immune-mediated toxicities (eg, arthritis, bullous
dermatitis, demyelination, encephalitis, erythema @ Avidoxy see Doxycycline,on page 695
multiforme, exfoliative dermatitis, Guillain-Barré syn- @ AVINza [DSC] see Morphine (Systemic) on page 1400
drome, hemolytic anemia, histiocytic necrotizing lym- @ Avita see Tretinoin (Topical) on page 1996
phadenitis, hypophysitis, hypopituitarism, iritis,
@ AVP see Vasopressin on page 2042
myasthenia gravis, myocarditis, myositis, pancreatitis,
pemphigoid, psoriasis, rhabdomyolysis, Stevens @ Av-Phos 250 Neutral see Potassium Phosphate and
Johnson Syndrome (SJS)/toxic epidermal necrolysis Sodium Phosphate on page 1667
(TEN), uveitis, vasculitis): _ @ Axert see Almotriptan on page 90
Immune-mediated toxicities, moderate or severe (not @ Axid [DSC] see Nizatidine on page 1468
described previously): Withhold treatment and eval-
uate. Administer high-dose systemic corticosteroids, ® Axid (Can) see Nizatidine on page 1468
and if appropriate, initiate hormone replacement Axiron [DSC] see Testosterone on page 1916
therapy. When toxicity improves to grade 1 or less, Axiron (Can) see Testosterone on page 1916
initiate a corticosteroid taper. May resume avelumab
Aygestin see Norethindrone on page 1470
treatment if symptoms improve to grade 0 or 1 after
corticosteroid taper. @ Ayr [OTC] see Sodium Chloride on page 1834
Life-threatening reactions (excluding endocrinopa- @ Ayr Nasal Mist Allergy/Sinus [OTC] see Sodium Chlor-
thies), recurrent severe immune-mediated reactions, ide on page 1834
or persistent grade 2 or 3 immune-mediated reac- @ Ayr Saline Nasal [OTC] see Sodium Chloride
tions lasting 12 weeks or longer, or requirement for
on page 1834
210 mg/day prednisone in adults (or equivalent) for
>12 weeks: Discontinue permanently. If appropriate, @ Ayr Saline Nasal Drops [OTC] see Sodium Chloride
administer high-dose systemic corticosteroids fol- on page 1834
lowed by a corticosteroid taper. @ Ayr Saline Nasal Gel [OTC] see Sodium Chloride
Renal Impairment: Pediatric on page 1834
Children 212 years and Adolescents: @ Ayr Saline Nasal Neti Rinse [OTC] see Sodium Chloride
Renal impairment prior to treatment initiation: There are on page 1834
no dosage adjustments provided in the manufac-
@ Ayr Saline Nasal No-Drip [OTC] see Sodium Chloride
turer’s labeling; however, no clinically meaningful
on page 1834
differences were observed in a population pharmaco-
kinetic analysis in patients with CrCl 15 to 89 mL/ @ AYR Saline Nasal Rinse [OTC] see Sodium Chloride
minute. on page 1834
Renal toxicity during treatment (nephritis and renal
dysfunction): AzaClTiDine (ay za SYE ti deen)
Serum creatinine >1.5 to 6 times ULN: Withhold treat-
ment. Administer high-dose systemic corticosteroids Medication Safety Issues
(prednisone initial dose of 1 to 2 mg/kg daily or Sound-alike/look-alike issues:
equivalent, followed by a taper). Resume avelumab AzaClT|IDine may be confused with azaTHIOprine, dec-
treatment if symptoms improve to grade 0 or 1 after itabine
corticosteroid taper. High alert medication:
Serum creatinine >6 times ULN: Discontinue perma- This medication is in a class the Institute for Safe
nently. Administer high-dose systemic corticoste- Medication Practices (ISMP) includes among its list of
roids (prednisone initial dose of 1 to 2 mg/kg daily drug classes which have a heightened risk of causing
or equivalent) followed by a corticosteroid taper. significant patient harm when used in error.
Hepatic Impairment: Pediatric Brand Names: US Vidaza
Children 212 years and Adolescents: Brand Names: Canada Vidaza
Hepatic impairment prior to treatment: There are no
Therapeutic Category Antineoplastic Agent, Antimeta-
dosage adjustments provided in the manufacturer's
bolite (Pyrimidine)
labeling; however, no clinically meaningful differences
were observed in a population pharmacokinetic anal-
Generic Availability (US) Yes
ysis in patients with mild (bilirubin SULN and AST Use Treatment of myelodysplastic syndrome (MDS) in
>ULN or bilirubin between 1 to 1.5 times ULN) or patients with the following subtypes: Refractory anemia
moderate (bilirubin between 1.5 to 3 times ULN) or refractory anemia with ringed sideroblasts (if accom-
impairment. Limited data is available in patients with panied by neutropenia or thrombocytopenia or requiring
severe (bilirubin >3 times ULN) impairment. 4 transfusions), refractory anemia with excess blasts,
Hepatotoxicity during treatment: refractory anemia with excess blasts in transformation,
AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to and chronic myelomonocytic leukemia (FDA approved in
3 times ULN: Withhold treatment. Administer high- adults)
dose systemic corticosteroids (prednisone initial Pregnancy Considerations Adverse events were
dose of 1 to 2 mg/kg daily or equivalent, followed observed in animal reproduction studies. Based on its
by a taper). Resume avelumab treatment if hepatitis mechanism of action, azacitidine may cause fetal harm if
symptoms improve to grade 0 or 1 after cortico- administered during pregnancy. Women of childbearing
steroid taper. |. potential should be advised to avoid pregnancy during
AST or ALT >5 times ULN or total bilirubin >3 times treatment; verify pregnancy status prior to therapy initia-
ULN: Discontinue permanently. Administer high- tion. In addition, males should be advised to avoid father-
dose systemic corticosteroids (prednisone initial ing a child while on azacitidine therapy and should use
dose of 1 to 2:mg/kg daily or equivalent) followed effective contraception during therapy.
by a corticosteroid taper. Breastfeeding Considerations It is not known if azaci-
Preparation for Administration Withdraw appropriate tidine is present in breast milk. Due to the potential for
volume from vial and transfer to IV bag containing 250 mL serious adverse reactions in the breastfed infant, breast-
NS or % NS. Mix by gently inverting bag (do not shake); feeding is not recommended by the manufacturer.

221
 AZACITIDINE

€ Contraindications Hypersensitivity to azacitidine, manni- Rare but important or life-threatening: Abscess (limb,
tol, or any component of the formulation; advanced malig- perirectal), aggravated bone pain, agranulocytosis, ana-
nant hepatic tumors phylactic shock, atrial fibrillation, azotemia, bacterial
Warnings/Precautions May cause hepatotoxicity in infection, blastomycosis, bone marrow failure, cardiac
patients with preexisting hepatic impairment. Progressive failure, catheter site hemorrhage, cellulitis, cerebral hem-
hepatic coma leading to death has been reported in orrhage, cholecystectomy, cholecystitis, congestive car-
patients with extensive tumor burden due to metastatic diomyopathy, decreased serum bicarbonate,
disease, especially those with a baseline albumin <30 g/L. dehydration, diverticulitis, fibrosis (interstitial and alveo-
Patients with hepatic impairment were excluded from lar), gastrointestinal hemorrhage, glycosuria, hemoph-
clinical studies for myelodysplastic syndrome (MDS). thalmos, hemoptysis, hepatic coma, hypersensitivity
Use is contraindicated in patients with advanced malig- reaction, hypophosphatemia, increased serum creati-
nant hepatic tumors. Monitor liver function tests prior to nine, injection site infection, interstitial pulmonary dis-
therapy initiation and before each cycle. Renal toxicities, ease, intracranial hemorrhage, leukemia cutis, melena,
including serum creatinine elevations, renal tubular acido- necrotizing fasciitis, neutropenic sepsis, orthostatic
sis (serum bicarbonate decrease to <20 mEq/L associated hypotension, pancytopenia, pneumonitis, polyuria, pul-
with alkaline urine and serum potassium <3 mEq/L), and monary infiltrates, pyoderma gangrenosum, renal failure,
renal failure (some fatal), have been reported with intra- renal tubular acidosis, respiratory distress, seizure, sep-
venous azacitidine when used in combination with other sis, sepsis syndrome, septic shock, splenomegaly,
chemotherapy agents. Monitor serum creatinine and elec- Sweet's syndrome, tissue necrosis at injection site, tox-
trolytes prior to therapy initiation and before each cycle.
oplasmosis, tumor lysis syndrome
Withhold or reduce the dose with unexplained decreases
Drug Interactions
in serum bicarbonate <20 mEq/L or if elevations in BUN or
Metabolism/Transport Effects None known.
serum creatinine occur. Patients with renal impairment
may be at increased risk for renal toxicity. Monitor closely Avoid Concomitant Use
for toxicity in patients with severe renal impairment (aza- Avoid concomitant use of AzaC!TIDine with any of the
citidine and metabolites are excreted renally). following: BCG (Intravesical); Deferiprone; Dipyrone;
Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac-
Neutropenia, thrombocytopenia, and anemia are com- cines (Live)
mon; may cause therapy delays and/or dosage reduc- Increased Effect/Toxicity
tions; monitor blood counts prior to each cycle (at a AzaClTIDine may increase the levels/effects of: Bariciti-
minimum), and as clinically indicated. Adjust dose in nib; CloZAPine; Deferiprone; Fingolimod; Leflunomide;
subsequent cycles based on nadir counts and hemato- Natalizumab; Tofacitinib; Vaccines (Live)
logic response. Azacitidine is associated with a moderate
emetic potential (Dupuis 2011; Hesketh 2017; Roila 2016); The levels/effects of AzaC/TIDine may be increased by:
antiemetics are recommended to prevent nausea and Chloramphenicol (Ophthalmic); Denosumab; Dipyrone;
vomiting. Injection site reactions commonly occurred with Ocrelizumab; Palifermin; Pimecrolimus; Promazine;
subcutaneous administration. Potentially significant drug- Roflumilast; Tacrolimus (Topical); Trastuzumab
drug interactions may exist, requiring dose or frequency Decreased Effect
adjustment, additional monitoring, and/or selection of AzaClTIDine may decrease the levels/effects of: BCG
alternative therapy. (Intravesical); Coccidioides immitis Skin Test; Lenogras-
Some dosage forms may contain polysorbate 80 (also tim; Lipegfilgrastim; Nivolumab; Pidotimod; Sipuleucel-T;
known as Tweens). Hypersensitivity reactions, usually a Tertomotide; Vaccines (Inactivated); Vaccines (Live)
delayed reaction, have been reported following exposure The levels/effects of AzaCITIDine may be decreased by:
to pharmaceutical products containing polysorbate 80 in Echinacea
certain individuals (Isaksson 2002; Lucente 2000; Shelley
Hazardous Drugs Handling Considerations
1995). Thrombocytopenia, ascites, pulmonary deteriora-
Hazardous agent (NIOSH 2016 [group 1]).
tion, and renal and hepatic failure have been reported in
premature neonates after receiving parenteral products Use appropriate precautions for receiving, handling,
containing polysorbate 80 (Alade 1986; CDC 1984). See administration, and disposal. Gloves (single) should be
manufacturer's labeling. worn during receiving, unpacking, and placing in storage.
Adverse Reactions
Cardiovascular: Chest pain, chest wall pain, heart mur- NIOSH recommends double gloving, a protective gown,
mur, hypertension, hypotension Peripheral edema, syn- ventilated engineering controls (a class || biological safety
cope, tachycardia cabinet or a compounding aseptic containment isolator),
Central nervous system: Anxiety, depression, dizziness, and closed system transfer devices (CSTDs) for prepara-
Fatigue, headache, hypoesthesia, insomnia, lethargy, tion. Double gloving, a gown, and (if dosage form allows)
malaise, pain, postoperative pain, rigors CSTDs are required during administration (NIOSH 2016).
Dermatologic: Cellulitis, diaphoresis, erythema, pallor, Storage/Stability
pruritus, night sweats, rash at injection site, skin lesion, Prior to reconstitution, store intact vials at room temper-
skin nodules, skin rash, urticaria, xeroderma ature of 25°C (77°F); excursions permitted to 15°C to
Endocrine & metabolic: Hypokalemia, pitting edema, 30°C (59°F to 86°F).
weight loss IV solution: Solutions for IV administration have very
Gastrointestinal: Abdominal distention, abdominal pain, limited stability and must be prepared immediately
abdominal tenderness, anorexia, constipation, diarrhea, prior to each dose. Administration must be completed
dyspepsia, dysphagia, gingival hemorrhage, hemor- within 1 hour of (vial) reconstitution.
rhoids, loose stools, nausea, stomatitis, tongue ulcer, SubQ suspension: Following reconstitution, suspension
vomiting may be stored at room temperature for up to 1 hour prior
Genitourinary: Dysuria, hematuria, urinary tract infection to immediate administration (administer within 1 hour of
Hematologic & oncologic: Anemia, bone marrow depres- reconstitution), If administration is delayed, refrigerate
sion (nadir: days 10 to 17; recovery: days 28 to 31), reconstituted suspension immediately (either in vial or
bruise, febrile neutropenia, hematoma, leukopenia, Lym- syringe); may be stored for up to 8 hours (if reconstituted
phadenopathy, neutropenia, oral hemorrhage, oral with room temperature SWFIl) or up to 22 hours (if
mucosal petechiae, petechia, postprocedural hemor- reconstituted with refrigerated SWFI). After removal from
rhage, thrombocytopenia refrigerator, may be allowed up to 30 minutes to reach
Hypersensitivity: Transfusion reaction
room temperature prior to immediate administration.
Infection: Herpes simplex infection
Mechanism of Action Antineoplastic effects may be a
Local: Bruising at injection site, erythema at injection site
result of azacitidine's ability to promote hypomethylation of
(more common with IV administration), hematoma at
DNA, restoring normal gene differentiation and prolifera-
injection site, induration at injection site, injection site
tion. Azacitidine also exerts direct toxicity to abnormal
granuloma, injection site reaction, itching at injection site,
pain at injection site (more common with IV administra-
hematopoietic cells in the bone marrow.
tion), skin discoloration at injection site, swelling at Pharmacodynamics/Kinetics (Adult data unless
injection site noted)
Neuromuscular & skeletal: Arthralgia, back pain, limb Absorption: SubQ: Rapid and complete
pain, muscle cramps, myalgia, weakness Distribution: Vg: IV: 76 + 26 L; does not cross blood-brain
Respiratory: Abnormal breath sounds, atelectasis, cough, barrier
dyspnea, epistaxis, nasal congestion, nasopharyngitis, Metabolism: Hepatic; hydrolysis to several metabolites
pharyngitis, pharyngolaryngeal pain, pleural effusion, Bioavailability: SubQ: ~89%
Pneumonia, post nasal drip, rales, rhinitis, rhinorrhea, Half-life elimination: IV, SubQ: ~4 hours
rhonchi, sinusitis, upper respiratory infection, wheezing Time to peak, plasma: SubQ: 30 minutes
Miscellaneous: Fever Excretion: Urine (50% to 85%); feces (<1%)

222
 AZATHIOPRINE

Pharmacodynamics/Kinetics: Additional Consider- patients, dosing adjustment suggested; monitor closely

ations for toxicity.
Renal function impairment: The AUC was increased by Hepatic Impairment: Pediatric There are no dosage
70% after a single subcutaneous dose and by 41% after adjustments provided in the manufacturer's labeling (has
multiple subcutaneous doses in patients with severe not been studied); use is contraindicated in patients with
renal impairment (CrCl <30 mL/minute), compared to advanced malignant hepatic tumors.
patients with normal renal function. This increase in Preparation for Administration If reconstituted solution
exposure did not correlate with increased adverse comes in contact with skin, wash immediately and thor-
effects. oughly with soap and water; if comes in contact with
Dosing mucous membranes, flush thoroughly with water.
Pediatric SubQ: Slowly add 4 mL SWEFI to each vial, resulting in a
Note: Dosing and frequency may vary by protocol and/or concentration of 25 mg/mL. Vigorously shake or roll vial
treatment phase; refer to specific protocol. until a suspension is formed (suspension will be cloudy).
Acute myeloid leukemia (AML): Limited data avail- The manufacturer recommends dividing doses >4 mL
able; efficacy results variable: equally into 2 syringes. Do not filter after reconstitution
SubQ: Children 22 years and Adolescents: 75 mg/m?/ (may remove active drug). Resuspend contents of
dose once daily for 7 days; dosing from a patient syringe by vigorously rolling between palms immediately
population (n=53) that included adults up to 84 prior to administration.
years; the minimum age of subjects in the trial was IV: Reconstitute vial with 10 mL SWFI to form a 10 mg/mL
5 years, although minimum inclusion criteria was 2 solution; vigorously shake or roll vial until solution is
years; used in combination with tretinoin and val- dissolved and clear. Further dilute in 50 to 100 mL of
proic acid for refractory or relapsed cases with NS or LR injection for infusion.
clinical activity observed (Soriano 2007) Discard unused portion (does not contain preservatives);
IV: Dosing regimens variable: Children and Adoles- do not save unused portions for later administration.
cents: 300 mg/m/dose once daily for 2 consecutive Administration If azacitidine suspension comes in con-
days has been used for induction and intensive tact with the skin, immediately wash with soap and water;
consolidation therapy in various combinations in if it comes into contact with mucous membranes, flush
newly diagnosed patients (Ravindranath 2005; thoroughly with water. Azacitidine is associated with a
Ribiero 2005). Note: Frequency of use of azacitidine moderate emetic potential (Basch 2011; Dupuis 2011;
therapy for AML (newly diagnosed) has decreased Roila 2010); premedication to prevent nausea and vomit-
as newer therapies have replaced previous pro- ing is recommended.
tocols. SubQ: The manufacturer recommends equally dividing
Dosing adjustment for toxicity: The presented dosing volumes >4 mL into two syringes and injecting into two
adjustments are based on experience in adult patients. separate sites; however, policies for maximum SubQ
Refer to specific protocol for management in pediatric administration volume may vary by institution; interpa-
patients if available. tient variations may also apply. Rotate sites for each
Hematologic toxicity: injection (thigh, abdomen, or upper arm). Administer
Adult: subsequent injections at least 1 inch from previous
For baseline WBC 23,000/mm3, ANC 21,500/mm%, and injection sites and never into areas where the site is
platelets >75,000/mm‘°: tender, bruised, red, or hardened. Allow refrigerated
Nadir count: ANC <500/mm® or platelets suspensions to come to room temperature up to 30
<25,000/mm%: Administer 50% of dose during next minutes prior to administration; suspension stored at
treatment course room temperature must be administered within 1 hour
Nadir count: ANC 500/mm® to 1,500/mmé or platelets after reconstitution. Resuspend by inverting the syringe 2
25,000 to 50,000/mm3: Administer 67% of dose to 3 times and then rolling the syringe between the palms
during next treatment course for 30 seconds.
Nadir count: ANC >1,500/mm® or platelets IV: Infuse over 10 to 40 minutes; infusion must be com-
>50,000/mm?: Administer 100% of dose during next pleted within 1 hour of vial reconstitution.
treatment course Monitoring Parameters Liver function tests (baseline),
For baseline WBC <3,000/mm?, ANC <1,500/mm%, or electrolytes (baseline and prior to each cycle), CBC with
platelets <75,000/mm? : Adjust dose as follows based differential and platelets (baseline and prior to each cycle,
on nadir counts and bone marrow biopsy cellularity at more frequently if indicated), renal function tests (at mini-
the time of nadir, unless clear improvement in differ- mum, serum bicarbonate, BUN and serum creatinine at
entiation at the time of the next cycle: baseline and prior to each cycle); monitor for nausea/
WBC or platelet nadir decreased 50% to 75% from vomiting and injection site reactions
baseline and bone marrow biopsy cellularity at time Dosage Forms Excipient information presented when
of nadir 30% to 60%: Administer 100% of dose available (limited, particularly for generics); consult spe-
during next treatment course cific product labeling.
WBC or platelet nadir decreased 50% to 75% from Suspension Reconstituted, Injection:
baseline and bone marrow biopsy cellularity at time Generic: 100 mg (1 ea)
of nadir 15% to 30%: Administer 50% of dose during Suspension Reconstituted, Injection [preservative free]:
next treatment course Vidaza: 100 mg (1 ea)
WBC or platelet nadir decreased 50% to 75% from Generic: 100 mg (1 ea)
baseline and bone marrow biopsy cellularity at time
of nadir <15%: Administer 33% of dose during next @ AZA-CR see AzaClT|IDine on page 221
treatment course Azactam see Aztreonam (Systemic) on page 234
WBC or platelet nadir decreased >75% from baseline
@ Azactam in Dextrose see Aztreonam (Systemic)
and bone marrow biopsy cellularity at time of nadir
on page 234
30% to 60%: Administer 75% of dose during next
treatment course @ Azacytidine see AzaClT|IDine on page 221
WBC or platelet nadir decreased >75% from baseline @ 5-Azacytidine see AzaClTIDine on page 221
and bone marrow biopsy cellularity at time of nadir @ Azasan see AzaTHlOprine on page 223
15% to 30%: Administer 50% of dose during next
treatment course
@ AzaSite see Azithromycin (Ophthalmic) on page 233
WBC or platelet nadir decreased >75% from baseline
and bone marrow biopsy cellularity at time of nadir AzaTHlOprine (ay za THYE oh preen)
<15%: Administer 33% of dose during next treat-
ment course ‘ Medication Safety Issues
Note: If a nadir defined above occurs, administer the Sound-alike/look-alike issues:
next treatment course 28 days after the start of the AzaTHlOprine may be confused with azaClTIDine, azi-
preceding course as long as WBC and platelet dothymidine, azithromycin, Azulfidine
counts are >25% above the nadir and rising. If a Imuran may be confused with Elmiron, Enduron, Imdur,
>25% increase above the nadir is not seen by day Inderal, Tenormin
28, reassess counts every 7 days. If a 25% increase High alert medication:
is not seen by day 42, administer 50% of the This medication is in a class the Institute for Safe
scheduled dose. Medication Practices (ISMP) includes among its list of
Electrolyte disturbances: Adult: If serum bicarbonate falls drug classes that have a heightened risk of causing
to <20 mEq/L (unexplained decrease): Reduce dose by significant patient harm when used in error.
50% for next treatment course Other safety concerns:
Renal Impairment: Pediatric There are no pediatric- Azathioprine is metabolized to mercaptopurine; concur-
specific recommendations; refer to pediatric specific rent use of these commercially-available products has
protocols if available. Based on experience in adult resulted in profound myelosuppression.

223
AZATHIOPRINE

Brand Names: US Azasan; Imuran Warnings/Precautions [US Boxed Warning]: Chronic

Brand Names: Canada Imuran immunosuppression with azathioprine (a purine anti-
Therapeutic Category Immunosuppressant Agent metabolite), increases the risk of malignancy. Malig-
Generic Availability (US) Yes nancies reported have included post-transplant
Use Adjunct with other agents in prevention of kidney lymphoma and hepatosplenic T-cell lymphoma
transplant rejection (FDA approved in adults); manage- (HSTCL) in patients with inflammatory bowel disease.
ment of active rheumatoid arthritis (FDA approved in Health care providers using this medication should be
adults); has also been used as an immunosuppressant very familiar with this risk, as well as with the muta-
in a variety of autoimmune diseases such as SLE, juvenile genic potential to both men and women, and with
idiopathic arthritis (JIA), JIA-associated uveitis, myasthe- possible hematologic toxicities. Patients should be
nia gravis, and autoimmune hepatitis, and as a steroid- informed of the risk for malignancy development.
sparing agent for inflammatory bowel disease HSTCL is a rare white blood cell cancer that is usually
Pregnancy Risk Factor D fatal and has predominantly occurred in adolescents and
Pregnancy Considerations young adults treated for Crohn disease or ulcerative colitis
Azathioprine crosses the placenta. and receiving TNF blockers (eg, adalimumab, certolizu-
mab pegol, etanercept, golimumab), azathioprine, and/or
Product labeling notes congenital anomalies, immunosup- mercaptopurine. Most cases of HSTCL have occurred in
pression, hematologic toxicities (lymphopenia, pancytope- patients treated with a combination of immunosuppres-
nia), and intrauterine growth retardation from case reports sant agents, although there have been reports of HSTCL
following use in maternal renal allograft recipients. How- in patients-receiving azathioprine or mercaptopurine
ever, intrauterine growth retardation and preterm delivery monotherapy. Renal transplant patients are known to be
are also reported in pregnancies following a kidney trans- at increased risk for malignancy (eg, skin cancer, lym-
plant. Stable immunosuppression is required in pregnant phoma), the risk is increased with aggressive immunosup-
women who have had a kidney transplant and an pression. Limit sun and ultraviolet light exposure and use
increased risk of fetal malformations has not been appropriate sun protection.
observed with azathioprine; lower doses are recom-
mended (Durst 2015; Hou 2013). Dose-related hematologic toxicities (leukopenia, thrombo-
cytopenia, and anemias, including macrocytic anemia
Available guidelines suggest that use of azathioprine is and/or pancytopenia) may occur; may be severe and/or
acceptable for the treatment of rheumatoid arthritis in . delayed. Thiopurine methyltransferase (TPMT) genotyp-
pregnant women (Flint 2016), although use for this indi- ing or phenotyping may help to identify patients who are at
cation is contraindicated by the manufacturer. Azathio- an increased risk for developing azathioprine toxicity.
prine may also be used for the adjunctive treatment of Patients with intermediate TPMT activity may be at
lupus nephritis in pregnant women (Hahn 2012). Women increased risk for hematologic toxicity at conventional
with Crohn disease or ulcerative colitis who are on main- azathioprine doses; patients with low or absent TPMT
tenance therapy with azathioprine may continue treatment activity are at risk for severe, life-threatening myelotoxicity.
during pregnancy (Nguyen 2016). Agents other than Myelosuppression may be more severe with renal trans-
azathioprine are recommended for the treatment of plants undergoing rejection. Monitor CBC with differential
immune thrombocytopenia in pregnant women (Neu- and platelets weekly during the first month, then twice a
nert 2011). month for 2 months, then monthly (or more frequently if
The manufacturer recommends that women of childbear- clinically indicated). May require treatment interruption or
ing potential should avoid becoming pregnant during treat- dose reduction. Leukopenia does not correlate with ther-
ment. Azathioprine is compatible for use in males with apeutic effect and the dose should not be increased
female partners of reproductive potential (Flint 2016). intentionally to lower the white blood cell count.

The Transplant Pregnancy Registry International (TPR) is Chronic immunosuppression increases the risk of serious,
a registry that follows pregnancies that occur in maternal sometimes fatal, infections (bacterial, viral, fungal, proto-
transplant recipients or those fathered by male transplant zoal, and opportunistic) including reactivation of latent
recipients. The TPR encourages reporting of pregnancies infections. Cases of JC virus-associated infection resulting
following solid organ transplant by contacting them at in progressive multifocal leukoencephalopathy (PML),
1-877-955-6877 or https://www.transplantpregnancy- have been reported in patients treated with immunosup-
registry.org. pressants, including azathioprine (some cases have been
Breastfeeding Considerations fatal). Risk factors for PML include treatment with immu-
The azathioprine metabolite 6-mercaptopurine (6-MP) is nosuppressants and immune system impairment. Con-
present in breast milk. sider a diagnosis of PML in any patient presenting with
Azathioprine is a prodrug which is rapidly metabolized to new-onset neurological manifestations; consultation with
6-MP. 6-MP is present in breast milk; however, it is a neurologist as clinically indicated may be warranted.
inactive until further metabolized to 6-TGN metabolites Consider decreasing the degree of immunosuppression
which are present only within red blood cells (Christen- with respect to the risk of organ rejection in transplant
sen 2008; Mottet 2016). Peak concentrations of 6-MP patients.
occur within 4 hours (Christensen 2008). A small study Use with caution in patients with liver disease or renal
measured the active metabolite concentrations in RBCs impairment; monitor hematologic function closely. Azathio-
of four breastfeeding women 23 months' postpartum on prine is metabolized to mercaptopurine; concomitant use
chronic azathioprine therapy. Women in the study had may result in profound myelosuppression and should be
normal thiopurine methyltransferase (TPMT) activity. All avoided. Patients with genetic deficiency of TPMT or
women had therapeutic concentrations of 6-TGN; how- concurrent therapy with drugs which may inhibit TPMT
ever, none of the infants had detectable concentrations are more sensitive to myelosuppressive effects. Patients
(Gardiner 2006). with intermediate TPMT activity may be at risk for
Azathioprine has a theoretical risk of immunosuppression, increased myelosuppression; those with low or absent
carcinogenesis, and growth restriction in a breastfed TPMT activity are at risk for developing severe myelotox-
infant; however, these events have not been confirmed
icity. TPMT genotyping or phenotyping may assist in
in the available small studies (Flint 2016). Due to poten- identifying patients at risk for developing toxicity. Consider
tial for serious adverse reactions in the infant, breast- TPMT testing in patients with abnormally low CBC unre-
feeding is not recommended by the manufacturer. The
sponsive to dose reduction. TPMT testing does not sub-
WHO also recommends breastfeeding be avoided during stitute for CBC monitoring. Guidelines from the Clinical
maternal treatment (WHO 2002). Although there are
Pharmacogenetics Implementation Consortium (CPIC) for
theoretical concerns of adverse events in breastfeeding reduced TPMT activity recommend dose reductions for
infants, other available guidelines do not recommend
patients with heterozygous activity or homozygous defi-
mothers be discouraged from breastfeeding during ther-
ciency (Relling 2011; Relling 2013). Potentially significant
apy (Durst 2015; Flint 2016). If there is concern, discard-
drug-drug interactions may exist, requiring dose or fre-
ing milk collected during the first 4 hours after the
quency adjustment, additional monitoring, and/or selec-
maternal dose would decrease potential exposure to
tion of alternative therapy. Xanthine oxidase inhibitors may
the breastfeeding infant (Huang 2014; Mahadevan
increase risk for hematologic toxicity; reduce azathioprine
2015). Monitoring the infant blood cell count 10 to 15
dose when used concurrently with allopurinol; patients
days after breastfeeding is initiated has also been sug-
with low or absent TPMT activity may require further dose
gested (Bernard 2013).
reductions or discontinuation.
Contraindications Hypersensitivity to azathioprine or any
component of the formulation; pregnancy (in patients with Hepatotoxicity (transaminase, bilirubin, and/or alkaline
rheumatoid arthritis [see Pregnancy Considerations]); phosphatase elevations) may occur, usually in renal trans-
patients with rheumatoid arthritis and a history of treat- plant patients and generally within 6 months of transplant;
ment with alkylating agents (eg, cyclophosphamide, chlor- normally reversible with discontinuation; monitor liver
ambucil, melphalan) may have a prohibitive risk of function periodically. Rarely, hepatic sinusoidal obstruction
malignancy with azathioprine treatment syndrome (SOS; formerly called veno-occlusive disease)

224
 AZATHIOPRINE

has been reported; discontinue if hepatic SOS is sus- NIOSH recommends single gloving for administration of
pected. The frequency of gastrointestinal adverse effects intact tablets or capsules. If manipulating tablets/capsules
(nausea and vomiting) may be decreased with dividing (eg, to prepare an oral suspension), NIOSH recommends
dose or administering after meals. Gastrointestinal hyper- double gloving, a protective gown, and preparation in a
sensitivity with severe nausea and vomiting has been controlled device; if not prepared in a controlled device,
reported; diarrhea, rash, fever, malaise, myalgia, hypo- respiratory and eye/face protection as well as ventilated
tension, and liver enzyme abnormalities may also occur. engineering controls are recommended. NIOSH recom-
Symptoms usually develop within the first several weeks mends double gloving, a protective gown, and (if there is a
of treatment and are generally reversible upon discontin- potential for vomit or spit up) eye/face protection for
uation; may recur upon rechallenge. [US Boxed Warn- administration of an oral liquid/feeding tube administra-
ing]: Should be prescribed by health care providers tion. For IV preparation, NIOSH recommends double
familiar with the risks, including hematologic toxic- gloving, a protective gown, ventilated engineering controls
ities and mutagenic potential. Immune response to (a class || biological safety cabinet or a compounding
vaccines may be diminished. aseptic containment isolator), and closed system transfer
Warnings: Additional Pediatric Considerations The devices (CSTDs) when compounding. Double gloving and
development of secondary hemophagocytic lymphohistio- a gown are required during IV administration (NIOSH
cytosis (HLH), a rare and frequently fatal activation of 2016). Assess risk to determine appropriate containment
macrophages which causes phagocytosis of all bone strategy (USP-NF 2017).
marrow blood cell lines, is increased (100-fold) in pediatric Storage/Stability
patients diagnosed with inflammatory bowel disease due Injection: Store at 20°C to 25°C (68°F to 77°F). Protect
to chronic inflammation; this risk is further increased with from light. Reconstituted solution should be used within
concomitant thiopurine (ie, azathioprine or mercaptopur- 24 hours. ‘
ine) therapy, Epstein-Barr virus, or possibly other infec- Tablet: Store at 15°C to 25°C (59°F to 77°F). Protect from
tions; if patient on thiopurine therapy presents with fever light and moisture.
for at least 5 days, cervical lymphadenopathy, and lym- Mechanism of Action Azathioprine is an imidazolyl
phopenia, discontinue immunosuppressive therapy and derivative of mercaptopurine; metabolites are incorpo-
further diagnostic evaluation for HLH should be per- rated into replicating DNA and halt replication; also block
formed; delay in diagnosis has been associated with the pathway for purine synthesis (Taylor 2005). The 6-
increased mortality (Biank, 2011). thioguanine nucleotide metabolites appear to mediate the
majority of azathioprine’s immunosuppressive and toxic
Adverse Reactions
effects.
Central nervous system: Malaise
Gastrointestinal: Diarrhea, nausea.and vomiting (rheuma-
Pharmacodynamics/Kinetics (Adult data unless
toid arthritis) noted)
Hematologic and oncologic: Leukopenia (more common in Onset of action: Immune thrombocytopenia (oral): Initial
renal transplant), neoplasia (renal transplant), thrombo- response: 30 to 90 days; Peak response: 30 to 120 days
(Neunert 2011)
cytopenia
Absorption: Oral: Well absorbed
Hepatic: Hepatotoxicity, increased serum alkaline phos-
phatase, increased serum bilirubin, increased serum
Protein binding: ~30%
Metabolism: Hepatic; metabolized to 6-mercaptopurine
transaminases
via glutathione S-transferase (GST) reduction. Further
Infection: Increased susceptibility to infection (more com-
metabolized (in the liver and GI tract) via three major
mon in renal transplant; includes bacterial, fungal, pro-
pathways: Hypoxanthine guanine phosphoribosyltrans-
tozoal, viral, opportunistic, and reactivation of latent
ferase (to active metabolites: 6-thioguanine-nucleotides,
infections)
or 6-TGNs), xanthine oxidase (to inactive metabolite: 6-
Neuromuscular & skeletal: Myalgia
thiouric acid), and thiopurine methyltransferase (TPMT)
Miscellaneous: Fever
(to inactive metabolite: 6-methylmercaptopurine)
Rare but important or life-threatening: Abdominal pain, Half-life elimination: Azathioprine and mercaptopurine:
acute myelocytic leukemia, alopecia, anemia, arthralgia,
Variable: ~2 hours (Taylor 2005)
bone marrow depression, hemorrhage, hepatic sinus-
Time to peak: Oral: 1 to 2 hours (including metabolites)
oidal obstruction syndrome (formerly known as hepatic Excretion: Urine (primarily as metabolites)
veno-occlusive disease), hepatosplenic T-cell lympho-
Pharmacodynamics/Kinetics: Additional Consider-
mas, hepatotoxicity (idiosyncratic) (Chalasani, 2014),
ations
hypersensitivity, hypotension, interstitial pneumonitis
Renal function impairment: Clearance (azathioprine and
(reversible), JC virus infection, macrocytic anemia,
metabolites) may be delayed in oliguric patients, partic-
malignant lymphoma, malignant neoplasm of skin, neg-
ularly in those with tubular necrosis in the immediate
ative nitrogen balance, pancreatitis, pancytopenia, pro-
post-transplant phase (cadaveric transplant).
gressive multifocal leukoencephalopathy, skin rash, Dosing
steatorrhea, Sweet's syndrome (acute febrile neutro-
Pediatric Note: Patients with intermediate TPMT activity
philic dermatosis)
may be at risk for increased myelosuppression; those
Drug Interactions with low or absent TPMT activity receiving conventional
Metabolism/Transport Effects None known. azathioprine doses are at risk for developing severe, life-
Avoid Concomitant Use threatening myelotoxicity. Dosage reductions are recom-
Avoid concomitant use of AzaTHI/Oprine with any of the mended for patients with reduced TPMT activity. Intra-
following: BCG (\Intravesical); Febuxostat; Mercaptopur- venous (IV) dose is equivalent to oral dose (dosing
ine; Natalizumab; Pimecrolimus; Tacrolimus (Topical) should be transitioned from IV to oral as soon as
Increased Effect/Toxicity tolerated).
AzaTHlOprine may increase the levels/effects of: Bar- Hepatitis, autoimmune: Limited data available: Chil-
icitinib; Cyclophosphamide; Fingolimod; Leflunomide; dren and Adolescents: Oral: Initial: 0.5 mg/kg/dose
Mercaptopurine; Natalizumab; Tofacitinib; Vaccines once daily; titrate as needed up to 2 mg/kg/dose once
(Live) daily; for long-term therapy, a low-dose of 1 to
1.5 mg/kg/day may be effective in some patients
The levels/effects of AzaTH/Oprine may be increased
(Della Corte, 2012; Vitfell-Pedersen, 2012)
by: 5-Aminosalicylic Acid Derivatives; Allopurinol; Angio-
Inflammatory bowel disease: Limited data available:
tensin-Converting Enzyme Inhibitors; Anti-TNF Agents;
Infants, Children, and Adolescents: Oral: 2 to
Denosumab; Febuxostat; InFLIXimab; Ocrelizumab;
2.5 mg/kg/dose once daily; titrate to effect; usual
Pimecrolimus; Ribavirin (Oral Inhalation); Ribavirin (Sys-
reported range: 1 to 3 mg/kg/dose once daily;
temic); Roflumilast; Sulfamethoxazole; Tacrolimus (Top-
reported maximum daily dose: 4 mg/kg/day or
ical); Trastuzumab; Trimethoprim 200 mg/day; may takes several weeks of therapy to
Decreased Effect be fully effective (Fuentes, 2003; Punati, 2011; Riello,
AzaTHlOprine may decrease the levels/effects of: BCG 2011; Sandhu, 2010). Some data suggest that pedia-
(Intravesical); Coccidioides immitis Skin Test; Nivolu- tric patients <6 years may require higher doses to
mab; Pidotimod; Sipuleucel-T; Tertomotide; Vaccines achieve remission; a median dose of 3.51 mg/kg/day
(Inactivated); Vaccines (Live); Vitamin K Antagonists (maximum daily dose: 5 mg/kg/day) was reported to
The levels/effects of AzaTH/Oprine may be decreased induce remission in 62% of patients $6 years of age
by: Echinacea vs 17% of those receiving lower doses (ie, <2 to
Hazardous Drugs Handling Considerations 3 mg/kg/day study group; median dose: 2.46 mg/kg/
day) (Grossman, 2008).
Hazardous agent (NIOSH 2016 [group 2)).
Immune thrombocytopenia (ITP), chronic refrac-
Use appropriate precautions for receiving, handling, tory: Limited data available: Children 22 years and
administration, and disposal. Gloves (single) should be Adolescents: Oral: Maintenance: 2 to 2.5 mg/kg/day,
worn during receiving, unpacking, and placing in storage. rounded to the nearest 50 mg (Boruchov, 2007) >
 AZATHIOPRINE

< Juvenile-idiopathic arthritis (rheumatoid arthritis):

Limited data available: Children and Adolescents:
Imuran: 50 mg [scored]
Generic: 50 mg
Oral: 2 to 2.5 mg/kg/dose once daily; data limited to Extemporaneous Preparations
single double-blind, placebo-controlled trial of pedia- A 50 mg/mL oral suspension may be prepared with tab-
tric patients (n=17 treatment group); efficacy results lets. Crush one-hundred-twenty 50 mg tablets in a mortar
were not statistically significant (response rate: Treat- and reduce to a fine powder. Add 40 mL of either cherry
ment: 41% vs placebo: 27%); data suggested a syrup (diluted 1:4 with Simple Syrup, USP); a 1:1 mixture
minimum trial of 12 weeks to fully assess therapeutic of Ora-Sweet and Ora-Plus; or a 1:1 mixture of Ora-Sweet
response (AHRQ, 2011; Hashkes, 2005; Kvien, 1986) SF and Ora-Plus, and mix toa uniform paste. Mix while
Lupus nephritis, mild: Limited data available: Chil- adding the vehicle in incremental proportions to almost
dren and Adolescents: Oral: 2 to 2.5 mg/kg/dose once 120 mL; transfer to a calibrated bottle, rinse mortar with
daily (Bertsias, 2012; Marks, 2010); Note: Some data vehicle, and add quantity of vehicle sufficient to make 120
suggest less effective in non-Caucasian pediatric mL. Label "shake well", "refrigerate", and “protect from
patients; some centers recommend use for primary light". Stable for 60 days refrigerated.
induction in Caucasian patients with less severe dis- Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopur-
ease (Adams, 2006; Marks, 2010). inol, Azathioprine, Clonazepam, and Flucytosine in Extemporane-
Myasthenia gravis, juvenile: Limited data available: ously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53
(16):1944-9.
Children and Adolescents: Oral: 1 to 3 mg/kg/dose
once daily (Ashraf, 2006; Lindner, 1997) Azathioprine Sodium see AzaTHlOprine on page 223
Transplantation, solid organ: Limited data available:
Infants, Children, and Adolescents: Oral: Initial: 3 to
@ 5-AZC see AzaClTIDine on page 221
5 mg/kg/dose once daily, beginning at the time of
transplant; maintenance: 1 to 3 mg/kg/dose once Azelaic Acid (a zeh LAY ik AS id)
daily (Denfield, 2010; Ford, 2006)
Uveitis, JIA-associated: Limited data available: Chil- Brand Names: US Azelex; Finacea
dren and Adolescents: Oral: Initial mean dose: Brand Names: Canada Finacea
2.4 mg/kg/dose once daily; reported range: 1.4 to Therapeutic Category Acne Products
3.2 mg/kg/dose once daily; in a retrospective review Generic Availability (US) No
of 41 children, a mean maintenance 2.1 mg/kg/dose Use Topical:
(range: 1 to 2.8 mg/kg/dose) once daily was reported Cream 20%: Azelex: Treatment of mild to moderate
as monotherapy and/or in combination with other inflammatory acne vulgaris (FDA approved in ages 212
immunosuppressive agents; infectious etiology was years and adults)
excluded; the authors recommend doses of Foam 15%: Finacea: Treatment of inflammatory papules
<3 mg/kg/day (Goebel, 2011) and pustules of mild to moderate rosacea (FDA
Dosage adjustment for concomitant use with allo- approved in ages 218 years and adults)
purinol: In pediatric patients, limited data is available; Gel 15%: Finacea: Treatment of inflammatory papules and
in adult patients, the following has been suggested: pustules of mild to moderate rosacea (FDA approved in
Reduce azathioprine dose to one-third or one-fourth adults)
the usual dose when used concurrently with allopurinol.
Pregnancy Risk Factor B
Patients with low or absent TPMT activity may require
Pregnancy Considerations Adverse events have been
further dose reductions or discontinuation.
observed in animal reproduction studies following oral
Dosage adjustment for toxicity: In pediatric patients,
administration. The amount of azelaic acid available sys-
limited data is available, in adult patients the following
temically following topical administration is minimal (<4%).
has been suggested:
Rapid WBC count decrease, persistently low WBC Breastfeeding Considerations It is not known if azelaic
count, or serious infection: Reduce dose or tempora- acid is excreted in breast milk. The amount of azelaic acid
rily withhold treatment. available systemically following topical administration is
Severe toxicity in renal transplantation: May require minimal (<4%); a significant change from baseline azelaic
discontinuation. acid levels in the milk is not expected. The manufacturer
Hepatic sinusoidal obstruction syndrome (SOS; veno- of the cream recommends that caution be exercised when
occlusive disease): Permanently discontinue. administering azelaic acid to nursing women. The manu-
Renal Impairment: Pediatric facturers of the gel and foam recommend a decision be
Infants, Children, and Adolescents (Aronoff, 2007): made whether to discontinue nursing or to discontinue the
GFR >50 mL/minute/1.73m?: No adjustment required. drug, taking into account the importance of treatment to
GFR 10 to 50 mL/minute/1.73m?: Administer 75% of the mother.
dose once daily. Contraindications
GFR <10 mL/minute/1.73m?: Administer 50% of dose Cream: Hypersensitivity to azelaic acid or any component
once daily. of the formulation
Hemodialysis (dialyzable; ~45% removed in 8 hours): Foam, gel: There are no contraindications listed in the
Administer 50% of normal dose once daily. manufacturer's labeling
CAPD: Administer 50% of normal dose once daily. Warnings/Precautions For external use only; not for
CRRT: Administer 75% of normal dose once daily. oral, ophthalmic, or vaginal use; avoid contact with the
Hepatic Impairment: Pediatric There are no dosage eyes, mouth, and other mucous membranes. Hypersensi-
adjustments provided in the manufacturer’s labeling. tivity reactions (eg, angioedema, dyspnea, eye swelling,
Administration Oral: Administer with food or may admin- facial swelling, skin reactions, urticaria) have been
ister in divided doses to decrease GI upset. reported; discontinue use if signs/symptoms occur. A
Monitoring Parameters CBC with differential and plate- few cases of hypopigmentation after use have been
lets (weekly during first month, twice monthly for months 2 reported; monitor for changes in skin color, especially in
and 3, then monthly; monitor more frequently with dosage patients with dark complexions. Skin irritation (eg, pruritus,
modifications), total bilirubin, liver function tests, creatinine burning, stinging) may occur, usually during the first few
clearance, TPMT genotyping or phenotyping (consider weeks of therapy. Discontinue use if severe skin irritation
TPMT testing in patients with abnormally low CBC unre- or sensitivity occurs. Use of occlusive dressings or wrap-
sponsive to dose reduction); monitor for.symptoms of pings should be avoided. Reassess use if no improvement
infection is seen after 12 weeks of therapy. Exacerbation of asthma
has been reported.
For use as immunomodulatory therapy in inflammatory
bowel disease (Crohn disease or ulcerative colitis), mon- The foam dosage form contains flammable propellants.
itor CBC with differential weekly for 1 month, then Avoid fire, flame and smoking during and immediately
biweekly for 1 month, followed by monitoring every 1-2 following use. Some dosage forms may contain polysor-
months throughout the course of therapy; monitor more bate 80 (also known as Tweens). Hypersensitivity reac-
frequently if symptomatic. LFTs should be assessed every tions, usually a delayed reaction, have been reported
3 months. Monitor for signs/symptoms of malignancy (eg, following exposure to pharmaceutical products containing
splenomegaly, hepatomegaly, abdominal pain, persistent polysorbate 80 in certain individuals (Isaksson 2002;
fever, night sweats, weight loss). Lucente 2000; Shelley 1995). Thrombocytopenia, ascites,
Test Interactions TPMT phenotyping results may not be pulmonary deterioration, and renal and hepatic failure
accurate following recent blood transfusions. have been reported in premature neonates after receiving
Dosage Forms Excipient information presented when parenteral products containing polysorbate 80 (Alade
available (limited, particularly for generics); consult spe- 1986; CDC 1984). See manufacturer's labeling.
cific product labeling. Warnings: Additional Pediatric Considerations
Solution Reconstituted, Injection: Some dosage forms may contain propylene glycol; in
Generic: 100 mg (1 ea) neonates large amounts of propylene glycol delivered
Tablet, Oral: orally, intravenously (eg, >3,000 mg/day), or topically
Azasan: 75 mg, 100 mg [scored] have been associated with potentially fatal toxicities which
 AZELASTINE (NASAL)

can include metabolic acidosis, seizures, renal failure, and Generic Availability (US) Yes
CNS depression; toxicities have also been reported in Use
children and adults including hyperosmolality, lactic acido- 0.1% solution: Treatment of the symptoms of perennial
sis, seizures and respiratory depression; use caution allergic rhinitis (Astepro: FDA approved in ages 26
(AAP 1997; Shehab 2009). months through 11 years), seasonal allergic rhinitis
Adverse Reactions (FDA approved in ages 22 years and adults), and vaso-
Dermatologic: Acne (gel), burning sensation of skin, con- motor rhinitis (FDA approved in ages 212 years and
tact dermatitis, desquamation, erythema, pruritus, skin adults); Note: Approved pediatric age ranges and uses
irritation, stinging of skin, tingling of skin, xeroderma, for generic products may vary; consult labeling for spe-
xerosis cific information.
Local: Application site pain, application site pruritus 0.15% solution: Treatment of the symptoms of perennial
Rare but important or life-threatening: Edema, exacerba- allergic rhinitis and seasonal allergic rhinitis (FDA
tion of asthma, exacerbation of herpes labialis, hyper- approved in ages 26 years and adults); Note: Approved
sensitivity reaction, hypertrichosis, hypopigmentation, pediatric age ranges and uses for generic products may
iridocyclitis, vitiligo vary; consult labeling for specific information.
Drug Interactions Pregnancy Risk Factor C
Metabolism/Transport Effects None known. Pregnancy Considerations Adverse events have been
Avoid Concomitant Use There are no known interac- observed in some animal reproduction studies. Azelastine
tions where it is recommended to avoid concomitant use. is systemically absorbed following nasal inhalation and
Increased Effect/Toxicity There are no known signifi- may have side effects similar to other antihistamines.
cant interactions involving an increase in effect. However, data related to the use of azelastine in preg-
Decreased Effect There are no known significant inter- nancy is limited; if treatment for rhinitis in a pregnant
actions involving a decrease in effect. woman is needed, other agents are preferred (Wallace
Storage/Stability 2008).
Store at 15°C to 30°C (59°F to 86°F); do not freeze. Store Breastfeeding Considerations It is not known if azelas-
cream on its side. Discard the gel pump 8 weeks after tine (nasal) is excreted in breast milk. The manufacturer
opening. recommends that caution be exercised when administer-
Foam: Store at 25°C (77°F); excursions are permitted ing azelastine (nasal) to nursing women.
between 15°C and 30°C (59°F and 86°F). Flammable; Contraindications There are no contraindications listed
avoid fire, flame, or smoking during and immediately in the manufacturer's labeling.
following application. Contents under pressure. Do not Warnings/Precautions May cause CNS depression,
puncture or incinerate. Do not expose to heat or store at which may impair physical or mental abilities; patients
temperatures above 49°C (120°F). Discard 8 weeks after must be cautioned about performing tasks that require
Opening. mental alertness (eg, operating machinery or driving).
Mechanism of Action Azelaic acid is a dietary constitu- Potentially significant interactions may exist, requiring
ent normally found in whole grain cereals; can be formed dose or frequency adjustment, additional monitoring,
endogenously. Exact mechanism is not known. /n vitro, and/or selection of alternative therapy.
azelaic acid possesses antimicrobial activity against Cuti- Adverse Reactions Adverse reactions may be dose-,
bacterium acnes and Staphylococcus epidermidis. May indication-, or product-dependent:
decrease microcomedo formation. Cardiovascular: Flushing, hypertension, tachycardia
Pharmacodynamics/Kinetics (Adult data unless Central nervous system: Abnormality in thinking, anxiety,
noted) bitter taste, depersonalization, depression, dizziness,
Onset of action (cream): Within 4 weeks drowsiness, dysesthesia, fatigue, headache, hypoesthe-
Absorption: Cream: ~3% to 5% penetrates stratum cor- sia, malaise, nervousness, sleep disorder, vertigo
neum; up to 10% found in epidermis and dermis; 4% Dermatologic: Contact dermatitis, eczema, folliculitis,
systemic furunculosis
Metabolism: Negligible after topical application; some Endocrine & metabolic: Albuminuria, amenorrhea,
beta-oxidation to shorter chain dicarboxylic acids weight gain
Half-life elimination: Topical: Healthy subjects: 12 hours Gastrointestinal: Abdominal pain, ageusia, aphthous sto-
Excretion: Urine (primarily as unchanged drug) matitis, constipation, diarrhea, dysgeusia (children), gas-
Dosing troenteritis, glossitis, increased appetite, nausea,
Pediatric Acne vulgaris: Children 212 years and Ado- toothache, vomiting, xerostomia
lescents: Cream (Azelex 20%): Topical: Apply a thin film Genitourinary: Hematuria, mastalgia
to affected, area(s) twice daily, in the morning and eve- Hepatic: Increased serum ALT
ning; may reduce to once daily if persistent skin irritation Hypersensitivity: Hypersensitivity reaction
occurs Infection: Cold symptoms (children), herpes simplex infec-
Renal Impairment: Pediatric There are no dosage tion, upper respiratory tract infection (children), viral
adjustments provided in the manufacturer’s labeling; infection
however, dosage adjustment unlikely needed due to Neuromuscular & skeletal: Back pain, dislocation of tem-
low systemic absorption. poromandibular joint, hyperkinesia, limb pain, myalgia,
Hepatic Impairment: Pediatric There are no dosage rheumatoid arthritis
adjustments provided in the manufacturer’s labeling; Ophthalmic: Conjunctivitis, eye pain, watery eyes
however, dosage adjustment unlikely needed due to Otic: Otitis media (infants and children)
low systemic absorption. Renal: Polyuria
Administration Topical: Apply a thin film and gently Respiratory: Asthma, bronchitis, bronchospasm, burning
massage into to clean, dry skin; wash hands following sensation of the nose, cough (more common in older
application. Avoid the use of occlusive dressings or wrap- children than infants and young children), epistaxis,
pings. For gel and foam formulation, cosmetics may be laryngitis, nasal congestion, nasal discomfort, nasal
applied after the gel has dried. Use only mild soaps or mucosa ulcer, paranasal sinus hypersecretion, paroxys-
soapless cleansing lotion for facial cleansing. For foam mal nocturnal dyspnea, pharyngolaryngeal pain, phar-
formulation, shake well before use. Not intended for intra- yngitis, postnasal drip, rhinitis (exacerbation), sinusitis,
vaginal, ophthalmic, or oral use. sneezing, sore nose (infants and children), sore throat
Monitoring Parameters Reduction in lesion size and/or Miscellaneous: Fever, laceration
inflammation; reduction in the number of lesions Rare but important or life-threatening: Altered sense of
Dosage Forms Excipient information presented when smell, anaphylactoid reaction, anosmia, atrial fibrillation,
available (limited, particularly for generics); consult spe- chest pain, confusion, drug tolerance, increased serum
cific product labeling. transaminases, insomnia, muscle spasm, urinary reten-
Cream, External: tion, xerophthalmia
Azelex: 20% (30 g, 50 g) Drug Interactions
Foam, External: Metabolism/Transport Effects Substrate of CYP1A2
Finacea: 15% (50 g) [contains benzoic acid, cetostearyl (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4
alcohol, polysorbate 80, propylene glycol] (minor); Note: Assignment of Major/Minor substrate sta-
Gel, External: tus based on clinically relevant drug interaction potential
Finacea: 15% (50 g) {contains benzoic acid, disodium Avoid Concomitant Use
edta, polysorbate 80, propylene glycol] Avoid concomitant use of Azelastine (Nasal) with any of
the following: Alcohol (Ethyl); CNS Depressants
Azelastine (Nasal) (a ZEL as teen) Increased Effect/Toxicity
The levels/effects of Azelastine (Nasal) may be
Brand Names: US) Astepro increased by: Alcohol (Ethyl); CNS Depressants
Brand Names: Canada Astelin ; Decreased Effect There are no known significant inter-
Therapeutic Category Antihistamine, Nasal actions involving a decrease in effect.

227
 AZELASTINE (NASAL)

€ Storage/Stability Store upright at 20°C to 25°C (68°F to Breastfeeding Considerations It is not known if azelas-
77°F); protect from freezing. tine (ophthalmic) is excreted in breast milk. The manufac-
Mechanism of Action Competes with histamine for H,- turer recommends-that caution be exercised when
receptor sites on effector cells and inhibits the release of administering azelastine (ophthalmic) to nursing women.
histamine and other mediators involved in the allergic Contraindications Hypersensitivity to azelastine or any
response; when used intranasally, reduces hyper-reactiv- component of the formulation
ity of the airways; increases the motility of bronchial Warnings/Precautions Solution contains benzalkonium
epithelial cilia, improving mucociliary transport chloride; wait at least 10 minutes after instilling solution
Pharmacodynamics/Kinetics (Adult data unless before inserting soft contact lenses. Do not use contact
noted) lenses if eyes are red.
Onset of action: 15 to 30 minutes (Wallace 2008); max- Adverse Reactions
imum effect: 3 hours Central nervous system: Fatigue, headache
Duration: 12 hours Dermatologic: Pruritus
Distribution: Vg: 14.5 L/kg Gastrointestinal: Bitter taste
Protein binding: Azelastine:- ~88%; Desmethylazelas- Ocular: Blurred vision (temporary), conjunctivitis, eye
tine: ~97% pain, transient burning/stinging
Metabolism: Hepatic via CYP; active metabolite, desme- Respiratory: Asthma, dyspnea, pharyngitis, rhinitis
thylazelastine Miscellaneous: Flu-like syndrome
Bioavailability: ~40% Drug Interactions
Half-life elimination: Azelastine: 22 hours (0.1% solution),
Metabolism/Transport Effects None known.
25 hours (0.15% solution) to 25 hours; Desmethylazelas-
Avoid Concomitant Use There are no known interac-
tine: 52 hours (0.1% solution), 57 hours (0.15% solution)
tions where it is recommended to avoid concomitant use.
Time to peak, serum: 2 to 3 hours (Azelastine [generic]
0.1% solution); 3 to 4 hours (Astepro) Increased Effect/Toxicity There are no known signifi-
Excretion: Feces (75%, <10% as unchanged drug) cant interactions involving an increase in effect.
Clearance: 0.5 L/hour/kg Decreased Effect There are no known significant inter-
Dosing actions involving a decrease in effect.
Pediatric Storage/Stability Store upright at controlled room tem- —
Perennial allergic rhinitis: Intranasal: perature of 2°C to 25°C (36°F to 77°F).
Infants 26 months and Children <6 years: 0.1% sol- Mechanism of Action Competes with histamine for H,-
ution: 1 spray per nostril twice daily. receptor sites on effector cells and inhibits the release of
Children 6 to <12 years: 0.1% or 0.15% solution: 1 histamine and other mediators involved in the allergic
spray per nostril twice daily response
Children 212 years and Adolescents: 0.15% solution: Pharmacodynamics/Kinetics (Adult data unless
2 sprays per nostril twice daily noted)
Seasonal allergic rhinitis: Intranasal: Onset of action: Peak effect: 3 minutes
Children 2 to <6 years: 0.1% solution: 1 spray per Duration: 8 hours
nostril twice daily Absorption: Plasma concentrations following ocular
Children 6 to <12 years: 0.1% or 0.15% solution: 1 administration are low for azelastine (0.02-0.25 ng/mL)
spray per nostril twice daily and n-desmethylazelastine (0.25-0.87 ng/mL)
Children 212 years and Adolescents: Dosing
0.1% solution: 1 or 2 sprays per nostril twice daily Pediatric Seasonal allergic conjunctivitis: Children =3
0.15% solution: 1 or 2 sprays per nostril twice daily years and Adolescents: Ophthalmic: Instill 1 drop into
or 2 sprays per nostril once daily affected eye(s) twice daily
Vasomotor rhinitis: Intranasal: Children 212 years
Renal Impairment: Pediatric There are no dosage
and Adolescents: 0.1% solution: 2 sprays per nostril
adjustments provided in the manufacturer's labeling;
twice daily
however, dosage adjustment unlikely needed due to
Renal Impairment: Pediatric There are no dosage low systemic absorption.
adjustments provided in the manufacturer's labeling.
Hepatic Impairment: Pediatric There are no dosage
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer's labeling;
adjustments provided in the manufacturer's labeling.
however, dosage adjustment unlikely needed due to
Administration Before initial use, the delivery system
low systemic absorption.
should be primed until a fine mist appears; when 3 or
Administration Do not allow the bottle tip to touch any
more days have elapsed since the last use, the pump
surface, the eyelids, or surrounding areas. Apply gentle
should be reprimed until a fine mist appears. Blow nose to
pressure to lacrimal sac during and immediately following
clear nostrils. Remove the dust cover. Keep head tilted
downward when spraying. Insert applicator into nostril,
instillation (1 minute) or instruct patient to gently close
keeping bottle upright, and close off the other nostril. eyelid after administration, to decrease systemic absorp-
Breathe in through nose. While inhaling, press pump to tion of ophthalmic drops (Urtti 1993; Zimmerman 1982).
release spray. Alternate sprays between nostrils. After Patients should not wear contact lenses if their eye is red.
each use, wipe the spray tip with a clean tissue or cloth. For contact lens users whose eyes are not red, wait at
Avoid spraying in eyes or mouth. least 10 minutes after instilling medication to insert contact
Dosage Forms Considerations Astelin and Astepro 30 lenses.
mL bottles contain 200 sprays each. Dosage Forms Excipient information presented when
Dosage Forms Excipient information presented when available (limited, particularly for generics); consult spe-
available (limited, particularly for generics); consult spe- cific product labeling. [DSC] = Discontinued product
cific product labeling. Solution, Ophthalmic, as hydrochloride:
Solution, Nasal, as hydrochloride: Optivar: 0.05% (6 mL [DSC]) [contains benzalkonium
Astepro: 0.15% (30 mL) [contains benzalkonium chlor- chloride]
ide, edetate disodium] Generic: 0.05% (6 mL)
Generic: 137 mcg/spray (30 mL); 0.1% (30 mL); 0.15%
(30 mL) Azelastine and Fluticasone-
(a ZEL as teen & floo TIK a sone)
Azelastine (Ophthalmic) (a ze. as teen) Brand Names: US Dymista; Ticalast
Medication Safety Issues Brand Names: Canada Dymista
Sound-alike/look-alike issues: Therapeutic Category Corticosteroid, Nasal; Histamine
Optivar may be confused with Optiray, Optive H, Antagonist, Second Generation
International issues: Generic Availability (US) No
Optivar [US] may be confused with Opthavir brand name Use Symptomatic relief of seasonal allergic rhinitis (FDA
for acyclovir [Mexico] approved in ages 26 years and adults)
Brand Names: US Optivar [DSC] Pregnancy Risk Factor C
Therapeutic Category Antiallergic, Ophthalmic Pregnancy Considerations Adverse events have been
Generic Availability (US) Yes observed in animal reproduction studies. Refer to individ-
Use Treatment of itching of the eye associated with allergic ual monographs.
conjunctivitis (FDA approved in ages 23 years and adults) Breastfeeding Considerations It is not known if azelas-
Pregnancy Risk Factor C tine or fluticasone are excreted in breast milk. The man-
Pregnancy Considerations Animal reproduction studies ufacturer recommends that caution be exercised when
have shown toxic effects to the fetus at maternally toxic administering azelastine and fluticasone to nursing
doses. women. Refer to individual monographs.

228
 AZITHROMYCIN (SYSTEMIC)

Contraindications Insert applicator tip 1/4 to /2 inch into nostril, Keeping bottle
There are no contraindications listed in the US labeling. upright, and close off the other nostril. Breathe in through
Canadian labeling: Hypersensitivity to azelastine, flutica- nose. While inhaling, press pump to release spray. After
sone, or any component of the formulation; untreated each use, wipe the spray tip with a clean tissue or cloth
fungal, bacterial, or tuberculosis infections of the respi- and replace cap. Avoid spraying directly into nasal sep-
ratory tract. tum, eyes or mouth. Discard after 120 medicated sprays
Warnings/Precautions See individual agents, have been used (do not count initial priming sprays), even
if bottle is not completely empty.
Warnings: Additional Pediatric Considerations In a Monitoring Parameters Mucous membranes for signs of
small pediatric study of fluticasone use conducted over 1 fungal infection, growth (pediatric patients), signs/symp-
year, no statistically significant effect on growth velocity or toms of HPA axis suppression/adrenal insufficiency; ocu-
clinically relevant changes in bone mineral density or HPA lar changes; possible eosinophilic conditions (including
axis function were observed in children 3 to 9 years of age Churg-Strauss syndrome)
receiving. fluticasone propionate nasal spray (200 mcg/
Additional Information When used short term as adjunc-
day; n=56) versus placebo (n=52); effects at higher doses
tive therapy in acute bacterial rhinosinusitis (ABRS), intra-
or in susceptible pediatric patients cannot be ruled out.
nasal steroids show modest symptomatic improvement
Adverse Reactions Reactions reported with combination and few adverse effects, improvement is primarily due to
product; also see individual agents. increased sinus drainage. Use should be considered
Central nervous system: Headache optional in ABRS; however, intranasal corticosteroids
Gastrointestinal: Dysgeusia should be routinely prescribed to ABRS patients who have
Respiratory: Epistaxis (frequency and severity may be a history of or concurrent allergic rhinitis (Chow, 2012).
, increased in children) Dosage Forms Considerations Dymista 23 g bottles
Rare but important or life-threatening: Abnormality in contain 120 metered sprays.
fhinking, anosmia, anxiety, application site irritation, atrial Dosage Forms Excipient information presented when
fibrillation, blurred vision, bronchospasm, burning sensa- available (limited, particularly for generics); consult spe-
tion, cataract, chest pain, confusion, conjunctivitis, diar- cific product labeling.
rhea, dizziness, drowsiness, drug tolerance, dry nose, Kit, Nasal:
dry throat, dyspnea, erythema, generalized ache, glau- Ticalast: Azelastine hydrochloride 0.1% [137 mcg/spray]
coma, hoarseness, hypersensitivity reaction, hyperten- and fluticasone propionate 0.037% [50 mcg/spray]
sion, increased heart rate, increased intraocular (23 g) & sterile saline wash (117 mL) [contains benzal-
pressure, insomnia (initial), muscle spasm, nasal konium chloride; 120 metered sprays]
obstruction, nasal septum perforation, nasal sores, nerv- Suspension, Nasal:
ousness, palpitations, paresthesia, restlessness, seda- Dymista: Azelastine hydrochloride 0.1% [137 mcg/spray]
tion, skin rash, sore throat, swelling of eye, therapeutic and fluticasone propionate 0.037% [50 mcg/spray]
response unexpected, urinary retention, vertigo, visual (23 g) [contains benzalkonium chloride; 120 metered
disturbance, weight loss, xerophthalmia sprays]
Drug Interactions
@ Azelastine/Fluticasone see Azelastine and Fluticasone
Metabolism/Transport Effects Refer to individual on page 228
components.
® Azelastine HCI see Azelastine (Nasal) on page 227
Avoid Concomitant Use
Avoid concomitant use of Azelastine and Fluticasone @ Azelastine HCI see Azelastine (Ophthalmic)
with any of the following: Alcohol (Ethyl); CNS Depres- on page 228
sants; CYP3A4 Inhibitors (Strong); Desmopressin @ Azelastine Hydrochloride see Azelastine (Nasal)
Increased Effect/Toxicity on page 227
Azelastine and Fluticasone may increase the levels/ @ Azelastine Hydrochloride see Azelastine (Ophthalmic)
effects of: Ceritinib; Desmopressin; Ritodrine on page 228
The levels/effects of Azelastine and Fluticasone may be @ Azelex see Azelaic Acid on page 226
increased by: Alcohol (Ethyl); CNS Depressants; @ Azidothymidine see Zidovudine on page 2083
CYP3A4 Inhibitors (Strong) @ Azidothymidine, Abacavir, and Lamivudine see Aba-
Decreased Effect There are no known significant inter- cavir, Lamivudine, and Zidovudine on page 30
actions involving a decrease in effect.
Storage/Stability Store at 20°C to 25°C (68°F to 77°F); Azithromycin (Systemic) (az ith roe MYE sin)
do not refrigerate or freeze. Protect from light. Store in
upright position with cap on. Medication Safety Issues
Mechanism of Action Azelastine competes with hista- Sound-alike/look-alike issues:
mine for H, receptor sites on effector cells-and-inhibits the Azithromycin may be confused with azathioprine, eryth-
release of histamine and other mediators involved in the romycin
allergic response; when used intranasally, reduces hyper- Zithromax may be confused with Fosamax, Zinacef,
reactivity of the airways; increases the motility of bronchial Zovirax
epithelial cilia, improving mucociliary transport. Related Information
Relative Infant Dose on page 2207
Fluticasone belongs to a group of corticosteroids which
Brand Names: US Zithromax; Zithromax Tri-Pak; Zithro-
utilizes a fluorocarbothioate ester linkage at the 17 carbon
max Z-Pak; Zmax
position; extremely potent vasoconstrictive and anti-
Brand Names: Canada Zithromax; Zmax SR
inflammatory activity.
Therapeutic Category Antibiotic, Macrolide
Pharmacodynamics/Kinetics (Adult data unless Generic Availability (US) Yes
noted) See individual agents. Use
Dosing Oral:
Pediatric Immediate release; oral suspension, tablets: Treatment
Seasonal allergic rhinitis: of acute otitis media due to H. influenzae, M. catarrha-
Children 4 to 5 years: Limited data available; efficacy lis, or S. pneumoniae (FDA approved in pediatric
not established: Intranasal: 1 spray (137 mcg azelas- patient ages 26 months); treatment of pharyngitis/ton-
tine/50 mcg fluticasone) per nostril twice daily was sillitis due to S. pyogenes (FDA approved in ages 22
evaluated in 61 patients as part of a larger pediatric years and adults); treatment of community-acquired
trial, data did not fully establish efficacy; safety profile pneumonia due to susceptible organisms, including
similar to older children (NCT01915823, 2014) C. pneumoniae, M. pneumoniae, H. influenzae, S.
Children 26 years and Adolescents: Intranasal: 1 spray pneumoniae (FDA approved in ages 26 months and
(137 meg azelastine/50 mcg fluticasone) per nostril adults). [Oral azithromycin is not indicated for use in
twice daily patients with pneumonia who have moderate to severe
disease and judged to be inappropriate for oral therapy
Renal Impairment: Pediatric There are no dosage
or have any risk factors such as cystic fibrosis, noso-
adjustments provided in the manufacturer's labeling.
comial infection, known or suspected bacteremia, hos-
Hepatic Impairment: Pediatric There are no dosage pitalization, elderly or debilitated patients, or patients
adjustments provided in the manufacturer's labeling. with significant underlying health problems that may
Administration For intranasal administration only. Prime compromise their ability to respond to their illness
pump (press 6 times or until fine spray appears) prior to (including immunodeficiency or functional asplenia)];
first use. If 14 or more days have elapsed since last use, treatment of sinusitis or COPD exacerbation due to H.
then reprime pump with 1 spray or until a fine mist influenzae, M. catarrhalis, or S. pneumoniae (FDA
appears. Shake bottle gently before using. Blow nose to
clear nostrils. Keep head tilted downward when spraying.
approved in adults); treatment of infections of the skin
and skin structure, acute pelvic inflammatory disease, >
229
 AZITHROMYCIN (SYSTEMIC)

| chancroid, and urethritis and cervicitis due to suscep-

tible strains of C. trachomatis, N. gonorrhoeae, M.
syndrome, toxic epidermal necrolysis and drug reaction
with eosinophilia and systemic symptoms [DRESS]) have
catarrhalis, H. influenzae, S. aureus, S. pyogenes, S. been reported (rare), including fatalities; reappearance of
pneumoniae, Mycoplasma pneumoniae, M. avium allergic reaction may occur shortly after discontinuation
complex, C. psittaci, and C. pneumoniae (FDA without further azithromycin exposure. May mask or delay
approved in adults). Has also been used for treatment symptoms of incubating gonorrhea or syphilis, so appro-
of babesiosis, pertussis, endocarditis prophylaxis in priate culture and susceptibility tests should be performed
penicillin allergic patients, for prophylaxis of peritonitis prior to initiating a treatment regimen. Prolonged use may
in patients undergoing invasive dental procedures, and result in fungal or bacterial superinfection, including C.
cystic fibrosis lung disease difficile-associated diarrhea (CDAD); CDAD has been
Extended release (Zmax); oral suspension: Treatment of observed >2 months postantibiotic treatment. Use caution
community-acquired pneumonia due to C. pneumo- with renal dysfunction. Macrolides (especially erythromy-
niae, M. pneumoniae, H. influenzae, S. pneumonia cin) have been associated with rare QT, prolongation and
(FDA approved in ages 26 months and adults); treat- ventricular arrhythmias, including torsade de pointes; con-
ment of acute bacterial sinusitis due to H. influenzae, sider avoiding use in patients with prolonged QT interval,
M. catarrhalis, or S. pneumoniae (FDA approved in congenital long QT syndrome, history of torsade de
adults) pointes, bradyarrhythmias, uncorrected hypokalemia or
Parenteral: Treatment of community-acquired pneumonia hypomagnesemia, clinically significant bradycardia,
due to susceptible C. pneumoniae, L. pneumophila, M. uncompensated heart failure, or concurrent use of Class
pneumoniae, H. influenzae, S. aureus, S. pneumoniae; IA (eg, quinidine, procainamide) or Class III (eg, amiodar-
treatment of pelvic inflammatory disease due to suscep- one, dofetilide; sotalol) antiarrhythmic agents or other
tible C. pneumonia, N. gonorrhoeae, or M. hominis (FDA drugs known to prolong the QT interval. Use with caution
approved in adults) in patients with myasthenia gravis. Use of azithromycin in
Pregnancy Risk Factor B neonates and infants (treatment up to 42 days of life) has
Pregnancy Considerations Adverse events were not been associated with infantile hypertrophic pyloric steno-
observed in animal reproduction studies. Azithromycin sis (IHPS); observe for non-bilious vomiting or irritability
crosses the placenta (Ramsey 2003). The maternal serum with feeding (Eberly 2015).
half-life of azithromycin is unchanged in early pregnancy Oral suspensions (immediate release and extended
and decreased at term; however, high concentrations of release) are not interchangeable.
azithromycin are sustained in the myometrium and adi- Adverse Reactions
pose tissue (Fischer 2012; Ramsey 2003). Azithromycin is
Cardiovascular: Chest pain, palpitations
recommended for the treatment of several infections,
Central nervous system: Dizziness, drowsiness, fatigue,
including chlamydia, gonococcal infections, and Mycobac-
headache, vertigo
terium avium complex (MAC) in pregnant patients (consult
Dermatologic: Dermatitis (children), pruritus, skin photo-
current guidelines) (CDC [Workowski 2015]; HHS [oppor-
sensitivity, skin rash (single-dose regimens tend to be
tunistic; adult] 2015).
associated with increased incidence)
Breastfeeding Considerations Azithromycin is Endocrine & metabolic: Decreased serum bicarbonate
excreted in breast milk. (adults), decreased serum glucose (adults), increased
The relative infant dose (RID) of azithromycin is 4% to 8% gamma-glutamy! transferase, increased lactate dehydro-
when calculated using the highest breast milk concentra- genase, increased serum potassium
tion located and compared to an infant therapeutic dose of Gastrointestinal: Abdominal pain (single-dose regimens
5 to 10 mg/kg/day. In general, breastfeeding is considered tend to be associated with increased incidence), ano-
acceptable when the RID is <10% (Anderson 2016; Ito rexia, diarrhea (more common with single-dose regi-
2000). Using the highest milk concentration (2.8 mcg/mL), mens), dysgeusia, dyspepsia, flatulence, gastritis,
the estimated daily infant dose via breast milk is loose stools (single-dose regimens tend to be associated
0.42 mg/kg/day. This milk concentration was. obtained with increased incidence), melena (adults, multiple-dose
following maternal administration of oral azithromycin as regimens), mucositis, nausea (more common with sin-
a 1g loading dose followed in 48 hours by azithromycin gle-dose regimens), oral candidiasis, vomiting (children:
500 mg for 3 days; milk concentrations increased over Single-dose regimens tend to be associated with
time and reached a peak 30 hours after the last oral dose increased incidence; adults: More common with single
(Kelsey 1994). 2 g dose)
Genitourinary: Genital candidiasis (adults, multiple-dose
Following a single dose of IV azithromycin 500 mg, azi- regimens), vaginitis
thromycin was measurable in breast milk for up to 48 Hematologic & oncologic: Change in neutrophil count
hours. The median half-life in breast milk was 15.6 hours (children), decreased hematocrit (adults), decreased
(Sutton 2015). hemoglobin (adults), decrease in absolute neutrophil
Decreased appetite, diarrhea, rash, and somnolence have count (children: 500 to 1,500 cells/mm®), eosinophilia,
been reported in nursing infants exposed to macrolide increased neutrophils (adults), lymphocytopenia, throm-
antibiotics (Goldstein 2009). In general, antibiotics that bocythemia (adults)
are present in breast milk may cause nondose-related Hepatic: Cholestatic jaundice, increased serum ALT,
modification of bowel flora. Monitor infants for Gl distur- increased serum AST, increased serum bilirubin
bances (WHO 2002). In addition, an increased risk for Local (adults with IV administration): Local inflammation,
infantile hypertrophic pyloric stenosis (IHPS) may be pain at injection site
present in infants who are exposed to macrolides via Neuromuscular & skeletal: Increased creatine phospho-
breast milk, especially during the first 2 weeks of life (Lund kinase
2014); however, data is conflicting (Goldstein 2009). The Renal: Increased blood urea nitrogen, increased serum
manufacturer recommends that caution be exercised creatinine, nephritis (adults, multiple-dose regimens)
when administering azithromycin to breastfeeding women. Respiratory: Bronchospasm
Miscellaneous: Fever (children)
The CDC's Sexually Transmitted Diseases Treatment Rare but important or life-threatening: Abnormal stools,
Guidelines state that azithromycin is one of the recom- acute generalized exanthematous pustulosis, acute
mended agents for the treatment of granuloma inguinale renal failure, ageusia, aggressive behavior, agitation,
in lactating women. For lymphogranuloma venereum, alteration in sodium, altered sense of smell, altered
azithromycin may be considered as an alternative agent serum glucose, anaphylaxis, anemia, angioedema,
in this patient population (CDC [Workowski 2015)). anosmia, anxiety, arthralgia, asthma, basophilia, bron-
Contraindications chitis, cardiac arrhythmia, Clostridium difficile associated
Hypersensitivity to azithromycin, erythromycin, other mac- diarrhea, conjunctivitis (children), constipation, convul-
rolide (eg, azalide or ketolide) antibiotics, or any compo- sions, cough, deafness, decreased serum potassium
nent of the formulation; history of cholestatic jaundice/ (children), decreased serum sodium, diaphoresis,
hepatic dysfunction associated with prior azithromycin DRESS syndrome, dyspnea, dysuria, eczema, edema,
use emotional lability, enteritis, erythema multiforme, exacer-
Note: The manufacturer does not list concurrent use of bation of myasthenia gravis, facial edema, flu-like symp-
pimozide as a contraindication; however, azithromycin is toms (children), fungal dermatitis (children), fungal
listed as a contraindication in the manufacturer's labeling infection (children), gastrointestinal disease, hearing
for pimozide. loss, hepatic failure, hepatic insufficiency, hepatic
Warnings/Precautions Use with caution in patients with necrosis, hepatitis, hepatotoxicity (idiosyncratic) (Chala-
preexisting liver disease; hepatocellular and/or cholestatic sani 2014), hostility, hyperactivity, hyperkinesia, hyper-
hepatitis, with or without jaundice, hepatic necrosis, failure sensitivity reaction, hypotension, increased monocytes,
and death have occurred. Discontinue immediately if increased serum alkaline phosphatase, increased serum
symptoms of hepatitis occur (malaise, nausea, vomiting, bicarbonate, increased serum phosphate, interstitial
abdominal colic, fever). Allergic (hypersensitivity) reac- nephritis, insomnia, irritability, jaundice, Lambert-Eaton
tions (eg, angicedema, anaphylaxis, Stevens-Johnson syndrome, leukopenia, maculopapular rash, malaise,

230
 AZITHROMYCIN (SYSTEMIC)

nervousness, neutropenia, otitis media, pain, pancreati- immediate or delayed release oral suspension,
tis, paresthesia, pharyngitis, pleural effusion, prolonged unchanged with tablet)
Q-T interval on ECG, pseudomembranous colitis, pyloric Half-life elimination: Terminal: Oral, IV:
stenosis, pyloric stenosis (infantile hypertrophic), rhinitis, Infants and Children 4 months to 15 years: 54.5 hours
seizure, Stevens-Johnson syndrome, syncope, thrombo- Adults: Immediate release: 68 to 72 hours; Extended
cytopenia, tinnitus, tongue discoloration, toxic epidermal release: 59 hours
necrolysis, urticaria, ventricular tachycardia, vesiculobul- Time to peak, serum: Oral: Immediate release: ~2 to 3
lous dermatitis, weakness hours; Extended release: 3 to 5 hours
Drug Interactions Excretion: Oral, IV: Biliary (major route 50%, unchanged);
Metabolism/Transport Effects Substrate of CYP3A4 urine (6% to 14% unchanged)
(minor); Note: Assignment of Major/Minor substrate sta- Pharmacodynamics/Kinetics: Additional Consider-
tus based on clinically relevant drug interaction potential; ations
Inhibits P-glycoprotein/ABCB1 Renal function impairment: C,,ax and AUC increased 61%
Avoid Concomitant Use and 35%, respectively, in subjects with severe renal
Avoid concomitant use of Azithromycin (Systemic) with impairment.
any of the following: Amiodarone; BCG (Intravesical); Geriatric: In elderly women, a higher C,,4. was observed
Cholera, Vaccine; Cisapride; Hydroxychloroquine; Maci- but there was no change in drug accumulation.
morelin; MiIFEPRIStone; Mizolastine; PAZOPanib; Pimo- Dosing
zide; Probucol; Promazine; QTc-Prolonging Agents Neonatal Note: Extended release suspension (Zmax) is
(Highest Risk); QuiNINE; Silodosin; Terfenadine; Top- not interchangeable with immediate-release formula-
otecan; VinCRIStine (Liposomal); Vinflunine tions. All oral doses are expressed as immediate release
Increased Effect/Toxicity azithromycin unless otherwise specified. With oral ther-
Azithromycin (Systemic) may increase the levels/effects apy, monitor for infantile hypertrophic pyloric stenosis
of: Afatinib; Amiodarone; AtorvaSTATin; Betrixaban; (IHPS).
Bilastine; Brentuximab Vedotin; Cardiac Glycosides; Cel- General dosing, susceptible infection (Red Book
iprolol; Cisapride; Colchicine; CycloSPORINE (Sys- [AAP 2012]):
temic); Dabigatran Etexilate; DOXOrubicin Oral: 10 to 20 mg/kg once daily
(Conventional); Edoxaban; Everolimus; Ivermectin (Sys- IV: 10 mg/kg once daily
temic); Lovastatin; Mizolastine; Naldemedine; Naloxe- Chlamydial conjunctivitis or chlamydial pneumonia:
gol; PAZOPanib; P-glycoprotein/ABCB1 Substrates; Limited data available: Oral: 20 mg/kg once daily for 3
Pimozide; Prucalopride; QTc-Prolonging Agents (High- days (CDC [Workowski 2015]; Hammerschlag 1998)
est Risk); QTc-Prolonging Agents (Moderate Risk); Qui- Pertussis, treatment and postexposure prophylaxis:
NINE; Ranolazine; RifAXIMin; Silodosin; Simvastatin;
Oral, !V: 10 mg/kg once daily for 5 days (Red Book
Tacrolimus (Systemic); Tacrolimus (Topical); Terfena- [AAP 2012])
dine; Topotecan; Venetoclax; VinCRIStine (Liposomal);
Pediatric Note: Extended-release suspension (Zmax) is
Vitamin K Antagonists not interchangeable with immediate-release formula-
tions. All doses are expressed as immediate-release
The levels/effects of Azithromycin (Systemic) may be azithromycin unless otherwise specified.
increased by: FLUoxetine; Hydroxychloroquine; Maci- General dosing, susceptible infection (Red Book
morelin; MiFEPRIStone; Nelfinavir; Probucol; Proma- [AAP 2012]): Infants, Children, and Adolescents:
zine; QTc-Prolonging Agents (Indeterminate Risk and Mild to moderate infection: Oral: 5 to 12 mg/kg/dose;
Risk Modifying); Vinflunine; Xipamide typically administered as 10 to 12 mg/kg/dose on day
Decreased Effect 1 followed by 5 to 6 mg/kg once daily for remainder of
Azithromycin (Systemic) may decrease the levels/effects treatment duration; usual maximum dose for the total
of: BCG (Intravesical); BCG Vaccine (Immunization); course: 1,500 to 2,000 mg
Cholera Vaccine; Lactobacillus and Estriol; Sodium Pico- Serious infection: 1V: 10 mg/kg once daily; maximum
sulfate; Typhoid Vaccine dose: 500 mg/dose
Food Interactions Rate and extent of GI absorption may Babesiosis: Infants, Children, and Adolescents: Oral:
be altered depending upon the formulation. Azithromycin 10 mg/kg once on day 1 (maximum dose: 500 mg/
suspension, not tablet form, has significantly increased dose), then 5 mg/kg once daily on days 2 to 10 (max-
absorption (46%) with food. Management: Immediate imum dose: 250 mg/dose) in combination with atova-
release suspension and tablet may be taken without quone; longer duration of therapy may be necessary in
regard to food; extended release suspension should be some cases; in immunocompromised patients, higher
taken on an empty stomach (at least 1 hour before or 2 doses (eg, adults: 600 to 1,000 mg daily) may be
hours following a meal). required (Red Book [AAP] 2012; IDSA
Storage/Stability [Wormser 2006])
Injection (Zithromax): Store intact vials of injectionatroom Bartonellosis: Oral:
temperature. Reconstituted solution is stable for 24 Cat scratch disease (B. henselae) with extensive lym-
hours when stored below 30°C (86°F). The diluted phadenopathy (IDSA [Stevens] 2014): Non-HIV-
exposed/-positive:
solution DSW, DSLR, D5%4NS, D51t/3NS, D51/2NS (with
Infants, Children, and Adolescents $45 kg: 10 mg/kg
or without 20 mEq/L KCI), Normosol-M in D5, Normosol-
once on day 1 (maximum dose: 500 mg/dose),
R in D5, LR, NS, or 1/2NS is stable for 24 hours at or
followed by 5 mg/kg once daily on days 2 to 5
below room temperature (30°C [86°F]) and for 7 days if
(maximum dose: 250 mg/dose)
stored under refrigeration (5°C [41°F}).
Children and Adolescents >45 kg: 500 mg as a single
Suspension, immediate release (Zithromax): Store dry
dose on day 1, then 250 mg once daily for 4 addi-
powder below 30°C (86°F). Store reconstituted suspen-
tional days
sion at 5°C to 30°C (41°F to 86°F) and use within
Cutaneous bacillary angiomatosis (B. henselae or B.
10 days.
quintana): HIV- exposed/-positive: Infants, Children,
Suspension, extended release (Zmax): Store dry powder
and Adolescents: 5 to 12 mg/kg once daily; maximum
$30°C (86°F). Following reconstitution, store at 25°C
dose: 600 mg/dose; usual treatment duration: 3
(77°F); excursions permitted to 15°C to 30°C (59°F to
months (CDC 2009)
86°F); do not refrigerate or freeze. Should be consumed
Chancroid (CDC 2010; Red Book [AAP] 2012): Oral:
within 12 hours following reconstitution.
<45 kg: 20 mg/kg as a single dose; maximum dose:
Tablet (Zithromax): Store between 15°C to 30°C (59°F 1,000 mg/dose
to 86°F). teat : 245 kg: 1,000 mg as a single dose
Mechanism of Action Inhibits RNA-dependent protein Chlamydial infections:
synthesis at the chain elongation step; binds to the 50S Cervicitis, urethritis (C. trachomatis): Children and Ado-
ribosomal subunit resulting in blockage of transpeptidation lescents 245 kg: Oral: 1,000 mg as a single dose
Pharmacodynamics/Kinetics (Adult data unless (CDC 2010; Red Book [AAP] 2012)
noted) Conjunctivitis: Infants: Oral, IV: 20 mg/kg once daily for
Absorption: Oral: Rapid from the GI tract 3 days (Red Book [AAP] 2012)
Distribution: Extensive tissue; distributes well into skin, Pneumonia, community-acquired (Bradley 2011):
lungs, sputum, tonsils, and cervix; penetration into CSF Infants >3 months, Children, and Adolescents:
is poor; Vg; 31 to 33 C/kg Mild infection or step-down therapy: Oral: 10 mg/kg
Protein binding (concentration dependent and dependent once on day 1 (maximum dose: 500 mg/dose) fol-
on alphat-acid glycoprotein concentrations): Oral, IV: lowed by 5 mg/kg once daily on days 2 to 5 (max-
T% to 51% imum dose: 250 mg/dose)
Metabolism: Hepatic to inactive metabolites Severe infection: IV: 10 mg/ kg once daily for at least
Bioavailability: Oral: Tablet, immediate release oral sus- 2 days, then transition to oral route with a single
pension: 34% to 52%; extended release oral suspension: daily dose of 5 mg/kg to complete course of therapy;
28% to 43%; variable effect with food (increased with maximum dose: 500 mg/dose

231
 AZITHROMYCIN (SYSTEMIC)

q Cystic fibrosis; improve lung function, reduce exac-

erbation frequency: Limited data available; dosing
Peritonitis (peritoneal dialysis), prophylaxis for
patients receiving peritoneal dialysis who require
regimen variable (Mogayzel 2013; Saiman 2003; Sai- dental procedures: Infants, Children, and Adoles-
man 2010): Children 26 years and Adolescents: Oral: cents: Oral: 15.mg/kg administered 30 to 60 minutes
18 to 35.9 kg: 250 mg three times weekly (Monday, before dental procedure; maximum dose: 500 mg/dose
Wednesday, Friday) (Warady [ISPD 2012])
236 kg: 500 mg three times weekly (Monday, Wednes- Pertussis (CDC 2005; Red Book [AAP] 2012): Oral, IV:
day, Friday) Infants 1 to 5 months: 10 mg/kg/dose once daily for
Diarrhea, infectious: 5 days
Campylobacter. Infants, Children, and Adolescents: Infants 26 months, Children, and Adolescents:
Oral: 10 mg/kg once daily for 3 days; maximum dose: 10 mg/kg once on day 1 (maximum dose: 500 mg/
500 mg/dose (Red Book [AAP] 2012) dose), followed by 5 mg/kg once daily on days 2 to 5
Shigellosis: Infants, Children, and Adolescents: Oral: (maximum dose: 250 mg/dose) :
AAP Recommendation: 12 mg/kg once on day 1 Pneumonia, community-acquired (excluding myco-
(maximum dose: 500 mg/dose), followed by bacterial [mycoplasma pneumoniae] and chlamy-
6 mg/kg once daily on days 2 to 5 (maximum dose: dial infections):
250 mg/dose) (Red Book [AAP] 2012) Oral:
Alternate dosing: 10 mg/kg once daily for 3 days Immediate release: Infants >3 months, Children, and
(Dupont 2009; Mackell 2005); WHO Guidelines rec- Adolescents: 10 mg/kg once on day 1 (maximum
ommend up to 20 mg/kg/dose and in some cases, a dose: 500 mg/dose), followed by 5 mg/kg (maxi-
wider range of duration of therapy (eg, 1 to 5 days) mum dose: 250 mg/dose) once daily on days 2 to
(WHO 2005) 5 (Bradley 2011)
Endocarditis; prophylaxis: Infants, Children, and Ado-
Extended-release oral suspension (Zmax): Infants 26
lescents: Oral: 15 mg/kg/dose 30 to 60 minutes before
months, Children, and Adolescents: 60 mg/kg as a
procedure; maximum dose: 500 mg/dose (Wil-
single dose; maximum dose: 2,000 mg/dose
son 2007)
IV: Infants >3 months, Children, and Adolescents:
Gonococcal infection; uncomplicated (cervicitis,
10 mg/kg once daily for at least 2 days, follow IV
urethritis, anorectal): Oral:
therapy by the oral route with a single daily dose of
Children <45 kg: 20 mg/kg as a single dose; maximum
5 mg/kg to complete a 5-day course of therapy;
dose: 1,000 mg/dose (Red Book [AAP] 2012)
maximum dose: 500 mg/dose (Bradley 2011)
Children >8 years and 245 kg and Adolescents:
Pneumonia, community acquired; mycoplasma
1,000 mg as a single dose (CDC 2012; Red Book
[AAP] 2012) pneumoniae, or chlamydial infection (Bradley
Group A streptococcal infection; treatment of strep- 2011): Infants >3 months, Children, and Adolescents:
tococcal tonsillopharyngitis: Mild infection or step-down therapy: Oral: 10 mg/kg
Manufacturer's labeling and AHA recommendations: once on day 1 (maximum dose: 500 mg/dose) fol-
Infants, Children, and Adolescents: Oral: 12 mg/kg/ lowed by 5 mg/kg once daily on days 2 to 5 (max-
dose once daily for 5 days; maximum dose: 500 mg/ imum dose: 250 mg/dose)
dose (AHA [Gerber 2009]) Severe infection: IV: 10 mg/kg once daily for at least 2
Alternate dosing: days (maximum dose: 500 mg/dose), then transition
IDSA recommendations: Note: Recommended as an to oral route with a single daily dose of 5 mg/kg to
alternative agent for group A streptococcal pharyng- complete course of therapy (maximum dose:
itis in penicillin-allergic patients. Infants, Children, 250 mg/dose)
and Adolescents: Oral: 12 mg/kg (maximum: Rhinosinusitis, bacterial: Oral: Infants 26 months,
500 mg/dose) on day 1 followed by 6 mg/kg/dose Children, and Adolescents: 10 mg/kg once daily for 3
(maximum: 250 mg/dose) once daily on days 2 days; maximum dose: 500 mg/dose; Note: Although
through 5 (IDSA [Shulman 2012]). FDA approved, macrolides are not recommended for
Three-day regimen: Limited data available: Children empiric therapy due to high rates of resistance
and Adolescents: Oral: 20 mg/kg/dose once daily for (Chow 2012).
3 days; maximum dose: 1,000 mg/dose (Cohen Sexual victimization, prophylaxis: Oral: Note: Use in
2004; O'Doherty 1996) combination with cefixime or ceftriaxone and comple-
Meningococcal disease, chemoprophylaxis of high- tion of hepatitis B virus immunization; also consider
tisk contacts: Infants, Children, and Adolescents: prophylaxis for trichomoniasis and bacterial vaginosis
Oral: 10 mg/kg as a single dose; maximum dose: (CDC 2010; Red Book [AAP] 2012).
500 mg/dose; Note: Not routinely recommended; may Children <45 kg: 20 mg/kg as a single dose
consider if fluoroquinolone resistance detected (Red Children 245 kg and Adolescents: 1,000 mg as a
Book [AAP] 2012) single dose
Mycobacterium avium complex (MAC) infection (HIV- Toxoplasma gondii, encephalitis (HIV-exposed/-pos-
exposed/-positive): itive); treatment and prevention: Oral: Adolescents:
Infants and Children (DHHS [pediatric] 2013): Oral: 900 to 1,200 mg once daily in combination with pyr-
Treatment: 10 to 12 mg/kg once daily in combination imethamine/leucovorin; treatment duration: 6 weeks or
with ethambutol, with or without rifabutin; maximum longer if extensive disease or incomplete response at 6
dose: 500 mg/dose; treatment duration at least 12 weeks (DHHS [adult] 2013)
months; dependent upon clinical response Renal Impairment: Pediatric
Primary prevention of first episode: Preferred: Infants 26 months, Children, and Adolescents:
20 mg/kg once weekly (maximum dose: 1,200 mg/ Use with caution in patients with GFR <10 mL/minute
dose) or alternatively, 5 mg/kg once daily (maximum (AUC increased by 35% compared to patients with
dose: 250 mg/dose)
normal renal function); however, no dosage adjust-
Secondary prevention of recurring episodes: 5 mg/kg
ment is provided in the manufacturer's labeling.
once daily in combination with ethambutol, with or
No supplemental dose or dosage adjustment neces-
without rifabutin; maximum dose: 250 mg/dose
sary, including patients on intermittent hemodialysis,
Adolescents (DHHS [adult] 2013): Oral:
peritoneal dialysis, or continuous renal replacement
Treatment: 500 to 600 mg daily in combination with
therapy (eg, CVVHD) (Aronoff 2007; Heintz 2009).
ethambutol
Primary prophylaxis: 1,200 mg once weekly or alter- Hepatic Impairment: Pediatric Azithromycin is pre-
natively, 600 mg twice weekly dominantly hepatically eliminated; however, there is no
Secondary prophylaxis: 500 to 600 mg daily in combi- dosage adjustment provided in the manufacturer's label-
nation with ethambutol ing. Use with caution due to potential for hepatotoxicity
Otitis media, acute (AOM): Infants 26 months, Chil- (rare); discontinue immediately for signs or symptoms of
dren, and Adolescents: Oral: Note: Due to increased hepatitis.
S pneumonia and H. influenzae resistance, azithromy- Preparation for Administration
cin is not routinely recommended as a treatment option Oral:
(AAP [Lieberthal 2013]) Immediate release oral suspension: Reconstitute pow-
Single-dose regimen: 30 mg/kg as a single dose; max- der for oral suspension with appropriate amount of
imum dose: 1,500 mg/dose; if patient vomits within 30 water as specified on the bottle. Shake vigorously until
minutes of dose, repeat dosing has been adminis- suspended.
tered although limited data available on safety Oral suspension 1,000 mg packet for a single dose:
Three-day regimen: 10 mg/kg once daily for 3 days; Prepare by mixing contents of 1 packet with approx-
_ maximum dose: 500 mg/dose imately 60 mL of water.
Five-day regimen: 10 mg/kg once on day 1 (maximum Extended release oral suspension: Prepare 2,000 mg
dose: 500 mg/dose), followed by 5 mg/kg (maximum azithromycin suspension by reconstituting with 60 mL
dose: 250 mg/dose) once daily on days 2 to 5 of water to a final concentration of 27 mg/mL

232
 AZITHROMYCIN (OPHTHALMIC)

Parenteral: Prepare initial solution by adding 4.8 mL of Breastfeeding Considerations It is not known if azi-
SWFI to the 500 mg vial resulting in a concentration of thromycin is excreted into breast milk following ophthalmic
100 mg/mL. Use of a standard syringe is recommended administration. The amount of azithromycin available sys-
due to the vacuum in the vial (which may draw additional temically following topical application of the ophthalmic
solution through an automated syringe). drops is estimated to be below quantifiable limits. Sys-
The initial solution should be further diluted to a concen- temic absorption would be required in order for azithro-
tration of 1 mg/mL to 2 mg/mL in NS, D5W, or LR. mycin to enter breast milk. The manufacturer
recommends that caution be exercised when administer-
Administration
ing azithromycin eye drops to nursing women. When
Oral:
administered orally or IV, azithromycin enters breast milk.
Immediate release: May administer without regard to
Refer to the Azithromycin (Systemic) monograph for
food; do not administer with antacids that contain details.
aluminum or magnesium. Contraindications Hypersensitivity to azithromycin or
Oral suspension, multiple doses: Shake well before use. any component of the formulation
Oral suspension 1,000 mg packet for a single dose: Warnings/Precautions For topical ophthalmic use only;
Administer the entire contents immediately after mix- do not inject subconjunctivally or introduce directly into the
ing; add an additional 60 mL of water, mix, and drink. anterior chamber of the eye. Whenever clinical judgment
Do not use to administer any other dose except dictates, examine the patient with the aid of magnification,
1,000 mg or 2,000 mg. such as slit-lamp biomicroscopy and, when appropriate,
Extended release oral suspension: Shake suspension fluorescein staining. Severe hypersensitivity reactions,
well before use; administer on an empty stomach 1 including anaphylaxis, angioedema, and dermatologic
hour before or 2 hours after a meal; must be adminis- reactions, have been reported with systemic use of azi-
tered within 12 hours of reconstitution. May be admin- thromycin. Prolonged use may lead to overgrowth of non-
istered without regard to antacids containing aluminum susceptible organisms, including fungi. Discontinue use
or magnesium. and institute alternative therapy if superinfection is sus-
Parenteral: Do not give IM or by direct IV injection. pected. Contains benzalkonium chloride which may be
absorbed by contact lenses; contact lens should not be
Administer IV infusion at a final concentration of
worn during treatment.
1 mg/mL over 3 hours; for a 2 mg/mL concentration,
Adverse Reactions
infuse over 1 hour; do not infuse over a period of less
Ophthalmic: Eye irritation
than 60 minutes.
Rare but important or life-threatening: Blurred vision,
Monitoring Parameters Liver function tests, WBC with contact dermatitis, corneal erosion, decreased visual
differential; number and type of stools/day for diarrhea; acuity, dysgeusia, eye pain, facial edema, local ocular
monitor patients receiving azithromycin and drugs known hypersensitivity reaction (includes burning sensation of
to interact with erythromycin (ie, theophylline, digoxin, eyes, eye discharge, eye irritation, eye pruritus, stinging
anticoagulants, triazolam) since there are still very few of eyes), nasal congestion, punctate keratitis, sinusitis,
studies examining drug-drug interactions with azithromy- skin rash, swelling of eye, urticaria, xerophthalmia
cin. When used as part of alternative treatment for gon- Drug Interactions
ococcal infection, test-of-cure 7 days after dose (CDC, Metabolism/Transport Effects None known.
2012). Avoid Concomitant Use There are no known interac-
Dosage Forms Excipient information presented when tions where it is recommended to avoid concomitant use.
available (limited, particularly for generics); consult spe- Increased Effect/Toxicity There are no known signifi-
cific product labeling. cant interactions involving an increase in effect.
Packet, Oral: Decreased Effect There are no known significant inter-
Zithromax: 1 g (3 ea, 10 ea) [cherry-banana flavor] actions involving a decrease in effect.
Generic: 1 g (3 ea, 10 ea) Storage/Stability Prior to use, store unopened under
Solution Reconstituted, Intravenous:
refrigeration at 2°C to 8°C (36°F to 46°F). After opening,
store at 2°C to 25°C (36°F to 77°F) for <14 days; discard
Zithromax: 500 mg (1 ea)
any remaining solution after 14 days.
Generic: 500 mg (1 ea)
Mechanism of Action Inhibits RNA-dependent protein
Solution Reconstituted, Intravenous [preservative free]:
synthesis at the chain elongation step; binds to the 50S
Generic: 500 mg (1 ea) ribosomal subunit resulting in blockage of transpeptidation
Suspension Reconstituted, Oral: Pharmacodynamics/Kinetics (Adult data unless
Zithromax: 100 mg/5 mL (15 mL) [cherry-vanilla-banana noted)
flavor] Absorption: Systemic absorption estimated to be negli-
Zithromax: 200 mg/5 mL (15 mL, 22.5 mL, 30 mL) gible
[cherry flavor] Dosing
Zmax: 2 g (1 ea) [cherry-banana flavor] Pediatric Bacterial conjunctivitis: Children and Ado-
Generic: 100 mg/5 mL (15 mL); 200 mg/5 mL (15 mL, lescents: Ophthalmic: Instill 1 drop in the affected eye(s)
22.5 mL, 30 mL) twice daily (8 to 12 hours apart) for 2 days, then 1 drop
Tablet, Oral: once daily for 5 days
Zithromax: 250 mg, 500 mg, 600 mg Renal Impairment: Pediatric There are no dosage
Zithromax Tri-Pak: 500 mg adjustments provided in the manufacturer's labeling.
Zithromax Z-Pak: 250 mg Hepatic Impairment: Pediatric There are no dosage
Generic: 250 mg, 500 mg, 600 mg adjustments provided in the manufacturer's labeling.
Administration For topical ophthalmic use only; not for
injection into the eye. Wash hands before and after
Azithromycin (Ophthalmic) (az ith roe mYE sin) instillation. Contact lenses should not be worn during
treatment of ophthalmic infections. Avoid touching tip of
Medication Safety Issues
applicator to eye or other surfaces. Invert closed bottle
Sound-alike/look-alike issues:
and shake once before each use. Remove cap with bottle
Azithromycin may be confused with azathioprine, eryth-
inverted. Tilt head back and gently squeeze inverted bottle
romycin to instill drop.
Brand Names: US AzaSite Additional Information During erythromycin ointment
Therapeutic Category Antibiotic, Ophthalmic shortage, azithromycin ophthalmic ointment has been
Generic Availability (US) No used as an alternative treatment for ophthalmia neonato-
Use Treatment of bacterial conjunctivitis due to susceptible rum; however, as of March 2010 the erythromycin short-
CDC coryneform group G, H. influenzae, S. aureus, S. age was resolved and the FDA recommends against the
mitis group, or S. pneumoniae (FDA approved in ages 21 use of alternative therapies, including azithromycin (CDC
year and adults) 2010).
Pregnancy Risk Factor B Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
Pregnancy Considerations Adverse events were not
cific product labeling.
observed in animal reproduction studies. The amount of
Solution, Ophthalmic:
azithromycin available systemically following topical appli- AzaSite: 1% (2.5 mL) [contains benzalkonium chloride,
cation of the ophthalmic drops is estimated to be below disodium edta]
quantifiable limits. Systemic absorption would be required
in order for azithromycin to cross the placenta and reach @ Azithromycin Dihydrate see Azithromycin (Systemic)
the fetus. When administered orally or IV, azithromycin on page 229
crosses the placenta. Refer to the Azithromycin (Sys- @ Azithromycin Monohydrate see Azithromycin (Sys-
temic) monograph for details. temic) on page 229

233
AZTREONAM (SYSTEMIC)

¢@ Azolen Tincture [OTC] see Miconazole (Topical) myalgia, numbness of tongue, oral mucosa ulcer, pan-
on page 1371 cytopenia, paresthesia, petechia, positive direct Coombs
@ AZT (Can) see Zidovudine on page 2083 test, prolonged partial thromboplastin time, prolonged
prothrombin time,’ pruritus, pseudomembranous colitis,
@ AZT + 3TC (error-prone abbreviation) see Lamivudine
purpura, seizure, thrombocytopenia, tinnitus, toxic epi-
and Zidovudine on page 1173
dermal necrolysis, urticaria, vaginitis, ventricular bige-
@ AZT, Abacavir, and Lamivudine see Abacavir, Lamivu- miny (transient), ventricular premature contractions
dine, and Zidovudine on page 30 (transient), vertigo, vulvovaginal candidiasis, weakness,
@ AZT (error-prone abbreviation) see Zidovudine wheezing
on page 2083 Drug Interactions
@ Azthreonam see Aztreonam (Oral Inhalation) Metabolism/Transport Effects None known.
on page 235 Avoid Concomitant Use 2
¢@ Azthreonam see Aztreonam (Systemic) on page 234 Avoid concomitant use of Aztreonam (Systemic) with any
of the following: BCG (Intravesical); Cholera Vaccine
Increased Effect/Toxicity There are no known signifi-
cant interactions involving an increase in effect.
Aztreonam (Systemic) (42 tree oh nam)
Decreased Effect
Medication Safety Issues Aztreonam_(Systemic) may decrease the levels/effects
Sound-alike/look-alike issues: of: BCG (Intravesical); BCG Vaccine (Immunization);
Aztreonam may be confused with azidothymidine Cholera Vaccine; Lactobacillus and Estriol; Sodium Pico-
Brand Names: US Azactam; Azactam in Dextrose sulfate; Typhoid Vaccine
Therapeutic Category Antibiotic, Miscellaneous Storage/Stability
Generic Availability (US) May be product dependent Vials: Prior to reconstitution, store at room temperature;
Use Injection: Treatment of patients with documented avoid excessive heat. After reconstitution, solutions for
multidrug resistant aerobic gram-negative infection in infusion in D5W, LR, NS, or other appropriate solution,
which beta-lactam therapy is contraindicated; used for with a final concentration of $20 mg/mL, should be used
UTI, lower respiratory tract infections, intra-abdominal within 48 hours if stored at room temperature or within 7
infections, and gynecological infections caused by sus- days if refrigerated. Solutions for infusion with a final
ceptible organisms (FDA approved in ages 29 months and concentration of >20 mg/mL (if prepared with SWFI or
adults); treatment of susceptible skin and skin structure NS only) should also be used within 48 hours if stored at
infections and septicemia (FDA approved in adults). Has
room temperature or within 7 days if refrigerated; all
also been used for the treatment of peritonitis in patients
other solutions for infusion with a final concentration
with peritoneal catheters.
>20 mg/mL must be used immediately after preparation
Pregnancy Risk Factor B
(unless prepared with SWFI or NS).
Pregnancy Considerations Adverse events have not
Premixed frozen containers: Store unused container fro-
been observed in animal reproduction studies. Aztreonam
zen at $-20°C (-4°F). Frozen container can be thawed at
crosses the placenta and can be detected in the fetus.
room temperature of 25°C (77°F) or in a refrigerator, 2°C
Breastfeeding Considerations Aztreonam is excreted
into breast milk in concentrations <1% of the correspond-
to 8°C (36°F to 46°F). Thawed solution should be used
ing maternal serum concentration. The manufacturer sug- within 48 hours if stored at room temperature or within 14
gests consideration be given to temporarily discontinuing days if stored under refrigeration. Do not freeze.
nursing during therapy. Mechanism of Action Inhibits bacterial cell wall syn-
Contraindications Hypersensitivity to aztreonam or any thesis by binding to one or more of the penicillin-binding
component of the formulation proteins (PBPs) which in turn inhibits the final transpepti-
Warnings/Precautions Rare cross-allergenicity to pen- dation step of peptidoglycan synthesis in bacterial cell
icillins, cephalosporins, or carbapenems may occur; use walls, thus inhibiting cell wall biosynthesis. Bacteria even-
with caution in patients with a history of hypersensitivity to tually lyse due to ongoing activity of cell wall autolytic
beta-lactams. Use caution in renal impairment; dosing enzymes (autolysins and murein hydrolases) while cell
adjustment required for the injectable formulation. Pro- wall assembly is arrested. Monobactam structure makes
longed use may result in fungal or bacterial superinfection, cross-allergenicity with beta-lactams unlikely.
including C. difficile-associated diarrhea (CDAD) and Pharmacodynamics/Kinetics (Adult data unless
pseudomembranous colitis; CDAD has been observed
noted)
>2 months postantibiotic treatment. Use with caution in
bone marrow transplant patients with multiple risk factors Absorption: IM: Well absorbed; IM and IV doses produce
for toxic epidermal necrolysis (TEN) (eg, sepsis, radiation comparable serum concentrations
therapy, drugs known to cause TEN); rare cases of TEN in Distribution: Injection: Widely into body tissues, cerebro-
this population have been reported. Patients colonized spinal fluid, bronchial secretions, peritoneal fluid, bile,
with Burkholderia cepacia have not been studied. Poten- and bone
tially significant interactions may exist, requiring dose or Va: Neonates: 0.26 to 0.36 L/kg; Children: 0.2 to 0.29 L/
frequency adjustment, additional monitoring, and/or selec- kg; Adults: 0.2 L/kg
tion of alternative therapy.
Relative diffusion of antimicrobial agents from blood into
Adverse Reactions CSF: Good only with inflammation (exceeds
Cardiovascular: Phlebitis (intravenous), thrombophlebitis usual MICs)
(intravenous) CSF:blood level ratio: Meninges: Inflamed: 8% to 40%;
Dermatologic: Skin rash (more common in children) Normal: ~1%
Gastrointestinal: Diarrhea, nausea, vomiting Protein binding: 56%
Hematologic & oncologic: Eosinophilia (more common in Metabolism: Injection: Hepatic (minor %)
children), neutropenia (more common in children),
Half-life elimination: Injection: ‘
thrombocythemia (more common in children)
Neonates: <7 days, $2.5 kg: 5.5 to 9.9 hours; <7 days,
Hepatic: Increased serum transaminases (children, more
common with high dose) >2.5 kg: 2.6 hours; 1 week to 1 month: 2.4 hours
Local: Discomfort at injection site (intramuscular), eryth- Children 2 months to 12 years: 1.7 hours
ema at injection site (intravenous: More common in Children with cystic fibrosis: 1.3 hours
children), pain at injection site (more common in chil- Adults: Normal renal function: 1.7 to 2.9 hours
dren), swelling at injection site (intramuscular) End-stage renal disease (ESRD): 6 to 8 hours
Renal: Increased serum creatinine (children) Time to peak: IM, IV push: Within 60 minutes; IV infusion:
Miscellaneous: Fever 1.5 hours
Rare but important or life-threatening: Abdominal cramps, Excretion: Injection: Urine (60% to 70% as unchanged
anaphylaxis, anemia, angioedema, breast tenderness, drug); feces (~13% to 15%)
bronchospasm, chest pain, Clostridium difficile associ- Pharmacodynamics/Kinetics: Additional Consider-
ated diarrhea, confusion, diaphoresis, diplopia, dizzi-
ations
ness, dysgeusia, dyspnea, erythema multiforme,
exfoliative dermatitis, flushing, gastrointestinal hemor- Renal function impairment: Serum half-life may be pro-
rhage, hepatitis, hepatobiliary disease, hypotension, longed.
increased serum alkaline phosphatase, increased serum Hepatic function impairment: Serum half-life may be pro-
ALT (adults), increased serum AST (adults), induration at longed.
injection site, insomnia, jaundice, leukocytosis, malaise, Geriatric: Serum half-life may be prolonged.
 AZTREONAM (ORAL INHALATION)

Dosing Administer by IVP over 3 to 5 minutes or by intermittent

Neonatal infusion over 20 to 60 minute.
General dosing, susceptible infection: IM, IV (Red IM: Administer by deep IM injection into a large muscle
Book [AAP 2015]): Note: Higher doses (ie, 50 mg/kg/ mass such as the upper outer quadrant of the gluteus
dose) may be required when treating Pseudomonas maximus or lateral part of the thigh. Doses >1,000 mg
infections should be administered |V. Do not mix with any local
anesthetic agent.
Postnatal Age Dose Monitoring Parameters Injection: Periodic renal and
hepatic function tests; monitor for stool frequency; monitor
<14 days 30 mg/kg/dose every 12 for signs of anaphylaxis during first dose
hours Test Interactions May interfere with urine glucose tests
15 to 28 days 30 mg/kg/dose every 8 containing cupric sulfate (Benedict's solution, Clinitest);
to 12 hours positive Coombs' test
30 mg/kg/dose every 12 Dosage Forms Excipient information presented when
hours
available (limited, particularly for generics); consult spe-
8 to 28 days 30 mg/kg/dose every 8 cific product labeling.
to 12 hours
Solution, Intravenous:
30 mg/kg/dose every 8 Azactam in Dextrose: 1 9/50 mL (50 mL); 2 g/50 mL (50
hours
>2 kg mL) [sodium free]
8 to 28 days 30 mg/kg/dose every 6 Solution Reconstituted, Injection:
hours
Azactam: 1 g (1 ea); 2 g (1 ea) [sodium free]
Generic: 1 g (1 ea); 2 g (1 ea)
Pediatric
General dosing, susceptible infection: Infants, Chil-
dren, and Adolescents (Red Book [AAP 2015]):
Aztreonam (Oral Inhalation) (AZ tree oh nam)
Mild to moderate infection: IM, IV: 90 mg/kg/day in Medication Safety Issues
divided doses every 8 hours; maximum daily dose: Sound-alike/look-alike issues:
3,000 mg/day Aztreonam may be confused with azidothymidine
Severe infection: IM, IV: 90 to 120 mg/kg/day in Brand Names: US Cayston
divided doses every 6 to 8 hours; maximum daily Brand Names: Canada Cayston
dose: 8 g/day
Therapeutic Category Antibiotic, Miscellaneous
Cystic fibrosis (Pseudomonas aeruginosa): \nfants,
Generic Availability (US) No
Children, and Adolescents: IV: 150 to 200 mg/kg/day
Use Inhalation (nebulized, Cayston): Improve respiratory
in divided doses every 6 to 8 hours (Kliegman 2016);
symptoms in cystic fibrosis patients with Pseudomonas
higher doses have been used: 200 to 300 mg/kg/day
aeruginosa in the lungs (FDA approved in ages 27 years
divided every 6 hours; maximum daily dose: 12 g/day
(Zobell 2012) and adults)
Intra-abdominal infections, complicated: Infants, Prescribing and Access Restrictions Cayston (aztreo-
Children, and Adolescents: IV: 90 to 120 mg/kg/day nam inhalation solution) is only available through a select
divided every 6 to 8 hours in combination with metro- group of specialty pharmacies and cannot be obtained
nidazole; maximum dose: 2,000 mg (Solomkin 2010) through a retail pharmacy. Because Cayston may only be
Peritonitis (peritoneal dialysis), treatment: Infants, used with the Altera Nebulizer System, it can only be
Children, and Adolescents: Intraperitoneal: Continu- obtained from the following specialty pharmacies; IV Sol-
ous: Loading dose: 1,000 mg per liter of dialysate; utions/Maxor; Foundation Care; Pharmaceutical Special-
maintenance dose: 250 mg per liter (ISPD ties Inc; TLCRx/ModernHEALTH; and Walgreens
[Warady 2012]) Specialty Pharmacy: This network of specialty pharmacies
Surgical prophylaxis, treatment: Children and Ado- ensures proper access to both the drug and device. To
lescents: IV: 30 mg/kg within 60 minutes before pro- obtain the medication and proper nebulizer, contact the
cedure; may repeat in 4 hours for prolonged Cayston Access Program at 1-877-7CAYSTON
procedure or excessive blood loss; maximum dose: (1-877-722-9786) or at www.cayston.com. In Canada,
2,000 mg (Bratzler 2013) Cayston is distributed by Innomar Solutions specialty
Renal Impairment: Pediatric pharmacy; Canadian healthcare providers and patients
Infants, Children, and Adolescents: IM, IV: The follow- may obtain additional information at http://cayston.ca/
ing adjustments have been recommended (Aronoff Pregnancy Risk Factor B
2007). Note: Renally adjusted dose recommenda- Pregnancy Considerations Animal reproduction studies
tions are based on doses of 90 to 120 mg/kg/day have not been conducted with aztreonam solution for
divided every 8 hours. inhalation; however, adverse events were not observed
GFR 230 mL/minute/1.73 m?: No adjustment required in animal reproduction studies conducted with the injec-
GFR 10-29 mL/minute/1.73 m2: 15 to 20 mg/kg every tion. Aztreonam crosses the placenta and reaches the
8 hours fetal circulation following IV administration; however, peak
GFR <10 mL/minute/1.73 m?: 7.5 to 10 mg/kg every plasma concentrations following inhalation of aztreonam
12 hours are significantly less than those observed following aztreo-
Intermittent hemodialysis: 7.5 to 10 mg/kg every 12 nam IV.
hours Breastfeeding Considerations Aztreonam is excreted
Peritoneal dialysis (PD): 7.5 to 10 mg/kg every 12 into breast milk following intravenous administration. The
hours peak plasma concentration of aztreonam following inha-
Continuous renal replacement therapy (CRRT): No lation is <1% of the peak concentration seen following IV
adjustment required. administration. Maternal use of inhaled aztreonam is not
Hepatic Impairment: Pediatric There are no dosage likely to pose a risk to breastfeeding infants.
adjustments provided in manufacturer's labeling. Use Contraindications Hypersensitivity to aztreonam or any
with caution (minor hepatic elimination occurs). component of the formulation
Preparation for Administration Warnings/Precautions Rare cross-allergenicity to pen-
Parenteral: icillins, cephalosporins, or carbapenems may occur; use
IM: Reconstitute vial with at least 3 mL SWFI, sterile with caution in patients with a history of hypersensitivity to
bacteriostatic water for injection, NS, or bacteriostatic beta-lactams. Patients colonized with Burkholderia cepa-
sodium chloride per gram.of aztreonam to a final cia have not been studied. Safety and efficacy has not
concentration of $333 mg/mL; immediately shake vig- been established in patients with FEV, <25% or >75%
orously. Do not mix with any local anesthetic agent. predicted. Compare patient's baseline FEV, prior to ther-
IV: apy and the presence of other symptoms when deciding if
Bolus injection: Reconstitute vial with 6 to 10 mL SWFI; post-treatment FEV, changes (eg, decline) are caused by
immediately shake vigorously a pulmonary exacerbation. Reserve use for CF patients
Infusion: Reconstitute vial with at least 3 mL SWFI per with known Pseudomonas aeruginosa. Bronchospasm
gram of aztreonam; immediately shake vigorously. may occur following nebulization; administer a bronchodi-
Reconstituted solutions are colorless to light yellow lator prior to treatment.
straw and may turn pink upon standing without affect- Adverse Reactions
ing potency. Further dilute in an appropriate solution Cardiovascular: Chest discomfort
(eg, DSW, NS) for infusion to a final concentration not Dermatologic: Skin rash
to exceed 20 mg/mL. Gastrointestinal: Abdominal pain, pharyngolaryngeal pain,
Administration vomiting
Parenteral: } Respiratory: Bronchospasm (patients experienced 215%
IV: IV route is preferred for doses >1,000 mg or in reduction in FEV,), cough, nasal congestion, wheezing
patients with severe life-threatening infections. Miscellaneous: Fever (more common in children) >
235
AZTREONAM (ORAL INHALATION)

Rare but important or life-threatening: Arthralgia, facial

rash, facial swelling, hypersensitivity reaction, joint swel- Bacitracin (Systemic) (bas i TRAY sin)
ling, pharyngeal edema
Drug Interactions Medication Safety issues
Sound-alike/look-alike issues: i
Metabolism/Transport Effects None known.
Bacitracin may be confused with Bactrim, Bactroban
Avoid Concomitant Use There are no known interac-
Brand Names: US BACiiM
tions where it is recommended to avoid concomitant use.
Brand Names: Canada BaciJect
Increased Effect/Toxicity There are no known signifi-
Therapeutic Category Antibiotic, Miscellaneous
cant interactions involving an increase in effect.
Generic Availability (US) Yes
Decreased Effect
Use Treatment of pneumonia and empyema in infants
Aztreonam (Oral Inhalation) may decrease the levels/
caused by susceptible staphylococci (FDA approved in
effects of: Lactobacillus and Estriol
infants); Note: Due to toxicity risks, systemic use of
Storage/Stability Prior to reconstitution, store at 2°C to
bacitracin is rare and should be limited to situations where
8°C (36°F to 46°F). Once removed from refrigeration,
less toxic alternatives would not be effective.
aztreonam and the diluent may be stored at room temper-
Pregnancy Considerations This product is not indicated
ature (up to 25°C [77°F]) for $28 days. Protect from light.
for use in women of reproductive age.
Use immediately after reconstitution.
Breastfeeding Considerations This product is not indi-
Mechanism of Action Inhibits bacterial cell wall syn-
cated for use in women of reproductive age.
thesis by binding to one or more of the penicillin-binding
Contraindications Hypersensitivity to bacitracin or any
proteins (PBPs), which in turn inhibits the final trans-
component of the formulation
peptidation step of peptidoglycan synthesis in bacterial
Warnings/Precautions [US Boxed Warning]: IM use
cell walls, thus inhibiting cell wall biosynthesis. Bacteria
may cause renal failure due to tubular and glomerular
eventually lyse due to ongoing activity of cell wall autolytic
necrosis; monitor renal function daily. Avoid concur-
enzymes (autolysins and murein hydrolases), while cell
rent use with other nephrotoxic drugs; discontinue use if
wall assembly is arrested. Monobactam structure makes
toxicity occurs. Maintain adequate fluid intake and hydra-
cross-allergenicity with beta-lactams unlikely.
tion throughout therapy. Do not exceed recommended
Pharmacodynamics/Kinetics (Adult data unless doses. Use with caution in patients who have been pre-
noted) viously exposed to bacitracin; anaphylactic reactions have
Absorption: Low systemic absorption occurred on repeat exposure especially with irrigation use
Protein binding: 56% (Damm 2011; Elsner 1990; Farley 1995). Prolonged use
Half-life elimination: Adults: 2.1 hours may result in fungal or bacterial superinfection, including
Excretion: Urine (10% [compared with 60% to 70% for C. difficile-associated diarrhea (CDAD) and pseudomem-
injection] as unchanged drug) branous colitis; CDAD has been observed >2 months
Dosing postantibiotic treatment. Do not administer intravenously
Pediatric Cystic fibrosis (Pseudomonas aeruginosa): because severe thrombophlebitis occurs. Should only be
Inhalation (nebulizer): Children 27 years and Adoles- used when adequate laboratory facilities are available and
cents: 75 mg via nebulization 3 times daily (at least 4 constant patient supervision is available.
hours apart) for 28 days; administer in repeated cycles of Warnings: Additional Pediatric Considerations Ana-
28 days on drug, followed by 28 days off drug phylactic reactions may occur on repeat exposure; ana-
Renal Impairment: Pediatric Inhalation (nebulized): phylaxis and other hypersensitivity reactions have been
No adjustment required. reported with application of bacitracin ointment and with
Hepatic Impairment: Pediatric There are no dosage intraprocedure irrigation use; use with caution in patients
adjustments provided in the manufacturer's labeling. who have been previously exposed to bacitracin (Damm,
Preparation for Administration Inhalation: Reconstitute 2011; Elsner, 1990; Farley, 1995). Procaine is recom-
immediately prior to use. Squeeze diluent into opened mended in the preparation of solutions to lessen pain of
glass vial of Cayston. Replace rubber stopper and gently injection; avoid use in patients with hypersensitivity to
swirl vial until contents have completely dissolved. procaine.
Administration Inhalation: Administer only using an Bacitracin is seldom used systemically; consider confir-
Altera nebulizer system; dose can be nebulized over 2 mation of use and route with prescriber prior to admin-
to 3 minutes. Administer alone; do not mix with other istration. Bacitracin is a mixture of antimicrobial
inhaled nebulizer medications. Administer doses 24 hours polypeptides and should be dosed in "units".
apart. Administer a bronchodilator before administration of Adverse Reactions
aztreonam (short-acting 15 minutes to 4 hours before; Dermatologic: Skin rash
long-acting: 30 minutes to 12 hours before). For patients Endocrine & metabolic: Albuminuria
on multiple inhaled therapies, administer bronchodilator Gastrointestinal: Nausea, vomiting
first, then mucolytic, and lastly, aztreonam. Genitourinary: Azotemia, casts in urine, nephrotoxicity
Monitoring Parameters Inhalation: FEV, Local: Pain at injection site
Dosage Forms Excipient information presented when Renal: Renal failure
available (limited, particularly for generics); consult spe- Rare but important or life-threatening: Anaphylaxis (intra-
cific product labeling. operative exposure [Damm, 2011])
Solution Reconstituted, Inhalation [preservative free]: Drug Interactions
Cayston: 75 mg (1 mL) [arginine free] Metabolism/Transport Effects None known.
Avoid Concomitant Use
@ Azulfidine see SulfaSALAzine on page 1882
Avoid concomitant use of Bacitracin (Systemic) with any
@ Azulfidine EN-tabs see SulfaSALAzine on page 1882 of the following: BCG (Intravesical); Cholera Vaccine:
® B-2-400 [OTC] see Riboflavin on page 1758 Colistimethate; Kanamycin; Neomycin; Polymyxin B;
@ B6 see Pyridoxine on page 1720 Streptomycin
Increased Effect/Toxicity
® B-12 Compliance Injection see Cyanocobalamin
Bacitracin (Systemic) may increase thelevels/effects of.
on page 528
Neuromuscular-Blocking Agents
@ B-663 see Clofazimine on page 484
The levels/effects of Bacitracin (Systemic) may be
® Baby Anbesol [OTC] see Benzocaine on page 257
increased by: Colistimethate; Kanamycin; Neomycin;
® Baby Aspirin see Aspirin on page 194 Polymyxin B; Streptomycin
@ Baby Ayr Saline [OTC] see Sodium Chloride Decreased Effect
on page 1834 Bacitracin (Systemic) may decrease the levels/effects of.
® BabyBIG see Botulism Immune Globulin (Intravenous- BCG (Intravesical); BCG Vaccine (Immunization); Chol-
Human) on page 289 era Vaccine; Lactobacillus and Estriol; Sodium Picosul-
fate
@ Bacid [OTC] see Lactobacillus on page 1166
Storage/Stability Solution for injection (IM use only):
@ Bacid (Can) see Lactobacillus on page 1166 Store unreconstituted vials in the refrigerator at 2°C te
@ BACIiiM see Bacitracin (Systemic) on page 236 8°C (36°F to 46°F). Once reconstituted, bacitracin is
stable for 1 week under refrigeration at 2°C to 8°C (36°F
® BaciJect (Can) see Bacitracin (Systemic) on page 236
to 46°F).
@ Bacillus Calmette-Guérin (BCG) Live see BCG Vaccine Mechanism of Action Inhibits bacterial cell wall syn-
(Immunization) on page 248 thesis by preventing transfer of mucopeptides into the
@ Bacitin (Can) see Bacitracin (Topical) on page 237 growing cell wall
 BACITRACIN (TOPICAL)

Pharmacodynamics/Kinetics (Adult data unless Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
noted) Mechanism of Action Inhibits bacterial cell wall syn-
Absorption: Rapidly following IM administration thesis by preventing transfer of mucopeptides into the
Distribution: Widely distributed in all body organs and is growing cell wall
demonstrable in ascitic and pleural fluids after IM Dosing
injection Pediatric Ophthalmic infection: Infants, Children, and
Excretion: Urine Adolescents: Ophthalmic: Apply ribbon 1 to 3 times daily
Dosing Administration Ophthalmic: For topical ophthalmic use
Neonatal Pneumonia and empyema; staphylococcal: only; apply directly to conjunctival sac; avoid gross con-
Note: Due to toxicity risks, systemic use of bacitracin tamination of ointment during application. For blepharitis;
should be limited to situations where less toxic alterna- after carefully removing all scales and crusts, apply uni-
tives would not be effective; systemic use in neonatal formly over lid margins.
patients is rare. Do not administer IV:
Dosage Forms Excipient information presented when
Neonates: IM:
available (limited, particularly for generics); consult spe-
$2.5 kg: 900 units/kg/day in 2 to 3 divided doses
cific product labeling. [DSC] = Discontinued product
>2.5 kg: 1000 units/kg/day in 2 to 3 divided doses
Ointment, Ophthalmic:
Pediatric
Pneumonia and empyema; staphylococcal: Note: Generic: 500 units/g (1 g [DSC], 3.5 g)
Due to toxicity risks, systemic use of bacitracin should
be limited to situations where less toxic alternatives Bacitracin (Topical) (bas i TRAY sin)
would not be effective; systemic use in pediatric
patients is rare. Do not administer IV: Medication Safety Issues
Infants: IM: Sound-alike/look-alike issues:
$2.5 kg: 900 units/kg/day in 2 to 3 divided doses Bacitracin may be confused with Bactrim, Bactroban
>2.5 kg: 1000 units/kg/day in 2 to 3 divided doses Brand Names: Canada Bacitin
Preparation for Administration Parenteral: IM: Bacitra- Therapeutic Category Antibiotic, Topical
cin sterile powder should be dissolved in NS; although the Generic Availability (US) Yes
manufacturer recommends using NS containing 2% pro-
Use Prevention of infection in minor cuts, scrapes, or burns
caine hydrochloride, this product is no longer available in
(FDA approved in pediatric patients [age not specified]
the US market. Concentration after reconstitution should
and adults)
be between 5,000 to 10,000 units/mL. Do not use diluents
containing parabens; cloudy solutions and precipitation Pregnancy Considerations Although large studies have
have occurred. not been conducted, absorption is limited following topical
- Administration Parenteral: Bacitracin is seldom used application; use during pregnancy has not been associ-
systemically, consider confirmation of use and route with ated with an increased risk of adverse fetal events (Leach-
prescriber prior to administration. For IM administration man, 2006; Murase, 2014).
only; administer to upper outer quadrant of the buttocks; Breastfeeding Considerations Absorption is limited
rotate administration site. Do not administer IV. following topical application (Murase, 2014). Although
Monitoring Parameters Renal function tests, fluid intake, large studies have not been conducted, use of topical
urine output bacitracin in breastfeeding women has not been associ-
Dosage Forms Excipient information presented when ated with an increased risk of adverse events in the
available (limited, particularly for generics); consult spe- nursing infant (Leachman, 2006).
cific product labeling. [DSC] = Discontinued product Contraindications Hypersensitivity to bacitracin or any
Solution Reconstituted, Intramuscular: component of the formulation
BACiiM: 50,000 units (1 ea) Warnings/Precautions Use with caution in patients who
Generic: 50,000 units (1 ea) have been previously exposed to bacitracin; anaphylactic
Solution Reconstituted, Intramuscular [preservative free]: reactions have occurred on repeat exposure (Elsner,
Generic: 50,000 units (1 ea [DSC]) 1990, Farley, 1995)

Topical anti-infective (self-medication, OTC use): Use

Bacitracin (Ophthalmic) (bas
iTRaY sin) longer than 1 week is not recommended unless directed
by prescriber. Do not use in eyes or over large areas of the
Medication Safety Issues
body. Seek advice from healthcare provider prior to use for
Sound-alike/look-alike issues:
deep puncture wounds, bites, or serious burns or if con-
Bacitracin may be confused with Bactrim, Bactroban
dition persists for longer than 1 week. Stop use and
Therapeutic Category Antibiotic, Ophthalmic
consult health care provider if allergic reaction or rash
Generic Availability (US) Yes
develops.
Use Treatment of superficial ocular infections involving the
conjunctiva or cornea due to bacterial infections (has Adverse Reactions Rare but important or life-threaten-
activity against gram-positive bacilli) (FDA approved in ing: Anaphylaxis (Elsner, 1990; Farley, 1995)
pediatric patients [age not specified] and adults) Drug Interactions
Pregnancy Considerations Bacitracin is not absorbed Metabolism/Transport Effects None known.
systemically following ophthalmic administration (Robert, Avoid Concomitant Use There are no known interac-
2001). lf ophthalmic agents are needed during pregnancy, tions where it is recommended to avoid concomitant use.
the minimum effective dose should be used in combina- Increased Effect/Toxicity There are no known signifi-
tion with punctual occlusion to decrease potential expo- cant interactions involving an increase in effect.
sure to the fetus (Samples, 1988). Decreased Effect There are no known significant inter-
Breastfeeding Considerations Bacitracin is not actions involving a decrease in effect.
absorbed systemically following ophthalmic administration Storage/Stability Topical ointment (OTC): Store at 15°C
(Robert, 2001). to 30°C (59°F to 86°F).
Contraindications Hypersensitivity to bacitracin or any Mechanism of Action Inhibits bacterial cell wall syn-
component of the formulation thesis by preventing transfer of mucopeptides into the
Warnings/Precautions Use with caution in patients who growing cell wall
have been previously exposed to bacitracin; anaphylactic Pharmacodynamics/Kinetics (Adult data unless
reactions have occurred on repeat exposure (Elsner,
noted) Absorption: Poor from mucous membranes and
1990; Farley, 1995). Should not be used in deep seated
intact or denuded skin
ocular infections or if infection is likely to become sys-
temic. Prolonged use may result in overgrowth of non- Dosing
susceptble organisms, particularly fungi; if new infection Pediatric Prevention of infection: Infants, Children, and
develops, initiate appropriate therapy. Adolescents: Topical: Apply small amount 1 to 3 times
Adverse Reactions daily; duration of therapy >7 days is not recommended,
Hypersensitivity: Hypersensitivity reaction (Hatinen, 1985) unless directed by health care provider.
Rare but important or life-threatening: Contact dermatitis Administration Clean the affected area. Apply a small
(Pichichero, 2011) amount of product (an amount equal to the surface area of
Drug Interactions s the tip of a finger); may cover with sterile bandage.
Metabolism/Transport Effects None known. Dosage Forms Excipient information presented when
Avoid Concomitant Use There are no known interac- available (limited, particularly for generics); consult spe-
tions where it is recommended to avoid concomitant use. cific product labeling.
Increased Effect/Toxicity There are no known signifi- Ointment, External, as zinc [strength expressed as base]:
cant interactions involving an increase in effect. Generic: 500 units/g (1 ea, 19, 149, 14.17 9g, 14.2 g,
Decreased Effect There are no known significant inter- 15g, 28g, 28.359, 28.49, 30g, 113.49, 425g,
actions involving a decrease in effect. 453.6 g, 453.9 g)

237
BACITRACIN AND POLYMYXIN B (OPHTHALMIC)

Mechanism of Action See individual agents.

Bacitracin and Polymyxin B Pharmacodynamics/Kinetics (Adult data unless
(Ophthalmic) (bas i TRAY sin & pol i MIKS in bee) noted) See individual agents.
Absorption: Insignificant from intact skin or mucous mem-
Brand Names: US Ak-Poly-Bac; Polycin; Polycin B brane D
[DSC] Dosing
Brand Names: Canada LID-Pack; Optimyxin
Pediatric Prevention of infection: Infants, Children, and
Therapeutic Category Antibiotic, Ophthalmic
Adolescents: Topical ointment: Apply to the affected area
Generic Availability (US) Yes
1 to 3 times daily; may cover with sterile bandage if
Use Treatment of superficial infections involving the con-
needed
junctiva and/or cornea caused by susceptible organisms
Administration Topical: Cleanse affected area before
(FDA approved in adults)
application. Apply a small amount of product (an amount
Pregnancy Risk Factor C
equal to the surface area of the tip of a finger); may be
Pregnancy Considerations Animal reproduction studies
have not been conducted with this combination. covered by a sterile bandage if necessary.
Breastfeeding Considerations. It is not known if baci- Dosage Forms Excipient information presented when
tracin or polymyxin B are excreted into breast milk. The available (limited, particularly for generics); consult spe-
manufacturer recommends that caution be exercised cific product labeling. [DSC] = Discontinued product
when administering to nursing women. Ointment, External:
Contraindications Hypersensitivity to bacitracin, poly- Double Antibiotic: Bacitracin 500 units and polymyxin B
myxin B, or any component of the formulation 10,000-units per g (1 ea, 14.17 g, 28.35 g, 28.4 g)
Adverse Reactions See individual agents. Polysporin: Bacitracin 500 units and polymyxin B 10,000
Hypersensitivity: Anaphylaxis units per g (1 ea [DSC], 14.2 g, 28.3 g)
Ophthalmic: Burning sensation of eyes, conjunctival eryth-
ema, eye pruritus, swelling of eye
Drug Interactions Bacitracin, Neomycin, and Polymyxin B
Metabolism/Transport Effects None known. (Ophthalmic)
Avoid Concomitant Use There are no known interac- (bas i TRAY sin, nee oh MYE sin, & pol i MIKS in bee)
tions where it is recommended to avoid concomitant use.
Brand Names: US Neo-Polycin
Increased Effect/Toxicity There are no known signifi-
Therapeutic Category Antibiotic, Ophthalmic
cant interactions involving an increase in effect.
Decreased Effect There are no known significant inter- Generic Availability (US) Yes
actions involving a decrease in effect. Use Short-term treatment of superficial infections involving
Mechanism of Action See individual agents. the conjunctiva and/or cornea caused by susceptible
Pharmacodynamics/Kinetics (Adult data unless organisms (FDA approved in adults)
noted) See individual agents. Pregnancy Risk Factor C
Absorption: Insignificant from intact skin or mucous mem- Pregnancy Considerations Animal reproduction studies
brane have not been conducted with this combination.
Dosing Breastfeeding Considerations It is not known if baci-
Pediatric Conjunctivitis: Infants, Children, and Adoles- tracin, neomycin, or polymyxin B are excreted in breast
cents: Ophthalmic: Apply to affected eye(s) 4 times daily milk. The manufacturer recommends that caution be
(Giggliotti 1984; Wald 1997) exercised when administering to breastfeeding women.
Renal Impairment: Pediatric There are no dosage Contraindications Hypersensitivity to neomycin, poly-
adjustments provided in the manufacturer's labeling. myxin B, bacitracin, or any component of the formulation
Hepatic Impairment: Pediatric There are no dosage Warnings/Precautions Neomycin may cause cutaneous
adjustments provided in the manufacturer’s labeling.
sensitization. Symptoms of neomycin sensitization include
Administration Ophthalmic: Do not use topical ointment
itching, reddening, edema, and failure to heal. Discontin-
in the eyes; wash hands before use; avoid contact of tube
uation of product and avoidance of similar products should
tip with skin or eye
Dosage Forms Excipient information presented when be considered. May retard corneal wound healing. Pro-
available (limited, particularly for generics); consult spe- longed use may lead to overgrowth of nonsusceptible
cific product labeling. [DSC] = Discontinued product organisms, including fungi. If superinfection is suspected,
Ointment, Ophthalmic: institute appropriate alternative therapy.
Polycin: Bacitracin 500 units and polymyxin B 10,000 Adverse Reactions
units per g (3.5 g) Local: Failure to heal, irritation, itching, swelling
Polycin B: Bacitracin 500 units and polymyxin B 10,000 Ophthalmic: Conjunctival edema
units per g (3.5 g [DSC]) Miscellaneous: Anaphylaxis
Generic: Bacitracin 500 units and polymyxin B 10,000 Drug Interactions
units per g (3.5 g) Metabolism/Transport Effects None known.
Ointment, Ophthalmic [preservative free]:
Avoid Concomitant Use There are no known interac-
AK-Poly-Bac: Bacitracin 500 units and polymyxin B
tions where it is recommended to avoid concomitant use.
10,000 units per g (3.5 g)
Increased Effect/Toxicity There are no known signifi-
cant interactions involving an increase in effect.
Bacitracin and Polymyxin B (Topical) Decreased Effect There are no known significant inter-
(bas i TRAY sin & pol i MIKS in bee)
actions involving a decrease in effect.
Brand Names: US Double Antibiotic [OTC]; Polysporin Storage/Stability Store at room temperature.
[OTC] Mechanism of Action
Therapeutic Category Antibiotic, Topical Bacitracin: Inhibits bacterial cell wall synthesis by prevent-
Generic Availability (US) Yes ing transfer of mucopeptides into the growing cell wall.
Use Prevent infection in minor cuts, scrapes, and burns Neomycin: Interferes with bacterial protein synthesis by
(OTC product: Approval ages not specified) binding to 30S ribosomal subunits.
Pregnancy Risk Factor C Polymyxin B: Binds to phospholipids, alters permeability,
Pregnancy Considerations Animal reproduction studies and damages the bacterial cytoplasmic membrane per-
have not been conducted with this combination. mitting leakage of intracellular constituents.
Breastfeeding Considerations It is not known if baci- Pharmacodynamics/Kinetics (Adult data unless
tracin or polymyxin B are excreted into breast milk. The
noted) See individual agents.
manufacturer recommends that caution be exercised
Dosing
when administering to nursing women.
Pediatric Conjunctivitis: Limited data available: Chil-
Contraindications Hypersensitivity to bacitracin, poly-
myxin B, or any component of the formulation dren and Adolescents: Ophthalmic: Apply 0.5 inch ribbon
Adverse Reactions See individual agents. every 3 to 4 hours for acute infections, or 2 to 3 times per
Drug Interactions day for mild to moderate infections, for 7 to 10 days
Metabolism/Transport Effects None known. (Pichichero 2011)
Avoid Concomitant Use There are no known interac- Renal Impairment: Pediatric There are no dosage
tions where it is recommended to avoid concomitant use. adjustments provided in the manufacturer's labeling.
Increased Effect/Toxicity There are no known signifi- Hepatic Impairment: Pediatric There are no dosage
cant interactions involving an increase in effect. adjustments provided in the manufacturer's labeling.
Decreased Effect There are no known significant inter- Administration Ophthalmic: Wash hands prior to applica-
actions involving a decrease in effect. tion; avoid contamination of the tip of the ointment tube

238
 BACITRACIN, NEOMYCIN, POLYMYXIN B, AND HYDROCORTISONE (OPHTHALMIC)

Dosage Forms Excipient information presented when

available (limited, particularly for generics); consult spe- Bacitracin, Neomycin, Polymyxin B, and
cific product labeling. Hydrocortisone (Ophthalmic)
Ointment, Ophthalmic: (bas i TRAY sin, nee oh MYE sin, pol i MIKS in bee, & hye droe KOR
Neo-Polycin: Bacitracin 400 units, neomycin 3.5 mg, and ti sone)
polymyxin B 10,000 units per g (3.5 g) Brand Names: US Neo-Polycin HC
Generic: Bacitracin 400 units, neomycin 3.5 mg, and
Therapeutic Category Antibiotic, Ophthalmic; Cortico-
polymyxin B 10,000 units per g (3.5 g) steroid, Ophthalmic
Generic Availability (US) Yes
Bacitracin, Neomycin, and Polymyxin B Use Prevention and treatment of susceptible inflammatory
(Topical) conditions where bacterial infection (or risk of infection) is
(bas i TRAY sin, nee oh MYE sin, & pol i MIKS in bee) present (FDA approved in adults)
Pregnancy Risk Factor C
Brand Names: US Curad Triple Antibiotic [OTC]; Medi- Pregnancy Considerations Adverse events have been
First Triple Antibiotic [OTC]; Neosporin. Original [OTC]; observed with topical corticosteroids in animal reproduc-
Triple Antibiotic [OTC] tion studies. If ophthalmic agents are needed during
Therapeutic Category Antibiotic, Topical pregnancy, the minimum effective dose should be used
Generic Availability (US) Yes in combination with punctual occlusion to decrease poten-
Use Prevent infection in minor cuts, scrapes, and burns tial exposure to the fetus (Samples, 1988). Refer to
(OTC product; FDA approval ages not specified) individual agents.
Pregnancy Risk Factor C Breastfeeding Considerations It is not known if sys-
_ Pregnancy Considerations Animal reproduction studies temic absorption following topical administration results in
detectable quantities in human milk. The manufacturers
have not been conducted with this combination.
recommend a decision be made whether to discontinue
Breastfeeding Considerations It is not known if baci-
nursing or to discontinue the drug, taking into account the
tracin, neomycin, or polymyxin B is excreted into breast
importance of treatment to the mother. Refer to individual
milk.
agents.
Contraindications Hypersensitivity to neomycin, poly- Contraindications Hypersensitivity to bacitracin, neomy-
myxin B, zinc bacitracin, or-any component of the for- cin, polymyxin B, hydrocortisone, or any component of the
mulation; mycobacterial or fungal infections; topical formulation; most viral diseases of the cornea and con-
ointments for external use only junctiva, including epithelial herpes simplex keratitis (den-
Warnings/Precautions Topical ointment: When used for dritic keratitis), vaccinia and varicella; mycobacterial
self-medication (OTC use), patients should notify health- ophthalmic infection; fungal diseases of ocular structures.
care provider if needed for >1 week. Should not be used Warnings/Precautions Steroids may mask infection,
for self-medication on deep or puncture wounds, animal enhance existing ocular infection, or reactivate latent
bites, or serious burns. Not for application to large areas of disease (eg, herpes infection of cornea); prolonged use
the body. may result in secondary bacterial or fungal superinfection
Adverse Reactions due to immunosuppression. Lack of prompt clinical
Dermatologic: Allergic contact dermatitis, reddening response may indicate resistance to therapy and warrant
Local: Failure to heal, irritation, itching, swelling discontinuation of therapy and further evaluation.
Miscellaneous: Anaphylaxis Neomycin may cause cutaneous sensitization. Symptoms
Drug Interactions of neomycin sensitization include itching, reddening,
Metabolism/Transport Effects None known. edema, and failure to heal. Discontinuation of product
Avoid Concomitant Use There are no known interac- and avoidance of similar products should be considered.
tions where it is recommended to avoid concomitant use.
Avoid prolonged use of corticosteroids, which may result
Increased Effect/Toxicity There are no known signifi-
in ocular hypertension and/or glaucoma, with damage to
cant interactions involving an increase in effect.
the optic nerve, defects in visual acuity and fields of vision,
Decreased Effect There are no known significant inter- and posterior subcapsular cataract formation. Use with
actions involving a decrease in effect. caution in glaucoma. Monitor intraocular pressure (rou-
Mechanism of Action See individual agents. tinely if duration of therapy is >10 days). Long-term use
Pharmacodynamics/Kinetics (Adult data unless may cause corneal and scleral thinning; potentially result-
noted) See individual agents. ing in perforation. Ophthalmic ointments may retard cor-
Dosing neal wound healing.
Pediatric Prevention of infection: Infants, Children, and
For topical use only. Do not inject subconjunctivally or
Adolescents: Topical: Apply to affected area1 to 3 times
introduce directly into anterior chamber of the eye. Use
daily following ocular cataract surgery may delay healing and
Renal Impairment: Pediatric There are no dosage increase the incidence of filtering blebs. Inadvertent con-
adjustments provided in the manufacturer’s labeling. tamination of multiple-dose ophthalmic tube tip has
However, dosage adjustment unlikely due to low sys- caused bacterial keratitis. Use of topical corticosteroids
temic absorption. to prevent scarring in the healing stages of herpes simplex
Hepatic Impairment: Pediatric There are no dosage infection should be done with extreme caution and close
adjustments provided in the manufacturer's labeling. observation; may reactivate disease. A maximum of 8 g
However, dosage adjustment unlikely due to low sys- should be prescribed initially; reevaluate patients (eg,
temic absorption. intraocular pressure and exams using magnification and
Administration Topical: Clean the affected area prior to fluorescein staining, where appropriate) prior to additional
use. Apply a small amount of product (an amount equal to refills. Use >10 days should include routine monitoring of
the surface area of the tip of a finger); may cover with intraocular pressure.
sterile bandage. Adverse Reactions See individual agents.
Dosage Forms Excipient information presented when Drug Interactions
available (limited, particularly for generics); consult spe- Metabolism/Transport Effects None known.
cific product labeling. [DSC] = Discontinued product Avoid Concomitant Use There are no known interac-
Ointment, External: tions where it is recommended to avoid concomitant use.
Curad Triple Antibiotic: Bacitracin 400 units, neomycin Increased Effect/Toxicity
3.5 mg, and polymyxin B 5000 units per g (1 ea) Bacitracin, Neomycin, Polymyxin B, and Hydrocortisone
(Ophthalmic) may increase the levels/effects of: Rito-
Medi-First Triple Antibiotic: Bacitracin 400 units, neo-
drine
mycin 3.5 mg, and polymyxin B 5000 units per g (1 ea)
Neosporin Original: Bacitracin 400 units, neomycin The levels/effects of Bacitracin, Neomycin, Polymyxin B,
3.5 mg, and polymyxin B 5000 units per g (1 ea, and Hydrocortisone (Ophthalmic) may be increased by:
14.2 g, 15 g [DSC], 28.3 g) Nonsteroidal Anti-Inflammatory Agents (Ophthalmic)
Triple Antibiotic: Bacitracin 400 units, neomycin 3.5 mg, Decreased Effect There are no known significant inter-
and polymyxin B 5000 units per g (1 ea, 1g, 9.4g, actions involving a decrease in effect.
149, 14.29, 15g, 28 g, 28.4 g, 30 g, 453.9 g) Storage/Stability Store at 15°C to 30°C (59°F to 86°F).
Generic: Bacitracin 400 units, neomycin 3.5 mg, and Mechanism of Action See individual agents.
polymyxin B 5000 units per g (1 ea [DSC], 14.17 g Pharmacodynamics/Kinetics (Adult data unless
[DSC], 28.35 g [DSC}]) noted) See individual agents.

239
 BACITRACIN, NEOMYCIN, POLYMYXIN B, AND HYDROCORTISONE (OPHTHALMIC)

4 Dosing
Pediatric Inflammatory ocular conditions: Limited
Topical ointment: Limit therapy to 7 days of treatment.
Warnings: Additional Pediatric Considerations The
data available: Children and Adolescents: Ophthalmic: extent of percutaneous absorption is dependent on sev-
Apply sparingly to inside of lower lid of affected eye(s) eral factors, including epidermal integrity (intact vs
every 3 to 4 hours has been used by some centers; abraded skin), formulation, age of the patient, prolonged
dosing based on experience with other combination duration of use, and the use of occlusive dressings.
ophthalmic products with similar ingredients Percutaneous absorption of topical steroids is increased
Renal Impairment: Pediatric There are no dosage in neonates (especially preterm neonates), infants, and
adjustments provided in the manufacturer's labeling; young children. Infants and small children may be more
however, dosage adjustment unlikely due to low sys- susceptible to HPA axis suppression, intracranial hyper-
temic absorption. tension, Cushing syndrome, or other systemic toxicities
Hepatic Impairment: Pediatric There are no dosage due to larger skin surface area to body mass ratio.
adjustments provided in the manufacturer's labeling; Adverse Reactions See individual agents.
however, dosage adjustment unlikely due to low sys- Drug Interactions
temic absorption. Metabolism/Transport Effects Refer to individual
Administration Ophthalmic: Do. not use topical ointment components.
in the eyes; wash hands before use; avoid contact of tube Avoid Concomitant Use
tip with skin or eye Avoid concomitant use of Bacitracin, Neomycin, Poly-
Monitoring Parameters If ophthalmic ointment is used myxin B, and Hydrocortisone (Topical) with any of the
>10 days or in patients with glaucoma, monitor intraocular following: Aldesleukin
pressure (IOP). Increased Effect/Toxicity
Dosage Forms Excipient information presented when Bacitracin, Neomycin, Polymyxin B, and Hydrocortisone
available (limited, particularly for generics); consult spe- (Topical) may increase the levels/effects of: Ceritinib;
cific product labeling. Deferasirox; Ritodrine
Ointment, Ophthalmic:
Decreased Effect
Neo-Polycin HC: Bacitracin 400 units, neomycin 3.5 mg,
Bacitracin, Neomycin, Polymyxin B, and Hydrocortisone
polymyxin B 10,000 units, and hydrocortisone 10 mg
(Topical) may decrease the levels/effects of: Aldesleukin;
per g (3.5 g) Corticorelin; Hyaluronidase
Generic: Bacitracin 400 units, neomycin 3.5 mg, poly-
myxin B 10,000 units, and hydrocortisone 10 mg per Storage/Stability Store at 15°C to 25°C (59°F to 77°F).
Mechanism of Action See individual agents.
g (3.5 g)
Pharmacodynamics/Kinetics (Adult data unless
noted) See individual agents.
Bacitracin, Neomycin, Polymyxin B, and Dosing
Hydrocortisone (Topical) Pediatric Superficial dermal infection: Limited data
(bas i TRAY sin, nee oh MYE sin, pol i MIKS in bee, & hye droe KOR available: Children and Adolescents: Topical: Apply 2
ti sone) to 4 times daily for up to 7 days (Bradley 2015)
Brand Names: US Cortisporin Renal Impairment: Pediatric There are no dosage
Brand Names: Canada Cortisporin Topical Ointment adjustments provided in manufacturer's labeling; how-
Therapeutic Category Antibiotic, Topical; Corticosteroid, ever, dosage adjustment unlikely due to low systemic
Topical absorption.
Generic Availability (US) No Hepatic Impairment: Pediatric There are no dosage
Use Treatment of corticosteroid-responsive dermatoses adjustments provided in manufacturer's labeling; how-
with secondary infection (FDA approved in adults) ever, dosage adjustment unlikely due to low systemic
Pregnancy Risk FactorC absorption.
Pregnancy Considerations Adverse events have been Administration For external use only. Apply sparingly to
observed with topical corticosteroids in animal reproduc- the affected area. Limit therapy to 7 days of treatment.
tion studies. Refer to individual agents. Monitoring Parameters Growth in pediatric patients;
Breastfeeding Considerations It is not known if sys- assess HPA axis suppression in patients using topical
temic absorption following-topical administration results in steroids applied to a large surface area or to areas under
detectable quantities in human milk. The manufacturers of occlusion (eg, ACTH stimulation test, morning plasma
the topical ointment recommend a decision be made cortisol test, urinary free cortisol test).
whether to discontinue nursing or to discontinue the drug, Dosage Forms Excipient information presented when
taking into account the importance of treatment to the available (limited, particularly for generics); consult spe-
mother. Refer to individual agents. cific product labeling.
Contraindications Hypersensitivity to bacitracin, neomy- Ointment, External:
cin, polymyxin B, hydrocortisone, or any component of the Cortisporin: Bacitracin 400 units, neomycin 3.5 mg, poly-
formulation. myxin B 5000 units, and hydrocortisone 10 mg per
Warnings/Precautions Topical corticosteroids may be g (15 g)
absorbed percutaneously. Absorption of topical cortico-
steroids may cause manifestations of Cushing syndrome, Bacitracin, Neomycin, Polymyxin B, and
hyperglycemia, or glycosuria. Absorption is increased by
the use of occlusive dressings, application to denuded Pramoxine
skin, or application to large surface areas. Systemic (bas i TRAY sin, nee oh MYE sin, pol i MIKS in bee, & pra MOKS
een)
absorption of topical corticosteroids may cause hyper-
cortisolism or suppression of hypothalamic-pituitary-adre- Brand Names: US Neosporin® + Pain Relief Ointment
nal (HPA) axis, particularly in younger children or in [OTC]; Tri Biozene [OTC]
patients receiving high doses for prolonged periods. HPA Therapeutic Category Antibiotic, Topical
axis suppression may lead to adrenal crisis. Prolonged Generic Availability (US) Yes
use may increase the incidence of secondary infection,
Use Prevention and treatment of susceptible superficial
mask acute infection (including fungal infections), prolong
topical infections and to provide temporary relief of pain
or exacerbate viral infections, or limit response to vac-
or discomfort (OTC: FDA approved in ages 22 years and
cines.
adults)
Children may absorb proportionally larger amounts of Contraindications Hypersensitivity to bacitracin, neomy-
corticosteroids after topical application and may be more cin, polymyxin B, pramoxine, or any component of the
prone to systemic effects. HPA axis suppression, intra- formulation
cranial hypertension, and Cushing syndrome have been Warnings/Precautions Use longer than 1 week is not
reported in children receiving topical corticosteroids. Pro- recommended unless directed by prescriber. Do not use in
longed use may affect growth velocity; growth should be eyes or over large areas of the body. Seek advice from
routinely monitored in pediatric patients. health care provider prior to use for deep puncture
Neomycin may cause cutaneous sensitization. Symptoms wounds, bites, or serious burns, or if condition lasts longer
of neomycin sensitization include itching, reddening, than 1 week. Stop use and consult healthcare provider if
edema, and failure to heal. Discontinuation of product rash or allergic reaction occurs.
and avoidance of similar products should be considered. Storage/Stability Store at room temperature.
Neomycin can induce permanent sensorineural hearing Dosing
loss due to cochlear damage; risk is greater with pro- Pediatric Prevention of infection and relief of pain
longed use. Prolonged treatment with corticosteroids has and discomfort: Children 22 years and Adolescents:
been associated with the development of Kaposi sarcoma Topical: Ointment: Apply a small amount (should not
(case reports); if noted, discontinuation of therapy should exceed surface area of fingertip) to affected area 1 to 3
be considered (Goedert 2002). times daily; may cover with sterile bandage if necessary

240
 BACLOFEN

Renal Impairment: Pediatric There are no dosage Contraindications

adjustments provided in the manufacturer's labeling; Hypersensitivity to baclofen or any component of the
however, dosage adjustment unlikely due to low sys- formulation
temic absorption. Intrathecal: IV, IM, SubQ, or epidural administration
Hepatic Impairment: Pediatric There are no dosage Warnings/Precautions [US Boxed Warning]: Abrupt
adjustments provided in the manufacturer's labeling; withdrawal of intrathecal baclofen, regardless of the
however, dosage adjustment unlikely due to low sys- cause, has resulted in sequelae (hyperpyrexia, altered
temic absorption. mental status, exaggerated rebound spasticity, and
Administration Topical: For application to the skin; avoid muscle rigidity, which, in rare cases, has advanced
eyes. Clean the affected area prior to use. Apply to to rhabdomyolysis), multiple organ-system failure,
affected area; may cover with a sterile bandage. Wash and death. Prevention of abrupt discontinuation
. hands after application. requires careful attention to programming and mon-
itoring of infusion system, refill scheduling and pro-
Dosage Forms Excipient information presented when
cedures, and pump alarms. Advise patients and
available (limited, particularly for generics); consult spe-
caregivers of the importance of keeping scheduled
cific product labeling.
refill visits and educate them on the early symptoms
Ointment, topical: Bacitracin 500 units, neomycin 3.5 mg,
of baclofen withdrawal. Give special attention to
polymyxin B 10,000 units, and pramoxine hydrochloride
patients at apparent risk (eg, spinal cord injuries at
10'mg (15 g, 30 g)
T-6 or above, communication difficulties, history of
Neosporin® + Pain Relief Ointment: Bacitracin 500 units,
withdrawal symptoms from oral or intrathecal baclo-
neomycin 3.5 mg, polymyxin B 10,000 units, and pra- fen). Consult the technical manual of the implantable
moxine hydrochloride 10 mg per g (15 g, 30 g) infusion system for additional postimplant clinician
Tri Biozene: Bacitracin 500 units, neomycin 3.5 mg, and patient information. In most cases, symptoms of
polymyxin B 10,000 units, and pramoxine hydrochlor- withdrawal (eg, return of baseline spasticity, hypotension,
ide 10 mg per g (15 g) paresthesia, pruritus) appear within hours to a few days
following interruption of therapy. Priapism may develop or
@ Bacitracin/Polymyxin B Sulfate see Bacitracin and
recur if treatment with intrathecal baclofen is interrupted.
Polymyxin B (Topical) on page 238
Clinically, the advanced intrathecal baclofen withdrawal
@ Bacitracin Zinc/Polymyx B Sulfate see Bacitracin and syndrome may resemble autonomic dysreflexia, infection
Polymyxin B (Topical) on page 238 (sepsis), malignant hyperthermia, neuroleptic-malignant
syndrome, or other conditions associated with a hyper-
Baclofen (Bak ioe fen) metabolic state or widespread rhabdomyolysis. Sug-
gested treatment for intrathecal baclofen withdrawal is
Medication Safety Issues restoration of intrathecal baclofen at or near the same
Sound-alike/look-alike issues: dosage as before therapy was interrupted. Abrupt with-
Baclofen may be confused with Bactroban drawal of oral therapy has been associated with halluci-
Lioresal may be confused with lisinopril, Lotensin nations and seizures; gradual dose reductions (over ~1 to
High alert medication: 2 weeks) are recommended in the absence of severe
The Institute for Safe Medication Practices (ISMP) adverse reactions.
includes this medication (intrathecal administration) Use with caution in patients with peptic ulcer disease,
among its list of drugs which have a heightened risk decreased GI motility, and/or gastrointestinal obstructive
of causing significant patient harm when used in error. disorders; respiratory disease; seizure disorder; urinary
Brand Names: US EnovaRX-Baclofen; Equipto-Baclofen obstruction; psychotic disorders, schizophrenia, or confu-
[DSC]; First-Baclofen 1; First-Baclofen 5; Gablofen; Lior- sional states; and in the elderly. Use with caution in
esal; Lioresal Intrathecal patients with renal impairment; baclofen is eliminated
Brand Names: Canada Lioresal; Lioresal D.S.; Lioresal primarily unchanged via the kidneys. Multiple cases
Intrathecal describing neurotoxicity due to oral baclofen accumulation
Therapeutic Category Skeletal Muscle Relaxant, Non- in adult patients with varying levels of renal impairment
paralytic have been reported in the literature. In patients with renal
Generic Availability (US) May be product dependent impairment, initiation of oral baclofen at lower doses and/
Use or extended intervals has been suggested (Aisen 1994;
Chen 1997; Chou 2006; El-Husseini 2011; Peces 1998;
Oral: Management of reversible spasticity associated with
Su, 2009; Viavonu 2014). May cause CNS depression,
multiple sclerosis or spinal cord lesions (FDA approved
which may impair physical or mental abilities; patients
in ages 212 years and adults)
must be cautioned about performing tasks which require
Intrathecal: Management of severe spasticity of spinal
mental alertness (eg, operating machinery or driving).
cord origin (eg, spinal cord injury, multiple sclerosis) or
Potentially significant interactions may exist, requiring
cerebral origin (eg, cerebral palsy, traumatic brain injury); ‘
dose or frequency adjustment, additional monitoring,
may also be considered as an alternative to destructive and/or selection of alternative therapy.
neurosurgical procedures (All indications: FDA approved
in ages 24 years and adults). Note: Patients should first Intrathecal use: Use intrathecal baclofen with caution in
respond to a screening dose of intrathecal baclofen prior patients with a history of autonomic dysreflexia; presence
to consideration for long-term infusion via an implantable of nociceptive stimuli or abrupt baclofen withdrawal may
pump. For spasticity of spinal cord origin, chronic infu- cause an autonomic dysreflexic episode.
sion via an implantable pump should be reserved for Appropriate use: For use only in an FDA-approved
patients unresponsive to oral baclofen therapy, or those implantable pump for intrathecal baclofen administration;
who experience intolerable CNS side effects at effective health care providers should be experienced with chronic
doses. Patients with spasticity due to traumatic brain intrathecal infusion therapy and resuscitative equipment
injury should wait at least one year after the injury before should be readily available. Ensure patient is infection-
consideration of long term intrathecal baclofen therapy. free and then evaluate patient’s response to bolus intra-
Pregnancy Risk Factor C thecal injection (screening phase) prior to implanting
Pregnancy Considerations Adverse events have been pump. Monitor closely during the initial phase of pump
observed in animal reproduction studies. Withdrawal use and when adjusting the dosing rate and/or the
symptoms in the neonate were noted in a case report concentration in the reservoir. Educate patients and
following the maternal use of oral baclofen 20 mg 4 times/ caregivers on proper home care of the pump and inser-
day throughout pregnancy (Ratnayaka 2001). Plasma tion site. Use extreme caution when filling an implantable
concentrations following administration of intrathecal pump; pumps should only be refilled through the reser-
baclofen are significantly less than those with oral doses; voir refill septum. Inadvertent injection into the subcuta-
exposure to the fetus is expected to be limited (Morton neous tissue can occur if the reservoir refill septum is not
2009). properly accessed. Some pumps are equipped with a
Breastfeeding Considerations Baclofen is present in catheter access port that allows direct access to the
breast milk. Very small amounts were found in the breast intrathecal catheter; direct injection into this catheter
milk of a female 14 days postpartum after oral use. access port or inadvertent injection into the subcutane-
Following a single oral dose of baclofen 20 mg, the total ous tissue may cause a life-threatening overdose.
amount of baclofen present in breast milk within 26 hours Except in overdose related emergencies, intrathecal
baclofen should be reduced slowly if discontinuation is
was 22 mcg (Eriksson 1981). Adverse events were not
necessary.
observed in a breastfed infant following maternal use of
intrathecal baclofen 200 mcg/day throughout pregnancy Overdose: Monitor closely for signs and symptoms of
and while breastfeeding (Morton 2009). Due to the poten- overdose which may appear suddenly or insidiously,
tial for adverse events in the breastfed infant, breastfeed- especially during the initial screening and dose-titration
ing is not recommended by the manufacturer. phase of treatment, and during reintroduction of therapy

241
 BACLOFEN

4 after a period of interruption. Signs/symptoms

dose may include drowsiness, dizziness, somnolence,
of over- Storage/Stability
Injection: Do not store above 30°C (86°F). Does not
hypothermia, respiratory depression, seizures, rostral require refrigeration. Do not freeze or heat sterilize.
progression of hypotonia and loss of consciousness Discard any unused solution.
progressing to coma. If overdose is suspected, patient Tablets: Store at 20°C to 25°C (68°F to 77°F). ;
should be evaluated immediately in a hospital setting Mechanism of Action Inhibits the transmission of both
and the pump reservoir emptied. monosynaptic and polysynaptic reflexes at the spinal cord
level, possibly by hyperpolarization of primary afferent
Intrathecal mass: Cases (most from pharmacy com- fiber terminals, with resultant relief of muscle spasticity
pounded preparations) of intrathecal mass formation at
Pharmacodynamics/Kinetics (Adult data unless
the implanted catheter tip have been reported; patients
noted)
may experience worsening or return of spasticity, pain,
Onset of action: Intrathecal bolus: 30 minutes to 1 hour;
inadequate response to dose adjustments and/or neuro-
Continuous infusion: 6 to 8 hours after infusion initiation
logical deficit/dysfunction. Neurosurgical evaluation and/ Peak effect: Intrathecal bolus: 4 hours (effects may last 4
or an appropriate imaging study should be considered if to 8 hours); Continuous infusion: 24 to 48 hours
amass is suspected. Absorption (dose dependent): Oral: Rapid; absorption
Pediatric: Children should be of sufficient body mass to from the Gl tract is thought to be dose dependent; in
accommodate the implantable pump for chronic infusion. pediatric patients (age range: 2 to 17 years) with cerebral
palsy, absorption from GI tract highly variable and
Oral use: Efficacy of oral baclofen has not been estab- delayed (reported time lag: 0.59 + 0.28 hours) (He 2014)
lished in patients with stroke, Parkinson disease, or cere- Bioavailability: Oral: 74% (Agarwal 2015)
bral palsy; therefore, use is not recommended. Not Protein binding: 30%
indicated for spasticity associated with rheumatic disor- Volume of distribution: Pediatric patients (age range: 2 to
ders. Use with caution when spasticity is utilized to sustain 17 years: Oral: Highly variable: 1.16 L/kg with 43.5%
upright posture and balance in locomotion, or when spas- interindividual variability (He 2014)
ticity is necessary to obtain increased function. Metabolism: Hepatic (15% of dose) (He 2014)
Adverse Reactions Half-life elimination:
Cardiovascular: Hypotension, peripheral edema Oral: :
Central nervous system: Abnormality in thinking, agitation, Pediatric patients with cerebral palsy (age range: 2 to
chills, coma, confusion, depression, dizziness, drowsi- 17 years): 4.5 hours (He 2014)
ness, headache, hypertonia, hypotonia, insomnia, pain, Adults: 3.75 + 0.96 hours (Brunton 2011)
paresthesia, seizure, speech disturbance Intrathecal: CSF elimination half-life: 1.51 hours over the
Dermatologic: Pruritus, urticaria first 4 hours
Gastrointestinal: Constipation, diarrhea, nausea, sialor- Time to peak, serum: Oral: 1 hour (0.5 to 4 hours)
rhea, vomiting, xerostomia (Brunton 2011)
Genitourinary: Difficulty in micturition, impotence, urinary Excretion: Urine (>70% as unchanged drug) and feces
frequency, urinary incontinence, urinary retention (Brunton 2011)
Neuromuscular & skeletal: Back pain, tremor, weakness Dosing
Ophthalmic: Ambylopia Pediatric
Respiratory: Dyspnea, hypoventilation, pneumonia Spasticity:
Miscellaneous: Accidental injury Oral: Note: Dose-related side effects (eg, sedation)
Rare but important or life-threatening: Abdominal pain, may be minimized by slow titration; lower initial doses
accommodation disturbance, akathisia, albuminuria, alo- than described below (2.5 to 10 mg daily) may be
pecia, amnesia, ankle edema, anorexia, anxiety, apnea, used with subsequent titration to 8 hourly doses.
ataxia, blurred vision, bradycardia, carcinoma, chest There is limited published data in infants and children;
pain, contact dermatitis, decreased libido, deep vein the following is a compilation of small prospective
thrombophlebitis, dehydration, dermal ulcer, diaphoresis, studies (Milla 1977; Scheinberg 2006) and one large
diplopia, dysarthria, dysautonomia, dysgeusia, dyspha- retrospective analysis of baclofen use in. children
gia, dystonia, dysuria, epilepsy, erectile dysfunction, (Lubsch 2006). Efficacy results variable (AAN [Del-
euphoria, excitement, facial edema, fecal incontinence, gado 2010)):
fever, gastrointestinal hemorrhage, hallucination, hema- Infants 24 months and Children <2 years: Limited
turia, hyperglycemia, hyperhidrosis, hypertension, data available: 10 to 20 mg daily divided every 8
hyperventilation, hypothermia, hysteria, inhibited ejacu- hours; begin at low end of range and titrate dose to
patient response, titration intervals of every 3 days
lation, intestinal obstruction, leukocytosis, loss of pos-
to weekly have been used in pediatric patients 22
tural reflex, malaise, miosis, muscle rigidity, myalgia,
years (Millia 1997; Scheinberg 2006). Maximum
mydriasis, nasal congestion, nephrolithiasis, nocturia,
daily dose: 40 mg/day (Lubsch 2006). Note: To
nystagmus, occult blood in stools, oliguria, opisthotonus,
minimize dose-related side effects (eg, sedation),
orgasm disturbance, pallor, palpitations, paranoia, per-
lower initial doses (eg, 2.5 mg once daily) and
sonality disorder, petechial rash, priapism, pulmonary
slower titration may be considered (eg, weekly)
embolism, scoliosis, scoliosis progression, sedation,
and has been reported in pediatric patients >2 years
sexual disorder, skin rash, slurred speech, strabismus,
(Scheinberg 2006).
suicidal ideation, syncope, taste disorder, tinnitus,
Children 2 to 7 years: Limited data available: 20 to
tongue irritation, vaginitis, vasodilatation, weight gain,
40 mg daily divided every 8 hours; begin at low end
weight loss of range (or even lower [2.5 to 10 mg daily] and
Drug Interactions titrate dose to patient response; titration intervals of
Metabolism/Transport Effects None known. every 3 days to weekly have been used in pediatric
Avoid Concomitant Use patients. Maximum daily dose: 60 mg/day (Lubsch
Avoid concomitant use of Baclofen with any of the 2006; Millia 1997; Scheinberg 2006)
following: Azelastine (Nasal); Bromperidol; Orphena- Children 28 years and Adolescents: Limited data
drine; Oxomemazine; Paraldehyde; Thalidomide available in children <12 years: 30 to 40 mg daily
Increased Effect/Toxicity divided every 8 hours; begin at low end of range (or
Baclofen may increase the levels/effects of: Alcohol even lower [10 mg to 15 mg daily in 3 divided
(Ethyl); Azelastine (Nasal); Blonanserin; Buprenorphine; doses]) and titrate dose to patient response, titration
CNS Depressants; Flunitrazepam; HY DROcodone; Laci- intervals of every 3 days to weekly have been used
dipine; Methotrimeprazine; MetyroSINE; Mirtazapine; (Millia 1997; Scheinberg 2006); some patients 212
Opioid Analgesics; Orphenadrine; OxyCODONE; Paral- years may require every 6 hour dosing; usual max-
dehyde; Piribedil; Pramipexole; ROPINIRole; Rotigotine; imum daily dose range: 60 to 80 mg/day (Lubsch
Selective Serotonin Reuptake Inhibitors; Suvorexant; 2006; Millia 1977). Note: Higher maximum daily
Thalidomide; Zolpidem doses (up to 200 mg/day) have been described in
some patients in a retrospective review, usually the
The levels/effects of Baclofen may be increased by: higher doses were needed over time (Lubsch 2006).
Brimonidine (Topical); Bromopride; Bromperidol; Canna- Intrathecal: Note: Dosage adjustments may be
bis; Chlormethiazole; Chlorphenesin Carbamate; Dime- required often during the first few months of therapy
thindene (Topical); Doxylamine; Dronabinol; Droperidol; to adjust for life style changes due to alleviation of
HydrOXYzine; Kava Kava; Lofexidine; Magnesium Sul- spasticity. Maintain lowest dose that produces
fate; Methotrimeprazine; Minocycline; Nabilone; Oxome- adequate response. Most patients require gradual
mazine; Perampanel; Rufinamide; Sodium Oxybate; increases over time to maintain optimal response.
Tapentadol; Tetrahydrocannabinol; Tolperisone; Trime- Sudden large requirements for a dose increase may
prazine indicate a catheter complication (eg, kink, dislodge-
Decreased Effect There are no known significant inter- ment). Titrate dose to allow sufficient muscle tone and
actions involving a decrease in effect. occasional spasms to optimize activities of daily living,

242
 BACLOFEN

support circulation, and possibly prevent DVT forma- Parenteral: Intrathecal: Screening dosage: Administer as
tion. Use extreme caution when filling the pump; a bolus injection by barbotage into the subarachnoid
follow manufacturer instructions carefully. With space over at least 1 minute, followed by maintenance
chronic therapy, 5% to 10% of patients will become infusion via implantable infusion pump; do not abruptly
refractory to dose adjustments; may consider a drug discontinue intrathecal baclofen administration
holiday (hospitalized patients only) with a gradual Monitoring Parameters Muscle rigidity, spasticity
withdrawal over 2 to 4 weeks and use of alternative (decrease in number and severity of spasms), modified
spasticity management methods. Following the drug Ashworth score. Regular electroencephalogram (EEG) in
holiday intrathecal baclofen may be resumed at the patients with epilepsy (loss of seizure control has been
initial continuous infusion dose. Limited data available reported).
in children <4 years old, dosing for this age group Dosage Forms Considerations
based on expert consensus recommendations (Ber- EnovaRX-Baclofen and Equipto-Baclofen creams are
weck 2014). compounded from kits. Refer to manufacturer’s labeling
Screening dose: for compounding instructions.
Children <4 years: Limited data available: Initial: 25 First-Baclofen suspension is a compounding kit. Refer to
meg; if response is inadequate, double the initial manufacturer’s labeling for compounding instructions.
dose and administer 24 hours after the first dose Dosage Forms Excipient information presented when
(Berweck 2014) available (limited, particularly for generics); consult spe-
Children 24 years and Adolescents: Initial: 50 mcg (1 cific product labeling. [DSC] = Discontinued product
mL) for 1 dose; following initial administration, Cream, External:
observe patient for 4 to 8 hours. A positive response EnovaRX-Baclofen: 1% (60g, 120g) [contains cetyl
consists of a significant decrease in muscle tone alcohol] ;
and/or frequency and/or severity of spasms. If Equipto-Baclofen: 2% (120 g [DSC])
response is inadequate, may give 75 mcg as a Generic: 2% (60 g)
second screening dose 24 hours after the first Solution, Intrathecal:
screening dose; observe patient for 4 to 8 hours. If Gablofen: 40,000 mcg/20 mL (20 mL [DSC})
response is still inadequate, may repeat a final Solution, Intrathecal [preservative free]:
screening dose of 100 mcg given 24 hours after Gablofen: 10,000 mcg/20 mL (20 mL); 20,000 mcg/20
the second screening dose. Patients not responding mL (20 mL) [antioxidant free]
to screening dose of 100 mcg should not be consid- Gablofen: 40,000 mcg/20 mL (20 mL)
ered for chronic infusion/implanted pump. Note: A Lioresal: 0.05 mg/mL (1 mL); 10 mg/20 mL (20 mL
25 mcg initial screening dose may be considered in [DSC]); 10 mg/5 mL 5 mL [DSC]); 40 mg/20 mL (20
very small pediatric patients. mL [DSC}) [antioxidant free]
Dose titration following pump implant: Children and Lioresal Intrathecal: 40 mg/20 mL (20 mL) [antioxi-
Adolescents: After positive response to screening dant free]
dose, a maintenance intrathecal infusion can be Lioresal Intrathecal: 500 mcg/mL (20 mL); 2000 mcg/mL
administered via an implanted intrathecal pump. (5 mL) [antioxidant free, pyrogen free]
Initial total daily dose via pump: Children and Adoles- Solution Prefilled Syringe, Intrathecal [preservative free]:
cents: Double the screening dose that gave a pos- Gablofen: 50 mcg/mL (1 mL) [antioxidant free, latex free]
itive response and administer over 24 hours, unless Gablofen: 50 mcg/mL (1 mL [DSC]); 10,000 mcg/20 mL
efficacy of the bolus dose was maintained for >8 (20 mL [DSC]); 40,000 mcg/20 mL (20 mL [DSC)});
hours, then infuse a dose equivalent to the screen- 20,000 mcg/20 mL (20 mL) [antioxidant free]
ing dose over 24 hours. Do not increase dose in first Gablofen: 10,000 mcg/20 mL (20 mL); 40,000 mcg/20
24 hours (to allow steady state to be achieved); mL (20 mL) [antioxidant free, pyrogen free]
thereafter, increase daily dose slowly by 5% to Suspension, Oral:
15% once every 24 hours until satisfactory response
First-Baclofen 1: 1 mg/mL (120 mL) [contains saccharin
is achieved; usual range: 50 to 100 mcg daily sodium, sodium benzoate]
(Berweck 2014). First-Baclofen 5: 5 mg/mL (60 mL, 120 mL) [contains
Titration to maintenance dose: Children 24 years and
saccharin sodium, sodium benzoate; grape flavor]
Adolescents: Daily dose may be increased 5% to
Tablet, Oral:
20% (maximum increase: 20%); may also be
Generic: 5 mg, 10 mg, 20 mg
decreased 10% to 20% for adverse effects.
Extemporaneous Preparations Note: A baclofen sus-
Some experts have suggested the following titration
pension (1 mg/mL or 5 mg/mL) is commercially available
parameters: Children and Adolescents (Berweck
as a compounding kit (First-Baclofen). Compounded oral
2014):
suspension may be available in multiple concentrations
Inpatient titration: May adjust by 10% to 20% of
(eg, up to 10 times more concentrated); use caution to
dose (usual dose change is 50 mcg); maximum
avoid confusion; verify concentration.
increment change: 100 mcg
5 mg/mL Oral Suspension (ASHP Standard Concen-
Outpatient titration: May adjust by 10% of daily
tration) (ASHP 2017)
dose (usual dose change is 25 mcg)
A 5 mg/mL oral suspension may be made with tablets.
Usual maintenance dose; Children and Adolescents:
Crush thirty 20 mg tablets in a mortar and reduce to a
100 to 2,000 mcg daily (Berweck 2014); the manu-
fine powder. Add a small amount of glycerin and mix to a
facturer provides the following:
uniform paste. Mix while adding Simple Syrup, NF in
Children 4 to 12 years: 24 to 1,199 mcg daily (aver-
incremental proportions to almost 120 mL; transfer to a
age: 274 mcg/day)
calibrated bottle, rinse mortar with vehicle, and add a
Children 212 years and Adolescents: 90 to 703 mcg
sufficient quantity of vehicle to make 120 mL. Label
daily; daily doses have ranged from 22 mcg to 1,400
"shake well" and "refrigerate." Stable for 35 days (John-
mcg; experience with doses >1,000 mcg daily is
son 1993).
limited
Johnson CE, Hart SM. Stability of an extemporaneously compounded
Renal Impairment: Pediatric baclofen oral liquid. Am J Hosp Pharm. 1993;50(11):2353-2355.
Oral: There are no dosage adjustments provided in the
manufacturer's labeling; however, baclofen is primar- 10 mg/mL Oral Suspension: Note: Commercially avail-
ily renally eliminated; use with caution; dosage reduc- able suspension is more dilute (eg, up to 10 times more
tion may be necessary. dilute); use caution to avoid confusion; verify concen-
Intrathecal: Children and Adolescents: There are no trations.
dosage adjustments provided in the manufacturer’s A 10 mg/mL oral suspension may be made with tablets.
labeling; however, baclofen is primarily renally elimi- Crush one-hundred-twenty 10 mg tablets in a mortar and
nated; use with caution; dosage reduction may be reduce to a fine powder. Add small portions (60 mL) of a
necessary. 1:1 mixture of Ora-Sweet and Ora-Plus and mix to a
Hepatic Impairment: Pediatric Oral, Intrathecal: There uniform paste; mix while adding the vehicle in incremen-
are no dosage adjustments provided in the manufactur- tal proportions to almost 120 mL; transfer to a calibrated
er's labeling. bottle, rinse mortar with vehicle, and add quantity of
Preparation for Administration Parenteral: Intrathecal: vehicle sufficient to make 120 mL. Label "shake well"
For screening dosages, dilute with preservative-free and "refrigerate." Stable for 60 days (Allen 1996).
Allen LV Jr, Erickson MA 3rd. Stability of baclofen, captopril, diltiazem
sodium chloride to a final concentration of 50 mcg/mL.
hydrochloride, dipyridamole, and flecainide acetate in extemporane-
For maintenance infusions, concentrations of 500 to 2,000 ously compounded oral liquids. Am J Health Syst Pharm. 1996;53
mcg/mL may be used; if preparing a concentration that is (18):2179-2184.
not commercially available, preservative-free sodium
chloride must be used. @ Bacteriostatic Water see Water for Injection (Bacterio-
Administration static) on page 2077
Oral: Administer with food or milk @ Bactocill in Dextrose see Oxacillin on page 1510

243
BALANCED SALT SOLUTION

@ Bactrim see Sulfamethoxazole and Trimethoprim Balmex® [OTC] see Zinc Oxide on page 2088
on page 1878 Balminil Decongestant (Can) see Pseudoephedrine
® Bactrim DS see Sulfamethoxazole and Trimethoprim on page 1712
on page 1878 @ Balminil DM E (Can) see Guaifenesin and Dextrome-
Bactroban see Mupirocin on page 1412 thorphan on page 967 ‘
Bactroban Nasal see Mupirocin on page 1412 @ Balminil Expectorant (Can) see GuaiFENesin
@ Baking Soda see Sodium Bicarbonate on page 1832 on page 964
@ BAL see Dimercaprol on page 648 Bainetar [OTC] [DSC] see Coal Tar on page 505

Balanced Salt Solution Balsalazide (bai SAL a zide)

(BAL anced salt soe LOO shun)
Medication Safety Issues
Brand Names: US BSS; BSS Plus Sound-alike/look-alike issues:
Brand Names: Canada BSS; BSS Plus; Eye-Stream Colazal may be confused with Clozaril
Therapeutic Category Ophthalmic Agent, Miscellaneous Brand Names: US Colazal; Giazo
Generic Availability (US) Yes Therapeutic Category 5-Aminosalicylic Acid Derivative;
Use Irrigation during various intraocular surgical proce- Anti-inflammatory Agent
dures involving perfusion of the eye (BSS: procedure <1 Generic Availability (US) May be product dependent
hour; BSS Plus: procedures 21 hour) (FDA approved in Use :
pediatric patients [age not specified] and adults) Capsules: Short-term treatment of mildly to moderately
Contraindications There are no contraindications listed active ulcerative colitis (FDA approved in ages 25 years
in the manufacturer labeling and adults); Pediatric patients (5-17 years): 8 weeks of
Warnings/Precautions Not for injection or IV infusion. Do therapy; Adult patients: 12 weeks of therapy
not mix with other additives (may cause corneal decom- Tablets (Giazo™): Short-term treatment (8 weeks) of
pensation). Use with caution in patients with diabetes; mildly to moderately active ulcerative colitis (FDA
intraoperative lens changes have been observed when approved in males 218 years and adults)
undergoing vitrectomy procedure. Pregnancy Risk Factor B
BSS Plus: Do not use unless Part | of the product is fully Pregnancy Considerations Adverse events have not
reconstituted with Part Il. been observed in animal reproduction studies. Mesal-
Adverse Reactions Ophthalmic: Corneal decompensa- amine (5-aminosalicylic acid) is the active metabolite of
tion, corneal edema, corneal opacity, ophthalmic inflam- balsalazide; mesalamine is known to cross the placenta.
mation Refer to the mesalamine monograph for additional infor-
Drug Interactions mation.
Metabolism/Transport Effects None known. Breastfeeding Considerations It is not known if balsa-
Avoid Concomitant Use There are no known interac- lazide is excreted in breast milk. The manufacturer rec-
tions where it is recommended to avoid concomitant use. ommends that caution be exercised when administering
Increased Effect/Toxicity There are no known signifi- balsalazide to nursing women. Mesalamine, 5-aminosali-
cant interactions involving an increase in effect. cylic acid, is the active metabolite of balsalazide. Low
Decreased Effect There are no known significant inter- levels of mesalamine enter breast milk; refer to the mesal-
actions involving a decrease in effect. amine monograph for additional information.
Storage/Stability Contraindications Hypersensitivity to balsalazide or its
Store at 2°C to 25°C (36°F to 77°F); do not freeze. metabolites, salicylates, or any component of the formu-
BSS Plus: Discard prepared solution after 6 hours. lation
Dosing Warnings/Precautions Pyloric stenosis may prolong
Pediatric Ocular irrigation: Infants, Children, and Ado- gastric retention of balsalazide. Renal toxicity and hepatic
lescents: Ophthalmic: Based on standard for each sur- failure have been observed with other mesalamine (5-
gical procedure aminosalicylic acid) products; use with caution in patients
Renal Impairment: Pediatric There are no dosage with known renal or hepatic disease. Symptomatic wor-
adjustments provided in manufacturer’s labeling. sening of ulcerative colitis may occur following initiation of
Hepatic Impairment: Pediatric There are no dosage treatment. May cause an acute intolerance syndrome
adjustments provided in manufacturer’s labeling. (cramping, acute abdominal pain, bloody diarrhea; some-
Preparation for Administration BSS Plus: Prior to times fever, headache, rash); discontinue if this occurs.
administration, add contents of the Part II vial to the May cause staining of teeth or tongue if capsule is opened
contents of the Part | bottle using a vacuum transfer and sprinkled on food.
device. Alternatively, use a 20 mL syringe to remove the Warnings: Additional Pediatric Considerations May
Part II solution from the vial and transfer exactly 20 mL to exacerbate symptoms of ulcerative colitis; reported inci-
the Part | container through the outer target area of the dence higher in children than adults (6% vs 1%). Children
rubber stopper. An excess volume of Part Il is provided in may experience a higher frequency of some adverse
each vial. Mix gently. Do not mix with other additives. Final effects than adults, including: Headache (15% vs 8%),
product pH: 7.4. abdominal pain (~13% vs 6%), and vomiting (10% vs
Administration Ophthalmic: Not for injection or IV infu- <4%).
sion. For administration by surgeon in surgical suite. Do Adverse Reactions
not use if discolored or contains a precipitate. Use an Central nervous system: Fatigue, headache (more com-
administration set with an air-inlet in the plastic spike mon in children than adults), insomnia
(bottle does not contain separate airway tube). Allow fluid Gastrointestinal: Abdominal cramps, abdominal pain
to freely flow to remove air from the tubing prior to (more common in children than adults), anorexia, con-
irrigation. stipation, diarrhea, dyspepsia, exacerbation of ulcerative
BSS Plus: If a second bottle of reconstituted BSS Plus is colitis, flatulence, hematochezia, nausea, stomatitis,
needed to complete a surgical procedure, vent vacuum vomiting, xerostomia
in the second bottle prior to attachment to the admin- Genitourinary: Dysmenorrhea, urinary tract infection
istration set. Hematologic & oncologic: Anemia i
Dosage Forms Excipient information presented when Neuromuscular & skeletal: Arthralgia, musculoskeletal
available (limited, particularly for generics); consult spe- pain, myalgia
cific product labeling. Respiratory: Cough, flu-like symptoms, pharyngitis, phar-
Solution, ophthalmic [irrigation; preservative free]: yngolaryngeal pain, respiratory infection, rhinitis
BSS: Sodium chloride 0.64%, potassium chloride Miscellaneous: Fever
0.075%, calcium chloride 0.048%, magnesium chloride
Rare but important or life-threatening: Alopecia, back pain,
0.03%, sodium acetate 0.39%, sodium citrate 0.17%
bowel urgency, bronchopneumonia, cholestatic jaundice,
(15 mL, 30 mL, 250 mL, 500 mL)
dizziness, dyspnea, edema, erythema nodosum, facial
BSS Plus: Sodium chloride 0.71%, potassium chloride
edema, fecal impaction, gastroenteritis, gastroesopha-
0.038%, calcium chloride 0.015%, magnesium chloride
geal reflux disease, hepatic cirrhosis, hepatic failure,
0.02%, sodium phosphate 0.042%, sodium bicarbon-
hepatic injury, hepatic necrosis, hepatotoxicity, hyper-
ate 0.21%, dextrose 0.092%, glutathione 0.018% (250
mL, 500 mL)
bilirubinemia, hypersensitivity reaction, increased blood
pressure, increased heart rate, increased liver enzymes,
Generic: Sodium chloride 0.64%, potassium chloride
0.075%, calcium chloride 0.048%, magnesium chloride increased serum AST, interstitial nephritis, jaundice,
0.03%, sodium acetate 0.39%, sodium citrate 0.17% Kawasaki-like syndrome, lethargy, malaise, myocarditis,
(18 mL, 200 mL, 250 mL, 500 mL) pain, pancreatitis, pericarditis, pleural effusion, pneumo-
nia (with and without eosinophilia), pruritus, renal failure,
® Bal in Oil see Dimercaprol on page 648 skin rash, vasculitis

244
 BARIUM

Drug Interactions Tablet, Oral, as disodium:

Metabolism/Transport Effects None known. Giazo: 1.1 g
Avoid Concomitant Use There are no known interac-
¢@ Balsalazide Disodium see Balsalazide on page 244
tions where it is recommended to avoid concomitant use.
Increased Effect/Toxicity Banophen [OTC] see DiphenhydrAMINE (Systemic)
Balsalazide may increase the levels/effects of: Heparin; on page 652
Heparins (Low Molecular Weight); Thiopurine Analogs; @ Banophen [OTC] see DiphenhydrAMINE (Topical)
Varicella Virus-Containing Vaccines on page 656
The levels/effects of Balsalazide may be increased by: @ Banzel see Rufinamide on page 1793
Nonsteroidal Anti-Inflammatory Agents @ Baraclude see Entecavir on page 745
Decreased Effect @ Baridium [OTC] [DSC] see Phenazopyridine
» Balsalazide may decrease the levels/effects of: Cardiac on page 1605
Glycosides
Storage/Stability Store at controlled room temperature of
20°C to 25°C (68°F to 77°F); excursions permitted to 15°C Barium (BA ree um)
to 30°C (59°F to 86°F).
Medication Safety Issues
Mechanism of Action Balsalazide is a prodrug, con-
Sound-alike/look-alike issues:
verted by bacterial azoreduction to 5-aminosalicylic acid
VoLumen may be confused with Voluven
(mesalamine, active), 4-aminobenzoyl-B-alanine (inert),
and their metabolites. 5-aminosalicylic acid may decrease Brand Names: US E-Z-Cat Dry; E-Z-Disk; E-Z-Dose; E-
inflammation by blocking the production of arachidonic Z-HD; E-Z-Paque; E-Z-Paste; Entero VU; Liquid E-Z-
acid metabolites topically in the colon mucosa. Paque; Liquid Polibar Plus; Liquid Polibar [DSC]; Polibar
ACB [DSC]; Readi-Cat'2; Tagitol V; Varibar Honey; Varibar
Pharmacodynamics/Kinetics (Adult data unless
Nectar; Varibar Pudding; Varibar Thin Honey; Varibar Thin
noted)
Liquid; Volumen
Onset of action: Delayed; may require several days to
weeks (2 weeks); similar in adults and children Therapeutic Category Radiopaque Agents
Absorption: Very low and variable; in children, reported Generic Availability (US) No
systemic absorption of 5-ASA (active) lower than adults Use Diagnostic aid for computed tomography or x-ray
(Cmax: 67% lower, AUC: 64% lower) examinations of the Gl tract (FDA approved in all ages).
Protein binding: Balsalazide: 299% Note: Approved ages in pediatric patients may vary; refer
Metabolism: Azoreduced in the colon to 5-aminosalicylic to product-specific labeling.
acid (active), 4-aminobenzoyl-B-alanine (inert), and N- Pregnancy Considerations Barium is not systemically
acetylated metabolites absorbed; use is not expected to result in exposure to the
Half-life elimination: Primary effect is topical (colonic fetus. In general, elective radiography of the abdomen is
mucosa); therapeutic effect appears not to be influenced avoided during pregnancy but should not be withheld
by the systemic half-life of balsalazide (1.9 hours) or its when essential for diagnosis (ACOG 2016).
metabolites (5-ASA [9.5 hours], N-Ac-5-ASA [10.4 Breastfeeding Considerations Barium is not systemi-
hours]) cally absorbed; use is not expected to result in exposure
Time to peak: Balsalazide: Capsule: 1 to 2 hours; Tablet: to a breastfeeding infant.
0.5 hours Contraindications
Excretion: Feces (65% as 5-aminosalicylic acid, 4-amino- Hypersensitivity to barium or any component of the for-
benzoyl-B-alanine, and N-acetylated metabolites); urine mulation; gastric or intestinal perforation (known or sus-
(<16% as N-acetylated metabolites); Parent drug: Urine pected).
or feces (<1%) Additional contraindications may vary (refer to specific
Pharmacodynamics/Kinetics: Additional Consider- product labeling):
ations Oral formulations: Known obstruction of the GI tract;
Ulcerative colitis: May have increased AUC. patients at high risk of GI perforation (eg, recent prior
Dosing Gl perforation, acute G] hemorrhage or ischemia, toxic
Pediatric megacolon, severe ileus, post Gl surgery or biopsy,
Ulcerative colitis: acute Gl injury or burn, recent radiotherapy to the
Children 25 years and Adolescents $17 years: Oral: pelvis); patients at high risk of aspiration (eg, patients
Capsules: 2.25 g/day or 6.75 g/day for up to 8 weeks with prior aspiration, tracheoesophageal fistula, obtun-
administered as either: dation).
2.25 g (three 750 mg capsules) 3 times daily (total Rectal formulations: Toxic megacolon (known or sus-
daily dose: 6.75 g/day) pected); recent rectal surgery or radiotherapy to the
or rectum or prostate; use within 6 days of large forceps or
750 mg (one capsule) 3 times daily (total daily dose: "hot" colonic biopsy or a snare polypectomy.
2.25 g/day) : Jed We Warnings/Precautions Severe hypersensitivity reactions
Note: Limited blinded clinical trial in children did not have been reported; manifestations include hypotension,
demonstrate significant improvement between total bronchospasm and other respiratory impairments, and
daily doses of 6.75 g or 2.25 g (Quiros, 2009). dermal reactions including rashes, urticaria, and itching.
Adolescents 218 years: Oral: A history of bronchial asthma, atopy (as evidenced by hay
Capsule: 2.25 g (three 750 mg capsules) 3 times fever and eczema), food allergies, or a previous reaction
daily for up to 8-12 weeks to a contrast agent may increase this risk. Emergency
Tablet (Giazo™): Males: 3.3 g (three 1.1 g tablets) equipment and trained personnel should be immediately
twice daily for up to 8 weeks available and should remain available for at least 30 to 60
Renal Impairment: Pediatric There are no dosage minutes following administration (delayed reactions may
adjustments provided in manufacturer’s labeling. Renal occur). Administration may result in leakage of barium at
toxicity has been observed with other 5-aminosalicylic any level of the Gl tract in the presence of conditions that
acid products; use with caution. increase the risk of perforation such as carcinomas, Gl
Hepatic Impairment: Pediatric There are no dosage fistula, inflammatory bowel disease, gastric or duodenal
adjustments provided in manufacturer’s labeling. ulcer, appendicitis, or diverticulitis, and in patients with a
Administration severe stenosis at any level of the GI tract, especially if it
Capsules: Should be swallowed whole or may be opened is distal to the stomach. The barium leakage has been
and sprinkled on applesauce. Applesauce mixture may associated with peritonitis and granuloma formation.
be chewed; swallow immediately, do not store mixture for Barium may occasionally intravasate into the venous
later use. When sprinkled on food, may cause staining of drainage of the large bowel and enter the circulation as
teeth or tongue. Color variation of powder inside capsule a "barium embolus" leading to potentially fatal complica-
(ranging from orange to yellow) is expected. tions which include systemic and pulmonary embolism,
Tablets: Administer with or without food. disseminated intravascular coagulation, septicemia, and
Monitoring Parameters Improvement or worsening of prolonged severe hypotension. Monitor patients for poten-
symptoms; renal function (prior to initiation, then periodi- tial intravasation during administration.
cally); liver function tests
Use with caution in debilitated patients and in patients with
Additional Information Balsalazide 750 mg is equivalent marked hypertension and advanced cardiac disease,
to mesalamine 267 mg.
Dosage Forms Excipient information presented when Oral administration: Barium may accumulate proximal to a
available (limited, particularly for generics); consult spe- constricting lesion of the colon, causing obstruction or
cific product labeling. impaction with development of baroliths (inspissated
Capsule, Oral, as disodium: barium associated with feces) and may lead to abdominal
Colazal: 750 mg
>
pain, appendicitis, bowel obstruction, or, rarely, perfora-
Generic: 750 mg tion. Patients should maintain adequate hydration during

245
 BARIUM

q and in the days following procedure and consider the

administration of laxatives to reduce the risk of delayed
Suspension, Oral, as sulfate:
Entero VU: 24% (600. mL) [contains polysorbate 80,
Gl transit and obstruction. Oral administration is associ- saccharin sodium, sodium benzoate]
ated with aspiration pneumonitis, especially in patients Liquid E-Z-Paque: 60% (355 mL, 1900 mL [DSC)) [con-
with a history of food aspiration or with compromised tains saccharin sodium, sodium benzoate] :
swallowing mechanism. In patients at risk for aspiration, Liquid Polibar: 100% (1900 mL [DSC]) [contains saccha-
use with caution and begin the procedure with a small rin sodium, sodium benzoate]
volume. Some products are contraindicated in patients at Readi-Cat 2: 2% (450 mL [DSC]) [contains benzoic acid,
high risk of aspiration and some are not recommended in saccharin sodium, sodium benzoate; banana smoothie
patients with a history of food aspiration (refer to specific flavor]
product labeling). Monitor patient closely for aspiration; Readi-Cat 2: 2% (450 mL) [contains benzoic acid, sac-
discontinue immediately if aspiration is suspected, and charin sodium, sodium benzoate, sorbitol; banana
monitor for development of aspiration pneumonitis. flavor]
Readi-Cat 2: 2% (450 mL) [contains benzoic acid, sac-
Rectal formulations: Use rectal formulations with caution
charin sodium, sodium benzoate, sorbitol; berry flavor]
when obstructive lesions of the colon are suspected;
Readi-Cat 2: 2% (450 mL) [contains benzoic acid, sac-
minimize the amount of barium. allowed to flow proximal
charin sodium, sodium benzoate, sorbitol; mochaccino
to obstructive lesions of the colon.
flavor]
Some formulations may contain sodium or sorbitol. Sorbi- Readi-Cat 2: 2% (450 mL) [contains benzoic acid, sac-
tol may cause severe reactions (eg, vomiting, hypoglyce- charin sodium, sodium benzoate, sorbitol; vanilla
mia, jaundice, hemorrhage, hepatomegaly, hyperuricemia, flavor] :
kidney failure) in patients with hereditary fructose intoler- Readi-Cat 2: 2% (450 mL) [contains saccharin sodium,
ance; avoid formulations containing sorbitol in patients sodium benzoate, sorbitol; orange flavor]
with hereditary fructose intolerance. Readi-Cat 2: 2.1% (450 mL [DSC]) [contains benzoic
acid, saccharin sodium, sodium benzoate]
Some dosage forms may contain sodium benzoate/ben-
Readi-Cat 2: 2.1% (450 mL) [contains benzoic acid,
zoic acid; benzoic acid (benzoate) is a metabolite of
saccharin sodium, sodium benzoate; berry smoothie
benzyl alcohol; large amounts of benzyl alcohol
flavor] :
(299 mg/kg/day) have been associated with a potentially
Tagitol V: 40% (60 mL) [contains saccharin sodium,
fatal toxicity ("gasping syndrome") in neonates; the "gasp-
sodium benzoate; apple flavor]
ing syndrome" consists of metabolic acidosis, respiratory
Varibar Honey: 40% (250 mL) [contains polysorbate 80,
distress, gasping respirations, CNS dysfunction (including
saccharin sodium, sodium benzoate; apple flavor]
convulsions, intracranial hemorrhage), hypotension and
Varibar Nectar: 40% (240 mL) [contains polysorbate 80,
cardiovascular collapse (AAP 1997; CDC 1982); some
saccharin sodium, sodium benzoate; apple flavor]
data suggests that benzoate displaces bilirubin from pro-
Varibar Thin Honey: 40% (250 mL) [contains polysorbate
tein binding sites (Ahlfors 2001); avoid or use dosage
80, saccharin sodium, sodium benzoate; apple flavor]
forms containing benzyl alcohol derivative with caution in
VoLumen: 0.1% (450 mL) [contains benzoic acid, sac-
neonates. See manufacturer's labeling.
charin sodium, sodium benzoate; blueberry flavor]
Some dosage forms may contain polysorbate 80 (also Suspension Reconstituted, Oral, as sulfate:
known as Tweens). Hypersensitivity reactions, usually a E-Z-HD: 98% (135 mL) [contains saccharin sodium]
delayed reaction, have been reported following exposure E-Z-Paque: 96% (176 g, 1200 g [DSC}) [contains propy-
to pharmaceutical products containing polysorbate 80 in lene glycol, saccharin sodium]
certain individuals (Isaksson 2002; Lucente 2000; Shelley Varibar Thin Liquid: 40% (148 g) [contains polysorbate
1995). Thrombocytopenia, ascites, pulmonary deteriora- 80, saccharin sodium]
tion, and renal and hepatic failure have been reported in Tablet, Oral, as sulfate:
premature neonates after receiving parenteral products E-Z-Disk: 700 mg
containing polysorbate 80 (Alade 1986; CDC 1984). See
manufacturer's labeling. @ Barium Sulfate see Barium on page 245
@ Basaglar (Can) see Insulin Glargine on page 1091
Some dosage forms may contain propylene glycol; large
amounts are potentially toxic and have been associated Basaglar KwikPen see Insulin Glargine on page 1091
hyperosmolality, lactic acidosis, seizures, and respiratory Basaljel (Can) see Aluminum Hydroxide on page 100
depression; use caution (AAP 1997; Zar 2007). See Base Ointment see Zinc Oxide on page 2088
manufacturer's labeling.
Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
Protect suspension from freezing; protect tablets from Basiliximab (ba si Lik si mab)
moisture. Once Varibar pudding, nectar, and honey have
been opened, use within 21 days. Medication Safety Issues
Sound-alike/look-alike issues:
Mechanism of Action Barium is an insoluble material
Basiliximab may be confused with bezlotoxumab.
that is opaque to x-rays and therefore provides a positive
High alert medication:
contrast for radiographic studies.
This medication is in a class the Institute for Safe
Pharmacodynamics/Kinetics (Adult data unless
Medication Practices (ISMP) includes among its list of
noted)
drug classes that have a heightened risk of causing
Absorption: None
significant patient harm when used in error.
Metabolism: Not metabolized
Brand Names: US Simulect
Excretion: Feces
Brand Names: Canada Simulect
Administration
Oral: Refer to individual product labeling for dosage and
Therapeutic Category Monoclonal Antibody
administration information. Generic Availability (US) No
Rectal: Refer to individual product labeling for dosage and Use In combination with an immunosuppressive regimen
administration information. (cyclosporine and corticosteroids), induction therapy for
Dosage Forms Excipient information presented when the prophylaxis of acute organ rejection in patients receiv-
available (limited, particularly for generics); consult spe- ing renal transplants (FDA approved in pediatric patients
cific product labeling. [DSC] = Discontinued product {age not specified] and adults); basiliximab has also been
Cream, Oral, as sulfate: used in liver and heart transplant patients —
E-Z-Paste: 60% (454 g) [contains methylparaben, pro- Pregnancy Risk Factor B
pylparaben, saccharin sodium] Pregnancy Considerations
Enema, Rectal, as sulfate: Adverse effects were not observed in animal reproduction
E-Z-Dose: 105% (650 mL) [contains saccharin sodium, studies. Basiliximab is a monoclonal IgG antibody which
sodium benzoate] targets IL-2 receptors. IgG is known to cross the placenta;
Kit, Rectal, as sulfate: IL-2 receptors play an important role in the development of
Polibar ACB: 96% [DSC] the immune system.
Packet, Oral, as sulfate:
Women of childbearing potential should use effective
E-Z-Cat Dry: 2% (50 ea) [contains saccharin sodium]
contraceptive measures before beginning treatment, dur-
Paste, Oral, as sulfate:
ing, and for 4 months after completion of basiliximab
Varibar Pudding: 40% (230 mL) [contains polysorbate
treatment.
80, saccharin sodium, sodium benzoate; vanilla flavor]
Suspension, Combination, as sulfate: The Transplant Pregnancy Registry International (TPR) is
Liquid Polibar Plus: 105% (1900 mL) [contains saccharin a registry that follows pregnancies that occur in maternal
sodium, sodium benzoate] transplant recipients or those fathered by male transplant
Readi-Cat 2: 2.1% (450 mL [DSC}) [contains saccharin recipients. The TPR encourages reporting of pregnancies
sodium, sodium benzoate] following solid organ transplant by contacting them at

246
 BASILIXIMAB

1-877-955-6877 or https://www.transplantpregnancy- increase in fasting plasma glucose, lymphoproliferative

registry.org. disorder
Breastfeeding Considerations It is not known if basilix- Drug Interactions
imab is present in human milk. Because many immuno- Metabolism/Transport Effects None known.
globulins are secreted in milk and the potential for serious Avoid Concomitant Use
adverse reactions exists, a decision should be made to Avoid concomitant use of Basiliximab with any of the
discontinue breastfeeding or discontinue the drug, taking following: BCG (Intravesical); Belimumab; Natalizumab;
into account the importance of the drug to the mother. Pimecrolimus; Tacrolimus (Topical); Vaccines (Live)
Contraindications Known hypersensitivity to basiliximab Increased Effect/Toxicity
or any component of the formulation Basiliximab may increase the levels/effects of: Bariciti-
Warnings/Precautions To be used as a component of an nib; Belimumab; Fingolimod; Leflunomide; Natalizumab;
immunosuppressive regimen which includes cyclosporine Tofacitinib; Vaccines (Live)
and corticosteroids. The incidence of lymphoproliferative
disorders and/or opportunistic infections may be The levels/effects of Basiliximab may be increased by:
Denosumab; Ocrelizumab; Pimecrolimus; Roflumilast:
increased by immunosuppressive therapy. Severe hyper-
Tacrolimus (Topical); Trastuzumab
sensitivity reactions, occurring within 24 hours, have been
reported. Reactions, including anaphylaxis, have occurred
Decreased Effect
both with the initial exposure and/or following re-exposure Basiliximab may decrease the levels/effects of: BCG
after several months. Use caution during re-exposure to a (Intravesical); Coccidioides immitis Skin Test; Nivolu-
mab; Pidotimod; Sipuleucel-T; Tertomotide; Vaccines
subsequent course of therapy in a patient who has pre-
viously received basiliximab; patients in whom concom-
(Inactivated); Vaccines (Live)
itant immunosuppression was prematurely discontinued The levels/effects of Basiliximab may be decreased by:
due to abandoned transplantation or early graft loss are Echinacea
- at increased risk for developing a severe hypersensitivity Storage/Stability Store intact vials refrigerated at 2°C to
reaction upon re-exposure. Discontinue permanently if a 8°C (36°F to 46°F). Should be used immediately after
severe reaction occurs. Medications for the treatment of reconstitution; however, if not used immediately, reconsti-
hypersensitivity reactions should be available for immedi- tuted solution may be stored at 2°C to 8°C for up to 24
ate use. Treatment may result in the development of hours or at room temperature for up to 4 hours. Discard
human antimurine antibodies (HAMA); however, limited the reconstituted solution if not used within 24 hours.
evidence suggesting the use of muromonab-CD3 or other Mechanism of Action Basiliximab is a chimeric (murine/
murine products is not precluded. [US Boxed Warning]: human) immunosuppressant monoclonal antibody which
Should be administered under the supervision of a blocks the alpha-chain of the interleukin-2 (IL-2) receptor
physician experienced in immunosuppression ther- complex; this receptor is expressed on activated T lym-
apy and organ transplant management. In renal trans- phocytes and is a critical pathway for activating cell-
plant patients receiving basiliximab plus prednisone, mediated allograft rejection
cyclosporine, and mycophenolate, new-onset diabetes, Pharmacodynamics/Kinetics (Adult data unless
glucose intolerance, and impaired fasting glucose were noted)
observed at rates significantly higher than observed in Duration: Mean: 36 days + 14 days (determined by IL-2R
patients receiving prednisone, cyclosporine, and myco- alpha saturation in patients also on cyclosporine and
phenolate without basiliximab (Aasebo 2010). Potentially corticosteroids)
significant drug-drug interactions may exist, requiring Distribution: Mean: Vg: Children 1 to 11 years: 4.8 + 2.1 L;
dose or frequency adjustment, additional monitoring, Adolescents 12 to 16 years: 7.8 + 5.1 L; Adults: 8.6 +
and/or selection of alternative therapy. 4.4L
Adverse Reactions Half-life elimination: Children 1 to 11 years: 9.5 + 4.5 days;
Cardiovascular: Abnormal heart sounds, angina pectoris, Adolescents 12 to 16 years: 9.1 + 3.9 days; Adults:
atrial fibrillation, cardiac arrhythmia, cardiac failure, chest Mean: 7.2 + 3.2 days
pain, hypertension, hypotension, peripheral edema, Excretion: Clearance:
tachycardia, thrombosis Children 1 to 11 years: 17 + 6 mL/hour; in pediatric liver
Central nervous system: Agitation, anxiety, depression, transplant patients, significant basiliximab loss through
dizziness, fatigue, headache, hypoesthesia, insomnia, ascites fluid can increase total body clearance and
malaise, pain, rigors reduce IL-2R (CD25) saturation duration; dosage
Dermatologic: Acne vulgaris, dermal ulcer, dermatological adjustments may be necessary (Cintorino 2006;
disease, hypertrichosis, pruritus, skin rash Kovarik 2002; Spada 2006)
Endocrine & metabolic: Acidosis, alouminuria, anasarca, Adolescents 12 to 16 years: 31 +19 mL/hour
dehydration, diabetes mellitus, hypercalcemia, hyper- Adults: 41 + 19 mL/hour
cholesterolemia, hyperglycemia, hyperkalemia, hyperli- Dosing
pidemia, hypertriglyceridemia, hyperuricemia, Pediatric Note: Patients previously administered basilix-
hypervolemia, hypocalcemia, hypoglycemia; hypokale- imab should only be re-exposed to a subsequent course
mia, hypomagnesemia, hyponatremia, hypophosphate- of therapy with extreme caution.
mia, increased nonprotein nitrogen, increased serum Renal transplantation: Infants, Children, and Adoles-
glucocorticoids, weight gain cents: IV:
Gastrointestinal: Abdominal pain, constipation, diarrhea, Patient weight <35 kg:
dyspepsia, enlargement of abdomen, esophagitis, flat- Initial dose: 10 mg administered within 2 hours prior
ulence, gastroenteritis, gastrointestinal hemorrhage, Gl to renal transplant surgery
moniliasis, gingival hyperplasia, hernia, melena, nausea, Second dose: 10 mg administered 4 days after
stomatitis (including ulcerative), vomiting transplantation; hold second dose if complications
Genitourinary: Bladder dysfunction, dysuria, genital occur (including severe hypersensitivity reactions
edema (male), hematuria, impotence, oliguria, ureteral or graft loss)
disease, urinary frequency, urinary retention, urinary Patient weight 235 kg:
tract infection Initial dose: 20 mg administered within 2 hours prior
Hematologic & oncologic: Anemia, hematoma, hemor- to renal transplant surgery
rhage, hypoproteinemia, leukopenia, polycythemia, pur- Second dose: 20 mg administered 4 days after
pura, thrombocytopenia transplantation; hold second dose if complications
Infection: Cytomegalovirus disease, herpes virus infection occur (including severe hypersensitivity reactions
(simplex and zoster), infection, sepsis, viral infection or graft loss)
Neuromuscular & skeletal: Arthralgia, arthropathy, back Liver transplantation: Infants, Children, and Adoles-
pain, bone fracture, leg pain, muscle cramps, myalgia, cents: IV: Limited data available (Cintorino, 2006;
neuropathy, paresthesia, tremor, weakness Kovarik, 2002; Spada, 2006):
Ophthalmic: Cataract, conjunctivitis, visual disturbance Patient weight <35 kg:
Renal: Renal insufficiency, renal tubular necrosis Initial dose: 10 mg administered within 6 hours of
Respiratory: Bronchitis, bronchospasm, cough, dyspnea, organ perfusion
pharyngitis, pneumonia, pulmonary edema, rhinitis, Second dose: 10 mg administered 4 days after
sinusitis, upper respiratory tract infection transplantation; hold second dose if complications
Miscellaneous: Accidental injury, cyst, fever, postoperative occur (including severe hypersensitivity reactions
wound complication or graft loss)
Rare but important or life-threatening: Anaphylaxis, capil- Third dose: 10 mg has been repeated on postoper-
lary leak syndrome, cytokine release syndrome, diabetes ative days 8-10 if ascites fluid loss exceeds 70 mL/
(new onset), hypersensitivity reaction (includes broncho- kg or >5 L
spasm, cardiac failure, dyspnea, hypotension, pruritus, Patient weight 235 kg:
pulmonary edema, respiratory failure, skin rash, sneez- Initial dose: 20 mg administered within 6 hours of
ing, tachycardia, urticaria), impaired glucose tolerance, organ perfusion

247
BASILIXIMAB

Second dose: 20 mg administered 4 days after Use

transplantation; hold second dose if complications Active immunization against Mycobacterium tuberculosis
occur (including severe hypersensitivity reactions in persons not previously infected and who are at high
or graft loss) risk for exposure (FDA approved in all ages); has also
Third dose: 20 mg has been repeated on postoper- been used for the*prevention of leprosy }
ative days 8-10 if ascites fluid loss exceeds 70 mL/ BCG vaccine is not routinely administered for the pre-
kg or if total ascites volume 25 L vention of M. tuberculosis in the US. The Center for
Heart transplantation: Infants, Children, and Adoles- Disease Control and Prevention (CDC) recommends
cents: IV: Limited data available (Ford, 2005; Grundy, vaccination be considered for the following (CDC
2009): 2011):
Patient weight <35 kg: ¢ Infants and children with a negative tuberculin skin
Initial dose: 10 mg administered immediately before test who are continually exposed to (and cannot be
cardiopulmonary by-pass started or within 6 hours separated from) persons who are untreated or inef-
of organ perfusion fectively treated for TB disease when the child cannot
Second dose: 10 mg administered 4 days after be given long-term treatment for infection or continual
transplantation; hold second dose if complications exposure to persons with TB caused by strains resist-
occur (including severe hypersensitivity reactions ant to isoniazid and rifampin.
or graft loss) ¢ Health care workers with a high percentage of
Patient weight 235 kg: patients with M. tuberculosis strains resistant to both
Initial dose: 20 mg administered immediately before isoniazid and rifampin, if there is ongoing transmis-
cardiopulmonary by-pass started or within 6 hours sion of the resistant strains and subsequent infection
of organ perfusion __is likely, or if comprehensive infection-control precau-
Second dose:-20 mg administered 4 days after tions have not been successful. In addition, health
transplantation; hold second dose if complications care workers should be counseled on the risks and
occur (including severe hypersensitivity reactions benefits of vaccination and treatment of latent TB
or graft loss) infection.
Renal Impairment: Pediatric There are no dosage Pregnancy Considerations Animal reproduction studies
adjustments provided in manufacturer's labeling. have not been conducted. BCG vaccine is not recom-
mended for use in pregnant women. Because of the
Hepatic Impairment: Pediatric There are no dosage
theoretical risk to the fetus, women known to be pregnant
adjustments provided in manufacturer’s labeling.
generally should not receive live, attenuated virus vac-
Preparation for Administration |V: Reconstitute with
cines; avoid conception for 4 weeks after vaccination with
preservative-free SVWFI (reconstitute 10 mg vial with 2.5
live vaccines (ACIP [Kroger 2017]).
mL, 20 mg vial with 5 mL). Shake gently to dissolve. May
Breastfeeding Considerations It is not known if BCG
further dilute reconstituted solution with 25 mL (10 mg) or
vaccine is excreted in breast milk. Due to the potential for
50 mL (20 mg) NS or D5W. When mixing the solution,
serious adverse reactions in the nursing infant, a decision
gently invert the bag to avoid foaming. Do not shake
should be made to discontinue breastfeeding or avoid use
solutions diluted for infusion.
of BCG vaccine, taking into account the importance of
Administration For lV administration only. Administer only BCG vaccination to the mother.
after assurance that patient will receive renal graft and Contraindications Prior hypersensitivity to the vaccine or
immunosuppression. Reconstituted basiliximab solution any component of the formulation; immunosuppressed
may be administered without further dilution as a bolus patients or persons with congenital or acquired immune
injection over 10 minutes or further diluted and infused deficiencies (eg, HIV infection, leukemia, lymphoma, can-
over 20 to 30 minutes. Bolus injection is associated with cer therapy, immunosuppressive therapy such as cortico-
nausea, vomiting, and local pain at the injection site. steroids); active tuberculosis
Monitoring Parameters CBC with differential, vital signs, Warnings/Precautions Contains live, attenuated
immunologic monitoring of T cells, renal function, serum mycobacteria. Use appropriate precautions for han-
glucose, signs or symptoms of hypersensitivity, infection dling and disposal. BCG is a biohazard; proper prep-
Reference Range Serum concentration >0.2 mcg/mL aration technique, handling, and disposal of all
Dosage Forms Excipient information presented when equipment in contact with BCG as a biohazard mate-
available (limited, particularly for generics); consult spe- rial is recommended. BCG infections have been
cific product labeling. reported in healthcare workers due to accidental exposure
Solution Reconstituted, Intravenous [preservative free]: (needlestick, skin laceration); nosocomial infections have
Simulect: 10 mg (1 ea); 20 mg (1 ea) been reported in patients receiving parenteral medications
prepared in areas where BCG was prepared. To avoid
@ BAT see Botulism Antitoxin, Heptavalent on page 287 cross contamination, do not prepare parenteral medica-
@ Bavencio see Avelumab on page 219 tions in an area where BCG has been prepared. Should
@ Baycadron [DSC] see Dexamethasone (Systemic) be administered with caution to persons in groups at high
on page 598 risk for HIV. Use is contraindicated in HIV-infected persons
(ACIP [Kroger 2017]), and HIV-infected persons thought to
@ Bayer Aspirin Extra Strength [OTC] see Aspirin
be infected with Mycobacterium tuberculosis should be
on page 194
strongly recommended for tuberculosis preventive ther-
® Bayer Aspirin Regimen Adult Low Strength [OTC] see apy. Determine PPD status prior to use. BCG vaccination
Aspirin on page, 194 is not recommended for persons with a positive PPD
@ Bayer Aspirin Regimen Children's [OTC] see Aspirin reaction. Use is contraindicated in immunocompromised
on page 194 patients (eg, patients receiving chemo/radiation therapy or
® Bayer Aspirin Regimen Regular Strength [OTC] see other immunosuppressive therapy [including high-dose
Aspirin on page 194
corticosteroids]). Household and close contacts of per-
sons with altered immunocompetence may receive most
@ Bayer Genuine Aspirin [OTC] see Aspirin on page 194 age appropriate vaccines (ACIP [Kroger 2017]). Live
@ Bayer Plus Extra Strength [OTC] see Aspirin vaccines should be administered 24 weeks prior to
on page 194 planned immunosuppression and avoided within 2 weeks
@ Bayer Women's Low Dose Aspirin [OTC] see Aspirin of immunosuppression when feasible; live vaccines
on page 194 should not be administered for at least 3 months after
immunosuppressive therapy (ACIP [Kroger 2017]; IDSA
@ Baza Antifungal [OTC] see Miconazole (Topical) {Rubin 2014)).
on page 1371
@ BCG, Live see BCG Vaccine (Immunization) Vaccination may not result in effective immunity in all
patients. Response depends upon multiple factors (eg,
on page 248
type of vaccine, age of patient) and may be improved by
administering the vaccine at the recommended dose,
BCG Vaccine (Immunization) route, and interval. Vaccines may not be effective if
(bee see jee vak SEEN) administered during periods of altered immune compe-
tence (ACIP [Kroger 2017]). The decision to administer or
Medication Safety Issues delay vaccination because of current or recent febrile
Sound-alike/look-alike issues: illness depends on the severity of symptoms and the
BCG (intravesical) to treat bladder cancer may be con- etiology of the disease. Defer administration in patients
fused with BCG (vaccine) for immunization with moderate or severe acute illness (with or without
Related Information fever); vaccination should not be delayed for patients with
Immunization Administration Recommendations on page mild acute illness (with or without fever) (ACIP: [Kroger
2182 2017]). Potentially significant drug-drug interactions may
Therapeutic Category Vaccine; Vaccine, Live (Bacterial) exist, requiring dose or frequency adjustment, additional
Generic Availability (US) Yes monitoring, and/or selection of alternative therapy.

248
 BCG VACCINE (IMMUNIZATION)

Local adverse effects may include moderate axillary or The levels/effects of BCG Vaccine (Immunization) may
cervical lymphadenopathy and induration/pustule forma- be decreased by: Antibiotics; Axicabtagene Ciloleucel;
tion at the injection site; lasting as long as 3 months or AzaTHlOprine; Corticosteroids (Systemic); Daclizumab;
more. Severe ulceration, regional suppurative lymphade- Dimethyl Fumarate; Fingolimod; Immune Globulins;
nitis with draining sinuses, and caseous lesions or puru- Immunosuppressants; Leflunomide; Mercaptopurine;
lent drainage occur within 5 months and persist for several Methotrexate; Ocrelizumab; Rabies Immune Globulin
weeks. Systemic adverse effects lasting 1 to 2 days and (Human); Tildrakizumab-asmn; Tisagenlecleucel; Vene-
similar to.a flu-like syndrome (fever, anorexia, myalgia, toclax
and neuralgia) are generally caused by hypersensitivity to Hazardous Drugs Handling Considerations
the vaccine. May cause BCG infection, particularly in Hazardous agent (NIOSH 2016 [group 1}).
immunocompromised patients. If signs and symptoms of
a systemic BCG infection occur (eg, fever of 2103°F or Use appropriate precautions for receiving, handling,
‘acute local reactions lasting longer than 2 to 3 days), administration, and disposal. Gloves (single) should be
permanently discontinue BCG vaccination and begin ther- worn during receiving, unpacking, and placing in storage.
apy with 22 antimycobacterial agents while conducting a NIOSH recommends double gloving, a protective gown,
diagnostic evaluation. Infection from vaccine is not sensi- and ventilated engineering controls (a class || biological
tive to pyrazinamide. BCG osteomyelitis affecting the safety cabinet or a compounding aseptic containment
epiphyses of the long bones is the most common dissemi- isolator), and closed system transfer devices (CSTDs)
nated infection and may occur 4 months to 2 years after for preparation. Double gloving and a gown are required
vaccination. during administration (NIOSH 2016).
Packaging may contain natural latex rubber or polysorbate Storage/Stability Store intact vials at 2°C to 8°C (36°F to
80 (also known as Tweens). Hypersensitivity reactions, 46°F). Protect from sunlight. Store reconstituted vaccine in
usually a delayed reaction, have been reported following refrigerator; use within 2 hours of mixing. Do not freeze
exposure to pharmaceutical products containing polysor- vaccine after reconstitution.
bate 80 in certain individuals (Isaksson 2002; Lucente Mechanism of Action BCG vaccine is an attenuated, live
2000; Shelley 1995). Thrombocytopenia, ascites, pulmo- bacterial culture of the Bacillus of Calmette and Guérin
nary deterioration, and renal and hepatic failure have been (BCG) strain of Mycobacterium bovis and induces active
reported in premature neonates after receiving parenteral immunity against Mycobacterium tuberculosis.
products containing polysorbate 80 (Alade 1986; CDC Dosing
1984). See manufacturer's labeling. Neonatal Note: Dosing and administration based on US
percutaneous product (TICE strain); formulation/dosing/
BCG vaccine should not be used for the active treatment route may vary in other regions (consult local product
of tuberculosis. Immediate treatment (including epinephr- labeling). If neonate known to be HIV-positive, vaccina-
ine 1 mg/mL) for anaphylactoid and/or hypersensitivity tion is not recommended (WHO 2017).
reactions should be available during vaccine administra- Immunization against tuberculosis: Percutaneous:
tion (ACIP. [Kroger 2017]). Syncope has been reported Half-strength dilution: 0.2 to 0.3 mL as a single dose.
with use of injectable yaccines and may result in serious Administer tuberculin test (5 TU) after 2 to 3 months;
secondary injury (eg, skull fracture, cerebral hemorrhage); repeat vaccination after 1 year of age for negative
typically reported in adolescents and young adults and tuberculin test if indications persist. Note: Initial lesion
within 15 minutes after vaccination. Procedures should be usually appears after 10 to 14 days consisting of small,
in place to avoid injuries from falling and to restore red papule at injection site and reaches maximum
cerebral perfusion if syncope occurs (ACIP [Kroger diameter of 3 mm in 4 to 6 weeks.
2017]). In order to maximize vaccination rates, the ACIP Leprosy, prophylaxis in areas with high incidence:
recommends simultaneous administration (ie, >1 vaccine Limited data available (Setia 2006; Zodbey 2007): Term
on the same day at different anatomic sites) of all age- and preterm neonates (GA: 34 to 36 weeks or admin-
appropriate vaccines (live or inactivated) for which a ister at time of hospital discharge): Percutaneous: Half-
person is eligible at a single clinic visit, unless contra- strength dilution: 0.2 to 0.3 mL as a single dose
indications exist (ACIP [Kroger 2017]). Antipyretics have (WHO 2017)
not been shown to prevent febrile seizures; antipyretics Pediatric Note: Dosing and administration based on US
may be used to treat fever or discomfort following vacci- percutaneous product (TICE strain); formulation/dosing/
nation (ACIP [Kroger 2017]). One study reported that route may vary in other regions (consult local product
routine prophylactic administration of acetaminophen prior labeling). According to ACIP, doses administered <4
to vaccination to prevent fever decreased the immune days before minimum interval or age are considered
response of some vaccines; the clinical significance of valid; however, local or state mandates may supersede
this reduction in immune response has not been estab- this timeframe (ACIP [Kroger 2017]).
lished (Prymula 2009). Immunization against tuberculosis: Infants, Chil-
Adverse Reactions Following vaccination, all serious dren, and Adolescents: Percutaneous: Full-strength:
adverse reactions must be reported to the U.S. 0.2 to 0.3 mL as a single dose; conduct postvaccinal
Department of Health and: Human Services (DHHS) tuberculin test (5 TU of PPD) in 2 to 3 months; if test is
Vaccine Adverse Event Reporting System (VAERS) negative, repeat vaccination (at age 21 year). Note:
1-800-822-7967 or online at https://vaers.hhs.gov/ Initial lesion usually appears after 10 to 14 days
esub/index. Local reactions may persist for up to 3 consisting of small, red papule at injection site and
months; more severe manifestations may occur up to 5 reaches maximum diameter of 3 mm in 4 to 6 weeks.
months after vaccination and persist for several weeks. Leprosy, prophylaxis in areas with high incidence:
Dermatologic: Pustules (at injection site), skin ulceration Limited data available (Setia 2006; Zodbey 2007):
at injection site Infants, Children, and Adolescents with no evidence
Hematologic & oncologic: Auxillary lymphadenopathy, cer- of immunity: Percutaneous: Full-strength: 0.2 to 0.3
vical lymphadenopathy, lymphadenitis (includes local mL as a single dose (WHO 2017)
and suppurative) Renal Impairment: Pediatric There are no dosage
Infection: BCG infection (BCG osteomyelitis; may occur adjustments provided in the manufacturer's labeling.
from 4 months to 2 years after vaccination) Hepatic Impairment: Pediatric There are no dosage
Local: Induration at injection site, injection site lesion, adjustments provided in the manufacturer's labeling.
itching at injection site, tenderness at injection site Preparation for Administration Prepare using aseptic
Respiratory: Flu-like symptoms technique. Do not prepare parenteral medications in an
Drug Interactions area where BCG has been prepared. Do not filter. Must be
Metabolism/Transport Effects None known. used within 2 hours of reconstitution.
Avoid Concomitant Use Full-strength: Reconstitute with 1 mL of SWFI; swirl gently,
Avoid concomitant use of BCG Vaccine (Immunization) do not vigorously shake
with any of the following: Belimumab; Daclizumab; Dupi- Half-strength dilution: Neonates: Reconstitute with 2 mL
lumab; Fingolimod; Immunosuppressants; Ocrelizumab; SWFI, swirl gently, do not vigorously shake
Tildrakizumab-asmn; Venetoclax Administration Note: Administration based on US percu-
Increased Effect/Toxicity taneous product (TICE strain); formulation/dosing/route
The levels/effects of BCG Vaccine (Immunization) may may vary in other regions (consult local product labeling).
be increased by: Axicabtagene Ciloleucel; AzaTHIO- Percutaneous: Should only be given percutaneously; do
prine; Belimumab; Corticosteroids (Systemic); Daclizu- not administer lV, SubQ, IM, or intradermally. Do not mix
mab; Dimethyl Fumarate; Dupilumab; Fingolimod; with other vaccines or injections; separate needles and
Immunosuppressants; Leflunomide; Mercaptopurine; syringes should be used for each injection (ACIP [Kroger
Methotrexate; Ocrelizumab; Tildrakizumab-asmn; Tisa- 2017]). Apply vaccine with syringe and needle by drop-
genlecleucel; Venetoclax ping onto 1- to 2-inch area of horizontally positioned
Decreased Effect surface of cleansed, dry site (deltoid region of arm
BCG Vaccine (Immunization) may decrease the levels/ preferred); pulling skin tight, puncture skin with multiple
effects of: Tuberculin Tests; Vaccines (Live) puncture device centered over the vaccine; apply

- 249
BCG VACCINE (IMMUNIZATION)

pressure for 5 seconds (do not "rock" device). After less systemic absorption may be preferred (Alhussien
successful puncture, spread vaccine evenly using the 2017; Namazy 2016; Wallace 2008).
edge of the device over puncture area; an additional 1 to Breastfeeding Considerations It is not known if beclo-
2 drops of vaccine may be added to ensure a very wet methasone is present in breast milk. The manufacturer
vaccination site. Apply loose covering and keep dry for recommends that caution be used when administering to
24 hours. When used for immunization against tuber- breastfeeding females.
culosis, US federal law requires that the name of med- Contraindications
ication; date of administration; the vaccine manufacturer; Hypersensitivity to beclomethasone or any component of
lot number of vaccine; and the administering person's the formulation
name, title, and address be entered into the patient's Documentation of allergenic cross-reactivity for intranasal
permanent medical record. Multiple puncture device for steroids is limited. However, the possibility of cross-
vaccination available from Organon Teknika sensitivity cannot be ruled out with certainty because of
(1-800-662-6842). similarities in chemical structure and/or pharmacologic
Monitoring Parameters PPD test prior to vaccination actions ;
and 2 to 3 months postvaccination. Monitor for flu-like Canadian labeling: Additional contraindications (not in
symptoms 272 hours, fever 2103°F, acute local reactions U.S. labeling): Active or quiescent tuberculosis or
lasting >2 to 3 days. Monitor for Syncope for 15 minutes untreated fungal, bacterial and viral infections.
following administration (ACIP [Kroger 2017]). If seizure- Warnings/Precautions Hypersensitivity reactions
like activity associated with syncope occurs, maintain (including anaphylaxis, angioedema, rash, urticaria, and
patient in supine or Trendelenburg position to reestablish wheezing) have been reported; discontinue for severe
adequate cerebral perfusion. reactions. May~cause hypercortisolism or suppression of
Test Interactions hypothalamic-pituitary-adrenal (HPA) axis, particularly in
PPD intradermal test: BCG results in reactive tuberculin younger children or in patients receiving high doses for
skin test; rule out active tuberculosis prior to initiating prolonged periods. HPA axis suppression may lead to
intravesicular BCG treatment. BCG vaccine may be adrenal crisis. Withdrawal and discontinuation of a cortico-
administered to persons with a PPD reaction of <6 mm steroid should be done slowly and carefully. Particular
induration; PPD should be used again 2 to 3 months care is required when patients are transferred from sys-
after vaccination to ensure reactivity to vaccine (docu- temic corticosteroids to inhaled products due to possible
ment in mm of induration). Vaccinees with a positive PPD adrenal-insufficiency or withdrawal from steroids, including
test (>5 mm) should not be tested again unless exposed an increase in allergic symptoms. Adult patients receiving
to tuberculosis. In this situation, an increase of induration >20 mg per day of prednisone (or equivalent) may be
may indicate a newly acquired TB infection. Vaccinees most susceptible. Fatalities have occurred due to adrenal
with a negative PPD test (<5 mm induration) may con- insufficiency in asthmatic patients during and after transfer
tinue periodic skin testing as long as the results remain from systemic corticosteroids to aerosol steroids; aerosol
<5 mm (CDC/ACIP, [Villarino 1996}). steroids do not provide the systemic steroid needed to
Interferon-gamma release assay (IGRA) tests for latent treat patients having trauma, surgery, or infections.
TB infection (LTBI) are not affected by BCG vaccination
history and are considered acceptable for monitoring Hypersensitivity reactions, including anaphylaxis, angioe-
occupational exposures in healthcare workers (Mazurek dema, rash and urticaria have been reported; discontinue
2010). for severe reactions. Avoid nasal corticosteroid use in
Dosage Forms Excipient information presented when patients with recent nasal septal ulcers, nasal surgery or
available (limited, particularly for generics); consult spe- nasal trauma until healing has occurred. Nasal septal
cific product labeling. perforation and localized Candida albicans infections of
Injectable, Injection: the nose and/or pharynx may occur. Nasal discomfort,
Generic: 50 mg (1 ea) epistaxis, and nasal ulceration may also occur; periodi-
cally examine nasal mucosa in patients on long-term
¢@ BCG Vaccine U.S.P. (percutaneous use product) see therapy. Monitor patients for adverse nasal effects; dis-
BCG Vaccine (Immunization) on page 248 continuation of therapy may be necessary if an infection
@ BCNU see Carmustine on page 371 occurs.
@ BCX-1812 see Peramivir on page 1598 Increased intraocular pressure, open-angle glaucoma,
@ Bebulin see Factor IX Complex (Human) [(Factors Il, IX, and cataracts have occurred with intranasal corticosteroid
X)] on page 818 use; use with caution in patients with a history of
increased intraocular pressure, cataracts and/or glau-
@ Becenum see Carmustine on page 371
coma. Consider routine eye exams in chronic users or in
patients who report visual changes.
Beclomethasone (Nasal) (be kioe METH a sone) Prolonged use of corticosteroids may increase the inci-
Brand Names: US Beconase AQ; Qnasl; Qnas! Child- dence of secondary infections, mask an acute infection
rens (including fungal infections), prolong or exacerbate viral
Brand Names: Canada Apo-Beclomethasone; Mylan- infections, or limit response to vaccines; avoid exposure to
Beclo AQ; Rivanase AQ chickenpox and/or measles, especially if not immunized.
Avoid use or use with caution in patients with latent/active
Therapeutic Category Corticosteroid, Intranasal
tuberculosis, untreated bacterial or fungal infections (local
Generic Availability (US) No
or systemic), viral or parasitic infections, or ocular herpes
Use
simplex.
Beconase AQ: Management of nasal symptoms associ-
ated with seasonal or perennial allergic and nonallergic Avoid using higher than recommended dosages; suppres-
(vasomotor) rhinitis and prevention of recurrence of sion of linear growth (ie, reduction of growth velocity),
nasal polyps following surgical removal (FDA approved reduced bone mineral density, or hypercortisolism (Cush-
in ages 26 years and adults) ing syndrome) may occur; titrate to lowest effective dose.
Qnas!: Management of nasal symptoms associated with Reduction in growth velocity may occur when cortico-
seasonal and perennial allergic rhinitis (FDA approved in steroids are administered to pediatric patients, even at
ages 24 years and adults) recommended doses via intranasal route (monitor
Intranasal corticosteroids have also been used as an growth). There have been reports of systemic cortico-
adjunct to antibiotics in empiric treatment of acute bac- steroid withdrawal symptoms (eg, joint/muscle pain, lassi-
terial rhinosinusitis primarily in patients with history of tude, depression) when withdrawing oral inhalation
allergic rhinitis (Chow 2012), in pediatric patients with therapy.
mild obstructive sleep apnea syndrome who cannot
For rhinitis, do not use in the presence of untreated
undergo adenotonsillectomy or who still have symptoms
localized infection involving the nasal mucosa; do not
after surgery (Marcus 2012), and for children with nasal
obstruction caused by adenoidal hypertrophy. continue use beyond 3 weeks in the absence of significant
symptomatic improvement. For nasal polyps, treatment
Pregnancy Risk Factor C
may need to be continued for several weeks or more
Pregnancy Considerations Adverse events have been
before a therapeutic result can be fully assessed; recur-
observed in some animal reproduction studies. Hypoa-
rence can occur after stopping treatment.
drenalism may occur in newborns following maternal use
Adverse Reactions
of corticosteroids in pregnancy; monitor.
Central nervous system: Dizziness, headache
Intranasal corticosteroids may be acceptable for the treat- Endocrine & metabolic: Adrenal suppression (at high
ment of rhinitis during pregnancy when used at recom- doses or in susceptible individuals), hypercorticoidism
mended doses (Lal 2016; Wallace 2008). Pregnant (at high doses or in susceptible individuals)
females adequately controlled on beclomethasone may Gastrointestinal: Nausea, oral candidiasis (rare; more
continue therapy; if initiating treatment during pregnancy; likely with aqueous solution)
use of an agent with more data in pregnant females and Immunologic: Immunosuppression
 BECLOMETHASONE (ORAL INHALATION)

Neuromuscular & skeletal: Decreased linear skeletal related obstructive nasal symptoms following 4 weeks
growth rate of beclomethasone therapy vs placebo (Demain
Ophthalmic: Intraocular pressure increased, lacrimation 1995). Positive efficacy findings were also observed
Respiratory: Epistaxis, nasal candidiasis (rare; more likely in a single-blind, placebo-controlled crossover study
with aqueous solution), nasal congestion, nasal mucosa of 53 children (mean age: 3.8 + 1.3 years) using a
irritation (erosion), nasopharyngitis (more common in total daily dose of 400 mcg/day (200 mcg twice daily
adults), pharyngeal candidiasis (rare; more likely with [using 50 mcg/spray formulation, not available in US])
aqueous solution), rhinorrhea, sneezing, upper respira- delivered as 100 mcg (2 sprays) per nostril twice
tory tract infection (children) daily (Criscuoli 2003). Lower daily dosage (200 mcg/
Miscellaneous: Fever (children), wound healing day) have not been found effective (Lepcha 2002).
impairment Nasal polyps (postsurgical prophylaxis), vasomo-
Rare but important or life-threatening: Ageusia, altered tor rhinitis: Intranasal: Beconase AQ (42 mcg/spray):
sense of smell, anaphylactoid reaction, anaphylaxis, Children 6 to 12 years: Initial: 1 spray (42 mcg) per
angioedema, anosmia, blurred vision, bronchospasm, nostril twice daily (total dose: 168 mcg daily); if
burning sensation, cataract, chorioretinitis, dry nose, response inadequate, may increase to 2 sprays
glaucoma, hypersensitivity reaction, nasal mucosa ulcer, (84 mcg) per nostril twice daily (total dose: 336
nasal septum perforation, skin rash, unpleasant taste, mcg daily); once symptoms are adequately con-
urticaria, wheezing trolled, decrease dose to 1 spray (42 mcg) per
Drug Interactions nostril twice daily (total dose: 168 mcg daily).
Metabolism/Transport Effects None known. Children and Adolescents 212 years: 1 or 2 sprays
Avoid Concomitant Use (42 mcg or 84 mcg) per nostril twice daily (total
Avoid concomitant use of Beclomethasone (Nasal) with dose: 168 to 336 mcg daily); maximum daily dose:
any of the following: Desmopressin 336 mcg/day
_Increased Effect/Toxicity Renal Impairment: Pediatric There are no dosage
Beclomethasone (Nasal) may increase the levels/effects adjustments provided in the manufacturer's labeling.
of: Ceritinib; Desmopressin; Ritodrine Hepatic Impairment: Pediatric There are no dosage
Decreased Effect There are no known significant inter- adjustments provided in the manufacturer's labeling.
actions involving a decrease in effect. Administration Shake well prior to each use. Blow nose
Storage/Stability to clear nostrils. Insert applicator into nostril, keeping
Beconase AQ: Store between 15°C to 30°C (59°F to bottle upright, and close off the other nostril. Breathe in
86°F). through nose. While inhaling, press pump to release
Qnasl: Store at 25°C (77°F), excursions permitted to 15°C spray. Avoid spraying directly onto the nasal septum or
to 30°C (59°F to 86°F). Do not puncture. Do not store into eyes. Discard after the "discard by" date or after
near heat or open flame. Do not expose to temperatures labeled number of doses has been used, even if bottle
higher than 49°C (120°F). is not completely empty.
Mechanism of Action Controls the rate of protein syn- Beconase AQ: Prior to initial use, prime pump 6 times (or
thesis; depresses the migration of polymorphonuclear until fine spray appears); repeat priming if product not
leukocytes, fibroblasts; reverses capillary permeability used for 27 days. Nasal applicator and dust cap may be
and lysosomal stabilization at the cellular level to prevent washed in warm water and dried thoroughly.
or control inflammation Qnasl: Prior to initial use, prime pump 4 times. If product
Pharmacodynamics/Kinetics (Adult data unless not used for 27 days, prime pump 2 times.
noted) Monitoring Parameters Mucous membranes for signs of
Onset of action: Within a few days up to 2 weeks fungal infection, growth (pediatric patients), signs/symp-
Distribution: Beclomethasone dipropionate (BDP): 20 L; toms of HPA axis suppression/adrenal insufficiency; ocu-
Beclomethasone-17-monopropionate (17-BMP): 424 L lar changes
Protein binding: BDP 87%; 17-BMP: 94% to 96% Additional Information When used short term as adjunc-
Metabolism: BMP is a prodrug (inactive); undergoes rapid tive therapy in acute bacterial rhinosinusitis (ABRS), intra-
conversion to 17-BMP (major active metabolite) during nasal steroids show modest symptomatic improvement
absorption; followed by additional metabolism via and few adverse effects; improvement is primarily due to
CYP3A4 to other, less active metabolites (beclometha- increased sinus drainage. Use should be considered
sone-21-monopropionate [21-BMP] and beclometha- optional in ABRS; however, intranasal corticosteroids
sone [BOH]) should be routinely prescribed to ABRS patients who have
Bioavailability: 17-BMP: 44% (43% from swallowed a history of or concurrent allergic rhinitis (Chow 2012).
portion) Dosage Forms Considerations
Half-life elimination: BDP: 0.5 hours; 17-BMP: 2.7 hours Beconase AQ 25 g canisters contain 180 sprays.
Excretion: Feces (60%); urine (<10% to 12%; as free and Qnas! 4.9 g canisters contains 60 actuations, and the
conjugated metabolites) 8.7 g canisters contain 120 actuations.
Dosing Dosage Forms Excipient information presented when
Pediatric Note: Product formulations are not inter- available (limited, particularly for generics); consult spe-
changeable: Beconase AQ: One spray delivers 42 cific product labeling.
mcg; Qnasl: One spray delivers 40 mcg or 80 mcg Aerosol Solution, Nasal, as dipropionate:
Allergic rhinitis: Intranasal: Qnasl: 80 mcg/actuation (8.7 g)
Beconase AQ (42 mcg/spray): Qnas! Childrens: 40 mcg/actuation (4.9 g)
Children 6 to <12 years: Initial: 1 spray (42 mcg) per Suspension, Nasal, as dipropionate:
nostril twice daily (total dose: 168 mcg daily); if Beconase AQ: 42 mcg/spray (25 g) [contains benzalko-
response inadequate, may increase to 2 sprays nium chloride]
(84 mcg) per nostril twice daily (total dose: 336
meg daily); once symptoms are adequately con-
trolled, decrease dose to 1 spray (42 mcg) per
Beclomethasone (Oral Inhalation)
(be kloe METH a sone)
nostril twice daily (total dose: 168 mcg daily).
Children 212 years and Adolescents: 1 or 2 sprays Brand Names: US Qvar; Qvar RediHaler
(42 mcg or 84 mcg) per nostril twice daily (total Brand Names: Canada QVAR
dose: 168 to 336 mcg daily); maximum daily dose: Therapeutic Category Adrenal Corticosteroid; Anti-
336 mcg/day. inflammatory Agent; Antiasthmatic; Corticosteroid, Inha-
Qnas!l: lant (Oral); Glucocorticoid
Children 4 to <12 years: Qnas! 40 mcg: 1 spray (40 Generic Availability (US) No
mcg) per nostril once daily (total dose: 80 mcg/ Use Long-term (chronic) control of persistent bronchial
day); maximum daily dose: 80 mcg/day. asthma (FDA approved in ages 25 years and adults);
Children 212 years and Adolescents: Qnasl 80 mcg: not indicated for the relief of acute bronchospasm. Also
2 sprays (160 mcg) per nostril once daily (total used to help reduce or discontinue oral corticosteroid
daily dose: 320 mcg/day); maximum daily dose: therapy for asthma.
320 mcg/day Pregnancy Considerations Uncontrolled asthma is
Nasal airway obstruction/adenoidal hypertrophy: associated with adverse events on pregnancy (increased
Limited data available; dosing regimens variable: risk of perinatal mortality, preeclampsia, preterm birth, low
Intranasal: Beconase AQ (42 mcg/spray): Children 5 birth weight infants). Poorly controlled asthma or asthma
to 12 years: Initial: 2 sprays (84 mcg) per nostril exacerbations may have a greater fetal/maternal risk than
twice daily (total dose: 336 mcg daily) for 4 weeks, what is associated with appropriately used asthma med-
followed by 1 spray (42 mcg) per nostril twice daily ications (ACOG 2008; GINA 2017).
(total dose: 168 mcg daily). Dosing based on a
double-blind, placebo-controlled crossover study Inhaled corticosteroids are recommended for the treat-
(n=17, age /range: 5 to 11 years); results showed ment of asthma during pregnancy (ACOG 2008; GINA
significant reduction in adenoid hypertrophy and 2017; Namazy 2016). Pregnant females adequately >
251
BECLOMETHASONE (ORAL INHALATION)

controlled on beclomethasone for asthma may continue Orally inhaled corticosteroids may cause a reduction in
therapy; if initiating treatment during pregnancy, use of an growth velocity in pediatric patients (~1 centimeter per
agent with more data in pregnant females may be pre- year [range: 0.3 to 1.8 cm per year] and related to dose
ferred (Namazy 2016). and duration of exposure). To minimize the systemic
Breastfeeding Considerations It is not known if beclo- effects of orally inhaled corticosteroids, each patient
methasone is present in breast milk following oral inhala- should be titrated to the lowest effective dose. Growth
tion; however, other corticosteroids are present in breast should be routinely monitored in pediatric patients. A
milk. According to the manufacturer, the decision to con- gradual tapering of dose may be required prior to dis-
tinue or discontinue breastfeeding during therapy should continuing therapy; there have been reports of systemic
take into account the risk of infant exposure, the benefits corticosteroid withdrawal symptoms (eg, joint/muscle
of breastfeeding to the infant, and benefits of treatment to pain, lassitude, depression) when withdrawing oral inha-
the mother. lation therapy. When transferring to oral inhalation therapy
from systemic corticosteroid therapy, previously sup-
The use of inhaled corticosteroids is not considered a pressed allergic conditions (rhinitis, conjunctivitis,
contraindication to breastfeeding (ACOG 2008). Females
eczema, arthritis, and eosinophilic conditions) may be
with asthma should be encouraged to breastfeed unmasked. Withdraw systemic corticosteroid therapy by
(GINA 2017). 2 gradually tapering the dose. Monitor lung function, beta-
Contraindications agonist use, asthma symptoms, and for signs and symp-
Hypersensitivity to beclomethasone or any component of toms of adrenal insufficiency (eg, fatigue, lassitude, weak-
the formulation; status asthmaticus, or other acute ness, nausea/vomiting, hypotension) during withdrawal.
asthma episodes requiring intensive measures
Documentation of allergenic cross-reactivity for cortico- Potentially significant drug-drug interactions may exist,
steroids is limited. However, because of similarities in requiring dose or frequency adjustment, additional mon-
chemical structure and/or pharmacologic actions, the itoring, and/or selection of alternative therapy.
possibility of cross-sensitivity cannot be ruled out with Warnings: Additional Pediatric Considerations
certainty. Reduction in growth velocity may occur when cortico-
steroids are administered to pediatric patients, even at
Canadian labeling: Additional contraindications (not in US
recommended doses via inhaled route; reduction in
labeling): Moderate to severe bronchiectasis requiring
growth velocity is related to dose and duration of expo-
intensive measures; untreated fungal, bacterial, or
sure; monitor growth. With beclomethasone-HFA (Qvar),
tubercular infections of the respiratory tract
the mean reduction in growth velocity was 0.5 cm/year
Warnings/Precautions May cause hypercortisolism or less than that with the previous beclomethasone CFC
suppression of hypothalamic-pituitary-adrenal (HPA) axis, inhaler formulation. Use of Qvar with a spacer device is
particularly in younger children or in patients receiving
not recommended in children <5 years of age due to the
high doses for prolonged periods. HPA axis suppression decreased amount of medication that is delivered with
may lead to adrenal crisis. Withdrawal and discontinuation increasing wait times; patients should be instructed to
of a corticosteroid should be done slowly and carefully.
inhale immediately if using a spacer device.
Particular care is required when patients are transferred
Adverse Reactions
from systemic corticosteroids to inhaled products due to
Central nervous system: Headache, pain, voice disorder
possible adrenal insufficiency or withdrawal from steroids,
Gastrointestinal: Diarrhea (children), nausea, oral candi-
including an increase in allergic symptoms. Adult patients
diasis, vomiting (children)
receiving 220 mg per day of prednisone (or equivalent)
Genitourinary: Dysmenorrhea, viral gastroenteritis
may be most susceptible. Fatalities have occurred due to
(children)
adrenal insufficiency in asthmatic patients during and after
Infection: Influenza (children)
transfer from systemic corticosteroids to aerosol steroids;
Neuromuscular & skeletal: Back pain, myalgia (children)
aerosol steroids do not provide the systemic steroid
Otic: Otitis (children)
needed to treat patients having trauma, surgery, or infec-
Respiratory: Allergic rhinitis, cough, nasopharyngitis, oro-
tions (particularly gastroenteritis), or other conditions with
pharyngeal pain, pharyngitis, sinusitis, upper respiratory
severe electrolyte loss. Select surgical patients on long-
tract infection, viral upper_respiratory tract infection
term, high-dose, inhaled corticosteroid should be given
Miscellaneous: Fever (children)
stress doses of hydrocortisone intravenously during the
Rare but important or life-threatening: Aggressive behav-
surgical period and the dose reduced rapidly within 24
ior, blurred vision, depression, dysgeusia (Tuccori 2011),
hours after surgery (NAEPP 2007).
psychomotor agitation, retinopathy, sleep disorder, suici-
Paradoxical bronchospasm that may be life-threatening dal ideation
may occur with use of inhaled bronchodilating agents; Drug Interactions
reaction should be distinguished from inadequate Metabolism/Transport Effects None known.
response. If paradoxical bronchospasm occurs, discon- Avoid Concomitant Use
tinue beclomethasone and institute alternative therapy. Avoid concomitant use of Beclomethasone (Oral Inhala-
Supplemental steroids (oral or parenteral) may be needed tion) with any of the following: Aldesleukin; BCG (Intra-
during stress or severe asthma attacks. Short-acting beta- vesical); Desmopressin; Loxapine; Natalizumab;
2 agonist (eg, albuterol) should be used for acute symp- Pimecrolimus; Tacrolimus (Topical)
toms and symptoms occurring between treatments. Use is Increased Effect/Toxicity
contraindicated in status asthmaticus or during other Beclomethasone (Oral Inhalation) may increase the
acute asthma episodes requiring intensive measures. levels/effects of: Amphotericin B; Baricitinib; Ceritinib;
Hypersensitivity reactions (eg, angioedema, broncho- Deferasirox; Desmopressin; Fingolimod; Leflunomide;
spasm, rash, and urticaria) may occur; discontinue use if Loop Diuretics; Loxapine; Natalizumab; Ritodrine; Thia-
reaction occurs. Prolonged use of corticosteroids may zide and Thiazide-Like Diuretics; Tofacitinib
increase the incidence of secondary infection, mask acute
infection (including fungal infections), prolong or exacer- The levels/effects of Beclomethasone (Oral Inhalation)
bate viral infections, or limit response to vaccines. Avoid may be increased by: Denosumab; Ocrelizumab; Pime-
use, if possible, in patients with ocular herpes, active or crolimus; Tacrolimus (Topical); Trastuzumab
quiescent respiratory or untreated viral, fungal, parasitic or Decreased Effect
bacterial systemic infections. Exposure to chickenpox and Beclomethasone (Oral Inhalation) may decrease the
measles should be avoided; if the patient is exposed, levels/effects of: Aldesleukin; BCG (intravesical); Cocci-
prophylaxis with varicella zoster immune globulin or dioides immitis Skin Test; Corticorelin; Hyaluronidase;
pooled intramuscular immunoglobulin, respectively, may Nivolumab; Pidotimod; Sipuleucel-T; Tertomotide; Vac-
be indicated; if chickenpox develops, treatment with anti- cines (Inactivated)
viral agents may be considered. Local oropharyngeal
The levels/effects of Beclomethasone (Oral Inhalation)
Candida albicans infections have been reported; if this
may be decreased by: Echinacea
occurs, treat appropriately while continuing therapy.
Storage/Stability Store at 25°C (77°F); excursions are
Patients should be instructed to rinse mouth with water
permitted between 15°C and 30°C (59°F and 86°F). Do
without swallowing after each use.
not use or store near heat or open flame; do not puncture
Use with caution in patients with major risk factors for canisters. Exposure to temperatures above 49°C (120°F)
decreased bone mineral count. Use with caution in may cause canister to burst. Never throw container into
patients with cataracts and/or glaucoma; blurred vision, fire or incinerator. Store on concave end of canister with
increased intraocular pressure, glaucoma, and cataracts actuator on top.
have occurred with prolonged use. Consider routine eye Mechanism of Action Controls the rate of protein syn-
exams in chronic users. Because of the risk of adverse thesis; depresses the migration of polymorphonuclear
effects, systemic corticosteroids should be used cau- leukocytes, fibroblasts; reverses capillary permeability
tiously in elderly patients in the smallest possible effective and lysosomal stabilization at the cellular level to prevent
dose for the shortest duration. or control inflammation
 BELLADONNA AND OPIUM

Pharmacodynamics/Kinetics (Adult data unless immediately due to decreased amount of medication that
noted) is delivered with a delayed inspiration. Note: Use of Qvar
Onset of action: Within 1 to 2 days in some patients; with a spacer device is not recommended in children <5
usually within 1 to 2 weeks; Maximum effect: 3 to 4 years of age due to the decreased amount of medication
weeks that is delivered with increasing wait times; patients should
Absorption: Readily; quickly hydrolyzed by pulmonary be instructed to inhale immediately if using a spacer
esterases to active metabolite (beclomethasone-17- device.
monopropionate [17-BMP]) during absorption Monitoring Parameters Check mucous membranes for
Distribution: Vg: Beclomethasone dipropionate (BDP): 20 signs of fungal infection; monitor growth in pediatric
L; 17-BMP: 424 L patients; monitor IOP with therapy >6 weeks. Monitor for
Protein binding: BDP 87%; 17-BMP: 94% to 96% symptoms of asthma, FEV;, peak flow, and/or other
Metabolism: BDP is a pro-drug (inactive); undergoes rapid pulmonary function tests
‘conversion to 17-BMP during absorption; followed by Additional Information Qvar: Does not contain chloro-
additional metabolism via CYP3A4 to other, less active fluorocarbons (CFCs), uses hydrofluoroalkane (HFA) as
metabolites (beclomethasone-21-monopropionate [21- the propellant; is a solution formulation; uses smaller-size
BMP] and beclomethasone [BOH]) particles which results in a higher percent of drug deliv-
Half-life elimination: ered to the respiratory tract and lower recommended
QVAR: BDP: 0.5 hours; 17-BMP: 2.8 hours doses than other products. An open-label, randomized,
RediHaler: BDP: 2 minutes; 17-BMP: 4 hours multicenter, 12-month study in 300 asthmatic children 5-11
Time to peak, plasma: Inhalation: years of age indicated that QVAR provided long-term
QVAR: BDP: 0.5 hours; 17-BMP: 0.7 hours control of asthma at approximately half the dose com-
RediHaler: BDP: 2 minutes; 17-BMP: 10 minutes pared with a CFC propelled beclomethasone MDI and
Excretion: Primary route of excretion is via feces (~60%); spacer (Pedersen, 2002).
<10% to 12% of oral dose excreted in urine as metab- Product Availability QVAR RediHaler (beclomethasone
olites dipropionate HFA): FDA approved August 2017; availabil-
Dosing ity anticipated in the first quarter of 2018.
Pediatric Note: Doses should be titrated to the lowest Dosage Forms Considerations QVAR 8.7 g canisters
effective dose once asthma is controlled: contain 120 inhalations.
Asthma, maintenance therapy: Inhalation, oral: Dosage Forms Excipient information presented when
Manufacturer's labeling (Qvar): available (limited, particularly for generics); consult spe-
Children 5-11 years: Initial: 40 mcg twice daily; max- cific product labeling.
imum dose: 80 mcg twice daily Aerosol Breath Activated, Inhalation, as dipropionate:
Children 212 years and Adolescents: Qvar RediHaler: 40 mcg/actuation (10.6 g); 80 mcg/
No previous inhaled corticosteroids: Initial: 40-80 actuation (10.6 g)
mcg twice daily; maximum dose: 320 mcg twice Aerosol Solution, Inhalation, as dipropionate:
daily Qvar: 40 mcg/actuation (8.7 g); 80 mcg/actuation (8.7 g)
Previous inhaled corticosteroid use: Initial: 40-160
@ Beclomethasone Dipropionate see Beclomethasone
mcg twice daily; maximum dose: 320 mcg twice
(Nasal) on page 250
daily
Note: Therapeutic ratio between Qvar and other @ Beconase AQ see Beclomethasone (Nasal)
beclomethasone inhalers (eg, CFC formulations; on page 250
however, none are currently available in U.S.) @ Belbuca see Buprenorphine on page 311
has not been established. @ Belladonna Alkaloids With Phenobarbital see Hyoscy-
Alternate dosing: NIH Asthma Guidelines (NAEPP, amine, Atropine, Scopolamine, and Phenobarbital
2007): HFA formulation (Qvar): on page 1032
Children 5-11 years: Administer in divided doses:
@ Belladonna Alk/Phenobarbital see Hyoscyamine, Atro-
"Low" dose: 80-160 mcg/day (40 mcg/puff: 2-4 puffs/
pine, Scopolamine, and Phenobarbital on page 1032
day or 80 mcg/puff: 1-2 puffs/day)
"Medium" dose: >160-320 mcg/day (40 mcg/puff:
4-8 puffs/day or 80 mcg/puff: 2-4 puffs/day) Belladonna and Opium (bela DON a & OH pee um)
"High" dose: >320 mcg/day (40 mcg/puff: >8 puffs/
day or 80 mcg/puff: >4 puff/day) Medication Safety Issues
Children 212 years and Adolescents: Sound-alike/look-alike issues:
"Low" dose: 80-240 mcg/day (40 mcg/puff: 2-6 puffs/ B&O may be confused with beano
day or 80 mcg/puff: 1-3 puffs/day) High alert medication:
"Medium" dose: >240-480 mcg/day (40 mcg/puff: The Institute for Safe Medication Practices (ISMP)
6-12 puffs/day or 80 mcg/puff: 3-6 puffs/day) includes this medication among its list of drug classes
"High" dose: >480 mcg/day (40 mcg/puff: >12 puffs/ which have a heightened risk of causing significant
day or 80 mcg/puff: 6 puffs/day) r patient harm when used in error.
Conversion from oral systemic corticosteroid to orally Geriatric Patients: High-Risk Medication:
inhaled corticosteroid: \nitiation of oral inhalation ther- Beers Criteria: Belladonna alkaloids are identified in the
apy should begin in patients whose asthma is rea- Beers Criteria as potentially inappropriate medications
sonably stabilized on oral corticosteroids (OCS). A to be avoided in patients 65 years and older (independ-
gradual dose reduction of OCS should begin ~7 days ent of diagnosis or condition) due to its highly anticho-
after starting inhaled therapy. U.S. labeling recom- linergic properties and uncertain effectiveness as an
mends reducing prednisone dose no more rapidly antispasmodic (Beers Criteria [AGS 2015]).
than $2.5 mg/day (or equivalent of other OCS) every Therapeutic Category Analgesic, Narcotic; Antispas-
1-2 weeks in adolescents or adults. If adrenal insuffi- modic Agent, Urinary
ciency occurs, temporarily increase the OCS dose Generic Availability (US) Yes
and follow with a more gradual withdrawal. Note: Use Relief of moderate to severe pain associated with
When transitioning from systemic to inhaled cortico- ureteral spasms not responsive to nonopioid analgesics
steroids, supplemental systemic corticosteroid ther- and to space intervals between injections of opioids (FDA
apy may be necessary during periods of stress or approved in ages >12 years and adults)
during severe asthma attacks. Pregnancy Risk Factor C
Renal Impairment: Pediatric There are no dosage Pregnancy Considerations Animal reproduction studies
adjustments provided in the manufacturer's labeling. have not been conducted with this combination. See
Hepatic Impairment: Pediatric There are no dosage individual agents.
adjustments provided in the manufacturer's labeling. Breastfeeding Considerations It is not known if mor-
Administration Qvar, metered dose inhaler: Canister phine or atropine is excreted in breast milk following rectal
does not need to be shaken prior to use. Prime canister administration of this combination. The manufacturer rec-
by spraying twice into the air prior to initial use or if not in ommends that caution be exercised when administering to
use for >10 days. Avoid spraying in face or eyes. Exhale breastfeeding women. See individual agents.
fully prior to bringing inhaler to mouth. Place inhaler in Contraindications Glaucoma; severe renal or hepatic
mouth, close lips around mouthpiece, and inhale slowly disease; bronchial asthma; opioid idiosyncrasies; respira-
and deeply while pressing down on the canister with your tory depression; convulsive disorders; acute alcoholism;
finger. Remove inhaler and hold breath for approximately delirium tremens; premature labor
5-10 seconds. Rinse mouth and throat after use to prevent Warnings/Precautions May cause CNS depression,
Candida infection. Do not wash or put inhaler in water; which may impair physical or mental abilities; patients
mouth piece may be cleaned with a dry tissue or cloth. must be cautioned about performing tasks which require
Discard after the "discard by" date or after labeled number mental alertness (eg, operating machinery or driving).
of doses has been used, even if container is not com- Usual precautions of opioid agonist therapy should be
pletely empty. Patients using a spacer should inhale observed. Use caution with known idiosyncrasy to >
253
 BELLADONNA AND OPIUM

d atropine or atropine-like compounds; hypersensitivity

reactions to other phenanthrene-derivative opioid agonists
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
(codeine, hydrocodone, hydromorphone, levorphanol, cific product labeling.
oxycodone, oxymorphone); debilitated patients; persons Suppository: Belladonna extract 16.2 mg and opium
dependent upon opioids; biliary tract impairment; adrenal 30 mg; belladonna extract 16.2 mg and opium 60 mg
insufficiency; pancreatitis; cardiac disease; prostatic
hyperplasia; increased intracranial pressure; toxic psycho- @ Benadryl see DiphenhydrAMINE (Systemic)
sis; myxedema. Potentially significant interactions may on page 652
exist, requiring dose or frequency adjustment, additional @ Benadryl [OTC] [DSC] see DiphenhydrAMINE (Sys-
monitoring, and/or selection of alternative therapy. temic) on page 652
Adverse Reactions ® Benadry! Allergy [OTC] see DiphenhydrAMINE (Sys-
Cardiovascular: Palpitations temic) on page 652
Central nervous system: Dizziness, drowsiness
@ Benadryl Allergy Childrens [OTC] see Diphenhydr-
Dermatologic: Pruritus, urticaria
AMINE (Systemic) on page 652
Gastrointestinal: Constipation, nausea, vomiting, xero-
stomia a @ Benadryl® Cream (Can) see DiphenhydrAMINE (Top-
Genitourinary: Urinary retention ical) on page 656
Ophthalmic: Blurred vision, photophobia @ Benadryl! Dye-Free Allergy [OTC] [DSC] see Diphen-
Rare but important or life-threatening: Hypogonadism hydrAMINE (Systemic) on page 652
(Brennan, 2013; Debono, 2011) @ Benadry! itch Relief [OTC] [DSC] see Diphenhydr-
Drug Interactions AMINE (Topical) on page 656
Metabolism/Transport Effects None known.
@ Benadryl® Itch Relief Stick (Can) see Diphenhydr-
Avoid Concomitant Use AMINE (Topical) on page 656
Avoid concomitant use of Belladonna and Opium with
any of the following: Aclidinium; Azelastine (Nasal); @ Benadryl Itch Stopping [OTC] see DiphenhydrAMINE
Bromperidol; Cimetropium; Eluxadoline; Glycopyrrolate (Topical) on page 656
(Oral Inhalation); |pratropium (Oral Inhalation); Levosul- @ Benadryl Maximum Strength [OTC] [DSC] see Diphen-
piride; Opioids (Mixed Agonist / Antagonist); Orphena- hydrAMINE (Topical) on page 656
drine; Oxatomide; Oxomemazine; Paraldehyde; @ Benadryl® Spray (Can) see DiphenhydrAMINE (Topical)
Potassium Chloride; Potassium Citrate; Thalidomide; on page 656
Tiotropium; Umeclidinium
Increased Effect/Toxicity
Belladonna and Opium may increase the levels/effects Benazepril (ben AY ze pril)
of: AbobotulinumtoxinA; Alvimopan; Anticholinergic
Medication Safety Issues
Agents; Azelastine (Nasal); Blonanserin; Cimetropium;
Sound-alike/look-alike issues:
Desmopressin; Diuretics; Eluxadoline; Flunitrazepam;
Benazepril may be confused with Benadryl
Glucagon; Glycopyrrolate (Oral Inhalation); HYDROco-
Lotensin may be confused with Lioresal, lorcaserin,
done; Methotrimeprazine; MetyroSINE; Mirabegron;
lovastatin
OnabotulinumtoxinA; Opioid Analgesics; Orphenadrine;
Brand Names: US Lotensin
OxyCODONE; Paraldehyde; Piribedil; Potassium Chlor-
ide; Potassium Citrate; Pramipexole; Ramosetron; Rima-
Brand Names: Canada Lotensin
botulinumtoxinB; ROPINIRole; Rotigotine; Selective Therapeutic Category Angiotensin-Converting Enzyme
Serotonin Reuptake Inhibitors; Serotonin Modulators; (ACE) Inhibitor; Antihypertensive Agent
Suvorexant; Thalidomide; Thiazide and Thiazide-Like Generic Availability (US) Yes
Diuretics; Tiotropium; Zolpidem Use Treatment of hypertension, either alone or in combi-
nation with a thiazide diuretic (FDA approved in ages 26
The levels/effects of Belladonna and Opium may be years and adults)
increased by: Aclidinium; Amantadine; Amphetamines; Pregnancy Risk Factor D
Anticholinergic Agents; Brimonidine (Topical); Bromopr- Pregnancy Considerations
ide; Bromperidol; Cannabis; Chlormethiazole; Chlorphe-
[US Boxed Warning]: Drugs that act on the renin-
nesin Carbamate; CNS Depressants; Dimethindene angiotensin system can cause injury and death to
(Topical); Dronabinol; Droperidol; Ipratropium (Oral Inha- the developing fetus. Discontinue as soon as possible
lation); Kava Kava; Lofexidine; Magnesium Sulfate; once pregnancy is detected. Benazepril crosses the
Methotrimeprazine; Minocycline; Nabilone; Oxatomide; placenta. Drugs that act on the renin-angiotensin system
Oxomemazine; Perampanel; Pramlintide; Rufinamide; are associated with oligohydramnios. Oligohydramnios,
Sodium Oxybate; Succinylcholine; Tapentadol; Tetrahy- due to decreased fetal renal function, may lead to fetal
drocannabinol; Umeclidinium
lung hypoplasia and skeletal malformations. Their use in
Decreased Effect pregnancy is also associated with anuria, hypotension,
Belladonna and Opium may decrease the levels/effects renal failure, skull hypoplasia, and death in the fetus/
of: Acetylcholinesterase Inhibitors; Amifampridine; Diu- neonate. Teratogenic effects may occur following maternal
retics; Gastrointestinal Agents (Prokinetic); Itopride; Lev- use of an ACE inhibitor during the first trimester, although
osulpiride; Nitroglycerin; Pegvisomant; Secretin this finding may be confounded by maternal disease.
The levels/effects of Belladonna and Opium may be Because adverse fetal events are well documented with
decreased by: Acetylcholinesterase Inhibitors; Amifam- exposure later in pregnancy, ACE inhibitor use in pregnant
pridine; Nalmefene; Naltrexone; Opioids (Mixed Agonist/ women is not recommended (Seely 2014; Weber 2014).
Antagonist) Infants exposed to an ACE inhibitor in utero should be
Storage/Stability Store at room temperature. Do not monitored for hyperkalemia, hypotension, and oliguria.
refrigerate. Oligohydramnios may not appear until after irreversible
Mechanism of Action The pharmacologically active fetal injury has occurred. Exchange transfusions or dialy-
agents present in the belladonna component are atropine sis may be required to reverse hypotension or improve
and scopolamine. Atropine blocks the action of acetylcho- renal function, although data related to the effectiveness in
line at parasympathetic sites in smooth muscle, secretory neonates is limited.
glands, and the CNS causing a relaxation of smooth Chronic maternal hypertension itself is also associated
muscle and drying of secretions. The principle agent in with adverse events in the fetus/infant and mother. ACE
opium is morphine. Morphine binds to opiate receptors in inhibitors are not recommended for the treatment of
the CNS, causing inhibition of ascending pain pathways, uncomplicated hypertension in pregnancy (ACOG 2013)
altering the perception of and response to pain. and they are specifically contraindicated for the treatment
Pharmacodynamics/Kinetics (Adult data unless of hypertension and chronic heart failure during pregnancy
noted) by some guidelines (Regitz-Zagrosek 2011). In addition,
Onset of action: Opium: Within 30 minutes ACE inhibitors should generally be avoided in women of
Absorption: Rectal absorption is dependent upon body reproductive age (ACOG 2013). If treatment for hyper-
hydration, not temperature tension or chronic heart failure in pregnancy is needed,
Metabolism: Hepatic other agents should be used (ACOG 2013; Regitz-Zagro-
Dosing sek 2011).
Pediatric Pain: Adolescents: Rectal: One suppository 1 Breastfeeding Considerations Small amounts of bena-
to 2 times daily; maximum daily dose: 4 suppositories/ zepril and benazeprilat are present in breast milk. Some
day guidelines consider benazepril to be acceptable for use in
Administration Rectal: Remove from foil; moisten finger breastfeeding women. Monitoring of the breastfeeding
and suppository; insert rectally child's: weight for the first 4 weeks is recommended
Controlled Substance C-I! (Regitz-Zagrosek 2011).

254
 BENAZEPRIL

Contraindications receiving insulin or oral antidiabetic agents; may be at

Hypersensitivity to benazepril, other ACE inhibitors, or any increased risk for episodes of hypoglycemia.
component of the formulation; history of angioedema
May be associated with deterioration of renal function and/
(with or without prior ACE inhibitor therapy); concomitant
or increases in BUN and serum creatinine, particularly in
use with aliskiren in patients with diabetes mellitus;
patients with low renal blood flow (eg, renal artery steno-
coadministration with or within 36 hours of switching to
sis, heart failure) whose GFR is dependent on efferent
or from a neprilysin inhibitor (eg, sacubitril).
arteriolar vasoconstriction by angiotensin Il; deterioration
Canadian labeling: Additional contraindications (not in US
may result in oliguria, acute renal failure, and progressive
labeling): Concomitant use with aliskiren in patients with
azotemia. Small increases in serum creatinine may occur
moderate to severe renal impairment (GFR <60 mL/
minute/1.73 m?); pregnancy; breastfeeding; rare heredi- following initiation; consider discontinuation only in
_ tary problems of galactose intolerance (eg, galactose- patients with progressive and/or significant deterioration
mia, Lapp Lactase deficiency or glucose-galactose in renal function (Bakris 2000). Use with caution in
malabsorption). patients with unstented unilateral/bilateral renal artery
Warnings/Precautions Anaphylactic reactions may stenosis. When unstented bilateral renal artery stenosis
occur rarely with ACE inhibitors. At any time during treat- is present, use is generally avoided due to the elevated
ment (especially following first dose) angioedema may risk of deterioration in renal function unless possible
occur rarely with ACE inhibitors. It may involve the head benefits outweigh risks. Potentially significant drug-drug
and neck (potentially compromising airway) or the intes- interactions may exist, requiring dose or frequency adjust-
tine (presenting with abdominal pain). African Americans ment, additional monitoring, and/or selection of alternative
and patients with idiopathic or hereditary angioedema may therapy.
be at an increased risk. Risk may also be increased with Avoid use in patients, with ascites due to cirrhosis or
concomitant use of mTOR inhibitor (eg, everolimus) ther- refractory ascites; if use cannot be avoided in patients
apy or a neprilysin inhibitor (eg, sacubitril). Prolonged with ascites due to cirrhosis, monitor blood pressure and
frequent monitoring may be required especially if tongue, renal function carefully to avoid rapid development of renal
glottis, or larynx are involved as they are associated with failure (AASLD [Runyon 2012]). Rare toxicities associated
airway obstruction. Patients with a history of airway sur- with ACE inhibitors include cholestatic jaundice (which
gery may have a higher risk of airway obstruction. Aggres- may progress to fulminant hepatic necrosis), agranulocy-
sive early and appropriate management is critical. tosis, neutropenia, or leukopenia with myeloid hypoplasia.
Contraindicated in patients with history of angioedema Patients with collagen vascular diseases (especially with
with or without prior ACE inhibitor therapy. Hypersensitiv- concomitant renal impairment) or renal impairment alone
ity reactions may be seen during hemodialysis (eg,
may be at increased risk for hematologic toxicity; periodi-
CVVHD) with high-flux dialysis membranes (eg, AN69), cally monitor CBC with differential in these patients.
and rarely, during low density lipoprotein apheresis with
Warnings: Additional Pediatric Considerations In
dextran sulfate cellulose. Rare cases of anaphylactoid
pediatric patients, an isolated dry hacking cough lasting
reactions have been reported in patients undergoing
>3 weeks was reported in seven of 42 pediatric patients
sensitization treatment with hymenoptera (bee, wasp)
(17%) receiving ACE inhibitors (von Vigier, 2000); a
venom while receiving ACE inhibitors.
review of pediatric randomized, controlled ACE inhibitor
Symptomatic hypotension with or without syncope can trials reported a lower incidence of 3.2%; a higher inci-
occur with ACE inhibitors (usually with the first several dence of cough has been reported in pediatric patients
doses); effects are most often observed in volume receiving benazepril (15.2%); however, this may have
depleted patients; close monitoring of patient is required resulted from differences in study methodology (Baker-
especially with initial dosing and dosing increases; blood Smith, 2010).
pressure must be lowered at a rate appropriate for the Adverse Reactions
patient's clinical condition. Initiation of therapy in patients Cardiovascular: Hypotension
with ischemic heart disease or cerebrovascular disease Central nervous system: Dizziness, drowsiness, head-
warrants close observation due to the potential conse- ache, orthostatic dizziness
quences posed by falling blood pressure (eg, MI, stroke). Rare but important or life-threatening: Alopecia, angioe-
Use with caution in hypertrophic cardiomyopathy with dema, anxiety, arthralgia, arthritis, asthma, bronchitis,
outflow tract obstruction (ACC/AHA [Gersh 2011]). Use constipation, decreased libido, dermatitis, diaphoresis,
with caution in severe aortic stenosis. In patients on dyspnea, ECG changes, eosinophilia, fatigue, flushing,
chronic ACE inhibitor therapy, intraoperative hypotension gastritis, hemolytic anemia, hypersensitivity, hypertonia,
may occur with induction and maintenance of general hyponatremia, impotence, increased liver enzymes,
anesthesia; use with caution before, during, or immedi- increased serum bilirubin, increased serum glucose,
ately after major surgery. Cardiopulmonary bypass, intra- increased uric acid, infection, insomnia, melena, myal-
operative blood loss, or vasodilating anesthesia increases gia, nausea, nervousness, pancreatitis, paresthesia,
endogenous renin release. Use of ACE inhibitors perio- pemphigus, proteinuria, pruritus, sinusitis, skin photo-
peratively will blunt angiotensin |}! formation.and may result sensitivity, skin rash, Stevens-Johnson syndrome,
in hypotension. However, discontinuation of therapy prior thrombocytopenia, urinary frequency, urinary tract infec-
to surgery is controversial. If continued preoperatively, tion, vomiting, weakness
avoidance of hypotensive agents during surgery is pru- Drug Interactions
dent (Hillis 2011). Based on current research and clinical
Metabolism/Transport Effects None known.
guidelines in patients undergoing non-cardiac surgery,
continuing ACE inhibitors is reasonable in the perioper-
Avoid Concomitant Use
Avoid concomitant use of Benazepril with any of the
ative period. If ACE inhibitors are held before surgery, it is
following: Bromperidol; Sacubitril
reasonable to restart postoperatively as soon as clinically
feasible (ACC/AHA [Fleisher 2014]). ACE inhibitors effec- Increased Effect/Toxicity
tiveness is less in black patients than in non-blacks. In Benazepril may increase the levels/effects of: Allopur-
addition, ACE inhibitors cause a higher rate of angioe- inol; Amifostine; Angiotensin Il; Antipsychotic Agents
dema in black than in non-black patients. [US Boxed (Second Generation [Atypical]); AzaTHlOprine; Brom-
Warning]: Drugs that act on the renin-angiotensin peridol; Drospirenone; DULoxetine; Ferric Gluconate;
system can cause injury and death to the developing Ferric Hydroxide Polymaltose Complex; Gelatin (Succi-
fetus. Discontinue as soon as possible once preg- nylated); Gold Sodium Thiomalate; Grass Pollen Aller-
nancy is detected. gen Extract (5 Grass Extract); Hypotension-Associated
Agents; Iron Dextran Complex; Levodopa; Lithium; Nitro-
Hyperkalemia may occur with ACE inhibitors; risk factors prusside; Nonsteroidal Anti-Inflammatory Agents; Phol-
include renal dysfunction, diabetes mellitus, concomitant codine; Pregabalin; Sacubitril; Sodium Phosphates
use of potassium-sparing diuretics, potassium supple-
ments and/or potassium-containing salts-Use cautiously, The levels/effects of Benazepril may be increased by:
if at all, with these agents and monitor potassium periodi- Alfuzosin; Aliskiren; Angiotensin || Receptor Blockers;
cally. Cough may occur with ACE inhibitors. Other causes Barbiturates; Benperidol; Brigatinib; Brimonidine (Top-
of cough should be considered (eg, pulmonary congestion ical); Canagliflozin; Dapoxetine; Diazoxide; Dipeptidy!
in patients with heart failure) and excluded prior to dis- Peptidase-lV Inhibitors; Eplerenone; Everolimus; Hepa-
continuation. Another ACE inhibitor, captopril, has been rin; Heparins (Low Molecular Weight); Herbs (Hypoten-
associated with neutropenia with myeloid hypoplasia and sive Properties); HydroCHLOROthiazide; Loop
agranulocytosis; anemia and thrombocytopenia have also Diuretics; Lormetazepam; Molsidomine; Naftopidil; Nic-
occurred. Patients with renal impairment are at high risk of ergoline; Nicorandil; Obinutuzumab; Pentoxifylline;
developing neutropenia. Patients with both renal impair- Phosphodiesterase 5 Inhibitors; Potassium Salts; Potas-
ment and collagen vascular disease (eg, systemic lupus sium-Sparing Diuretics; Prostacyclin Analogues; Quina-
erythematosus) ‘are at an even higher risk of developing golide; Salicylates; Sirolimus; Temsirolimus; Thiazide
neutropenia. Periodically monitor CBC with differential in and Thiazide-Like Diuretics; TiZANidine; Tolvaptan; Tri-
these patients. Use with caution in patients with diabetes methoprim

255
 BENAZEPRIL

é Decreased Effect
Benazepril may decrease the levels/effects of: Hydro-
least 1 additional minute. Add Ora-Sweet 75 mL to
suspension and shake to disperse. Will make 150 mL of
CHLOROthiazide a 2 mg/mL suspension. Label "shake well" and "refriger-
ate". Stable for 30 days.
The levels/effects of Benazepril may be decreased by: Lotensin prescribing information, Validus Pharmaceuticals LLC, Par-
Amphetamines; Aprotinin; Brigatinib; Bromperidol; Herbs sippany, NJ, 2017.
(Hypertensive Properties); Icatibant; Lanthanum; Meth-
ylphenidate; Nonsteroidal Anti-Inflammatory Agents; @ Benazepril HCI see Benazepril on page 254
Salicylates; Yohimbine @ Benazepril Hydrochloride see Benazepril on page 254
Storage/Stability Store at <30°C (86°F). Protect from @ BeneFIX see Factor IX (Recombinant) on page 822
moisture.
@ BeneFix (Can) see Factor IX (Recombinant)
Mechanism of Action Competitive inhibition of angioten- on page 822
sin | being converted to angiotensin II, a potent vaso-
constrictor, through the angiotensin |-converting enzyme # Benemid [DSC] see Probenecid on page 1681
(ACE) activity, with resultant lower levels of angiotensin II @ Benflumetol and Artemether see Artemether and
which causes an increase in plasma renin activity and a Lumefantrine on page 181
reduction in aldosterone secretion @ Benicar see Olmesartan on page 1490
Pharmacodynamics/Kinetics (Adult data unless @ Benoxyl (Can) see Benzoyl Peroxide on page 259
noted)
Reduction in plasma angiotensin-converting enzyme
(ACE) activity: Benralizumab (ben ra LIZ ue mab)
Onset of action: Peak effect: 1 to 2 hours after 2 to 20 mg
dose (Nussberger-1987; Nussberger 1989) Brand Names: US Fasenra
Duration: >90% inhibition for 24 hours after 5 to 20 mg Brand Names: Canada Fasenra
dose (Balfour 1991) Therapeutic Category Interleukin-5 Receptor Antago-
Reduction in blood pressure: nist; Monoclonal Antibody, Anti-Asthmatic
Peak effect: Single dose: 2 to 4 hours; Continuous Generic Availability (US) No
therapy: 2 weeks (Fogari 1990) Use Treatment of severe asthma with an eosinophilic
Absorption: Rapid (37%); food does not alter significantly; phenotype as add-on maintenance therapy (FDA
metabolite (benazeprilat) itself unsuitable for oral admin- approved in ages 212 years and adults). Note: Not
istration due to poor absorption indicated for treatment of other eosinophilic conditions or
Distribution: Vg: ~8.7 L (Balfour 1991) ‘for the relief of acute bronchospasm or status asthmati-
Protein binding: cus.
Benazepril: ~97% Pregnancy Considerations
Benazeprilat: ~95% Adverse events were not observed in animal reproduction
Metabolism: Rapidly and extensively hepatic to its active studies. IgG monoclonal antibodies, including benralizu-
metabolite, benazeprilat, via enzymatic hydrolysis; mab, are expected to cross the placenta with higher
extensive first-pass effect concentrations in the third trimester.
Half-life elimination: Benazeprilat: Effective: 10 to 11
Uncontrolled asthma is associated with adverse events on
hours; Terminal: Children: 5 hours, Adults: 22 hours
pregnancy (increased risk of preeclampsia, preterm birth,
Time to peak:
low birth weight infants). Asthma should be closely moni-
Parent drug: 0.5 to 1 hour
tored in pregnant women.
Active metabolite (benazeprilat): Fasting: 1 to 2 hours;
Nonfasting: 2 to 4 hours Breastfeeding Considerations It is not known if benra-
Excretion: lizumab is present in breast milk; however, IgG is excreted
in human milk and excretion of benralizumab is expected.
Urine (trace amounts as benazepril; 20% as benazepri-
lat; 12% as other metabolites)
According to the manufacturer, the decision to breastfeed
Clearance: Nonrenal clearance (ie, biliary, metabolic) during therapy should consider the risk of infant exposure,
the benefits of breastfeeding to the infant, and the benefits
appears to contribute to the elimination of benazeprilat
(11% to 12%), particularly patients with severe renal of treatment to the mother.
impairment; hepatic clearance is the main elimination Contraindications Hypersensitivity to benralizumab or
route of unchanged benazepril any component of the formulation
Dialysis: ~6% of metabolite removed within 4 hours of Warnings/Precautions Hypersensitivity reactions (eg,
dialysis following 10 mg of benazepril administered 2 anaphylaxis, angioedema, urticaria, rash) may occur, typ-
hours prior to procedure; parent compound not found in ically within hours of administration. Delayed hypersensi-
dialysate tivity reactions, occurring days after administration, have
Pharmacodynamics/Kinetics: Additional Consider- also been reported. Discontinue use in patients who
ations experience a hypersensitivity reaction. Do not discontinue
systemic or inhaled corticosteroids abruptly upon initiation
Renal function impairment: In those with CrCl 30 mL/
minute or less, peak benazeprilat levels and initial half-
of benralizumab. Reductions in corticosteroid dose should
be gradual, if appropriate. Clinicians should note that a
life increase and time to steady state may be delayed.
reduction in corticosteroid dose may be associated with
Dosing
withdrawal symptoms and/or unmask conditions previ-
Pediatric Hypertension: Note: Dosage must be titrated
ously suppressed by systemic corticosteroid therapy.
according to patient’s response; use lowest effective
dose It is unknown if administration of benralizumab will influ-
Children 26 years and Adolescents: Oral: Initial: ence a patient's immune response against parasitic infec-
0.2 mg/kg/dose once daily as monotherapy; maximum tions. Therefore, patients with preexisting helminth
initial dose: 10 mg/day; maintenance: 0.1-0.6 mg/kg/ infections should undergo treatment of the infection prior
dose once daily; maximum daily dose: 40 mg/day to initiation of benralizumab therapy. Patients who become
Renal Impairment: Pediatric Children and Adoles- infected during benralizumab treatment and do not
cents: CrCl <30 mL/minute/1.73 m?: Use is not recom- respond to antihelminth therapy should discontinue ben-
mended (insufficient data exists; dose not established) ralizumab until the infection resolves. Not indicated for the
Administration Oral: May be administered without regard treatment of acute asthma symptoms (eg, acute broncho-
to food. spasm) or acute exacerbations, including status asthma-
Monitoring Parameters Blood pressure (supervise for at ticus. Appropriate rescue medication should be available.
least 2 hours after the initial dose or any dosage increase Patients who experience continued uncontrolled asthma
for significant orthostasis); renal function, WBC, serum or worsening of symptoms following treatment initiation
potassium; monitor for angioedema and anaphylactoid with benralizumab should seek medical attention.
reactions Adverse Reactions
Test Interactions May lead to false-negative aldosterone/ Central nervous system: Headache
renin ratio (ARR) (Funder 2016) Hypersensitivity: Hypersensitivity reaction
Dosage Forms Excipient information presented when Immunologic: Antibody development
available (limited, particularly for generics); consult spe- Respiratory: Pharyngitis
cific product labeling. Miscellaneous: Fever
Tablet, Oral, as hydrochloride: Drug Interactions
Lotensin: 10 mg, 20 mg, 40 mg Metabolism/Transport Effects None known.
Generic: 5 mg, 10 mg, 20 mg, 40 mg Avoid Concomitant Use
Extemporaneous Preparations A 2 mg/mL oral sus- Avoid concomitant use of Benralizumab with any of the
pension may be made with tablets. Mix fifteen benazepril following: Belimumab
20 mg tablets in an amber polyethylene terephthalate Increased Effect/Toxicity
bottle with Ora-Plus 75 mL. Shake for 2 minutes, allow Benralizumab may increase the levels/effects of: Beli-
suspension to stand for 21 hour, then shake again for at mumab

256
 BENZOCAINE

Decreased Effect There are no known significant inter- Dosing

actions involving a decrease in effect. Pediatric Skin Protectant: Children 26 years and Ado-
Storage/Stability Store in original carton at 2°C to 8°C lescents: Topical: Apply to skin 15 minutes prior to
(36°F to 46°F). Do not freeze or shake. Protect from light. potential exposure to poison ivy, poison oak, or poison
Use within 24 hours after removal from refrigerator. sumac; may reapply every 4 hours for continued protec-
Mechanism of Action Benralizumab, a humanized tion or sooner if needed
monoclonal antibody (lgG1, kappa), is an interleukin-5 Renal Impairment: Pediatric There are no dosage
antagonist. IL-5 is the major cytokine responsible for the adjustments provided in the manufacturer's labeling.
growth and differentiation, recruitment, activation, and Hepatic Impairment: Pediatric There are no dosage
survival of eosinophils (a cell type associated with inflam- adjustments provided in the manufacturer's labeling.
mation and an important component in the pathogenesis Administration Topical: For external use only; flammable,
of asthma). Benralizumab, by inhibiting IL-5 signaling, keep away from flame or fire. Shake well prior to use.
reduces the production and survival of eosinophils; how- Apply to clean, dry skin 15 minutes prior to exposure;
ever, the mechanism of benralizumab action in asthma avoid contact with eyes; do not use on open wounds.
has not been definitively established. Remove with soap and water after risk of exposure.
Pharmacodynamics/Kinetics (Adult data unless Monitoring Parameters Signs and symptoms of expo-
noted) Note: Pharmacokinetic data in pediatric patients sure to poison oak, ivy, or sumac (rash, swelling, blisters)
12 to 4,7 years of age is similar to adult observations Dosage Forms Excipient information presented when
Distribution: 3.2 L (central); 2.5 L (peripheral) available (limited, particularly for generics); consult spe-
Metabolism: Undergoes proteolytic degradation via cific product labeling.
enzymes that are widely distributed in the body and not Lotion, topical:
restricted to hepatic tissue. Ivy Block: 5% (30 mL, 120 mL) [contains benzyl alcohol,
Bioavailability: ~58% ethanol 25%]
-Half-life elimination: 15 days
Excretion: Nonrenal @ Bentyl see Dicyclomine on page 632
Dosing @ Bentylol (Can) see Dicyclomine on page 632
Pediatric Asthma, eosinophilic phenotype; add-on
Benuryl (Can) see Probenecid on page 1681
maintenance therapy: Children 242 years and Adoles-
cents: SubQ: 30 mg every 4 weeks for the first 3 doses @ Benylin® D for Infants (Can) see Pseudoephedrine
then once every 8 weeks on page 1712
Renal Impairment: Pediatric There are no dosage of Benylin Chest Congestion Extra Strength (Can) see
adjustments provided in the manufacturer's labeling GuaiFENesin on page 964
(has not been studied); however, adjustment based on Sd Benylin DM-E (Can) see Guaifenesin and Dextromethor-
renal function is unlikely to be necessary as benralizu- phan on page 967
mab is not renally cleared.
0 Benzac AC (Can) see Benzoyl Peroxide on page 259
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in the manufacturer's labeling (has Sd Benzac AC Wash see Benzoyl Peroxide on page 259
not been studied); however, adjustment based on hep- BenzaClin see Clindamycin and Benzoyl Peroxide
atic function is unlikely to be necessary as benralizumab on page 476
is degraded by widely distributed proteolytic enzymes Benzac W Gel (Can) see Benzoyl Peroxide on page 259
that are not restricted to hepatic tissue.
Administration SubQ: May be administered undiluted Benzac W Wash [DSC] see Benzoyl Peroxide
subcutaneously into the upper arm, thigh, or abdomen. on page 259
Prior to administration, allow prefilled syringe to warm at Benzac W Wash (Can) see Benzoyl Peroxide
room temperature for about 30 minutes. Solution is clear on page 259
to opalescent, colorless to slight yellow liquid; particles Benzathine Benzylpenicillin see Penicillin G Benza-
may be present in the solution that appear translucent or thine on page 1582
white to off-white; do not use if cloudy or discolored.
Benzathine Penicillin G see Penicillin G Benzathine
Syringe may contain a small air bubble; do not expel the
on page 1582
air bubble prior to administration.
Monitoring Parameters Anaphylaxis/hypersensitivity Benzatropine see Benztropine on page 267
reactions; peak flow and/or other pulmonary function BenzEFoam see Benzoyl Peroxide on page 259
tests; monitor for signs of infection BenzEFoamultra see Benzoyl Peroxide on page 259
Dosage Forms Excipient information presented when
Benzene Hexachloride see Lindane on page 1224
available (limited, particularly for generics); consult spe-
cific product labeling. BenzePrO see Benzoyl Peroxide on page 259
Solution Prefilled Syringe, Subcutaneous [preservative BenzePrO Creamy Wash see Benzoyl Peroxide
free]: on page 259
Fasenra: 30 mg/mL (1 mL) BenzePrO Foaming Cloths see Benzoyl Peroxide
@ Bensal HP see Salicylic Acid on page 1796 on page 259
BenzePrO Short Contact see Benzoyl! Peroxide
on page 259
Bentoquatam (BEN toe kwa tam)
Benzhexol Hydrochloride see Trihexyphenidy!
Brand Names: US Ivy Block [OTC] on page 2008
Therapeutic Category Topical Skin Product Benziq see Benzoyl Peroxide on page 259
Generic Availability (US) No Benziq LS see Benzoyl Peroxide on page 259
Use Skin protectant for the prevention of allergic contact
dermatitis to poison oak, ivy, and sumac (FDA approved in Benziq Wash see Benzoyl Peroxide on page 259
ages 26 years and adults) ¢
¢$¢¢
Benzmethyzin see Procarbazine on page 1684
Contraindications Hypersensitivity to bentoquatam or
any component of the formulation; use on open rash
Benzocaine (BEN zoe kane)
Warnings/Precautions Appropriate use: For external
use only; avoid contact with eyes. Medication Safety Issues
Adverse Reactions Rare but important or life-threaten- Sound-alike/look-alike issues:
ing: Erythema - Orabase may be confused with Orinase
Drug Interactions Brand Names: US Aftertest Topical Pain Relief [OTC];
Metabolism/Transport Effects None known. Anacaine; Anbesol Cold Sore Therapy [OTC]; Anbesol JR
Avoid Concomitant Use There are no known interac- [OTC] [DSC]; Anbesol Maximum Strength [OTC]; Anbesol
tions where it is recommended to avoid concomitant use. [OTC]; Baby Anbesol [OTC]; Benz-O-Sthetic [OTC]; Bi-
Increased Effect/Toxicity There are no known signifi- Zets/Benzotroches [OTC]; Blistex Medicated [OTC];
cant interactions involving an increase in effect. Cepacol Dual Relief [OTC] [DSC]; Cepacol INSTAMAX
Decreased Effect There are no known significant inter- [OTC]; Cepacol Sensations Hydra [OTC] [DSC]; Cepacol
actions involving a decrease in effect. Sensations Warming [OTC] [DSC]; Chiggerex [OTC]
Storage/Stability Store at 15°C to 30°C (59°F to 86°F). [DSC]; Chiggertox [OTC] [DSC]; Dent-O-Kain/20 [OTC];
Flammable; do not use near open flame. Dentapaine [OTC]; Dermoplast [OTC] [DSC]; Foille [OTC];
Mechanism of Action An organoclay substance which is HurriCaine One [OTC]; Hurricaine [OTC]; HurriPak Starter
capable of absorbing or binding to urushiol, the active Kit [OTC]; lvy-Rid [OTC]; Kank-A Mouth Pain [OTC]; Ora-
principle in poison oak, ivy, and sumac. Bentoquatam film [OTC]; Oral Pain Relief Max St [OTC] [DSC]; Pinna-

>
serves as a barrier, blocking urushiol skin contact/absorp- caine Otic [DSC]; Sore Throat Relief [OTC]; Topex Topical
tion. : Anesthetic; Trocaine Throat [OTC]; Zilactin Baby [OTC]

257
BENZOCAINE

Brand Names: Canada Anbesol® Baby; Zilactin Baby®; High systemic levels and toxic effects (eg, methemoglobi-
Zilactin-B® nemia, irregular heartbeats, respiratory depression, seiz-
Therapeutic Category Analgesic, Topical; Local Anes- ures, death) have been reported in patients who (without
thetic, Oral; Local Anesthetic, Topical supervision of a trained professional) have applied topical
Generic Availability (US) May be product dependent anesthetics in large amounts (or to large areas of the
skin), left these products on for prolonged periods of time,
Use or have used wraps/dressings to cover the skin following
Topical/External: Temporary relief of pain and itching
application.
associated with minor cuts, scrapes, minor burns, sun-
Warnings: Additional Pediatric Considerations
burn, and insect bites (OTC product: Spray 20%, oint-
There is a significant safety risk of methemoglobinemia
ment 5%: FDA approved in ages 22 years and adults)
with benzocaine use. The majority of cases of methemo-
Topical/Oral: Temporary relief of pain associated with
globinemia associated with benzocaine use have been in
fever blisters and cold sores (OTC product: Ointment
20%: FDA approved in ages 22 years and adults); infants and children <2 years of age for treatment of
temporary relief of pain associated with toothache, sore
teething and mouth pain; also at greater risk for develop-
gums, canker sores, braces, minor dental procedures, or ment are patients with asthma, bronchitis, emphysema,
dentures (OTC product: Gel/Solution [10%, 20%]: FDA mucosal damage, or inflammation at the application site,
approved in ages 22 years and adults; Lozenge: FDA heart disease, and malnutrition. The FDA has strength-
approved in ages 25 years; Spray 5%: FDA approved in ened their warning against using topical OTC benzocaine
ages 26 years and adults); suppression of gag reflex for teething pain and are urging manufacturers to stop
(OTC product: Spray 20%: FDA approved in ages 22 marketing OTC oral benzocaine products for treatment of
years and adults). Note: Although product is available in teething in infants and children <2 years of age and to add
a gel formulation for relief of pain associated with teeth- contraindications to use in teething and treatment in
ing in infants 24 months, the FDA, AAP, and American infants and children <2 years (FDA Safety Announcement
Academy of Pediatric Dentistry do not recommend use 2018). The use of OTC topical anesthetics (eg, benzo-
due to safety concerns related to increased methemo- caine) for teething pain is also discouraged by AAP and
globinemia risk in infants and children <2 years of age The American Academy of Pediatric Dentistry (AAP 2011;
(AAP 2011a, FDA 2011). AAPD 2012). The AAP recommends managing teething
Note: Approved ages and uses for generic products may pain with a chilled (not frozen) teething ring or gently
vary; consult labeling for specific information. rubbing/massaging with the caregiver's finger.
Contraindications Some dosage forms may contain propylene glycol; in
Hypersensitivity to benzocaine, para-aminobenzoic acid neonates large amounts of propylene glycol delivered
(PABA), or any component of the formulation orally, intravenously (eg, >3,000 mg/day), or topically
OTC labeling: When used for self-medication, do not use if have been associated with potentially fatal toxicities which
you have allergy to local anesthetics (procaine, buta- can include metabolic acidosis, seizures, renal failure, and
caine, benzocaine, or other "caine" anesthetics). Do CNS depression; toxicities have also been reported in
not use over deep or puncture wounds, infections, seri- children and adults including hyperosmolality, lactic acido-
ous burns, or lacerations. sis, seizures and respiratory depression; use caution
Warnings/Precautions Methemoglobinemia has been (AAP 1997; Shehab 2009),
reported following topical use, particularly with higher Adverse Reactions
concentration (14% to 20%) spray formulations applied Central nervous system: Localized burning, stinging sen-
to the mouth or mucous membranes. When applied as a sation
spray to the mouth or throat, multiple sprays (or sprays of Dermatologic: Contact dermatitis, localized erythema,
longer than indicated duration) are not recommended. localized rash, urticaria
Use caution with breathing problems (asthma, bronchitis, Hematologic & oncologic: Methemoglobinemia
emphysema, in smokers), inflamed/damaged mucosa, Hypersensitivity: Hypersensitivity
heart disease, children <6 months of age, and hemoglobin Local: Local pruritus, localized edema, localized ten-
or enzyme abnormalities (glucose-6-phosphate dehydro- derness
genase deficiency, hemoglobin-M disease, NADH-meth-
Drug Interactions
emoglobin reductase deficiency, pyruvate-kinase
Metabolism/Transport Effects None known.
deficiency). Alternatives to benzocaine sprays, such as
topical lidocaine preparations, should be considered for
Avoid Concomitant Use There are no known interac-
patients at higher risk of this reaction. The classical clinical tions where it is recommended to avoid concomitant use.
finding of methemoglobinemia is chocolate brown-colored Increased Effect/Toxicity
arterial blood. However, suspected cases should be con- Benzocaine may increase the levels/effects of: Prilo-
firmed by co-oximetry, which yields a direct and accurate caine; Sodium Nitrite
measure of methemoglobin levels. Standard pulse oxime- The levels/effects of Benzocaine may be increased by:
try readings or arterial blood gas values are not reliable. Dapsone (Topical); Nitric Oxide; Tetracaine (Topical)
Clinically significant methemoglobinemia requires imme- Decreased Effect There are no known significant inter-
diate treatment (Anderson 1988; Cooper 1997; Moore
actions involving a decrease in effect.
2004). Due to risk of methemoglobinemia, AAP, FDA,
Storage/Stability
and the American Academy of Pediatric Dentistry do
Store at room temperature; do not refrigerate. Protect from
NOT recommend use for teething and mouth pain in
freezing and humidity.
infants and children <2 years of age (AAP 2011; AAPD
Spray: Flammable; store away from and do not use near
2012; FDA 2018).
fire, open flame and heat. Contents under pressure; do
Some dosage forms may contain benzyl alcohol; large not puncture or incinerate can. Do not store
amounts of benzyl alcohol (299 mg/kg/day) have been >48°C (>120°F).
associated with a potentially fatal toxicity ("gasping syn- Mechanism of Action Blocks both the initiation and
drome") in neonates; the "gasping syndrome" consists of conduction of nerve impulses by decreasing the neuronal
metabolic acidosis, respiratory distress, gasping respira- membrane's permeability to sodium ions, which results in
tions, CNS dysfunction (including convulsions, intracranial inhibition of depolarization with resultant blockade of con-
hemorrhage), hypotension and cardiovascular collapse duction
(AAP ["Inactive" 1997]; CDC 1982); some data suggests Pharmacodynamics/Kinetics (Adult data unless
that benzoate displaces bilirubin from protein binding sites noted)
(Ahlfors 2001); avoid or use dosage forms containing Onset: Anesthetic effect: Spray: 15 to 30 seconds.
benzyl alcohol with caution in neonates. See manufactur- Absorption: Poor through intact skin; well absorbed from
er's labeling. Some dosage forms may contain propylene mucous membranes and traumatized skin
glycol; large amounts are potentially toxic and have been Metabolism: Hepatic (to a lesser extent) and plasma via
associated hyperosmolality, lactic acidosis, seizures and hydrolysis by cholinesterase (Tucker 1986)
respiratory depression; use caution (AAP 1997; Zar 2007).
Dosing
See manufacturer's labeling.
Pediatric Note: General dosing recommendations pro-
When used for self-medication, notify healthcare provider vided; refer to specific product labeling for dosing
if condition worsens, or does not improve within 7 days; instructions. Due to risk of methemoglobinemia, AAP,
clears up and occurs again within a few days; or if FDA, and the American Academy of Pediatric Dentistry
accompanied by additional symptoms (eg, swelling, rash, do NOT recommend use for teething and mouth pain in
headache, nausea, vomiting, or fever). Do not use topical infants and children <2 years (AAP 2011; AAPD 2012;
products on open wounds; avoid contact with the eyes. Do FDA Safety Announcement 2018).
not use for a prolonged time and/or on large portions of Dermal irritation (insect bites, minor cuts, scrapes,
the body. When topical anesthetics are used prior to minor burns, sunburn): Topical: 20% spray, 5% oint-
cosmetic or medical procedures, the lowest amount of ment: Children 22 years and Adolescents: Apply to
anesthetic necessary for pain relief should be applied. affected area 3 to 4 times daily as needed.

258
 BENZOYL PEROXIDE

Mouth and gum irritation (including fever blisters Hurricaine: 20% (30 g) [contains polyethylene glycol,
and cold sores): Topical: saccharin sodium; watermelon flavor]
Oral 10% or 20% gel/liquid: Children 22 years and Hurricaine: 20% (5.25 g, 30 g) [contains polyethylene
Adolescents: Apply thin layer to affected area up to glycol, saccharin sodium; wild cherry flavor]
4 times daily as needed. Zilactin Baby: 10% (9.4 g) [alcohol free, dye free, sac-
Oral 5% spray: Children 26 years and Adolescents: charin free]
Use 1 spray to affected area up to 4 times daily. Kit, Mouth/Throat:
Sore throat/mouth, gag reflex suppression: HurriPak Starter Kit: 20% [contains polyethylene glycol,
Oral: Oral lozenge: Children 25 years and Adolescents: saccharin sodium]
Allow 1 lozenge to dissolve slowly in mouth; may Liquid, External:
repeat every 2 hours as needed. Chiggertox: 2.1% (30 mL [DSC])
Topical: Note: Consult product labeling for specific Liquid, Mouth/Throat:
dose recommendations. Anbesol: 10% (12 mL) [contains brilliant blue fcf (fd&c
Oral spray 5%: Children 26 years and Adolescents: blue #1), fd&c yellow #10 (quinoline yellow), fd&c
Use 1 spray to affected area or throat up to 4 times yellow #6 (sunset yellow), methylparaben, saccharin;
daily. cool mint flavor]
Oral spray 20%: Children 22 years and Adolescents: Anbesol Maximum Strength: 20% (12 mL) [contains
(Spray on affected area or throat up to 4 times daily. benzyl alcohol, brilliant blue fcf (fd&c blue #1), fd&c
Renal Impairment: Pediatric There are no dosage red #40, fd&c yellow #10 (quinoline yellow), methylpar-
adjustments provided in the manufacturer's labeling. aben, polyethylene glycol, propylene glycol, saccharin]
Hepatic Impairment: Pediatric There are no dosage Benz-O-Sthetic: 20% (56 g) [contains benzyl alcohol,
adjustments provided in the manufacturer's labeling. brilliant blue fcf (fd&c blue #1), fd&c red #40, fd&c
Administration Note: Some products may contain flam- yellow #10 (quinoline yellow), polyethylene glycol, pro-
pylene glycol, saccharin]
~ mable ingredients, do not use near fire, flame or heat.
Some products may stain certain fabrics; avoid contact Cepacol Dual Relief: 5% (22.2 mL [DSC]) [sugar free]
with clothing or furniture. Dent-O-Kain/20: 20% (9 mL) [contains benzyl! alcohol,
brilliant blue fcf (fd&c blue #1), d&c yellow #11 (quino-
Oral gel/solution (topical): Apply with cotton applicator or
line yellow ss), fd&c red #40, propylene glycol, sac-
fingertip to affected area. Children <12 years of age
charin]
should be supervised during use.
Hurricaine: 20% (30 mL) [contains polyethylene glycol,
Oral lozenge: Allow to dissolve slowly in mouth. Do not
saccharin sodium]
crush, chew, or swallow whole.
Oral Pain Relief Max St: 20% (15 mL [DSC]) [contains
Topical ointment: Apply evenly. Do not apply over large
benzyl alcohol, brilliant blue fcf (fd&c blue #1), fd&c red
areas, deep or puncture wounds, animal bites, or serious
#40, fd&c yellow #10 (quinoline yellow), methylpara-
burns.
ben, polyethylene glycol, propylene glycol, saccharin]
Topical spray: Shake spray well prior to use. Hold 6 to 12
Lozenge, Mouth/Throat:
inches from the affected area or may use with extension
Bi-Zets/Benzotroches: 15 mg (10 ea) [orange flavor]
tube for finer direct application (eg, oral mucosal spray).
Cepacol INSTAMAX: Benzocaine 15 mg and menthol
For application to face (eg, for cold sores), first spray into 20 mg (16 ea) [contains fd&c red #40, fd&c yellow
palm of hand, then touch hand to face; avoid contact with
#10 (quinoline yellow)]
the eyes. Do not apply to deep or puncture wounds,
Cepacol Sensations Hydra: 3 mg (20 ea [DSC]) [con-
infections, lacerations, or to serious burns. Children <12
tains brilliant blue fcf (fd&c blue #1), fd&c yellow #10
years of age should be supervised during use. (quinoline yellow)]
Monitoring Parameters Monitor patients for signs and Cepacol Sensations Warming: 4 mg (20 ea [DSC]) [con-
symptoms of methemoglobinemia such as pallor, fatigue, tains fd&c red #40, fd&c yellow #10 (quinoline yellow)]
cyanosis, nausea, muscle weakness, dizziness, confu- Sore Throat Relief: 10 mg (2 ea) [wild cherry flavor]
sion, agitation, dyspnea, and tachycardia. The classical Trocaine Throat: 10 mg (1 ea)
Clinical finding of methemoglobinemia is chocolate brown- Ointment, External:
colored arterial blood. However, suspected cases should Anacaine: 10% (30 g).
be confirmed by co-oximetry, which yields a direct and Anbesol Cold Sore Therapy: 20% (9 g) [contains aloe,
accurate measure of methemoglobin levels. Standard vitamin e]
pulse oximetry readings or arterial blood gas values are Blistex Medicated: (6.3 g) [contains cetyl alcohol, ede-
not reliable. Clinically significant methemoglobinemia tate calcium disodium, saccharin sodium, sd alcohol]
requires. immediate treatment. Chiggerex: 2% (52.5 g [DSC])
Dosage Forms Excipient information presented when Foille: 5% (28 g)
available (limited, particularly for generics); consult spe- Solution, Mouth/Throat:
cific product labeling. [DSC] = Discontinued product Benz-O-Sthetic: 20% (30 mL) [contains polyethylene
Aerosol, External: glycol, saccharin]
Dermoplast: Benzocaine 20% and menthol 0.5% (56 g Hurricaine: 20% (30 mL) [contains polyethylene glycol,
[DSC]) [contains methylparaben] saccharin sodium; pina colada flavor]
Ivy-Rid: 2% (85 g) Hurricaine: 20% (30 mL) [contains polyethylene glycol,
Aerosol, Mouth/Throat: saccharin sodium; wild cherry flavor]
Hurricaine: 20% (57 g) [contains polyethylene glycol, HurriCaine One: 20% (2 ea, 25 ea) [contains polyethy-
saccharin; mint flavor] lene glycol, saccharin sodium]
Hurricaine: 20% (57 g) [contains polyethylene glycol, Kank-A Mouth Pain: 20% (9.75 mL) [contains benzyl
saccharin sodium] alcohol, propylene glycol, saccharin sodium]
Hurricaine: 20% (57 g) [contains polyethylene glycol, Solution, Otic:
saccharin sodium; wild cherry flavor] Pinnacaine Otic: 20% (15 mL [DSC])
Topex Topical Anesthetic: 20% (57 g) [cherry flavor] Stick, External:
Gel, Mouth/Throat: Aftertest Topical Pain Relief: 10% (4 mL) [contains
Anbesol: 10% (9 g) [contains benzyl alcohol, brilliant menthol, propylene glycol]
blue fef (fd&c blue #1), fd&c yellow #10 (quinoline Strip, Mouth/Throat:
yellow), fd&c yellow #6 (sunset yellow), methylparaben, Ora-film: 6% (12 ea) [contains brilliant blue fcf (fd&c blue
propylene glycol, saccharin; cool mint flavor] #1), menthol, methylparaben, propylparaben, tartrazine
Anbesol JR: 10% (9 g [DSC]) [contains methylparaben] (fd&c yellow #5)]
Anbeso! Maximum Strength: 20% (9 g) [contains brilliant Swab, Mouth/Throat:
blue fof (fd&c blue #1), fd&c red #40, fd&c yellow #10 Benz-O-Sthetic: 20% (2 ea [DSC]) [contains benzyl
(quinoline yellow), methylparaben, saccharin] alcohol, polyethylene glycol, saccharin sodium]
Baby Anbesol: 7.5% (9g) ¢ Benz-O-Sthetic: 20% (2 ea) [contains benzyl alcohol,
Benz-O-Sthetic: 20% (15g) [contains benzyl alcohol, polyethylene glycol, saccharin sodium; cherry flavor]
saccharin sodium] Hurricaine: 20% (72 ea) [contains polyethylene glycol,
Benz-O-Sthetic: 20% (29g) [contains benzyl alcohol, saccharin sodium; wild cherry flavor]
saccharin sodium; bubble-gum flavor]
@ Benz-O-Sthetic [OTC] see Benzocaine on page 257
Benz-O-Sthetic: 20% (29 g) [contains benzyl alcohol,
saccharin sodium; cherry flavor] @ Benzoyl Metronidazole see MetroNIDAZOLE (Sys-
Dentapaine: 20% (11 g) temic) on page 1362
Hurricaine: 20% (5.25 g, 30 g) [contains polyethylene
glycol, saccharin sodium] Benzoyl Peroxide (BEN zoe il peer OKS ide)
Hurricaine: 20% (28.4 g) [contains polyethylene glycol,
saccharin sodium; mint flavor] Medication Safety Issues
Hurricaine: 20% (30 g) [contains polyethylene glycol, Sound-alike/look-alike issues:
saccharin sodium; pina colada flavor] Benzoyl peroxide may be confused with benzyl alcohol i
BENZOYL PEROXIDE

Benoxyl may be confused with Brevoxyl, Peroxyl Benzyl alcohol and derivatives: Some dosage forms may
Benzac may be confused with Benza contain benzyl alcohol; large amounts of benzyl alcohol
Brevoxyl may be confused with Benoxyl (299 mg/kg/day) have been associated with a potentially
Fostex may be confused with pHisoHex fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Brand Names: US Acne Medication 10 [OTC]; Acne ing syndrome" consists of metabolic acidosis, respiratory
Medication 5 [OTC]; Acne Medication [OTC] [DSC]; distress, gasping respirations, CNS dysfunction (including
Acne-Clear [OTC]; AcneFree Acne Clearing System convulsions, intracranial hemorrhage), hypotension and
[OTC]; AcneFree Severe Clearing Syst [OTC]; Advanced cardiovascular collapse (AAP 1997; CDC 1982); some
Acne Wash [OTC]; Benzac AC Wash; Benzac W Wash data suggests that benzoate displaces bilirubin from pro-
[DSC]; BenzEFoam; BenzEFoamUltra; BenzePrO; Ben- tein binding sites (Ahlfors 2001); avoid or use dosage
zePrO Creamy Wash; BenzePrO Foaming Cloths; Benze- forms containing benzyl alcohol with caution in neonates.
PrO Short Contact; Benziq; Benziq LS; Benziq Wash; See manufacturer's labeling.
Benzoyl Peroxide Cleanser [OTC]; Benzoyl Peroxide Warnings: Additional Pediatric Considerations
Wash [OTC]; BP Cleansing [OTC] [DSC]; BP Foam; BP Some dosage forms may contain propylene glycol; in
Foaming Wash [DSC]; BP Gel [OTC]; BP Wash; BP Wash neonates large amounts of propylene glycol delivered
[OTC]; BPO Creamy Wash [OTC] [DSC]; BPO Foaming orally, intravenously (eg, >3,000 mg/day), or topically
Cloths; BPO [DSC]; BPO-10 Wash [OTC] [DSC]; BPO-5 have been associated with potentially fatal toxicities which
Wash [OTC] [DSC]; Clearplex V [OTC] [DSC]; Clearplex X can include metabolic acidosis, seizures, renal failure, and
[DSC]; Clearskin [OTC]; Desquam-X Wash [OTC] [DSC]; CNS depression; toxicities have also been reported in
Inova; Neutrogena Clear Pore [OTC]; OC8 [OTC]; Oscion children and adults including hyperosmolality, lactic acido-
Cleanser [DSC]; PanOxyl Wash [OTC]; PanOxyl [OTC]; sis, seizures and respiratory depression; use caution
PanOxyl-4 Creamy Wash [OTC]; PanOxyl-8 Creamy (AAP 1997; Shehab 2009).
Wash [OTC] [DSC]; PR Benzoyl Peroxide Wash; Riax; Adverse Reactions Dermatologic: Contact dermatitis,
SE BPO Wash [DSC]; Zaclir Cleansing desquamation, erythema, skin irritation, stinging of the
Brand Names: Canada Acetoxy!; Benoxyl; Benzac AC; skin, xeroderma
Benzac W Gel; Benzac W Wash; Desquam-X; Oxyderm; Drug Interactions
PanOxyl; Solugel Metabolism/Transport Effects None known.
Therapeutic Category Acne Products; Topical Skin Avoid Concomitant Use There are no known interac-
Product tions where it is recommended to avoid concomitant use.
Generic Availability (US) May be product dependent Increased Effect/Toxicity
Use Benzoyl Peroxide may increase the levels/effects of:
OTC products: Treatment of acne (FDA approved in Dapsone (Topical)
pediatric patients [age not specified] and adults). Note: Decreased Effect
Approved ages may vary by products; see product Benzoyl Peroxide may decrease the levels/effects of:
specific labeling. lsotretinoin (Topical)
Prescription products: Treatment of mild to moderate acne Storage/Stability Store at 15°C to 30°C (59°F to 86°F).
vulgaris (FDA approved in ages 212 years and adults) Mechanism of Action Releases free-radical oxygen
Pregnancy Risk Factor C which oxidizes bacterial proteins in the sebaceous follicles
Pregnancy Considerations Animal reproduction studies decreasing the number of anaerobic bacteria and
have not been conducted. Topical products are recom- decreasing irritating-type free fatty acids
mended as initial therapy for the treatment of acne in Pharmacodynamics/Kinetics (Adult data unless
pregnant females; benzoyl peroxide is one of the preferred noted)
agents (Chien 2016; Kong 2013; Leechman 2006). Absorption: ~5% via skin; gel more penetrating than
Breastfeeding Considerations It is not known if benzoyl cream
peroxide is present in breast milk. Metabolism: Converted to benzoic acid in skin
Although the manufacturer recommends that caution be
Dosing
exercised when administering benzoyl peroxide to breast- Pediatric
feeding women, benzoyl peroxide is considered compat- Acne: Children 27 years and Adolescents (Eichenfield
ible with breastfeeding (WHO 2002). In general, the use of 2013): Limited data available in ages <12 years: Top-
topical agents is preferred over systemic agents for the ical:
treatment of facial acne in women who are breastfeeding Topical formulations: Apply sparingly once daily; grad-
and benzoyl peroxide is one of the preferred agents. Avoid ually increase to 2 to 3 times daily if needed. If
applying large amounts over prolonged periods of time to excessive dryness or peeling occurs, reduce dose
decrease the potential for systemic absorption (Butler frequency or concentration. If excessive stinging or
burning occurs, remove with mild soap and water;
2014; Kong 2013; Leechman 2006). Avoid direct infant
contact with treated skin. resume use the next day.
Topical cleansers: Wash once or twice daily; control
Contraindications Hypersensitivity to benzoyl peroxide
amount of drying or peeling by modifying dose fre-
or any other component of the formulation.
quency or concentration
Warnings/Precautions For external use only; avoid con-
Renal Impairment: Pediatric There are no dosage
tact with eye, eyelids, lips, mouth, and mucous mem-
adjustments provided in the manufacturer's labeling.
branes. Inform patients to use skin protection (eg,
sunscreen) and minimize prolonged exposure to sun or
Hepatic Impairment: Pediatric There are no dosage
tanning beds. May bleach hair, colored fabric, or carpet.
adjustments provided in the manufacturer's labeling.
Skin irritation (eg, burning, itching, peeling, redness, swel- Administration Topical: For external use only. Avoid
ling) may occur; discontinue use if severe irritation devel- contact with eyes, eyelids, lips, and mucous membranes;
ops. Concomitant use of benzoyl peroxide with sulfone rinse with water if accidental contact occurs. Some prod-
products (eg, dapsone, sulfacetamide) may cause tempo- ucts may bleach or discolor hair, dyed fabrics, or carpet-
ing; avoid contact with hair, clothing, furniture, or
rary discoloration (yellow/orange) of facial hair and skin.
Application of products at separate times during the day or carpeting. Avoid unnecessary sun exposure; apply
washing off benzoyl peroxide prior to application of other sunscreen if going outside.
products may avoid skin discoloration (Dubina 2009). Cleansers: Wet skin areas to be treated prior to admin-
istration. Rinse thoroughly and pat dry.
Rare but serious and potentially life-threatening allergic Cloths: Wet face with water. Wet cloth with a little water
reactions or severe irritation have been reported with use and work into a full lather. Cleanse face with cloth for 10
of topical OTC benzoyl peroxide or salicylic acid contain- to 20 seconds. Rinse thoroughly and pat dry. Throw
ing products; it has not been determined if the reactions away cloth; do not flush.
are due to the active ingredients (benzoyl peroxide or Foam: Prime can prior to initial use; refer to manufac-
salicylic acid), the inactive ingredients, or a combination turer's labeling for priming instructions. Holding can
of both. Hypersensitivity reactions may occur within upright, dispense foam into palm of hand or applicator
minutes to a day or longer after product use and differ pad and cover entire affected area and rub in until
from local skin irritation (redness, burning, dryness, itch- completely absorbed. Some products can remain on skin
ing, peeling or slight swelling) that may occur at the site of and others should be rinsed off after a brief period of time
product application. Treatment should be discontinued if (refer to manufacturer's labeling). Rinse applicator with
hives or itching develop; patients should seek emergency water and allow to dry after use; wash hands with soap
medical attention if reactions such as throat tightness, and water after use.
difficulty breathing, feeling faint, or swelling of the eyes, Other dose forms: After cleansing skin, smooth small
face, lips, mouth, or tongue develop. Before using a top- amount over affected area. If bothersome dryness or
ical OTC acne product for the first time, consumers should peeling occurs, reduce dose frequency. or drug concen-
apply a small amount to 1 or 2 small affected areas for 3 tration. If excessive stinging or burning occurs after any
days to make sure hypersensitivity symptoms do not single application, remove with mild soap and water;
develop (FDA Drug Safety Communication 2014). resume use the next day.

260
 BENZTROPINE

Additional Information Granulation may indicate effec- BP Wash: 5.25% (175 g [DSC]); 7% (473 mL) [contains
tiveness; gels are more penetrating than creams and last benzyl alcohol, cetyl alcohol, propylene glycol, trol-
longer than creams or lotions amine (triethanolamine)]
Dosage Forms Excipient information presented when BP Wash: 10% (142 g, 227 g) [contains cetearyl alcohol,
available (limited, particularly for generics); consult spe- methylparaben]
cific product labeling. [DSC] = Discontinued product BPO-10 Wash: 10% (227 g [DSC}) [contains methylpar-
Bar, External: aben, propylene glycol, propylparaben]
PanOxyl: 10% (1 ea [DSC}) BPO-5 Wash: 5% (227 g [DSC]) [contains methylpara-
Cream, External: ben, propylene glycol, propylparaben]
Clearskin: 10% (30 g) Desquam-X Wash: 5% (140g [DSC]); 10% (140g
Foam, External: [DSC]) [contains edetate disodium]
_ BenzEFoam: 5.3% (60 g, 100 g) [contains cetearyl alco- Neutrogena Clear Pore: 3.5% (125 mL) [contains diso-
hol, disodium edta, methylparaben, propylene glycol, dium edta, menthol]
propylparaben] PanOxyl: 2.5% (156-g) [soap free; contains ceteary|
BenzEFoamultra: 9.8% (100 g) [contains cetearyl alco- alcohol]
hol, disodium edta, methylparaben, propylene glycol, PanOxyl Wash: 10% (156 g) [contains alcohol, usp,
propylparaben] methylparaben]
BenzePrO: 5.3% (60 g, 100 g) [contains cetearyl alco- PanOxyl-4 Creamy Wash: 4% (170 g) [contains ceteary|
hol, disodium edta, methylparaben, propylene glycol, alcohol, methylparaben]
propylparaben, trolamine (triethanolamine)] PanOxyl-8 Creamy Wash: 8% (170.1 g [DSC]) [contains
BenzePrO Short Contact: 9.8% (100 g) [contains cetearyl alcohol, methylparaben]
cetearyl alcohol, disodium edta, methylparaben, propy- PR Benzoyl Peroxide Wash: 7% (180 g, 473 mL) [con-
lene glycol, propylparaben] tains cetyl alcohol, edetate disodium, propylene glycol]
BP. Foam: 5.3%, (60 g, 100 g); 9.8% (100g) [contains SE BPO Wash: 7% (180 g [DSC]) [contains edetate
methylparaben, propylparaben] disodium, methylparaben]
Riax: 5.5% (100 g); 9.5% (100 g) [contains methylpar- Liquid Extended Release, External:
aben, propylparaben] Advanced Acne Wash: 4.4% (104 mL)
Generic: 5.3% (60 g, 100 g); 9.8% (100 g, 113 g) Lotion, External:
Gel, External: Acne Medication 5: 5% (29.5 mL, 30 mL [DSC}) [odor-
Acne Medication 5: 5% (42.5 g) [contains edetate less; contains disodium edta]
disodium] Acne Medication: 10% (30 mL [DSC}) [odorless; contains
Acne Medication 10: 10% (42.5 g) [contains edetate edetate disodium]
disodium] Acne Medication 10: 10% (29.5 mL) [odorless; contains
Acne-Clear: 10% (42.5 g) edetate disodium]
Benziq: 5.25% (50 g) [contains benzyl alcohol, disodium Benzoyl Peroxide Cleanser: 3% (340.2 g [DSC]); 6%
edta, trolamine (triethanolamine)] (170.3 g, 340.2 g); 9% (340.2 g [DSC]) [contains cety|
Benziq LS: 2.75% (50 g) [contains trolamine (triethanol- alcohol, edetate disodium, propylene glycol]
amine)] BP Cleansing: 4% (297 g [DSC]) [contains cetyl alcohol,
BP Gel: 5% (60g) [contains benzyl alcohol, edetate propylene glycol]
disodium, trolamine (triethanolamine)] Oscion Cleanser: 6% (170.3 g [DSC], 340.2 g [DSC])
BP Gel: 5.5% (60 g); 10% (60 g) [contains benzyl alco- Zaclir Cleansing: 8% (297 g)
hol, disodium edta, trolamine (triethanolamine)] Miscellaneous, External:
BPO: 4% (42:5 .g [DSC]); 8% (42.5 g [DSC]) [contains BenzePrO Foaming Cloths: 6% (60 ea) [contains cetyl
benzyl alcohol, cetyl alcohol] alcohol]
Clearplex V: 5% (45 g [DSC]) BPO Foaming Cloths: 3% (60 ea [DSC]); 6% (60 ea); 9%
Clearplex X: 10% (45 g [DSC]) (60 ea [DSC]) [contains methylparaben]
OC8: 7% (45 g) [contains disodium edta, propylene
@ Benzoyl Peroxide and Adapalene see Adapalene and
glycol]
Benzoyl Peroxide on page 62
PanOxyl: 3% (10 g [DSC]) [contains disodium edta]
Generic: 2.5% (60 g); 5% (60 g, 90 g); 6.5% (113 g); 8% @ Benzoyl Peroxide and Clindamycin see Clindamycin
(113 g); 10% (56 g, 60 g, 90 g) and Benzoyl Peroxide on page 476
Kit, External: @ Benzoyl Peroxide Cleanser [OTC] see Benzoy! Perox-
AcneFree Acne Clearing System: Wash 2.5% and lotion ide on page 259
3.7% [contains disodium edta, polysorbate 80, propy- Benzoyl! Peroxide Wash [OTC] see Benzoyl Peroxide
lene glycol] on page 259
AcneFree Severe Clearing Syst: Wash 2.5% and lotion
10% [contains benzalkonium chloride, butylparaben,
cetyl alcohol, disodium edta;-edetate sodium (tetraso- Benztropine (BENZ troe peen)
dium), ethylparaben, isobutylparaben, methylisothiazo-
linone, methylparaben, propylene glycol, Medication Safety Issues
propylparaben, soybeans (glycine max)] Sound-alike/look-alike issues:
Benzoyl Peroxide Wash: Wash 8% (170.1 g) and bar Benztropine may be confused with bromocriptine
soap 5% (2 x 21 g) [DSC], Liquid wash 4% (170.1 g) Geriatric Patients: High-Risk Medication:
and bar soap 5% (2 x 21 g) [DSC] [contains ceteary| Beers Criteria: Benztropine (oral) is identified in the
alcohol, methylparaben] Beers Criteria as a potentially inappropriate medication
BPO Creamy Wash: Wash 4% (170.1 g) and bar soap to be avoided in patients 65 years and older due to its
5% (2 x 21 g) [DSC], Wash 8% (170.1 g) and bar soap highly anticholinergic properties. It is not recommended
5% (2 x 21 g) [DSC] [contains disodium edta, methyl- for the prevention of extrapyramidal symptoms with
paraben] antipsychotics. In the treatment of Parkinson disease,
Inova: Pad 4% (30s) and tocopherol 5% (28s), Pad 8% more effective agents are available (Beers Criteria
(30s) and tocopherol 5% (28s) [contains disodium edta, [AGS 2015}).
methylparaben] Pharmacy Quality Alliance (PQA): Benztropine (oral) is
Liquid, External: identified as a high-risk medication in patients 65 years
Benzac AC Wash: 5% (226 g) and older on the PQA's, Use of High-Risk Medications
Benzac W Wash: 5% (226 g [DSC]) in the Elderly (HRM) performance measure, a safety
BenzePrO Creamy Wash: 7% (180 g) [contains cetyl measure used by the Centers for Medicare and Med-
alcohol, edetate disodium, propylene glycol] icaid Services (CMS) for Medicare plans.
Benziq Wash: 5.25% (175 g) [contains benzyl alcohol, Brand Names: US Cogentin
cetyl alcohol, disodium edta, propylene glycol] Brand Names: Canada Benztropine Omega; Kynesia;
Benzoyl Peroxide Wash: 5% (148 g, 237 g) [contains PMS-Benztropine
cetyl alcohol, edetate disodium, propylene glycol] Therapeutic Category Anti-Parkinson's Agent; Anticholi-
Benzoyl Peroxide Wash: 5% (142 g, 227 g) [contains nergic Agent; Antidote, Drug-induced Dystonic Reactions
edetate disodium] Generic Availability (US) Yes
Benzoyl Peroxide Wash: 10% (148 g, 237 g) [contains Use Adjunctive treatment of parkinsonism (FDA approved
cetyl alcohol, edetate disodium, propylene glycol] in adults); treatment of drug-induced extrapyramidal
Benzoyl Peroxide Wash: 10% (142 g, 227 g) [contains effects (except tardive dyskinesia) (FDA approved in
edetate disodium] adults)
BP Foaming Wash: 10% (227 g [DSC]) [contains Pregnancy Considerations Animal reproduction studies
cetearyl alcohol, methylparaben] have not been conducted. Paralytic ileus (which resolved
BP Wash: 2.5% (227 g); 5% (113 g, 142 g, 227 g) [con- rapidly) was reported in two newborns exposed to a
tains ceteary! alcohol, methylparaben] - combination of benztropine and chlorpromazine during p
261
BENZTROPINE

the second and third trimesters and the last 6 weeks of Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
pregnancy, respectively (Falterman 1980). Mechanism of Action Possesses both anticholinergic
Breastfeeding Considerations It is not known if benz- and antihistaminic effects. In vitro anticholinergic activity
tropine is excreted in breast milk. Anticholinergic agents approximates that of atropine; in vivo it is only about half
may suppress lactation. as active as atropine. Animal data suggest its antihista-
Contraindications minic activity and duration of action approach that of
Hypersensitivity to benztropine mesylate or any compo- pyrilamine maleate.
nent of the formulation. Pharmacodynamics/Kinetics (Adult data unless
Children <3 years of age (due to atropine-like adverse noted)
effects including severe anhidrosis and fatal hyperther- Onset of action:
mia) and should be used cautiously in older children. IM, IV: Within a few minutes; there is no significant
Warnings/Precautions May cause anticholinergic effects difference between onset of effect after intravenous or
(constipation, xerostomia, blurred vision, urinary reten- intramuscular injection ;
tion). Use with caution in children >3 years of age due to Oral: Within 1 hour
its anticholinergic effects (dose has not been established). Metabolism: Hepatic (N-oxidation, N-dealkylation, and
Use is contraindicated in childfen <3 years of age. Use ring hydroxylation) (from animal studies only)
with caution in hot weather or during exercise. May cause (Brocks 1999)
anhydrosis and hyperthermia, which may be severe. The Time to peak, plasma: Oral: 7 hours (Brocks 1999)
risk is increased in hot environments, particularly in the Dosing
elderly, alcoholics, patients with CNS disease, and those Pediatric Note: |V route should be reserved for situations
with prolonged outdoor exposure. If there is evidence of when oral or IM are not appropriate.
anhidrosis, consider decreasing dose so the ability to Drug-induced extrapyramidal reaction: Children and
maintain body heat equilibrium by perspiration is not Adolescents: Oral, IM, IV (not preferred):
impaired. Children 23 years: 0.02-0.05 mg/kg/dose 1-2 times
Use with caution in patients >65 years of age; response in daily; use in children <3 years should be reserved
elderly may be altered. Initiate at low doses in the elderly for life-threatening emergencies (Bellman, 1974;
and increase as needed while monitoring for adverse Habre, 1999; Joseph, 1995; Teoh, 2002)
events. Adolescents: 1-4 mg every 12-24 hours (Nelson, 1996)
Renal Impairment: Pediatric There are no dosage
Use with caution in patients with tachycardia, glaucoma, adjustments provided in the manufacturer's labeling.
prostatic hyperplasia (especially in the elderly), any ten- Hepatic Impairment: Pediatric There are no dosage
dency toward urinary retention, and obstructive disease of adjustments provided in the manufacturer's labeling.
the Gl or GU tracts. Avoid use in angle-closure glaucoma. Administration
When given in large doses or to susceptible patients, may
Oral: May be given with or without food; administration
cause weakness and inability to move particular muscle
with food may decrease GI upset.
groups. Parenteral: IV route should be reserved for situations
May be associated with confusion, visual hallucinations, or when oral or IM are not appropriate. Manufacturer's
excitement (generally at higher dosages). Intensification labeling states there is no difference in onset of effect
of symptoms or toxic psychosis may occur in patients with after IV or IM injection and therefore there is usually no
mental disorders. May cause CNS depression, which may need to use the IV route. No specific instructions on
impair physical or mental abilities; patients must be cau- administering benztropine IV are provided in the labeling.
tioned about performing tasks which require mental alert- The IV route has been reported in the literature in adults
ness (eg, operating machinery or driving). Benztropine (slow IV push when reported), although specific instruc-
does not relieve symptoms of tardive dyskinesia and tions are lacking (Sachdev, 1993; Schramm, 2002).
may potentially exacerbate symptoms. Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
Potentially significant drug-drug interactions may exist,
cific product labeling.
requiring dose or frequency adjustment, additional mon-
Solution, Injection, as mesylate:
itoring, and/or selection of alternative therapy.
Cogentin: 1 mg/mL (2 mL)
Adverse Reactions Generic: 1 mg/mL (2 mL)
Cardiovascular: Tachycardia
Solution, Injection, as mesylate [preservative free]:
Central nervous system: Confusion, depression, disorien-
Generic: 1 mg/mL (2 mL)
tation, heatstroke, hyperthermia, lethargy, memory
Tablet, Oral, as mesylate:
impairment, nervousness, numbness of fingers, psy-
Generic: 0.5 mg, 1 mg, 2 mg
chotic symptoms (exacerbation of preexisting symp-
toms), toxic psychosis, visual hallucination @ Benztropine Mesylate see Benztropine on page 267
Dermatologic: Skin rash @ Benztropine Omega (Can) see Benztropine
Gastrointestinal: Constipation, nausea, paralytic ileus,
on page 261
vomiting, xerostomia
Genitourinary: Dysuria, urinary retention
Ophthalmic: Blurred vision, mydriasis Benzyl Alcohol (BEN zit! AL koe hol)
Drug Interactions
Metabolism/Transport Effects Substrate of CYP2D6 Medication Safety Issues
(minor); Note: Assignment of Major/Minor substrate sta- Sound-alike/look-alike issues:
tus based on clinically relevant drug interaction potential Benzyl alcohol may be confused with benzoyl peroxide
Avoid Concomitant Use Brand Names: US AverTeaX [OTC]; Ulesfia; Zilactin
Avoid concomitant use of Benztropine with any of the [OTC]
following: Aclidinium; Cimetropium; Eluxadoline; Glyco- Therapeutic Category Analgesic, Topical; Antiparasitic
pyrrolate (Oral Inhalation); Ipratropium (Oral Inhalation); Agent, Topical; Pediculocide; Topical Skin Product
Levosulpiride; Oxatomide; Potassium Chloride; Potas- Generic Availability (US) No
sium Citrate; Tiotropium; Umeclidinium Use
Increased Effect/Toxicity Dermal topical: Lotion (Ulesfia): Treatment of head lice
Benztropine may increase the levels/effects of: Abobo- infestation (FDA approved in ages 26 months and
tulinumtoxinA; Anticholinergic Agents; Cannabinoid- adults) ¢
Containing Products; Cimetropium; Eluxadoline; Gluca- Oral topical:
gon; Glycopyrrolate (Oral Inhalation); Mirabegron; Ona- Gel (Zilactin): Temporary relief of pain from cold sores/
botulinumtoxinA; Opioid Analgesics; Potassium fever blisters, canker sores, mouth sores, and/or gum
Chloride; Potassium Citrate; Ramosetron; Rimabotuli- irritations (FDA approved in ages 22 years and adults)
numtoxinB; Thiazide and Thiazide-Like Diuretics; Tio- Cream (AverTeaX): Temporary relief of pain caused by
tropium; Topiramate cold sores/fever blisters (FDA approved in adults)
Pregnancy Risk Factor B
The levels/effects of Benztropine may be increased by:
Pregnancy Considerations Adverse events have not
Aclidinium; Amantadine; Chloral Betaine; Ipratropium
been observed in animal reproduction studies.
(Oral Inhalation); Mianserin; Oxatomide; Pramlintide;
Breastfeeding Considerations It is unknown if benzyl
Umeclidinium
alcohol is excreted in breast milk. The manufacturer
Decreased Effect
recommends that caution be exercised when administer-
Benztropine may decrease the levels/effects of: Acetyl-
ing benzyl alcohol to nursing women.
cholinesterase Inhibitors; Amifampridine; Gastrointesti-
Contraindications There are no contraindications listed
nal Agents (Prokinetic); loflupane | 123; Itopride;
in the manufacturer's labeling.
Levosulpiride; Nitroglycerin; Secretin
Warnings/Precautions Benzyl alcohol exposure to the
The levels/effects of Benztropine may be decreased by: eye should be avoided. If exposure occurs, flush immedi-
Acetylcholinesterase Inhibitors; Amifampridine ately. Keep out of the reach of children and only use under

262
 BENZYLPENICILLOYL POLYLYSINE

direct adult supervision. Lotion for the treatment of head immediately wipe the area with a moist gauze pad or
lice is not recommended for infants <6 months due to the tissue.
potential for increased absorption. Do not use gel for oral Lotion: Apply under adult supervision to dry hair, until
pain in infants or children younger than 2 years. entire scalp and hair are saturated. Leave on for 10
minutes then rinse thoroughly. Wash hands after appli-
Benzyl alcohol and derivatives: Patients <1 month of age
cation. Use in conjunction with an overall lice manage-
or premature neonates with a corrected gestational age
ment program. Dry ‘clean or wash all clothing, hats,
<44 weeks could be at risk if treated with topical benzyl
bedding, and towels in hot water. Wash all personal care
alcohol. Large amounts of benzyl alcohol (299 mg/kg/day)
items (eg, combs, brushes, hair clips) in hot water. A lice
have been associated with a potentially fatal toxicity
comb may be used to remove dead lice after both
("gasping syndrome") in neonates; the "gasping syn-
treatments.
drome" consists of metabolic acidosis, respiratory dis-
tress, gasping respirations, CNS dysfunction (including Dosage Forms Excipient information presented when
convulsions, intracranial hemorrhage), hypotension, and available (limited, particularly for generics); consult spe-
cardiovascular collapse (AAP ["Inactive" 1997]; CDC, cific product labeling.
1982); some data suggests that benzoate displaces bilir- Gel, Mouth/Throat:
ubin from protein binding sites (Ahlfors, 2001); avoid or Zilactin: 10% (7.1 g) [contains propylene glycol, sd
use dgsage forms containing benzyl alcohol with caution alcohol]
in neonates. See manufacturer's labeling. Lotion, External:
Ulesfia: 5% (227 g) [contains polysorbate 80, trolamine
Self-medication (OTC use): Discontinue use and notify (triethanolamine)]
health care provider if condition worsens or does not Ointment, Mouth/Throat:
improve within 7 days, or if swelling, rash, or fever devel- AverleaX: 1% (7.4 mL) [contains cetyl alcohol, propy-
ops. Do not use for >7 days unless instructed by health lene glycol, trolamine (triethanolamine)]
care professional.
Warnings: Additional Pediatric Considerations @ Benzylpenicillin Benzathine see Penicillin G Benza-
Some dosage forms may contain propylene glycol; in thine on page 1582
neonates large amounts of propylene glycol delivered @ Benzylpenicillin Potassium see Penicillin G (Paren-
orally, intravenously (eg, >3,000 mg/day), or topically teral/Aqueous) on page 1583
have been associated with potentially fatal toxicities which
@ Benzylpenicillin Sodium see Penicillin G (Parenteral/
can include metabolic acidosis, seizures, renal failure, and
Aqueous) on page 1583
CNS depression; toxicities have also been reported in
children and adults including hyperosmolality, lactic acido-
sis, seizures and respiratory depression; use caution Benzylpenicilloy! Polylysine
(AAP 1997; Shehab 2009). (BEN zil pen i SIL oyl pol i LIE seen)
Adverse Reactions
Dermatologic: Erythema, pruritus
Brand Names: US Pre-Pen
Central nervous system: Hypoesthesia (local), local anes- Therapeutic Category Diagnostic Agent
thesia Generic Availability (US) No
Local: Local irritation, local pain Use Adjunct in assessing the risk of administering penicillin
Ophthalmic: Eye irritation (penicillin G or benzylpenicillin) in patients suspected of a
Rare but important or life-threatening: Dermatitis, desqua- Clinical penicillin hypersensitivity (FDA approved in pedia-
mation, excoriation, paresthesia, seborrheic dermatitis of tric patients [age not specified] and adults). Has also been
scalp, skin rash, thermal injury, xeroderma used as an adjunct in assessment of hypersensitivity to
Drug Interactions other beta-lactam antibiotics (penicillins and cephalospor-
Metabolism/Transport Effects None known. ins) to determine the safety of penicillin administration in
Avoid Concomitant Use There are no known interac- patients with a history of reaction to cephalosporins
tions where it is recommended to avoid concomitant use. Pregnancy Risk Factor C
Increased Effect/Toxicity There are no known signifi- Pregnancy Considerations Animal reproduction studies
cant interactions involving an increase in effect. have not been conducted with benzylpenicilloy! polylysine.
Decreased Effect There are no known significant inter- The Centers for Disease Control and Prevention (CDC)
actions involving a decrease in effect. states that penicillin skin testing may be useful in assess-
Storage/Stability ing suspected penicillin hypersensitivity in pregnant
Gel: Store at 15°C to 30°C (59°F to 68°F). Keep away women diagnosed with syphilis (of any stage) due to a
from fire or flame. lack of proven alternatives to the use of penicillin in this
Lotion: Store at 20°C to 25°C (68°F to 77°F); excursions population (CDC, 2006).
are permitted between 15°C and 30°C (59°F and 86°F); Contraindications Systemic or marked local reaction to a
do not freeze. previous administration of benzylpenicilloyl polylysine skin
Mechanism of Action Inhibits respiration of lice by test; patients with a known severe hypersensitivity to
obstructing respiratory spiracles causing lice asphyxiation. penicillin should not be tested
No ovicidal activity. Warnings/Precautions Rare systemic allergic reactions,
Pharmacodynamics/Kinetics (Adult data unless including anaphylaxis, have been associated with penicil-
noted) Absorption: Lotion: Following a prolonged appli- lin skin testing. Penicillin skin testing should only be
cation (30 minutes), serum concentrations were detect- performed by skilled medical personnel under direct
able (<3 mcg/mL) at 30 and 60 minutes postexposure in supervision of a physician, and testing should be per-
patients 6 months to 11 years of age. formed only in an appropriate healthcare setting prepared
Dosing for the immediate treatment with epinephrine. To decrease
Pediatric the risk of a systemic allergic reaction, the manufacturer
Head lice: Infants 26 months, Children, and Adoles- recommends puncture skin testing prior to intradermal
cents: Lotion (Ulesfia): Apply appropriate volume for testing. Patients with a reliable history of a severe life-
hair length to dry hair, saturate the scalp completely, threatening penicillin allergy, including Stevens-Johnson
leave on for 10 minutes, rinse thoroughly with water; syndrome or TEN, should NOT receive penicillin skin
repeat in 7 days testing. Responses to skin testing may be attenuated by
Hair length 0 to 2 inches: 4 to 6 ounces concurrent administration of antihistamines. Consider
Hair length 2 to 4 inches: 6 to 8 ounces delaying testing until antihistamines can be withheld to
Hair length 4 to 8 inches: 8 to 12 ounces fs allow time for their effects to dissipate.
Hair length 8 to 16 inches: 12 to 24 ounces According to the manufacturer, a negative skin test is
Hair length 16 to 22 inches: 24 to 32 ounces associated with an incidence of immediate allergic reac-
Hair length >22 inches: 32 to 48 ounces
tions of <5% after penicillin administration and a positive
Oral pain: Children 22 years and Adolescents: Topical:
skin test may indicate >50% incidence of allergic reaction
Gel (Zilactin): Apply to affected area up to 4 times/
occurring after penicillin administration.
day; do not use for more than 7 days
Renal Impairment: Pediatric There are no dosage Adequate penicillin skin testing should ideally involve
adjustments provided in the manufacturer’s labeling. reagents of both the major antigenic determinant (pen-
Hepatic Impairment: Pediatric There are no dosage icilloyl-polylysine) and minor determinants (penicilloate or
adjustments provided in the manufacturer’s labeling. penilloate). Benzylpenicilloy! polylysine alone does not
Administration For topical use only; avoid contact with identify those patients who react to a minor antigenic
eyes. Do not swallow. determinant. The minor determinant mixture (MDM) is
Gel: Dry affected area and apply only with moistened not commercially available in the U.S.; however, diluted
cotton swab or clean finger. Allow to dry 30 to 60 penicillin G (concentration: 10,000 units/mL) has been
seconds. Do not peel off protective film; to remove film, used as a minor determinant for skin testing purposes
first apply another coat of benzyl alcohol to film and (Bernstein, 2008). Penicillin skin testing does not predict »

263
 BENZYLPENICILLOYL POLYLYSINE

q the occurrence of late reactions

idiopathic reactions).
(eg, type Il, Ill, IV or epinephrine should also be available. Observe 20
minutes for reaction.
Adverse Reactions Monitoring Parameters Observe 15 minutes (puncture)
Cardiovascular: Hypotension or 20 minutes (intradermal) for reaction.
Dermatologic: Erythema, pruritus, urticaria (including local Additional Information Penicillin skin testing is the pre-
reaction at skin test site) ferred method of evaluating patients with possible pen-
Hypersensitivity: Angioedema, hypersensitivity reaction icillin specific IgE-mediated (Type |!) immediate
(including anaphylaxis; rare) hypersensitivity reactions, when performed using the
Local: Local inflammation (intense; at skin test site)
appropriate major and minor determinant reagents. Test-
Respiratory: Dyspnea
ing detects the presence or absence of penicillin-specific
Drug Interactions
IgE antibodies; therefore, it is not useful to detect non-IgE
Metabolism/Transport Effects None known.
mediated reactions. Patients testing positive to benzylpe-
Avoid Concomitant Use There are no known interac-
nicilloyl polylysine possess IgE antibodies against the
tions where it is recommended to avoid concomitant use.
benzylpenicilloy! structural group (B-lactam ring). The
Increased Effect/Toxicity There are no known signifi-
possibility exists for patients to have selective IgE anti-
cant interactions involving an increase in effect.
bodies directed against the R-group side chain structure of
Decreased Effect
certain penicillins, rather than the core beta-lactam struc-
The levels/effects of Benzylpenicilloyl Polylysine may be
decreased by: Alpha-/Beta-Agonists; Alpha1-Agonists; ture. Therefore, these patients may test negative to the
Antihistamines penicillin major and minor determinants, but be allergic to
Storage/Stability Refrigerate at 2°C to 8°C (36°F to semisynthetic penicillins (eg, amoxicillin, ampicillin) only
46°F); discard if left at room temperature for longer than and tolerate other penicillin compounds (Bernstein 2008).
1 day. Skin testing has also been used in some centers to
Mechanism of Action Benzylpenicilloyl polylysine, a determine safety of penicillin administration in patients
conjugate of the benzylpenicilloy! structural group with prior reactions to cephalosporins.
(hapten) and the poly-l-lysine carrier (protein), is an anti- Dosage Forms Excipient information presented when
gen which reacts with benzylpenicilloyl IgE antibodies to available (limited, particularly for generics); consult spe-
elicit the release of chemical mediators, thereby producing cific product labeling.
type | (immediate or accelerated) urticarial reactions in Injection, solution:
patients hypersensitive to penicillins. Pre-Pen®: 6 x 10° M (0.25 mL)
Dosing
Pediatric Diagnostic aid for detection of penicillin @ Benzylpenicilloyl-polylysine see Benzylpenicilloyl Pol-
allergy (penicillin G and benzylpenicillin): Limited ylysine on page 263
data available for assessment of other beta-lactams
and cephalosporins allergy: Children and Adolescents:
Beractant (ber AKT ant)
Note: Benzylpenicilloy! polylysine should always be
applied first via the puncture technique. Do not admin- Medication Safety Issues
ister intradermally to patients who have positive Sound-alike/look-alike issues:
reactions to a puncture test.
Survanta may be confused with Sufenta
Puncture scratch test: Apply a small drop of the skin test
Brand Names: US Survanta
solution using a 22- to 28-gauge needle and make a
single shallow puncture of the epidermis through the Brand Names: Canada Survanta
drop of solution. A positive reaction consists of a pale Therapeutic Category Lung Surfactant
wheal surrounding the puncture site which develops Generic Availability (US) No
within 10 minutes and ranges from 5 to 15 mm or more Use Prevention of respiratory distress syndrome (RDS) in
in diameter (wheal may be surrounded by erythema premature neonates with birth weight <1,250 g or with
and variable degrees of itching). If a positive response evidence of surfactant deficiency (FDA approved in new-
is evident, the solution should be wiped off immediately. borns); treatment of RDS in neonates with x-ray confirma-
If the puncture test is negative or equivocal (<5 mm tion of RDS and requiring mechanical ventilation (FDA
wheal, with little or no erythema and no itching) 15 approved in newborns); has also been used for treatment
minutes following the puncture test, an intradermal test of meconium aspiration syndrome in term and near-term
may be performed. newborns
Intradermal test: Using a 0.5 to 1 mL tuberculin syringe
Pregnancy Considerations Beractant is only indicated
with a 3/s- to %/s-inch, 26- to 30-gauge short bevel
for use in premature neonates
needle; inject a volume of skin test solution sufficient
to raise a small intradermal bleb ~3 mm in diameter Breastfeeding Considerations Beractant is only indi-
intradermally and duplicate at least 2 cm apart. A cated for use in premature neonates
control of 0.9% sodium chloride or allergen-diluting Contraindications There are no contraindications listed
solution should be injected at least 5 cm from the in the manufacturer's labeling
antigen test site. Most skin responses to the intra- Warnings/Precautions Marked impairment of ventilation
dermal test will develop within 5 to 15 minutes. A during or shortly after dosing may indicate mucous plug~
response to the skin test is read at 20 minutes. ging of the endotracheal tube; suctioning all neonates
Interpretation of intradermal test: prior to administration may decrease chance of endotra-
(-) Negative: No increase in size of original bleb or no cheal tube obstruction. Replace endotracheal tube imme-
greater reaction compared to the control site. diately if obstruction is not removed with suctioning. There
(+) Ambiguous: Wheal only slightly larger than original is an increased risk of post-treatment nosocomial sepsis in
bleb with or without erythematous flare and slightly treated neonates this increased risk was not associated
larger than control site; or discordance between
with increased mortality. Transient episodes of bradycar-
duplicate test sites.
dia and decreased oxygen saturation may occur. Discon-
(+) Positive: Itching and marked increase in size of
tinue dosing procedure and initiate measures to alleviate
original bleb to 25 mm. Wheal may exhibit pseudo-
the condition; may reinstitute after the patient is stable.
pods and be >20 mm in diameter.
Control site should be reactionless. If wheal >2 to 3 mm Rales and moist breath sounds may occur; endotracheal
develops at control site, repeat the test. If same suctioning or other remedial action is necessary if clear-
reaction occurs, consultation is necessary. cut signs of airway obstruction are present.
Renal Impairment: Pediatric There are no dosage For endotracheal administration only. Use in neonates
adjustments provided in manufacturer’s labeling. <600 grams birth weight or >1,750 grams birth weight
Hepatic Impairment: Pediatric There are no dosage has not been evaluated. Rapidly affects oxygenation and
adjustments provided in manufacturer's labeling.
lung compliance; restrict use to a highly-supervised clin-
Administration ical setting with immediate availability of clinicians experi-
Puncture test: Administer initially by puncture technique
enced in intubation and ventilatory management of
on the inner volar aspect of the forearm; observe 15
premature neonates. Produces rapid improvements in
minutes for reaction. If negative reaction, follow with an
intradermal injection. lung oxygenation and compliance that may require fre-
Intradermal test: Do not administer intradermally to quent adjustments to oxygen delivery and ventilator set-
patients with a positive reaction to a puncture test (wheal tings; hyperoxia may occur within minutes of
of 5 to 15 mm or more in diameter). Administer the administration.
intradermal test on the upper, outer arm, below the Adverse Reactions The following occurred during the
deltoid muscle in the event a severe hypersensitivity dosing procedure:
reaction occurs and a tourniquet needs to be applied. Cardiovascular: Bradycardia (transient)
During the skin test, immediate treatment with Respiratory: Oxygen desaturation

264
 BESIFLOXACIN

Rare but important or life-threatening: Apnea, emphysema complications (Lotze 1998). A smaller trial (n=20; GA:
(pulmonary interstitial), hypercapnia, hypertension, 40.2 + 0.3 weeks) administered a higher dose of 6 mL/
hypotension, increased susceptibility to infection (post- kg (150 mg/kg) of surfactant earlier after delivery (ie,
treatment nosocomial sepsis), obstruction of endotra- during the first 6 hours of life); compared to the control
cheal tube, pneumothorax (including pneumopericar- group who received room air, the surfactant group had
dium), vasoconstriction a significantly lower need for ECMO (5% vs 30%,
Drug Interactions p=0.037), no air leaks (0% vs 25%, p=0.024), shorter
Metabolism/Transport Effects None known. duration of mechanical ventilation (7.7 days vs 10.8
Avoid Concomitant Use days, p=0.047), shorter duration of oxygen therapy (13
Avoid concomitant use of Beractant with any of the days vs 19.6 days, p=0.031), and a shorter duration of
following: Ceritinib admission (15.9 days vs 24.3 days, p=0.003) (Fin-
Increased Effect/Toxicity diay 1996).
Beractant may increase the levels/effects of: Bradycar- Renal Impairment: Pediatric There are no dosage
dia-Causing Agents; Ceritinib; lvabradine; Lacosamide adjustments provided in the manufacturer's labeling.
Hepatic Impairment: Pediatric There are no dosage
The levels/effects of Beractant may be increased by: adjustments provided in the manufacturer's labeling.
Bretylium; Ruxolitinib; Terlipressin; Tofacitinib
Administration Specific administration method may vary
Decreased Effect There are no known significant inter- with ventilation technique.
actions involving a decrease in effect.
Endotracheal/Intratracheal: Allow beractant to stand at
Storage/Stability Store intact vials in refrigerator between room temperature for 20 minutes or warm in the hand
2°C and 8°C (35.6°F and 46.4°F); protect from light and for at least 8 minutes prior to administration; artificial
store vials in original carton until ready for use. Unopened, warming methods should NOT be used. Inspect solution
unused vials that have been warmed to room temperature to verify complete mixing of the suspension; do not
_may be returned to the refrigerator within 24 hours of shake; if settling occurs during storage, gently swirl.
warming and stored for future use. Do not remove vial Suction infant prior to administration.
from the refrigerator for >24 hours; do not warm and return
Endotracheal: Administration to through endotra-
to refrigerator more than once. cheal tube using a 5-French end-hole catheter:
Mechanism of Action Replaces deficient or ineffective The infant should be stable before proceeding with
endogenous lung surfactant in neonates with respiratory administration. Insert a 5-French end-hole catheter into
distress syndrome (RDS) or in neonates at risk of devel- the infant's endotracheal tube. Administer the dose in
oping RDS. Surfactant prevents the alveoli from collapsing four 1 mL/kg aliquots. Each quarter-dose is instilled
during expiration by lowering surface tension between air over 2 to 3 seconds followed by at least 30 seconds
and alveolar surfaces. of manual ventilation or until stable; each quarter-dose
Pharmacodynamics/Kinetics (Adult data unless is administered with the infant in a different position;
noted) Onset of action: Improved oxygenation: Within slightly downward inclination with head turned to the
minutes right, then repeat with head turned to the left; then
Dosing slightly upward inclination with head turned to the right,
Neonatal then repeat with head turned to the left. Following
Respiratory distress syndrome (RDS): Limited data administration of one full dose, withhold suctioning for
available in premature neonates <600 g or >1,750 g: 1 hour unless signs of significant airway obstruction.
Prophylactic therapy: Premature neonates: Endotra- Intratracheal: Administration method for spontane-
cheal: 4 mL/kg (100 mg phospholipids/kg) as soon ously breathing newborns who do not require
as possible after birth preferably within 15 minutes; as endotracheal intubation: Minimally invasive surfac-
many as 4 doses may be administered during the first tant therapy (MIST): Limited data available: Adminis-
48 hours of life, no more frequently than every 6 tration via a thin catheter (2.5- to 5-French) has been
hours; usually requires no more frequent dosing than suggested as a less invasive method. The catheter is
every 12 hours unless surfactant is being inactivated placed between the vocal cords under direct laryngo-
by an infectious process, meconium, or blood (AAP scopy and the surfactant dose is administered over 1 to
[Polin 2014]). The need for additional doses is deter- 3 minutes. In some studies, premedication with atro-
mined by evidence of continuing respiratory distress pine was used (Kribs 2007).
or if the neonate is still intubated and requiring at least Monitoring Parameters Continuous heart rate and trans-
30% inspired oxygen to maintain a PaOz $80 torr. cutaneous O, saturation should be monitored during
Note: For newborns who do not require mechanical administration; frequent ABG sampling is necessary to
ventilation for severe RDS, current guidelines recom- prevent postdosing hyperoxia and hypocarbia.
mend using CPAP immediately after birth with sub- Additional Information Beractant contains surfactant-
sequent selective surfactant administration (AAP associated proteins SP-B and SP-C (<1 mg/mL).
[Polin 2014)). Dosage Forms Excipient information presented when
Rescue treatment: 5 available (limited, particularly for generics); consult spe-
Manufacturer's labeling: Endotracheal: 4 mL/kg
cific product labeling.
(100 mg phospholipids/kg) as soon as the diagnosis
Suspension, Intratracheal:
of RDS is made; may repeat if needed, no more
Survanta: Phospholipids 25 mg/mL (4 mL, 8 mL)
frequently than every 6 hours to a maximum of 4
doses during the first 48 hours of life; usually ® Berinert see C1 Inhibitor (Human) on page 330
requires no more frequent dosing than every 12
hours unless surfactant is being inactivated by an
infectious process, meconium, or blood (AAP [Polin Besifloxacin (be si FLOX a sin)
2014]). The need for additional doses is determined
Brand Names: US Besivance
by evidence of continuing respiratory distress or if
Brand Names: Canada Besivance
the neonate is still intubated and requiring at least
30% inspired oxygen to maintain a PaO» <80 torr. Therapeutic Category Antibiotic, Fluoroquinolone; Anti-
biotic, Ophthalmic; Ophthalmic Agent
Alternate dosing: Minimally invasive surfactant ther-
apy (MIST)/less invasive surfactant application Generic Availability (US) No
(LISA) for patients spontaneously breathing: Limited Use Treatment of bacterial conjunctivitis (FDA approved in
data available: Intratracheal: 4 mL/kg (100 mg phos- ages 21 year and adults)
pholipids/kg); dosing based on a trial in neonates on Pregnancy Considerations Systemic concentrations of
nasal CPAP for RDS treatment (n=29); eligible besifloxacin following ophthalmic administration are low. If
patients ranged in gestational age from 23 to 27 ophthalmic agents are needed during pregnancy, the
weeks; an additional dose was allowed after 12 to minimum effective dose should be used in combination
24 hours if FiO. 240% was needed to maintain with punctual occlusion for 3 to 5 minutes after application
oxygen saturation >85% (Kribs 2007) to decrease potential exposure to the fetus (Samples
Meconium aspiration syndrome (MAS), severe: Lim- 1988).
ited data available: Term newborns: Endotracheal: 4 to Breastfeeding Considerations It is not known if besi-
6 mL/kg (100 to 150 mg phospholipids/kg); repeat floxacin is present in breast milk. According to the manu-
every 6 hours up to a total of 4 doses. Dosing based facturer, the decision to breastfeed during therapy should
on two randomized, placebo-controlled trials. The consider the risk of infant exposure, the benefits of
larger trial compared surfactant treatment at a dose of breastfeeding to the infant, and benefits of treatment to
4 mL/kg (100 mg/kg) in 167 infants with respiratory the mother.
failure (including 87 with MAS) (GA: 39 + 1.8 weeks; Contraindications There are no contraindications listed
PNA: 31 + 22 hours) with a control group who received in the manufacturer's labeling.
room air; the surfactant group had a lower need for Canadian labeling: Additional contraindications (not in US
ECMO compared to the control group (36.8% vs 51.9% labeling): Hypersensitivity to besifloxacin, any compo-
for the MAS patients) without an increase in pulmonary nent of the formulation, or other quinolones.

265
 BESIFLOXACIN

4 Warnings/Precautions Severe hypersensitivity reac- Use Treatment of homocystinuria to reduce elevated

tions, including anaphylaxis, have occurred with systemic homocysteine blood concentrations (FDA approved in
quinolone therapy. Prompt discontinuation of drug should pediatric patients [age not specified] and adults); homo-
occur if skin rash or other symptoms arise. Prolonged use cystinuria includes deficiencies or defects in cystathionine
may result in fungal or bacterial superinfection; discon- beta-synthase (CBS), 5,10-methylenetetrahydrofolate
tinue use and initiate alternative therapy if superinfection reductase (MTHFR), and cobalamin cofactor metabolism
occurs. For topical ophthalmic use only. Do not inject (cbl)
ophthalmic solution subconjunctivally or introduce directly Prescribing and Access Restrictions Cystadane may
into the anterior chamber of the eye. Contact lenses be obtained by contacting AnovoRx at
should not be worn during treatment of ophthalmic infec- [email protected].
tions. Pregnancy Risk Factor C
Adverse Reactions Pregnancy Considerations Animal reproduction studies
Central nervous system: Headache have not been conducted.
Ophthalmic: Blurred vision, conjunctival erythema, eye Breastfeeding Considerations It is not known if betaine
irritation, eye pain, eye pruritus is excreted in breast milk. According to the manufacturer,
Drug Interactions Mi use in nursing women only if clearly needed.
Metabolism/Transport Effects None known. Contraindications There are no contraindications listed
Avoid Concomitant Use There are no known interac- in the manufacturer's labeling.
tions where it is recommended to avoid concomitant use. Warnings/Precautions Use caution in patients with cys-
Increased Effect/Toxicity There are no known signifi- tathionine beta-synthase (CBS) deficiency; treatment with
cant interactions involving an increase in effect. betaine may cause large increases of plasma methionine
Decreased Effect There are no known significant inter- concentrations. Cerebral edema may be associated with
actions involving a decrease in effect. hypermethioninemia.
Storage/Stability Store between 15°C to 25°C (59°F to Betaine anhydrous, a prescription medication indicated for
77°F). Protect from light. the treatment of homocystinuria and betaine hydrochlor-
Mechanism of Action Inhibits both DNA gyrase and ide, a nutritional supplement, are not to be used inter-
topoisomerase IV. DNA gyrase is an essential bacterial changeably (ISMP 2016).
enzyme required for DNA replication, transcription, and Adverse Reactions
repair. Topoisomerase IV is an essential bacterial enzyme Gastrointestinal: Diarrhea, dysgeusia, gastrointestinal dis-
required for decatenation during cell division. Inhibition tress, nausea y
effect is bactericidal. Rare but important or life-threatening: Abnormal skin odor,
Pharmacodynamics/Kinetics (Adult data unless agitation, alopecia, anorexia, cerebral edema (associ-
noted) Half-life elimination: ~7 hours ated with hypermethioninemia), dental disease, depres-
Dosing sion, glossitis, irritability, personality disorder, sleep
Pediatric Bacterial conjunctivitis: Children and Ado- disorder, urinary incontinence, urticaria, vomiting
lescents: Ophthalmic: Instill 1 drop into affected eye(s) 3 Drug Interactions
times daily (4 to 12 hours apart) for 7 days Metabolism/Transport Effects None known.
Renal Impairment: Pediatric There are no dosage Avoid Concomitant Use There are no known interac-
adjustments provided in the manufacturer's labeling; tions where it is recommended to avoid concomitant use.
however, dosage adjustment unlikely due to low sys- Increased Effect/Toxicity There are no known signifi-
temic absorption. cant interactions involving an increase in effect.
Hepatic Impairment: Pediatric There are no dosage Decreased Effect There are no known significant inter-
adjustments provided in the manufacturer's labeling; actions involving a decrease in effect.
however, dosage adjustment unlikely due to low sys- Storage/Stability Store at 15°C to 30°C (59°F to 86°F).
temic absorption. Protect from moisture
Administration Ophthalmic: For topical ophthalmic use Mechanism of Action Betaine is an endogenous metab-
only. Wash hands before and after instillation. Invert bottle olite of choline. Betaine acts as a methyl group donor in
while closed and shake bottle once prior to each admin- the remethylation of homocysteine to methionine. Homo-
istration. Avoid contaminating the applicator tip with cystinuria is an inborn error of metabolism in which
affected eye(s), fingers, or other sources. elevated plasma homocysteine levels can lead to mental
Monitoring Parameters Signs and symptoms of infection retardation, ocular abnormalities, osteoporosis, premature
or hypersensitivity reaction atherosclerosis and thromboembolic disease. Remethyla-
Dosage Forms Excipient information presented when tion is one of the two divergent pathways in the metabo-
available (limited, particularly for generics); consult spe- lism of homocysteine. The second pathway involves
cific product labeling. transulfuration of homocysteine to produce cysteine. A
Suspension, Ophthalmic: number of enzymes and cofactors are also involved in
Besivance: 0.6% (5 mL) [contains benzalkonium chlor- these pathways.
ide, edetate disodium dihydrate] Dosing
Neonatal Homocystinuria: Note: The overall role of
® Besifloxacin HCI see Besifloxacin on page 265 betaine in management of homocystinuria and effective-
@ Besifloxacin Hydrochloride see Besifloxacin ness is variable and dependent upon several factors,
on page 265 including specific enzyme deficiency, genetic mutation(s),
¢ Besivance see Besifloxacin on page 265
and clinical condition; dose should be individualized.
Term neonate: Oral: 50 mg/kg/dose twice daily; increase
¢ 8,8-Dimethylcysteine see Penicill[AMINE on page 1580 at weekly intervals in 50 mg/kg/day increments;
¢ 9-Beta-D-Ribofuranosyladenine see Adenosine increase gradually until plasma total homocysteine is
on page 64 undetectable or present in small amounts (Al Tawari
Sa Beta Care Betatar Gel [OTC] see Coal Tar on page 505 2002; Diekman 2014; Schiff 2011). Note: Minimal addi-
tional benefit expected with doses >150 to 200 mg/kg/
e Betaderm (Can) see Betamethasone (Topical)
day or exceeding a twice daily dosing schedule (Morris
on page 269
2017); however, case reports in infants suggest more
Sd 17-beta E2 see Estradiol (Systemic) on page 779 frequent dosing may be necessary in some patients
Sd 17-beta estradiol see Estradiol (Systemic) on page 779 (Schiff 2011; Ucar 2010).
Sd Beta HC [OTC] see Hydrocortisone (Topical) Pediatric
on page 1013 Homocystinuria: Note: The overall role of betaine in
management of homocystinuria and effectiveness is
variable and dependent upon several factors, including
Betaine (Bay ta cen) specific enzyme deficiency, genetic mutation(s), and
clinical condition; dose should be individualized.
Medication Safety Issues Infants and Children <3 years: Oral: 50 mg/kg/dose
Sound-alike/look-alike issues: twice daily; increase at weekly intervals in 50 mg/kg/
Betaine anhydrous may be confused with betaine hydro- day increments until plasma total homocysteine is
chloride (a nutritional supplement) undetectable or present in small amounts. Note:
Betaine may be confused with Betadine Minimal additional benefit has been observed with
Cystadane may be confused with cysteamine, cysteine dosages >150 to 200 mg/kg/day or exceeding a twice
Brand Names: US Cystadane daily dosing schedule (Morris 2017); however, case
Brand Names: Canada Cystadane reports in infants suggest more frequent dosing may
Therapeutic Category Homocystinuria, Treatment Agent be necessary in some patients (Schiff 2011;
Generic Availability (US) No Ucar 2010).

266
 BETAMETHASONE (SYSTEMIC)

Children 23 years and Adolescents: Oral: 3,000 mg at risk of preterm delivery. A single course of betametha-
twice daily; increase gradually until plasma total sone is recommended for women between 24 and 34
homocysteine is undetectable or present in small weeks gestation who are at risk of delivering within 7
amounts; in some patients, doses up to 20 g/day days, including those with ruptured membranes or multiple
have been needed to control homocysteine plasma gestations. A single course of betamethasone may be
concentrations. Note: Minimal benefit has been considered for women beginning at 23 weeks gestation,
observed with dosages >20 g/day or exceeding a who are at risk of delivering within 7 days, in consultation
twice daily dosing schedule. with the family. In addition, a single course of betametha-
Renal Impairment: Pediatric There are no dosage sone may be given to women between 34 0/7 weeks and
adjustments provided in the manufacturer's labeling. 36 6/7 weeks who are at risk of preterm delivery within 7
Hepatic Impairment: Pediatric There are no dosage days and who have not previously received corticoste-
. adjustments provided in the manufacturer's labeling. roids; use of concomitant tocolytics is not currently rec-
Preparation for Administration Oral: Shake lightly ommended and administration of late preterm
before removing cap from bottle. Measure prescribed corticosteroids has not been evaluated in women with
amount with provided measuring scoop and dissolve in intrauterine infection, multiple gestations, pregestational
120 to 180 mL of water, juice, milk, or formula, or mix with diabetes, or women who delivered previously by cesarean
food for immediate ingestion. section at term. Multiple repeat courses are not recom-
Administration Oral: Administer without regard to food mended. However, in women with pregnancies less than
immediately after reconstitution; do not use if powder does 34 weeks gestation at risk for delivery within 7 days and
not completely dissolve or gives a colored solution. who had a course of antenatal corticosteroids >14 days
Monitoring Parameters Variable based upon enzyme prior, a single repeat course may be considered; use of a
deficiency and genetic mutation; should include: Serum repeat course in women with preterm prelabor rupture of
total homocysteine, methionine, and other amino acids as membranes is controversial (ACOG 171 2016; ACOG
applicable; frequency varies based on clinical condition 713 2017, ACOG 188 2018).
(Diekman 2011; Morris 2017) When systemic corticosteroids are needed in pregnancy
Additional Information Vitamin Bg, vitamin Bj, and for rheumatic disorders, it is generally recommended to
folate have been helpful in the management of homocys- use the lowest effective dose for the shortest duration of
tinuria and are often used in conjunction. time, avoiding high doses during the first trimester. Intra-
Dosage Forms Excipient information presented when articular dosing may also be used during pregnancy
available (limited, particularly for generics); consult spe- (Godtestam Skorpen 2016; Makol 2011; @stensen 2009).
cific product labeling. Breastfeeding Considerations Corticosteroids are
Powder, Oral, as anhydrous: present in breast milk.
Cystadane: 1 g/scoop (180 g)
The onset of milk secretion after birth may be delayed and
@ Betaine Anhydrous see Betaine on page 266 the volume of milk produced may be decreased by ante-
Betaject (Can) see Betamethasone (Systemic) natal betamethasone therapy; this affect was seen when
on page 267 delivery occurred 3 to 9 days after the betamethasone
@ Betaloc (Can) see Metoprolol on page 1358 dose in women between 28 and 34 weeks gestation.
Antenatal betamethasone therapy did not affect milk pro-
@ Betamet Acet/Betamet Na pH see Betamethasone duction when birth occurred <3 days or >10 days of
(Systemic) on page 267 treatment (Henderson 2008).
The manufacturer notes that when used systemically,
Betamethasone (Systemic) maternal use of corticosteroids have the potential to cause
(bay ta METH a sone)
adverse events in a breastfed infant (eg, growth suppres-
Related Information sion, interfere with endogenous corticosteroid production)
Corticosteroids Systemic Equivalencies on page 2113 and therefore, recommends that caution be exercised
Brand Names: US Betamethasone Combo; Celestone when administering betamethasone to breastfeeding
Soluspan; Pod-Care 100C; ReadySharp Betamethasone women. Corticosteroids are generally considered compat-
ible with breastfeeding when used in usual doses (Gotes-
Brand Names: Canada Betaject; Celestone Soluspan
tam Skorpen 2016; WHO 2002); however, monitoring of
Therapeutic Category Corticosteroid, Systemic
the breastfeeding infant for adverse reactions is recom-
Generic Availability (US) Yes
mended (WHO 2002).
Use Contraindications
IM: Anti-inflammatory or immunosuppressant agent in the
Hypersensitivity to any component of the formulation; IM
treatment of a variety of diseases when oral therapy not
administration contraindicated in immune thrombocyto-
feasible including those of allergic, hematologic, derma- penia (formerly known as idiopathic thrombocytopenic
tologic, endocrine, gastrointestinal, ophthalmic, neoplas-
purpura).
tic, rheumatic, autoimmune, nervous system, renal, and
Canadian labeling: Additional contraindications (not in US
respiratory origin (FDA approved in pediatric patients
labeling): Herpes simplex of the eye; systemic fungal
[age not specified] and adults)
infections; vaccinia; cerebral malaria; use in areas with
Intra-articular or soft tissue administration: Adjunctive
local infection.
therapy for short-term administration (to tide the patient
Documentation of allergenic cross-reactivity for glucocorti-
over an acute episode or exacerbation) in acute gouty coids is limited. However, because of similarities in
arthritis, acute and subacute bursitis, acute nonspecific
chemical structure and/or pharmacologic actions, the
tenosynovitis, epicondylitis, rheumatoid arthritis, synovi-
possibility of cross-sensitivity cannot be ruled out with
tis of osteoarthritis (FDA approved in pediatric patients
certainty.
[age not specified] and adults)
Warnings/Precautions Avoid concurrent use of other
Intralesional: Treatment of alopecia areata; discoid lupus
corticosteroids.
erythematosus; keloids; localized hypertrophic, infil-
trated, inflammatory lesions of granuloma annulare, May cause hypercortisolism or suppression of hypothala-
lichen planus, lichen simplex chronicus (neurodermati- mic-pituitary-adrenal (HPA) axis, particularly in younger
tis), and psoriatic plaques; necrobiosis lipoidica diabeti- children or in patients receiving high doses for prolonged
corum (FDA approved in pediatric patients [age not periods. HPA axis suppression may lead to adrenal crisis.
specified] and adults); has also been used for treatment Withdrawal and discontinuation of a corticosteroid should
of infantile hemangioma. be done slowly and carefully. Particular care is required
Pregnancy Considerations Betamethasone crosses the when patients are transferred from systemic corticoste-
placenta (Brownfoot 2013) and is partially metabolized by roids to inhaled products due to possible adrenal insuffi-
placental enzymes to an inactive metabolite (Murphy ciency or withdrawal from steroids, including an increase
2007). Some studies have shown an association between in allergic symptoms. Adult patients receiving >20 mg per
first trimester systemic corticosteroid use and oral clefts or day of prednisone (or equivalent) may be most suscep-
decreased birth weight; however, information is conflicting tible. Fatalities have occurred due to adrenal insufficiency
and may be influenced by maternal dose/indication for use in asthmatic patients during and after transfer from sys-
(Lunghi 2010; Park-Wyllie 2000; Pradat 2003). Hypoa- temic corticosteroids to aerosol steroids; aerosol steroids
drenalism may occur in newborns following maternal use do not provide the systemic steroid needed to treat
of corticosteroids daring pregnancy; monitor. patients having trauma, surgery, or infections. In stressful
situations, HPA axis-suppressed patients should receive
Because antenatal corticosteroid administration may
adequate supplementation with natural glucocorticoids
reduce the incidence of intraventricular hemorrhage,
(hydrocortisone or cortisone) rather than betamethasone
necrotizing enterocolitis, neonatal mortality, and respira-
(due to lack of mineralocorticoid activity).
tory distress syndrome, the injection is often used for
antenatal fetal/lung maturation in patients with preterm Acute myopathy has been reported with high-dose cortico-
premature rupture of membranes or preterm labor who are steroids, usually in patients with neuromuscular

267
BETAMETHASONE (SYSTEMIC)

transmission disorders; may involve ocular and/or respi- Central nervous system: Abnormal sensory symptoms,
ratory muscles; monitor creatine kinase; recovery may be arachnoiditis, depression, emotional lability, euphoria,
delayed. Corticosteroid use may cause psychiatric dis- headache, increased intracranial pressure, insomnia,
turbances, including depression, euphoria, insomnia, malaise, meningitis; myasthenia, neuritis, neuropathy,
mood swings, and personality changes. Preexisting psy- paraplegia, paresthesia, personality changes, pseudotu-
chiatric conditions may be exacerbated by corticosteroid mor cerebri, psychic disorder, seizure, spinal cord com-
use. Prolonged use of corticosteroids may also increase pression, vertigo
the incidence of secondary infection, mask acute infection Dermatologic: Acne vulgaris, allergic dermatitis, atrophic
(including fungal infections), prolong or exacerbate viral striae, diaphoresis, ecchymoses, erythema, exfoliation of
infections, or limit response to killed or inactivated vac- skin, fragile skin, hyperpigmentation, hypertrichosis,
cines. Special pathogens (Amoeba, Candida, Cryptococ- hypopigmentation, skin atrophy, skin rash, subcutaneous
cus, Mycobacterium, Nocardia, Pneumocystis, atrophy, suppression of skin test reaction, thinning hair,
Strongyloides, or Toxoplasma) may be activated or an urticaria, xeroderma 2
infection exacerbation may occur (may be fatal). Amebia- Endocrine & metabolic: Amenorrhea, calcinosis, cushin-
sis or Strongyloides infections should be particularly ruled goid state, decreased glucose tolerance, decreased
out. Exposure to varicella zoster (chickenpox) should be serum potassium, fluid retention, glycosuria, growth sup-
avoided; corticosteroids should not be used to treat ocular pression (pediatric), hirsutism, HPA-axis suppression,
herpes simplex. Corticosteroids should not be used for hypokalemic alkalosis, impaired glucose tolerance/pre-
cerebral malaria or viral hepatitis. Close observation is diabetes, insulin resistance (increased requirements for
required in patients with latent tuberculosis and/or TB insulin or-oral hyperglycemic agents), moon face, neg-
reactivity; restrict use in active TB (only in conjunction ative nitrogen balance, protein catabolism, sodium reten-
with antituberculosis treatment). Prolonged treatment with tion, weight gain
corticosteroids has been associated with the development Gastrointestinal: Abdominal distention, change in bowel
of Kaposi sarcoma (case reports); if noted, discontinuation habits, hiccups, increased appetite, intestinal perfora-
of therapy should be considered. High-dose corticoste- tion, nausea, pancreatitis, peptic ulcer, ulcerative esoph-
roids should not be used to manage acute head injury. agitis
Rare cases of anaphylactoid reactions have been Genitourinary: Bladder dysfunction, spermatozoa disorder
observed in patients receiving corticosteroids. (decreased motility and number)
Use with caution in patients with thyroid disease, hepatic Hematologic & oncologic: Petechia
impairment, renal impairment, cardiovascular disease, Hepatic: Hepatomegaly, increased liver enzymes
diabetes, glaucoma, cataracts, myasthenia gravis, Hypersensitivity: Anaphylactoid reaction, anaphylaxis,
patients at risk for osteoporosis, patients at risk for seiz- angioedema
ures, or GI diseases (diverticulitis, fresh intestinal anasto- Infection: Infection (decreased resistance), sterile abscess
moses, peptic ulcer, ulcerative colitis) due to perforation Local: Injection site reaction (intra-articular use). postin-
risk. Use caution following acute MI (corticosteroids have jection flare (intra-articular use)
been associated with myocardial rupture). Use with cau- Neuromuscular & skeletal: Amyotrophy, aseptic necrosis
tion in patients with HF and/or hypertension; long-term use of femoral head, aseptic necrosis of humeral head, bone
has been associated with fluid retention and electrolyte fracture, Charcot arthropathy, lipotrophy, myopathy,
disturbances. Dietary modifications may be necessary. osteoporosis, rupture of tendon, steroid myopathy
Use with caution in patients with a recent history of Ophthalmic: Blindness, blurred vision, cataract, exoph-
myocardial infarction (Ml); left ventricular free wall rupture thalmos, glaucoma, increased intraocular pressure, pap-
has been reported after the use of corticosteroids. Use illedema
with caution in patients with renal impairment; fluid and Respiratory: Pulmonary edema
sodium retention and increased potassium and calcium Miscellaneous: Wound healing impairment
excretion may occur. Dietary modifications may be neces- Drug Interactions
sary. Not recommended for the treatment of optic neuritis; Metabolism/Transport Effects None known.
may increase frequency of new episodes. Intra-articular Avoid Concomitant Use
injection. may result in joint tissue damage. Injection into Avoid concomitant use of Betamethasone (Systemic)
an infected site should be avoided. Injection into a pre- with any of the following: Aldesleukin; BCG (Intravesi-
viously infected join is usually not recommended. If infec- cal); Desmopressin; Indium 111 Capromab Pendetide;
tion is suspected, joint fluid examination is recommended. Macimorelin; Mifamurtide; MiFEPRIStone; Natalizumab;
If septic arthritis occurs after injection, institute appropriate Pimecrolimus; Tacrolimus (Topical)
antimicrobial therapy. Suspension for injection is for intra- Increased Effect/Toxicity
muscular, intra-articular or intralesional use only, do not Betamethasone (Systemic) may increase the levels/
administer intravenously. Corticosteroids are not approved effects of: Acetylcholinesterase Inhibitors; Amphotericin
for epidural injection. Serious neurologic events (eg, spi- B; Androgens; Baricitinib; Ceritinib; Deferasirox; Desir-
nal cord infarction, paraplegia, quadriplegia, cortical blind- udin; Desmopressin; Fingolimod; Leflunomide; Loop
ness, stroke), some resulting in death, have been reported Diuretics; Natalizumab; Nicorandil; Nonsteroidal Anti-
with epidural injection of corticosteroids, with and without Inflammatory Agents (COX-2 Selective); Nonsteroidal
use of fluoroscopy. Intra-articular injected corticosteroids Anti-Inflammatory Agents (Nonselective); Quinolones;
may be systemically absorbed. May produce systemic as Ritodrine; Sargramostim; Thiazide and Thiazide-Like
well as local effects. Appropriate examination of any joint Diuretics; Tofacitinib; Vaccines (Live); Warfarin
fluid present is necessary to exclude a septic process.
Avoid injection into an infected site. Do not inject into The levels/effects of Betamethasone (Systemic) may be
unstable joints. Intra-articular injection may result in dam- increased by: Aprepitant; CYP3A4 Inhibitors (Strong);
age to joint tissues. Potentially significant drug-drug inter- Denosumab; DilTl|AZem; Estrogen Derivatives; Fosapre-
actions may exist, requiring dose or frequency adjustment, pitant; Indacaterol; MiFEPRIStone; Neuromuscular-
additional monitoring, and/or selection of alternative ther- Blocking Agents (Nondepolarizing); Ocrelizumab; Pime-
apy. Because of the risk of adverse effects, systemic crolimus; Roflumilast; Salicylates; Tacrolimus (Topical);
corticosteroids should be used cautiously in the elderly Telaprevir; Trastuzumab
in the smallest possible effective dose for the shortest Decreased Effect
duration. Withdraw therapy with gradual tapering of dose. Betamethasone (Systemic) may decrease the levels/
effects of: Aldesleukin; Antidiabetic Agents; Axicabta-
Prolonged use in children may affect growth velocity; gene Ciloleucel; BCG (Intravesical); Calcitriol (Sys-
growth should be routinely monitored in pediatric patients. temic); Coccidioides immitis Skin Test; Corticorelin;
Warnings: Additional Pediatric Considerations Hyaluronidase; Indium 111 Capromab Pendetide; Isonia-
Adrenal suppression with failure to thrive has been zid; Macimorelin; Mifamurtide; Nivolumab; Pidotimod;
reported in infants after receiving intralesional corticoste- Salicylates; Sipuleucel-T; Tacrolimus (Systemic); Telap-
roid injections for treatment of hemangioma (Goyal, 2004). revir; Tertomotide; Tisagenlecleucel; Urea Cycle Disor-
May cause osteoporosis (at any age) or inhibition of bone der Agents; Vaccines (Inactivated); Vaccines (Live)
growth in pediatric patients. Use with caution in patients
with osteoporosis. In a population-based study of children, The levels/effects of Betamethasone (Systemic) may be
risk of fracture was shown to be increased with >4 courses decreased by: CYP3A4 Inducers (Strong); Echinacea;
of corticosteroids; underlying clinical condition may also MiFEPRIStone; Mitotane
impact bone health and osteoporotic effect of corticoste- Storage/Stability Store at 25°C (77°F); excursions are
roids (Leonard, 2007). permitted between 15°C and 30°C (59°F and 86°F).
Adverse Reactions Protect from light.
Cardiovascular: Bradycardia, cardiac arrhythmia, cardio- Mechanism of Action Controls the rate of protein syn-
megaly, circulatory shock, edema, embolism (fat), hyper- thesis; depresses the migration of polymorphonuclear
tension, hypertrophic cardiomyopathy, myocardial leukocytes, fibroblasts; reverses capillary permeability
rupture (following recent Ml), syncope, tachycardia, and lysosomal stabilization at the cellular level to prevent
thromboembolism, thrombophlebitis, vasculitis or control inflammation

268
 BETAMETHASONE (TOPICAL)

Pharmacodynamics/Kinetics (Adult data unless

noted) Betamethasone (Topical) (bay ta METH a sone)
Protein binding: 64% (Peterson 1983)
Metabolism: Hepatic (Peterson 1983) Medication Safety Issues
Half-life elimination: 6.5 hours (Peterson 1983) Sound-alike/look-alike issues:
Time to peak, serum: IV: 10 to 36 minutes (Peterson 1983) Luxiq may be confused with Lasix
Excretion: Urine (<5% as unchanged drug) (Peter- Related Information
son 1983) Corticosteroids Systemic Equivalencies on page 2113
Dosing Topical Corticosteroids on page 2114
Pediatric Note: Dosages expressed as combined Brand Names: US AlphaTrex [DSC]; Diprolene; Dipro-
amount of betamethasone sodium phosphate and beta- lene AF; Luxig; Sernivo
»methasone acetate; 1 mg is equivalent to betametha- Brand Names: Canada Betaderm; Beteflam; Betnesol;
sone sodium phosphate 0.5 mg and betamethasone Celestoderm V; Celestoderm V/2; Diprolene; Diprosone;
acetate 0.5 mg. Dosage should be based on severity Luxiq; Prevex B; Rivasone; Rolene; Rosone; Valisone
of disease and patient response; use lowest effective Scalp Lotion
dose for shortest period of time to avoid HPA axis Therapeutic Category Corticosteroid, Topical
suppression Generic Availability (US) May be product dependent
General dosing, treatment of inflammatory and aller- Use
gic conditions: Infants, Children, and Adolescents: Betamethasone dipropionate (augmented): Treatment of
IM: Initial: 0.02 to 0.3 mg/kg/day (0.6 to 9 mg/m?2/day) inflammation and pruritus associated with corticosteroid-
in 3 or 4 divided doses responsive dermatoses of the skin (Cream, lotion, and
Infantile hemangioma, severe: Limited data available: ointment: FDA approved in ages 213 years and adults;
Infants and Children: Intralesional: Dosage dependent Gel: FDA approved in ages 212 years and adults)
upon size of lesion: Commonly reported: 6 mg admin- Betamethasone dipropionate spray: Treatment of mild to
istered as a 6 mg/mL (in combination with triamcino- moderate plaque psoriasis (FDA approved in ages 218
lone injection) divided into multiple injections along the years and adults)
lesion, perimeter; reported range: 1.5 to 18 mg/dose; Betamethasone valerate:
doses usually administered every 8 to 14 weeks; Cream, lotion, and ointment: Treatment of inflammation
reported range: 6 to 25 weeks (Buckmiller, 2008; and pruritus associated with corticosteroid-responsive
Chowadri, 1994; Kushner, 1985; Praseyono, 2011). Dos- dermatoses of the skin (FDA approved in pediatric
ing based on small trials and case-series, mostly patients [age not specified] and adults)
reported in infants and children <4 years of age. The Foam: Treatment of inflammation and pruritus associ-
largest experience (n=70, age range: 2 months to 12 ated with corticosteroid-responsive dermatoses of the
years) prospectively used a betamethasone/triamcino- scalp including psoriasis (FDA approved in adults)
lone combination injection (1.5 to 18 mg betametha- Pregnancy Risk Factor C
sone acetate) and showed that 89.23% of lesions with Pregnancy Considerations Adverse events have been
an initial volume <20 cc? regressed by more than 50%, observed with corticosteroids in animal reproduction stud-
but only 22.2% of lesions with an initial volume >20 cc? ies. Topical corticosteroids are preferred over systemic for
displayed a good or excellent response (Chowdri, treating conditions, such as psoriasis or atopic dermatitis
1994). Another trial (n=25, age range: 7 weeks to 2 in pregnant women; high potency corticosteroids are not
years) used lower doses of 3 to 12 mg (in combination recommended during the first trimester. Topical products
with triamcinolone); 16 patients experienced a marked are not recommended for extensive use, in large quanti-
response (Kushner, 1985). ties, or for long periods of time in pregnant women (Bae
Renal Impairment: Pediatric There are no dosage 2011; Koutroulis 2011; Leachman 2006). Refer to the
adjustments provided in the manufacturer's labeling. Betamethasone systemic monograph for additional infor-
Hepatic Impairment: Pediatric There are no dosage mation.
adjustments provided in the manufacturer's labeling. Breastfeeding Considerations
Preparation for Administration If suspension is coad- Corticosteroids are excreted in human milk. It is not known
ministered with a local anesthetic, it may be mixed in if systemic absorption following topical administration
syringe with 1% or 2% lidocaine HCI (without parabens). results in detectable quantities in human milk. Do not
Withdraw the dose of betamethasone suspension from the apply topical corticosteroids to nipples; hypertension was
vial into the syringe, then draw up the local anesthetic into noted in a nursing infant exposed to a topical cortico-
the syringe, and shake the syringe briefly. Do not inject the steroid while nursing (Leachman 2006).
local anesthetic directly into the suspension vial. The manufacturer notes that when used systemically,
Administration Note: May be coadministered with a local maternal use of corticosteroids have the potential to
anesthetic. cause adverse events in a nursing infant (eg, growth
IM: Do not give injectable suspension IV suppression, interfere with endogenous corticosteroid
Intrabursal: Tendinitis, tenosynovitis: Inject into affected production) and therefore recommends that caution be
tendon sheaths (not directly into tendons) exercised when administering betamethasone to nursing
Intralesional: Using a 25-gauge tuberculin syringe with 1/2- women.
inch needle inject a uniform depot; for infantile heman- Contraindications
gioma, 26- and 27-gauge needles have been used for Hypersensitivity to betamethasone, other corticosteroids,
administration. Should be injected directly into the lesion or any component of the formulation
area. Do not inject subcutaneously. Cream, Lotion: Untreated bacterial, tubercular, and fungal
Monitoring Parameters Intraocular pressure (if therapy skin infections; viral diseases (eg, herpes simplex,
>6 weeks); weight, height, and linear growth (with chronic chicken pox, vaccinia)
use); assess HPA suppression. Monitor blood pressure, Canadian labeling: Additional contraindications (not in US
serum glucose, potassium, calcium, hemoglobin, occult labeling): Treatment of rosacea, acne vulgaris, perioral
blood loss, and clinical presence of adverse effects. dermatitis, or pruritus without inflammation (foam); skin
Test Interactions May suppress the wheal and flare manifestations relating to tuberculosis or syphilis, erup-
reactions to skin test antigens tions following vaccinations; application to eyes (foam);
Dosage Forms Excipient information presented when <18 years of age (patch). Note: Product labels may vary
available (limited, particularly for generics); consult spe- (refer also to product labels).
cific product labeling. Warnings/Precautions Very high potency topical prod-
Kit, Injection: ucts are not for treatment of rosacea, perioral dermatitis;
Pod-Care 100C: Betamethasone sodium phosphate not for use on face, groin, or axillae; not for use in a
3 mg and betamethasone acetate 3 mg per 1 mL diapered area. Avoid concurrent use of other corticoste-
[contains benzalkonium chloride, disodium edta] roids.
ReadySharp Betamethasone: Betamethasone sodium
phosphate 3 mg and betamethasone acetate 3 mg May cause hypercortisolism or suppression of hypothala-
per 1 mL [contains benzalkonium chloride, diso- mic-pituitary-adrenal (HPA) axis, particularly in younger
dium edta] children or in patients receiving high doses for prolonged
Suspension, Injection: é periods. HPA axis suppression may lead to adrenal crisis.
Betamethasone Combo: Betamethasone sodium phos-
Topical corticosteroids, including betamethasone, may
phate 3 mg and betamethasone acetate 3 mg per 1 mL increase the risk of posterior subcapsular cataracts and
(2 mL) glaucoma. Monitor for ocular symptoms. Avoid contact
Celestone Soluspan: Betamethasone sodium phosphate
with eyes.
3 mg and betamethasone acetate 3mg per 1 mL (5
mL) [contains benzalkonium chloride, edetate Topical corticosteroids may be absorbed percutaneously.
disodium] Absorption of topical corticosteroids may cause manifes-
Generic: Betamethasone sodium phosphate 3 mg and tations of Cushing syndrome (rare), hyperglycemia, or
betamethasone acetate 3 mg per 1 mL (5 mL) glycosuria. Absorption is increased by the use of occlusive

269
BETAMETHASONE (TOPICAL)

dressings, application to denuded skin, application to incinerate container. Do not expose to heat or store at
large surface areas, or prolonged use. Potentially signifi- temperatures above 49°C (120°F).
cant interactions may exist, requiring dose or frequency Patch [Canadian product]: Store at 15°C to 25°C (59°F to
adjustment, additional monitoring, and/or selection of 77°F). Use immediately after opening sachet.
alternative therapy. Mechanism of Action Topical corticosteroids have anti-
inflammatory, antipruritic, and vasoconstrictive properties.
Discontinue if skin irritation or contact dermatitis should
May depress the formation, release, and activity of endog-
occur; do not use in patients with decreased skin circu-
enous chemical mediators of inflammation (kinins, hista-
lation. Withdraw therapy with gradual tapering of dose by
mine, liposomal enzymes, prostaglandins) through the
reducing the frequency of application or substitution of a induction of phospholipase Ap inhibitory proteins (lipocor-
less potent steroid. Allergic contact dermatitis can occur
tins) and sequential inhibition of the release of arachidonic
and is usually diagnosed by failure to heal rather than
acid. Betamethasone has intermediate to very high range
Clinical exacerbation; discontinue use if irritation occurs potency (dosage-form dependent). é
and treat appropriately.
Pharmacodynamics/Kinetics (Adult data unless
For topical use only; avoid contact with eyes. Not for oral, noted)
ophthalmic, or intravaginal use. Augmented (eg, very high Absorption: Topical corticosteroids are absorbed percuta-
potency) product use in patients <13 years of age is not neously. The extent of absorption is dependent on
recommended. Not for treatment of rosacea, perioral several factors, including epidermal integrity (intact vs
dermatitis, or if skin atrophy is present at treatment site; abraded skin), formulation, age of the patient, prolonged
not for facial, groin, axillary, oral, ophthalmic, or intra- duration of_use, and the use of occlusive dressings.
vaginal use. Children may absorb proportionally larger Percutaneous absorption of topical steroids is increased
amounts after topical application and may be more prone in neonates (especially preterm neonates), infants, and
to systemic effects. HPA axis suppression, intracranial young children.
hypertension, and Cushing syndrome have been reported Metabolism: Hepatic
in children receiving topical corticosteroids. Prolonged use Excretion: Urine and bile
may affect growth velocity; growth should be routinely Dosing
monitored in pediatric patients. Use lowest dose possible Pediatric Note: Dosage should be based on severity of
for shortest period of time to avoid HPA axis suppression. disease and patient response; use smallest amount for
Foam contains flammable propellants. Avoid fire, flame, shortest period of time to avoid HPA axis suppression.
and smoking during and immediately following adminis- Therapy should be discontinued when control is
tration. Patch [Canadian product] has not been studied in achieved.
psoriasis of the face, scalp or intertriginous areas; con- Dermatoses (corticosteroid-responsive): Topical:
tains methyl and propyl parahydroxybenzoate, which may Betamethasone valerate:
cause hypersensitivity (Sometimes delayed). Cream/ointment: Children and Adolescents: Apply a
Warnings: Additional Pediatric Considerations The thin film to the affected area once to 3 times daily;
extent of percutaneous absorption is dependent on sev- usually once or twice daily application is effective.
eral factors, including epidermal integrity (intact vs Lotion: Children and Adolescents: Apply a few drops
abraded skin), formulation, age of the patient, prolonged to the affected area twice daily; in some cases, more
duration of use, and the use of occlusive dressings. frequent application may be necessary; following
Percutaneous absorption of topical steroids is increased improvement reduce to once daily application
in neonates (especially preterm neonates), infants, and Betamethasone dipropionate (augmented formulation):
young children. Infants and small children may be more Cream/ointment: Adolescents: Apply a thin film to
susceptible to HPA axis suppression, intracranial hyper- affected area once or twice daily; maximum dose:
tension, Cushing syndrome, or other systemic toxicities 50 g/week; evaluate continuation of therapy if no
due to larger skin surface area to body mass ratio. HPA improvement within 2 weeks of treatment.
axis suppression was observed in 32% of infants and Gel: Children and Adolescents 212 years: Apply a thin
children (age range: 3 months to 12 years) being treated layer to the affected area once or twice daily; rub in
with betamethasone dipropionate cream (0.05%) for gently; maximum dose: 50 g/week; not recom-
atopic dermatitis in an open-label trial (n=60); the inci- mended for use longer than 2 weeks
dence was greater younger patients vs older children Lotion: Adolescents: Apply a few drops to the affected
(mean reported incidence for age ranges: $1 year: 50%; area once or twice daily; rub in gently; maximum
2 to 8 years: 32% to 38%; 9 to 12 years: 17%). dose: 50 mL/week; not recommended for use for
longer than 2 weeks.
Some dosage forms may contain propylene glycol; in Renal Impairment: Pediatric There are no dosage
neonates large amounts of propylene glycol delivered adjustments provided in the manufacturer's labeling.
orally, intravenously (eg, >3,000 mg/day), or topically
Hepatic Impairment: Pediatric There are no dosage
have been associated with potentially fatal toxicities which adjustments provided in the manufacturer's labeling.
can include metabolic acidosis, seizures, renal failure, and
Administration Topical: For external use only. Apply
CNS depression; toxicities have also been reported in
sparingly to affected areas. Not for use on broken skin
children and adults including hyperosmolality, lactic acido-
or in areas of infection. Do not apply to wet skin unless
sis, seizures and respiratory depression; use caution
directed; do not cover with occlusive dressing. Do not
(AAP 1997; Shehab 2009).
apply very high potency agents to face, groin, axillae, or
Adverse Reactions diaper area. Wash hands after use.
Central nervous system: Paresthesia Betamethasone dipropionate spray: Spray directly onto
Dermatologic: Acne vulgaris, alopecia, pruritus affected areas (spray only enough to sufficiently cover
Endocrine & metabolic: HPA axis suppression the area); rub in gently. Shake well before use. Do not
Local: Application site reactions (includes burning, sting- use if atrophy is present at the treatment site. Do not
ing, and itching; most reactions were mild) cover with occlusive dressing unless directed otherwise
Ophthalmic: Conjunctivitis by health care provider. For topical use only; not for oral,
Rare but important or life-threatening: Bullous dermatitis, ophthalmic, or vaginal use; avoid use on the face, scalp,
cataract, contact dermatitis, dermatitis, dysgeusia, eryth- axilla, groin, or other intertriginous areas.
ema, erythematous rash, folliculitis, glaucoma, hyper- Betamethasone valerate:
glycemia, hypersensitivity reaction, increased Foam: Invert can and dispense a small amount onto a
intraocular pressure, localized vesiculation, retinopathy saucer or other cool surface. Do not dispense directly
(central serous), skin discoloration, skin rash, telangiec- into hands as foam will begin to melt immediately upon
tasia contact with warm skin. Pick up small amounts of foam
Drug Interactions and gently massage into affected areas until foam
Metabolism/Transport Effects None known. disappears. Repeat until entire affected scalp area is
Avoid Concomitant Use treated. Avoid fire, flame, and/or smoking during and
Avoid concomitant use of Betamethasone (Topical) with immediately following application.
any of the following: Aldesleukin Lotion: Shake well prior to use.
Increased Effect/Toxicity Monitoring Parameters Growth in pediatric patients;
Betamethasone (Topical) may increase the levels/effects assess HPA axis suppression (eg, ACTH stimulation test,
of: Ceritinib; Deferasirox; Ritodrine morning plasma cortisol test, urinary free cortisol test),
Decreased Effect ocular symptoms
Betamethasone (Topical) may decrease the levels/ Test Interactions May suppress the wheal and flare
effects of: Aldesleukin; Corticorelin; Hyaluronidase reactions to skin test antigens
Storage/Stability Additional Information
Cream, lotion, ointment, spray: Store at 15°C to 30°C Very high potency (super high potency): Augmented beta-
(59°F to 86°F). Discard any unused spray after 4 weeks. methasone dipropionate ointment, lotion, gel
Foam: Store at 20°C to 25°C (68°F to 77°F). Avoid fire, High potency: Augmented betamethasone dipropionate
flame, or smoking during use. Do not puncture or cream, betamethasone dipropionate cream and ointment
 BETAXOLOL (OPHTHALMIC)

Intermediate potency: Betamethasone dipropionate lotion, Use Treatment of elevated intraocular pressure in patients
betamethasone valerate cream with chronic open-angle glaucoma or ocular hypertension
Dosage Forms Excipient information presented when (ophthalmic solution: FDA approved in adults; ophthalmic
available (limited, particularly for generics); consult spe- suspension [Betoptic S]: FDA approved in pediatric
cific product labeling. [DSC] = Discontinued product patients [age not specified] and adults)
Cream, External, as dipropionate [strength expressed as Pregnancy Risk Factor C
base]: Pregnancy Considerations Animal reproduction studies
Generic: 0.05% (15 g, 45 g) have not been conducted with the ophthalmic drops.
Cream, External, as dipropionate augmented [strength When administered orally, betaxolol crosses the placenta
expressed as base]: and can be detected in the amniotic fluid and umbilical
Diprolene AF: 0.05% (15 g, 50 g) cord blood (Morselli 1990). The amount of betaxolol
Generic: 0.05% (15g, 50 g) available systemically following topical application of the
Cream, External, as valerate [strength expressed as ophthalmic drops is significantly less in comparison to oral
base]: doses (Vainio-Jylha 2001). However, the same adverse
Generic: 0.1% (15 g, 45 g) effects observed with systemic administration may occur.
Emulsion, External, as dipropionate [strength expressed If ophthalmic agents are needed during pregnancy, the
as base]: » . minimum effective dose should be used in combination
Sernivo: 0.05% (120 mL) [contains cetostearyl alcohol, with punctual occlusion to decrease potential exposure to
methylparaben, propylparaben] the fetus (Johnson 2001; Salim 2014; Samples 1988).
Foam, External, as valerate: Breastfeeding Considerations It is not known if betax-
Luxig: 0.12% (50 g, 100 g) [contains alcohol, usp, cetyl olol is present in breast milk following ophthalmic admin-
alcohol, propylene glycol] istration. The minimum ‘effective dose should be used in
_ Generic: 0.12% (50 g, 100 g) combination with punctual occlusion to decrease potential
Gel, External, as dipropionate augmented [strength exposure to the breastfeeding infant (Johnson 2001;
expressed as base]: Salim 2014; Samples 1988). The manufacturer recom-
AlphaTrex: 0.05% (15 g [DSC], 50 g [DSC}) mends that caution be used if administered to a breast-
Generic: 0.05% (15 g, 50 g) feeding woman.
Lotion, External, as dipropionate. [strength expressed as Contraindications
base]: Hypersensitivity to betaxolol or any component of the
Generic: 0.05% (60 mL) formulation; sinus bradycardia; heart block greater than
Lotion, External, as dipropionate augmented [strength first-degree (except in patients with a functioning artificial
expressed as base]: pacemaker); cardiogenic shock; uncompensated cardiac
Diprolene: 0.05% (30 mL, 60 mL) [contains isopropyl failure
alcohol, propylene glycol] Canadian labeling: Additional contraindications (not in US
Generic: 0.05% (30 mL, 60 mL) labeling): Reactive airway disease including bronchial
Lotion, External, as valerate [strength expressed as base]: asthma or a history of bronchial asthma; severe chronic
Generic: 0.1% (60 mL) obstructive pulmonary disease (COPD); sick sinus syn-
Ointment, External, as dipropionate [strength expressed drome sino-atrial block
as base]: Warnings/Precautions Systemic absorption of betaxolol
Generic: 0.05% (15 g, 45 g) and adverse effects may occur with ophthalmic use,
Ointment, External, as dipropionate augmented [strength including severe respiratory and cardiac reactions. Use
expressed as base]: with caution in patients with compensated heart failure
Diprolene: 0.05% (15 g, 50 g) and monitor for a worsening of the condition. Discontinue
Generic: 0.05% (15 g, 45 g, 50 g) at first signs of cardiac failure. In a scientific statement
Ointment, External, as valerate [strength expressed as from the American Heart Association, betaxolol has been
base]: determined to be an agent that may exacerbate underlying
Generic: 0.1% (15 g, 45 g) myocardial dysfunction (magnitude: major) (AHA [Page
2016]). In general, patients with bronchospastic disease
Betamethasone Acetate see Betamethasone (Sys- should not receive beta-blockers; if used at all, should be
temic) on page 267 used cautiously with close monitoring; asthma exacerba-
@ Betamethasone Combo see Betamethasone (Systemic) tion and pulmonary distress has been reported during
on page 267 betaxolol use. Use with caution in patients with cardiovas-
cular insufficiency; if signs of decreased cerebral blood
@ Betamethasone Dipropionate see Betamethasone
flow occur, consider alternative therapy. Use with caution
(Topical) on page 269
in patients with diabetes mellitus; may potentiate hypo-
@ Betamethasone Dipropionate and Calcipotriene glycemia and/or mask signs and symptoms. May mask
Hydrate see Calcipotriene and Betamethasone signs of hyperthyroidism (eg, tachycardia); if hyperthyroid-
on page 334 ism is suspected, carefully manage and monitor; abrupt
@ Betamethasone Dipropionate, Augmented see Beta- withdrawal may exacerbate symptoms of hyperthyroidism
methasone (Topical) on page 269 or precipitate thyroid storm. Use with caution in patients
Betamethasone/Propylene Glyc see Betamethasone with myasthenia gravis; may worsen disease. Use caution
(Topical) on page 269 with history of severe anaphylaxis to allergens; patients
taking beta-blockers may become more sensitive to
@ Betamethasone Sodium Phosphate see Betametha- repeated challenges. Treatment of anaphylaxis (eg, epi-
sone (Systemic) on page 267 nephrine) in patients taking beta-blockers may be ineffec-
@ Betamethasone Sod Phos/Acetate see Betamethasone tive or promote undesirable effects. Use with caution in
(Systemic) on page 267 patients with vascular insufficiency due to potential effects
@ Betamethasone Valerate see Betamethasone (Topical) on blood pressure and pulse; if signs/symptoms of
on page 269 reduced cerebral blood flow or Raynaud phenomenon
develop during therapy, consider alternative therapy.
@ Betapace see Sotalol on page 1856
@ Betapace AF see Sotalol on page 1856 Should not be used alone in angle-closure glaucoma (has
no effect on pupillary constriction). Ophthalmic solution/
@ Betaquik [OTC] see Medium Chain Triglycerides
suspension contains benzalkonium chloride which may be
on page 1286 absorbed by contact lenses; remove contact lens prior to
@ Betasal [OTC] see Salicylic Acid on page 1796 administration and wait 15 minutes before reinserting.
@ Betasept Surgical Scrub [OTC] see Chlorhexidine Inadvertent contamination of multiple-dose ophthalmic
Gluconate (Topical) on page 421 solutions has caused bacterial keratitis. Choroidal detach-
ment has been reported with aqueous suppressant ther-
@ Betaxin (Can) see Thiamine on page 1936
apy after filtration procedures. Potentially significant
interactions may exist, requiring dose or frequency adjust-
Betaxolol (Ophthalmic) (be taxs ob to!) ment, additional monitoring, and/or selection of alternative
therapy.
Medication Safety Issues Adverse Reactions
Sound-alike/look-alike issues: Ophthalmic: Anisocoria, blurred vision, choroidal detach-
Betoptic S may be confused with Betagan, Timoptic ment, corneal staining, crusting of eyelash, decreased
Brand Names: US Betoptic-S corneal sensitivity, decreased visual acuity, eye dis-
Brand Names: Canada Betoptic S; Sandoz-Betaxolol charge, eye discomfort (short-term), eye pain, eye pruri-
Therapeutic Category Beta-Adrenergic Blocker; Beta- tus, eye redness, foreign body sensation of eye,
Adrenergic Blocker, Ophthalmic hypersensitivity reaction (ophthalmic), keratitis, lacrima-
Generic Availability (US) May be product dependent tion, ocular edema, ophthalmic inflammation, ?
271
BETAXOLOL (OPHTHALMIC)

photophobia, punctate corneal staining (with or without Dosage Forms Excipient information presented when
dendritic formations), superficial punctate keratitis, available (limited, particularly for generics); consult spe-
xerophthalmia cific product labeling.
Rare but important or life-threatening: Alopecia, altered Solution, Ophthalmic:
sense of smell, asthma, bradycardia, bronchospasm, Generic: 0.5% (5 mL, 10 mL, 15 mL) '
cardiac failure, depression, dizziness, dysgeusia, dysp- Suspension, Ophthalmic:
nea, exacerbation of myasthenia gravis, glossitis, heart Betoptic-S: 0.25% (10 mL, 15 mL)
block, headache, insomnia, lethargy, respiratory failure,
thickening of bronchial secretions, toxic epidermal nec- @ Betaxolol HCI see Betaxolol (Ophthalmic) on page 271
rolysis, urticaria, vertigo ¢@ Betaxolol Hydrochloride see Betaxolol (Ophthalmic)
Drug Interactions on page 271
Metabolism/Transport Effects Substrate of CYP1A2 @ Beteflam (Can) see Betamethasone (Topical)
(minor), CYP2D6 (minor); Note: Assignment of Major/ on page 269 :
Minor substrate status based on clinically relevant drug
interaction potential
Avoid Concomitant Use Bethanechol (be THAN e kole)
Avoid concomitant use of Betaxolol (Ophthalmic) with
Medication Safety Issues
any of the following: Floctafenine; Methacholine; Riva-
Sound-alike/look-alike issues:
stigmine
Bethanechol may be confused with betaxolol
Increased Effect/Toxicity
Brand Names: US Urecholine
Betaxolol (Ophthalmic) may increase the levels/effects
Brand Names: Canada Duvoid; PHL-Bethanechol; PMS-
of: Alpha1-Blockers; Alpha2-Agonists; Antipsychotic
Bethanechol
Agents (Phenothiazines); Bupivacaine; Cardiac Glyco-
Therapeutic Category Cholinergic Agent
sides; Cholinergic Agonists; Disopyramide; Ergot Deriv-
atives; Fingolimod; Grass Pollen Allergen Extract (5 Generic Availability (US) Yes
Grass Extract); Insulins; Lidocaine (Systemic); Lidocaine Use Treatment of acute postoperative and postpartum
(Topical); Mepivacaine; Methacholine; Midodrine; Sulfo- nonobstructive (functional) urinary retention and retention
nylureas due to neurogenic atony of the urinary bladder with
retention (All indications: FDA approved in adults)
The levels/effects of Betaxolol (Ophthalmic) may be Pregnancy Risk Factor C
increased by: Acetylcholinesterase Inhibitors; Alpha2- Pregnancy Considerations Animal reproduction studies
Agonists; Aminoquinolines (Antimalarial); Amiodarone; have not been conducted.
Antipsychotic Agents (Phenothiazines); Calcium Chan- Breastfeeding Considerations It is not known if betha-
nel Blockers (Nondihydropyridine); Dipyridamole; Diso- nechol is excreted in breast milk. Due to the potential for
pyramide; Dronedarone; Floctafenine; Methoxyflurane; serious adverse reactions in the nursing infant, a decision
NIFEdipine; Opioids (Anilidopiperidine); Propafenone; should be made whether to discontinue nursing or to
Regorafenib; Reserpine; Rivastigmine discontinue the drug, taking into account the importance
Decreased Effect of treatment to the mother.
Betaxolol (Ophthalmic) may decrease the levels/effects Contraindications Hypersensitivity to bethanechol or any
of: Beta2-Agonists; EPINEPHrine (Nasal); EPINEPHrine component of the formulation; hyperthyroidism, peptic
(Oral Inhalation); Epinephrine (Racemic); EPINEPHrine ulcer disease, epilepsy, asthma, pronounced bradycardia
(Systemic); Theophylline Derivatives or hypotension, vasomotor instability, coronary artery dis-
The levels/effects of Betaxolol (Ophthalmic) may be ease, or parkinsonism; mechanical obstruction of the Gl or
decreased by: Barbiturates; Nonsteroidal Anti-Inflamma- GU tract or when the strength or integrity of the Gl or
tory Agents; Rifamycin Derivatives bladder wall is in question; when increased muscular
Storage/Stability Store ophthalmic suspension upright at activity of the Gl tract or bladder might prove harmful
2°C to 25°C (36°F to 77°F). Store ophthalmic solution: at (eg, following urinary bladder surgery, Gl resection and
20°C to 25°C (68°F to 77°F). anastomosis, possible GI obstruction); bladder neck
Mechanism of Action Competitively blocks beta,-recep- obstruction, spastic Gl disturbances, acute inflammatory
tors, with little or no effect on betaz-receptors; with oph- lesions of the Gl tract, peritonitis, marked vagotonia.
thalmic use, reduces intraocular pressure by reducing the Warnings/Precautions Potential for reflux infection in
production of aqueous humor bacteriuric patients if the sphincter fails to relax as betha-
Pharmacodynamics/Kinetics (Adult data unless nechol contracts the bladder.
noted) Warnings: Additional Pediatric Considerations As a
Onset of action: Within 30 minutes cholinergic, prokinetic agent, bethanechol was historically
Peak effect: Intraocular pressure reduction: ~2 hours used to treat infants and children with GERD. However,
Duration: 212 hours the risk of adverse effects risks outweigh efficacy benefits
Absorption: Rapidly absorbed into the systemic circulation and use is no longer recommended (AAP [Lightdale
(concentrations ~1/10 to 1/20 of oral dosing) (Vainio- 2013], NASPGHAN/ESPGHAN [Vandenplas 2009].
Jylha, 2001) Adverse Reactions
Excretion: Urine (>80%, as unchanged drug [15%] and Cardiovascular: Flushing, hypotension, tachycardia
inactive metabolites) Central nervous system: Colic, headache, malaise,
Dosing seizure
Neonatal Elevated intraocular pressure: Neonates 21 Dermatologic: Diaphoresis
week PNA: Ophthalmic suspension (Betopic S): Instill 1 Gastrointestinal: Abdominal cramps, borborygmi, diar-
drop into affected eye(s) twice daily (Plager, 2009) rhea, eructation, nausea, salivation, vomiting
Pediatric Elevated intraocular pressure: Infants, Chil- Genitourinary: Urinary urgency
dren, and Adolescents: Ophthalmic suspension (Betoptic Ophthalmic: Lacrimation, miosis
S): Instill 1 drop into affected eye(s) twice daily Respiratory: Asthma, bronchoconstriction
Renal Impairment: Pediatric Infants, Children, and Drug Interactions
Adolescents: There are no dosage adjustments provided Metabolism/Transport Effects None known.
in manufacturer's labeling (has not been studied). Avoid Concomitant Use There are no known interac-
Hepatic Impairment: Pediatric Infants, Children, and tions where it is recommended to avoid concomitant use.
Adolescents: There are no dosage adjustments provided Increased Effect/Toxicity
in manufacturer's labeling (has not been studied). The levels/effects of Bethanechol may be increased by:
Administration Ophthalmic: Administer other topically Acetylcholinesterase Inhibitors; Beta-Blockers
applied ophthalmic medications at least 10 minutes before Decreased Effect
Betopic S; wash hands before use; invert closed bottle Bethanechol may decrease the levels/effects of: Cime-
and shake bottle; remove cap carefully so that tip does not tropium
touch anything; hold bottle between thumb and index Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
finger; use index finger of other hand to pull down the Mechanism of Action Due to stimulation of the para-
lower eyelid to form a pocket for the eye drop, tilt head sympathetic nervous system, bethanechol increases blad-
back and instill in eye(s); do not allow the dispenser tip der muscle tone causing contractions which initiate
to touch the eye. Apply gentle pressure to lacrimal sac urination. Bethanechol also stimulates gastric motility,
during and immediately following instillation (1 minute) or increases gastric tone and may restore peristalsis.
instruct patient to gently close eyelid after administration, Pharmacodynamics/Kinetics (Adult data unless
to decrease systemic absorption of ophthalmic drops noted)
(Urtti, 1993; Zimmerman, 1982). Some solutions contain Onset of action: 30 minutes; Peak effect: ~60 to 90
benzalkonium chloride; wait at least 15 minutes after minutes
instilling solution before inserting soft contact lenses. Duration: ~1 hour (with therapeutic doses); up to 6 hours
Monitoring Parameters Intraocular pressure with large doses (300 to 400 mg)

272
 BEVACIZUMAB

Dosing Use Treatment of metastatic colorectal cancer (Avastin,

Pediatric Urinary retention, nonobstructive: Limited Mvasi: FDA approved in adults); treatment of unresect-
data available: Children and Adolescents: Oral: 0.3 to able, locally advanced recurrent or metastatic nonsqua-
0.6 mg/kg/day in 3 to 4 divided doses; maximum dose: mous, non-small cell lung cancer (Avastin, Mvasi: FDA
10 mg/dose for children. Note: Usual adult dose is 10 to approved in adults); treatment of recurrent glioblastoma
50 mg 3 to 4 times daily (Gearhart 2010; Goldman 2012; (Avastin: FDA approved in adults); treatment of glioblas-
Kliegman 2007) toma (as a single agent) with progressive disease (Mvasi:
Renal Impairment: Pediatric There are no dosage FDA approved in adults); treatment of metastatic renal cell
adjustments provided in the manufacturer’s labeling. cancer (Avastin, Mvasi: FDA approved in adults); treat-
Hepatic Impairment: Pediatric There are no dosage ment of persistent, recurrent, or metastatic cervical cancer
adjustments provided in the manufacturer’s labeling. (Avastin, Mvasi: FDA approved in adults); treatment of
Administration Oral: Administer 1 hour before meals or 2 ovarian (epithelial), fallopian tube, or primary peritoneal
hours after meals to reduce nausea and vomiting cancer (platinum-resistant recurrent) (Avastin: FDA
Monitoring Parameters Monitor for signs of bronchocon- approved in adults). Note: Mvasi (bevacizumab-awwb) is
striction or urinary tract infection approved as a biosimilar agent; approved uses may vary
Dosage Forms Excipient information presented when (consult product labeling).
available (limited, particularly for generics); consult spe- Has also been used in the treatment of pediatric refractory
cific product labeling. solid tumors and primary CNS tumors; has been used
Tablet, Oral, as chloride: intravitreally for retinopathy of prematurity (Stage 3+).
Urecholine: 5 mg, 10 mg [scored] Pregnancy Considerations Based on findings in animal
Urecholine: 25 mg, 50 mg [scored; contains fd&c yellow reproduction studies and on the mechanism of action,
#10 (quinoline yellow), fd&c yellow #6 (sunset yellow)] bevacizumab may cause fetal harm if administered to a
Generic: 5 mg, 10 mg, 25 mg, 50 mg pregnant woman. Information from postmarketing reports
Extemporaneous Preparations following exposure in pregnancy is limited. Women of
5 mg/mL Oral Suspension (ASHP Standard Concen- reproductive potential should use effective contraception
tration) (ASHP 2017) during therapy and for 6 months following the last bev-
A 5 mg/mL suspension may be made with tablets and acizumab dose. Bevacizumab treatment may also
either a 1:1 mixture of Ora-Plus and Ora-Sweet or Ora- increase the risk of ovarian failure and impair fertility; long
Plus and Ora-Sweet SF or 1:4 concentrated cherry syrup term effects on fertility are not known.
and simple syrup, NF mixture. Crush twelve 50 mg Breastfeeding Considerations It is not known if bev-
tablets in a mortar and reduce to a fine powder. Add acizumab is present in breast milk. Immunoglobulins are
small portions of chosen vehicle and mix to a uniform excreted in breast milk, and it is assumed that bevacizu-
paste; mix while adding the vehicle in incremental pro- mab may appear in breast milk. Due to the potential for
portions to almost 120 mL; transfer to a calibrated bottle, serious adverse reactions in the breastfed infant, breast-
rinse mortar with vehicle, and add quantity of vehicle feeding is not recommended during treatment and for 6
sufficient to make 120 mL. Label "shake well" and months following the last dose of bevacizumab products.
"refrigerate." Stable for 60 days refrigerated (preferred) Contraindications
or at room temperature (Allen 1998; Nahata 2004). There are no contraindications listed in the manufacturer's
Allen LV Jr, Erickson MA. Stability of bethanechol chloride, pyrazina- US labeling.
mide, quinidine sulfate, rifampin, and tetracycline hydrochloride in
Canadian Jabeling: Hypersensitivity to bevacizumab, any
extemporaneously compounded oral liquids. Am J Health Syst
Pharm. 1998;55(17):1804-1809. component of the formulation, Chinese hamster ovary
Nahata MC and Pai VB. Pediatric Drug Formulations. 6th ed. Cincin- cell products or other recombinant human or humanized
nati, OH: Harvey Whitney Books Co; 2014. antibodies; untreated CNS metastases
Warnings/Precautions GI perforation, (sometimes
1 mg/mL Oral Suspension
fatal) in patients receiving bevacizumab products
A 1 mg/mL solution may be made with tablets. Crush
ranges from 0.3% to 3%; discontinue bevacizumab
twelve 10 mg tablets in a mortar and reduce to a fine
products in patients with GI perforation. A higher
powder. Add small portions of sterile water and mix to a
incidence of GI perforation is associated with a history of
uniform paste; mix while adding sterile water in incre-
prior pelvic radiation. Most cases of GI perforation
mental proportions to almost 120 mL; transfer to a
occurred within 50 days of the first bevacizumab dose.
calibrated bottle, rinse mortar with sterile water, and
Perforation may be complicated by intra-abdominal
add quantity of sterile water sufficient to make 120 mL.
abscess, fistula formation, and/or diverting ostomy
Label "shake well" and "refrigerate". Stable for 30 days
requirement. Serious fistulae (including tracheoesopha-
(Schlatter 1997).
Schlatter JL, Saulnier JL. Bethanechol chloride oral solutions: stability
geal, bronchopleural, biliary, vaginal, renal, and bladder
and use in infants. Ann Pharmacother. 1997;31(3):294-296. fistulas) have been reported at a higher incidence in
patients receiving bevacizumab products (compared to
@ Bethanechol Chloride see Bethanechol on page 272 patients receiving chemotherapy), with the highest inci-
@ Bethkis see Tobramycin (Oral Inhalation) on page 1965 dence occurring in patients with cervical cancer. Most
fistulae occurred within 6 months of the first bevacizumab
@ Betimol see Timolol (Ophthalmic) on page 1953
dose. Patients who develop gastrointestinal vaginal fistula
@ Betnesol (Can) see Betamethasone (Topical) may also have bowel obstruction which requires surgical
on page 269 intervention and diverting ostomy. Avoid bevacizumab
@ Betoptic-S see Betaxolol (Ophthalmic) on page 271 products in patients with ovarian cancer with evidence of
@ Betoptic S (Can) see Betaxolol (Ophthalmic) recto-sigmoid involvement (by pelvic examination) or
on page 2717 bowel involvement (on CT scan), or clinical symptoms of
bowel obstruction. Discontinue in patients who develop
gastrointestinal perforation, tracheoesophageal fistula,
Bevacizumab (be wuh Siz uh mab) any grade 4 fistula, or fistula formation involving any
internal organ. In a scientific statement from the American
Medication Safety Issues Heart Association, bevacizumab has been determined to
Sound-alike/look-alike issues: be an agent that may either cause reversible direct
Avastin may be confused with Astelin myocardial toxicity or exacerbate underlying myocardial
Bevacizumab may be confused with bevacizumab- dysfunction (magnitude: moderate/major) (AHA [Page
awwb, bezlotoxumab, brentuximab, cetuximab, ranibi- 2016]). Bevacizumab is not indicated for use in combina-
zumab, riTUXimab tion with anthracycline-based chemotherapy. The inci-
High alert medication: ; dence of grade 23 left ventricular dysfunction was higher
This medication is in a class the Institute for Safe in patients receiving bevacizumab with chemotherapy
Medication Practices (ISMP) includes among its list of compared to patients who received chemotherapy alone
drug classes which have a heightened risk of causing (1% vs 0.6%). Among patients who received prior anthra-
significant patient harm when used in error. cycline therapy, the incidence of HF was higher in patients
International issues: receiving bevacizumab with chemotherapy, compared to
Avastin [US, Canada, and multiple international markets] patients who received chemotherapy alone (4% vs 0.6%).
may be confused with Avaxim, a brand name for In previously untreated patients with hematologic malig-
hepatitis A vaccine [Canada and multiple international nancy, the incidence of HF and left ventricular ejection
markets] 7; fraction (LVEF) decline were increased in patients receiv-
Brand Names: US Avastin ing bevacizumab with anthracycline-based chemotherapy
Brand Names: Canada Avastin (compared to patients receiving anthracycline-based che-
Therapeutic Category Antineoplastic Agent, Monoclonal motherapy alone). The proportion of patients with a LVEF
Antibody; Antineoplastic Agent, Vascular Endothelial decline (from baseline) of 220% or a decline from baseline
Growth Factor (VEGF) Inhibitor; Vascular Endothelial of 10% to <50%, was higher in patients receiving bevaci-
Growth Factor (VEGF) Inhibitor zumab with chemotherapy compared to patients receiving
Generic Availability (US) No chemotherapy alone (10% vs 5%). Time to onset of left

273
 BEVACIZUMAB

d ventricular dysfunction or HF was 1 to 6 months after the

first bevacizumab dose in most patients; HF resolved in
was demonstrated in approximately one-fifth of females
who received bevacizumab. The long-term effects of
nearly two-thirds of patients. Discontinue bevacizumab bevacizumab on fertility are unknown. Females of repro-
products in patients who develop HF. ductive potential should be informed of the potential risk of
ovarian failure prior to bevacizumab initiation. Cases of
Severe or fatal hemorrhage, including hemoptysis,
posterior reversible encephalopathy syndrome (PRES)
gastrointestinal bleeding, hematemesis, central nerv-
have been reported. Symptoms (which include headache,
ous system hemorrhage, epistaxis, and vaginal bleed-
seizure, confusion, lethargy, blindness and/or other vision,
ing occur up to 5-fold more frequently in patients
or neurologic disturbances) may occur from 16 hours to 1
receiving bevacizumab products. Do not administer
year after treatment initiation. PRES may also be asso-
bevacizumab products to patients with a recent his-
ciated with mild to severe hypertension. MRI is necessary
tory of hemoptysis (22.5 mL red blood). Discontinue in
for confirmation of PRES diagnosis. Discontinue bevaci-
patients who develop grade 3 to 4 hemorrhage. Seri-
zumab products in patients who develop PRES. Resolu-
ous or fatal pulmonary hemorrhage has been reported in
tion of symptoms usually occurs within days after
nearly one-third of patients receiving bevacizumab plus
discontinuation; however, neurologic sequelae may
chemotherapy for non-small cell lung cancer (NSCLC)
remain. The safety of treatment reinitiation after PRES is
with squamous cell histology (not an FDA-approved indi-
not known.
cation), as well as a small portion of NSCLC with non-
squamous histology; while no cases occurred in patients Bevacizumab products are associated with an increased
receiving chemotherapy alone. Minor hemorrhages, incidence and severity of proteinuria. Grade 3 (urine dip-
including grade 1 epistaxis may commonly occur. Bevaci- stick 4+.0r >3:8_g protein/24 hours) and grade 4 (nephrotic
zumab may cause and/or worsen hypertension. The inci- syndrome) proteinuria have occurred in clinical studies.
dence of severe hypertension is increased with The overall incidence of all grades of proteinuria in one
bevacizumab products. Manage hypertension with anti- study was 20%. The median onset of proteinuria was 5.6
hypertensive therapy. Monitor BP every 2 to 3 weeks months (range: 0.5 to 37 months) after bevacizumab
during bevacizumab treatment and regularly after discon- initiation and the median time to resolution was ~6
tinuation if bevacizumab-induced hypertension occurs or months. Proteinuria remained unresolved in 40% of
worsens. Withhold bevacizumab treatment in patients with patients after median follow-up of 11.2 months and
severe hypertension that is uncontrolled with medical required bevacizumab discontinuation in nearly one-third
management (resume bevacizumab after blood pressure of patients. A pooled analysis from 7 studies found that
is controlled). Discontinue bevacizumab products in 5% of patients receiving bevacizumab products in combi-
patients who experience a hypertensive crisis or hyper- nation with chemotherapy experienced grades 2 to 4
tensive encephalopathy. Infusion reactions (eg, hyperten- proteinuria (urine dipstick 2+ or >1 g protein/24 hours or
sion, hypertensive crisis [associated with neurologic signs/ nephrotic syndrome), which resolved in nearly three-
symptoms], wheezing, oxygen desaturation, hypersensi- fourths of patients; bevacizumab was reinitiated in 42%
tivity [grade 3], chest pain, rigors, headache, diaphoresis) of patients, although nearly half of patients who reinitiated
may occur with the first infusion (uncommon); severe experienced recurrent grades 2 to 4 proteinuria. Nephrotic
reactions were rare. Decrease the infusion rate for mild/ syndrome has occurred (rarely) in patients receiving bev-
Clinically insignificant infusion reactions. Interrupt infusion acizumab, sometimes with fatal outcome. In some cases,
for clinically significant infusion reactions and consider kidney biopsy of patients with proteinuria demonstrated
resuming at a slower rate following resolution. Discontinue findings consistent with thrombotic microangiopathy. A
bevacizumab for severe infusion reaction and administer large retrospective analysis comparing bevacizumab with
appropriate medical therapy (eg, epinephrine, corticoste- chemotherapy to chemotherapy alone found higher rates
roids, IV antihistamines, bronchodilators, and/or oxygen). of serum creatinine elevations (1.5 to 1.9 times baseline)
Bevacizumab, in combination with chemotherapy (or bio- in patients who received bevacizumab; serum creatinine
logic therapy), is associated with an increased risk of did not return to baseline in approximately one-third of
treatment-related mortality; a higher risk of fatal adverse patients who received bevacizumab. Monitor proteinuria
events was identified in a meta-analysis of 16 trials in (by serial dipstick urine analysis) for proteinuria develop-
which bevacizumab was used for the treatment of various ment or worsening of proteinuria throughout bevacizumab
cancers (breast cancer, colorectal cancer, NSCLC, pan- therapy. Further assess with a 24-hour urine collection for
creatic cancer, prostate cancer, and renal cell cancer) and 22+ urine dipstick readings. Withhold bevacizumab for
compared to chemotherapy alone (Ranpura 2011). Cases proteinuria 22 g/24 hours; resume when <2 g/24 hours.
of necrotizing fasciitis, including fatalities, have been Discontinue bevacizumab products in patients who
reported in patients receiving bevacizumab, usually sec- develop nephrotic syndrome. Urine protein/creatinine ratio
ondary to wound healing complications, GI perforation or (UPCR) does not appear to correlate with 24-hour urine
fistula formation. Discontinue in patients who develop protein. Bevacizumab products are associated with an
necrotizing fasciitis. Serious eye infections and vision loss increased incidence of arterial thromboembolic events
due to endophthalmitis have been reported from intra- (ATE), including cerebral infarction, stroke, Ml, TIA,
vitreal administration (off-label use/route). According to a angina, and other ATEs, when used in combination with
position paper by the American Association of Maxillofa- chemotherapy. The highest incidence of ATE occurred in
cial Surgeons (AAOMS), medication-related osteonecro- patients with glioblastoma. History of ATE, diabetes, or
sis of the jaw (MRONJ) has been associated with 265 years of age may present an even greater risk:
bisphosphonates and other antiresorptive agents (deno- Although patients with cancer are already at risk for
sumab), and antiangiogenic agents (eg, bevacizumab, VTE, a meta-analysis of 15 controlled trials has demon-
sunitinib) used for the treatment of osteoporosis or malig- strated an increased risk for VTE in patients who received
nancy. Antiangiogenic agents, when given concomitantly bevacizumab (Nalluri 2008). Patients receiving bevacizu-
with antiresorptive agents, are associated with an mab plus chemotherapy had a higher incidence of grade 3
increased risk of ONJ. Other risk factors for MRONJ or higher VTE compared to those patients who received
include dentoalveolar surgery (eg, tooth extraction, dental chemotherapy alone. Discontinue bevacizumab in
implants), preexisting inflammatory dental disease, and patients with severe ATE or grade 4 VTE, including
concomitant corticosteroid use. The AAOMS suggests pulmonary embolism (the safety of re-initiating bevacizu-
that if medically permissible, initiation of antiangiogenic mab following ATE is unknown).
agents for cancer therapy should be delayed until optimal
[US Boxed Warning]: The incidence of wound healing
dental health is attained (if extractions are required, anti-
and surgical complications, including serious and
angiogenesis therapy should delayed until the extraction
fatal complications, is increased in patients receiving
site has mucosalized or until after adequate osseous
bevacizumab products; discontinue in patients who
healing). Once antiangiogenic therapy for oncologic dis-
develop wound healing complications that require
ease is initiated, procedures that involve direct osseous
medical intervention. Withhold bevacizumab products
injury and placement of dental implants should be
at least 28 days prior to elective surgery. Do not
avoided. Patients developing ONJ during therapy should
administer bevacizumab products for at least 28 days
receive care by an oral surgeon (AAOMS [Ruggiero
after surgery and until the surgical wound is fully
2014]). Cases of non-mandibular ONJ has also been
healed. In a controlled study in which bevacizumab was
reported in pediatric patients who have received bevaci-
not administered within 28 days of major surgical proce-
zumab (bevacizumab is not approved for use in pediatric
dures, the incidence of wound healing complications
patients).
(including serious/fatal complications) was higher in
In premenopausal women with solid tumors receiving patients with mCRC who underwent surgery while receiv-
adjuvant therapy, the incidence of ovarian failure was ing bevacizumab compared to patients who did not
34% for bevacizumab with chemotherapy versus 2% for receive bevacizumab. In a controlled clinical study in
chemotherapy alone. Recovery of ovarian function patients with relapsed or recurrent glioblastoma, the inci-
(resumption of menses, positive serum B-HCG pregnancy dence of wound healing events was higher in patients who
test, or FSH level <30 mlU/mL) at all time points in the received bevacizumab compared to patients who did not
post-treatment period after bevacizumab discontinuation receive bevacizumab. In a retrospective review of central

274
 BEVACIZUMAB

venous access device placements (a minor procedure), a mesenteric thrombosis, myocardial infarction, nasal sep-
greater risk of wound dehiscence was observed when port tum perforation, nephrotic syndrome, ocular hyperemia,
placement and bevacizumab administration were sepa- osteonecrosis of the jaw, pancytopenia, permanent
rated by <14 days (Erinjeri 2011). If possible, it may be vision loss, polyserositis, pulmonary hypertension, rectal
more appropriate to wait until at least 6 to 8 weeks after fistula, renal failure, renal fistula, renal thrombotic micro-
bevacizumab discontinuation for major surgical proce- angiopathy, retinal detachment, retinal hemorrhage,
dures (Cortes 2012; Gordon 2009). An increase in dia- reversible posterior leukoencephalopathy syndrome,
stolic and systolic blood pressures were noted in a sepsis, tracheoesophageal fistula, transient ischemic
retrospective review of patients with renal insufficiency attacks, vaginal fistula, visual disturbance, vitreous hem-
(CrCl $60 mL/minute) who received bevacizumab for renal orrhage, vitreous opacity
cell cancer (Gupta 2011). Potentially significant drug-drug Drug Interactions
interactions may exist, requiring dose or frequency adjust- Metabolism/Transport Effects None known.
ment, additional monitoring, and/or selection of alternative Avoid Concomitant Use
therapy. Consult drug interactions database for more Avoid concomitant use of Bevacizumab with any of the
detailed information. Patients 265 years of age have an following: Anthracyclines; BCG (Intravesical); Belimu-
increased incidence of arterial. thrombotic events. mab; Deferiprone; Dipyrone; SUNItinib
Warnings: .Additional Pediatric Considerations Increased Effect/Toxicity
Some experts recommend caution regarding use in pre- Bevacizumab may increase the levels/effects of: Anthra-
mature neonates for retinopathy of prematurity (ROP) cyclines; Belimumab; Bisphosphonate Derivatives; Clo-
outside of controlled, clinical trials (Quinn 2011); systemic ZAPine; Deferiprone; SORAfenib; SUNItinib
absorption after intravitreal administration with decreases
in VEGF serum concentration (as low as 9% of baseline The levels/effects of Bevacizumab may be increased by:
systemic concentration) have been reported in a case Chloramphenicol (Ophthalmic); Dipyrone; Promazine;
series of 11 neonates (Sato 2012); short- and long-term SUNItinib
implications of systemic exposure are unknown; monitor- Decreased Effect
ing is recommended. Osteonecrosis of the jaw has been Bevacizumab may decrease the levels/effects of: BCG
associated with bevacizumab use alone or in combination (Intravesical)
with other chemotherapies, steroids, and bisphospho- Storage/Stability Store intact vials at 2°C to 8°C (36°F to
nates. A report of three pediatric patients (ages: 10 years, 46°F) in original carton; do not freeze. Protect from light;
13 years, and 17 years) has also described cases of do not shake. Solutions diluted in NS are stable for up to 8
osteonecrosis of the wrist and knee (Fangusaro 2013). hours under refrigeration. Discard unused portion of vial.
Adverse Reactions Reported monotherapy and as part Mechanism of Action Bevacizumab is a recombinant,
of combination chemotherapy regimens. humanized monoclonal antibody which binds to, and
Cardiovascular: Arterial thrombosis, chest pain, deep vein neutralizes, vascular endothelial growth factor (VEGF),
thrombosis, hypertension, hypotension, intra-abdominal preventing its association with endothelial receptors, FIt-
thrombosis (venous), left ventricular dysfunction, periph- 1 and KDR. VEGF binding initiates angiogenesis (endo-
eral edema, pulmonary embolism, syncope; thrombosis, thelial proliferation and the formation of new blood ves-
venous thromboembolism, venous thromboembolism sels). The inhibition of microvascular growth is believed to
(with oral anticoagulants) retard the growth of all tissues (including metastatic
Central nervous system: Anxiety, dizziness, fatigue, head- tissue).
ache, insomnia, myasthenia, pain, peripheral sensory Pharmacodynamics/Kinetics (Adult data unless
neuropathy, taste disorder, voice disorder noted)
Dermatologic: Acne vulgaris, alopecia, cellulitis, dermal Distribution: CV% central volume: 2.9 (22%) L
ulcer, exfoliative dermatitis, nail disease, palmar-plantar Half-life elimination:
erythrodysesthesia, xeroderma IV:
Endocrine & metabolic: Dehydration, hyperglycemia, Pediatric patients (age: 1 to 21 years): Median: 11.8
hyperkalemia, hypokalemia, hypoalbuminemia, hypocal- days (range: 4.4 to 14.6 days) (Glade Bender 2008)
cemia, hypomagnesemia, hyponatremia, ovarian failure, Adults: ~20 days (range: 11 to 50 days)
weight loss Intravitreal: ~5 to 10 days (Bakri 2007; Krohne 2008)
Gastrointestinal: Abdominal pain, anorexia, colitis, consti- Pharmacodynamics/Kinetics: Additional Consider-
pation, decreased appetite, diarrhea, dyspepsia, gastri- ations
tis, gastroesophageal reflux disease, gastrointestinal Gender: Men had a higher clearance and larger volume of
fistula, gastrointestinal hemorrhage, gastrointestinal per- distribution in the central compartment when compared
foration, gingival hemorrhage (minor), gingival pain, with women. There is no evidence that this difference
gingivitis, hemorrhoids, intestinal obstruction, mucosal decreases the efficacy of bevacizumab in men.
inflammation, nausea, oral mucosa ulcer, rectal pain, Tumor burden: Patients with a higher tumor burden had a
stomatitis, vomiting, xerostomia higher clearance of bevacizumab compared with
Genitourinary: Pelvic pain, proteinuria, urinary tract infec- patients who had a tumor burden below the median.
tion, vaginal hemorrhage There is no evidence suggesting that this difference
Hematologic & oncologic: Bruise, febrile neutropenia, leads to decreased efficacy.
hemorrhage, hemorrhage (CNS), leukopenia, lymphocy- Dosing
topenia, neutropenia, neutropenic infection, pulmonary Neonatal Note: Trials in neonatal patients were con-
hemorrhage, thrombocytopenia ducted using the product Avastin 25 mg/mL vial for
Hepatic: Increased serum AST injection of bevacizumab. Mvasi (bevacizumab-awwb)
Infection: Abscess (tooth), infection (pneumonia, catheter is a biosimilar of Avastin; however, reported experience
infection, or wound infection) with the biosimilar product in neonatal patients is lacking.
Neuromuscular & skeletal: Arthralgia, back pain, dysarth- Retinopathy of prematurity (ROP): Limited data avail-
ria, limb pain, myalgia, neck pain, weakness able; dosing regimens variable; dose not established:
Ophthalmic: Blurred vision PMA 231 weeks and PNA 228 days: Intravitreal injec-
Otic: Deafness, tinnitus tion: Usual dosing: 0.625 mg (0.025 mL) as a single
Renal: Increased serum creatinine dose in the affected eye; dosing was used in 70
Respiratory: Allergic rhinitis, cough, dyspnea, epistaxis, premature neonates (140 eyes) with Stage 3+ ROP in
pneumonitis, nasal congestion, nasal sign & symptoms a prospective, randomized comparative trial with laser
(mucosal disorder), oropharyngeal pain, rhinitis, rhinor- therapy; the primary outcome studied was recurrence
rhea, sinusitis, upper respiratory tract infection of ROP, which was lower in the treatment group (6%)
Miscellaneous: Fistula, fistula (anal), fistula (gastrointesti- compared to conventional laser therapy (26%) (Mintz-
nal-vaginal), infusion related reaction, postoperative Hittner 2011). This same dose was used in a larger
wound complication (including dehiscence) retrospective trial of 85 preterm neonates (162 eyes)
Rare but important or life-threatening: Anaphylaxis, anas- with Stage 3 ROP as either primary therapy or salvage
tomotic ulcer, angina pectoris, antibody development therapy after laser treatment; ROP regression occurred
(anti-bevacizumab and neutralizing), bladder fistula, in 83% of treated eyes (Wu 2013). Other doses
bronchopleural fistula, cerebral infarction, conjunctival reported range from 0.37 to 1.25 mg in the affected
hemorrhage, endophthalmitis (infectious and sterile), eye (Harder 2013; Micieli 2009; Spandau 2013). Some
eye discomfort, eye pain, fistula of bile duct, fulminant experts recommend caution regarding use outside of a
necrotizing fasciitis, gallbladder perforation, gastrointes- clinical trial (Quinn 2011); systemic absorption with
tinal ulcer, hemolytic anemia (microangiopathic; when decreases in VEGF serum concentration have been
used in combination with sunitinib), hemoptysis, hemor- reported in a case series of 11 neonates after intra-
rhagic stroke, hypersensitivity, hypertensive crisis, vitreal administration of doses consistent with those in
hypertensive encephalopathy, increased intraocular reported in the literature (Sato 2012).
pressure, inflammation of anterior segment of eye (toxic Pediatric Note: Refer to individual protocols; details
anterior segment syndrome) (Sato 2010), intestinal concerning dosing in combination regimens should also
necrosis, intraocular inflammation (iritis, vitritis), be consulted. Trials in pediatric patients were conducted
BEVACIZUMAB

using the product Avastin 25 mg/mL vial for injection of solution prior to bevacizumab administration and steri-
bevacizumab. Mvasi (bevacizumab-awwb) is a biosimilar lized before and after administration with a drop of
of Avastin; however, reported experience with the bio- povidone-iodine 5%, ophthalmic solution. Following the
similar product in pediatric oncology patients is lacking. procedure, a topicalyophthalmic antibiotic drop was also
Refractory solid tumor: Limited data available: Chil- administered every 6 hours for 7 days (Mintz-Hitt-
dren and Adolescents: IV: 5 to 15 mg/kg/dose every 2 ner 2011).
weeks in a 28-day course (Glade Bender 2008) or 5 Monitoring Parameters
to 10 mg/kg every 2 to 3 weeks (Benesch 2008) IV administration: Monitor for signs of an infusion reaction
Primary CNS tumor; recurrent/refractory (high/low during infusion; blood pressure (continue to monitor
grade gliomas, medulloblastoma): Limited data blood pressure during and after bevacizumab has been
available; efficacy results variable: Children and Ado- discontinued). Monitor CBC with differential; signs/symp-
lescents: IV: 10 mg/kg/dose every 2 weeks (Aguilera toms of GI perforation, fistula or abscess (including
2011; Aguilera 2013; Packer 2009; Parekh 2011; abdominal pain, constipation, vomiting, fever); signs/
Reismuller 2010) or days 1 and 15 of each 28-day symptoms of bleeding including hemoptysis, Gl bleed-
cycle (Kang 2008); mostly used in combination with ing, CNS bleeding, and/or epistaxis. Signs of wound
irinotecan with/without temozolomide or 15 mg/kg/ dehiscence or healing complications. Monitor blood
dose every 3 weeks has also been used (Parekh pressure every 2 to 3 weeks; more frequently if hyper-
2011; Reismiuller 2010). In general, when treating tension develops during therapy. Continue to monitor
high-grade glioma, patients with contrast-enhancing blood pressure after discontinuing due to bevacizumab-
disease showed greater response or remained stable, induced hypertension. Monitor for proteinuria/nephrotic
while patients with noncontrast-enhancing disease syndrome with urine dipstick; collect 24-hour urine in
had disease progression (Parekh 2011); others have patients with 22+ reading. Monitor for signs/symptoms
observed only minimal efficacy in patients with high of thromboembolism (arterial and venous).
grade glioma (Narayana 2010) Intravitreal administration: Monitor blood pressure, heart
Dosing adjustment for toxicity: The presented dosing rate, respiratory rate, and oxygen saturation prior to,
adjustments are based on experience in adult oncology during, and after the procedure; monitor for signs and
patients; specific recommendations for pediatric symptoms of infection or ocular inflammation; consider
patients are limited. Refer to specific protocol for man- short--and long-term monitoring for sequelae of systemic
agement in pediatric patients if available. absorption when used in neonates (Sato 2012)
Adult: IV administration (systemic): There are no rec- Product Availability Mvasi (bevacizumab-awwb): FDA
ommended dosage reductions. Temporary suspen- approved September 2017; anticipated availability is cur-
sion is recommended for severe infusion reactions, rently unknown. Mvasi has been approved as a biosimilar,
at least 4 weeks prior'to (and after) elective surgery, in not as an interchangeable product. Consult the prescrib-
moderate to severe proteinuria (in most studies, treat- ing information for additional information.
ment was withheld for 22 g proteinuria/24 hours), or in Dosage Forms Considerations Bevacizumab-awwb
patients with severe hypertension which is not con- (Mvasi) is approved as a biosimilar to bevacizumab (Avas-
trolled with medical management. Permanent discon- tin).
tinuation is recommended (by the manufacturer) in
Dosage Forms Excipient information presented when
patients who develop wound dehiscence and wound
available (limited, particularly for generics); consult spe-
healing complications requiring intervention, necrotiz-
cific product labeling.
ing fasciitis, fistula (gastrointestinal and nongastroin-
Solution, Intravenous [preservative free]:
testinal), gastrointestinal perforation, intra-abdominal
Avastin: 100 mg/4 mL (4 mL); 400 mg/16 mL (16 mL)
abscess, hypertensive crisis, hypertensive encephal-
opathy, serious bleeding/hemorrhage, severe arterial ¢ Bevacizumab-awwb see Bevacizumab on page 273
thromboembolic event, life-threatening (grade 4) e Bevacizumab, inj see Bevacizumab on page 273
venous thromboembolic events (including pulmonary
embolism), nephrotic syndrome, or PRES. e Bexsero see Meningococcal Group B Vaccine
Renal Impairment: Pediatric There are no dosage on page 1298
adjustments provided in the manufacturer's labeling. Biacna (Can) see Clindamycin and Tretinoin
Hepatic Impairment: Pediatric There are no dosage on page 476
adjustments provided in the manufacturer's labeling. Biaxin [DSC] see Clarithromycin on page 466
Preparation for Administration !V infusion: Dilute in
Biaxin (Can) see Clarithromycin on page 466
100 mL NS prior to infusion (the manufacturer recom-
mends a total volume of 100 mL). Do not mix with Biaxin XL [DSC] see Clarithromycin on page 466
dextrose-containing solutions (concentration-dependent Biaxin XL (Can) see Clarithromycin on page 466
degradation may occur). Biaxin XL Pac [DSC] see Clarithromycin on page 466
Administration
Biaxin BID (Can) see Clarithromycin on page 466
Parenteral: IV infusion: Infuse the initial dose over 90
minutes; second infusion may be shortened to 60 Bicarb see Sodium Bicarbonate on page 1832
minutes if the initial infusion is well-tolerated. Third and Bicarbonate see Sodium Bicarbonate on page 1832
subsequent infusions may be shortened to 30 minutes if Bicillin L-A see Penicillin G Benzathine on page 1582
the 60-minute infusion is well-tolerated. Monitor closely
during the infusion for signs/symptoms of an infusion Bicitra see Sodium Citrate and Citric Acid on page 1837
reaction. After tolerance at the 90-, 60-, and 30-minute BiCNU see Carmustine on page 371
infusion rates has been established, some institutions Bidex [OTC] see GuaiFENesin on page 964
use an off-label 10-minute infusion rate (0.5 mg/kg/
$eBIG-IV see Botulism
6%
¢Sa
% Immune Globulin (Intravenous-
minute) in adults for bevacizumab dosed at 5 mg/kg
Human) on page 289
(Reidy 2007). In a study evaluating the safety of the
0.5 mg/kg/minute infusion rate, proteinuria and hyper- Biltricide see Praziquantel on page 1665
tension incidences were not increased with the shorter Binosto see Alendronate on page 81
infusion time (Shah 2013). Do not administer IV push. Do ¢
¢¢Bio-D-Mulsion [OTC] [DSC] see Cholecalciferol
not administer with dextrose solutions. Temporarily with- on page 434
hold bevacizumab for 4 weeks prior to elective surgery
and for at least 4 weeks (and until the surgical incision is Bio-D-Mulsion Forte [OTC] [DSC] see Cholecalciferol
fully healed) after surgery. Do not administer via IV push. on page 434
Intravitreal injection: Inject undiluted bevacizumab solu- Bio-Amitriptyline (Can) see Amitriptyline on page 117
tion. The major clinical trial for ROP used an insulin Bio-Amlodipine (Can) see AmLOD!IPine on page 120
syringe (0.3 mL syringe with a 31-gauge, 5/16-inch nee-
Biobase (Can) see Alcohol (Ethyl) on page 76
dle) to accurately deliver the dose; each 1 unit on an
insulin syringe is equivalent to 0.01 mL; typical bevaci- Biobase-G (Can) see Alcohol (Ethyl) on page 76
zumab dose of 0.625 mg would equate to 2.5 units on an Bio-Diazepam (Can) see DiazePAM on page 622
insulin syringe using a 25 mg/mL solution. Note: Trials in Bio-Flurazepam (Can) see Flurazepam on page 897
neonatal patients were conducted using the product
Avastin 25 mg/mL vial for injection of bevacizumab. Bio-Furosemide (Can) see Furosemide on page 929
Mvasi (bevacizumab-awwb) is a biosimilar of Avastin; Bio Glo see Fluorescein on page 885
however, reported experience with the biosimilar in neo- Bio-K+ (Can) see Lactobacillus on page 1166
natal patients is lacking. Some dosage forms (eg, pre-
Bio-Modafinil (Can) see Modafinil on page 1391
filled syringes) may not allow accurate measurement of
neonatal doses; therefore, use should be avoided. e¢¢e¢
$$$
e @ Bio-Moxifloxacin (Can) see Moxifloxacin (Systemic)
In an ROP trial, the injection site was anesthetized with a on page 1408
drop of tetracaine hydrochloride 0.5% ophthalmic solu- Sd Bioniche Promethazine (Can) see Promethazine
tion or proparacaine hydrochloride 0.5% ophthalmic on page 1689

276
 BISACODYL

¢@ Bion Tears [OTC] [DSC] see Artificial Tears Brand Names: Canada Apo-Bisacody! [OTC]; BisacodyI-
on page 185 Odan [OTC]; Carter's Little Pills [OTC]; Codulax [OTC];
@ Bio-Ondansetron (Can) see Ondansetron Dulcolax For Women [OTC]; Dulcolax [OTC]; PMS-Bisa-
on page 1502 codyl [OTC]; ratio-Bisacody! [OTC]; Silver Bullet Supposi-
tory [OTC]; Soflax EX [OTC]; The Magic Bullet [OTC];
@ BioQuin Durules (Can) see QuiNIDine on page 1730
Woman's Laxative [OTC]
@ BioRx Sponix Anti-Fungal [OTC] see Undecylenic Acid Therapeutic Category Laxative, Stimulant
and Derivatives on page 2018 Generic Availability (US) May be product dependent
@ Bio-Statin see Nystatin (Oral) on page 1477 Use Treatment of constipation (OTC products; FDA
approved in ages 26 years and adults); bowel cleansing
prior to procedures or examination (FDA approved in
Biotin (BYE oh tin)
children 212 years and adults; consult specific product
Brand Names: US Biotin Forte [OTC]; Meribin [OTC] formulations for appropriate age groups)
Therapeutic Category Biotinidase Deficiency, Treatment Pregnancy Considerations Systemic exposure follow-
Agent; Nutritional Supplement; Vitamin, Water Soluble ing maternal use of bisacody| is limited. Plasma concen-
Generic Availability (US) Yes trations of BHPM (the active metabolite of bisacodyl) are
Use Dietary supplement of biotin (Dietary supplement, low (median: 61 ng/mL; range: 20 to 118 ng/mL) and the
consult product specific labeling for manufacturer recom- pharmacokinetics are highly variable following oral doses
mended ages); has also been used to treat biotinidase of 10 mg/day for 7 days to women immediately postpar-
deficiency tum (Friedrich 2011).
Mechanism of Action Functions as a coenzyme; Treatment of constipation in pregnant women is similar to
involved in carboxylation, transcarboxylation, and decar- that of nonpregnant patients and medications may be
* boxylation reactions of gluconeogenesis, lipogenesis, fatty used when diet and lifestyle modifications are not effec-
acid synthesis, propionate metabolism, and the catabo- tive. Agents other than bisacody! are preferred as initial
lism of leucine treatment. Stimulant laxatives, including bisacodyl, are not
Dosing recommended for chronic use, but may be used intermit-
Neonatal tently when needed (ACG [Christie 2007)).
‘Adequate intake (Al): 5 mcg/day (~0.7 mcg/kg/day) Breastfeeding Considerations It is not known if bisa-
(1OM 1998) | codyl is present in breast milk. Systemic exposure follow-
Biotinidase deficiency: Limited data available: Oral: 5 ing maternal use is limited. Neither bisacodyl nor its active
to 20 mg once daily (Wolf 2003; Wolf 2010) metabolite (BHPM) were detectable in breast milk follow-
Pediatric ing administration of bisacody! 10 mg once daily for 7 days
Adequate intake (Al): Note: There is no official RDA to eight breastfeeding women (lower limit of detection: 1
(IOM 1998). ng/mL) (Friedrich 2011).
Infants: Warnings/Precautions Consult a health care provider
1 to 6 months: 5 mcg/day (~0.7 mcg/kg/day) prior to use if stomach pain, nausea, vomiting, or a sudden
7 to 12 months: 6 mcg/day (~0.7 mcg/kg/day) change in bowel movements lasting >2 weeks occurs, or if
Children and Adolescents: you have already used a laxative for >1 week. Use may
1 to 3 years: 8 mcg/day cause stomach discomfort, faintness, rectal burning and
4 to 8 years: 12 mcg/day mild cramps. Discontinue use and consult a health care
9 to 13 years: 20 mcg/day provider if use >1 week is needed. Do not chew or crush
14 to 18 years: 25 mcg/day tablets; do not use if you cannot swallow without chewing;
Biotinidase deficiency, symptomatic: Limited data do not administer within 1 hour after taking an antacid,
available: Infants, Children, and Adolescents: Oral: 5 milk, or any dairy products. Enema and suppositories are
to 20 mg once daily (McVoy 1990; Mic6é 2011; Salbert for rectal use only, discontinue use and consult a health
1993; Wolf 2003; Wolf 2010) care provider if rectal bleeding occurs or if no bowel
Renal Impairment: Pediatric There are no dosage movement is produced after use.
adjustments provided in the manufacturer's labeling.
Some dosage forms may contain sodium benzoate/ben-
Hepatic Impairment: Pediatric There are no dosage
zoic acid; benzoic acid (benzoate) is a metabolite of
adjustments provided in the manufacturer’s labeling.
benzyl alcohol; large amounts of benzyl alcohol
Administration Oral: May be administered without regard (299 mg/kg/day) have been associated with a potentially
to meals; may be preferable to take with meals fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Reference Range Serum biotinidase activity ing syndrome" consists of metabolic acidosis, respiratory
Test Interactions Biotin can significantly interfere with distress, gasping respirations, CNS dysfunction (including
certain lab tests and cause incorrect test results that convulsions, intracranial hemorrhage), hypotension, and
may go undetected, possibly leading to inappropriate cardiovascular collapse (AAP ["Inactive" 1997]; CDC
patient management or misdiagnosis (FDA Medwatch 1982); some data suggest that benzoate displaces bilir-
Alert 2017). ubin from protein binding sites (Ahlfors, 2001); avoid or
Dosage Forms Excipient information presented when use dosage forms containing benzyl alcohol derivative
available (limited, particularly for generics); consult spe- with caution in neonates. See manufacturer’s labeling.
cific product labeling. Adverse Reactions Rare but important or life-threaten-
Capsule, Oral: ing: Abdominal cramps (mild), electrolyte disturbance
Meribin: 5 mg (metabolic acidosis or alkalosis, hypocalcemia), nausea,
Capsule, Oral [preservative free]: rectal irritation (burning), vertigo, vomiting
Generic: 5000 mcg Drug Interactions
Tablet, Oral: Metabolism/Transport Effects None known.
Biotin Forte: 3 mg, 5 mg Avoid Concomitant Use There are no known interac-
Generic: 1000 mcg, 5 mg, 10 mg tions where it is recommended to avoid concomitant use.
Tablet, Oral [preservative free]:
Increased Effect/Toxicity
Generic: 300 mcg, 1000 mcg
Bisacodyl may increase the levels/effects of: Polyethy-
Biotin Forte [OTC] see Biotin on page 277 lene Glycol-Electrolyte Solution
@ Biphentin (Can) see Methylphenidate on page 1343
Decreased Effect
The levels/effects of Bisacodyl may be decreased by:
@ Bisac-Evac [OTC] see Bisacodyl on page 277 Antacids
Storage/Stability
Bisacody] (bis a KOE ail) Oral: Store at 20°C to 25°C (68°F to 77°F); protect from
humidity.
Medication Safety Issues Rectal: Store at <30°C (86°F).
Sound-alike/look-alike issues: Mechanism of. Action Stimulates peristalsis by directly
Doxidan may be confused with doxepin irritating the smooth muscle of the intestine, possibly the
_Dulcolax (bisacodyl) may be confused with Dulcolax colonic intramural plexus; alters water and electrolyte
(docusate) secretion producing net intestinal fluid accumulation and
Related Information laxation
Oral Medications That Should Not Be Crushed or Altered Pharmacodynamics/Kinetics (Adult data unless
on page 2217 noted)
Brand Names: US Bisac-Evac [OTC]; Bisacodyl EC Onset of action: Oral: 6 to 12 hours; Rectal: 0.25 to 1 hour
[OTC]; Biscolax [OTC]; Correct [OTC]; Ducodyl [OTC]; (suppository), 5 to 20 minutes (enema)
Dulcolax [OTC]; Ex-Lax Ultra [OTC]; Fleet Bisacodyl Half-life: BHPM: ~8 hours (Friedrich 2011)
[OTC]; Fleet Laxative [OTC] [DSC]; The Magic Bullet Distribution: Vg: BHPM: 289 L (after multiple doses) (Frie-
[OTC]; Womens Laxative [OTC] drich 2011)
BISACODYL

Metabolism: Bisacodyl is metabolized to an active metab- Biscolax [OTC] see Bisacodyl on page 277
olite (BHPM) in the colon; BHPM is then converted in the @ Bismatrol see Bismuth Subsalicylate on page 278
liver to a glucuronide salt (Friedrich 2011)
@ Bismatrol [OTC] see'Bismuth Subsalicylate
Absorption: Oral, rectal: Systemic, <5% (Wald 2003)
on page 278 t
Excretion: BHPM: Urine, bile (Friedrich 2011)
Dosing ¢@ Bismatro! Maximum Strength [OTC] see Bismuth Sub-
Pediatric salicylate on page 278
Constipation:
Oral: Bismuth Subsalicylate (812 muth sub sa LIs i late)
Manufacturer's labeling:
Children 6 to <12 years: 5 mg once daily Medication Safety Issues
Children 212 years and Adolescents: 5 to 15 mg Sound-alike/look-alike issues:
once daily Kaopectate may be confused with Kayexalate
Alternate dosing: Limited data available (Tabbers Other safety concerns:
[NASPGHAN/ESPGHAN], 2014): Maalox Total Relief is a different formulation than other
Children 23 years to 10 years: 5 mg once daily Maalox liquid antacid products which contain aluminum
Children >10 years and Adolescents: 5 to 10 mg hydroxide, magnesium hydroxide, and simethicone.
once daily Canadian formulation of Kaopectate does not contain
Rectal: bismuth; the active ingredient in the Canadian formu-
Manufacturer's labeling: lation is ‘attapulgite.
Suppository: Brand Names: US Bismatrol Maximum Strength [OTC];
Children 6 to-<12 years: 5 mg (1/2 suppository) Bismatrol [OTC]; Diotame [OTC] [DSC]; Geri-Pectate
once daily [OTC]; GoodSense Stomach Relief [OTC]; Kao-Tin
Children 212 years and Adolescents: 10 mg once [OTC]; Peptic Relief [OTC]; Pepto-Bismol InstaCool
daily [OTC]; Pepto-Bismol To-Go [OTC]; Pepto-Bismol [OTC];
Enema: Children 212 years and Adolescents: 10 mg Pink Bismuth [OTC]; Stomach Relief Max St [OTC];
once daily Stomach Relief Plus [OTC]; Stomach Relief [OTC]
Alternate dosing: Limited data available (Tabbers Therapeutic Category Gastrointestinal Agent, Miscella-
[NASPGHAN/ESPGHAN] 2014): Suppository/ neous
enema: Generic Availability (US) Yes
Children 22 to 10 years: 5 mg (1/2 suppository) once
Use
daily
Relief of diarrhea and dyspepsia (gas, upset stomach,
Children >10 years and Adolescents: 5 to 10 mg
indigestion, heartburn, nausea) (OTC products: FDA
once daily
approved in ages 212 years and adults); has also been
Renal Impairment: Pediatric There are no dosage
used for treatment of Helicobacter pylori-associated
adjustments provided in manufacturer's labeling.
antral gastritis.
Hepatic Impairment: Pediatric There are no dosage Note: Approved ages and uses for generic products may
adjustments provided in manufacturer's labeling. vary; consult product labeling for specific information.
Administration Pregnancy Considerations Following oral administra-
Oral: Administer on an empty stomach with water; patient tion, bismuth and salicylates cross the placenta. The use
should swallow tablet whole; do not break or chew
of salicylates in pregnancy may adversely affect the new-
enteric-coated tablet; do not administer within 1 hour of
born (Lione, 1988). Use during pregnancy is not recom-
ingesting antacids, alkaline material, milk, or dairy prod-
mended (Mahadevan 2007).
ucts
Breastfeeding Considerations Low amounts of salicy-
Rectal:
lates enter breast milk; refer to the aspirin monograph for
Suppository: Remove foil, insert into rectum with pointed
additional information (Bar-Oz, 2004). A case report
end first. Retain in rectum for 15 to 20 minutes.
describes bowel obstruction in a breast-fed infant whose
Enema: Shake well; remove protective shield, insert tip
mother applied a bismuth-containing ointment to her
into rectum with slight side to side movement; squeeze
nipples prior to breastfeeding (Anonymous 1974).
the bottle until nearly all liquid expelled (some liquid will
remain in unit after use). Gently remove the unit, a
Contraindications OTC labeling: When used for self-
medication, do not use if you are allergic to salicylates
small amount of liquid will remain in unit after use.
or are taking other salicylates; have an ulcer, bleeding
Dosage Forms Excipient information presented when
problem or bloody/black stool
available (limited, particularly for generics); consult spe-
cific product labeling. [DSC] = Discontinued product Warnings/Precautions Bismuth subsalicylate should be
Enema, Rectal: used with caution if patient is taking aspirin. Bismuth
Fleet Bisacodyl: 10 mg/30 mL (37 mL) products may be neurotoxic with very large doses. Some
Suppository, Rectal: dosage forms may contain sodium benzoate/benzoic acid;
Bisac-Evac: 10 mg (1 ea, 8 ea, 12 ea, 50 ea, 100 ea, 500 benzoic acid (benzoate) is a metabolite of benzyl alcohol;
ea, 1000 ea) large amounts of benzyl alcohol (299 mg/kg/day) have
Biscolax: 10 mg (12 ea, 100 ea) been associated with a potentially fatal toxicity ("gasping
Dulcolax: 10 mg (4 ea, 8 ea, 16 ea, 28 ea, 50 ea) syndrome") in neonates; the "gasping syndrome" consists
The Magic Bullet: 10 mg (10 ea, 12 ea [DSC], 100 ea) of metabolic acidosis, respiratory distress, gasping respi-
Generic: 10 mg (12 ea, 50 ea, 100 ea) rations, CNS dysfunction (including convulsions, intracra-
Tablet Delayed Release, Oral: nial hemorrhage), hypotension and cardiovascular
Bisacodyl EC: 5 mg collapse (AAP ["Inactive" 1997]; CDC 1982); some data
Bisacodyl EC: 5 mg [contains fd&c yellow #10 (quinoline suggests that benzoate displaces bilirubin from protein
yellow), fd&c yellow #6 (sunset yellow)]} binding sites (Ahlfors 2001); avoid or use dosage forms
Bisacodyl EC: 5 mg [contains fd&c yellow #10 aluminum containing benzyl alcohol derivative with caution in neo-
lake, fd&c yellow #6 aluminum lake] nates. Potentially significant drug-drug interactions may
Bisacodyl EC: 5 mg [contains fd&c yellow #10 aluminum exist, requiring dose or frequency adjustment, additional
lake, fd&c yellow #6 aluminum lake, methylparaben, monitoring, and/or selection of alternative therapy.
propylparaben, sodium benzoate] When used for self-medication (OTC labeling): Children
Correct: 5 mg and teenagers who have or are recovering from chick-
Ducodyl: 5 mg enpox or flu-like symptoms should not use subsalicylate.
Dulcolax: 5 mg [contains fd&c yellow #10 (quinoline Changes in behavior (along with nausea and vomiting)
yellow), methylparaben, propylparaben, sodium ben- may be an early sign of Reye syndrome; patients should
zoate] be instructed to contact their health care provider if these
Ex-Lax Ultra: 5 mg [contains fd&c yellow #6 (sunset occur. A temporary harmless darkening of the stool and/or
yellow), methylparaben] tongue may occur with use. Contact a health care provider
Fleet Laxative: 5 mg [DSC] before use if fever or mucus in the stool occurs. Discon-
Womens. Laxative: 5 mg [contains fd&c blue #1 alumi- tinue use and contact health care provider if any of the
num lake, sodium benzoate, tartrazine (fd&c yel- following occur: diarrhea lasts >2 days or other symptoms
low #5)]
lasts >14 days, diarrhea with a fever, symptoms get
Bisacodyl EC [OTC] see Bisacodyl on page 277 worse, hearing loss, or ringing in the ears.
SO Bisacodyl-Odan [OTC] (Can) see Bisacodyl
Warnings: Additional Pediatric Considerations Do
not use aspirin-containing products in children and ado-
on page 277
lescents who have or who are recovering from chickenpox
Sa bis(chloroethyl) nitrosourea see Carmustine or flu symptoms (due to the association with Reye syn-
on page 371 drome); when using aspirin, changes in behavior (along
@ bis-chloronitrosourea see Carmustine on page 371 with nausea and vomiting) may be an early sign of Reye

278
 BISMUTH SUBSALICYLATE

syndrome; instruct patients and caregivers to contact their Dyspepsia (gas, upset stomach, indigestion, heartburn,
health care provider if these symptoms occur. nausea):
Adverse Reactions Subsalicylate formulation: Children 212 years and Adolescents: Do not exceed 8
Central nervous system: Anxiety, confusion, depression, doses/24 hours (regular strength), 4 doses/24 hours
headache, slurred speech (maximum strength)
Gastrointestinal: Fecal discoloration (grayish black; Regular strength: Oral: 524 mg every 30 minutes to
impaction may occur in infants and debilitated patients), 1 hour as needed
tongue discoloration (darkening) ; Maximum strength: Oral: 1,050 mg every 1 hour as
Neuromuscular & skeletal: Muscle spasm, weakness needed
Otic: Hearing loss, tinnitus Diarrhea, chronic: Limited data available: Oral liquid:
Drug Interactions Infants 22 months: Oral: 44 mg every 4 to 6 hours
Metabolism/Transport Effects None known. Children <2 years: Oral: 44 mg every 4 hours or
Avoid Concomitant Use 87 mg every 6 hours
Children 2 to <3 years: Oral: 87 mg every 4 to 6 hours
Avoid concomitant use of Bismuth Subsalicylate with any
Children 3 to <4 years: Oral: 87 mg every 4 hours
of the following: Bismuth Subcitrate; Dexketoprofen;
Children 4 to 6 years: Oral: 175 mg every 4 hours
Influenza Virus Vaccine (Live/Attenuated); Sulfinpyra-
Dosing based on two studies; the first was a prospec-
zone’
tive, double-blind, placebo-controlled clinical trial of
Increased Effect/Toxicity
29 infants and children with chronic diarrhea (>6
Bismuth Subsalicylate may increase the levels/effects of:
weeks); after 7 days of bismuth therapy, patients in
Ajmaline; Angiotensin-Converting Enzyme Inhibitors;
the treatment group (n=15, age 2 to 30 months)
Anticoagulants; Bismuth Subcitrate; Blood Glucose Low- gained significantly more weight and had signifi-
ering Agents; Carbonic Anhydrase Inhibitors; Cortico- cantly improved stool characteristics (consistency/
steroids (Systemic); Dexketoprofen; Methotrexate; frequency) compared to placebo; to prevent recur-
PRALAtrexate; Salicylates; Thrombolytic Agents; Val- rence of symptoms, the authors also suggested
proate Products; Varicella Virus-Containing Vaccines; tapering the medication at the end of therapy (Gry-
Vitamin K Antagonists boski 1985). A second study compared bismuth
The levels/effects of Bismuth Subsalicylate may be subsalicylate with cholestyramine; patients were
increased by: Agents with Antiplatelet Properties; treated with bismuth (n=19) for 7 days; bismuth
Ammonium Chloride; Ginkgo Biloba; Herbs (Anticoagu- was found to be as effective as cholestyramine in
lant/Antiplatelet Properties); Influenza Virus Vaccine binding of bile acids and at decreasing stool fre-
(Live/Attenuated); Loop Diuretics; Nonsteroidal Anti- quency (Gryboski 1990).
Inflammatory Agents (Nonselective); Potassium Phos- Helicobacter pylori-associated antral gastritis: Lim-
phate ited data available:
Children and Adolescents: Oral: 8 mg/kg/day divided 2
Decreased Effect
times daily for 10 to 14 days; some pediatric trials
Bismuth Subsalicylate may decrease the levels/effects
administered in divided doses 4 times daily. Note:
of; Angiotensin-Converting Enzyme Inhibitors; Benzbro-
Administered as part of triple or quadruple therapy.
marone; Dexketoprofen; Hyaluronidase; Loop Diuretics;
(Choi 2006; ESPGHAN/NASPGHAN [Koletzko 2011];
Nonsteroidal Anti-Inflammatory Agents (Nonselective);
Gold 2000).
Probenecid; Sulfinpyrazone; Tetracyclines
Renal Impairment: Pediatric There are no dosage
The levels/effects of Bismuth Subsalicylate may be adjustments provided in the manufacturer’s labeling.
decreased by: Corticosteroids (Systemic); Dexketopro- Avoid use in patients with renal failure.
fen; Nonsteroidal Anti-Inflammatory Agents (Nonse- Hepatic Impairment: Pediatric There are no dosage
lective) adjustments provided in the manufacturer's labeling.
Storage/Stability Store at room temperature. Avoid Administration
excessive heat. Protect from freezing. Oral:
Mechanism of Action Bismuth subsalicylate exhibits Liquid: Shake well before using.
both antisecretory and antimicrobial action. This agent Tablets, chewable: Chew or allow to dissolve in mouth
may provide some anti-inflammatory action as well. The before swallowing.
salicylate moiety provides antisecretory effect and the Tablets, nonchewable caplets: Swallow whole with a full
bismuth exhibits antimicrobial directly against bacterial glass of water.
and viral gastrointestinal pathogens. Test Interactions Increased uric acid, increased AST;
Pharmacodynamics/Kinetics (Adult data unless bismuth absorbs x-rays and may interfere with diagnostic
noted) procedures of Gl tract
Absorption: Bismuth: <1%; Subsalicylate: >80% Dosage Forms Excipient information presented when
Distribution: Salicylate: Vg: 170 mL/kg + available (limited, particularly for generics); consult spe-
Protein binding, plasma: Bismuth and salicylate: >90% cific product labeling. [DSC] = Discontinued product
Suspension, Oral:
Metabolism: Bismuth subsalicylate is converted to bis-
Bismatrol Maximum Strength: 525 mg/15 mL (236 mL)
muth and salicylic acid in the Gl tract.
[contains benzoic acid, d&c red #22 (eosine), saccharin
Half-life elimination: Terminal: Bismuth: 21 to 72 days;
sodium; wintergreen flavor]
Salicylate: 2 to 5 hours
Geri-Pectate: 262 mg/15 mL (355 mL) [contains fd&c
Excretion: Bismuth: Urine and biliary; Salicylate: Urine
red #40]
(10% excreted unchanged)
Pepto-Bismol: 262 mg/15 mL (118 mL) [contains benzoic
Dosing
acid, d&c red #22 (eosine), saccharin sodium; original
Pediatric Note: Multiple concentrations of oral liquid
flavor]
formulations exist; close attention must be paid to the
Stomach Relief: 525 mg/15 mL (237 mL) [contains d&c
concentration when ordering or administering. Children red #22 (eosine), saccharin sodium]
and adolescents who have or are recovering from Stomach Relief Max St: 525 mg/15 mL (237 mL) [con-
chicken pox or flu-like symptoms should not use bismuth tains d&c red #22 (eosine), saccharin sodium]
subsalicylate due to the association of Reye syndrome. Stomach Relief Plus: 525 mg/15 mL (240 mL, 480 mL)
Refer to product specific labeling for approved pediatric Suspension, Oral, as subsalicylate:
ages. Dosing presented as mg of bismuth subsalicylate. Bismatrol: 262 mg/15 mL (236 mL) [contains benzoic
Diarrhea: ee - acid, d&c red #22 (eosine), saccharin sodium; winter-
Children 3 to <12 years (Kliegman 2007): Limited data green flavor]
available: Regular strength: Note: Do not exceed 8 Geri-Pectate: 262 mg/15 mL (355 mL)
doses/24 hours: Kao-Tin: 262 mg/15 mL (236 mL, 473 mL) [contains fd&c
3 to <6 years: Oral: 87 mg every 30 minutes to 1 hour red #40, saccharin sodium, sodium benzoate]
as needed Peptic Relief: 262 mg/15 mL (237 mL) [sugar free;
6 to <9 years: Oral: 175 mg every 30 minutes to 1 contains benzoic acid, d&c red #22 (eosine), saccharin
hour as needed sodium; mint flavor]
9 to <12 years: Oral: 262 mg every 30 minutes to 1 Pepto-Bismol: 262 mg/15 mL (473 mL) [contains ben-
hour as needed zoic acid, d&c red #22 (eosine), saccharin sodium]
Children 212 years and Adolescents: Do not exceed 8 Pink Bismuth: 262 mg/15 mL (236 mL)
doses/24 hours (regular strength), 4 doses/24 hours Pink Bismuth: 262 mg/15 mL (237 mL) [contains benzoic
(maximum strength) acid, d&c red #22 (eosine), saccharin sodium]
Regular strength: Oral: 524 mg every 30 minutes to 1 Stomach Relief: 527 mg/30 mL (240 mL, 480 mL)
hour as needed Tablet Chewable, Oral:
Maximum strength: Oral: 1,050 mg every 1 hour as GoodSense Stomach Relief: 262 mg [gluten free; con-
needed tains saccharin sodium]

279
BISMUTH SUBSALICYLATE

Pepto-Bismol InstaCool: 262 mg [sugar free; contains serious adverse reactions in the breastfed infant, breast-
saccharin sodium; peppermint flavor] feeding is not recommended by the manufacturer.
Stomach Relief: 262 mg [contains aspartame] Contraindications Hypersensitivity to bleomycin or any
Generic: 262 mg component of the formulation
Tablet Chewable, Oral, as subsalicylate: Warnings/Precautions [US Boxed Warning]: Occur-
Bismatrol: 262 mg [contains aspartame] rence of pulmonary fibrosis (commonly presenting
Diotame: 262 mg [DSC] as pneumonitis; occasionally progressing to pulmo-
Peptic Relief: 262 mg [DSC] nary fibrosis) is the most ‘severe toxicity. Risk is
Peptic Relief: 262 mg [contains saccharin sodium] higher in elderly patients or patients receiving >400
Pepto-Bismol To-Go: 262 mg [sugar free; contains fd&c units total lifetime dose; other possible risk factors
red #40 aluminum lake, saccharin sodium; cherry include smoking and patients with prior radiation therapy
flavor] or receiving concurrent oxygen (especially high inspired
Pink Bismuth: 262 mg [DSC] oxygen doses). A review of patients receiving bleomycin
Pink Bismuth: 262 mg [contains saccharin sodium] for the treatment of germ cell tumors suggests risk for
Generic: 262 mg pulmonary toxicity is increased in patients >40 years of
age, with glomerular filtration rate <80 mL/minute,
@ Bis-POM PMEA see Adefovir on page 63
advanced disease, and cumulative doses >300 units
@ Bistropamide see Tropicamide on page 2015 (O'Sullivan 2003). Pulmonary toxicity may include bron-
@ Bivalent Human, Papillomavirus Vaccine see Papillo- chiolitis obliterans and organizing pneumonia (BOOP),
mavirus (Types 16, 18) Vaccine (Human, Recombinant) eosinophilic hypersensitivity, and interstitial pneumonitis,
on page 1557 progressing to pulmonary fibrosis (Sleijfer 2001); pulmo-
Bivigam see Immune Globulin on page 1056 nary toxicity may be due to a lack of the enzyme which
inactivates bleomycin (bleomycin hydrolase) in the lungs
Bi-Zets/Benzotroches [OTC] see Benzocaine (Morgan 2011; Sleijfer 2001). If pulmonary changes occur,
on page 257 withhold treatment and investigate if drug-related. In a
@ BL4162A see Anagrelide on page 147 study of patients with testicular cancer receiving bleomy-
@ Black Widow Spider Species Antivenin see Antivenin cin as part of the BEP regimen, pulmonary function testing
(Latrodectus mactans) on page 166 (including forced vital capacity [FVC], forced expiratory
volume in 1 second [FEV,], and diffusing capacity of the
@ Black Widow Spider Species Antivenom see Antivenin
lungs for carbon monoxide [DLCO]) was performed prior
(Latrodectus mactans) on page 166
to treatment, before each chemotherapy cycle, and then
@ Blenoxane see Bleomycin on page 280 repeated at 1 year, 3 years, and 5 years during follow up; if
@ Bleo see Bleomycin on page 280 the carbon monoxide diffusing capacity corrected for
hemoglobin content [DLCOc] decreased more than 25%
during therapy (compared with baseline), bleomycin was
Bleomycin (ice oh MYE sin) discontinued to avoid further pulmonary toxicity (Lauritsen
Medication Safety Issues 2016). In children, a younger age at treatment, cumulative
Sound-alike/look-alike issues: dose 2400 units/m? (combined with chest irradiation), and
Bleomycin may be confused with Cleocin renal impairment are associated with a higher incidence of
High alert medication: pulmonary toxicity (Huang 2011). Positron emission
This medication is in a class the Institute for Safe tomography/computed tomography (PET/CT) may have
Medication Practices (ISMP) includes among its list of a role in determining early response to therapy in patients
drugs which have a heightened risk of causing signifi- with Hodgkin lymphoma; a negative interim PET/CT result
cant patient harm when used in error. after 2 cycles may indicate that bleomycin can be safely
International issues: f omitted from the ABVD treatment regimen (Johnson
Some products available internationally may have vial 2016). Longer follow-up is necessary to determine the
strength and dosing expressed as international units or effect of bleomycin omission on long-term morbidity and
milligrams (instead of units or USP units). Refer to mortality in these patients.
prescribing information for specific strength and dosing A severe idiosyncratic reaction consisting of hypo-
information. tension, mental confusion, fever, chills, and wheezing
Other safety concerns: (similar to anaphylaxis) has been reported in 1% of
During shortages within the US, temporary importation of lymphoma patients treated with bleomycin. Since
international products may be allowed by the FDA. The these reactions usually occur after the first or second
imported bleomycin vial and product labeling may dose, careful monitoring is essential after these doses.
express strength and dosing as international units Use caution when administering O2 during surgery to
instead of USP units (1,000 international units = 1 patients who have received bleomycin; the risk of bleo-
USP unit). mycin-related pulmonary toxicity is increased. Use caution
Brand Names: Canada Blenoxane; Bleomycin Injection, with renal impairment (CrCl <50 mL/minute), may require
USP dose adjustment. May cause renal or hepatic toxicity. [US
Therapeutic Category Antineoplastic Agent, Antibiotic Boxed Warning]: Should be administered under the
Generic Availability (US) Yes supervision of an experienced cancer chemotherapy
Use Palliative treatment of squamous cell carcinoma (of physician. Potentially significant drug-drug interactions
the head and neck, penis, cervix, or vulva), testicular may exist, requiring dose or frequency adjustment, addi-
carcinoma, Hodgkin lymphoma, and non-Hodgkin lym- tional monitoring, and/or selection of alternative therapy.
phoma; sclerosing agent to contro! malignant effusions Some products available internationally may have vial
(FDA approved in adults); has also been used in the strength and dosing expressed as international units or
treatment of germ cell tumors and pediatric Hodgkin milligrams (instead of units or USP units). During short-
lymphoma ages within the US, temporary importation of international
Pregnancy Risk Factor D products may be allowed by the FDA. The imported
Pregnancy Considerations Adverse effects were bleomycin vial and product labeling may express strength
observed in animal reproduction studies. According to and dosing as international units instead of USP units.
the manufacturer, women of childbearing potential should One USP unit of bleomycin = 1 mg (by potency) = 1,000
avoid becoming pregnant during bleomycin treatment. international units (Stefanou 2001). Refer to prescribing
The European Society for Medical Oncology has pub- information for specific dosing information.
lished guidelines for diagnosis, treatment, and follow-up Adverse Reactions
of cancer during pregnancy; the guidelines recommend The pathogenesis of respiratory adverse effects is not
referral to a facility with expertise in cancer during preg- certain, but may be due to damage of pulmonary,
nancy and encourage a multidisciplinary team (obstetri- vascular, or connective tissue. Response to steroid
cian, neonatologist, oncology team). In general, if therapy is variable and somewhat controversial.
chemotherapy is indicated, it should be avoided in the first Cardiovascular: Phlebitis
trimester and there should be a 3-week time period Central nervous system: Tumor pain
between the last chemotherapy dose and anticipated Dermatologic: Alopecia (may be dose-related and rever-
delivery, and chemotherapy should not be administered sible with discontinuation), atrophic striae, erythema,
beyond week 33 of gestation (Peccatori 2013). When exfoliation of the skin (particularly on the palmar and
multiagent therapy is needed to treat Hodgkin lymphoma plantar surfaces of the hands and feet), hyperkeratosis,
during pregnancy, bleomycin (as a component of the hyperpigmentation, localized vesiculation, nailbed
ABVD [doxorubicin, bleomycin, vinblastine, and dacarba- changes (may be dose-related and reversible with
zine] regimen) may be used, starting with the second discontinuation), onycholysis, pruritus, skin rash, skin
trimester (Follows 2014; Peccatori 2013). sclerosis, thickening of skin
Breastfeeding Considerations It is not known if bleo- Endocrine & metabolic: Weight loss
mycin is present in breast milk. Due to the potential for Gastrointestinal: Anorexia, mucositis, stomatitis

280
 BLEOMYCIN

Hypersensitivity: Anaphylactoid reaction (including chills, USP units. Refer to individual protocols for specific
confusion, fever, hypotension, wheezing; onset may be dosage and interval information. All doses of bleomycin
immediate or delayed for several hours; includes idio- are associated with a minimal emetic potential (Dupuis
syncratic reaction in lymphoma patients) 2011); no routine prophylaxis is recommended (Dupuis
Neuromuscular & skeletal: Scleroderma (diffuse) 2013).
Respiratory: Hypoxia, interstitial pneumonitis (acute or Test dose for lymphoma patients: Limited data avail-
chronic), pulmonary fibrosis, rales, tachypnea able: Note: Test doses may not be predictive of a
Rare but important or life-threatening: Angioedema, bone reaction (Lam 2005) and/or may produce false-neg-
marrow depression (rare), cerebrovascular accident, ative results; some protocols no longer require; refer
cerebral arteritis, chest pain, coronary artery disease, to institution/protocol specific guidelines. Children and
hepatotoxicity, hyperpigmentation (flagellate), ischemic Adolescents: IM, IV, SubQ: Because of the possibility
-heart disease, malaise, myocardial infarction, nausea, of an anaphylactoid reaction, the manufacturer rec-
nephrotoxicity, pericarditis, Raynaud’s phenomenon, ommends administering 1 to 2 units of bleomycin
scleroderma (scleroderma-like skin changes), Stevens- before the first 1 to 2 doses; monitor vital signs every
Johnson syndrome, thrombotic thrombocytopenic pur- 15 minutes; wait a minimum of 1 hour before admin-
pura, toxic epidermal necrolysis, vomiting istering remainder of dose; if no acute reaction
Drug Interactions occurs, then the regular dosage schedule may be
Metabolism/Transport Effects None known. followed
Avoid Concomitant Use Hodgkin lymphoma (combination regimen): Limited
Avoid concomitant use of Bleomycin with any of the data available:
following: BCG (Intravesical); Brentuximab Vedotin; ABVE-PC (intermediate-risk or high-risk Hodgkin lym-
Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac- phoma): Children and Adolescents: IV or SubQ: 5
cines (Live) units/m? on day 1 and 10 units/m? on day 8 of a
‘Increased Effect/Toxicity 21-day cycle for 2 to 4 cycles (in combination with
Bleomycin may increase the levels/effects of: Baricitinib; doxorubicin, vincristine, etoposide, prednisone, and
Fingolimod; Leflunomide; Natalizumab; Tofacitinib; Vac- cyclophosphamide) (Dharmarajan 2015; Friedman
cines (Live) 2014; Schwartz 2009)
ABVD (high-risk Hodgkin lymphoma): Children and
The levels/effects of Bleomycin may be increased by: Adolescents: IV: 10 units/m? on days 1 and 15 of a
Brentuximab Vedotin; Denosumab; Filgrastim; Gemcita- 28-day treatment cycle for 2 to 6 cycles in combina-
bine; Lenograstim; Lipegfilgrastim; Ocrelizumab; Palifer- tion with doxorubicin, vinblastine, dacarbazine
min; Pimecrolimus; Roflumilast; Sargramostim; (Hutchinson 1998)
Tacrolimus (Topical); Trastuzumab BEACOPP (high-risk Hodgkin lymphoma): Children
Decreased Effect and Adolescents: IV: 10 units/m? on day 7 of a 21-
Bleomycin may decrease the levels/effects of: BCG day treatment cycle for 2 to 4 cycles in combination
(Intravesical); Coccidioides immitis Skin Test; Lenogras- with etoposide, doxorubicin, cyclophosphamide, vin-
tim; Lipegfilgrastim; Nivolumab; Phenytoin; Pidotimod; cristine, procarbazine, and prednisone (Kelly 2002)
Sipuleucel-T; Tertomotide; Vaccines (Inactivated); Vac- Stanford V (high-risk Hodgkin lymphoma): Adolescent
cines (Live) 216 years: IV: 5 units/m2/dose in weeks 2, 4, 6, 8,
10, and 12 of a 12-week treatment cycle for 1 cycle
The levels/effects of Bleomycin may be decreased by:
in combination with mechlorethamine, vinblastine,
Echinacea
vincristine, doxorubicin, etoposide, and prednisone
Hazardous Drugs Handling Considerations
(Gordon 2013; Horning 2000; Horning 2002)
Hazardous agent (NIOSH 2016 [group 1]).
Malignant germ cell cancer (combination therapy):
Use appropriate precautions for receiving, handling, Limited data available: PEB regimen (Cushing 2004):
administration, and disposal. Gloves (single) should be Infants: IV: 0.5 mg/kg on day 1 of a 21-day treatment
worn during receiving, unpacking, and placing in storage. cycle for 4 cycles in combination with cisplatin and
etoposide
NIOSH recommends double gloving, a protective gown, Children and Adolescents: IV: 15 units/m? on day 1 of
ventilated engineering controls (a class || biological safety a 21-day treatment cycle for 4 cycles in combination
cabinet or a compounding aseptic containment isolator), with cisplatin and etoposide
and closed system transfer devices (CSTDs) for prepara- Dosing adjustment for toxicity: The presented dosing
tion. Double gloving, a gown, and (if dosage form allows) adjustments are based on experience in adult patients;
CSTDs are required during administration (NIOSH 2016). specific recommendations for pediatric patients are
Storage/Stability Store intact vials at 2°C to 8°C (36°F to limited. Refer to specific protocol for management in
46°F). Stable for 24 hours in NS at room temperature. pediatric patients if available.
Mechanism of Action Bleomycin inhibits synthesis of Adult:
DNA; binds to DNA leading to single- and double-strand Pulmonary changes: Discontinue until determined not
breaks; also inhibits (to a lesser degree)
RNA and protein to be drug-related.
synthesis Pulmonary diffusion capacity for carbon monoxide
Pharmacodynamics/Kinetics (Adult data unless (DLco) <30% to 35% of baseline in adults: Discon-
noted) tinue treatment.
Absorption: IM, SubQ, and intrapleural administration: Renal Impairment: Pediatric There are no pediatric
100%, 70%, and 45%, respectively, of I1V serum concen- specific recommendations; based on experience in adult
trations patients, dosing adjustment suggested.
Distribution: Vg: IV: 17.5 Lim? Hepatic Impairment: Pediatric There are no dosage
Protein binding: 1% adjustments provided in the manufacturer's labeling (has
Metabolism: Enzymatic inactivation by bleomycin hydro- not been studied); however, adjustment for hepatic
lase, a cytosolic cysteine proteinase enzyme; bleomycin impairment is not necessary (King 2001).
hydrolase is widely distributed in normal tissues (except Preparation for Administration Note: During shortages
for the skin and lungs) within the US, temporary importation of international prod-
Half-life elimination: Terminal: IV: 2 hours ucts may be allowed by the FDA. The imported bleomycin
Time to peak, serum: IM, SubQ, Intrapleural: 30 to 60 vial and product labeling may express strength and dosing
minutes as international units instead of USP units and preparation
Excretion: Urine (~65% [IV], 40% [Intrapleural]) instructions may be different; consult product specific
Pharmacodynamics/Kinetics: Additional Consider- labeling.
ations \V: Reconstitute 15-unit vial with 5 mL with NS and the 30-
Renal function impairment: The half-life increases expo- unit vial with 10 mL NS for a resultant concentration of 3
nentially as CrCl decreases. units/mL (3 mg/mL)
Pediatric: Children younger than 3 years of age have a IM or SubQ: Reconstitute 15-unit vial with 1 to 5 mL of
higher total body clearance than adults. SWFI, bacteriostatic water for injection, or NS and the
Dosing 30-unit vial with 2 to 10 mL of SWFI, bacteriostatic water
Pediatric for injection, or NS. A concentration of 3 to 15 units/mL
Note: The risk for pulmonary toxicity increases with can be used for subcutaneous or IM injection.
cumulative lifetime*dose >400 USP units. International Intrapleural: Adults: Mix in 50 to 100 mL of NS
considerations: Dosages below are expressed as Administration
USP units; 1 USP unit = 1 mg (by potency) = 1,000 IM, SubQ: Administer at a concentration of 3 to 15 units/
international units (Stefanou 2001). During shortages mL; may cause pain at injection site
within the US, temporary importation of international lV: Administer lV slowly over at least 10 minutes; may be
products may be allowed by the FDA. The imported further diluted for administration by continuous |V infu-
bleomycin vial and product labeling may express sion; slower administration may produce less severe
strength and dosing as international units instead of pulmonary toxicity

281
BLEOMYCIN

Intrapleural: Adults: Use of topical anesthetics or opioid advise patients to reports signs/symptoms suggestive of
analgesia is usually not necessary. CRS; may require therapy interruption or discontinuation.
Vesicant/Extravasation Risk May be an irritant The median time to CRS was 2 days following the start of
Monitoring Parameters Pulmonary function tests, infusion. In 1 study, patients with a high tumor burden
including total lung volume, forced vital capacity, diffusion (250% leukemic blasts or >15,000/mm$ peripheral blood
capacity for carbon monoxide; vital capacity, total lung leukemic blast counts), or elevated lactate dehydrogenase
capacity, and pulmonary capillary blood volume may be were pre-treated with dexamethasone (10 to 24 mg/m?/
better indicators of changes induced by bleomycin (Sleifjer day for up to 5 days and concluding 3 days prior to
2001), chest x-ray; renal function, hepatic function, vital initiating blinatumomab) to reduce the incidence of severe
signs, and temperature initially; CBC with differential and CRS (Topp 2015). Tocilizumab may be considered in the
platelet count; check body weight at regular intervals management of severe or life-threatening CRS associated
Dosage Forms Considerations During shortages within with bi-specific T-cell engaging (BiTE) therapy (Lee 2014;
the US, temporary importation of international products Maude 2014). [US Boxed Warning]: Neurological tox-
may be allowed by the FDA. The imported bleomycin vial icities, which may be severe, life-threatening, or fatal,
and product labeling may express strength and dosing as have occurred. Interrupt or discontinue therapy as
international units instead of USP units (1,000 interna- recommended. Neurotoxicity has occurred in almost
tional units = 1 USP unit). two-thirds of patients with acute lymphoblastic leukemia
Dosage Forms Excipient information presented when (ALL) in clinical trials. The median time to onset was within
available (limited, particularly for generics); consult spe- the first 2 weeks of therapy. Common neurological symp-
cific product labeling. toms include headache and tremor (symptoms may differ
Solution Reconstituted, Injection: in children <2 years of age, and elderly patients have a
Generic: 15 units (1 ea); 30 units (1 ea) higher incidence of neurotoxicity). Grade 3 or higher
Solution Reconstituted, Injection [preservative free]: neurotoxicity (eg, encephalopathy, convulsions, speech
Generic: 15 units (1 ea); 30 units (1 ea) disorders, disturbances in consciousness, confusion and
disorientation, and coordination and balance disorders)
@ Bleomycin Injection, USP (Can) see Bleomycin has also been observed; other manifestations have
on page 280 included cranial nerve disorders. Neurotoxicity may be
Bleomycin Sulfate see Bleomycin on page 280 managed with dexamethasone (Topp 2015). Patients are
@ Bleph-10 see Sulfacetamide (Ophthalmic) on page 1875 at risk for loss of consciousness due to neurologic events
while taking blinatumomab; advise patients to avoid driv-
@ Bleph 10 DPS (Can) see Sulfacetamide (Ophthalmic)
ing, participating in hazardous occupations, or operating
on page 1875
heavy or dangerous machinery during treatment. Patients
with a history of (or current) clinically relevant CNS
Blinatumomab (bin a TOOM oh mab) pathology were excluded from clinical trials. Monitor
patients for signs/symptoms of neurotoxicity, and advise
Medication Safety Issues patients to reports signs/symptoms suggestive of neuro-
Sound-alike/look-alike issues: logic toxicity; may require therapy interruption or discon-
Blinatumomab may be confused with bezlotoxumab. tinuation. The majority of symptoms resolved after
High alert medication interrupting therapy. Leukoencephalopathy (as seen on
This medication is in a class the Institute for Safe MRI) has been reported, particularly in those patients
Medication Practices (ISMP) includes among its list of who received prior treatment with cranial irradiation and
drug classes that have a heightened risk of causing antileukemia chemotherapy (eg, high-dose methotrexate,
significant patient harm when used in error. intrathecal cytarabine).
Other safety concerns
Preparation and administration errors have occurred. Do Neutropenia and neutropenic fever, including life-threat-
not flush infusion line, particularly when changing infu- ening episodes, have been reported. Monitor blood counts
sion bags or at completion of infusion; may result in throughout therapy; may require therapy interruption if
overdose and complications. IV bag contains overfill prolonged neutropenia occurs. Anemia and thrombocyto-
and volume will be more than the volume administered penia may also occur. Serious infections such as sepsis,
to the patient to account for IV line priming and to pneumonia, bacteremia, opportunistic infections, and
ensure that the full dose is administered. Carefully catheter-related infections have been reported in approx-
follow preparation and administration instructions. imately one-fourth of patients with ALL in clinical trials
Refer to manufacturer labeling for further information. (may be life-threatening or fatal). Consider prophylactic
Brand Names: US Blincyto antibiotics if appropriate, and monitor closely for signs/
Brand Names: Canada Blincyto symptoms of infection. Treat promptly if infection occurs.
Therapeutic Category Antineoplastic Agent, Anti-CD19/ Transient increases in liver enzymes (associated both with
CD3; Antineoplastic Agent, Monoclonal Antibody and without CRS) may occur during therapy. In patients
with ALL, the median time to enzyme elevation was 3 to
Generic Availability (US) No
19 days; grade 3 or higher elevations were observed in a
Use Treatment of Philadelphia chromosome-negative (Ph-)
small percentage of patients. Monitor ALT, AST, GGT, and
relapsed or refractory B-cell precursor acute lymphoblas-
total bilirubin at baseline and during treatment. Interrupt
tic leukemia (ALL) (FDA approved in ages 21 month and
therapy if transaminases are >5 times ULN or if total
adults)
bilirubin is >3 times ULN. Fatal cases of pancreatitis in
Medication Guide Available Yes
patients receiving blinatumomab plus dexamethasone
Pregnancy Considerations Animal reproductions stud-
have been reported in the postmarketing setting. Monitor
ies have not been conducted. Based on the mechanism of
for signs/symptoms of pancreatitis; may require therapy
action, blinatumomab may cause fetal harm when admin-
interruption or discontinuation. Life-threatening or fatal
istered to a pregnant woman. Newborns exposed in utero
tumor lysis syndrome (TLS) has been observed. Admin-
may develop B-cell lymphocytopenia; monitor B-lympho-
ister measures to prevent TLS (eg, pretreatment nontoxic
cytes prior to administering live virus vaccines. Verify
cytoreduction, and hydration during treatment). Monitor for
pregnancy status of women of reproductive potential prior
signs/symptoms of TLS (eg, acute renai failure, hyper-
to initiating treatment; effective contraception should be
kalemia, hypocalcemia, hyperuricemia, and/or hyperphos-
used during treatment and for at least 48 hours after the
phatemia); may require treatment interruption or
last dose.
discontinuation. Pediatric patients experienced an
Breastfeeding Considerations It is not known if blina-
increased rate of anemia, thrombocytopenia, vomiting,
tumomab is present in breast milk. Due to the potential for
pyrexia, and hypertension as compared to adult patients.
serious adverse reactions in the breastfeeding infant,
While the incidence of neurologic toxicities in patients <2
breastfeeding is not recommended by the manufacturer
years of age did not differ from other age groups, the
during treatment and for at least 48 hours after the last
manifestations were different; reported toxicities were
dose.
agitation, headache, insomnia, somnolence, and irritabil-
Contraindications Known hypersensitivity to blinatumo-
ity. Elderly patients experienced an increased rate of
mab or any component of the formulation
neurotoxicity (including cognitive disorder), encephalop-
Warnings/Precautions [US Boxed Warning]: Cytokine athy, confusion, and serious infections as compared to
release syndrome (CRS), which may be life-threaten-
patients <65 years of age.
ing or fatal, has occurred. Interrupt or discontinue
therapy as recommended. CRS manifestations may Preparation and administration errors have occurred. Do
include pyrexia, headache, nausea, weakness, hypoten- not flush infusion line, particularly when changing infusion
sion, increased transaminases, elevated total bilirubin, bags or at completion of infusion; may result in overdose
and disseminated intravascular coagulation (DIC). Symp- and complications. lV bag contains overfill and volume will
toms of infusion reactions, capillary leak syndrome (CLS), be more than the volume administered to the patient to
and hemophagocytic histiocytosis/macrophage activation account for IV line priming and to ensure that the full dose
syndrome (MAS) may overlap with CRS symptoms. Mon- is administered. Follow preparation and administration
itor closely for signs/symptoms of these conditions, and instructions carefully. Refer to manufacturer labeling for

282
 BLINATUMOMAB

further information. Potentially significant drug-drug inter- The levels/effects of Blinatumomab may be increased
actions may exist, requiring dose or frequency adjustment, by: Chloramphenicol (Ophthalmic); Denosumab; Dipyr-
additional monitoring, and/or selection of alternative ther- one; Ocrelizumab; Pimecrolimus; Promazine; Roflumi-
apy. Vaccination with live virus vaccines is not recom- last; Tacrolimus (Topical); Trastuzumab
mended for at least 2 weeks prior to blinatumomab Decreased Effect
initiation, during treatment, and until immune system Blinatumomab may decrease the levels/effects of: BCG
recovery following the last cycle of therapy. (Intravesical); Coccidioides immitis Skin Test; Nivolu-
mab; Pidotimod; Sipuleucel-T; Tertomotide; Vaccines
Diluent may contain benzyl alcohol; large amounts of
(Inactivated); Vaccines (Live)
benzyl alcohol (299 mg/kg/day) have been associated
with a potentially fatal toxicity ("gasping syndrome") in The levels/effects of Blinatumomab may be decreased
neonates; the "gasping syndrome" consists of metabolic by: Echinacea
acidosis, respiratory distress, gasping respirations, CNS Storage/Stability Store intact vials (drug and solution
dysfunction (including convulsions, intracranial hemor- stabilizer) in the original package at 2°C to 8°C (36°F to
rhage), hypotension and cardiovascular collapse (AAP 46°F); protect from light. Do not freeze. Intact vials of both
["Inactive" 1997]; CDC 1982); some data suggests that drug and stabilizer may be stored for up to 8 hours at room
benzoate displaces bilirubin from protein binding sites temperature. Reconstituted solution is stable for up to 4
(Ahlfors 2001); avoid or use dosage forms containing hours at 23°C to 27°C (73°F to 81°F) or up to 24 hours at
benzyl alcohol with caution in neonates. See manufactur- 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion
er's labeling. Due to the addition of bacteriostatic saline, (preservative free) are stable in NS for up to 48 hours at
the 7-day infusion bags of blinatumomab contain benzyl 23°C to 27°C (73°F to 81°F) or up to 8 days at 2°C to 8°C
alcohol and are not recommended for use in patients (36°F to 46°F). Solutions diluted for infusion (with pres-
weighing <22 kg. Some dosage forms may contain poly- ervative) are stable in NS for up to 7 days at 23°C to 27°C
_ sorbate 80 (also known as Tweens). Hypersensitivity (73°F to 81°F) or up to 14 days at 2°C to 8°C (36°F to
reactions, usually a delayed reaction, have been reported 46°F). Infusion should be completed within these time
following exposure to pharmaceutical products containing frames; if IV bag of solution for infusion is not administered
polysorbate 80 in certain individuals (Isaksson 2002; within the time frames and temperatures indicated, dis-
Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, card; do not refrigerate again.
pulmonary deterioration, and renal and hepatic failure Mechanism of Action Blinatumomab is a bispecific T-cell
have been reported in premature neonates after receiving engager (BiTE) which binds to CD19 expressed on B-cells
parenteral products containing polysorbate 80 (Alade and CD3 expressed on T-cells. It activates endogenous T
1986; CDC 1984). See manufacturer's labeling. cells by connecting CD3 in the T-cell receptor complex
Adverse Reactions with CD19 on B-cells (malignant and benign), thus forming
Cardiovascular: Capillary leak syndrome, cardiac arrhyth- a cytolytic synapse between a cytotoxic T-cell and the
mia, chest discomfort, chest pain, circulatory shock, cancer target B-cell (Topp 2014). Blinatumomab mediates
edema, flushing, hypertension, hypertensive crisis, the production of cytolytic proteins, release of inflamma-
hypotension, peripheral edema, septic shock tory cytokines, and proliferation of T cells, which result in
Central nervous system: Altered mental status, aphasia, lysis of CD19-positive cells.
brain disease, chills, cognitive dysfunction, confusion, Pharmacodynamics/Kinetics (Adult data unless
cranial nerve dysfunction (includes facial nerve disorder, noted)
trigeminal nerve disorder), depression, disorientation, Distribution: Pediatric patients 0 to 17 years: 3.14 + 2.97 L/
disturbance in attention, disturbed coordination, dizzi- m?; Adults: 4.35 L
ness, drowsiness, equilibrium disturbance, facial pare- Half-life elimination: Pediatric patients 0 to 17 years: 2.04 +
sis, headache, hyperthermia, hypoesthesia, impaired 1.35 hours; Adults: 2.1 hours
consciousness, insomnia, intention tremor, lethargy, Excretion: Urine (negligible amounts)
memory impairment, neurotoxicity, noncardiac chest Dosing
pain, pain, seizure, sixth nerve palsy, speech disturb- Pediatric
ance, stupor, suicidal ideation, trigeminal neuralgia Note: Hospitalization is recommended for the first 9 days
Dermatologic: Allergic dermatitis, erythema multiforme, of cycle 1, and the first 2 days of cycle 2. Close
skin rash, urticaria observation by a healthcare professional (or hospital-
Endocrine & metabolic: Hot flash, hypovolemic shock, ization) is recommended for initiation of all subsequent
weight gain cycles or for therapy reinitiation (eg, treatment is inter-
Hematologic & oncologic: Anemia, decreased absolute rupted for 4 or more hours). Do not flush infusion line,
lymphocyte count, decreased serum immunoglobulins particularly when changing infusion bags or at comple-
(may include IgA, IgG, IgM), febrile neutropenia, hema- tion of infusion; may result in overdose.
tologic abnormality (hematophagic histiocytosis), hypo- Premedicate with dexamethasone IV 5 mg/m? (max-
gammaglobulinemia, leukocytosis, leukopenia, imum dose: 20 mg/dose) 1 hour prior to the first dose
lymphadenopathy, neutropenia, thrombocytopenia, of the first cycle, prior to a step dose (eg, Cycle 1 day
tumor lysis syndrome c 5 8), or when restarting therapy after an interruption of
Hepatic: Increased serum alkaline phosphatase, 24 hours in the first cycle
increased serum ALT, increased serum AST, increased Acute lymphoblastic leukemia (B-cell precursor),
serum bilirubin, increased serum transaminases Philadelphia chromosome-negative, relapsed/
Hypersensitivity: Anaphylaxis, angioedema, cytokine refractory: Infants, Children, and Adolescents: Each
release syndrome, fixed drug eruption, hypersensitivity treatment cycle is 6 weeks and consists of 4 weeks of
reaction continuous infusion followed by a 2-week treatment-
Immunologic: Antibody development (most were neutral- free interval (allow at least 2 weeks treatment-free
izing) between cycles). Therapy involves 2 induction cycles
Infection: Bacteremia, bacterial infection, fungal infection, followed by 3 additional cycles for consolidation (total
infection, opportunistic infection, sepsis, serious infec- of up to 5 cycles).
tion, staphylococcal infection, viral infection Patients <45 kg: BSA-directed:
Local: Catheter infection Cycle 1:
Neuromuscular & skeletal: Back pain, limb pain, muscu- Days 1 to 7: IV: 5 mcg/m2/day (maximum daily
loskeletal chest pain, ostealgia, tremor (may include dose: 9 mcg/day) administered as a continuous
essential tremor, intentional tremor, resting tremor) infusion
Respiratory: Acute asthma, acute respiratory tract failure, Days 8 to 28: IV: 15 mcg/m2/day (maximum daily
bronchospasm, cough, dyspnea, dyspnea on exertion, dose: 28 mcg/day) administered as a continuous
pneumonia, productive cough, respiratory distress, infusion
tachypnea, wheezing Cycles 2 through 5: Days 1 to 28: IV: 15 mcg/m?/day
Miscellaneous: Fever, infusion-related reaction (maximum daily dose: 28 mcg/day) administered
Rare but important or life-threatening: Leukoencephalop- as a continuous infusion
athy, pancreatitis Patients 245 kg: Fixed dosing:
Drug Interactions Cycle 1:
Metabolism/Transport Effects None known. Days 1 to 7: IV: 9 mcg daily administered as a
Avoid Concomitant Use continuous infusion
Avoid concomitant use of Blinatumomab with any of the Days 8 to 28: IV: 28 mcg daily administered as a
following: BCG (Intravesical); Deferiprone; Dipyrone; continuous infusion
Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac- Cycles 2 through 5: IV: Days 1 to 28: IV: 28 mcg
cines (Live) daily administered as a continuous infusion
Increased Effect/Toxicity Dosing adjustment for toxicity: Infants, Children, and
Blinatumomab \may increase the levels/effects of: Bar- Adolescents: If the interruption after an adverse event
icitinib; Busulfan; CloZAPine; Deferiprone; Fingolimod; is no longer than 7 days, continue the same cycle to a
Leflunomide; Natalizumab; Tofacitinib; Vaccines (Live) total of 28 days of infusion inclusive of days before and

283
BLINATUMOMAB

after the interruption in that cycle. If an interruption due dexamethasone one hour prior to the first dose of the first
to an adverse event is longer than 7 days, start a new cycle, prior to a step dose (eg, Cycle 1 day 8), or when
cycle. restarting therapy after an interruption of 24 hours in the
Cytokine release syndrome (CRS): first cycle
Grade 3: Interrupt therapy until resolved, then resume \V: Note: Preparation and administration errors have
dosing at 9 mcg daily (or 5 mcg/m?/day if <45 kg). occurred; carefully follow administration instructions.
Increase dose to 28 mcg daily (or 15 mcg/m2/day if Prior to infusion:
<45 kg) after 7 days if toxicity does not recur. 24- or 48-hour infusion: Attach the IV tubing (use only
Grade 4: Discontinue permanently polyolefin, non-DEHP PVC, or EVA tubing) to the bag
Neurologic toxicity: with a sterile, non-pyrogenic, low protein-binding 0.2
Grade 3: Interrupt therapy for at least 3 days and until micron in-line filter. Remove air from the IV bag.
toxicity is <Grade 1 (mild), then resume dosing at 9 Prime the IV tubing only with the prepared infu-
meg daily (or 5 mcg/m/day if <45 kg). Increase sion solution; do not prime with NS.
dose to 28 mcg daily (or 15 mcg/m?/day if <45 kg) 7-day infusion: Patients weighing 222 kg: Attach the IV
after 7 days if toxicity does not recur. If toxicity tubing (use only polyolefin, non-DEHP PVC, or EVA
occurred at the 9 mcg daily dose (or 5 mcg/m?2/day tubing) to the bag; an in-line filter is not required for
dose if <45 kg), or if it takes more than 7 days to the 7-day infusion bag. Remove air from the IV bag.
resolve, discontinue permanently. Prime the IV tubing only with the prepared infu-
Grade 4: Discontinue permanently sion solution; do not prime with NS.
Seizure: Discontinue permanently if more than 1 Infusion: —__
seizure occurs. 24- or 48-hour infusion: Administer 240 mL as a con-
Other clinically relevant toxicity: tinuous IV infusion at a constant flow rate of 10 mL/
Grade 3: Interrupt therapy until toxicity is <Grade 1 hour for 24 hours or 5 mL/hour for 48 hours (depend-
(mild), then resume dosing at 9 mcg daily (or 5 mcg/ ing on dose and concentration) through a dedicated
m?/day if <45 kg). Increase dose to 28 mcg daily (or lumen. Use a programmable, lockable, nonelasto-
15 mcg/m?2/day if <45 kg) after 7 days if toxicity does meric infusion pump with an alarm. Infusion bag
not recur. If toxicity takes more than 14 days to contains overfill (to account for tubing and priming
resolve, discontinue permanently. volume). Do not flush infusion line, particularly when
Grade 4: Discontinue permanently changing infusion bags or at completion of infusion;
Renal Impairment: Pediatric All patients: may result in excess dosage and complications. Do
CrCl 230 mL/minute: There are no dosage adjustments not infuse other medications through the same line.
provided in the manufacturer's labeling; however, a 7-day infusion: Patients weighing 222 kg: Administer
pharmacokinetic analysis showed that clearance val- 100 mL as a continuous IV infusion at a constant flow
ues in patients with CrCl 30 to 59 mL/minute were rate of 0.6 mL/hour for 7 days through a dedicated
similar to the range observed in patients with normal lumen. Use a programmable, lockable, nonelasto-
renal function. meric infusion pump with an alarm; an in-line filter is
CrCl <30 mL/minute: There are no dosage adjustments not required for the 7-day infusion bag. Infusion bag
provided in the manufacturer's labeling (has not been contains overfill (to account for tubing priming vol-
studied). ume). Do not flush infusion line, particularly when
Hemodialysis: There are no dosage adjustments pro- changing infusion bags or at completion of infusion;
vided in the manufacturer's labeling (has not been may result in excess dosage and complications. Do
studied). not infuse other medications through the same line.
Hepatic Impairment: Pediatric All patients: Monitoring Parameters CBC with differential, liver func-
Baseline hepatic impairment: There are no dosage tion tests (ALT, AST, GGT, and total bilirubin) at baseline
adjustments provided in the manufacturer's labeling and throughout therapy; signs/symptoms of cytokine
(has not been studied). release syndrome, infusion reactions, neurotoxicity, infec-
Hepatotoxicity during treatment: Interrupt therapy: if tion, pancreatitis and tumor lysis syndrome
transaminases are >5 times ULN or if bilirubin is >3 Dosage Forms Considerations Provided with IV solu-
times ULN tion stabilizer to coat the prefilled NS bag prior to addition
Preparation for Administration Note: Preparation and of reconstituted blinatumomab (do NOT use IV solution
administration errors have occurred; follow preparation stabilizer for reconstitution of blinatumomab).
instructions carefully. Refer to manufacturer's labeling for Dosage Forms Excipient information presented when
further information. available (limited, particularly for generics); consult spe-
Reconstitute each vial of lyophilized powder with 3 mL of cific product labeling.
preservative-free SWFI (do not reconstitute vials with Solution Reconstituted, Intravenous [preservative free]:
the IV solution stabilizer); direct stream toward the side Blincyto: 35 mcg (1 ea) [contains polysorbate 80]
of the vial and gently swirl to avoid excess foaming. Do @ Blincyto see Blinatumomab on page 282
not shake; final reconstituted concentration is 12.5
mcg/mL. Reconstituted solution should be clear to @ Blistex Medicated [OTC] see Benzocaine on page 257
slightly opalescent, colorless to slightly yellow; do not @ BLM see Bleomycin on page 280
use if cloudy or if precipitation occurs. Note: Some Bloxiverz see Neostigmine on page 1439
doses may require reconstitution of more than 1 vial of
BMS-188667 see Abatacept on page 32
lyophilized powder.
24- or 48-hour infusion: Add 270 mL NS to an empty IV BMS-232632 see Atazanavir on page 197
bag; use only polyolefin, non-DEHP PVC (non-di-ethyl- BMS 337039 see ARIPiprazole on page 174
hexylphthalate PVC), or ethyl vinyl acetate (EVA) infu- BMS-936558 see Nivolumab on page 1464
sion bags or pump cassettes. Transfer 5.5 mL of IV
B&O see Belladonna and Opium on page 253
solution stabilizer to the IV bag; gently mix to avoid
foaming. Transfer the appropriate dose volume of BOL-303224-A see Besifloxacin on page 265
reconstituted blinatumomab solution to the IV bag @
$eBoostrix see Diphtheria and Tetanus Toxoids, and Acel-
and gently mix; refer to manufacturer labeling for the lular Pertussis Vaccine on page 664
specific volume of reconstituted drug to be added. If not . Boostrix-Polio (Can) see Diphtheria and Tetanus Tox-
used immediately, store at 2°C to 8°C (36°F to 46°F) for oids, Acellular Pertussis, and Poliovirus Vaccine
up to 8 days (infusion must be completed within this on page 660
time frame).
@ Boro-Packs [OTC] see Aluminum Acetate on page 100
7-day infusion (patients weighing 222 kg): Add 90 mL
bacteriostatic NS to an empty IV bag; use only poly-
olefin, non-DEHP PVC, or ethyl vinyl acetate (EVA) Bosentan (boe SEN tan)
infusion bags or pump cassettes. Transfer 2.2 mL of
IV solution stabilizer to the IV bag; gently mix to avoid Medication Safety Issues
foaming. Transfer the appropriate dose volume of Sound-alike/look-alike issues:
reconstituted blinatumomab solution to the IV bag Tracleer may be confused with TriCor
and gently mix; refer to manufacturer labeling for the High alert medication:
specific volume of reconstituted drug to be added. Add The Institute for Safe Medication Practices (ISMP)
NS to the IV bag to make a final volume of 110 mL includes this medication among its list of drugs which
(resulting in 0.74% benzyl alcohol); gently mix (avoid have a heightened risk of causing significant patient
foaming). If not used immediately, store at 2°C to 8°C harm when used in error.
(36°F to 46°F) for up to 14 days (infusion must be Related Information
completed within this time frame). Oral Medications That Should Not Be Crushed or Altered
Administration Premedication: For pediatric patients, on page 2217
premedicate with dexamethasone 5 mg/m? IV (maximum Brand Names: US Tracleer
dose: 20 mg/dose) and in adults 20 mg; administer Brand Names: Canada Tracleer

284
 BOSENTAN

Therapeutic Category Endothelin Receptor Antagonist transdermal, and implantable contraceptives, should
Generic Availability (US) No not be used as the sole means of contraception
Use Treatment of pulmonary arterial hypertension (PAH) because these may not be effective in patients receiv-
[WHO Group |] in patients with NYHA Class Il, Ill, or IV ing bosentan. Obtain monthly pregnancy tests.
symptoms to improve exercise capacity and decrease the [US Boxed Warning]: Because of the risks of hepato-
rate of clinical deterioration (FDA approved in ages >12 toxicity and birth defects, bosentan is only available
years and adults); Note: Clinical trials establishing effec- through the Tracleer REMS Program. The Tracleer
tiveness included primarily patients with NYHA Functional REMS Program is a component of the bosentan Risk
Class |I-IV symptoms. Evaluation and Mitigation Strategy (REMS). Patients,
Medication Guide Available Yes prescribers, and pharmacies must enroll with the
Pregnancy Considerations [US Boxed Warning]: program. Call 1-866-228-3546 or visit http://www.-
Bosentan is likely to cause major birth defects if used tracleer.com/hcp/prescribing-tracleer.asp for more infor-
by pregnant women based on animal data. Therefore, mation.
pregnancy must be excluded before the start of treat-
ment with bosentan. Throughout treatment and for 1 Dose-related decreases in hematocrit/hemoglobin may be
month after stopping bosentan, women of childbear- observed, usually within the first few weeks of therapy with
ing potential must use 2 reliable methods of contra- subsequent stabilization of levels by 4 to 12 weeks of
ception unless the patient has an intrauterine device treatment. Monitor hemoglobin prior to treatment initiation,
(IUD) or tubal sterilization in which case no other after 1 and 3 months, and every 3 months thereafter.
contraception is needed. Hormonal contraceptives, Significant decreases in hemoglobin require further eval-
including oral, injectable, transdermal, and implant- uation to determine the cause and specific management.
able contraceptives, should not be used as the sole Development of peripheral edema due to treatment and/or
means of contraception because these may not be disease state (pulmonary arterial hypertension) may
‘effective in patients receiving bosentan. Obtain occur. There have also been postmarketing reports of fluid
monthly pregnancy tests. When a hormonal or barrier retention requiring treatment (eg, diuretics, fluid manage-
contraceptive is used, one additional method of contra- ment, hospitalization) for heart failure. If clinically signifi-
ception is still needed if a male partner has had a vasec- cant fluid retention develops (with or without weight gain),
tomy. When initiating treatment for women of reproductive further evaluation is necessary to determine cause and
potential, a negative pregnancy test should be docu- appropriate treatment or discontinuation of therapy. Use
mented within the first 5 days of anormal menstrual period with caution in patients with underlying heart failure due to
and 211 days after the last unprotected intercourse. A potential complications from fluid retention. In a scientific
missed menses or suspected pregnancy should be statement from the American Heart Association, bosentan
reported to a healthcare provider and prompt immediate has been determined to be an agent that may exacerbate
pregnancy testing. Sperm counts may be reduced in men underlying myocardial dysfunction (magnitude: major)
during treatment. Women with pulmonary arterial hyper- (AHA [Page 2016]). If signs of pulmonary edema occur,
tension (PAH) are encouraged to avoid pregnancy consider possibility of pulmonary veno-occlusive disease;
(McLaughlin 2009; Taichman 2014). may require discontinuation of bosentan. Hypersensitivity
Breastfeeding Considerations It is not known if bosen- reactions, including Drug Reaction with Eosinophilia and
tan is present in breast milk. Due to the potential for Systemic Symptoms (DRESS), anaphylaxis, rash and
serious adverse reactions in the breastfed infant, breast- angioedema have been observed. Decreased sperm
feeding is not recommended by the manufacturer. counts have been observed in men during treatment;
Contraindications bosentan may have an adverse effect on spermatogene-
Hypersensitivity to bosentan or any component of the sis. Potentially significant drug-drug interactions may
formulation; concurrent use of cyclosporine or glyburide; exist, requiring dose or frequency adjustment, additional
use in women who are or may become pregnant. monitoring, and/or selection of alternative therapy.
Canadian labeling: Additional contraindications (not in US Adverse Reactions
labeling): Moderate to severe hepatic impairment (eg, Cardiovascular: Chest pain, edema, flushing, hypoten-
ALT or AST >3 times ULN, particularly when total bilir- sion, palpitations, syncope
ubin >2 times ULN). Central nervous system: Headache
Warnings/Precautions [US Boxed Warning]: Bosen- Endocrine & metabolic: Fluid retention
tan is associated with transaminase elevations (ALT Hematologic & oncologic: Anemia
or AST 23 times ULN), and in a small number of cases Hepatic: Increased serum ALT (dose-related), increased
may occur with elevations in bilirubin. Monitor trans- serum AST (dose-related)
aminases at baseline then monthly thereafter. Adjust Neuromuscular & skeletal: Arthralgia
dosage if elevations in liver enzymes occur without Respiratory: Respiratory tract infection, sinusitis
symptoms of hepatic injury or elevated bilirubin. In Rare but important or life-threatening: Anaphylaxis,
the postmarketing surveillance (with close monitor- DRESS syndrome, fluid retention, hepatic cirrhosis (pro-
ing), there have been rare cases of unexplained hep- longed therapy), hepatic failure (rare), hypersensitivity
atic cirrhosis after prolonged therapy (>12 months) in reaction, leukopenia, neutropenia, severe anemia, skin
patients with multiple comorbidities and drug thera- rash, thrombocytopenia
pies. There have also been cases of hepatic failure. Drug Interactions
Treatment should be stopped in patients who develop Metabolism/Transport Effects Substrate of CYP2C9
elevated transaminases either in combination with (minor), CYP3A4 (minor), OATP1B1/SLCO1B1; Note:
symptoms of hepatic injury (unusual fatigue, jaun- Assignment of Major/Minor substrate status based on
dice, nausea, vomiting, abdominal pain, and/or fever) clinically relevant drug interaction potential; Induces
or elevated bilirubin (22 times ULN); safety of reintro- CYP2C9 (weak), CYP3A4 (moderate)
duction is unknown. Avoid use in patients with base- Avoid Concomitant Use
line serum transaminases >3 times ULN at baseline Avoid concomitant use of Bosentan with any of the
(monitoring for hepatotoxicity may be more difficult) following: Antihepaciviral Combination Products; Asu-
or moderate-to-severe hepatic impairment. The combi- naprevir; Axitinib; Bedaquiline; Bosutinib; Cobimetinib;
nation of hepatocellular injury (transaminase elevations >3 CycloSPORINE (Systemic); Dasabuvir; Deflazacort;
times ULN) and bilirubin increased 22 times ULN are a Elbasvir; Flibanserin; GlyBURIDE; Grazoprevir; Nerati-
marker for potential serious hepatotoxicity. Transaminase nib; Nisoldipine; Olaparib; Ranolazine; Simeprevir; Soni-
elevations are dose dependent, generally asymptomatic, degib; Ulipristal; Velpatasvir; Venetoclax
occur both early and late in therapy, progress slowly, and Increased Effect/Toxicity
are usually reversible after treatment interruption ordis- Bosentan may increase the levels/effects of: Clarithro-
continuation. Transaminase elevations may also sponta- mycin; lfosfamide
neously reverse while continuing bosentan treatment.
The levels/effects of Bosentan may be increased by:
Consider the benefits of treatment versus the risk of
Atazanavir; Boceprevir; Clarithromycin; Cobicistat;
hepatotoxicity when initiating therapy in patients with
CycloSPORINE (Systemic); CYP2C9 Inhibitors (Moder-
WHO Class II symptoms.
ate); CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors
[US Boxed Warning]: Bosentan is likely to cause (Strong); Darunavir; Elttombopag; Fosamprenavir; Gem-
major birth defects if used by pregnant women based fibrozil; GlyBURIDE; Indinavir; Lopinavir; Nelfinavir;
on animal data. Therefore, pregnancy must be Phosphodiesterase 5 Inhibitors; RifAMPin; Ritonavir;
excluded before the start of treatment with bosentan. Saquinavir; Telaprevir; Teriflunomide; Tipranavir; Tol-
Throughout treatment and for 1 month after stopping vaptan
bosentan, women of childbearing potential must use 2 Decreased Effect
reliable methods of contraception unless the patient Bosentan may decrease the levels/effects of: Antihepa-
has an intrautetine device (IUD) or tubal sterilization civiral Combination Products; Asunaprevir; Atazanavir;
in which case’ no other contraception is needed. Axitinib; Bedaquiline; Benzhydrocodone; Boceprevir;
Hormonal contraceptives, including oral, injectable, Bosutinib; Clarithromycin; CloZAPine; Cobimetinib; >
BOSENTAN

Codeine; CycloSPORINE (Systemic); CYP3A4 Sub- subsequent discontinuation at 96 hours of treatment

strates (High risk with Inducers); Daclatasvir; Darunavir; (Nakwan 2009).
Dasabuvir; Deflazacort; Elbasvir; Estriol (Systemic); Pediatric
Estriol (Topical); Estrogen Derivatives (Contraceptive); Pulmonary arterial hypertension:
FentaNYL; Flibanserin; Fosamprenavir; Glecaprevir Infants 27 months and Children: Limited data avail-
and Pibrentasvir; GlyBURIDE; Grazoprevir; GuanFA- able (Barst 2003; Ivy 2004; Maiya 2006; Rose-
CINE; HYDROcodone; Ibrutinib; Ifosfamide; Indinavir; nzweig 2005):
Lopinavir; Lurasidone; Macimorelin; Mirodenafil; Nalde- Fixed dosing:
medine; Nelfinavir; Neratinib; NiMODipine; Nisoldipine; 5 to <10 kg: Initial: 15.6 mg daily for 4 weeks;
Olaparib; Palbociclib; Perampanel; Phosphodiesterase 5 increase to maintenance dose of 15.6 mg twice
Inhibitors; Progestins (Contraceptive); Ranolazine; Rola- daily
pitant; Saquinavir; Simeprevir; Simvastatin; Sonidegib; 10 to 20 kg: Initial: 31.25 mg daily for 4 weeks;
Telaprevir; Tipranavir; Ulipristal; Velpatasvir; Venetoclax; increase to maintenance dose of 31:25 mg twice
Vitamin K Antagonists; Zolpidem daily
>20 to 40 kg: Initial: 31.25 mg twice daily for 4
The levels/effects of Bosentan may be decreased by:
weeks; increase to maintenance dose of 62.5 mg
GlyBURIDE; RifAMPin
twice daily
Food Interactions Bioavailability of bosentan is not
>40 kg: Initial: 62.5 mg twice daily for 4 weeks;
affected by food. Bosentan serum concentrations may
increase to maintenance dose of 125 mg twice
be increased by grapefruit juice. Management: Avoid
daily
grapefruit/grapefruit juice.
Weight-based dosing: Children 22 years: Initial: 0.75
Hazardous Drugs Handling Considerations to 1 mg/kg/dose twice daily for 4 weeks (maximum
Hazardous agent (NIOSH 2016 [group 3)). dose: 62.5 mg); then increase to maintenance
Use appropriate precautions for receiving, handling, dose of 2 mg/kg/dose twice daily (maximum dose:
administration, and disposal. Gloves (single) should be $40 kg: 62.5 mg; maximum dose: >40 kg:
worn during receiving, unpacking, and placing in storage. 125 mg); a higher daily dose of 4 mg/kg/dose twice
daily has been studied but has not been shown to
NIOSH recommends single gloving for administration of produce higher serum concentrations than
intact tablets or capsules. If manipulating tablets/capsules 2 mg/kg/dose and is not recommended by authors
(eg, to prepare an oral suspension), NIOSH recommends of the trial (Beghetti 2009; Beghetti 2009a, Villa-
double gloving, a protective gown, and preparation in a nueva 2006) '
controlled device; if not prepared in a controlled device, Adolescents <40 kg: Initial and maintenance: 62.5 mg
respiratory and eye/face protection as well as ventilated twice daily
engineering controls are recommended. NIOSH recom- Adolescents 240 kg: Initial: 62.5 mg twice daily for 4
mends double gloving, a protective gown, and (if there is a weeks; increase to maintenance dose of 125 mg
potential for vomit or spit up) eye/face protection for twice daily; Note: Doses >125 mg twice daily do
administration of an oral liquid/feeding tube administration not provide additional benefit sufficient to offset the
(NIOSH 2016). Assess risk to determine appropriate con- increased risk of hepatic injury. When discontinuing
tainment strategy (USP-NF 2017). treatment, consider a reduction in dosage to
Storage/Stability Store film-coated and dispersible tab- 62.5 mg twice daily for 3 to 7 days to avoid clinical
lets at 20°C to 25°C (68°F to 77°F); excursions permitted deterioration.
to 15°C to 30°C (59°F to 86°F). Store divided dispersible Dosage adjustment with concomitant protease
tablet pieces in the opened blister for up to 7 days. inhibitor therapy: There are no pediatric-specific rec-
Mechanism of Action Endothelian receptor antagonist ommendations; based on experience in adult patients,
that blocks endothelin receptors on endothelium and dosage adjustment suggested for concurrent use with
vascular smooth muscle (stimulation of these receptors atazanavir/ritonavir, darunavir/ritonavir, fosamprenavir,
is associated with vasoconstriction). Bosentan blocks both indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saqui-
ET, and ETz receptors, with a slightly higher affinity for the navir/ritonavir, or tipranavir/ritonavir.
A subtype. Renal Impairment: Pediatric No dosage adjustment
Pharmacodynamics/Kinetics (Adult data unless required. Bosentan is unlikely to be removed by dialysis
noted) (due to high molecular weight and extensive plasma
Distribution: Vg: ~18 L (does not distribute into RBCs) protein binding).
Protein binding, plasma: >98%, primarily to albumin Hepatic Impairment: Pediatric
Metabolism: Hepatic via CYP2C9 and 3A4 to three metab- Baseline: All patients:
olites (one active, contributing ~10% to 20% pharmaco- Mild impairment (Child-Pugh class A): No dosage
logic activity); steady-state plasma concentrations are adjustment necessary.
50% to 65% of those attained after single dose (most Moderate to severe impairment (Child-Pugh class B
likely due to autoinduction of liver enzymes); steady- and C) and/or baseline transaminase >3 times ULN:
state is attained within 3 to 5 days Avoid use; systemic exposure is significantly
Bioavailability: ~50% increased in patients with moderate impairment (has
Half-life elimination: ~5 hours; prolonged with heart failure, not been studied in severe impairment).
possibly in PAH Hepatoxicity during therapy: Adjustment based on trans-
Time to peak, plasma: 3 to 5 hours aminase elevation:
Excretion: Feces (as metabolites); urine (<3% as Transaminase elevations accompanied by clinical
unchanged drug) symptoms of hepatotoxicity (unusual fatigue, nausea,
Pharmacodynamics/Kinetics: Additional Consider- vomiting, abdominal pain, fever, or jaundice) or a
ations serum bilirubin 22 times ULN: Discontinue treatment.
Renal function impairment: In patients with severe renal AST/ALT >3 times but <5 times ULN:
impairment (CrCl 15 to 30 mL/minute), concentrations of Children 3 to $12 years: Confirm with additional test; if
the 3 metabolites may increase 2-fold, although it is not confirmed, interrupt treatment with no prior dose
clinically significant. reduction. If transaminase levels return to pretreat-
Hepatic function impairment: Exposure to bosentan may ment values, may reintroduce treatment at the dose
be significantly increased. in hepatic impairment. used prior to treatment interruption. When reintro-
Pediatric: Exposure to bosentan reaches a plateau at ducing treatment, recheck transaminases within 3
lower doses in pediatric patients than in adults, and days and at least every 2 weeks thereafter.
doses >2 mg/kg twice daily do not increase the exposure Adolescents: Confirm with additional test; if con-
to bosentan in pediatric patients. firmed, reduce dose to 62.5 mg twice daily or inter-
Dosing rupt treatment and monitor at least every 2 weeks. If
Neonatal Persistant pulmonary hypertension (PPHN): transaminase levels return to pretreatment values,
Very limited data available: Full-term neonate: Oral: may continue or reintroduce treatment (at the start-
1 mg/kg/dose twice daily short-term use (2 to 16 days) ing dose), as appropriate. When reintroducing treat-
in three full-term neonates has been reported. In the ment, recheck transaminases within 3 days and at
initial report, two full-term neonates (8 days and 14 days least every 2 weeks thereafter.
old) with persistent pulmonary hypertension of the new- AST/ALT >5 times but <8 times ULN:
born (PPHN) and transposition of the great arteries Children 3 to $12 years: Confirm with additional test; if
received bosentan prior to cardiac surgery; patients also confirmed, stop treatment. Monitor transaminase
received other therapies (Goissen 2008). A case report levels at least every 2 weeks. If transaminase levels
describes the use of bosentan monotherapy for PPHN in return to pretreatment values, consider reintroduc-
a full-term neonate as primary course of treatment ini- tion at the dose used prior to treatment interruption.
tiated at 29 hours of life; therapy was weaned after. 72 When reintroducing treatment, recheck transami-
hours through the following dose reductions: 0.5 mg/kg/ nases within 3 days and at least every 2 weeks
dose twice daily followed by 0.5 mg/kg once daily and thereafter.

286
 BOTULISM ANTITOXIN, HEPTAVALENT

Adolescents: Confirm with additional test; if con- CDC is available at https://www.cdc.gov/laboratory/drug-

firmed, stop treatment. Monitor transaminase levels service/formulary.htm|.
at least every 2 weeks. If transaminase levels return Pregnancy Considerations Animal reproduction studies
to pretreatment values, may reintroduce treatment have not been conducted. Based on limited information
(at the starting dose) as appropriate. When reintro- with the use of the previous equine products (BAT-AB;
ducing treatment, recheck transaminases within 3 BAT-E), there is no indication that treatment of pregnant
days and at least every 2 weeks thereafter. patients with botulism should differ from standard therapy
AST/ALT >8 times ULN: Stop treatment and do not (Arnon 2001). In general, medications used as antidotes
reintroduce. should take into consideration the health and prognosis of
Administration Oral: May be administered without regard the mother; antidotes should be administered to pregnant
to meals. Avoid grapefruit and grapefruit juice. Women of women if there is a clear indication for use and should not
childbearing potential should avoid splitting, crushing, or be withheld because of fears of teratogenicity (Bailey
handling broken tablets and exposure to the generated 2003).
dust (tablets should be dissolved in water if necessary). Breastfeeding Considerations It is not known if botu-
Monitoring Parameters Serum transaminase (AST and lism antitoxin is present in breast milk. Due to the potential
ALT) and bilirubin should be determined prior to the for serious adverse reactions in the breastfed infant, the
initiation of therapy and at monthly intervals thereafter. manufacturer recommends a decision be made whether to
Monitor for clinical signs and symptoms of liver injury (eg, discontinue nursing or to discontinue the drug, taking into
abdominal pain, fatigue, fever, jaundice, nausea, vomit- account the importance of treatment to the mother.
ing). Hemoglobin and hematocrit should be measured at Contraindications There are no contraindications listed
baseline, after 1 and 3 months of treatment, and every 3 in the manufacturer’s labeling.
months thereafter. Warnings/Precautions Severe hypersensitivity reac-
tions, including anaphylaxis and anaphylactoid reactions,
~ A woman of childbearing potential must have a negative may occur. The risk is greatest in patients with a history of
pregnancy test prior to the initiation of therapy, monthly hypersensitivity to horses or equine blood products,
thereafter, and 1 month after stopping therapy. asthma, or hay fever; initiate treatment at the lowest
Additional Information The addition of bosentan to achievable infusion rate (<0.01 mL/minute) is recom-
epoprostenol therapy in 8 children (8-18 years of age) mended. Monitor all patients for acute allergic reactions
with idiopathic PAH allowed for a reduction in the epo- during and following the infusion; discontinue antitoxin
prostenol dose (and its associated side effects) in 7 of the administration in patients who develop a hypersensitivity
8 children. Epoprostenol was able to be discontinued in 3 reaction. Immediate treatment (including epinephrine
of the 8 children (Ivy, 2004). 1 mg/mL) should be available. Delayed allergic reaction
Dosage Forms Excipient information presented when or serum sickness (eg, arthralgia, fever, lymphadenop-
available (limited, particularly for generics); consult spe- athy, myalgia, urticarial or maculopapular rash) may occur
cific product labeling. 10 to 21 days after administration. Monitor all patients for
Tablet, Oral: delayed allergic reactions.
Tracleer: 62.5 mg, 125 mg
Infusion reactions (eg, arthralgia, chills, fatigue, fever,
Tablet Soluble, Oral:
headache, myalgia, nausea, vasovagal reactions, vomit-
Tracleer: 32 mg [scored; contains aspartame]
ing) may occur; monitor all patients for infusion reactions
Extemporaneous Preparations Note: Tablets are not
during and following the infusion. In patients who develop
scored; a commercial pill cutter should be used to prepare
an infusion reaction, decrease the infusion rate and treat
a 31.25 mg dose from the 62.5 mg tablet; the half-cut
symptomatically; if symptoms worsen, discontinue the
62.5 mg tablets are stable for up to 4 weeks when stored
infusion. Product of equine (horse) plasma; may poten-
at room temperature in the high-density polyethylene tially contain infectious agents (eg, viruses) which could
plastic bottle provided by the manufacturer.
transmit disease. Infections thought to be transmitted by
Crushing of the tablets is not recommended; bosentan this product should be reported to the manufacturer at
tablets will disintegrate rapidly (within 5 minutes) in 5 to 25 1-800-768-2304.
mL of water to create a suspension. An appropriate aliquot Antitoxin is most effective if administered as early as
of the suspension can be used to deliver the prescribed possible (ideally within 12 to 48 hours) after the onset of
dose. Any remaining suspension should be discarded. neurologic symptoms (Fagan 2011a). Antitoxin does not
Bosentan should not be mixed or dissolved in liquids with reverse existing paralysis, but it arrests its progression.
a low (acidic) pH (eg, fruit juices) due to poor solubility; the
drug is most soluble in solutions with a pH >8.5. Each vial contains a minimum antitoxin potency. The total
volume contained in one vial (regardless of vial size) will
@ Botox see OnabotulinumtoxinA on page 1498 differ by lot number (~10 to 22 mL per vial); therefore,
@ Botox Cosmetic see OnabotulinumtoxinA on page 1498 withdrawal of the entire vial contents will be required to
@ Botulinum Antitoxin see Botulism Antitoxin, Heptava- calculate the dose. May contain maltose which may falsely
lent on page 287 elevate glucose readings. Some dosage forms may con-
tain polysorbate 80 (also known as Tweens). Hypersensi-
@ Botulinum Toxin Type A see AbobotulinumtoxinA tivity reactions, usually a delayed reaction, have been
on page 34 reported following exposure to pharmaceutical products
® Botulinum Toxin Type A see OnabotulinumtoxinA containing polysorbate 80 in certain individuals (Isaksson
on page 1498 2002; Lucente 2000; Shelley 1995). Thrombocytopenia,
@ Botulism Antitoxin see Botulism Antitoxin, Heptavalent ascites, pulmonary deterioration, and renal and hepatic
on page 287 failure have been reported in premature neonates after
receiving parenteral products containing polysorbate 80
@ Botulism Antitoxin 7/Maltose see Botulism Antitoxin,
(Alade 1986; CDC 1984). See manufacturer's labeling.
Heptavalent on page 287
Warnings: Additional Pediatric Considerations The
safety and efficacy information in pediatric patients is
Botulism Antitoxin, Heptavalent derived from animal model studies. Dosing in pediatric
(BOT yoo lism an tee TOKS in hep ta VAY lent) patients is based on the Salisbury Rule. Limited pediatric
data safety data available; a CDC expanded access
Therapeutic Category Antitoxin clinical study including 15 pediatric subjects (age range:
Generic Availability (US) Yes 10 days to 17 years) reported adverse reactions in two
Use Treatment of symptomatic botulism following docu- patients; one subject experienced tachycardia, bradycar-
mented or suspected exposure to any of the seven dia, and asystole during infusion; pyrexia was reported in
serotypes of botulinum neurotoxin serotypes (serotypes the other patient.
A, B, C, D, E, F, or G) (FDA approved in pédiatric patients Adverse Reactions
[age not specified] and adults) Cardiovascular: Edema
Prescribing and Access Restrictions Heptavalent bot- Central nervous system: Chills, headache
ulism antitoxin is not available for general public use. All Dermatologic: Pruritus, skin rash, urticaria
supplies are currently owned by the federal government Gastrointestinal: Nausea, sore throat
for inclusion in the Strategic National Stockpile and are Miscellaneous: Fever
distributed by the Centers for Disease Control and Pre- Rare but important or life-threatening: Agitation, anaphy-
vention (CDC). Clinicians who suspect botulism in a lactic shock, anaphylactoid reaction, anaphylaxis,
patient are instructed to call their state health depart- angioedema, anxiety, asystole, bradycardia, broncho-
ment’s ernergency 24-hour telephone number; the state spasm, chest discomfort, erythema, hyperhidrosis,
health department will contact the CDC to request release hypersensitivity reaction, hypotension, increased blood
of botulism antitoxin, if indicated. State health depart- pressure, infusion related reaction, jitteriness, leukocy-
ments can contact the CDC at their 24-hour telephone tosis, serum sickness, tachycardia, urinary retention,
number at (770) 488-7100. Additional information from the vomiting

287
BOTULISM ANTITOXIN, HEPTAVALENT

Drug Interactions >30 kg: Percentage (%) of Adult Dose to be

Metabolism/Transport Effects None known. Administered = Weight (kg) + 30
Avoid Concomitant Use There are no known interac- The following doses are recommended using the
tions where it is recommended to avoid concomitant use. above equations:
Increased Effect/Toxicity There are no known signifi- 10 to 14 kg: 20% of one vial
cant interactions involving an increase in effect. 15 to 19 kg: 30% of one vial
Decreased Effect There are no known significant inter- 20 to 24 kg: 40% of one vial
actions involving a decrease in effect. 25 to 29 kg: 50% of one vial
Storage/Stability Store intact vials frozen at <-15°C 30 to 34 kg: 60% of one vial
(s5°F) until use; once thawed, may be stored at 2°C to 35 to 39 kg: 65% of one vial
8°C (36°F to 48°F) for up to 36 months or until 48 months 40 to 44 kg: 70% of one vial
from date of manufacture (whichever comes first). 45 to 49 kg: 75% of one vial
Mechanism of Action Contains toxin-specific F(ab')> and 50 to 54 kg: 80% of one vial
F(ab’)s-related antibody fragments which bind and neu- 255 kg: One vial
tralize free botulinum neurotoxinA, B, C, D, E, F, and G. Adolescents 217 years: One vial
As a result, the neurotoxins are prevented from interacting Renal Impairment: Pediatric There are no dosage
with the cholinergic nerve ending and internalizing into adjustment provided in manufacturer's labeling (has not
target cells, thereby minimizing nerve damage and been studied).
severity of the disease. Clinicians should note that botu- Hepatic Impairment: Pediatric There are no dosage
lism antitoxin does not reverse preexisting toxic manifes- adjustment provided in manufacturer's labeling (has not
tations. been studied).
Pharmacodynamics/Kinetics (Adult data unless Preparation for Administration Bring vial to room tem-
noted) perature prior to preparation. Do not shake vial during
Distribution: Vg: preparation to avoid foaming.
Antitoxin serotype A: 3.6 L Intradermal: Skin sensitivity testing: Dilute in NS to a
Antitoxin serotype B: 9.6 L 1:1,000 dilution (first step) or 1:100 dilution (second step)
Antitoxin serotype C: 6.1 L IV: Botulism treatment: Dilute to a 1:10 dilution in NS. The
Antitoxin serotype D: 1.5 L total volume contained in one vial (regardless of vial
Antitoxin serotype E: 14.2 L size) will differ by lot number (~10 to 22 mL per vial);
Antitoxin serotype F: 3.4 L therefore, in patients receiving a dose equal to 1 vial, 90
Antitoxin serotype G: 2.4 L to 200 mL of NS will be required to prepare a 1:10
Half-life elimination:
dilution. In order to calculate partial vial doses (eg, neo-
Antitoxin serotype A: 8.6 hours
natal/pediatric dosing), withdraw the entire contents of
Antitoxin serotype B: 34.2 hours
the vial to determine the total volume in the vial since
Antitoxin serotype C: 29.6 hours
varies with lot number and then calculate percentage
Antitoxin serotype D: 7.5 hours
partial dose and diluent volume to prepare 1:10 dilution.
Antitoxin serotype E: 7.8 hours
Do not use if the solution is turbid, cloudy, or contains
Antitoxin serotype F: 14.1 hours
particles. Discard any unused portion. -
Antitoxin serotype G: 11.7 hours
Dosing Administration
Neonatal Note: Consider a pretreatment skin sensitivity Intradermal: Skin sensitivity testing: Administer enough
test in patients at risk for severe hypersensitivity reac- diluted antitoxin intradermally on the volar surface of
tion. The total volume contained in one vial (regardless the forearm to raise a small wheal; perform concurrent
of vial size) will differ by lot number (~10 to 22 mL per positive (histamine) and negative (saline) control tests.
vial). In order to calculate partial vial doses (eg, neonatal IV: Botulism treatment: Consider a pretreatment skin
dosing), withdrawal of the entire contents of the vial to sensitivity test in patients at risk for severe hypersensi-
determine the total volume in the vial is required. tivity reactions. Treatment doses should be diluted to a
Skin sensitivity test: Intradermal: 0.02 mL of a 1:1,000 1:10 dilution prior to administration. Use of an in-line filter
dilution in NS administered intradermally on the volar is optional. A slower infusion rate should be used during
surface of the forearm; if the test is negative, repeat the the first 30 minutes of treatment; if tolerated, may
test using a 1:100 dilution. Perform concurrent positive increase rate every 30 minutes up to the maximum
(histamine) and negative (saline) control tests. A pos- infusion rate for the remainder of the infusion. Monitor
itive reaction is a wheal with surrounding erythema 23 vital signs throughout the infusion. Initiate and increase
mm larger than the negative control test (saline) when the infusion rate as follows:
read at 15 to 20 minutes. The histamine control test Pediatric:
must be positive for valid interpretation. A negative Infants <1 year: Initial: 0.01 mL/kg/minute; may
reaction does not rule out the possibility of an immedi- increase the rate by 0.01 mL/kg/minute every 30
ate or delayed reaction with treatment. minutes to a maximum infusion rate of 0.03 mL/kg/
Botulism, treatment: IV: 10% of the adult dose (one minute
vial), regardless of body weight Children 21 year and Adolescents <17 years: Initial:
Pediatric Note: Consider a pretreatment. skin sensitivity 0.01 mL/kg/minute (maximum initial rate: 0.5 mL/
test in patients at risk for severe hypersensitivity reac- minute); may increase the rate by 0.01 mL/kg/minute
tions. The total volume contained in one vial (regardless every 30 minutes to a maximum infusion rate of 0.03
of vial size) will differ by lot number (~10 to 22 mL per mL/kg/minute (maximum rate: 2 mL/minute)
vial). In order to calculate partial vial doses (eg, pediatric Adolescents 217 years: Initial: 0.5 mL/minutes; may
dosing), withdrawal of the entire contents of the vial to double the infusion rate, if tolerated, every 30 minutes
determine the total volume in the vial is required. to a maximum infusion rate of 2 mL/minute
Skin sensitivity test: Infants, Children, and Adoles- Adult: Initial: 0.5 mL/minutes; may double the infusion
cents: Intradermal: 0.02 mL of a 1:1,000 dilution in NS rate, if tolerated, every 30 minutes to a maximum
administered intradermally on the volar surface of the infusion rate of 2 mL/minute
forearm; if the test is negative, repeat the test using a
Monitoring Parameters Monitor vital signs and for the
1:100 dilution. Perform concurrent positive (hista-
presence of infusion-related reactions and acute hyper-
mine) and negative (saline) control tests. A positive
sensitivity reactions during and immediately following
reaction is a wheal with surrounding erythema 23 mm
infusion; monitor for delayed allergic reactions for 10 to
larger than the negative control test (saline) when
21 days after administration.
read at 15 to 20 minutes. The histamine control test
must be positive for valid interpretation. A negative Test Interactions Blood glucose: Administration may
reaction does not rule out the possibility of an imme- result in falsely elevated blood glucose concentrations
diate or delayed reaction with treatment. due to the presence of maltose in the botulism antitoxin,
Botulism, treatment: specifically when blood glucose is measured using glu-
Infants <1 year: IV: 10% of the adult dose (one vial), cose dehydrogenase pyrroloquinoline-quinone (GDH-
regardless of body weight PQQ) method.
Children 21 year and Adolescents <17 years: IV: 20% Dosage Forms Excipient information presented when
to 100% of the adult dose dependent upon patient available (limited, particularly for generics); consult spe-
weight; minimum dose: 20% of one vial; maximum cific product labeling.
dose: One vial Injection, solution [preservative free]: Each vial contains
The percentage of the adult dose to be administered no less than serotype A antitoxin 4500 units, serotype B
is based on patient weight according to the follow- antitoxin 3300 units, serotype C antitoxin 3000 units,
- ing Salisbury Rule equations: serotype D antitoxin 600 units, serotype E antitoxin
<30 kg: Percentage (%) of Adult Dose to be 5100 units, serotype F antitoxin 3000 units, and sero-
Administered = Weight (kg) x 2 type G antitoxin 600 units (20 mL, 50 mL)

288
 BOTULISM IMMUNE GLOBULIN (INTRAVENOUS-HUMAN)

Respiratory: Abnormal breath sounds (decreased), atelec-

Botulism Immune Globulin tasis, cough, dyspnea, lower respiratory tract infection,
(Intravenous-Human) nasal congestion, oxygen saturation decreased, rales,
(BOT yoo lism i MYUN GLOB you lin, in tra VEE nus, YU man) rhonchi, stridor, tachypnea
Miscellaneous: Fever, infusion related reaction (related to
Medication Safety Issues rate: <5%, includes back pain, chills, fever, muscle
Sound-alike/look-alike issues: cramps, nausea, vomiting, wheezing)
BabyBIG may be confused with HBIG Drug Interactions
Brand Names: US BabyBIG Metabolism/Transport Effects None known.
Therapeutic Category Immune Globulin Avoid Concomitant Use There are no known interac-
Generic Availability (US) No tions where it is recommended to avoid concomitant use.
Use Treatment of infant botulism caused by toxin type A or Increased Effect/Toxicity There are no known signifi-
B (FDA approved in ages <1 year) cant interactions involving an increase in effect.
Prescribing and Access Restrictions Access to botu- Decreased Effect
lism immune globulin is restricted through the Infant Botulism Immune Globulin (Intravenous-Human) may
Botulism Treatment and Prevention Program (IBTPP). decrease the levels/effects of: Vaccines (Live)
Healthcare providers must contact the IBTPP on-call Storage/Stability Prior to reconstitution, store between
physician at (510) 231-7600 to review treatment indica- 2°C to 8°C (36°F to 46°F). Infusion should begin within 2
tions and to obtain the medication. For more information, hours of reconstitution and be completed within 4 hours of
refer to http://www.infantbotulism.org or contact reconstitution.
[email protected]. Mechanism of Action BIG-IV is purified immunoglobulin
Pregnancy Considerations Botulism immune globulin is derived from the plasma of adults immunized with botu-
_ only indicated for use in infants <1 year of age. linum toxoid types A and B. BIG-IV provides antibodies to
Contraindications Hypersensitivity to human immune neutralize circulating toxins.
globulin preparations or any component of the formulation;
Pharmacodynamics/Kinetics (Adult data unless
selective immunoglobulin A deficiency
noted) Half-life elimination: Infants: 28 days
Warnings/Precautions Hypersensitivity and anaphylac-
Dosing
tic reactions can occur; immediate treatment (including
Neonatal Infant botulism: Dosage is specific to the
epinephrine 1 mg/mL) should be available. Aseptic men-
manufactured lot. As of November 2013: IV: Total dose
ingitis syndrome (AMS) has been reported with intrave-
is 50 mg/kg as a single IV infusion. Start as soon as
nous immune globulin administration (rare); may occur
diagnosis of infant botulism is made; refer to product
with high doses (22 g/kg). Immune globulin. intravenous
specific information.
(IGIV) has been associated with antiglobulin hemolysis;
monitor for signs of hemolytic anemia. Hyperproteinemia, Pediatric
increased serum viscosity, and hyponatremia may occur Infant botulism: Infants: Dosage is specific to the
following administration of IGIV products; distinguish manufactured lot. As of November 2013: IV: Total dose
hyponatremia from pseudohyponatremia to prevent vol- is 50 mg/kg as a single IV infusion. Start as soon as
ume depletion, a further increase in serum viscosity, and a diagnosis of infant botulism is made; refer to product
higher risk of thrombotic events. These adverse events specific information.
have not reported with botulism immune globulin. Throm- Dosing adjustment for toxicity: Infants: Infusion reac-
botic events have been reported with administration of tions: Slow the infusion rate or temporarily interrupt
IGIV; use with caution in patients with a history of athero- infusion for minor reaction (ie, flushing). Discontinue
sclerosis or cardiovascular and/or thrombotic risk factors infusion and administer epinephrine for anaphylactic
or patients with known/suspected hyperviscosity. Consider reaction or significant hypotension.
a baseline assessment of blood viscosity in patients at risk Renal Impairment: Pediatric Infants: There are no
for hyperviscosity. Infuse at lowest practical rate in dosage adjustments provided in the manufacturer's
patients at risk for thrombotic events. Monitor for trans- labeling. Use with caution; the rate of infusion and
fusion-related acute lung injury (TRALI); noncardiogenic concentration of solution should be minimized in patients
pulmonary edema has been reported with IGIV use. with renal impairment or those at risk for renal dysfunc-
TRALI is characterized by severe respiratory distress, tion.
pulmonary edema, hypoxemia, and fever in the presence Hepatic Impairment: Pediatric Infants: There are no
of normal left ventricular function. Usually occurs within dosage adjustments provided in the manufacturer's
1-6 hours after infusion. labeling.
Preparation for Administration |V infusion: Reconsti-
Acute renal dysfunction (increased serum creatinine, oli-
tute 100 mg vial with 2 mL SWFI; swirl gently to wet
guria, acute renal failure) can rarely occur; usually within 7
powder; do not shake. Allow ~30 minutes for powder to
days of use (more likely with products stabilized with
dissolve; resulting concentration 50 mg/mL.
sucrose). Use with caution in patients with renal disease,
Administration lV infusion: Infusion should be started
diabetes mellitus, volume depletion, sepsis, paraproteine-
within 2 hours of reconstitution and be completed within
mia, and nephrotoxic medications due to risk of renal
4 hours of reconstitution. Do not administer IM or SubQ.
dysfunction. In patients at risk of renal dysfunction, the
Initial: Begin at 25 mg/kg/hour for the first 15 minutes; if
rate of infusion and concentration of solution should be
well tolerated may increase to a maximum rate of
minimized. Patients should not be volume depleted prior
50 mg/kg/hour; infusion should take 67.5 minutes to
to therapy. Product of human plasma; may potentially
contain infectious agents which could transmit disease. complete at the recommended rates and should be
Screening of donors, as well as testing and/or inactivation concluded within 4 hours of reconstitution (unless infu-
or removal of certain viruses, reduces the risk. Infections
sion rate is decreased or temporarily interrupted due to
thought to be transmitted by this product should be an adverse reaction). Use low volume tubing for admin-
reported to the manufacturer. For IV infusion only; do not istration via a separate line. If this is not possible, piggy-
exceed recommended rate of administration. Not indi- back BabyBIG into a preexisting line containing either
cated for use in adults. Safety and efficacy established NS or a dextrose solution (D2.5W, D5W, D10W, or
for infants <1 year of age; not indicated for children 21 D20W) with or without added NaCl. Do not dilute more
year of age. than 1:2 with any of the above solutions. Drug concen-
Adverse Reactions Adverse reactions reported in open- tration should be no less than 25 mg/mL. Administer via
label study except where otherwise noted; may reflect an in-line or syringe-tip filter (18 micron). Do not admin-
pathophysiology of infant botulism. ister if solution is turbid. Infusion should be slowed or
Cardiovascular: Cold exremities, decreased blood pres- temporarily interrupted for minor side effects; discontinue
sure (transient), edema, heart murmur, increased blood in case of hypotension or anaphylaxis. Epinephrine
pressure (transient), tachycardia should be available for the treatment of acute allergic
Central nervous system: Agitation, decreased body tem- reaction.
perature, irritability, neurologic abnormality (neurogenic Monitoring Parameters Vital signs and blood pressure
bladder) monitored continuously during the infusion. BUN and
Dermatologic: Contact dermatitis, erythematous rash, serum creatinine should be monitored prior to initial infu-
pallor fs sion. Periodic monitoring of renal function tests and urine
Endocrine & metabolic: Dehydration, hyponatremia, meta- output in patients at risk for developing renal failure.
bolic acidosis Aseptic meningitis syndrome (may occur hours to days
Gastrointestinal: Abdominal distention, dysphagia, loose following IGIV therapy). Signs of relapse (may occur up to
stools, oral candidiasis, vomiting 1 month following recovery).
Hematologic & oncologic: Anemia, decreased hemoglobin Additional Information Prior to November 2013, dosing
Local: Erythema at injection site, injection site reaction recommendations were for Lot 4 for a total dose of
Otic: Otitis media (reported in placebo-controlled study) 75 mg/kg/dose.

289
BOTULISM IMMUNE GLOBULIN (INTRAVENOUS-HUMAN)

Dosage Forms Excipient information presented when cause CNS depression, which may impair physical or
available (limited, particularly for generics); consult spe- mental abilities; patients must be cautioned about per-
cific product labeling. forming tasks which require mental alertness (eg, operat-
Injection, powder for reconstitution [preservative free]: ing machinery or driving).
BabyBIG: ~100 mg [contains albumin (human), sucrose;
Some formulations may contain benzalkonium chloride
supplied with diluent]
which may be absorbed by soft contact lenses; remove
¢@ Boudreaux's® Butt Paste [OTC] see Zinc Oxide contacts prior to administration and wait 15 minutes before
on page 2088 reinserting. Inadvertent contamination of multiple-dose
@ Bovine Lung Surfactant see Beractant on page 264 ophthalmic solutions has caused bacterial keratitis. Poten-
tially significant interactions may exist, requiring dose or
@ Bovine Lung Surfactant see Calfactant on page 351
frequency adjustment, additional monitoring, and/or selec-
@ BP Cleansing [OTC] [DSC] see Benzoyl Peroxide tion of alternative therapy.
on page 259
Self-medication (OTC use): Discontinue use and contact
@ BP Foam see Benzoyl Peroxide on page 259
health care provider if eye pain or changes in vision occur;
@ BP Foaming Wash [DSC] see Benzoy! Peroxide redness or irritation of the eye continues, or condition
on page 259 worsens or persists for >3 days. Do not use if solution
@ BP Gel [OTC] see Benzoyl Peroxide on page 259 changes color or becomes cloudy.
@ BPM-DM-Phen [OTC] [DSC] see Brompheniramine, Warnings: Additional Pediatric Considerations May
Dextromethorphan, and Phenylephrine on page 297 cause CNSdepression, particularly in young children; the
@ BPO [DSC] see Benzoyl Peroxide on page 259 most Common adverse effect reported in a study of
pediatric glaucoma patients was somnolence and
@ BPO-5 Wash [OTC] [DSC] see Benzoyl Peroxide
decreased alertness (50% to 83% in children 2 to 6 years
on page 259
of age); these effects resulted in a 16% discontinuation of
@ BPO-10 Wash [OTC] [DSC] see Benzoyl Peroxide treatment rate; children >7 years (>20 kg) had a much
on page 259 lower rate of somnolence (25%); apnea, bradycardia,
@ BPO Creamy Wash [OTC] [DSC] see Benzoyl Peroxide hypotension, hypothermia, hypotonia, and somnolence
on page 259 have been reported in infants receiving brimonidine.
# BPO Foaming Cloths see Benzoyl Peroxide Adverse Reactions Adverse reactions may be formula-
on page 259 tion dependent; reactions reported with Alphagan P:
BProtected Pedia D-Vite [OTC] see Cholecalciferol Cardiovascular: Hypertension, hypotension
on page 434 Central nervous system: Dizziness, drowsiness (more
common in children), fatigue, foreign body sensation of
of BProtected Pedia Iron [OTC] see Ferrous Sulfate
eye, headache, impaired consciousness (children),
on page 852
insomnia
¢ BProtected Vitamin C [OTC] see Ascorbic Acid Dermatologic: Erythema of eyelid, skin rash
on page 186 Endocrine & metabolic: Hypercholesterolemia
BP Wash see Benzoyl Peroxide on page 259 Gastrointestinal: Dyspepsia, xerostomia
Brenzys (Can) see Etanercept on page 789 Hypersensitivity: Local ocular hypersensitivity reaction
(5% to 9%), hypersensitivity reaction
Brethaire see Terbutaline on page 1915
Infection: Infection
Brethine see Terbutaline on page 1915 Neuromuscular & skeletal: Weakness
Brevibloc see Esmolol on page 774 Ophthalmic: Allergic conjunctivitis, blepharitis, blepharo-
Brevibloc in NaCl see Esmolol on page 774 conjunctivitis, blurred vision, burning sensation of eyes,
cataract, conjunctival edema, conjunctival hemorrhage,
Brevibloc Premixed see Esmolol on page 774
conjunctival hyperemia, conjunctivitis, decreased visual
Brevibloc Premixed DS see Esmolol on page 774 acuity, dry eye syndrome, epiphora, eye discharge, eye
Brevital (Can) see Methohexital on page 1331 irritation, eyelid disease, eyelid edema, eye pain, eye
Brevital Sodium see Methohexital on page 1331 pruritus, follicular conjunctivitis, keratitis, photophobia,
Bricanyl see Terbutaline on page 1915 stinging of eyes, superficial punctate keratitis, visual
disturbance, visual field defect, vitreous detachment,
$+
OOBricanyl Turbuhaler (Can) see Terbutaline
$$$
vitreous opacity, watery eyes
on page 1915 Respiratory: Bronchitis, cough, dyspnea, flu-like symp-
@ Bridion see Sugammadex on page 1873 toms, pharyngitis, rhinitis, sinus infection, sinusitis
Rare but important or life-threatening: Anterior uveitis,
Brimonidine (Ophthalmic) (br MoE ni deen) apnea (infants), bradycardia, corneal erosion, depres-
sion, dermatological reaction (erythema, eyelid pruritus,
Medication Safety Issues vasodilatation), dry nose, dysgeusia, hordeolum, hypo-
Sound-alike/look-alike issues: thermia (infants), hypotonia (infants), iritis, keratocon-
Brimonidine may be confused with bromocriptine junctivitis sicca, miosis, nausea, tachycardia
Brand Names: US Alphagan P; Lumify [OTC] Drug Interactions
Brand Names: Canada Alphagan; Alphagan P; Brimoni- Metabolism/Transport Effects None known.
dine P Avoid Concomitant Use
Therapeutic Category Alpha-Adrenergic Agonist, Oph- Avoid concomitant use of Brimonidine (Ophthalmic) with
thalmic; Glaucoma, Treatment Agent any of the following: Azelastine (Nasal); Bromperidol;
Generic Availability (US) Yes lobenguane | 123; Mianserin; Orphenadrine; Oxomema-
Use Lowering of IOP in patients with open-angle glaucoma zine; Paraldehyde; Thalidomide
or ocular hypertension (FDA approved in ages 22 years Increased Effect/Toxicity
and adults) Brimonidine (Ophthalmic) may increase the levels/
Pregnancy Risk Factor B effects of: Alcohol (Ethyl); Azelastine (Nasal); Beta-
Pregnancy Considerations Teratogenic effects were not Blockers; Blonanserin; Buprenorphine; CNS Depres-
observed in animal reproduction studies. sants; Flunitrazepam; HYDROcodone; Methotrimepra-
Breastfeeding Considerations It is not known if brimo- zine; MetyroSINE; Opioid Analgesics; Orphenadrine;
nidine is excreted in breast milk. Due to the potential for OxyCODONE; Paraldehyde; Piribedil; Pramipexole;
serious adverse reactions in the nursing infant, the man- ROPINIRole; Rotigotine; Selective Serotonin Reuptake
ufacturer recommends a decision be made whether to Inhibitors; Suvorexant; Thalidomide; Zolpidem
discontinue nursing or to discontinue the drug, taking into
account the importance of treatment to the mother. The levels/effects of Brimonidine (Ophthalmic) may be
Contraindications Hypersensitivity to brimonidine or any increased by: Beta-Blockers; Brimonidine (Topical); Bro-
component of the formulation; neonates and infants <2 mopride; Bromperidol; Cannabis; Chlormethiazole;
years; concomitant MAO inhibitor therapy Chlorphenesin Carbamate; Dimethindene (Topical);
Warnings/Precautions Exercise caution in treating Doxylamine; Dronabinol; Droperidol; HydrOXYzine;
patients with severe cardiovascular disease. Use with Kava Kava; Lofexidine; Magnesium Sulfate; Methotrime-
caution in patients with depression, cerebral or coronary prazine; Minocycline; Monoamine Oxidase Inhibitors;
insufficiency, Raynaud phenomenon, orthostatic hypoten- Nabilone; Oxomemazine; Perampanel; Rufinamide;
sion, or thromboangiitis obliterans. Use with caution in Sodium Oxybate; Tapentadol; Tetrahydrocannabinol; Tri-
patients with hepatic or renal impairment (has not been meprazine
studied). Systemic absorption has been reported; children Decreased Effect
are at higher risk of systemic adverse events (Levy 2004); Brimonidine (Ophthalmic) may decrease the levels/
use is contraindicated in children <2 years of age. May effects of: lobenguane | 123

290
 BRINZOLAMIDE AND BRIMONIDINE

The levels/effects of Brimonidine (Ophthalmic) may be Drug Interactions

decreased by: Mianserin; Mirtazapine; Serotonin/Nore- Metabolism/Transport Effects Refer to individual
pinephrine Reuptake Inhibitors; Tricyclic Antidepres- components.
sants Avoid Concomitant Use
Storage/Stability Store at 15°C to 25°C (59°F to 77°F). Avoid concomitant use of Brinzolamide and Brimonidine
Mechanism of Action A relatively selective alpha-2 with any of the following: Azelastine (Nasal); Bromper-
adrenergic agonist; causes reduction of aqueous humor idol; Carbonic Anhydrase Inhibitors; lobenguane | 123;
formation and increased uveoscleral outflow Mianserin; Orphenadrine; Oxomemazine; Paraldehyde;
Pharmacodynamics/Kinetics (Adult data unless Thalidomide
noted) Increased Effect/Toxicity
Metabolism: Hepatic (extensive) Brinzolamide and Brimonidine may increase the levels/
Half-life elimination: ~2 to 3 hours effects of: Alcohol (Ethyl); Alpha-/Beta-Agonists (Indi-
Time to peak, plasma: 0.5 to 4 hours rect-Acting); Amantadine; Azelastine (Nasal); Beta-
Excretion: Urine (74%) Blockers; Blonanserin; Buprenorphine; Carbonic Anhy-
Dosing drase Inhibitors; CNS Depressants; Flunitrazepam;
Pediatric Glaucoma, ocular hypertension: Children 22 HYDROcodone; Methotrimeprazine; MetyroSINE;
years and Adolescents: Ophthalmic: Instill 1 drop into Opioid Analgesics; Orphenadrine; OxyCODONE; Paral-
lower conjunctival sac of affected eye(s) 3 times daily dehyde; Piribedil; Pramipexole; ROPINIRole; Rotigotine;
(approximately every 8 hours) Selective Serotonin Reuptake Inhibitors; Suvorexant;
Renal Impairment: Pediatric There are no dosage Thalidomide; Zolpidem
adjustments provided in the manufacturer's labeling. The levels/effects of Brinzolamide and Brimonidine may
Hepatic Impairment: Pediatric There are no dosage be increased by: Beta-Blockers; Brimonidine (Topical);
adjustments provided in the manufacturer's labeling Bromopride; Bromperidol; Cannabis; Chlormethiazole;
Administration Ophthalmic: Instill into conjunctival sac Chlorphenesin Carbamate; CYP3A4 Inhibitors (Strong);
avoiding contact of bottle tip with skin or eye. Apply gentle Dimethindene (Topical); Doxylamine; Dronabinol; Dro-
pressure to lacrimal sac during and immediately following peridol; HydrOXYzine; Kava Kava; Lofexidine; Magne-
instillation (1 minute) or instruct patient to gently close sium Sulfate; Methotrimeprazine; Minocycline;
eyelid after administration, to decrease systemic absorp- Monoamine Oxidase Inhibitors; Nabilone; Oxomema-
tion of ophthalmic drops (Urtti 1993; Zimmerman 1982). zine; Perampanel; Rufinamide; Sodium Oxybate; Tapen-
Administer other topical ophthalmic medications at least 5 tadol; Tetrahydrocannabinol; Trimeprazine
minutes apart; generic formulation contains benzalkonium Decreased Effect
chloride which may be absorbed by soft contact lenses; Brinzolamide and Brimonidine may decrease the levels/
wait at least 15 minutes after administration to insert soft effects of: lobenguane | 123
contact lenses.
Monitoring Parameters IOP; fatigue or drowsiness The levels/effects of Brinzolamide and Brimonidine may
Dosage Forms Excipient information presented when be decreased by: Mianserin; Mirtazapine; Serotonin/
available (limited, particularly for generics); consult spe- Norepinephrine Reuptake Inhibitors; Tricyclic Antide-
cific product labeling. pressants
Solution, Ophthalmic, as tartrate: Storage/Stability Store at 2°C to 25°C (36°F to 77°F).
Alphagan P: 0.1% (5 mL, 10 mL, 15 mL); 0.15% (5 mL, Mechanism of Action
10 mL, 15 mL) Brinzolamide inhibits carbonic anhydrase, leading to
Lumify: 0.025% (2.5 mL, 7.5 mL) [contains benzalkonium decreased aqueous humor secretion. This results in a
chloride] reduction of intraocular pressure (IOP).
Generic: 0.15% (5 mL, 10 mL, 15 mL); 0.2% (5 mL, 10 Brimonidine has selective agonism for alphaz-receptors
mL, 15 mL) and causes reduction of aqueous humor formation and
increased uveoscleral outflow
@ Brimonidine and Brinzolamide see Brinzolamide and Pharmacodynamics/Kinetics (Adult data unless
Brimonidine on page 291 noted)
@ Brimonidine P (Can) see Brimonidine (Ophthalmic) Absorption: Brinzolamide: Topical: Into systemic circula-
on page 290 tion
@ Brimonidine Tartrate see Brimonidine (Ophthalmic) Distribution: Brinzolamide: Accumulates extensively in red
on page 290 blood cells, binding to carbonic anhydrase (brinzolamide
and metabolite)
@ Brineura see Cerliponase Alfa on page 410
Protein binding: Brinzolamide: ~60%
Metabolism:
Brinzolamide and Brimonidine Brimonidine: Extensively, hepatic
(brin ZOH la mide & bri MOE ni deen) Brinzolamide: To N-desethy! brinzolamide
Half-life elimination:
Brand Names: US. Simbrinza Brimonidine: 2 to 3 hours
Brand Names: Canada Simbrinza Brinzolamide: 111 days
Therapeutic Category Alpha Agonist, Ophthalmic; Car- Time to peak, serum concentration: Brimonidine: Within
bonic Anhydrase Inhibitor (Ophthalmic); Ophthalmic 0.5 to 4 hours
Agent, Antiglaucoma Excretion:
Use Reduction of elevated intraocular pressure (IOP) in Brimonidine: Urine (74%)
patients with ocular hypertension or open-angle glaucoma Brinzolamide: Urine (predominantly as unchanged drug)
(FDA approved in ages 22 years and adults) Dosing
Pregnancy Risk Factor C : Pediatric Elevated intraocular pressure: Children 22
Pregnancy Considerations Animal reproduction studies years and Adolescents: Ophthalmic: Instill 1 drop in
have not been conducted with this combination product; affected eye(s) 3 times daily
refer to individual monographs. Renal Impairment: Pediatric
Breastfeeding Considerations It is not known if brinzo- Mild to moderate renal impairment (CrCl 230 mL/
lamide or brimonidine are excreted into breast milk follow- minute); There are no dosage adjustment provided in
ing ophthalmic application. Due to the potential for serious the manufacturer's labeling; brinzolamide and metabo-
adverse reactions in the nursing infant, the manufacturer lite are excreted predominately by the kidney; use with
recommends a decision be made whether to discontinue caution.
nursing or to discontinue the drug, taking into account the Severe renal impairment (CrCl <30 mL/minute): Use is
importance of treatment to the mother. not recommended (has not been studied); brinzolamide
Contraindications and metabolite are excreted predominately by the
Hypersensitivity to brinzolamide, brimonidine, or any com- kidney.
ponent of the formulation; children <2 years of age Hepatic Impairment: Pediatric There are no dosage
Canadian labeling: Additional contraindications (not in US adjustments provided in manufacturer's labeling (has not
labeling): Hypersensitivity to sulfonamides; concurrent been studied); use with caution.
monoamine oxidase (MAO) inhibitor therapy or antide- Administration Shake bottle well priortoadministration. If
pressant therapy that affects noradrenergic transmission using additional topical ophthalmic preparations, separate
(eg, tricyclic antidepressants, mianserin); severe renal administration by at least 5 minutes. Remove contact
impairment; hyperchloremic acidosis lenses prior to administration and wait 15 minutes after
Warnings/Precautions See individual agents. administration before reinserting. Apply gentle pressure to
Adverse Reactions Also see individual agents. lacrimal sac immediately following instillation (1 minute) or
Gastrointestinal: Dysgeusia, xerostomia instruct patient to gently close eyelid after administration
Hypersensitivity: Local ocular hypersensitivity reaction to decrease systemic absorption of ophthalmic drops
Ophthalmic: Blurred vision, eye irritation (Urtti, 1993; Zimmerman, 1982). Instruct patients to avoid >
291
BRINZOLAMIDE AND BRIMONIDINE

allowing the tip of the dispensing container to contact the abilities. Risk is greatest early in treatment, but may occur
eye or surrounding structures. Ocular solutions can at any time. Patients must be cautioned about performing
become contaminated by common bacteria known to tasks that require mental alertness (eg, operating machi-
cause ocular infections. Serious damage to the eye and nery, driving).
subsequent loss of vision may occur from using contami-
Poor metabolizers of CYP2C19 may require dose reduc-
nated solutions.
tion. Use caution in patients with hepatic impairment;
Monitoring Parameters Ophthalmic exams and IOP
dosage adjustment recommended. Not recommended in
periodically
patients with ESRD undergoing dialysis. Anticonvulsants
Dosage Forms Excipient information presented when
should not be discontinued abruptly because of the pos-
available (limited, particularly for generics); consult spe-
sibility of increasing seizure frequency; therapy should be
cific product labeling.
withdrawn gradually to minimize the potential of increased
Suspension, ophthalmic:
seizure frequency, unless safety concerns require a more
Simbrinza: Brinzolamide 1% and brimonidine tartrate
rapid withdrawal. Potentially significant drug-drug interac-
0.2% (8 mL) [contains benzalkonium chloride]
tions may exist, requiring dose or frequency adjustment,
@ Brinzolamide and Brimonidine Tartrate see Brinzola- additional monitoring, and/or selection of alternative
mide and Brimonidine on page 291 therapy.
@ Brinzolamide/Brimonid Tartrate see Brinzolamide and Adverse Reactions
Brimonidine on page 2917 Central nervous system: Abnormal gait, ataxia, dizziness,
drowsiness, equilibrium disturbance, euphoria (IV),
@ Brisdelle see PARoxetine on page 1563
fatigue, hypersomnia, infusion site pain (IV), intoxicated
British Anti-Lewisite see Dimercaprol on page 648 feeling (IV), irritability, lethargy, malaise, psychiatric dis-
turbance (includes psychotic and nonpsychotic), seda-
Brivaracetam (priv a RA se tam) tion, suicidal ideation, vertigo
Gastrointestinal: Constipation, dysgeusia (IV), nausea,
Related Information vomiting
Oral Medications That Should Not Be Crushed or Altered Hematologic & oncologic: Decreased white blood cell
on page 2217 count i
Brand Names: US Briviact Hypersensitivity: Hypersensitivity reaction
Brand Names: Canada Briviera Neuromuscular & skeletal: Asthenia
Therapeutic Category Anticonvulsant, Miscellaneous Ophthalmic: Nystagmus 7
Generic Availability (US) No Rare but important or life-threatening: Angioedema, bron-
Use chospasm, decreased neutrophils
Oral: Adjunctive therapy in the treatment of partial-onset Drug Interactions
seizures (FDA approved in ages 216 years and adults) Metabolism/Transport Effects Substrate of
lV: Adjunctive therapy in the treatment of partial-onset CYP2C19 (major); Note: Assignment of Major/Minor
seizures when oral administration not feasible (FDA substrate status based on clinically relevant drug inter-
approved in ages 216 years and adults) action potential
Medication Guide Available Yes Avoid Concomitant Use
Pregnancy Considerations Avoid concomitant use of Brivaracetam with any of the
Adverse events have been observed in animal reproduc- following: Azelastine (Nasal); Bromperidol; Orphena-
tion studies. drine; Oxomemazine; Paraldehyde; Thalidomide
Increased Effect/Toxicity
Females exposed to brivaracetam during pregnancy are Brivaracetam may increase the levels/effects of: Azelas-
encouraged to enroll themselves into the North American tine (Nasal); Blonanserin; Buprenorphine; CarBAMaze-
Antiepileptic Drug (NAAED) Pregnancy Registry by calling pine; CNS Depressants; Flunitrazepam; HYDROcodone;
1-888-233-2334. Additional information is available at Methotrimeprazine; MetyroSINE; Mirtazapine; Opioid
http:/Awww.aedpregnancyregistry.org. Analgesics; Orphenadrine; OxyCODONE; Paraldehyde;
Breastfeeding Considerations It is not known if brivar- Phenytoin; Piribedil; Pramipexole; ROPINIRole; Rotigo-
acetam is present in breast milk. According to the manu- tine; Selective Serotonin Reuptake Inhibitors; Suvorex-
facturer, the decision to breastfeed during therapy should ant; Thalidomide; Zolpidem
consider the risk of infant exposure, the benefits of
breastfeeding to the infant, and benefits of treatment to The levels/effects of Brivaracetam may be increased by:
the mother. Alcohol (Ethyl); Brimonidine (Topical); Bromopride;
Contraindications Hypersensitivity to brivaracetam or Bromperidol; Cannabis; Chlormethiazole; Chlorphenesin
any component of the formulation Carbamate; Dimethindene (Topical); Doxylamine; Dro-
Warnings/Precautions Bronchospasm and angioedema nabinol; Droperidol; HydrOXYzine; Kava Kava; Lofexi-
have been reported. Discontinue therapy if a hypersensi- dine; Magnesium Sulfate; Methotrimeprazine;
tivity reaction develops. Multiorgan hypersensitivity syn- Minocycline; Nabilone; Oxomemazine; Perampanel;
drome (also known as Drug Rash Eosinophilia and Rufinamide; Sodium Oxybate; Tapentadol; Tetrahydro-
Systemic Symptoms or DRESS), is a serious condition cannabinol; Trimeprazine
sometimes induced by antiepileptic drugs. DRESS initially Decreased Effect
presents with fever and rash, then with other organ system The levels/effects of Brivaracetam may be decreased by:
involvement that may include eosinophilia, lymphadenop- CarBAMazepine; CYP2C19 Inducers (Strong); Dabrafe-
athy, hepatitis, nephritis, and/or myocarditis. If any of nib; Enzalutamide; LevETIRAcetam; Lumacaftor; Meflo-
these hypersensitivity reactions are suspected and an quine; Mianserin; Orlistat; Phenytoin; RifAMPin
alternative cause cannot be established, discontinue bri- Food Interactions Food may delay but does not affect the
varacetam. May cause hematologic abnormalities; signifi- extent of absorption. Management: Administer without
cant decreased white blood cell count (<3.0 x 109/L) and regard to meals.
decreased neutrophil count (<1.0 x 10%/L) have been Storage/Stability
reported. Store at 25°C (77°F); excursions permitted between 15°C
Psychosis, paranoia, hallucinations, and behavioral symp-
to 30°C (59°F to 86°F).
toms (including abnormal behavior, adjustment disorder, Oral solution: Do not freeze. Discard any oral solution
affect liability, aggression, agitation, altered mood, anger, remaining after 5 months of first opening the bottle.
anxiety, apathy, belligerence, depression, irritability, mood Injection: Do not freeze. May store solution diluted in NS,
swings, nervousness, psychomotor hyperactivity, restless- LR, or D5W for <4 hours at room temperature in polyvinyl
ness, and tearfulness) may occur; clinical trials reported chloride (PVC) bags. Discard any unused portion.
events in 13% of adult patients receiving brivaracetam Mechanism of Action The precise mechanism by which
compared with 8% receiving placebo (adverse events in brivaracetam exerts its antiepileptic activity is unknown.
pediatric patients were similar to those observed in adult Brivaracetam displays a high and selective affinity for
patients). Pooled analysis of trials involving various anti- synaptic vesicle protein 2A (SV2A) in the brain, which
epileptics (regardless of indication) showed an increased may contribute to the antiepileptic effect.
risk of suicidal thoughts/behavior (incidence rate: 0.43% Pharmacodynamics/Kinetics (Adult data unless
treated patients compared with 0.24% of patients receiv- noted)
ing placebo); risk observed as early as 1 week after Absorption: Oral: Rapidly and almost completely
initiation and continued through duration of trials (most absorbed; delayed by 3 hours with a high-fat meal
trials $24 weeks). Monitor all patients for notable changes Distribution: 0.5 L/kg
in behavior that might indicate suicidal thoughts or depres- Protein binding: $20% to plasma proteins
sion; notify the health care provider immediately if symp- Metabolism: Hepatic and extrahepatic amidase mediated
toms occur. May cause CNS depression (impaired hydrolysis of the amide moiety to form carboxylic acid
coordination, ataxia, abnormal gait, fatigue, dizziness, metabolite (primary route) and hydroxylation primarily by
and somnolence), which may impair physical or mental CYP2C19 to form the hydroxy metabolite (secondary

292
 BROMOCRIPTINE

route). Metabolites are inactive, including an additional

hydroxy acid metabolite. Bromocriptine (broe moe KRIP teen)
Half-life elimination: ~9 hours
Time to peak: Oral: 1 hour (fasting, range: 0.25 to 3 hours)
Medication Safety Issues
Sound-alike/look-alike issues:
Excretion: Urine (>95%; <10% unchanged); feces (<1%)
Bromocriptine may be confused with benztropine, brimo-
Pharmacodynamics/Kinetics: Additional Consider- nidine
ations Cycloset may be confused with Glyset
Renal function impairment: In adult patients with creati- Parlodel may be confused with pindolol, Provera
nine clearance <30 mL/minute/1.73 m? not requiring Brand Names: US Cycloset; Parlodel
dialysis, plasma AUC of brivaracetam was moderately Therapeutic Category Anti-Parkinson's Agent, Dopa-
‘increased (21%), while the AUCs of the acid, hydroxy, mine Agonist; Antidiabetic Agent, Dopamine Agonist; Anti-
and hydroxyacid metabolites were increased 3-fold, 4- diabetic Agent, Oral; Ergot Derivative
fold, and 21-fold, respectively. Renal clearance of these Generic Availability (US) Yes
inactive metabolites was decreased 10-fold. Use Treatment of dysfunctions associated with hyperpro-
Hepatic function impairment: In adult patients with hepatic lactinemia, including amenorrhea with or without galactor-
cirrhosis, Child-Pugh classes A, B, and C, showed 50%, rhea, infertility, or hypogonadism (FDA approved in
57%,‘and 59% increases in brivaracetam exposure, adults); treatment of prolactin-secreting adenomas (FDA
respectively; the effect of hepatic impairment is expected approved in ages 211 years and adults); treatment of
acromegaly (FDA approved in adults); treatment of Par-
to be comparable in pediatric patients.
kinson disease (FDA approved in adults); treatment of
Geriatric: Plasma half-life was 7.9 hours and 9.3 hours in
type 2 diabetes mellitus as an adjunct to diet and exercise
the 65 to 75 and >75 years of age groups, respectively.
(Cycloset: FDA approved in adults); has also been used
_ Steady-state plasma clearance was slightly lower than in for neuroleptic malignant syndrome
younger patients.
CYP2C19 poor metabolizers: In patients possessing Note: Although FDA approved, bromocriptine is not gen-
genetic variations in CYP2C19, production of the erally used in patients with type 2 diabetes but may be
hydroxy metabolite is decreased 2-fold or 10-fold, and tried in specific situations (ADA 2017)
the blood level of brivaracetam itself is increased by 22% Pregnancy Risk Factor B
or 42%, respectively, in individuals with one or both
Pregnancy Considerations
Bromocriptine crosses the placenta (Molitch 2015). Data
mutated alleles.
collected from women taking bromocriptine during preg-
Dosing
nancy suggest the incidence of birth defects is not
Pediatric increased with use. However, the majority of women
Partial onset seizures; adjunct therapy: Adolescents discontinued use within 8 weeks of pregnancy.
216 years: Oral, IV: Initial: 50 mg twice daily; may
decrease to 25 mg twice daily or increase up to Women with hyperprolactinemia may be infertile, have
100 mg twice daily based on individual patient amenorrhea and galactorrhea. A mechanical contracep-
tive should be used during therapy until normal ovulatory
response and tolerability; maximum daily dose:
menses is established. Contraception can then be discon-
200 mg/day. Note: Use injection when oral administra-
tinued if pregnancy is desired. Bromocriptine should be
tion is temporarily not feasible; clinical study experi- discontinued if pregnancy is confirmed unless needed for
ence with brivaracetam injection is limited to 4 treatment of a rapidly expanding macroadenoma. When
consecutive days of treatment. Avoid abrupt with- used for the treatment of acromegaly or Parkinson dis-
drawal: decrease dose gradually. ease, consider discontinuing therapy during pregnancy. If
Dosing adjustment for concomitant therapy with treatment is withdrawn, monitor for signs and symptoms of
rifampin: Adolescents 216 years: Increase brivarace- an enlarging prolactin secreting tumor. Regardless of
tam dosage by up to 100% (ie, double the brivarace- indication, if bromocriptine is needed in a pregnant
tam dose). woman, monitor closely for hypertensive disorders during
Renal Impairment: Pediatric pregnancy and immediately postpartum.
Adolescents 216 years: During treatment with bromocriptine, fertility may occur
Mild to severe impairment: No dosage adjustment prior to restoration of menses in infertile women, therefore
necessary. a pregnancy test is recommended every 4 weeks during
End-stage renal disease requiring dialysis: Use is not the amenorrheic period. Once menses resume, preg-
recommended (has not been studied). nancy tests should be done any time a menstrual period
Hepatic Impairment: Pediatric Adolescents 216 is missed. Women not seeking pregnancy should be
years: Mild to severe impairment (Child Pugh classes advised to use appropriate contraception.
A, B, and C): Initial: 25 mg twice daily, up to a maximum Breastfeeding Considerations
of 75 mg twice daily ‘ Use is contraindicated in nursing women when used for
the treatment of type 2 diabetes and in postpartum
Administration
women with a history of coronary artery disease or other
Oral: Administer with or without food.
severe cardiovascular conditions (unless withdrawal of
Oral solution: Use a calibrated measuring device to medication is medically contraindicated).
measure (household teaspoon or tablespoon is not Bromocriptine is known to inhibit lactation. A previous
an adequate measuring device). May also be adminis- indication for prevention of postpartum lactation was
tered using a nasogastric tube or gastronomy tube. withdrawn voluntarily by the manufacturer following
Tablets: Swallow tablets whole with liquid; do not chew or reports of serious adverse reactions, including stroke,
crush. MI, seizures, and severe hypertension.
Parenteral: IV: Administer IV over 2 to 15 minutes; may Contraindications Hypersensitivity to bromocriptine,
administer undiluted or diluted with NS, LR, or DSW. ergot alkaloids, or any component of the formulation
Monitoring Parameters CBC with differential, liver and Additional product-specific contraindications:
renal function, and symptoms of depression and suicidal- Cycloset: Syncopal migraine; breastfeeding
ity (eg, anxiety, depression, behavior changes) Parlodel: Uncontrolled hypertension; pregnancy (risk to
benefit evaluation must be performed in women who
Controlled Substance C-V
become pregnant during treatment for acromegaly,
Dosage Forms Excipient information presented when prolactinoma, or Parkinson disease - hypertension dur-
available (limited, particularly-for generics); consult spe- ing treatment should generally result in efforts to with-
cific product labeling. draw); postpartum women with a history of coronary
Solution, Intravenous [preservative free]: artery disease or other severe cardiovascular condi-
Briviact: 50 mg/5 mL (5 mL) tions (unless withdrawal of medication is medically
Solution, Oral: contraindicated)
Briviact: 10 mg/mL (300 mL) [contains methylparaben; Warnings/Precautions Use caution in patients with a
raspberry flavor] history of peptic ulcer disease, dementia, or cardiovascu-
Tablet, Oral: lar disease (myocardial infarction, residual atrial, nodal, or
Briviact: 10 mg, 25mg, 50 mg, 75 mg, 100 mg ventricular arrhythmia). Use with extreme caution in
patients with psychosis. Use in patients with severe
@ Briviact see Brivaracetam on page 292 psychotic disorder is not recommended. Hypotension,
Brivlera (Can) see Brivaracetam on page 292 including orthostatic hypotension and syncope, may
occur, particularly upon initiation of therapy and dose
@ BRL 43694 see Granisetron on page 958 escalation. In addition, hypertension, seizures, MI, and
@ Brohist D [OTC] see Brompheniramine and Phenylephr- stroke have been reported. In a scientific statement from
ine on page 295 ‘ the American Heart Association, bromocriptine has been
 BROMOCRIPTINE

q determined to be an agent that may cause direct myocar-

dial toxicity (magnitude: major) (AHA [Page 2016)).
Infection: Increased susceptibility to infection
Neuromuscular & skeletal: Weakness
Severe headache or visual changes may precede events. Ophthalmic: Amblyopia
The onset of reactions may be immediate or delayed Respiratory: Flu-like symptoms, nasal congestion, rhinitis.
(often may occur in the second week of therapy). Dis- sinusitis ; q
continue therapy and evaluate promptly hypertension, Rare but important or life-threatening: Acquired valvular
severe, progressive, or unremitting headache (with or heart disease, alopecia, bradycardia, cardiac arrhythmia,
without visual disturbance), or evidence of CNS toxicity cerebrovascular accident (postpartum), confusion, con-
develops. May cause CNS depression, which may impair strictive pericarditis, depression, dysphagia, epileptiform
physical or mental abilities, and episodes of sudden sleep seizures, ergot alkaloids toxicity, erythromelalgia, gastro-
onset, particularly in patients with Parkinson disease; intestinal ulcer, hallucination, hypertension (postpartum),
patients must be cautioned about performing tasks that increased cerebrospinal fluid pressure, insomnia, myo-
require mental alertness (eg, operating machinery or cardial infarction (postpartum), narcolepsy, paresthesia,
driving). Consider dosage reduction or discontinuation of pericardial effusion, peripheral edema, pleural effusion,
therapy if symptoms occur. pleurisy, psychomotor agitation, pulmonary fibrosis, ret-
roperitoneal fibrosis, seizure (postpartum), status epilep-
Potentially significant drug-drug interactions may exist,
ticus (postpartum), tachycardia, transient blindness,
requiring dose or frequency adjustment, additional mon-
urinary incontinence, urinary retention, vasodepressor
itoring, and/or selection of alternative therapy. Instruct
syncope, ventricular tachycardia
patients to limit or avoid concomitant ethanol use; may
Drug Interactions
potentiate the side effects.
Metabolism/Transport Effects Substrate of CYP3A4
Dopamine agonists have been associated with compul- (major); Note: Assignment of Major/Minor substrate sta-
sive behaviors and/or loss of impulse control, which has tus based on clinically relevant drug interaction potential
manifested as new or increased gambling urges, sexual Avoid Concomitant Use
urges, uncontrolled spending, or other intense urges. Avoid concomitant use of Bromocriptine with any of the
Dose reduction or discontinuation of therapy reverses following: Alpha-/Beta-Agonists; Alpha1-Agonists; Ami-
these behaviors in some, but not all cases. Visual or sulpride; Bromperidol; Conivaptan; CYP3A4 Inhibitors
auditory hallucinations may occur when administered (Strong); Dapoxetine; Fusidic Acid (Systemic); Idelalisib;
alone or concomitantly with levodopa; dose reductions Lorcaserin; Methylene Blue; Nitroglycerin; Protease
or discontinuation may be necessary. Symptoms may Inhibitors; Roxithromycin; Serotonin 5-HT1D Receptor
persist for several weeks following discontinuation. Risk Agonists; Sulpiride '
for melanoma development is increased in Parkinson Increased Effect/Toxicity
disease patients; drug causation or factors contributing Bromocriptine may increase the levels/effects of: Alcohol
to risk have not been established. Monitor all patients (Ethyl); Alpha-/Beta-Agonists; Alpha1-Agonists; Amifos-
closely for melanoma and perform periodic skin examina- tine; Bromperidol; BuPROPion; DULoxetine; Hypoglyce-
tions. Avoid use of Parlodel in patients with rare hereditary mia-Associated Agents; Hypotension-Associated
problems of galactose intolerance, severe lactase defi- Agents; Levodopa; Metoclopramide; Nitroprusside; Phol-
ciency, or glucose-galactose malabsorption. Use with codine; Serotonin 5-HT1D Receptor Agonists; Serotonin
caution in patients with hepatic impairment; dosage Modulators; TraMADol
adjustment may be necessary due to extensive hepatic
metabolism. The levels/effects of Bromocriptine may be increased by:
Alcohol (Ethyl); Alfuzosin; Alpha-Lipoic Acid; Androgens;
In the treatment of acromegaly, discontinuation is recom- Antiemetics (6HT3 Antagonists); Anti-Parkinson Agents
mended if tumor expansion occurs during therapy. Digital (Monoamine Oxidase Inhibitor); Barbiturates; Beta-
vasospasm (cold sensitive) may occur in some patients Blockers; Blood Pressure Lowering Agents; Brimonidine
with acromegaly; may require dosage reduction. In (Topical); Ceritinib; Chloroprocaine; Conivaptan;
patients treated with pituitary irradiation, withhold therapy CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors
for 4 to 8 weeks on a yearly basis to assess both the (Strong); Dapoxetine; Diazoxide; Diethylstilbestrol;
Clinical effects of radiation on the disease process as well Fosaprepitant; Fusidic Acid (Systemic); Guanethidine;
as the effects of bromocriptine. Digital vasospasm (cold Herbs (Hypotensive Properties); Idelalisib; Linezolid;
sensitive) may occur in some patients with acromegaly; Lorcaserin; Lormetazepam; Metaxalone; Methylene
may require dosage reduction. Should not be used post- Blue; Methylphenidate; Molsidomine; Monoamine Oxi-
partum in women with coronary artery disease or other dase Inhibitors; Naftopidil; Nicergoline; Nicorandil; Nitro-
cardiovascular disease. Use of bromocriptine to control or glycerin; Obinutuzumab; Opioid Analgesics; Palbociclib;
prevent lactation or in patients with uncontrolled hyper- Pegvisomant; Pentoxifylline; Phosphodiesterase 5 Inhib-
tension is not recommended. itors; Prostacyclin Analogues; Protease Inhibitors; Pro-
Monitoring and careful evaluation of visual changes during thionamide; Quinagolide; Quinolones; Reboxetine;
the treatment of hyperprolactinemia is recommended to Roxithromycin; Salicylates; Selective Serotonin Reup-
differentiate between tumor shrinkage and traction on the take Inhibitors; Serotonin 5-HT1D Receptor Agonists;
optic chiasm; rapidly progressing visual field loss requires Simeprevir; Somatostatin Analogs; Stiripentol; Tedizolid;
neurosurgical consultation. Discontinuation of bromocrip- TraMADol
tine in patients with macroadenomas has been associated Decreased Effect
with rapid regrowth of tumor and increased prolactin Bromocriptine may decrease the levels/effects of: Ami-
serum levels. Cases of pleural and pericardial effusions, sulpride; Antipsychotic Agents (First Generation [Typi-
as well as pleural, pulmonary and/or retroperitoneal fib- cal]); Nitroglycerin
rosis and constrictive pericarditis have been reported with
The levels/effects of Bromocriptine may be decreased
prolonged and high-dose daily use. Cardiac valvular fib-
by: Amisulpride; Antipsychotic Agents (First Generation
rosis has also been associated with ergot alkaloids.
[Typical]); Antipsychotic Agents (Second Generation
In the management of type 2 diabetes mellitus, Cycloset [Atypical]); Bromopride; Bromperidol; Hyperglycemia-
("quick-release" tablet) should not be interchanged with Associated Agents; Metoclopramide; Quinolones; Rito-
any other bromocriptine product due to formulation differ- drine; Sulpiride; Thiazide and Thiazide-Like Diuretics
ences and resulting pharmacokinetics. Therapy is not Storage/Stability Store below 25°C (77°F). Protect Par-
appropriate in patients with diabetic ketoacidosis (DKA) lodel from light.
or type 1 diabetes mellitus. Mechanism of Action Semisynthetic ergot alkaloid deriv-
ative and a sympatholytic dopamine Dz receptor agonist
Cerebrospinal fluid rhinorrhea has been observed in some
which activates postsynaptic dopamine receptors in the
prolactin-secreting adenoma patients. Dopaminergic
tuberoinfundibular (inhibiting pituitary prolactin secretion)
agents have been associated with a syndrome resembling
and nigrostriatal pathways (enhancing coordinated motor
neuroleptic malignant syndrome on abrupt withdrawal or
control).
significant dosage reduction after long-term use; gradual
dosage reduction is recommended when discontinuing In the treatment of type 2 diabetes mellitus, the mecha-
therapy. nism of action is unknown; however, bromocriptine is
Adverse Reactions believed to affect circadian rhythms which are mediated,
Cardiovascular: Hypotension (including postural/ortho- in part, by dopaminergic activity, and are believed to play a
static), Raynaud's phenomenon, syncope, vasospasm role in obesity and insulin resistance. It is postulated that
(digital) bromocriptine (when administered during the morning and
Central nervous system: Dizziness, drowsiness, fatigue, released into the systemic circulation in a rapid, ‘pulse-like’
headache, lightheadedness dose) may reset hypothalamic circadian activities which
Endocrine & metabolic: Hypoglycemia have been altered by obesity, thereby resulting in the
Gastrointestinal: Abdominal cramps, anorexia, constipa- reversal of insulin resistance and decreases in glucose
tion, diarrhea, dyspepsia, gastrointestinal hemorrhage, production, without increasing serum insulin concentra-
nausea, vomiting, xerostomia tions (Gaziano 2010; Pijl 2000).

294
 BROMPHENIRAMINE AND PHENYLEPHRINE

Pharmacodynamics/Kinetics (Adult data unless Use Temporary relief of symptoms associated with the
noted) common cold, allergic rhinitis, and other upper respiratory
Distribution: Vg: ~61L allergies (OTC: FDA approved in pediatric patients 26
Protein binding: 90% to 96% (primarily albumin) years and adults). Note: Approved ages and uses for
Metabolism: Primarily hepatic via CYP3A; extensive first- generic products may vary; consult labeling for specific
pass biotransformation (Cycloset: ~93%) information.
Bioavailability: Cycloset: 65% to 95% Contraindications Use with or within 14 days of MAO
Half-life elimination: Cycloset: ~6 hours;’Parlodel: 4.85 inhibitor therapy; do not use to sedate a child
hours Warnings/Precautions Use caution with hypertension,
Time to peak, serum: Cycloset: 53 minutes; Parlodel: 2.5 + diabetes, respiratory disease, cardiovascular disease,
2 hours thyroid disease, increased intraocular pressure, glau-
‘Excretion: Feces (~82%); urine (2% to 6%) coma, pyloroduodenal obstruction, or prostatic hyperpla-
sia. Causes sedation, caution must be used in performing
Pharmacodynamics/Kinetics: Additional Consider-
tasks which require alertness (eg, operating machinery or
ations Hepatic function impairment: Plasma levels may
driving). Sedative effects of CNS depressants or ethanol
increase with hepatic impairment.
are potentiated. Use with caution in the elderly; may be
Dosing more sensitive to adverse effects. When used for self
Pediatric ~ medication (OTC), notify healthcare provider if symptoms
Hyperprolactinemia secondary to pituitary adenoma: do not improve within 7 days or are accompanied by fever.
Children and Adolescents <16 years: Limited data Discontinue and contact healthcare provider if nervous-
available in age <11 years: Oral: Initial: 1.25 to ness, dizziness or sleeplessness occur. Antihistamines
2.5 mg daily; dosage may be increased as tolerated may cause excitation in young children. Do not exceed
to achieve a therapeutic response; usual effective pediatric dosing recommendations. If no recommenda-
range: 5 to 7.5 mg/day in divided doses; maximum tions exist on OTC labeling for patient's age, the product
daily dose: 10 mg/day (Fideleff 2009; Gillam 2004) should not be administered without the guidance of a
Adolescents 216 years: Oral: Initial: 1.25 to 2.5 mg physician.
daily; may be increased by 2.5 rng daily as tolerated Warnings: Additional Pediatric Considerations
every 2 to 7 days until optimal response; usual Safety and efficacy for the use of cough and cold products
effective range: 5 to 7.5 mg/day in divided doses; in pediatric patients <4 years of age is limited; the AAP
maximum daily dose: 15°mg/day (Fideleff 2009; Gil- warns against the use of these products for respiratory
lam 2004) illnesses in this age group. Serious adverse effects
Renal Impairment: Pediatric There are no dosage including death have been reported (in some cases, high
adjustments provided in the manufacturer’s labeling blood concentrations of pseudoephedrine were found).
(has not been studied). Many of these products contain multiple active ingre-
dients, increasing the risk of accidental overdose when
Hepatic Impairment: Pediatric There are no dosage
used with other products. The FDA notes that there are
adjustments provided in the manufacturer's labeling;
no approved OTC uses for these products in pediatric
however, adjustment may be necessary due to extensive
patients <2 years of age. Health care providers are
metabolism; use with caution.
reminded to ask caregivers about the use of OTC cough
Administration Oral: May be taken with food to decrease and cold products in order to avoid exposure to multiple
Gl distress medications containing the same ingredient. Multiple
Cycloset: Administer within 2 hours of waking in the concentrations of oral liquid formulations (drops, elixir,
morning; take with food to decrease GI distress and liquid) exist; close attention must be paid to the
Monitoring Parameters Blood pressure and heart rate concentration when ordering or administering. Antihist-
(orthostatic vital signs; baseline and periodically there- amines should not be used to make an infant or child
after); hepatic, renal, hematopoietic, and cardiovascular sleepy (AAP 2012; FDA 2008).
function (periodically); visual field (prolactinoma; periodic); Some dosage forms may contain propylene glycol; in
pregnancy test during amenorrheic period; growth hor- neonates large amounts of propylene glycol delivered
mone (acromegaly; periodic); prolactin levels; GI bleeding orally, intravenously (eg, >3,000 mg/day), or topically
(patients with history of peptic ulcer); melanoma skin have been associated with potentially fatal toxicities
examinations (regular assessment); HbA1c and serum which can include metabolic acidosis, seizures, renal
glucose (type 2 diabetes mellitus) failure, and CNS depression; toxicities have also been
Dosage Forms Excipient information presented when reported in children and adults including hyperosmolality,
available (limited, particularly for generics); consult spe- lactic acidosis, seizures, and respiratory depression; use
cific product labeling. [DSC] = Discontinued product caution (AAP 1997; Shehab 2009).
Capsule, Oral: Adverse Reactions See individual agents.
Parlodel: 5 mg Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
Generic: 5 mg 2 i Pharmacodynamics/Kinetics (Adult data unless
Tablet, Oral: noted) See individual monograph for Pseudoephedrine.
Cycloset: 0.8 mg Brompheniramine component only:
Parlodel: 2.5 mg [DSC] Distribution: Vg: Mean: Children 6 to 12 years: 20 L/kg
Parlodel: 2.5 mg [scored] (Simons 1999); Adults: 11.7 L/kg (Simons 1982)
Generic: 2.5 mg Protein binding: 39% to 49% (Martinez-Gomez 2007)
Metabolism: Hepatic, extensive (Simons 2004)
@ Bromocriptine Mesylate see Bromocriptine Half-life elimination: Mean: Children 6 to 12 years: 12.4
on page 293 hours (Simons 1999); Adults: 24.9 hours
(Simons 1982)
Time to peak, serum: Oral: Children 6 to 12 years: 3.2
Brompheniramine and Phenylephrine hours (Simons 1999); Adults: 2 to 4 hours
(brome fen IR a meen & fen il EF rin)
(Simons 1982)
Medication Safety Issues Excretion: Urine (50%, as inactive metabolites)
Geriatric Patients: High-Risk Medication: (Bruce 1968)
Beers Criteria: Brompheniramine, a first-generation anti- Dosing
histamine, is identified in the Beers Criteria as a poten- Pediatric Note: Multiple concentrations of oral liquid
tially inappropriate medication to be avoided in patients formulations exist; close attention must be paid to the
65 years and older (independent of diagnosis or con- concentration when ordering or administering.
dition) due to its potent anticholinergic properties result- Cough and upper respiratory allergy symptoms:
Oral:
ing in increased risk of confusion, dry mouth,
Liquid:
constipation, and other anticholinergic effects or tox-
Brompheniramine 1 mg/phenylephrine 2.5 mg per 5
icity; use should also be avoided due to reduced
mL:
clearance with advanced age and tolerance associated
Children 2 to <6 years: 5 mL every 4 hours as
with use as a hypnotic (Beers Criteria [AGS 2015)).
needed; maximum daily dose: 30 mL/24 hours
Brand Names: US Brohist D [OTC]; Brovex PEB [OTC] Children 6 to 12 years: 10 mL every 4 hours as
[DSC]; Dimaphen, Children's [OTC]; Dimetapp Children's needed; maximum daily dose: 60 mL/24 hours
Cold & Allergy [OTC]; Entre-B [OTC]; Glenmax PEB Children 212 years and Adolescents: 20 mL every 4
[OTC]; LoHist PEB [OTC] [DSC]; Relhist BP [OTC] hours as needed; maximum daily dose: 120 mL/24
[DSC]; Ru-Hist D [OTC]; Rynex PE [OTC]; Triaminic Cold hours
& Allergy [OTC]; Vazobid-PD [OTC] Brompheniramine 4 mg and phenylephrine 10 mg per
Therapeutic Category Antihistamine/Decongestant 5 mL: Children 212 years and Adolescents: 5 mL
Combination / every 4 hours; maximum daily dose: 30 mL/24
Generic Availability (US) Yes hours

295
BROMPHENIRAMINE AND PHENYLEPHRINE

Tablets: Brompheniramine 4 mg and phenylephrine Use Temporary relief of symptoms associated with allergic
10 mg per tablet: rhinitis; Note: Approved ages and uses for generic prod-
Children 26 to 12 years: 1/2 tablet every 4 hours as ucts may vary; consult labeling for specific information.
needed; maximum daily dose: 3 tablets/24 hours (6 Oral:
doses) Capsules (Lodrane-D): FDA approved in ages 212 years
Children 212 years and Adolescents: 1 tablet every 4 and adults
hours as needed; maximum daily dose: 6 tablets/24 Elixir (Q-Tapp): FDA approved in ages 26 years and
hours adults
Renal Impairment: Pediatric There are no dosage Liquid:
adjustments provided in the manufacturer's labeling. Brotapp: FDA approved in ages 26 years and adults
Hepatic Impairment: Pediatric There are no dosage Rynex PSE: FDA approved in ages 22 years and adults
adjustments provided in the manufacturer's labeling. Contraindications Use with or within 14 days of MAO
Administration Oral: Administer with an accurate meas- inhibitor therapy; do not use to sedate a child —
uring device; do not use a household teaspoon (over- Warnings/Precautions May cause CNS depression,
dosage may occur). RY which may impair physical or mental abilities; patients
Test Interactions See individual agents. must be cautioned about performing tasks which require
Dosage Forms Excipient information presented when mental alertness (eg, operating machinery or driving).
available (limited, particularly for generics); consult spe- Effects may be potentiated when used with other sedative
cific product labeling. [DSC] = Discontinued product drugs or ethanol. Use caution with hypertension, ischemic
Liquid, oral: heart disease, hyperthyroidism, asthma, increased intra-
BroveX PEB: Brompheniramine maleate 4 mg and phe- ocular pressure, diabetes mellitus, and BPH. Use with
nylephrine hydrochloride 10 mg per 5 mL (473 mL caution in the elderly; may be more sensitive to adverse
[DSC]) [dye free, ethanol free, gluten free, sugar free; effects.
contains propylene glycol; bubblegum flavor]
Dimaphen Children's: Brompheniramine maleate 1 mg Benzyl alcohol and derivatives: Some dosage forms may
and phenylephrine hydrochloride 2.5 mg per 5 mL (118 contain sodium benzoate/benzoic acid; benzoic acid (ben-
mL, 237 mL) [ethanol free, gluten free; contains propy- zoate) is a metabolite of benzyl alcohol; large amounts of
lene glycol, sodium 2 mg/5 mL, sodium benzoate; benzyl alcohol (299 mg/kg/day) have been associated
grape flavor] with a potentially fatal toxicity ("gasping syndrome") in
Dimetapp Children’s Cold & Allergy: Brompheniramine neonates; the "gasping syndrome" consists of metabolic
maleate 1 mg and phenylephrine hydrochloride 2.5 mg acidosis, respiratory distress, gasping respirations, CNS
per 5 mL (118 mL, 237 mL) [ethanol free; contains dysfunction (including convulsions, intracranial hemor-
sodium 3 mg/5 mL, propylene glycol, sodium benzoate; rhage), hypotension, and cardiovascular collapse (AAP
grape flavor] ["Inactive" 1997]; CDC 1982); some data suggests that
Glenmax PEB: Brompheniramine maleate 4 mg and benzoate displaces bilirubin from protein binding sites
phenylephrine hydrochloride 10 mg per 5 mL (473 (Ahlfors, 2001); avoid or use dosage forms containing
mL) [alcohol free, dye free, sugar free; contains propy- benzy! alcohol derivative with caution in neonates. See
lene glycol, saccharin sodium, sodium benzoate, sorbi- manufacturer's labeling.
tol; fruit gum flavor] When used for self-medication (OTC), notify healthcare
LoHist PEB: Brompheniramine maleate 4 mg and phe- provider if symptoms do not improve within 7 days or are
nylephrine hydrochloride 10 mg per 5 mL (473 mL accompanied by fever. Discontinue and contact health-
[DSC]) [dye free, ethanol free, sugar free; contains care provider if nervousness, dizziness, or sleeplessness
propylene glycol, sodium benzoate; bubble gum flavor] occur. Antihistamines may cause excitation in young
Rynex PE: Brompheniramine maleate 1 mg and phenyl- children.
ephrine hydrochloride 2.5 mg per 5 mL (473 mL)
Warnings: Additional Pediatric Considerations
[ethanol free, gluten free, sugar free; contains propy-
Safety and efficacy for the use of cough and cold products
lene glycol; bubblegum flavor]
in pediatric patients <4 years of age is limited; the AAP
Suspension, oral:
warns against the use of these products for respiratory
Entre-B: Brompheniramine maleate 6 mg and phenyl-
illnesses in this age group. Serious adverse effects includ-
ephrine hydrochloride 10 mg per 5 mL (118 mL) [con-
ing death have been reported (in some cases, high blood
tains benzoic acid, propylene glycol; bubble gum flavor]
concentrations of pseudoephedrine were found). Many of
Vazobid-PD: Brompheniramine maleate 1.2 mg and
these products contain multiple active ingredients,
phenylephrine hydrochloride 2 mg per 1 mL (118 mL)
increasing the risk of accidental overdose when used with
[contains aspartame, sodium benzoate; bubblegum
other products. The FDA notes that there are no approved
flavor]
OTC uses for these products in pediatric patients <2 years
Syrup, oral:
of age. Health care providers are reminded to ask care-
Triaminic Cold & Allergy: Brompheniramine maleate
givers about the use of OTC cough and cold products in
1.mg and phenylephrine hydrochloride 2.5 mg per 5
order to avoid exposure to multiple medications containing
mL (118 mL) [contains propylene glycol, sodium ben-
the same ingredient. Multiple concentrations of oral liquid
zoate; grape flavor]
formulations (drops, elixir, and liquid) exist; close attention
Tablet, oral:
Brohist D: Brompheniramine maleate 4 mg and phenyl- must be paid to the concentration when ordering or
ephrine hydrochloride 10 mg
administering. Antihistamines should not be used to make
Relhist BP: Brompheniramine maleate 4 mg and phenyl- an infant or child sleepy (AAP 2012; FDA 2008).
ephrine hydrochloride 10 mg [DSC] Some dosage forms may contain propylene glycol; in
Ru-Hist D: Brompheniramine maleate 4 mg and phenyl- neonates large amounts of propylene glycol delivered
ephrine hydrochloride 10 mg orally, intravenously (eg, >3,000 mg/day), or topically
have been associated with potentially fatal toxicities which
Brompheniramine and can include metabolic acidosis, seizures, renal failure, and
CNS depression; toxicities have also been reported in
Pseudoephedrine children and adults including hyperosmolality, lactic acido-
(brome fen IR a meen & soo doe e FED rin)
sis, seizures and respiratory depression; use caution
Medication Safety Issues (AAP 1997; Shehab 2009).
Geriatric Patients: High-Risk Medication: Adverse Reactions
Beers Criteria: Brompheniramine, a first-generation anti- Cardiovascular: Cardiac arrhythmia, flushing, hyperten-
histamine, is identified in the Beers Criteria as a poten- sion, palpitations, tachycardia
tially inappropriate medication to be avoided in patients Central nervous system: Central nervous system stimula-
65 years and older (independent of diagnosis or con- tion, convulsions, dizziness, excitability (children; rare),
dition) due to its potent anticholinergic properties result- hallucination, headache, insomnia, irritability, lassitude,
ing in increased risk of confusion, dry mouth, nervousness, sedation
constipation, and other anticholinergic effects or tox- Dermatologic: Pallor
icity; use should also be avoided due to reduced Gastrointestinal: Anorexia, diarrhea, dyspepsia, nausea,
clearance with advanced age and tolerance associated vomiting, xerostomia
with use as a hypnotic (Beers Criteria [AGS 2015)). Genitourinary: Dysuria, urinary retention (with BPH)
Brand Names: US Brotapp [OTC] [DSC]; Brovex PSB Neuromuscular & skeletal: Tremor, weakness
[OTC] [DSC]; J-Tan D PD [OTC] [DSC]; Lodrane D [OTC]; Ophthalmic: Diplopia
Q-Tapp Cold & Allergy [OTC] [DSC]; Rynex PSE [OTC] Renal: Polyuria
Therapeutic Category Antihistamine/Decongestant Respiratory: Dyspnea
Combination Drug Interactions
Generic Availability (US) Yes Metabolism/Transport Effects None known.

296
 BROMPHENIRAMINE, DEXTROMETHORPHAN, AND PHENYLEPHRINE

Avoid Concomitant Use Children 6 to <12 years: 10 mL every 4 to 6 hours as

Avoid concomitant use of Brompheniramine and Pseu- needed; maximum daily dose: 40 mL/24 hours
doephedrine with any of the following: Aclidinium; Aze- Children 212 and Adolescents: 20 mL every 4 to 6
lastine (Nasal); Bromperidol; Cimetropium; Eluxadoline; hours as needed; maximum daily dose: 80 mL/24
Ergot Derivatives; Glycopyrrolate (Oral Inhalation); hours
lobenguane | 123; Ipratropium (Oral Inhalation); Levo- Renal Impairment: Pediatric There are no dosage
sulpiride; Monoamine Oxidase Inhibitors; Orphenadrine; adjustments provided in manufacturer's labeling.
Oxatomide; Oxomemazine; Paraldehyde; Potassium Hepatic Impairment: Pediatric There are no dosage
Chloride; Potassium Citrate; Thalidomide; Tiotropium; adjustments provided in manufacturer's labeling.
Umeclidinium Administration Oral: Administer liquid with an accurate
Increased Effect/Toxicity measuring device; do not use a household teaspoon
‘Brompheniramine and Pseudoephedrine may increase (overdosage may occur).
the levels/effects of: AbobotulinumtoxinA; Alcohol Test Interactions See individual agents.
(Ethyl); Amezinium; Anticholinergic Agents; Azelastine Dosage Forms Excipient information presented when
(Nasal); Blonanserin; Buprenorphine; Cimetropium; available (limited, particularly for generics); consult spe-
CNS Depressants; Doxofylline; Eluxadoline; Flunitraze- cific product labeling. [DSC] = Discontinued product
pam; Glucagon; Glycopyrrolate (Oral Inhalation); Capsule, oral:
HYDROcodone; Methotrimeprazine; MetyroSINE; Mira- Lodrane D: Brompheniramine maleate 4 mg and pseu-
begron; Mirtazapine; OnabotulinumtoxinA; Opioid Anal- doephedrine hydrochloride 60 mg
gesics; Orphenadrine; OxyCODONE; Paraldehyde; Liquid, oral:
Piribedil; Potassium Chloride; Potassium Citrate; Prami- Brotapp: Brompheniramine maleate 1 mg and pseudoe-
pexole; Ramosetron; RimabotulinumtoxinB; ROPINIR- phedrine hydrochloride 15 mg per 5 mL (120 mL
ole; Rotigotine; Selective Serotonin Reuptake [DSC], 240 mL [DSC], 480 mL [DSC]) [ethanol free,
Inhibitors; Suvorexant; Sympathomimetics; Thalidomide; sugar free; contains propylene glycol, sodium ben-
Thiazide and Thiazide-Like Diuretics; Tiotropium; Top- zoate; grape flavor]
iramate; Zolpidem BroveX PSB: Brompheniramine maleate 4 mg and pseu-
doephedrine hydrochloride 20 mg per 5 mL (473 mL
The levels/effects of Brompheniramine and Pseudoe-
[DSC]) [dye free, ethanol free, sugar free; contains
phedrine may be increased by: Aclidinium; Alkalinizing propylene glycol; cotton candy flavor]
Agents; Amantadine; AtoMOXetine; Brimonidine (Top-
Q-Tapp Cold & Allergy: Brompheniramine maleate 1 mg
ical); Bromopride; Bromperidol; Cannabis; Carbonic
and pseudoephedrine hydrochloride 15 mg per 5 mL
Anhydrase Inhibitors; Chloral Betaine; Chlormethiazole;
(118 mL [DSC)) [ethanol free; contains propylene gly-
Chloroprocaine; Chlorphenesin Carbamate; Cocaine col, sodium 2 mg/5 mL, sodium benzoate; grape flavor]
(Topical); Dimethindene (Topical); Doxylamine; Dronabi- Rynex PSE: Brompheniramine maleate 1 mg and pseu-
nol; Droperidol; Ergot Derivatives; Guanethidine;
doephedrine hydrochloride 15 mg per 5 mL (473 mL)
HydrOXYzine; lpratropium (Oral Inhalation); Kava Kava; (ethanol free, sugar free; contains propylene glycol;
Linezolid; Lofexidine; Magnesium Sulfate; Methotrime-
orange flavor)
prazine; Mianserin; Minocycline; Monoamine Oxidase
Liquid, oral [drops]:
Inhibitors; Nabilone; Oxatomide; Oxomemazine; Peram- J-Tan D PD: Brompheniramine maleate 1 mg and pseu-
panel; Pramlintide; Rufinamide; Serotonin/Norepinephr-
doephedrine hydrochloride 7.5 mg per 1 mL (30 mL
ine Reuptake Inhibitors; Sodium Oxybate; Tapentadol; [DSC]) [dye free, ethanol free, sugar free; contains
Tedizolid; Tetrahydrocannabinol; Trimeprazine; Umecli- propylene glycol; cotton candy flavor]
dinium
Decreased Effect
Brompheniramine and Pseudoephedrine may decrease Brompheniramine, Dextromethorphan,
the levels/effects of: Acetylcholinesterase Inhibitors; and Phenylephrine
Amifampridine; Benzylpenicilloy! Polylysine; Betahistine; (brome fen IR a meen dex troe meth OR fan & fen il EF rin)
Gastrointestinal Agents (Prokinetic); Hyaluronidase;
lobenguane | 123; ltopride; Levosulpiride; Nitroglycerin; Medication Safety Issues
Pitolisant; Secretin Geriatric Patients: High-Risk Medication:
Beers Criteria: Brompheniramine, a first-generation anti-
The levels/effects of Brompheniramine and Pseudoe- histamine, is identified in the Beers Criteria as a poten-
phedrine may be decreased by: Acetylcholinesterase tially inappropriate medication to be avoided in patients
Inhibitors; Alpha1-Blockers; Amifampridine; Amphet- 265 years (independent of diagnosis or condition) due
amines; Spironolactone; Urinary Acidifying Agents to its potent anticholinergic properties resulting in
Storage/Stability Store at room temperature. increased risk of confusion, dry mouth, constipation,
Mechanism of Action Brompheniramine maleate is an and other anticholinergic effects or toxicity; use should
antihistamine with H,-receptor activity; pseudoephedrine, also be avoided due to reduced clearance with
a sympathomimetic amine and isomer of ephedrine, acts advanced age and tolerance associated with use as a
as a decongestant in respiratory tract mucous membranes hypnotic (Beers Criteria [AGS 2015)).
with less vasoconstrictor action than ephedrine in normo- Brand Names: US Alahist DM [OTC] [DSC]; AP-Hist DM
tensive individuals. [OTC]; BPM-DM-Phen [OTC] [DSC]; BrovexX PEB DM
Pharmacodynamics/Kinetics (Adult data unless [OTC] [DSC]; Cold/Cough Childrens [OTC]; Dimaphen
noted) See individual monograph for Pseudoephedrine. DM Cold/Cough Child [OTC] [DSC]; Dimaphen DM Cold/
Brompheniramine component only: Cough [OTC]; Dimetapp DM Cold/Cough [OTC]; Enda-
Duration: 4 to 6 hours Cof-DM [OTC]; Glenmax PEB DM FORTE [OTC]; Glen-
Distribution: Mean: Vg: Children 6 to 12 years: 20 L/kg max PEB DM [OTC]; LoHist-DM [OTC]; LoHist-PEB-DM
(Simons 1999), Adults: 11.7 L/kg (Simons 1982) [OTC] [DSC]; M-Hist DM [OTC] [DSC]; Niva-Hist DM
Protein binding: 39% to 49% (Martinez-Gomez 2007) [OTC] [DSC]; Relcof DM [OTC] [DSC]; Rynex DM
_ Metabolism: Hepatic via cytochrome P450 system, exten- [OTC]; TGQ 7.5PEH/4BRM/15DM [OTC] [DSC]; TL-Hist
sive (Simons 2004) DM [OTC] [DSC]
Half-life elimination: Mean: Children 6 to 12 years: 12.4 Generic Availability (US) Yes
hours (Simons 1999), Adults: ~25 hours (Simons 1982) Use Temporary relief of symptoms associated with the
Time to peak, serum: Oral: Mean: Children: 6 to 12 years: common cold, hay fever (allergic rhinitis), or other upper
3.2 hours (Simons 1999), Adults: 2 to 4 hours respiratory allergies. Note: Approved ages and uses for
(Simons 1982) - generic products may vary; consult labeling for specific
Excretion: Urine (50%, as inactive metabolites) information.
(Bruce 1968) Contraindications OTC labeling: When used for self-
Dosing medication, do not use to sedate or make a child sleep;
Pediatric Note: Multiple concentrations of oral liquid with or within 14 days of stopping a monoamine oxidase
formulations (elixir and liquid) exist; close attention must inhibitor (MAO) inhibitor therapy.
be paid to the concentration when ordering or adminis- Warnings/Precautions See individual agents.
tering Warnings: Additional Pediatric Considerations
Allergic rhinitis and nasal congestion: Safety and efficacy for the use of cough and cold products
Capsules (Brompheniramine 4 mg and pseudoephe- in pediatric patients <4 years of age is limited; the AAP
drine 60 mg): Oral: Children 212 and Adolescents: 1 warns against the use of these products for respiratory
capsule every 4 to 6 hours as needed; maximum daily illnesses in this age group. Serious adverse effects includ-
dose: 4 capsules/24 hours ing death have been reported (in some cases, high blood
Liquid and elixir (Brompheniramine 1 mg and 15 mg concentrations of pseudoephedrine were found). Many of
pseudoephedrine per 5 mL): Oral: these products contain multiple active ingredients,
Children 2 to <6 years: 5 mL every 4 to 6 hours as increasing the risk of accidental overdose when used with
needed; maximum daily dose: 20 mL/24 hours other products. The FDA notes that there are no approved >
297
BROMPHENIRAMINE, DEXTROMETHORPHAN, AND PHENYLEPHRINE

OTC uses for these products in pediatric patients <2 years Dextromethorphan: Decreases the sensitivity of cough
of age. Healthcare providers are reminded to ask care- receptors and interrupts cough impulse transmission by
givers about the use of OTC cough and cold products in depressing the medullary cough center through sigma
order to avoid exposure to multiple medications containing receptor stimulation i
the same ingredient. Multiple concentrations of oral liquid Phenylephrine: Stimulates postsynaptic alpha-receptors,
formulations (drops, elixir, and liquid) exist; close attention resulting in vasoconstriction, which reduces nasal con-
must be paid to the concentration when ordering or gestion
administering. Antihistamines should not be used to make Pharmacodynamics/Kinetics (Adult data unless
an infant or child sleepy (AAP 2012; FDA 2008). noted) See individual monographs for Dextromethorphan
and Phenylephrine.
Some dosage forms may contain propylene glycol; in
Brompheniramine component only:
neonates large amounts of propylene glycol delivered
Distribution: Vg: Children 6 to 12 years: ~20 L/kg
orally, intravenously (eg, >3,000 mg/day), or topically
(Simons 1999); Adults: ~12 L/kg (Simons 1982)
have been associated with potentially fatal toxicities which
Protein binding: 39% to 49% (Martinez-Gomez 2007)
can include metabolic acidosis, seizures, renal failure, and
Metabolism: Hepatic, extensive (Simons 2004)
CNS depression; toxicities have also been reported in
Half-life elimination: Children 6 to 12 years: 12.4 hours
children and adults including hyperosmolality, lactic acido-
(Simons 1999); Adults: ~25 hours (Simons 1982)
sis, seizures and respiratory depression; use caution
Time to peak, serum: Oral: Children: 3 to 3.5 hours
(AAP 1997; Shehab 2009).
(Simons 1999); Adults: 2 to 4 hours (Simons 1982)
Adverse Reactions Also see individual agents.
Excretion: Urine (50%, as inactive metabolites)
Central nervous system: Drowsiness
(Bruce 1968)
Drug Interactions Dosing
Metabolism/Transport Effects Refer to individual Pediatric Note: Multiple concentrations of oral liquid
components.
formulations exist; close attention must be paid to the
Avoid Concomitant Use concentration when ordering or administering.
Avoid concomitant use of Brompheniramine, Dextrome- Cough and upper respiratory allergy symptoms:
thorphan, and Phenylephrine with any of the following: Oral: :
Aclidinium; Azelastine (Nasal); Bromperidol; Cime- Brompheniramine 1 mg/dextromethorphan 5 mg/phe-
tropium; Dapoxetine; Eluxadoline; Ergot Derivatives; nylephrine 2.5 mg per 5 mL:
Glycopyrrolate (Oral Inhalation); Hyaluronidase; loben- Children 2 to <6 years: 5 mL every 4 hours as
guane | 123; Ipratropium (Oral Inhalation); Levosulpiride; needed. Maximum daily dose: 30 mL/24 hours
Methylene Blue; Monoamine Oxidase Inhibitors; Orphe- Children 6 to 12 years: 10 mL every 4 hours as
nadrine; Oxatomide; Oxomemazine; Paraldehyde; needed. Maximum daily dose: 60 mL/24 hours
Potassium Chloride; Potassium Citrate; Thalidomide; Children 212 years and Adolescents: 20 mL every 4
Tiotropium; Umeclidinium hours as needed. Maximum daily dose: 120 mL/24
Increased Effect/Toxicity hours
Brompheniramine, Dextromethorphan, and Phenylephr- Brompheniramine 2 mg/dextromethorphan 10 mg/phe-
ine may increase the levels/effects of: Abobotulinumtox- nylephrine 5 mg per 5 mL:
inA; Alcohol (Ethyl); Amezinium; Anticholinergic Agents; Children 26 to 12 years: 5 mL -every 4 hours as
Antipsychotic Agents; Azelastine (Nasal); Blonanserin; needed. Maximum daily dose: 30 mL/24 hours
Buprenorphine; Cimetropium; CNS Depressants; Doxo- Children 212 years and Adolescents: 10 mL every 4
fylline; Eluxadoline; Flunitrazepam; Glucagon; Glycopyr- hours as needed. Maximum daily dose: 60 mL/24
rolate (Oral Inhalation); HYDROcodone; Memantine; hours
Methotrimeprazine; Metoclopramide; MetyroSINE; Mira- Brompheniramine 4 mg/dextromethorphan 15 mg/phe-
begron; Mirtazapine; OnabotulinumtoxinA; Opioid Anal- nylephrine 7.5 mg per 5 mL:
gesics; Orphenadrine; OxyCODONE; Paraldehyde; Children 26 to 12 years: 2.5 mL every 4 hours as
Perhexiline; Piribedil; Potassium Chloride; Potassium needed. Maximum daily dose: 15 mL/24 hours
Citrate; Pramipexole; Ramosetron; Rimabotulinumtox- Children 212 years and Adolescents: 5 mL every 4
inB; ROPINIRole; Rotigotine; Selective Serotonin Reup- hours as needed. Maximum daily dose: 30 mL/24
take Inhibitors; Serotonin Modulators; Suvorexant; hours
Sympathomimetics; Thalidomide; Thiazide and Thia- Brompheniramine 4 mg/dextromethorphan 20 mg/phe-
zide-Like Diuretics; Tiotropium; Topiramate; Zolpidem nylephrine 10 mg per 5 mL:
The levels/effects of Brompheniramine, Dextromethor- Children 26 to 12 years: 2.5 mL every 4 hours as
phan, and Phenylephrine may be increased by: Abirater- needed. Maximum daily dose: 15 mL/24 hours
one Acetate; Acetaminophen; Aclidinium; Ajmaline; Children 212 years and Adolescents: 5 mL every 4
Amantadine; Antiemetics (G5HT3 Antagonists); Antipsy- hours as needed. Maximum daily dose: 30 mL/24
chotic Agents; Asunaprevir; AtoMOXetine; Brimonidine hours
(Topical); Bromopride; Bromperidol; Cannabis; Chloral Renal Impairment: Pediatric There are no dosage
Betaine; Chlormethiazole; Chloroprocaine; Chlorphene- adjustments provided in the manufacturer's labeling.
sin Carbamate; Cobicistat; Cocaine (Topical); CYP2D6 Hepatic Impairment: Pediatric There are no dosage
Inhibitors (Moderate); CYP2D6 Inhibitors (Strong); adjustments provided in the manufacturer's labeling.
Dapoxetine; Darunavir; Dimethindene (Topical); Doxyl- Administration Administer with an accurate measuring
amine; Dronabinol; Droperidol; Ergot Derivatives; Gua- device; do not use a household teaspoon (overdosage
nethidine; Hyaluronidase; HydrOXYzine; Imatinib; may occur).
Ipratropium (Oral Inhalation); Kava Kava; Lofexidine; Dosage Forms Excipient information presented when
Lumefantrine; Magnesium Sulfate; Metaxalone; Metho- available (limited, particularly for generics); consult spe-
trimeprazine; Methylene Blue; Methylphenidate; Mian- cific product labeling. [DSC] = Discontinued product
serin; Minocycline; Monoamine Oxidase Inhibitors; Elixir, Oral:
Nabilone; Oxatomide; Oxomemazine; Panobinostat; Cold/Cough Childrens: Brompheniramine maleate 1 mg,
Parecoxib; Peginterferon Alfa-2b; Perampanel; Perhexi- dextromethorphan hydrobromide 5 mg, and phenyl-
line; Pramlintide; Propacetamol; QuiNIDine; QuiNINE; ephrine hydrochloride 2.5 mg per 5 mL (118 mL) [alco-
Rufinamide; Selective Serotonin Reuptake Inhibitors; hol free; contains brilliant blue fcf (fd&c blue #1),
Sodium Oxybate; Tapentadol; Tetrahydrocannabinol:; disodium edta, fd&c red #40, propylene glycol, saccha-
Tipranavir; Tricyclic Antidepressants; Trimeprazine; rin sodium, sodium benzoate]
Umeclidinium Dimaphen DM Cold/Cough: Brompheniramine maleate
Decreased Effect 1 mg, dextromethorphan hydrobromide 5 mg, and phe-
Brompheniramine, Dextromethorphan, and Phenylephr- nylephrine hydrochloride 2.5 mg per 5 mL (118 mL)
ine may decrease the levels/effects of: Acetylcholines- [alcohol free, gluten free; contains brilliant blue fef (fd&c
terase Inhibitors; Amifampridine; Benzylpenicilloyl| blue #1), edetate disodium, fd&c red #40, propylene
Polylysine; Betahistine; Gastrointestinal Agents (Proki- glycol, saccharin sodium, sodium benzoate; grape
netic); lobenguane | 123; loflupane | 123; Itopride; flavor]
Levosulpiride; Nitroglycerin; Pitolisant; Secretin Dimaphen DM Cold/Cough Child: Brompheniramine
maleate 1 mg, dextromethorphan hydrobromide 5 mg,
The levels/effects of Brompheniramine, Dextromethor- and phenylephrine hydrochloride 2.5 mg per 5 mL (118
phan, and Phenylephrine may be decreased by: Acetyl- mL [DSC)) [alcohol free, pseudoephedrine free; con-
cholinesterase Inhibitors; Alpha1t-Blockers; tains brilliant blue fef (fd&c blue #1), fd&c red #40,
Amifampridine; Amphetamines; CloZAPine; Peginter- propylene glycol, saccharin sodium, sodium benzoate;
feron Alfa-2b; Tricyclic Antidepressants grape flavor]
Storage/Stability Store at room temperature. Liquid, Oral:
Mechanism of Action Alahist DM: Brompheniramine maleate 4 mg, dextrome-
Brompheniramine: Competes with histamine for H,-recep- thorphan hydrobromide 15 mg, and phenylephrine
tor sites on effector cells hydrochloride 7.5 mg per 5 mL (473 mL [DSC)) [alcohol

298
 BUDESONIDE (SYSTEMIC)

free, dye free, sugar free; contains propylene glycol, @ Brompheniramine Maleate and Pseudoephedrine
saccharin sodium; strawberry flavor] Hydrochloride see Brompheniramine and Pseudoephe-
AP-Hist DM: Brompheniramine maleate 4 mg, dextro- drine on page 296
methorphan hydrobromide 15 mg, and phenylephrine @ Brompheniramine Maleate and Pseudoephedrine Sul-
hydrochloride 7.5 mg per 5 mL (473 mL) [alcohol free, fate see Brompheniramine and Pseudoephedrine
dye free, sugar free; contains propylene glycol, sac- on page 296
charin sodium; strawberry flavor]
@ Brompheniramine/Phenylephrine see Bromphenir-
BroveX PEB DM: Brompheniramine maleate 4 mg, dex-
tromethorphan hydrobromide 20 mg, and phenylephr- amine and Phenylephrine on page 295
ine hydrochloride 10 mg per 5 mL (473 mL [DSC]) @ Brompheniramine Tannate and Phenylephrine Tan-
[alcohol free; contains propylene glycol, saccharin nate see Brompheniramine and Phenylephrine
‘sodium; bubble-gum flavor] on page 295
Dimetapp DM Cold/Cough: Brompheniramine maleate @ Broncho Saline [OTC] see Sodium Chloride
1 mg, dextromethorphan hydrobromide 5 mg, and phe- on page 1834
nylephrine hydrochloride 2.5 mg per 5 mL (118 mL, 237
@ Brotapp [OTC] [DSC] see Brompheniramine and Pseu-
mL) [alcohol free; contains brilliant blue fcf (fd&c blue
doephedrine on page 296
#1), fd&c red #40, propylene glycol, saccharin sodium,
sodium benzoate; grape flavor] @ BroveX PEB [OTC] [DSC] see Brompheniramine and
EndaCof-DM: Brompheniramine maleate 1 mg, dextro- Phenylephrine on page 295
methorphan hydrobromide 5 mg, and phenylephrine @ BroveX PEB DM [OTC] [DSC] see Brompheniramine,
hydrochloride 2.5 mg per 5 mL (473 mL) [alcohol free, Dextromethorphan, and Phenylephrine on page 297
sugar free; contains benzoic acid, edetate disodium, @ BroveX PSB [OTC] [DSC] see Brompheniramine and
fd&c red #40, propylene glycol, saccharin sodium; Pseudoephedrine on page 296
strawberry flavor]
BSS see Balanced Salt Solution on page 244
Glenmax PEB DM: Brompheniramine maleate 2 mg,
dextromethorphan hydrobromide 10 mg, and phenyl- BSS see Bismuth Subsalicylate on page 278
ephrine hydrochloride 5 mg per 5 mL (473 mL) [alcohol BSS Plus see Balanced Salt Solution on page 244
free, dye free, sugar free; contains propylene glycol, BTX-A see OnabotulinumtoxinA on page 1498
saccharin sodium, sodium benzoate, sorbitol; straw-
berry flavor] : @
¢
eeB-type Natriuretic Peptide (Human) see Nesiritide
Glenmax PEB DM FORTE: Brompheniramine maleate on page 1440
4 mg, dextromethorphan hydrobromide 20 mg, and @ Buckleys Chest Congestion [OTC] see GuaiFENesin
phenylephrine hydrochloride 10 mg per 5 mL (473 on page 964
mL) [alcohol free, dye free, sugar free; contains propy- @ Buckleys Cough [OTC] see Dextromethorphan
lene glycol, saccharin sodium, sodium benzoate, sorbi- on page 618
tol; fruit flavor]
@ Budeprion SR see BuPROPion on page 320
LoHist-PEB-DM: Brompheniramine maleate 4 mg, dex-
tromethorphan hydrobromide 20 mg, and phenylephr-
ine hydrochloride 10 mg per 5 mL (473 mL [DSC]) Budesonide (Systemic) (yoo DEs oh nide)
[alcohol free, sugar free; contains benzoic acid, edetate
disodium, fd&c red #40, propylene glycol, saccharin Related Information
sodium; bubble-gum flavor] Oral Medications That Should Not Be Crushed or Altered
M-Hist DM: Brompheniramine maleate 4 mg, dextrome- on page 2217
thorphan hydrobromide 15 mg, and phenylephrine Brand Names: US Entocort EC; Uceris
hydrochloride 7.5 mg per 5 mL (473 mL [DSC}) [alcohol Brand Names: Canada Cortiment; Entocort
free, dye free, sugar free; contains propylene glycol, Therapeutic Category Adrenal Corticosteroid; Anti-
saccharin sodium, sodium benzoate, sorbitol; straw- inflammatory Agent; Glucocorticoid
berry flavor] Generic Availability (US) May be product dependent
Niva-Hist DM: Brompheniramine maleate 4 mg, dextro- Use
methorphan hydrobromide 15 mg, and phenylephrine Entocort EC: Treatment of mild to moderate active Crohn
hydrochloride 7.5 mg per 5 mL (473 mL [DSC}) [alcohol disease of the ileum and/or ascending colon (FDA
free, dye free, sugar free; contains saccharin sodium, approved in ages 28 years weighing >25 kg and adults)
sodium benzoate; strawberry flavor] and maintenance of remission for up to 3 months (FDA
Relcof DM: Brompheniramine maleate 4 mg, dextrome- approved in adults); has also been used for treatment of
thorphan hydrobromide 15 mg, and phenylephrine protein-losing enteropathy in patients after Fontan pro-
hydrochloride 7.5 mg per 5 mL (473 mL [DSC]}) [alcohol cedure
free, dye free, sugar free; contains saccharin sodium, Uceris ER: Induction of remission from active, mild to
sodium benzoate] BPS 5 moderate ulcerative colitis (FDA approved in adults)
Rynex DM: Brompheniramine maleate 1 mg, dextrome- An oral suspension (prepared with inhalation product) has
thorphan hydrobromide 5 mg, and phenylephrine been used for treatment of eosinophilic esophagitis.
hydrochloride 2.5 mg per 5 mL (118 mL, 473 mL) Pregnancy Risk Factor C (tablet)
[alcohol free, dye free, gluten free, sugar free; contains Pregnancy Considerations Some studies have shown
methylparaben, propylene glycol, propylparaben; tutti- an association between first trimester systemic cortico-
frutti flavor] steroid use and oral clefts (Park-Wyllie 2000; Pradat
TGQ 7.5PEH/4BRM/15DM: Brompheniramine maleate 2003). Systemic corticosteroids may also influence fetal
4 mg, dextromethorphan hydrobromide 15 mg, and growth (decreased birth weight); however, information is
phenylephrine hydrochloride 7.5 mg per 5 mL (473
conflicting (Lunghi 2010). Hypoadrenalism may occur in
mL [DSC}) [contains methylparaben, propylene glycol,
newborns following maternal use of corticosteroids in
propylparaben; strawberry flavor] pregnancy (monitor). When systemic corticosteroids are
TL-Hist DM: Brompheniramine maleate 4 mg, dextro-
needed in pregnancy, it is generally recommended to use
methorphan hydrobromide 15 mg, and phenylephrine
the lowest effective dose for the shortest duration of time,
hydrochloride 7.5 mg per 5 mL (473 mL [DSC}) [con-
avoiding high doses during the first trimester (Leachman
tains methylparaben, propylene glycol, propylparaben]
2006; Lunghi 2010). Budesonide may be used for the
Generic: Brompheniramine maleate 4 mg, dextrome-
induction of remission in pregnant women with inflamma-
thorphan hydrobromide 20 mg, and phenylephrine
tory bowel disease (Habal 2012; Nguyen 2016).
hydrochloride 10 mg per 5 mL (473 mL [DSC)])
Breastfeeding Considerations Budesonide is present
Syrup, Oral:
in breast milk. According to the manufacturer, the decision
BPM-DM-Phen: Brompheniramine maleate 2 mg, dex-
to breastfeed during therapy should take into account the
tromethorphan hydrobromide 10 mg, and phenylephr-
risk of exposure to the infant and the benefits of treatment
ine hydrochloride 5 mg per 5 mL (473 mL [DSC])
to the mother. If there is concern about exposure to the
[contains benzoic acid, disodium edta, fd&c red #40,
infant, some guidelines recommend waiting 4 hours after
propylene glycol, saccharin sodium]
the maternal dose of an oral systemic corticosteroid
LoHist-DM: Brompheniramine maleate 2 mg, dextrome-
before breastfeeding in order to decrease potential expo-
thorphan hydrobromide 10 mg, and phenylephrine
sure to the breastfed infant (based on a study using
hydrochloride 5 mg per 5 mL (473 mL) [alcohol free,
prednisolone) (Habal 2012; Ost 1985).
dye free, gluten free, sugar free; contains methylpar-
aben, propylene glycol, propylparaben; strawberry Contraindications
flavor] Hypersensitivity to budesonide or any component of the
formulation.
@ Brompheniramine Maleate and Phenylephrine Hydro- Documentation of allergenic cross-reactivity for cortico-
chloride see Brompheniramine and Phenylephrine steroids is limited. However, because of similarities in
on page 295 chemical structure and/or pharmacologic actions, the >

299
BUDESONIDE (SYSTEMIC)

possibility of cross-sensitivity cannot be ruled out with Dermatologic: Acne vulgaris, alopecia, dermatitis, derma-
certainty. tological disease, diaphoresis, eczema
Canadian labeling: Additional contraindications (not in US Endocrine & metabolic: Adrenocortical insufficiency (more
labeling): Active tuberculosis; systemic or local bacterial, common in foam); bruise, decreased cortisol (more
fungal or viral infections; hypersensitivity to soya or common in foam), hirsutism, hypokalemia, intermenst-
peanut (Cortiment) rual bleeding, menstrual disease, moon face, redistrib-
Warnings/Precautions May cause hypercortisolism or ution of body fat, weight gain
suppression of hypothalamic-pituitary-adrenal (HPA) axis, Gastrointestinal: Abdominal distention, anal disease, con-
particularly in younger children, or in patients receiving stipation, diarrhea, dyspepsia, enteritis, epigastric pain,
high doses for prolonged periods. HPA axis suppression exacerbation of Crohn's disease, flatulence, gastrointes-
may lead to adrenal crisis. Withdrawal and discontinuation tinal fistula, glossitis, hemorrhoids, increased appetite,
of a corticosteroid should be done slowly and carefully. intestinal obstruction, nausea, oral candidiasis, upper
Particular care is required when patients are transferred abdominal pain ;
from systemic corticosteroids to inhaled products or corti- Genitourinary: Dysuria, hematuria, nocturia, pyuria, uri-
costeroids with lower systemic effect due to possible nary frequency, urinary tract infection
adrenal insufficiency or withdrawal from steroids, including Hematologic & oncologic: Abnormal neutrophils, anemia,
an increase in allergic symptoms. Adult patients receiving C-reactive protein increased, increased erythrocyte sed-
>20 mg per day of prednisone (or equivalent) may be imentation rate, leukocytosis, purpura
most susceptible. Fatalities have occurred due to adrenal Hepatic: Increased serum alkaline phosphatase
insufficiency in asthmatic patients during and after transfer Hypersensitivity: Tongue edema
from systemic corticosteroids to aerosol steroids; aerosol Infection: Abscess, viral infection
steroids do not provide the systemic steroid needed to Neuromuscular & skeletal: Ankle edema, arthralgia, arthri-
treat patients having trauma, surgery, or infections. tis, hyperkinesia, muscle cramps, myalgia, tremor,
weakness
Acute myopathy has been reported with high-dose cortico-
Ophthalmic: Eye disease, visual disturbance
steroids, usually in patients with neuromuscular trans-
Otic: Otic infection
mission disorders; may involve ocular and/or respiratory
Respiratory: Bronchitis, dyspnea, flu-like symptoms, phar-
muscles; monitor creatine kinase; recovery may be
yngeal disease, respiratory tract infection, rhinitis,
delayed. Corticosteroid use may cause psychiatric dis-
sinusitis
turbances, including euphoria, insomnia, mood swings,
Miscellaneous: Fever
personality changes, severe depression or psychotic man-
ifestations. Preexisting psychiatric conditions may be exa- Rare but important or life-threatening: Allergic dermatitis,
anaphylaxis, emotional lability, hyperglycemia, maculo-
cerbated by corticosteroid use. Prolonged use of
papular rash, pancreatitis, peripheral edema, pruritus,
corticosteroids may increase the incidence of secondary
infection, mask acute infection (including fungal infec- pseudotumor cerebri, rectal bleeding
tions), prolong or exacerbate viral infections, or limit Drug Interactions
response to killed or inactivated vaccines. Exposure to Metabolism/Transport Effects Substrate of CYP3A4
chickenpox or measles should be avoided; corticosteroids (major); Note: Assignment of Major/Minor substrate sta-
should not be used to treat ocular herpes simplex. Cortico- tus based on clinically relevant drug interaction potential
steroids should not be used for cerebral malaria, fungal Avoid Concomitant Use ;
infections, viral hepatitis. Close observation is required in Avoid concomitant use of Budesonide (Systemic) with
patients with latent tuberculosis and/or TB reactivity; any of the following: Aldesleukin; BCG (Intravesical);
restrict use in active TB (only fulminating or disseminated Conivaptan; CYP3A4 Inhibitors (Moderate); CYP3A4
TB in conjunction with antituberculosis treatment). Ame- Inhibitors (Strong); Fusidic Acid (Systemic); Grapefruit
biasis should be ruled out in any patient with recent travel Juice; Idelalisib; Natalizumab; Pimecrolimus; Tacrolimus
to tropic climates or unexplained diarrhea prior to initiation (Topical)
of corticosteroids. Use with extreme caution in patients Increased Effect/Toxicity
with Strongyloides infections; hyperinfection, dissemina- Budesonide (Systemic) may increase the levels/effects
tion and fatalities have occurred. Prolonged treatment with of: Baricitinib; Ceritinib; Deferasirox; Fingolimod; Leflu-
corticosteroids has been associated with the development nomide; Natalizumab; Ritodrine; Tofacitinib
of Kaposi sarcoma (case reports); if noted, discontinuation
The levels/effects of Budesonide (Systemic) may be
of therapy should be considered (Goedert 2002).
increased by: Ceritinib; Conivaptan; CYP3A4 Inhibitors
Avoid use in patients with severe hepatic impairment (Moderate); CYP3A4 Inhibitors (Strong); Denosumab;
(Child-Pugh class C). Consider reduced dosage in Fosaprepitant; Fusidic Acid (Systemic); Grapefruit Juice;
patients with moderate hepatic impairment (Child-Pugh Idelalisib; Ocrelizumab; Palbociclib; Pimecrolimus;
Class B); monitor for hypercortisolism. Long-term use of Roflumilast; Simeprevir; Stiripentol; Tacrolimus (Topical);
corticosteroids in patients with hepatic impairment, includ- Trastuzumab
ing cirrhosis, has been associated with fluid retention. Use Decreased Effect
with caution in patients with thyroid disease, renal impair- Budesonide (Systemic) may decrease the levels/effects
ment, diabetes, glaucoma, cataracts, myasthenia gravis, of: Aldesleukin; BCG (Intravesical); Coccidioides immitis
osteoporosis, patients at risk for seizures or seizure dis- Skin Test; Corticorelin; Hyaluronidase; Nivolumab; Pido-
order, or GI diseases (diverticulitis, fresh intestinal anasto- timod; Sipuleucel-T; Tertomotide; Vaccines (Inactivated)
moses, active or latent, peptic ulcer, ulcerative colitis,
abscess or other pyogenic infection). Use with caution in The levels/effects of Budesonide (Systemic) may be
patients with HF and/or hypertension; use has been decreased by: Antacids; Bile Acid Sequestrants; Echi-
associated with fluid retention, electrolyte disturbances, nacea
and hypertension. Use caution following acute MI (cortico- Food Interactions Grapefruit juice may double systemic
steroids have been associated with myocardial rupture). exposure of orally administered budesonide. Administra-
tion of capsule or tablet with a high-fat meal delays peak
Rare cases of anaphylactoid reactions have been concentrations (but does not alter the extent of absorption.
observed in patients receiving corticosteroids. Potentially Management: Avoid grapefruit juice with oral capsules or
significant interactions may exist, requiring dose or fre- tablets.
quency adjustment, additional monitoring, and/or selec- Storage/Stability Store at 25°C (77°F); excursions per-
tion of alternative therapy. mitted to 15°C to 30°C (59°F to 86°F). Protect from light
Some dosage forms may contain polysorbate 80 (also and moisture.
known as Tweens). Hypersensitivity reactions, usually a Mechanism of Action Controls the rate of protein syn-
delayed reaction, have been reported following exposure thesis; depresses the migration of polymorphonuclear
to pharmaceutical products containing polysorbate 80 in leukocytes, fibroblasts; reverses capillary permeability
certain individuals (Isaksson 2002; Lucente 2000; Shelley and lysosomal stabilization at the cellular level to prevent
1995). Thrombocytopenia, ascites, pulmonary deteriora- or control inflammation. Has potent glucocorticoid activity
tion, and renal and hepatic failure have been reported in and weak mineralocorticoid activity.
premature neonates after receiving parenteral products Pharmacodynamics/Kinetics (Adult data unless
containing polysorbate 80 (Alade 1986; CDC 1984). See noted)
manufacturer's labeling. Distribution:
Adverse Reactions Children 29 years and Adolescents <14 years: IV: 2.2 +
Cardiovascular: Chest pain, edema, facial edema, flush- 0.4 Likg
ing, hypertension, palpitations, tachycardia Adults: 2.2 to 3.9 L/kg
Central nervous system: Agitation, amnesia, confusion, Protein binding: 85% to 90%
dizziness, drowsiness, fatigue, headache, insomnia, Metabolism: Hepatic via CYP3A4 to two metabolites: 16
malaise, nervousness, paresthesia, sleep disorder, alpha-hydroxyprednisolone and 6 beta-hydroxybudeso-
vertigo nide; both are <1% as active as parent

300
 BUDESONIDE (NASAL)

Bioavailability: High first-pass effect; Capsule: Children 29 Monitoring Parameters Serum glucose, electrolytes;
years and Adolescents <14 years: 3% to 17%; Adults: blood pressure, weight and other growth parameters,
9% to 21% presence of infection; monitor IOP with therapy >6 weeks;
Half-life elimination: IV: bone mineral density; assess HPA axis suppression (eg,
Children 29 years and Adolescents $14 years: 1.9 hours ACTH stimulation test, morning plasma cortisol test, uri-
Adults: 2 to 3.6 hours nary free cortisol test)
Time to peak: Capsule: Children 29 years and Adoles- Additional Information Budesonide capsules (Entocort
cents <14 years: Median: 5 hours; Adults: 0.5 to 10
EC) contain granules in a methylcellulose matrix; the
hours; Tablet (extended release): 13.3 + 5.9 hours
granules are coated with a methacrylic acid polymer to
Excretion: Urine (60%) and feces as metabolites
protect from dissolution in the stomach; the coating dis-
Pharmacodynamics/Kinetics: Additional Consider-
solves at a pH >5.5 (duodenal pH); the methylcellulose
ations Hepatic function impairment: Increased systemic
matrix controls the release of drug in a time-dependent
exposure (22.5-fold) has been reported in moderate hep-
manner (until the drug reaches the ileum and ascending
atic impairment.
colon).
Dosing
Pediatric Dosage Forms Excipient information presented when
Crohn disease (mild to moderate); treatment: available (limited, particularly for generics); consult spe-
Manufacturer's labeling: Children 28 years and Adoles- cific product labeling.
cents weighing >25 kg: Oral: Capsule (Entocort EC): Capsule Delayed Release Particles, Oral:
9 mg once daily for up to 8 weeks then 6 mg once Entocort EC: 3 mg
daily for 2 weeks Generic: 3 mg
Alternate dosing: Limited data available: Children 26 Tablet Extended Release 24 Hour, Oral:
years and Adolescents: Oral: Capsule (Entocort EC): Uceris: 9 mg [contains soybean lecithin]
Induction: 9 mg once daily or in divided doses every 8 Extemporaneous Preparations Oral viscous budeso-
hours for 7 to 8 weeks, followed by a maintenance nide liquid/suspension: An oral viscous budesonide
dose of 6 mg daily for 3 to 4 weeks; therapy was suspension may be made using nebulization suspension
discontinued after a total duration of 10 to 12 weeks (eg, Pulmicort Respules) and Splenda (sucralose) pack-
(Escher 2004; Levine 2003; Levine 2009). In another ets. Mix 10 packets of Splenda (10 g sucralose) for every
study of patients 10 to 19 years of age, a trend for 1 mg of budesonide until slurry is formed. Respules/vials
higher remission rates using an initial dose of 12 mg containing budesonide 0.5 mg/2 mL is reported most often
daily for 4 weeks, followed by 9 mg daily for 3 weeks, and provides a volume of ~8 to 12 mL. Use of 2.5 mL of
followed by 6 mg daily for 3 weeks was observed Neocate Nutra for every 1 mg of budesonide has also
(Levine 2009).
been reported. Oral viscous budesonide suspension
Eosinophilic esophagitis: Limited data available:
should be prepared immediately prior to ingestion (Aceves
Note: Requires extemporaneous preparation of oral
2007; Dohil 2010; Rubinstein 2014).
viscous budesonide suspension using the inhalation
Aceves SS, Bastian JF, Newbury RO, Dohil R. Oral viscous budeso-
suspension (see Extemporaneous Preparations). nide: a potential new therapy for eosinophilic esophagitis in children.
Although there are other dosage forms of oral budeso- Am J Gastroenterol. 2007;102(10):2271-2279
nide, they are enteric coated and should not be used Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous
for this indication; therapeutic efficacy for eosinophilic budesonide is effective in children with eosinophilic esophagitis in a
esophagitis requires topical corticosteroid effect in the randomized, placebo-controlled trial. Gastroenterology. 2010;139
esophagus. After administration of a budesonide dose, (2):418-429.
avoid ingesting any solid or liquid food for at least 30 Rubinstein E, Lee JJ, Fried A, et al. Comparison of 2 delivery vehicles
for viscous budesonide to treat eosinophilic esophagitis in children. J
minutes.
Pediatr Gastroenterol Nutr. 2014;59(3):317-320.
Children <10 years: Oral: Viscous liquid/suspension
(using inhalation suspension): Initial: 1 mg once daily
or divided twice daily. (Aceves 2005; Aceves 2007; Budesonide (Nasal) (byoo DES oh nide)
Liacouras 2011; Rubinstein 2014)
Children 210 years and Adolescents: Oral: Viscous Brand Names: US Rhinocort Allergy [OTC]; Rhinocort
liquid/suspension (using inhalation suspension): Aqua [DSC]
2 mg once daily or divided twice daily (Aceves Brand Names: Canada Mylan-Budesonide AQ; Rhino-
2007; Liacouras 2011; Rubinstein 2014) cort Aqua; Rhinocort Turbuhaler
Protein-losing enteropathy (PLE) following Fontan: Therapeutic Category Adrenal Corticosteroid; Anti-
Limited data available: Children 27 years and Adoles- inflammatory Agent; Corticosteroid, Intranasal; Glucocorti-
cents: Oral capsule (Entocort EC): Initial: 9 mg once coid
daily or in divided doses every 8 hours; after clinical Generic Availability (US) Yes
improvement and albumin >3 g/dL may then wean Use Management of nasal symptoms (congestion, rhinitis,
dose over several weeks to.3.mg once daily or every
sneezing, itchy nose) associated with allergic rhinitis or
other day; if during the weaning process the serum
hayfever (OTC: FDA approved in ages 26 years and
albumin decreases to <2.5 g/dL, do not further reduce
adults); has also been used for mild obstructive sleep
dose, consider dosage increase. Dosing based on
several case series describing institutional experien- apnea syndrome.
ces, the majority of pediatric patients described were Intranasal corticosteroids have also been used as an
27 years of age (n=17) (John 2011; Schumacher 2011; adjunct to antibiotics in empiric treatment of acute bac-
Thacker 2010; Turner 2012). Reported experience in terial rhinosinusitis primarily in patients with history of
children <7 years is very limited (n=1); in one report, an allergic rhinitis (Chow 2012).
initial dose of 6 mg once daily was recommended for Pregnancy Risk Factor B
children <4 years (Thacker 2010). Pregnancy Considerations Adverse events have been
Renal Impairment: Pediatric There are no dosage observed with corticosteroids in animal reproduction stud-
adjustments provided in the manufacturer's labeling ies. Hypoadrenalism may occur in newborns following
(has not been studied); use with caution. maternal use of corticosteroids in pregnancy; monitor.
Hepatic Impairment: Pediatric There are no pediatric Studies of pregnant women using intranasal budesonide
specific recommendations; based on experience in adult have not demonstrated an increased risk of abnormalities.
patients, dosage adjustment suggested. Budesonide Intranasal corticosteroids are recommended for the treat-
undergoes hepatic metabolism; bioavailability is ment of rhinitis during pregnancy; the lowest effective
increased in cirrhosis; monitor closely for signs—and dose should be used (NAEPP, 2005; Wallace, 2008);
symptoms of hypercorticism. budesonide is preferred (Wallace, 2008).
Administration Breastfeeding Considerations Following use of bude-
Oral: May be administered without regardto meals. sonide powder for oral inhalation, ~0.3% to 1% of the
Capsule: Swallow whole; do not break, chew, or crush.
maternal dose was found in breast milk. The maximum
Opening the capsule and sprinkling over applesauce
concentration appeared within 45 minutes of dosing.
has been evaluated in vitro and no change in the
Plasma budesonide levels obtained from infants ~90
release properties of budesonide was found
(Espmarker 2002); this method of administration has minutes after breastfeeding (~140 minutes after maternal
also been used fn patients unable to swallow the dose) were below the limit of quantification. Milk concen-
capsules in a study evaluating budesonide use in trations following the use of the nasal inhaler are expected
Crohn disease (Thacker 2010). to be similar. The use of inhaled corticosteroids is not
Tablet: Swallow whole; do not break, chew, or crush. considered a contraindication to breastfeeding (NAEPP,
Viscous liquid/suspension: Swallow extemporaneously 2005). The manufacturer recommends using only when
prepared liquid immediately after preparation; avoid Clinically appropriate, at the lowest effective dose, and
ingesting any/solid or liquid food for at least 30 minutes administering the dose following a feeding in order to
after budesonide administration. s minimize potential exposure to the nursing infant.

301
BUDESONIDE (NASAL)

Contraindications Hypersensitivity to budesonide or any The levels/effects of Budesonide (Nasal) may be

component of the formulation increased by: Cobicistat; CYP3A4 Inhibitors (Strong);
OTC labeling: When used for self-medication, do not use Telaprevir
in children <6 years of age. Decreased Effect There are no known significant inter-
Canadian labeling: Additional contraindications (not in US actions involving a decrease in effect. }
labeling): Tuberculosis (active or quiescent); untreated Storage/Stability US labeling: Store with valve up at 20°C
bacterial, fungal, or viral infections; use in children <6 to 25°C (68°F to 77°F); do not freeze. Protect from light.
years of age Canadian labeling: Store at 15°C to 30°C (59°F to 86°F).
Warnings/Precautions Hypersensitivity reactions (eg, Mechanism of Action Controls the rate of protein syn-
anaphylactic reactions, angioedema, pruritus, urticaria, thesis; depresses the migration of polymorphonuclear
rash, dermatitis) may occur. Nasal septal perforation, leukocytes, fibroblasts; reverses capillary permeability
nasal ulceration, epistaxis, and localized Candida albicans and lysosomal stabilization at the cellular level to prevent
infections of the nose and/or pharynx may occur, Monitor or control inflammation. Has potent glucocorticoid activity
patients periodically for adverse nasal effects; discontinu- and weak mineralocorticoid activity.
ation of therapy may be necessary if an infection occurs. Pharmacodynamics/Kinetics (Adult data unless
May delay wound healing; avoid nasal corticosteroid use noted)
in patients with recent nasal septal ulcers, nasal surgery or Onset of action: Rhinocort Aqua: Within 10 hours
nasal trauma until healing has occurred. Prolonged use of Peak effect: Up to 2 weeks
corticosteroids may also increase the incidence of secon- Distribution: ~2 to 3 L/kg
dary infection, mask acute infection (including fungal Protein binding: 85% to 90%
infections), prolong or exacerbate viral infections, or limit Metabolism: Hepatic via CYP3A4 to two metabolites: 16
response to vaccines. Exposure to chickenpox should be alpha-hydroxyprednisolone and 6 beta-hydroxybudeso-
avoided. Avoid use or use with caution in patients with nide; both are <1% as active as parent
latent/active tuberculosis, untreated bacterial or fungal Bioavailability: Rhinocort Aqua: ~34%; Rhinocort Tur-
infections (local or systemic), viral or parasitic infections, buhaler [Canadian product]: 22%; Oral: ~10% (limited
or ocular herpes simplex. The Canadian labeling contra- by high first-pass effect)
indicates use in patients with active or quiescent TB or Half-life elimination: 2 to 3 hours 5
with untreated bacterial, fungal, or viral infections. Use Time to peak, plasma: Nasal: 30 minutes
with caution in patients with cataracts and/or glaucoma; Excretion: Urine (~66%) and feces as metabolites
increased intraocular pressure, glaucoma, and cataracts Dosing
have occurred with prolonged use. Consider routine eye Pediatric
exams in chronic users or in patients who report visual Allergic rhinitis, hayfever; relief of nasal symptoms:
changes. OTC formulation (32 mcg/spray):
Children 6 to <12 years: Intranasal: Initial: 1 spray (32
May cause hypercortisolism or suppression of hypothala-
mcg) per nostril once daily; dose may be increased if
mic-pituitary-adrenal (HPA) axis, particularly in younger
needed to 2 sprays (64 mcg) per nostril once daily;
children or in patients receiving high doses for prolonged
after improvement of symptoms, decrease dose to 1
periods. HPA axis suppression may lead to adrenal crisis.
spray (32 mcg) per nostril once daily. If duration of
Withdrawal and discontinuation of a corticosteroid should
therapy exceeds 2 months, consider additional mon-
be done slowly and carefully. Pediatric patients may be
itoring parameters (eg, growth). Maximum daily dose:
more susceptible to systemic toxicity. Particular care is
128 mcg/day.
required when patients are transferred from systemic
Children 212 years and Adolescents: Intranasal: Initial:
corticosteroids to inhaled products due to possible adrenal
2 sprays (64 mcg) per nostril once daily; after
insufficiency or withdrawal from steroids, including an
improvement of symptoms, decrease dose to 1 spray
increase in allergic symptoms. Adult patients receiving
(32 mcg) per nostril once daily. Usual maximum daily
220 mg per day of prednisone (or equivalent) may be
dose: 128 mcg/day. Note: Based on previous FDA-
most susceptible.
approved manufacturer labeling (Rhinocort Aqua pre-
Avoid using higher than recommended dosages; suppres- scribing information 2010), some patients who do not
sion of linear growth (ie, reduction of growth velocity), achieve adequate control may benefit from increased
reduced bone mineral density, hypercortisolism (Cushing dosage of 4 sprays (128 mcg) per nostril once daily;
syndrome) or suppression of hypothalamic-pituitary-adre- a reduced dosage may be effective after initial control
nal (HPA) axis may occur; titrate to lowest effective dose. is achieved.
Reduction in growth velocity may occur when cortico- Sleep apnea/disturbances, obstructive (mild): Lim-
steroids are administered to pediatric patients, even at ited data available (Dehlink 2016; Kaditis 2016): Chil-
recommended doses via intranasal route (monitor dren 26 years and Adolescents: Intranasal: 1 spray (32
growth). Withdrawal and discontinuation of a corticoste- mcg) per nostril once daily (at bedtime) or twice daily
roid should be done slowly and carefully. Potentially for 6 weeks. Once daily dosing based on a double-
significant drug-drug interactions may exist, requiring blind, placebo-controlled, cross-over trial in 62 children
dose or frequency adjustment, additional monitoring, (age range: 6 to 12 years) who received 1 spray (32
and/or selection of alternative therapy. mcg) in each nostril once daily at bedtime; treated
patients showed decreased severity of respiratory dis-
Self-medication (OTC use): Consult a health care provider turbance and adenoid tissue size; results also showed
before use if you have had recent nose ulcers or nose therapeutic effect prolonged for at least 8 weeks follow-
surgery; have a nose injury that has not healed; are using ing discontinuation of therapy; respiratory and sleep
a steroid medicine for asthma, allergies or skin rash; have parameters did not worsen during this time (Kheirand-
an eye infection; and/or have or had glaucoma or cata- ish-Gozal 2008). A placebo-controlled trial of 60 chil-
racts. When using this product, symptoms may get better dren with sleep disordered breathing (treatment group,
on the first day of treatment; however, it may take up to 2 n=30; age range: 4 to 10 years) who received 1 spray
weeks of daily use to feel the most relief. Discontinue use (32 mcg) in each nostril twice daily showed a significant
and consult a health care provider if symptoms do not improvement in quality of life and symptoms compared
improve after 2 weeks, or if an infection (eg, persistent to placebo (Gudnadottir 2018). Consensus recommen-
fever), changes in vision, or frequent nosebleeds occur. dations suggest a trial of 6 to 12 weeks of intranasal
Do not spray into eyes or mouth or use more than directed corticosteroid as one of the initial therapeutic steps in
or for the common cold. the management in treatment of obstructive sleep
Adverse Reactions apnea along with weight loss (Dehlink 2016; Kadi-
Respiratory: Bronchospasm, cough, epistaxis, nasal tis 2016).
mucosa irritation, pharyngitis Renal Impairment: Pediatric There are no dosage
Rare but important or life-threatening: Anosmia, cataract, adjustments provided in the manufacturer's labeling
crusting of nose, dizziness, fatigue, glaucoma, growth (not studied).
suppression, headache, hypersensitivity reaction, nasal Hepatic Impairment: Pediatric There are no dosage
septum perforation, nausea, pharyngeal disease (irrita- adjustments provided in the manufacturer's labeling.
tion, itchy throat, throat pain), wheezing Systemic availability of budesonide may be increased
Drug Interactions in patients with hepatic impairment; monitor closely for
Metabolism/Transport Effects Substrate of CYP3A4 signs and symptoms of hypercorticism; dosage reduction
(minor); Note: Assignment of Major/Minor substrate sta- may be required.
tus based on clinically relevant drug interaction potential Administration Shake gently prior to each use. Before
Avoid Concomitant Use first use, prime by pressing pump until a fine spray
Avoid concomitant use of Budesonide (Nasal) with any of appears (~8 times). If 22 days between use, repeat
the following: Desmopressin priming until a fine spray appears (~1 time). If >14 days
Increased Effect/Toxicity between use, rinse applicator and allow to dry, then repeat
Budesonide (Nasal) may increase the levels/effects of: priming until a fine spray appears (~2 sprays). Blow nose
Ceritinib; Desmopressin; Ritodrine to clear nostrils before each use. Insert applicator into

302
 BUDESONIDE (ORAL INHALATION)

nostril, keeping bottle upright, and close off the other possibility of cross-sensitivity cannot be ruled out with
nostril. Breathe in through nose and while inhaling (sniff- certainty.
ing), press pump to release spray. After administration Canadian labeling: Additional contraindications (not in US
lean head backward for a few seconds; avoid blowing labeling): Moderate-to-severe bronchiectasis, pulmonary
nose for 15 minutes after use. Do not spray into eyes or tuberculosis (active or quiescent), untreated respiratory
mouth. infection (bacterial, fungal, or viral)
Monitoring Parameters Mucous membranes for signs of Warnings/Precautions May cause hypercortisolism or
fungal infection, growth (pediatric patients; consider with suppression of hypothalamic-pituitary-adrenal (HPA) axis,
therapy 212 weeks), signs/symptoms of HPA axis sup- particularly in younger children, in patients receiving high
pression/adrenal insufficiency; ocular changes doses for prolonged periods. HPA axis suppression may
Additional Information When used short term as adjunc- lead to adrenal crisis. Withdrawal and discontinuation of a
tive therapy in acute bacterial rhinosinusitis (ABRS), intra- corticosteroid should be done slowly and carefully. Partic-
nasal steroids show modest symptomatic improvement ular care is required when patients are transferred from
and few adverse effects; improvement is primarily due to systemic corticosteroids to inhaled products or cortico-
increased sinus drainage. Use should be considered steroids with lower systemic effect due to possible adrenal
optional in ABRS; however, intranasal corticosteroids insufficiency or withdrawal from steroids, including an
should be routinely prescribed to ABRS patients who have increase in allergic symptoms. Adult patients receiving
a history of or concurrent allergic rhinitis (Chow 2012). 220 mg per day of prednisone (or equivalent) may be
Dosage Forms Considerations most susceptible. Fatalities have occurred due to adrenal
Rhinocort Aqua: 8.6 g bottles contain 120 sprays. insufficiency in asthmatic patients during and after transfer
Rhinocort Allergy: 5 mL bottles contain 60 sprays, 8.43 mL from systemic corticosteroids to aerosol steroids; aerosol
bottles contain 120 sprays steroids do not provide the systemic steroid needed to
Dosage Forms Excipient information presented when treat patients having trauma, surgery, or infections (partic-
~ available (limited, particularly for generics); consult spe- ularly gastroenteritis), or other conditions with severe
cific product labeling. [DSC] = Discontinued product electrolyte loss. Select surgical patients on long-term,
Suspension, Nasal: high-dose, inhaled corticosteroid (ICS), should be given
Rhinocort Allergy: 32 mcg/actuation (56 mL, 8.43 mL) stress doses of hydrocortisone intravenously during the
{contains disodium edta, polysorbate 80] surgical period and the dose reduced rapidly within 24
Rhinocort Aqua: 32 mcg/actuation (8.6 g [DSC]) [con- hours after surgery (NAEPP 2007).
tains disodium edta, polysorbate 80] Paradoxical bronchospasm that may be life-threatening
Generic: 32 mcg/actuation (8.6 g [DSC], 8.43 mL) may occur with use of inhaled bronchodilating agents;
reaction should be distinguished from inadequate
Budesonide (Oral Inhalation) response. If paradoxical bronchospasm occurs, discon-
(byoo DES oh nide) tinue budesonide and institute alternative therapy. Hyper-
sensitivity reactions (eg, anaphylaxis, angioedema,
Related Information bronchospasm, rash, contact dermatitis and urticaria),
Oral Medications That Should Not Be Crushed or Altered including anaphylaxis may occur; discontinue use if reac-
on page 2217 tion occurs Supplemental steroids (oral or parenteral) may
Brand Names: US Pulmicort; Pulmicort Flexhaler be needed during stress or severe asthma attacks. Short-
Brand Names: Canada Pulmicort Turbuhaler acting betaz-agonist (eg, albuterol) should be used for
Therapeutic Category Adrenal Corticosteroid; Anti- acute symptoms and symptoms occurring between treat-
inflammatory Agent; Antiasthmatic; Corticosteroid, Inha- ments. Use is contraindicated in status asthmaticus or
lant (Oral); Glucocorticoid during other acute episodes of asthma requiring intensive
Generic Availability (US) May be product dependent measures. Rare cases of vasculitis (eosinophilic granulo-
Use matosis with polyangiitis [formerly known as Churg-
Nebulization: Maintenance therapy and prophylaxis of Strauss]) or other systemic eosinophilic conditions can
bronchial asthma (FDA approved in ages 1 to 8 years); occur; often associated with decrease and/or withdrawal
not indicated for the relief of acute bronchospasm of oral corticosteroid therapy following initiation of inhaled
Oral inhalation: Maintenance therapy and prophylaxis of corticosteroid.
bronchial asthma with or without oral corticosteroids Prolonged use of corticosteroids may also increase the
(FDA approved in ages 26 years and adults); not incidence of secondary infection, mask acute infection
indicated for the relief of acute bronchospasm (including fungal infections), prolong or exacerbate viral
Pregnancy Risk Factor B infections, or limit response to vaccines. Avoid use, if
Pregnancy Considerations possible, in patients with ocular herpes, active or quies-
Studiesof pregnant women using inhaled budesonide cent respiratory tuberculosis, or untreated viral, fungal,
have not demonstrated an increased risk of congenital parasitic or bacterial systemic infections. Exposure to
abnormalities. chickenpox and measles should be avoided; if the patient
is exposed, prophylaxis with varicella zoster immune
Uncontrolled asthma is associated with adverse events on
globulin or pooled intramuscular immunoglobulin, respec-
pregnancy (increased risk of perinatal mortality, pre-
tively, may be indicated; if chickenpox develops, treatment
eclampsia, preterm birth, low birth weight infants). Poorly
with antiviral agents may be considered Local orophar-
controlled asthma or asthma exacerbations may have a
yngeal Candida albicans infections have been reported; if
greater fetal/maternal risk than what is associated with
this occurs, treat appropriately while continuing therapy.
appropriately used asthma medications. Inhaled cortico-
Patients should be instructed to rinse mouth with water
steroids are recommended for the treatment of asthma
without swallowing after each use.
during pregnancy; budesonide is preferred (ACOG 2008;
GINA 2017; Namazy 2016). Use with caution in patients with hepatic impairment;
Breastfeeding Considerations budesonide undergoes hepatic metabolism; drug may
Budesonide is present in breast milk. accumulate with hepatic impairment. Use with caution in
Following use of the powder for oral inhalation, ~0.3% to patients with cataracts and/or glaucoma; blurred vision,
1% of the maternal dose was present in breast milk. The increased intraocular pressure, glaucoma, and cataracts
maximum concentration appeared within 45 minutes of have occurred with prolonged use. Consider routine eye
dosing. Plasma budesonide levels obtained from infants exams in chronic users. Use with caution in patients with
~90 minutes after breastfeeding (~140 minutes after major risk factors for decreased bone mineral count such
maternal dose) were below the limit of quantification. as prolonged immobilization, family history of osteoporo-
According to the manufacturer, the decision to continue or sis, postmenopausal status, tobacco use, advanced age,
discontinue breastfeeding during therapy should take poor nutrition, or chronic use of drugs that can reduce
into account the risk of minimal exposure to the infant bone mass (eg, anticonvulsants or oral corticosteroids);
and the benefits of breastfeeding to the mother. How- long-term use of inhaled corticosteroids have been asso-
ever, the use of inhaled corticosteroids is not considered ciated with decreases in bone mineral density.
a contraindication to breastfeeding (ACOG 2008).
Potentially significant interactions may exist, requiring
Females with asthma should be encouraged to breast-
dose or frequency adjustment, additional monitoring,
feed (GINA 2017).
and/or selection of alternative therapy.
Contraindications
Hypersensitivity to budesonide or any component of the Orally-inhaled corticosteroids may cause a reduction in
formulation; severe hypersensitivity to milk proteins (Pul- growth velocity in pediatric patients (~1 centimeter per
micort Flexhaler); primary treatment of status asthmati- year [range: 0.3 to 1.8 cm per year] and related to dose
cus or other acute episodes of asthma requiring and duration of exposure). To minimize the systemic
intensive measures effects of orally-inhaled corticosteroids, each patient
Documentation’ of allergenic cross-reactivity for cortico- should be titrated to the lowest effective dose. Growth
steroids is limited. However, because of similarities in should be routinely monitored in pediatric patients. A
chemical structure and/or pharmacologic actions, the gradual tapering of dose may be required prior to

303
BUDESONIDE (ORAL INHALATION)

discontinuing therapy; there have been reports of sys- Increased Effect/Toxicity

temic corticosteroid withdrawal symptoms (eg, joint/ Budesonide (Oral Inhalation) may increase the levels/
muscle pain, lassitude, depression) when withdrawing oral effects of: Amphotericin B; Ceritinib; Deferasirox; Des-
inhalation therapy. When transferring to oral inhalation mopressin; Loop Diuretics; Loxapine; Ritodrine; Thiazide
therapy from systemic corticosteroid therapy, previously and Thiazide-Like Diuretics ‘
suppressed allergic conditions (rhinitis, conjunctivitis,
eczema, arthritis, and eosinophilic conditions) may be The levels/effects. of Budesonide (Oral Inhalation) may
unmasked. Withdraw systemic corticosteroid therapy by
be increased by: CYP3A4 Inhibitors (Strong); Telaprevir
gradually tapering the dose. Monitor lung function, beta- Decreased Effect
agonist use, asthma symptoms and for signs and symp- Budesonide (Oral Inhalation) may decrease the levels/
toms of adrenal insufficiency (eg, fatigue, lassitude, weak- effects of: Aldesleukin; Corticorelin; Hyaluronidase
ness, nausea/vomiting, hypotension) during withdrawal. Storage/Stability
Pulmicort Flexhaler contains lactose; very rare anaphylac- Dry powder inhaler: Store at 20°C to 25°C (68°F to 77°F).
tic reactions have been reported in patients with severe Discard when the dose counter reads "0".
milk protein allergy. Some dosage forms may contain Nebulization suspension: Store upright at 20°C to 25°C
polysorbate 80 (also known as Tweens). Hypersensitivity (68°F to 77°F). Keep in aluminum package to protect
reactions, usually a delayed reaction, have been reported from light until ready for use. Do not refrigerate or freeze.
following exposure to pharmaceutical products containing Once aluminum package is opened, unused suspension
polysorbate 80 in certain individuals (Isaksson 2002; should be used within 2 weeks. Continue to protect
Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, unopened ampules from light'in foil envelope.
pulmonary deterioration, and renal and hepatic failure Mechanism of Action Controls the rate of protein syn-
have been reported in premature neonates after receiving thesis; depresses the migration of polymorphonuclear
parenteral products containing polysorbate 80 (Alade leukocytes, fibroblasts; reverses capillary permeability
1986; CDC 1984). See manufacturer's labeling. and lysosomal stabilization at the cellular level to prevent
Warnings: Additional Pediatric Considerations A 12- or control inflammation. Has potent glucocorticoid activity
week study in infants (n=141; 6 to 12 months of age) and weak mineralocorticoid activity.
receiving budesonide nebulizations (0.5 mg or 1 mg once Pharmacodynamics/Kinetics (Adult data unless
daily) vs placebo demonstrated a budesonide dose noted) ;
dependent suppression of linear growth; in addition, Onset of action: Nebulization: 2 to 8 days; Inhalation: 24
although mean changes from baseline did not indicate hours
budesonide-induced adrenal suppression, six infants Peak effect: Nebulization: 4 to 6 weeks; Inhalation: 1 to 2
who received budesonide had subnormal stimulated corti- weeks
sol levels at week 12. Children and adolescents (n=18; 6 Distribution:
to 15 years) receiving budesonide nebulizations of 1 and Children 4 to 6 years: 3 L/kg
2 mg twice daily showed a significant reduction in urinary Adults: 2.2 to 3.9 L/kg
cortisol excretion; this reduction was not seen when Protein binding: 85% to 90%
patients were dosed at 1 mg/day (maximum recom- Metabolism: Hepatic via CYP3A4 to two metabolites: 16
mended dose). Long-term effects of chronic use of bude- alpha-hydroxyprednisolone and 6 beta-hydroxybudeso-
sonide nebulization on immunological or developmental nide; both are <1% as active as parent
processes of upper airways, mouth, and lung are Bioavailability:
unknown. Nebulization: Children 4 to 6 years: 6%
Adverse Reactions Oral inhalation: 39% of an inhaled metered dose is
Cardiovascular: Chest pain (suspension), syncope (pow- available systemically
der) Half-life elimination:
Central nervous system: Emotional lability (suspension), Children 4 to 6 years: 2.3 hours (after nebulization)
fatigue (suspension), headache, hypertonia (powder), Children and Adolescents 10 to 14 years: 1.5 hours
insomnia (powder), pain (powder), voice disorder Adults: 2 to 3.6 hours
(powder), Time to peak:
Dermatologic: Contact dermatitis (suspension), eczema Nebulization: Pulmicort Respules: Children: 20 minutes
(suspension), pruritus (Suspension), pustular rash (sus- Oral inhalation: Pulmicort Flexhaler:
pension), skin rash Children and Adolescents: 15 to 30 minutes
Endocrine & metabolic: Weight gain Adults: 10 minutes
Gastrointestinal: Abdominal pain, anorexia (Suspension), Excretion: Urine (60%) and feces as metabolites
diarrhea (suspension), dysgeusia (powder), dyspepsia, Clearance:
gastroenteritis (Suspension), nausea, oral candidiasis Children 4 to 6 years: 0.5 L/minute (~50% greater than
(powder), viral gastroenteritis (powder), vomiting, xero- healthy adults after weight adjustment)
stomia (powder) Adults: 0.9 to 1.8 L/minute
Hematologic & oncologic: Cervical lymphadenopathy Pharmacodynamics/Kinetics: Additional Consider-
(suspension), ecchymosis (powder), purpura (sus- ations Hepatic function impairment: Patients with cirrho-
pension) sis had more than doubled systemic availability after oral
Hypersensitivity: Hypersensitivity reaction ingestion.
Infection: Candidiasis (suspension), herpes simplex infec- Dosing
tion (suspension), infection, viral infection (suspension) Pediatric Asthma: Note: Doses should be titrated to the
Neuromuscular & skeletal: Arthralgia, back pain (powder), lowest effective dose once asthma is controlled:
bone fracture, hyperkinesia (suspension), myalgia, neck Nebulization: Pulmicort Respules:
pain (powder), weakness Infants: Limited data available: Initial: 0.25 mg twice
Ophthalmic: Conjunctivitis (Suspension), eye infection daily or 0.5 mg once daily; maximum daily dose:
(suspension) 1 mg/day (Baker 1999; GINA 2009)
Otic: Otalgia (suspension), otic infection (suspension), Children and Adolescents:
otitis externa (suspension), otitis media (more common Manufacturer's labeling: Children <8 years or Children
in suspension) >8 years and Adolescents unable to effectively use
Respiratory: Allergic rhinitis (powder), cough, epistaxis metered-dose inhalers:
(suspension), flu-like symptoms (suspension), nasal Previously treated with bronchodilators alone: Initial:
congestion (powder), nasopharyngitis (powder), phar- 0.25 mg twice daily or 0.5 mg once daily; maxi-
yngitis, respiratory infection (more common in suspen- mum daily dose: 0.5 mg/day
sion), respiratory tract infection (powder), rhinitis, Previously treated with inhaled corticosteroids: Ini-
sinusitis, stridor (Suspension), viral upper respiratory tial: 0.25 mg twice daily or 0.5 mg once daily;
tract infection (powder) maximum daily dose: 1 mg/day
Miscellaneous: Fever Previously treated with oral corticosteroids: Initial:
Rare but important or life-threatening: Adrenocortical 0.5 mg twice daily or 1 mg once daily; maximum
insufficiency, aggressive behavior, anxiety, avascular daily dose: 1 mg/day
necrosis of femoral head, bronchitis, bruise, depression, Symptomatic children not responding to nonsteroi-
glaucoma, growth suppression, hypercorticoidism, dal asthma medications: Initial: 0.25 mg once daily
increased intraocular pressure, irritability, nervousness, may be considered
osteoporosis, pain, pharyngitis, psychosis, throat irrita- NIH Asthma Guidelines (NAEPP 2007): Administer
tion, wheezing once daily or in divided doses twice daily
Drug Interactions Children <4 years:
Metabolism/Transport Effects None known. "Low" dose: 0.25 to 0.5 mg/day
Avoid Concomitant Use "Medium" dose: >0.5 to 1 mg/day
Avoid concomitant use of Budesonide (Oral Inhalation) "High" dose: >1 mg/day
with any of the following: Aldesleukin; Desmopressin; Children 5 to 11 years:
Loxapine "Low" dose: 0.5 mg/day

304
 BUDESONIDE AND FORMOTEROL

"Medium" dose: 1 mg/day Extemporaneous Preparations Oral budesonide vis-

"High" dose: 2 mg/day cous liquid/suspension: Prepare immediately prior to
Oral inhalation: Pulmicort Flexhaler: ingestion from aqueous budesonide solution (1 mg per 2
Manufacturer's labeling: mL) or nebulized solution (0.5 mg per 2 mL [Pulmicort
Children and Adolescents age 6 to 17 years: Initial: Respules]) mixed to slurry consistency with 10 packets of
180 mcg twice daily (some patients may be initiated Splenda or 2.5 cm® of Neocate Nutra per milligram of
at 360 mcg twice daily); maximum single dose: budesonide. (Dellon 2013; Dohil 2010; Rubinstein 2014)
360 mcg Dellon ES, Gonsalves N, Hirano |, Furuta GT, Liacouras CA, Katzka
Adolescents 218 years: Initial: 360 mcg twice daily DA; American College of Gastroenterology. ACG clinical guideline:
(some patients may be initiated at 180 mcg twice Evidenced based approach to the diagnosis and management of
esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J
daily); maximum single dose: 720 mcg
Gastroenterol. 2013 May;108(5):679-92; quiz 693.
. Alternate dosing: NIH Asthma Guidelines (NAEPP Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous
2007): Administer in divided doses twice daily budesonide is effective in children with eosinophilic esophagitis in a
Children 5 to 11 years: randomized, placebo-controlled trial. Gastroenterology. 2010;139
"Low" dose: 180 to 400 mcg/day (90 mcg/inhalation, (2):418-429.
2 to 4 inhalations per day or 180 mcg/inhalation, 1 Rubinstein E, Lee JJ, Fried A, et al. Comparison of 2 delivery vehicles
to 2 inhalations per day) for viscous budesonide to treat eosinophilic esophagitis in children. J
Pediatr Gastroenterol Nutr. 2014;59(3):317-320.
"Medium" dose: >400 to 800 mcg/day (180 mcg/
inhalation, 2 to 4 inhalations per day) @ Budesonide and Eformoterol see Budesonide and For-
"High" dose: >800 mcg/day (180 meg/inhalation, >4 moterol on page 305
inhalations per day)
Children 212 years and Adolescents:
"Low" dose: 180 to 600 mcg/day (90 mcg/inhalation, Budesonide and Formoterol
(byoo DES oh nide & for MOH te rol)
2 to 6 inhalations per day or 180 mcg/inhalation, 1
to 3 inhalations per day) Brand Names: US Symbicort
"Medium" dose: >600 to 1,200 mcg/day (180 mcg/ Brand Names: Canada Symbicort
inhalation, 3 to 6 inhalations per day)
Therapeutic Category Adrenal Corticosteroid; Adrener-
"High" dose: >1,200 mcg/day (180 mcg/inhalation,
gic Agonist Agent; Anti-inflammatory Agent; Antiasth-
>6 inhalations per day)
matic; Betaz-Adrenergic Agonist; Bronchodilator;
Conversion from oral systemic corticosteroid to orally
Corticosteroid, Inhalant (Oral); Glucocorticoid
inhaled corticosteroid: Initiation of oral inhalation ther-
Use Maintenance treatment of asthma (FDA approved in
apy should begin in patients whose asthma is reason-
ages 212 years and adults); maintenance treatment of
ably stabilized on oral corticosteroids (OCS). A gradual
dose reduction of OCS should begin ~7 to 10 days after airflow obstruction associated with chronic obstructive
starting inhaled therapy. Manufacturer's labeling rec- pulmonary disease (COPD), including chronic bronchitis
ommends reducing prednisone dose by 2.5 mg/day (or and emphysema (FDA approved in adults); NOT indicated
equivalent of other OCS) on a weekly basis (patients for the relief of acute bronchospasm
using oral inhaler) or by $25% every 1 to 2 weeks Medication Guide Available Yes
(patients using respules). When transitioning from sys- Pregnancy Considerations Adverse events were
temic to inhaled corticosteroids, supplemental systemic observed in animal reproduction studies using this combi-
corticosteroid therapy may be necessary. during peri- nation. Refer to individual agents.
ods of stress or during severe asthma attacks. Breastfeeding Considerations It is not known if formo-
Renal Impairment: Pediatric Inhalation, Nebulization: terol is present in breast milk; budesonide is present in
There are no dosage adjustments provided in the man- small amounts. According to the manufacturer, the deci-
ufacturer's labeling (has not been studied). sion to continue or discontinue breastfeeding during ther-
Hepatic Impairment: Pediatric Inhalation, Nebuliza- apy should take into account the risk of infant exposure,
tion: There are no dosage adjustments provided in the the benefits of breastfeeding to the infant, and benefits of
manufacturer's labeling (has not been studied). How- treatment to the mother. Refer to individual agents.
ever, budesonide undergoes hepatic metabolism; drug Contraindications
may accumulate with hepatic impairment; use with cau- Hypersensitivity to budesonide, formoterol, or any compo-
tion; monitor closely. nent of the formulation; primary treatment of status
Administration asthmaticus or other acute episodes of asthma or COPD
Inhalation: where intensive measures are required.
Nebulization: Shake gently with a circular motion before Documentation of allergenic cross-reactivity for cortico-
use. Administer only with a compressed air driven jet steroids and/or sympathomimetics are limited. However,
nebulizer; do not use an ultrasonic nebulizer; do not because of similarities in chemical structure and/or phar-
mix with other medications; use adequate flow rates macologic actions, the possibility of cross-sensitivity
and administer via appropriate size face mask or cannot be ruled out with certainty.
mouthpiece. Avoid exposure of nebulized medication
to eyes. Rinse mouth following treatments to decrease Canadian labeling: Additional contraindications (not in US
risk of oral candidiasis (wash face if using face mask). labeling): Hypersensitivity to inhaled lactose.
Oral inhaler: Pulmicort Flexhaler: Hold inhaler in upright Warnings/Precautions The use of long-acting beta-2
position (mouthpiece up) to load dose. Do not shake agonists (_LABAs) as monotherapy is associated with an
prior to use. Unit should be primed prior to first use. It increased risk of asthma-related deaths. In a large,
will not need to be primed again, even if not used for a randomized, placebo-controlled US trial, salmeterol was
long time. Place mouthpiece between lips and inhale associated with an increase in asthma-related deaths
forcefully and deeply. Do not exhale through inhaler; do (SMART 2006); risk is considered a class effect of LABA
not use a spacer. Dose indicator does not move with monotherapy. Additional data from other clinical trials
every dose, usually only after 5 doses. Discard when suggest LABA monotherapy increases the risk of
dose indicator reads "0". Rinse mouth with water after asthma-related hospitalization in pediatric and adolescent
use to reduce incidence of candidiasis. patients. However, data from large randomized, double-
Monitoring Parameters Monitor growth. in pediatric blind, active-controlled trials do not show a significant
patients; inhalation: Check mucous membranes for signs increase in the risk of serious asthma-related events
of fungal infection; Asthma: FEV,, peak flow, and/or other (including hospitalizations, intubations, and death) in
pulmonary function tests; long-term use: Regular eye adult, adolescent, and pediatric (aged 4 to 11 years)
examinations and IOP, blood pressure, glucose, signs patients when fixed-dose LABAs are used with inhaled
and symptoms of hypercorticism, or adrenal suppression. corticosteroids combined in a single inhaler compared
Dosage Forms Considerations Pulmicort Flexhaler 180 with inhaled corticosteroid monotherapy. In addition,
mcg/actuation canisters contain 120 actuations and the 90 patients receiving fluticasone/salmeterol had fewer severe
mcg/actuation canisters contain 60 inhalations. asthma exacerbations compared with patients receiving
Dosage Forms Excipient information presented when fluticasone alone (Peters 2016; Stempel 2016a; Stempel
available (limited, particularly for generics); consult spe- 2016b). Current guidelines recommend the use of an
cific product labeling. inhaled corticosteroid before adding a LABA (GINA
Aerosol Powder Breath Activated, Inhalation: 2015; NIH/NHLBI 2007). Assess patients at regular inter-
Pulmicort Flexhaler: 90 mcg/actuation (1 ea); 180 mcg/ vals once asthma control is maintained on combination
actuation (1 ea) [contains milk protein] therapy to determine if step-down therapy is appropriate
Suspension, Inhalation: (without loss of asthma control), and the patient can be
Pulmicort: 0.25 mg/2 mL (2 mL); 0.5 mg/2 mL (2 mL); maintained on an inhaled corticosteroid only. LABAs are
4 mg/2 mL (2 mL) [contains disodium edta, polysor- not appropriate in patients whose asthma is adequately
bate 80] | controlled on low- or medium-dose inhaled corticoste-
Generic: 0.25/mg/2 mL (2 mL); 0.5 mg/2 mL (2 mL); roids. LABAs may increase the risk of asthma-related
4 mg/2 mL (2 mL) : hospitalization in pediatric and adolescent patients. >
305
BUDESONIDE AND FORMOTEROL

Do not use for acute bronchospasm or acute symptomatic exposure to measles, prophylaxis with pooled intramus-
COPD. Short-acting beta-2 agonist (eg, albuterol) should cular immunoglobulin may be indicated.
be used for acute symptoms and symptoms occurring
between treatments. Do not initiate in patients with sig- Withdraw systemic corticosteroid therapy with gradual
nificantly worsening or acutely deteriorating asthma or tapering of dose; consider reducing the daily prednisone
COPD. Increased use and/or ineffectiveness of short-act- dose by 2.5 mg on a weekly basis beginning after at least
ing beta-2 agonists may indicate rapidly deteriorating 1 week of inhalation therapy. Monitor lung function, beta
disease and should prompt re-evaluation of the patient's agonist use, asthma symptoms, and for signs and symp-
condition. Data are not available to determine if LABA use toms of adrenal insufficiency (fatigue, lassitude, weak-
increases the risk of death in patients with COPD. ness, nausea and vomiting, hypotension) during
withdrawal. Potentially significant drug-drug interactions
Immediate hypersensitivity reactions (urticaria, angioe- may exist, requiring dose or frequency adjustment, addi-
dema, rash, bronchospasm) have been reported. Do not
tional monitoring, and/or selection of alternative therapy.
exceed recommended dose; serious adverse events,
Adverse Reactions Also see individual agents.
including fatalities, have been associated with excessive
use of inhaled sympathomimetics. Rarely, paradoxical
Central nervous system: Headache (more common in
bronchospasm may occur with use of inhaled bronchodi- adolescents and adults)
lating agents; this should be distinguished from inad- Gastrointestinal: Abdominal distress, oral candidiasis,
equate response. Pneumonia and other lower vomiting
respiratory tract infections have been reported in patients Infection: Influenza
with COPD following the use of inhaled corticosteroids; Neuromuscular_& skeletal: Back pain
monitor COPD patients closely since pneumonia symp- Respiratory: Bronchitis, lower respiratory tract infection,
toms may overlap symptoms of exacerbations. nasal congestion, nasopharyngitis, pharyngitis (chil-
dren), pharyngolaryngeal pain, pulmonary infection, rhi-
Use caution in patients with seizure disorders, diabetes,
nitis (children), sinusitis, upper respiratory tract infection
hepatic impairment, ocular disease, osteoporosis, thyroid
(more common in adolescents and adults)
disease, or hypokalemia. Local oropharyngeal Candida
Rare but important or life-threatening: Agitation, anaphy-
infections have been reported; if this occurs, treat appro-
priately while either continuing or interrupting (if neces-
laxis, angina pectoris, angioedema, atrial arrhythmia,
sary) budesonide/formotero!l therapy. Rare cases of behavioral changes, bronchospasm, bruise, cataract,
vasculitis (eosinophilic granulomatosis with polyangiitis cough, decreased linear skeletal growth rate (pediatric
[formerly known as Churg-Strauss]) or other systemic patients), depression, dermatitis, dizziness, extrasys-
eosinophilic conditions can occur; often associated with toles, glaucoma, hypercorticoidism signs and symptoms,
decrease and/or withdrawal of oral corticosteroid therapy hyperglycemia, hypersensitivity reaction, hypertension,
following initiation of inhaled corticosteroid. hypokalemia, hypotension, immunosuppression,
increased intraocular pressure, insomnia, muscle
Use with caution in patients with cardiovascular disease cramps, nausea, nervousness, palpitations, pruritus,
(arrhythmia, coronary insufficiency, or hypertension); beta
restlessness, skin rash, tachycardia, throat irritation,
agonists may cause elevation in blood pressure, heart rate
tremor, urticaria, ventricular arrhythmia, voice disorder
and result in CNS stimulation/excitation. Beta-2 agonists
Drug Interactions
may also increase risk of arrhythmias and ECG changes,
such as flattening of the T wave, prolongation of the QTc Metabolism/Transport Effects Refer to individual
interval, and ST segment depression. Use with caution components.
following acute MI; corticosteroids have been associated Avoid Concomitant Use
with myocardial rupture. Avoid concomitant use of Budesonide and Formoterol
with any of the following: Aldesleukin; Beta2-Agonists
Long-term use of inhaled corticosteroids have been asso- (Long-Acting); Beta-Blockers (Nonselective); Desmo-
ciated with decreases in bone mineral density. Use with pressin; lobenguane | 123; Loxapine
caution in patients with major risk factors for decreased
Increased Effect/Toxicity
bone mineral count such as prolonged immobilization,
Budesonide and Formoterol may increase the levels/
family history of osteoporosis, postmenopausal status,
tobacco use, advanced age, poor nutrition, or chronic
effects of: Amphotericin B; Atosiban; Beta2-Agonists
use of drugs that can reduce bone mass (eg, anticonvul- (Long-Acting); Ceritinib; Deferasirox; Desmopressin;
sants or oral corticosteroids); high doses and/or long-term Doxofylline; Loop Diuretics; Loxapine; QTc-Prolonging
use of inhaled corticosteroids have been associated with Agents (Highest Risk); QTc-Prolonging Agents (Moder-
decreases in bone mineral density. ate Risk); Ritodrine; Sympathomimetics; Thiazide and
Thiazide-Like Diuretics
May cause hypercortisolism or suppression of hypothala-
mic-pituitary-adrenal (HPA) axis, particularly in younger The levels/effects of Budesonide and Formoterol may be
children or in patients receiving high doses for prolonged increased by: AtoMOXetine; Caffeine and Caffeine Con-
periods. HPA axis suppression may lead to adrenal crisis. taining Products; Cannabinoid-Containing Products;
Withdrawal and discontinuation of a corticosteroid should Cocaine (Topical); CYP3A4 Inhibitors (Strong); Guane-
be done slowly and carefully. Particular care is required thidine; Inhalational Anesthetics; Linezolid; MiFEPRI-
when patients are transferred from systemic corticoste- Stone; Monoamine Oxidase Inhibitors; Tedizolid;
roids to inhaled products due to possible adrenal insuffi- Telaprevir; Theophylline Derivatives; Tricyclic Antide-
ciency or withdrawal from steroids, including an increase pressants
in allergic symptoms. Adult patients receiving >20 mg per Decreased Effect
day of prednisone (or equivalent) may be most suscep- Budesonide and Formoterol may decrease the levels/
tible. Fatalities have occurred due to adrenal insufficiency effects of: Aldesleukin; Corticorelin; Hyaluronidase;
in asthmatic patients during and after transfer from sys-
lobenguane | 123
temic corticosteroids to aerosol steroids; aerosol steroids
do not provide the systemic steroid needed to treat The levels/effects of Budesonide and Formoterol may be
patients having trauma, surgery, or infections. Do not decreased by: Beta-Blockers (Beta1 Selective); Beta-
use this product to transfer patients from oral cortico- Blockers (Nonselective); Betahistine
steroid therapy. Storage/Stability
Orally inhaled corticosteroids may cause a reduction in Symbicort 80/4.5, Symbicort 160/4.5: Store at 20°C to
growth velocity in pediatric patients (~1 centimeter per 25°C (68°F to 77°F) with mouthpiece down; temper-
year [range: 0.3 to 1.8 cm per year] and related to dose atures above 49°C (120°F) may cause bursting. Con-
and duration of exposure). To minimize the systemic tents under pressure; do not puncture, incinerate, or
effects of orally inhaled corticosteroids, each patient store near heat or open flame. Discard inhaler after the
should be titrated to the lowest effective dose. Growth labeled number of inhalations have been used (the dose
should be routinely monitored in pediatric patients. counter will read "0") or within 3 months after removal
from foil pouch.
Prolonged use of corticosteroids may increase the inci-
Symbicort Turbuhaler [Canadian product]: Store at room
dence of secondary infection, mask acute infection
(including fungal infections), prolong or exacerbate viral temperature of 15°C to 30°C (59°F to 77°F).
infections, or limit response to vaccines. Avoid use if Mechanism of Action
possible in patients with ocular herpes; active or quiescent Formoterol: Relaxes bronchial smooth muscle by selec-
tuberculosis infections of the respiratory tract; or untreated tive action on beta2 receptors with little effect on heart
viral, fungal, or bacterial or parasitic systemic infections. rate; formoterol has a long-acting effect.
Exposure to chickenpox or measles should be avoided; if Budesonide: A corticosteroid which controls the rate of
the patient is exposed to chickenpox, prophylaxis with protein synthesis, depresses the migration of polymor-
varicella zoster immune globulin or pooled intravenous phonuclear leukocytes/fibroblasts, and reverses capillary
immunoglobulin, may be indicated; if chickenpox devel- permeability and lysosomal stabilization at the cellular
ops, treatment with antiviral agents may be considered. If level to prevent or control inflammation.
 BUMETANIDE

Pharmacodynamics/Kinetics (Adult data unless Therapeutic Category Antihypertensive Agent; Diuretic,

noted) See individual agents. Loop
Onset of action: Asthma: 15 minutes; maximum benefit: Generic Availability (US) Yes
may take 22 weeks Use Management of edema secondary to heart failure or
Dosing hepatic or renal disease, including nephrotic syndrome
Pediatric (FDA approved in adults); has also been used to reverse
Asthma; maintenance treatment: Oral inhalation: oliguria in preterm neonates and for the treatment of
Children 5 to 11 years: Budesonide 80 mcg/formoterol hypertension alone or in combination with other antihy-
4.5 mcg: Two inhalations twice daily; maximum daily pertensive agents
dose: 4 inhalations (Budesonide 320 mcg/formoterol Pregnancy Risk Factor C
18 mcg)/day (Morice 2008; NAEPP 2007) Pregnancy Considerations Adverse events have been
‘Children 212 years and Adolescents: Note: Initial dose observed in some animal reproduction studies.
prescribed should be based upon asthma severity: Breastfeeding Considerations It is not known if bume-
Budesonide 80 mcg/formoterol 4.5 mcg: Two inhala- tanide is present in breast milk. Breastfeeding is not
tions twice daily; maximum daily dose: 4 inhalations recommended by the manufacturer. Diuretics have the
(Budesonide 320 mcg/formoterol 18 mcg)/day. In potential to decrease milk volume and suppress lactation.
patients not adequately controlled following 1 to 2 Contraindications Hypersensitivity to bumetanide or any
weeks of therapy, consider the higher dose combi- component of the formulation; anuria; hepatic coma;
nation. patients in states of severe electrolyte depletion until the
Budesonide 160 mcg/formoterol 4.5 mcg: Two inha- condition improves or is corrected.
lations twice daily; maximum daily dose: 4 inhala- Canadian labeling: Additional contraindications (not in US
tions (Budesonide 640 mcg/formoterol 18 mcg)/day labeling): Hypersensitivity to other sulfonamide deriva-
Renal Impairment: Pediatric There are no dosage tives; hepatic encephalopathy; galactose intolerance,
adjustments provided in the manufacturer's labeling glucose-galactose malabsorption, or Lapp lactase defi-
(has not been studied). ciency.
Hepatic Impairment: Pediatric There are no dosage Note: Although the product labeling states this medica-
adjustments provided in the manufacturer’s labeling (has tion may be contraindicated with other sulfonamide-
not been studied); use with caution and monitor closely; containing drug classes, the scientific basis of this
may lead to accumulation of budesonide and formoterol. statement has been challenged. See "Warnings/Pre-
Administration Prior to first use, inhaler must be primed cautions" for more detail.
by releasing 2 test sprays into the air (away from the face); Warnings/Precautions [US Boxed Warning]: Exces-
shake well for 5 seconds before each spray. Inhaler must sive amounts can lead to profound diuresis with fluid
be reprimed if inhaler has not been used for >7 days or and electrolyte loss; close medical supervision and
has been dropped. Shake well for 5 seconds before each dose evaluation are required. Potassium supplementa-
use. Discard after labeled number of inhalations has been tion and/or use of potassium-sparing diuretics may be
used or within 3 months after foil wrap has been removed; necessary to prevent hypokalemia. In contrast to thiazide
do not use immerse in water or use "float test" to deter- diuretics, a loop diuretic can also lower serum calcium
mine number of inhalations left. concentrations. Electrolyte disturbances can predispose a
Monitoring Parameters Monitor growth in pediatric patient to serious cardiac arrhythmias. In cirrhosis, initiate
patients (via stadiometry). Check mucous membranes bumetanide therapy with conservative dosing and close
for signs of fungal infection. Monitor asthma symptoms, monitoring of electrolytes; avoid sudden changes in fluid
FEV,, peak flow, and/or other pulmonary function tests; and electrolyte balance and acid/base status which may
monitor signs/symptoms of HPA axis suppression/adrenal lead to hepatic encephalopathy. In vitro studies using
insufficiency; ocular effects (eg, cataracts, increased intra- pooled sera from critically-ill neonates have shown bume-
ocular pressure, glaucoma); bone mineral density. Monitor tanide to be a potent displacer of bilirubin; avoid use in
blood pressure, heart rate, CNS stimulation, serum glu- neonates at risk for kernicterus. Potentially significant
cose, and serum potassium. Monitor for increased use of interactions may exist, requiring dose or frequency adjust-
short-acting betaz-agonist inhalers; may be marker of a ment, additional monitoring, and/or selection of alternative
deteriorating asthma condition. therapy.
Dosage Forms Considerations Symbicort 6.9 g canis- Monitor fluid status and renal function in an attempt to
ters contain 60 actuations, and the 10.2 g canisters con- prevent oliguria, azotemia, and reversible increases in
tain 120 actuations. BUN and creatinine; close medical supervision of aggres-
Dosage Forms Excipient information presented when sive diuresis required. Larger doses may be necessary in
available (limited, particularly for generics); consult spe- patients with impaired renal function to obtain the same
cific product labeling. therapeutic response (Brater 1998). Diuretic resistance
Aerosol for oral inhalation: d may occur in some patients, despite higher doses of loop
Symbicort 80/4.5: Budesonide 80 mcg and formoterol diuretic treatment, and can usually be overcome by intra-
fumarate dihydrate 4.5 mcg per actuation (6.9 g); bude- venous administration, the use of two diuretics together
sonide 80 mcg and formoterol fumarate dihydrate 4.5 (eg, furosemide and chlorothiazide), or the use of a
mcg per actuation (10.2 g) diuretic with a positive inotropic agent. When such combi-
Symbicort 160/4.5: Budesonide 160 mcg and formoterol nations are used, serum electrolytes need to be monitored
fumarate dihydrate 4.5 mcg per actuation (6 g); bude- even more closely (ACC/AHA [Yancy 2013]; HFSA 2010).
sonide 160 mcg and formoterol fumarate dihydrate 4.5 Bumetanide-induced ototoxicity (usually transient) may
mcg per actuation (10.2 g) occur with rapid IV administration, renal impairment,
excessive doses, and concurrent use of other ototoxins
® Buffasal [OTC] see Aspirin on page 194 (eg, aminoglycosides). Asymptomatic hyperuricemia has
@ Bufferin [OTC] see Aspirin on page 194 been reported with use. If given the morning of surgery,
@ Bufferin Extra Strength [OTC] see Aspirin on page 194 bumetanide may render the patient volume depleted and
blood pressure may be labile during general anesthesia.
® Buffinol [OTC] see Aspirin on page 194
Benzyl alcohol and derivatives: Some dosage forms may
contain benzy! alcohol; large amounts of benzyl alcohol
Bumetanide (byoo METa nide) (299 mg/kg/day) have been associated with a potentially
Medication Safety Issues fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Sound-alike/look-alike issues: ing syndrome" consists of metabolic acidosis, respiratory
Bumetanide may be confused with Buminate distress, gasping respirations, CNS dysfunction (including
Bumex may be confused with Brevibloc, Buprenex convulsions, intracranial hemorrhage), hypotension and
Geriatric Patients: High-Risk Medication: cardiovascular collapse (AAP ["Inactive" 1997]; CDC
Beers Criteria: Diuretics are identified in the Beers Cri- 1982); some data suggests that benzoate displaces bilir-
teria as a potentially inappropriate medication to be ubin from protein binding sites (Ahlfors, 2001); avoid or
used with caution in patients 65 years and older due use dosage forms. containing benzyl alcohol with caution
to the potential to cause or exacerbate syndrome of in neonates. See manufacturer's labeling.
inappropriate antidiuretic hormone secretion (SIADH) Sulfonamide ("sulfa") allergy: The FDA-approved product
or hyponatremia; monitor sodium concentration closely labeling for many medications containing a sulfonamide
when initiating or adjusting the dose in older adults chemical group includes a broad contraindication in
(Beers Criteria [AGS 2015)). patients with a prior allergic reaction to sulfonamides.
International issues: There is a potential for cross-reactivity between members
Bumex [US] may be confused with Permax brand name of a specific class (eg, two antibiotic sulfonamides). How-
for pergolide [multiple international markets] ever, concerns for cross-reactivity have previously
Brand Names: US Bumex extended to all compounds containing the sulfonamide
Brand Names: Canada Burinex structure (SO2NH2). An expanded understanding of >
307
BUMETANIDE

allergic mechanisms indicates cross-reactivity between Mechanism of Action Inhibits reabsorption of sodium
antibiotic sulfonamides and nonantibiotic sulfonamides and chloride in the ascending loop of Henle and proximal
may not occur or at the very least this potential is renal tubule, interfering with the chloride-binding cotran-
extremely low (Brackett 2004; Johnson 2005; Slatore sport system, thus causing increased excretion of water,
2004; Tornero 2004). In particular, mechanisms of cross- sodium, chloride, magnesium, phosphate, and calcium; it
reaction due to antibody production (anaphylaxis) are does not appear to act on the distal tubule
unlikely to occur with nonantibiotic sulfonamides. T-cell- Pharmacodynamics/Kinetics (Adult data unless
mediated (type IV) reactions (eg, maculopapular rash) are noted)
less well understood and it is not possible to completely Onset of action: Oral, IM: 0.5 to 1 hour; IV: 2 to 3 minutes
exclude this potential based on current insights. In cases Peak effect: Oral: 1 to 2 hours; IV: 15 to 30 minutes
where prior reactions were severe (Stevens-Johnson syn- Duration: Oral: 4 to 6 hours; IV: 2 to 3 hours
drome/TEN), some clinicians choose to avoid exposure to Distribution: Vg: Neonates and Infants: 0.26 to 0.39 L/kg;
these classes. Adults: 9 to 25 L ;
Adverse Reactions Protein binding: 94% to 96%; Neonates: 97%
Central nervous system: Dizziness Metabolism: Partially hepatic
Endocrine & metabolic: Abnormal serum calcium, abnor- Bioavailability: 59% to 89% (median: 80%)
mal lactate dehydrogenase, hyponatremia, hyperglyce- Half-life elimination:
mia, phosphorus change, variations in bicarbonate Premature and full term neonates: 6 hours (range up to
Genitourinary: Azotemia 15 hours)
Neuromuscular & skeletal: Muscle cramps Infants <2-months: 2.5 hours
Renal: Increased serum creatinine Infants 2 to 6 months: 1.5 hours
Respiratory: Variations in COz content Adults: 1 to 1.5 hours
Rare but important or life-threatening: Abdominal pain, Excretion: Urine (81% of total dose; 45% of which is
abnormal alkaline phosphatase, abnormal bilirubin lev- unchanged drug); feces (2% of total dose)
els, abnormal hematocrit, abnormal hemoglobin level, Clearance:
abnormal transaminase, arthritic pain, asterixis, auditory Preterm and full term neonates: 0.2 to 1.1 mL/minute/kg
impairment, blood cholesterol abnormal, brain disease Infants <2 months: 2.17 mL/minute/kg
(in patients with preexisting liver disease), change in Infants 2 to 6 months: 3.8 mL/minute/kg
creatinine clearance, change in prothrombin time, Adults: 2.9 + 0.2 mL/minute/kg
change in WBC count, chest pain, dehydration, diapho- Pharmacodynamics/Kinetics: Additional Consider-
resis, diarrhea, dyspepsia, ECG changes, erectile dys- ations Renal function impairment: The half-life is pro-
function, fatigue, glycosuria, headache, hyperventilation, longed.
hypotension, musculoskeletal pain, nausea, nipple ten- Dosing
derness, orthostatic hypotension, otalgia, ototoxicity, Neonatal
premature ejaculation, proteinuria, pruritus, renal failure, Edema, diureis: Limited data available: Note: Doses in
skin rash, Stevens-Johnson syndrome, thrombocytope- the higher end of the range may be required for
nia, toxic epidermal necrolysis, urticaria, vertigo, vomit- patients with heart failure:
ing, weakness, xerostomia Preterm: Oral, IM, IV: 0.01 to 0.05 mg/kg/dose every 24
Drug Interactions to 48 hours (Lopez-Samplas 1997; Shankaran 1995);
Metabolism/Transport Effects None known. a retrospective trial reported a mean dose of
Avoid Concomitant Use 0.03 mg/kg/dose every 12 to 24 hours for oliguric
Avoid concomitant use of Bumetanide with any of the acute renal failure (n=35; PMA: 24 to 36 weeks)
following: Bromperidol; Desmopressin; Levosulpiride; (maximum reported dose: 0.06 mg/kg/dose) (Oliveros
Mecamylamine; Promazine 2011)
Increased Effect/Toxicity Term: Oral, IM, IV: 0.01 to 0.05 mg/kg/dose every 12 to
Bumetanide may increase the levels/effects of: Ajmaline; 24 hours (Sullivan 1996; Ward 1977)
Allopurinol; Amifostine; Aminoglycosides; Angiotensin- Pediatric Note: Dose equivalency for adult patients with
Converting Enzyme Inhibitors; Antipsychotic Agents normal renal function (approximate): Bumetanide 1 mg =
(Second Generation [Atypical]); Bilastine; Bromperidol; furosemide 40 mg = torsemide 20 mg = ethacrynic acid
Cardiac Glycosides; Cefotiam; Cefpirome; Ceftizoxime; 50 mg
Cephalothin; ClSplatin; Desmopressin; Dofetilide; Edema, diuresis: Limited data available: Infants and
DULoxetine; Foscarnet; Hypotension-Associated Children: Oral, IM, IV: 0.015 to 0.1 mg/kg/dose every
Agents; lvabradine; Levodopa; Levosulpiride; Lithium; 6 to 24 hours (maximum dose: 10 mg/day) (Kliegman
Mecamylamine; Methotrexate; Neuromuscular-Blocking 2007); a prospective, open-label dose-range study in
Agents; Nitroprusside; Nonsteroidal Anti-Inflammatory infants (mean age: 2 months; range: 0 to 6 months)
Agents; Pholcodine; Promazine; RisperiDONE; Salicy- reported a maximal diuretic response at doses 0.035 to
lates; Sodium Phosphates; Tobramycin (Oral Inhalation); 0.04 mg/kg/dose every 6 to 8 hours, and no additional
Topiramate clinical benefit (ie, urine output) at doses >0.05 mg/kg/
dose (Sullivan 1996)
The levels/effects of Bumetanide may be increased by:
Renal Impairment: Pediatric There are no pediatric
Alfuzosin; Barbiturates; Benperidol; Beta2-Agonists;
specific recommendations; based on experience in adult
Brigatinib; Brimonidine (Topical); Canagliflozin; Cefaze-
patients, use in contraindicated in anuria; and use with
done; Cephradine; Corticosteroids (Orally Inhaled); Cor-
caution in renal insufficiency due to increased risk of
ticosteroids (Systemic); CycloSPORINE (Systemic);
adverse effects.
Diacerein; Diazoxide; Empagliflozin; Herbs (Hypotensive
Hepatic Impairment: Pediatric There are no pediatric
Properties); lpragliflozin; Licorice; Lormetazepam;
specific recommendations; based on experience in adult
Methotrexate; Molsidomine; Naftopidil; Nicergoline; Nic-
patients, use is contraindicated in hepatic coma. Use
orandil; Obinutuzumab; Opioid Analgesics; Pentoxifyl-
with caution in cirrhosis and ascites due to increased
line; Phosphodiesterase 5 Inhibitors; Probenecid;
risk of precipitating hepatic coma; initiate with conserva-
Prostacyclin Analogues; Quinagolide; Reboxetine;
tive doses and monitoring.
Xipamide
Preparation for Administration Parenteral: Intermittent
Decreased Effect
IV infusion: May be diluted in DSW, LR, or NS (Rudy 1991)
Bumetanide may decrease the levels/effects of: Antidia-
Administration
betic Agents; Lithium; Neuromuscular-Blocking Agents
Oral: Administer with food to decrease GI irritation
The levels/effects of Bumetanide may be decreased by: Parenteral:
Amphetamines; Bile Acid Sequestrants; Brigatinib; IV: Administer undiluted by direct IV injection over 1 to 2
Bromperidol; Fosphenytoin; Herbs (Hypertensive Prop- minutes
erties); Methotrexate; Methylphenidate; Nonsteroidal Intermittent IV infusion: Further dilute and administer
Anti-Inflammatory Agents; Opioid Analgesics; Phenytoin; over 5 minutes (Rudy 1991)
Probenecid; Salicylates; Yohimbine Monitoring Parameters Blood pressure, serum electro-
Food Interactions Bumetanide serum levels may be lytes, renal function, urine output
decreased if taken with food. Management: It has been Test Interactions May lead to false-negative aldosterone/
recommended that bumetanide be administered without renin ratio (ARR) (Funder 2016).
food (Bard 2004). Dosage Forms Excipient information presented when
Storage/Stability available (limited, particularly for generics); consult spe-
IV: Store vials at 15°C to 30°C (59°F to 86°F). Infusion cific product labeling.
solutions in D5W, NS, or LR should be used within 24 Solution, Injection:
hours after preparation. Light sensitive; discoloration Generic: 0.25 mg/mL (2 mL, 4 mL, 10 mL)
may occur when exposed to light. Tablet, Oral:
Tablet: Store at 15°C to 30°C (59°F to 86°F); protect from Bumex: 0.5 mg [contains fd&c blue #1 aluminum lake,
light. fd&c yellow #10 aluminum lake]

308
 BUPIVACAINE

Bumex: 1 mg [contains fd&c yellow #10 (quinoline equipment, oxygen, and other resuscitative drugs should
yellow)] be available for immediate use. Continuous intra-articular
Bumex: 2 mg infusion of local anesthetics after arthroscopic or other
Generic: 0.5 mg, 1 mg, 2 mg surgical procedures is not an approved use; chondrolysis
(primarily shoulder joint) has occurred following infusion,
@ Bumex see Bumetanide on page 307
with some patients requiring arthroplasty or shoulder
® Buminate see Albumin on page 70 replacement. May contain sodium metabisulfite; use cau-
@ Bunavail see Buprenorphine and Naloxone on page 317 tion in patients with asthma or a sulfite allergy.
@ Bupheny! see Sodium Phenylbutyrate on page 1843 Warnings: Additional Pediatric Considerations
Infants may be at greater risk for bupivacaine toxicity
because a,-acid-glycoprotein concentration, the major
Bupivacaine (byoo Piva kane) serum protein to which bupivacaine is bound, is lower in
neonates and infants compared with older children leading
Medication Safety Issues
to an increase of free fraction of local anesthetic; use
Sound-alike/look-alike issues:
epidural infusions with caution in neonates and infants
Bupivacaine may be confused with mepivacaine, ropiva-
and monitor closely. Fat emulsion has been used to
caine
manage local anesthetic toxicity (refer to Fat Emulsion
Marcaine® may be confused with Narcan®
monograph for additional information) (McCloskey 1992).
High alert medication:
The Institute for Safe Medication Practices (ISMP) Adverse Reactions Note: Most effects are dose related,
includes this medication (epidural administration) and are often due to accelerated absorption from the
among its list of drug classes which have a heightened injection site, unintentional intravascular injection, or slow
risk of causing significant patient harm when used in metabolic degradation. The development of any central
error. nervous system symptoms may be an early indication of
Brand Names: US Bupivacaine Spinal; Marcaine; Mar- more significant toxicity (seizure).
caine Preservative Free; Marcaine Spinal; P-Care M; Cardiovascular: Bradycardia, cardiac arrest, heart block,
ReadySharp Bupivacaine; Sensorcaine; Sensorcaine- hypotension, palpitations, ventricular arrhythmia
MPF; Sensorcaine-MPF Spinal Central nervous system: Anxiety, dizziness, restlessness
Brand Names: Canada Marcaine; Sensorcaine Gastrointestinal: Nausea, vomiting
Therapeutic Category Local Anesthetic, Injectable Hypersensitivity: Anaphylactoid reaction, hypersensitivity
Generic Availability (US) Yes reaction (urticaria, pruritus, angioedema)
Use Local or regional anesthesia; spinal anesthesia; anes- Neuromuscular & skeletal: Chondrolysis (continuous intra-
thesia for diagnostic and therapeutic procedures and articular administration), weakness
obstetrical procedures (FDA approved in ages 212 years Ophthalmic: Blurred vision, miosis
and adults); specific uses vary by product: Otic: Tinnitus
0.25%: Local infiltration, peripheral nerve block, sympa- Respiratory: Apnea, hypoventilation (usually associated
thetic block, caudal or epidural block with unintentional subarachnoid injection during high
0.5%: Peripheral nerve block, caudal and epidural block spinal anesthesia)
0.75% Retrobulbar block, epidural block. Note: Not for Rare but important or life-threatening: Seizure; usually
obstetrical anesthesia; reserve for surgical procedures associated with unintentional subarachnoid injection dur-
where a high degree of muscle relaxation and prolonged ing high spinal anesthesia: cranial nerve palsy, fecal
effect are necessary. incontinence, headache, loss of anal sphincter control,
Pregnancy Risk Factor C loss of perineal sensation, paralysis, paresthesia, persis-
Pregnancy Considerations Adverse events were tent anesthesia, septic meningitis, sexual disorder (loss
observed in animal reproduction studies. Bupivacaine of function), urinary incontinence
crosses the placenta. Bupivacaine is approved for use at Drug Interactions
term in obstetrical anesthesia or analgesia. [U.S. Boxed Metabolism/Transport Effects Substrate of CYP1A2
Warning]: The 0.75% is not recommended for obstet- (minor), CYP2C19 (minor), CYP2D6 (minor), CYP3A4
rical anesthesia. Bupivacaine 0.75% solutions have been (minor); Note: Assignment of Major/Minor substrate sta-
associated with cardiac arrest following epidural anesthe-
tus based on clinically relevant drug interaction potential
sia in obstetrical patients and use of this concentration is
Avoid Concomitant Use
not recommended for this purpose. Use in obstetrical
Avoid concomitant use of Bupivacaine with any of the
paracervical block anesthesia is contraindicated.
following: Bromperidol
Breastfeeding Considerations Bupivacaine is excreted
in breast milk. Due to the potential for serious adverse
Increased Effect/Toxicity
Bupivacaine may increase the levels/effects of: Amifos-
reactions in the nursing infant, a decision should be made
whether to discontinue nursing or to discontinue the drug, tine; Antipsychotic Agents (Second Generation [Atypi-
taking into account the importance of_treatment to the cal]); Bromperidol; Bupivacaine (Liposomal);
mother. DULoxetine; Hypotension-Associated Agents; Levo-
Contraindications dopa; Neuromuscular-Blocking Agents; Nitroprusside;
Hypersensitivity to bupivacaine hydrochloride, amide-type Pholcodine
local anesthetics, or any component of the formulation; The levels/effects of Bupivacaine may be increased by:
obstetrical paracervical block anesthesia Alfuzosin; Barbiturates; Benperidol; Beta-Blockers;
Note: Use as intravenous regional anesthesia (Bier block) Blood Pressure Lowering Agents; Brimonidine (Topical);
is considered contraindicated per accepted clinical prac- Diazoxide; Herbs (Hypotensive Properties); Hyaluroni-
tice due to reports of cardiac arrest and death. dase; Lormetazepam; Molsidomine; Naftopidil; Nicergo-
Canadian labeling: Additional contraindications (not in US line; Nicorandil; Obinutuzumab; Pentoxifylline;
labeling): Obstetric paracervical block anesthesia; Phosphodiesterase 5 Inhibitors; Prostacyclin Analogues;
severe shock and in heart block where there is inflam- Quinagolide
mation and/or sepsis near the proposed injection site. Decreased Effect
Warnings/Precautions Do not use solutions contain- Bupivacaine may decrease the levels/effects of: Techne-
ing preservatives for caudal or epidural block. Use tium Tc 99m Tilmanocept
with caution in patients with hepatic impairment. Local The levels/effects of Bupivacaine may be decreased by:
anesthetics have been associated with rare occurrences
Bromperidol
of sudden respiratory arrest; convulsions due to systemic
Storage/Stability Store at controlled room temperature of
toxicity leading to cardiac arrest have also been reported,
20°C to 25°C (68°F to 77°F).
presumably following unintentional intravascular injection.
Intravenous regional anesthesia (Bier block) is not rec- Mechanism of Action Blocks both the initiation and
ommended; cardiac arrest and death have occurred with
conduction of nerve impulses by decreasing the neuronal
this method of administration. [US Boxed Warning]: The membrane's permeability to sodium ions, which results in
0.75% concentration is not recommended for obstet- inhibition of depolarization with resultant blockade of con-
rical anesthesia; cardiac arrest with difficult resusci- duction
tation or death has occurred. A test dose is Pharmacodynamics/Kinetics (Adult data unless
recommended priorto epidural administration (prior to noted)
initial dose) and all reinforcing doses with continuous Onset of action: Anesthesia (route and dose dependent):
catheter technique. Use caution with cardiovascular dys- Epidural: Up to 17 minutes to spread to T6 dermatome
function including patients with hypotension or heart block. (Scott 1980)
Bupivacaine-containing products have been associated Infiltration: Fast (Barash 2009); Dental injection: 2 to 10
with rare occurrences of arrhythmias, cardiac arrest, and minutes
death. Use caution in debilitated, elderly, or acutely ill Spinal: Within 1 minute; maximum dermatome level
patients; dose reduction may be required. Resuscitative achieved within 15 minutes in most cases >
 BUPIVACAINE

q Duration (route and dose dependent): Spinal Anesthesia: Limited data available (Walker
Epidural: 2 to 7.7 hours (Barash 2009) 2012): Usual concentration: 0.25 or 0.5% solution
Infiltration: 2 to 8 hours (Barash 2009); Dental injection: (isobaric) or 0.75% bupivacaine in 8.25% dextrose
Up to 7 hours solution (hyperbaric): Intrathecal: 0.5 to 1 mg/kg (Bon-
Spinal: 1.5 to 2.5 hours (Tsai 2007) nett 2004; Coté 2013; Frawley 2009; Johr 2015; Roch-
Distribution: Vg: Infants: 3.9 + 2 L/kg; Children: 2.7 + 0.2 ette 2005; Somri 2007; Williams 2001)
Likg Pediatric Note: Dose varies with procedure, depth of
Protein binding: 84% to 95% anesthesia, vascularity of tissues, duration of anesthe-
Metabolism: Hepatic; forms metabolite (pipecoloxyli- sia, and condition of patient. Preservative-free formula-
dine [PPX]) tions are recommended for administration into the CNS
Half-life elimination (age dependent): Neonates: 8.1 space (eg, epidural, caudal, spinal) Consider incremen-
hours; Adults: 2.7 hours tal administration with negative aspiration prior to each
Time to peak, plasma: Caudal, epidural, or peripheral injection; however, absence of blood in the syringe does
nerve block: 30 to 45 minutes not guarantee that intravascular injection has been
Excretion: Urine (~6% unchanged) avoided (Mulroy 2010). Consider incremental adminis-
Clearance: Infants: 7.1 + 3.2 mL/kg/minute; Children: 10 tration with negative aspiration prior to each injection;
+ 0.7 mL/kg/minute however, absence of blood in the syringe does not
guarantee that intravascular injection has been avoided
Pharmacodynamics/Kinetics: Additional Consider-
(Mulroy 2010). Should only be administered under the
ations Geriatric: Elderly patients reached the maximal
supervision of a qualified physician experienced in the
spread of analgesia and maximal motor blockade more
use of anesthetics. In pediatric patients, dosing should
rapidly than younger patients. Elderly patients also exhib-
be based on lean body mass (Coté 2013).
ited higher peak plasma concentrations following admin-
Central nerve block/anesthesia:
istration of this product. The total plasma clearance was
Caudal block: Reported dosing variable based on
decreased in these patients.
procedure; dependent on necessary dermatome
Dosing level and corresponding volume of space:
Neonatal Note: Dose varies with procedure, depth of Infants and Children: Limited data available: Usual
anesthesia, vascularity of tissues, duration of anesthe- concentration <0.25% solution with or without epi-
sia, and condition of patient; should only be administered nephrine: Usual reported dose range: 0.5 to 1.3
under the supervision of a qualified physician experi- mL/kg (maximal volume of drug: 20 mL); dose
enced in the use of anesthetics. Preservative-free for- should not exceed 2 mg/kg plain solution, or 3
mulations are recommended for administration into the mg/kg with epinephrine. In infants, routine use of
CNS space (eg, epidural, caudal, spinal). Consider concentrations <0.25% have been suggested to
incremental administration with negative aspiration prior reduce risk of bupivacaine cardiotoxicity (Coté
to each injection; however, absence of blood in the 2013; Ingelmo 2007; Ivani 1998; Ivani 2002; Kar-
syringe does not guarantee that intravascular injection kera 2016; Miller 2015; Payne 1993; Schrock
has been avoided (Mulroy 2010). Dosing units variable 2003; Schwartz 2010)
(mL/kg, mg/kg); use extra precaution to ensure accu- Adolescents: Usual concentration 0.25 to 0.5% sol-
racy. ution with or without epinephrine: 15 to 30 mL
Central nerve block/anesthesia: Epidural block: Reported dosing variable; among
Caudal block: Limited data available: Term neonate: other factors, dose dependent on necessary derma-
Usual concentration $0.25% solution: Usual reported tome level and corresponding volume of epidural
dose range: 0.5 to 1.25 mL/kg; dose should not space (Coté 2013):
exceed 2.5 mg/kg. Routine use of concentrations Infants: Limited data available: Usual concentration
0.25% have been suggested to reduce risk of bupi- <0.25% with or without epinephrine: 0.7 to 0.75
vacaine cardiotoxicity (Coté 2013; Deng 2008; Lin mL/kg; maximum dose: 2.5 mg/kg; Note: For
2010; Lénnqvist 2010; Kost-Byerly 2008; infants (particularly young infants), if repeat injec-
Schwartz 2010). tions necessary, a decreased dose may be neces-
Epidural Block: Limited data available: Term neonate: sary to prevent drug accumulation. Some experts
Usual concentration <0.25% solution: Usual dose: 1 suggest if at least 45 minutes since initial dose,
mL/kg; dose should not exceed 2.5 mg/kg; required reduce dose to 1/3 of the initial or if at least 90
dose may vary; among other factors, dose also minutes since initial dose, then reduce dese to half
dependent on desired dermatome level and corre- of the initial. If additional doses are necessary,
sponding volume of epidural space (Coté 2013; Miller doses should be reduced to half of the previous
2015). If repeat injections necessary, a decreased dose (lvani 1999; Miller 2015; Monsel 2007).
dose is necessary to prevent drug accumulation. Children: Limited data available: Usual concentra-
Some experts suggest if at least 45 minutes since tion 0.25% solution: Initial: 0.3 to 0.6 mL/kg (max-
initial dose, reduce dose to ‘/3 of the initial or if at least imal volume of drug: 20 mL); maximum dose: 2.5
90 minutes since initial dose, then reduce dose to half mg/kg (Ingelmo 2007; Ingelmo 2007a)
of the initial. If additional doses are necessary, doses Adolescents: 0.25% or 0.5% solution: 10 to 20 mL
should be reduced to half of the previous dose administered in 3 to 5 mL increments; if high
(Miller 2015). degree of muscle relaxation and prolonged effects
needed, may consider 0.75% solution: 10 to 20 mL
Epidural, continuous infusion: Limited data available
Epidural, continuous infusion: Limited data available
(Berde 1992; Lonnqvist 2010; Miller 2015): Note:
in infants and children <12 years (Berde 1992; Miller
Use has generally been replaced by other agents
2015; Moriarty 2012): Note: Use has generally been
(eg, ropivacaine) (L6nnqvist 2010; Moriarty 2012).
replaced by other agents (eg, ropivacaine) (Miller
Loading dose: Usual concentration <0.25% solution: 2
2015; Moriarty 2012).
to 2.5 mg/kg
Loading dose: Usual concentration: 0.25%: 2 to
Infusion: Usual infusion concentration range 0.05 to
2.5 mg/kg
0.25% solution: 0.2 to 0.25 mg/kg/hour
Infusion:
Peripheral nerve blocks: Limited data available (JOhr
Infants <4 months: 0.2 mg/kg/hour
2015): Note: Dose volume and concentration varies Infants 24 months: 0.25 mg/kg/hour
with procedure, depth of anesthesia, vascularity of
Children and Adolescents: 0.3 mg/kg/hour
tissues, duration of anesthesia, and condition of Peripheral nerve block: Limited data available in
patient. Term neonate: Usual Concentration: 0.125 to infants and children: Note: Dose varies with location
0.25% solution: Volume of dose (mL/kg, specific to site of block (ie, procedure), depth of anesthesia, vascu-
and may be variable among patients) and not to exceed larity of tissues, duration of anesthesia, and condition
the maximum dose: 2 mg/kg (Coté 2013; Miller 2015) of patient.
Commonly suggested doses (Coté 2013): Infants 26 months and Children: Usual concentration
Head and neck: 0.05 mL/kg 0.125% or 0.25% solution with or without epinephr-
Upper extremity: ine: The volume of dose (mL/kg) and concentration
Brachial plexus: 0.2 to 0.3 mL/kg of solution are site specific based upon anatomy and
Digital nerve: 0.05 mL/kg variable among patients and procedure; see below
Truncal blocks: ranges. For infants <6 months, maximum doses
Transversus abdominis plane: 0.2 to 0.5 mL/kg should be reduced by 30% (Coté 2013; Miller
(J6hr 2015) 2015). Maximum dose plain solution: 2 mg/kg or
Rectus sheath: 0.1 mL/kg 150:mg whichever is less or maximum dose with
llioinguinal: 0.075 mL/kg epinephrine: 3 mg/kg or 200 mg of bupivacaine
, Lower extremity blocks: whichever is less.
Femoral nerve: 0.2 to 0.3 mL/kg Commonly suggested doses (Coté 2013):
Sciatic nerve: 0.2 to 0.3 mL/kg Head and neck: 0.05 mL/kg

310
 BUPRENORPHINE

Upper extremity:
Brachial plexus: 0:2 to 0.3 mL/kg Buprenorphine (byoo pre NOR feen)
Digital nerve: 0.05 mL/kg
Truncal blocks: Medication Safety Issues
Transversus abdominis plane: 0.2 to 0.5 mL Sound-alike/look-alike issues:
(J6hr 2015) Buprenex may be confused with Brevibloc, Bumex
Rectus sheath: 0.1 mL/kg High alert medication:
llioinguinal: 0.075 mL/kg The Institute for Safe Medication Practices (ISMP)
Lower extremity blocks: includes this medication among its list of drug classes
Femoral nerve: 0.2 to 0.3 mL/kg which have a heightened risk of causing significant
Sciatic nerve: 0.2 to 0.3 mL/kg patient harm when used in error.
Adolescents: 0.25% or 0.5% solution with or without Brand Names: US Belbuca; Buprenex; Butrans; Probu-
epinephrine: 5 mL; maximum daily dose: 400 phine Implant Kit; Sublocade
mg/day Brand Names: Canada Belbuca; Butrans
Local anesthesia: Infants, Children, and Adolescents: Therapeutic Category Analgesic, Narcotic; Opioid Par-
Limited data in infants and children: Usual concen- tial Agonist
tration 0.25% solution: Infiltrate area local; maximum Generic Availability (US) May be product dependent
dose in infants and children: 2.5 mg/kg or 150 mg Use
whichever is less; maximum dose in adolescents: Oral:
175 mg (Coté 2013) Buccal film: Management of moderate to severe chronic
Renal Impairment: Pediatric There are no dosage pain in patients requiring an around-the-clock opioid
adjustments provided in the manufacturer’s labeling; analgesic for an extended period of time (FDA
use with caution. approved in adults)
- Hepatic Impairment: Pediatric There are no dosage Sublingual tablet: Treatment of opioid dependence (FDA
adjustments provided in the manufacturer’s labeling; use approved in ages 216 years and adults). Note:
with caution. Approved ages in pediatric population may vary with
Preparation for Administration Epidural continuous generic formulations; consult product-specific labeling.
infusion: Use preservative-free formulation, further dilute Parenteral:
with preservative-free NS. Immediate release: Management of moderate to severe
pain (FDA approved in ages 22 years and adults)
Administration Solutions containing preservatives should
Extended release: Treatment of moderate to severe
not be used for epidural or caudal blocks; for epidural
opioid use disorder in patients who have initiated treat-
infusion, may use undiluted or diluted with preservative-
ment with 8 to 24 mg of a transmucosal buprenorphine-
free NS. Consider incremental administration with nega-
containing product, followed by. dose adjustment for a
tive aspiration prior to each injection; however, absence of
minimum of 7 days (FDA approved in adults)
blood in the syringe does not guarantee that intravascular
Subdermal implant: Maintenance treatment of opioid
injection has been avoided (Mulroy 2010).
dependence in patients who have achieved and sus-
Reference Range Toxicity: 2 to 4 mcg/mL; unbound tained prolonged clinical stability on low to moderate
bupivacaine: 20.3 mcg/mL (Coté 2013; Miller 2015); some
doses ($8 mg/day) of a transmucosal buprenorphine-
data suggests that the rate of rise of the serum level is containing product for 3 months or longer with no need
more predictive of toxicity than the actual value (Scott for supplemental dosing or adjustments (FDA approved
1975) in ages 216 years and adults)
Additional Information For epidural infusion, lower dos- Transdermal: Management of moderate to severe chronic
ages of bupivacaine may be effective when used in pain in patients requiring an around-the-clock opioid
combination with opioid analgesics analgesic for an extended period of time (FDA approved
Dosage Forms Excipient information presented when in ages 218 years and adults)
available (iimited, particularly for generics); consult spe- Prescribing and Access Restrictions
cific product labeling. [DSC] = Discontinued product Extended-release injection: Prescribing of the extended
Kit, Injection, as hydrochloride: release injection is limited to healthcare providers who
P-Care M: 0.5% meet qualifying requirements, have notified the Secre-
Kit, Injection, as hydrochloride [preservative free]: tary of Health and Human Services (HHS) of their intent
ReadySharp Bupivacaine: 0.5% to prescribe this product for the treatment of opioid
Solution, Epidural, as hydrochloride: dependence and have been assigned a unique identi-
Generic: 0.1% in NaCl 0.9% (100 mL, 250 mL); 0.25% in fication number to include on every prescription.
NaCl 0.9% (50 mL, 200 mL, 250 mL, 400 mL, 500 mL) Subdermal implant: Prescribing of implants and inserting
Solution, Injection, as hydrochloride: or removing implants are limited to healthcare providers
Marcaine: 0.25% (50 mL); 0.5% (50 mL) [contains meth- who have completed a live training program. Additionally,
ylparaben] inserting or removing implants is limited to healthcare
Sensorcaine: 0.25% (50 mL);.0.5% (50 mL) [contains providers who have demonstrated procedural compe-
methylparaben] tency. As a prerequisite for participating in the live train-
Generic: 0.25% (30 mL [DSC], 50 mL); 0.5% (50 mL, 100 ing program, the healthcare provider must have
mL, 125 mL, 270 mL, 300 mL, 400 mL, 450 mL, 500 performed at least one qualifying surgical procedure in
mL, 540 mL, 600 mL); 0.1% in NaCl 0.9% (500 mL); the last 3 months. Qualifying procedures are those
0.125% in NaCl 0.9% (550 mL, 600 mL, 750 mL); 0.2% performed under local anesthesia using aseptic techni-
in NaCl 0.9% (500 mL [DSC}); 0.25% in NaCl 0.9% que and include, at a minimum, making skin incisions or
(500 mL, 550 mL, 600 mL); 0.375% in NaCl 0.9% (100 placing sutures. Buprenorphine subdermal implant will
mL, 270 mL, 300 mL) only be distributed to certified prescribers through a
Solution, Injection, as hydrochloride [preservative free]: restricted distribution program. Information concerning
Marcaine: 0.75% (10 mL, 30 mL) the insertion and removal procedures can be obtained
Marcaine Preservative Free: 0.25% (10 mL, 30 mL); by calling 1-844-859-6341.
0.5% (10 mL, 30 mL) Sublingual tablet: Prescribing of tablets for opioid depend-
Sensorcaine-MPF: 0.25% (10 mL, 30 mL); 0.5% (10 mL, ence is limited to physicians who have met the qualifi-
30 mL); 0.75% (10 mL, 30 mL) [methylparaben free] cation criteria and have received a DEA number specific
Generic: 0.25% (10 mL, 20 mL [DSC], 30 mL); 0.5% (10 to prescribing this product. Tablets will be available
mL, 20 mL [DSC], 30 mL); 0.75% (10 mL, 20 mL [DSC], through pharmacies and wholesalers which normally
30 mL); 0.1% in NaCl 0.9% (400 mL [DSC]); 0.25% in provide controlled substances.
NaCl 0.9% (550 mL [DSC]}) ~ Medication Guide Available Yes
Solution, Intrathecal, as hydrochloride: Pregnancy Considerations
Generic: 0.75% [7.5 mg/mL] (2 mL) [US Boxed Warning]: Prolonged use of opioids during
Solution, Intrathecal, as hydrochloride [preservative free]: pregnancy can result in neonatal opioid withdrawal
Bupivacaine Spinal: 0.75% [7.5 mg/mL] (2 mL) syndrome, which may be life-threatening if not recog-
Marcaine Spinal: 0.75% [7.5 mg/mL] (2 mL) nized and requires management according to proto-
Sensorcaine-MPF Spinal: 0.75% [7.5 mg/mL] (2 mL) cols developed by neonatology experts. If opioid use
Solution Prefilled Syringe, Epidural, as hydrochloride: is required for a prolonged period in a pregnant
Generic: 0.25% in NaCl 0.9% (10 mL); 0.5% in NaCl woman, advise the patient of the risk of neonatal
0.9% (10 mL) “* opioid withdrawal syndrome and ensure appropriate
treatment will be available.
@ Bupivacaine HCI see Bupivacaine on page 309
Buprenorphine crosses the placenta; buprenorphine and
@ Bupivacaine Hydrochloride see Bupivacaine
norbuprenorphine can be detected in newborn serum,
on page 309
urine, and meconium following in utero exposure (CSAT
@ Bupivacaine Spinal see Bupivacaine on page 309 2004). Based on available data, an increased risk of major
@ Buprenex see Buprenorphine on page 311 malformations has not been observed. Following chronic

311
BUPRENORPHINE

opioid therapy in pregnancy, adverse events in the new- analgesic requirements; acute respiratory depression;
born (including withdrawal) may occur; monitoring of the hypercapnia; cor pulmonale; obstructive airway (other
neonate is recommended. The minimum effective dose than asthma); status asthmaticus; acute alcoholism or
should be used if opioids are needed (Chou 2009). The alcohol dependence; delirium tremens; convulsive dis-
onset of withdrawal in infants of women receiving bupre- orders; severe CNS depression; increased cerebrospinal
norphine during pregnancy ranged from day 1 to day 8 of or intracranial pressure; head injury; concurrent use or
life, most occurring on day 1. Symptoms of withdrawal use within 14 days of MAOIs; myasthenia gravis; severe
may include agitation, apnea, bradycardia, convulsions, hepatic insufficiency; opioid dependent patients and for
hypertonia, myoclonus, respiratory depression, and opioid withdrawal treatment; pregnancy or during labor
tremor. Based on available data, there does not appear and delivery; breastfeeding; known or suspected oral
to be a dose-response relationship with the incidence of mucositis (buccal film only)
neonatal abstinence syndrome. Warnings/Precautions An opioid-containing analgesic
regimen should be tailored to each patient's needs and
Buprenorphine is currently considered an alternate treat- based upon the type of pain being treated (acute versus
ment for pregnant women who need therapy for opioid chronic), the route of administration, degree of tolerance
addiction (CSAT 2004; Dow 2012; Kampman [ASAM for opioids (naive versus chronic user), age, weight, and
2015]); however, use in pregnancy for this purpose is medical condition. The optimal analgesic dose varies
increasing (ACOG 2012; Soyka 2013). Because dose widely among patients. Doses should be titrated to pain
adjustments cannot be made, it may not be appropriate relief/prevention. When switching patients from buprenor-
to initiate use of the implant in pregnant women; women phine to naltrexone, do not initiate naltrexone until 7 to 14
who become pregnant while using the implant should be days after-buprenorphine discontinuation. No time delay is
closely monitored. Buprenorphine should not be used to required when switching patients from buprenorphine to
treat pain during labor. Women receiving buprenorphine methadone (Kampman [ASAM 2015)).
for the treatment of addiction should be maintained on
their daily dose of buprenorphine in addition to receiving May cause CNS depression, which may impair physical or
the same pain management options during labor and mental abilities; patients must be cautioned about per-
delivery as opioid-naive women; maintenance doses of forming tasks that require mental alertness (eg, operating
buprenorphine will not provide adequate pain relief. Opioid machinery, driving). [US Boxed Warning]: Serious, life-
agonist-antagonists should be avoided for the treatment of threatening, or fatal respiratory depression may
labor pain in women maintained on buprenorphine due to occur. Monitor closely for respiratory depression,
the risk of precipitating acute withdrawal. In addition, especially during initiation or dose escalation. Misuse
buprenorphine should not be given to women in labor or abuse by chewing, swallowing, snorting, or inject-
taking methadone (ACOG 2012). ing buprenorphine extracted from the buccal film or
transdermal system will result in the uncontrolled
Amenorrhea may develop secondary to substance abuse; delivery of buprenorphine and pose a significant risk
pregnancy may occur following the initiation of buprenor- of overdose and death. Misuse by self-injection of bupre-
phine maintenance treatment. Contraception counseling norphine or the concomitant use of buprenorphine and
is recommended to prevent unplanned pregnancies (Dow benzodiazepines (or other CNS depressants, including
2012). Long-term opioid use may cause secondary hypo- alcohol) may result in coma or death. Carbon dioxide
gonadism, which may lead to sexual dysfunction or infer- retention from opioid-induced respiratory depression can
tility (Brennan 2013). exacerbate the sedating effects of opioids. If the extended
Breastfeeding Considerations release injection is discontinued due to respiratory depres-
Buprenorphine is present in breast milk. sion, monitor the patient for ongoing respiratory depres-
Based on data from six women taking a median oral dose sion for several months due to its extended release
of buprenorphine 0.29 mg/kg/day, 5 to 8 days postpar- characteristics. Use with caution in patients with compro-
tum, the concentrations of buprenorphine and its metab- mised respiratory function (eg, chronic obstructive pulmo-
olite in breast milk were low (0.2% and 0.12% of the nary disease, cor pulmonale, decreased respiratory
weight adjusted maternal dose, respectively). Using data reserve, hypoxia, hypercapnia, or preexisting respiratory
from seven women taking an average oral dose of depression). Accidental exposure to even one dose, espe-
buprenorphine 7 mg/day, ~1 month postpartum, the con- cially in children, can result in a fatal overdose. Use with
centrations of buprenorphine and its metabolite in breast caution and monitor for respiratory depression in patients
milk were also low (0.38% and 0.18% of the weight with significant chronic obstructive pulmonary disease or
adjusted maternal dose, respectively). When used for cor pulmonale and those with a substantially decreased
pain management (immediate-release injection, patch), respiratory reserve, hypoxia, hypercapnia, or preexisting
the manufacturers do not recommend use in breastfeed- respiratory depression, particularly when initiating and
ing women. When used for opioid addiction (sublingual titrating therapy; critical respiratory depression may occur,
tablet, extended-release injection), the manufacturer rec- even at therapeutic dosages. Consider the use of alter-
ommends that caution be used if breastfeeding. native nonopioid analgesics in these patients. Use opioids
Breastfed infants exposed to large doses of opioids with caution for chronic pain and titrate dosage cautiously
should be monitored for apnea and sedation (Montgom- in patients with risk factors for sleep-disordered breathing,
ery 2012). including HF and obesity. Avoid opioids in patients with
When buprenorphine is used to treat opioid addiction in moderate to severe sleep-disordered breathing (Dowell
breastfeeding women, most guidelines allow breastfeed- [CDC 2016]). When using buprenorphine for treatment
ing as long as the infant is tolerant to the dose and other of opioid dependence, treat acute pain with nonopioid
contraindications do not exist (eg, not using additional analgesics whenever possible. If treatment with a high-
drugs or alcohol, HIV negative); caution should be used affinity full opioid analgesic is required, monitor closely for
when breastfed infants not previously exposed (ACOG respiratory depression, as high doses may be necessary
2012; CSAT 2004; Kampman [ASAM 2015]; Montgom- to achieve pain relief. Use with caution in elderly patients;
ery 2012). If additional illicit substances are being may be more sensitive to adverse effects (eg, life-threat-
abused, women treated with buprenorphine should ening respiratory depression). In chronic pain, monitor
pump and discard breast milk until sobriety is estab- opioid use closely in this age group due to an increased
lished (ACOG 2012; Dow 2012). potential for risks, including certain risks such as falls/
Contraindications fracture, cognitive impairment, and constipation (Dowell
Hypersensitivity (eg, anaphylaxis) to buprenorphine or any [CDC 2016]). Consider the use of alternative nonopioid
component of the formulation. analgesics in these patients. Also use with caution in
Buccal film, immediate-release injection, transdermal debilitated or cachectic patients; there is a greater poten-
patch: Additional contraindications: Significant respira- tial for life-threatening respiratory depression, even at
tory depression; acute or severe asthma in an unmoni- therapeutic dosages. Consider the use of alternative non-
tored setting or in the absence of resuscitative opioid analgesics in these patients.
equipment; GI obstruction, including paralytic ileus
Hypersensitivity reactions, including bronchospasm,
(known or suspected).
angioneurotic edema, and anaphylactic shock, have been
Documentation of allergenic cross-reactivity for opioids is
reported. The most common symptoms include rash,
limited. However, because of similarities in chemical
hives, and pruritus.
structure and/or pharmacologic actions, the possibility
of cross-sensitivity cannot be ruled out with certainty. Hepatitis has been reported; hepatic events ranged from
Canadian labeling: Transdermal patch and buccal film transient, asymptomatic transaminase elevations to hep-
(Additional contraindications; not in US labeling): Hyper- atic failure; in many cases, patients had preexisting hep-
sensitivity to other opioids; suspected surgical abdomen atic impairment. Monitor liver function tests in patients at
(eg, acute appendicitis or pancreatitis); mild, intermittent increased risk for hepatotoxicity (eg, history of alcohol
or short duration pain that can otherwise be managed; abuse, preexisting hepatic dysfunction, IV drug abusers)
management of acute pain, including use in outpatient or prior to and during therapy. Remove buprenorphine sub-
day surgeries; management of perioperative pain relief, dermal implant if signs and symptoms of buprenorphine
or in other situations characterized by rapidly varying toxicity develop concurrent.with hepatic impairment. If

312
 BUPRENORPHINE

signs and symptoms of toxicity or overdose occur within 2 dependency exists. Other factors associated with
weeks of extended-release injection, removal of the depot increased risk for misuse include younger age and psy-
may be required. Use buccal film and sublingual tablet chotropic medication use. Consider offering naloxone
with caution in patients with moderate hepatic impairment; prescriptions in patients with factors associated with an
dosage adjustment recommended in severe hepatic increased risk for overdose, such as history of overdose or
impairment. Use immediate-release injection with caution substance use disorder, higher opioid dosages (250 mor-
in patients with severe impairment. Subdermal implants phine milligram equivalents/day orally), and concomitant
should not be used in patients with preexisting moderate benzodiazepine use (Dowell [CDC 2016]). The misuse of
to severe hepatic impairment. Transdermal patch should buccal film by swallowing or of transdermal patch by
not be used in patients with severe hepatic impairment; placing it in the mouth, chewing it, swallowing it, or using
consider alternative therapy with more flexibility for dosing it in ways other than indicated may cause choking, over-
adjustments. Patients with preexisting moderate or severe dose, and death. Use with caution in patients with delirium
hepatic impairment are not candidates for the extended- tremens. Buccal film and transdermal patch are indicated
release injection. If moderate or severe impairment devel- for the management of pain severe enough to require
ops during treatment with the extended-release injection, daily, around-the-clock, long-term opioid treatment; should
continue with caution and monitor for toxicity for several not be used for as-needed pain relief. Therapy with the
months. buccal film or transdermal patch is not appropriate for use
in the management of addictions. Handle removed depots
Avoid use in patients with CNS depression or coma as
or implants with adequate security, accountability, and
these patients are susceptible to intracranial effects of
proper disposal, per facility procedure for a Schedule III
COz retention. Use with extreme caution in patients with
drug product, and per applicable federal, state, and local
head injury, intracranial lesions, or elevated intracranial
regulations. To properly dispose of transdermal patch, fold
pressure (ICP); exaggerated elevation of ICP may occur.
it over on itself and flush down the toilet; alternatively, seal
Buprenorphine can produce miosis and changes in the
the used patch in the provided Patch-Disposal Unit and
level of consciousness that may interfere with patient
dispose of in the trash. When used for chronic pain (out-
evaluation. May cause severe hypotension, including
side of end-of-life or palliative care, active cancer treat-
orthostatic hypotension and syncope; use with caution in
ment, sickle cell disease, or medication-assisted
patients with hypovolemia, cardiovascular disease (includ-
ing acute Ml), or drugs that may exaggerate hypotensive
treatment for opioid use disorder) in outpatient setting in
effects (including phenothiazines or general anesthetics). adults, opioids should not be used as first-line therapy for
Monitor for symptoms of hypotension following initiation or chronic pain management (pain >3-month duration or
dose titration. Avoid use in patients with circulatory shock. beyond time of normal tissue healing) due to limited
short-term benefits, undetermined long-term benefits,
May obscure diagnosis or clinical course of patients with
acute abdominal conditions. Use with caution in patients and association with serious risks (eg, overdose, MI, auto
with a history of ileus or bowel obstruction; buccal film, accidents, risk of developing opioid use disorder). Pre-
immediate-release injection, and transdermal patch are ferred management includes nonpharmacologic therapy
contraindicated in patients with known or suspected GI and nonopioid therapy (eg, NSAIDs, acetaminophen, cer-
obstruction, including paralytic ileus. Use with caution in tain anticonvulsants and antidepressants). If opioid ther-
patients with biliary tract dysfunction, including acute apy is initiated, it should be combined with
pancreatitis; may cause constriction of sphincter of Oddi. nonpharmacologic and nonopioid therapy, as appropriate.
Use with caution in patients with a history of seizure Prior to initiation, known risks of opioid therapy should be
disorders; may cause or exacerbate preexisting seizures. discussed and realistic treatment goals for pain/function
Use with caution in patients with adrenal insufficiency, should be established, including consideration for discon-
including Addison disease. Long-term opioid use may tinuation if benefits do not outweigh risks. Therapy should
cause adrenal insufficiency (nausea, vomiting, anorexia, be continued only if clinically meaningful improvement in
fatigue, weakness, dizziness and low blood pressure) or pain/function outweighs risks. Therapy should be initiated
secondary hypogonadism, which may lead to sexual at the lowest effective dosage using immediate-release
dysfunction, infertility, mood disorders, and osteoporosis opioids (instead of extended-release/long-acting opioids).
(Brennan 2013). Use with caution in patients with renal Risk associated with use increases with higher opioid
impairment, morbid obesity, toxic psychosis, thyroid dys- dosages. Risks and benefits should be re-evaluated when
function, or prostatic hyperplasia and/or urinary stricture. increasing dosage to 250 morphine milligram equivalents
Potentially significant drug-drug interactions may exist, (MME)/day orally; dosages 290 MME/day orally should be
requiring dose or frequency adjustment, additional mon- avoided unless carefully justified (Dowell [CDC 2016)).
itoring, and/or selection of alternative therapy. [US Boxed Buprenorphine has been observed to cause QTc prolon-
Warning]: Buccal film, extended-release and immedi- gation. Do not exceed a dose of 900 mcg every 12 hours
ate-release injection, transdermal patch: Concomitant buccal film or one 20 meg/hour transdermal patch. Avoid
use of benzodiazepines or other CNS depressants, using in patients with a personal or family history of long
including alcohol and opioids, may result in profound QT syndrome or in patients taking concurrent class IA or III
sedation, respiratory depression, coma, and death. antiarrhythmics or other medications that prolong the QT
Reserve concomitant prescribing of opioids and ben- interval. Use with caution in patients with hypokalemia,
zodiazepines or other CNS depressants for use in hypomagnesemia, or clinically unstable cardiac disease,
patients for whom alternative treatment options are including unstable heart failure, unstable atrial fibrillation,
inadequate. Limit dosages and durations to the mini- symptomatic bradycardia, or active MI. Avoid exposure of
mum required. Follow patients for signs and symp- transdermal patch application site and surrounding area to
toms of respiratory depression and sedation. direct external heat sources (eg, heating pads, electric
Prohibiting medication-assisted treatment of opioid use blankets, heat or tanning lamps, hot baths/saunas, hot
disorder may increase the risk of morbidity and mortality, water bottles, or direct sunlight). Buprenorphine release
therefore patients should be educated on the risks of from the patch is temperature-dependent and may result
concomitant use with benzodiazepines, sedatives, opioid in overdose. Patients who experience fever or increase in
analgesics, and alcohol. Strategies should be developed core temperature should be monitored closely and adjust
to manage use of prescribed or illicit benzodiazepines or dose if signs or respiratory depression or CNS depression
other CNS depressants at initiation of or during treatment
occur. Application-site reactions, including rare cases of
with buprenorphine; adjustments to induction procedures severe reactions (eg, vesicles, discharge, "burns"), have
and additional monitoring may be required. If appropriate,
been observed with transdermal patch use; onset varies
delay or omit buprenorphine dose if a patient is sedated at
from days to months after initiation; patients should be
time of buprenorphine dosing. Discontinuation of benzo-
instructed to report severe reactions promptly and discon-
diazepines or other CNS depressants is preferred; gradual
tinue therapy. Oral mucositis may result in more rapid
tapering of benzodiazepine or other CNS depressant,
absorption and higher buprenorphine plasma levels in
decreasing to lowest effective dose, or monitoring in a
patients using buccal film; reduce dose in patients with
higher level of care for taper may be appropriate. Benzo-
oral mucositis and monitor closely for signs and symptoms
diazepines are not the treatment of choice for anxiety or
of toxicity or overdose. [US Boxed Warning]: Prolonged
insomnia for patients in buprenorphine treatment; make
use during pregnancy can cause neonatal withdrawal
sure patients are appropriately diagnosed and consider
syndrome, which may be life-threatening if not recog-
alternative medications for anxiety and insomnia prior to
nized and treated according to according to protocols
co-administration of benzodiazepines and buprenorphine.
developed by neonatology experts. If opioid use is
[US Boxed Warning]: Use exposes patients and other required for a prolonged period in a pregnant woman,
users to the risks of addiction, abuse, and misuse, advise the patient of the risk of neonatal withdrawal
potentialiy leading to overdose and death. Assess syndrome and ensure that appropriate treatment will
each patient's risk before prescribing; monitor all be available. Signs and symptoms include irritability,
patients regularly for development of these behaviors hyperactivity and abnormal sleep pattern, high-pitched
or conditions. Use with caution in patients with a history cry, tremor, vomiting, diarrhea, and failure to gain weight.
of drug abuse or acute alcoholism; potential for drug Onset, duration, and severity depend on the drug used, >
313
 BUPRENORPHINE

4 duration of use, maternal dose, and rate of drug elimina-

tion by the newborn.
keloid formation, connective tissue disease
derma) or history of recurrent MRSA infections. Subder-
(ie, sclero-

mal implant is not appropriate for patients who are new to

Reversal of partial opioid agonists or mixed opioid agonist/
treatment or have not-sustained prolonged clinical sey.
antagonists (eg, buprenorphine, pentazocine) may be
on buprenorphine <8 mg/day.
incomplete and large doses of naloxone may be required.
Adverse Reactions
Concurrent use of opioid agonist/antagonist analgesics
Buccal film:
may precipitate withdrawal symptoms and/or reduced
Cardiovascular: Hypertension, peripheral edema
analgesic efficacy in patients following prolonged therapy
Central nervous system: Anxiety, depression, dizziness,
with mu opioid agonists. Abrupt discontinuation following
drowsiness, falling, fatigue, headache, insomnia, opioid
prolonged use may also lead to withdrawal symptoms and
withdrawal syndrome
is not recommended; taper dose gradually when discon-
Dermatologic: Hyperhidrosis, pruritus, skin rash
tinuing. Withdrawal signs and symptoms will be delayed in
Endocrine & metabolic: Hot flash
patients who discontinue the extended-release injection or
Gastrointestinal: Abdominal pain, constipation,
have it removed; transmucosal buprenorphine may be
decreased appetite, diarrhea, gastroenteritis, nausea,
needed to treat withdrawal in these patients.
vomiting, xerostomia
Tablets, which are used for induction treatment of opioid Genitourinary: Urinary tract infection
dependence, should not be started until objective and Hematologic & oncologic: Anemia, bruise
clear signs of moderate withdrawal are evident. If sub- Neuromuscular & skeletal: Back pain, muscle spasm
dermal implants are not immediately replaced in contrala- Respiratory: Bronchitis, nasopharyngitis, oropharyngeal
teral arm after removal, maintain patients on their previous pain, paranasal sinus congestion, sinusitis, upper res-
dosage of sublingual buprenorphine. piratory tract infection
Miscellaneous: Fever
[US Boxed Warning]: Serious harm or death could
Implant:
result if extended-release injection is administered
Cardiovascular: Chest pain,
IV. The injection forms a solid mass upon contact with
Central nervous system: Chills, depression, dizziness,
body fluids and may cause occlusion, local tissue
drowsiness, fatigue, headache, migraine, pain, pares-
damage, and thromboembolic events, including life-
thesia, sedation, sensation of cold
threatening pulmonary emboli if administered IV.
Dermatologic: Excoriation (including scratch), localized
Because of the risk of serious harm or death that
erythema (at implant site), skin lesion, skin rash
could result from IV self-administration, buprenor-
Gastrointestinal: Constipation, flatulence, nausea, tooth-
phine extended-release injection is only available
ache, upper abdominal pain, vomiting
through a restricted program called the Sublocade
Hematologic & oncologic: Local hemorrhage (at
REMS Program. Health care settings and pharmacies
implant site)
that order and dispense buprenorphine extended-
Local: Localized edema (at implant site), local pain (at
release injection must be certified in this program
implant site), local pruritus (at implant site), local
and comply with the REMS requirements. Administer
swelling
via subcutaneous route only. Do not administer IM or IV.
Neuromuscular & skeletal: Asthenia, back pain, limb pain
There is no maximum recommended duration for the use Respiratory: Cough, dyspnea, oropharyngeal pain
of buprenorphine sublingual tablets in the maintenance Miscellaneous: Fever, laceration
treatment of opioid addiction; patients may require treat- Injection:
ment indefinitely. Advise patients of the potential to Cardiovascular: Hypotension
relapse to illicit drug use following discontinuation of opioid Central nervous system: Dizziness, drowsiness, fatigue,
agonist/partial agonist medication-assisted treatment. If headache, sedation, vertigo
the extended-release injection is discontinued or the depot Dermatologic: Diaphoresis, injection site pruritus
is removed, monitor the patient for several months for Endocrine & metabolic: Increased gamma-glutamyl
signs and symptoms of withdrawal. After steady-state transferase
has been achieved (4 to 6 months), patients discontinuing Gastrointestinal: Constipation, nausea, vomiting
extended-release injections may have detectable plasma Hepatic: Increased serum alanine aminotransferase,
levels of buprenorphine for 12 months or longer. increased serum aspartate aminotransferase
Local: Bruising at injection site, erythema at injection
In patients undergoing elective surgery (excluding caesar-
site, induration at injection site, pain at injection site,
ean section), discontinuation of buprenorphine 24 to 36
swelling at injection site
hours before anticipated need for surgical anesthesia may
Neuromuscular & skeletal: Increased creatine phospho-
be considered. Short-acting opioids may be given during
kinase
and/or after surgery. In patients unable to abruptly dis-
Ophthalmic: Miosis
continue buprenorphine prior to surgery, full opioid ago-
Respiratory: Hypoventilation
nists may be added to the buprenorphine to maintain
Sublingual tablet:
proper anesthesia; however, increased doses may be
Central nervous system: Headache, insomnia
required to overcome buprenorphine receptor blockade.
Dermatologic: Diaphoresis
If opioid therapy is required as part of anesthesia, patients
Gastrointestinal: Abdominal pain, constipation, nausea,
should be continuously monitored in an anesthesia care
vomiting
setting by persons not involved in in the conduct of the
Infection: Infection
surgical or diagnostic procedure. This guidance applies to
Transdermal patch:
anyone who has been treated with extended release
Cardiovascular: Chest pain, hypertension, peripheral
buprenorphine injection within the past 6 months. The
edema
decision whether to discontinue buprenorphine prior to
Central nervous system: Anxiety, depression, dizziness,
elective surgery should be made in consultation with the
drowsiness, falling, fatigue, headache, hypoesthesia,
surgeon and anesthesiologist (Kampman [ASAM 2015)).
insomnia, migraine, pain, paresthesia
[US Boxed Warning]: Insertion and removal of implant Dermatologic: Hyperhidrosis, pruritus, skin rash
are associated with the risk of implant migration, Gastrointestinal: Anorexia, constipation, diarrhea, dys-
protrusion, and expulsion. Rare but serious compli- pepsia, nausea, stomach discomfort, upper abdominal
cations including nerve damage and migration result- pain, vomiting, xerostomia
ing in embolism and death may result from improper Genitourinary: Urinary tract infection
insertion in the upper arm. Additional complications Infection: Influenza
may include local migration, protrusion, and expul- Local: Application site erythema, application site irrita-
sion. Incomplete insertions or infections may lead to tion, application site pruritus, application site rash
protrusion or expulsion. Because of the risks associ- Neuromuscular & skeletal: Arthralgia, asthenia, back
ated with insertion and removal, buprenorphine pain, joint swelling, limb pain, muscle spasm, muscu-
implant is available only through a restricted program. loskeletal pain, myalgia, neck pain, tremor
All health care providers must successfully complete Respiratory: Bronchitis, cough, dyspnea, nasopharyngi-
a live training program on the insertion and removal tis, pharyngolaryngeal pain, sinusitis, upper respiratory
procedures and become certified, prior to performing tract infection
insertions or prescribing buprenorphine implants. Miscellaneous: Fever
Patients must be monitored to ensure that the implant Rare but important or life-threatening: Abdominal dis-
is removed by a health care provider certified to comfort, abnormal dreams, abnormal hepatic function
perform insertions. Infection may occur at site of inser- tests, acute sinusitis, amblyopia, anaphylactic shock,
tion or removal, with excessive palpation shortly after angina pectoris, apnea, application site dermatitis,
insertion and improper removal increasing the risk. Exam- bradycardia, cellulitis, coma, constipation, contact der-
ine the insertion site one week following insertion for signs matitis, cough, cyanosis, decreased appetite,
of infection or problems with wound healing. Use sub- decreased serum testosterone, depression, diplopia,
dermal implants with caution in patients with a history of diverticulitis, dyspepsia, dysphoria, dyspnea,

314
 BUPRENORPHINE

exacerbation of asthma, excoriation, fatigue, hallucina- Pharmacodynamics/Kinetics (Adult data unless

tion, hepatic encephalopathy, hepatic failure, hepatic noted)
necrosis, hepatitis (including cytolytic), hepatorenal Onset of action: Analgesic: Immediate-release IM: 215
syndrome, hypersensitivity reaction, hypertension, minutes
hyperventilation, hypoesthesia, hypogonadism Peak effect: Immediate-release IM: ~1 hour
(Brennan 2013; Debono 2011), hypotension, hypoven- Duration: Immediate-release IM: 26 hours; Extended-
tilation, increased serum ALT, increased serum AST, release SubQ: 28 days
injection site reaction, intestinal obstruction, jaundice, Absorption: Immediate-release IM and SubQ: 30% to
laceration, loss of consciousness, memory impairment, 40%. Application of a heating pad onto the transdermal
mental deficiency, mental status changes, migraine, system may increase blood concentrations of buprenor-
miosis, musculoskeletal pain, nasal congestion, neck phine 26% to 55%. Ingestion of liquids decreases sys-
- pain, orthostatic hypotension, paresthesia, prolonged temic exposure to buprenorphine from buccal film by
Q-T interval on ECG, psychosis, respiratory distress, 23% to 37%.
rhinorrhea, seizure, skin rash, slurred speech, syn- Distribution: CSF concentrations are ~15% to 25% of
cope, tachycardia, tooth abscess, toothache, tremor, plasma concentrations
urinary incontinence, urinary retention, vasodilatation, Vai
visual disturbance, weakness, Wenckebach period on Premature neonates (GA: 27 to 32 weeks): 6.2 + 2.1 L/
ECG, withdrawal syndrome kg (Barrett 1993)
Drug Interactions Children 4 to 7 years: 3.2 + 2 L/kg (Olkkola 1989)
Metabolism/Transport Effects Substrate of CYP3A4 Adults: 97 to 187 L/kg
(major); Note: Assignment of Major/Minor substrate sta- Protein binding: High (~96%, primarily to alpha- and beta
tus based on clinically relevant drug interaction potential globulin)
Avoid Concomitant Use Metabolism: Primarily hepatic via N-dealkylation by
Avoid concomitant use of Buprenorphine with any of the CYP3A4 to norbuprenorphine (active metabolite), and
following: Atazanavir; Azelastine (Nasal); Bromperidol; to a lesser extent via glucuronidation by UGT1A1 and
Conivaptan; Eluxadoline; Fusidic Acid (Systemic); Idela- 2B7 to buprenorphine 3-O-glucuronide; the major metab-
lisib; Monoamine Oxidase Inhibitors; Opioid Analgesics; olite, norbuprenorphine, also undergoes glucuronidation
Opioids (Mixed Agonist / Antagonist); Orphenadrine; via UGT1A3; extensive first-pass effect
Oxomemazine; Paraldehyde; Thalidomide Bioavailability (relative to IV administration): Buccal film:
Increased Effect/Toxicity 46% to 65%; Immediate-release IM: 70%; Sublingual
Buprenorphine may increase the levels/effects of: Alvi- tablet: 29%; Transdermal patch: ~15%
mopan; Azelastine (Nasal); Blonanserin; Desmopressin; Half-life elimination:
Diuretics; Eluxadoline; Flunitrazepam; Methotrimepra- Premature neonates (GA: 27 to 32 weeks): Immediate-
zine; MetyroSINE; Monoamine Oxidase Inhibitors; release IV: 20 + 8 hours (Barrett 1993)
Orphenadrine; Paraldehyde; Piribedil; Pramipexole; Children 4 to 7 years: Immediate-release IV: ~1 hour
QTc-Prolonging Agents (Highest Risk); Ramosetron; (Olkkola 1989)
ROPINIRole; Rotigotine; Selective Serotonin Reuptake Adults: IV: 2.2 to 3 hours; Buccal film: 27.6 + 11.2 hours;
Inhibitors; Serotonin Modulators; Suvorexant; Thalido- Apparent terminal half-life: Sublingual tablet: ~37
mide; Zolpidem hours; Transdermal patch: ~26 hours. Note: Extended
elimination half-life for sublingual administration may
The levels/effects of Buprenorphine may be increased
be due to depot effect (Kuhlman 1996).
by: Alcohol (Ethyl); Amphetamines; Anticholinergic
Time to peak, plasma: Buccal film: 2.5 to 3 hours;
Agents; Aprepitant; Atazanavir; Boceprevir; Brimonidine
Extended-release SubQ: 24 hours, with steady state
(Topical); Bromopride; Bromperidol; Cannabis; Ceritinib;
achieved after 4 to 6 months; Subdermal implant: 12
Chlormethiazole; Chlorphenesin Carbamate; CNS
hours after insertion, with steady state achieved by week
Depressants; Cobicistat; Conivaptan; CYP3A4 Inhibitors
4; Sublingual: 30 minutes to 1 hour (Kuhlman 1996);
(Moderate); CYP3A4 Inhibitors (Strong); Daclatasvir;
Transdermal patch: Steady state achieved by day 3
Dimethindene (Topical); Dronabinol; Droperidol; Fosap-
Excretion: Feces (~70%; 33% as unchanged drug; 5% as
repitant; Fosnetupitant; Fusidic Acid (Systemic); Idelali-
conjugated drug; 21% as norbuprenorphine; and 2% as
sib; Kava Kava; Lofexidine; Magnesium Sulfate;
conjugated norbuprenorphine); urine (27% to 30%; 1%
Methotrimeprazine; MiFEPRIStone; Minocycline; Nabi-
as unchanged drug; 9.4% as conjugated drug; 2.7% as
lone; Netupitant; Ombitasvir, Paritaprevir, and Ritonavir;
norbuprenorphine; and 11% as conjugated norbuprenor-
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir; Oxo-
phine)
memazine; Palbociclib; Perampanel; Rufinamide; Sime-
Clearance: Related to hepatic blood flow
previr; Sodium Oxybate; Stiripentol; Succinylcholine;
Premature neonates (GA: 27 to 32 weeks): 0.23 + 0.07
Tetrahydrocannabinol
L/hour/kg (Barrett 1993)
Decreased Effect Children 4 to 7 years: 3.6 + 1.1 L/hour/kg (Olk-
Buprenorphine may decrease the levels/effects of: Ata- kola 1989)
zanavir; Diuretics; Gastrointestinal Agents (Prokinetic); Adults: 0.78 to 1.32 L/hour/kg
Opioid Analgesics; Pegvisomant
Pharmacodynamics/Kinetics: Additional Consider-
The levels/effects of Buprenorphine may be decreased ations
by: Boceprevir; Bosentan; CYP3A4 Inducers (Moderate); Hepatic function impairment: Because buprenorphine is
CYP3A4 Inducers (Strong); Dabrafenib; Deferasirox; extensively metabolized, plasma levels and half-life were
Efavirenz; Enzalutamide; Etravirine; Mitotane; Nalme- increased in patients with moderate and severe hepatic
fene; Naltrexone; Opioids (Mixed Agonist / Antagonist); impairment.
Pitolisant; Sarilumab; Siltuximab; St John's Wort; Tocili- Geriatric: The pharmacokinetics are similar between
zumab younger adults and elderly, although elderly patients
Storage/Stability showed a trend toward higher plasma concentrations
Extended-release injection: Store refrigerated at 2°C to immediately after transdermal system removal.
8°C (36°F to 46°F). Discard if left at room temperature Dosing
(15°C to 30°C [59°F to 86°F]) for more than 7 days. Neonatal Neonatal abstinence syndrome (NAS)
Immediate-release injection: Store at 20°C to 25°C (68°F (opioid exposure): Limited data available; dosing regi-
to 77°F); excursions permitted between 15°C to 30°C mens variable (Hall 2016; Kraft 2008; Kraft 2017): Full-
(59°F to 86°F). Protect from prolonged exposure to light. term neonates: Sublingual solution (0.075 mg/mL): Ini-
Buccal film, transdermal patch, sublingual tablet: Store at tial: 5.3 mcg/kg/dose every 8 hours; dosing based on
25°C (77°F); excursions permitted between 15°C to birth weight; may increase dose in 25% increments
30°C (59°F to 86°F). based on targeted NAS scores; a rescue dose of 50%
Subdermal implant: Store at 20°C to 25°C (68°F to 77°F); of the previous dose may be used for inadequate control
excursions permitted between 15°C to 30°C (59°F between scheduled doses; once a maximum daily dose
to 86°F). of 60 mcg/kg/day reached, phenobarbital therapy may
Mechanism of Action Buprenorphine exerts its analgesic be added. After 2 days of symptom stability, buprenor-
effect via high-affinity binding to mu opiate receptors in the phine may be weaned based on NAS scores using 10%
CNS; displays partial! mu agonist and weak kappa antag- daily dose reductions. Dosing based on a randomized,
onist activity. Due to it being a partial mu agonist, its blinded, comparative trial with morphine (n=63 [bupre-
analgesic effects plateau at higher doses and it then norphine group: n=33]); in the clinical trial, doses were
behaves like an antagonist. The extended-release formu- increased if a single NAS score was 212 or NAS scale
lation is injected subcutaneously as a liquid; subsequent scores 224 total on 3 measures; results showed a
precipitation following injection results in a solid depot significant decrease in length of NAS treatment and
which will gradually release BEDreCOnp rie via diffusion hospital stay compared to morphine treatment arm (Kraft
and biodegradation of the depot. 2017).

315
 BUPRENORPHINE

q Pediatric when objective and clear signs of moderate opioid

Acute pain (moderate to severe): Dose should be withdrawal appear, and not less than 4 hours after
titrated to appropriate effect; buprenorphine has an last use of heroin or other short-acting opioids or
analgesic ceiling in adults. The following recommenda- not less than 24 hours after last use of methadone
tions are guidelines and do not represent the maximum or other long-acting opioids. Titrating dose to:clin-
doses that may be required in all patients. ical effectiveness should be done as rapidly as
Children 2 to 12 years: IM, slow IV injection: Initial: possible to prevent undue withdrawal symptoms
Opioid-naive: 2 to 6 mcg/kg/dose every 4 to 6 hours and patient drop-out during the induction period.
(APS 2016); Note: Not all children have faster clear- Maintenance: Target dose: 16 mg/day; reported
ance rates than adults; some children may require range: 4 to 24 mg/day; doses higher than
dosing intervals of every 6 to 8 hours; observe clinical 24 mg/day have not been demonstrated to provide
effects to establish the proper dosing interval. any clinical advantage; patients should be
Adolescents: IM, slow IV injection: Initial: Opioid-naive: switched to the buprenorphine/naloxone combina-
0.3 mg every 6 to 8 hours as needed; initial dose may tion product for maintenance and unsupervised
be repeated once in 30 to 60 minutes if clinically therapy
needed *. Subdermal implant: Adolescents 216 years: Insert 4
Chronic pain (moderate to severe): Adolescents 218 implants subdermally in the inner side of the upper
years: Transdermal patch: arm. Remove no later than 6 months after the date of
Opioid-naive patients: Initial: 5 meg/hour applied once insertion; if continued treatment is desired, insert 4
every 7 days new implants subdermally in the inner side of the
Opioid-experienced patients (conversion from other contralateral arm. After 1 insertion in each arm, dis-
opioids to buprenorphine patch): Discontinue all_other continue treatment with subdermal implants.
around-the-clock opioid drugs when buprenorphine To convert back to sublingual tablet: On day of implant
therapy is initiated. Short-acting analgesics as removal, resume buprenorphine treatment at pre-
needed may be continued until analgesia with trans- vious sublingual dose
dermal buprenorphine is attained. There is a potential Renal Impairment: Pediatric There are no dosage
for buprenorphine to precipitate withdrawal in patients adjustments provided in manufacturer's labeling (has
already receiving opioids. not been studied); use with caution. In pharmacokinetic
Patients who were receiving daily dose of <30 mg of studies, renal impairment (including administration pre-
oral morphine equivalents: \nitial: 5 meg/hour or posthemodialysis) was not associated with increased
applied once every 7 days buprenorphine plasma concentrations.
Patients who were receiving daily dose of 30 to 80 mg Hepatic Impairment: Pediatric
of oral morphine equivalents: Taper the current Injection (immediate release): Children 22 years and
around-the-clock opioid for up to 7 days to Adolescents: Use caution due to extensive hepatic
<30 mg/day of oral morphine or equivalent before metabolism; dosage adjustments may be necessary.
initiating therapy. Initial: 10 meg/hour applied once Subdermal implant: Adolescents 216 years:
every 7 days. Mild impairment: There are no dosage adjustments
Patients who were receiving daily dose of >80 mg of provided in the manufacturer's labeling (has not been
oral morphine equivalents: Buprenorphine transder- studied).
mal patch, even at the maximum dose of 20 mcg/ Moderate or severe impairment: Use is not recom-
hour applied once every 7 days, may not provide mended.
adequate analgesia; consider the use of an alternate Administration
analgesic. Oral:
Dose titration (opioid-naive or opioid-experienced Buccal: Adults: Prior to placing the film, moisten inside of
patients): May increase dose in 5 mcg/hour, 7.5 cheek with tongue or water. Apply film with a dry finger
meg/hour, or 10 meg/hour increments (using no more immediately after removing it from packaging. Place
than two 5 meg/hour patches); titrate no more fre- yellow side of film against the inside of the moistened
quently than every 72 hours; maximum dose: 20 mcg/ cheek; press and hold the film in place for 5 seconds
hour applied once every 7 days due to risk of QTc with finger (film should stay in place after this period).
prolongation associated with higher doses. Keep film in place until it dissolves completely (usually
Discontinuation of therapy: Taper dose gradually every within 30 minutes of application). Do not chew, swallow,
7 days to prevent withdrawal in the physically depend- touch, or move film after placement. Avoid eating or
ent patient; consider initiating immediate-release drinking until film dissolves. Do not cut or tear the film.
opioids, if needed for signs and symptoms of with- Avoid application to areas of the mouth with any open
drawal. sores or lesions. To dispose of film; remove foil over-
Opioid dependence: Note: Do not start induction with wrap from any unused, unneeded films and dispose by
buprenorphine until objective and clear signs of with- flushing down the toilet.
drawal are apparent (otherwise withdrawal may be Sublingual solution: Neonates: Place dose under tongue;
precipitated). insert pacifier to help reduce swallowing of dose (Kraft
Sublingual tablet: Note: The combination product, 2008; Kraft 2011; Kraft 2017)
buprenorphine and naloxone, is preferred therapy Sublingual tablet: Adolescents 216 years and Adults:
over buprenorphine monotherapy for induction treat- Place tablet under the tongue until dissolved; do not
ment (and stabilization/maintenance treatment) for chew or swallow (swallowing tablets before dissolved
short-acting opioid dependence (US Department of reduces bioavailability). If 2 or more tablets are needed
Health and Human Services 2005) per dose, all tablets may be placed under the tongue at
American Society of Addiction Medicine Guidelines once, or 2 tablets may be placed under the tongue at a
(Kampman [ASAM 2015]): Limited data available: time; to ensure consistent bioavailability, subsequent
Adolescents: Sublingual tablet: doses should always be taken the same way.
Note: Buprenorphine treatment initiation should Parenteral:
begin after mild to moderate opioid withdrawal Immediate-release injection: Children 22 years, Adoles-
signs appear (to avoid precipitated withdrawal), cents, and Adults:
which is generally at least 6 to 12 hours after last IM: Administer via deep IM injection
use of short-acting opioids (eg, heroin, oxycodone) IV: Administer slowly, over at least 2 minutes
and 24 to 72 hours after last use of long-acting Extended-release injection: Adults: For insertion by
opioids (methadone). health care providers trained in the injection technique
Induction: Initial: 2 to 4 mg; if no signs of precipitated and certified through the REMS program. Administer
withdrawal after 60 to 90 minutes, may increase in extended-release injection as an abdominal subcuta-
increments of 2 to 4 mg. Once initial dose is neous injection only, using only the syringe and safety
tolerated, may increase to a dose that is clinically needle included with product. Do not administer IV or
effective and provides 24 hours of stabilization. IM. Inject between the transpyloric and transtubercular
After induction and titration, daily dose usually planes in an area with adequate subcutaneous tissue
28 mg/day are necessary. In patients continuing that is free of skin conditions (eg, nodules, lesions,
to use opioids, consider increasing the dose by 4 excessive pigment). Rotate the injection site between
to 8 mg to a daily dose of 212 to 16 mg/day. injections. Subsequent precipitation following injection
Maximum daily dose 24 mg/day. results in a solid depot which will gradually release
Manufacturer's labeling: Adolescents 216 years: buprenorphine. The patient may have a lump for sev-
Induction: Day 1: 8 mg/day divided in 2 to 4 mg eral weeks that will decrease over time; advise patient
increments; day 2 and subsequent induction days not to rub or massage the injection site. In the event the
dose dependent upon patient response. In 1 study, depot from an extended-release injection must be
patients received 8 mg on day 1, followed by removed, it can be surgically excised under local anes-
16 mg on day 2; induction usually accomplished thesia within 14 days of injection. See prescribing
over 3 to 4 days. Treatment should begin only information for details.

316
 BUPRENORPHINE AND NALOXONE

Subdermal/Topical: under refrigeration and at room temperature for 30 days

Subdermal implant: Adolescents 216 years: For insertion when stored in amber glass bottles and for 7 days when
under local anesthesia by health care providers trained stored in oral syringes (Anagnostis 2011; Anagnostis
in the insertion and removal procedure through the 2013).
REMS program. See prescribing information for details. Anagnostis EA, Sadaka RE, Sailor LA, et al, “Formulation of Bupre-
Transdermal patch: Adolescents 218 years and Adults: norphine for Sublingual Use in Neonates," J Pediatr Pharmacol Ther,
2011, 16(4):281-4.
Apply patch to intact, nonirritated skin only. Apply to a
Anagnostis EA, personal communication, March 2013.
hairless or nearly hairless skin site. If hairless site is not
available, do not shave skin (as absorption from patch
can be increased); hair at application site should be Buprenorphine and Naloxone
clipped. Prior to application, if the site must be cleaned, (byoo pre NOR feen & nal OKS one)
- clean with clear water and allow to dry completely; do
not use soaps, alcohol, lotions, or abrasives due to
Medication Safety Issues
potential for increased skin absorption. Do not use High alert medication:
any patch that has been damaged, cut, or manipulated The Institute for Safe Medication Practices (ISMP)
in any way. Remove patch from protective pouch includes this medication among its list of drug classes
immediately before application. Remove the protective which have a heightened risk of causing significant
backing and apply the sticky side of the patch to 1 of 8 patient harm when used in error.
possible application sites (upper outer arm, upper Other safety concerns:
chest, upper back, or the side of the chest [each site Potential for over- or underdosing when switching among
on either side of the body]). Up to 2 patches may be various formulations and between strengths of the
applied at the same time adjacent to one another at the sublingual films: Not all strengths of sublingual tab-
same application site. Firmly press patch in place and lets and films are bioequivalent to one another. In
hold for ~15 seconds. Change patch every 7 days. addition, systemic exposure between the various
Rotate patch application sites whenever a patch is strengths of sublingual films may be different; pharma-
replaced or added; wait 221 days before reapplying cists should not substitute one or more film strengths
another patch to the same skin site. Avoid exposing for another (eg, dispense three 4 mg films for one
application site to external heat sources (eg, heating 12 mg film, or vice-versa) without physician approval.
pad, electric blanket, heat lamp, hot tub). Incidental Any patient switching between sublingual tablet and
exposure to water while bathing or showering is accept- sublingual film formulation or between one or more
able based on experience during clinical studies. If strengths of the sublingual films should be monitored
there is difficulty with patch adhesion, the edges of for over- or underdosing.
the system may be taped in place with first-aid tape. Related Information
If the patch falls off during the 7-day dosing interval, Oral Medications That Should Not Be Crushed or Altered
dispose of the patch and apply a new patch to a on page 2217
different skin site. Dispose of patches using the Brand Names: US Bunavail; Suboxone; Zubsolv
Patch-Disposal Unit or by folding the adhesive sides Brand Names: Canada Suboxone
of the patch together and then flushing down the toilet. Therapeutic Category Analgesic, Narcotic; Opioid Par-
Monitoring Parameters Pain relief, respiratory rate, tial Agonist
mental status, blood pressure; liver enzymes (baseline Generic Availability (US) Yes: Sublingual tablet
and periodic), symptoms of withdrawal, CNS depression, Use Maintenance treatment of opioid dependence as part
application site reactions (transdermal patch) of a complete plan that includes counseling and psycho-
Chronic pain (long-term therapy outside of end-of-life or social support (Sublingual tablet: FDA approved in ages
216 years and adults; Sublingual film: FDA approved in
palliative care, active cancer treatment, sickle cell dis-
ease, or medication-assisted treatment for opioid use adults)
disorder): Evaluate benefits/risks of opioid therapy within Prescribing and Access Restrictions In the US pre-
1 to 4 weeks of treatment initiation and with dose scribing of tablets for opioid dependence is limited to
increases. Re-evaluate benefits/risks every 3 months dur- physicians who have met the qualification criteria and
ing therapy or more frequently in patients at increased risk have received a DEA number specific to prescribing this
of overdose or opioid use disorder. Urine drug testing is product. Tablets will be available through pharmacies and
recommended prior to initiation and with consideration for wholesalers which normally provide controlled substan-
re-checking at least yearly (includes controlled prescrip- ces.
tion medications and illicit drugs of abuse). State prescrip- Medication Guide Available Yes
tion drug monitoring program (PDMP) data should be Pregnancy Considerations Neonatal opioid withdrawal
reviewed by clinicians prior to initiation and periodically syndrome may occur after chronic maternal exposure to
during therapy (frequency ranging from every prescription opioids. In the treatment of addiction involving opioid use
to every 3 months) (Dowell [CDC 2016)]). in pregnant women, the buprenorphine/naloxone combi-
Controlled Substance C-lll —. --—-~ Sete nation product is not recommended for use (insufficient
Dosage Forms Considerations Note: Subdermal evidence); however, the buprenorphine monoproduct is a
implant and subcutaneous implant both refer to Probu- reasonable and recommended option for use (Kampman
phine. [ASAM 2015]). Women who become pregnant while on
Dosage Forms Excipient information presented when this combination should generally be transitioned to the
available (limited, particularly for generics); consult spe- single agent (buprenorphine) product (ACOG 2012). See
cific product labeling. [DSC] = Discontinued product individual agents.
Film, Buccal: Breastfeeding Considerations
Belbuca: 75 mcg (60 ea); 150 mcg (60 ea); 300 meg (60 Buprenorphine and its active metabolite, norbuprenor-
ea); 450 mcg (60 ea); 600 mcg (60 ea); 750 mcg (1 ea, phine, are present in breast milk. It is not known if
60 ea); 900 mcg (60 ea) [contains methylparaben, naloxone is present in breast milk; however, systemic
propylparaben, saccharin sodium, sodium benzoate; absorption following oral administration is low (Smith
peppermint flavor] 2012) and any exposure of naloxone to a breastfed
Implant, Subcutaneous: infant would therefore be limited.
Probuphine Implant Kit: 74.2 mg (4 ea) In general, breastfeeding is not recommended by the
Patch Weekly, Transdermal: manufacturers of buprenorphine-containing products;
Butrans: 5 meg/hr (4 ea); 7.5 meg/hr (4 ea); 10 meg/hr (4 the manufacturers of Zubsolv, Suboxone, and Bunavail
ea); 15 mceg/hr (4 ea); 20 mcg/hr (4 ea) recommend that caution be exercised when administer-
Generic: 5 mcg/hr (1 ea [DSC], 4 ea); 7.5 mcg/hr (4ea); ing this specific combination product to breastfeeding
10 meg/hr (1 ea [DSC], 4 ea); 15 mcg/hr (1 ea [DSC], 4 women. According to the manufacturer, the decision to
ea); 20 mcg/hr (1 ea [DSC], 4 ea) continue or discontinue breastfeeding during therapy
Solution, Injection: should take into account the risk of infant exposure,
Buprenex: 0.3 mg/mL (1 mL) the benefits of breastfeeding to the infant, and benefits
Generic: 0.3 mg/mL (1 mL) of treatment to the mother. See individual agents.
Solution Prefilled Syringe, Subcutaneous: Contraindications
Sublocade: 100 mg/0.5 mL (0.5 mL); 300 mg/1.5 mL Hypersensitivity (eg, anaphylactic shock) to buprenor-
(1.5 mL) phine, naloxone, or any component of the formulation.
Tablet Sublingual, Sdblingual: Documentation of allergenic cross-reactivity for opioids is
Generic: 2 mg, 8\mg limited. However, because of similarities in chemical
Extemporaneous Preparations A 0:075 mg/mL solu- structure and/or pharmacologic actions, the possibility
tion can be made using the 0.3 mg/mL injection, 95% of cross-sensitivity cannot be ruled out with certainty.
ethanol, and simple syrup. Add 1.26 mL of 95% ethanol Canadian labeling (sublingual tablets): Additional contra-
to 0.3 mg buprenorphine obtained from an 0.3 mg/1 mL indications (not in US labeling): Opioid-naive patients;
ampule, mix well, and add quantity of simple syrup severe respiratory insufficiency; severe hepatic impair-
sufficient to obtain 4 mL (final volume). Solution is stable ment; acute alcoholism, delirium tremens, or convulsive
BUPRENORPHINE AND NALOXONE

disorders; known or suspected mechanical GI obstruc- and alcohol. Strategies should be developed to manage
tion or diseases/conditions that affect bowel transit; use of prescribed or illicit benzodiazepines or other CNS
suspected surgical abdomen (eg, acute appendicitis or depressants at initiation of or during treatment with bupre-
pancreatitis); severe CNS depression, increased cere- norphine; adjustments to induction procedures and addi-
brospinal or intracranial pressure, or head injury; con- tional monitoring may be required. If appropriate, delay or
current use or within 2 weeks of MAO inhibitors. omit buprenorphine dose if a patient is sedated at time of
Warnings/Precautions May cause CNS depression, buprenorphine dosing. Discontinuation of benzodiaze-
which may impair physical or mental abilities; patients pines or other CNS depressants is preferred; gradual
must be cautioned about performing tasks that require tapering of benzodiazepine or other CNS depressant,
mental alertness (eg, operating machinery, driving). Hep- decreasing to lowest effective dose, or monitoring in a
atitis has been reported; hepatic events ranged from higher level of care for taper may be appropriate. Benzo-
transient, asymptomatic transaminase elevations to hep- diazepines are not the treatment of choice for anxiety or
atic failure; in many cases, patients had preexisting hep- insomnia for patients in buprenorphine treatment; make
atic impairment. Monitor liver function tests in patients at sure patients are appropriately diagnosed and consider
increased risk for hepatotoxicity (eg, history of alcohol alternative medications for anxiety and insomnia prior to
abuse, preexisting hepatic dysfunction, IV drug abusers) coadministration of benzodiazepines and buprenorphine.
prior to and during therapy. Hypersensitivity, including
bronchospasm, angioneurotic edema, and anaphylactic Prolonged use of opioids during pregnancy can cause
shock, have been reported. May cause severe hypoten- neonatal opioid withdrawal syndrome, which may be life-
sion, including orthostatic hypotension and syncope; use threatening if not recognized and treated according to
with caution in patients with hypovolemia, cardiovascular protocols developed by neonatology experts. If opioid
disease (including acute MI), or drugs that may exagger- use is required for a prolonged period in a pregnant
ate hypotensive effects (including phenothiazines or gen- woman, advise the patient of the risk of neonatal with-
eral anesthetics). Monitor for symptoms of hypotension drawal syndrome and ensure that appropriate treatment
following initiation or dose titration. Use with caution in will be available. Signs and symptoms include irritability,
patients with circulatory shock. Serious, life-threatening, hyperactivity and abnormal sleep pattern, high-pitched cry,
or fatal respiratory depression may occur. Monitor closely tremor, vomiting, diarrhea, and failure to gain weight.
for respiratory depression, especially during initiation or Onset, duration, and severity depend on the drug used,
dose escalation. Misuse by self-injection of buprenorphine duration of use, maternal dose, and rate of drug elimina-
or the concomitant use of buprenorphine and benzodia- tion by the newborn.
zepines (or other CNS depressants, including alcohol)
may result in coma or death. Carbon dioxide retention Dispose of unused subcutaneous and buccal films as long
from opioid-induced respiratory depression can exacer- as they are no longer needed by removing from foil patch
bate the sedating effects of opioids. Use with caution in and flushing down the toilet. If multiple films are no longer
patients with compromised respiratory function (eg, needed, flush each film individually. Use exposes patients
chronic obstructive pulmonary disease, cor pulmonale, and other users to the risks of addiction, abuse, and
decreased respiratory reserve, hypoxia, hypercapnia, or misuse, potentially leading to overdose and death. Assess
preexisting respiratory depression). each patient's risk prior to prescribing; monitor all patients
regularly for development of these behaviors or condi-
May obscure diagnosis or clinical course of patients with tions. Use with caution in patients with a history of drug
acute abdominal conditions. Use with caution in patients abuse or acute alcoholism; potential for drug dependency
with adrenal insufficiency, including Addison disease. exists. Other factors associated with an increased risk for
Long-term opioid use may cause secondary hypogonad-
misuse include younger age and psychotropic medication
ism, which may lead to sexual dysfunction, infertility, mood
use. Consider offering naloxone prescriptions in patients
disorders, and osteoporosis (Brennan 2013). Use with
with factors associated with an increased risk for over-
caution in patients with a history of ileus or bowel obstruc-
dose, such as history of overdose or substance use
tion, delirium tremens, prostatic hyperplasia and/or urinary
disorder, higher opioid dosages (250 morphine milligram
stricture, toxic psychosis, and thyroid dysfunction. Use
equivalents/day orally), and concomitant benzodiazepine
with caution in patients with biliary tract dysfunction,
use (Dowell [CDC 2016]). Buprenorphine/naloxone is not
including acute pancreatitis; may cause constriction of
appropriate for pain management; deaths have been
sphincter of Oddi. Use with caution in patients with
reported in opioid-naive patients receiving oral buprenor-
impaired consciousness or coma because these patients
are susceptible to intracranial effects of CO, retention. phine for analgesia. There is no maximum recommended
Use with extreme caution in patients with head injury, duration for maintenance treatment of opioid addiction;
intracranial lesions, or elevated intracranial pressure; patients may require treatment indefinitely. Advise patients
exaggerated elevation of ICP may occur. Can produce of the potential to relapse to illicit drug use following
miosis and changes in the level of consciousness that may discontinuation of opioid agonist/partial agonist medica-
interfere with patient evaluation. Use is not recommended tion-assisted treatment. Concurrent use of opioid agonist/
in patients with moderate hepatic impairment for induction antagonist analgesics may precipitate withdrawal symp-
therapy (Suboxone) or in patients with severe hepatic toms and/or reduced analgesic efficacy in patients follow-
impairment. Use with caution in patients with moderate ing prolonged therapy with mu opioid agonists. Abrupt
hepatic impairment for maintenance treatment; due to discontinuation following prolonged use may also lead to
reduced clearance of naloxone and potential for reduced withdrawal symptoms and is not recommended; taper
buprenorphine efficacy, use may not be appropriate. Use dose gradually when discontinuing. Treatment of opioid
with caution in patients who are morbidly obese (DeVido dependence with buprenorphine/naloxone should not be
2015). Use with caution and titrate dosage cautiously in started until effects of withdrawal are evident. Reversal of
patients with risk factors for sleep-disordered breathing, partial opioid agonists or mixed opioid agonist/antagonists
including HF and obesity (Cheatle 2015, DeVido 2015). (eg, buprenorphine, pentazocine) may be incomplete and
Use with caution and monitor for respiratory depression in large doses of naloxone may be required. When using
patients with significant chronic obstructive pulmonary buprenorphine for treatment of opioid dependence, treat
disease, cor pulmonale or kyphoscoliosis, and those with acute pain with nonopioid analgesics whenever possible.
a substantially decreased respiratory reserve, hypoxia, If treatment with a high-affinity full opioid analgesic is
hypercapnia, or preexisting respiratory depression, partic- required, monitor closely for respiratory depression, as
ularly when initiating or titrating therapy; critical respiratory high doses may be necessary to achieve pain relief.
depression may occur, even at therapeutic dosages. Use Adverse Reactions Also see individual agents.
with caution in cachectic or debilitated patients; there is a Cardiovascular: Palpitations (sublingual film), vasodila-
greater potential for critical respiratory depression, even at tation
therapeutic dosages. Use with caution in elderly patients; Central nervous system: Anxiety, disturbance in attention
may be more sensitive to adverse effects (eg, life-threat- (sublingual film), headache, insomnia, intoxicated feeling
ening respiratory depression). Use with caution in patients (sublingual film), irritability, pain, restlessness, with-
with a history of seizure disorders; may cause or exacer- drawal syndrome
bate preexisting seizures. Dermatologic: Diaphoresis, piloerection
Potentially significant interactions may exist, requiring Gastrointestinal: Abdominal pain, constipation, glossalgia
dose or frequency adjustment, additional monitoring, (sublingual film), oral hypoesthesia (sublingual film),
and/or selection of alternative therapy. Concomitant use nausea (sublingual tablet), oral mucosa erythema (sub-
of benzodiazepines or other CNS depressants, including lingual film), stomach discomfort, vomiting
alcohol and opioids, may result in profound sedation, Neuromuscular & skeletal: Arthralgia
respiratory depression, coma, and death. Prohibiting med- Ophthalmic: Blurred vision (sublingual film), increased
ication-assisted treatment of opioid use disorder may lacrimation
increase the risk of morbidity and mortality, therefore Respiratory: Rhinorrhea
patients should be educated on the risks of concomitant Rare but important or life-threatening: Glossitis, oral bul-
use with benzodiazepines, sedatives, opioid analgesics, lae, oral mucosa ulcer, peripheral edema, stomatitis

318
 BUPRENORPHINE AND NALOXONE

Drug Interactions Half-life elimination: Suboxone: Buprenorphine 24 to 42

Metabolism/Transport Effects Refer to individual hours; Naloxone 2 to 12 hours; Bunavail: Buprenorphine
components. 16.4 to 27.5 hours; Naloxone*1.9 to 2.4 hours.
Avoid Concomitant Use Protein binding: Naloxone: ~45%, primarily to albumin
Avoid concomitant use of Buprenorphine and Naloxone Pharmacodynamics/Kinetics: Additional Consider-
with any of the following: Atazanavir; Azelastine (Nasal); ations
Bromperidol; Conivaptan; Eluxadoline; Fusidic Acid Hepatic function impairment: Because both drugs are
(Systemic); Idelalisib; Methylnaltrexone; Monoamine extensively metabolized, the plasma levels will be
Oxidase Inhibitors; Naldemedine; Naloxegol; Opioid expected to be higher and the half-life values have been
Analgesics; Opioids (Mixed Agonist / Antagonist); shown to be longer in patients with moderate and severe
Orphenadrine; Oxomemazine; Paraldehyde; Thalido- hepatic impairment; the significance of the effects are
mide greater for naloxone compared to buprenorphine and for
Increased Effect/Toxicity patients with severe hepatic impairment compared to
Buprenorphine and Naloxone may increase the levels/ patients with moderate hepatic impairment.
effects of: Alvimopan; Azelastine (Nasal); Blonanserin; Dosing
Desmopressin; Diuretics; Eluxadoline; Flunitrazepam; Pediatric Note: Sublingual tablets and film contain a
Methotrimeprazine; MetyroSINE; Monoamine Oxidase free-base ratio of buprenorphine:naloxone of 4:1. Doses
Inhibitors; Naldemedine; Naloxegol; Orphenadrine; based on buprenorphine content; titrate to appropriate
Paraldehyde; Piribedil; Pramipexole; QTc-Prolonging effect.
Agents (Highest Risk); Ramosetron; ROPINIRole; Roti- Opioid dependence, maintenance treatment: Adoles-
gotine; Selective Serotonin Reuptake Inhibitors; Seroto- cents 216 years: Sublingual tablets: Sublingual:
nin Modulators; Suvorexant; Thalidomide; Zolpidem Manufacturer’s labeling:
Induction: Not recommended; initial treatment should
The levels/effects of Buprenorphine and Naloxone may begin using buprenorphine sublingual tablets (see
be increased by: Alcohol (Ethyl); Amphetamines; Anti- buprenorphine monograph)
cholinergic Agents; Aprepitant; Atazanavir; Boceprevir; Maintenance: Target dose: 16 mg/day as a single
Brimonidine (Topical); Bromopride; Bromperidol; Canna- daily dose; dosage should be adjusted in increments
bis; Ceritinib; Chlormethiazole; Chlorphenesin Carba- of 2 mg or 4 mg to a dose that adequately sup-
mate; CNS Depressants; Cobicistat; Conivaptan; presses opioid withdrawal; usual range:
CYP3A4 Inhibitors (Moderate); CYP3A4 Inhibitors 4-24 mg/day; Note: Combination product for main-
(Strong); Daclatasvir; Dimethindene (Topical); Dronabi- tenance and for unsupervised therapy (if patient's
nol; Droperidol; Fosaprepitant; Fosnetupitant; Fusidic clinical stability permits)
Acid (Systemic); Idelalisib; Kava Kava; Lofexidine; Mag- Alternate dosing [Center for Substance Abuse Treat-
nesium Sulfate; Methotrimeprazine; Methylnaltrexone; ment Guidelines (CSAT), 2004]:
MiFEPRIStone; Minocycline; Nabilone; Netupitant; Induction (for patients dependent on short-acting
Ombitasvir, Paritaprevir, and Ritonavir; Ombitasvir, Par- opioids and whose last dose of opioids was
itaprevir, Ritonavir, and Dasabuvir; Oxomemazine; Pal- >12-24 hours prior to induction):
bociclib; Perampanel; Rufinamide; Simeprevir; Sodium Day 1: Initial: 4 mg; may repeat dose after >2 hours
Oxybate; Stiripentol; Succinylcholine; Tetrahydrocanna- if withdrawal symptoms not relieved; Day 1 max-
binol imum daily dose: 8 mg/day
Decreased Effect Day 2:
Buprenorphine and Naloxone may decrease the levels/ ¢ If no withdrawal symptoms, repeat total daily
effects of: Atazanavir; Diuretics; Gastrointestinal Agents dose from Day 1
(Prokinetic); Opioid Analgesics; Pegvisomant ¢ If withdrawal symptoms are present, increase
The levels/effects of Buprenorphine and Naloxone may Day 1 dose by 4 mg; if withdrawal symptoms
be decreased by: Boceprevir; Bosentan; CYP3A4 not relieved after >2 hours, may administer an
Inducers (Moderate); CYP3A4 Inducers (Strong); Dab- additional 4 mg; Day 2 maximum daily dose:
rafenib; Deferasirox; Efavirenz; Enzalutamide; Etravir- 16 mg/day
ine; Mitotane; Nalmefene; Naltrexone; Opioids (Mixed Subsequent induction days:
Agonist / Antagonist); Pitolisant; Sarilumab; Siltuximab; ¢ If withdrawal symptoms are not present, daily
St John's Wort; Tocilizumab dose is established (stabilization dose).
¢ If withdrawal symptoms are present, increase
Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
dose in increments of 2 mg or 4 mg each day
excursions permitted to 15°C to 30°C (59°F to 86°F).
as needed for symptom relief. Target daily dose
Protect from freezing and moisture.
by the end of the first week: 12 mg or 16 mg/day;
Mechanism of Action
maximum daily dose: 32 mg/day
Buprenorphine: Buprenorphine exerts its analgesic effect
Stabilization: Usual dose: 16-24 mg/day; maximum
via high affinity binding to mu opiate receptors in the
dose: 32 mg/day
CNS; displays partial mu agonist and weak kappa antag-
Renal Impairment: Pediatric There are no dosage
onist activity
adjustments are provided in manufacturer's labeling.
Naloxone: Pure opioid antagonist that competes and
displaces opioids at opioid receptor sites
Hepatic Impairment: Pediatric Moderate to severe
impairment: Dosage adjustments recommended; how-
Pharmacodynamics/Kinetics (Adult data unless
ever, no specific dosage adjustment recommendations
noted) Also see individual agents.
provided by manufacturer; monitor patients closely.
Absorption: Absorption widely is variable among patients
Administration
following sublingual and buccal use, but variability within
Sublingual film: Film should be placed under the tongue.
each individual patient is low.
Keep under the tongue until film dissolves completely;
Bioavailability:
film should not be chewed, swallowed, or moved after
Buccal film: The exposure of one buprenorphine 4.2 mg/
placement. If more than 1 film is needed, the additional
naloxone 0.7 mg sublingual film is equivalent to one
film should be placed under the tongue on the opposite
buprenorphine 8 mg/naloxone 2 mg sublingual tablet.
side from the first film to minimize overlapping as much
The naloxone exposure from buccal film was 33% less
as possible.
than buprenorphine/naloxone sublingual tablets. The
Sublingual tablets: Place tablet under the tongue until
coadministration of liquids reduced the systemic expo-
dissolved; do not swallow. If 2 or more tablets are
sure up to 59% for buprenorphine and up to 76% for
needed per dose, all tablets may be placed under the
naloxone, depending.on the pH of the liquid. 3
tongue at once, or 2 tablets may be placed under the
Sublingual: Although pharmacokinetics were similar
tongue at a time; to ensure consistent bioavailability,
between the sublingual formulations, bioequivalence
subsequent doses should always be taken the
is variable. $9
same way,
Sublingual film: Potential for greater bioavailability with
Monitoring Parameters Symptoms of withdrawal, respi-
certain strengths of the sublingual film compared to
ratory rate, mental status, blood pressure; liver function
the same strength of the sublingual tablet. In addition,
tests (baseline and periodically during therapy)
the sizes and compositions among the sublingual film
strengths are different which may result in’ different Chronic pain (long-term therapy outside of end-of-life or
systemic exposures. palliative care, active cancer treatment, sickle cell dis-
Sublingual tablet: Zubsolv has different bioavailability ease, or medication-assisted treatment for opioid use
when compared to other buprenorphine/naloxone disorder): Evaluate benefits/risks of opioid therapy within
sublingual tablets. One Zubsolv buprenorphine 1 to 4 weeks of treatment initiation and with dose
5.7 mg/naloxone 1.4 mg sublingual tablet provides increases. Re-evaluate benefits/risks every 3 months dur-
equivalent buprenorphine exposure and 12% lower ing therapy or more frequently in patients at increased risk
naloxone exposure compared to one buprenorphine of overdose or opioid use disorder. Urine drug testing is
8 mg/naloxone 2 mg sublingual tablet. ~ | recommended prior to initiation and with consideration for >

319
 BUPRENORPHINE AND NALOXONE

q re-checking at least yearly (includes controlled prescrip-

tion medications and illicit drugs of abuse). State prescrip-
treatment should be weighed against other treatment
options and untreated depression. For women who dis-
tion drug monitoring program (PDMP) data should be continue antidepressant medications during pregnancy
reviewed by clinicians prior to initiation and periodically and who may be at high risk for postpartum depression,
during therapy (frequency ranging from every prescription the medications can be restarted following delivery. 'Treat-
to every 3 months) (Dowell [CDC 2016)). ment algorithms have been developed by the ACOG and
Additional Information Naloxone has been added to the the APA for the management of depression in women prior
formulation to decrease the abuse potential of dissolving to conception and during pregnancy (ACOG 2008; APA
tablets or film in water and using as an injection (precip- 2010; Yonkers 2009). There is insufficient information
itation of severe withdrawal would occur in opioid depend- related to the use of bupropion to recommend use in
ent patients if the tablets or film were misused in this pregnancy (ACOG 2010).
manner).
Pregnant women exposed to antidepressants during preg-
Controlled Substance C-IIl nancy are encouraged to enroll in the National Pregnancy
Dosage Forms Excipient information presented when Registry for Antidepressants (NPRAD). Women 18 to 45
available (limited, particularly for generics); consult spe- years of age or their health care providers may contact the
cific product labeling. i registry by calling 844-405-6185. Enrollment should be
Film, buccal: done as early in pregnancy as possible.
Bunavail: Buprenorphine 2.1 mg and naloxone 0.3 mg
Breastfeeding Considerations
(30s); buprenorphine 4.2 mg and naloxone 0.7 mg
Bupropion and its active metabolites are present in breast
(30s); buprenorphine 6.3 mg and naloxone 1 mg
milk. Ss
(30s) [citrus flavor]
The manufacturer reports the relative infant dose (RID) of
Film, sublingual:
bupropion and its active metabolites to be ~2% of a
Suboxone: Buprenorphine 2 mg and naloxone 0.5 mg
weight-adjusted maternal dose. In one report, the RID
(30s); buprenorphine 4 mg and naloxone 1 mg (30s);
of bupropion ranged from 1.4% to 10.6% of the maternal
buprenorphine 8 mg and naloxone 2 mg (30s); bupre-
dose when calculated using actual infant weights and
norphine 12 mg and naloxone 3 mg (30s) [lime flavor]
maternal doses ranging from 150 to 300 mg/day (Davis
Generic: Buprenorphine 8 mg and naloxone 2 mg
2009). In general, breastfeeding is considered accept-
(1s, 30s)
able when the RID is <10% (Anderson 2016; Ito 2000);
Tablet, sublingual:
however, some sources note breastfeeding should only
Zubsolv: Buprenorphine 0.7 mg and naloxone 0.18 mg;
be considered if the RID is <5% for psychotropic agents
buprenorphine 1.4 mg and naloxone 0.36 mg; bupre-
(Larsen 2015). When an RID is >25%, breastfeeding
norphine 2.9 mg and naloxone 0.71 mg; buprenor-
should generally be avoided (Anderson 2016; Ito
phine 5.7 mg and naloxone 1.4 mg; buprenorphine
2000). Bupropion and its active metabolites can also
8.6 mg and naloxone 2.1 mg; buprenorphine 11.4 mg
be detected in the serum and urine of breastfeeding
and naloxone 2.9 mg [menthol flavor]
infants (Davis 2009; Neuman 2014).
Generic: Buprenorphine 2 mg and naloxone 0.5 mg;
Seizures and sleep disturbances have been reported in
buprenorphine 8 mg and naloxone 2 mg
breastfeeding infants following bupropion exposure via
@ Buprenorphine HCI see Buprenorphine on page 311 breast milk (Chaudron 2004; Hale 2010; Neuman 2014).
Infants of mothers using psychotropic medications
@ Buprenorphine HCI/Naloxone HCI see Buprenorphine
should be monitored daily for changes in sleep, feeding
and Naloxone on page 317
patterns, and behavior (Bauer 2013) as well as infant
@ Buprenorphine Hydrochloride see Buprenorphine growth and neurodevelopment (Sachs 2013; Srira-
on page 311 man 2015).
@ Buprenorphine Hydrochloride and Naloxone Hydro- When first initiating an antidepressant in a breastfeeding
chloride Dihydrate see Buprenorphine and Naloxone woman, agents other than bupropion are preferred
on page 317 (Berle 2011); however, maternal use of bupropion is
@ Buproban [DSC] see BuPROPion on page 320 not considered a reason to discontinue breastfeeding
(Sriraman 2015). The manufacturer recommends that
caution be exercised when administering bupropion to
BuPROPion (byoo PROE pee on) breastfeeding women.
Contraindications
Medication Safety Issues
Hypersensitivity to bupropion or any component of the
Sound-alike/look-alike issues:
formulation; seizure disorder; history of anorexia/bulimia;
Aplenzin may be confused with Albenza, Relenza
patients undergoing abrupt discontinuation of ethanol or
BuPROPion may be confused with busPIRone
sedatives, including benzodiazepines, barbiturates, or
Forfivo XL may be confused with Forteo
antiepileptic drugs; use of MAO inhibitors (concurrently
Wellbutrin XL may be confused with Wellbutrin SR
or within 14 days of discontinuing either bupropion or the
Zyban may be confused with Diovan
MAO inhibitor); initiation of bupropion in a patient receiv-
Related Information ing linezolid or intravenous methylene blue
Oral Medications That Should Not Be Crushed or Altered 24-hour extended release: Additional contraindications:
on page 2217 Other conditions that increase seizure risk, including
Brand Names: US Aplenzin; Buproban [DSC]; Forfivo arteriovenous malformation, severe head injury, severe
XL; Wellbutrin SR; Wellbutrin XL; Wellbutrin [DSC]; Zyban stroke, CNS tumor, CNS infection
Brand Names: Canada Wellbutrin SR; Wellbutrin XL; Canadian labeling: Additional contraindications (not in US
Zyban labeling): Concurrent use or use within 14 days of
Therapeutic Category Antidepressant, Dopamine-Reup- thioridazine; concurrent use with other dosage forms of
take Inhibitor; Smoking Cessation Aid bupropion
Generic Availability (US) Yes Warnings/Precautions [US Boxed Warning]: Antide-
Use Treatment of major depressive disorder (Aplenzin, pressants increase the risk of suicidal thinking and
Forfivo XL, Wellbutrin, Wellbutrin SR, Wellbutrin XL: behavior in children, adolescents, and young adults in
FDA approved in adults), seasonal affective disorder short-term trials. These trials did not show an
(SAD) (Aplenzin, Wellbutrin XL: FDA approved in adults); increased risk in patients 265 years of age. In patients
adjunct in smoking cessation (Buproban, Zyban: FDA of all ages who are started on antidepressant therapy,
approved in adults); has also been used to treat ADHD monitor closely for worsening and for emergence of
Medication Guide Available Yes suicidal thoughts and behaviors, particularly during the
Pregnancy Risk Factor C initial 1 to 2 months of therapy or during periods of dosage
Pregnancy Considerations Adverse events have been adjustments (increases or decreases); advise families
observed in some animal reproduction studies. Bupropion and caregivers of the need for close observation and
and its metabolites were found to cross the placenta in in communication with the prescriber. A medication guide
vitro studies (Earhart 2010). An increased risk of congen- concerning the use of antidepressants should be dis-
ital malformations has not been observed following mater- pensed with each prescription.
nal use of bupropion during pregnancy; however, data
The possibility of a suicide attempt is inherent in major
specific to cardiovascular malformations is inconsistent.
depression and may persist until remission occurs. Wor-
The long-term effects on development and behavior have
sening depression and severe abrupt suicidality that are
not been studied.
not part of the presenting symptoms may require discon-
The ACOG recommends that antidepressant therapy dur- tinuation or modification of drug therapy. Use caution in
ing pregnancy be individualized; treatment of depression high-risk patients during initiation of therapy. Prescriptions
during pregnancy should incorporate the clinical expertise should be written for the smallest quantity consistent with
of the mental health clinician, obstetrician, primary health good patient care. The patient's family or caregiver should
care provider, and pediatrician. According to the American be alerted to monitor patients for the emergence of
Psychiatric Association (APA), the risks of medication suicidality and associated behaviors such as anxiety,

320
 BUPROPION

agitation, panic attacks, insomnia, irritability, hostility, with caution if tasks requiring alertness such as operating
impulsivity, akathisia, hypomania, and mania; patients machinery or driving are undertaken. May cause mild
should be instructed to notify their health care provider if pupillary dilation, which in susceptible individuals can lead
any of these symptoms or worsening depression or psy- to an episode of narrow-angle glaucoma. Consider eval-
chosis occur. uating patients who have not had an iridectomy for
narrow-angle glaucoma risk factors. Anaphylactoid/ana-
Serious neuropsychiatric events have occurred in patients
phylactic reactions have occurred, with symptoms of pru-
taking bupropion for smoking cessation, including
ritus, urticaria, angioedema, and dyspnea. Serious
changes in mood (eg, depression, mania), psychosis,
reactions have been (rarely) reported, including erythema
hallucinations, paranoia, delusions, homicidal ideation,
multiforme, Stevens-Johnson syndrome and anaphylactic
hostility, agitation, aggression, anxiety, panic, suicidal
shock. Arthralgia, myalgia, and fever with rash and other
ideation, suicide attempt, and completed suicide. The
symptoms suggestive of delayed hypersensitivity resem-
majority occurred during bupropion treatment; some
bling serum sickness have been reported. Potentially
occurred during treatment discontinuation. A causal rela-
significant drug-drug interactions may exist, requiring
tionship is uncertain as depressed mood may be a symp-
dose or frequency adjustment, additional monitoring,
tom of nicotine withdrawal. Some cases also occurred in
and/or selection of alternative therapy. Using doses higher
patients taking bupropion who continued to smoke. Neuro-
than prescribed may result in increased motor activity,
psychiatric effects occurred in patients with and without
agitation/excitement and euphoria. Inhalation of crushed
preexisting psychiatric disease; some patients experi-
tablets or injection of dissolved bupropion has been
enced a worsening of their psychiatric illnesses. However,
reported, some resulting in seizures and death.
subsequent controlled trials in patients with or without
psychiatric disorders have not identified significant differ- 24-hour extended release tablet: Insoluble tablet shell
ences in neuropsychiatric effects for patients taking bupro- may remain intact and be visible in the stool.
_pion, varenicline, nicotine patches, or placebo (Anthenelli Warnings: Additional Pediatric Considerations The
2016; Cinciripini 2013). Observe all patients taking bupro- American Heart Association recommends that all children
pion for neuropsychiatric reactions. Instruct patients to diagnosed with ADHD who may be candidates for medi-
stop taking bupropion and contact a health care provider cation, such as bupropion, should have a thorough car-
if neuropsychiatric reactions occur. diovascular assessment prior to initiation of therapy.
These recommendations are based upon reports of seri-
May cause delusions, hallucinations, psychosis, concen-
ous cardiovascular adverse events (including sudden
tration disturbance, paranoia, and confusion; most com-
death) in patients (both children and adults) taking usual
mon in depressed patients and patients with a diagnosis of
doses of stimulant medications. Most of these patients
bipolar disorder. Symptoms, may abate with dose reduc-
were found to have underlying structural heart disease
tion and/or withdrawal of treatment. May precipitate a
(eg, hypertrophic obstructive cardiomyopathy). This
manic, mixed, or hypomanic episode; risk is increased in
assessment should include a combination of thorough
patients with bipolar disorder or who have risk factors for
medical history, family history, and physical examination.
bipolar disorder. Screen patients for a history of bipolar
An ECG is not mandatory but should be considered.
disorder and the presence of risk factors including a family
history of bipolar disorder, suicide, or depression. Bupro- Adverse Reactions
Cardiovascular: Cardiac arrhythmia, chest pain, flushing,
pion is not FDA approved for bipolar depression.
hypertension (may be severe), hypotension, palpitations,
May cause a dose-related risk of seizures. Use is contra- tachycardia
indicated in patients with a history of seizures or certain Central nervous system: Abnormal dreams, abnormality in
conditions with high seizure risk (eg, history of anorexia/ thinking, agitation, akathisia, anxiety, central nervous
bulimia or patients undergoing abrupt discontinuation of system stimulation, confusion, depression, dizziness,
ethanol, benzodiazepines, barbiturates, or antiepileptic drowsiness, dystonia, headache, hostility, insomnia, irri-
drugs). 24-hour extended-release formulations are also tability, lack of concentration, memory impairment,
contraindicated in patients with certain conditions with migraine, nervousness, pain, paresthesia, sensory dis-
high seizure risk (eg, arteriovenous malformation, severe turbance, sleep disorder, twitching
head injury, severe stroke, CNS tumor, and CNS infec- Dermatologic: Diaphoresis, pruritus, skin rash, urticaria,
tion). Use caution with concurrent use of antipsychotics, xeroderma
antidepressants, theophylline, systemic corticosteroids, Endocrine & metabolic: Decreased libido, hot flash, men-
stimulants (including cocaine), anorexiants, or hypoglyce- strual disease, weight gain, weight loss
mic agents, or with excessive use of ethanol, benzodia- Gastrointestinal: Abdominal pain, anorexia, constipation,
zepines, sedative/hypnotics, or opioids. Use with caution diarrhea, dysgeusia, dyspepsia, dysphagia,
flatulence,
in seizure-potentiating metabolic disorders (hypoglycemia, increased appetite, nausea, oral mucosa ulcer, vomiting,
hyponatremia, severe hepatic impairment, and hypoxia). xerostomia
The dose-dependent risk of seizures may be reduced by Genitourinary: Urinary frequency, urinary tract infection,
gradual dose increases and by not exceeding the max- urinary urgency, vaginal hemorrhage
imum daily dose. Do not coadminister-with other bupro- Hypersensitivity: Hypersensitivity reaction
pion-containing formulations. Permanently discontinue if Infection: Infection
seizure occurs during therapy. Chewing, crushing, inject- Neuromuscular & skeletal: Arthralgia, arthritis, dyskinesia,
ing, or dividing long-acting products may increase seiz- myalgia, neck pain, tremor, weakness
ure risk. Ophthalmic: Blurred vision, diplopia
Otic: Auditory disturbance, tinnitus
May cause CNS stimulation (restlessness, anxiety, insom-
Renal: Polyuria
nia) or anorexia. May increase the risks associated with
Respiratory: Bronchitis, cough, epistaxis, increased
electroconvulsive therapy (ECT); consider discontinuing,
cough, nasopharyngitis, pharyngitis, rhinitis, sinusitis,
when possible, prior to ECT treatment (APA 2010). May
upper respiratory infection
cause weight loss; use caution in patients where weight
Miscellaneous: Accidental injury, fever
loss is not desirable. The incidence of sexual dysfunction
Rare but important or life-threatening: Abnormal accom-
with bupropion is generally lower than with SSRIs (Clay-
modation, abnormal stools, akinesia, alopecia, amnesia,
ton 2004).
anaphylactoid reaction, anemia, angioedema, angle-clo-
May elevate blood pressure and cause hypertension. sure glaucoma, aphasia, ataxia, atrioventricular block,
Events have been observed in patients with or without cerebrovascular accident, colitis, coma, complete atrio-
evidence of preexisting hypertension. The risk is ventricular block, cystitis, deafness, delayed hypersensi-
increased when used concomitantly with monoamine oxi- tivity, delirium, delusions, depersonalization,
dase inhibitors, nicotine replacement, or other drugs that derealization, drug-induced Parkinson disease, dry eye
increase dopaminergic or noradrenergic activity. Assess syndrome, dysarthria, dyspareunia, dysphoria, dysuria,
blood pressure before treatment and monitor periodically. ecchymoses, edema, EEG pattern changes, ejaculatory
Use caution in patients with cardiovascular disease, disorder, erythema multiforme, esophagitis, euphoria,
hypertension, or coronary artery disease; treatment-emer- exfoliative dermatitis, extrapyramidal reaction, extrasys-
gent hypertension (including some severe cases) has toles, facial edema, gastric ulcer, gastroesophageal
been reported, both with bupropion alone and in combi- reflux disease, gastrointestinal hemorrhage, gingival
nation with nicotine transdermal systems. All children hemorrhage, gingivitis, glossitis, glycosuria, gynecomas-
diagnosed with ADHD (off-label use of bupropion) who tia, hallucination, hepatic injury, hepatic insufficiency,
_ may be candidates for stimulant medications should have hepatitis, hirsutism, homicidal ideation, hyperglycemia,
a thorough cardiovascular assessment to identify risk hyperkinesia, hypertonia, hypoglycemia, hypokinesia,
factors for sudden cardiac death prior to initiation of drug hypomania, hyponatremia, impotence, increased intra-
therapy. Use with caution in patients with hepatic or renal ocular pressure, increased libido, inguinal hernia, intes-
dysfunction and in elderly patients; reduced dose and/or tinal perforation, jaundice, leg cramps, leukocytosis,
frequency may be recommended. Elderly patients may be leukopenia, lymphadenopathy, maculopapular rash,
at greater risk of accumulation during chronic dosing. May manic behavior, menopause, muscle rigidity, myasthe-
cause motor or cognitive impairment in some patients; use nia, mydriasis, myocardial infarction, myoclonus,

321
 BUPROPION

q neuralgia, neuropathy, orthostatic hypotension, painful

erection, pancreatitis, pancytopenia, panic, paranoia,
Metabolite: Hydroxybupropion: Immediate release: ~3
hours; Extended release: ~6 to 7 hours
peripheral edema, phlebitis, pneumonia, prostatic dis- Excretion: Urine (87%, primarily as metabolites); feces
ease, psychosis, pulmonary embolism, restlessness, (10%, primarily as.metabolites)
rhabdomyolysis, salpingitis, sciatica, seizure (dose- Pharmacodynamics/Kinetics: Additional Consider-
related), serum sickness-like reaction, SIADH, sialor- ations
rhea, skin photosensitivity, Stevens-Johnson syndrome, Renal function impairment: Elimination of bupropion and/
stomatitis, suicidal ideation, syncope, tardive dyskinesia, or major metabolites may be reduced.
thrombocytopenia, tongue edema, urinary incontinence, Hepatic function impairment: Elimination of hydroxybupro-
urinary retention, vaginitis, vasodilatation, vertigo pion is reduced in patients with alcoholic liver disease.
Drug Interactions Bupropion Cmax increased 70%, AUC increased 3-fold,
Metabolism/Transport Effects Substrate of CYP1A2 and mean half-life increased to 29 hours in patients with
(minor), CYP2A6 (minor), CYP2B6 (major), CYP2C9 severe hepatic impairment. Mean half-life for active
(minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 metabolites increased 2- to 5-fold in patients with severe
(minor); Note: Assignment of Major/Minor substrate sta- hepatic impairment.
tus based on clinically relevant drug interaction potential; Geriatric: May be at risk of accumulation of bupropion and
Inhibits CYP2D6 (strong), OCT2 its metabolites.
Avoid Concomitant Use Gender: AUC was approximately 13% higher in men.
Avoid concomitant use of BuPROPion with any of the Dosing
following: Mequitazine; Monoamine Oxidase Inhibitors; Pediatric Note: Bupropion is available as either hydro-
Pimozide; Tamoxifen; Thioridazine chloride or hydrobromide (Aplenzin) salt formulations
Increased Effect/Toxicity which are not interchangeable on a mg per mg basis;
BuPROPion may increase the levels/effects of: Agents dosage expressed in terms of the salt formulation.
With Seizure Threshold Lowering Potential; Ajmaline; Patients must be able to swallow sustained or extended
Alcohol (Ethyl); ARIPiprazole; ARIPiprazole Lauroxil; release products whole.
AtoMOXetine; Brexpiprazole; Citalopram; CloZAPine; Attention-deficit/hyperactivity disorder: Limited
CYP2D6 Substrates (High risk with Inhibitors); Dapox- data available: Children 26 years-(Dopheide 2009;
etine; Deutetrabenazine; DOXOrubicin (Conventional); Pliszka 2007) and Adolescents: Oral:
DULoxetine; Eliglustat; Fesoterodine; FLUoxetine; Flu- Immediate release, hydrochloride salts: Initial:
voxaMINE; lloperidone; Indoramin; lohexol; lomeprol; 3 mg/kg/day in 2 to 3 divided doses; maximum initial
lopamidol; Lofexidine; Lorcaserin; Mequitazine; Meto- dose: 150 mg/day; titrate dose as needed to a
prolol; Nebivolol; Nicergoline; OCT2 Substrates; PARox- maximum daily dose of 6 mg/kg/day or 300 mg/
etine; Perhexiline; Pimozide; Pitolisant; Tamsulosin; day with no single dose >150 mg (Dopheide 2009;
Tetrabenazine; Thioridazine; Timolol (Ophthalmic); Tra- Pliszka 2007).
MADoI:; Tricyclic Antidepressants; Tropisetron; Valbena- Sustained release (Wellbutrin SR) and extended
zine; Vortioxetine release (Wellbutrin XL), hydrochloride salts: May
be used in place of regular tablets, once the daily
The levels/effects of BuPROPion may be increased by: dose is titrated using the immediate release product
Alcohol (Ethyl); Amifampridine; Anti-Parkinson Agents and the titrated 12-hour dosage corresponds to a
(Dopamine Agonist); CYP2B6 Inhibitors (Weak); MiFE- sustained release tablet (Wellbutrin SR) or the 24-
PRIStone; Monoamine Oxidase Inhibitors; Thiotepa hour dosage range corresponds to an extended
Decreased Effect release tablet size (Wellbutrin XL)
BuPROPion may decrease the levels/effects of: Benzhy- Depression, refractory to SSRIs: Limited data avail-
drocodone; Codeine; Digoxin; HYDROcodone; Iloperi- able; Note: May be most beneficial in patients with
done; loflupane | 123; Nicergoline; Primaquine; comorbid ADHD, conduct disorder, substance abuse
Tamoxifen; TraMADol problems or who want to quit smoking (Dopheide
2006). Treatment should be periodically evaluated at
The levels/effects of BuPROPion may be decreased by:
appropriate intervals to ensure lowest effective dose
Antihepaciviral Combination Products; CYP2B6
is used.
Inducers (Moderate); Dabrafenib; Dipyrone; Efavirenz;
Immediate release, hydrochloride salt: Children 8 to
Isavuconazonium Sulfate; Lopinavir; Lumacaftor; Niloti-
$11 years: Oral: Initial: 37.5 mg twice daily; titrate to
nib; Ritonavir
response; usual dosage range: 100 to 400 mg/day
Storage/Stability Store at 15°C to 30°C (59°F to 86°F). (Dopheide 2006)
Protect from light and moisture.
Sustained release, hydrochloride salt (Wellbutrin SR):
Mechanism of Action Aminoketone antidepressant Children 211 years and Adolescents: Oral: Initial:
structurally different from all other marketed antidepres- 2 mg/kg up to 100 mg administered as a morning
sants; like other antidepressants the mechanism of bupro- dose; may titrate as needed every 2 to 3 weeks
pion's activity is not fully understood. Bupropion is a using the following titration schedule: Step 2:
relatively weak inhibitor of the neuronal uptake of norepi- Increase up to 3 mg/kg every morning; Step 3:
nephrine and dopamine, and does not inhibit monoamine Increase up to 3 mg/kg every morning and 2 mg/kg
oxidase or the reuptake of serotonin. Metabolite inhibits at 5 pm (17:00); Step 4: Increase up to 3 mg/kg/
the reuptake of norepinephrine. The primary mechanism dose twice daily; maximum dose: 150 mg; reported
of action is thought to be dopaminergic and/or noradre- mean effective dose: Morning: 2.2 mg/kg and after-
nergic. noon: 1.7:mg/kg (Daviss 2001)
Pharmacodynamics/Kinetics (Adult data unless Extended release, hydrochloride salt (Wellbutrin XL):
noted) Children 212 years and Adolescents: Oral: Initial:
Onset of action: 1 to 2 weeks 150 mg once daily; may titrate after 2 weeks to
Duration of action: 1 to 2 days 300 mg once daily if adequate response not
Absorption: Rapid achieved; dosing based on a pharmacokinetic study
Distribution: Vg: ~20 to 47 L/kg (Laizure 1985) in eight patients with depression (Daviss 2006);
Protein binding: 84% doses as high as 400 mg/day have been reported
Metabolism: Extensively hepatic via CYP2B6 to hydrox- (Dopheide 2006); may also be used once the daily
ybupropion; non-CYP-mediated metabolism to erythro- dose is titrated using the immediate release product
hydrobupropion and threohydrobupropion. Metabolite and the 24-hour dosage range corresponds to an
activity ranges from 20% to 50% potency of bupropion. extended release tablet size (Wellbutrin XL).
Bupropion also undergoes oxidation to form the glycine Smoking cessation: Limited data available: Adoles-
conjugate of meta-chlorobenzoic acid, the major urinary cents 214 years and 240.5 kg: Sustained release,
metabolite. hydrochloride salt (Buproban, Zyban): Oral: Initial:
Half-life: 150 mg once daily for 3 days; increase to 150 mg
Distribution: 3 to 4 hours twice daily; treatment should start while the patient is
Elimination: still smoking in order to allow drug to reach steady-
Hydrochloride salt: ~21 hours after chronic dosing (+ 9 state levels prior to smoking cessation; generally,
hours); Metabolites (after a single dose): Hydroxybu- patients should stop smoking during the second week
propion: 20 + 5 hours; Erythrohydrobupropion: 33 + of treatment; maximum daily dose: 300 mg/day;
10 hours; Threohydrobupropion: 37 + 13 hours short-term efficacy was demonstrated in 104 adoles-
Hydrobromide salt: 21 + 7 hours; Metabolites: Hydrox- cents who received therapy for 7 weeks with cessa-
ybupropion: 24 + 5 hours; Erythrohydrobupropion: 31 tion counseling (Muramoto 2007).
+ 8 hours; Threohydrobupropion: 51 + 9 hours Dosing conversion between hydrochloride salt
Time to peak, serum: immediate (Wellbutrin), sustained (Wellbutrin
Bupropion: Immediate release: Within 2 hours; 12-hour SR), and extended release (Wellbutrin XL) prod-
extended release (sustained release): Within 3 hours; ucts: Convert using same total daily dose (up to the
24-hour extended release: ~5 hours; 12 hours (fed) maximum recommended dose for a given dosage
 BUROSUMAB-TWZA

form), but adjust frequency as indicated for sustained Tablet Extended Release 24 Hour, Oral, as hydrochloride:
(twice daily) or extended (once daily) release Forfivo XL: 450 mg
products. Wellbutrin XL: 150 mg, 300 mg
Discontinuation of therapy: Upon discontinuation of Generic: 150 mg, 300 mg
antidepressant therapy, gradually taper the dose to
@ Bupropion HCI see BUuPROPion on page 320
allow for the detection of reemerging symptoms. With-
drawal symptoms resulting from abrupt discontinua- @ Bupropion Hydrobromide see BuPROPion
tion are unlikely because bupropion has minimal on page 320
serotonergic activity (APA 2010). @ Bupropion Hydrochloride see BuPROPion
Manufacturer's labeling: Wellbutrin XL: In patients on page 320
receiving 300 mg once daily, taper dose down to Burinex (Can) see Bumetanide on page 307
150 mg once daily for 2 weeks priorto discontinuing.
MAO inhibitor recommendations:
Switching to or from an MAO inhibitor antidepressant: Burosumab-twza (bur oh SUE mab twza)
Allow 14 days to elapse between discontinuing an
Brand Names: US Crysvita
MAO inhibitor intended to treat depression and
Therapeutic Category Anti-FGF23 Monoclonal Antibody;
initiation of bupropion.
Electrolyte Supplement, Parenteral
Allow 14 days to elapse between discontinuing
Generic Availability (US) No
bupropion and initiation of an MAO inhibitor
Use Treatment of X-linked hypophosphatemia (XLH) (FDA
intended to treat depression.
approved in ages 21 year and adults).
Use with reversible MAO inhibitors (such as linezolid
Pregnancy Considerations
or IV methylene blue):
Burosumab-twza is a human IgG monoclonal antibody
Do not initiate bupropion in patients receiving line-
and may be transferred across the placenta. Maternal
zolid or IV methylene blue; consider other inter-
serum phosphorus concentrations should be monitored.
ventions for psychiatric condition.
If urgent treatment with linezolid or IV methylene Health care providers are encouraged to report exposures
blue is required in a patient already receiving of burosumab-twza during pregnancy to the Ultragenyx
bupropion and potential benefits outweigh potential Adverse Event reporting line (888-756-8657).
risks, discontinue bupropion promptly and admin- Breastfeeding Considerations It is not known if buro-
ister linezolid or IV methylene blue. Monitor for sumab-twza is present in breast milk. However, burosu-
increased risk of hypertensive reactions for 2 mab-twza is an IgG monoclonal antibody and maternal
weeks or until 24 hours after the last dose of IgG immunoglobulins are excreted in breast milk. Accord-
linezolid or IV methylene blue, whichever comes ing to the manufacturer, the decision to breastfeed during
first. May resume bupropion 24 hours after the last therapy should consider the risk of infant exposure, the
dose of linezolid or IV methylene blue. benefits of breastfeeding to the infant, and benefits of
Renal Impairment: Pediatric There are no pediatric- treatment to the mother.
specific recommendations; based on experience in adult Contraindications Concomitant use of oral phosphate
patients, dosing adjustment suggested; use with caution. and active vitamin D analogs; serum phosphorus within
Hepatic Impairment: Pediatric There are no pediatric- or above normal range for age; severe renal impairment or
specific recommendations; based on experience in adult end-stage renal disease
patients, dosing adjustment suggested. Warnings/Precautions May cause hypersensitivity reac-
Administration tions (eg, rash, urticaria). Discontinue therapy immediately
Oral: May be taken without regard to meals. Do not crush, if serious hypersensitivity reactions occur. Elevated serum
phosphorus may increase the risk of nephrocalcinosis;
chew, or divide sustained or extended release tablets
dose reduction or interruption of therapy may be required.
(hydrochloride and hydrobromide salt formulations);
Local injection site reactions may occur. Most reactions
swallow whole. The insoluble shell of the extended-
are mild in severity, occur within 1 day of injection, and
release tablet may remain intact during Gl transit and
typically resolve within 1 to 3 days with no treatment.
is eliminated in the feces.
Discontinue use if severe injection site reactions occur.
Immediate release: Administer with at least 6 hours
New onset or worsening of existing restless leg syndrome
between successive doses; do not exceed 150 mg in
(RLS) has been reported in adults.
a single dose
Adverse Reactions
Sustained release: Typically administer 2 times daily with
Central nervous system: Dizziness, headache (more com-
at least 8 hours between successive doses
mon in children), restless leg syndrome (adults)
Extended release: Administer once daily with at least 24
Dermatologic: Rash at injection site (children), skin rash
hours between successive doses
(children), urticaria (children)
Monitoring Parameters Heart_rate, blood pressure Endocrine & metabolic: Hyperphosphatemia (adults), vita-
(baseline and periodically especially when used in con- min D deficiency (more common in children)
junction with nicotine transdermal replacement); renal and Gastrointestinal: Constipation (adults), toothache (chil-
hepatic function, body weight. Monitor mental status for dren), tooth infection (adults), vomiting (children)
depression, suicidal ideation (especially at the beginning Hypersensitivity: Hypersensitivity reaction
of therapy or when doses are increased or decreased), Immunologic: Antibody development
anxiety, social functioning, mania, panic attacks, tics; Infection: Tooth abscess (children)
periodically monitor for symptom resolution Local: Injection site reaction (children; including urticaria,
ADHD: Evaluate patients for cardiac disease prior to erythema, rash, swelling, bruising, pain, pruritus, and
initiation of therapy for ADHD with thorough medical hematoma)
history, family history, and physical exam; consider Neuromuscular & skeletal: Back pain (adults), limb pain
ECG; perform ECG and echocardiogram if findings (children), myalgia (children)
suggest cardiac disease; promptly conduct cardiac eval- Miscellaneous: Fever (children)
uation in patients who develop chest pain, unexplained Drug Interactions
syncope, or any other symptom of cardiac disease Metabolism/Transport Effects None known.
during treatment. Avoid Concomitant Use
Reference Range Therapeutic levels (trough, 12 hours Avoid concomitant use of Burosumab-twza with any of
after last dose): 50 to 100 ng/mL r the following: Phosphate Supplements; Vitamin D Ana-
Test Interactions May interfere with urine detection of logs
amphetamine/methamphetamine (false-positive). Increased Effect/Toxicity
Decreased prolactin levels. The levels/effects of Burosumab-twza may be increased
Dosage Forms Excipient information presented when by: Phosphate Supplements; Vitamin D Analogs
available (limited, particularly for generics); consult spe- Decreased Effect There are no known significant inter-
cific product labeling. [DSC] = Discontinued product actions involving a decrease in effect.
Tablet, Oral, as hydrochloride: Storage/Stability Store at 36°F to 46°F (2°C to 8°C) in the
Wellbutrin: 75 mg [DSC], 100 mg [DSC] original carton; do not freeze. Protect from light. Do not
Generic: 75 mg, 100mg shake.
Tablet Extended Release 12 Hour, Oral, as hydrochloride: Mechanism of Action Binds to and inhibits the activity of
Buproban: 150 mg [DSC] fibroblast growth factor 23 (FGF23), thereby restoring
Wellbutrin SR: 100 mg, 150 mg, 200 mg renal phosphate reabsorption and increasing the serum
Zyban: 150 mg , concentration of 1,25 dihydroxy vitamin D.
Generic: 100 mg, 150 mg, 200 mg Pharmacodynamics/Kinetics (Adult data unless
Tablet Extended Release 24 Hour, Oral, as hydrobromide: noted)
Aplenzin: 174 mg, 348 mg, 522 mg : Distribution: Vg: 8 L
BUROSUMAB-TWZA

Metabolism: Degraded into small peptides and amino Adolescents 218 years: If serum phosphorus above
acids via catabolic pathways normal range: Hold dose; reassess fasting serum
Half-life elimination: ~19 days phosphorus every 4 weeks; once serum phospho-
Time to peak: 8 to 11 days rus falls below the normal range, may reinitiate
Pharmacodynamics/Kinetics: Additional Consider- burosumab-twza at a reduced dose. Recheck fast-
ations Body weight: Clearance and volume of distribution ing serum phosphorus 2 weeks after dose adjust-
of burosumab-twza increases with body weight. ment; based on results, determine: if additional
Dosing dosing adjustment necessary.
Pediatric
Hypophosphatemia, X-linked (XLH): Note: Prior to Re-Initiation Dosing
initiating burosumab-twza, oral phosphates and active Previous dose (mg/dose) Re-initiation ee (mg/dose)
vitamin D analogs should be discontinued for at least 1 every 4wees every *weeks
week. Confirm that baseline fasting serum phosphorus
concentration is below the reference range for patient
age before initiating burosumab-twza.
Initial:
Children and Adolescents <17 years: SubQ: 0.8 mg/
kg/dose every 2 weeks; minimum dose: 10 mg/
dose; calculated dose should be rounded to the
nearest 10 mg; maximum dose: 90 mg/dose.
Adolescents 218 years: SubQ: 1 mg/kg/dose every 4 Renal Impairment: Pediatric Children and Adoles-
weeks; round dose to the nearest 10 mg; maximum cents:
dose: 90 mg/dose. Mild to moderate impairment: There are no dosing
Monitoring of therapy: Evaluate fasting serum phos- adjustments provided in the manufacturer's labeling
phorus every 4 weeks for first 12 weeks of therapy (has not been studied); use with caution. Increased
and as appropriate thereafter (eg, after dosing adjust- serum phosphorus may occur with renal impairment;
ments). Adjust dose accordingly based on fasting in addition, burosumab-twza may also cause hyper-
serum phosphorus level; see Reference Range for phosphatemia with risk of nephrocalcinosis; serum
phosphorus age-based normal limits. phosphorus levels should be monitored very closely.
Dosing adjustment based on serum phosphorus: Severe renal impairment or eritcelade renal disease:
If low serum phosphorous: Use is contraindicated.
Children and Adolescents $17 years: If serum phos- Hepatic Impairment: Pediatric Thers are no dosing
phorus below the reference range for age: adjustments provided in the manufacturer's labeling (has
Increase dose stepwise based on the following not been studied); use with caution.
table. Recheck fasting serum phosphorus 4 weeks Administration Note: The product is available in multiple
after dose adjustment; burosumab-twza should not concentrations; verify appropriate product selection for
be adjusted more frequently than every 4 weeks. dose. Should be administered by a health care provider.
Maximum dose: 2 mg/kg/dose, not to exceed Missed doses should be administered as soon as possible
90 mg/dose. at prescribed doses.
SubQ: Administer undiluted SubQ in upper arms, upper
Weight-Band Dosing: Fixed Dosing“ Increases® thighs, buttocks, or any quadrant of the abdomen; rotate
1st dose 2nd dose injection sites. Avoid injection sites where skin is tender,
Initial dose increase to increase to bruised, red, hard, or not intact. The maximum SubQ
Weight-band (mg/dose) mg/dose volume per injection site is 1.5 mL; larger dose volumes
(kg) need to be split between 2 injection sites. Inspect vial
prior to use; do not use if solution is discolored, cloudy, or
contains particulate matter.
Monitoring Parameters Hypersensitivity reactions, local
injection-site reactions, fasting serum phosphorus
32 to 43 Reference Range
Fasting serum phosphorus (Kliegman 2016):
1 to 3 years: 3.8 to 6.5 mg/dL
4 to 11 years: 3.7 to 5.6 mg/dL
69 to 80 12 to 15 years: 2.9 to 5.4 mg/dL
16 to 19 years: 2.7 to 4.7 mg/dL
Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
cific product labeling.
Presented doses already rounded Solution, Subcutaneous [preservative free]:
Dosing titration increments of approximately 0.4 mg/kg have also
been used (Crysvita European Medicines Agency 2018) Crysvita: 10 mg/mL (1 mL); 20 mg/mL (1 mL); 30 mg/mL
(1 mL) [contains polysorbate 80]
Adolescents 218 years: There are no dosage adjust-
ments provided in the manufacturer's labeling for ¢ Burow's Solution see Aluminum Acetate on page 100
low serum phosphorous. @ Buscopan (Can) see Scopolamine (Systemic)
If high serum phosphorous: on page 1806
Children and Adolescents $17 years: If serum phos-
phorus >5 mg/dL: Hold dose; reassess fasting BuSpar see BusPlRone on page 324
serum phosphorus in 4 weeks and every 4 weeks
thereafter; once serum phosphorus below refer- BusPIRone (byoo SPYE rone)
ence range for age, may reinitiate burosumab-twza
at a reduced dose. Recheck fasting serum phos- Medication Safety Issues
phorus in 4 weeks and follow dosing adjustment Sound-alike/look-alike issues:
recommendations based on result; the following BusP!IRone may be confused with buPROPion
table provides fixed dosing for reduced dosage to Therapeutic Category Antianxiety Agent
re-initiate therapy. Generic Availability (US) Yes
Use Management of anxiety disorders
Re-Initiation Dosing: Fixed Dosing
Pregnancy Risk Factor B
Previous dose (mg/dose) Re-initiation bt fe giaese) Pregnancy Considerations Adverse events have not
every 2 weeks ee weeks been observed in animal reproduction studies.
Breastfeeding Considerations
It is not known if buspirone is present in breast milk.
In one case report, buspirone was not detected in the
breast milk of a mother taking 15 mg three times daily
during pregnancy and postpartum (samples obtained 13
days after delivery; limit of detection not noted)
(Brent 1998).
Breastfeeding is not recommended by the manufacturer.
Contraindications Hypersensitivity to buspirone or any
component of the formulation; concomitant use of MAOIs
intended to treat depression or within 14 days of discontin-
uing MAOIs intended to treat depression; concomitant use
of MAOls within 14 days of discontinuing buspirone;

324
 BUSPIRONE

initiation of buspirone in patients receiving reversible Modulators; Serotonin Reuptake Inhibitor/Antagonists;

MAOIs (eg, linezolid, |\V methylene blue). Suvorexant; Thalidomide; Zolpidem
Warnings/Precautions Use. in severe hepatic or renal
The levels/effects of BusPlRone may be increased by:
impairment is not recommended. May rarely cause CNS
Antiemetics (5HT3 Antagonists); Antipsychotic Agents;
depression, which may impair physical or mental abilities;
Aprepitant; Brimonidine (Topical); Bromopride; Bromper-
patients must be cautioned about performing tasks that
idol; Calcium Channel Blockers (Nondihydropyridine);
require mental alertness (eg, operating machinery or
Cannabis; Ceritinib; Chlormethiazole; Chlorphenesin
driving). Potentially significant interactions may exist,
Carbamate; Conivaptan; CYP3A4 Inhibitors (Moderate);
requiring dose or frequency adjustment, additional mon-
CYP3A4 Inhibitors (Strong); Dapoxetine; Dimethindene
itoring, and/or selection of alternative therapy. Akathisia,
(Topical); Doxylamine; Dronabinol; Droperidol; Erythro-
or restlessness, has been reported in small number of
patients; may be a result of central dopamine receptor
mycin (Systemic); Fosaprepitant; Fosnetupitant; Fusidic
Acid (Systemic); Grapefruit Juice; HydrOXYzine; Idelali-
antagonism. Monitor for signs of any dopamine-related
sib; Kava Kava; Lofexidine; Magnesium Sulfate; Metax-
movement disorders (eg, dystonia, akathisia, pseudo-par-
alone; Methotrimeprazine; Methylphenidate;
kinsonism, tardive dyskinesia). Buspirone does not exhibit
MiFEPRIStone; Minocycline; Nabilone; Nefazodone;
cross-tolerance with benzodiazepines or other sedative/
Netupitant; Oxomemazine; Palbociclib; Perampanel;
hypnotic agents. If substituting buspirone for any of these
Resveratrol; Rufinamide; Selective Serotonin Reuptake
agentS, gradually withdraw the drug(s) prior to initiating
Inhibitors; Simeprevir; Sodium Oxybate; Stiripentol;
buspirone.
Tapentadol; Tetrahydrocannabinol; Trimeprazine
Potentially life-threatening serotonin syndrome has Decreased Effect
occurred with serotonergic agents, including buspirone, BusPlRone may decrease the levels/effects of: |oflupane
particularly when used in combination with other seroto- 1123 :
- nergic agents (eg, triptans, TCAs, fentanyl, lithium, trama-
dol, buspirone, St John's wort, tryptophan) or agents that The levels/effects of BusP/Rone may be decreased by:
impair metabolism of serotonin (eg, MAOIs intended to Bosentan; CYP3A4 Inducers (Moderate); CYP3A4
treat psychiatric disorders, other MAOIs [ie, linezolid and Inducers (Strong); Dabrafenib; Deferasirox; Enzaluta-
IV methylene blue]). Monitor patients closely for signs of mide; Mitotane; Pitolisant; Sarilumab; Siltuximab; St
serotonin syndrome, such as mental status changes (eg, John's Wort; Tocilizumab; Yohimbine
agitation, hallucinations, delirium, coma); autonomic insta- Food Interactions Food may decrease the absorption of
bility (eg, tachycardia, labile blood pressure, diaphoresis, buspirone, but it may also decrease the first-pass metab-
flushing, hyperthermia); neuromuscular changes (eg, olism, thereby increasing the bioavailability of buspirone.
tremor, rigidity, myoclonus); Gl symptoms (eg, nausea, Grapefruit juice may cause increased buspirone concen-
vomiting, diarrhea); and/or seizures. Discontinue treat- trations. Management: Administer with or without food, but
ment (and any concomitant serotonergic agent) immedi- must be consistent. Avoid intake of large quantities of
ately if signs/symptoms arise. grapefruit juice.
Warnings: Additional Pediatric Considerations Bus- Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
pirone does not possess antipsychotic activity and should excursions permitted between 15°C to 30°C (59°F t
not be used in place of appropriate antipsychotic treat- 86°F). Protect from light.
ment; two pediatric cases of possible psychotic deterio- Mechanism of Action The mechanism of action of
ration have been reported (Soni, 1992). buspirone is unknown. Buspirone has a high affinity for
Adverse Reactions serotonin 5-HT,, and 5-HT> receptors, without affecting
Cardiovascular: Chest pain benzodiazepine-GABA receptors. Buspirone has moder-
Central nervous system: Abnormal dreams, ataxia, con- ate affinity for dopamine Dz receptors.
fusion, dizziness, drowsiness, excitement, headache, Pharmacodynamics/Kinetics (Adult data unless
nervousness, numbness, outbursts of anger, paresthesia noted)
Dermatologic: Diaphoresis, skin rash Absorption: Rapid and complete; bioavailability is limited
Gastrointestinal: Diarrhea, nausea, sore throat by extensive first-pass effect; only ~1% of the oral dose
Neuromuscular & skeletal: Musculoskeletal pain, tremor, reaches the systemic circulation unchanged
weakness Distribution: Vg: 5.3 L/kg (Gammans 1986)
Ophthalmic: Blurred vision Protein binding: ~86%
Otic: Tinnitus Metabolism: Hepatic oxidation, primarily via CYP3A4 to
Respiratory: Nasal congestion several metabolites including an active metabolite, 1-
Rare but important or life-threatening: Alcohol abuse, pyrimidinylpiperazine (1-PP; exhibits about 25% of the
alopecia, amenorrhea, angioedema, anorexia, bradycar- activity of buspirone); extensive first-pass effect
dia, bruise, cardiac failure, cardiomyopathy, cerebrovas- Bioavailability: Increased with food
cular accident, claustrophobia, cogwheel rigidity, Half-life elimination: 2 to 3 hours; increased with renal or
conjunctivitis, dyskinesia, dystonia, edema, eosinophilia, hepatic impairment
epistaxis, extrapyramidal reaction, galactorrhea, halluci- Time to peak, serum: 40 to 90 minutes
nation, hemorrhagic diathesis, hypersensitivity reaction, Excretion: Urine: 29% to 63% (primarily as metabolites);
hypertension, hyperventilation, hypotension, increased feces: 18% to 38%
intraocular pressure, increased serum ALT, increased Pharmacodynamics/Kinetics: Additional Consider-
serum AST, increased serum transaminases, irritable ations
bowel syndrome, leukopenia, memory impairment, men- Renal function impairment: AUC increased 4-fold.
strual disease, myocardial infarction, parkinsonian-like Hepatic function impairment: AUC increased 13-fold.
syndrome, pelvic inflammatory disease, personality dis- Dosing
order, photophobia, psychosis, rectal hemorrhage, rest- Pediatric Anxiety disorders: Children and Adolescents:
less leg syndrome, seizure, serotonin syndrome, slowed Oral: Limited information is available; dose is not well
reaction time, slurred speech, suicidal ideation, syncope, established. One pilot study of 15 children, 6-14 years of
thrombocytopenia, thyroid disease, urinary incontinence, age (mean 10 years), with mixed anxiety disorders, used
visual disturbance (tunnel vision) initial doses of 5 mg daily; doses were individualized with
Drug Interactions increases in increments of 5 mg/day every week as
Metabolism/Transport Effects Substrate of CYP2D6 needed to a maximum dose of 20 mg/day divided into
(minor), CYP3A4 (major); Note: Assignment of Major/ 2 doses; the mean dose required: 18.6 mg/day (Simeon,
Minor substrate status based on clinically relevant drug 1994). Some authors (Carrey, 1996 and Kutcher, 1992),
interaction potential. ob based on their clinical experience, recommend higher
Avoid Concomitant Use doses (eg, 15-30 mg/day in 2 divided doses). An open-
Avoid concomitant use of BusPlRone with any of the label study in 25 prepubertal inpatients (mean age: 8 +
following: Azelastine (Nasal); Bromperidol; Conivaptan; 1.8 years; range: 5-11 years) with anxiety symptoms and
Dapoxetine; Fusidic Acid (Systemic); Idelalisib; Methyl- moderately aggressive behavior used initial doses of
ene Blue; Monoamine Oxidase Inhibitors; Orphenadrine; 5 mg daily; doses were titrated upwards (over 3 weeks)
Oxomemazine; Paraldehyde; Thalidomide by 5-10 mg every 3 days to a maximum dose of
Increased Effect/Toxicity 50 mg/day; doses >5 mg/day were administered in 2
BusP/lRone may increase the levels/effects of: Alcohol divided doses/day; buspirone was discontinued in 25%
(Ethyl); Antipsychotic Agents; Azelastine (Nasal); Blo- of the children due to increased aggression and agitation
nanserin; Buprenorphine; CNS Depressants; Flunitraze- or euphoric mania; mean optimal dose (n=19):
pam; HYDROcodone; Methotrimeprazine; Methylene 28 mg/day; range: 10-50 mg/day; median: 30 mg/day
Blue; Metoclopramide; MetyroSINE; Mirtazapine; Mono- (Pfeffer, 1997). Two placebo-controlled 6-week trials in
amine Oxidase Inhibitors; Nefazodone; Opioid Analge- children and adolescents (n=559; age: 6-17 years) with
sics; Orphenadrine; OxyCODONE; Paraldehyde; generalized anxiety disorder studied doses of 7.5-30 mg
Piribedil; Pramipexole; ROPINIRole; Rotigotine; Selec- twice daily (15-60 mg/day); no significant differences
tive Serotonin Reuptake Inhibitors; Serotonin between buspirone and placebo with respect to >
325
BUSPIRONE

generalized anxiety disorder symptoms were observed Contraindications

(see package insert). Hypersensitivity to busulfan or any component of the
Renal Impairment: Pediatric Patients with impaired formulation; oral busulfan is contraindicated in patients
renal function demonstrated increased plasma levels without a definitive diagnosis of chronic myeloid leuke-
and a prolonged half-life of buspirone. Use in patients mia
with severe renal impairment not recommended. Canadian labeling: Additional contraindications (not in the
Hepatic Impairment: Pediatric Patients with impaired US labeling): Oral busulfan: Neutropenia or thrombocy-
hepatic function demonstrated increased plasma levels topenia; disease that has demonstrated resistance to
and a prolonged half-life of buspirone. Use in patients busulfan
with severe hepatic impairment not recommended. Warnings/Precautions [US Boxed Warning]: Severe
Administration Oral: Administer in a consistent manner in and prolonged bone marrow suppression commonly
occurs; reduce dose or discontinue oral busulfan for
relation to food (ie, either always with food or always
unusual suppression; may require bone marrow
without food); may administer with food to decrease Gl
biopsy. Hematopoietic progenitor cell transplantation
upset
is required to prevent potentially fatal complications
Monitoring Parameters Mental-status, signs and symp-
from prolonged myelosuppression due to IV busulfan.
toms of anxiety, liver and renal function; signs of dopa-
May result in severe neutropenia, thrombocytopenia, ane-
mine-related movement disorders (eg, dystonia, akathisia, mia, bone marrow failure, and/or severe pancytopenia;
pseudo-parkinsonism). pancytopenia may be prolonged (1 month up to 2 years)
Test Interactions The presence of buspirone may result and may be-reversible. When used for transplantation,
in a false positive on a urinary assay for metanephrine/ monitor CBC with: differential daily during treatment and
catecholamine; discontinue buspirone 248 hours prior to until engraftment. The onset of neutropenia is a median of
collection of urine sample for catecholamines. 4 days post-transplant; recovery is within a median of 13
Dosage Forms Excipient information presented when days following allogeneic transplant (with prophylactic G-
available (limited, particularly for generics); consult spe- CSF use in most patients). Thrombocytopenia occurred at
cific product labeling. a median of 5 to 6 days. Use with caution in patients with
Tablet, Oral, as hydrochloride: compromised bone marrow reserve (due to prior treat-
Generic: 5 mg, 7.5 mg, 10 mg, 15 mg, 30 mg ment or radiation therapy). Monitor closely for signs of
infection (due to neutropenia) or bleeding (due to throm-
@ Buspirone Hydrochloride see BusPlRone on page 324 bocytopenia). May require antibiotic therapy and platelet
@ Bussulfam see Busulfan on page 326 and red blood cell support.
Seizures have been reported with IV busulfan and with
Busulfan (byoo SUL fan) high-dose oral busulfan. When using as a conditioning
regimen for transplant, initiate prophylactic anticonvulsant
Medication Safety Issues therapy (eg, phenytoin, levetiracetam, benzodiazepines,
Sound-alike/look-alike issues: or valproic acid) prior to treatment. Use with caution in
Myleran may be confused with Alkeran, Leukeran, mel- patients predisposed to seizures, with a history of seiz-
phalan, Mylicon ures, head trauma, or with other medications associated
High alert medication: with inducing seizures. Phenytoin increases busulfan
This medication is in a class the Institute for Safe clearance by 215%; busulfan kinetics and dosing recom-
Medication Practices (ISMP) includes among its list of mendations for high-dose HSCT conditioning were studied
drug classes which have a heightened risk of causing with concomitant phenytoin. If alternate anticonvulsants
significant patient harm when used in error. are used, busulfan clearance may be decreased and
Other safety concerns: dosing should be monitored accordingly.
A solvent in IV busulfan, N, N-dimethylacetamide, is Bronchopulmonary dysplasia with pulmonary fibrosis
incompatible with many closed system transfer devices ("busulfan lung") is associated with chronic busulfan use;
(CSTDs) used for preparing injectable antineoplastics. onset is delayed with symptoms occurring at an average
The plastic components of CSTDs may dissolve and of 4 years (range: 4 months to 10 years) after treatment;
result in subsequent leakage and potential infusion of may be fatal. Symptoms generally include a slow onset of
dissolved plastic into the patient (ISMP [Smetzer cough, dyspnea, and fever (low-grade), although acute
2015)). symptomatic onset may also occur. Diminished diffusion
Brand Names: US Busulfex; Myleran capacity and decreased pulmonary compliance have been
Brand Names: Canada Busulfex; Myleran noted with pulmonary function testing. Differential diag-
Therapeutic Category Antineoplastic Agent, Alkylating nosis should rule out opportunistic pulmonary infection or
Agent leukemic pulmonary infiltrates; may require lung biopsy.
Generic Availability (US) May be product dependent Discontinue busulfan if toxicity develops. Pulmonary tox-
Use icity may be additive if administered with other cytotoxic
Oral: Palliative treatment of chronic myelogenous leuke- agents also associated with pulmonary toxicity. Cardiac
mia (CML) [FDA approved in pediatric patients (age not tamponade has been reported in children with thalasse-
specified) and adults]; has also been used as a con- mia treated with high-dose oral busulfan in combination
ditioning regimen prior to hematopoietic stem cell trans- with cyclophosphamide. Abdominal pain and vomiting
plant. Note: Although an FDA-labeled indication, the use
preceded tamponade in most children. Monitor for signs/
symptoms and evaluate/treat promptly if cardiac tampo-
of busulfan for palliative treatment of chronic myeloge-
nade is suspected. Busulfan has been causally related to
nous leukemia in pediatric patients is no longer consid-
the development of secondary malignancies (tumors and
ered a treatment option by experts.
acute leukemias); chromosomal alterations may also
Parenteral: Conditioning regimen prior to allogeneic hem-
occur. Busulfan is associated with a moderate emetic
atopoietic progenitor cell transplantation for CML in
potential (depending on dose and/or administration route);
combination with cyclophosphamide (FDA approved in antiemetics may be recommended to prevent nausea and
pediatric patients [age not specified] and adults) vomiting (Dupuis 2011).
Pregnancy Risk Factor D
Pregnancy Considerations High busulfan area under the concentration versus time
Adverse events were observed in animal reproduction curve (AUC) values (>1500 micromolareminute) are asso-
studies. May cause fetal harm if administered during ciated with increased risk of hepatic sinusoidal obstruction
pregnancy. The solvent in IV busulfan, DMA, is also syndrome (SOS; formerly called veno-occlusive disease
associated with teratogenic effects in animal studies. [VOD]) due to conditioning for allogenic HSCT; patients
with a history of radiation therapy, prior chemotherapy (23
Females of childbearing potential should use effective cycles), or prior stem cell transplantation are at increased
contraception to avoid pregnancy during treatment and risk; monitor liver function tests (serum transaminases,
for 6 months after completion of therapy. Males with alkaline phosphatase, and bilirubin) daily until 28 days
female partners of reproductive potential should use effec- post-transplant to detect hepatotoxicity (which may pre-
tive contraception during treatment and for 3 months after clude hepatic SOS). Oral busulfan doses above 16 mg/kg
completion of therapy. (based on IBW) and concurrent use with alkylating agents
may also increase the risk for hepatic SOS. The solvent in
Busulfan may impair fertility in females and males. IV busulfan, dimethylacetamide (DMA) may be associated
Breastfeeding Considerations It is not known if busul- with hepatotoxicity, hallucinations, somnolence, lethargy,
fan is present in breast milk. According to the manufac- and confusion. N,N-dimethylacetamide is incompatible
turer, the decision to discontinue breastfeeding during with many closed-system transfer devices (CSTDs) used
therapy or to discontinue busulfan should take into for preparing injectable antineoplastics (ISMP [Smetzer
account the benefits of treatment to the mother; breast- 2015]). [US Boxed Warning]: According to the manu-
feeding should be discontinued during IV busulfan treat- facturer, oral busulfan should not be used until CML
ment. diagnosis has been established. The responsible

326
 BUSULFAN

health care provider should be experienced in assess- Avoid Concomitant Use

ing response to chemotherapy. Cellular dysplasia in Avoid concomitant use of Busulfan with any of the
many organs has been observed (in addition to lung following: BCG (Intravesical); Deferiprone; Dipyrone;
dysplasia); giant hyperchromatic nuclei have been noted Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac-
in adrenal glands, liver, lymph nodes, pancreas, thyroid, cines (Live)
and bone marrow. May obscure routine diagnostic cyto- Increased Effect/Toxicity
logic exams (eg, cervical smear). Potentially significant Busulfan may increase the levels/effects of: Baricitinib;
drug-drug interactions may exist, requiring dose or fre- CloZAPine; Deferiprone; Fingolimod; |fosfamide; Leflu-
quency adjustment, additional monitoring, and/or selec- nomide; Natalizumab; Tofacitinib; Vaccines (Live)
tion of alternative therapy.
Adverse Reactions The levels/effects of Busulfan may be increased by:
Intravenous: Acetaminophen; Antifungal Agents (Azole Derivatives,
Cardiovascular: Atrial fibrillation, cardiac arrhythmia, car- Systemic); Blinatumomab; Chloramphenicol (Ophthal-
diac tamponade (children with thalassemia), cardiome- mic); Deferasirox; Denosumab; Dipyrone; MetroNIDA-
galy, catheter site thrombosis (central venous catheter), ZOLE (Systemic); Ocrelizumab; Palifermin;
chest pain, complete atrioventricular block, ECG abnor- Pimecrolimus; Promazine; Propacetamol;, Roflumilast;
mality, edema, flushing, hypertension, hypotension, left Tacrolimus (Topical); Trastuzumab
heart failure, pericardial effusion, tachycardia, thrombo- Decreased Effect
sis, vasodilatation, ventricular premature contractions Busulfan may decrease the levels/effects of: BCG (Intra-
Central nervous system: Agitation, anxiety, brain disease, vesical); Coccidioides immitis Skin Test; Lenograstim;
cerebral hemorrhage, chills, coma, confusion, delirium, Lipegfilgrastim; Nivolumab; Pidotimod; Sipuleucel-T; Ter-
depression, dizziness, drowsiness, hallucination, head- tomotide; Vaccines (Inactivated); Vaccines (Live)
ache, insomnia, lethargy, pain The levels/effects of Busulfan may be decreased by:
Dermatologic: Acne vulgaris, alopecia, erythema nodo- Echinacea; Fosphenytoin; Phenytoin
sum, exfoliative dermatitis, maculopapular rash, pruritus, Hazardous Drugs Handling Considerations
skin discoloration, skin rash, vesicular eruption, vesicu-
Hazardous agent (NIOSH 2016 [group 1)).
lobullous dermatitis
Endocrine & metabolic: Hot flash, hyperglycemia, hyper- Use appropriate precautions for receiving, handling,
volemia, hypocalcemia, hypokalemia, hypomagnesemia, administration, and disposal. Gloves (single) should be
hyponatremia, hypophosphatemia, weight gain worn during receiving, unpacking, and placing in storage.
Gastrointestinal: Abdominal pain, anorexia, constipation,
NIOSH recommends single gloving for administration of
dyspepsia, esophagitis, diarrhea, gastrointestinal. full-
intact tablets or capsules. If manipulating tablets/capsules
ness, hematemesis, hiccups, intestinal obstruction,
(eg, to prepare an oral suspension), NIOSH recommends
mucositis, nausea (more common in adults), pancreati-
double gloving, a protective gown, and preparation in a
tis, rectal disease, rectal pain, stomatitis (more common
controlled device; if not prepared in a controlled device,
in adults), vomiting, xerostomia
Genitourinary: Dysuria, hematuria, hemorrhagic cystitis, respiratory and eye/face protection as well as ventilated
oliguria engineering controls are recommended. NIOSH recom-
mends double gloving, a protective gown, and (if there is a
Hematologic & oncologic: Anemia, bone marrow depres-
potential for vomit or spit up) eye/face protection for
sion, lymphocytopenia (children), neutropenia (onset: 4
days; median recovery: 13 days [with G-CSF support]), administration of an oral liquid/feeding tube administra-
tion. For IV preparation, NIOSH recommends double
prolonged prothrombin time, thrombocytopenia (median
onset: 5 to 6 days) gloving, a protective gown, ventilated engineering controls
Hepatic: Hepatic sinusoidal obstruction syndrome (for- (a class II biological safety cabinet or a compounding
merly known as hepatic veno-occlusive disease; more aseptic containment isolator), and (if compatible) closed
common in children), hepatomegaly, hyperbilirubinemia, system transfer devices (CSTDs). Double gloving, a
increased serum alkaline phosphatase, increased serum gown, and (if compatible and dosage form allows) CSTDs
ALT, jaundice are required during IV administration (NIOSH 2016).
Hypersensitivity: Hypersensitivity reaction Storage/Stability
Immunologic: Graft versus host disease (children) Injection: Store intact vials under refrigeration at 2°C to
Infection: Infection 8°C (36°F to 46°F). Solutions diluted in sodium chloride
Local: Inflammation at injection site, pain at injection site (NS) injection or dextrose 5% in water (D5W) for infusion
Neuromuscular & skeletal: Arthralgia, back pain, myalgia, are stable for up to 8 hours at room temperature (25°C
weakness [77°F]); the infusion must also be completed within that
Otic: Ear disease 8-hour timeframe. Dilution of busulfan injection in NS is
Renal: Increased blood urea nitrogen, increased serum stable for up to 12 hours refrigerated (2°C to 8°C); the
creatinine infusion must be completed within that 12-hour time-
Respiratory: Asthma, atelectasis, cough, dyspnea, epis- frame.
taxis, hemoptysis, hyperventilation, hypoxia, pharyngitis, Tablet: Store at 25°C (77°F); excursions permitted to 15°C
pleural effusion, pneumonia (children), pulmonary alveo- to 30°C (59°F to 86°F).
lar hemorrhage, pulmonary disease, pulmonary intersti- Mechanism of Action Busulfan is an alkylating agent
tial fibrosis, rhinitis, sinusitis which reacts with the N-7 position of guanosine and
Miscellaneous: Fever interferes with DNA replication and transcription of RNA.
Busulfan has a more marked effect on myeloid cells than
Oral: on lymphoid cells and is also very toxic to hematopoietic
Central nervous system: Seizure (despite prophylactic stem cells. Busulfan exhibits little immunosuppressive
seizure therapy) activity. It interferes with the normal function of DNA by
Dermatologic: Skin hyperpigmentation alkylation and cross-linking the strands of DNA.
Endocrine & metabolic: Amenorrhea, ovarian failure Pharmacodynamics/Kinetics (Adult data unless
Hematologic & oncologic:. Bone marrow depression
noted)
(including anemia, leukopenia, thrombocytopenia),
Absorption: Rapid and complete
pancytopenia
Distribution: Vg: Pediatric (IV): ~0.64 L/kg; crosses blood
Respiratory: Pulmonary interstitial fibrosis
brain barrier and distributes into CSF with levels equal to
IV and/or Oral: Rare but important or life-threatening: plasma
Acute leukemia, adrenocortical insufficiency, alopecia Protein binding: ~32% to plasma proteins and 47% to red
(permanent), aplastic anemia (may be irreversible), blood cells
azoospermia, capillary leak syndrome, cardiomyopathy Metabolism: Extensively hepatic (may increase with multi-
(endocardial fibrosis), cataract (rare), cheilosis, choles- ple doses); glutathione conjugation followed by oxidation
tatic jaundice, corneal thinning, erythema multiforme, Bioavailability: Oral: Children 213 years and adults: 80%
esophageal varices (with continuous busulfan and thio- (range: 47% to 103%); Children 1.5 to 6 years: 68%
guanine therapy), febrile neutropenia, fragile skin, gyne- (range: 22% to 120%)
comastia, hepatic fibrosis (centrilobular sinus), hepatic Half-life elimination: 2 to 3 hours
necrosis, hepatic sinusoidal obstruction syndrome (for- Time to peak, serum: Oral: ~1 hour; lV: Within 5 minutes
merly known as hepatic veno-occlusive disease) (oral), Excretion: Urine (25% to 60% predominantly as metabo-
lens disease (including particulate matter deposition), lites; <2% as unchanged drug)
malignant neoplasm, myasthenia gravis, porphyria cuta- Clearance: Children: 3.37 mL/minute/kg; Adults: 2.52
nea tarda, pulmonary fibrosis (with bronchopulmonary mL/minute/kg (range: 1.49 to 4.31 mL/minute/kg)
dysplasia), recall skin sensitization (skin rash), sepsis, Pharmacodynamics/Kinetics: Additional Consider-
sterility, testicular atrophy, thrombotic thrombocytopenic ations Renal function impairment: In a patient with
purpura, tumor lysis syndrome chronic renal failure undergoing autologous stem cell
Drug Interactions transplantation, the apparent oral clearance of busulfan
Metabolism/Transport Effects None known. during a 4-hour hemodialysis session was increased 65%, »
BUSULFAN

but the 24-hour oral clearance of busulfan was increased Acute Myeloid Leukemia: Limited data available:
only 11%. Adolescents 216 years: Oral: 1 mg/kg/dose every
Dosing 6 hours for 16 doses on days -9 to -6 in combina-
Pediatric Note: Dose, frequency, number of doses, and/ tion with cyclophosphamide (Cassileth 1998)
or start date may vary by protocol and treatment phase. Thalassemia major. Limited data available: |
Refer to individual protocols and/or therapeutic drug Class 1 or Class 2 (ie, low-risk for GVHD or trans-
monitoring. Premedicate with prophylactic anticonvul- plant mortality):
sant therapy (eg, phenytoin, levetiracetam, benzodiaze- Infants and Children <3 years: Oral: 1.25 mg/kg
pines, or valproic acid) beginning 12 hours prior to high- every 6 hours for 16 doses on day -9 to day -6
dose busulfan treatment and continuing for 24 hours prior to transplant in combination with cyclo-
after last busulfan dose. phosphamide and antithymocyte globulin
Dosing presented as mg/kg and mg/m?; use extra pre- (horse) (Hussein 2013)
caution. Busulfan is associated with a moderate emetic Children 23 years and Adolescents: Oral:
potential (depending on dose and/or administration 1 mg/kg/dose every 6 hours for 16 doses prior
route); antiemetics are recommended to prevent nau- to transplant; on days -9 to -6 in combination
sea and vomiting (Dupuis 2011). Antiemetics are rec- with cyclophosphamide and antithymocyte glob-
ommended when used for transplantation.
ulin (horse) (Hussein 2013)
Hematopoietic stem cell transplant (HSCT) condi-
Class 3 (ie, high-risk disease): Children 210 years
tioning regimen:
and Adolescents: Oral: 2 mg/kg/dose every 12
IV: Infants, Children, and Adolescents: Note: Dosing
hours.for 4 doses on days -8 and -7 in combina-
based on actual body weight, including obese indi-
viduals (Bubalo 2014): tion with fludarabine and antithymocyte globulin
Initial: Therapeutic drug monitoring should be con- (horse) (Hussein 2013)
sidered early in regimen (eg, after first dose) and Renal Impairment: Pediatric
doses adjusted accordingly. IV: There are no dosage adjustments provided in the
$12 kg: IV: 1.1 mg/kg/dose every 6 hours for 16 manufacturer's labeling (has not been studied).
doses (over 4 days followed by cyclophosphamide) Oral: There are no dosage adjustments provided in the
>12 kg: IV: 0.8 mg/kg/dose every 6 hours for 16 manufacturer's labeling; elimination appears to be inde-
doses (over 4 days followed by cyclophosphamide) pendent of renal function; some clinicians suggest
Dosing adjustment: Doses adjusted based upon adjustment is not necessary (Aronoff 2007).
AUC or steady state concentration (CSS) depend- Hepatic Impairment: Pediatric
ing upon protocol. The desired AUCs or CSSs are IV: There are no dosage adjustments provided in the
variable and may be dependent upon multiple manufacturer's labeling (has not been studied).
factors, including indication for transplant, type of Oral: There are no dosage adjustments provided in the
transplant, and donor source; specific protocols manufacturer's labeling.
should be consulted. A desired AUC of 900 to Preparation for Administration Parenteral: Dilute with
1,350 micromolar/minute has been suggested per NS or D5W. The dilution volume should be 10 times the
the manufacturer, and CSS of 600 to 900 ng/mL +
volume of busulfan injection, ensuring that the final con-
10% has also been reported (Bolinger 2013; Horn
centration of busulfan is 0.5 mg/mL. Always add busulfan
2006; Law 2012). Adjusted dose may be deter-
to the diluent, and not the diluent to the busulfan. Mix with
mined from the following formulas:
several inversions. Do not use polycarbonate syringes or
Adjusted dose (mg) = Actual dose (mg) x [target
filter needles for preparation or administration. Busulfan
AUC (micromolareminute) / actual AUC (micro-
molareminute)]} for injection contains N,N-dimethylacetamide, which is
Adjusted dose (mg) = Actual dose (mg) x [target incompatible with many closed-system transfer devices
CSS (ng/mL) / actual CSS (ng/mL)] (CSTDs); the plastic components of CSTDs may dissolve
Reduced intensity conditioning regimens: Limited and result in subsequent leakage and potential infusion of
data available: dissolved plastic into the patient (ISMP [Smetzer 2015]).
12-dose regimen: Children 22 and Adolescents: IV: Administration Busulfan is associated with a moderate
0.8 mg/kg/dose every 6 hours for 12 doses start- emetic potential (depending on dose and/or administration
ing on Day -6; used in combination with fludar- route); antiemetics may be recommended to prevent
abine and melphalan for patients receiving nausea and vomiting (Dupuis 2011). Antiemetics are rec-
haploidentical, peripheral blood HSCT for acute ommended when used for transplantation.
leukemia (Jaiswal 2015) Oral: May be administered without regard to meals. To
8-dose regimen: Infants, Children, and Adoles- facilitate ingestion of high doses (for HSCT), may insert
cents: 0.8 mg/kg/dose for one dose on either multiple tablets into clear gelatin capsules for adminis-
day -7 (related donor) or day -10 (unrelated donor tration.
or cord recipient) prior to transplant, followed by 7 Parenteral: Infuse over 2 hours through a central venous
additional doses of ~0.8 mg/kg/dose every 6 catheter; use an administration set with a minimal resid-
hours (actual dose based on pharmacokinetic ual priming volume (2 to 5 mL for adults and 1 to 3 mL for
analysis after initial dose) beginning days -3 and pediatric patients); flush line before and after each
-2 (related donor) or days -6:and -5 (unrelated infusion with 5 mL of DSW or NS. Do not use polycar-
donor or cord recipient) prior to transplant; used bonate syringes or filter needles for preparation or
in combination with fludarabine and antithymo- administration. j
cyte globulin (rabbit). In clinical trials, there was
Vesicant/Extravasation Risk May be an irritant
no minimum age for inclusion; the youngest
patient treated was 2 years (Pulsipher 2009).
Monitoring Parameters CBC with differential and plate-
Once-Daily Dosing: Limited data available: Note: let count (weekly for palliative treatment in adults; daily
Dosing based on actual body weight up to 120% until engraftment for HSCT); liver function tests, bilirubin,
of IBW, then dose based on adjusted dosing and alkaline phosphatase daily through 28 days post
weight (ideal body weight plus 50% of the differ- transplant.
ence between ideal and actual weight) based on If conducting therapeutic drug monitoring for AUC calcu-
experience from adult patients (De Lima 2004). lations in HSCT, monitor busulfan plasma concentrations
Infants <1 year: |V: 80 mg/m?2/dose over 3 hours at appropriate collection times (record collection times);
once daily for 4 days prior to HSCT, starting on
for IV infusion; collect blood sample from a different port
Day -8 (combined with cyclophosphamide or
than that used for infusion. Blood samples should be
fludarabine and etoposide); dose adjustment
placed on wet ice immediately after collection and should
(Days -7 to -5) to target AUC 4,384 to 4,628
be centrifuged (at 4°C [39.2°F]) within 1 hour. The
micromolareminute/liter/day has been reported
plasma, harvested into appropriate cryovial storage
(Lee 2012; Lee 2015)
Children 21 year and Adolescents: IV: 120 mg/ tubes, should be frozen immediately at -20°C (-4°F). All
m?/dose over 3 hours once daily for 4 days prior plasma samples should be sent frozen (on dry ice) to the
to HSCT, starting on Day -8 (combined with assay laboratory for the determination of plasma busul-
cyclophosphamide or fludarabine and etopo- fan concentrations. Specific collection times may vary,
side); dose adjustment (Days -7 to -5) to target consult specific protocols; for calculating AUC, the man-
AUC 4,384 to 4,628 micromolareminute/liter/day ufacturer suggests the following:
has been reported (Lee 2012; Lee 2015) From the end of the infusion of the first dose, collect at 2
Oral: Note: Dosing based on actual body weight, hours, 4 hours, and 6 hours (immediately prior to the
including obese individuals (Bubalo 2014): Note: next dose).
Not routinely used for HSCT conditioning regimens, Any other dose, collect a pre-infusion concentration, then
\V formulation is the preferred dosage form. Dosing at 2 hours (end of infusion), 4 hours, and 6 hours
variable dependent upon indication for HSCT. (immediately prior to the next dose).

328
 BUTALBITAL, ACETAMINOPHEN, AND CAFFEINE

Dosage Forms Excipient information presented when such) as acute generalized exanthematous pustulosis,
available (limited, particularly for generics); consult spe- Stevens-Johnson syndrome (SJS), and toxic epidermal
cific product labeling. necrolysis (TEN). Discontinue treatment if severe skin
Solution, Intravenous: reactions develop. May cause CNS depression, which
Busulfex: 6 mg/mL (10 mL) may impair physical or mental abilities; patients must be
Generic: 6 mg/mL (10 mL) cautioned about performing tasks which require mental
Solution, Intravenous [preservative free]: alertness (eg, operating machinery or driving). Effects
Generic: 6 mg/mL (10 mL) may be potentiated when used with other sedative drugs
Tablet, Oral: or ethanol. Use caution in patients with acute abdominal
Myleran: 2 mg conditions. Use with caution in patients with history of drug
Extemporaneous Preparations A 2 mg/mL oral -sus- abuse, known G6PD deficiency, severe hepatic impair-
pension can be prepared in a vertical flow hood with ment, severe renal impairment, respiratory disease. Caf-
tablets and simple syrup. Crush one-hundred-twenty feine may cause CNS and cardiovascular stimulation, as
2 mg tablets in a mortar and reduce to a fine powder. well as Gl irritation in high doses. Use with caution in
Add small portions of simple syrup and mix to a uniform patients with a history of peptic ulcer or GERD; avoid in
paste; mix while adding the simple syrup in incremental patients with symptomatic cardiac arrhythmias. Potentially
proportions to almost 120 mL; transfer to a graduated significant drug-drug interactions may exist, requiring
cylinder, rinse mortar and pestle with simple syrup, and dose or frequency adjustment, additional monitoring,
add quantity of vehicle sufficient to make 120 mL. Transfer and/or selection of alternative therapy.
contents of the graduated cylinder into an amber prescrip- Warnings: Additional Pediatric Considerations
tion bottle. Label "shake well", "refrigerate", and "caution Some dosage forms may contain propylene glycol; in
chemotherapy". Stable for 30 days. neonates large amounts of propylene glycol delivered
Allen LV, "Busulfan Oral Suspension," US Pharm, 1990, 15:94-5. orally, intravenously (eg, >3,000 mg/day), or topically
have been associated with potentially fatal toxicities which
@ Busulfanum see Busulfan on page 326
can include metabolic acidosis, seizures, renal failure, and
Busulfex see Busulfan on page 326 CNS depression; toxicities have also been reported in
@ Busulphan see Busulfan on page 326 children and adults including hyperosmolality, lactic acido-
Butalb/Acetaminophen/Caffeine see Butalbital, Acet- sis, seizures, and respiratory depression; use caution
aminophen, and Caffeine on page 329 (AAP 1997; Shehab 2009).
Adverse Reactions Also see individual agents.
Cardiovascular: Tachycardia
Butalbital, Acetaminophen, and Caffeine Central nervous system: Agitation, confusion, depression,
(byoo TAL bi tal, a seet a MIN oh fen, & KAF een) dizziness, drowsiness, euphoria, excitement, fatigue,
Medication Safety Issues headache, increased energy, intoxicated feeling, leth-
argy, numbness, paresthesia, sedation, seizure, shak-
Sound-alike/look-alike issues:
iness
Fioricet may be confused with Fiorinal, Florinef, Lorcet,
Percocet Dermatologic: Hyperhidrosis, pruritus
Repan may be confused with Riopan Endocrine & metabolic: Hot flash
Gastrointestinal: Abdominal pain, constipation, dysphagia,
Geriatric Patients: High-Risk Medication:
flatulence, heartburn, nausea, vomiting, xerostomia
Beers Criteria: Butalbital is identified in the Beers Criteria
as a potentially inappropriate medication to be avoided
Genitourinary: Diuresis
in patients 65 years and older (independent of diag- Hypersensitivity: Hypersensitivity reaction
nosis or condition) due to its high rate of physical Neuromuscular & skeletal: Leg pain, muscle fatigue
dependence, tolerance to sleep benefits, and
Ophthalmic: Heavy eyelids
Otic: Otalgia, tinnitus
increased risk of overdose at low dosages (Beers
Criteria [AGS 2015]). Respiratory: Nasal congestion
Pharmacy Quality Alliance (PQA): Butalbital is identified Miscellaneous: Fever
as a high-risk medication in patients 65 years and older Rare but important or life-threatening: Acute generalized
on the PQA’s, Use of High-Risk Medications in the exanthematous pustulosis, erythema multiforme, Ste-
Elderly (HRM) performance measure, a safety meas- vens-Johnson syndrome, toxic epidermal necrolysis
ure used by the Centers for Medicare and Medicaid Drug Interactions
Services (CMS) for Medicare plans. Metabolism/Transport Effects Refer to individual
Other safety concerns: components.
Duplicate therapy issues: This product contains acetami- Avoid Concomitant Use
nophen, which may be a component of other combina- Avoid concomitant use of Butalbital, Acetaminophen,
tion products. Do not exceed the maximum and Caffeine with any of the following: Acebrophylline;
recommended daily dose of acetaminophen. Azelastine (Nasal); Bromperidol; Doxofylline; Hemin;
Brand Names: US Alagesic LQ; Esgic; Fioricet; Margesic lobenguane | 123; Methoxyflurane; Mianserin; Orphena-
[DSC]; Vanatol LQ; Zebutal drine; Oxomemazine; Paraldehyde; Somatostatin Ace-
Therapeutic Category Analgesic, Miscellaneous; Barbi- tate; Stiripentol; Thalidomide; Ulipristal; Voriconazole
turate Increased Effect/Toxicity
Generic Availability (US) Yes: Capsule, tablet Butalbital, Acetaminophen, and Caffeine may increase
Use Treatment of tension or muscle contraction headache the levels/effects of: Azelastine (Nasal); Blonanserin;
(FDA approved in ages 212 years and adults) Blood Pressure Lowering Agents; Buprenorphine; Busul-
| Pregnancy Risk Factor C fan; CloZAPine; CNS Depressants; Dasatinib; Doxofyl-
line; Flunitrazepam; Formoterol; HYDROcodone;
Pregnancy Considerations Animal reproduction studies
Imatinib; Indacaterol; lohexol; lomeprol; lopamidol:;
have not been conducted with this combination. With-
Methotrimeprazine; Methoxyflurane; MetyroSINE; Mipo-
drawal seizures were reported in an infant 2 days after
mersen; Mirtazapine; Olodaterol; Opioid Analgesics;
birth following maternal use of a butalbital product during
Orphenadrine; OxyCODONE; Paraldehyde; Phenylephr-
the last 2 months of pregnancy; butalbital was detected in
ine (Systemic); Piribedii; Pramipexole; Prilocaine; ROPI-
the newborns serum. Also refer to individual monographs
NIRole; Rotigotine; Selective Serotonin Reuptake
for information specific to acetaminophen or caffeine:
Inhibitors; Sodium Nitrite; SORAfenib; Suvorexant; Sym-
Breastfeeding Considerations Barbiturates, caffeine,
pathomimetics; Thalidomide; Thiazide and Thiazide-Like
and acetaminophen are excreted in breast milk. Also refer
Diuretics; TIZANidine; Zolpidem
to individual agents for information specific to acetamino-
phen or caffeine. The levels/effects of Butalbital, Acetaminophen, and
Contraindications Hypersensitivity or intolerance to any Caffeine may be increased by: Abiraterone Acetate;
component of the formulation; porphyria ~ Acebrophylline; Alcohol (Ethyl); AtoMOXetine; Brimoni-
Warnings/Precautions [US Boxed Warning]: Acetami- dine (Topical); Bromopride; Bromperidol; BuPROPion;
nophen may cause severe hepatotoxicity, potentially Cannabis; Chloramphenicol (Systemic); Chlormethia-
requiring liver transplant or resulting in death; hep- zole; Chlorphenesin Carbamate; Ciprofloxacin (Sys-
atotoxicity is usually associated with excessive acet- temic); Cocaine (Topical); CYP1A2 Inhibitors
aminophen intake (>4 g/day). Risk is increased with (Moderate); CYP1A2 Inhibitors (Strong); Dapsone (Top-
alcohol use, preexisting liver disease, and intake of more ical); Dasatinib; Deferasirox; Dimethindene (Topical);
than one source of acetaminophen-containing medica- Doxylamine; Dronabinol; Droperidol; Felbamate; Flu-
tions. Chronic daily dosing in adults has also resulted in cloxacillin; Guanethidine; HydrOXYzine; Isoniazid; Kava
liver damage in some patients. Hypersensitivity and ana- Kava; Linezolid; Lofexidine; Magnesium Sulfate; Metho-
phylactic reactions have been reported with acetamino- trimeprazine; MetyraPONE; Mianserin; Minocycline;
phen use; discorjtinue immediately if symptoms of allergic Nabilone; Nitric Oxide; Norfloxacin; Obeticholic Acid;
. or hypersensitivity reactions occur. Rarely, acetaminophen Oxomemazine; Peginterferon Alfa-2b; Perampanel;
may cause serious and potentially fatal skin reactions Pipemidic Acid; Primidone; Probenecid; Rufinamide;

329
BUTALBITAL, ACETAMINOPHEN, AND CAFFEINE

Sodium Oxybate; Somatostatin Acetate; SORAfenib; Vanatol LQ: Butalbital 50 mg, acetaminophen 325 mg,
Stiripentol; Tapentadol; Tedizolid; Tetracaine (Topical); and caffeine 40 mg per 15 mL (480 mL) [contains
Tetrahydrocannabinol; Trimeprazine; Valproate Prod- ethanol 7%; propylene glycol]
ucts; Vemurafenib Tablet, oral: j I
Decreased Effect Esgic: Butalbital 50 mg, acetaminophen: 325 mg, and
Butalbital, Acetaminophen, and Caffeine may decrease caffeine 40 mg
the levels/effects of: Adenosine; Beta-Blockers; Calcium Generic: Butalbital 50 mg, acetaminophen 325 mg, and
Channel Blockers; Chloramphenicol (Systemic); Cyclo- caffeine 40 mg
SPORINE (Systemic); Doxycycline; Estrogen Deriva- ¢ Butrans see Buprenorphine on page 311
tives (Contraceptive); Felbamate; Griseofulvin; Hemin;
lobenguane | 123; LamoTRigine; Lithium; Methoxyflur- @ BW-430C see LamoTRigine on page 1174
ane; Mianserin; Progestins (Contraceptive); Propaceta- @ BW524W91 see Emtricitabine on page 726
mol; Regadenoson; Teniposide; Theophylline @ BWB1090U see Mivacurium on page 1389
Derivatives; Tricyclic Antidepressants; Ulipristal; Val-
@ Ci Esterase Inhibitor see C1 Inhibitor (Human)
proate Products; Vitamin K Antagonists; Voriconazole on page 330
The levels/effects of Butalbital, Acetaminophen, and @ C1-INH see C1 Inhibitor (Human) on page 330
Caffeine may be decreased by: Barbiturates; CarBAMa- @ C1-Inhibitor see C1 Inhibitor (Human) on page 330
zepine; Fosphenytoin-Phenytoin; Mianserin; Multivita-
mins/Minerals (with ADEK, Folate, Iron); Pyridoxine;
@ C1INHRP see C1 Inhibitor (Human) on page 330
Rifamycin Derivatives; Teriflunomide @ C2B8 Monoclonal Antibody see RiTUXimab
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). on page 1779
Mechanism of Action 311C90 see ZOLMitriptan on page 2094
Butalbital: Short- to intermediate-acting barbiturate. Barbi- @ C-500 [OTC] see Ascorbic Acid on page 186
turates depress the sensory cortex, decrease motor
activity, alter cerebellar function, and produce drowsi-
ness, sedation, hypnosis, and dose-dependent respira- C1 Inhibitor (Human) (cee won in-HIB
iterHYU man)
tory depression.
Brand Names: US Berinert; Cinryze; Haegarda
Acetaminophen: Although not fully elucidated, the analge-
Brand Names: Canada Berinert; Cinryze; Haegarda
sic effects are believed to be due to activation of
Therapeutic Category Blood Product Derivative
descending serotonergic inhibitory pathways in the
CNS. Interactions with other nociceptive systems may Generic Availability (US) No
be involved as well (Smith 2009). Antipyresis is pro- Use
duced from inhibition of the hypothalamic heat-regulating Berinert: Treatment of acute abdominal, facial, or laryng-
center. eal attacks of hereditary angioedema (HAE) (FDA
Caffeine: Increases levels of 3'5' cyclic AMP by inhibiting approved in pediatric patients [age not specified] and
phosphodiesterase; CNS stimulant which increases adults)
Cinryze, Haegarda: Routine prophylaxis against angioe-
medullary respiratory center sensitivity to carbon dioxide,
dema attacks in patients with HAE (FDA approved in
stimulates central inspiratory drive, and improves skel-
adolescents and adults); Cinryze has also been used for
etal muscle contraction (diaphragmatic contractility).
treatment of acute abdominal, facial, and laryngeal
Pharmacodynamics/Kinetics (Adult data unless
attacks of HAE
noted) Also see individual monographs for Acetamino-
Prescribing and Access Restrictions Assistance with
phen and Caffeine. procurement and reimbursement of Cinryze is available
Absorption: Butalbital: Well absorbed
for health care providers and patients through the CINRY-
Protein binding: Butalbital: 45% ZESolutions program (telephone: 1-877-945-1000) or at
Half-life elimination: Butalbital: 35 hours http://www.cinryze.com/Cinryze_Solutions/Default.aspx
Excretion: Butalbital: Urine (59% to 88% as unchanged Pregnancy Considerations
drug and metabolites) C1 esterase inhibitor is endogenous to human plasma.
Dosing Information is available following maternal administration
Pediatric for the prevention and treatment of hereditary angioedema
Note: Dosing based on products containing: Butalbital (HAE) attacks, and use has not been associated with
50 mg, acetaminophen 325 mg, and caffeine 40 mg adverse pregnancy outcomes due to C1 inhibitor (human)
per 15 mL solution or per tablet/capsule. Some for- (Baker 2013; Fox 2017; Martinez-Saguer 2010).
mulations may contain more acetaminophen; consult
product-specific labeling. C1 inhibitor (human) is the preferred treatment for HAE
Headache, tension or muscle contraction: Children during pregnancy and may be used for acute attacks,
212 years and Adolescents: Oral: 1 to 2 tablets or short-term prophylaxis, and long-term prophylaxis. Pre-
capsules or 15 to 30 mL solution every 4 hours; procedural prophylaxis before uncomplicated natural
maximum daily dose: 6 tablets or capsules/day or delivery is not mandatory; however, C1 inhibitor (human)
90 mL/day of solution should be immediately available for on-demand use. Pre-
Renal Impairment: Pediatric There are no dosage procedural prophylaxis is recommended before labor and
delivery when symptoms have been recurring frequently
adjustments provided in the manufacturer's labeling;
during the third trimester and the patient's history includes
use with caution, especially with severe impairment.
genital edema caused by mechanical trauma; during
Hepatic Impairment: Pediatric There are no dosage
forceps delivery or vacuum extraction; before a caesarean
adjustments provided in the manufacturer's labeling; use
section; before surgery or general anesthesia when intu-
with caution, especially with severe impairment.
bation is required; and before interventions such as cho-
Administration May take without regard to food; if Gl rionic villus sampling, amniocentesis, and induced
upset occurs, may take with food; use measuring device surgical abortion. Women with HAE should be monitored
for liquid preparation, not household spoon closely during pregnancy and for at least 72 hours after
Test Interactions Acetaminophen may produce false- delivery (WAO/EEACI [Maurer 2018)).
positive tests for urinary 5-hydroxyindoleacetic acid. Breastfeeding Considerations
Dosage Forms Excipient information presented when It is not known if C1 inhibitor (human) is present in breast
available (limited, particularly for generics); consult spe- milk following maternal administration; however, C1
cific product labeling. [DSC] = Discontinued product esterase inhibitor is endogenous to human plasma.
Capsule, oral: According to the manufacturer, the decision to breastfeed
Esgic: Butalbital 50 mg, acetaminophen 325 mg, and during therapy should take into account the risk of infant
caffeine 40 mg exposure, the benefits of breastfeeding to the infant, and
Fioricet: Butalbital 50 mg, acetaminophen 300 mg, and benefits of treatment to the mother. Lactation may
caffeine 40 mg increase the frequency of attacks, and women should
Margesic: Butalbital 50 mg, acetaminophen 325 mg, and be monitored closely. C1 inhibitor (human) is the pre-
caffeine 40 mg [DSC] ferred treatment for HAE during lactation (WAO/EEACI
Zebutal: Butalbital 50 mg, acetaminophen 325 mg, and [Maurer 2018]).
caffeine 40 mg Contraindications History of anaphylactic or life-threat-
Generic: Butalbital 50 mg, acetaminophen 300 mg, and ening hypersensitivity reactions to C1 inhibitor (human) or
caffeine 40 mg; Butalbital 50 mg, acetaminophen any component of the formulation
325 mg, and caffeine 40 mg Warnings/Precautions Severe hypersensitivity reactions
Liquid, oral: (eg, urticaria, hives, tightness of the chest, wheezing,
Alagesic LQ: Butalbital 50 mg, acetaminophen 325 mg, hypotension, anaphylaxis) may occur during or after
and caffeine 40 mg per 15 mL (480 mL) [contains administration. Signs/symptoms of hypersensitivity reac-
ethanol 7%; propylene glycol] tions may be similar to the attacks associated with
 C1 INHIBITOR (HUMAN)

hereditary angioedema, therefore, consideration should Half-life elimination:

be given to treatment methods. In the event of acute or Berinert:
severe hypersensitivity reactions, discontinue treatment Children and Adolescents (6 to 13 years, n=5): 22
immediately. Serious arterial and venous thromboembolic hours (range: 20 to 24 hours)
events have been reported at recommended doses and Adults (following a single dose): 22 hours (range: 17 to
when used off-label at doses higher than recommended. 24 hours)
Risk factors may include the presence of an indwelling Cinryze: Adults: 56 hours (range: 11 to 108 hours)
venous catheter/access device, prior history of thrombo- Haegarda: Adolescents and Adults: 69 hours
sis, underlying atherosclerosis, use of oral contraceptives Time to peak: Cinryze: ~4 hours; Haegarda: 59 hours
or certain androgens, morbid obesity, and immobility. Dosing
Consider potential risk of thrombosis with use, and closely Pediatric Note: Products are not interchangeable.
monitor patients with preexisting risks for thrombotic Hereditary angioedema (HAE) attacks; routine pro-
events. Product of human plasma; may potentially contain phylaxis:
infectious agents (eg, viruses, the variant Creutzfeldt- Cinryze: Children 26 years (limited data available)
Jakob disease [vCJD] agent and, theoretically, the Creutz- and Adolescents: IV: 1,000 units every 3 to 4 days
feldt-Jakob disease [CJD] agent) that could transmit dis- (ie, twice weekly) (Lumry 2013); according to the
ease. Screening of donors, as well as testing and/or manufacturer's labeling, in adolescents and adults if
inactivation or removal of certain viruses, reduces the risk. an adequate response it not achieved, doses up to
Infections thought to be transmitted by this product should 2,500 units (S100 units/kg/dose) every 3 to 4 days
be reported to the manufacturer. Due to the potential for may be considered.
airway obstruction, patients suffering from an acute lar- Haegarda: Adolescents: SubQ: 60 units/kg/dose
yngeal hereditary angioedema (HAE) attack and self- every3or4days .
administering should be informed to immediately seek Hereditary angioedema (HAE) attacks (abdominal,
medical attention following treatment. facial or laryngeal); treatment:
Adverse Reactions Berinert: Children 25 years and Adolescents: IV: 20
Central nervous system: Dizziness, headache units/kg
Dermatologic: Erythema, pruritus, skin rash Cinryze: Limited data available: Children 26 years and
Gastrointestinal: Abdominal distress, abdominal pain, dys- Adolescents: IV: 1,000 units; may repeat dose in 1
geusia, nausea, vomiting, xerostomia hour if needed (Lumry 2013)
Hypersensitivity: Angioedema (including exacerbation of Renal Impairment: Pediatric There are no dosage
hereditary angioedema), hypersensitivity reaction adjustments provided in the manufacturer's labeling
Infection: Fungal infection (vulvovaginal), viral infection (has not been studied).
Local: Injection site reaction Hepatic Impairment: Pediatric There are no dosage
Respiratory: Flu-like symptoms, nasopharyngitis, upper adjustments provided in the manufacturer's labeling (has
respiratory tract infection not been studied).
Miscellaneous: Fever, infusion-related reaction Preparation for Administration Parenteral: Allow vial
Rare but important or life-threatening: Anaphylaxis, anxi- and diluent (SWF) to come to room temperature prior to
ety, cerebrovascular accident, chest pain, chills, deep reconstitution.
vein thrombosis, diarrhea, fatigue, malaise, migraine, IV:
pain, shock, sinusitis, swelling, thrombosis, transient Berinert: Reconstitute each vial with 10 mL of SWFI
ischemic attacks, urticaria using the provided transfer set or a commercially
Drug Interactions available double-ended needle and vented filter spike;
Metabolism/Transport Effects None known. final concentration: 50 units/mL. After combining with
Avoid Concomitant Use There are no known interac- diluent, gently swirl (do not shake) vial to completely
tions where it is recommended to avoid concomitant use. dissolve powder. Do not use if turbid, discolored, or
Increased Effect/Toxicity contains particles. A silicone-free syringe is recom-
The levels/effects of C1 Inhibitor (Human) may be mended for reconstitution and administration.
increased by: Androgens; Estrogen Derivatives; Proges- Cinryze: Do not use product if there is no vacuum in the
tins vial. Reconstitute each vial with 5 mL of SWFI using the
Decreased Effect There are no known significant inter- provided transfer set or a commercially available dou-
actions involving a decrease in effect. ble-ended needle; final concentration 100 units/mL.
Storage/Stability After combining with diluent, gently swirl (do not shake)
Berinert, Cinryze: Store intact vials at 2°C to 25°C (36°F to vial to completely dissolve powder. Reconstituted prod-
77°F); do not freeze. Store in original carton; protect from uct should be clear and colorless or slightly blue; do not
light. Use within 3 hours (Cinryze) or 8 hours (Berinert) of use if turbid, discolored, or contains particles. A sili-
reconstitution (Canadian labeling recommends immedi- cone-free syringe is recommended for reconstitution
ate use after reconstitution); do not refrigerate or freeze and administration.
reconstituted solution. Discard any unused product. SubQ: Haegarda: Reconstitute 2,000 unit vials with 4 mL
Haegarda: Store intact vials at <30°C (86°F); do not of SWFI and 3,000 unit vials with 6 mL SWFI using the
freeze. Store in original carton; protect from light. Use provided transfer set or a commercially available double-
within 8 hours of reconstitution; do not refrigerate or ended needle and vented filter spike; final concentration:
freeze reconstituted solution. Discard any unused 500 units/mL. After combining with diluent, gently swirl
product. (do not shake) vial to completely dissolve powder. Do not
Mechanism of Action C1 inhibitor, one of the serine use if turbid, discolored, or contains particles. A silicone-
proteinase inhibitors found in human blood, plays a role free syringe is recommended for reconstitution and
in regulating the complement and intrinsic coagulation administration.
(contact system) pathway, and is also involved in the Administration Parenteral:
fibrinolytic and kinin pathways. C1 inhibitor therapy in IV:
patients with C1 inhibitor deficiency, such as HAE, is Berinert: A silicone-free syringe is recommended for
believed to suppress contact system activation via inacti- administration. Administer IV at recommended infusion
vation of plasma kallikrein and factor Xlla, thus preventing rate: 4 mL/minute (200 units/minute); use within 8
bradykinin production. Unregulated bradykinin production hours of reconstitution; discard any unused product.
is thought to contribute to the increased vascular perme- Cinryze: A silicone-free syringe is recommended for
ability and angioedema observed in HAE. administration. Administer lV at recommended infusion
Pharmacodynamics/Kinetics (Adult data unless rate: 1 mL/minute (over 10 minutes; 100 units/minute);
noted) - G use within 3 hours of reconstitution; discard any unused
Onset. of action: Cinryze: Increased plasma C1 inhibitor product.
levels observed ~1 hour or less J Self-administration: Following patient or caregiver train-
Onset of symptom relief: Berinert: Median: 15 minutes per ing and instructions on self-administration, patient or
attack; Cinryze: Pediatric patients 6 to 17 years: Median: caregiver may self-administer treatment (Berinert) or
30 minutes per attack; for the majority of patient unequiv- prophylaxis (Cinryze) therapy. Epinephrine should be
ocal symptom relief reported within 1 hour (range: 15 to available during self-administration in the event of an
135 minutes) (Lumry 2013) acute, severe hypersensitivity reaction. Patient suffer-
Duration of action: Time to complete resolution of heredi- ing from an acute laryngeal HAE attack and self-
tary angioedema (HAE) symptoms: Berinert: Median: 8.4 administering should be informed to seek immediate
hours medical attention following treatment (potential for air-
Distribution: way obstruction to occur).
Berinert: V;: Children and Adolescents: (6 to 13 years, SubQ: Haegarda: A silicone-free syringe is recommended
n=5): 0.02 L/kg) (range: 0.017 to 0.026 L/kg); Adults: for administration. Administer SubQ in the abdominal
0.018 L/kg (range: 0.011 to 0.028 L/kg) area or other SubQ injection sites. Rotate injection sites.
Haegarda: Vg: Adolescents and Adults: 0:05 L/kg Use within 8 hours of reconstitution; discard any unused
Bioavailability: Haegarda: 42.7% product.

331
 C1 INHIBITOR (HUMAN)

< Self-administration: Following patient training and

instructions on self-administration, patient may self-
products contain 200 mg of caffeine per tablet approx-
imately the amount of caffeine similar to one cup of coffee;
administer prophylaxis therapy. Epinephrine should be limit the use of other caffeine-containing beverages or
available during self-administration in the event of an foods.
acute, severe hypersensitivity reaction. Patient suffer-
Caffeine citrate should not be interchanged with caf-
ing from an acute laryngeal hereditary angioedema
feine and sodium benzoate. Avoid use of products
(HAE) attack and self-administering should be informed
containing sodium benzoate in neonates; has been asso-
to seek immediate medical attention following treat-
ciated with a potentially fatal toxicity ("gasping syn-
ment (potential for ainway obstruction to occur).
drome"). Neonates receiving caffeine citrate should be
Monitoring Parameters Monitor patient closely for
closely monitored for the development of necrotizing
hypersensitivity reaction and thrombotic events during or
enterocolitis. Caffeine serum levels should be closely
after administration.
monitored to optimize therapy and prevent serious toxicity.
Additional Information Concomitant use with transcutaneous electrical nerve
Cinryze: 1 unit corresponds to C1 inhibitor present in 1 mL
stimulation may lessen analgesia (Marchand 1995).
of normal fresh plasma
Warnings: Additional Pediatric Considerations Dur-
Berinert: A single 500 unit vial contains 400-625 units of
ing a caffeine citrate double-blind, placebo-controlled
C1 inhibitor
study, six of 85 patients developed necrotizing enteroco-
Dosage Forms Excipient information presented when litis (NEC); five of these six patients had received caffeine
available (limited, particularly for generics); consult spe- citrate; although no causal relationship has been estab-
cific product labeling.
lished, neonates who receive caffeine citrate should be
Kit, Intravenous:
closely monitored for the development of NEC. Caffeine
Berinert: 500 units
serum levels should be closely monitored to optimize
Solution Reconstituted, Intravenous [preservative free]:
therapy and prevent serious toxicity.
Cinryze: 500 units (1 ea)
Solution Reconstituted, Subcutaneous: The incidence of cerebellar hemorrhage was shown to be
Haegarda: 2000 units (1 ea); 3000 units (1 ea) increased in patients receiving high-dose caffeine citrate
(80 mg/kg total load over 36 hours) compared to those
@ CaEDTA see Edetate CALCIUM Disodium on page 708 receiving standard doses (36% vs 10%) in a randomized,
@ Cafcit see Caffeine on page 332 controlled trial in preterm neonates (n=74; GA $30 weeks;
@ CAFdA see Clofarabine on page 481 PNA #24 hours); in addition, this group also had subtle
neurobehavioral differences including increased tone and
@ Cafergor (Can) see Ergotamine and Caffeine
abnormal movements at term equivalent age (McPherson
on page 762
2015). In a post hoc analysis of this same group of
@ Cafergot see Ergotamine and Caffeine on page 762 neonates the high-dose group also trended towards a
higher incidence of seizures (40% vs 58%; p = 0.1) and
Caffeine (kar cen) an increase in seizure duration (48.9 vs 170.9 seconds;
p = 0.1) as indicated by continuous limited channel aEEG
Brand Names: US Cafcit; Keep Alert [OTC]; No Doz monitoring over the first 72 hours of life, although this was
Maximum Strength [OTC]; Stay Awake Maximum Strength not statistically significant. No difference in the number of
[OTC]; Stay Awake [OTC]; Vivarin [OTC] clinical seizures requiring treatment or status epilepticus
Therapeutic Category Central Nervous System Stimu- were noted between the groups; also no difference in the
lant; Diuretic; Respiratory Stimulant rates of IVH, hypoglycemia or perinatal hypoxic ischemia
Generic Availability (US) Yes: Tablet, caffeine and were noted (Vesoulis 2016). Authors noted that these
sodium benzoate injection, injection, oral solution adverse effects discouraged the potential for a larger trial;
Use if use deemed necessary, close monitoring is recom-
Caffeine citrate: Treatment of apnea of prematurity (FDA mended (McPherson 2015; Vesoulis 2016),
approved in infants with GA 28 to <33 weeks) Adverse Reactions Primarily serum-concentration
Caffeine (base): Restore mental alertness or wakefulness related.
when experiencing fatigue (OTC Product: FDA approved Cardiovascular: Angina pectoris, chest pain, flushing,
in ages 212 years and adults) palpitations, sinus tachycardia, supraventricular tachy-
Caffeine and sodium benzoate: Treatment (in conjunction cardia, vasodilatation, ventricular arrhythmia
with supportive measures) of acute respiratory depres- Central nervous system: Agitation, delirium, dizziness,
sion associated with overdose of CNS depressant drugs hallucination, headache, insomnia, irritability, psychosis,
(not a preferred agent) (FDA approved in adults); has restlessness
also been used for treatment of postdural puncture head- Dermatologic: Urticaria
aches Gastrointestinal: Esophageal motility disorder (sphincter
Pregnancy Risk Factor C tone decreased), gastritis
Pregnancy Considerations Adverse events were Genitourinary: Diuresis
observed in animal reproduction studies. Caffeine crosses Neuromuscular & skeletal: Fasciculations
the placenta; serum concentrations in the fetus are similar Ophthalmic: Increased intraocular pressure (>180 mg caf-
to those in the mother (Grosso 2005). Based on current feine), miosis
studies, usual dietary exposure to caffeine is unlikely to Drug Interactions
cause congenital malformations (Brent 2011). However, Metabolism/Transport Effects Substrate of CYP1A2
available data shows conflicting results related to maternal (major), CYP2C9 (minor), CYP2D6 (minor), CYP2E1
caffeine use and the risk of other adverse events, such as (minor), CYP3A4 (minor); Note: Assignment of Major/
spontaneous abortion or growth retardation (Brent 2011; Minor substrate status based on clinically relevant drug
Jahanfar 2013). The half-life of caffeine is prolonged interaction potential; Inhibits CYP1A2 (weak)
during the second and third trimesters of pregnancy and Avoid Concomitant Use
maternal and fetal exposure is also influenced by maternal Avoid concomitant use of Caffeine with any of the
smoking or drinking (Brent 2011; Koren 2000). Current following: Acebrophylline; Doxofylline; lobenguane |
guidelines recommend limiting caffeine intake from all 123; Stiripentol
sources to $200 mg/day (ACOG 2010). Increased Effect/Toxicity
Breastfeeding Considerations Caffeine is detected in Caffeine may increase the levels/effects of: CloZAPine;
breast milk (Berlin 1981; Hildebrant 1983; Ryu 1985a); Doxofylline; Formoterol; Indacaterol; lohexol; lomeprol;
concentrations may be dependent upon maternal con- lopamidol; Olodaterol; Sympathomimetics; TiZANidine
sumption and her ability to metabolize (eg, smoker versus
The levels/effects of Caffeine may be increased by:
nonsmoker) (Brent 2011). The ability of the breastfeeding Abiraterone Acetate; Acebrophylline; AtoMOXetine;
child to metabolize caffeine is age-dependent (Hildebrant
BuPROPion; Cannabinoid-Containing Products; Cipro-
1983). Irritability and jitteriness have been reported in the
floxacin (Systemic); Cocaine (Topical); CYP1A2 Inhibi-
breastfeeding infant exposed to high concentrations of
tors (Moderate); CYP1A2 Inhibitors (Strong);
caffeine in breast milk (Martin 2007). Infant heart rates
Deferasirox; Guanethidine; Linezolid; Norfloxacin; Obe-
and sleep patterns were not found to be affected in
ticholic Acid; Peginterferon Alfa-2b; Pipemidic Acid; Stir-
normal, full-term infants exposed to lesser amounts of
ipentol; Tedizolid; Vemurafenib
caffeine (Ryu 1985b).
Decreased Effect
Contraindications Hypersensitivity to caffeine or any
Caffeine may decrease the levels/effects of: Adenosine;
component of the formulation; sodium benzoate is not
Bromperidol; lobenguane | 123; Lithium; Regadenoson
for use in neonates
Warnings/Precautions Use with caution in patients with The levels/effects of Caffeine may be decreased by:
a history of peptic ulcer, gastroesophageal reflux, impaired Teriflunomide
renal or hepatic function, seizure disorders, or cardiovas- Storage/Stability Store at 20°C to 25°C (68°F to 77°F).
cular disease. Avoid use in patients with symptomatic Caffeine citrate: Injection and oral solution contain no
cardiac arrhythmias, agitation, anxiety, or tremor. OTC preservatives; injection is chemically stable for at least
 CAFFEINE

24 hours at room temperature when diluted to 10 mg/mL Renal Impairment: Pediatric There are no dosage
(as caffeine citrate) with D5W, D50W, Intralipid® 20%, adjustments provided in the manufacturer’s labeling
and Aminosyn® 8.5%; also compatible with dopamine (has not been studied); use with caution.
(600 mcg/mL), calcium gluconate 10%, heparin (1 unit/ Hepatic Impairment: Pediatric There are no dosage
mL), and fentanyl (10 mcg/mL) at room temperature for adjustments provided in the manufacturer’s labeling (has
24 hours. not been studied); use with caution.
Mechanism of Action Increases levels of 3'5' cyclic AMP Preparation for Administration Parenteral:
by inhibiting phosphodiesterase; CNS stimulant which Caffeine citrate: May further dilute with D5W to a final
increases medullary respiratory center sensitivity to car- concentration of 10 mg caffeine citrate/mL
bon dioxide, stimulates central inspiratory drive, and Caffeine sodium benzoate: Note: Perform visual inspec-
improves skeletal muscle contraction (diaphragmatic con- tion of vial; do not use if particulates are present. Use a
tractility); prevention of apnea may occur by competitive 5-micron filter needle to withdraw the required volume.
inhibition of adenosine Remove filter needle and replace with an appropriate
Pharmacodynamics/Kinetics (Adult data unless needle before administration or if adding to an infusion
noted) solution (American Regent 2016).
Distribution: Vg: For postdural puncture headaches, dilute in 1,000 mL
Neonates: 0.8 to 0.9 L/kg NS (Jarvis 1986).
Childten >9 months to Adults: 0.6 L/kg Administration
Protein binding: 17% (children) to 36% (adults) Oral: May be administered without regard to feedings or
Metabolism: Hepatic, via demethylation by CYP1A2. meals; may administer injectable formulation (caffeine
Note: In neonates, interconversion between caffeine citrate) orally
and theophylline has been reported (caffeine levels are Parenteral: 5
~25% of measured theophylline after theophylline Caffeine citrate: |V: May administer undiluted or further
administration and ~3% to 8% of caffeine would be diluted with D5W. Infuse loading dose over at least 30
expected to be converted to theophylline) minutes; maintenance dose may be infused over at
Half-life elimination: least 10 minutes.
Neonates: 72 to 96 hours (range: 40 to 230 hours) Caffeine sodium benzoate: IV: Note: Use a 0.22-
Children >9 months and Adults: 5 nours micron in-line filter when administering (American
Time to peak, serum: Oral: Within 30 minutes to 2 hours Regent 2016).
Excretion: i Direct injection: Administer slowly
Neonates <1 month: 86% excreted unchanged in urine Spinal headaches: Further dilute and infuse over 1
Infants >1 month and Adults: In urine, as metabolites hour; follow with 1,000 mL NS infused over 2 hours
Clearance: (Choi 1996; Jarvis 1986)
Neonates: 8.9. mL/hour/kg (range: 2.5 to 17) Monitoring Parameters
Adults: 94 mL/hour/kg Apnea of prematurity: Heart rate, number and severity of
Pharmacodynamics/Kinetics: Additional Consider- apnea spells, serum caffeine concentration (as appro-
ations Pregnancy, smoking, and cirrhosis: Half-life is priate)
increased. Stimulant: Insomnia, tachycardia
Dosing Reference Range
Neonatal Therapeutic: Apnea of prematurity: 8 to 20 mcg/mL
Apnea of prematurity: Caffeine citrate: Note: Dose Potentially toxic: >20 mcg/mL
expressed as caffeine citrate; caffeine base is 1/2 the Toxic: >50 mcg/mL
dose of the caffeine citrate: Dosage Forms Excipient information presented when
Manufacturer’s labeling: GA 228 weeks and <33 available (limited, particularly for generics); consult spe-
weeks: cific product labeling. [DSC] = Discontinued product
Loading dose: IV: 20 mg/kg caffeine citrate as a one- Injection, solution, as citrate [preservative free]:
time dose Cafcit: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL
Maintenance dose: Oral, |V: 5 mg/kg/dose. caffeine caffeine base]
citrate once daily, beginning 24 hours after load- Generic: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL
ing dose caffeine base]
Alternate dosing: GA <32 weeks: Injection, solution [with sodium benzoate]:
Loading dose: IV: 20 to 40 mg/kg caffeine citrate Generic: Caffeine 125 mg/mL and sodium benzoate
(Mohammed 2015; Schmidt 2006); loading doses 125 mg/mL (2 mL)
as high as 80 mg/kg of caffeine citrate have been Solution, oral, as citrate [preservative free]:
reported (Gray 2011; Steer 2004), but should be Cafcit: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL
utilized with caution (See Note) caffeine base] [DSC]
Maintenance dose: Oral, IV: 5 to 20 mg/kg/dose Generic: 60 mg/3 mL (3 mL) [equivalent to 10 mg/mL
caffeine citrate once daily-starting 24 hours after caffeine base]
the loading dose (Gray 2011; Mohammed 2015; Tablet, oral:
Schmidt 2006) Keep Alert: 200 mg
Note: Higher doses (Load: 40 mg/kg and 80 mg/kg; NoDoz Maximum Strength: 200 mg
maintenance dose: 20 mg/kg/dose) were shown to Stay Awake: 200 mg
significantly decrease the incidence of apnea, need Stay Awake Maximum Strength: 200 mg
for oxygen therapy, and extubation failures; inci- Vivarin: 200 mg
dence of tachycardia was conflicting with one study Generic: 200 mg
showing an increased incidence with higher doses Extemporaneous Preparations A 10 mg/mL oral solu-
compared to low dose (23% vs 8%) while the other tion of caffeine (as citrate) may be prepared from 10g
showed no significant difference between low and citrated caffeine powder combined with 10 g citric acid
high dose (Mohammed 2015; Steer 2004). Loading USP and dissolved in 1000 mL distilled water. Label
doses of 80 mg/kg must be used with caution; one "shake well". Stable for 3 months at room temperature
study evaluating the prophylactic use of high-dose (Nahata, 2014).
caffeine (total dose of 80 mg/kg over 36 hours)
compared to standard dose showed patients in the A 20 mg/mL oral solution of caffeine (as citrate) may be
high-dose group had a higher incidence of cerebel- made from 10 g citrated caffeine powder and dissolved in
lar hemorrhage (36% vs 10%) along with increased 250 mL sterile water for irrigation. Stir solution until com-
tone and abnormal movements (McPherson 2015); pletely clear, then add a 2:1 mixture of simple syrup and
although not statistically significant, these patients cherry syrup in sufficient quantity to make 500 mL. Label
also trended towards a higher incidence of seizures "shake well" and "refrigerate". Stable for 90 days (Eisen-
berg, 1984).
and increased EEG measured seizure duration over
Eisenberg MG and Kang N, "Stability of Citrated Caffeine Solutions for
the first 72 hours; however, there was no difference Injectable and Enteral Use," Am J Hosp Pharm, 1984, 41(11):2405-6.
in the number of clinical seizures requiring treat- Nahata MC and Pai VB, Pediatric Drug Formulations, 6th ed, Cincin-
ment, status epilepticus, |VH, hypoglycemia, or peri- nati, OH; Harvey Whitney Books Co, 2014.
natal hypoxic ischemia between the 2 groups
(Vesoulis 2016). ¢@ Caffeine and Ergotamine see Ergotamine and Caffeine
Pediatric Note: CAffeine citrate should not be inter- on page 762
changed with the caffeine sodium benzoate formulation. ® Caffeine and Sodium Benzoate see Caffeine
Caffeine and sodium benzoate dosing presented as the on page 332
combination (caffeine base amount is 50% of the caf- @ Caffeine Citrate see Caffeine on page332
feine and sodium benzoate combination). @ Caffeine Sodium Benzoate see Caffeine on page 332
Stimulant: OTC labeling: Caffeine (base): Children 212
years and Adolescents: Oral: 100 to 200 mg every 3 to @ Caladryl [OTC] see Calamine on page 334
4 hours as needed { @ Calagesic [OTC] see Calamine on page 334

333
CALAMINE

@ Calcimar (Can) see Calcitonin on page 335

Calamine (KAL a meen) @ Calci-Mix [OTC] [DSC] see Calcium Carbonate
on page 340
Brand Names: US Caladry| [OTC]; Calagesic [OTC];
GoodSense Calamine [OTC] Calcionate [OTC] [DSC] see Calcium Glubionate
Therapeutic Category Topical Skin Product on page 346
Generic Availability (US) Yes
Use Temporary relief of pain and itching associated with Calcipotriene and Betamethasone
rashes due to poison ivy, poison oak, or poison sumac; (kal si POE try een & bay ta METH a sone)
insect bites; minor skin irritation; or minor cuts and to dry
oozing and weeping of poison ivy, poison oak, and poison Brand Names: US Enstilar; Taclonex
sumac (in combination with zinc oxide: FDA approved in Brand Names: Canada Dovobet; Enstilar
ages 26 months and adults; in combination with pramox- Therapeutic Category Corticosteroid, Topical;-Vitamin D
ine: FDA approved in ages 22 years and adults); has also Analog
been used for skin irritation and itching due to varicella Generic Availability (US) Yes: Ointment
(chicken pox) infection. Note: Approved ages in pediatric Use Treatment of plaque psoriasis (ointment: FDA
patients may vary among products, consult product spe- approved in ages 212 years and adults; foam and sus-
cific labeling. pension: FDA approved in ages 218 years and adults);
Contraindications Hypersensitivity to any component of treatment of scalp psoriasis (suspension: FDA approved
the formulation in ages 212.years and’ adults)
Warnings/Precautions For external use only; avoid con- Pregnancy Risk Factor C
tact with eyes and mucous membranes. When using for Pregnancy Considerations Animal reproduction studies
self-medication (OTC use), discontinue use and contact have not been conducted with this topical combination.
healthcare provider if needed for >7 days or if condition See individual agents.
worsens. Breastfeeding Considerations It is not known if calci-
Warnings: Additional Pediatric Considerations potriene or betamethasone are excreted into breast milk
Some dosage forms may contain propylene glycol; in following topical application. The manufacturer recom-
neonates large amounts of propylene glycol delivered mends that caution be used if administered to breastfeed-
orally, intravenously (eg, >3,000 mg/day), or topically ing women. Do not apply to the breast if breastfeeding.
have been associated with potentially fatal toxicities which See individual agents.
can include metabolic acidosis, seizures, renal failure, and Contraindications
CNS depression; toxicities have also been reported in There are no contraindications listed within the manufac-
children and adults including hyperosmolality, lactic acido- turer's labeling.
sis, seizures and respiratory depression; use caution Canadian labeling: Additional contraindications (not in
(AAP. 1997; Shehab 2009). U.S. labeling): Hypersensitivity to calcipotriene, betame-
Drug Interactions thasone, or any component of the formulation; viral
Metabolism/Transport Effects None known. (herpes simplex, varicella, vaccinia), fungal or bacterial
Avoid Concomitant Use There are no known interac- infection of the skin; parasitic infections; tuberculosis of
tions where it is recommended to avoid concomitant use. the skin; syphilitic skin infections; ophthalmic use; cal-
Increased Effect/Toxicity There are no known signifi- cium metabolism disorders; perioral dermatitis; atrophic
cant interactions involving an increase in effect. skin; striae atrophicae; fragility of skin veins; ichthyosis;
Decreased Effect There are no known significant inter- acne vulgaris; acne rosacea; rosacea; ulcers; wounds;
actions involving a decrease in effect. perianal and genital pruritus; guttate, erythrodermic and
Storage/Stability Store at room temperature of 15°C to pustular psoriasis; severe hepatic disorders (gel only);
30°C (59°F to 86°F). severe renal insufficiency (gel only).
Dosing Warnings/Precautions Use with caution in patients
Pediatric known or suspected disorders of calcium metabolism;
Skin irritation: Note: Approved ages in pediatric may cause transient increases in serum and urinary
patients may vary among products, consult product
calcium (reversible); if hypercalcemia or hypercalciuria
occurs, discontinue treatment until levels return to normal.
specific labeling.
Systemic absorption of topical corticosteroids may cause
Calamine/zinc oxide products: Infants 26 months, Chil-
dren, and Adolescents: Topical: Apply to affected area hypercortisolism or suppression of hypothalamic-pituitary-
as often as needed; other calamine products are used adrenal (HPA) axis, particularly in younger children,
up to 3 to 4 times daily
patients receiving high doses for prolonged periods, use
over large surface areas, under occlusion, or on altered
Calamine/pramoxine products: Children 22 years and
Adolescents: Topical: Apply to affected area up to 3 to skin barrier, and use in patients with hepatic failure. HPA
4 times daily
axis suppression may lead to adrenal crisis and may occur
during treatment or after withdrawal of treatment. If HPA
Administration Topical: Shake well before using. Apply to
axis suppression occurs, an attempt to withdraw the drug,
clean, dry skin; may apply using cotton or a soft cloth.
reduce the application frequency, or substitute a less
Avoid contact with the eyes and mucous membranes; do
potent corticosteroid. HPA suppression is usually rever-
not use on open wounds or burns.
sible; if glucocorticoid insufficiency occurs, supplemental
Dosage Forms Excipient information presented when
systemic steroids may be needed. Hyperglycemia and
available (limited, particularly for generics); consult spe-
unmasking of latent diabetes mellitus may result from
cific product labeling. [DSC] = Discontinued product
systemic absorption of topical corticosteroids.
Lotion, External:
Caladryl: Calamine 8% and pramoxine hydrochloride 1% Topical corticosteroids may be absorbed percutaneously.
(177 mL) [contains methylparaben, polysorbate 80, Absorption of topical corticosteroids may cause manifes-
propylene glycol, propylparaben] tations of Cushing syndrome, hyperglycemia, or glycosu-
Calagesic: Calamine 8% and pramoxine hydrochloride ria. Absorption is increased by the use of occlusive
1% (177 mL) [contains alcohol, usp, methylparaben, dressings, application to denuded skin, or application to
polysorbate 80, propylene glycol, propylparaben] large surface areas. Prolonged treatment with corticoste-
Generic: 8% (120 mL [DSC], 177 mL, 180 mL, 240 mL roids has been associated with the development of Kaposi
[DSC}]); Calamine 8% and zinc oxide 8% (118 mL) sarcoma (case reports); if noted, discontinuation of ther-
Suspension, External: apy should be considered (Goedert, 2002). Allergic con-
GoodSense Calamine: Calamine 8% and zinc oxide 8% tact dermatitis can occur; it is usually diagnosed by failure
(177 mL) to heal rather than clinical exacerbation. Further evalua-
tion (eg, patch testing) may be necessary.
# Calamine Lotion see Calamine on page 334
@ Calan see Verapamil on page 2050 Local adverse reactions may occur, including atrophy,
striae, telangiectasias, burning, itching, irritation, dryness,
@ Calan SR see Verapamil on page 2050 folliculitis, acneiform eruptions, hypopigmentation, perioral
@ Calax [OTC] (Can) see Docusate on page 677 dermatitis, allergic contact dermatitis, secondary infection,
@ Calazime Skin Protectant [OTC] [DSC] see Zinc Oxide and miliaria. These reactions are more likely to occur with
on page 2088 occlusive use, prolonged use or use of higher potency
corticosteroids; some reactions may be irreversible.
@ Cal-Carb Forte [OTC] see Calcium Carbonate
on page 340 Use appropriate antibacterial or antifungal agents to treat
@ Calci-Chew [OTC] see Calcium Carbonate on page 340 concomitant skin infections; if infection persists, discon-
tinue use of calcipotriene and betamethasone until infec-
@ Calcidol [OTC] see Ergocalciferol on page 759
tion has resolved. Do not use on the face, axillae, groin, or
@ Calciferol [OTC] see Ergocalciferol on page 759 in the presence of preexisting skin atrophy at the treat-
@ Calcijex (Can) see Calcitriol (Systemic) on page 336 ment site. Not for oral, ophthalmic, or intravaginal use. Do

334
 CALCITONIN

not use occlusive dressings unless directed by a health Suspension: Topical: Apply to affected area of skin
care provider; discontinue use if irritation occurs. Children once daily for up to 8 weeks; maximum weekly
may be at higher risk of systemic side effects due to a dose: 100 g/week
greater skin surface area:body weight ratio. Foam con- Scalp psoriasis:
tains flammable propellants. Avoid fire, flame, and smok- Children 212 years and Adolescents <17 years:
ing during and immediately following administration. Suspension: Topical: Apply to affected area of
Warnings: Additional Pediatric Considerations The scalp once daily for up to 8 weeks; maximum
extent of percutaneous steroid absorption is dependent on weekly dose: 60 g/week
several factors, including epidermal integrity (intact vs Adolescents 218 years: Suspension: Topical: Apply
abraded skin), formulation, age of the patient, prolonged to affected area of scalp once daily for up to 8
duration of use, and the use of occlusive dressings. weeks; maximum weekly dose: 100 g/week
Percutaneous absorption of topical steroids is increased Renal Impairment: Pediatric There are no dosage
in pediatric patients compared to adults, particularly in adjustments provided in the manufacturer's labeling.
neonates (especially preterm neonates), infants, and Hepatic Impairment: Pediatric There are no dosage
young children. Younger pediatric patients (ie, infants adjustments provided in the manufacturer's labeling.
and small children) may be more susceptible to HPA axis Administration Topical: Wash hands before and after
suppression, intracranial hypertension, Cushing syn- use. Do not apply to face, axillae, or groin or in the
drome, or other systemic toxicities due to larger skin presence of preexisting skin atrophy at the treatment site;
surface area to body mass ratio. After 4 weeks of scalp not for oral, ophthalmic, or intravaginal use. Avoid use of
treatment with topical calcipotriene/betamethasone sus- occlusive dressings over treated areas unless directed by
pension, adrenal suppression was observed in 3.3% of a health care provider.
patients (one of 30 subjects [age range: 12 to 17 years]). Foam: Shake before use. Rub into affected area gently.
Adverse Reactions Also see individual agents. Ointment: Rub into affected area gently and completely.
Dermatologic: Burning sensation of skin, ecchymoses, Suspension: Shake well before use. If applying to the
erythema, exfoliative dermatitis, folliculitis, hand derma- scalp, do not apply within 12 hours of chemical hair
tosis, pruritus, psoriasis, skin atrophy, skin depigmenta- treatment. Do not wash hair or take a bath or shower
tion, skin irritation directly after use.
Rare but important or life-threatening: Acneiform eruption, Monitoring Parameters I!n patients at risk for hyper-
application site irritation, application site pruritus, contact calcemia, baseline serum calcium levels and then periodi-
dermatitis, exacerbation of psoriasis, eye irritation, facial cally during treatment.
edema, HPA-axis suppression, hypercalcemia, hyper- Test Interactions See individual agents.
calciuria, hyperpigmentation, hypopigmentation, otitis Dosage Forms Excipient information presented when
externa, papular rash, psoriasis flare, psoriasis available (limited, particularly for generics); consult spe-
(rebound), pustular psoriasis, pustular rash, skin pain, cific product labeling.
skin rash, telangiectasia, urticaria, xeroderma Foam, topical:
Drug Interactions Enstilar: Calcipotriene 0.005% and betamethasone
Metabolism/Transport Effects None known. dipropionate 0.064% (60 g)
Avoid Concomitant Use Ointment, topical:
Avoid concomitant use of Calcipotriene and Betametha- Taclonex: Calcipotriene 0.005% and betamethasone
sone with any of the following: Aldesleukin; Aluminum dipropionate 0.064% (60 g, 100 g)
Hydroxide; Multivitamins/Fluoride (with ADE); Multivita- Generic: Calcipotriene 0.005% and betamethasone
mins/Minerals (with ADEK, Folate, Iron); Sucralfate; dipropionate 0.064% (60 g, 100 g)
Vitamin D Analogs Suspension, topical:
Increased Effect/Toxicity Taclonex: Calcipotriene 0.005% and betamethasone
Calcipotriene and Betamethasone may increase the dipropionate 0.064% (60 g, 120 g) [contains castor oil]
levels/effects of: Aluminum Hydroxide; Cardiac Glyco-
@ Calcipotriene/Betamethasone see Calcipotriene and
sides; Ceritinib; Deferasirox; Ritodrine; Sucralfate; Vita-
Betamethasone on page 334
min D Analogs
@ Calcipotriol and Betamethasone Dipropionate see
The levels/effects of Calcipotriene and Betamethasone Calcipotriene and Betamethasone on page 334
may be increased by: Calcium Salts; Multivitamins/Fluo-
@ Calcite-500 (Can) see Calcium Carbonate on page 340
ride (with ADE); Multivitamins/Minerals (with ADEK,
Folate, Iron); Thiazide and Thiazide-Like Diuretics
Decreased Effect Calcitonin (kal si TOE nin)
Calcipotriene and Betamethasone may decrease the
levels/effects of: Aldesleukin; Corticorelin; Hyaluroni- Medication Safety Issues
dase Sound-alike/look-alike issues:
Storage/Stability i Seue " Calcitonin may be confused with calcitriol
Store at 20°C to 25°C (68°F to 77°F); excursions permit- Fortical may be confused with Foradil
ted between 15°C to 30°C (59°F to 86°F). Do not Miacalcin may be confused with Micatin
refrigerate suspension, and discard 6 months from date Administration issues:
opened. Keep suspension bottle in outer carton when Calcitonin nasal spray is administered as a single spray
not in use. into one nostril daily, using alternate nostrils each day.
Foam: Contents under pressure. Avoid heat, flame, or Brand Names: US Fortical [DSC]; Miacalcin
smoking during use. Do not puncture or incinerate con- Brand Names: Canada Calcimar
tainer. Do not expose to heat or store at temperatures Therapeutic Category Antidote, Hypercalcemia
>49°C (120°F); do not freeze. Use within 6 months after Generic Availability (US) Yes
opening. Use
Gel [Canadian product}: Store at 15°C to 30°C (59°F to Parenteral: Treatment of Paget's disease of bone; adjunc-
86°F). Do not refrigerate. Protect bottle from light. Use tive therapy for hypercalcemia; postmenopausal osteo-
within 6 months after opening bottle or assembling porosis (FDA approved in adults); has also been used for
applicator, or before expiration date. osteogenesis imperfecta
Mechanism of Action See individual agents. Intranasal: Postmenopausal osteoporosis in women >5
Pharmacodynamics/Kinetics (Adult data unless years postmenopause with low bone mass (FDA
noted) See individual agents. approved in adults)
Dosing a : Pregnancy Considerations Endogenous calcitonin
Pediatric Note: Use for shortest amount of time neces- does not cross the placenta (Dochez 2015). Information
sary and discontinue therapy once control achieved. related to the use of calcitonin in pregnancy is limited
Plaque psoriasis: (Koren 2018; Krysiak 2011; Richa 2018; Turek 2012).
Children 212 years and Adolescents $17 years: Oint- Breastfeeding Considerations
ment: Topical: Apply to affected area of skin once Calcitonin is endogenous to breast milk in lactating
daily for up to 4 weeks. Application to >30% of body women (Bucht 1986; Koldovsky 1995); concentrations
surface area is not recommended. Maximum following administration of calcitonin-salmon are not
weekly dose: 60 g/week known.
Adolescents 218 yéars: According to the manufacturer, the decision to breastfeed
Foam: Topical: Apply to affected area of skin once during therapy should consider the risk of infant expo-
daily for up to 4 weeks; maximum dose: 60 g every sure, the benefits of breastfeeding to the infant, and the
4 days benefits of treatment to the mother.
Ointment: Topical: Apply to affected area of skin Contraindications Hypersensitivity to calcitonin salmon
once daily for up to 4 weeks. Application to >30% or any component of the formulation
of body surface area is not recommended; max- Warnings/Precautions A skin test should be performed
imum weekly dose: 100 g/week ; prior to initiating therapy of calcitonin salmon in patients

335
 CALCITONIN

4 with suspected sensitivity; anaphylactic shock, anaphy-

laxis, bronchospasm, and swelling of the tongue or throat
Fortical: After opening, store for up to 30 days at 20°C to
25°C (68°F to 77°F); excursions permitted to 15°C to
have been reported; have epinephrine immediately avail- 30°C (59°F to 86°F). Store in upright position.
able for a possible hypersensitivity reaction. A detailed Miacalcin: After opening, store for up to 35 days at room
skin testing protocol is available from the manufacturer. temperature of 15°C to 30°C (59°F to 86°F). Store in
Rhinitis and epistaxis have been reported; mucosal alter- upright position.
ations may occur. Perform nasal examinations with visual- Mechanism of Action Peptide sequence similar to
ization of the nasal mucosa, turbinates, septum and human calcitonin; functionally antagonizes the effects of
mucosal blood vessels prior to initiation of therapy, peri- parathyroid hormone. Directly inhibits osteoclastic bone
odically during therapy, and at any time nasal symptoms resorption; promotes the renal excretion of calcium, phos-
occur. Temporarily withdraw use if ulceration of nasal phate, sodium, magnesium, and potassium by decreasing
mucosa occurs. Discontinue for severe ulcerations >1.5 tubular reabsorption; increases the jejunal secretion of
mm, those that penetrate below the mucosa, or those water, sodium, potassium, and chloride
associated with heavy bleeding. Patients >65 years of Pharmacodynamics/Kinetics (Adult data unless
age may experience a higher incidence of nasal adverse noted)
events with calcitonin nasal spray. Onset of action:
Hypercalcemia: IM, SubQ: ~2 hours
Hypocalcemia with tetany and seizure activity has been Paget's disease: Within a few months; may take up to 1
reported. Hypocalcemia and other disorders affecting year for neurologic symptom improvement
mineral metabolism (eg, vitamin D deficiency) should be Duration: Hypercaicemia: IM, SubQ: 6 to 8 hours; follow-
corrected before initiating therapy; monitor serum calcium ing multiple doses, hypercalcemic effect diminishes
and symptoms of hypocalcemia during therapy. Adminis- within 24 to 48 hours (Nilsson 1978; Stevenson 1988)
ter in conjunction with calcium and vitamin D when treating Absorption: Intranasal: Rapidly but highly variable and
Paget disease or postmenopausal osteoporosis. Fracture lower than IM administration
reduction efficacy has not been demonstrated; use has Distribution: Vg: 0.15 to 0.3 L/kg
not been shown to increase spinal bone mineral density in Metabolism: Metabolized in kidneys, blood and peripheral
early postmenopausal women. Use should be reserved for tissue 2
postmenopausal women for whom alternative treatments Bioavailability: IM: 66%; SubQ: 71%; Nasal: ~3% to 5%
are not suitable (eg, patients for whom other therapies are (relative to IM)
contraindicated or for patients who are intolerant or unwill- - Half-life elimination (terminal): IM 58 minutes; SubQ 59 to
ing to use other therapies). Consider potential benefits of 64 minutes; Nasal: ~18 to 23 minutes
therapy against risks in osteoporosis treatment, including Time to peak, plasma: SubQ ~23 minutes; Nasal: ~10 to
the potential risk for malignancy with long-term use. Anal- 13 minutes
yses of randomized controlled trials (in osteoporosis and Excretion: Urine (as inactive metabolites)
osteoarthritis) using the nasal spray and oral formulations Clearance: Salmon calcitonin: 3.1 mL/kg/minute
have demonstrated a statistically significant increase in Dosing
the risk of the development of cancer in calcitonin-treated Pediatric Osteogenesis imperfecta: Infants >6 months,
patients (compared to placebo). The risk for malignancies Children, and Adolescents: IM, SubQ: 2 units/kg/dose 3
is associated with long-term use of calcitonin (trials ranged times/week (Castells, 1979)
from 6 months to 5 years in duration). Periodically reas- Renal Impairment: Pediatric There are no dosage
sess continued use of calcitonin therapy, carefully consid- adjustments provided in the manufacturer's labeling.
ering the risks versus benefits. Similar risk for other routes Hepatic Impairment: Pediatric There are no dosage
(subcutaneous, IM, IV) cannot be ruled out. Antibody adjustments provided in the manufacturer's labeling.
formation to calcitonin-salmon has been reported with Administration
the injection and nasal spray. Consider the possibility of Intranasal: Before first use, allow bottle to reach room
antibody formation in patients who initially respond to temperature, then prime pump by releasing at least 5
therapy but later do not respond to treatment. Coarse sprays until full spray is produced. To administer, place
granular casts and casts containing renal tubular epithelial nozzle into nostril with head in upright position. Spray
cells were observed following use in young adults on bed into one nostril daily; alternate nostrils to reduce irrita-
rest during a study to examine the effect of immobilization tion. Do not prime pump before each daily use. Discard
on osteoporosis; no other renal abnormalities were after 30 doses.
reported and sediment normalized after discontinuation; Parenteral: May be administered SubQ or IM; do not
consider monitoring urine sediment periodically; however, exceed 2 mL volume per injection site; SubQ is preferred
the clinical significance of this finding is unknown. for outpatient self administration unless the injection
Adverse Reactions volume is >2 mL; IM is preferred if the injection volume
Cardiovascular: Flushing is >2 mL (use multiple injection sites if dose volume is
Central nervous system: Depression, dizziness, pares- >2 mL).
thesia Monitoring Parameters Serum electrolytes and calcium;
Dermatologic: Erythematous rash alkaline phosphatase and 24-hour urine collection for
Gastrointestinal: Abdominal pain, nausea hydroxyproline excretion (Paget's disease); urinalysis
Hematologic & oncologic: Lymphadenopathy, malignant (urine sediment); serum calcium; periodic nasal exams
neoplasm (intranasal use only)
Infection: Infection Dosage Forms Excipient information presented when
Local: Injection site reaction (injection) available (limited, particularly for generics); consult spe-
Neuromuscular & skeletal: Back pain, myalgia, osteoar- cific product labeling. [DSC] = Discontinued product
thritis Solution, Injection:
Ophthalmic: Abnormal lacrimation, conjunctivitis Miacalcin: 200 units/mL (2 mL) [contains phenol]
Respiratory: Bronchospasm, flu-like symptoms, rhinitis Solution, Nasal:
(including ulcerative), sinusitis, upper respiratory tract Fortical: 200 units/actuation (3.7 mL [DSC})
infection Miacalcin: 200 units/actuation (3.7 mL [DSC])
Rare but important or life-threatening; all routes: Alopecia, Generic: 200 units/actuation (3.7 mL)
altered sense of smell, anorexia, antibody development
(drug efficacy can be affected), edema, excoriation @ Calcitonin (Salmon) see Calcitonin on page 335
(nasal mucosa), hearing loss, hypersensitivity reaction, Cal-Citrate [OTC] see Calcium Citrate on page 345
nocturia, polyuria, tachycardia
Drug Interactions
Calcitriol (Systemic) (kai si TRYE ole)
Metabolism/Transport Effects None known.
Avoid Concomitant Use There are no known interac- Medication Safety Issues
tions where it is recommended to avoid concomitant use. Sound-alike/look-alike issues:
Increased Effect/Toxicity Calcitriol may be confused with alfacalcidol, calcifediol,
Calcitonin may increase the levels/effects of: Zoledronic Calciferol, calcitonin, calcium carbonate, captopril,
Acid colestipol, paricalcitol, ropinirole
Decreased Effect Administration issues:
Calcitonin may decrease the levels/effects of: Lithium Dosage is expressed in mcg (micrograms), not mg
Storage/Stability (milligrams); rare cases of acute overdose have been
Injection: Store under refrigeration at 2°C to 8°C (36°F to reported
46°F); protect from freezing. The following stability infor- Brand Names: US Rocaltrol
mation has also been reported: May be stored at room Brand Names: Canada Calcijex; Calcitriol Injection; Cal-
‘temperature for up to 14 days (Cohen, 2007). citriol-Odan; Rocaltrol
Nasal: Store unopened bottle under refrigeration at 2°C to Therapeutic Category Vitamin D Analog
8°C (36°F to 46°F); do not freeze. Generic Availability (US) Yes

336
 CALCITRIOL (SYSTEMIC)

Use Adverse Reactions

Injection: Management of hypocalcemia and resultant Cardiovascular: Cardiac arrhythmia, hypertension
metabolic bone disease in patients on chronic renal Central nervous system: Apathy, drowsiness, headache,
dialysis (FDA approved in ages 218 years) hyperthermia, metallic taste, psychosis, sensory dis-
Oral: Management of secondary hyperparathyroidism and turbance
resultant metaboiic bone disease in patients with mod- Dermatologic: Erythema, erythema multiforme, pruritus,
erate to severe chronic renal failure not yet on dialysis skin rash, urticaria
(FDA approved in ages 23 years and adults); manage- Endocrine & metabolic: Albuminuria, calcinosis,
ment of hypocalcemia in patients with hypoparathyroid- decreased libido, dehydration, growth suppression,
ism (FDA approved in ages 21 year and adults) and hypercalcemia, hypercholesterolemia, polydipsia, weight
pseudohypoparathyroidism (FDA approved in ages 26 loss
years and adults) Gastrointestinal: Abdominal pain, anorexia, constipation,
Pregnancy Risk Factor C nausea, pancreatitis, stomach pain, vomiting, xero-
Pregnancy Considerations Adverse effects have been stomia
observed in some animal reproduction studies. Maternal Genitourinary: Hypercalciuria, nocturia, urinary tract
calcitriol may be detected in the fetal circulation. Mild infection
hypercalcemia has been reported in a newborn following Hepatic: Increased serum ALT, increased serum AST
maternal use of calcitriol during pregnancy. Adverse Hypersensitivity: Hypersensitivity reaction
effects on fetal development were not observed with use Local: Pain at injection site (mild)
of calcitriol during pregnancy in women (N=9) with pseu- Neuromuscular & skeletal: Dystrophy, myalgia, ostealgia,
dovitamin D-dependent rickets. Doses were adjusted weakness
every 4 weeks to keep calcium concentrations within Ophthalmic: Conjunctivitis, photophobia
‘normal limits (Edouard 2011). If calcitriol is used for the Renal: Calcium nephrolithiasis, increased blood urea
management of hypoparathyroidism in pregnancy, dose nitrogen, increased serum creatinine, polyuria
adjustments may be needed as pregnancy progresses Respiratory: Rhinorrhea
and again following delivery. Vitamin D and calcium levels Rare but important or life-threatening: Agitation, anaphy-
should be monitored closely and kept in the lower normal laxis, apprehension, hypermagnesemia, hyperphospha-
range (Callies 1998). temia, hypervitaminosis D, increased hematocrit,
Breastfeeding Considerations Low levels of calcitriol increased hemoglobin, increased neutrophils, increased
are found in breast milk (~2 pg/mL) serum alkaline phosphatase, insomnia, limb pain, lym-
Contraindications phocytosis
US labeling: Oral, injection: Hypersensitivity to calcitriol or Drug Interactions
any component of the formulation; hypercalcemia, vita- Metabolism/Transport Effects Substrate of CYP3A4
min D toxicity
(major); Note: Assignment of Major/Minor substrate sta-
Canadian labeling: Oral, injection: Hypersensitivity to cal-
tus based on Clinically relevant drug interaction potential
citriol, vitamin D or its analogues or derivatives, or any
Avoid Concomitant Use
component of the formulation or container; hypercalce-
Avoid concomitant use of Calcitriol (Systemic) with any
mia, vitamin D toxicity
of the following: Aluminum Hydroxide; Burosumab-twza;
Warnings/Precautions Oral, injection: Adequate dietary
Conivaptan; Fusidic Acid (Systemic); Idelalisib; Multi-
(supplemental) calcium is necessary for clinical response
vitamins/Fluoride (with ADE); Multivitamins/Minerals
to vitamin D. Excessive vitamin D may cause severe
(with ADEK, Folate, Iron); Sucralfate; Vitamin D Analogs
hypercalcemia, hypercalciuria, and hyperphosphatemia.
Discontinue use immediately in adult patients with a
Increased Effect/Toxicity
calcium-phosphate product (serum calcium times phos- Calcitriol (Systemic) may increase the levels/effects of:
phorus) >70 mg@/dL?, may resume therapy at decreased Aluminum Hydroxide; Burosumab-twza; Cardiac Glyco-
doses when levels are appropriate. Other forms of vitamin sides; Magnesium Salts; Sucralfate; Vitamin D Analogs
D should be withheld during therapy to avoid the potential The levels/effects of Calcitriol (Systemic) may be
for hypercalcemia to develop. In addition, several months increased by: Aprepitant; Calcium Salts; Ceritinib; Con-
may be required for ergocalciferol levels to return to base- ivaptan; CYP3A4 Inhibitors (Moderate); CYP3A4 Inhib-
line in patients switching from ergocalciferol therapy to itors (Strong); Danazol; Fosaprepitant; Fosnetupitant;
calcitriol. Monitor calcium levels closely with initiation of Fusidic Acid (Systemic); Idelalisib; MIFEPRIStone; Multi-
therapy and with dose adjustments; discontinue use vitamins/Fluoride (with ADE); Multivitamins/Minerals
promptly in patients who develop hypercalcemia. Avoid (with ADEK, Folate, Iron); Netupitant; Palbociclib; Sime-
abrupt dietary modifications (eg, increased intake of dairy previr; Stiripentol; Thiazide and Thiazide-Like Diuretics
products) which may lead to hypercalcemia; adjust cal- Decreased Effect
cium intake if indicated and maintain adequate hydration.
The levels/effects of Calcitriol (Systemic) may be
Chronic hypercalcemia can resultin generalized vascular decreased by: Bile Acid Sequestrants; Bosentan; Corti-
and soft tissue calcification. Immobilized patients may be
costeroids (Systemic); CYP3A4 Inducers (Moderate);
at a higher risk for hypercalcemia.
CYP3A4 Inducers (Strong); Dabrafenib; Deferasirox;
Use oral calcitriol with caution in patients with malabsorp- Enzalutamide; Mineral Oil; Mitotane; Orlistat; Pitolisant;
tion syndromes (efficacy may be limited and/or response Sarilumab; Sevelamer; Siltuximab; St John's Wort; Toci-
may be unpredictable). Use of calcitriol for the treatment of lizumab
secondary hyperparathyroidism associated with CKD is Storage/Stability Oral capsule, injection, solution: Store
not recommended in patients with rapidly worsening kid- at room temperature of 15°C to 30°C (59°F to 86°F).
ney function or in noncompliant patients. Increased serum Protect from light.
phosphate levels in patients with renal failure may lead to Mechanism of Action Calcitriol, the active form of vita-
calcification; the use of an aluminum-containing phos- min D (1,25 hydroxyvitamin D3), binds to and activates the
phate binder is recommended along with a low phosphate vitamin D receptor in kidney, parathyroid gland, intestine,
diet in these patients. Use with caution in patients taking and bone, stimulating intestinal calcium transport and
cardiac glycosides; digitalis toxicity is potentiated by hypo- absorption. It reduces PTH levels and improves calcium
calcemia. Concomitant use with magnesium-containing and phosphate homeostasis by stimulating bone resorp-
products such as antacids may lead to hypermagnesemia tion of calcium and increasing renal tubular reabsorption
in patients receiving chronic renal dialysis. of calcium. Decreased renal conversion of vitamin D to its
Aluminum: The parenteral product may contain aluminum; primary active metabolite (1,25 hydroxyvitamin D) in
toxic aluminum concentrations may be seen with high chronic renal failure leads to reduced activation of vitamin
doses, prolonged, use, or renal dysfunction. Premature D receptor, which subsequently removes inhibitory sup-
neonates are at higher risk due to immature renal function pression of parathyroid hormone (PTH) release; increased
and aluminum intake from other parenteral sources. serum PTH (secondary hyperparathyroidism) reduces cal-
Parenteral aluminum exposure of >4 to 5 mcg/kg/day is cium excretion and enhances bone resorption.
associated with CNS and bone toxicity; tissue loading may Pharmacodynamics/Kinetics (Adult data unless
occur at lower doses (Federal Register 2002). See man- noted)
‘ufacturer’s labeling. Products may contain coconut (cap- Onset of action: Oral: 2 hours; maximum effect: 10 hours
sule) or palm seed oil(oral solution). Some products may Duration: Oral, IV: 3 to 5 days
contain tartrazine. Absorption: Oral: Rapid
Warnings: Additional Pediatric Considerations Mon- Protein binding: 99.9%
itor serum calcium levels closely; the calcitriol dosage Metabolism: Primarily to calcitroic acid and a lactone
should be adjusted accordingly; serum calcium times metabolite
phosphorus product (Ca x P) should not exceed 65 mg?/ Half-life elimination: Children 1.8-16 years undergoing
dL? for infants and children <12 years of age and 55 mg?/ peritoneal dialysis: 27.4 hours; Healthy adults: 5 to 8
dL? for adolescents (KDOQI 2005). hours; Hemodialysis: 16 to 22 hours

337
CALCITRIOL (SYSTEMIC)

Time to peak, serum: Oral: 3 to 6 hours; Hemodialysis: 8 Children 26 years and Adolescents: Oral: 0.5 to 2 meg
to 12 hours once daily
Excretion: Feces (27%); urine (7%, unchanged in 24 Secondary hyperparathyroidism associated with
hours) moderate to severe CKD in patients not yet on
Clearance: Children 1.8 to 16 years undergoing perito- dialysis (predialysis): Note: KDIGO recommends
neal dialysis: 15.3 mL/hour/kg against routine vitamin D supplement or analog use
Pharmacodynamics/Kinetics: Additional Consider- to suppress PTH concentrations in the absence of
ations Renal function impairment: The half-life is suspected or documented deficiency (KDIGO 2012).
Children <3 years: Oral: 0.01 to 0.015 meg/kg/dose
increased by at least 2-fold.
once daily
Dosing
Children 23 years and Adolescents: Oral: 0.25 mcg
Neonatal once daily; may increase if necessary to 0.5
Hypocalcemia secondary to hypoparathyroidism: mceg/day .
Oral: 1 meg once daily for the first 5 days of life Vitamin D-dependent rickets: Infants, Children, and
Alternate regimen: Oral: 0.02 to 0.06 mcg/kg/day; sim- Adolescents: Oral: Initial: 0.25 to 2 mcg once daily;
ilar dosage has also been described in neonates with adjust dose base on clinical response, use lower dose
DiGeorge syndrome (Miller 1983) once rickets has healed (Kliegman 2016)
Hypocalcemic tetany: Renal Impairment: Pediatric No dosage adjustment
IV: 0.05 mcg/kg once daily for 5 to 12 days necessary.
Oral: Initial: 0.25 mceg/dose once daily, followed by 0.01 Hepatic Impairment: Pediatric There are no dosage
to 0.10 mcg/kg/day divided in 2 doses (maximum adjustments provided in the manufacturer's labeling (has
daily dose: 2 mcg) not been studied).
Pediatric Administration
Hypocalcemia in patients with chronic kidney dis- Oral: May be administered with or without meals; when
ease (CKD)/Metabolic bone disease: Limited data administering small doses from the liquid-filled capsules,
available: Indicated when serum levels of 25(OH)D consider the following concentration for Rocaltrol:
are >30 ng/mL (75 nmol/L) and serum levels of intact 0.25 mcg capsule = 0.25 mcg per 0.17 mL
parathyroid hormone (iPTH) are above the target 0.5 mcg capsule = 0.5 mcg per 0.17 mL
range for the stage of CKD; serum levels of corrected Parenteral: May be administered undiluted as a bolus
total calcium are <9.5 to 10 mg/dL (2.37 mmol/L) and dose IV through the catheter at the end of hemodialysis.
serum levels of phosphorus in children are less than Monitoring Parameters :
age-appropriate upper limits of normal (K/DOQI Manufacturer's labeling:
Guidelines 2005): Oral therapy:
Children and Adolescents: Dialysis patients: Serum calcium (at least twice weekly
CKD Stages 2 to 4: Oral: during titration, followed by monthly once on optimal
<10 kg: 0.05 mcg every other day dose), phosphorus, magnesium, and alkaline phos-
10 to 20 kg: 0.1 to 0.15 mcg daily phate monitored periodically
>20 kg: 0.25 mcg daily Hypoparathyroid patients: Serum calcium (check at least
Dosage adjustment: twice weekly during dose titration, followed by periodi-
If iPTH decrease is <30% after 3 months of cally), phosphorus, 24-hour urinary calcium monitored
periodically
therapy and serum levels of calcium and phos-
Predialysis patients: Serum calcium (check at least twice
phorus are within the target ranges based upon
weekly during dose titration), phosphorus, alkaline
the CKD Stage, increase dosage by 50%.
phosphatase, creatinine, and intact PTH, initially; then
If iPTH decrease <target range for CKD stage
serum calcium, phosphorus, alkaline phosphatase, and
hold calcitriol therapy until iPTH increases to
creatinine monthly x 6 months, then periodically. Intact
above target range; resume therapy at half the
PTH should be monitored every 3 to 4 months.
previous dosage (if dosage <0.25 mcg capsule IV therapy: Serum calcium and phosphorus twice weekly
or 0.05 mcg liquid, use every other day therapy). (following initiation and during dosage adjustments) and
If serum levels of total corrected calcium exceed periodically during therapy; magnesium, alkaline phos-
10.2 mg/dL (2.37 mmol/L) hold calcitriol therapy phatase, and 24 hour urinary calcium and phosphorous
until serum calcium decreased to <9.8 mg/dL periodically
(2.37 mmol/L); resume therapy at half the pre- KDIGO guidelines (2009) and KDOQI Commentary
vious dosage (if dosage <0.25 mcg capsule or (Uhlig 2010):
0.05 meg liquid, use every other day therapy). Frequency of monitoring should be based on the pres-
If serum levels of phosphorus increase to >age- ence and magnitude of abnormalities, as well as the
appropriate upper limits, hold calcitriol therapy rate of CKD progression. Reasonable intervals are:
(initiate or increase phosphate binders until the CKD stage 2 to 3: Serum calcium and phosphorus, every
levels of serum phosphorus decrease to age- 6 to 12 months; PTH: Monitor based on baseline level
appropriate limits); resume therapy at half the and CKD progression; alkaline phosphatase once; 25
previous dosage. hydroxyvitamin D once then based on level and treat-
CKD Stage 5 on dialysis: Oral, IV: Serum calcium ments. Note: Adults may not need monitoring until
times phosphorus product (Ca x P) should not CKD stage 3.
exceed 65 mg?/dL? for infants and children <12 CKD stage 4: Serum calcium and phosphorus every 3 to
years of age and 55 mg/dL? for adolescents, 6 months; PTH every 6 to 12 months; alkaline phos-
serum phosphorus should be within target, serum phatase every 12 months or more frequently in the
calcium <10 mg/dL (2.37 mmol/L) or <10.5 mg/dL presence of increased PTH, 25 hydroxyvitamin D once
(2.5 mmol/L) if PTH >1,000 pg/mL: Note: If under- yearly.
going hemodialysis, doses should be given on CKD stage 5 (includes 5D): Serum calcium and phos-
dialysis days. phorus every 1 to 3 months; PTH every 3 to 6 months;
alkaline phosphatase every 12 months or more fre-
iPTH 300 to 500 pg/mL: 0.0075 mcg/kg 3 times
quently in the presence of increased PTH, 25 hydrox-
weekly; maximum dose: 0.25 mcg/dose
yvitamin D once then based on level and treatments.
iPTH >500 to 1,000 pg/mL: 0.015 mcg/kg 3 times
Reference Range
weekly; maximum dose: 0.5 mcg/dose
Corrected total serum calcium: Children, Adolescents, and
iPTH >1,000 pg/mL: 0.025 mcg/kg 3 times weekly;
Adults: CKD stages 2 to 5D: Maintain normal ranges;
maximum dose: 1 mcg/dose
preferably on the lower end for stage 5 (KDIGO 2009;
Dosage adjustment: If iPTH decrease is <30%
KDOQI 2005)
after 3 months of therapy and serum levels of Phosphorus (KDIGO 2009): Children, Adolescents, and
calcium and phosphorus are within the target Adults:
ranges based upon the CKD Stage 5, increase CKD stages 2 to 5: Maintain normal ranges
dosage by 50% CKD stage 5D: Lower elevated phosphorus levels
Note: Intermittent administration of calcitriol by toward the normal range
IV or oral routes is more effective than daily Additional Information Chronic kidney disease (CKD)
oral calcitriol in lowering iPTH levels (KDIGO 2013; KDOQI 2002): Children 22 years, Adoles-
(KDIGO 2005). cents, and Adults: GFR <60 mL/minute/1.73 m? or kidney
Hypoparathyroidism/pseudohypoparathyroidism: damage for >3 months; stages of CKD are described
Oral (evaluate dosage at 2- to 4-week intervals): below:
Infants: Limited data available: 0.02 to 0.06 mcg/kg CKD stage 1: Kidney damage with normal or increased
‘once daily (Sperling 2014) GFR; GFR >90 mL/minute/1.73 m?
Children 1 to 5 years: Oral: 0.25 to 0.75 mcg once CKD stage 2: Kidney damage with mild decrease in GFR;
daily GFR 60 to 89 mL/minute/1.73 m?

338
 CALCIUM ACETATE

CKD stage 3: Moderate decrease in GFR; GFR 30 to 59 children and adults including hyperosmolality, lactic acido-
mL/minute/1.73 m? sis, seizures and respiratory depression; use caution
CKD stage 4: Severe decrease in GFR; GFR 15 to 29 mL/ (AAP, 1997; Shehab, 2009).
minute/1.73 m? Adverse Reactions
CKD stage 5: Kidney failure; GFR <15 mL/minute/1.73 m? Endocrine & metabolic: Hypercalcemia
or dialysis Gastrointestinal: Diarrhea (oral solution), nausea, vom-
Dosage Forms Excipient information presented when iting 5
available (limited, particularly for generics); consult spe- Rare but important or life-threatening: Dizziness, edema,
cific product labeling. pruritus, weakness
Capsule, Oral:
Drug Interactions
Rocaltrol: 0.25 mcg, 0.5 mcg [contains fd&c yellow #6
Metabolism/Transport Effects None known.
(sunset yellow), methylparaben, propylparaben]
Generic: 0.25 mcg, 0.5 mcg Avoid Concomitant Use
Solution, Intravenous: Avoid concomitant use of Calcium Acetate with any of
Generic: 1 mcg/mL (1 mL) the following: Calcium Salts
Solution, Oral: Increased Effect/Toxicity
Rocaltrol: 1 mcg/mL (15 mL) Calcium Acetate may increase the levels/effects of:
Generic: 1 meg/mL (15 mL) Cardiac Glycosides; CefTRIAXone; Vitamin D Analogs

@ Calcitriol Injection (Can) see Calcitriol (Systemic) The levels/effects of Calcium Acetate may be increased
on page 336 by: Calcium Salts; Multivitamins/Fluoride (with ADE);
Calcitriol-Odan (Can) see Calcitriol (Systemic) Multivitamins/Minerals (with ADEK, Folate, Iron); Thia-
on page 336 zide and Thiazide-Like Diuretics
Decreased Effect
@ Calcium 600 [OTC] see Calcium Carbonate
on page 340 Calcium Acetate may decrease the levels/effects of:
Alpha-Lipoic Acid; Bictegravir; Bisphosphonate Deriva-
tives; Calcium Channel Blockers; Deferiprone; DOBUT-
Calcium Acetate (KAL see um AS e tate) amine; Dolutegravir; Eltrombopag; Estramustine;
Multivitamins/Fluoride (with ADE); Phosphate Supple-
Medication Safety Issues ments; Quinolones; Strontium Ranelate; Tetracyclines;
Sound-alike/look-alike issues:
Thyroid Products; Trientine
PhosLo® may be confused with Phos-Flur®, ProSom
Brand Names: US Calphron [OTC]; Eliphos [DSC]; The levels/effects of Calcium Acetate may be decreased
PhosLo [DSC]; Phoslyra by: Alpha-Lipoic Acid; Trientine
Brand Names: Canada PhosLo® Food Interactions Foods that contain maltitol may have
Therapeutic Category Calcium Salt; Electrolyte Supple- an additive laxative effect with the oral solution formulation
ment, Parenteral (contains maltitol).
Generic Availability (US) May be product dependent Mechanism of Action Combines with dietary phosphate
Use Treatment of hyperphosphatemia in end-stage renal to form insoluble calcium phosphate which is excreted in
failure (FDA approved in adults) feces
Pregnancy Risk Factor C Pharmacodynamics/Kinetics (Adult data unless
Pregnancy Considerations Animal reproduction studies noted)
have not been conducted. Calcium crosses the placenta. Absorption: 30% to 40%; requires vitamin D; minimal
The amount of calcium reaching the fetus is determined by unless chronic, high doses are given; calcium is
maternal physiological changes. Intestinal absorption of
absorbed in soluble, ionized form; solubility of calcium
calcium increases during pregnancy. If use is required in
is increased in an acid environment
pregnant patients with end stage renal disease, fetal harm
Excretion: Primarily feces (as unabsorbed calcium);
is not expected if maternal calcium concentrations are
urine (20%)
monitored and maintained within normal limits as recom-
mended (IOM, 2011). Dosing
Breastfeeding Considerations Calcium is excreted in Pediatric Note: Dose expressed in mg of calcium
breast milk. The amount of calcium in breast milk is acetate. Phosphate binding capacity: Calcium acetate
homeostatically regulated and not altered by maternal 1 g binds 45 mg of phosphorus (KDOQ! 2005)
calcium intake (IOM, 2011). Control of hyperphosphatemia in end-stage renal
Contraindications Hypersensitivity to any component of failure: Limited data available; dose should be individ-
the formulation; hypercalcemia, renal calculi ualized: Children and Adolescents: Oral: Reported ini-
Warnings/Precautions Constipation, bloating, and gas tial dose: 667 to 1,000 mg with each meal; titrate (every
are common with calcium supplements. Hypercalcemia 2 to 4 weeks) to response and as serum calcium levels
and hypercalciuria are most likely to occur in hypopara- allow (Gulati 2010; Wallot 1996). Note: KDOQI guide-
thyroid patients receiving high doses of vitamin D. Use lines recommend limiting the calcium provided from
with caution in patients who may be at risk of cardiac phosphate binders to 1,500 mg elemental calcium per
arrhythmias. Use with caution in digitalized patients; day and total intake to 2,000 mg elemental calcium
hypercalcemia may precipitate cardiac arrhythmias. Cal- from all sources (KDOQI 2010)
cium administration interferes with absorption of some Renal Impairment: Pediatric No dosage adjustment
minerals and drugs; use with caution. Oral solution may necessary.
contain maltitol (a sugar substitute) which may cause a Hepatic Impairment: Pediatric There are no dosage
laxative effect. Multiple salt forms of calcium exist; close adjustments provided in the manufacturer's labeling.
attention must be paid to the salt form when ordering and
Administration Oral: Administer with plenty of fluids with
administering calcium; incorrect selection or substitution
meals to optimize effectiveness
of one salt for another without proper dosage adjustment
may result in serious over or under dosing.
Monitoring Parameters Serum calcium (twice weekly
during initial dose adjustments), serum phosphorus;
In CKD patients with vascular (arterial) calcification and/or serum calcium-phosphorus product; intact parathyroid
adynamic bone disease and/or serum PTH levels that are hormone (iPTH)
persistently low, consider using non-calcium-based phos- Reference Range
phate binders (eg, sevelamer, lanthanum) as an alterna- Corrected total serum calcium: Children, Adolescents, and
tive to calcium-based phosphate binders (eg, calcium Adults: CKD stages 2 to 5D: Maintain normal ranges;
acetate, calcium carbonate) or restricting the dose of the preferably on the lower end for stage 5 (KDIGO 2009;
calcium-based phosphate binder (Allison 2013; KDIGO
KDOQ! 2005)
2009). A meta-analysis observed a trend towards a
Phosphorus (KDIGO 2009):
decrease in all-cause mortality in CKD patients receiving
CKD stages 3 to 5: Maintain normal ranges
non-calcium-based phosphate binders compared with
CKD stage 5D: Lower elevated phosphorus levels
those receiving calcium-based phosphate binders (Jamal
2013); however, further research is needed to identify toward the normal range
causes of mortality and fully assess safety of long-term Additional Information Due to a poor correlation
use based on binder type. between the serum ionized calcium (free) and total serum
Warnings: Additional Pediatric Considerations calcium, particularly in states of low albumin or acid/base
Some dosage forms may contain propylene glycol; in imbalances, direct measurement of ionized calcium is
neonates large amounts of propylene glycol delivered recommended. If ionized calcium is unavailable, in low
orally, intravenously (eg, >3,000 mg/day), or topically albumin states, the corrected total serum calcium may be
have been associated with potentially fatal toxicities which estimated by this equation (assuming a normal albumin of
can include metabolic acidosis, seizures, renal failure, and 4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas-
CNS depression; toxicities have also been reported in ured total calcium

339
 CALCIUM ACETATE

4 Elemental Calcium Content of Calcium

Salts
Brand Names:
Caltrate Select;
Canada
Os-Cal;
Apo-Cal; Calcite-500; Caltrate;
Tums Chews Extra Strength;
Tums Extra Strength; Tums Regular Strength; Tums
Elemental
Calcium Calcium Smoothies; Tums Ultra Strength
Calcium Salt Therapeutic Category Antacid; Calcium Salt; Electrolyte
(mg/1 g of (mEq/g)
salt— Supplement, Oral
Calcium acetate Generic Availability (US) May be product dependent
Calcium carbonate Use Relief of acid indigestion, heartburn, sour stomach,
Calcium chloride
and Gl upset associated with these symptoms; calcium
supplement (All indications: OTC product: FDA approved
cast oe |e AG in ages 22 years and adults); has also been used for
Calcium glubionate treatment of hyperphosphatemia in chronic kidney dis-
Saenger
Calcium |
2}93 48
4.65 ease; Note: Approved ages and uses for OTC products
vary; consult labeling for specific information.
|Calcium lactate
lactate |

err [on wo |
Pregnancy Considerations Calcium crosses the pla-
(abel phosphate
centa. Intestinal absorption of calcium increases during
pregnancy. The amount of calcium reaching the fetus is
Chronic os disease (CKD) (KDIGO 2013; KDOQI
determined by maternal physiological changes. Calcium
2002): Children 22 years, ee and Adults:
requirements are the same in pregnant and nonpregnant
GFR <60 mL/minute/1.73 m? or kidney damage for >3
females (LOM, 2011). Calcium-based antacids are consid-
months; stages of CKD are described below:
ered_low risk during pregnancy; excessive use should be
CKD Stage 1: Kidney damage with normal or increased
avoided (Mahadevan, 2006).
GFR; GFR >90 mL/minute/1.73 m?
Breastfeeding Considerations Calcium is excreted in
CKD Stage 2: Kidney damage with mild decrease in
breast milk. The amount of calcium in breast milk is
GFR; GFR 60 to 89 mL/minute/1.73 m*
homeostatically regulated and not altered by maternal
CKD Stage 3: Moderate decrease in GFR; GFR 30 to 59
calcium intake. Calcium requirements are the same in
mL/minute/1.73 m?
lactating and nonlactating females (IOM 2011). Calcium-
CKD Stage 4: Severe decrease in GFR; GFR 15 to 29
based antacids are probably compatible with breastfeed-
mL/minute/1.73 m? ing (Mahadevan, 2006).
CKD Stage 5: Kidney failure; GFR <15 mL/minute/1.73
Contraindications Hypersensitivity to any component of
m? or dialysis
the formulation
Dosage Forms Considerations
Warnings/Precautions Constipation, bloating, and gas
Calcium acetate is approximately 25% elemental calcium
are common with calcium supplements. Calcium absorp-
Calcium acetate 667 mg = elemental calcium 169 mg =
tion is impaired in achlorhydria; administration is followed
calcium 8.45 mEq = calcium 4.23 mmol
by increased gastric acid secretion within 2 hours of
Dosage Forms Excipient information presented when administration especially with high doses. Common in
available (limited, particularly for generics); consult spe- the elderly; use an alternate salt (eg, citrate) and admin-
cific product labeling. [DSC] = Discontinued product ister with food. Hypercalcemia and hypercalciuria are
Capsule, Oral: most likely to occur in hypoparathyroid patients receiving
PhosLo: 667 mg [DSC] high doses of vitamin D. Use caution when administering
Generic: 667 mg calcium supplements to patients with a history of kidney
Solution, Oral: stones. Patients with renal insufficiency are more sensitive
Phoslyra: 667 mg/5 mL (473 mL) [contains methylpar- or susceptible to the effects of excess calcium; use with
aben, propylene glycol] caution. It is recommended to concomitantly administer
Tablet, Oral: vitamin D for optimal calcium absorption when used for the
Calphron: 667 mg treatment or prevention of conditions related to bone
Eliphos: 667 mg [DSC] health (eg, osteoporosis). Multiple salt forms of calcium
Generic: 667 mg, 668 mg exist; close attention must be paid to the salt form when
® Calcium Acetate and Aluminum Sulfate see Aluminum ordering and administering calcium; incorrect selection or
Acetate on page 100 substitution of one salt for another without proper dosage
adjustment may result in serious over or under dosing.
@ Calcium Antacid [OTC] see Calcium Carbonate Adverse Reactions Well tolerated
on page 340 Central nervous system: Headache, laxative effect
@ Calcium Antacid Extra Strength [OTC] see Calcium Endocrine & metabolic: Hypercalcemia, hypophosphate-
Carbonate on page 340 mia, milk-alkali syndrome (with very high, chronic dosing
@ Calcium Antacid Ultra Max St [OTC] see Calcium and/or renal failure [headache, nausea, irritability, and
Carbonate on page 340 weakness or alkalosis, hypercalcemia, renal
impairment])
Gastrointestinal: Abdominal pain, anorexia, constipation,
Calcium Carbonate (KAL see um KAR bun ate) flatulence, hyperacidity (acid rebound), nausea, vomit-
ing, xerostomia
Medication Safety Issues
Drug Interactions
Sound-alike/look-alike issues:
Calcium carbonate may be confused with calcitriol
Metabolism/Transport Effects None known.
Children’s Pepto may be confused with Pepto-Bismol Avoid Concomitant Use
products Avoid concomitant use of Calcium Carbonate with any of
Maalox and Children’s Maalox may be confused with
the following: Calcium Acetate
other Maalox products Increased Effect/Toxicity
Mylanta may be confused with Mynatal Calcium Carbonate may increase the levels/effects of:
Os-Cal [DSC] may be confused with Asacol Amphetamines; Calcium Acetate; Calcium Polystyrene
International issues: Sulfonate; Cardiac Glycosides; Dexmethylphenidate;
Remegel [Hungary, Great Britain, and Ireland] may be Methylphenidate; QuiNIDine; Sodium Polystyrene Sulfo-
confused with Renagel brand name for sevelamer [US, nate; Vitamin D Analogs
Canada, and multiple international markets] The levels/effects of Calcium Carbonate may be
Remegel: Brand name for calcium carbonate [Hungary, increased by: Multivitamins/Fluoride (with ADE); Thia-
Great Britain, and Ireland], but also the brand name for zide and Thiazide-Like Diuretics
aluminum hydroxide and magnesium carbonate [Neth- Decreased Effect
erlands] Calcium Carbonate may decrease the levels/effects of:
Brand Names: US Alcalak [OTC] [DSC]; Antacid Cal- Acalabrutinib; Allopurinol; Alpha-Lipoic Acid; Antipsy-
cium Extra Strength [OTC]; Antacid Calcium [OTC]; Ant- chotic Agents (Phenothiazines); Atazanavir; Bictegravir;
acid Extra Strength [OTC]; Antacid [OTC]; Cal-Carb Forte Bisacodyl; Bismuth Subcitrate; Bisphosphonate Deriva-
[OTC]; Cal-Gest Antacid [OTC]; Cal-Mint [OTC]; Calci- tives; Bosutinib; Bromperidol; Calcium Channel Block-
Chew [OTC]; Calci-Mix [OTC] [DSC]; Calcium 600 ers; Captopril; Cefditoren; Cefpodoxime; Cefuroxime;
[OTC]; Calcium Antacid Extra Strength [OTC]; Calcium Chloroquine; Corticosteroids (Oral); Cysteamine (Sys-
Antacid Ultra Max St [OTC]; Calcium Antacid [OTC]; temic); Dabigatran Etexilate; Dasatinib; Deferiprone;
Calcium High Potency [OTC]; Caltrate 600 [OTC]; Florical Delavirdine; Diacerein; DOBUTamine; Dolutegravir;
[OTC]; Maalox Childrens [OTC]; Maalox [OTC]; Oysco Eltrombopag; Elvitegravir; Erlotinib; Estramustine; Fosi-
500 [OTC]; Titralac [OTC]; Tums Chewy Bites [OTC]; nopril; Gabapentin; Gefitinib; Hyoscyamine; Iron Salts;
Tums Chewy Delights [OTC]; Tums E-X 750 [OTC]; Tums Itraconazole; Ketoconazole (Systemic); Lanthanum;
Extra Strength 750 [OTC]; Tums Freshers [OTC] [DSC]; Ledipasvir; Mesalamine; Methenamine; Multivitamins/
Tums Kids [OTC]; Tums Lasting Effects [OTC]; Tums Fluoride (with ADE); Multivitamins/Minerals (with ADEK,
Smoothies [OTC]; Tums Ultra 1000 [OTC]; Tums [OTC] Folate, Iron); Mycophenolate; Neratinib; Nilotinib;

340
 CALCIUM CARBONATE

PAZOPanib; Penicil[AMINE; Phosphate Supplements; Children 6 to 11 years: Oral: 750 to 800 mg of

Potassium Phosphate; Quinolones; Raltegravir; Rilpivir- calcium carbonate as symptoms occur for up to 2
ine; Riociguat; Rosuvastatin; Sotalol; Strontium Rane- weeks; maximum daily dose: 3,000 mg/day of cal-
late; Sulpiride; Tetracyclines; Thyroid Products; cium carbonate
Trientine; Velpatasvir Children 212 years and Adolescents: Oral: 500 to
3,000 mg of calcium carbonate as symptoms
The levels/effects of Calcium Carbonate may be
occur for up to 2 weeks; maximum daily dose:
decreased by: Alpha-Lipoic Acid; Trientine.
7,500 mg/day of calcium carbonate
Food Interactions Food may increase calcium absorp-
Calcium dietary supplementation: Oral:
tion. Calcium may decrease iron absorption. Bran, foods
Children 2 to 4 years: 750 mg of calcium carbonate
high in oxalates, or whole grain cereals may decrease
twice daily
calcium absorption. Management: Administer with food.
Children 24 years and Adolescents: 750 mg of cal-
Storage/Stability Store between 15°C to 30°C (59°F to cium carbonate 3 times daily
86°F). Protect oral suspension from freezing.
Hypocalcemia: Dose depends on clinical condition
Mechanism of Action As dietary supplement, used to
and serum calcium concentration: Dose expressed
prevent or treat negative calcium balance; in osteoporosis,
as elemental calcium: Limited data available: Oral:
it helps to prevent or decrease the rate of bone loss.
Infants and Children: 45 to 65 mg/kg/day in 4 divided
Calcium is an integral component of the skeleton and also
doses (Nelson 1996)
moderates nerve and muscle performance and allows
Hyperphosphatemia in chronic kidney disease:
normal cardiac function. Also used to treat hyperphospha-
Infants, Children, and Adolescents: Limited data avail-
temia in patients with chronic kidney disease by combining
able: Oral: Calcium provided from phosphate binders
with dietary phosphate to form insoluble calcium phos-
should be limited to 1,500 mg/day of elemental cal-
-phate, which is excreted in-feces. Calcium salts as ant-
cium and total calcium intake (including dietary sour-
acids. neutralize gastric acidity resulting in increased
ces and calcium-based phosphate binders) should
gastric. and duodenal bulb pH; they additionally inhibit
not exceed 2,000 mg/day of elemental calcium
proteolytic activity of pepsin if the pH is increased >4
(KDOQI [Uhlig 2010])
and increase lower esophageal sphincter tone (IOM,
Rickets (due to vitamin D deficiency); treatment:
2011).
Limited data available: Infants and Children: Dose
Pharmacodynamics/Kinetics (Adult data unless expressed as elemental calcium: Oral: 30 to
noted) 75 mg/kg/day in 3 divided doses; begin at higher
Absorption: Minimal unless chronic, high doses; absorp- end of range and titrate downward over 2 to 4 weeks
tion predominantly in the duodenum and dependent on (Misra 2008)
calcitriol and vitamin D; mean absorption of calcium Renal Impairment: Pediatric Infants, Children, and
intake varies with age (infants 60%, prepubertal children Adolescents: No initial dosage adjustment. necessary;
28%, pubertal children 34%, adults 25%); during preg- however, accumulation may occur with renal impairment
nancy, calcium absorption doubles; calcium is absorbed and subsequent doses may require adjustment based on
in soluble, ionized form; solubility of calcium is increased serum calcium concentrations.
in an acid environment (IOM 2011); decreased absorp- Hepatic Impairment: Pediatric Infants, Children, and
tion occurs in patients with achlorhydria, renal osteodys-
Adolescents: There are no dosage adjustments provided
trophy, steatorrhea, or uremia
in the manufacturer's labeling. No initial dosage adjust-
Distribution: Primarily in bones, teeth (IOM, 2011)
ment necessary; subsequent doses should be guided by
Protein binding: ~40%, primarily to albumin (Wills 1971)
serum calcium concentrations. In adult patients in the
Excretion: Primarily feces (75%; as unabsorbed calcium);
anhepatic stage of liver transplantation, equal rapid
urine (22%) (l1OM, 2011)
increases in ionized concentrations occur suggesting
Dosing that calcium gluconate does not require hepatic metab-
Neonatal olism for release of ionized calcium (Martin 1990).
Adequate intake (Al): Oral: 200 mg/day of elemental
Administration
calcium; requirements may vary on prematurity, post-
Oral: Administer with plenty of fluids with or immediately
natal age, and other clinical factors; serum calcium
following meals; if using for phosphate-binding, admin-
concentrations should be monitored closely to deter- ister with meals
mine patient-specific needs (IOM 2011)
Suspension: Shake well before administration
Enteral nutrition, maintenance requirement (dietary
Chewable tablets: Thoroughly chew tablets before swal-
intake; formula, breast milk): Preterm neonates, birth
lowing
weight <2,000 g: Oral: 150 to 220 mg/kg/day of ele-
Monitoring Parameters Serum calcium (ionized calcium
mental calcium (Abrams 2013)
preferred if available), phosphate, magnesium, heart rate,
Hypocalcemia: Dose depends onclinical-condition and
ECG
serum calcium concentration: Dose expressed as ele-
Reference Range
mental calcium: 50 to 150 mg/kg/day in 4 to 6 divided
doses; not to exceed 1,000 mg/day (Avery 1994; Rigo
Normal Values
2007; Thomas 2012) Serum
Rickets (radiographic evidence), treatment: Dose Concentration
expressed as elemental calcium: Oral: Initial: Cord blood 9 to 11.5 mg/dL
20 mg/kg/day in 2 to 4 divided doses, increased as Newborn 3 to 24
tolerated to usual range of 60 to 70 mg/kg/day in 2 to 4 hours
9 to 10.6 mg/dL
divided doses; maximum daily dose: 80 mg/kg/day Newborn 24 to 48
X 7 to 12 mg/dL
(Abrams 2013); frequency derived from other calcium Calcium, total hours
salts 4 to 7 days 9 to 10.9 mg/dL
Pediatric Child 8.8 to 10.8 mg/dL
Adequate intake (Al) (IOM 2011): Dose expressed as Adolescent to
elemental calcium: Oral: 8.4 to 10.2 mg/dL
Adult
1 to 6 months: 200 mg/day Cord blood 5 to 6 mg/dL
7 to 12 months: 260 mg/day
Newborn 3 to 24
Recommended daily allowance (RDA) (IOM 2011): hours 4.3 to 5.1 mg/dL
Dose expressed as elemental calcium; during preg- Calcium, ionized, whole Newborn 24 to 48
nancy and lactation, requirements may change: Oral: blood 4 to 4.7 mg/dL
hours
1 to 3 years: 700 mg/day 4.8 to 4.92 mg/dL
4 to 8 years: 1,000 mg/day 22 days (2.24 to 2.46
9 to 18 years: 1,300 mg/day mEq/L)
Antacid: Note: Chronic antacid therapy not recom-
mended for management of GERD in pediatric Additional Information Due to a poor correlation
patients (AAP [Lightdale 2013]; Vandenplas 2009). between the serum ionized calcium (free) and total serum
OTC products may vary in approved ages and uses; calcium, particularly in states of low albumin or acid/base
consult product specific labeling for details. Dose imbalances, direct measurement of ionized calcium is
expressed as calcium carbonate. recommended. If ionized calcium is unavailable, in low
Children 2 to 5 years, weighing >10.9 kg: Oral: 375 to albumin states, the corrected total serum calcium may be
400 mg of calcium carbonate as symptoms occur estimated by this equation (assuming a normal albumin of
for up to 2’ weeks; maximum daily dose: 1,500 mg/ 4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas-
day of calcium carbonate ured total calcium

341
CALCIUM CARBONATE

Elemental Calcium Content of Calcium Calcium Antacid: 500 mg [contains brilliant blue fef (fd&c
Salts blue #1), fd&c red #40, fd&c yellow #10 (quinoline
yellow), fd&c yellow #6 (sunset yellow)]
Elemental
Calcium Calcium
Calcium Antacid: 500 mg [contains brilliant blue fcf (fd&c
Calcium Salt (mEq/g) blue #1), fd&c red #40, fd&c yellow #6 (sunset yellow),
(mg/1 g of
salt form) soybeans (glycine max), tartrazine (fd&c yellow #5);
Calcium acetate assorted flavor]
Calcium carbonate
Calcium Antacid: 500 mg [contains fd&c blue #1 alumi-
num lake]
Calcium chloride
Calcium Antacid: 500 mg [contains fd&c blue #1 alumi-
Calcium citrate num lake, fd&c yellow #10 aluminum lake, fd&c yellow
Calcium glubionate #6 aluminum lake; assorted fruit flavor]
Calcium gluconate Calcium Antacid Extra Strength: 750 mg [DSC] [assorted
fruit flavor]
Calcium lactate
Calcium Antacid Extra Strength: 750 mg [contains bril-
Calcium phosphate liant blue fef (fd&c blue #1), fd&c red #40}
(tribasic)
Calcium Antacid Extra Strength: 750 mg [contains bril-
liant blue fcf (fd&c blue #1), fd&c red #40, fd&c yellow
Dosage Forms Considerations 1 g calcium carbonate #6 (sunset yellow), tartrazine (fd&c yellow #5); assorted
= elemental calcium 400 mg = calcium 20 mEq = calcium flavor] ~~
10 mmol Calcium Antacid Extra Strength: 750 mg [DSC] [contains
Dosage Forms Excipient information presented when fd&c blue #1 aluminum lake, fd&c red #40 alumi-
available (limited, particularly for generics); consult spe- num lake]
cific product labeling. [DSC] = Discontinued product Calcium Antacid Extra Strength: 750 mg [gluten free;
Capsule, Oral: contains brilliant blue fcf (fd&c blue #1), fd&c yellow
Calci-Mix: 1250 mg (elemental calcium 500 mg) [DSC] #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]
Florical: 364 mg (elemental calcium 145 mg) and fluo- Calcium Antacid Ultra Max St: 1000 mg {contains brilliant
ride 3.75 mg blue fef (fd&c blue #1), fd&c red #40, fd&c yellow #6
Powder, Oral: (sunset yellow), soybeans (glycine max), tartrazine
Generic: Elemental calcium 800 mg/2 g (480 g) (fd&c yellow #5)]
Suspension, Oral: Maalox: 600 mg [contains aspartame; wild berry flavor]
Generic: 1250 mg (elemental calcium 500 mg) per 5 mL Maalox Childrens: 400 mg [contains aspartame; wild
(5 mL, 473 mL, 500 mL) berry flavor]
Tablet, Oral: Titralac: 420 mg [low sodium, sugar free; contains sac-
Cal-Carb Forte: 1250 mg (elemental calcium 500 mg) charin]
Calcium 600: 1500 mg (elemental calcium 600 mg) Tums: 500 mg [peppermint flavor]
[scored] Tums: 500 mg [gluten free]
Calcium 600: 1500 mg (elemental calcium 600 mg) [con- Tums: 500 mg [gluten free; contains fd&c blue #1 alumi-
tains fd&c yellow #6 aluminum lake, soy polysac- num lake, fd&c red #40 aluminum lake, fd&c yellow #6
carides] aluminum lake, tartrazine (fd&c yellow #5)}
Calcium High Potency: 1500 mg (elemental calcium Tums Chewy Bites: 750 mg [contains corn starch, fd&c
600 mg) blue #1 aluminum lake, fd&c blue #2 aluminum lake,
Caltrate 600: 1500 mg (elemental calcium 600 mg) fd&c red #40 aluminum lake, fd&c yellow #5 aluminum
[scored] lake, fd&c yellow #6 aluminum lake, methylparaben,
Florical: 364 mg (elemental calcium 145 mg) and fluo- propylparaben, sodium benzoate, soybean lecithin,
ride 3.75 mg soybean oil]
Oysco 500: 1250 mg (elemental calcium 500 mg) [con- Tums Chewy Delights: 1177 mg [contains coconut oil
tains brilliant blue fcf (fd&c blue #1), tartrazine (fd&c (copra/cocos nucifera oil), corn starch, fd&c yellow #6
yellow #5)] (sunset yellow), soybean lecithin]
Generic: 648 mg, 1250 mg (elemental calcium 500 mg), Tums Chewy Delights: 1177 mg [contains fd&c red #40
1500 mg (elemental calcium 600 mg) aluminum lake, soybean lecithin; cherry flavor]
Tablet, Oral [preservative free]: Tums E-X 750: 750 mg
Calcium 600: 1500 mg (elemental calcium 600 mg) [lac- Tums E-X 750: 750 mg [assorted flavor]
tose free, salt free, sugar free] Tums E-X 750: 750 mg [gluten free; contains fd&c blue
Generic: 1250 mg (elemental calcium 500 mg), 1500 mg #1 aluminum lake, fd&c red #40 aluminum lake;
(elemental calcium 600 mg) assorted berries flavor]
Tablet Chewable, Oral: Tums E-X 750: 750 mg [sugar free]
Alcalak: 420 mg [DSC] Tums Extra Strength 750: 750 mg [gluten free; contains
Antacid: 420 mg [DSC], 500 mg fd&c blue #1 aluminum lake, fd&c red #40 aluminum
Antacid: 500 mg [peppermint flavor] lake, fd&c yellow #5 aluminum lake, fd&c yellow #6
Antacid: 500 mg [contains brilliant blue fcf (fd&c blue aluminum lake; assorted fruit flavor]
#1), fd&c yellow #10 (quinoline yellow), fd&c yellow Tums Extra Strength 750: 750 mg [sugar free; contains
#6 (sunset yellow)] fd&c red #40 aluminum lake, fd&c yellow #5 alumi-
Antacid: 500 mg [contains fd&c blue #1 aluminum lake, num lake] - ;
fd&c red #40 aluminum lake, fd&c yellow #5 aluminum Tums Freshers: 500 mg [DSC] [gluten free; contains
lake, fd&c yellow #6 aluminum lake] brilliant blue fcf (fd&c blue #1); mint flavor]
Antacid Calcium: 500 mg [peppermint flavor] Tums Freshers: 500 mg [DSC] [kosher certified; con-
Antacid Calcium: 500 mg [gluten free; peppermint flavor] tains brilliant blue fcf (fd&c blue #1), tartrazine (fd&c
Antacid Calcium Extra Strength: 750 mg [DSC] [contains yellow #5)]
fd&c blue #1 aluminum lake, fd&c red #40 aluminum Tums Freshers: 500 mg [DSC] [kosher certified; con-
lake; assorted flavor] tains brilliant blue fcf (fd&c blue #1), tartrazine (fd&c
Antacid Calcium Extra Strength: 750 mg [gluten free; yellow #5); spearmint flavor]
contains fd&c blue #1 aluminum lake, fd&c red #40 Tums Kids: 750 mg [scored; contains fd&c blue #1
aluminum lake; assorted fruit flavor] aluminum lake, fd&c red #40 aluminum lake; cherry
Antacid Extra Strength: 750 mg [contains brilliant blue fcf flavor]
(fd&c blue #1), fd&c red #40] Tums Lasting Effects: 500 mg [contains fd&c red #40
Antacid Extra Strength: 750 mg [contains fd&c red #40, aluminum lake, fd&c yellow #6 aluminum lake, tartra-
fd&c yellow #6 (sunset yellow), tartrazine (fd&c yel- zine (fd&c yellow #5)]
low #5)] Tums Smoothies: 750 mg [peppermint flavor]
Cal-Gest Antacid: 500 mg [DSC] [contains fd&c blue #1 Tums Smoothies: 750 mg [contains fd&c blue #1 alumi-
aluminum lake, fd&c yellow #10 aluminum lake, fd&c num lake, fd&c red #40 aluminum lake, fd&c yellow #6
yellow #6 aluminum lake] aluminum lake, soybeans (glycine max); assorted trop-
Cal-Gest Antacid: 500 mg [contains fd&c blue #1 alumi- ical fruit flavor]
num lake, fd&c yellow #10 aluminum lake, fd&c yellow Tums Smoothies: 750 mg [contains fd&c blue #1 alumi-
#6 aluminum lake; assorted fruit flavor] num lake, fd&c red #40 aluminum lake, soybeans
Cal-Mint: Elemental calcium 260 mg [animal products (glycine max); berry flavor]
free, gelatin free, gluten free, lactose free, no artificial Tums Smoothies: 750 mg [gluten free; contains corn
color(s), no artificial flavor(s), starch free, sugar free, starch, fd&c blue #1 aluminum lake, fd&c red #40
yeast free] aluminum lake, fd&c yellow #5 aluminum lake, fd&c
Calci-Chew: 1250 mg (elemental calcium 500 mg) yellow #6 aluminum lake, soybeans (glycine max)]
[cherry flavor] Tums Ultra 1000: 1000 mg
Calcium Antacid: 500 mg [DSC] Tums Ultra 1000: 1000 mg [peppermint flavor]

342
 CALCIUM CHLORIDE

Tums Ultra 1000: 1000 mg [contains fd&c blue #1 alu- use, or renal dysfunction. Premature neonates are at
minum lake, fd&c red #40 aluminum lake, fd&c yellow higher risk due to immature renal function and aluminum
#5 aluminum lake, fd&c yellow #6 aluminum lake; intake from other parenteral sources. Parenteral alumi-
assorted berries flavor] num exposure of >4 to 5 mcg/kg/day is associated with
Tums Ultra 1000: 1000 mg [contains fd&c red #40 alu- CNS and bone toxicity; tissue loading may occur at lower
minum lake, fd&c yellow #6 aluminum lake, tartrazine doses (Federal Register, 2002). See manufacturer's label-
(fd&c yellow #5); assorted tropical fruit flavor] ing. Avoid metabolic acidosis (ie, administer only up to 2 to
Tums Ultra 1000: 1000 mg [gluten free; contains fd&c 3 days then change to another calcium salt).
blue #1 aluminum lake, fd&c red #40 aluminum lake,
fd&c yellow #6 aluminum lake, tartrazine (fd&c yel- Ceftriaxone may complex with calcium causing precipita-
low #5)] tion, Fatal lung and kidney damage associated with cal-
Generic: 500 mg, 750 mg, Elemental calcium 260 mg cium-ceftriaxone precipitates has been observed in
premature and term neonates. Due to reports of precip-
itation reaction in neonates, do not coadminister ceftriax-
Calcium Chloride (Kat see um KLOR ide) one with calcium-containing solutions, even via separate
infusion lines/sites or at different times in any neonate.
Medication Safety Issues Ceftriaxone should not be administered simultaneously
Sound-alike/look-alike issues: with any calcium-containing solution via a Y-site in any
Calcium chloride may be confused with calcium gluco- patient. However, ceftriaxone and calcium-containing sol-
nate utions may be administered sequentially of one another
Administration issues: for use in patients other than neonates if infusion lines
Calcium chloride may be confused with calcium gluco- are thoroughly flushed (with a compatible fluid) between
nate. infusions. Multiple salt forms of calcium exist; close atten-
Confusion with the different intravenous salt forms of tion must be paid to the salt form when ordering and
calcium has occurred. There is a threefold difference administering calcium; incorrect selection or substitution
in the primary cation concentration between calcium of one salt for another without proper dosage adjustment
chloride (in which 1 g = 14 mEq [270 mg] of elemental may result in serious over or under dosing.
Ca++) and calcium gluconate (in which 1 g = 4.65 mEq Adverse Reactions IV:
[90 mg] of elemental Ca++). Cardiovascular (following rapid IV injection): Bradycardia,
Prescribers should specify which salt form is desired. cardiac arrest, cardiac arrhythmia, hypotension, syn-
Dosages should be expressed either as mEq, mg, or
cope, vasodilatation
grams of the salt form. Central nervous system: Feeling abnormal (sense of
Therapeutic Category Calcium Salt; Electrolyte Supple- oppression; with rapid IV injection), tingling sensation
ment, Parenteral (with rapid IV injection)
’ Generic Availability (US) Yes Endocrine & metabolic: Hot flash (with rapid IV injection),
Use Treatment of hypocalcemia and conditions secondary hypercalcemia
to hypocalcemia (eg, tetany, seizures, arrhythmias); treat- Gastrointestinal: Dysgeusia (chalky taste), gastrointestinal
ment of cardiac disturbances secondary to hyperkalemia; irritation, increased serum amylase
adjunctive treatment of magnesium sulfate overdose [All Local: Local tissue necrosis (following extravasation)
indications: FDA approved in pediatric patients (age not Renal: Nephrolithiasis
specified) and adults]; has also been used for calcium Rare but important or life-threatening: Cutaneous calcifi-
channel blocker toxicity, or beta-blocker toxicity refractory cation
to glucagon and vasopressors Drug Interactions
Pregnancy Risk Factor C Metabolism/Transport Effects None known.
Pregnancy Considerations Animal reproduction studies Avoid Concomitant Use
have not been conducted. Calcium crosses the placenta. Avoid concomitant use of Calcium Chloride with any of
The amount of calcium reaching the fetus is determined by the following: Calcium Acetate
maternal physiological changes. Calcium requirements
Increased Effect/Toxicity
are the same in pregnant and nonpregnant females
Calcium Chloride may increase the levels/effects of:
(1OM 2011). Information related to use as an antidote in
Calcium Acetate; Cardiac Glycosides; CeffRIAXone;
pregnancy is limited. In general, medications used as
Vitamin D Analogs
antidotes should take into consideration the health and
prognosis of the mother; antidotes should be administered The levels/effects of Calcium Chloride may be increased
fo pregnant women if there is a clear indication for use and by: Multivitamins/Fluoride (with ADE); Multivitamins/Min-
should not be withheld because of fears of teratogenicity erals (with ADEK, Folate, Iron); Thiazide and Thiazide-
(Bailey 2003). Medications used for the treatment of Like Diuretics
cardiac arrest in pregnancy are the same as in the non- Decreased Effect
pregnant woman. Doses and indications should follow Calcium Chloride may decrease the levels/effects of:
current Advanced Cardiovascular Life Support guidelines. Bictegravir; Bisphosphonate Derivatives; Calcium Chan-
Appropriate medications should not be withheld due to nel Blockers; Deferiprone; DOBUTamine; Dolutegravir;
concerns of fetal teratogenicity (Jeejeebhoy [AHA] 2015). Eltrombopag; Multivitamins/Fluoride (with ADE); Phos-
Breastfeeding Considerations Calcium is excreted in phate Supplements; Tetracyclines; Thyroid Products;
breast milk. The amount of calcium in breast milk is Trientine
homeostatically regulated and not altered by maternal
calcium intake. Calcium requirements are the same in The levels/effects of Calcium Chloride may be
lactating and nonlactating females (IOM 2011). decreased by: Trientine
Contraindications Known or suspected digoxin toxicity; Storage/Stability
not recommended as routine treatment in cardiac arrest Store intact vials at 20°C to 25°C (68°F to 77°F); excur-
(includes asystole, ventricular fibrillation, pulseless ven- sions permitted to 15°C to 30°C (59°F to 86°F). Do not
tricular tachycardia, or pulseless electrical activity) refrigerate solutions; IV infusion solutions in DSW, LR,
NS, or other appropriate solutions are stable for 24 hours
Warnings/Precautions For IV use only; do not inject
at room temperature.
SubQ or IM; avoid rapid IV administration (do not exceed
100 mg/minute except in emergency situations). Vesicant; Although calcium chloride is not routinely used in the
ensure proper catheter or needle position prior to and preparation of parenteral nutrition, it is important to note
during infusion; avoid extravasation; extravasation may that phosphate salts may precipitate when mixed with
result in severe necrosis and sloughing. Monitor the IV calcium salts. Solubility is improved in amino acid paren-
site closely. Use with caution-in patients with hyperphos- teral nutrition solutions. Check with a pharmacist to
phatemia, respiratory acidosis, renal impairment, or res- determine compatibility.
piratory failure; acidifying effect of calcium chloride may Mechanism of Action Moderates nerve and muscle
potentiate acidosis. Use with caution in patients with performance via action potential excitation threshold reg-
chronic renal failure to avoid hypercalcemia; frequent ulation
monitoring of serum calcium and phosphorus is neces- Pharmacodynamics/Kinetics (Adult data unless
sary. Use with caution in hypokalemic or digitalized noted)
patients since acute rises in serum calcium levels may Protein binding: ~40%, primarily to albumin (Wills, 1971)
precipitate cardiac arrhythmias; use is contraindicated Excretion: Primarily feces (80% as insoluble calcium
with known or suspected digoxin toxicity. Hypomagnese- salts); urine (20%)
_mia is a common cause of hypocalcemia; therefore, Dosing
correction of hypocalcemia may be difficult in patients with Neonatal
concomitant hypomagnesemia. Evaluate serum magne- Daily maintenance calcium: |V: Dosage expressed in
sium and correct hypomagnesemia (if necessary), partic- terms of elemental calcium: 3-4 mEq/kg/day
ularly if initial treatment of hypocalcemia is refractory. The Parenteral nutrition, maintenance requirement (Mir-
parenteral product’may contain aluminum; toxic aluminum tallo, 2004): IV: Dosage expressed in terms of elemen-
concentrations may be seen with high doses, prolonged tal calcium: 2-4 mEq/kg/day
CALCIUM CHLORIDE

Hypocalcemia: |V: Dosage expressed in mg of calcium concentration of each ion. The pH of the solution is
chloride: 10-20 mg/kg/dose, repeat every 4-6 hours if primarily dependent upon the amino acid concentra-
needed tion. The higher the percentage amino acids, the lower
Cardiac arrest in the presence of hyperkalemia or the pH and the more soluble the calcium and phos-
hypocalcemia, hypermagnesemia, or calcium chan- phate. Individual commercially available amino acid
nel blocker toxicity: IV, |.0.: Dosage expressed in mg
solutions vary significantly with respect to pH lowering
of calcium chloride: 20 mg/kg; may repeat in 10
minutes if necessary; if effective, consider IV infusion potential and consequent calcium phosphate compati-
of 20-50 mg/kg/hour bility; consult product specific labeling for additional
Tetany: IV: Dosage expressed in mg of calcium chlor- information.
ide: 10 mg/kg over 5-10 minutes; may repeat after 6 Vesicant; ensure proper needle or catheter placement
hours or follow with an infusion with a maximum dose of prior to and during IV infusion. Avoid extravasation.
200 mg/kg/day Early/acute calcium extravasation: \f acute extravasation
Pediatric Note: One gram of calcium chloride salt is occurs, stop infusion immediately and disconnect
equal to 270 mg of elemental calcium. (leave needle/cannula in place); gently aspirate
Daily maintenance calcium: |V: Dosage expressed in
extravasated solution (do NOT flush the line); initiate
terms of elemental calcium
Infants and Children <25 kg: 1-2 mEq/kg/day hyaluronidase antidote; remove needle/cannula; apply
Children 25-45 kg: 0.5-1.5 mEq/kg/day dry cold compresses; elevate extremity (Hurst 2004;
Children >45 kg and Adolescents: 0.2-0.3 mEq/kg/ Reynolds.2014).
day or 10-20 mEq/day Delayed calcium extravasation: lf delayed extravasation
Parenteral nutrition, maintenance requirement (Mir- suspected, closely monitor site; most calcifications
tallo, 2004): IV: Note: Dosage expressed in terms of spontaneously resolve. However, if a severe manifes-
elemental calcium tation of calcinosis cutis occurs, may initiate sodium
Infants and Children <50 kg: 0.5-4 mEq/kg/day
thiosulfate antidote (Reynolds 2014).
Children >50 kg and Adolescents: 10-20 mEq/day
Hypocalcemia: Note: In general, IV calcium gluconate
Vesicant/Extravasation Risk Vesicant
is preferred over IV calcium chloride in nonemergency Monitoring Parameters Serum calcium (ionized calcium
settings due to the potential for extravasation with preferred if available), phosphate, magnesium, heart rate,
calcium chloride. Dosage expressed in mg of calcium — ECG
chloride. Reference Range
Infants, Children, and Adolescents:
Manufacturer's recommendations: IV: 2.7-5 mg/kg/ Normal Values
dose every 4-6 hours; maximum dose: 1000 mg Serum
Alternative dosing: IV: 10-20 mg/kg/dose; maximum Concentration
dose: 1000 mg; repeat every 4-6 hours if needed Cord blood 9-11.5 mg/dL
Cardiac arrest in the presence of hyperkalemia or Newborn 3-24
hypocalcemia, hypermagnesemia, or calcium
channel antagonist toxicity (PALS recommenda-
tions): Infants, Children, and Adolescents: IV, 1.0.: Calcium, total
Dosage expressed in mg of calcium chloride: 4-7 days
20 mg/kg/dose (maximum dose: 2000 mg); may
Child
repeat in 10 minutes if necessary; if effective, con-
sider IV infusion of 20-50 mg/kg/hour; Note: Routine Adolescent to Adult
use in cardiac arrest is not recommended due to the Cord blood
lack of improved survival (Hegenbarth, 2008; Klein- Newborn 3-24
man, 2010)
Calcium, ionized,
Calcium channel blocker toxicity: Infants, Children, whole blood Newborn 24-48
hours 4-4.7 mg/dL
and Adolescents: IV: Dosage expressed in mg of
calcium chloride: 20 mg/kg/dose infused over 5-10 4,8-4.92 mg/dl.
minutes; if effective, consider IV infusion of (2.24-2.46 mEq/L)
20-50 mg/kg/hour (Kleinman, 2010)
Hypocalcemia secondary to citrated blood infu- Additional Information Due to a poor correlation
sion: Infants, Children, and Adolescents: IV: 0.45
between the serum ionized calcium (free) and total serum
mEq elemental calcium for each 100 mL citrated
calcium, particularly in states of low albumin or acid/base
blood infused
Tetany: Infants, Children, and Adolescents: IV: Dosage imbalances, direct measurement of ionized calcium is
expressed in mg of calcium chloride: 10 mg/kg over recommended. If ionized calcium is unavailable, in low
5-10 minutes; may repeat after 6 hours or follow with albumin states, the corrected total serum calcium may be
an infusion with a maximum dose of 200 mg/kg/day estimated by this equation (assuming a normal albumin of
Renal Impairment: Pediatric No initial dosage adjust- 4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas-
ment necessary; however, accumulation may occur with ured total calcium
renal impairment and subsequent doses may require
adjustment based on serum calcium concentrations. Elemental Calcium Content of Calcium
Hepatic Impairment: Pediatric No initial dosage Salts
adjustment necessary; subsequent doses should be
guided by serum calcium concentrations. Elemental
Calcium Calcium
Preparation for Administration Parenteral: !V infusion: (mg/1 g of | (mEq/g)
Dilute to a maximum concentration of 20 mg/mL.
Administration
Parenteral: Do not use scalp vein or small hand or foot
veins for IV administration; central-line administration is
the preferred route. Not for endotracheal administration.
Do not inject calcium salts IM or administer SubQ since
severe necrosis and sloughing may occur; extravasation
of calcium can result in severe necrosis and tissue
sloughing. Stop the infusion if the patient complains of
pain or discomfort. Warm solution to body temperature
prior to administration. Do not infuse calcium chloride in
the same IV line as phosphate-containing solutions.
IV: For direct IV injection infuse slow IVP over 3 to 5
minutes or at a maximum rate of 50 to 100 mg calcium Dosage Forms Considerations 1 g calcium chloride =
chloride/minute; in situations of cardiac arrest, calcium elemental calcium 273 mg = calcium 13.6 mEq = calcium
chloride may be administered over 10 to 20 seconds. 6.8 mmol
IV infusion: Further dilute and administer 45 to 90 mg Dosage Forms Excipient information presented when
calcium chloride/kg over 1 hour; 0.6 to 1.2 mEq cal-
available (limited, particularly for generics); consult spe-
cium/kg over 1 hour
cific product labeling.
Parenteral nutrition solution: Although calcium chloride is
_ not routinely used in the preparation of parenteral Solution, Intravenous:
nutrition, it is important to note that calcium-phosphate Generic: 10% (10 mL)
stability in parenteral nutrition solutions is dependent Solution, Intravenous [preservative free]:
upon the pH of the solution, temperature, and relative Generic: 10% (10 mL)

344
 CALCIUM CITRATE

Dosing
Calcium Citrate (KAL see um SIT rate) Pediatric Note: Calcium citrate 1,000 mg = 211 mg
elemental calcium = 10.5 mEq calcium
Medication Safety Issues
Adequate intake (Al) (IOM 2011): Dosage expressed
Sound-alike/look-alike issues:
in terms of elemental calcium: Oral:
Citracal may be confused with Citrucel
1 to 6 months: 200 mg/day
Brand Names: US Cai-Citrate [OTC]; Calcitrate [OTC]
7 to 12 months: 260 mg/day
Brand Names: Canada Osteocit
Recommended daily allowance (RDA) (IOM 2011):
Therapeutic Category Calcium Salt; Electrolyte Supple-
Dosage expressed in terms of elemental calcium:
ment, Oral
Generic Availability (US) Yes Oral:
1 to 3 years: 700 mg/day
Use Dietary supplement (FDA approved in adults); has
also been used for treatment of hypocalcemia 4 to 8 years: 1,000 mg/day
Pregnancy Considerations Calcium crosses the pla- 9 to 18 years: 1,300 mg/day
centa. Intestinal absorption of calcium increases during Hypocalcemia: Dose depends on clinical condition
pregnancy. The amount of calcium reaching the fetus is and serum calcium concentration: Dose expressed
determined by maternal physiological changes. Calcium as elemental calcium: Limited data available: Infants
requirements are the same in pregnant and nonpregnant and Children: Oral: 45 to 65 mg/kg/day in 4 divided
females (IOM, 2011). doses (Nelson 1996)
Breastfeeding Considerations Calcium is excreted in Renal Impairment: Pediatric There are no dosage
breast milk. The amount of calcium in breast milk is adjustments provided in the manufacturer's labeling;
homeostatically regulated and not altered by maternal however, accumulation may occur with renal impairment
calcium intake. Calcium requirements are the same in and subsequent doses may require adjustment based on
lactating and nonlactating females (IOM, 2011). serum calcium concentrations.
Warnings/Precautions Constipation, bloating, and gas Hepatic Impairment: Pediatric There are no dosage
are common with calcium supplements. Use with caution adjustments provided in the manufacturer's. labeling;
in patients with renal failure to avoid hypercalcemia; subsequent doses should be guided by serum calcium
frequent monitoring of serum calcium and phosphorus is concentrations.
necessary. Use caution when administering calcium sup- Administration Oral: May administer with or without food;
plements to patients with a history of kidney stones.
granule formulation should be administered with food.
Hypercalcemia and hypercalciuria are most likely to occur
Administration with food may increase absorption (AAP
in hypoparathyroid patients receiving high doses of vita-
[Golden 2014]; Straub 2007).
min D. Calcium absorption is impaired in achlorhydria;
common in elderly. Citrate may be preferred because Monitoring Parameters Serum calcium (ionized calcium
better absorbed. Calcium administration interferes with preferred if available), phosphate, magnesium
absorption of some minerals and drugs; use with caution. Reference Range
It is recommended to concomitantly administer vitamin D Pediatric (Kliegman 2016):
for optimal calcium absorption. Taking calcium ($500 mg)
with food improves absorption. Multiple salt forms of Normal Values
calcium exist; close attention must be paid to the salt form Age Serum
Concentration
when ordering and administering calcium; incorrect selec-
tion or substitution of one salt for another without proper Cord blood 9 to 11.5 mg/dL
dosage adjustment may result in serious over or under Newborn 3 to 24
ours 9 to 10.6 mg/dL
dosing.
Adverse Reactions Mild hypercalcemia (calcium: Newborn 24 to 48
Rats 7 to 12 mg/dL
>10.5 mg/dL) may be asymptomatic or manifest as ano- Calcium, total
rexia, constipation, nausea, and vomiting. More severe 4 to 7 days 9 to 10.9 mg/dL
hypercalcemia (calcium: >12 mg/dL) is associated with Child 8.8 to 10.8 mg/dL
coma, confusion, delirium, and stupor. Adolescent to
Central nervous system: Headache ‘Adult 8.4 to 10.2 mg/dL
Endocrine & metabolic: Hypercalcemia, hypophosphate- Cord blood 5 to 6 mg/dL
mia, increased thirst
Newborn 3 to 24
Gastrointestinal: Abdominal pain, anorexia, constipation, Rotirs 4.3 to 5.1 mg/dL
nausea, vomiting
Calcium, ionized Newborn 24 to 48
Drug Interactions ours 4 to 4.7 mg/dL
Metabolism/Transport Effects None known. 4.8 to 4.92 mg/dL
Avoid Concomitant Use ae 22 days (2.24 to 2.46
Avoid concomitant use of Calcium Citrate with any of the mEq/L)
following: Calcium Acetate Adult: Serum calcium: 8.5 to 10.5 mg/dL (2.12 to 2.62
Increased Effect/Toxicity mmol/L) (IOM 2011)
Calcium Citrate may increase the levels/effects of: Alu- Additional Information Due to a poor correlation
minum Hydroxide; Calcium Acetate; Cardiac Glycosides; between the serum ionized calcium (free) and total serum
Vitamin D Analogs calcium, particularly in states of low albumin or acid/base
The levels/effects of Calcium Citrate may be increased imbalances, direct measurement of ionized calcium is
by: Multivitamins/Fluoride (with ADE); Multivitamins/Min- recommended. If ionized calcium is unavailable, in low
erals (with ADEK, Folate; Iron); Thiazide and Thiazide- albumin states, the corrected total serum calcium may be
Like Diuretics estimated by this equation (assuming a normal albumin of
Decreased Effect 4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas-
Calcium Citrate may decrease the levels/effects of: ured total calcium
Alpha-Lipoic Acid; Bictegravir; Bisphosphonate Deriva-
tives; Calcium Channel Blockers; Deferiprone; DOBUT- Elemental Calcium Content of Calcium
amine; Dolutegravir; Eltrombopag; Estramustine; Salts
Multivitamins/Fluoride (with ADE); Phosphate Supple-
Elemental
ments; Quinolones; Strontium Ranelate; Tetracyclines; Calcium Calcium
Thyroid Products; Trientine Calcium Salt (mEq/g)
(mg/1 g of
salt form)
The levels/effects of Calcium Citrate may be decreased
Calcium acetate 12.7
by: Alpha-Lipoic Acid; Trientine if
Storage/Stability Store at room temperature. Calcium carbonate
Mechanism of Action Moderates nerve and muscle Calcium chloride
performance via action potential excitation threshold reg- Calcium citrate
‘ulation
Pharmacodynamics/Kinetics (Adult data unless Calcium gluconate
noted)
Calcium lactate
Absorption: 25% to 35%, requires vitamin D; varies with
age (infants 60%, prepubertal children 28%, pubertal Calcium phosphate
(tribasic)
children 34%, young adults 25%); decreased absorption
occurs in patients with achlorhydria, renal osteodystro-
phy, steatorrhea, or uremia Dosage Forms Considerations 1 g calcium citrate =
Protein binding: 45% elemental calcium 211 mg = calcium 10.5 mEq = calcium
Excretion: Primarily in the feces as unabsorbed calcium 5.25 mmol

345
 CALCIUM CITRATE

4 Dosage Forms Excipient information presented when Decreased Effect

available (limited, particularly for generics); consult spe- Calcium Glubionate may decrease the levels/effects of:
cific product labeling. Alpha-Lipoic Acid; Bictegravir; Bisphosphonate Deriva-
Capsule, Oral [preservative free]: tives; Calcium Channel Blockers; Deferiprone; DOBUT-
Cal-Citrate: 150 mg [dye free] amine; Dolutegravir; Eltrombopag; Estramustine;
Granules, Oral: Multivitamins/Fluoride (with ADE); Phosphate Supple-
Generic: 760 mg/3.5 g (480 g) ments; Quinolones; Strontium Ranelate; Tetracyclines;
Tablet, Oral: Thyroid Products; Trientine
Generic: 250 mg, 1040 mg
Tablet, Oral [preservative free]: The levels/effects of Calcium Glubionate may be
Calcitrate: 950 mg [lactose free, milk derivatives/prod- decreased by: Alpha-Lipoic Acid; Trientine
ucts, no artificial color(s), no artificial flavor(s), sodium Food Interactions Food may increase calcium absorp-
free, soy free, sugar free, wheat free, yeast free] tion. Calcium may decrease iron absorption. Bran, foods
Generic: 200 mg high in oxalates, or whole grain cereals may decrease
calcium absorption. Management: Administer preferably
@ Calcium Disodium Edetate see Edetate CALCIUM
with food.
Disodium on page 708
Storage/Stability Store at room temperature.
@ Calcium Disodium EDTA see Edetate CALCIUM Diso- Mechanism of Action As dietary supplement, used to
dium on page 708 prevent or treat negative calcium balance. The calcium in
@ Calcium Disodiumethylenediaminetetraacetic Acid calcium salts moderates nerve and muscle performance
see Edetate CALCIUM Disodium on page 708 and allows normal cardiac function.
@ Calcium Folinate see Leucovorin Calcium on page 1188 Pharmacodynamics/Kinetics (Adult data unless
noted)
Absorption: Minimal unless chronic, high doses; absorp-
Calcium Glubionate (KAL see um gloo BYE oh nate)
tion predominantly in the duodenum and dependent on
Medication Safety Issues calcitriol and vitamin D; mean absorption of calcium
Sound-alike/look-alike issues: intake varies with age (infants 60%, prepubertal children
Calcium glubionate may be confused with calcium gluc- 28%, pubertal children 34%, adults 25%); during preg-
onate nancy, calcium absorption doubles; calcium is absorbed
Brand Names: US Calcionate [OTC] [DSC] in soluble, ionized form; solubility of calcium is increased
Therapeutic Category Calcium Salt; Electrolyte Supple- in an acid environment (IOM 2011); decreased absorp-
ment, Oral tion occurs in patients with achlorhydria, renal osteodys-
Generic Availability (US) Yes trophy, steatorrhea, or uremia
Use Dietary supplement (OTC product: FDA approved in Distribution: Primarily in bones, teeth (IOM 2011)
infants, children, and adults); has also been used for Protein binding: ~40%, primarily to albumin (Wills 1971)
treatment of hypocalcemia and rickets Excretion: Primarily feces (75%; as unabsorbed calcium);
Pregnancy Considerations Calcium crosses the pla- urine (22%) (LOM 2011)
centa. Intestinal absorption of calcium increases during Dosing
pregnancy. The amount of calcium reaching the fetus is Neonatal Note: Syrup is a hyperosmolar solution.
determined by maternal physiological changes. Calcium Adequate intake (Al): Oral: 200 mg/day of elemental
requirements are the same in pregnant and nonpregnant calcium; requirements may vary on prematurity, post-
females (IOM, 2011). natal age, and other clinical factors; serum calcium
Breastfeeding Considerations Calcium is excreted in concentrations should be monitored closely to deter-
breast milk. The amount of calcium in breast milk is mine patient-specific needs (IOM 2011)
homeostatically regulated and not altered by maternal Enteral nutrition, maintenance requirement (dietary
calcium intake. Calcium requirements are the same in intake; formula, breast milk): Preterm neonates, birth
lactating and nonlactating females (IOM, 2011). weight <2,000 g: Oral: 150 to 220 mg/kg/day of ele-
Warnings/Precautions Constipation, bloating, and gas mental calcium (Abrams 2013)
are common with calcium supplements. Calcium absorp- Hypocalcemia: Dose depends on clinical condition and
tion is impaired in achlorhydria; administration is followed
serum calcium concentration:
by increased gastric acid secretion within 2 hours of
Dose expressed in mg of elemental calcium: Oral: 50
administration especially with high doses. Common in
to 150 mg/kg/day in 4 to 6 divided doses; not to
the elderly, use an alternate salt (eg, citrate) and admin-
exceed 1,000 mg/day (Avery 1994; Rigo 2007; Tho-
ister with food. Hypercalcemia and hypercalciuria are
mas 2012)
most likely to occur in hypoparathyroid patients receiving
high doses of vitamin D. Use caution when administering Dose expressed in mg of calcium glubionate: Oral:
calcium supplements to patients with a history of kidney 1,200 mg/kg/day in 4 divided doses (Avery 1994)
stones. Calcium administration interferes with absorption Rickets (radiographic evidence), treatment: Dose
of some minerals and drugs; use with caution. It is expressed as elemental calcium: Oral: Initial:
recommended to concomitantly administer vitamin D for 20 mg/kg/day in 4 divided doses, increased as toler-
optimal calcium absorption. Taking calcium ($500 mg) ated to usual range of 60 to 70 mg/kg/day in 4 divided
with food improves absorption. Multiple salt forms of doses; maximum daily dose of 80 mg/kg/day (Abrams
calcium exist; close attention must be paid to the salt form 2013; Avery 1994)
when ordering and administering calcium; incorrect selec- Pediatric
tion or substitution of one salt for another without proper Adequate intake (Al) (IOM 2011): Dose expressed as
dosage adjustment may result in serious over or under elemental calcium: Oral:
dosing. 1 to 6 months: 200 mg/day
Warnings: Additional Pediatric Considerations Oral 7 to 12 months: 260 mg/day
syrup is hyperosmolar; in neonates, this may cause Recommended daily allowance (RDA) (IOM 2011):
increased frequency of bowel movements (diarrhea) and Dose expressed as elemental calcium; during preg-
Gl intolerance. nancy and lactation, requirements may change: Oral:
Adverse Reactions Symptoms reported with hypercalce- 1 to 3 years: 700 mg/day
mia. 4 to 8 years: 1,000 mg/day
Endocrine & metabolic: Increased thirst 9 to 18 years: 1,300 mg/day
Gastrointestinal: Abdominal pain, anorexia, constipation, Calcium dietary supplement: Dosage below based
nausea, vomiting, xerostomia on product containing: 1.8 g calcium glubionate/5 mL
Renal: Polyuria (115 mg elemental calcium/5 mL)
Drug Interactions Infants: 5 mL 5 times a day; may mix with juice or
Metabolism/Transport Effects None known. formula
Avoid Concomitant Use Children <4 years: 10 mL 3 times a day
Avoid concomitant use of Calcium Glubionate with any of Children 24 years and Adolescents: 15 mL 3 times
the following: Calcium Acetate a day ‘
Increased Effect/Toxicity Hypocalcemia: Dose depends on clinical condition
Calcium Glubionate may increase the levels/effects of: and serum calcium concentration:
Calcium Acetate; Cardiac Glycosides; Vitamin D Ana-
Dose expressed as elemental calcium: Infants and
logs
Children: 45 to 65 mg/kg/day in 4 divided doses
The levels/effects of Calcium Glubionate may be (Nelson 1996)
increased by: Multivitamins/Fluoride (with ADE); Multi- Dose expressed as calcium glubionate: Infants and
vitamins/Minerals (with ADEK, Folate, Iron); Thiazide Children: 600 to 2,000 mg/kg/day in 4 divided doses
and Thiazide-Like Diuretics up to a maximum of 9 g/day

346
 CALCIUM GLUCONATE

Rickets (due to vitamin D deficiency); treatment:

Limited data available: Infants and Children: Dose Calcium Gluconate (KAL see um GLOO koe nate)
expressed as elemental calcium: Oral: 30 to
Medication Safety Issues
75 mg/kg/day in 3 divided doses; begin at higher Sound-alike/look-alike issues:
end of range and titrate downward over 2 to 4 weeks Calcium gluconate may be confused with calcium glubi-
(Misra 2008) onate, cupric sulfate
Renal Impairment: Pediatric Infants, Children, and Administration issues:
Calcium gluconate may be confused with calcium chlor-
Adolescents: No initial dosage adjustment necessary;
ide.
however, accumulation may occur with renal impairment
Confusion with the different intravenous salt forms of
and subsequent doses may require adjustment based on calcium has occurred. There is a threefold difference
serum calcium concentrations. in the primary cation concentration between calcium
Hepatic Impairment: Pediatric No initial dosage gluconate (in which 1 g = 4.65 mEq [90 mg] of ele-
adjustment necessary; subsequent doses should be mental Ca++) and calcium chloride (in which 1 g = 14
mEq [270 mg] of elemental Ca++).
guided by serum calcium concentrations. In adult
Prescribers should specify which salt form is desired.
patients:in the anhepatic stage of liver transplantation, Dosages should be expressed either as mEq, mg, or
equal rapid increases in ionized concentrations occur grams of the salt form.
suggesting that calcium gluconate does not require Brand Names: US Cal-Glu [OTC]
hepatic metabolism for release ofionized calcium (Martin Therapeutic Category Antidote, Hydrofluoric Acid; Cal-
|. . 1990). cium Salt; Electrolyte Supplement, Oral; Electrolyte Sup-
Administration Oral: Administer with plenty of fluids with plement, Parenteral
Generic Availability (US) Yes
or following meals
Use
Monitoring Parameters Serum calcium (ionized calcium Parenteral: Treatment of hypocalcemia and conditions
preferred if available), phosphate, magnesium, heart rate, secondary to hypocalcemia (eg, tetany, seizures,
ECG arrhythmias); treatment of cardiac disturbances secon-
Reference Range , dary to hyperkalemia; adjunctive treatment of rickets,
osteomalacia, and magnesium sulfate overdose;
Normal Values decrease capillary permeability in allergic conditions,
Serum nonthrombocytopenic purpura, and exudative dermato-
Concentration ses (eg, dermatitis herpetiformis, pruritus secondary to
Cord blood 9 to 11.5 mg/dL certain drugs) (All indications: FDA approved in all ages);
has also been used for calcium channel blocker toxicity,
hydrofluoric acid burns, and as a supplement in total
parenteral nutrition admixtures
Calcium, total Oral: Dietary supplementation of calcium (OTC: FDA
approved in adults)
Pregnancy Considerations Animal reproduction studies
have not been conducted. Calcium crosses the placenta.
Adolescent to
Adult The amount of calcium reaching the fetus is determined by
maternal physiological changes. Calcium requirements
are the same in pregnant and nonpregnant females
(1OM 2011). Information related to use as an antidote in
pregnancy is limited. In general, medications used as
Calcium, ionized, whole Newborn 24 to 48
blood Hours 4 to 4.7 mg/dL antidotes should take into consideration the health and
prognosis of the mother; antidotes should be administered
4.8 to 4.92 mg/dL to pregnant women if there is a clear indication for use and
(2.24 to 2.46
mEq/L) should not be withheld because of fears of teratogenicity
(Bailey 2003). Medications used for the treatment of
cardiac arrest in pregnancy are the same as in the non-
Test Interactions Decreased magnesium pregnant woman. Doses and indications should follow
Additional Information Due to a poor correlation current Advanced Cardiovascular Life Support guidelines.
between the serum ionized calcium (free) and total serum Appropriate medications should not be withheld due to
calcium, particularly in states of low albumin or acid/base concerns of fetal teratogenicity (Jeejeebhoy [AHA] 2015).
imbalances, direct measurement of-ionized_calcium is Breastfeeding Considerations Calcium is present in
breast milk. The amount of calcium in breast milk is
recommended. If ionized calcium is unavailable, in low
homeostatically regulated and not altered by maternal
albumin states, the corrected total serum calcium may be calcium intake. Calcium requirements are the same in
estimated by this equation (assuming a normal albumin of lactating and nonlactating females (IOM 2011). According
4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas- to the manufacturer, the decision to continue or discon-
ured total calcium tinue breastfeeding during therapy should take into
account the risk of infant exposure, the benefits of breast-
Elemental Calcium Content of Calcium feeding to the infant, and benefits of treatment to the
Salts mother.
Contraindications Hypercalcemia; concomitant use of IV
Elemental calcium gluconate with ceftriaxone in neonates ($28 days
Calcium Calcium
(mg/1 g of of age).
salt form) Warnings/Precautions Multiple salt forms of calcium
Calcium acetate exist; close attention must be paid to-the salt form when
Calcium carbonate ordering and administering calcium; incorrect selection or
substitution of one salt for another without proper dosage
Calcium chloride
adjustment may result in serious over or under dosing.
Calcium citrate : Avoid too-rapid IV administration (do not exceed
Calcium glubionate 200 mg/minute in adults and 100 mg/minute in pediatric
Calcium gluconate [oebegg 02) patients); may result in vasodilation, hypotension, brady-
cardia, arrhythmias, syncope, and cardiac arrest. Paren-
teral calcium is a vesicant; ensure proper catheter or
Calcium phosphate
(tribasic) 320 needle position prior to and during infusion. Avoid extrav-
asation; may result in necrosis. Monitor the IV site closely.
Safety for long-term use has not been established. Use
Dosage Forms Considerations 1 g calcium glubionate with caution in severe hyperphosphatemia or severe
= elemental calcium 63.8 mg = calcium 3.2 mEq = calcium hypokalemia. Hypercalcemia may occur in patients with
1.6 mmol renal failure; frequent determination of serum calcium is
Dosage Forms Excipient information presented when necessary. Use caution with chronic renal disease. Use
caution when administering calcium supplements to
available (limited, particularly for generics); consult spe-
patients with a history of kidney stones. Hypomagnesemia
cific product labeling. [DSC] = Discontinued product is a common cause of hypocalcemia; therefore, correction
Syrup, Oral: of hypocalcemia may be difficult in patients with concom-
Calcionate: 1.8 g/5 mL (473 mL [DSC)}) [fruit flavor] itant hypomagnesemia. Evaluate serum magnesium and >
347
 CALCIUM GLUCONATE

| correct hypomagnesemia (if necessary), particularly if

initial treatment of hypocalcemia is refractory.
Cardiac arrest in the presence of hyperkalemia
hypocalcemia, hypermagnesemia, or calcium chan-
or

nel blocker toxicity: Dose expressed as calcium

The parenteral product may contain aluminum; toxic alu-
gluconate: IV, |.0.: 60 to 100 mg/kg/dose; may repeat
minum concentrations may be seen with high doses,
in 10 minutes if necessary; if effective, consider IV
prolonged use, or renal dysfunction. Premature neonates
infusion (Avery 1994; Hegenbarth 2008)
are at higher risk due to immature renal function and
Hypocalcemia: Dose depends on clinical condition and
aluminum intake from other parenteral sources. Paren-
serum calcium concentration; monitor closely:
teral aluminum exposure of >4 to 5 mcg/kg/day is asso-
ciated with CNS and bone toxicity; tissue loading may General dosing:
occur at lower doses (Federal Register 2002). See man- Dose expressed as calcium gluconate: IV:
ufacturer's labeling. 200 mg/kg every 6 to 12 hours or 400 mg/kg/day
as a continuous infusion (Avery 1994; Scott 1984)
Constipation, bloating, and gas are common with oral Dose expressed as elemental calcium:
calcium supplements (especially carbonate salt). Admin- IV: Usual range: 40 to 75 mg/kg/day as a continuous
istering oral calcium with food and vitamin D will optimize infusion (Cloherty 2012; MacDonald 2016); for
calcium absorption. Some products may contain tartra- asymptomatic hypocalcemia tapering regimen
zine, which may cause allergic reactions in susceptible has been suggested: Initial: 80 mg/kg/day as a
individuals. continuous infusion for 48 hours then reduce to
Potentially significant drug-drug interactions may exist, 40 mg/kg/day continuous infusion typically for 24
requiring dose or frequency adjustment, additional mon- hours (once normal serum calcium concentration
itoring, and/or selection of alternative therapy. documented) (Jain 2010)
Adverse Reactions Oral: 50 to 150 mg/kg/day in 4 to 6 divided doses;
Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, not to exceed 1,000 mg/day (MacDonald 2016;
decreased blood pressure, syncope, vasodilation Rigo 2007). Note: In general, other calcium salts
Central nervous system: Anxiety, feeling hot may be more preferable oral dosage forms in neo-
Gastrointestinal: Unusual taste (chalky) natal patients; however, the 10% calcium gluco-
Neuromuscular & skeletal: Tingling sensation nate injection may be given orally (Mimouni 1994).
Drug Interactions Symptomatic (ie, seizures, tetany); Dose expressed as
Metabolism/Transport Effects None known. calcium gluconate: IV: 100 to 200 mg/kg/dose over
Avoid Concomitant Use 5 to 10 minutes; followed by a continuous infusion 500
Avoid concomitant use of Calcium Gluconate with any of to 800 mg/kg/day (Cloherty 2012; Jain 2010; Mimouni
the following: Calcium Acetate 1994; Nelson 1996; Root 1976; Zhou 2009)
Increased Effect/Toxicity Parenteral nutrition, maintenance requirement: Dose
Calcium Gluconate may increase the levels/effects of: expressed as elemental calcium: IV: 2 to 4 mEq/kg/
Calcium Acetate; Cardiac Glycosides; CeffRIAXone; day (Mirtallo 2004)
Vitamin D Analogs Rickets (radiographic evidence), treatment: Dose
expressed as elemental calcium: Oral: Initial:
The levels/effects of Calcium Gluconate may be
20 mg/kg/day in 2 to 4 divided doses, increased as
increased by: Multivitamins/Fluoride (with ADE); Multi-
tolerated to usual range of 60 to 70 mg/kg/day in 2 to 4
vitamins/Minerals (with ADEK, Folate, Iron); Thiazide
divided doses; maximum daily dose of 80 mg/kg/day
and Thiazide-Like Diuretics
(Abrams 2013; Avery 1994)
Decreased Effect
Calcium Gluconate may decrease the levels/effects of: Pediatric
Alpha-Lipoic Acid; Bictegravir; Bisphosphonate Deriva- Adequate intake (Al) (IOM 2011): Dose expressed as
tives; Calcium Channel Blockers; Deferiprone; DOBUT- elemental calcium: Oral:
amine; Dolutegravir; Eltrombopag; Estramustine; 1 to 6 months: 200 mg/day
Multivitamins/Fluoride (with ADE); Phosphate Supple- 7 to 12 months: 260 mg/day
ments; Quinolones; Strontium Ranelate; Tetracyclines; Recommended daily allowance (RDA) (IOM 2011):
Thyroid Products; Trientine Dose expressed as elemental calcium; during preg-
nancy and lactation, requirements may change: Oral:
The levels/effects of Calcium Gluconate may be 1 to 3 years: 700 mg/day
decreased by: Alpha-Lipoic Acid; Trientine 4 to 8 years: 1,000 mg/day
Storage/Stability 9 to 18 years: 1,300 mg/day
IV: Store intact vials at 20°C to 25°C (68°F to 77°F). Do Parenteral nutrition, maintenance requirement (Mir-
not freeze. Discard unused portion within 4 hours after tallo 2004): Note: Dose expressed as elemental
initial puncture. calcium; IV:
Oral: Store at room temperature; consult product labeling Infants and Children $50 kg: 0.5 to 4 mEq/kg/day
for specific requirements. Children >50 kg and Adolescents: 10 to 20 mEq/day
Mechanism of Action Hypocalcemia: Dose depends on clinical condition
Moderates nerve and muscle performance via action
and serum calcium concentration:
potential threshold regulation. General dosing: Infants, Children, and Adolescents:
In hydrogen fluoride exposures, calcium gluconate pro-
Dose expressed as calcium gluconate: IV: 200 to
vides a source of calcium ions to complex free fluoride
500 mg/kg/day as a continuous infusion or in 4
ions and prevent or reduce toxicity; administration also
divided doses; maximum dose: Infants and Children:
helps to correct fluoride-induced hypocalcemia.
1,000 mg/dose; Adolescents: 2,000 to 3,000 mg/
Pharmacodynamics/Kinetics (Adult data unless
dose (Edmondson 1990; Zhou 2009)
noted)
Symptomatic (ie, seizures, tetany): Infants, Children,
Absorption: Oral: Minimal unless chronic, high doses are
and Adolescents: Dose expressed as calcium gluc-
given; predominantly in the duodenum and dependent
onate: IV: 100 to 200 mg/kg/dose over 5 to 10
on calcitriol and vitamin D; mean absorption of calcium
minutes; usual adult dose: 1,000 to 2,000 mg/dose;
intake varies with age (infants 60%, prepubertal children
28%, pubertal children 34%, adults 25%); during preg- may repeat after 6 hours or follow with a continuous
nancy, calcium absorption doubles; calcium is absorbed
infusion of 200 to 800 mg/kg/day (Edmondson 1990;
in soluble, ionized form; solubility of calcium is increased Kelly 2013; Misra 2008; Nelson 1996; Zhou 2009)
in an acidic environment (IOM 2011); decreased absorp- Chronic therapy in asymptomatic patient: Infants and
tion occurs in patients with achlorhydria, renal osteodys- Children: Dose expressed as calcium gluconate:
trophy, steatorrhea, or uremia Oral: 500 mg/kg/day in divided doses every 4 to 8
Distribution: Primarily in skeleton (99%) hours (Nelson 1996); Note: In general, other oral
Protein binding: ~40%, primarily to albumin calcium salts (eg, carbonate, glubionate) are a more
Excretion: Primarily feces (75%; as unabsorbed calcium preferable oral dosage form option in young pedia-
salts); urine (20%) (IOM 2011) tric patients; however, the 10% calcium gluconate
Dosing injection may be given orally (Mimouni 1994).
Neonatal Rickets (due to vitamin D deficiency); treatment:
Adequate intake (Al): Oral: 200 mg/day of elemental Infants and Children: Dose expressed as elemental
calcium; requirements may vary on prematurity, post- calcium: Oral: 30 to 75 mg/kg/day in 3 divided doses;
natal age, and other clinical factors; serum calcium begin at higher end of range and titrate downward
concentrations should be monitored closely to deter- over 2 to 4 weeks (Misra 2008). Note: In general,
mine patient-specific needs (IOM 2011) other oral calcium salts (eg, carbonate, glubionate)
Enteral nutrition, maintenance requirement (dietary are a more preferable oral dosage formulation option
intake; formula, breastmilk): Preterm neonates, birth in young pediatric patients; however, the 10% calcium
weight <2,000 g: Oral: 150 to 220 mg/kg/day of ele- gluconate injection may be given orally (Mim-
mental calcium (Abrams 2013) ouni 1994).

348
 CALCIUM GLUCONATE

Cardiac arrest in the presence of hyperkalemia or to avoid too rapid increases in the serum calcium and
hypocalcemia, hypermagnesemia, or calcium extravasation. In acute situations of symptomatic hypo-
channel blocker toxicity:. Infants, Children, and Ado- calcemia, infusions over 5 to 10 minutes have been
lescents: Dose expressed as calcium gluconate: |V, described in pediatric patients (Kelly 2013; Misra 2008)
1.0.: 60 to 100 mg/kg/dose (maximum dose: IV infusion: Administer at a rate not to exceed
3,000 mg); may repeat in 10 minutes if necessary; if 200 mg/minute. Note: Due to the potential presence
effective, consider IV infusion (Hegenbarth 2008). of particulates, American Regent, Inc recommends the
Note: Routine use in cardiac arrest is not recom- use of a 0.22 micron in-line filter for |V administration of
mended due to the lack of improved survival (PALS admixture (1.2 micron filter if admixture contains lipids)
[Kleinman] 2010). (Important Drug Administration Information, American
Calcium channel blocker toxicity; hypotension/ Regent 2013); a similar recommendation has not been
» conduction disturbances: Infants, Children, and noted by other manufacturers.
Adolescents: Dose expressed in mg of calcium gluc- Parenteral nutrition solution: Calcium-phosphate stability
onate: IV, |.0.: 60 mg/kg/dose administered over 30 in parenteral nutrition solutions is dependent upon the
to 60 minutes (Hegenbarth 2008). Note: Calcium PH of the solution, temperature, and relative concen-
chloride may provide a more rapid increase of ionized tration of each ion. The pH of the solution is primarily
calcium in critically ill children. Calcium gluconate may dependent upon the amino acid concentration. The
be’ substituted if calcium chloride is not available. higher the percentage amino acids the lower the pH,
Hydrofluoric acid burns, treatment: Limited data the more soluble the calcium and phosphate. Individual
available: Children and Adolescents: commercially available amino acid solutions vary sig-
SubQ: 5% to 10% solution: 0.5 mL/cm? of burned nificantly with respect to pH lowering potential and
tissue (Dibbell 1970; Hatzifotis 2004; Kirkpatrick consequent calcium phosphate compatibility; consult
1995; Krenzelok 1999). Infiltration should be carried product specific labeling for additional information.
0.5 cm away from the margin of the injured tissue Vesicant; ensure proper needle or catheter placement
into the surrounding uninjured areas. Repeat if pain prior to and during IV infusion. Avoid extravasation.
recurs. Local anesthesia may be required to perform Early/acute calcium extravasation: \f acute extravasa-
procedure; pain resolution is the therapeutic end- tion occurs, stop infusion immediately and disconnect
point and if a local anesthetic is utilized, it may be (leave needle/cannula in place); gently aspirate
difficult to determine the success of therapy. Note: extravasated solution (do NOT flush the line); initiate
Never use calcium chloride for subcutaneous hyaluronidase antidote; remove needle/cannula;
injection. apply dry cold compresses; elevate extremity (Hurst
Intra-arterial: Add 10 mL of a 10% solution to 50 mL of 2004; Reynolds 2014).
D5W. Infuse over 4 hours into the artery that pro- Delayed calcium extravasation: |f delayed extravasa-
vides the vascular supply to the affected area (Hat- tion suspected, closely monitor site; most calcifica-
zifotis 2004; Kirkpatrick 1995). Pain usually resolves tions spontaneously resolve. However, if a severe
by the end of the infusion; repeat if pain recurs. This manifestation of calcinosis cutis occurs, may initiate
intervention should be used only by those sodium thiosulfate antidote (Reynolds 2014).
accustomed to this technique. Extreme care Vesicant/Extravasation Risk Vesicant
should be taken to avoid the extravasation. A Monitoring Parameters Serum calcium (ionized calcium
poison information center or clinical toxicologist preferred if available), phosphate, magnesium, heart rate,
should be consulted prior to implementation. ECG
Inhalation: 2.5% nebulization solution: Mix 1.5 mL of Reference Range
10% calcium gluconate solution with 4.5 mL NS to
make a 2.5% solution and administer via nebuliza- Normal Values
Age Serum
tion (Upfal 1990). Concentration
Renal Impairment: Pediatric Infants, Children, and Cord blood 9 to 11.5 mg/dL
Adolescents: No initial dosage adjustment necessary; Newborn 3 to 24
however, accumulation may occur with renal impairment 9 to 10.6 mg/dL
hours
and subsequent doses may require adjustment based on Newborn 24 to 48
Calcium, total Bone 7 to 12 mg/dL
serum calcium concentrations.
Hepatic Impairment: Pediatric Infants, Children, and
Adolescents: No initial dosage adjustment necessary; Child 8.8 to 10.8 mg/dL
subsequent doses should be guided by serum calcium
concentrations. In adult patients in the anhepatic stage
of liver transplantation, equal rapid increases in ionized
Newborn 3 to 24
concentrations occur suggesting that calcium gluconate hours 4.3 to 5.1 mg/dL
does not require hepatic metabolism for release of ion- Calcium, ionized, whole
blood Newborn 24 to 48 4 to 4.7 mg/dL
ized calcium (Martin 1990). hours
Preparation for Administration Parenteral: Observe 4.8 to 4.92 mg/dL
the vial for the presence of particulates. If particulates (2.24 to 2.46 mEq/L)
are observed, place vial in a 60°C to 80°C water bath
for 15 to 30 minutes (or until solution is clear); occasionally Test Interactions |V administration may produce falsely
shake to dissolve; cool to body/room temperature before decreased serum and urine magnesium concentrations
use. Do not use vial if particulates do not dissolve. Note: Additional Information Due to a poor correlation
Due to the potential presence of particulates, American between the serum ionized calcium (free) and total serum
Regent, Inc recommends the use of a 5 micron filter when calcium, particularly in states of low albumin or acid/base
preparing calcium gluconate-containing IV solutions imbalances, direct measurement of ionized calcium is
(Important Drug Administration Information, American recommended. If ionized calcium is unavailable, in low
Regent 2013); a similar recommendation has not been albumin states, the corrected total serum calcium may be
noted by other manufacturers. estimated by this equation (assuming a normal albumin of
IV infusion: Further dilute in D5W or NS; a maximum 4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas-
concentration of 50 mg/mL has been used by some ured total calcium
centers. Usual adult concentrations: 1,000 mg/100 mL
D5W or NS; 2,000 mg/100 mL D5W or NS. Maximum
concentration in parenteral nutrition solutions is variable Elemental Calcium Content of Calcium
depending upon concentration and solubility (consult Salts
detailed reference).
Administration | Elemental
Oral: Administer with plenty of fluids with or following Calcium
Calcium Salt
meals. The 10% calcium gluconate injection may be (mEq/g)
administered orally in young pediatric patients (Mimouni
Calcium acetate
1994)
Parenteral: Do not inject calcium salts IM or administer Calcium carbonate
SubQ since severe necrosis and sloughing may occur; Calcium chloride
extravasation of calcium can result in severe necrosis
and tissue sloughing. Do not use scalp vein or small
hand or foot veins for IV administration. Not for endo-
tracheal administration.
IV: Administer undiluted slowly (~1.5 mL calcium gluco-
nate 10% per minute; not to exceed 200 mg/minute Calcium phosphate
except in emergency situations; consider cardiac mon- (tribasic)
itoring) through a small needle into a large vein in order

349
 CALCIUM GLUCONATE

q Dosage Forms Considerations 1 g calcium gluconate Decreased Effect

= elemental calcium 93 mg = calcium 4.65 mEq = calcium Calcium Lactate may decrease the levels/effects of:
2.33 mmol Alpha-Lipoic Acid; Bictegravir; Bisphosphonate Deriva-
Dosage Forms Excipient information presented when tives; Calcium Channel Blockers; Deferiprone; DOBUT-
available (limited, particularly for generics); consult spe- amine; Dolutegravir; Eltrombopag; Estramustine;
cific product labeling. [DSC] = Discontinued product Multivitamins/Fluoride (with ADE); Phosphate Supple-
Capsule, Oral [preservative free]: ments; Quinolones; Strontium Ranelate; Tetracyclines;
Cal-Glu: 500 mg [dye free] Thyroid Products; Trientine
Solution, Intravenous:
The levels/effects of Calcium Lactate may be decreased
Generic: 10% (10 mL, 50 mL, 100 mL); 1% in Dextrose
5% (100 mL [DSC]); 1% in NaCl 0.9% (100 mL); 2% in by: Alpha-Lipoic Acid; Trientine
Dextrose 5% (50 mL, 100 mL [DSC]); 2% in NaCl 0.9% Storage/Stability Store at room temperature. —
(50 mL, 100 mL); 3% in NaCl 0.9% (100 mL); 4% in Mechanism of Action As dietary supplement, used to
NaCl 0.9% (50 mL) e prevent ortreat negative calcium balance; in osteoporosis,
Solution, Intravenous [preservative free]: it helps to prevent or decrease the rate of bone loss. The
Generic: 10% (10 mL, 50 mL, 100 mL) calcium in calcium salts moderates nerve and muscle
Solution Prefilled Syringe, Intravenous: performance and allows normal cardiac function.
Generic: 4% in NaCl 0.9% (50 mL) Pharmacodynamics/Kinetics (Adult data unless
Tablet, Oral: noted)
Generic: 50 mg, 500 mg Absorption: 25% to 35%, requires vitamin D; varies with
age (infants 60%, prepubertal children 28%, pubertal
@ Calcium High Potency [OTC] see Calcium Carbonate
children 34%, young adults 25%); decreased absorption
on page 340
occurs in patients with achlorhydria, renal osteodystro-
phy, steatorrhea, or uremia
Calcium Lactate (KAL see um LAK tate)
Protein binding: 45%
Brand Names: US Cal-Lac [OTC] Excretion: Primarily in the feces as unabsorbed calcium
Therapeutic Category Calcium Salt; Electrolyte Supple- Dosing
ment, Oral Pediatric Note: Calcium lactate 1,000 mg = 130 mg
Generic Availability (US) Yes elemental calcium = 6.5 mEq calcium
Use Dietary supplement (OTC product: FDA approved in Adequate intake (Al) (IOM 2011): Dosage expressed
adults); has also been used for the treatment of hypo- in terms of elemental calcium: Oral:
calcemia 1 to 6 months: 200 mg/day
Pregnancy Considerations Calcium crosses the pla- 7 to 12 months: 260 mg/day
centa. Intestinal absorption of calcium increases during Recommended daily allowance (RDA) (IOM 2011):
pregnancy. The amount of calcium reaching the fetus is Dosage expressed in terms of elemental calcium:
determined by maternal physiological changes. Calcium Oral:
requirements are the same in pregnant and nonpregnant 1 to 3 years: 700 mg/day
females (IOM, 2011). 4 to 8 years: 1,000 mg/day
Breastfeeding Considerations Calcium is excreted in 9 to 18 years: 1,300 mg/day
breast milk. The amount of calcium in breast milk is Hypocalcemia: Dose depends on clinical condition
homeostatically regulated and not altered by maternal and serum calcium concentration: Dose expressed
calcium intake. Calcium requirements are the same in as elemental calcium: Limited data available: Infants
lactating and nonlactating females (IOM, 2011). and Children: Oral: 45 to 65 mg/kg/day in 4 divided
Warnings/Precautions Constipation, bloating, and gas doses (Nelson 1996)
are common with calcium supplements. Use with caution Renal Impairment: Pediatric There are no dosage
in patients with renal failure to avoid hypercalcemia; adjustments provided in the manufacturer's labeling;
frequent monitoring of serum calcium and phosphorus is however, accumulation may occur with renal impairment
necessary. Use caution when administering calcium sup- and subsequent doses may require adjustment based on
plements to patients with a history of kidney stones. serum calcium concentrations.
Hypercalcemia and hypercalciuria are most likely to occur Hepatic Impairment: Pediatric There are no dosage
in hypoparathyroid patients receiving high doses of vita- adjustments provided in the manufacturer's labeling;
min D. Calcium absorption is impaired in achlorhydria; subsequent doses should be guided by serum calcium
common in elderly, use an alternate salt (eg, citrate) and concentrations.
administer with food. Calcium administration. interferes Administration Oral: Administer with plenty of fluids with
with absorption of some minerals and drugs; use with or following meals
caution. It is recommended to concomitantly administer
Monitoring Parameters Serum calcium (ionized calcium
vitamin D for optimal calcium absorption. Taking calcium
preferred if available), phosphate, magnesium
($500 mg) with food improves absorption. Multiple salt
Reference Range
forms of calcium exist; close attention must be paid to
Pediatric (Kliegman 2016):
the salt form when ordering and administering calcium;
incorrect selection or substitution of one salt for another
Normal Values
without proper dosage adjustment may result in serious Serum
over or under dosing. sy do lei 9Concentration
Adverse Reactions Rare but important or life-threaten- Cord blood 9 to 11.5 mg/dL
ing: Confusion, constipation, dizziness, headache, hyper- Newborn 3 to 24 9 to 10.6 mg/dL
hours
calcemia, hypercalciuria, hypomagnesemia, hypo-
Newborn 24 to 48
phosphatemia, milk-alkali syndrome, nausea, vomiting,
Calcium, total
xerostomia
4 to 7 days 9 to 10.9 mg/dL
Drug Interactions
Child 8.8 to 10.8 mg/dL
Metabolism/Transport Effects None known.
Adolescent to
Avoid Concomitant Use Adult
8.4 to 10.2 mg/dL
Avoid concomitant use of Calcium Lactate with any of Cord blood 5 to 6 mg/dL
the following: Calcium Acetate
Newborn 3 to 24
Increased Effect/Toxicity hours
4.3 to 5.1 mg/dL
Calcium Lactate may increase the levels/effects of: Cal- Calcium, ionized Newborn 24 to 48
hours
4 to 4.7 mg/d
cium Acetate; Cardiac Glycosides; Vitamin D Analogs
4.8 to 4.92 mg/dL
The levels/effects of Calcium Lactate may be increased 22 days (2.24 to 2.46
by: Multivitamins/Fluoride (with ADE); Multivitamins/Min- mEq/L)
erals (with ADEK, Folate, Iron); Thiazide and Thiazide- Adult; Serum calcium: 8.5 to 10.5 mg/dL (2.12 to 2.62
Like Diuretics mmol/L) (1OM 2011)

350
 CALFACTANT

Additional Information Due to a poor correlation shake. Visible flecks of the suspension and foaming under
between the serum ionized calcium (free) and total serum the surface are normal. Calfactant should be stored
calcium, particularly in states of tow albumin or acid/base upright (3 mL vial) and under refrigeration at 2°C to 8°C
imbalances, direct measurement of ionized calcium is (36°F to 46°F); protect from light; document date and time
recommended. If ionized calcium is unavailable, in low removed from refrigeration. Warming before administra-
albumin states, the corrected total serum calcium may be tion is not necessary. Unopened and unused vials of
estimated by this equation (assuming a normal albumin of calfactant that have been warmed to room temperature
4 g/dL); [(4 — patient's albumin) x 0.8] + patient's meas- can be returned to refrigeration storage within 24 hours for
ured total calcium future use. Repeated warming to room temperature
should be avoided. Each single-use vial should be entered
Elemental Calcium Content of Calcium only once and the vial with any unused material should be
; Salts discarded after the initial entry.
Mechanism of Action Endogenous lung surfactant is
Elemental
Calcium Calcium essential for effective ventilation because it modifies
Calcium Salt (mEq/g) alveolar surface tension, thereby stabilizing the alveoli.
(mg/1 g of
salt form) Lung surfactant deficiency is the cause of respiratory
Calcium acetate AN distress syndrome (RDS) ‘in premature infants and lung
Calcium carbonate 400 surfactant restores surface activity to the lungs of these
infants.
Calcium chloride 273
Pharmacodynamics/Kinetics (Adult data unless
Calcium citrate Ai
211 noted) No human studies of absorption, biotransforma-
Calcium glubionate 63.8 tion, or excretion have been performed
_ | Calcium gluconate 93 Dosing
Calcium lactate 130 Neonatal
Respiratory distress syndrome (RDS):
Calcium phosphate
(tribasic) 390. Prophylactic therapy: Premature newborns (<29 weeks'
gestation): Endotracheal: 3 mL/kg as soon as possi-
ble after birth, preferably within 30 minutes; additional
Dosage Forms Considerations
doses may be given every 12 hours up to a total of 3
648 mg calcium lactate = elemental calcium 84 mg =
doses. In studies, repeat doses have been adminis-
calcium 4.2 mEq = calcium 2.1 mmol
tered as frequently as every 6 hours for a total of up to
Dosage Forms Excipient information presented when
4 doses if the neonate was still intubated and required
available (limited, particularly for generics); consult spe-
at least 30% inspired oxygen to maintain arterial
cific product labeling.
oxygen saturations >90% or with a PaO» <80 torr on
Capsule, Oral [preservative free]:
>30% inspired oxygen (Bloom 2005; Kattwinkel
Cal-Lac: 500 mg [dye free]
2000). However, guidelines suggest that dosing inter-
Tablet, Oral:
vals more frequent than every 12 hours should not be
Generic: 100 mg
necessary, unless surfactant is being inactivated by
Tablet, Oral [preservative free]:
an infectious process, meconium, or blood (AAP
Generic: 648 mg
[Polin 2014]).
@ Calcium Leucovorin see Leucovorin Calcium Rescue treatment: Newborns $72 hours: Endotracheal:
on page 1188 3 mL/kg as soon as the diagnosis of RDS is made;
additional doses may be given every 12 hours up to a
¢ Calcium Levoleucovorin see LEVOleucovorin
total of 3 doses. In studies, repeat doses have been
on page 1207
administered as frequently as every 6 hours for a total
@ Caldolor see Ibuprofen on page 1034 of up to 4 doses if the neonate was still intubated and
required at least 30% inspired oxygen to maintain
Calfactant (kaf at ant) arterial oxygen saturations >90% or with a PaO2
<80 torr on >30% inspired oxygen (Bloom 2005;
Brand Names: US Infasurf Kattwinkel 2000). However, guidelines suggest that
Therapeutic Category Lung Surfactant dosing intervals more frequent than every 12 hours
Generic Availability (US) No should not be necessary, unless surfactant is being
Use Prevention of respiratory distress syndrome (RDS) in inactivated by an infectious process, meconium, or
premature infants at significant risk (FDA approved in blood (AAP [Polin 2014)).
newborns <29 weeks gestational age); treatment of RDS Renal Impairment: Pediatric There are no dosage
in neonates with clinical and radiologic confirmation and adjustments provided in the manufacturer’s labeling.
requiring mechanical ventilation (FDA approved in new- Hepatic Impairment: Pediatric There are no dosage
borns $72 hours of age) PDs ta ase adjustments provided in the manufacturer’s labeling.
Contraindications There are no contraindications listed Administration Endotracheal tube administration: Gently
in the manufacturer's labeling. swirl to redisperse suspension; do not shake; administer
Warnings/Precautions For intratracheal administration dosage divided into two aliquots of 1.5 mL/kg each into the
only. Rapidly affects oxygenation and lung compliance; endotracheal tube; after each instillation, reposition the
restrict use to a highly-supervised clinical setting with infant with either the right or left side dependent; admin-
immediate availability of clinicians experienced in intuba- istration is made while ventilation is continued over 20 to
tion and ventilatory management of premature infants. 30 breaths for each aliquot, with small bursts timed only
Transient episodes of bradycardia, decreased oxygen during the inspiratory cycles; a pause followed by evalua-
saturation, endotracheal tube blockage or reflux of calfac- tion of the respiratory status and repositioning should
tant into endotracheal tube may occur. Discontinue dosing separate the two aliquots; calfactant dosage has also
procedure and initiate measures to alleviate the condition; been divided into four equal aliquots and administered
may reinstitute after the patient is stable. Produces rapid with repositioning in four different positions (prone, supine,
improvements in lung oxygenation and compliance that right and left lateral)
may require frequent adjustments to oxygen delivery and Monitoring Parameters Continuous heart rate and trans-
ventilator settings. cutaneous O>, saturation should be monitored during
Adverse Reactions administration; frequent ABG sampling is necessary to
Cardiovascular: Bradycardia prevent postdosing hyperoxia and hypocarbia
Gastrointestinal: Endotracheal tube reflux Additional Information Calfactant contains surfactant-
Respiratory: Airway obstruction, cyanosis associated proteins SP-B and SP-C (0.7 mg/mL protein,
Drug Interactions’ : including 0.26 mg/mL SP-B).
Metabolism/Transport Effects None known. Dosage Forms Excipient information presented when
Avoid Concomitant Use available (limited, particularly for generics); consult spe-
Avoid concomitant use of Calfactant with any of the cific product labeling.
following: Ceritinib Suspension, Intratracheal:
Increased Effect/Toxicity Infasurf: 35 mg phospholipids and 0.7 mg protein per mL
Calfactant may increase the levels/effects of: Bradycar- (3 mL, 6 mL)
dia-Causing Agents; Ceritinib; lvabradine; Lacosamide
Cal-Gest Antacid [OTC] see Calcium Carbonate
The levels/effects of Calfactant may be increased by: on page 340
Bretylium; Ruxolitinib; Terlipressin; Tofacitinib @ Cal-Glu [OTC] see Calcium Gluconate on page 347
Decreased Effect There are no known significant inter-
@ Cal-Lac [OTC] see Calcium Lactate on page 350
actions involving a decrease in effect.
Storage/Stability Gentle swirling or agitation of the vial of @ Cal-Mint [OTC] see Calcium Carbonate on page 340
suspension is often necessary for redispersion. Do not @ CaloMist see Cyanocobalamin on page 528
CANAKINUMAB

@ Calphron [OTC] see Calcium Acetate on page 339 deterioration, and renal and hepatic failure have been
@ Caltrate (Can) see Calcium Carbonate on page 340 reported in premature neonates after receiving parenteral
products containing polysorbate 80 (Alade 1986; CDC
Caltrate 600 [OTC] see Calcium Carbonate on page 340
1984). See manufacturer's labeling.
@ Caltrate Select (Can) see Calcium Carbonate Warnings: Additional Pediatric Considerations
on page 340 Reactivation of TB has been reported in pediatric patients
@ Cambia see Diclofenac (Systemic) on page 628 receiving biologic response modifiers (infliximab and eta-
@ Camila see Norethindrone on page 1470 nercept); prior to therapy, patients with no TB risk factors
¢ Camphorated Tincture of Opium (error-prone syno-
should be screened for latent TB infection (LTBI) with an
nym) see Paregoric on page 1559 age appropriate test (ie, <5 years of age: tuberculin skin
test, and 25 years of age: IGRA [interferon gamma release
Camptosar see Irinotecan (Conventional) on page 1125 assay]); if any TB risk factors are present or symptoms,
Camptothecin-11 see Irinotecan (Conventional) both LTBI screening tests should be performed (AAP
on page 1125 [Davies 2016])
Influenza reported in 17% of patients during clinical trials.
Canakinumab (can a KIN ue mab) Vertigo has been reported exclusively in patients with
MWS (9% to 14%); events appear self-resolving with
Brand Names: US laris
continued therapy. Infection reported more frequently in
Brand Names: Canada llaris
children than-adults (Kuemmerle-Deschner 2011) for both
Therapeutic Category Interleukin-1 Receptor Antago- CAPS and JIA. Treatment for CAPS has been associated
nist; Monoclonal Antibody
with higher incidence of reported adverse reactions includ-
Generic Availability (US) No ing diarrhea (20%), nasopharyngitis (34%), and rhini-
Use Treatment of cryopyrin-associated periodic syndromes
tis (17%).
(CAPS), including familial cold autoinflammatory syn-
Adverse Reactions
drome (FCAS) and Muckle-Wells syndrome (MWS)
Central nervous system: Headache, vertigo
(FDA approved in ages 24 years and adults); treatment
Endocrine & metabolic: Decreased serum calcium (Lach-
of active systemic juvenile idiopathic arthritis (SJIA) (FDA
approved in ages 22 years weighing at least 7.5 kg); mann 2009), weight gain
treatment of tumor necrosis factor receptor associated Gastrointestinal: Diarrhea, gastroenteritis, nausea, upper
periodic syndrome (TRAPS), hyperimmunoglobulin D syn- abdominal pain
drome (HIDS)/mevalonate kinase deficiency (MKD) and Genitourinary: Proteinuria (Lachmann 2009)
familial Mediterranean fever (FMF) (FDA approved in Hematologic & oncologic: Decreased neutrophils (transi-
ages 22 years and adults) ent), decreased platelet count (mild and transient),
Medication Guide Available Yes decreased white blood cell count, eosinophilia (Lach-
Pregnancy Considerations Adverse events have been mann 2009)
observed in animal reproduction studies. Canakinumab is Hepatic: Increased serum ALT, increased serum AST,
a recombinant IgG monoclonal antibody; IgG is known to increased serum bilirubin (Lachmann 2009), increased
cross the placenta in a linear fashion as pregnancy serum transaminases
progresses; potential fetal exposure is likely to be greater Immunologic: Antibody development (non-neutralizing)
during the second and third trimesters. Infection: Infection (less common with serious infection),
Breastfeeding Considerations It is not known if cana- influenza
kinumab is present in breast milk. However, canakinumab Local: Injection site reaction
is a recombinant IgG monoclonal antibody; human IgG is Neuromuscular and skeletal: Musculoskeletal pain
present in breast milk. According to the manufacturer, the Renal: Decreased creatinine clearance (Lachmann 2009)
decision to continue or discontinue breastfeeding during Respiratory: Bronchitis, nasopharyngitis, pharyngitis, rhi-
therapy should take into account the risk of infant expo- nitis, upper respiratory tract infection
sure, the benefits of breastfeeding to the infant, and Rare but important or life-threatening: Hypersensitivity
benefits of treatment to the mother. reaction
Contraindications Drug Interactions
Hypersensitivity to canakinumab or any component of the Metabolism/Transport Effects None known.
formulation Avoid Concomitant Use
Canadian labeling: Additional contraindications (not in US Avoid concomitant use of Canakinumab with any of the
labeling): Active, severe infections following: Anti-TNF Agents; BCG (Intravesical); Belimu-
Warnings/Precautions Hypersensitivity reactions mab; Interleukin-1 Inhibitors; Interleukin-1 Receptor
(excluding anaphylactic reactions) have been reported Antagonist; Natalizumab; Pimecrolimus; Tacrolimus
with use; symptoms may be similar to those that are (Topical); Vaccines (Live)
disease-related. Caution should be exercised when con- Increased Effect/Toxicity
sidering use in patients with a history of new/recurrent
Canakinumab may increase the levels/effects of: Barici-
infections, with conditions that predispose them to infec-
tinib; Belimumab; Fingolimod; Leflunomide; Natalizu-
tions, or with latent or localized infections. Therapy should
mab; Tofacitinib; Vaccines (Live)
not be initiated in patients with active or chronic infections.
Patients should be evaluated for latent tuberculosis infec- The levels/effects of Canakinumab may be increased by:
tion with a tuberculin skin test prior to starting therapy. Anti-TNF Agents; Denosumab; Interleukin-1 Inhibitors;
Treat latent TB infections prior to initiating canakinumab Interleukin-1 Receptor Antagonist; Ocrelizumab; Pime-
therapy. During and following treatment, monitor for signs/ crolimus; Roflumilast; Tacrolimus (Topical); Trastuzumab
symptoms of active TB. Macrophage activation syndrome Decreased Effect
(MAS may develop in patients with SJIA and should be Canakinumab may decrease the levels/effects of: BCG
treated aggressively. Infection or worsening SJIA may be (Intravesical); Coccidioides immitis Skin Test; Nivolu-
triggers for MAS. mab; Pidotimod; Sipuleucel-T; Tertomotide; Vaccines
Use may impair defenses against malignancies; impact on (Inactivated); Vaccines (Live)
the development and course of malignancies is not fully
The levels/effects of Canakinumab may be decreased
defined. A decrease in WBC, neutrophils, and platelets
by: Echinacea
was observed in clinical trials; some changes were tran-
sient and/or mild (eg, thrombocytopenia). One case of
Storage/Stability Store intact vial at 2°C to 8°C (36°F to
neutropenia (ANC <1,500/mm°) was reported; monitor 46°F); do not freeze. After reconstitution of powder, vials
blood counts as indicated. may be stored at room temperature for up to 1 hour or ina
refrigerator at 2°C to 8°C (36°F to 46°F) for up to 4 hours.
Potentially significant drug-drug interactions may exist, Protect from light prior to and after reconstitution. Discard
requiring dose or frequency adjustment, additional mon- any unused portion.
itoring, and/or selection of alternative therapy. Immuniza- Mechanism of Action Canakinumab reduces inflamma-
tions should be up to date including pneumococcal and tion by binding to interleukin-1 beta (IL-1beta) (no binding
influenza vaccines before initiating therapy. Live vaccines to IL-1 alpha or IL-1 receptor antagonist [IL-1ra]) and
should not be given concurrently. Administration of inacti- preventing interaction with cell surface receptors. Cryo-
vated (killed) vaccines while on therapy may not be pyrin-associated periodic syndromes (CAPS) refers to
effective.
rare genetic syndromes caused by mutations in the
Some dosage forms may contain polysorbate 80 (also nucleotide-binding domain, leucine rich family (NLR),
known as Tweens). Hypersensitivity reactions, usually a pyrin domain containing 3 (NLRP-3) gene or the cold-
delayed reaction, have been reported following exposure induced autoinflammatory syndrome-1 (CIAS1) gene.
to pharmaceutical products containing polysorbate 80 in Cryopyrin, a protein encoded by this gene, regulates IL-
certain individuals (Isaksson 2002; Lucente 2000; Shelley 1beta activation. Deficiency of cryopyrin results in exces-
1995). Thrombocytopenia, ascites, pulmonary sive inflammation.

352
 CANDESARTAN

Pharmacodynamics/Kinetics (Adult data unless >40 kg: SubQ: Initial: 150 mg every 4 weeks; if
‘noted) inadequate response after 7 days may repeat dose
Onset of action: Maximum effect: Within 8 days CRP and (150 mg) and increase maintenance dose to
serum amyloid normalization 300 mg every 4 weeks if full treatment response
Distribution: Vass: Children: 0.097 L/kg (3.2 L in 33 kg); (Ilaris prescribing information, Canada 2017; Ilaris
Adults: CAPS: 0.086 L/kg (6 L in 70 kg); FMF, HIDS/ prescribing information, United Kingdom 2017)
MKD, TRAPS: 0.09 L/kg (6.34 L in 70 kg). Hyperimmunoglobulin D syndrome (HIDS)/mevalo-
Protein binding: Binds to serum IL-1 beta nate kinase deficiency (MKD): Children 22 years
Bioavailability: Subcutaneous: 66% and Adolescents: Patient weight:
Half-life elimination: Children 24 years: 22.9 to 25.7 days; 7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4
Adults: 26 days weeks; if inadequate response after 7 days may
Time to peak, serum: Children 24 years: 2 to 7 days; repeat dose (2 mg/kg) and increase maintenance
Adults: ~7 days dose to 4 mg/kg/dose every 4 weeks if full treatment
Clearance: Varies according to body weight: response (llaris prescribing information, Canada
Children $40 kg: SJIA: 0.11 L/day in 33 kg 2017; \laris prescribing information, United Kingdom
Children >40 kg and Adults: CAPS: 0.174 L/day in 70 kg 2017)
Children, Adolescents, and Adults: FMF, HIDS/MKD, >40 kg: SubQ: Initial: 150 mg every 4 weeks; if
TRAPS: 0.17 Li/day in 70 kg inadequate response after 7 days may repeat dose
Dosing (150 mg) and increase maintenance dose to
Pediatric 300 mg every 4 weeks if full treatment response
Cryopyrin-associated periodic syndromes (CAPS): (llaris prescribing information, Canada 2017; llaris
Patient syndromes included in trials were: Familial prescribing information, United Kingdom 2017)
cold autoinflammatory syndrome (FCAS), Muckle- Juvenile idiopathic arthritis; systemic: Children 22
Wells syndrome (MWS), chronic infantile neurological years weighing at least 7.5 kg and Adolescents:
cutaneous articular syndrome/neonatal onset multi- SubQ: 4 mg/kg/dose every 4 weeks; maximum dose:
systemic inflammatory disease (CINCA/NOMID), 300 mg
and familial cold urticaria (FCU); data has shown that Tumor necrosis factor receptor associated periodic
pediatric patients require higher doses than adults syndrome (TRAPS): Children 22 years and Adoles-
(Kuemmerle-Deschner 2011). cents: Patient weight:
Manufacturer's labeling: Children 24 years and Ado- 7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4
lescents: weeks; if inadequate response after 7 days may
15 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 8 repeat dose (2 mg/kg) and increase maintenance
weeks; may increase to 3 mg/kg/dose if response dose to 4 mg/kg/dose every 4 weeks if full treatment
inadequate response (llaris prescribing information, Canada
>40 kg: SubQ: 150 mg/dose every 8 weeks 2017; llaris prescribing information, United Kingdom
Alternate dosing: Limited data available: 2017)
Children 2 to <4 years and weighing 27.5 kg: SubQ: >40 kg: SubQ: Initial: 150 mg every 4 weeks; if
4 mg/kg/dose every 8 weeks; if no response after 7 inadequate response after 7 days may repeat dose
days, may repeat 4 mg/kg dose, if response (150 mg) and increase maintenance dose to
achieved then may continue patient on intensified 300 mg every 4 weeks if full treatment response
maintenance of 8 mg/kg/dose every 8 weeks (llaris (llaris prescribing information, Canada 2017; llaris
prescribing information, United Kingdom 2017) prescribing information, United Kingdom 2017)
Children 24 years and Adolescents: Renal Impairment: Pediatric Children 22 years and
7.5 kg to <15 kg: SubQ: 4 mg/kg/dose every 8 Adolescents: There are no dosage adjustments provided
weeks. If no response after 7 days, may admin- in the manufacturer's labeling; has not been studied.
istered a second 4 mg/kg/dose, if full treatment Hepatic Impairment: Pediatric Children 22 years and
response achieved then may continue patient on Adolescents: There are no dosage adjustments provided
intensified maintenance of 8 mg/kg/dose every 8 in the manufacturer's labeling; has not been studied.
weeks (llaris prescribing information, United Preparation for Administration SubQ: Lyophilized
Kingdom 2017) powder for injection: Reconstitute vial with 1 mL SWFI
15 kg to 40 kg: SubQ: 2 mg/kg/dose every 8 (preservative free). Swirl the vial at a 45-degree angle for
weeks. If response not satisfactory after 7 days, ~1 minute (do not shake), then allow solution to sit for 5
may repeat 2 mg/kg dose, if full treatment minutes. Continue product dissolution by gently turning
response achieved then may continue patient vial (without touching rubber stopper) upside down and
on intensified maintenance of 4 mg/kg/dose back 10 times; do not shake; after reconstitution, protect
every 8 weeks. If after 7 days (ie, day 14) a from light. Allow to sit at room temperature for ~15 minutes
satisfactory response still not achieved, may until solution is clear. Do not shake. Solution may have a
administer another 4 mg/kg dose, if full treatment slight brownish-yellow tint; do not use if distinctly brown in
response achieved then may continue patient on color or if particulate matter is present in the solution.
intensified maintenance of 8 mg/kg/dose every 8 Each reconstituted vial results in a final concentration of
weeks (Ilaris prescribing information, United 150 mg/mL.
Kingdom 2017; Kuemmerle-Deschner 2011). Administration SubQ: Do not shake; administer subcuta-
Another dose-escalation regimen describes titra- neously at a concentration of 150 mg/mL by a health care
tion in 2 mg/kg/dose increments every 7 days up provider; avoid sites with scar tissue
to a maximum dose of 8 mg/kg/dose (llaris pre- Monitoring Parameters CBC with differential, C-reactive
scribing information, Canada 2017) protein (CRP), serum amyloid A; LFTs at baseline; signs
>40 kg: SubQ: 150 mg every 8 weeks. If response or symptoms of infection; latent TB screening (prior to
not satisfactory after 7 days, may repeat 150 mg/ initiating therapy), body weight. Eye examinations for
dose, if full treatment. response achieved then
patients with CAPS (Caorsi 2013) and symptoms of dis-
may continue patient on intensified maintenance ease for patients with CAPS, SJIA, TRAPS, FMF, or HIDS/
of 300. mg every 8 weeks. If after 7 days (ie, day MKD (Arostegui 2015; Brik 2014; Caorsi 2013; Lachmann
14) a satisfactory response still not. achieved,
2009; Ruperto 2012; Torene 2017) were also monitored in
may administer another 300 mg/dose, if full treat-
Clinical trials.
ment response achieved then may continue
Dosage Forms Excipient information presented when
patient on intensified maintenance of 600 mg
available (limited, particularly for generics); consult spe-
every 8 weeks (Ilaris prescribing information,
cific product labeling. [DSC] = Discontinued product
United Kingdom 2017; Kuemmerle-Deschner
Solution, Subcutaneous:
2011). Another dose-escalation regimen
llaris: 150 mg/mL (1 mL) [contains polysorbate 80]
describes titration in 150 mg increments every 7
Solution Reconstituted, Subcutaneous [preservative free]:
days up to a maximum dose of 600 mg (llaris
llaris: 150 mg (1 ea [DSC}]) [contains polysorbate 80]
prescribing information, Canada 2017).
Familial Mediterranean Fever (FMF): Children 22 @ Canasa see Mesalamine on page 1313
years and Adolescents: Note: In trial, canakinumab
@ Cancidas see Caspofungin on page 376
was used as monotherapy and in combination with
daily colchicine. Patient weight:
7.5 to 40 kg: SubQ: Initial: 2 mg/kg/dose every 4 Candesartan (kan de SAR tan)
weeks; if inadequate response after 7 days may
repeat dose (2 mg/kg) and increase maintenance Medication Safety Issues
dose to 4 mg/kg/dose every 4 weeks if full treatment Sound-alike/look-alike issues:
response (llaris prescribing information, Canada Atacand may be confused with antacid
2017; Ilaris prescribing information, United Kingdom Brand Names: US Atacand
2017) Brand Names: Canada Atacand

353
 CANDESARTAN

‘ Therapeutic Category Angiotensin || Receptor Blocker; or previous angioedema associated with ACE-inhibitor
Antihypertensive Agent therapy may be at an increased risk. Prolonged frequent
Generic Availability (US) Yes monitoring may be required, especially if tongue, glottis, or
Use Treatment of hypertension alone or in combination larynx are involved, as they are associated with airway
with other antihypertensive agents (FDA approved in ages obstruction. Patients with a history of airway surgery may
21 year and adults); treatment of heart failure (NYHA class have a higher risk of airway obstruction. Discontinue
\I-IV) (FDA approved in adults) therapy immediately if angioedema occurs. Aggressive
Pregnancy Risk Factor D early management is critical. Intramuscular (IM) adminis-
Pregnancy Considerations [US Boxed Warning]: tration of epinephrine may be necessary. Do not read-
Drugs that act on the renin-angiotensin system can minister to patients who have had angioedema with ARBs.
cause injury and death to the developing fetus. Dis- Avoid use in patients with ascites due to cirrhosis or
continue as soon as possible once pregnancy is refractory ascites; if use cannot be avoided in patients
detected. The use of drugs which act on the renin- with ascites due to cirrhosis, monitor blood pressure and
angiotensin system are associated with oligohydramnios. renal function carefully to avoid rapid development of renal
Oligohydramnios, due to decreased fetal renal function, failure (AASLD [Runyon 2012)).
may lead to fetal lung hypoplasia and skeletal malforma- In patients on chronic angiotensin receptor blocker (ARB)
tions. Use is also associated with anuria, hypotension, therapy, intraoperative hypotension may occur with induc-
renal failure, skull hypoplasia, and death in the fetus/ tion and maintenance of general anesthesia; however,
neonate. The exposed fetus should be monitored for fetal discontinuation of therapy prior to surgery is controversial.
growth, amniotic fluid volume, and organ formation. If continued preoperatively, avoidance of hypotensive
Infants exposed in utero should be monitored for hyper- agents during surgery is prudent (Hillis 2011). Based on
kalemia, hypotension,-and oliguria (exchange transfusions current research and clinical guidelines in patients under-
or dialysis may be needed). These adverse events are going non-cardiac surgery, continuing angiotensin-recep-
generally associated with maternal use in the second and tor blockers (ARB) is reasonable in the perioperative
third trimesters. period. If ARBs are held before surgery, it is reasonable
Untreated chronic maternal hypertension is also associ- to restart postoperatively as soon as clinically feasible
ated with adverse events in the fetus, infant, and mother. (ACC/AHA [Fleisher 2014]). ‘
The use of angiotensin || receptor blockers is not recom- Adverse Reactions
mended to treat chronic uncomplicated hypertension in Cardiovascular: Angina pectoris, hypotension, myocardial
pregnant women and should generally be avoided in infarction, palpitations, tachycardia
women of reproductive potential (ACOG 2013). Central nervous system: Anxiety, depression, dizziness,
Breastfeeding Considerations It is not known if cande- drowsiness, headache, paresthesia, vertigo
sartan is present in breast milk. Due to the potential for Dermatologic: Diaphoresis, skin rash
serious adverse reactions in the breastfeeding infant, the Endocrine & metabolic: Hyperglycemia, hyperkalemia,
manufacturer recommends a decision be made whether to hypertriglyceridemia, hyperuricemia
discontinue breastfeeding or to discontinue the drug, Gastrointestinal: Dyspepsia, gastroenteritis
taking into account the importance of treatment to the Genitourinary: Hematuria
mother. Neuromuscular & skeletal: Back pain, increased creatine
Contraindications phosphokinase, myalgia, weakness _
Hypersensitivity to candesartan or any component of the Renal: Increased serum creatinine
formulation; concomitant use with aliskiren in patients Respiratory: Dyspnea, epistaxis, pharyngitis, rhinitis,
with diabetes mellitus upper respiratory tract infection
Canadian labeling: Additional contraindications (not in US Miscellaneous: Fever
labeling): Concomitant use with aliskiren in patients with Rare but important or life-threatening: Atrial fibrillation,
moderate-to-severe renal impairment (GFR <60 mL/ bradycardia, cardiac failure, cerebrovascular accident,
minute/1.73 m2); pregnancy; breastfeeding; children <1 confusion, hepatic insufficiency, hepatitis, hypersensitiv-
year of age; rare hereditary problems of galactose intol- ity, leukopenia, loss of consciousness, pancreatitis,
erance, Lapp lactase deficiency or glucose-galactose pneumonia, presyncope, pulmonary edema, renal fail-
malabsorption ure, rhabdomyolysis, thrombocytopenia
Warnings/Precautions [US Boxed Warning]: Drugs Drug Interactions
that act on the renin-angiotensin system can cause Metabolism/Transport Effects Substrate of CYP2C9
injury and death to the developing fetus. Discontinue (minor); Note: Assignment of Major/Minor substrate sta-
as soon as possible once pregnancy is detected. May tus based on clinically relevant drug interaction potential
cause hyperkalemia; avoid potassium supplementation Avoid Concomitant Use
unless specifically required by healthcare provider. Avoid Avoid concomitant use of Candesartan with any of the
use or use a smaller dose in patients who are volume following: Bromperidol
depleted; correct depletion first. May be associated with Increased Effect/Toxicity
deterioration of renal function and/or increases in serum Candesartan may increase the levels/effects of: Amifos-
creatinine, particularly in patients with low renal blood flow tine; Angiotensin-Converting Enzyme Inhibitors; Antipsy-
(eg, renal artery stenosis, heart failure) whose glomerular chotic Agents (Second Generation [Atypical]);
filtration rate (GFR) is dependent on efferent arteriolar Bromperidol; CycloSPORINE (Systemic); Drospirenone;
vasoconstriction by angiotensin II; deterioration may result DULoxetine; Hypotension-Associated Agents; Levo-
in oliguria, acute renal failure, and progressive azotemia. dopa; Lithium; Nitroprusside; Nonsteroidal Anti-Inflam-
Small increases in serum creatinine may occur following matory Agents; Pholcodine; Potassium-Sparing
initiation; consider discontinuation only in patients with Diuretics; Sodium Phosphates
progressive and/or significant deterioration in renal func-
tion. Use with caution in unstented unilateral/bilateral renal The levels/effects of Candesartan may be increased by:
artery stenosis, preexisting renal insufficiency, or signifi- Alfuzosin; Aliskiren; Antihepaciviral Combination Prod-
cant aortic/mitral stenosis. Systemic exposure increases ucts; Barbiturates; Benperidol; Brigatinib; Brimonidine
in hepatic impairment. US manufacturer labeling recom- (Topical); Canagliflozin; Dapoxetine; Diazoxide; Eplere-
mends a dosage adjustment in patients with moderate none; Heparin; Heparins (Low Molecular Weight); Herbs
hepatic impairment; pharmacokinetics have not been (Hypotensive Properties); Lormetazepam; Molsidomine;
studied in severe hepatic impairment. Use caution when Naftopidil; Nicergoline; Nicorandil; Obinutuzumab; Pen-
initiating in heart failure; may need to adjust dose, and/or toxifylline; Phosphodiesterase 5 Inhibitors; Potassium
concurrent diuretic therapy, because of candesartan- Salts; Prostacyclin Analogues; Quinagolide; Tolvaptan;
induced hypotension. In surgical patients on chronic Trimethoprim
angiotensin receptor blocker (ARB) therapy, intraoperative Decreased Effect
hypotension may occur with induction and maintenance of Candesartan may decrease the levels/effects of: Angio-
general anesthesia Potentially significant drug-drug inter- tensin II
actions may exist, requiring dose or frequency adjustment,
The levels/effects of Candesartan may be decreased by:
additional monitoring, and/or selection of alternative ther-
Amphetamines; Brigatinib; Bromperidol; Herbs (Hyper-
apy. Pediatric patients with a GFR <30 mL/minute/1.73 m?
tensive Properties); Methylphenidate; Nonsteroidal Anti-
should not receive candesartan; has not been evaluated.
Inflammatory Agents; Yohimbine
Avoid use in infants <1 year of age due to potential effects
Storage/Stability Store at 25°C (77°F); excursions per-
on the development of immature kidneys.
mitted to 15°C to 30°C (59°F to 86°F).
Angioedema has been reported rarely with some angio- Mechanism of Action Candesartan is an angiotensin
tensin Il receptor antagonists (ARBs) and may occur at receptor antagonist. Angiotensin || acts as a vasoconstric-
any time during treatment (especially following first dose). tor. In addition to causing direct vasoconstriction, angio-
It may involve the head and neck (potentially compromis- tensin || also stimulates the release of aldosterone. Once
ing airway) or the intestine (presenting with abdominal aldosterone is released, sodium as well as water are
pain). Patients with idiopathic or hereditary angioedema reabsorbed. The end result is an elevation in blood

354
 CAPREOMYCIN

pressure. Candesartan binds to the AT1 angiotensin II Monitoring Parameters Blood pressure, serum creati-
receptor. This binding prevents angiotensin II from binding nine, BUN, baseline and periodic serum electrolytes (par-
to the receptor thereby blocking the vasoconstriction and ticularly K), urinalysis
the aldosterone secreting effects of angiotensin II. Test Interactions May lead to false-negative aldosterone/
Pharmacodynamics/Kinetics (Adult data unless renin ratio (ARR) (Funder 2016).
noted) Dosage Forms Excipient information presented when
Onset of action: 2 to 3 hours; antihypertensive effect: available (limited, particularly for generics); consult spe-
Within 2 weeks cific product labeling.
Peak effect: 6 to 8 hours; maximum antihypertensive Tablet, Oral, as cilexetil:
effect: 4 to 6 weeks Atacand: 4 mg, 8 mg, 16 mg, 32 mg [scored]
Duration: >24 hours Generic: 4 mg, 8 mg, 16 mg, 32 mg
Absorption: Candesartan: Rapid and complete following Extemporaneous Preparations Oral suspension may
conversion from candesartan cilexetil by Gl esterases be made in concentrations ranging from 0.1 to 2 mg/mL;
Distribution: Vg: 0.13 L/kg typically 1 mg/mL oral suspension suitable for majority of
Protein binding: >99% prescribed doses; any strength tablet may be used. A
Metabolism: Converted to active candesartan, via ester 1 mg/mL (total volume: 160 mL) oral suspension may be
hydrolysis during absorption from GI tract; hepatic made with tablets and a 1:1 mixture of Ora-Plus® and
(minor) via O-deethylation to inactive metabolite Ora-Sweet SF®. Prepare the vehicle by adding 80 mL of
Bioavailability, absolute: Candesartan: 15% Ora-Plus® and 80 mL of Ora-Sweet SF® or, alternatively,
Half-life elimination (dose dependent): 5 to 9 hours use 160 mL of Ora-Blend SF®. Add a small amount of
Time to peak: Children (1 to 17 years); Adults: 3 to 4 hours vehicle to five 32 mg tablets and grind into a smooth paste
Excretion: Feces (67%); urine (33%; 26% as using a mortar and pestle, Transfer the paste to a cali-
unchanged drug) brated amber PET bottle, rinse the mortar and pestle
Clearance: Total body: 0.37 mL/minute/kg; Renal: 0.19 clean using the vehicle, add this to the bottle, and then
mL/minute/kg; decreased with severe renal impairment add a quantity of vehicle sufficient to make 160 mL. The
Pharmacodynamics/Kinetics: Additional Consider- suspension is stable at room temperature for 100 days
ations unopened or 30 days after the first opening; do not freeze;
Renal function impairment: In hypertensive patients with label "shake well before use." (Atacand prescribing infor-
CrCl <30 mL/minute/1.73 m2, the AUC and Cmax are mation, 2013).
approximately doubled. In heart failure patients with
@ Candesartan Cilexetil see Candesartan on page 353
renal impairment, AUC is 36% and 65% higher and Cpyax
is 15% and 55% higher in patients with mild and mod- @ CanesOral (Can) see Fluconazole on page 867
erate renal impairment, respectively. @ Canesten Topical (Can) see Clotrimazole (Topical)
Hepatic function impairment: The AUC and Cmax on page 499
increased 30% and 56% in mild impairment and 145% Canesten Vaginal (Can) see Clotrimazole (Topical)
and 73% in moderate impairment, respectively. on page 499.
Geriatric: Crax is ~50% higher; AUC is ~80% higher.
@ Capastat Sulfate see Capreomycin on page 355
Dosing
Pediatric Note: Use of a lower initial dose is recom- @ Capex see Fluocinolone (Topical) on page 882
mended in volume- and salt-depleted patients; if possi- Capital/Codeine [DSC] see Acetaminophen and
ble, correct volume depletion prior to administration; Codeine on page 42
dosage must be individualized @ Capoten see Captopril on page 358
Hypertension:
Children 1 to <6 years: Oral: Initial: 0.2 mg/kg/day
once daily; titrate to response (within 2 weeks, Capreomycin (kap ree oh MYE sin)
antihypertensive effect usually observed); usual
range: 0.05 to 0.4 mg/kg/day divided once or twice Medication Safety Issues
daily; maximum daily dose: 0.4 mg/kg/day; higher Sound-alike/look-alike issues:
doses have not been studied. Capastat may be confused with Cepastat
Children and Adolescents 6 to <17 years: Oral: Brand Names: US Capastat Sulfate
<50 kg: Initial: 4 to 8 mg/day once daily; titrate to Therapeutic Category Antibiotic, Miscellaneous; Antitu-
response (within 2 weeks, antihypertensive effect bercular Agent
usually observed); usual range: 2 to 16 mg/day Generic Availability (US) No
divided once or twice daily; maximum daily dose: Use Treatment of pulmonary tuberculosis (TB) in conjunc-
32 mg/day; higher doses have not been studied. tion with at least one other antituberculosis agent when
>50 kg: Initial: 8 to 16 mg/day once daily; titrate to primary anti-TB agents are ineffective (drug-resistant) or
response (within 2 weeks, antihypertensive effect patient does not tolerate or resistant tubercle bacilli
usually observed); usual range: 4-to.32-mg/day present (FDA approved in adults)
divided once or twice daily; maximum daily dose: Pregnancy Risk Factor C
32 mg/day; higher doses have not been studied. Pregnancy Considerations Adverse events have been
Adolescents 217 years: Oral: Initial: 16 mg once daily; reported in animal reproduction studies. [US Boxed
titrate to response (within 2 weeks, antihypertensive Warning]: Safety has not been established in pregnant
effect usually observed; maximum effect seen within women; avoid use during pregnancy because of the risk
4 to 6 weeks); usual range: 8 to 32 mg/day divided of fetal nephrotoxicity and congenital hearing loss (MMWR
once or twice daily; blood pressure response is 2003).
dose-related over the range of 2 to 32 mg; larger Breastfeeding Considerations It is not known if cap-
doses do not appear to have a greater effect and reomycin is excreted in breast milk. The manufacturer
there is relatively little experience with such doses recommends that caution be exercised when administer-
Renal Impairment: Pediatric ing capreomycin to nursing women.
Children and Adolescents 1 to <17 years: Contraindications Hypersensitivity to capreomycin or
CrCl 230 mk/minute/1.73 m*: There are no dosage any component of the formulation
adjustments provided in the manufacturer's labeling; Warnings/Precautions May cause impairment of cranial
has not been studied in pediatric patients with renal nerve VIII, which may be irreversible; perform audiometric
impairment. assessment and assessment of vestibular function prior to
CrCl <30 mL/minute/1.73_m?: Use is not recom- initiation and periodically during treatment. May cause
mended (has not been-studied). . nephrotoxicity, including tubular necrosis, increased BUN
Not removed by dialysis. or serum creatinine, and abnormal urinary sediment; slight
Hepatic Impairment: Pediatric ; elevations in BUN and serum creatinine with urinary
Mild hepatic impairment (Child-Pugh Class A): No initial RBCs, WBCs, and casts have been observed with pro-
dosage adjustment required longed treatment. Monitor renal function at baseline and
Moderate hepatic impairment (Child-Pugh Class B): periodically during treatment. A BUN >30 mg/dL or other
There are no dosage adjustments provided in the evidence of decreasing renal function should prompt
manufacturer’s labeling for pediatric patients. clinical evaluation and dosage adjustment or therapy
Severe hepatic impairment (Child-Pugh Class C): discontinuation. [US Boxed Warnings]: Use in patients
There are no dosage adjustments provided in manu- with renal impairment or preexisting auditory impair-
facturer's labeling (has not been studied); however, ment must be undertaken with great caution, and the
systemic exposure increases significantly in moderate risk of additional cranial nerve VIII impairment or renal
impairment. injury should be weighed against the benefits to be
Administration Oral: May be administered without regard derived from therapy. Because other parenteral anti-
to meals. An oral suspension may be prepared for children tuberculous agents (eg, streptomycin, viomycin) also
unable to swallow tablets (refer to Extemporaneous Prep- have similar and sometimes irreversible toxic effects,
aration information). particularly on cranial nerve VIII and renal function, >
355
 CAPREOMYCIN

| simultaneous administration of these agents with

capreomycin is not recommended. Use with nonanti-
Dosing
Pediatric
tuberculous drugs (eg, polymyxin A sulfate, colistin Active tuberculosis infection; treatment multidrug
sulfate, gentamicin, tobramycin, vancomycin, neomy- resistant (MDR) (second-line therapy): Limited data
cin) having ototoxic or nephrotoxic potential should available: Note: Always use as part of a multidrug
be undertaken only with great caution. Use caution with regimen. Any regimens using less than once daily
renal impairment, in elderly patients, and in patients who dosing should administer dosing as directly observed
demonstrate some form of allergy; dosage reductions are therapy (DOT). Treatment regimens for MDR TB are
recommended for known or suspected renal impairment. variable depending upon sensitivity and clinical
Electrolyte imbalances (hypocalcemia, hypokalemia, and response. Capreomycin frequency and dosing differs
hypomagnesemia) have been reported with use. Monitor depending on treatment regimen selected; consult
electrolytes periodically during treatment. Prolonged use current drug-sensitive TB guidelines for detailed infor-
may result in fungal or bacterial superinfection, including mation (ATS/CDC/IDSA [Nahid 2016]; Schaaf 2015).
C. difficile-associated diarrhea (CDAD) and pseudomem- Primary pulmonary disease:
branous colitis; CDAD has been observed >2 months Once-daily therapy:
postantibiotic treatment. [US Boxed Warning]: Safety Infants, Children, and Adolescents <15 years,
in pregnant women or pediatric patients not estab- weighing <40 kg: Note: Suggested expert dosing
lished. Potentially significant drug-drug interactions may range is large and variable (Schaaf 2015): IM, IV:
exist, requiring dose or frequency adjustment, additional 15 to 30 mg/kg/dose once daily; some experts
monitoring, and/or selection of alternative therapy. recommend an initial dose range of 15 to
Warnings: Additional Pediatric Considerations May 20 mg/kg/dose once daily; maximum daily dose:
cause renal injury including tubular necrosis, elevated 1,000 mg/day; monitor serum concentrations
BUN or serum creatinine, and abnormal urinary sediment;
(ATS/CDC/IDSA [Nahid 2016]; DHHS [pediatric]
BUN elevation and abnormal urinary sediment are asso- 2013; Schaaf 2015; Seddon 2012)
ciated with prolonged therapy and the clinical significance
Children and Adolescents <15 years weighing >40
of these findings is not fully established. Proteinuria
kg or Adolescents 215 years: IM, IV: 15 mg/kg/
frequently reported; electrolyte disturbances (hypokale-
dose once daily; maximum daily dose: 1,000 mg/
mia, hypomagnesemia, and hypocalcemia) may result
day; monitor serum concentrations (ATS/CDC/
from renal injury (CDC, 2003). Discontinuation of therapy
IDSA [Nahid 2016]; HHS [adult] 2016; Sed-
due to renal toxicity has been reported in 20% to 25% of
don 2012) ;
patients (CDC; 2003). Monitor renal function; urinalysis
Three-times weekly DOT: Children and Adolescents
and electrolytes at baseline and periodically (monthly)
<15 years weighing >40 kg or Adolescents 215
throughout therapy (CDC, 2003; Seddon, 2012). May
years: IM, IV: 25 mg/kg/dose three times weekly;
cause hearing loss; some cases may be irreversible.
maximum dose: 1,000 mg/dose (ATS/CDC/IDSA
Tinnitus and vertigo have also been reported; more com-
mon in elderly patients and patients with preexisting renal [Nahid 2016]
Twice-weekly DOT: Infants, Children, and Adoles-
impairment. In pediatric patients treated for multidrug-
resistant TB, the reported incidence of hearing loss is cents <15 years, weighing <40 kg: IM, IV: 25 to
variable (7% to 24%) with regimens that included either 30 mg/kg/dose twice weekly; maximum dose:
capreomycin or an aminoglycoside; the majority of chil- 1,000 mg/dose (ATS/CDC/IDSA [Nahid 2016])
dren received amikacin compared to capreomycin; spe- Meningitis (independent of HIV-status): Infants, Chil-
cific incidence with capreomycin not determined (Drobac, dren, and Adolescents: Suggested expert dosing
2006; Seddon, 2013). range is large and variable (Schaaf 2015): IM, IV:
Adverse Reactions 15 to 30 mg/kg/dose once daily; some experts rec-
Otic: Ototoxicity ommend an initial range of 15 to 20 mg/kg/dose
Genitourinary: Nephrotoxicity (increased blood urea once daily; maximum daily dose: 1,000 mg/day;
nitrogen) monitor serum concentrations (ATS/CDC/IDSA
Hematologic: Eosinophilia (dose-related, mild) {[Nahid 2016]; DHHS [pediatric] 2013; Red Book
Rare but important or life-threatening: Hepatic insuffi- [AAP 2015]; Schaaf 2015)
ciency (decreased sulfobromophthalein excretion), Renal Impairment: Pediatric Drug clearance is
hypersensitivity (includes fever, maculopapular rash, decreased and half-life increased with decreasing renal
urticaria), hypocalcemia, hypokalemia, hypomagnese- function; specific recommendations in pediatric patients
mia, increased serum creatinine, injection site reaction are lacking; consider dosing adjustment and frequent
(includes abscess at injection site, bleeding at injection therapeutic drug monitoring in patients with renal impair-
site, induration at injection site, and pain at injection site), ment (ATS/CDC/IDSA [Nahid 2016]).
leukocytosis, leukopenia, nephritis (toxic), renal tubular Hepatic Impairment: Pediatric There are no dosage
necrosis, thrombocytopenia (rare), tinnitus, urine sedi- adjustments provided in the manufacturer's labeling;
mentation abnormality, vertigo some suggest that no extra precautions are needed
Drug Interactions (CDC 2003).
Metabolism/Transport Effects None known. Preparation for Administration Parenteral: Reconsti-
Avoid Concomitant Use tute powder for injection with 2 mL of NS or SWFI; allow
Avoid concomitant use of Capreomycin with any of the 2 to 3 minutes for dissolution.
following: BCG (intravesical); Cholera Vaccine; Meca- IV: Further dilute in NS 100 mL.
mylamine IM: Concentration for administration dependent upon dose
Increased Effect/Toxicity 1,000 mg dose: Administer contents of reconstituted vial
Capreomycin may increase the levels/effects of: Amino- Doses <1,000 mg dose: See table:
glycosides; Colistimethate; Mecamylamine; Neuromus-
cular-Blocking Agents; Polymyxin B Capreomycin Dilution for Doses
Decreased Effect <1,000 mg
Capreomycin may decrease the levels/effects of: BCG Diluent Capreomycin Final
(Intravesical); BCG Vaccine (Immunization); Cholera Volume _| Solution Volume | Concentration
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate (mL) (mL) (approximate)
Storage/Stability Store intact vials at 15°C to 30°C (59°F
to 86°F). Following reconstitution, may store under refrig-
eration for up to 24 hours.
Mechanism of Action Capreomycin is a cyclic polypep-
tide antimicrobial. It is administered as a mixture of
capreomycin IA and capreomycin IB. The mechanism of
action of capreomycin is not well understood. Mycobacte-
rial species that have become resistant to other agents are Administration Parenteral:
usually still sensitive to the action of capreomycin. How- IV: Administer over 60 minutes.
ever, significant cross-resistance with viomycin, kanamy- IM: Administer by deep IM injection into large
cin, and neomycin occurs. muscle mass
Pharmacodynamics/Kinetics (Adult data unless Monitoring Parameters
noted) Pediatric patients: Audiometric measurements and vestib-
Absorption: Oral: Not absorbed ular function (baseline, periodically while on therapy, and
Half-life elimination: CrCl 100 to 110 mL/minute: 5 to 6 discontinuation of therapy); renal function (baseline,
hours; CrCl 50 to 80 mL/minute: 7 to 10 hours; CrCl 20 to periodically while on therapy, and following discontinua-
40 mL/minute: 12 to 20 hours; CrCl 10 mL/minute: 29 tion of therapy); baseline and frequent assessment of
hours; CrCl 0 mL/minute: 55 hours serum electrolytes (including calcium, magnesium, and
Time to peak, serum: IM: 1 to 2 hours potassium), liver function tests, growth parameters (ATS/
Excretion: Urine (52% unchanged within 12 hours) CDCI/IDSA [Nahid 2016]; Schaaf 2015; Seddon 2012).

356
 CAPSAICIN

Adults: Audiometric measurements and vestibular func- For external use only; avoid contact with eyes, mouth,
tion at baseline and during therapy; renal function at genitals, or any or other mucous membranes. Do not use
baseline and weekly during therapy; frequent assess- immediately before or after activities such as bathing,
ment of serum electrolytes (including calcium, magne- swimming, showering, sun bathing, strenuous exercise,
sium, and potassium), liver function tests steam bath, sauna, or other heat or sunlight exposure to
Reference Range Tuberculosis treatment: Pediatric the treated area. Stop use and consult a healthcare
patients: Although exact pharmacokinetic/dynamic amino- provider if excessive redness, blistering burning or irrita-
glycoside targets are unknown for M. Tuberculosis; tion develops, symptoms get worse, symptoms persist for
experts suggest peak values (Cmax): 35 to 45 mcg/mL >7 days, symptoms resolve and then recur, or if difficulty
for once-daily therapy; and for twice-weekly: 65 to 80 breathing or swallowing occurs. Do not handle contact
meg/mL (Schaaf 2015) lenses for 1 hour after handling, applying, or removing
Dosage Forms Excipient information presented when capsaicin (product specific).
available (limited, particularly for generics); consult spe-
RX labeling: Do not cover with bandage or compression.
cific product labeling.
Use only on intact skin; do not use on wounds, damaged,
Solution Reconstituted, Injection, as sulfate:
broken, infected, sensitive or inflamed skin. Do not apply
Capastat Sulfate: 1 g (1 ea)
to face or scalp: Do not use concurrently with other
@ Capredmycin Sulfate see Capreomycin on page 355 external pain-relieving products.
OTC labeling: Transient burning may occur and generally
Capsaicin (kap say sin) disappears after several days.

Medication Safety Issues Patch: Avoid inhaling airborne material from dried residue.
Sound-alike/look-alike issues: Remove patches gently and slowly to decrease risk of
Zostrix may be confused with Zestril, Zovirax aerosolization; inhalation of airborne capsaicin may result
Brand Names: US Aflexeryl-MC [OTC] [DSC]; Aleveer in coughing or sneezing.
[OTC] [DSC]; Allevess [OTC]; Captracin [DSC]; Capzasin- Qutenza: If skin not intended to be treated comes in
HP [OTC]; Capzasin-P [OTC]; DiabetAid Pain and Tingling contact with capsaicin, apply provided cleansing gel for
Relief [OTC]; Flexin; Levatio; MaC Patch [DSC]; MenCaps one minute and wipe off with dry gauze; then wash the
[OTC]; Neuvaxin [DSC]; Qroxin [DSC]; Qutenza; Relee- area with soap and water. Post-application pain should be
via; Releevia MC; RelyyT [DSC]; Renovo; Salonpas Gel- treated with local cooling methods (ice pack) and/or
Patch Hot [OTC]; Salonpas Hot [OTC] [DSC]; Sinelee analgesics.
[DSC]; Solaice [DSC]; Sure Result SR Relief [OTC];
Trixaicin HP [OTC]; Trixaicin [OTC] [DSC]; Zostrix HP Benzyl alcohol and derivatives: Some dosage forms may
[OTC]; Zostrix Maximum Strength Natural Foot Pain Relief contain benzyl! alcohol; large amounts of benzyl! alcohol
[OTC]; Zostrix Maximum Strength Natural Pain Relief (299 mg/kg/day) have been associated with a potentially
[OTC]; Zostrix Original Strength Natural Pain Relief [OTC] fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Brand Names: Canada Zostrix; Zostrix H.P. ing syndrome" consists of metabolic acidosis, respiratory
Therapeutic Category Analgesic, Topical; Topical Skin distress, gasping respirations, CNS dysfunction (including
Product; Transient Receptor Potential Vanilloid 1 (TRPV1) convulsions, intracranial hemorrhage), hypotension and
Agonist cardiovascular collapse (AAP ["Inactive" 1997]; CDC,
Generic Availability (US) Yes: Cream 1982); some data suggests that benzoate displaces bilir-
ubin from protein binding sites (Ahlfors, 2001); avoid or
Use
use dosage forms containing benzyl alcohol with caution
Temporary relief of minor aches and pain of muscles and
in neonates. See manufacturer’s labeling.
joints associated with backache, strains, sprains, arthri-
tis, bruises, cramps, or muscle stiffness or soreness:
Adverse Reactions The following adverse events
OTC lotion 0.025% (DiabetAid Pain and Tingling Relief): occurred with topical patch administration.
FDA approved in ages 22 years and adults Cardiovascular: Hypertension (transient)
OTC patches <0.05%: FDA approved in ages 212 years Dermatologic: Local dryness, papule, pruritus
and adults Gastrointestinal: Nausea, vomiting
OTC patch 0.05% (Allvess): FDA approved in ages 216 Local: Local pain, local pruritus, local swelling, localized
years and adults edema, localized erythema
OTC cream, gel, liquid: FDA approved in adults Respiratory: Bronchitis, nasopharyngitis, sinusitis
Note: With OTC products, approved ages and uses may Rare but important or life-threatening: Abnormal skin odor,
vary; consult product specific labeling. application site reactions (includes bruise, dermatitis,
Management of neuropathic pain associated with post- desquamation, excoriation, hyperesthesia, inflammation,
herpetic neuralgia (patch 8% [Qutenza]: FDA approved paresthesia, urticaria), burning sensation of skin, cough,
in adults) - ; dizziness, dysgeusia, headache, hypoesthesia, periph-
eral edema, peripheral sensory neuropathy, throat irri-
Pregnancy Risk Factor B
tation
Pregnancy Considerations Adverse events have not
Drug Interactions
been observed in animal reproduction studies with cap-
saicin patch or liquid. Systemic absorption is limited Metabolism/Transport Effects Substrate of CYP2E1
following topical administration of the patch; plasma con- (minor); Note: Assignment of Major/Minor substrate sta-
centrations are below the limit of detection 3 to 6 hours tus based on clinically relevant drug interaction potential
after the patch is removed. Avoid Concomitant Use There are no known interac-
Breastfeeding Considerations It is not known if cap- tions where it is recommended to avoid concomitant use.
saicin is excreted in breast milk following topical admin- Increased Effect/Toxicity There are no known signifi-
istration. Some manufacturers recommend not cant interactions involving an increase in effect.
breastfeeding on the day of treatment after the patch Decreased Effect There are no known significant inter-
has been applied to reduce any potential infant exposure. actions involving a decrease in effect.
Contraindications Storage/Stability Store at room temperature; protect from
Hypersensitivity to capsaicin, menthol, or any component light.
of the formulation. Mechanism of Action Capsaicin, a transient receptor
OTC labeling: When used for self-medication, do not use potential vanilloid 1 receptor (TRPV1) agonist, activates
on wounds, damaged, broken, or irritated skin; do not TRPV1 ligand-gated cation channels on nociceptive nerve
cover with bandage; do not use in combination with fibers, resulting in depolarization, initiation of action poten-
external heat source (eg, heating pad). tial, and pain signal transmission to the spinal cord;
Warnings/Precautions May cause serious burns (eg, capsaicin exposure results in subsequent desensitization
first- to third-degree chemical burns) at the application of the sensory axons and inhibition of pain transmission
site. In some cases, hospitalization has been required. initiation. In arthritis, capsaicin induces release of sub-
Discontinue use and seek medical attention if signs of skin stance P, the principal chemomediator of pain impulses
injury (eg, pain, swelling, or blistering) occur following from the periphery to the CNS, from peripheral sensory
application (FDA Drug Safety Communication, 2012). neurons; after repeated application, capsaicin depletes
May cause CNS depression, which may impair physical the neuron of substance P and prevents reaccumulation.
or mental abilities; patients must be cautioned about The functional link between substance P and the capsai-
performing tasks that require mental alertness (eg, oper- cin receptor, TRPV1, is not well understood.
ating machinery or driving). Use with caution in patients Pharmacodynamics/Kinetics (Adult data unless
with uncontrolled hypertension, or a history of cardiovas- noted)
cular or cerebrovascular events; transient increases in Onset of action: OTC products (capsaicin 0.025% to
blood pressure due to treatment-related pain have 0.1%): 2 to 4 weeks of continuous therapy; Qutenza
occurred during and after application of RX patch. patch: 1 week after application
CAPSAICIN

Absorption: Topical patch (capsaicin 8%): Systemic Dosage Forms Excipient information presented when
absorption is transient and low (<5 ng/mL) in approx- available (limited, particularly for generics); consult spe-
imately one-third of patients when measured following cific product labeling. [DSC] = Discontinued product
60-minute application. In patients with quantifiable con- Cream, topical: f ;
centrations, most fell below the limit of quantitation at 3-6 Capzasin-HP: 0.1% (42.5 g) [contains benzyl! alcohol]
hours postapplication. Capzasin-P: 0.035% (42.5 g) [contains benzyl alcohol]
Half-life elimination: Topical patch (capsaicin 8%): 1.64 Sure Result SR Relief: 0.025% (118 mL)
hours (Babbar 2009) Trixaicin: 0.025% (60 g [DSC]) [contains benzy| alcohol]
Dosing Trixaicin HP: 0.075% (60 g) [contains benzyl alcohol]
Pediatric Zostrix HP: 0.1% (60 g) [contains benzyl alcohol]
Muscle ache and joint pain, minor: Topical: Zostrix Maximum Strength Natural Pain Relief: 0.1%
Lotion 0.025% (DiabetAid Tingling and Pain Relief) (56.6 g) [contains benzyl alcohol] :
Children 22 years and Adolescents: Topical: Apply Zostrix Maximum Strength Natural Foot Pain Relief:
to affected area not more than 3 to 4 times/day 0.1% (56.6 g) [contains benzyl alcohol]
Patch: Note: With OTC products, approved ages and Zostrix Original Strength Natural Pain Relief: 0.033%
uses may vary; consult product specific labeling. (56.6 g) [contains benzyl alcohol]
Product strength <0.05%: Adolescents 212 years: Generic: 0.025% (60 g)
Topical: Gel, topical:
Flexin (0.0375%): Apply 1 patch to affected area; Capzasin-P: 0.025% (42.5 g) [contains menthol]
may change 2 to 3 times/day; maximum daily dose: Liquid, topical:
3 patches/day eee aS aoe (29.5 mL)
i oy. otion, topical:
ae spate aad i msteal a DiabetAid Pain and Tingling Relief: 0.025% (120 mL)
maximum daily dose: 4 patches/day; do not use for Patch, topical: ‘
>5 consecutive days Aflexeril MC: 0.0375% (15s [DSC]) [contains men-
MaC (0,0375%): Apply 1 patch to affected area for thol 5%]
up to 8 hours; : change patch 2 to 3 times/day;
; : Allevess: " 0.05% (15s) [contains menthol
, 5%]
maximum daily dose: 4 patches/24 hours Aleveer: 0.0375% (15s) [contains menthol 5%, and
MenCaps
vi rai(0.0225%):
Ce Apply 1 patch to affected area
aie Bloat © 3 ores aloe] IDSC}
Captracin: F
0.0375% (15s [DSC}) [contains menthol 5%]
daily : Flexin: 0.0375% (15s) [contains menthol 5%]
: 6 ont Levatio: 0.03% (15s) [contains menthol 5%]
pan Peebichee Moat atin ack ae MaC Patch: 0.0375% (15s) [contains menthol 5%] [DSC]
times daily; maximum daily dose: 3 patches/day MenCaps: 0.0225% (15s) [contains menthol 4.5%]
us a oe °%)- Appl Neuvaxin: 0.0375% (15s [DSC]) [contains menthol 5%]
Pyramid atthe
tbrbasin oe eeeae! Qroxin: 0.0375% (15s [DSC]) [contains menthol 5%]
P mANGS the : y Qutenza: 8% (1s, 2s) [contains metal; supplied with
change patch up to 3 to 4 times daily cleansing gel]
Product strength 0.05%: Adolescents 216 years: Top- 99
Ae i f , Releevia: 0.0375% (15s) [contains menthol 5%]
ical Allevess patch APpiyijapateitoekceicd aes,
may change patch 1 to 2 times daily
Releevia MC: 0.0375% (15s) [contains menthol 5%]
: 4 Ae RelyyT: 0.025% (15s [DSC]) [contains menthol 5%]
Renal Impairment: Pediatric There are no dosage Renovo: 0.0375% (15s) [contains menthol 5%]
adjustments provided in the manufacturer’s labeling. Sinelee: 0.0375%, 0.05% (15s [DSC]) [contains men-
Hepatic Impairment: Pediatric There are no dosage thol 5%] ‘
adjustments provided in the manufacturer’s labeling. Solaice: 0.05% (15s [DSC]) [contains menthol 5%]
Administration Salonpas Gel-Patch Hot: 0.025% (3s, 6s) [contains
Topical: vite: " i ’ menthol]
Cream, gel, liquid, and lotion: Avoid contact with eyes Salonpas Hot: 0.025% (1s [DSC}) [contains natural rub-
and mucous membranes. Avoid applying on wounds, ber/natural latex in packaging]
damaged, or irritated skin. Gently rub into painful area ae
until thoroughly absorbed. Wash hands with soap and @ Capsaicin/Menthol see Capsaicin on page 357
water immediately after applying (unless hands are part
of the treatment area). If applying cream to hands, wait - ;
30 minutes before washing hands. Do not use with a Captopril vee
heating pad. Avoid direct exposure of treated area to Medication Safety Issues
heat or sunlight. Do not bandage. Sound-alike/look-alike issues:
Patch: Avoid contact with face, scalp, eyes, mouth, and Captopril may be confused with calcitriol, Capitrol, car-
mucous membranes. Avoid applying on wounds or vedilol
damaged or sensitive skin. Apply patch externally to International issues:
clean and dry affected area. Remove protective film Acepril [Great Britain] may be confused with Accupril
prior to application. May cut patch to desired size prior which is a brand name for quinapril in the US
to removing the film (product specific). Do not use Acepril: Brand name for captopril [Great Britain], but also
within 1 hour prior to a bath or immediately after bath- the brand name for enalapril [Hungary, Switzerland];
ing. Do not use with a heating pad or any compression lisinopril [Malaysia]
bandage or device. Wash hands with soap and water Therapeutic Category Angiotensin-Converting Enzyme
after applying. (ACE) Inhibitor; Antihypertensive Agent
Qutenza (capsaicin 8%): Patch should only be applied Generic Availability (US) Yes
by physician or by a healthcare professional under the Use Treatment of hypertension, heart failure, left ventricu-
close supervision of a physician. The treatment area lar dysfunction after myocardial infarction, and diabetic
must be identified and marked by a physician. The nephropathy (All indications: FDA approved in adults)
patch can be cut to match size/shape of treatment area. Pregnancy Risk Factor D
If necessary, excessive hair present on and surround- Pregnancy Considerations [US Boxed Warning]:
ing the treatment area may
: be clipped
PS (not shaved) to Drugs that act on the renin-angiotensin system can
promote adherence. Prior to application, the treatment cause injury and death to the developing fetus. Dis-
area should be cleansed with mild soap and water and continue as soon as possible once pregnancy is
dried thoroughly. The treatment area should be anes- detected. Captopril crosses the placenta (Hurault de
thetized with a topical anesthetic prior to patch appli- Ligny 1987). Drugs that act on the renin-angiotensin
cation. Anesthetic should be removed with a dry wipe system are associated with oligohydramnios. Oligohy-
and area should be cleansed again with soap/water, dramnios, due to decreased fetal renal function, may lead
and dried. Patch may then be applied to dry, intact skin to fetal lung hypoplasia and skeletal malformations. Their
within 2 hours of opening the sealed patch; apply patch use in pregnancy is also associated with anuria, hypo-
using nitrile gloves (latex gloves should NOT be used). tension, renal failure, skull hypoplasia, and death in the
During application, slowly peel back the release liner fetus/neonate. Teratogenic effects may occur following
under the patch. Patch should remain in place for 60 maternal use of an ACE inhibitor during the first trimester,
minutes. Do not touch the patch while it is on the skin. although this finding may be confounded by maternal
Remove patches gently and slowly. Following patch disease. Because adverse fetal events are well docu-
removal, apply cleansing gel to the treatment area mented with exposure later in pregnancy, ACE inhibitor
and leave in place for at least 1 minute. All treatment use in pregnant women is not recommended (Seely 2014;
materials should be disposed of according to biomed- Weber 2014). Infants exposed to an ACE inhibitor in utero
ical waste procedures. should be monitored for hyperkalemia, hypotension, and
Monitoring Parameters Qutenza: Blood pressure peri- oliguria. Oligohydramnios may not appear until after irre-
odically versible fetal injury has occurred. Exchange transfusions

358
 CAPTOPRIL

or dialysis may be required to reverse hypotension or injury and death to the developing fetus. Discontinue
improve renal function, although data related to the effec- as soon as possible once pregnancy is detected.
tiveness in neonates is limited.
Hyperkalemia may occur with ACE inhibitors; risk factors
Chronic maternal hypertension itself is also associated include renal dysfunction, diabetes mellitus, concomitant
with adverse events in the fetus/infant and mother. ACE use of potassium-sparing diuretics, potassium supple-
inhibitors are not recommended for the treatment of ments and/or potassium containing salts. Use cautiously,
uncomplicated hypertension in pregnancy (ACOG 2013) if at all, with these agents and monitor potassium closely.
and they are specifically contraindicated for the treatment Cough may occur with ACE inhibitors. Other causes of
of hypertension and chronic heart failure during pregnancy cough should be considered (eg, pulmonary congestion in
by some guidelines (Regitz-Zagrosek 2011). In addition,
patients with heart failure) and excluded prior to discontin-
ACE inhibitors should generally be avoided in women of
uation.
reproductive age (ACOG 2013). If treatment for hyper-
tension or chronic heart failure in pregnancy is needed, May be associated with deterioration of renal function and/
other agents should be used (ACOG 2013; Regitz-Zagro- or increases in BUN and serum creatinine, particularly in
sek 2011). patients with low renal blood flow (eg, renal artery steno-
Breastfeeding. Considerations Captopril is present in sis, heart failure) whose GFR is dependent on efferent
breast milk. Concentrations of captopril in breast milk are arteriolar vasoconstriction by angiotensin II; deterioration
~1% of those in maternal blood. According to the manu- may result in oliguria, acute renal failure, and progressive
facturer, the decision to continue or discontinue breast- azotemia. Small benign increases in serum creatinine may
feeding during therapy should take into account the risk of occur following initiation; consider discontinuation only in
exposure to the infant and the benefits of treatment to the
patients with progressive and/or significant deterioration in
mother. Some guidelines consider captopril to be accept-
renal function (Bakris 2000). Use with caution in patients
able for use in breastfeeding women. Monitoring of the
with unstented unilateral/bilateral renal artery stenosis.
breastfeeding child's weight for the first 4 weeks is rec-
When unstented bilateral renal artery stenosis is present,
ommended (Regitz-Zagrosek 2011).
use is generally avoided due to the elevated: risk of
Centraindications
deterioration in renal function unless possible benefits
Hypersensitivity to captopril, any other ACE inhibitor, or
any component of the formulation; angioedema related outweigh risks. ACE inhibitors effectiveness is less in
to previous treatment with an ACE inhibitor; concomitant black patients than in non-blacks. In addition, ACE inhib-
use with aliskiren in patients with diabetes mellitus; itors cause a higher rate of angioedema in black than in
coadministration with or within 36 hours of switching to non-black patients. Potentially significant drug-drug inter-
or from a neprilysin inhibitor (eg, sacubitril). actions may exist, requiring dose or frequency adjustment,
Canadian labeling: Additional contraindications (not in US additional monitoring, and/or selection of alternative
labeling): Concomitant use with aliskiren in patients with therapy.
moderate to severe renal impairment (GFR <60 mL/
In patients on chronic ACE inhibitor therapy, intraoperative
minute/1.73 m?).
hypotension may occur with induction and maintenance of
Warnings/Precautions Anaphylactic reactions may
general anesthesia; use with caution before, during, or
occur rarely with ACE inhibitors. At any time during treat-
ment (especially following first dose) angioedema may immediately after major surgery. Cardiopulmonary
occur rarely with ACE inhibitors; may involve the head bypass, intraoperative blood loss, or vasodilating anes-
and neck (potentially compromising airway) or the intes- thesia increases endogenous renin release. Use of ACE
tine (presenting with abdominal pain). African-Americans inhibitors perioperatively will blunt angiotensin I! formation
and patients with idiopathic or hereditary angioedema may and may result in hypotension. However, discontinuation
be at an increased risk. Risk may also be increased with of therapy prior to surgery is controversial. If continued
concomitant use of mTOR inhibitor (eg, everolimus) ther- preoperatively, avoidance of hypotensive agents during
apy or a neprilysin inhibitor (eg, sacubitril). Prolonged surgery is prudent (Hillis 2011). Based on current research
frequent monitoring may be required especially if tongue, and clinical guidelines in patients undergoing non-cardiac
glottis, or larynx are involved as they are associated with surgery, continuing ACE inhibitors is reasonable in the
airway obstruction. Patients with a history of airway sur- perioperative period. If ACE inhibitors are held before
gery may have a higher risk of airway obstruction. Aggres- surgery, it is reasonable to restart postoperatively as soon
sive early and appropriate management is critical. Use in as clinically feasible (ACC/AHA [Fleisher 2014]).
patients with previous angioedema associated with ACE
inhibitor therapy is contraindicated. Severe anaphylactoid Avoid use in patients with ascites due to cirrhosis or
reactions may be seen during hemodialysis (eg, CVVHD) refractory ascites; if use cannot be avoided in patients
with high-flux dialysis membranes (eg, AN69), and rarely, with ascites due to cirrhosis, monitor blood pressure and
during low density lipoprotein apheresis with dextran renal function carefully to avoid rapid development of renal
sulfate cellulose. Rare cases of anaphylactoid reactions failure (AASLD [Runyon 2012]). Rare toxicities associated
have been reported in patients undergoing sensitization with ACE inhibitors include cholestatic jaundice (which
treatment with hymenoptera (bee, wasp) venom while may progress to fulminant hepatic necrosis, some fatal),
receiving ACE inhibitors. agranulocytosis, neutropenia with myeloid hypoplasia;
Symptomatic hypotension with or without syncope can
anemia and thrombocytopenia have also occurred. If
occur with ACE inhibitors (usually with the first several neutropenia develops (neutrophil count <1,000/mm‘), dis-
doses); effects are most often observed in volume continue therapy. Patients with collagen vascular diseases
depleted patients; close monitoring of patient is required (especially with concomitant renal impairment) or renal
especially with initial dosing and dosing increases; blood impairment alone may be at increased risk for hematologic
pressure must be lowered at a rate appropriate for the toxicity; closely monitor CBC with differential for the first 3
patient's clinical condition. Initiation of therapy in patients months of therapy and periodically thereafter in these
with ischemic heart disease or cerebrovascular disease patients. Total urinary proteins >1 g per day have been
warrants close observation due to the potential conse- reported (<1%); nephrotic syndrome occurred in about
quences posed by falling blood pressure (eg, MI, stroke). one-fifth of proteinuric patients. In most cases, proteinuria
Use with caution in hypertrophic cardiomyopathy with subsided or cleared within six months (whether or not
outflow tract obstruction (ACCF/AHA [Gersh 2011]). Use captopril was continued).
with caution in seyere aortic stenosis. In patients on Warnings: Additional Pediatric Considerations Neo-
chronic ACE inhibitor therapy, intraoperative hypotension nates and young infants appear to be more sensitive to
may occur with induction and maintenance of general adverse effects (Gantenbein 2008). ACE inhibitors have
anesthesia; use with caution before, during, or immedi- been associated with nephrotoxicity in neonates; risk may
ately after major surgery. Cardiopulmonary bypass, intra- be higher in preterm neonates; a retrospective study
operative blood loss, or vasodilating anesthesia increases
evaluated ACE inhibitor (captopril or enalapril) nephrotox-
endogenous renin release. Use of ACE inhibitors perio-
icity in 206 neonates (term [n=168] and preterm [n=38])
peratively will blunt angiotensin I! formation and may result
with cardiovascular disease; nearly 42% of neonates were
in hypotension. However, discontinuation of therapy prior
to surgery is controversial. If continued preoperatively, in the pRIFLE (pediatric risk, injury, failure, loss, and end-
avoidance of hypotensive agents during surgery is pru- stage renal disease) category of risk or higher; 30% of all
dent (Hillis 2011). Extemporaneous preparations of liquid patients were in the renal failure category; when sepa-
formulations may vary; this may affect the rate and extent rated out into term and preterm, >50% of preterm neo-
of absorption causing intrapatient variability regarding nates were in the renal failure category while receiving an
dosing and safety, profile for the patient; use with caution ACE inhibitor and were significantly more likely to be in the
and monitor closely if dosage formulations are changed renal failure category compared to term neonates (Lindle
(Bhatt 2011; Mulla 2007). [US Boxed Warning]: Drugs 2014). Initiate dosing at lower end of the range in preterm .
that act on the renin-angiotensin system can cause neonates.

359
 CAPTOPRIL

4 An observational study of 66 pediatric patients with heart

failure reported hypotension in 15% of patients during
Weight); Herbs (Hypotensive Properties); Imatinib; Loop
Diuretics; Lormetazepam; Lumefantrine; Molsidomine;
therapy initiation at typical starting doses; close monitoring Naftopidil; Nicergoline; Nicorandil; Obinutuzumab; Pan-
in an inpatient setting and low starting doses has been obinostat; Peginterferon Alfa-2b; Pentoxifylline; Perhexi-
suggested in these patients (Momma 2006; line; Phosphodiesterase 5 Inhibitors; Potassium Salts;
Orchard 2010). Potassium-Sparing Diuretics; Prostacyclin Analogues;
An ACE inhibitor cough is a dry, hacking, nonproductive Quinagolide; QuiNINE; Salicylates; Sirolimus; Temsiroli-
one that usually occurs within the first few months of mus; Thiazide and Thiazide-Like Diuretics; TiZANidine;
treatment and should generally resolve within 1 to 4 weeks Tolvaptan; Trimethoprim
after discontinuation of the ACE inhibitor; in pediatric Decreased Effect
patients, an isolated dry hacking cough lasting >3 weeks The levels/effects of Captopril may be decreased by:
was reported in seven of 42 pediatric patients (17%) Amphetamines; Antacids; Aprotinin; Brigatinib; Bromper-
receiving ACE inhibitors (von Vigier 2000); a review of idol; Herbs (Hypertensive Properties); Icatibant; Lantha-
pediatric randomized-controlled ACE inhibitor trials num; Methylphenidate; Nonsteroidal Anti-Inflammatory
reported a lower incidence of 3.2% (Baker-Smith 2010). Agents; Peginterferon Alfa-2b; Salicylates; Yohimbine
Other causes of cough should be considered (eg, pulmo- Food Interactions Captopril serum concentrations may
nary congestion in patients with heart failure) and
be decreased if taken with food. Long-term use of capto-
excluded prior to discontinuation.
pril may lead to a zine deficiency which can result in
Adverse Reactions
altered taste perception. Management: Take on an empty
Cardiovascular: Angina pectoris, cardiac arrest, cardiac
stomach 1 hour before or 2 hours after meals.
arrhythmia, cardiac failure, chest pain, flushing, hypo-
tension, myocardial infarction, orthostatic hypotension, Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
palpitations, Raynaud's phenomenon, syncope, tachy- protect from moisture.
cardia Mechanism of Action Competitive inhibitor of angioten-
Central nervous system: Ataxia, cerebrovascular insuffi- sin-converting enzyme (ACE); prevents conversion of
ciency, confusion, depression, drowsiness, myasthenia, angiotensin | to angiotensin II, a potent vasoconstrictor;
nervousness results in lower levels of angiotensin Il which causes an
Dermatologic: Bullous pemphigoid, erythema multiforme, increase in plasma renin activity and a reduction in
exfoliative dermatitis, pallor, pruritus, skin rash (maculo- aldosterone secretion.
papular or urticarial; in patients with rash, a positive ANA Pharmacodynamics/Kinetics (Adult data unless
and/or eosinophilia has been noted), Stevens-Johnson noted)
syndrome
Onset of action: Within 15 minutes; Peak effect: Blood
Endocrine & metabolic: Gynecomastia, hyperkalemia,
pressure reduction: 1 to 1.5 hours after dose
hyponatremia (symptomatic)
Maximum effect: Antihypertensive: 60 to 90 minutes; may
Gastrointestinal: Cholestasis, dysgeusia (loss of taste or
diminished perception), dyspepsia, glossitis, pancreatitis require several weeks of therapy before full hypotensive
Genitourinary: Impotence, nephrotic syndrome, oliguria, effect is seen
proteinuria, urinary frequency Duration: Dose related, may require several weeks of
Hematologic: Agranulocytosis, anemia, neutropenia (in therapy before full hypotensive effect
patients with renal insufficiency or collagen-vascular Absorption: 60% to 75%; rapid
disease), pancytopenia, thrombocytopenia Distribution: Vgsg: 0.7 L/kg (Duchin 1982)
Hepatic: Hepatic necrosis (rare), hepatitis, increased Bioavailability: ~60% to 75% (Kubo 1985); reduced 30%
serum alkaline phosphatase, increased serum bilirubin, to 40% by food
increased serum transaminases, jaundice Protein binding: 25% to 30%
Hypersensitivity: Anaphylactoid reaction, angioedema, Metabolism: 50% metabolized
hypersensitivity reaction (rash, pruritus, fever, arthralgia, Half-life elimination:
and eosinophilia; depending on dose and renal function) Infants with CHF: 3.3 hours; range: 1.2 to 12.4 hours
Neuromuscular & skeletal: Myalgia, weakness (Pereira 1991)
Ophthalmic: Blurred vision
Children: 1.5 hours; range: 0.98 to 2.3 hours (Levy 1991)
Renal: Increased serum creatinine, polyuria, renal failure,
Adults, healthy volunteers: ~1.7 hours (Duchin 1982). In
renal insufficiency, renal insufficiency (worsening; may
2 studies, patients with chronic renal failure demon-
occur in patients with bilateral renal artery stenosis or
strated ~2-fold longer half-lives as compared to normal
hypovolemia)
Respiratory: Bronchospasm, cough, eosinophilic pneumo- subjects (Giudicelli 1984; Onoyama 1981). Half-life
nitis, rhinitis was up to 21 hours in patients with severe renal impair-
Rare but important or life-threatening: Alopecia, angina ment and up to 32 hours in patients on chronic hemo-
pectoris, anorexia, aphthous stomatitis, aplastic anemia, dialysis in another study (Duchin 1984)
cholestatic jaundice, eosinophilia, glomerulonephritis, Time to peak: Within 1 to 2 hours
Guillain-Barre syndrome, hemolytic anemia, Hunting- Excretion: Urine (>95%) within 24 hours (40% to 50% as
ton's chorea (exacerbation), hyperthermia, increased unchanged drug)
erythrocyte sedimentation rate, insomnia, interstitial Dosing
nephritis, Kaposi's sarcoma, peptic ulcer, pericarditis, Neonatal Note: Review dosing closely; due to pharma-
psoriasis, seizure (in premature infants), systemic lupus cokinetic immaturity, premature neonates or very young
erythematosus, vasculitis, visual hallucination (ie, PNA <7 days) term neonates require a much lower
(Doane, 2013) dose (in some cases 10 times lower dose); use extra
Drug Interactions precaution to ensure appropriate dosing.
Metabolism/Transport Effects Substrate of CYP2D6 Heart failure (afterload reduction); hypertension:
(major); Note: Assignment of Major/Minor substrate sta- Limited data available: Note: Reserve use in neonates
tus based on Clinically relevant drug interaction potential
with a clear indication for ACE inhibitor therapy; in
Avoid Concomitant Use
neonates (particularly premature), captopril use is fre-
Avoid concomitant use of Captopril with any of the
quently associated with acute kidney injury (including
following: Bromperidol; Sacubitril
renal failure in some instances) even when utilized at
Increased Effect/Toxicity
Captopril may increase the levels/effects of: Allopurinol;
standard doses in neonates (Gantenbein 2008; Lindle
Amifostine; Angiotensin II; Antipsychotic Agents (Second 2014). Dosage must be titrated according to patient's
Generation [Atypical]); AzaTHlOprine; Bromperidol; Dro- response; use lowest effective dose; lower doses (~1/2
spirenone; DULoxetine; Ferric Gluconate; Ferric Hydrox- of those listed) should be used in patients who are
ide Polymaltose Complex; Gelatin (Succinylated); Gold sodium and water depleted due to diuretic therapy.
Sodium Thiomalate; Grass Pollen Allergen Extract (5 Premature neonates: Oral: Initial: 0.01 mg/kg/dose
Grass Extract); Hypotension-Associated Agents; Iron every 8 to 12 hours; titrate dose as needed; usual
Dextran Complex; Levodopa; Lithium; Nitroprusside; range: 0.01 to 0.05 mg/kg/dose every 8 to 12 hours
Nonsteroidal Anti-Inflammatory Agents; Perhexiline; (Eichenwald 2017; O'Dea 1988)
Pholcodine; Pregabalin; Sacubitril; Sodium Phosphates Term neonates (Artman 1987; Eichenwald 2017; Flynn
The levels/effects of Captopril may be increased by: 2000; Friedman 1985):
Abiraterone Acetate; Ajmaline; Alfuzosin; Aliskiren; PNA <7 days: Oral: Initial: 0.01 mg/kg/dose every 8 to
Angiotensin || Receptor Blockers; Asunaprevir; Barbitu- 12 hours; titrate dose as needed; usual range: 0.01
rates; Benperidol; Brigatinib; Brimonidine (Topical); Can- to 0.05 mg/kg/dose every 8 to 12 hours (Eichen-
agliflozin; Cobicistat; CYP2D6 Inhibitors (Moderate); wald 2017)
CYP2D6 Inhibitors (Strong); Dapoxetine; Darunavir; PNA >7 days: Oral: Initial: 0.05 to 0.1 mg/kg/dose
Diazoxide; Dipeptidyl Peptidase-IV Inhibitors; Eplere- every 8 to 24 hours; titrate dose upward to maximum
none; Everolimus; Heparin; Heparins (Low Molecular of 0.5 mg/kg/dose every 6 to 24 hours

360
 CARBAMAZEPINE

Pediatric @ Captracin [DSC] see Capsaicin on page 357

Heart failure (afterload reduction): Limited data avail- @ Capzasin-HP [OTC] see Capsaicin on page 357
able: Note: Initiate therapy at lower end of range and
@ Capzasin-P [OTC] see Capsaicin on page 357
titrate upward to prevent symptomatic hypotension
(Momma 2006): @ Carafate see Sucralfate on page 1870
Infants: Oral: Initial: 0.1 to 0.3 mg/kg/dose every 6 to 24 @ Carbaglu see Carglumic Acid on page 370
hours; titrate as needed; reported daily dose range:
0.3 to 3.5 mg/kg/day divided every 6 to 12 hours;
maximum daily dose: 6 mg/kg/day (Artman 1987; CarBAMazepine (kar ba MAZ e peen)
Park 2014; Scammell 1987; Shaw 1988) Medication Safety Issues
Children and Adolescents: Oral: Initial: 0.3 to
Sound-alike/look-alike issues:
0.5 mg/kg/dose every 8 to 12 hours; titrate as
CarBAMazepine may be confused with OXcarbazepine
needed; in clinical trials, usual reported dosage range
Epitol may be confused with Epinal
was 0.9 to 3.9 mg/kg/day in divided doses; maximum
TEGretol, TEGretol-XR may be confused with Mebaral,
daily dose: 6 mg/kg/day (Artman 1987; Momma
Toprol-XL, Toradol, TRENtal
2006; Park 2014); in adults, the target dose is
High alert medication:
150 mg/day (ACCF/AHA [Yancy 2013])
The Institute for Safe Medication Practices (ISMP)
Hypertension: Limited data available: Note: Dosage
includes this medication among its list of drugs that
must be titrated according to patient's response; use
have a heightened risk of causing significant patient
lowest effective dose; lower doses (~1/2 of those listed)
harm when used in error.
should be used in patients who are sodium- and water-
Geriatric Patients: High-Risk Medication:
depleted due to diuretic therapy
Beers Criteria: Carbamazepine is identified in the Beers
Weight-directed dosing:
Criteria as a potentially inappropriate medication to be
Infants: Oral: Initial: 0.05 mg/kg/dose every 6 to 24
used with caution in patients 65 years and older due to
hours (AAP [Flynn 2017]); higher initial doses of
the potential to cause or exacerbate syndrome of
0.15 to 0.3 mg/kg/dose every 6 to 24 hours have
inappropriate antidiuretic hormone secretion (SIADH)
been recommended by some experts and may be
or hyponatremia; monitor sodium concentration closely
needed in patients with severe hypertension (Mirkin
when initiating or adjusting the dose in older adults
1985; Park 2014); titrate dose carefully upward as
(Beers Criteria [AGS 2015)).
needed to maximum of.6 mg/kg/day; monitor for
hypotension (AAP [Flynn 2017]; Park 2014) Related Information
Children and Adolescents: Oral: Initial: 0.3 to Oral Medications That Should Not Be Crushed or Altered
0.5 mg/kg/dose every 8 hours; may titrate as on page 2217
needed up to maximum daily dose: 6 mg/kg/day in Brand Names: US Carbatrol; Epitol; Equetro; TEGretol;
3 divided doses (AAP [Flynn 2017]; NHLBI 2012); TEGretol-xR
maximum daily dose: 450 mg/day Brand Names: Canada Mazepine; Tegretol
Fixed dosing: Adolescents: Oral: Initial: 12.5 to 25 mg/ Therapeutic Category Anticonvulsant, Miscellaneous
dose every 8 to 12 hours; increase by 25 mg/dose at Generic Availability (US) Yes
1- to 2-week intervals based on patient response; Use
maximum daily dose: 450 mg/day (Park 2014) Carbatrol, Epitol, Tegretol, Tegretol-XR: Treatment of gen-
Renal Impairment: Pediatric Infants, Children, and eralized tonic-clonic, partial (especially complex partial),
Adolescents: The following adjustments have been rec- and mixed partial or generalized seizure disorder (Car-
ommended (Aronoff 2007). Note: Renally adjusted dose batrol, Tegretol: FDA approved in pediatric patients [age
recommendations are based on doses of 0.1 to not specified] and adults; Tegretol-XR: FDA approved in
0.5 mg/kg/dose every 6 to 8 hours; maximum daily dose: ages 26 years and adults); relief of pain in trigeminal
6 mg/kg/day. neuralgia or glossopharyngeal neuralgia (Carbatrol,
GFR 10 to 50 mL/minute/1.73. m?: Administer 75% Epitol, Tegretol, Tegretol XR: FDA approved in adults)
of dose Equetro: Treatment of acute manic and mixed episodes
GFR <10 mL/minute/1.73 m2: Administer 50% of dose associated with bipolar | disorders (FDA approved in
Intermittent hemodialysis: Administer 50% of dose adults)
Peritoneal dialysis (PD): Administer 50% of dose Medication Guide Available Yes
Continuous renal replacement therapy (CRRT): Admin- Pregnancy Risk Factor D (product specific)
ister 75% of dose Pregnancy Considerations Studies in pregnant women
Hepatic Impairment: Pediatric There are no dosage have demonstrated a risk to the fetus. Carbamazepine
adjustments provided in the manufacturer's labeling (has and its metabolites can be found in the fetus and may be
not been studied). associated with teratogenic effects, including spina bifida,
Administration Oral: Administer on an empty stomach 1 craniofacial defects, cardiovascular malformations, and
hour before or 2 hours after meals/feeds; if crushing tablet hypospadias. The risk of teratogenic effects is higher with
and dissolving in water, allow adequate time for complete anticonvulsant polytherapy than monotherapy.
dissolution (>10 minutes) (Bhatt 2011)
Monitoring Parameters Blood pressure, BUN, serum Developmental delays have also been observed following
creatinine, renal function, urine dipstick for protein, serum in utero exposure to carbamazepine (per manufacturer);
potassium, WBC with differential, especially during first 3 however, socioeconomic factors, maternal and paternal
months of therapy for patients with renal impairment and/ !Q, and polytherapy may contribute to these findings.
or collagen vascular disease; monitor for angioedema and Pregnancy may cause small decreases of carbamazepine
anaphylactoid reactions; hypovolemia, postural hypoten- plasma concentrations in the second and third trimesters;
sion, and neurologic status when beginning therapy, monitoring should be considered. When used for the
adjusting dosage, and on a regular basis throughout treatment of bipolar disorder, use of carbamazepine
Test Interactions Positive Coombs' [direct]; may cause should be avoided during the first trimester of pregnancy
false-positive results in urine acetone determinations if possible. The use of a single medication for the treat-
using sodium nitroprusside reagent; may lead to false- ment of bipolar disorder or epilepsy in pregnancy is
negative aldosterone/renin ratio (ARR) (Funder 2016) preferred. Carbamazepine may decrease plasma concen-
Dosage Forms Excipient information presented when trations of hormonal contraceptives; breakthrough bleed-
ing or unintended pregnancy may occur and alternate or
available (limited, particularly for generics); consult spe-
cific product labeling. back-up methods of contraception should be considered.
Tablet, Oral: Patients exposed to carbamazepine during pregnancy are
Generic: 12.5 mg, 25 mg, 50 mg, 100 mg encouraged to enroll themselves into the AED Pregnancy
Extemporaneous Preparations 1 mg/mL Oral Solu- Registry by calling 1-888-233-2334. Additional information
tion (ASHP Standard Concentration) (ASHP 2017) is available at www.aedpregnancyregistry.org.
A 1mg/mL oral solution may be made by allowing two Breastfeeding Considerations Carbamazepine and its
50 mg tablets to dissolve in 50 mL of distilled water. Add active epoxide metabolite are found in breast milk. Carba-
the contents of one 500 mg sodium ascorbate injection mazepine can also be detected in the serum of nursing
ampul or one 500 mg ascorbic acid tablet and allow to infants. Transient hepatic dysfunction has been observed
dissolve. Add quantity of distilled water sufficient to make in some case reports. Nursing should be discontinued if
100 mL. Label "shake well" and "refrigerate." Stable for adverse events are observed. According to the manufac-
56 days refrigerated or 28 days (ascorbic acid tablet) or turer, the decision to continue or discontinue breastfeed-
14 days (sodium ascorbate injection) at room temper- ing during therapy should take into account the risk of
ature. exposure to the infant and the benefits of treatment to the
Nahata MC, Morosco RS, Hipple TF.. Stability of captopril in liquid mother. Respiratory depression, seizures, nausea, vomit-
containing ascorbic acid or sodium ascorbate. Am J Hosp Pharm.
1994;51(13):1707-1708. ing, diarrhea, and/or decreased feeding have been
observed in neonates exposed to carbamazepine in utero
»
Nahata MC, Morosco RS, Hipple TF. Stability of captopril in three liquid
dosage forms. Am J Hosp Pharm. 1994;51(1):95-96. and may represent a neonatal withdrawal syndrome.

361
CARBAMAZEPINE

Contraindications for ECG abnormalities). Use with caution in patients with

Hypersensitivity to carbamazepine, tricyclic antidepres- hepatic impairment; avoid use in patients with hepatic
sants, or any component of the formulation; bone mar- porphyria (eg, acute intermittent porphyria, variegate por-
row depression; with or within 14 days of MAO inhibitor phyria, porphyria cutanea tarda). Use with caution in
use; concomitant use of nefazodone or boceprevir; con- patients with renal impairment. Avoid use of IV product
comitant use of delavirdine or other non-nucleoside in moderate or severe renal impairment. Renal toxicity has
reverse transcriptase inhibitors that are substrate of been reported; monitor renal function at baseline and
CYP3A4 periodically thereafter. Hepatotoxicity ranging from slight
Canadian labeling: Additional contraindications (not in US elevations in liver enzymes to rare hepatic failure has
labeling): Atrioventricular (AV) heart block; hepatic dis- been reported and may occur concomitantly with other
ease; history of hepatic porphyria (acute intermittent immunoallergenic syndromes such as multiorgan hyper-
porphyria, variegate porphyria, porphyria cutanea tarda); sensitivity (DRESS syndrome) and serious. dermatologic
serious blood disorder; concurrent use with itraconazole reactions including Stevens-Johnson syndrome; monitor
and voriconazole baseline and periodic liver function, particularly in patients
Warnings/Precautions [US Boxed Warning]: The risk with a history of liver disease; discontinue carbamazepine
of developing anemia or agranulocytosis is increased immediately in cases of aggravated liver dysfunction or
during treatment. Complete pretreatment hematolog- active liver disease. In some cases, hepatic effects may
ical testing should be obtained prior to use; monitor progress despite discontinuation of carbamazepine. Rare
patient closely if white blood cells or platelet counts cases of a hepatic failure and vanishing bile duct syn-
decrease during therapy; discontinue if significant drome involving destruction and disappearance of the
bone marrow suppression occurs. A spectrum of hem- intrahepatic bilesducts have been reported. Clinical
atologic effects has been reported with use (eg, agranu- courses of vanishing bile duct syndrome have been var-
locytosis, aplastic anemia, neutropenia, leukopenia, iable ranging from fulminant to indolent. May activate
thrombocytopenia, pancytopenia, and anemias); patients latent psychosis and/or cause confusion or agitation;
with a previous history of adverse hematologic reaction to elderly patients may be at an increased risk for psychiatric
any drug may be at increased risk. Early detection of effects.
hematologic change is important; advise patients of early Carbamazepine is not effective in absence, myoclonic, or
signs and symptoms including fever, sore throat, mouth
akinetic seizures; carbamazepine administration may
ulcers, infections, easy bruising, and petechial or purpuric
increase the frequency of seizures in patients with these
hemorrhage.
types of seizures. Exacerbation of certain seizure types
[US Boxed Warning]: Severe and sometimes fatal have been seen after initiation of carbamazepine therapy
dermatologic reactions, including toxic epidermal in children with mixed seizure disorders. Anticonvulsants
necrolysis (TEN) and Stevens-Johnson syndrome should not be discontinued abruptly because of the pos-
(SJS), may occur during therapy. The risk is increased sibility of increasing seizure frequency; therapy should be
in patients with the variant HLA-B*1502 allele, found withdrawn gradually to minimize the potential of increased
most often in patients of Asian ancestry. Patients with seizure frequency, unless safety concerns require a more
an increased likelihood of carrying this allele should rapid withdrawal. May cause CNS depression, which may
be screened prior to initiating therapy. Avoid use in impair physical or mental abilities; patients must be cau-
patients testing positive for the allele; discontinue tioned about performing tasks which require alertness (eg,
therapy in patients who have a serious dermatologic operating machinery or driving). Potentially significant
reaction. The risk of SUS or TEN may also be increased if interactions may exist, requiring dose or frequency adjust-
carbamazepine is used in combination with other antiepi- ment, additional monitoring, and/or selection of alternative
leptic drugs associated with these reactions. Presence of therapy. Carbamazepine has mild anticholinergic activity;
the HLA-B*1502 allele has not been found to predict the use with caution in patients with increased intraocular
risk of less serious dermatologic reactions such as anti- pressure, or sensitivity to anticholinergic effects. Hypona-
convulsant hypersensitivity syndrome or nonserious rash. tremia caused by the syndrome of inappropriate antidiu-
[US Boxed Warning]: Patients with an increased like- retic hormone secretion (SIADH) may occur during
lihood of carrying the HLA-B*1502 allele, such as those therapy. Risk may be increased in the elderly or in patients
of Asian descent, should be screened for the variant also taking diuretics and may be dose-dependent. Con-
HLA-B*1502 allele prior to initiating therapy. This sider discontinuing therapy in patients with symptomatic
genetic variant has been associated with a signifi- hyponatremia.
cantly increased risk of developing Stevens-Johnson
Administration of the suspension will yield higher peak and
syndrome and/or toxic epidermal necrolysis. Patients
lower trough serum levels than an equal dose of the tablet
with a positive result should not be started on carba-
form; consider a lower starting dose given more frequently
mazepine. The risk of developing a hypersensitivity reac-
(same total daily dose) when using the suspension. The
tion may be increased in patients with the variant HLA-
suspension may contain sorbitol; avoid use in patents with
A*3101 allele. These hypersensitivity reactions include
hereditary fructose intolerance. Vials of the injectable
SJS/TEN, maculopapular eruptions, and drug reaction
product contain the excipient cyclodextrin (Sulfobutylether
with eosinophilia and systemic symptoms (DRESS/multi-
beta-cyclodextrin), which may accumulate in patients with
organ hypersensitivity). The HLA-A*3107 allele may occur
renal insufficiency, although the clinical significance of this
more frequently patients of African-American, Arabic,
finding is uncertain (Luke 2010).
Asian, European, Indian, Latin American, and Native
Warnings: Additional Pediatric Considerations Sub-
American ancestry. Hypersensitivity has also been
stitution of Tegretol with generic carbamazepine has
reported in patients experiencing reactions to other anti-
resulted in decreased carbamazepine levels and
convulsants; the history of hypersensitivity reactions in the
increased seizure activity, as well as increased carbama-
patient or their immediate family members should be
zepine levels and toxicity. Monitoring of carbamazepine
reviewed. Approximately 25% to 30% of patients allergic
serum concentrations is mandatory when patients are
to carbamazepine will also have reactions with oxcarba-
switched from any product to another.
zepine. Also, rare cases of anaphylaxis and angioedema
have been reported (may be fatal); may occur after first Some dosage forms may contain propylene glycol; in
dose or subsequent doses. Discontinue therapy if symp- neonates large amounts of propylene glycol delivered
toms occur. Do not rechallenge patients if such reactions orally, intravenously (eg, >3,000 mg/day), or topically
occur; initiate alternative treatment. Potentially serious, have been associated with potentially fatal toxicities which
sometimes fatal multiorgan hypersensitivity reactions can include metabolic acidosis, seizures, renal failure, and
(also known as drug reaction with eosinophilia and sys- CNS depression; toxicities have also been reported in
temic symptoms [DRESS]) have been reported with some children and adults including hyperosmolality, lactic acido-
antiepileptic drugs including carbamazepine; monitor for sis, seizures and respiratory depression; use caution
signs and symptoms of possible disparate manifestations (AAP, 1997; Shehab, 2009).
associated with lymphatic, hepatic, renal, and/or hemato- Adverse Reactions
logic organ systems; gradual discontinuation and conver- Cardiovascular: Arterial insufficiency (cerebral artery),
sion to alternate therapy may be required. atrioventricular block, cardiac arrhythmia, cardiac failure,
Antiepileptics are associated with an increased risk of
collapse, coronary artery disease (aggravation), edema,
suicidal behavior/thoughts with use (regardless of indica- exacerbation of hypertension, hypertension, hypoten-
tion); risk observed as early as 1 week after initiation and
sion, pulmonary embolism, syncope, thromboembolism,
thrombophlebitis
continued through duration of trials (most trials <24
weeks). Monitor all patients for signs/symptoms of depres- Central nervous system: Abnormality in thinking, agitation,
ataxia, chills, confusion, depression, dizziness, drowsi-
sion, suicidal tendencies, and other unusual behavior
ness, fatigue, headache, hyperacusis, involuntary body
changes during therapy and instructed to inform their
healthcare provider immediately if symptoms occur.
movements, neuroleptic malignant syndrome, paresthe-
sia, peripheral neuritis, speech disturbance, talkative-
Administer carbamazepine with caution to patients with ness, twitching, unsteadiness, vertigo, visual
history of cardiac damage or ECG abnormalities (or at risk hallucination

362
 CARBAMAZEPINE

Dermatologic: Acute generalized exanthematous pustulo- Rotigotine; Selective Serotonin Reuptake Inhibitors;
sis, alopecia, diaphoresis, dyschromia, erythema multi- Thalidomide
forme, erythema nodosum, erythematous rash,
The levels/effects of CarBAMazepine may be increased
exfoliative dermatitis, maculopapular rash, onychomad-
by: Allopurinol; Brimonidine (Topical); Brivaracetam; Bro-
esis, pruritic rash, pruritus, skin photosensitivity, skin
mopride; Calcium Channel Blockers (Nondihydropyri-
rash, Stevens-Johnson syndrome, toxic epidermal nec-
dine); Cannabis; Carbonic Anhydrase Inhibitors;
rolysis, urticaria
Chloramphenicol (Ophthalmic); Chlorphenesin Carba-
Endocrine & metabolic: Acute porphyria, albuminuria,
mate; Cimetidine; Ciprofloxacin (Systemic); Clarithromy-
decreased serum calcium, glycosuria, hirsutism, hypo-
cin; Conivaptan; CYP3A4 Inhibitors (Moderate);
natremia, porphyria cutanea tarda, porphyria (variegate),
CYP3A4 Inhibitors (Strong); Danazol; Darunavir; Dime-
SIADH
thindene (Topical); Dipyrone; Doxylamine; Dronabinol;
Gastrointestinal: Abdominal pain, anorexia, constipation,
Droperidol; Erythromycin (Systemic); Fluconazole;
diarrhea, gastric distress, glossitis, nausea, pancreatitis,
FLUoxetine; FluvoxaMINE; Fusidic Acid (Systemic);
stomatitis, vomiting, xerostomia,
Grapefruit Juice; HydrOXYzine; Idelalisib; Isoniazid;
Genitourinary: Acute urinary retention, azotemia, defec-
Kava Kava; LamoTRigine; LevETIRAcetam; Lofexidine;
tive spermatogenesis, impotence, microscopic urine
Loxapine; Magnesium Sulfate; Methotrimeprazine; Min-
deposits, oliguria, reduced fertility (male), urinary fre-
ocycline; Nabilone; Nefazodone; Oxomemazine; Proma-
quency'
zine; Protease Inhibitors; QUEtiapine; QuiNINE;
Hematologic & oncologic: Adenopathy, agranulocytosis,
Resveratrol; Sodium Oxybate; Stiripentol; Tapentadol;
aplastic anemia, bone marrow depression, eosinophilia,
Telaprevir; Tetrahydrocannabinol; Thiazide and Thia-
hypogammaglobulinemia, leukocytosis, leukopenia, lym-
zide-Like Diuretics; TraMADol; Trimeprazine; Valproate
phadenopathy, pancytopenia, purpura, thrombocyto-
Products; Zolpidem
penia
Hepatic: Abnormal hepatic function tests, cholestatic jaun- Decreased Effect
dice, hepatic failure, hepatitis, hepatocellular jaundice, CarBAMazepine may decrease the levels/effects of:
increased liver enzymes Abemaciclib; Abiraterone Acetate; Acalabrutinib; Acet-
Hypersensitivity: Hypersensitivity reaction aminophen; Afatinib; Albendazole; Antihepaciviral Com-
Immunologic: DRESS syndrome bination Products; Apixaban; Apremilast; Aprepitant;
Neuromuscular & skeletal: Arthralgia, exacerbation of ARIPiprazole; ARIPiprazole Lauroxil; Artemether; Asu-
systemic lupus erythematosus, leg cramps, lupus-like naprevir; Axitinib; Bazedoxifene; BCG (Intravesical);
syndrome, myalgia, osteoporosis, tremor, weakness Bedaquiline; Benperidol; Bictegravir; Boceprevir; Borte-
Ophthalmic: Blurred vision, conjunctivitis, diplopia, zomib; Bosutinib; Brentuximab Vedotin; Brexpiprazole;
Brigatinib; Brivaracetam; Bromperidol; BusP|Rone;
increased intraocular pressure, nystagmus, oculomotor
disturbance, punctate cataract Cabozantinib; Calcifediol; Calcium Channel Blockers
Otic: Tinnitus (Dihydropyridine); Calcium Channel Blockers (Nondihy-
Renal: Increased blood urea nitrogen, renal failure dropyridine); Canagliflozin; Cannabidiol; Cannabis; Car-
Respiratory: Dry throat, pulmonary hypersensitivity iprazine; Caspofungin; Ceritinib; Chlormethiazole;
Miscellaneous: Fever Citalopram; Clarithromycin; Clindamycin (Systemic);
Rare but important or life-threatening: Anaphylaxis, CloZAPine; Cobicistat; Cobimetinib; Copanlisib; Cortico-
angioedema, aseptic meningitis, decreased thyroid hor- steroids (Systemic); Crizotinib; CycloSPORINE (Sys-
mones, dysgeusia (Syed 2016), eyelid edema, glottis temic); CYP2B6 Substrates (High risk with Inducers);
edema, hepatotoxicity (idiosyncratic: Chalasani 2014), CYP3A4 Substrates (High risk with Inducers); Dabiga-
intrahepatic cholestasis (vanishing bile duct syndrome), tran Etexilate; Daclatasvir; Dasabuvir; Dasatinib; Defla-
laryngeal edema, lip edema, suicidal tendencies zacort; Delamanid; Delavirdine; Dexamethasone
Drug Interactions (Systemic); Dienogest; Diethylstilbestrol; Dolutegravir;
DOXOrubicin (Conventional); Doxycycline; Dronabinol;
Metabolism/Transport Effects Substrate of CYP2C8
Dronedarone; Edoxaban; Efavirenz; Elbasvir; Eliglustat;
(minor), CYP3A4 (major); Note: Assignment of Major/
Elvitegravir; Enzalutamide; Erlotinib; Eslicarbazepine;
Minor substrate status based on clinically relevant drug
Estriol (Systemic); Estriol (Topical); Estrogen Derivatives
interaction potential; Induces CYP1A2 (weak), CYP2B6
(Contraceptive); Etizolam; Etoposide; Etoposide Phos-
(moderate), CYP3A4 (strong), UGT1A1
phate; Etravirine; Everolimus; Evogliptin; Exemestane;
Avoid Concomitant Use
Ezogabine; Felbamate; Fingolimod; Flibanserin; Flunar-
Avoid concomitant use of CarBAMazepine with any of
izine; Fosnetupitant; Fosphenytoin; Fostamatinib; Gefiti-
the following: Abemaciclib; Antihepaciviral Combination
nib; Gemigliptin; Gestrinone; Glecaprevir and
Products; Apixaban; Apremilast; Aprepitant; Artemether;
Pibrentasvir; Grazoprevir, GuanFACINE; Haloperidol;
Asunaprevir; Axitinib; Azelastine (Nasal); BCG (Intra-
Hydrocortisone (Systemic); Ibrutinib; Idelalisib; lfosfa-
vesical); Bedaquiline; Boceprevir; Bortezomib; Bosutinib;
mide; Imatinib; Irinotecan Products; lsavuconazonium
Brigatinib; Cariprazine; Ceritinib; CloZAPine; Cobicistat;
Sulfate; Itraconazole; |vabradine; lvacaftor; Ixabepilone;
Cobimetinib; Conivaptan; Copanlisib;-Crizotinib; Dacla-
Ixazomib; Lacosamide; LamoTRigine; Lapatinib; Ledi-
tasvir; Dasabuvir; Deferiprone; Deflazacort; Delamanid;
pasvir; LevETIRAcetam; Linagliptin; Lopinavir; Lumefan-
Delavirdine; Dienogest; Dipyrone; Dronedarone; Efavir-
trine; Lurasidone; Macimorelin; Macitentan; Manidipine;
enz; Elbasvir; Eliglustat; Elvitegravir; Etravirine; Fliban-
Maraviroc; Mebendazole; Methadone; MethylIPREDNI-
serin; Fosnetupitant; Fostamatinib; Fusidic Acid
Solone; Mianserin; Midostaurin; MiFEPRIStone; Mirode-
(Systemic); Gemigliptin; Glecaprevir and Pibrentasvir;
nafil; Naldemedine; Naloxegol; Nefazodone; Neratinib;
Grazoprevir; Ibrutinib; Idelalisib; Irinotecan Products;
Netupitant; Neuromuscular-Blocking Agents (Nondepo-
Isavuconazonium Sulfate; Itraconazole; lvabradine; Iva-
larizing); Nevirapine; NIFEdipine; Nilotinib; NiMODipine;
caftor; Ixazomib; Lapatinib; Ledipasvir; Lumefantrine;
Nisoldipine; OLANZapine; Olaparib; Osimertinib; OXcar-
Lurasidone; Macimorelin; Macitentan; Midostaurin;
bazepine; Palbociclib; Paliperidone; Panobinostat;
MiFEPRIStone; Monoamine Oxidase Inhibitors; Nalde-
PAZOPanib; Perampanel; Phenytoin; Pimavanserin;
medine; Naloxegol; Nefazodone; Neratinib; Netupitant;
Piperaquine; PONATinib; Praziquantel; PrednisoLONE
Nevirapine; NIFEdipine; Nilotinib; NiMODipine; Nisoldi-
(Systemic); PredniSONE; Progestins (Contraceptive);
pine; Olaparib; Orphenadrine; Oxomemazine;. Palboci-
Propacetamol; Propafenone; Protease Inhibitors; QUE-
clib; Panobinostat; Paraldehyde; PAZOPanib;
tiapine; QuiNINE; Radotinib; Ramelteon; Ranolazine;
Piperaquine; PONATinib; Praziquantel; Ranolazine;
Reboxetine; Regorafenib; Ribociclib; Rilpivirine; Risper-
Regorafenib; Ribociclib; Rilpivirine; Rivaroxaban; Roflu-
iDONE; Rivaroxaban; Roflumilast; Rolapitant; Romi-
milast; RomiDEPsin; Simeprevir; Sofosbuvir; Sonidegib;
DEPsin; Rufinamide; Ruxolitinib; SAXagliptin;
SORAfenib; Stiripentol; Suvorexant; Tasimelteon; Telap-
Sertraline; Simeprevir; Sirolimus; Sofosbuvir; Sonidegib;
revir; Tenofovir Alafenamide; Thalidomide; Ticagrelor;
SORAfenib; Sulthiame; SUNItinib; Suvorexant; Tadalafil;
Tofacitinib; Tolvaptan; Toremifene; Trabectedin; TraMA-
Tamoxifen; Tasimelteon; Telaprevir; Temsirolimus; Teno-
Dol; Ulipristal; Valbenazine; Vandetanib; Velpatasvir;
fovir Alafenamide; Tetrahydrocannabinol; Theophylline
Venetoclax; VinCRIStine (Liposomal); Vinflunine; Vora-
Derivatives; Thiothixene; Thyroid Products; TiaGABine;
paxar; Voriconazole; Voxilaprevir
Ticagrelor; Tofacitinib; Tolvaptan; Topiramate; Toremi-
Increased Effect/Toxicity fene; Trabectedin; TraMADol; Tricyclic Antidepressants;
CarBAMazepine may increase the levels/effects of: Tropisetron; Udenafil; Ulipristal; Valbenazine; Valproate
Adenosine; Alcohol (Ethyl); Azelastine (Nasal); Blonan- Products; Vandetanib; Vecuronium; Velpatasvir; Vemur-
serin; Buprenorphine; Clarithromycin; ClomiPRAMINE;
afenib; Venetoclax; Vilazodone; VinCRIStine (Liposo-
CloZAPine; CNS Depressants; Deferiprone; Desmo-
mal); Vinflunine; Vitamin K Antagonists; Vorapaxar;
pressin; Doxercalciferol; Eslicarbazepine; Flunitraze-
Voriconazole; Vortioxetine; Voxilaprevir; Zaleplon; Zipra-
pam; Fosphenytoin; HYDROcodone; Ifosfamide;
sidone; Zolpidem; Zuclopenthixol
Isoniazid; Lacosamide; Lithium; Methotrimeprazine;
MetyroSINE; Monoamine Oxidase Inhibitors; Opioid The levels/effects of CarBAMazepine may be decreased
Analgesics; Orphenadrine; OxyCODONE; Paraldehyde; by: Bosentan; CYP3A4 Inducers (Moderate); CYP3A4
Phenytoin; Piribedil; Pramipexole; ROPINIRole; Inducers (Strong); Dabrafenib; Deferasirox; Efavirenz;

363
CARBAMAZEPINE

Enzalutamide; Felbamate; Fosphenytoin; Mefloquine; Pharmacodynamics/Kinetics: Additional Consider-

Methylfolate; Mianserin; Mitotane; Orlistat; Phenytoin; ations
Pitolisant; Rufinamide; Sarilumab; Siltuximab; St John's Hepatic function impairment: Patients with hepatic impair-
Wort; Theophylline Derivatives; Tocilizumab; TraMADol ment may experience elevated concentrations when
Food Interactions Carbamazepine serum levels may be switching from oral to IV carbamazepine administration
increased if taken with food and/or grapefruit juice. Man- (in comparison to patients with normal hepatic function).
agement: Avoid concurrent ingestion of grapefruit juice. Dosing
Maintain adequate hydration, unless instructed to restrict Pediatric Dosage must be adjusted according to
fluid intake. patient's response and serum concentrations.
Hazardous Drugs Handling Considerations Seizure disorder: Note: To convert from a solid dosage
Hazardous agent (NIOSH 2016 [group 2]). form (tablets [immediate or extended release] or cap-
Use appropriate precautions for receiving, handling, sules [extended release]) to oral suspension, use the
administration, and disposal. Gloves (single) should be same total mg daily dose and divided into 4 daily
worn during receiving, unpacking, and placing in storage. doses; monitor serum concentrations. Carbamazepine
suspension may be administered rectally as mainte-
NIOSH recommends single gloving for administration of nance doses, if oral therapy is not possible; when using
intact tablets or capsules. If manipulating tablets/capsules carbamazepine suspension rectally, administer the
(eg, to prepare an oral suspension), NIOSH recommends same total daily dose, but administer in small, diluted,
double gloving, a protective gown, and preparation in a multiple doses; dilute the oral suspension with an equal
controlled device; if not prepared in a controlled device,
volume of water; if defecation occurs within the first 2
respiratory and eye/face protection as well as ventilated
hours, repeat the dose (Graves, 1987).
engineering controls- are recommended. NIOSH recom-
Infants and Children: Oral:
mends double gloving, a protective gown, and (if there is a
<6 years: Initial: 10 to 20 mg/kg/day divided twice or 3
potential for vomit or spit up) eye/face protection for
times daily as immediate release tablets or 4 times
administration of an oral liquid/feeding tube administration
daily as suspension; increase dose every week until
(NIOSH 2016). Assess risk to determine appropriate con-
optimal response and therapeutic levels are
tainment strategy (USP-NF 2017).
achieved; maintenance dose: Divide into 3-4 doses
Storage/Stability
daily (immediate release tablets or suspension);
Carbatrol, Equetro: Store at controlled room temperature
maximum recommended daily dose: 35 mg/kg/day
(25°C [77°F]); excursions permitted to 15°C to 30°C
(59°F to 86°F); protect from light and moisture. 6 to 12 years: Initial: 100 mg twice daily [immediate
Carnexiv: Store intact vials at 20°C to 25°C (68°F to 77°F); release tablets or extended release tablets (Tegre-
excursions permitted to 15°C to 30°C (59°F to 86°F). tol-XR)] or 50 mg of suspension 4 times daily
The prepared solution may be stored at 20°C to 25°C (200 mg/day); increase by up to 100 mg/day at
(68°F to 77°F) for up to 4 hours, or up to 24 hours at 2°C weekly intervals using a twice daily regimen of
to 8°C (36°F to 46°F). Discard any unused product. extended release tablets or 3 to 4 times daily regi-
Tegretol-XR: Store at controlled room temperature, 15°C men of other formulations until optimal response and
to 30°C (59°F to 86°F); protect from moisture. therapeutic levels are achieved; usual maintenance:
Tegretol tablets and chewable tablets: Store at <30°C 400 to 800 mg/day; maximum recommended daily
(86°F); protect from light and moisture. dose: 1000 mg/day
Tegretol suspension: Store at $30°C (86°F); shake well Adolescents: Initial: 200 mg twice daily (immediate
before using. release tablets, extended release tablets [Tegretol-
Mechanism of Action In addition to anticonvulsant XR], or extended release capsules [Carbatrol]) or
effects, carbamazepine has anticholinergic, antineuralgic, 100 mg of suspension 4 times daily (400 mg daily);
antidiuretic, muscle relaxant, antimanic, antidepressive, increase by up to 200 mg/day at weekly intervals
and antiarrhythmic properties; may depress activity in using a twice daily regimen of extended release
the nucleus ventralis of the thalamus or decrease synaptic tablets or capsules, or a 3 to 4 times/day regimen of
transmission or decrease summation of temporal stimula- other formulations until optimal response and thera-
tion leading to neural discharge by limiting influx of sodium peutic levels are achieved; usual dose: 800 to
ions across cell membrane or other unknown mecha- 1200 mg/day
nisms; stimulates the release of ADH and potentiates its Maximum recommended daily doses:
action in promoting reabsorption of water; chemically Adolescents $15 years: 1000 mg/day
related to tricyclic antidepressants Adolescents >15 years: 1200 mg/day
Pharmacodynamics/Kinetics (Adult data unless Renal Impairment: Pediatric
noted) Dosage adjustments are not required nor recommended
Absorption: Slowly from the Gl tract in the manufacturer’s labeling; however, the following
Distribution: Vg: Neonates: 1.5 L/kg; Children: 1.9 L/kg; guidelines have been used by some clinicians (Aronoff,
Adults: 0.59 to 2 L/kg; carbamazepine and its active 2007):
epoxide metabolite distribute into breast milk Infants, Children, and Adolescents: Note: Renally
Protein binding: Carbamazepine: 75% to 90%, bound to adjusted dose recommendations are based on doses
alpha,-acid glycoprotein and nonspecific binding sites on of 10 to 20 mg/kg/day divided every 8 to 12 hours.
albumin; may be decreased in newborns; Epoxide GFR 210 mL/minute/1.73 m?: No dosage adjustment
metabolite: 50% required
Metabolism: Induces liver enzymes to increase metabo- GFR <10 mL/minute/1.73 m?: Administer 75% of
lism and shorten half-life over time; metabolized in the normal dose
liver by cytochrome P450 3A4 to active epoxide metab- Intermittent hemodialysis: Administer 75% of normal
olite; epoxide metabolite is metabolized by epoxide dose; on dialysis days give dose after hemodialysis
hydrolase to the trans-diol metabolite; ratio of serum Peritoneal dialysis (PD): Administer 75% of nor-
epoxide to carbamazepine concentrations may be higher mal dose
in patients receiving polytherapy (vs monotherapy) and
Continuous renal replacement therapy (CRRT):
in infants (vs older children); boys may have faster
Administer 75% of normal dose; monitor serum
carbamazepine clearances and may, therefore, require
concentrations
higher mg/kg/day doses of carbamazepine compared to
Hepatic Impairment: Pediatric Infants, Children, and
girls of similar age and weight
Bioavailability: Oral: 75% to 85%; relative bioavailability of
Adolescents: There are no dosage adjustments provided
extended release tablet to suspension: 89%; relative in the manufacturer's labeling. Use with caution in hep-
bioavailability of IV to oral formulation: 70% atic impairment and consider dose reduction; metabo-
Half-life elimination: Note: Half-life is variable because of lized primarily in the liver.
autoinduction which is usually complete 3 to 5 weeks Administration
after initiation of a fixed carbamazepine regimen. Oral: Administer with food to decrease GI upset
Carbamazepine: Initial: 25 to 65 hours; Extended Immediate release:
release: 35 to 40 hours; Multiple doses: Children: 8 to Chewable and conventional tablets: Administer with
14 hours; Adults: 12 to 17 hours meals; may be given 2 to 3 times daily.
Epoxide metabolite: Initial: 34 + 9 hours Oral suspension: Shake well before use; administer
Time to peak, serum: Unpredictable: with meals; must be given on a 3 to 4 times daily
Immediate release: Multiple doses: Suspension: 1.5 schedule. When carbamazepine suspension has
hour; tablet: 4 to 5 hours been combined with chlorpromazine or thioridazine
Extended release: Carbatrol, Equetro: 12 to 26 hours solutions, a precipitate forms which may result in loss
(single dose), 4 to 8 hours (multiple doses); Tegretol- of effect. Therefore, it is recommended that the car-
XR: 3 to 12 hours bamazepine suspension dosage form not be admin-
Excretion: Urine 72% (1% to 3% as unchanged drug); istered at the same time with other liquid medicinal
feces (28%) agents or diluents.

364
 CARBAMIDE PEROXIDE

Extended release: Use

Capsules (Carbatro!, Equetro): Consists of three differ- Oral (10% solution): Temporary use in cleansing of canker
ent types of beads: Immediate release, extended sore and minor wounds or gum inflammation due to
release, and enteric release. The bead types are minor dental procedures, dentures, orthodontic applian-
combined in a ratio to allow. twice daily dosing. Cap- ces, accidental injury, or other irritations of mouth and
sules may be opened and contents sprinkled over gums; aids in removal of phlegm, mucus, or other
food such as a teaspoon of applesauce; do not store secretions associated with occasional sore mouth
medication/food mixture for later use; drink fluids after (OTC product: FDA approved in ages 22 years and
dose to make sure mixture is completely swallowed; adults)
may be administered with or without food; do not Otic (6.5% solution): Aid to soften, loosen, and remove
crush or chew. excessive earwax (OTC product: FDA approved in ages
‘Tablet (Tegretol-XR): Administer with meals; should be 212 years and adults)
dosed twice daily; examine XR tablets for cracks or Warnings/Precautions
chips or other damage; do not use damaged Oral: Self-medication (OTC) use: Instruct patient to dis-
extended release tablets without release portal. Swal- continue use and consult health care provider if swelling,
low tablet whole; do not crush or chew. rash, or fever develops or if irritation, pain, or redness
Monitorjng Parameters HLA-B*1502 genotype screen- persists or worsens. Patients should consult health care
ing prior to therapy initiation in patients of Asian descent; provider for use longer than 7 days.
CBC with platelet count, reticulocytes, serum iron, liver
Otic: Self-medication (OTC use): Instruct patient to consult
function tests, ophthalmic examinations (including slit-
health care provider prior to use if ear drainage or dis-
Jamp, fundoscopy, and tonometry), urinalysis, BUN, lipid
charge, ear pain, irritation, rash in ear, dizziness, or ear-
panel, serum drug concentrations, thyroid function tests,
drum perforation is present or if they had recent ear
serum sodium; pregnancy test; observe patient for exces-
surgery. Patients should consult health care provider for
sive sedation especially when instituting or increasing
use longer than 4 days or if condition persists.
therapy; signs of edema, skin rash, and hypersensitivity
Warnings: Additional Pediatric Considerations
reactions; signs and symptoms of suicidality (eg, anxiety,
Some dosage forms may contain propylene glycol; in
depression, behavior changes).
neonates large amounts of propylene glycol delivered
Reference Range Timing of serum samples: Absorption
orally, intravenously (eg, >3,000 mg/day), or topically
is slow; peak levels occur 8 to 65 hours after ingestion of
have been associated with potentially fatal toxicities which
the first dose; the half-life ranges from 8 to 60 hours;
can include metabolic acidosis, seizures, renal failure, and
therefore, steady-state is achieved in 2 to 5 days
CNS depression; toxicities have also been reported in
Epilepsy: Therapeutic concentrations: 4 to 12 mcg/mL (SI:
children and adults including hyperosmolality, lactic acido-
17 to 51 micromoles/L). Patients who require higher
sis, seizures and respiratory depression; use caution
levels (8 to 12 mcg/mL [SI: 34 to 51 micromoles/L])
(AAP 1997; Shehab 2009).
should be carefully monitored. Side effects (especially
Adverse Reactions
CNS) occur commonly at higher levels. If other anticon-
Dermatologic: Localized erythema, skin rash
vulsants (enzyme inducers) are given, therapeutic range
Infection: Superinfection
is 4 to 8 mcg/mL (SI: 17 to 34 micromoles/L) due to
Local: Local irritation, redness
increase in unmeasured active epoxide metabolite.
Drug Interactions
Test Interactions May cause false-positive serum TCA
Metabolism/Transport Effects None known.
screen; may interact with some pregnancy tests
Product Availability Carnexiv (carbamazepine injection):
Avoid Concomitant Use There are no known interac-
tions where it is recommended to avoid concomitant use.
FDA approved October 2016; anticipated availability is
currently unknown. Consult the prescribing information
Increased Effect/Toxicity There are no known signifi-
cant interactions involving an increase in effect.
for additional information.
Dosage Forms Excipient information presented when Decreased Effect There are no known significant inter-
actions involving a decrease in effect.
available (limited, particularly for generics); consult spe-
cific product labeling. Storage/Stability Store at <25°C (77°F). Keep tip on
Capsule Extended Release 12 Hour, Oral: bottle when not in use.
Carbatrol: 100 mg [contains fd&c blue #2 (indigotine)] Mechanism of Action Carbamide peroxide releases
Carbatrol: 200 mg, 300 mg hydrogen peroxide which serves as a source of nascent
Equetro: 100 mg, 200 mg, 300 mg [contains fd&c blue oxygen upon contact with catalase; deodorant action is
#2 (indigotine)] probably due to inhibition of odor-causing bacteria; soft-
Generic: 100 mg, 200 mg, 300 mg ens impacted cerumen due to its foaming action
Suspension, Oral: Pharmacodynamics/Kinetics (Adult data unless
TEGretol: 100 mg/5 mL (450 mL) [contains fd&c yellow noted) Onset of action: ~24 hours
#6 (sunset yellow), propylene glycol; citrus-vanilla Dosing
flavor] : q Pediatric
Generic: 100 mg/5 mL (450 mL) Ear wax removal:
Tablet, Oral: Children <12 years: Limited data available: Otic (6.5%
Epitol: 200 mg [scored] solution): Usual range: 1 to 5 drops twice daily for up
TEGretol: 200 mg [scored; contains fd&c red #40] to 4 days; individualize the dose according to patient
Generic: 200 mg size (Dimmitt 2005)
Tablet Chewable, Oral: Children 212 years and Adolescents: Otic (6.5%
Generic: 100 mg solution): Instill 5 to 10 drops twice daily for up to
Tablet Extended Release 12 Hour, Oral: 4 days
TEGretol-XR: 100 mg, 200 mg, 400 mg Mouth, gum, or dental irritation: Children 22 years
Generic: 100 mg, 200 mg, 400 mg and Adolescents: Oral (10% solution): Use up to 4
Extemporaneous Preparations Note: Commercial oral times daily after meals and at bedtime either by direct
suspension is available (20 mg/mL) application to the affected area or as an oral rinse for
up to 7 days. For direct application, place several
A 40 mg/mL oral suspension may be made with tablets. drops undiluted on affected area then expectorate
Crush twenty 200 mg tablets in a mortar and reduce to a after 2 to 3 minutes. For use as an oral rinse, place
fine powder. Add small portions of Simple Syrup, NF and 10 to 20 drops onto tongue, mix with saliva, swish for
mix to a uniform paste; mix while adding the vehicle in 21 minute, then expectorate.
incremental proportions to almost 100 mL; transferto a Administration
calibrated bottle, rinse mortar with vehicle, and add suffi- Oral: For topical use only; do not swallow. For direct
cient quantity of vehicle to make 100 mL. Label "shake application, place several drops undiluted solution on
well" and "refrigerate". Stable for 90 days. affected area with an applicator or cotton swab then
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th expectorate after 2 to 3 minutes. For use as an oral
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
rinse, place drops onto tongue, mix with saliva, swish for
21 minute, then expectorate. Patient should not rinse
Carbamide Peroxide (kar ba mide per OKS ide) mouth or drink fluids for 5 minutes after oral adminis-
tration.
Brand Names: US Auraphene-B [OTC]; E-R-O Ear Otic: For otic use only. Prior to use, may warm by holding
Drops [OTC] [DSC]; E-R-O Ear Wax Removal System bottle in hands. Tilt head sideways and apply drops into
[OTC] [DSC]; Ear Drops Earwax Aid [OTC]; Ear Drops ear. For children younger than 3 years of age, pull the
[OTC]; Earwax Treatment Drops [OTC]; Gly-Oxide [OTC]; outer ear outward and downward. For children 3 years of
GoodSense Ear Wax Removal [OTC]; Thera-Ear [OTC] age and older, pull the outer ear outward and upward.
[DSC] } Solution will foam on contact with earwax; a crackling
Therapeutic Category Otic Agent, Cerumenolytic sound may occur. Keep drops in ear for several minutes
Generic Availability (US) Yes by keeping head tilted or placing cotton in ear. ,
365
CARBAMIDE PEROXIDE

Remaining wax after treatment may be removed by were taking carbinoxamine-containing products. Use may
gently flushing ear with warm water using a soft rubber diminish mental alertness in children; in young children
bulb ear syringe. Do not allow applicator tip to enter ear particularly, carbinoxamine-containing products may pro-
canal. duce excitation. Some of these products may contain
Dosage Forms Excipient information presented when sodium metabisulfite, a sulfite that may cause allergic-type
available (limited, particularly for generics); consult spe- reactions including anaphylaxis and life-threatening or
cific product labeling. [DSC] = Discontinued product less severe asthmatic episodes, in susceptible patients.
Solution, Mouth/Throat: Potentially significant interactions may exist, requiring
Gly-Oxide: 10% (15 mL, 60 mL) [contains propylene dose or frequency adjustment, additional monitoring,
glycol] and/or selection of alternative therapy.
Solution, Otic: Warnings: Additional Pediatric Considerations
Auraphene-B: 6.5% (15 mL) Safety and efficacy for the use of cough and cold products
E-R-O Ear Drops: 6.5% (15 mL [DSC]) [contains in pediatric patients <4 years of age is limited; the AAP
glycerin] warns against the use of these producis for respiratory
E-R-O Ear Wax Removal System: 6.5% (15 mL [DSC]) illnesses in this age group. Serious adverse effects includ-
Ear Drops: 6.5% (15 mL) [contains propylene glycol] ing death have been reported. Many of these products
Ear Drops Earwax Aid: 6.5% (15 mL) [contains propy- contain multiple active ingredients, increasing the risk of
lene glycol] accidental overdose when used with other products.
Ear Drops Earwax Aid: 6.5% (15 mL [DSC]) [contains Health care providers are reminded to ask caregivers
propylene glycol, trolamine (triethanolamine)] about the use-of OTC cough and cold products in order
Earwax Treatment Drops: 6.5% (15 mL) [contains glyc- to avoid exposure to multiple medications containing the
erin, propylene glycol] same ingredient (AAP 2012; FDA 2008).
Earwax Treatment Drops: 6.5% (15 mL [DSC}) [contains
propylene glycol, trolamine (triethanolamine)] Some dosage forms may contain propylene glycol; in
GoodSense Ear Wax Removal: 6.5% (15 mL) [contains neonates large amounts of propylene glycol delivered
propylene glycol] orally, intravenously (eg, >3,000 mg/day), or topically
Thera-Ear: 6.5% (15 mL [DSC]) have been associated with potentially fatal toxicities which
can include metabolic acidosis, seizures, renal failure, and
® Carbatrol see CarBAMazepine on page 367 CNS depression; toxicities have also been reported in
children and adults including hyperosmolality, lactic acido-
Carbinoxamine (kar bi NOKS a meen) sis, seizures and respiratory depression; use caution
(AAP, 1997; Shehab, 2009).
Medication Safety Issues Adverse Reactions Frequency not defined.
Geriatric Patients: High-Risk Medication: Cardiovascular: Chest tightness, extrasystoles, hypoten-
Beers Criteria: Carbinoxamine, a first-generation anti- sion, palpitations, tachycardia
histamine, is identified in the Beers Criteria as a poten- Central nervous system: Ataxia (most frequent), chills,
tially inappropriate medication to be avoided in patients confusion, dizziness (most frequent), drowsiness (most
65 years and older (independent of diagnosis or con- frequent), euphoria, excitability, fatigue, headache, hys-
dition) due to its highly anticholinergic properties includ- teria, insomnia, irritability, nervousness, neuritis, pares-
ing risk of confusion, dry mouth, constipation, and other thesia, restlessness, sedation (most frequent), seizure,
anticholinergic effects and toxicities, reduced clearance vertigo
with advanced age, and tolerance associated with use Dermatologic: Diaphoresis, skin photosensitivity, skin
as a hypnotic (Beers Criteria [AGS 2015]). rash, urticaria
Pharmacy Quality Alliance (PQA): Carbinoxamine, as a Endocrine & metabolic: Increased uric acid
single agent or as part of a combination (excludes OTC Gastrointestinal: Anorexia, constipation, diarrhea, epigas-
products), is identified as a high-risk medication in tric distress (most frequent), nausea, vomiting, xero-
patients 65 years and older on the PQA’s, Use of stomia
High-Risk Medications in the Elderly (HRM) perform- Genitourinary: Difficulty in micturition, early menses, uri-
ance measure, a safety measure used by the Centers nary frequency, urinary retention
for Medicare and Medicaid Services (CMS) for Medi- Hematologic & oncologic: Agranulocytosis, hemolytic ane-
care plans. mia, thrombocytopenia
Brand Names: US Arbinoxa [DSC]; Karbinal ER; RyVent Hypersensitivity: Anaphylactic shock, hypersensitivity
Therapeutic Category Antihistamine reaction
Generic Availability (US) May be product dependent Neuromuscular & skeletal: Tremor
Use Symptomatic treatment of seasonal and perennial Ophthalmic: Blurred vision, diplopia
allergic rhinitis; vasomotor rhinitis; allergic conjunctivitis; Otic: Labyrinthitis, tinnitus
mild manifestations of urticaria and angioedema; derma- Respiratory: Dry nose, dry throat, nasal congestion, thick-
tographism; adjunct therapy for anaphylactic reactions ening of bronchial secretions (most frequent), wheezing
(after acute manifestations controlled); amelioration of Drug Interactions
blood and plasma allergic reactions (All indications: FDA Metabolism/Transport Effects None known.
approved in ages 22 years and adults). Note: Approved Avoid Concomitant Use
ages and uses for generic products may vary; consult Avoid concomitant use of Carbinoxamine with any of the
labeling for specific information. following: Aclidinium; Azelastine (Nasal); Bromperidol;
Pregnancy Risk Factor C Cimetropium; Eluxadoline; Glycopyrrolate (Oral Inhala-
Pregnancy Considerations Animal reproduction studies tion); Ipratropium (Oral Inhalation); Levosulpiride; Orphe-
have not been conducted. Maternal antihistamine use has nadrine; Oxatomide; Oxomemazine; Paraldehyde;
generally not resulted in an increased risk of birth defects; Potassium Chloride; Potassium Citrate; Thalidomide;
however, information specific for the use of carbinoxamine Tiotropium; Umeclidinium
during pregnancy has not been located. Although antihist- Increased Effect/Toxicity
amines are recommended for some indications in preg- Carbinoxamine may increase the levels/effects of: Abo-
nant women, the use of other agents with specific botulinumtoxinA; Alcohol (Ethyl); Amezinium; Anticholi-
pregnancy data may be preferred. nergic Agents; Azelastine (Nasal); Blonanserin;
Breastfeeding Considerations It is not known if carbi- Buprenorphine; Cimetropium; CNS Depressants; Elux-
noxamine is excreted in breast milk. Premature infants adoline; Flunitrazepam; Glucagon; Glycopyrrolate (Oral
and newborns have a higher risk of intolerance to antihist- Inhalation); HYDROcodone; Methotrimeprazine; Metyro-
amines. Use while breastfeeding is contraindicated by the SINE; Mirabegron; Mirtazapine; OnabotulinumtoxinA;
manufacturer. Antihistamines may decrease maternal Opioid Analgesics; Orphenadrine; OxyCODONE; Paral-
serum prolactin concentrations when administered prior
dehyde; Piribedil; Potassium Chloride; Potassium Cit-
to the establishment of nursing.
rate; Pramipexole; Ramosetron; RimabotulinumtoxinB;
Contraindications Hypersensitivity to carbinoxamine or ROPINIRole; Rotigotine; Selective Serotonin Reuptake
any component of the formulation; coadministration with
Inhibitors; Suvorexant; Thalidomide; Thiazide and Thia-
monoamine oxidase inhibitors (MAOIs); children <2 years zide-Like Diuretics; Tiotropium; Topiramate; Zolpidem
of age; breastfeeding women
Warnings/Precautions Use caution with asthma, The levels/effects of Carbinoxamine may be increased
increased intraocular pressure, narrow angle glaucoma, by: Aclidinium; Amantadine; Brimonidine (Topical); Bro-
hyperthyroidism, cardiovascular disease, hypertension, mopride; Bromperidol; Cannabis; Chloral Betaine; Chlor-
pyloroduodenal obstruction, stenosing peptic ulcer, symp- methiazole; Chlorphenesin Carbamate; Dimethindene
tomatic prostatic hyperplasia, or urinary retention. Causes (Topical); Doxylamine; Dronabinol; Droperidol; HydrOX-
sedation; caution must be used in performing tasks which Yzine; Ipratropium (Oral Inhalation); Kava Kava; Lofex-
require mental alertness (eg, operating machinery or idine; Magnesium Sulfate; Methotrimeprazine;
driving). Use is contraindicated in children age <2 years; Mianserin; Minocycline; Nabilone; Oxatomide; Oxome-
deaths have been reported in children age <2 years who mazine; Perampanel; Pramlintide; Rufinamide; Sodium

366
 CARBOPLATIN

Oxybate; Tapentadol; Tetrahydrocannabinol; Trimepra- High alert medication:

zine; Umeclidinium This medication is in a class the Institute for Safe
Decreased Effect Medication Practices (ISMP) includes among its list of
Carbinoxamine may decrease the levels/effects of: Ace- drug classes which have a heightened risk of causing
tylcholinesterase Inhibitors; Amifampridine; Benzylpeni- significant patient harm when used in error.
cilloy! Polylysine; Betahistine; Gastrointestinal Agents Geriatric Patients: High-Risk Medication:
Beers Criteria: Carboplatin is identified in the Beers
(Prokinetic); Hyaluronidase; Itopride; Levosulpiride;
Criteria as a potentially inappropriate medication to be
Nitroglycerin; Pitolisant; Secretin
used with caution in patients 65 years and older due to
The levels/effects of Carbinoxamine may be decreased its potential to cause or exacerbate syndrome of inap-
by: Acetylcholinesterase Inhibitors; Amifampridine; propriate antidiuretic hormone secretion (SIADH) or
Amphetamines hyponatremia; monitor sodium concentration closely
Storage/Stability when initiating or adjusting the dose in older adults
Arbinoxa™: Store at 20°C to 25°C (68°F to 77°F); protect (Beers Criteria [AGS 2015)]).
from light. Brand Names: Canada Carboplatin Injection; Carbopla-
tin Injection BP
Palgic®: Store at 15°C to 30°C (59°F to 86°F); protect
from light.
Therapeutic Category Antineoplastic Agent, Alkylating
Agent; Antineoplastic Agent, Platinum Analog
Mechanism of Action Carbinoxamine competes with
Generic Availability (US) Yes
histamine for H,-receptor sites on effector cells in the
Use Treatment of advanced ovarian carcinoma (FDA
! gastrointestinal tract, blood vessels, and respiratory tract.
approved in adults); has also been used in the treatment
Pharmacodynamics/Kinetics (Adult data unless of central nervous system tumors (gliomas, neuroblasto-
' noted) mas), retinoblastoma, sarcomas (Ewing sarcoma, osteo-
Duration of effect: ~4 hours (immediate release) sarcoma), Wilms tumor, and as a conditioning regimen
Absorption: Well absorbed from the Gl tract prior to hematopoietic stem cell transplantation
Metabolism: Hepatic (Simons 2004) Pregnancy Risk Factor D
Half-life elimination: 17 hours (extended release) Pregnancy Considerations Adverse events have been
Time to peak, serum;: 1.5 to 5 hours observed in animal reproduction studies. May cause fetal
Excretion: Urine (Maurer 1988) harm if administered during pregnancy. Women of child-
Dosing bearing potential should avoid becoming pregnant during
Pediatric treatment.
Allergic rhinitis/urticaria/allergic reactions: Oral: Breastfeeding Considerations It is not known if carbo-
Immediate release: platin is present in breast milk. Due to the potential for
Children 2 to 5 years: Oral solution: toxicity in the breastfed infant, the manufacturer recom-
Weight-directed: 0.2 to 0.4 mg/kg/day in divided mends discontinuing breastfeeding during carboplatin
doses 3 to 4 times daily treatment.
Contraindications History of severe allergic reaction to
Fixed dose: 1 to 2 mg/dose 3 to 4 times daily;
carboplatin, cisplatin, other platinum-containing formula-
maximum daily dose: 0.4 mg/kg/day
tions, mannitol, or any component of the formulation;
Children 6 to 11 years: Oral solution or tablet: 2 to
should not be used in patients with severe bone marrow
4 mg/dose 3 to 4 times daily depression or significant bleeding
Children 212 years and Adolescents: Oral solution or Warnings/Precautions [US Boxed Warning]: Bone
tablet: 4 to 8 mg/dose 3 to 4 times daily marrow suppression, which may be severe, is dose
Extended release suspension: Note: Fixed dose pre- related; may result in infection (due to neutropenia) or
sented in children 2 to 11 years equates to approx- bleeding (due to thrombocytopenia); anemia may
imately 0.2 to 0.4 mg/kg/day require blood transfusion. Reduce dosage in patients
Children 2 to 3 years: 3 to 4 mg/dose every 12 hours with bone marrow suppression; cycles should be delayed
Children 4 to 5 years: 3 to 8 mg/dose every 12 hours until WBC and platelet counts have recovered. In patients
Children 6 to 11 years: 6 to 12 mg/dose every 12 receiving single agent carboplatin, the median nadir typi-
hours cally occurs at day 21. Patients who have received prior
Children 212 years and Adolescents: 6 to 16 mg/dose myelosuppressive therapy and patients with renal dys-
every 12 hours function are at increased risk for bone marrow suppres-
Renal Impairment: Pediatric There are no dosage sion. Anemia is cumulative. Monitor blood counts closely.
adjustments provided in manufacturer's labeling. High doses (>4 times the recommended dose) have
resulted in severe abnormalities of liver function tests.
Hepatic Impairment: Pediatric There are no dosage
adjustments provided in manufacturer's labeling. When calculating the carboplatin dose using the Calvert
Administration Oral: Administer on an empty stomach formula and an eGFR, the laboratory method used to
with water. 7 measure serum creatinine may impact dosing. Compared
Dosage Forms Excipient information presented when to other methods, standardized isotope dilution mass
available (limited, particularly for generics); consult spe- spectrometry (IDMS) may underestimate serum creatinine
cific product labeling. [DSC] = Discontinued product values in patients with low creatinine values (eg,
<0.7 mg/dL) and may overestimate GFR in patients with
Solution, Oral, as maleate:
normal renal function. This may result in higher calculated
Arbinoxa: 4 mg/5 mL (473 mL [DSC)]) [contains methyl-
carboplatin doses and increased toxicities. If using IDMS,
paraben, propylene glycol, propylparaben; bubble-gum
the FDA recommends that clinicians consider capping
flavor] estimated GFR at a maximum of 125 mL/minute to avoid
Generic: 4 mg/5 mL (118 mL, 473 mL) potential toxicity.
Suspension Extended Release, Oral, as maleate:
Karbinal ER: 4 mg/5 mL (480 mL) [contains methylpar- [US Boxed Warning]: Anaphylactic-like reactions have
aben, polysorbate 80, propylparaben, sodium metabi- been reported with carboplatin; may occur within
sulfite; strawberry-banana flavor] minutes of administration. Epinephrine, corticoste-
Tablet, Oral, as maleate: roids, and antihistamines have been used to treat
symptoms. The risk of allergic reactions (including ana-
Arbinoxa: 4 mg [DSC] [scored]
phylaxis) is increased in patients previously exposed to
RyVent: 6 mg
platinum therapy. Skin testing and desensitization proto-
Generic: 4 mg, 6 mg
cols have been reported (Confina-Cohen 2005; Lee 2004;
¢@ Carbinoxamine Maleate see Carbinoxamine Markman 2003). When administered as sequential infu-
on page 366 / Z sions, taxane derivatives (docetaxel, paclitaxel) should be
administered before the platinum derivatives (carboplatin,
@ Carbocaine see Mepivacaine on page 130 cisplatin) to limit myelosuppression and to enhance effi-
@ Carbocaine Preservative-Free see Mepivacaine cacy. Ototoxicity may occur when administered concom-
on page 1306 itantly with aminoglycosides. Clinically significant hearing
@ Carbolith (Can) see Lithium on page 1237 loss has been reported to occur in pediatric patients when
carboplatin was administered at higher-than-recom-
mended doses in combination with other ototoxic agents
CARBOplatin (KAR boe pla tin) (eg, aminoglycosides). In a study of children receiving
carboplatin for the treatment of retinoblastoma, those <6
Medication Safety Issues months at treatment initiation were more likely to experi-
Sound-alike/look-alike issues: ence ototoxicity; long-term audiology monitoring is recom-
CARBOplatin may be confused with ClSplatin, oxalipla- mended (Qaddoumi 2012). Loss of vision (usually
tin / reversible within weeks of discontinuing) has been
Paraplatin may be confused with Platinol reported with higher-than-recommended doses. »
367
 CARBOPLATIN

4 Peripheral neuropathy occurs infrequently, the incidence

of peripheral neuropathy is increased in patients >65
Increased Effect/Toxicity
CARBOplatin may increase the levels/effects of: Barici-
years of age and those who have previously received tinib; Bexarotene (Systemic); CloZAPine; Deferiprone;
cisplatin treatment. Patients >65 years of age are more Fingolimod; Leflunomide; Natalizumab; Taxane Deriva-
likely to develop severe thrombocytopenia. tives; Tofacitinib; Topotecan; Vaccines (Live)
Carboplatin has a limited potential for nephrotoxicity The levels/effects of CARBOplatin may be increased by:
unless administered concomitantly with aminoglycosides. Aminoglycosides; Chloramphenicol (Ophthalmic); Deno-
Use caution with concomitant administration with amino- sumab; Dipyrone; Ocrelizumab; Palifermin; Pimecroli-
glycosides or other nephrotoxic medications. [US Boxed mus; Promazine; Roflumilast; SORAfenib; Tacrolimus
Warning]: Vomiting may occur. Carboplatin is associ-
(Topical); Trastuzumab
ated with a moderate to high emetic potential in adult
Decreased Effect -
patients (dose dependent) and a high emetic potential in
CARBOplatin may decrease the levels/effects of: BCG
pediatric patients; antiemetics are recommended to pre-
(Intravesical); Coccidioides immitis Skin Test; Fospheny-
vent nausea and vomiting (Dupuis 2011; Hesketh 2017;
Roila 2016). Nausea and vomiting may be more severe in toin-Phenytoin; Lenograstim; Lipegfilgrastim; Nivolumab;
patients who have received prior emetogenic therapy. [US Pidotimod; Sipuleucel-T; Tertomotide; Vaccines (Inacti-
Boxed Warning]: Should be administered under the vated); Vaccines (Live)
supervision of an experienced cancer chemotherapy The levels/effects of CARBOplatin may be decreased by:
physician. Potentially significant interactions may exist, Echinacea
requiring dose or frequency adjustment, additional mon-
Hazardous Drugs Handling Considerations
itoring, and/or selection of alternative therapy.
Hazardous agent (NIOSH 2016 [group 1)).
Warnings: Additional Pediatric Considerations Oto-
toxicity has been reported with platinum-based (ie, cispla- Use appropriate precautions for receiving, handling,
tin and carboplatin) chemotherapy; the reported incidence administration, and disposal. Gloves (single) should be
in pediatric patients with cisplatin is 13% to 95% and is worn during receiving, unpacking, and placing in storage.
highly variable due to different assessment tools, which
NIOSH recommends double gloving, a protective gown,
also affects reported severity levels and risk factor deter-
mination. In a multicenter trial of 333 patients (mean age:
ventilated engineering controls (a class,|]biological safety
4 years; range: 0.3 to 29 years; 80% of patients were <5 cabinet or a compounding aseptic containment isolator),
years at time of diagnosis) treated for high-risk neuro- and closed system transfer devices (CSTDs) for prepara-
blastoma with cisplatin induction therapy followed by an tion. Double gloving, a gown, and (if dosage form allows)
HSCT myeloablative regimen which included carboplatin CSTDs are required during administration (NIOSH 2016).
in some patients (ie, multiple-exposure), audiological eval- Storage/Stability Store intact vials at room temperature
uations (including baseline) were completed using multi- at 25°C (77°F); excursions permitted to 15°C to 30°C
ple assessment tools. At the time of evaluation, the (59°F to 86°F). Protect from light. Further dilution to a
majority of patients were <5 years of age at time of initial concentration as low as 0.5 mg/mL is stable at room
exposure and results showed some degree of hearing loss temperature (25°C) for 8 hours in NS or D5W. Stability
in 264% of patients following single exposure (cisplatin has also been demonstrated for dilutions in DSW in PVC
induction) and >80% of those with multiple-exposure bags at room temperature for 9 days (Benaji 1994);
(cisplatin induction plus carboplatin myeloablation) however, the manufacturer recommends use within 8
regardless of grading scale. Overall, the hearing loss hours due to lack of preservative. Multidose vials are
was graded as moderate or severe in 41% to 85% of stable for up to 14 or 15 days after opening when stored
patients depending on the scale with a higher incidence at 25°C (77°F) following multiple needle entries (refer to
(66% to 85%) in those with who received both cisplatin specific product labeling for stability information).
induction and carboplatin myeloablation; >50% required a
Mechanism of Action Carboplatin is a platinum com-
hearing aid (Landier 2014).
pound alkylating agent which covalently binds to DNA;
Adverse Reactions
interferes with the function of DNA by producing inter-
Central nervous system: Neurotoxicity, pain, peripheral
strand DNA cross-links. Carboplatin. is apparently not
neuropathy
cell-cycle specific.
Dermatologic: Alopecia
Endocrine & metabolic: Hypocalcemia, hypokalemia,
Pharmacodynamics/Kinetics (Adult data unless
hypomagnesemia, hyponatremia noted)
Gastrointestinal: Abdominal pain, constipation, diarrhea, Distribution: Vg: 16 L (based on a dose of 300 to
dysgeusia, mucositis, nausea (without vomiting), stoma- 500 mg/m); into liver, kidney, skin, and tumor tissue
titis, vomiting Protein binding: Carboplatin: 0%; Platinum (from carbo-
Hematologic & oncologic: Anemia, bleeding complica- platin): Irreversibly binds to plasma proteins
tions, bone marrow depression (dose related and dose Metabolism: Minimally hepatic to aquated and hydroxy-
limiting; nadir at ~21 days with single-agent therapy), lated compounds
hemorrhage, leukopenia, neutropenia, thrombocyto- Half-life elimination: CrCl >60 mL/minute: Carboplatin: 2.6
penia to 5.9 hours (based on a dose of 300 to 500 mg/m?);
Hepatic: Increased serum alkaline phosphatase, Platinum (from carboplatin): 25 days
increased serum AST, increased serum bilirubin Excretion: Urine (~70% as carboplatin within 24 hours; 3%
Hypersensitivity: Hypersensitivity to 5% as platinum within 1 to 4 days)
Infection: Infection Pharmacodynamics/Kinetics: Additional Consider-
Neuromuscular & skeletal: Weakness ations
Ophthalmic: Visual disturbance
Renal function impairment: In patients with CrCl <60 mL/
Otic: Ototoxicity
minute, the total body and renal clearance decreases as
Renal: Decreased creatinine clearance, increased blood
CrCl decreases.
urea nitrogen, increased serum creatinine
Dosing
Rare but important or life-threatening: Anaphylaxis, ano-
Pediatric
rexia, bronchospasm, cardiac failure, cerebrovascular
Note: Dosing and frequency may vary by protocol and/or
accident, dehydration, embolism, erythema, febrile neu-
tropenia, hemolytic anemia (acute), hemolytic-uremic treatment phase; refer to specific protocol. In pediatric
syndrome, hypertension, hypotension, injection site patients, dosing may be based on either BSA (mg/m2),
reaction (pain, redness, swelling), limb ischemia (acute), weight (mg/kg), or a modified Calvert formula calcu-
malaise, metastases, pruritus, skin rash, tissue necrosis lation (mg); use extra precaution to verify dosing
(associated with extravasation), urticaria, vision loss parameters and units of GFR/estimated CrCl during
Drug Interactions calculations, as errors can lead to significant over/
Metabolism/Transport Effects None known. under dosing. Some protocols suggest weight or age
Avoid Concomitant Use cut-offs for weight-based (mg/kg) dosing; refer to spe-
Avoid concomitant use of CARBOplatin with any of the cific protocol. Carboplatin is associated with a high
following: BCG (\ntravesical); Deferiprone; Dipyrone; emetic potential in pediatric patients (Dupuis 2011);
Natalizumab; Pimecrolimus; SORAfenib; Tacrolimus antiemetics are recommended to prevent nausea and
(Topical); Vaccines (Live) vomiting (Dupuis 2013).

368
 CARBOPLATIN

Calvert Formula, modified: Limited data available; Children >3 years: IV: 560 mg/m? on day 0 every 28
multiple formulas have been used; formula may be days in combination with etoposide and vincristine
protocol-specific (Liem 2003): Some protocols may for 6 cycles (VEC regimen)
calculate pediatric carboplatin doses using one of Sarcomas; Ewing sarcoma, osteosarcoma: Children
the following modified Calvert formulas: and Adolescents: IV: 400 mg/m?/day for 2 days every
21 days in combination with ifosfamide and etoposide
Modified Calvert Formulas (ICE regimen) (Van Winkle 2005)
Wilms tumor, relapsed or refractory:
Target AUC: Protocol specific dependent upon indication; value Abu-Ghosh 2002; Daw 2009: Children and Adoles-
presented in terms of mg/mL and minute units (eg, mg/mL/minute or
mg/mL-minute are frequently reported). cents: IV: 400 mg/m2/day for 2 days or modified
Note: Ensure appropriate GFR value“ is used for calculation and
Calvert using Marina/St. Jude formula with a target
resulting carboplatin dose (mg or mg/m‘) units. AUC=6 for 1 day in combination with ifosfamide and
etoposide every 21 days (ICE regimen)
Total dose (mg) = Target AUC x [uncorrected or raw Spreafico 2008: Reinduction prior to autologous stem
GFR (mL/minute) + (0.36 x kg body weight)] cell rescue: Children <12 years: IV: 600 mg/m? for 1
dose in combination with ifosfamide and etoposide
Mann/Pein Dosing adjustment for toxicity: The presented dosing
formula
(Mann' ! Total dose mg) = Target AUC x [uncorrected or raw adjustments are based on experience in adult patients;
1998; Mann GFR (mL/minute) + (15 x BSA(m?))] specific recommendations for pediatric patients are
2000; Pein
limited. Refer to specific protocol for management in
pediatric patients if available.
Marina/St.
Adult: Post-treatment nadir: Platelets <50,000 cells/
Dose (mg/m?) = Target AUC x [(0.93 x corrected GFR
normalized to patient's BSA (mL/minute/m)) + 15] mm? or ANC <500 ceélls/mm?: Administer 75% of dose
(Allen 2010;
~ Marina Renal Impairment: Pediatric
1993) Infants, Children, and Adolescents: The following dos-
AGER definitions: age adjustments have been recommended (Aronoff
Raw GFR = uncorrected GFR = mL/minute 2007):
Normalized GFR = corrected GFR = mL/minute/1.73 m*
GFR >50 mL/minute/1.73 m2: No dosage adjustment
®Marina/St. Jude formula: Uses a corrected GFR normalized to patient's necessary
BSA (mL/minute/m*); converting GER to this may be done as follows:
Corrected GFR (mL/minute/1.73 m?)/1.73 = GFR (mL/minute/m*) GFR <50 mL/minute/1.73 m?: Use modified Calvert
Uncorrected GFR (mL/minute)/patient's BSA = GFR (mL/minute/m?) formula (see protocol for specific details) incorporat-
Note: Calvert formula was based on using chromic ing patient's GFR
edetate (51Cr-EDTA) plasma clearance to establish Continuous renal replacement therapy (CRRT): Use
GFR. This or 99mTc- DTPA nuclear medicine GFR modified Calvert formula (see protocol for specific
details) incorporating GFR of 33 mL/minute
study is preferred over estimating CrCl per Schwartz
Hemodialysis, peritoneal dialysis: Use modified Cal-
equation as CrCl theoretically exceeds measured
vert formula (see protocol for specific details) incor-
GFR by >12% in subjects with normal renal function
porating GFR <10 mL/minute
(Allen 2010) (see Warnings/Precautions for addi-
Hepatic Impairment: Pediatric There are no dosage
tional information).
adjustments provided in the manufacturer's labeling;
Hematopoietic stem cell transplant (HSCT): Limited
however, carboplatin undergoes minimal hepatic metab-
data available:
olism; dosage adjustment may not be needed.
Cohen 2015: Consolidation with myeloablative che-
Preparation for Administration Note: Needles or IV
motherapy: Infants 26 months and Children <3
administration sets that contain aluminum should not be
years: IV: 17 mg/kg over 2 hours on days 0 and 1
used in the preparation or administration of carboplatin;
of a 21-day cycle in combination with thiotepa for 3 aluminum can react with carboplatin resulting in precip-
cycles. itate formation and loss of potency.
Gilheeney 2010, Kushner 2001: Myeloablative: Chil- Parenteral: IV: Solution for injection: Manufacturer’s label-
dren and Adolescents: IV: ~500 mg/m? over 4 hours ing states solution can be further diluted to concentra-
for 3 doses on days -5 to -3; dosing utilized Calvert tions as low as 0.5 mg/mL in NS or D5W; in adults,
formula with a target AUC=7 in combination regimen doses are generally diluted in either 100 mL or 250 mL
with thiotepa and topotecan of NS or D5W.
Spreafico 2008: Consolidation after reinduction Concentrations used for desensitization vary based on
chemo (relapsed Wilms Tumor): Children <12 years: protocol.
IV; 200 mg/m? for 4 doses on days -6 to -3 in Administration Carboplatin is associated with a moderate
combination with melphalan and etoposide emetic potential in adult patients and a high emetic
Glioma: Limited data available (Packer 1997): Infants potential in pediatric patients; antiemetics are recom-
23 months, Children, and Adolescents: mended to prevent nausea and vomiting (Basch 2011;
Induction: |V: 175 mg/m? once weekly-for 4 weeks Dupuis 2011; Roila 2010).
every 6 weeks (2-week recovery period between Parenteral: Note: Needles or IV administration sets that
courses) in combination with vincristine for 2 cycles contain aluminum should not be used in the preparation
Maintenance: IV: 175 mg/m? weekly for 4 weeks, with or administration of carboplatin; aluminum can react with
a 3-week recovery period between courses in com- carboplatin resulting in precipitate formation and loss of
bination with vincristine for <12 cycles potency.
Neuroblastoma, localized and unresectable: Limited IV: Administer over 15 to 60 minutes although some
data available: protocols may require infusions up to 24 hours. When
Infants: IV: 6.6 mg/kg on days 1, 2, and 3 in combi- administered as a part of a combination chemotherapy
nations with etoposide for 2 cycles (CE regimen), regimen, sequence of administration may vary by regi-
followed by cyclophosphamide, doxorubicin, and men; refer to specific protocol for sequence recommen-
vincristine (CAdO regimen) (Rubie 2001) dation.
Children <10 kg: IV: 100 to 140 mg/m?/day on days 1, Vesicant/Extravasation Risk May be an irritant
2, and 3 every 21 days in combination with etopo- Monitoring Parameters CBC with differential and plate-
side for 2 cycles (CE regimen), followed by cyclo- let count, serum electrolytes, serum creatinine and BUN,
phosphamide, doxorubicin, and vincristine (CAdO nuclear medicine measured GFR or creatinine clearance,
regimen) (Rubie 1998) liver function tests; audiology evaluations in pediatric
Children 210 kg and Adolescents: IV: 200 mg/m?/day patients
on days 1, 2, and 3 every 21 days in combination Dosage Forms Excipient information presented when
with etoposide for 2 cycles (CE regimen), followed available (limited, particularly for generics); consult spe-
by cyclophosphamide, doxorubicin,-and vincristine cific product labeling.
(CAdO regimen) (Rubie 1998) Solution, Intravenous:
Retinoblastoma: Limited data available: Generic: 50 mg/5 mL (5 mL); 150 mg/15 mL (15 mL);
Rodriguez-Galindo 2003: Infants and Children: 450 mg/45 mL (45 mL); 600 mg/60 mL (60 mL)
GFR 250 mL/minute/m?: IV: 560 mg/m? in combina- Solution, Intravenous [preservative free]:
tion with vincristine every 21 days for 8 cycles Generic: 50 mg/5 mL (5 mL); 150 mg/15 mL (15 mL);
GFR <50 mL/minute/m?: IV: Dosing utilized modified 450 mg/45 mL (45 mL); 600 mg/60 mL (60 mL)
Calvert formula with a target AUC=6.5 in combina- @ Carboplatin Injection (Can) see CARBOplatin
tion regimen with vincristine every 21 days for 8 on page 367
cycles
@ Carboplatin Injection BP (Can) see CARBOplatin
Friedman 2000:
on page 367 z
Infants and Children <3 years: IV: 18.6 mg/kg on
day 0 every 28 days in combination with etoposide @ Carboxypeptidase-G2 see Glucarpidase on page 952
and vincristine for 6 cycles (VEC regimen) @ Cardene see NiCARdipine on page 1447

369
CARGLUMIC ACID

@ Cardene IV see NiCARdipine on page 1447 Mechanism of Action N-acetylglutamate synthase

Cardene SR [DSC] see NiCARdipine on page 1447 (NAGS) is a mitochondrial enzyme which produces N-
@ Cardizem see DilTIAZem on page 643 acetylglutamate (NAG). NAG is a required allosteric acti-
vator of the hepatic’ mitochondrial enzyme, carbamoyl
@ Cardizem CD see DilTl|AZem on page 643
phosphate synthetase 1 (CPS 1), which converts ammo-
@ Cardizem LA see DilTl|AZem on page 643 nia into urea in the first step of the urea cycle. In NAGS-
@ Cardura see Doxazosin on page 687 deficient patients, carglumic acid serves as a replacement
@ Cardura-1 (Can) see Doxazosin on page 687 for NAG.
@ Cardura-2 (Can) see Doxazosin on page 687 Pharmacodynamics/Kinetics (Adult data unless
Cardura-4 (Can) see Doxazosin on page 687 noted)
Distribution: Vg: ~2657 L
@ Cardura XL see Doxazosin on page 687
Metabolism: Via intestinal flora to carbon dioxide
Half-life elimination: Median: 5.6 hours (range: 4.3 to 9.5
Carglumic Acid (kar GLU mikAs id) hours)
Time to peak: Median: 3 hours
Brand Names: US Carbaglu
Excretion: Feces (s60% as unchanged drug); urine (9%
Brand Names: Canada Carbaglu
as unchanged drug)
Therapeutic Category Antidote; Metabolic Alkalosis
Dosing
Agent; Urea Cycle Disorder (UCD) Treatment Agent
Generic Availability (US) No Neonatal
Acute hyperammonemia; adjunct therapy: Oral:
Use Adjunctive therapy-for treatment of acute hyperammo-
nemia due to N-acetylglutamate synthase (NAGS) defi- 100-250 mg/kg/day given in 2 or 4 divided doses; titrate
ciency (FDA approved in all ages); maintenance therapy to age-appropriate plasma ammonia concentrations;
for chronic hyperammonemia due to NAGS deficiency concomitant ammonia-lowering therapy recommended.
(FDA approved in all ages) Chronic hyperammonemia: Oral: Usual dose:
Prescribing and Access Restrictions Carbaglu is not <100 mg/kg/day given in 2 or 4 divided doses; titrate
available through pharmaceutical wholesalers or retail to age-appropriate plasma ammonia concentrations
pharmacies, but only through direct shipping from the Pediatric
Accredo specialty pharmacy. Prescribers must contact Acute hyperammonemia: Infants, Children, and Ado-
Accredo Health Group at 888-454-8860 or refer to www.- lescents: Oral: 100 to 250 mg/kg/day given in 2 or 4
accredo.com to initiate patients on this product. divided doses; titrate to age-appropriate plasma
Pregnancy Risk Factor C ammonia concentrations; concomitant ammonia-low-
Pregnancy Considerations Adverse events have been ering therapy recommended
observed in animal reproduction studies. There are no
Chronic hyperammonemia: Infants, Children, and
adequate and well-controlled studies in pregnant women.
Adolescents: Oral: Usual dose: <100 mg/kg/day given
However, due to the potential for irreversible fetal neuro-
logic damage for untreated NAGS deficiency, women with in 2 or 4 divided doses; titrate to age-appropriate
this condition must remain on treatment throughout preg- plasma ammonia concentrations
nancy. Renal Impairment: Pediatric There are no dosage
Breastfeeding Considerations It is not known if carglu- adjustments provided in the manufacturer's labeling
mic acid is excreted in breast milk. Breastfeeding is not (has not been studied).
recommended. Hepatic Impairment: Pediatric There are no dosage
Contraindications adjustments provided in the manufacturer’s labeling (has
There are no contraindications listed in the manufacturer’s not been studied).
labeling. Preparation for Administration
Canadian labeling: Additional contraindications (not in US Oral: Each 200 mg tablet should be dispersed in at least
labeling): Hypersensitivity to carglumic acid or any com-
2.5 mL of water (no other foods/liquids) and adminis-
ponent of the formulation; breastfeeding
tered immediately.
Warnings/Precautions Acute symptomatic hyperammo-
Oral syringe: Disperse each 200 mg tablet in 2.5 mL of
nemia is a life-threatening emergency; management of
water to yield a concentration of 80 mg/mL (shake gently
hyperammonemia due to N-acetylglutamate synthase
(NAGS) deficiency should be done in coordination with in container). Appropriate volume of dispersion should
those experienced in the management of metabolic dis- be drawn up in an oral syringe and administered imme-
orders. With hyperammonemia, complete protein restric- diately (discard unused dispersion).
tion should be maintained for 24-48 hours and caloric Nasogastric tube: Disperse each 200 mg tablet in water
supplementation should be maximized to reverse catabo- (2.5 mL per tablet for pediatric patients; 22.5 mL per
lism and nitrogen turnover. tablet for adults) and shake gently; administer immedi-
Adverse Reactions ately.
Central nervous system: Drowsiness, headache Administration
Dermatologic: Hyperhidrosis, skin rash Oral: Administer immediately before meals.
Endocrine & metabolic: Weight loss Tablets should not be crushed or swallowed whole. After
Gastrointestinal: Abdominal pain, anorexia, diarrhea, dys-
dispersion in water, administer immediately. Tablets do
geusia, vomiting
not dissolve completely, and some particles may
Hematologic & oncologic: Anemia, decreased hemoglobin
remain; rinse container with water and administer rinse
Infection: Infection, influenza
Neuromuscular & skeletal: Weakness immediately.
Otic: Otic infection Oral syringe: After dispersion of tablets in water, draw up
Respiratory: Nasopharyngitis, pneumonia, tonsillitis appropriate volume and administer immediately (dis-
Miscellaneous: Fever card unused dispersion). After initial administration,
Rare but important or life-threatening: Acidosis, acquired refill oral syringe with a minimum of 1 to 2 mL of water
blood coagulation disorder, brain damage, brain disease, and administer immediately.
central nervous system dysfunction, cerebral edema, Nasogastric tube: After dispersion of tablets in water,
coma, decreased white blood cell count, developmental immediately administer through a nasogastric tube, fol-
delay (motor development), eating disorder, eosinophilia, lowed by flush with additional water to clear the tube
epilepsy, hyperammonemia, hyponatremia, increased (tablets do not dissolve completely; some particles may
intracranial pressure, increased liver enzymes, lactic
remain). Carglumic acid tablets should not be mixed with
acidosis, lethargy, low serum ferritin, otitis media, respi-
any other foods or liquids other than water.
ratory failure, seizure, sepsis, thrombocytopenia
Monitoring Parameters Plasma ammonia concentra-
Drug Interactions
tions; physical signs/symptoms of hyperammonemia (eg,
Metabolism/Transport Effects None known.
Avoid Concomitant Use There are no known interac- lethargy, ataxia, confusion, vomiting, seizures, memory
tions where it is recommended to avoid concomitant use. impairment)
Increased Effect/Toxicity There are no known signifi- Dosage Forms Excipient information presented when
cant interactions involving an increase in effect. available (limited, particularly for generics); consult spe-
Decreased Effect There are no known significant inter- cific product labeling.
actions involving a decrease in effect. Tablet, Oral:
Storage/Stability Before opening, store refrigerated at Carbaglu: 200 mg [scored]
2°C to 8°C (36°F to 46°F). After opening, do not refrigerate
or store above 30°C (86°F). Protect from moisture. Dis- @ Carimune NF see Immune Globulin on page 1056
card 1 month after opening. @ Caripul (Can) see Epoprostenol on page 756

370
 CARMUSTINE

occurs in patients who have received prolonged treat-

Carmustine (kar mus teen) ment, pulmonary fibrosis has been reported with cumu-
lative doses below 1,400 mg/m?. Interstitial fibrosis at
Medication Safety Issues lower doses has occurred (rare). In addition to high
Sound-alike/look-alike issues: cumulative doses, other risk factors for pulmonary tox-
Carmustine may be confused with bendamustine, lomus- icity include history of lung disease and baseline pre-
tine dicted forced vital capacity (FVC) or carbon monoxide
High alert medication: / diffusing capacity (DLCO) <70%. Baseline and periodic
This medication is in a class the Institute for Safe pulmonary function tests are recommended. For high-
Medication Practices (ISMP) includes among its list of dose treatment (transplant; off-label dose), acute lung
drug classes which have a heightened risk of causing
injury may occur ~1 to 3 months post transplant; advise
significant patient harm when used in error.
patients to contact their transplant physician for dyspnea,
Brand Names: US BiCNU; Gliadel Wafer cough, or fever; interstitial pneumonia may be managed
Brand Names: Canada BiCNU; Gliadel Wafer with a course of corticosteroids. Children are at higher
Therapeutic Category Antineoplastic Agent, Alkylating risk of delayed pulmonary toxicity with 1V carmustine.
Agent; Antineoplastic Agent, Alkylating Agent (Nitro-
sourea) ‘ Reversible increases in transaminases, bilirubin, and
Generic Availability (US) No alkaline phosphatase have been reported (rare) with
Use the IV formulation. Monitor liver function tests periodi-
Injection: Treatment of brain tumors (glioblastoma, brain- cally during treatment. May require dosage adjustment
stem glioma, medulloblastoma, astrocytoma, ependy- or discontinuation in patients with renal impairment. Do
moma, and metastatic brain tumor); multiple myeloma, not administer carmustine IV in patients with compro-
Hodgkin lymphoma, and non-Hodgkin lymphomas mised renal function Renal failure, progressive azotemia,
(relapsed or refractory) (FDA approved in adults); has and decreased kidney size have been reported in
also been used for myeloablative therapy prior to stem patients who have received large cumulative doses or
cell transplant prolonged treatment. Renal toxicity has also been
Wafer (implant): Adjunct to surgery in patients with recur- reported in patients who have received lower cumulative
rent glioblastoma multiforme; adjunct to surgery and doses. Monitor renal function tests periodically during
radiation in patients with newly diagnosed high grade treatment.
malignant glioma (FDA approved in adults)
Carmustine IV is associated with a moderate to high
Pregnancy Risk Factor D
emetic potential (dose-related); antiemetics are recom-
Pregnancy Considerations Adverse events have been mended to prevent nausea and vomiting (Dupuis 2011;
observed in animal reproduction studies. Based on the
Hesketh 2017; Roila 2016). Rapid-infusions are associ-
mechanism of action, carmustine may cause fetal harm if
ated with skin flushing and suffusion of the conjunctiva
administered to a pregnant woman. Females of reproduc-
(onset: <2 hours; duration ~4 hours). Carmustine is also
tive potential should use highly effective contraceptives
associated with injection site burning and local tissue
during and for at least 6 months following treatment. Males
reactions, including swelling, pain, erythema, and
of reproductive potential should use highly effective con-
necrosis have been reported. Monitor infusion site
traceptives during and for at least 3 months following
closely for infiltration or injection site reactions. Avoid
treatment. May impair male fertility. Advise males of
extravasation. Investigational administration (intraarterial
potential risk of infertility and to seek fertility/family plan-
intracarotid route [not an approved route]) has been
ning counseling prior to receiving carmustine wafer
implants. associated with ocular toxicity. The diluent for |V carmus-
tine contains ethanol.
Breastfeeding Considerations It is not known if car-
mustine is present in breast milk. Due to the potential for Wafer implant:
serious adverse reactions in the breastfed infant, the Seizures occurred in patients who received carmustine
manufacturer recommends breastfeeding be discontinued wafer implants, including new or worsening seizures and
during treatment. treatment-emergent seizures. Just over half of treat-
Contraindications ment-emergent seizures occurred within 5 days of sur-
IV: Hypersensitivity to carmustine or any component of the gery; the median onset of first new or worsened post-
formulation operative seizure was 4 days. Optimal anti-seizure ther-
Implant: There are no contraindications listed in the man- apy should be initiated prior to surgery. Monitor (post-
ufacturer's labeling. operatively) for seizures. Brain edema has been reported
Warnings/Precautions in patients with newly diagnosed glioma, including one
Injection: report of intracranial mass effect unresponsive to cortico-
[US Boxed Warning]: Carmustine IV causes bone steroids which led to brain herniation. Monitor closely for
marrow suppression, primarily thrombocytopenia intracranial hypertension related to brain edema, inflam-
(which may lead to bleeding) and leukopenia (which mation, or necrosis of brain tissue surrounding resection.
may cause infection). Monitor blood counts weekly Re-operation to remove wafers (or remnants) may be
for at least 6 weeks following each dose. Adjust necessary for refractory cases. Cases of meningitis have
dosage based on nadir blood counts from prior dose occurred in patients with recurrent glioma receiving
for dosage adjustment. Do not administer a repeat wafer implants. Two cases were bacterial (one patient
course until blood counts recover. Hematologic tox- required removal of implants 4 days after implantation
icity is dose-limiting, may be severe, and is generally and the other developed meningitis following reoperation
delayed and cumulative; thrombocytopenia is usually for recurrent tumor). Another case was determined to be
more severe than leukopenia. Myelosuppression gener-
chemical meningitis and resolved with corticosteroids.
ally occurs 4 to 6 weeks after administration; thrombo- Monitor postoperatively for signs/symptoms of meningitis
cytopenia occurs at ~4 weeks and persists for 1 to 2
and CNS infection.
weeks; leukopenia occurs at 5 to 6 weeks and persists
for 1 to 2 weeks. Anemia may occur (less common and Monitor closely for known craniotomy-related complica-
less severe than leukopenia or thrombocytopenia). Pla- tions (seizure, intracranial infection, abnormal wound
telet counts should be >100,000/mm® and leukocytes healing, brain edema), Wafer migration may occur; avoid
should be >4,000/mm‘® prior to a repeat course (repeat communication between the resection cavity and the
courses should not be administered more frequently than ventricular system to prevent wafer migration; communi-
every 6 weeks). Long-term IV use is associated with the cations larger than the wafer should be closed prior to
development of secondary malignancies (acute leuke- implantation; wafer migration into the ventricular system
mias and bone marrow dysplasias). may cause obstructive hydrocephalus. Monitor for signs/
[US Boxed Warning]: Carmustine IV is associated symptoms of obstructive hydrocephalus.
with dose-related pulmonary toxicity; patients Impaired neurosurgical wound healing, including would
receiving cumulative doses >1,400 mg/m? are at sig- dehiscence, delayed healing, and subdural, subgleal or
nificantly higher risk. Delayed onset of pulmonary wound effusions may occur with carmustine wafer
fibrosis may occur years after treatment (may be implant treatment; cerebrospinal fluid leaks have also
fatal), particularly in children. Pulmonary toxicity has been reported. Monitor post-operatively for impaired
occurred in children and adolescents up to 17 years after neurosurgical wound healing.
treatment; this occurred in ages 1 to 16 for the treatment
of intracranial tumors; cumulative doses ranged from 770 Potentially significant drug-drug interactions may exist,
to 1,800 mg/m? (in combination with cranial radiother- requiring dose or frequency adjustment, additional mon-
apy). Pulmonary toxicity is characterized by pulmonary itoring, and/or selection of alternative therapy.
infiltrates and/or fibrosis and has been reported from 9 Adverse Reactions
days to 43 months after nitrosourea treatment (including Implant:
carmustine). Although pulmonary toxicity generally Cardiovascular: Chest pain

371
 CARMUSTINE

4 Central nervous system: Cerebral edema, cerebral hem-

orrhage, depression, intracranial hypertension, menin-
Reconstituted solutions are stable for 24 hours refriger-
ated (2°C to 8°C) and protected from light. Examine
gitis, seizure (less common with new or worsening) reconstituted vials for crystal formation prior to use. If
Dermatologic: Skin rash crystals are observed, they may be redissolved by
Gastrointestinal: Abdominal pain, constipation, nausea, warming the vial to room temperature with agitation.
vomiting Solutions diluted for infusion to a concentration of
Genitourinary: Urinary tract infection 0.2 mg/mL in D5W or NS in glass or polypropylene
Infection: Abscess containers and protected from light should be used
Neuromuscular & skeletal: Back pain, weakness within 8 hours when stored at room temperature
Miscellaneous: Fever, wound healing impairment (25°C); infusion solutions are also stable for 24 hours
IV: refrigerated followed by an additional 6 hours at room
Cardiovascular: Chest pain, flushing (with rapid infu- temperature. Although the manufacturer recommends
sion), occlusive arterial disease, tachycardia glass or polypropylene containers be used, stability of a
Central nervous system: Brain disease, headache, 1 mg/mL solution in D5W has also been demonstrated
seizure for up to 6 hours (with a 6% to 7% loss of potency) in
Dermatologic: Alopecia, burning sensation of skin, polyolefin containers (Trissel 2006).
hyperpigmentation Wafer: Store at or below -20°C (-4°F). Unopened outer foil
Gastrointestinal: Anorexia, diarrhea, nausea, vomiting pouches may be kept at room temperature for up to 6
Genitourinary: Gynecomastia hours at a time for up to 3 cycles within a 30-day period.
Hematologic & oncologic: Acute leukemia, anemia, bone Mechanism of Action Carmustine interferes with the
marrow dysplasia, leukemia, leukopenia (common; normal function of DNA and RNA by alkylation and
onset: 5 to 6 weeks; recovery: after 1 to 2 weeks), cross-linking the strands of DNA and RNA, and by possi-
thrombocytopenia (common: onset: ~4 weeks; recov- ble protein modification; may also inhibit enzyme proc-
ery: after 1 to 2 weeks) esses by carbamylation of amino acids in protein.
Hepatic: Increased serum alkaline phosphatase, Pharmacodynamics/Kinetics (Adult data unless
increased serum bilirubin, increased serum transami- noted)
nases Distribution: IV: 3.3 L/kg; readily crosses blood-brain
Hypersensitivity: Hypersensitivity reaction barrier producing CSF levels 250% of blood plasma
Infection: Opportunistic infection levels; highly lipid soluble
Local: Burning sensation at injection site, erythema at . Metabolism: Rapidly hepatic; forms active metabolites
injection site, pain at injection site, swelling at injection Half-life elimination: IV: 15 to 75 minutes
site, tissue necrosis at injection site Excretion: IV: Urine (~60% to 70%) within 96 hours; lungs
Ophthalmic: Blurred vision, conjunctival edema, conjunc- (~10% as COz)
tival hemorrhage, ophthalmic signs and symptoms Dosing
(loss of depth perception), suffusion of the conjunctiva Pediatric
(with rapid infusion) Note: Children are at increased risk for pulmonary
Renal: Azotemia (progressive), nephron atrophy, renal toxicity due to carmustine, weigh risk vs benefit before
failure use. Refer to individual protocols; dosing and fre-
Respiratory: Interstitial pulmonary disease, pneumonitis, quency may vary. Pediatric specific recommendations
pulmonary fibrosis (occurring up to 17 years after treat- for dosing in obese patients due to insufficient data; in
ment), pulmonary infiltrates adult patients, it is suggested to utilize patient's actual
Rare but important or life-threatening: Febrile neutropenia
body weight (full weight) for calculation of body surface
(Chopra 1993), sepsis (implant), venous thrombosis at area- or weight-based dosing, particularly when the
injection site (IV)
intent of therapy is curative; manage regimen-related
Drug Interactions toxicities in the same manner as for nonobese patients;
Metabolism/Transport Effects None known. if a dose reduction is utilized due to toxicity, consider
Avoid Concomitant Use resumption of full weight-based dosing with subse-
Avoid concomitant use of Carmustine with any of the quent cycles, especially if cause of toxicity (eg, hepatic
following: BCG (Intravesical); Deferiprone; Dipyrone; or renal impairment) is resolved (Griggs 2012)
Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac- Brain tumors, myeloablative therapy prior to autol-
cines (Live) ogous stem cell rescue: Very limited data available;
Increased Effect/Toxicity Infants, Children, and Adolescents: IV: 100 mg/m?/
Carmustine may increase the levels/effects of: Bariciti- dose twice daily for 3 days (total: 600 mg/m?) as part
nib; CloZAPine; Deferiprone; Fingolimod; Leflunomide; of a high dose combination chemotherapy regimen is
Natalizumab; Tofacitinib; Vaccines (Live) most commonly reported in trials with mixed results
The levels/effects of Carmustine may be increased by: (Dunkel 1998; Finlay 2008); however, a phase | trial
Chloramphenicol (Ophthalmic); Cimetidine; Denosumab; identified a lower dose of 100 mg/m/dose once daily
Dipyrone; Melphalan; Ocrelizumab; Palifermin; Pimecro- for 3 days (total: 300 mg/m?) in combination with
limus; Promazine; Roflumilast; Tacrolimus (Topical); thiotepa as the maximum tolerated regimen with a
Trastuzumab high degree of pulmonary toxicity observed (Gil-
Decreased Effect man 2011).
Carmustine may decrease the levels/effects of: BCG Non-Hodgkin lymphoma; relapsed or resistant,
(Intravesical); Coccidioides immitis Skin Test; Lenogras- high-dose chemotherapy prior to autologous
tim; Lipegfilgrastim; Nivolumab; Pidotimod; Sipuleucel-T; bone marrow transplant: Limited data available:
Tertomotide; Vaccines (Inactivated); Vaccines (Live) BEAM regimen: Adolescents 215 years: IV:
300 mg/m2/dose for 1 dose followed by etoposide,
The levels/effects of Carmustine may be decreased by: cytarabine, and melphalan (Mills 1995)
Echinacea CBV regimen: Children and Adolescents: IV:
Hazardous Drugs Handling Considerations 100 mg/m?/dose once daily for 3 days (total dose:
Hazardous agent (NIOSH 2016 [group 1)). 300 mg/m?) on days -8 through -6 in combination
with cyclophosphamide and etoposide (Harris 2011)
Use appropriate precautions for receiving, handling,
Dosing adjustment for toxicity: The presented dosing
administration, and disposal. Gloves (single) should be
adjustments are based on experience in adult patients;
worn during receiving, unpacking, and placing in storage.
specific recommendations for pediatric patients are
NIOSH recommends double gloving, a protective gown, limited. Refer to specific protocol for management in
ventilated engineering controls (a class I! biological safety pediatric patients if available.
cabinet or a compounding aseptic containment isolator), Adult:
and (if applicable) closed system transfer devices Hematologic toxicity: Based on nadir counts with
(CSTDs) for preparation. Double gloving, a gown, and (if previous dose (manufacturer's labeling). IV:
dosage form allows) CSTDs are required during admin- If leukocytes 23,000/mm% and platelets >75,000/mm?:
istration (NIOSH 2016). Administer 100% of dose
Storage/Stability If leukocytes 2,000 to 2,999/mm% or platelets 25,000
Injection: Store intact vials and provided diluent at 2°C to to 74,999/mm®: Administer 70% of dose
8°C (36°F to 46°F). Carmustine has a low melting point If leukocytes <2,000/mm* or platelets <25,000/mm?:
(30.5°C to 32°C [86.9°F to 89.6°F]); exposure to temper- Administer 50% of dose
ature at or above the melting point will cause the drug to Renal Impairment: Pediatric lV: There are no dosage
liquefy and appear as an oil film on the vials; if drug adjustments provided in the manufacturer’s labeling;
liquefies, discard the vials as this is a sign of decom- experience in adult patients suggests that dose should
position. If there is a question of proper refrigeration be reduced in renal impairment.
upon receipt of product, inspect vials; a small amount Hepatic Impairment: Pediatric |V: There are no dos-
of dry flakes or dry congealed mass is acceptable and age adjustments provided in the manufacturer’s labeling;
the vial should be refrigerated immediately. use with caution, dosage adjustment may be necessary.
 CARVEDILOL

Preparation for Administration Parenteral: Reconsti- Use Treatment of mild to severe chronic heart failure of
tute initially with 3 mL of supplied diluent (dehydrated cardiomyopathic or ischemic origin (usually in addition to
alcohol injection, USP); then further dilute with 27 mL standard therapy) (FDA approved in ages 218 years and
SWFI, this provides a concentration of 3.3 mg/mL in adults); management of hypertension, alone or in combi-
ethanol 10%; protect from light. May further dilute in nation with other agents (FDA approved in ages 218 years
D5W in either glass or polyolefin containers due to sig- and adults); reduction of cardiovascular mortality in
nificant absorption to PVC containers. patients with left ventricular dysfunction following MI
Administration A (FDA approved in ages 218 years and adults)
Parenteral: Infuse over 2 hours (infusions <2 hours may Pregnancy Considerations Adverse events have been
lead to injection site pain or burning); infuse through a observed in animal reproduction studies. Adverse events,
free-flowing saline or dextrose infusion, or administer such as fetal/neonatal bradycardia, hypoglycemia, and
through a central catheter to alleviate venous pain/irrita- reduced birth weight, have been observed following in
tion. Significant absorption to PVC containers; should be utero exposure to beta-blockers as a class. Adequate
prepared in either glass or polyolefin containers. facilities for monitoring infants at birth is generally recom-
High-dose carmustine (transplant dose): Infuse over at mended.
least 2 hours to avoid excessive flushing, agitation, and
Untreated chronic maternal hypertension and preeclamp-
hypotension; was infused over 1 hour in some trials
sia are also associated with adverse events in the fetus,
(Chopra 1993). High-dose carmustine may be fatal if
infant, and mother (ACOG 2015; Magee 2014). Although
not followed by stem cell rescue. Monitor vital signs
beta-blockers may be used when treatment of hyper-
frequently during infusion; patients should be supine
tension or heart failure in pregnancy is indicated, agents
during infusion and may require the Trendelenburg
other than carvedilol are preferred (ACOG 2013; ESC
position, fluid support, and vasopressor support.
[Regitz-Zagrosek 2011]; Magee 2014).
Wafer: Double glove before handling; outer gloves should
Breastfeeding Considerations It is not known if carve-
be discarded as chemotherapy waste after handling
dilol is present in breast milk. According to the manufac-
wafers. Any wafer or remnant that is removed upon
turer, the decision to continue or discontinue
repeat surgery should be discarded as chemotherapy
breastfeeding during therapy should take into account
waste. The outer surface of the external foil pouch is not
the risk of infant exposure, the benefits of breastfeeding
sterile. Open pouch gently; avoid pressure on the wafers
to the infant, and benefits of treatment to the mother.
to prevent breakage. Wafers that are broken in half may
Breastfeeding is not recommended for women with heart
be used, however, wafers broken into more than 2
failure related to peripartum cardiomyopathy due to the
pieces should be discarded in a biohazard container.
high metabolic demands of lactation and breastfeeding
Oxidized regenerated cellulose (Surgicel) may be placed
(ESC [Regitz-Zagrosek 2011]; Sliwa 2010).
over the wafer to secure; irrigate cavity prior to closure.
Contraindications
Vesicant/Extravasation Risk Irritant; infiltration may
Serious hypersensitivity to carvedilol or any component of
result in local pain, erythema, swelling, burning and skin
the formulation; decompensated cardiac failure requiring
necrosis; the alcohol-based diluent may be an irritant,
intravenous inotropic therapy; bronchial asthma or
especially with high doses.
related bronchospastic conditions; second- or third-
Monitoring Parameters CBC with differential and plate- degree AV block, sick sinus syndrome, and severe
let count (weekly for at least 6 weeks after a dose), bradycardia (except in patients with a functioning artifi-
pulmonary function tests (FVC, DLCO; at baseline and
cial pacemaker); cardiogenic shock; severe hepatic
frequently during treatment), liver function (periodically), impairment
renal function tests (periodically); monitor blood pressure Documentation of allergenic cross-reactivity for drugs
and vital signs during administration, monitor infusion site alpha/beta adrenergic blocking agents is limited. How-
for possible infiltration ever, because of similarities in chemical structure and/or
Wafer: Complications of craniotomy (seizures, intracranial pharmacologic actions, the possibility of cross-sensitivity
infection, brain edema) cannot be ruled out with certainty.
Dosage Forms Excipient information presented when Warnings/Precautions Heart failure patients may expe-
available (limited, particularly for generics); consult spe- rience a worsening of renal function (rare); risk factors
cific product labeling. include ischemic heart disease, diffuse vascular disease,
Solution Reconstituted, Intravenous: underlying renal dysfunction, and/or systolic BP <100 mm
BiCNU: 100 mg (1 ea) [contains alcohol, usp] Hg. Initiate cautiously and monitor for possible deteriora-
Wafer, Implant: tion in patient status (eg, symptoms of HF). Worsening
Gliadel Wafer: 7.7 mg (8 ea) [contains polifeprosan 20] heart failure or fluid retention may occur during upward
titration; dose reduction or temporary discontinuation may
Sa Carmustine Polymer Wafer see Carmustine be necessary. Adjustment of other medications (ACE
on page 371 inhibitors and/or diuretics) may also be required. Brady-
Carmustine Sustained-Release Implant Wafer see cardia may occur; reduce dosage if heart rate drops to <55
Carmustine on page 371 beats/minute. Bradycardia may be observed more fre-
quently in elderly patients (>65 years of age); dosage
@ Carmustinum see Carmustine on page 371
reductions may be necessary.
@ Carnitine see LevOCARNitine on page 1200
Symptomatic hypotension with or without syncope may
Carnitor see LevOCARNitine on page 1200
occur with carvedilol (usually within the first 30 days of
Carnitor SF see LevOCARNitine on page 1200 therapy); close monitoring of patient is required especially
CaroSpir see Spironolactone on page 1860 with initial dosing and dosing increases; blood pressure
@ Carrington Antifungal [OTC] see Miconazole (Topical) must be lowered at a rate appropriate for the patient's
on page 1371 clinical condition. Initiation with a low dose, gradual up-
titration, and administration with food may help to
® Carter's Little Pills [OTC] (Can) see Bisacodyl
decrease the occurrence of hypotension or syncope.
on page 277
Advise patients to avoid driving or other hazardous tasks
@ Cartia XT see DilTlIAZem on page 643 during initiation of therapy due to the risk of syncope.
Beta-blocker therapy should not be withdrawn abruptly
Carvedilol (kar ve dil ole) (particularly in patients with CAD), but gradually tapered
to avoid acute tachycardia, hypertension, and/or ischemia.
Medication Safety Issues _ Chronic beta-blocker therapy should not be routinely with-
Sound-alike/look-alike issues: drawn prior to major surgery.
Carvedilol may be confused with atenolol, captopril, In general, patients with bronchospastic disease should
carbidopa, carteolol not receive beta-blockers; if used at all, should be used
Coreg may be confused with Corgard, Cortef, Cozaar cautiously with close monitoring. May precipitate or aggra-
Related Information vate symptoms of arterial insufficiency in patients with
Oral Medications That Should Not Be Crushed or Altered PVD; use with caution and monitor for progression of
on page 2217 arterial obstruction. Use with caution in patients with
Brand Names: US Coreg; Coreg CR diabetes; may potentiate hypoglycemia and/or mask signs
Brand Names: Canada Apo-Carvedilol; Auro-Carvedilol; and symptoms (eg, sweating, anxiety, tachycardia). In
Dom-Carvedilol; JAMP-Carvedilol; Mylan-Carvedilol; patients with heart failure and diabetes, use of carvedilol
Novo-Carvedilol; PMS-Carvedilol; RAN-Carvedilol; ratio- may worsen hyperglycemia; may require adjustment of
Carvedilol antidiabetic agents. May mask signs of hyperthyroidism
Therapeutic Category Antihypertensive Agent; Beta- (eg, tachycardia); if hyperthyroidism is suspected, care-
Adrenergic Blocker, Nonselective With Alpha-Blocking fully manage and monitor; abrupt withdrawal may exacer-
Activity / bate symptoms of hyperthyroidism or precipitate thyroid
Generic Availability (US) Yes storm. May induce or exacerbate psoriasis. Use with >
373
CARVEDILOL

caution in patients suspected of having Prinzmetal variant Antipsychotic Agents (Phenothiazines); Antipsychotic
angina. Use with caution in patients with myasthenia Agents (Second Generation [Atypical]); Betrixaban;
gravis. Use with caution in patients with mild to moderate Bilastine; Bradycardia-Causing Agents; Brentuximab
hepatic impairment; use is contraindicated in patients with Vedotin; Bromperidol; Bupivacaine; Cardiac Glycosides;
severe impairment. Use with caution in patients with Celiprolol; Ceritinib; Cholinergic Agonists; Colchicine;
pheochromocytoma; adequate alpha-blockade is required CycloSPORINE (Systemic); Dabigatran Etexilate;
prior to use. Use caution with history of severe anaphy- Digoxin; Disopyramide; DOXOrubicin (Conventional);
laxis to allergens; patients taking beta-blockers may DULoxetine; Edoxaban; Ergot Derivatives; Everolimus;
become more sensitive to repeated challenges. Treatment Fingolimod; Grass Pollen Allergen Extract (5 Grass
of anaphylaxis (eg, epinephrine) in patients taking beta- Extract); Hypotension-Associated Agents; Insulins; lvab-
blockers may be ineffective or promote undesirable radine; Lacosamide; Levodopa; Lidocaine (Systemic);
effects. Lidocaine (Topical); Mepivacaine; Methacholine; Mido-
drine; Naldemedine; Naloxegol; Nitroprusside; PAZOPa-
Intraoperative floppy iris syndrome has been observed in nib; Perhexiline; P-glycoprotein/ABCB1 Substrates;
cataract surgery patients who were on or were previously Pholcodine; Prucalopride; Ranolazine; RifAXIMin; Silo-
treated with alpha,-blockers; there appears to be no dosin; Sulfonylureas; Topotecan; Venetoclax; VinCRIS-
benefit in discontinuing alpha-blocker therapy prior to tine (Liposomal)
surgery. Instruct patients to inform ophthalmologist of
carvedilol use when considering eye surgery. Potentially The levels/effects of Carvedilol may be increased by;
significant interactions may exist, requiring dose or fre- Abiraterone Acetate; Acetylcholinesterase Inhibitors;
quency adjustment, additional monitoring, and/or selec- Ajmaline; Alfuzosin; Alpha2-Agonists; Aminoquinolines
tion of alternative therapy. (Antimalarial); Amiodarone; Antipsychotic Agents (Phe-
nothiazines); Asunaprevir; Barbiturates; Benperidol; Bre-
Some dosage forms may contain polysorbate 80 (also tylium; Brigatinib; Brimonidine (Topical); Calcium
known as Tweens). Hypersensitivity reactions, usually a Channel Blockers (Nondihydropyridine); Cimetidine;
delayed reaction, have been reported following exposure Cobicistat; CYP2C9. Inhibitors (Moderate); CYP2D6
to pharmaceutical products containing polysorbate 80 in Inhibitors (Moderate); CYP2D6 Inhibitors (Strong); Dar-
certain individuals (Isaksson, 2002; Lucente 2000; Shel- unavir; Diazoxide; Digoxin; Dipyridamole; Disopyramide;
ley, 1995). Thrombocytopenia, ascites, pulmonary deteri- Dronedarone; Floctafenine; Herbs (Hypotensive Proper-
oration, and renal and hepatic failure have been reported ties); Imatinib; Lormetazepam; Lumacaftor; Lumefan-
in premature neonates after receiving parenteral products
trine; Methoxyflurane; Molsidomine; Naftopidil;
containing polysorbate 80 (Alade, 1986; CDC, 1984). See NiCARgipine; Nicergoline; Nicorandil; NIFEdipine; Obi-
manufacturer’s labeling.
nutuzumab; Opioids (Anilidopiperidine); Panobinostat;
Adverse Reactions Peginterferon Alfa-2b; Pentoxifylline; Perhexiline; P-gly-
Cardiovascular: Angina, AV block, bradycardia, cerebro- coprotein/ABCB1 Inhibitors; Phosphodiesterase 5 Inhib-
vascular accident, edema (including generalized, itors; Propafenone; Prostacyclin Analogues;
dependent, and peripheral), hyper-/hypotension, Quinagolide; QuiNINE; Ranolazine; Regorafenib; Reser-
hyper-/hypovolemia, orthostatic hypotension, palpitation, pine; Rivastigmine; Ruxolitinib; Selective Serotonin
syncope Reuptake Inhibitors; Terlipressin; Tofacitinib
Central nervous system: Depression, dizziness, fatigue, Decreased Effect
fever, headache, hypoesthesia, hypotonia, insomnia,
Carvedilol may decrease the levels/effects of: Beta2-
malaise, somnolence, vertigo, weakness
Agonists; EPINEPHrine (Nasal); EPINEPHrine (Oral
Endocrine & metabolic: Diabetes mellitus, gout, hyper- Inhalation); Epinephrine (Racemic); EPINEPHrine (Sys-
cholesterolemia, hyper-/hypoglycemia, hyponatremia,
temic); Theophylline Derivatives
hyperkalemia, hypertriglyceridemia, hyperuricemia
Gastrointestinal: Abdominal pain, diarrhea, melena, nau- The levels/effects of Carvedilol may be decreased by:
sea, periodontitis, vomiting, weight gain/loss Amphetamines; Barbiturates; Brigatinib; Bromperidol;
Genitourinary: Impotence Herbs (Hypertensive Properties); Lumacaftor; Methyl-
Hematologic: Anemia, prothrombin decreased, purpura, phenidate; Nonsteroidal Anti-Inflammatory Agents;
thrombocytopenia Peginterferon Alfa-2b; P-glycoprotein/ABCB1 Inducers;
Hepatic: Alkaline phosphatase increased, GGT increased, Rifamycin Derivatives; Yohimbine
transaminases increased Food Interactions Food decreases rate but not extent of
Neuromuscular & skeletal: Arthralgia, arthritis, back pain, absorption. Management: Administration with food mini-
muscle cramps, paresthesia mizes risks of orthostatic hypotension.
Ophthalmic: Blurred vision Storage/Stability
Renal: Albuminuria, BUN increased, creatinine increased, Coreg: Store at <30°C (<86°F). Protect from moisture.
glycosuria, hematuria, nonprotein nitrogen increased, Coreg CR: Store at 25°C (77°F); excursions permitted to
renal insufficiency 15°C to 30°C (59°F to 86°F). Protect from light.
Respiratory: Cough, dyspnea, nasopharyngitis, dyspnea, Mechanism of Action As a racemic mixture, carvedilol
nasal congestion, pulmonary edema, rales, rhinitis, sinus has nonselective beta-adrenoreceptor and alpha-adrener-
congestion gic blocking activity. No intrinsic sympathomimetic activity
Miscellaneous: Allergy, flu-like syndrome, injury, sudden has been documented. Associated effects in hypertensive
death patients include reduction of cardiac output, exercise- or
Rare but important or life-threatening: Anaphylactoid reac- beta-agonist-induced tachycardia, reduction of reflex
tion, alopecia, angioedema, aplastic anemia, amnesia, orthostatic tachycardia, vasodilation, decreased periph-
asthma, bronchospasm, bundle branch block, choles- eral vascular resistance (especially in standing position),
tatic jaundice, concentration decreased, diaphoresis, decreased renal vascular resistance, reduced plasma
erythema multiforme, exfoliative dermatitis, Gl hemor- renin activity, and increased levels of atrial natriuretic
rhage, HDL decreased, hearing decreased, hyperbiliru- peptide. In CHF, associated effects include decreased
binemia, hypersensitivity reaction, hypokalemia, pulmonary capillary wedge pressure, decreased’ pulmo-
hypokinesia, interstitial pneumonitis, leukopenia, libido nary artery pressure, decreased heart rate, decreased
decreased, migraine, myocardial ischemia, nervous- systemic vascular resistance, increased stroke volume
ness, neuralgia, nightmares, pancytopenia, paresis, index, and decreased right atrial pressure (RAP).
peripheral ischemia, photosensitivity, pruritus, rash Pharmacodynamics/Kinetics (Adult data unless
(erythematous, maculopapular, and psoriaform), respira- noted) ‘
tory alkalosis, seizure, Stevens-Johnson syndrome, Onset of action: Antihypertensive effect: Alpha-blockade:
tachycardia, tinnitus, toxic epidermal necrolysis, urinary Within 30 minutes; Beta-blockade: Within 1 hour
incontinence, urticaria, xerostomia Peak antihypertensive effect: ~1 to 2 hours
Drug Interactions Absorption: Oral: Rapid and extensive, but with large first
Metabolism/Transport Effects Substrate of CYP1A2 pass effect; first pass effect is stereoselective with R(+)
(minor), CYP2C9 (minor), CYP2D6 (major), CYP2E1 enantiomer achieving plasma concentrations 2 to 3 times
(minor), CYP3A4 (minor), P-glycoprotein/ABCB1; Note: higher than S(-) enantiomer; delayed with food
Assignment of Major/Minor substrate status based on Distribution: Vg: 115 L; distributes into extravascular
Clinically relevant drug interaction potential; Inhibits P- tissues
glycoprotein/ABCB1 Protein binding: >98%, primarily to albumin
Avoid Concomitant Use Metabolism: Extensively (98%) hepatic, via CYP2C9,
Avoid concomitant use of Carvedilol with any of the 2D6, 3A4, 2C19, 1A2, and 2E1 (2% excreted
following: Beta2-Agonists; Bromperidol; Ceritinib; Flocta- unchanged); metabolized predominantly by aromatic
fenine; Methacholine; PAZOPanib; Rivastigmine; Silodo- ring oxidation and glucuronidation; oxidative metabolites
sin; Topotecan; VinCRIStine (Liposomal) undergo conjugation via glucuronidation and sulfation;
Increased Effect/Toxicity three active metabolites (4-hydroxyphenyl metabolite is
Carvedilol may increase the levels/effects of: Afatinib; 13 times more potent than parent drug for beta-block-
Alphai-Blockers; Alpha2-Agonists; Amifostine; ade, however, active metabolites achieve plasma

374
 CARVEDILOL

concentrations of only 1/10 of those for carvedilol); first- Hypertension: Adolescents 218 years:
pass effect; plasma concentrations in the elderly and Immediate release tablets: Oral: Initial: 6.25 mg twice
those with cirrhotic liver disease are 50% and 4 to 7 daily; if tolerated, dose should be maintained for 1-2
times higher, respectively. Metabolism is subject to weeks, then increased to 12.5 mg twice daily; max-
genetic polymorphism; CYP2D6 poor metabolizers have imum daily dose: 50 mg/day
a 2- to 3-fold higher plasma concentration of the R(+) Extended release capsules: Oral: Initial: 20 mg once
enantiomer and a 20% to 25% increase in the S(-) daily; if tolerated, dose should be maintained for 1-2
enantiomer compared to extensive metabolizers. weeks, then increased to 40 mg once daily if neces-
Bioavailability: Immediate release: ~25% to 35% (due to sary; maximum daily dose: 80 mg/day
significant first-pass metabolism); Extended release: Left ventricular dysfunction following MI: Adoles-
~85% of immediate release; high-fat meal increases cents 218 years: Note: Initiate only after patient is
AUC and Crhax ~20%; bioavailability is increased in hemodynamically stable and fluid retention has been
patients with CHF minimized.
Half-life elimination: Immediate release tablets: Oral: Initial: 3.125-6.25 mg
Infants and Children 6 weeks to 3.5 years (n=8): 2.2 ‘twice daily; increase dosage incrementally (eg, from
hours (Laer 2002) 6.25 to 12.5 mg twice daily) at intervals of 3-10 days,
Children and Adolescents 5.5 to 19 years (n=7): 3.6 as tolerated, to a target dose of 25 mg twice daily
hours (Laer 2002) Extended release capsules: Oral: Initial: 10-20 mg
Adults 7 to. 10 hours; some have reported lower values: once daily; increase dosage incrementally at intervals
Adults 24 to 37 years (n=9): 5.2 hours (Laer 2002) of 3-10 days, as tolerated, to a target dose of 80 mg
R(+)-carvedilol: 5 to 9 hours once daily
S(-)-carvedilol: 7 to 11 hours Conversion from immediate release to extended
Time to peak, plasma: Extended release: ~5 hours release (Coreg CR®): Adolescents 218 years:
Excretion: Primarily feces; urine (<2%, unchanged) Current dose immediate release tablets 3.125 mg twice
Pharmacodynamics/Kinetics: Additional Consider- daily: Convert to extended release capsules 10 mg
once daily
ations
Current dose immediate release tablets 6.25 mg twice
Renal function impairment: Plasma concentrations may
daily: Convert to extended release capsules 20 mg
be higher (40% to 50% in moderate to severe renal
once daily
impairment).
Current dose immediate release tablets 12.5 mg twice
Hepatic function impairment: Severe hepatic impairment
daily: Convert to extended release capsules 40 mg
(cirrhosis) patients have a 4- to 7-fold increase in con-
once daily
centrations.
Current dose immediate release tablets 25 mg twice
Geriatric: Plasma levels are about 50% higher.
daily: Convert to extended release capsules 80 mg
Heart failure: AUC and C,,, increased up to 100%.
once daily
Dosing Renal Impairment: Pediatric
Pediatric Note: Immediate release and extended release No adjustment required. Note: Mean AUCs were 40% to
products are not interchangeable on a mg:mg basis due 50% higher in adult patients with moderate to severe
to pharmacokinetic differences. Individualize dosage for renal dysfunction who received immediate release
each patient; monitor patients closely during initiation carvedilol, but the ranges of AUCs were similar to
and upwards titration of dose; reduce dosage for hypo- patients with normal renal function
tension or bradycardia (adolescents 218 years: 55 bpm; Hemodialysis: Hemodialysis does not significantly clear
younger patients may alternate target). Pharmacokinetic carvedilol.
data suggests a faster carvedilol elimination in young Hepatic Impairment: Pediatric
pediatric patients (<3.5 years) which may require more Mild to moderate impairment (Child-Pugh class A or B):
frequent dosing (3 times daily) and a higher target dose There are no dosage adjustments provided in manu-
per kg (Laer, 2002; Shaddy, 2007). facturer’s labeling; use with caution; monitor for symp-
Heart failure: Prior to initiating therapy, other CHF toms of drug-induced toxicity.
medications should be stabilized and fluid retention Severe impairment (Child-Pugh class C): Use is contra-
minimized. indicated as drug is extensively metabolized by the
Infants, Children, and Adolescents <17 years: Limited liver. Note: Adult patients with severe cirrhotic liver
data available, efficacy results variable; optimal dose disease achieved carvedilol serum concentrations
not established: Oral: Immediate release tablets: Ini- four- to sevenfold higher than normal patients follow-
tial: Reported mean: 0.075-0.08 mg/kg/dose twice ing a single dose of immediate release carvedilol
daily; titrate as tolerated; may increase dose by Administration
typically 50% every 2 weeks; usual reported main- Immediate release tablets: Administer with food to
tenance (target) dose range: 0.3-0.75 mg/kg/dose decrease the risk of orthostatic hypotension.
twice daily; the usual titration time to reach target Extended release capsules: Administer with food, prefera-
dose was 11-14 weeks (Bruns, 2001; Rusconi, bly in the morning; do not crush or chew capsule;
2004); maximum daily dose: 50 mg/day. Dosing swallow whole; do not take in divided doses. Capsule
based on two retrospective analyses of a total 70 may be opened and contents sprinkled on a spoonful of
pediatric patients (age range: 3 months to 19 years) applesauce; swallow applesauce/medication mixture
which showed improvement in left ventricular function immediately; do not chew; do not store for later use; do
and heart failure symptoms (67% to 68% of patients not use warm applesauce; do not sprinkle capsule con-
showed improvement in NYHA class). However, in a tents on food other than applesauce; drink fluids after
large, a multicenter, double-blind, placebo-controlled, dose to make sure mixture is completely swallowed.
dose-finding trial in 161 pediatric patients (treatment Monitoring Parameters Heart rate, blood pressure
group: n=103, median age range: 33-43 months), a (determine need for dosage increase based on trough
lower target dose range of 0.2-0.4 mg/kg/dose twice blood pressure measurements and tolerance on standing
daily did not result in a statistical difference in compo- systolic pressure 1 hour after dosing), weight; Sc,, BUN,
site clinical end point scores compared to placebo; liver function; in patient with increased risk for developing
the authors suggested multiple factors for negative renal dysfunction, monitor renal function during dosage
efficacy findings including that the study may have titration
been underpowered due to unexpected, high Test Interactions May lead to false-positive aldosterone/
improvement of the placebo-arm; a subset analysis renin ratio (ARR) (Funder 2016).
suggests ventricular morphology may play a role_in Dosage Forms Excipient information presented when
efficacy (Shaddy, 2007). available (limited, particularly for generics); consult spe-
Adolescents 218 years: cific product labeling.
Immediate release tablets: Oral: Initial: 3.125 mg Capsule Extended Release 24 Hour, Oral, as phosphate:
twice daily for 2 weeks; if tolerated, may increase Coreg CR: 10 mg, 20 mg, 40 mg, 80 mg
to 6.25 mg twice daily. May double the dose every 2 Generic: 10 mg, 20 mg, 40 mg, 80 mg
weeks to the highest dose tolerated by patient. Tablet, Oral:
Maximum recommended dose: Coreg: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg
Mild to moderate heart failure: Generic: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg
<85 kg: 25 mg twice daily Extemporaneous Preparations A 1.25 mg/mL carvedi-
>85 kg: 50 mg twice daily lol oral suspension may be made with tablets and one of
Severe heart failure: 25 mg twice daily two different vehicles (Ora-Blend or 1:1 mixture of Ora-
Extended release capsules: Oral: Initial: 10 mg once Sweet and Ora-Plus). Crush five 25 mg tablets in a mortar
daily for 2 weeks; if tolerated, may double the dose and reduce to a fine powder; add 15 mL of purified water
(eg, 20 mg, 40 mg) every 2 weeks up to 80 mg once and mix to a uniform paste. Mix while adding chosen
daily; maintain on lower dose if higher dose is not vehicle in incremental proportions to almost 100 mL;
tolerated ; transfer to a calibrated amber bottle, rinse mortar with >
375
 CARVEDILOL

. vehicle, and add quantity of vehicle sufficient to make 100

mL. Label "shake well". Stable for 84 days when stored in
Genitourinary: Nephrotoxicity (adults; serum creatinine 22
xX baseline value or 21 mg/dL in patients with serum
amber prescription bottles at room temperature (Loyd, creatinine above ULN range), urinary tract infection
2006). Hematologic & oncologic: Anemia (adults), blood coagu-
lation disorder, decreased hematocrit (adults),
Carvedilol oral liquid suspensions (0.1 mg/mL and decreased hemoglobin (adults), decreased white blood
1.67 mg/mL) made from tablets, water, Ora-Plus, and cell count (adults), febrile neutropenia, neutropenia,
Ora-Sweet were stable for 12 weeks when stored in glass petechia, thrombocytopenia
amber bottles at room temperature (25°C). Use one Hepatic: Decreased serum albumin (adults), hepatic fail-
3.125 mg tablet for the 0.1 mg/mL suspension or two ure, hepatomegaly, hepatotoxicity, hyperbilirubinemia,
25 mg tablets for the 1.67 mg/mL suspension; grind the increased serum alkaline phosphatase (adults),
tablet(s) and compound a mixture with 5 mL of water, 15 increased serum ALT (more common in adults),
mL Ora-Plus, and 10 mL Ora-Sweet. Final volume of each increased serum AST (more common. in adults),
suspension: 30 mL; label "shake well" (data on file, increased serum bilirubin (adults), jaundice
GlaxoSmithKline, Philadelphia, PA: DOF #132 [Note: Infection: Bacteremia, sepsis (adults)
Manufacturer no longer disseminates this document)). Local: Catheter infection (infants, children, and adoles-
Loyd A Jr, "Carvedilol 1.25 mg/mL Oral Suspension," /nt J Pharm
cents), infusion site reaction (pain/pruritus/swelling),
Compounding, 2006, 10(3):220.
localized phlebitis (adults)
Neuromuscular & skeletal: Arthralgia, back pain, limb
Caspofungin (kas poe FUN jin) pain, tremor, weakness
Renal: Hematutia (adults), increased blood urea nitrogen
Brand Names: US Cancidas (adults), increased serum creatinine (adults), renal
Brand Names: Canada Cancidas failure
Therapeutic Category Antifungal Agent, Echinocandin; Respiratory: Cough (adults), dyspnea (adults), epistaxis,
Antifungal Agent, Systemic hypoxia, pleural effusion (adults), pneumonia (adults),
Generic Availability (US) Yes rales (adults), respiratory distress (adults), respiratory
Use Treatment of invasive aspergillosis in patients who are failure (adults), tachypnea :
refractory to or intolerant of other therapies; treatment of Miscellaneous: Fever, infusion related reaction, septic
candidemia, intra-abdominal abscess, peritonitis, and shock (adults)
pleural space infection caused by susceptible Candida Rare but important or life-threatening: Anaphylaxis, eryth-
species; treatment of esophageal candidiasis; empiric ema multiforme, hepatitis, histamine release (including
therapy of presumed fungal infection in febrile neutropenic facial swelling, bronchospasm, sensation of warmth),
patients (All indications: FDA approved in ages 23 months increased gamma-glutamyl transferase, pancreatitis,
and adults) Stevens-Johnson syndrome, swelling, toxic epidermal
Pregnancy Risk Factor C necrolysis
Pregnancy Considerations Adverse events have been Drug Interactions
observed in animal reproduction studies. When treatment Metabolism/Transport Effects None known.
of invasive Aspergillus or Candida infections is needed Avoid Concomitant Use
during pregnancy, other agents are preferred (HHS [adult] Avoid concomitant use of Caspofungin with any of the
2017; IDSA [Pappas 2016}). following: Saccharomyces boulardii
Breastfeeding Considerations It is not known if caspo- Increased Effect/Toxicity
fungin is present in breast milk. The manufacturer recom- The levels/effects of Caspofungin may be increased by:
mends that caution be exercised when administering CycloSPORINE (Systemic)
caspofungin to nursing women. Decreased Effect
Contraindications Caspofungin may decrease the levels/effects of: Sac-
Hypersensitivity to caspofungin or any component of the charomyces boulardii; Tacrolimus (Systemic)
formulation The levels/effects of Caspofungin may be decreased by:
Documentation of allergenic cross-reactivity for echino- Inducers of Drug Clearance; RifAMPin
candin antifungals is limited. However, because of sim- Storage/Stability Store intact vials at 2°C to 8°C (36°F to
ilarities in chemical structure and/or pharmacologic 46°F). Reconstituted solution may be stored at $25°C
actions, the possibility of cross-sensitivity cannot be ($77°F) for up to 1 hour prior to preparation of infusion
ruled out with certainty. solution. Solutions diluted in NS, 1/2NS, 1/4NS, or LR for
Warnings/Precautions Increased transaminases and infusion should be used within 24 hours when stored at
rare cases of clinically significant hepatic dysfunction $25°C (S77°F) or within 48 hours when stored at 2°C to
(including failure and hepatitis) have been reported in 8°C (36°F to 46°F).
pediatric and adult patients. Monitor liver function tests Mechanism of Action Inhibits synthesis of B(1,3)-D-
during therapy; if tests become abnormal or worsen, glucan, an essential component of the cell wall of suscep-
consider discontinuation. Anaphylaxis, other hypersensi- tible fungi. Highest activity is in regions of active cell
tivity reactions, histamine-related reactions (eg, angioe- growth. Mammalian cells do not require 8(1,3)-D-glucan,
dema, facial swelling, bronchospasm, rash, sensation of limiting potential toxicity.
warmth), and cases of Stevens-Johnson syndrome and Pharmacodynamics/Kinetics (Adult data unless
toxic epidermal necrolysis (some fatal) have been noted)
reported. Discontinue if a hypersensitivity reaction occurs. Distribution: CSF concentrations: Nondetectable [<10 ng/
Administer supportive treatment if needed. Potentially mL (n=1)] (Saez-Llorens 2009)
significant drug-drug interactions may exist, requiring Protein binding: ~97% to albumin
dose or frequency adjustment, additional monitoring, Metabolism: Slowly, via hydrolysis and N-acetylation as
and/or selection of alternative therapy. Use caution in well as by spontaneous degradation, with subsequent
hepatic impairment. Dosage reduction required in adults metabolism to component amino acids. Overall metabo-
with moderate hepatic impairment; safety and efficacy lism is extensive.
have not been established in children with any degree of Half-life elimination: Beta (distribution): 9 to 11 hours (~8
hepatic impairment and adults with severe hepatic impair- hours in children <12 years); Terminal: 40 to 50 hours;
ment. beta phase half-life is 32% to 43% lower in pediatric
Adverse Reactions patients than in adult patients
Cardiovascular: Atrial fibrillation, bradycardia, cardiac Excretion: Urine (41%; primarily as metabolites, ~1% of
arrhythmia, edema, flushing, hypertension, hypotension total dose as unchanged drug); feces (35%; primarily as
(more common in adults), myocardial infarction, periph- metabolites)
eral edema (adults), tachycardia Pharmacodynamics/Kinetics: Additional Consider-
Central nervous system: Anxiety, chills (more common in ations
adults), confusion, depression, dizziness, drowsiness, Renal function impairment: AUC is increased 30% to 49%
fatigue, headache, insomnia, seizure in patients with CrCl <49 mL/minute after administration
Dermatologic: Decubitus ulcer (adults), erythema, pruritus of a single 70 mg dose. No effect on caspofungin con-
(infants, children, and adolescents), skin lesion, skin centrations was seen in patients with mild to end-stage
rash, urticaria renal impairment after administration of multiple daily
Endocrine & metabolic: Hypercalcemia, hyperglycemia doses.
(adults), hypervolemia, hypokalemia, hypomagnesemia Hepatic function impairment: AUC is increased by ~55%
(adults) in patients with mild hepatic impairment (Child-Pugh
Gastrointestinal: Abdominal distention, abdominal pain, class A) and by 76% in patients with moderate hepatic
anorexia, constipation, decreased appetite, diarrhea impairment (Child-Pugh class B).
(more common in adults), dyspepsia, mucosal inflamma- Geriatric: AUC is increased by ~28%.
tion, nausea (more common in adults), upper abdominal Gender: AUC in women was ~22% higher than in men
pain, vomiting after repeat dosing.

376
 CASTOR OIL

Dosing caspofungin dose to 70 mg/m?/dose once daily; max-

Neonatal Note: Caspofungin treatment duration should imum dose: 70 mg/dose
be based on patient status and clinical response. Renal Impairment: Pediatric
Candidiasis, invasive infections: Limited data avail- Infants 23 months, Children, and Adolescents: No
able: IV: adjustment needed
BSA-directed dosing: 25 mg/m?/dose once daily (Brad-
End-stage renal disease (ESRD) requiring dialysis:
ley 2017; IDSA [Pappas 2016]); dosing based on a
pharmacokinetic study of 18 neonates (PNA: <12 Poorly dialyzed; no supplemental dose or dosage
weeks; GA 228 weeks (all except one patient); weight adjustment necessary in patients on intermittent
at enrollment: 2500 g; most [n=16] were 21 kg); hemodialysis (IHD). No supplemental dose or dosage
results showed similar serum concentrations to stand- adjustment needed in peritoneal dialysis or continu-
- ard adult doses. Reported trough concentrations were ous renal replacement therapy (eg, CVVHD) (Aronoff
slightly elevated and not correlated with increased 2007; Heintz 2009).
adverse events (Saez-Llorens 2009).
Hepatic Impairment: Pediatric There are no dosage
Weight-directed dosing: 2 mg/kg/dose once daily;
adjustments provided in the manufacturer's labeling (has
treatment should continue for at least 2 weeks after
the first negative blood culture and signs and symp- not been studied); based on experience in adult patients,
toms have resolved (IDSA [Pappas 2016]); dosing dosage reduction may be necessary; use with caution.
based on a prospective, randomized, double-blind Preparation for Administration Bring refrigerated vial
study and a case series; the prospective trial enrolled to room temperature. Reconstitute vials using 10.8 mL
32 patients with invasive candidiasis and randomized NS, SWFI, or bacteriostatic water for injection, resulting in
them: to receive caspofungin (n=15; GA: 27.9 + 1.3 a concentration of 5 mg/mL for the 50 mg vial, and
weeks; PNA at onset of candida infection: 21.1 + 3.1
7 mg/mL for the 70 mg vial (vials contain overfill). Mix
days) or amphotericin B as initial treatment; results
gently to dissolve until clear solution is formed; do not
showed that the caspofungin group had a significantly
higher response rate compared to the amphotericin B use if cloudy or contains particles. Solution should be
group (86.7% favorable response vs 41.7%); the further diluted with NS, t/2NS, 1/4NS, or LR to a final
caspofungin group also experienced significantly concentration not to exceed 0.5 mg/mL.
fewer adverse effects (Mohamed 2012); the case Administration Administer by slow IV infusion over 1 hour
series included seven premature neonates (GA: 23 (manufacturer); higher doses (eg, 150 mg) have been
to 24 weeks, PNA at treatment, range: 13 to 53 days) infused over ~2 hours (Betts 2009). Monitor during infu-
with Candida infections refractory to amphotericin B; sion; isolated cases of possible histamine-related reac-
results showed this regimen to be effective and well
tions have occurred during clinical trials (rash, flushing,
tolerated for the treatment of C. parapsilosis and C.
albicans (Jeon 2014) pruritus, facial edema).
Pediatric Note: Caspofungin treatment duration should Monitoring Parameters Periodic liver function tests,
be based on patient status and clinical response. serum potassium, CBC, hemoglobin; signs of anaphylaxis
Aspergillosis, invasive; treatment: Note: Guidelines or histamine-related reactions
recommend caspofungin for salvage therapy or where Dosage Forms Excipient information presented when
other antifungals are contraindicated; not recom- available (limited, particularly for generics); consult spe-
mended for routine use for primary treatment (IDSA
cific product labeling.
[Patterson 2016]). Infants 23 months, Children, and
Solution Reconstituted, Intravenous, as acetate:
Adolescents <18 years: IV: Initial 70 mg/m?/dose on
day 1, then 50 mg/m2/dose once daily; may increase Generic: 50 mg (1 ea); 70 mg (1 ea)
to 70 mg/m?2/dose once daily if clinical response inad- Solution Reconstituted, Intravenous, as acetate [preser-
equate; maximum dose: 70 mg/dose vative free]:
Fungal infections, empiric therapy in neutropenic Cancidas: 50 mg (1 ea); 70 mg (1 ea)
patients: Infants 23 months, Children, and Adoles- Generic: 50 mg (1 ea); 70 mg (1 ea)
cents <18 years: IV: Initial dose: 70 mg/m?/dose on
day 1, then 50 mg/m2/dose once daily; may increase @ Caspofungin Acetate see Caspofungin on page 376
to 70 mg/m2/dose once daily if clinical response inad-
equate; maximum dose: 70 mg/dose
Castor Oil (KAs tor oy!)
Candida infections, treatment:
Non-HIV-exposed/-positive: Therapeutic Category Laxative, Stimulant
Infants <3 months: Limited data available: IV:
25 mg/m2/dose once daily; dosing based on a
Generic Availability (US) No
pharmacokinetic study of 18 infants (PNA s12 Use Treatment of occasional constipation (OTC product:
weeks) that showed similar serum concentrations FDA approved in 22 years and adults)
to standard adult doses (50 mg/day). Reported Pregnancy Considerations Ingestion of castor oil may
trough concentrations were slightly elevated and be associated with induction of labor. Use of castor oil as a
not correlated with increased adverse events laxative during pregnancy should be avoided (Cullen,
(Saez-Llorens 2009). 2007; Hall, 2011; Wald, 2003).
Infants 23 months, Children, and Adolescents <18
Warnings/Precautions Do not use for longer than 1
years: IV: Initial 70 mg/m?/dose on day 1, then
50 mg/m2/dose once daily; may increase to week or when abdominal pain, nausea, vomiting, or rectal
70 mg/m2/dose once daily if clinical response inad- bleeding are present unless directed by health care pro-
equate; maximum dose: 70 mg/dose. For esoph- vider.
ageal disease, treat for 7 to 14 days after symptom Adverse Reactions
resolution. For candidemia, treat until 2 weeks after Cardiovascular: Hypotension
the last positive blood culture. Central nervous system: Dizziness, pelvic congestion
HIV-exposed/-positive: Treatment duration varies
syndrome
based on site of infection: For esophageal disease,
Endocrine & metabolic: Electrolyte disturbance
treat for a minimum of 3 weeks and for at least 2
weeks after resolution of symptoms and for candi- Gastrointestinal: Abdominal cramps, diarrhea, nausea
demia, treat until 2 weeks after the last positive Drug Interactions
blood culture (HHS [Ol pediatric 2016)): Metabolism/Transport Effects None known.
Infants <3 months: Limited data available: IV: Avoid Concomitant Use There are no known interac-
25 mg/m/dose once daily tions where it is recommended to avoid concomitant use.
Infants 23 months, Children, and Adolescents <17 Increased Effect/Toxicity There are no known signifi-
years: IV: Initial 70 mg/m?/dose on day 1, then
cant interactions involving an increase in effect.
50 mg/m2/dose once daily; maximum dose:
70 mg/dose Decreased Effect There are no known significant inter-
Adolescents 218 years: IV: Initial 70 mg on day 1, actions involving a decrease in effect.
then 50 mg once daily Storage/Stability Protect from heat.
Dosing adjustment for concomitant administration: Mechanism of Action Acts primarily in the small intes-
Patients receiving rifampin: \nfants 23 months, Chil- tine; hydrolyzed to ricinoleic acid which reduces net
dren, and Adolescents: IV: 70 mg/m2/dose caspofun- absorption of fluid and electrolytes and stimulates peri-
gin once daily; maximum dose: 70 mg/dose
stalsis
Patients receiving carbamazepine, dexamethasone,
phenytoin, nevirapine, or efavirenz (and possibly Pharmacodynamics/Kinetics (Adult data unless
other enzyme inducers): \nfants 23 months, Children, noted) Onset of action: 1 to 3 hours (Brunton 2006) but
and Adolescents: IV: May require an increase in may take up to 12 hours

377
CASTOR OIL

Dosing Extended release tablet: Treatment of acute bacterial

Pediatric exacerbations of chronic bronchitis, secondary bacterial
Note: Produces bowel evacuation in 6 to 12 hours. Use infections of acute bronchitis (FDA approved in ages 216
of castor oil has generally been replaced with other years and adults)
laxatives (eg, PEG solutions, lactulose) less likely to Pregnancy Risk Factor B 4
cause adverse effects (eg, electrolyte disturbances) Pregnancy Considerations Adverse events were not
(Tabbers 2014): observed in animal reproduction studies. An increased
Constipation, occasional: Oral: risk of teratogenic effects has not been observed following
Children 2 to 11 years: 5 to 15 mL as a single daily maternal use of cefaclor.
dose as needed Breastfeeding Considerations Small amounts of cefa-
Children 212 years and Adolescents: 15 to 60 mL as a clor are excreted in breast milk. The manufacturer recom-
single daily dose as needed mends that caution be exercised when administering
Renal Impairment: Pediatric There are no dosage cefaclor to nursing women. Nondose-related effects could
adjustments provided in the manufacturer's labeling. include modification of bowel flora.
Hepatic Impairment: Pediatric There are no dosage Contraindications Hypersensitivity to cefaclor, any com-
adjustments provided in the manufacturer’s labeling. ponent of the formulation, or other cephalosporins
Administration Oral: Do not administer at bedtime Warnings/Precautions Anaphylactic reactions have
because of rapid onset of action; chill or administer with occurred. If a serious hypersensitivity reaction occurs,
milk, juice, or carbonated beverage to improve palatability; discontinue and institute emergency supportive meas-
administer on an empty stomach for quicker onset (Brun- ures, including. airway management and treatment (eg,
ton 2006) epinephrine, antihistamines and/or corticosteroids). Use
Monitoring Parameters Stool output, electrolytes with caution in patients with a history of gastrointestinal
disease, particularly colitis. Use with caution in patients
Dosage Forms Excipient information presented when
with renal impairment. Prolonged use may result in fungal
available (limited, particularly for generics); consult spe-
or bacterial superinfection, including C. difficile-associated
cific product labeling.
diarrhea (CDAD) and pseudomembranous colitis; CDAD
Oil, Oral:
has been observed >2 months postantibiotic treatment.
Generic: (59 mL, 118 mL, 177 mL, 473 mL)
Use with caution in patients with a history of penicillin
Cataflam see Diclofenac (Systemic) on page 628 allergy. An extended-release tablet dose of 500 mg twice
daily is clinically equivalent to an immediate-release cap-
Cataflam [DSC] see Diclofenac (Systemic) on page 628
sule dose of 250 mg 3 times daily; an extended-release
@ Catapres see CloNIDine on page 490 tablet dose of 500 mg twice daily is NOT clinically equiv-
® Catapres-TTS-1 see CloNIDine on page 490 alent to 500 mg 3 times daily of other cefaclor formula-
@ Catapres-TTS-2 see CloNIDine on page 490 tions. Potentially significant interactions may exist,
requiring dose or frequency adjustment, additional mon-
@ Catapres-TTS-3 see CloNIDine on page 490 itoring, and/or selection of alternative therapy.
@ Cathflo Activase see Alteplase on page 96
Benzyl alcohol and derivatives: Some dosage forms may
Caverject see Alprostadil on page 94 contain sodium benzoate/benzoic acid; benzoic acid (ben-
# Caverject Impulse see Alprostadil on page 94 zoate) is a metabolite of benzyl! alcohol; large amounts of
@ Cavilon [OTC] see Miconazole (Topical) on page 1371 benzyl! alcohol (299 mg/kg/day) have been associated
with a potentially fatal toxicity ("gasping syndrome") in
@ CaviRinse [DSC] see Fluoride on page 886
neonates; the "gasping syndrome” consists of metabolic
@ Cayston see Aztreonam (Oral Inhalation) on page 235 acidosis, respiratory distress, gasping respirations, CNS
@ CB-1348 see Chlorambucil on page 417 dysfunction (including convulsions, intracranial hemor-
@ CBDCA see CARBOplatin on page 367 rhage), hypotension, and cardiovascular collapse (AAP
["Inactive" 1997]; CDC, 1982); some data suggests that
® CBZ see CarBAMazepine on page 361 benzoate displaces bilirubin from protein binding sites
® ccllV4 [Flucelvax Quadrivalent] see Influenza Virus (Ahlfors, 2001); avoid or use dosage forms containing
Vaccine (Inactivated) on page 1073 benzyl alcohol derivative with caution in neonates. See
@ CCNU see Lomustine on page 1240 manufacturer’s labeling.
Warnings: Additional Pediatric Considerations May
@ CCP-Letrozole (Can) see Letrozole on page 1187
cause serum sickness-like reaction (estimated incidence
@ CD19CAR-CD3zeta-4-1BB-Expressing Autologous T ranges from 0.024% to 0.2% per drug course); majority of
Lymphocytes see Tisagenlecleucel on page 1958 reactions have occurred in children <5 years of age with
@ 2-CdA see Cladribine on page 465 symptoms of fever, rash, erythema multiforme, and
@ CDCA see Chenodiol on page 414 arthralgia, often occurring during the second or third
exposure.
@ CDDP see ClSplatin on page 458 Adverse Reactions
CDP-771 see Gemtuzumab Ozogamicin on page 944 Dermatologic: Rash (includes erythematous rash, macu-
@ CE see Estrogens (Conjugated/Equine, Systemic) lopapular rash, or morbilliform rash)
on page 783 Gastrointestinal: Diarrhea
Genitourinary: Vaginitis, vulvovaginal candidiasis
CE see Estrogens (Conjugated/Equine, Topical)
Hematologic & oncologic: Eosinophilia
on page 787
Hepatic: Increased serum transaminases
@ Ceclor see Cefaclor on page 378 Rare but important or life-threatening: Agitation, agranu-
@ Cedax [DSC] see Ceftibuten on page 397 locytosis, anaphylaxis, angioedema, aplastic anemia,
arthralgia, cholestatic jaundice, confusion, dizziness,
® CEE see Estrogens (Conjugated/Equine, Systemic)
on page 783 drowsiness, hallucination, hemolytic anemia, hepatitis,
hyperactivity, insomnia, interstitial nephritis, irritability,
@ CEE see Estrogens (Conjugated/Equine, Topical) nausea, nervousness, neutropenia, paresthesia, pro-
on page 787 longed prothrombin time, pruritus, pseudomembranous
@ CeeNU see Lomustine on page 1240 colitis, seizure, serum sickness, Stevens-Johnson syn-
drome, thrombocytopenia, toxic epidermal necrolysis,
urticaria, vomiting
Cefaclor (SEF a kior) Drug Interactions
Medication Safety Issues Metabolism/Transport Effects Substrate of OAT3
Sound-alike/look-alike issues: Avoid Concomitant Use
Cefaclor may be confused with cephalexin Avoid concomitant use of Cefaclor with any of the
Related Information following: BCG (Intravesical); Cholera Vaccine
Oral Medications That Should Not Be Crushed or Altered Increased Effect/Toxicity
on page 2217 Cefaclor may increase the levels/effects of: Aminoglyco-
Brand Names: Canada Apo-Cefaclor; Ceclor; Novo- sides; Vitamin K Antagonists
Cefaclor; Nu-Cefaclor; PMS-Cefaclor The levels/effects of Cefaclor may be increased by:
Therapeutic Category Antibiotic, Cephalosporin (Sec- Probenecid; Teriflunomide; Tolvaptan
ond Generation) Decreased Effect
Generic Availability (US) Yes Cefaclor may decrease the levels/effects of: BCG (Intra-
Use vesical); BCG Vaccine (Immunization); Cholera Vaccine;
Capsule and suspension: Treatment of otitis media, lower Lactobacillus and Estriol; Sodium Picosulfate; Typhoid
reSpiratory tract infections, pharyngitis/tonsillitis, urinary Vaccine
tract infections, and skin/skin structure infections (FDA Food Interactions The bioavailability of cefaclor
approved in ages 21 month and adults) extended-release tablets is decreased 23% and the

378
 CEFADROXIL

maximum concentration is decreased 67% when taken on GFR <10 mL/minute/1.73 m?: Administer 50% of the
an empty stomach. Management: Administer with food. recommended dose.
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). End-stage renal disease (ERD) on intermittent
Refrigerate suspension after reconstitution and discard hemodialysis (IHD) (supplemental dose posthemo-
after 14 days. dialysis needed): Administer 50% of the recom-
Mechanism of Action Inhibits bacterial cell wall syn- mended dose.
thesis by binding to one or more of the penicillin-binding Peritoneal dialysis: Administer 50% of the recom-
proteins (PBPs), which in turn inhibits the final trans- mended dose.
peptidation step of peptidoglycan synthesis in bacterial Hemodialysis: Hemodialysis shortens half-life by 25%
cell walls, thus inhibiting cell wall biosynthesis. Bacteria to 35%
eventually lyse due to ongoing activity of cell wall autolytic Moderately dialyzable (20% to 50%) (Aronoff 2007)
enzymes (autolysins and murein hydrolases) while cell Hepatic Impairment: Pediatric There are no dosage
wall assembly is arrested. adjustments provided in the manufacturer's labeling.
Pharmacodynamics/Kinetics (Adult data unless Preparation for Administration Oral suspension: Refer
noted) to manufacturer's product labeling for reconstitution
Absorption: Oral: Well absorbed; acid stable instructions.
Distribution: Distributes into tissues and fluids including Administration
bone, pleural and synovial fluid Oral: Administer around-the-clock to promote less varia-
Protein binding: 25% (Aronoff 2007) tion in peak and trough serum levels.
Half-life elimination: 0.6 to 0.9 hours; prolonged with renal Capsules and oral suspension: Administer without
impairment (2.3 to 2.8 hours in anuria) regard to meals; shake oral suspension well before
Time to peak: Capsules, oral suspension: 30 to 60 using. .
' minutes; Extended-release tablets: 2.5 hours
Extended release tablets: Do not chew, crush, or split;
Excretion: Urine (60% to 85% as unchanged drug) administer with or within 1 hour of food.
Dosing Monitoring Parameters With prolonged therapy, monitor
Pediatric CBC and stool frequency periodically
General dosing, susceptible infection: Mild to mod-
Test Interactions Positive direct Coombs', false-positive
erate infection: Infants, Children, and Adolescents:
urinary glucose test using cupric sulfate (Benedict's sol-
Oral, immediate release: 20 to 40 mg/kg/day divided
ution, Clinitest, Fehling's solution).
every 8 to 12 hours. Maximum daily dose: 1,500 mg/
Dosage Forms Excipient information presented when
day (Red Book [AAP 2015])
available (limited, particularly for generics); consult spe-
Bronchitis: Adolescents 216 years: Extended release
tablet: Note: An extended release tablet dose of cific product labeling.
500 mg twice daily is clinically equivalent to an imme- Capsule, Oral:
Generic: 250 mg, 500 mg
diate release capsule dose of 250 mg 3 times daily;
an extended release tablet dose of 500 mg twice daily Suspension Reconstituted, Oral:
is NOT clinically equivalent to 500 mg 3 times daily of Generic: 125 mg/5 mL (150 mL); 250 mg/5 mL (150 mL);
other cefaclor formulations. 375 mg/5 mL (100 mL)
Acute bacterial exacerbations of chronic bronchitis: Tablet Extended Release 12 Hour, Oral:
Oral: Extended release: 500 mg every 12 hours for Generic: 500 mg
7 days
Secondary bacterial infection of acute bronchitis: Cefadroxil (sef a DROKS il)
Oral: Extended release: 500 mg every 12 hours for
7 days Medication Safety Issues
Lower respiratory tract infections: Infants, Children, Sound-alike/look-alike issues:
and Adolescents: Oral immediate release: 20 to Duricef may be confused with Ultracet
40 mg/kg/day divided every 8 hours; maximum daily Brand Names: Canada Apo-Cefadroxil; PRO-Cefadroxil;
dose: 1,000 mg/day. If beta-hemolytic streptococcus/ Teva-Cefadroxil
S. pyogenes suspected, treat for at least 10 days. Therapeutic Category Antibiotic, Cephalosporin (First
Otitis media: Infants, Children, and Adolescents: Oral Generation)
immediate release: 40 mg/kg/day divided every 8 to Generic Availability (US) Yes
12 hours (oral suspension) or every 8 hours (cap-
Use Treatment of pharyngitis/tonsillitis; skin and soft tissue
sule); maximum daily dose: 1,000 mg/day. If beta-
infections (including impetigo), and urinary tract infections
hemolytic streptococcus/S. pyogenes suspected,
(FDA approved in children [age not specified] and adults)
treat for at least 10 days. Note: Cefaclor is not a
recommended treatment option in the AAP guidelines Pregnancy Risk Factor B
(Lieberthal 2013). Pregnancy Considerations Adverse events have not
Pharyngitis/tonsillitis: Infants, Children, and Adoles- been observed in animal reproduction studies. Cefadroxil
cents: Oral immediate release: 20 mg/kg/day divided crosses the placenta. Limited data is available concerning
every 8 to 12 hours (oral suspension) or every 8 hours the use of cefadroxil in pregnancy; however, adverse fetal
(capsule); maximum daily dose: 1,000 mg/day. If effects were not noted in a small clinical trial.
beta-hemolytic streptococcus/S. pyogenes confirmed, Breastfeeding Considerations Very small amounts of
treat for at least 10 days. Note: Cefaclor is not a cefadroxil are excreted in breast milk. The manufacturer
recommended treatment option in the IDSA guide- recommends that caution be exercised when administer-
lines and is not considered preferred by the AHA ing cefadroxil to nursing women. Nondose-related effects
due to its broad spectrum (AHA [Gerber 2009], IDSA could include modification of bowel flora.
[Shulman 2012]). Contraindications Hypersensitivity to cefadroxil, any
Skin and skin structure infections, uncomplicated: component of the formulation, or other cephalosporins
Infants, Children, and Adolescents: Oral: Immediate Warnings/Precautions Use with caution in patients with
release: 20 to 40 mg/kg/day divided every 8 hours; renal impairment (CrCl <50 mL/minute/1.73 m2); dosage
maximum daily dose: 1,000 mg/day. If due to beta- adjustment may be needed. Hypersensitivity reactions,
hemolytic streptococcus/S. pyogenes, treat for at including anaphylaxis, may occur. If an allergic reaction
least 10 days. occurs, discontinue treatment and institute appropriate
Urinary tract infections: Infants, Children, and Ado- supportive measures. Use with caution in patients with a
lescents: Oral: Immediate release: 20 to 40 mg/kg/ history of penicillin allergy. Use with caution in patients
day divided every 8 hours; maximum daily dose: with a history of gastrointestinal disease, particularly col-
1.000 mg/day itis. Prolonged use may result in fungal or bacterial super-
Renal Impairment; Pediatric infection, including C. difficile-associated diarrhea (CDAD)
Manufacturer's labeling: and pseudomembranous colitis; CDAD has been
Oral, immediate release: Infants, Children, and Ado- observed >2 months postantibiotic treatment. Only IM
lescents: There are no dosage adjustments pro- penicillin has been shown to be effective in the prophylaxis
vided in the manufacturer's labeling; however, half- of rheumatic fever. Cefadroxil is generally effective in the
life is increased in anuric patients; use with caution. eradication of streptococci from the oropharynx; efficacy
Oral, extended release: There are no dosage adjust- data for cefadroxil in the prophylaxis of subsequent rheu-
ments provided in the manufacturer's labeling. matic fever episodes are not available. Potentially signifi-
Alternative recommendations (Aronoff 2007): Dosing cant drug-drug interactions may exist, requiring dose or
based on usual dose of 20 to 40 mg/kg/day in divided frequency adjustment, additional monitoring, and/or selec-
doses every 8 to 12 hours tion of alternative therapy.
Infants, Children, and Adolescents: Oral, immediate
release: | Suspension may contain sulfur dioxide (sulfite); hyper-
GFR 210 mU/minute/1.73 m?: No dosage adjust- sensitivity reactions, including anaphylaxis and/or asth-
ment necessary. t matic exacerbations, may occur (may be life threatening). >
379
 CEFADROXIL

q Dosage form specific issues: Some dosage forms may

contain sodium benzoate/benzoic acid; benzoic acid (ben-
Skin and skin structure infections: Children and
Adolescents: Oral: 15 mg/kg/dose every 12 hours;
zoate) is a metabolite of benzyl alcohol; large amounts of maximum daily dose: 1,000 mg/day
benzyl alcohol (299 mg/kg/day) have been associated Urinary tract infections: Children and Adolescents:
with a potentially fatal toxicity ("gasping syndrome") in Oral: 15 mg/kg/dose every 12 hours; maximum daily
neonates; the "gasping syndrome" consists of metabolic dose: 2,000 mg/day
acidosis, respiratory distress, gasping respirations, CNS Renal Impairment: Pediatric
dysfunction (including convulsions, intracranial hemor- Infants, Children, and Adolescents: There are no dos-
rhage), hypotension, and cardiovascular collapse (AAP age adjustments provided in the manufacturer's label-
["Inactive" 1997]; CDC 1982); some data suggests that ing for this age group; however, the following have
benzoate displaces bilirubin from protein binding sites been used by some Clinicians (Aronoff 2007): Dosing
(Ahlfors, 2001); avoid or use dosage forms containing based on a usual dose of 30 mg/kg/day in divided
benzyl alcohol derivative with caution in neonates. Some doses every 12 hours: [
dosage forms may contain propylene glycol; large CrCl 230 mL/minute/1.73 m2: No dosage adjustment
amounts are potentially toxic and have been associated necessary
with hyperosmolality, lactic acidosis, seizures, and respi- CrCl 10 to 29 mL/minute/1.73 m2: 15 mg/kg/dose
ratory depression; use caution (AAP 1997; Zar 2007). See every 24 hours
manufacturer’s labeling. CrCl <10 mL/minute/1.73 m?: 15 mg/kg/dose every
Warnings: Additional Pediatric Considerations 36 hours
Some dosage forms may contain propylene glycol; in Hemodialysis, intermittent: 15 mg/kg/dose every 24
neonates large amounts of propylene glycol delivered hours
orally, intravenously (eg, >3,000 mg/day), or topically Peritoneal dialysis: 15 mg/kg/dose every 36 hours
have been associated with potentially fatal toxicities which Hepatic Impairment: Pediatric There are no dosage
can include metabolic acidosis, seizures, renal failure, and adjustments provided in the manufacturer's labeling.
CNS depression; toxicities have also been reported in Preparation for Administration Oral: Reconstitute pow-
children and adults including hyperosmolality, lactic acido- der for oral suspension with appropriate amount of water
sis, seizures, and respiratory depression; use caution as specified on the bottle. Shake vigorously until sus-
(AAP 1997; Shehab 2009). pended.
Adverse Reactions Administration Oral: May be administered without regard
Gastrointestinal: Diarrhea to food; administration with food may decrease nausea or
Rare but important or life-threatening: Agranulocytosis, vomiting; shake suspension well before use.
anaphylaxis, angioedema, cholestasis, Clostridium diffi- Monitoring Parameters Stool frequency, resolution of
cile associated diarrhea, dyspepsia, erythema multi- infection
forme, erythematous rash, genital candidiasis, hepatic Test Interactions Positive direct Coombs’, false-positive
failure, increased serum transaminases, maculopapular urinary glucose test using cupric sulfate (Benedict's sol-
rash, neutropenia, pseudomembranous colitis, serum ution, Clinitest®, Fehling's solution), false-positive serum
sickness, Stevens-Johnson syndrome, thrombocytope- or urine creatinine with Jaffé reaction
nia, vaginitis Dosage Forms Excipient information presented when
Drug Interactions available (limited, particularly for generics); consult spe-
Metabolism/Transport Effects None known. cific product labeling.
Avoid Concomitant Use Capsule, Oral:
Avoid concomitant use of Cefadroxil with any of the Generic: 500 mg
following: BCG (Intravesical); Cholera Vaccine Suspension Reconstituted, Oral:
Increased Effect/Toxicity Generic: 250 mg/5 mL (50 mL, 100 mL); 500 mg/5 mL
Cefadroxil may increase the levels/effects of: Vitamin K (75 mL, 100 mL)
Antagonists Tablet, Oral:
Generic: 1g
The levels/effects of Cefadroxil may be increased by:
Probenecid ® Cefadroxil Monohydrate see Cefadroxil on page 379
Decreased Effect
Cefadroxil may decrease the levels/effects of: BCG
(Intravesical); BCG Vaccine (Immunization); Cholera CeFAZolin (sef A zoe lin)
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Medication Safety Issues
Typhoid Vaccine
Sound-alike/look-alike issues:
Storage/Stability Store capsules, tablets and unreconsti- CeFAZolin may be confused with cefoTEtan, cefOXitin,
tuted oral suspension at 20°C to 25°C (68°F to 77°F); cefprozil, ceffAZidime, cefTRIAXone, cephalexin
excursions are permitted to 15°C to 30°C (59°F to 86°F).
Brand Names: Canada Cefazolin For Injection; Cefazolin
After reconstitution, oral suspension may be stored for 14
For Injection, USP
days under refrigeration (4°C).
Therapeutic Category Antibiotic, Cephalosporin (First
Mechanism of Action Inhibits bacterial cell wall syn- Generation)
thesis by binding to one or more of the penicillin-binding
Generic Availability (US) Yes
proteins (PBPs) which in turn inhibits the final transpepti-
Use Treatment of susceptible infections involving the res-
dation step of peptidoglycan synthesis in bacterial cell
piratory tract,-skin and skin structure, urinary tract, biliary
walls, thus inhibiting cell wall biosynthesis. Bacteria even-
tract, bone and joint, genitals, and septicemia (FDA
tually lyse due to ongoing activity of cell wall autolytic
approved in ages 21 month and adults); perioperative
enzymes (autolysins and murein hydrolases) while cell
prophylaxis (FDA approved in adults); treatment of bacte-
wall assembly is arrested.
rial endocarditis (FDA approved in adults); has also been
Pharmacodynamics/Kinetics (Adult data unless
used for bacterial endocarditis prophylaxis for dental and
noted)
upper respiratory procedures; prophylaxis of peritonitis in
Absorption: Rapid and well absorbed from Gl tract
patients with peritoneal dialysis (PD) catheters undergoing
Distribution: Vg: 0.31 L/kg
invasive dental procedures, gastrointestinal or genitouri-
Protein binding: 20%
nary procedures, touch contamination prophylaxis of PD
Half-life elimination: 1 to 2 hours; 20 to 24 hours in renal
catheter, and treatment of peritonitis in patients with
failure
peritoneal catheters
Time to peak serum concentration: Within 70 to 90
Pregnancy Risk Factor B
minutes
Excretion: Urine (>90% as unchanged drug within 24 Pregnancy Considerations Adverse effects have not
hours) been observed in animal reproduction studies. Cefazolin
crosses the placenta. Adverse events have not been
Dosing
reported in the fetus following administration of cefazolin
Pediatric
prior to cesarean section. Cefazolin is recommended for
General dosing, susceptible infection: Mild to mod-
group B streptococcus prophylaxis in pregnant patients
erate infection: Infants, Children, and Adolescents:
with a nonanaphylactic penicillin allergy. It is also one of
Oral: 15 mg/kg/dose twice daily; maximum daily dose:
the antibiotics recommended for prophylactic use prior to
2,000 mg/day (Red Book [AAP 2015])
cesarean delivery and may be used in certain situations
Impetigo: Children and Adolescents: Oral: 30 mg/kg/
prior to vaginal delivery in women at high risk for endo-
day in a single dose or divided every 12 hours;
carditis.
maximum daily dose: 1,000 mg/day
Pharyngitis/tonsillitis: Children and Adolescents: Due to pregnancy-induced physiologic changes, the phar-
‘Oral: 30 mg/kg/day in a single dose or divided every macokinetics of cefazolin are altered. The half-life is
12 hours for 10 days; maximum daily dose: shorter, the AUC is smaller, and the clearance and volume
1,000 mg/day of distribution are increased.

380
 CEFAZOLIN

Breastfeeding Considerations Small amounts of cefa- Half-life elimination: IM or IV: Neonates: 3 to 5 hours;
zolin are excreted in breast milk. The manufacturer rec- Adults: 1.8 hours (IV); ~2 hours (IM) (prolonged with
ommends that caution be exercised when administering renal impairment)
cefazolin to nursing women. Nondose-related effects Time to peak, serum: IM: 0.5 to 2 hours; IV: Within 5
could include modification of bowel flora. minutes
Contraindications Hypersensitivity to cefazolin, other Excretion: Urine (70% to 80% as unchanged drug)
cephalosporin antibiotics, penicillins, other beta-lactams, Dosing
or any component of the formulation. Neonatal
Warnings/Precautions Hypersensitivity reactions, General dosing, susceptible infection (Bradley 2016;
including anaphylaxis, may occur. If an allergic reaction Red Book [AAP] 2015): IM, IV:
occurs, discontinue treatment and institute appropriate Body weight $2 kg: 25 mg/kg/dose every 12 hours
supportive measures. Use with caution in patients with a Body weight >2 kg:
history of penicillin allergy. Use with caution in patients PNA <7 days: 25 mg/kg/dose every 12 hours
with renal impairment; dosage adjustment required. Pro- PNA 8 to 60 days: 25 mg/kg/dose every 8 hours
longed use may result in fungal or bacterial superinfection, Alternate dosing: Note: Dosing based on a pharmaco-
including C. difficile-associated diarrhea (CDAD) and kinetic study in 36 neonates (GA: Median: 37 weeks;
pseudomembranous colitis; CDAD has been observed range: 24 to 40 weeks; PNA: Median: 9 days; range: 1
>2 months postantibiotic treatment. May be associated to 30 days) (De Cock 2014): IV:
with increased INR, especially in nutritionally-deficient Body weight <2 kg:
patients, prolonged treatment, hepatic or renal disease. PNA <7 days: 25 mg/kg/dose every 12 hours
Use with caution in patients with a history of seizure PNA 8 to 28 days: 25 mg/kg/dose every 8 hours
| disorder; high levels, particularly in the presence of renal Body weight >2 kg:
impairment, may increase risk of seizures. Potentially PNA <7 days: 50 mg/kg/dose every 12 hours
significant drug-drug interactions may exist, requiring PNA 8 to 28 days: 50 mg/kg/dose every 8 hours
dose or frequency adjustment, additional monitoring, Surgical prophylaxis: PNA >72 hours: IV: 30 mg/kg;
and/or selection of alternative therapy. administer within 60 minutes before procedure (Red
Adverse Reactions Book [AAP 2015])
Cardiovascular: Localized phlebitis Pediatric
Central nervous system: Seizure General dosing, susceptible infection (Red Book
Dermatologic: Pruritus, skin rash, Stevens-Johnson syn- [AAP 2015]): Infants, Children, and Adolescents: IM,
drome IV:
Gastrointestinal: Abdominal cramps, anorexia, diarrhea, Mild to moderate infections: 25 to 50 mg/kg/day div-
nausea, oral candidiasis, pseudomembranous colitis,
ided every 8 hours; maximum dose: 1,000 mg/dose
vomiting Severe infections: 100 to 150 mg/kg/day divided
Genitourinary: Vaginitis every 8 hours; maximum dose: 2,000 mg/dose
Hepatic: Hepatitis, increased serum transaminases Endocarditis, bacterial:
Hematologic: Eosinophilia, leukopenia, neutropenia,
Prophylaxis for dental and upper respiratory proce-
thrombocythemia, thrombocytopenia
dures: Infants, Children, and Adolescents: IM, IV:
Hypersensitivity: Anaphylaxis
50 mg/kg 30 to 60 minutes before procedure; max-
Local: Pain at injection site
imum dose: 1,000 mg/dose (AHA [Wilson 2007)).
Renal: Increased blood urea nitrogen, increased serum
Note: AHA guidelines (Baltimore 2015) limit the
creatinine, renal failure
use of prophylactic antibiotics to patients at the
Miscellaneous: Fever
highest risk for infective endocarditis (IE) or adverse
Drug Interactions
outcomes (eg, prosthetic heart valves, patients with
Metabolism/Transport Effects None known. previous IE, unrepaired cyanotic congenital heart
Avoid Concomitant Use disease, repaired congenital heart disease with
Avoid concomitant use of CeFAZolin with any of the prosthetic material or device during first 6 months
following: BCG (Intravesical); Cholera Vaccine after procedure, repaired congenital heart disease
Increased Effect/Toxicity with residual defects at the site or adjacent to site of
CeFAZolin may increase the levels/effects of: Fosphe- prosthetic patch or device, and heart transplant
nytoin; Phenytoin; Vitamin K Antagonists recipients with cardiac valvulopathy).
The levels/effects of CeFAZolin may be increased by: Treatment: Children and Adolescents: IV: 100 mg/kg/
Probenecid day in divided doses every 8 hours; usual adult
Decreased Effect dose: 2,000 mg/dose; maximum daily dose: 12 g/
CeFAZolin may decrease the levels/effects of: BCG day; treat for at least 4 weeks; longer durations may
(Intravesical); BCG Vaccine (Immunization); Cholera be necessary; may use with or without gentamicin
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate; (AHA [Baltimore 2015])
Typhoid Vaccine Peritonitis (peritoneal dialysis) (ISPD [Warady
Storage/Stability 2012]): Limited data available: Infants, Children, and
Store intact vials at room temperature and protect from Adolescents:
temperatures exceeding 40°C. Reconstituted solutions Prophylaxis:
of cefazolin are light yellow to yellow. Protection from Touch contamination of PD line: Intraperitoneal:
light is recommended for the powder and for the recon- 125 mg per liter
stituted solutions. Reconstituted solutions are stable for Invasive dental procedures: IV: 25 mg/kg adminis-
24 hours at room temperature and for 10 days under tered 30 to 60 minutes before procedure; maxi-
refrigeration. Stability of parenteral admixture in D5W, mum dose: 1,000 mg/dose
D5LR, D51%4NS, D51/2NS, DSNS, D10W, LR, or NS at Gastrointestinal or genitourinary procedures: IV:
room temperature (25°C) is 48 hours. Stability of paren- 25 mg/kg administered 60 minutes before proce-
teral admixture at refrigeration temperature (4°C) is 14 dure; maximum dose: 2,000 mg/dose
days. ; Treatment: Intraperitoneal:
DUPLEX: Store at 20°C to 25°C (68°F to 77°F); excur- Intermittent: 20 mg/kg every 24 hours in the long
sions permitted to 15°C to 30°C (59°F to 86°F) prior to dwell
activation. Following activation, stable for 24 hours at Continuous: Loading dose: 500 mg per liter of dial-
room temperature and for 7 days under refrigeration. ysate; maintenance: 125 mg per liter of dialysate
GALAXY: Store at or below -20°C (-4°F). Thawed solution Pneumonia, community-acquired pneumonia
stable for 48 hours at room temperature and for 30 days (CAP), S. aureus , methicillin susceptible: Infants
under refrigeration, Do not refreeze. ¢ >3 months, Children, and Adolescents: IV: 50 mg/kg/
Mechanism of Action Inhibits bacterial cell wall syn- dose every 8 hours (Bradley 2011); usual maximum
thesis by binding to one or more of the penicillin-binding dose for severe infections: 2,000 mg/dose (Red Book
proteins (PBPs) which in turn inhibits the final transpepti- [AAP 2015])
dation step of peptidoglycan synthesis in bacterial cell Skin and soft tissue infections, S. aureus, methicil-
walls, thus inhibiting cell wall biosynthesis. Bacteria even- lin susceptible (mild to moderate): (IDSA [Stevens
tually lyse due to ongoing activity of cell wall autolytic 2014]): Infants, Children, and Adolescents:
enzymes (autolysins and murein. hydrolases) while cell S, aureus, methicillin susceptible skin and soft tissue
wall assembly is arrested. infections including pyomyositis: IV: 50 mg/kg/day
Pharmacodynamics/Kinetics (Adult data unless divided every 8 hours; maximum dose: 1,000 mg/
noted) dose; higher doses may be required in severe
Distribution: Widely into most body tissues and fluids cases; duration of therapy at least 5 days, but longer
including gallbladder, liver, kidneys, bone, sputum, bile, may be necessary in some cases, eg, febrile and
pleural, and synovial; CSF penetration is poor neutropenic patients: 7 to 14 days; pyomyositis: 14
Protein binding: 80% (Marshall 1999) to 21 days

381
 CEFAZOLIN

< S. aureus, methicillin susceptible necrotizing infection

of skin, fascia, or muscle: IV: 100 mg/kg/day divided Cefdinir (ser di ner)
every 8 hours; maximum dose: 1,000 mg/dose; con-
tinue therapy until surgical debridement no longer Therapeutic Category Antibiotic, Cephalosporin (Third
necessary, clinical improvement and afebrile for 48 Generation)
to 72 hours Generic Availability (US) Yes
Streptococcal, nonpurulent skin infection (cellulitis): Use Treatment of susceptible acute bacterial otitis media
IV: 100 mg/kg/day divided every 8 hours; maximum (FDA approved in ages 6 months to 12 years); treatment
dose: 1,000 mg/dose; duration of therapy at least 5 of susceptible acute maxillary sinusitis, pharyngitis/tonsil-
days, but longer may be necessary in some cases litis, and uncomplicated skin and skin structure infections
Surgical prophylaxis: Infants, Children, and Adoles- (FDA approved in ages 26 months and adults); treatment
cents: IV: 30 mg/kg 30 to 60 minutes before proce- of susceptible acute exacerbations of chronic bronchitis
dure, may repeat in 4 hours for prolonged procedure and community-acquired pneumonia (FDA. approved in
or excessive blood loss (eg, >1,500 mL in adults); adolescents and adults)
maximum dose dependent upon patient weight: Pregnancy Risk Factor B
Weight <120 kg: 2,000 mg/dose; weight 2120 kg: Pregnancy Considerations Teratogenic events have
3,000 mg/dose (Bratzler 2013; Red Book [AAP] 2015) not been observed in animal reproduction studies. An
Renal Impairment: Pediatric increase in most types of birth defects was not found
IM, IV: following first trimester exposure to cephalosporins.
Infants >1 month, Children, and Adolescents: After Breastfeeding Considerations Cefdinir was not detect-
initial loading dose is administered, modify dose able inbreast milk following a single cefdinir 600 mg dose.
based on the degree of renal impairment: In general, if antibiotics are present in breast milk, non-
CrCl >70 mL/minute: No dosage adjustment required dose-related modification of bowel flora may occur. Mon-
CrCl 40 to 70 mL/minute: Administer 60% of the usual itor infants for GI disturbances, such as thrush and
daily dose divided every 12 hours diarrhea (WHO 2002).
CrCl 20 to 40 mL/minute: Administer 25% of the usual Contraindications Hypersensitivity to cefdinir, any com-
daily dose divided every 12 hours ponent of the formulation, or other cephalosporins.
CrCl 5 to 20 mL/minute: Administer 10% of the usual Warnings/Precautions Administer cautiously to penicil-
daily dose given every 24 hours lin-sensitive patients, especially IgE-mediated reactions
Hemodialysis: 25 mg/kg/dose every 24 hours (Aron- (eg, anaphylaxis, urticaria). Prolonged use may result in
off 2007) fungal or bacterial superinfection, including C. difficile-
Peritoneal dialysis: 25 mg/kg/dose every 24 hours associated diarrhea (CDAD) and pseudomembranous
(Aronoff 2007) colitis; CDAD has been observed >2 months postantibiotic
Continuous renal replacement therapy: 25 mg/kg/ treatment. Use with caution in patients with a history of
dose every 8 hours (Aronoff 2007) colitis. Use caution with renal dysfunction (CrCl <30 mL/
Hepatic Impairment: Pediatric There are no dosage minute); dose adjustment may be required. Cases of
adjustments provided in the manufacturer's labeling. reddish stools have been reported with concomitant use
Preparation for Administration Parenteral: of cefdinir and iron-containing products due to the forma-
IM: Dilute 500 mg vial with 2 mL SWF and 1 g vial with tion of a nonabsorbable complex in the GI tract. Potentially
2.5 mL SWFI resulting in a concentration of 225 mg/mL significant drug-drug interactions may exist, requiring
and 330 mg/mL, respectively. dose or frequency adjustment, additional monitoring,
IVP: Reconstitute appropriate vial size and further dilute to and/or selection of alternative therapy.
a maximum concentration: 100 mg/mL (Klaus 1989); in Warnings: Additional Pediatric Considerations l|ron-
fluid-restricted patients, a concentration of 138 mg/mL containing infant formulas do not affect the pharmacoki-
using SWFI results in a maximum recommended osmo- netics of cefdinir but may result in the development of red-
lality for peripheral infusion (Robinson 1987). appearing, nonbloody stools; this occurs when cefdinir is
Intermittent IV infusion: Further dilute with a compatible coadministered with iron-containing products and an
solution (eg, DSW, NS) to a maximum final concentration insoluble iron-cefdinir complex forms; patients/parents
of 20 mg/mL should be counseled. Administer cautiously to penicillin-
Administration Parenteral: sensitive patients, especially IgE-mediated reactions (eg,
IM: Deep IM injection into a large muscle mass. anaphylaxis, urticaria). Prolonged use may result in fungal
IV: May be administered IVP over 3 to 5 minutes or IV or bacterial superinfection, including C. difficile-associated
intermittent infusion over 10 to 60 minutes. diarrhea (CDAD) and pseudomembranous colitis; CDAD
Monitoring Parameters Renal function periodically when has been observed >2 months postantibiotic treatment.
used in combination with other nephrotoxic drugs, hepatic Use with caution in patients with a history of colitis. Use
function tests, and CBC; prothrombin time in patients at caution with renal dysfunction (CrCl <30 mL/minute); dose
risk; number and type of stools/day for diarrhea; monitor adjustment may be required. Potentially significant drug-
for signs of anaphylaxis during first dose drug interactions may exist, requiring dose or frequency
Test Interactions Positive direct and indirect Coombs’, adjustment, additional monitoring, and/or selection of
false-positive urinary glucose test using cupric sulfate alternative therapy.
(Benedict's solution, Clinitest, Fehling's solution), false- Adverse Reactions
positive serum or urine creatinine with Jaffé reaction. Central nervous system: Headache
Dermatologic: Skin rash
Some penicillin derivatives may accelerate the degrada- Endocrine & metabolic: Decreased serum bicarbonate,
tion of aminoglycosides in vitro, leading to a potential glycosuria, hyperglycemia, hyperphosphatemia,
underestimation of aminoglycoside serum concentration. increased gamma-glutamyl! transferase, increased lac-
Dosage Forms Excipient information presented when tate dehydrogenase
available (limited, particularly for generics); consult spe- Gastrointestinal: Abdominal pain, diarrhea, nausea, vom-
cific product labeling. [DSC] = Discontinued product iting
Solution, Intravenous: Genitourinary: Proteinuria, occult blood in urine, urine
Generic: 1 g/50 mL in Dextrose 4% (50 mL); 2 g/100 mL abnormality (increased leukocytes), urine alkalinization,
in Dextrose 4% (100 mL); 2 g/100 mL in NaCl 0.9% vaginitis, vulvovaginal candidiasis
(120 mL) Hematologic: Abnormal neutrophils (functional disorder of
Solution Prefilled Syringe, Intravenous: polymorphonuclear neutrophils), change in WBC count,
Generic: 1 g/10 mL (10 mL); 2 g/20 mL (20 mL); 1 g/10 eosinophilia, lymphocytopenia, lymphocytosis, thrombo-
mL in NaC! 0.9% (10 mL); 2.9/10 mL in NaCl 0.9% cythemia
(10 mL) Hepatic: Increased serum alkaline phosphatase,
Solution Reconstituted, Injection: increased serum ALT
Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g (1 Renal: Increased urine specific gravity
ea); 100 g (1 ea); 300 g (1 ea) Rare but important or life-threatening: Abnormal stools,
Solution Reconstituted, Injection [preservative free]: anaphylaxis, anorexia, asthma, blood coagulation disor-
Generic: 500 mg (1 ea); 1 g (1 ea); 10 g (1 ea); 20 g (1 der, bloody diarrhea, candidiasis, cardiac failure, chest
ea [DSC]) pain, cholestasis, conjunctivitis, constipation, cutaneous
Solution Reconstituted, Intravenous: candidiasis, decreased hemoglobin, decreased urine
Generic: 1 g (1 ea); 1 g and Dextrose 4% (1 ea); 2 g and specific gravity, disseminated intravascular coagulation,
Dextrose 3% (1 ea) dizziness, drowsiness, dyspepsia, enterocolitis (acute),
@ Cefazolin For Injection (Can) see CeFAZolin eosinophilic pneumonitis, erythema multiforme, eryth-
ema nodosum, exfoliative dermatitis, facial edema, fever,
on page 380
flatulence, fulminant hepatitis, granulocytopenia, hemo-
® Cefazolin For Injection, USP (Can) see CeFAZolin lytic anemia, hemorrhagic colitis, hemorrhagic diathesis,
on page 380 hepatic failure, hepatitis (acute), hyperkalemia, hyper-
@ Cefazolin Sodium see CeFAZolin on page 380 kinesia, hypersensitivity angiitis, hypertension,

382
 CEFDITOREN

hypocalcemia, hypophosphatemia, immune thrombocy- Skin and skin structure infection, uncomplicated:
topenia, increased amylase, increased blood urea nitro- Infants 26 months and Children: Oral: 14 mg/kg/day
gen, increased monocytes, increased serum AST, in divided doses twice daily for 10 days; maximum
increased serum bilirubin, insomnia, interstitial pneumo- daily dose: 600 mg/day
nitis (idiopathic), intestinal obstruction, involuntary body Adolescents: Oral: 300 mg every 12 hours for 10 days
movements, jaundice, laryngeal edema, leukopenia, leu- Sinusitis, acute maxillary: Note: Due to decreased S.
korrhea, loss of consciousness, maculopapular rash, pneumonia sensitivity, cefdinir is no longer recom-
melena, myocardial infarction, pancytopenia, peptic mended as monotherapy for the initial empiric treat-
ulcer, pneumonia (drug-induced), pruritus, pseudomem- ment of sinusitis (Chow 2012)
branous colitis, renal disease, renal failure (acute), res- Infants 26 months and Children: Oral: 14 mg/kg/day
piratory failure (acute), rhabdomyolysis, serum sickness, in divided doses every 12 to 24 hours for 10 days;
shock, Stevens-Johnson syndrome, stomatitis, thrombo- maximum daily dose: 600 mg/day
cytopenia, toxic epidermal necrolysis, upper gastrointes- Adolescents: Oral: 300 mg every 12 hours or 600 mg
tinal hemorrhage, weakness, xerostomia every 24 hours for 10 days
Drug Interactions Renal Impairment: Pediatric
Metabolism/Transport Effects None known. Infants 26 months and Children:
Avoid Cancomitant Use CrCl 230 mL/minute/1.73 m?: No adjustment required
Avoid concomitant use of Cefdinir with any of the follow- CrCl <30 mL/minute/1.73 m2: 7 mg/kg/dose once
ing: BCG (Intravesical); Cholera Vaccine daily; maximum daily dose: 300 mg/day
Adolescents:
Increased Effect/Toxicity
CrCl 230 mL/minute: No adjustment required
Cefdinir may increase the levels/effects of: Aminoglyco-
CrCl <30 mL/minute: 300 mg once daily
| sides; Vitamin K Antagonists
Hemodialysis: Dialyzable (63%): Infants 26 months,
The levels/effects of Cefdinir may be increased by: Children, and Adolescents: Initial dose: 7 mg/kg/dose
Probenecid (maximum dose: 300 mg) every other day. At the
Decreased Effect conclusion of each hemodialysis session, an addi-
Cefdinir may decrease the levels/effects of: BCG (Intra- tional dose (7 mg/kg/dose up to 300 mg) should be
vesical); BCG Vaccine (Immunization); Cholera Vaccine; given. Subsequent doses should be administered
Lactobacillus and Estriol; Sodium Picosulfate; Typhoid every other day.
Vaccine Hepatic Impairment: Pediatric There are no dosing
adjustments provided in the manufacturer's labeling (has
The levels/effects of Cefdinir may be decreased by: |ron not been studied).
Salts; Multivitamins/Minerals (with ADEK, Folate, Iron) Preparation for Administration Oral: Reconstitute pow-
. Storage/Stability Store at 20°C to 25°C (68°F to 77°F). der for oral suspension with appropriate amount of water
Store reconstituted suspension at room temperature 20°C as specified on the bottle. Shake vigorously until sus-
to 25°C (68°F to 77°F) for 10 days. pended.
Mechanism of Action Inhibits bacterial cell wall syn- Administration Oral: May administer with or without food;
thesis by binding to one or more of the penicillin-binding administer with food if stomach upset occurs; administer
proteins (PBPs) which in turn inhibits the final transpepti- cefdinir at least 2 hours before or after antacids or iron
dation step of peptidoglycan synthesis in bacterial cell supplements; shake suspension well before use.
walls, thus inhibiting cell wall biosynthesis. Bacteria even- Monitoring Parameters Evaluate renal function before
tually lyse due to ongoing activity of cell wall autolytic and during therapy; with prolonged therapy, monitor coag-
enzymes (autolysins and murein, hydrolases) while cell ulation tests, CBC, liver function test periodically, and
wall assembly is arrested. number and type of stools/day for diarrhea. Observe for
Pharmacodynamics/Kinetics (Adult data unless signs and symptoms of anaphylaxis during first dose.
noted) Test Interactions False-positive reaction for urinary
Distribution: Penetrates into blister fluid, middle ear fluid, ketones may occur with nitroprusside- but not nitroferri-
tonsils, sinus, and lung tissues; Vg: cyanide-based tests. False-positive urine glucose results
Children 6 months to 12 years: 0.67.+ 0.38 L/kg may occur when using Clinitest®, Benedict's solution, or
Adults: 0.35 + 0.29 L/kg Fehling’s solution; glucose-oxidase-based reaction sys-
Protein binding: 60% to 70% tems (eg, Clinistix®, Tes-Tape®) are recommended. May
Metabolism: Minimal cause positive direct Coombs’ test.
Bioavailability: Capsule: 16% to 21%; suspension 25% Dosage Forms Excipient information presented when
Half-life elimination: 1.7 (+ 0.6) hours with normal renal available (limited, particularly for generics); consult spe-
function cific product labeling.
Time to peak, plasma: 2 to 4 hours Capsule, Oral:
Excretion: Primarily urine (~12% to 18% as Generic: 300 mg
unchanged drug) Suspension Reconstituted, Oral:
Pharmacodynamics/Kinetics: Additional Consider- Generic: 125 mg/5 mL (60 mL, 100 mL); 250 mg/5 mL
ations Renal function impairment: Clearance is reduced. (60 mL, 100 mL)
Dosing
Pediatric Cefditoren (sef de TOR en)
General dosing, susceptible infection (Red Book
2012): Mild to moderate infections: Infants, Children, Medication Safety Issues
and Adolescents: Oral: 14 mg/kg/day in divided doses International issues:
1 to 2 times daily; maximum daily dose: 600 mg/day Spectracef [US, Great Britain, Mexico, Portugal, Spain]
Bronchitis, acute exacerbation: Oral: Adolescents: may be confused with Spectrocef brand name for
300 mg every 12 hours for 5 to 10 days or 600 mg cefotaxime [Italy]
every 24 hours for 10 days Brand Names: US Spectracef
Otitis media, acute: Infants 26 months and Children: Therapeutic Category Antibiotic, Cephalosporin
Oral: 14 mg/kg/day in divided doses every 12 to 24 Generic Availability (US) Yes
hours for 5 to 10 days; maximum daily dose: 600 mg/ Use Treatment of mild to moderate infections caused by
day. Variable duration of therapy: If <2 years of age or susceptible bacteria including acute bacterial exacerba-
severe symptoms (any age): 10-day course; if 2 to 5 tion of chronic bronchitis, community-acquired pneumo-
years of age with mild to moderate symptoms: 7-day nia, pharyngitis or tonsillitis, and uncomplicated skin and
course; if 26 years of age with mild to moderate skin-structure infections (FDA approved in ages 212 years
symptoms: 5- to 7-day course (AAP [Lieberthal and adults)
2013]). Note: Recommended by the AAP as an Pregnancy Risk Factor B
alternative agent for initial treatment in penicillin aller- Pregnancy Considerations Adverse events have not
gic patients (AAP [Lieberthal 2013)). been observed in animal reproduction studies. An
Pharyngitis/Tonsillitis: Note: Although FDA approved increase in most types of birth defects was not found
at twice daily dosing, duration <10 days is not recom- following first trimester exposure to cephalosporins.
mended (Shulman 2012). Breastfeeding Considerations It is not known whether
Infants 26 months and Children: Oral: 7 mg/kg/dose cefditoren is excreted in human milk. The manufacturer
every 12 hours for 5 to 10 days or 14 mg/kg/dose recommends caution when using cefditoren during breast-
every 24 hours for 10 days; maximum daily dose: feeding. If cefditoren reaches the breast milk, the limited
600 mg/day oral absorption may minimize the effect on the nursing
Adolescents: Oral: 300 mg every 12 hours for 5 to 10 infant. Nondose-related effects could include modification
days or 600 mg every 24 hours for 10 days of bowel flora. 7
Pneumonia, community-acquired: Adolescents: Contraindications Hypersensitivity to cefditoren, any
Oral: 300 mg every 12 hours for 10 days component of the formulation, other cephalosporins, or

383
CEFDITOREN

milk protein; carnitine deficiency or inborn errors of metab- Time to peak: 1.5 to 3 hours
olism that may result in clinically significant carnitine Excretion: Urine (as cefditoren and pivaloyicarnitine)
deficiency. Pharmacodynamics/Kinetics: Additional Consider-
Warnings/Precautions Use with caution in patients with ations
a history of penicillin allergy, especially IgE-mediated Renal function impairment:
reactions (eg, anaphylaxis, urticaria). Prolonged use Moderate impairment (CrCl 30 to 49 mL/minute/1.73
may result in fungal or bacterial superinfection, including m?): Unbound Cmax is 90% higher, AUC is 232% higher
C. difficile-associated diarrhea (CDAD) and pseudomem- Severe impairment (CrCl less than 30 mL/minute/1.73
branous colitis; CDAD has been observed >2 months m?): Unbound Cmax is 114% higher, AUC is 324%
postantibiotic treatment. Caution in individuals with seiz- higher
ure disorders; high levels, particularly in the presence of Geriatric: Cjnax is increased 26% and AUC
33%, half-life is
renal impairment, may increase risk of seizures. Use 16% to 26% longer, and renal clearance is 20% to 24%
caution in patients with renal or hepatic impairment; mod- lower. ;
ify dosage in patients with severe renal impairment. Dosing
Cefditoren causes renal excretion of carnitine; do not Pediatric
use in patients with carnitine deficiency; not for long-term General dosing, susceptible infection; mild to mod-
therapy due to the possible development of carnitine erate infections: Children 212 years and Adoles-
deficiency over time. May prolong prothrombin time; use cents: Oral: 200 to 400 mg twice daily (Red Book
with caution in patients with a history of bleeding disorder. [AAP, 2012])
Cefditoren tablets contain sodium caseinate, which may Bronchitis, chronic; acute bacterial exacerbation:
cause hypersensitivity reactions in patients with milk Children 212 years and Adolescents: Oral: 400 mg
protein hypersensitivity; this does not affect patients with twice daily for 10 days
lactose intolerance. Pneumonia, community-acquired: Children 212
Warnings: Additional Pediatric Considerations Car- years and Adolescents: Oral: 400 mg twice daily for
nitine deficiency may result from prolonged use; cefditoren 14 days
causes renal excretion of carnitine; plasma carnitine con- Pharyngitis, tonsillitis:
centrations usually return to normal range within 7 to 10 Manufacturer's labeling: Children 212 years and Ado-
days after discontinuation of therapy. Therapy with cefdi- lescents: Oral: 200 mg twice daily for 10 days
toren is contraindicated in patients with carnitine defi- Alternate dosing: Infants 28 months and Children:
ciency or inborn errors of metabolism that may result in Limited data available: Oral: 3 mg/kg/dose 3 times
clinically significant carnitine deficiency. daily for 5 days; dosing based’ on a prospective
Adverse Reactions study comparing 5 days of cefditoren (n=103, age
Central nervous system: Headache range: 0.7 to 12.4 years) to 10 days of amoxicillin
Endocrine & metabolic: Increased serum glucose (n=155); efficacy and tolerability were similar for
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, both groups; cefditoren was administered as a gran-
nausea, vomiting ule formulation that is not available in the U.S.
Genitourinary: Hematuria, urine abnormality (increased (Ozaki, 2008)
leukocytes), vulvovaginal candidiasis Skin and skin structure infections, uncomplicated:
Hematologic & oncologic: Decreased hematocrit Children 212 years and Adolescents: Oral: 200 mg
Rare but important or life-threatening: Acute renal failure, twice daily for 10 days
decreased serum albumin, arthralgia, asthma, change in Renal Impairment: Pediatric
WBC count (decrease or increase), coagulation time Children 212 years and Adolescents:
increased, decreased serum calcium, decreased serum CrCl 250 mL/minute/1.73 m?: No dosage adjustment
sodium, eosinophilic pneumonitis, erythema multiforme, necessary
fungal infection, hyperglycemia, hypersensitivity reac- CrCl 30-49 mL/minute/1.73 m?: Maximum dose:
tion, increased blood urea nitrogen, increased serum 200 mg twice daily
potassium, interstitial pneumonitis, leukopenia, leukor- CrCl <30 mL/minute/1.73 m2: Maximum dose: 200 mg
rhea, positive direct Coombs test, pseudomembranous once daily
colitis, skin rash, Stevens-Johnson syndrome, thrombo- End stage renal disease: Appropriate dose has not
cythemia, thrombocytopenia, toxic epidermal necrolysis been determined
Drug Interactions Hepatic Impairment: Pediatric
Metabolism/Transport Effects None known. Children 212 years and Adolescents:
Avoid Concomitant Use There are no known interac- Mild to moderate impairment (Child-Pugh Class A or
tions where it is recommended to avoid concomitant use. B): No dosage adjustment necessary.
Increased Effect/Toxicity Severe impairment (Child-Pugh Class C): There are no
Cefditoren may increase the levels/effects of: Vitamin K dosage adjustment guidelines provided in the manu-
Antagonists facturer's labeling (not studied).
The levels/effects of Cefditoren may be increased by: Administration Oral: Administer with meals.
Probenecid Monitoring Parameters Assess patient at beginning and
Decreased Effect throughout therapy for infection; observe for changes in
The levels/effects of Cefditoren may be decreased by: bowel frequency, monitor for signs of anaphylaxis during
Antacids; Histamine H2 Receptor Antagonists; Proton first dose
Pump Inhibitors Test Interactions May induce a positive direct Coomb’s
Food Interactions Moderate- to high-fat meals increase test. May cause a false-negative ferricyanide test. Glu-
bioavailability and maximum plasma concentration. Man- cose oxidase or hexokinase methods recommended for
agement: Take with meals. Maintain adequate hydration, blood/plasma glucose determinations. False-positive urine
unless instructed to restrict fluid intake. glucose test when using copper reduction based assays
Storage/Stability Store at 25°C (77°F); excursions per- (eg, Clinitest®).
mitted between 15°C and 30°C (59°F and 86°F). Protect Dosage Forms Excipient information presented when
from light and moisture. available (limited, particularly for generics); consult spe-
Mechanism of Action Inhibits bacterial cell wall syn- cific product labeling. [DSC] = Discontinued product
thesis by binding to one or more of the penicillin-binding Tablet, Oral:
proteins (PBPs) which in turn inhibits the final transpepti- Spectracef: 200 mg [DSC], 400 mg [contains sodium
dation step of peptidoglycan synthesis in bacterial cell caseinate]
walls, thus inhibiting cell wall biosynthesis. Bacteria even- Generic: 200 mg, 400 mg
tually lyse due to ongoing activity of cell wall autolytic
@ Cefditoren Pivoxil see Cefditoren on page 383
enzymes (autolysins and murein hydrolases) while cell
wall assembly is arrested.
Pharmacodynamics/Kinetics (Adult data unless Cefepime (SEF e pim)
noted)
Distribution: 9.3 + 1.6 L Medication Safety Issues
Protein binding: 88% (in vitro), primarily to albumin Sound-alike/look-alike issues:
Metabolism: Cefditoren pivoxil is hydrolyzed by esterases Cefepime may be confused with cefixime, cefTAZidime
to cefditoren (active) and pivalate; cefditoren is not Brand Names: US Maxipime
appreciable metabolized Brand Names: Canada Maxipime
Bioavailability: ~14% to 16%, increased by moderate- to Therapeutic Category Antibiotic, Cephalosporin (Fourth
high-fat meal (mean AUC by 70%; maximum plasma Generation)
_ concentration by 50%) Generic Availability (US) Yes
Half-life elimination: 1.6 + 0.4 hours; increased with mod- Use Treatment of pneumonia, uncomplicated skin and soft
erate (2.7 hours) and severe (4.7 hours) renal tissue infections, and complicated and uncomplicated
impairment urinary tract infections (including pyelonephritis) caused

384
 CEFEPIME

by susceptible organisms, and as empiric therapy for The levels/effects of Cefepime may be increased by:
febrile neutropenic patients (FDA approved in ages 22 Probenecid
months and adults); used in combination with metronida- Decreased Effect
zole for complicated intra-abdominal infections (FDA Cefepime may decrease the levels/effects of: BCG
approved in adults); has also been used for the treatment (Intravesical); BCG Vaccine (Immunization); Cholera
of peritonitis in patients with peritoneal catheters and Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
endocarditis Typhoid Vaccine
Pregnancy Risk Factor B Storage/Stability
Pregnancy Considerations Adverse events were not Vials: Store intact vials at 20°C to 25°C (68°F to 77°F).
observed in animal reproduction studies. Cefepime Protect from light. After reconstitution, stable in NS and
crosses the placenta. D5W for 24 hours at 20°C to 25°C (68°F to 77°F) and 7
Breastfeeding Considerations Small amounts of cefe- days at 2°C to 8°C (36°F to 46°F). Refer to the manu-
pime are excreted in breast milk. The manufacturer rec- facturer's product labeling for other acceptable reconsti-
ommends that caution be exercised when administering tution solutions.
cefepime to nursing women. Nondose-related effects Dual chamber containers: Store unactivated containers at
could include modification of bowel flora. 20°C to 25°C (68°F to 77°F); excursions permitted to
Contraindications Hypersensitivity to cefepime, other 15°C to 30°C (59°F to 85°F). Do not freeze. Following
cephalosporins, penicillins, other beta-lactam antibiotics, reconstitution, use within 12 hours if stored at room
or any component of the formulation temperature or within 5 days if stored under refrigeration.
Warnings/Precautions Severe neurological reactions Premixed solution: Store frozen at -20°C (-4°F). Thawed
(some fatal) have been reported, including encephalop- solution is stable for 24 hours at room temperature or 7
_ athy, aphasia, myoclonus, seizures, and nonconvulsive days under refrigeration; do not refreeze.
status epilepticus; risk may be increased in the presence Mechanism of Action Inhibits bacterial cell wall syn-
of renal impairment (CrCl <60 mL/minute); ensure dose thesis by binding to one or more of the penicillin-binding
adjusted for renal function and discontinue therapy if proteins (PBPs) which in turn inhibits the final transpepti-
patient develops neurotoxicity; effects are often reversible dation step of peptidoglycan synthesis in bacterial cell
upon discontinuation of cefepime. Serious adverse reac- walls, thus inhibiting cell wall biosynthesis. Bacteria even-
tions have occurred in elderly patients with renal insuffi- tually lyse due to ongoing activity of cell wall autolytic
ciency given unadjusted doses of cefepime, including life- enzymes (autolysis and murein hydrolases) while cell wall
threatening or fatal occurrences of encephalopathy, myo- assembly is arrested.
clonus, and seizures. Hypersensitivity reactions may Pharmacodynamics/Kinetics (Adult data unless
occur; use with caution in patients with a history of noted)
penicillin sensitivity; cross hyper-sensitivity may occur. If
Absorption: IM: Rapid and complete
a hypersensitivity reaction occurs, discontinue therapy
Distribution: Vg:
and institute supportive measures. Prolonged use may
Neonates (Capparelli, 2005):
result in fungal or bacterial superinfection, including C.
PMA <30 weeks: 0.51 L/kg
difficile-associated diarrhea (CDAD) and pseudomembra-
PMA >30 weeks: 0.39 L/kg
nous colitis; CDAD has been observed >2 months post-
Infants and Children 2 months to 11 years: 0.3 L/kg
antibiotic treatment. May be associated with increased
Adults: 18 L, 0.26 L/kg; penetrates into inflammatory fluid
INR, especially in nutritionally-deficient patients, pro-
at concentrations ~80% of serum concentrations and
longed treatment, hepatic or renal disease. Use with
into bronchial mucosa at concentrations ~60% of
caution in patients with a history of seizure disorder; high
plasma concentrations; crosses the blood-brain barrier
levels, particularly in the presence of renal impairment,
Protein binding, plasma: ~20%
may increase risk of seizures. Potentially significant drug-
Metabolism: Minimally hepatic
drug interactions may exist, requiring dose or frequency
Half-life elimination:
adjustment, additional monitoring, and/or selection of
Neonates: 4 to 5 hours (Lima-Rogel 2008)
alternative therapy.
Children 2 months to 6 years: 1.77 to 1.96 hours
Warnings: Additional Pediatric Considerations The
Adults: 2 hours
manufacturer does not recommend the use of cefepime in
Hemodialysis: 13.5 hours
pediatric patients for the treatment of serious infections
Continuous peritoneal dialysis: 19 hours
due to Haemophilus influenzae type b, for suspected
meningitis, or for meningeal seeding from a distant infec- Time to peak: IM: 1 to 2 hours; IV: 0.5 hours
tion site. However, limited data suggest that cefepime may Excretion: Urine (85% as unchanged drug)
be a valuable alternative for treating bacterial meningitis in Pharmacodynamics/Kinetics: Additional Consider-
children in conjunction with other agents like vancomycin ations Renal function impairment: Total body clearance is
in areas with a high incidence of cephalosporin nonsus- decreased proportionally with creatinine clearance.
ceptible pneumococci (Haase 2004). Dosing
Adverse Reactions Neonatal
Cardiovascular: Localized phlebitis General dosing, susceptible infection:
Central nervous system: Headache Mild to moderate infection (Bradley 2016; Red Book
Dermatologic: Pruritus, skin rash [AAP 2015]): IM, IV: 30 mg/kg/dose every 12 hours
Endocrine & metabolic: Hypophosphatemia Severe infection (eg, meningitis, Pseudomonas) (Brad-
Gastrointestinal: Diarrhea, nausea, vomiting ley 2016): Note: Pharmacokinetic studies suggest
Hematologic & oncologic: Eosinophilia, positive direct that every 12-hour dosing provides adequate concen-
Coombs test (without hemolysis) trations for severe infections (including meningitis and
Hepatic: Abnormal partial thromboplastin time, abnormal pseudomonal infections) during the neonatal period
prothrombin time, increased serum ALT, increased (Lima-Rogel 2008)
serum AST Body weight <1 kg:
Hypersensitivity: Hypersensitivity (in patients with a his- PNA 0 to 14 days: IM, IV: 50 mg/kg/dose every 12
tory of penicillin allergy) hours
Miscellaneous: Fever PNA 215 days: IM, IV: 50 mg/kg/dose every 8 hours
Rare but important or life-threatening: Agranulocytosis, Body weight 1 to 2 kg:
anaphylactic shock, anaphylaxis, anemia, aphasia, brain PNA 0 to 7 days: IM, IV: 50 mg/kg/dose every 12
disease, Clostridium difficile associated diarrhea, colitis, hours
coma, confusion, decreased hematocrit, erythema, hal- PNA 28 days: IM, IV: 50 mg/kg/dose every 8 hours
lucination, hypercalcemia, hyperkalemia, hyperphospha- Body weight >2 kg: IM, IV: 50 mg/kg/dose every 8
temia, hypocalcemia, increased blood urea nitrogen, hours
increased serum alkaline phosphatase, increased serum Pediatric
bilirubin, increased serum creatinine, leukopenia, local General dosing, susceptible infection (Red Book
inflammation, local pain, neurotoxicity, neutropenia, oral [AAP 2015]): Infants, Children, and Adolescents: IM,
candidiasis, pseudomernbranous colitis, seizure, status IV:
epilepticus (nonconvulsive), stupor, thrombocytopenia, Mild to moderate infection: 50 mg/kg/dose every 12
vaginitis hours; maximum dose: 2,000 mg/dose
Drug Interactions Severe infection: 50 mg/kg/dose every 8 to 12 hours;
Metabolism/Transport Effects None known. maximum dose: 2,000 mg/dose
Avoid Concomitant Use Cystic fibrosis, acute pulmonary exacerbation:
Avoid concomitant use of Cefepime with any of the Infants, Children, and Adolescents: IV: 50 mg/kg/dose
following: BCG (Intravesical); Cholera Vaccine every 8 hours; maximum dose: 2,000 mg/dose;
Increased Effect/Toxicity patients with more resistant pseudomonal isolates
Cefepime may increase the levels/effects of: Aminogly- (MIC 216 mg/L) may require 50 mg/kg/dose every 6
cosides; Vitamin K Antagonists , hours (Zobell 2013)

385
 CEFEPIME

< Endocarditis, prosthetic valve, treatment

year of replacement: Children and Adolescents: IV:
within 1 administered by direct IV injection over 3 to 5 minutes
at final concentrations of 40 mg/mL (Garrelts 1999) and
50 mg/kg/dose every 8 to 12 hours in combination 100 mg/mL (Jaruratanasirikul 2002; Lipman 1999) for
with vancomycin and rifampin for 6 weeks plus gen- severe infections
tamicin for the first 2 weeks; maximum dose: IM: Administer ‘by deep IM injection into large
2,000 mg/dose (AHA [Baltimore 2015]) muscle mass
Febrile neutropenia, empiric therapy: Infants, Chil- Monitoring Parameters With prolonged therapy, monitor
dren, and Adolescents: IV: 50 mg/kg/dose every 8 renal and hepatic function periodically; number and type of
hours; maximum dose: 2,000 mg/dose (Red Book stools/day for diarrhea; CBC with differential. Observe for
[AAP 2015]); duration of therapy dependent upon signs and symptoms of anaphylaxis during first dose.
febrile neutropenia risk-status; in high-risk patients, Test Interactions Positive direct Coombs’, false-positive
may discontinue empiric antibiotics if all of the follow- urinary glucose test using cupric sulfate (Benedict's sol-
ing criteria met: Negative blood cultures at 48 hours; ution, Clinitest®, Fehling's solution), false-positive serum
afebrile for at least 24 hours, and evidence of marrow or urine creatinine with Jaffé reaction, false-positive uri-
recovery. In low-risk patients, may discontinue empiric nary proteins and steroids
antibiotics after 72 hours duration in patients with a Dosage Forms Excipient information presented when
negative blood culture and who have been afebrile for available (limited, particularly for generics); consult spe-
24 hours regardless of marrow recovery status; fol- cific product labeling.
low-up closely (Lehrnbecher 2017). Solution, Intravenous, as hydrochloride:
Intra-abdominal infection, complicated: Infants, Generic:.1_g/50 mL (50 mL); 2 g/100 mL (100 mL)
Children, and Adolescents: IV: 50 mg/kg/dose every Solution Reconstituted, Injection, as hydrochloride:
12 hours in combination with metronidazole; maxi- Maxipime: 1 g (1 ea); 2 g (1 ea)
mum dose: 2,000 mg/dose. Note: IDSA guidelines Generic: 1 g (1 ea); 2 g (1 ea)
recommend duration of 4 to 7 days (provided source Solution Reconstituted, Injection, as hydrochloride [pres-
controlled) (IDSA [Solomkin 2010)). ervative free]:
Meningitis: Infants, Children, and Adolescents: IV: Generic: 2 g (1 ea)
50 mg/kg/dose every 8 hours; maximum dose: Solution Reconstituted, Intravenous, as hydrochloride:
2,000 mg/dose (Tunkel 2004) Maxipime: 1 g (1 ea); 2 g (1 ea)
Peritonitis (peritoneal dialysis) (ISPD [Warady Generic: 1 g/50 mL (1 ea); 2 g/50 mL (1 ea)
2012]): Infants, Children, and Adolescents: Intraper-
itoneal: ® Cefepime HCI see Cefepime on page 384
Intermittent: 15 mg/kg/dose every 24 hours into the @ Cefepime HCI/D5W see Cefepime on page 384
long dwell @ Cefepime Hydrochloride see Cefepime on page 384
Continuous: Loading dose: 500 mg per liter of dialy-
sate; maintenance dose: 125 mg per liter
Pneumonia, moderate to severe: Infants 22 months, Cefixime (sef Ks eem)
Children, and Adolescents:
Due to P. aeruginosa: |V: 50 mg/kg/dose every 8 Medication Safety Issues
hours for 10 days; maximum dose: 2,000 mg/dose Sound-alike/look-alike issues:
Not due to P. aeruginosa: IV: 50 mg/kg/dose every 12 Cefixime may be confused with cefepime
hours for 10 days; maximum dose: 2,000 mg/dose Suprax may be confused with Sporanox
Skin and skin structure infections, uncomplicated: International issues:
Infants 22 months, Children, and Adolescents: IV: Cefiton: Brand name for cefixime [Portugal] may be
50 mg/kg/dose every 12 hours for 10 days; maximum confused with Ceftim brand name for ceftazidime [Por-
dose: 2,000 mg/dose tugal]; Ceftime brand name for ceftazidime [Thailand];
Urinary tract infection, complicated and uncompli- Ceftin brand name for cefuroxime [US, Canada]
cated: Infants 22 months, Children, and Adolescents: Brand Names: US Suprax
Mild to moderate infection: IM, IV: 50 mg/kg/dose Brand Names: Canada Auro-Cefixime; Suprax
every 12 hours for 7 to 10 days; maximum dose: Therapeutic Category Antibiotic, Cephalosporin (Third
1,000 mg/dose. Note: IM may only be considered Generation)
for mild to moderate infections due to E. coli. Generic Availability (US) May be product dependent
Severe infection: IV: 50 mg/kg/dose every 12 hours Use Treatment of urinary tract infections, otitis media,
for 10 days; maximum dose: 2,000 mg/dose acute exacerbations of chronic bronchitis due to suscep-
Renal Impairment: Pediatric tible organisms which may include S. pneumoniae and
Manufacturer's labeling: Infants 22 months, Children, pyogenes, H. influenzae, M. catarrhalis, E. coli, and P
and Adolescents: There are no dosage adjustments mirabilis; treatment of pharyngitis and tonsillitis due to S.
provided in the manufacturer's labeling; however, pyogenes; treatment of uncomplicated cervical/urethral
similar dosage adjustments to adults would be gonorrhea due to N. gonorrhoeae (All indications: FDA
anticipated based on comparable pharmacokinetics approved in ages 26 months and adults); has also been
between children and adults. used for management of irinotecan-associated diarrhea,
Alternative dosing recommendations (Aronoff 2007): prophylaxis for sexual victimization, and management of
Infants, Children, and Adolescents: Note: Renally low risk febrile neutropenia
adjusted dose recommendations are
on based Note: Due to concerns of resistance, the CDC no longer
doses of 50 mg/kg/dose every 8 to 12 hours. recommends use of cefixime as a first-line regimen in the
GFR >50 mL/minute/1.73 m2: No adjustment treatment of uncomplicated gonorrhea in the US; ‘cef-
needed triaxone is the preferred cephalosporin in combination
GFR 10 to 50 mL/minute/1.73 m?: 50 mg/kg/dose with azithromycin (CDC 2012; CDC [Workowski 2015)).
every 24 hours Pregnancy Risk Factor B
GFR <10 mL/minute/1.73 m?: 50 mg/kg/dose every Pregnancy Considerations Teratogenic effects were not
48 hours observed in animal reproduction studies. Cefixime
Intermittent hemodialysis: 50 mg/kg/dose every 24 crosses the placenta and can be detected in the amniotic
hours fluid (OzyUncti 2010).
Peritoneal dialysis (PD): 50 mg/kg/dose every 24 Breastfeeding Considerations It is not known if cefix-
hours ime is excreted in breast milk. The manufacturer recom-
Continuous renal replacement therapy (CRRT): mends that consideration be given to discontinuing
50 mg/kg/dose every 12 hours nursing temporarily during treatment. If present in breast
Hepatic Impairment: Pediatric No dosage adjust- milk, nondose-related effects could include modification of
ments necessary. bowel flora.
Preparation for Administration Parenteral: Contraindications Hypersensitivity to cefixime, any com-
IV: Reconstitute 500 mg vial with 5 mL and 1 or 2 g vial ponent of the formulation, or other cephalosporins or
with 10 mL of a compatible diluent (resulting concen- penicillins
tration of 100 mg/mL for 500 mg and 1g vial and Warnings/Precautions Hypersensitivity and anaphylaxis
160 mg/mL for 2g vial); further dilute in D5W, NS, have been reported in patients receiving beta-lactam
D10W, D5NS, or DSLR; final concentration should not drugs. Use caution in patients with a history of hyper-
exceed 40 mg/mL. sensitivity to cephalosporins, penicillins, or other beta-
IM: Reconstitute 500 mg or 1 g vial with 1.3 mL or 2.4 mL, lactams. If administered to penicillin-sensitive patients,
respectively, of SWFI, NS, D5W, lidocaine 0.5% or 1%, use with caution and discontinue use if allergic reaction
or bacteriostatic water for injection to a final concentra- occurs. Severe cutaneous reactions (eg, toxic epidermal
tion of 280 mg/mL necrolysis, Stevens-Johnson syndrome, drug rash with
Administration Parenteral: eosinophilia and systemic symptoms [DRESS]) have been
IV: Administer as an intermittent IV infusion over 30 reported. If a reaction occurs, discontinue and institute
minutes; in adult clinical trials, cefepime has been supportive therapy. Immune-mediated hemolytic anemia

386
 CEFIXIME

(including fatalities) have been reported. Monitor patient Pharmacodynamics/Kinetics (Adult data unless
(including hematologic parameters and drug-induced anti- noted) Note: Chewable tablets and oral suspension are
body testing when clinically appropriate) during and for 2 bioequivalent. However, oral suspension and capsule
to 3 weeks after therapy. If hemolytic anemia occurs formulation are not considered bioequivalent.
during therapy, discontinue use. May cause acute renal
failure including tubulointerstitial nephritis. If renal failure Absorption: 40% to 50%; Note: Capsule AUC reduced by
~15% and Cmax by ~25% when taken with food.
occurs, discontinue and initiate appropriate supportive
Distribution: Widely throughout the body and reaches
therapy. Prolonged use may result in fungal or bacterial
therapeutic concentration in most tissues and body
superinfection, including C. difficile-associated diarrhea
fluids, including synovial, pericardial, pleural, peritoneal;
(CDAD) and pseudomembranous colitis; CDAD has been
bile, sputum, and urine; bone, myocardium, gallbladder,
observed >2 months postantibiotic treatment. Use with
and skin and soft tissue
caution in patients with renal impairment; may increase
Protein binding: 65%
the risk of seizures if dosage not reduced; modify dosage.
Half-life elimination: Normal_renal function: 3 to 4 hours;
Use with caution in patients with a history of gastro-
Moderate impairment (CrCl 20 to 40 mL/minute): 6.4
intestinal disease. Should not be administered to patients hours; Renal failure: Up to 11.5 hours
with a history of cephalosporin-associated hemolytic ane- Time to peak, serum: Suspension: 2 to 6 hours; Capsule:
mia; recurrence of hemolysis is more severe.
3 to 8 hours; Delayed with food
Chewable tablets contain phenylalanine; avoid use or use Excretion: Urine (50% of absorbed dose as active drug);
with caution in patients with phenylketonuria (PKU). feces (10%)
Pharmacodynamics/Kinetics: Additional Consider-
Benzyl alcohol and derivatives: Some dosage forms may ations
contain sodium benzoate/benzoic acid; benzoic acid (ben- Geriatric: Average AUCs at steady state in elderly patients
zoate) is a metabolite of benzyl alcohol: large amounts of are ~40% higher than average AUCs in healthy adults.
benzyl alcohol (299 mg/kg/day) have been associated Dosing
with a potentially fatal toxicity ("gasping syndrome”) in Pediatric Note: Unless otherwise specified, any dosage
neonates; the "gasping syndrome" consists of metabolic form may be used.
acidosis, respiratory distress, gasping respirations, CNS General dosing; susceptible infection (mild to mod-
dysfunction (including convulsions, intracranial hemor- erate): Infants, Children, and Adolescents: Oral:
rhage), hypotension, and cardiovascular collapse (AAP 8 mg/kg/day divided every 12 to 24 hours; maximum
["Inactive" 1997]; CDC 1982); some data suggests that daily dose: 400 mg/day (Red Book [AAP 2015])
benzoate displaces bilirubin from protein binding sites Febrile neutropenia (low-risk): Limited data avail-
(Ahlfors 2001); avoid or use dosage forms containing able: Infants, Children, and Adolescents: Oral:
benzyl alcohol derivative with caution in neonates. See 8 mg/kg/day in divided doses every 12 to 24 hours;
manufacturer’s labeling. in most trials, cefixime therapy was initiated as step-
Warnings: Additional Pediatric Considerations May down therapy after 48 to 72 hours of empiric paren-
cause diarrhea; reported incidence (~16%) similar in chil- teral antibiotic therapy with first cefixime dose admin-
dren receiving oral suspension and adults receiving tablet istered at the end of the last IV infusion (Klaassen
dosage form. Use caution when interchanging product 2000; Lehrnbecher 2017; Paganini 2000; Shenep
formulations; oral suspension and chewable tablets are 2001). Note: In clinical trials, doses were repeated if
bioequivalent but oral immediate release tablets are not patient vomited within 2 hours.
bioequivalent; for some infections (eg, otitis media), dos- Gonococcal infection, uncomplicated infections of
ing recommendations are product specific. the cervix, urethra, or rectum: Children 245 kg and
Adverse Reactions Adolescents: Oral: 400 mg as a single dose in combi-
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, nation with oral azithromycin as a single dose (CDC
flatulence, loose stools, nausea [Workowski 2015]). Note: CDC no longer recom-
Rare but important or life-threatening: Acute renal failure, mends cefixime as a first-line agent (ceftriaxone is
anaphylactoid reaction, anaphylaxis, angioedema, can- the preferred cephalosporin in combination with azi-
didiasis, dizziness, drug fever, eosinophilia, erythema thromycin); cefixime should only be used if ceftriax-
multiforme, facial edema, fever, headache, hepatitis, one is unavailable. In addition, cefixime is not an
hyperbilirubinemia, increased blood urea nitrogen, option for the treatment of uncomplicated gonorrhea
increased serum creatinine, increased serum transami- of the pharynx due to limited efficacy; if it must be
nases, jaundice, leukopenia, neutropenia, prolonged used instead of ceftriaxone, a test-of-cure follow up
prothrombin time, pruritus, pseudomembranous colitis, should be performed 14 days after treatment (CDC
seizure, serum sickness-like reaction, skin rash, Ste- [Workowski 2015]). In Canada, due to increased
vens-Johnson syndrome, thrombocytopenia, toxic epi- antimicrobial resistance, the Public Health Agency of
dermal necrolysis, urticaria, vaginitis, vomiting Canada recommends 800 mg as a single dose for
treatment of uncomplicated gonococcal infections
Drug Interactions =
(Public Health Agency of Canada 2012).
Metabolism/Transport Effects None known.
Irinotecan-associated diarrhea, prophylaxis: Lim-
Avoid Concomitant Use ited data available: Infants, Children, and Adoles-
Avoid concomitant use of Cefixime with any of the cents: Oral: 8 mg/kg once daily; begin 5 days before
following: BCG (Intravesical); Cholera Vaccine oral irinotecan therapy and continue throughout
Increased Effect/Toxicity course (Wagner 2008)
Cefixime may increase the levels/effects of: Aminoglyco- Otitis media, acute: Oral suspension or chewable
sides; Vitamin K Antagonists tablets: Infants, Children, and Adolescents: Oral:
The levels/effects of Cefixime may be increased by: 8 mg/kg/day divided every 12 to 24 hours; maximum
Probenecid daily dose: 400 mg/day
Pharyngitis or tonsillitis; S. pyogenes: Note: Not
Decreased Effect
preferred for treatment in IDSA Guidelines due to
Cefixime may decrease the levels/effects of: BCG (Intra-
unnecessary broad spectrum, and lack of selectivity
vesical); BCG Vaccine (Immunization); Cholera Vaccine;
for antibiotic resistant flora (IDSA [Schulman 2012]);
Lactobacillus and Estriol; Sodium Picosulfate; Typhoid
Infants, Children, and Adolescents: Oral: 8 mg/kg/day
Vaccine
in divided doses every 12 to 24 hours for 210 days;
Food Interactions Food delays cefixime absorption.
maximum daily dose: 400 mg/day
Management: May administer with or without food. Pneumonia, community-acquired (CAP); haemo-
Storage/Stability philus influenza types A-F or nontypeable; mild
Capsule, chewable tablet: Store at 20°C to 25°C (68°F to infection or step-down therapy: Infants 23 months,
T Thats) Children, and Adolescents: Oral: 8 mg/kg/day in div-
Powder for suspension: Prior to reconstitution, store at ided doses every 12 to 24 hours; maximum daily
20°C to 25°C (68°F to 77°F). After reconstitution, sus- dose: 400 mg/day (IDSA/PIDS [Bradley 2011]) Red
pension may be stored for 14 days at room temperature Book [AAP 2015})
or under refrigeration. Rhinosinusitis, acute bacterial: Infants, Children,
Mechanism of Action Inhibits bacterial cell wall syn- and Adolescents: Oral: 4 mg/kg/dose every 12 hours
thesis by binding to one or more of the penicillin-binding with concomitant clindamycin for 10 to 14 days;
proteins (PBPs); which in turn inhibits the final trans- maximum daily dose: 400 mg/day. Note: Recom-
peptidation step of peptidoglycan synthesis in bacterial mended in patients with non-type | penicillin allergy,
cell walls, thus inhibiting cell wall biosynthesis. Bacteria after failure of initial therapy or in patients at risk for
eventually lyse due to ongoing activity of cell wall autolytic antibiotic resistance (eg, daycare attendance, age <2
enzymes (autolysins and murein hydrolases) while cell years, recent hospitalization, antibiotic use within the
wall assembly is arrested. past month) (Chow 2012).

387
CEFIXIME

Typhoid fever (Salmonella typhi): Limited data avail- surgical procedures [eg, gastrointestinal and genitourinary
able; efficacy results variable: Infants, Children and tract surgeries and hysterectomy (abdominal or vaginal)]
Adolescents: Oral: 7.5 to 10 mg/kg/dose every 12 and caesarian section (FDA approved in all ages); has
hours for 7 to 14 days (Cao 1999; Girgis 1995; also been used forthe treatment of peritonitis in patients
Stephens 2002) with peritoneal catheters y
Urinary tract infection; acute: Oral: Pregnancy Risk Factor B
Manufacturer's labeling: Infants 26 months, Children, Pregnancy Considerations Adverse events have not
and Adolescents: 8 mg/kg/day in divided doses been observed in animal reproduction studies. Cefotaxime
every 12 to 24 hours; maximum daily dose: crosses the human placenta and can be found in fetal
400 mg/day tissue. An increase in most types of birth defects was not
Alternate dosing: Infants 22 months and Children <2 found following first trimester exposure to cephalosporins.
years: Initial: 8 mg/kg/day every 24 hours for 7 to 14 During pregnancy, peak cefotaxime serum concentrations
days; in patients <24 months, shorter courses (1 to 3 are decreased and the serum half-life is shorter. Cefotax-
days) have been shown to be inferior to longer ime is approved for use in women undergoing cesarean
durations of therapy (AAP 2011) section (consult current guidelines for appropriate use).
Renal Impairment: Pediatric Breastfeeding Considerations Low concentrations of
Infants 26 months, Children, and Adolescents: Very cefotaxime are found in breast milk. The manufacturer
limited data available; some clinicians have sug- recommends that caution be exercised when administer-
gested the following (Daschner 2005; Dhib 1991): ing cefotaxime to nursing women. Nondose-related effects
Mild to moderate impairment: No adjustment recom- could include modification of bowel flora. The pregnancy-
mended related changes in cefotaxime pharmacokinetics continue
Severe impairment (eg, GFR $10 to 20 mL/minute/ into the early postpartum period.
1.73 m?): Reduce dose by 50% Contraindications Hypersensitivity to cefotaxime, any
Anuric: Reduce dose by 50% component of the formulation, or other cephalosporins
Hemodialysis, peritoneal dialysis: Not significantly Warnings/Precautions A potentially life-threatening
removed arrhythmia has been reported in patients who received a
Hepatic Impairment: Pediatric There are no dosage rapid (<1 minute) bolus injection via central venous cath-
adjustments provided in the manufacturer's labeling. eter. Granulocytopenia and more rarely agranulocytosis
Preparation for Administration Oral: Powder for sus- may develop during prolonged treatment (>10 days).
pension: Reconstitute powder for oral suspension with Minimize tissue inflammation by changing infusion sites
appropriate amount of water as specified on the bottle. when needed. Use with caution in patients with a history of
Shake vigorously until suspended. penicillin allergy, especially |gE-mediated reactions (eg,
Administration Oral: May be administered with or without anaphylaxis, urticaria). Prolonged use may result in fungal
food; administer with food to decrease Gl distress; shake or bacterial superinfection, including C. difficile-associated
suspension well before use; chewable tablets must be diarrhea (CDAD) and pseudomembranous colitis; CDAD
chewed or crushed before swallowing. has been observed >2 months postantibiotic treatment.
Monitoring Parameters With prolonged therapy, monitor Use with caution in patients with renal impairment; dosage
renal and hepatic function periodically; number and type of adjustment may be required. Use with caution in patients
stools/day for diarrhea. Observe for signs and symptoms with a history of colitis. Potentially significant drug-drug
of anaphylaxis during first dose. When used as part of interactions may exist, requiring dose or frequency adjust-
alternative treatment for gonococcal infection, test-of-cure ment, additional monitoring, and/or selection of alternative
7 days after dose (CDC 2012). therapy.
Test Interactions Positive direct Coombs’, false-positive Adverse Reactions
urinary glucose test using cupric sulfate (Benedict's sol- Dermatologic: Pruritus, skin rash
ution, Clinitest®, Fehling's solution), may cause false- Gastrointestinal: Colitis, diarrhea, nausea, vomiting
positive serum or urine creatinine with the alkaline pic- Hematologic & oncologic: Eosinophilia
rate-based Jaffé reaction for measuring creatinine; false- Local: Induration at injection site (IM), inflammation at
positive urine ketones using tests with nitroprusside (but injection site (IV), pain at injection site (IM), tenderness
not those using nitroferricyanide). at injection site (IM)
Dosage Forms Excipient information presented when Miscellaneous: Fever
available (limited, particularly for generics); consult spe- Rare but important or life-threatening: Acute generalized
cific product labeling. exanthematous pustulosis, acute renal failure, agranulo-
Capsule, Oral: cytosis, anaphylaxis, bone marrow failure, brain disease,
Suprax: 400 mg candidiasis, cardiac arrhythmia (after rapid IV injection
Suspension Reconstituted, Oral: via central catheter), cholestasis, Clostridium difficile
Suprax: 100 mg/5 mL (50 mL) [strawberry flavor] associated diarrhea, erythema multiforme, granulocyto-
Suprax: 200 mg/5 mL (50 mL, 75 mL); 500 mg/5 mL (10 penia, hemolytic anemia, hepatitis, increased blood urea
mL, 20 mL) [contains sodium benzoate; strawberry nitrogen, increased gamma-glutamyl transferase,
flavor] increased lactate dehydrogenase, increased serum alka-
Generic: 100 mg/5 mL (50 mL); 200 mg/5 mL (50 mL, line phosphatase, increased serum ALT, increased
75 mL) serum AST, increased serum bilirubin, increased serum
Tablet Chewable, Oral:
creatinine, injection site phlebitis, interstitial nephritis,
Suprax: 100 mg, 200 mg [contains aspartame, fd&c red
jaundice, leukopenia, neutropenia, pancytopenia, posi-
#40 aluminum lake; tutti-frutti flavor]
tive direct Coombs test, pseudomembranous colitis,
® Cefixime Trihydrate see Cefixime on page 386 Stevens-Johnson syndrome, thrombocytopenia, toxic
epidermal necrolysis, vaginitis
@ Cefotan see CefoTEtan on page 390
Drug Interactions
Metabolism/Transport Effects None known.
Cefotaxime (sef oh TAKS eem) Avoid Concomitant Use
Avoid concomitant use of Cefotaxime with any of the
Medication Safety Issues
following: BCG (Intravesical); Cholera Vaccine
Sound-alike/look-alike issues:
Increased Effect/Toxicity
Cefotaxime may be confused with cefOXitin, cefuroxime
Cefotaxime may increase the levels/effects of: Amino-
International issues:
glycosides; Vitamin K Antagonists
Spectrocef [Italy] may be confused with Spectracef
brand name for cefditoren [US, Great Britain, Mexico, The levels/effects of Cefotaxime may be increased by:
Portugal, Spain] Probenecid
Brand Names: US Claforan in D5W [DSC]; Claforan Decreased Effect
[DSC] Cefotaxime may decrease the levels/effects of: BCG
Brand Names: Canada Cefotaxime Sodium For Injec- (Intravesical); BCG Vaccine (Immunization); Cholera
tion; Claforan Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Therapeutic Category Antibiotic, Cephalosporin (Third Typhoid Vaccine
Generation) Storage/Stability Store intact vials below 30°C (86°F).
Generic Availability (US) May be product dependent Protect from light. Reconstituted solution is stable for 12 to
Use Treatment of susceptible lower respiratory tract, skin 24 hours at room temperature, 7 to 10 days when refri-
and skin structure, bone and joint, intra-abdominal, genito- gerated, for 13 weeks when frozen. For IV infusion in NS
urinary tract, and gynecologic infections, bacteremia/sep- or D5W, solution is stable for 24 hours at room temper-
ticemia and documented or suspected central nervous ature, 5 days when refrigerated, or 13 weeks when frozen
system infections (eg, meningitis, ventriculitis)) (FDA in Viaflex plastic containers. Thawed solutions of frozen
approved in all ages); prevention of postoperative surgical premixed bags are stable for 24 hours at room temper-
site infection in contaminated or potentially contaminated ature or 10 days when refrigerated.

388
 CEFOTAXIME

Mechanism of Action Inhibits bacterial cell wall syn- Enteric bacterial infections, empiric treatment (HIV-
thesis by binding to one or more of the penicillin-binding exposed/-positive): Adolescents: IV: 1,000 mg every
proteins (PBPs) which in turn inhibits the final transpepti- 8 hours (HHS [Ol adult 2018})
dation step of peptidoglycan synthesis in bacterial cell Gonorrhea, disseminated infections (including
walls, thus inhibiting cell wall biosynthesis. Bacteria even- arthritis and arthritis-dermatitis syndrome) (as an
tually lyse due to ongoing activity of cell wall autolytic alternative to ceftriaxone) (CDC [Workowski 2015]):
enzymes (autolysins and murein hydrolases) while cell Adolescents: IV: 1,000 mg every 8 hours in combina-
wall assembly is arrested. Cefotaxime has activity in the tion with azithromycin for a total duration of at least
presence of some beta-lactamases, both penicillinases 7 days.
and cephalosporinases, of gram-negative and gram-pos- Intra-abdominal infection, complicated: Infants, Chil-
itive bacteria. Enterococcus species may be intrinsically dren, and Adolescents: IV: 150 to 200 mg/kg/day div-
resistant to cefotaxime. Most extended-spectrum beta- ided every 6 to 8 hours; maximum dose: 2,000 mg; use
lactamase (ESBL)-producing and carbapenemase-pro- in combination with metronidazole (IDSA [Solo-
ducing isolates are resistant to cefotaxime. mkin 2010})
Pharmacodynamics/Kinetics (Adult data unless Lyme disease, cardiac or CNS manifestations or
noted) recurrent arthritis: Infants, Children, and Adolescents:
Distribution: Widely to body tissues and fluids including IV: 150 to 200 mg/kg/day in divided doses every 6 to 8
aqueous humor, ascitic and prostatic fluids, bone; pen- hours for 14 to 28 days; maximum daily dose: 6 g/day
etrates CSF best when meninges are inflamed (AAN [Halperin 2007]; IDSA [Wormser 2006])
Protein binding: 31% to 50% Meningitis: Infants, Children, and Adolescents: IV: 225
Metabolism: Partially hepatic to active metabolite, desa- to 300 mg/kg/day divided every 6 to 8 hours; maximum
dose: 2,000 mg/dose; use in combination with vanco-
cetylcefotaxime
Half-life elimination: mycin for empiric coverage (IDSA [Tunkel 2004]; IDSA
Cefotaxime: Infants $1500 g: 4.6 hours; Infants >1500 g: [Tunkel 2017]); some experts recommend 300 mg/kg/
day divided every 4 to 6 hours with a maximum daily
3.4 hours; Children: 1.5 hours; Adults: 1 to 1.5 hours;
prolonged with renal and/or hepatic impairment
dose of 12 g/day (Red Book [AAP 2018})
Peritonitis (peritoneal dialysis) (ISPD [Warady 2012)):
Desacetylcefotaxime: 1.3 to 1.9 hours; prolonged with
Infants, Children, and Adolescents: Intraperitoneal:
renal impairment (Ings 1982)
Intermittent: 30 mg/kg/dose every 24 hours in the long
Time to peak, serum: IM: Within 30 minutes
dwell
Excretion: Urine (~60% as unchanged drug and metabo-
Continuous: Loading dose: 500 mg per liter of dialy-
lites)
sate; maintenance dose: 250 mg per liter; Note:
Dosing
125 mg/liter has also been recommended as a main-
Neonatal tenance dose (Aronoff 2007)
General dosing, susceptible infection: IM, IV:
Pneumonia:
Gestational age-directed dosing (Red Book [AAP Bacterial pneumonia (HIV-exposed/-positive): Infants,
2018)): Children, and Adolescents: IV: 150 to 200 mg/kg/day
divided every 6 to 8 hours; maximum dose: 2,000 mg/
dose (HHS [Ol adult 2018]; HHS [Ol pediatric 2016])
Community-acquired pneumonia (CAP): Infants >3
months, Children, and Adolescents: IV: 50 mg/kg/
dose every 8 hours; maximum dose: 2,000 mg; Note:
May consider addition of vancomycin or clindamycin
to empiric therapy if community-acquired MRSA sus-
232 weeks aS pected. In children 25 years, a macrolide antibiotic
should be added if atypical pneumonia cannot be
ruled out (IDSA/PIDS [Bradley 2011]).
Weight-directed dosing (Bradley 2018): Salmonellosis (HIV-exposed/-positive): Adolescents:
IV: 1,000 mg every 8 hours (HHS [OI adult 2018])

wars
Body Postnatal

<14 days 50 mg/kg/dose every 12 hours

Skin and soft tissue infections, necrotizing: Infants,
Children, and Adolescents: IV: 50 mg/kg/dose every 6
hours in combination with metronidazole or clindamy-
<1 kg cin; maximum dose: 2,000 mg/dose. Continue until
further debridement is not necessary, patient has clin-
ically improved, and patient is afebrile for 48 to 72
hours (IDSA [Stevens 2014}).
1t0.2kg Surgical prophylaxis: Children and Adolescents: IV:
50 mg/kg within 60 minutes prior to the procedure;
may repeat in 3 hours if procedure is lengthy or if there
is excessive blood loss; maximum dose: 1,000 mg
>2 kg
(ASHP/IDSA [Bratzler 2013])
Urinary tract infection: Infants and Children 2 to 24
Gonococcal infections, disseminated (including sep- months: IM, IV: 150 mg/kg/day divided every 6 to 8
sis, arthritis, and meningitis)/scalp abscess: |M, IV: hours (AAP 2011)
25 mg/kg/dose every 12 hours for 7 days; therapy Renal Impairment: Pediatric
should be extended to 10 to 14 days if meningitis is Infants, Children, and Adolescents: The following
documented (CDC [Workowski 2015]) adjustments have been recommended (Aronoff
Meningitis (IDSA [Tunkel 2004]): IV: Note: Treat for a 2007). Note: Renally adjusted dose recommenda-
minimum of 21 days; use smaller doses and longer tions are based on doses of 100 to 200 mg/kg/day
intervals for neonates <2 kg. divided every 8 hours.
PNA $7 days and 22 kg: 100 to 150 mg/kg/day divided GFR 30 to 50 mL/minute/1.73 m?: 35 to 70 mg/kg/
every 8 to 12 hours dose every 8 to 12 hours
PNA >7 days and 22 kg: 150 to 200 mg/kg/day divided GFR 10 to 29 mL/minute/1.73 m?: 35 to 70 mg/kg/
every 6 to 8 hours dose every 12 hours
Pediatric ‘ GFR <10 mL/minute/1.73 m2: 35 to 70 mg/kg/dose
General dosing, susceptible infection: Infants, Chil- every 24 hours
dren, and Adolescents: IM, IV: 150 to 180 mg/kg/day in Intermittent hemodialysis: 35 to 70 mg/kg/dose every
divided doses every 8 hours; maximum daily dose: 8 g/ 24 hours
day; higher doses necessary for treatment of meningi- Peritoneal dialysis (PD): 35 to 70 mg/kg/dose every
tis (Bradley 2018; Red Book [AAP 2018}) 24 hours
Acute bacterial rhinosinusitis, severe infection Continuous renal replacement therapy (CRRT): 35 to
requiring hospitalization: Children and Adolescents: 70 mg/kg/dose every 12 hours
IV: 100 to 200 mg/kg/day divided every 6 hours for 10 Hepatic Impairment: Pediatric There are no dosage
to 14 days; maximum dose: 2,000 mg (IDSA adjustments provided in the manufacturer's labeling.
[Chow 2012]) Preparation for Administration Parenteral:
Endocarditis, treatment: Children and Adolescents: IV: IM: Reconstitute powder for injection with SWF] to a final
200 mg/kg/day in divided doses every 6 hours; max- concentration between 230 to 330 mg/mL (see manu-
imum daily dose: 12 g/day; treat for at least 4 to 6 facturer's labeling for specific details). Shake to dissolve.
weeks; longer durations may be necessary; may use in IV:
combination with gentamicin for some organisms (AHA IVP: Reconstitute vials with at least 10 mL SWFI to a
[Baltimore 2015]) maximum concentration of 200 mg/mL. >
389
 CEFOTAXIME

4 Intermittent infusion: Reconstitute powder for injection

with SWFI, resultant concentration dependent upon
gastrointestinal disease, particularly colitis. Prolonged use
may result in fungal or bacterial superinfection, including
product (single dose vials or Pharmacy Bulk vial; see C. difficile-associated diarrhea (CDAD) and pseudomem-
manufacturer's labeling for specific details). Dilute dose branous colitis; CDAD has been observed >2 months
to a final concentration of 10 to 40 mg/mL with NS, postantibiotic treatment. May be associated with
D5W, D10W, D5NS, D51/72NS, D51/4NS, or LR; some increased INR and subsequent bleeding, especially in
centers have used concentrations up to 60 mg/mL. nutritionally deficient patients, prolonged treatment, or
Administration Parenteral: patients with cancer, hepatic or renal disease. Monitor
IM: Administer by deep IM injection into a large muscle coagulation parameters and manage as clinically indi-
mass such as the upper outer quadrant of the gluteus cated (eg, administration of phytonadione). Potentially
maximus. Doses of 2,000 mg should be divided and significant interactions may exist, requiring dose or fre-
administered at two different sites. quency adjustment, additional monitoring, andlor selec-
IV: tion of alternative therapy.
IVP: May be administered over 3 to 5 minutes; avoid Adverse Reactions
rapid injection (<1 minute) due to association with Gastrointestinal: Diarrhea
arrhythmias w Hepatic: Increased serum transaminases
Intermittent infusion: Infuse over 15 to 30 minutes. Hypersensitivity: Hypersensitivity reaction
Monitoring Parameters Observe for signs and symp- Rare but important or life-threatening: Agranulocytosis,
toms of anaphylaxis during first dose; monitor infusion site anaphylaxis, eosinophilia, fever, hemolytic anemia, hem-
for extravasation; with prolonged therapy, monitor renal, orrhage, increased blood urea nitrogen, increased serum
hepatic, and hematologic function periodically; number creatinine, leukopenia, nausea, nephrotoxicity, phlebitis,
and type of stools/day for diarrhea prolonged prothrombin time, pruritus, pseudomembra-
Test Interactions Positive direct Coombs’, false-positive nous colitis, skin rash, thrombocythemia, thrombocyto-
urinary glucose test using cupric sulfate (Benedict's sol- penia, urticaria, vomiting
ution, Clinitest®, Fehling's solution), false-positive serum Drug Interactions
or urine creatinine with Jaffé reaction Metabolism/Transport Effects None known.
Dosage Forms Excipient information presented when Avoid Concomitant Use
available (limited, particularly for generics); consult spe- Avoid concomitant use of CefoTEtan with any of the
cific product labeling. [DSC] = Discontinued product following: BCG (Intravesical); Cholera Vaccine
Solution, Intravenous:
Increased Effect/Toxicity
Claforan in D5W: 1 g/50 mL (50 mL [DSC}); 2 g/50 mL
CefoTEtan may increase the levels/effects of: Alcohol
(50 mL [DSC})
(Ethy!); Aminoglycosides; Carbocisteine; Vitamin K
Solution Reconstituted, Injection:
Antagonists i
Claforan: 500 mg (1 ea [DSC]); 1 g (1 ea [DSC]); 2 g (1
ea [DSC]); 10 g (1 ea [DSC}) The levels/effects of CefoTEtan may be increased by:
Generic: 500 mg (1 ea); 1g (1 ea); 2g (1 ea); 10g Probenecid
(1 ea) Decreased Effect
Solution Reconstituted, Injection [preservative free]: CefoTEtan may decrease the levels/effects of: BCG
Generic: 1 g (1 ea) (Intravesical); BCG Vaccine (Immunization); Cholera
Solution Reconstituted, Intravenous: Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Claforan: 1 g (1 ea [DSC]); 2 g (1 ea [DSC]) Typhoid Vaccine
® Cefotaxime Sodium see Cefotaxime on page 388 Food Interactions Concurrent use with ethanol may
cause a disulfiram-like reaction. Management: Monitor
@ Cefotaxime Sodium For Injection (Can) see Cefotax- patients.
ime on page 388
Storage/Stability
Vials: Store intact vials at 20°C to 25°C (68°F to 77°F).
CefoTEtan (SEF oh tee tan) Reconstituted solution is stable for 24 hours at 25°C
(77°F),96 hours at 5°C (41°F) and 7 days at -20°C
Medication Safety Issues (-4°F). In disposable glass or plastic syringes, solution
Sound-alike/look-alike issues: is stable for 24 hours at 25°C (77°F) and 96 hours at 5°C
CefoTEtan may be confused with ceFAZolin, cefOXitin, (41°F).
cefTAZidime, Ceftin, ceffRIAXone Duplex containers: Store at 20°C to 25°C (68°F to 77°F)
Brand Names: US Cefotan prior to reconstitution; excursions permitted to 15°C to
Therapeutic Category Antibiotic, Cephalosporin (Sec- 30°C (59°F to 86°F). Foil strip should not be removed
ond Generation) until ready for use; after foil strip removal, use product
Generic Availability (US) Yes within 7 days. After reconstitution, use within 12 hours if
Use Treatment of susceptible lower respiratory tract, skin stored at room temperature or within 5 days if stored
and skin structure, bone and joint, urinary tract, gyneco- under refrigeration.
logic, and intra-abdominal infections (FDA approved in Mechanism of Action Inhibits bacterial cell wall syn-
adults); surgical prophylaxis (FDA approved in adults); thesis by binding to one or more of the penicillin-binding
has also been used in the prophylaxis of peritonitis in proteins (PBPs) which in turn inhibits the final transpepti-
patients with peritoneal catheters undergoing gastrointes- dation step of peptidoglycan synthesis in bacterial cell
tinal or genitourinary procedures walls, thus inhibiting cell wall biosynthesis. Bacteria even-
Pregnancy Risk Factor B tually lyse due to ongoing activity of cell wall autolytic
Pregnancy Considerations Adverse events have not enzymes (autolysins and murein hydrolases) while cell
been observed in animal reproduction studies. Cefotetan wall assembly is arrested.
crosses the placenta and produces therapeutic concen- Pharmacodynamics/Kinetics (Adult data unless
trations in the amniotic fluid and cord serum. Cefotetan is noted)
one of the antibiotics recommended for use with cesarean Distribution: Widely to body tissues and fluids including
delivery. bile, gallbladder, kidney, skin, tonsils, uterus, sputum,
Breastfeeding Considerations Very small amounts of prostatic and peritoneal fluids
cefotetan are excreted in human milk. The manufacturer Protein binding: 88%
recommends caution when giving cefotetan to a breast- Half-life elimination: 3 to 4.6 hours, prolonged in patients
feeding mother. with moderately impaired renal function (up to 10 hours)
Contraindications Hypersensitivity to cefotetan, any Time to peak, serum: IM: 1 to 3 hours
component of the formulation, or other cephalosporins; Excretion: Urine (51% to 81%, as unchanged drug)
previous cephalosporin-associated hemolytic anemia Dosing
Warnings/Precautions Hypersensitivity reactions, Pediatric
including anaphylaxis, may occur. If an allergic reaction
General dosing, susceptible infection (Red Book
occurs, discontinue treatment and institute appropriate
[AAP 2012]): Infants, Children, and Adolescents: IM,
supportive measures.
IV:
Use with caution in patients with a history of penicillin Mild to moderate infection: 30 mg/kg/dose every 12
allergy. May rarely cause hemolytic anemia (including hours, maximum single dose: 2,000 mg
fatalities); associated with a higher risk of hemolytic Severe infection: 50 mg/kg/dose every 12 hours;
anemia relative to other cephalosporins (approximately maximum dose: 3,000 mg/dose
threefold); monitor carefully during use and consider intra-abdominal infection, complicated: Infants,
cephalosporin-associated immune anemia in patients Children, and Adolescents: IV: 20 to 40 mg/kg/dose
who have received cefotetan within 2 to 3 weeks (either every 12 hours. Note: Due to high rates of B. fragilis
as’ treatment or prophylaxis). Discontinue drug, if appli- group resistance, not recommended for the treatment
cable, and institute supportive measures as clinically of community-acquired intra-abdominal infections
indicated. Use with caution in patients with a history of (Solomkin 2010).

390
 CEFOXITIN

Pelvic inflammatory disease: Adolescents: IV: Peak serum concentrations of cefoxitin during pregnancy
2,000 mg every 12 hours; used in combination with may be similar to or decreased compared to nonpregnant
doxycycline (CDC 2010) values. Maternal half-life may be shorter at term. Preg-
Peritonitis, prophylaxis for patients receiving peri- nancy-induced hypertension increases trough concentra-
toneal dialysis undergoing gastrointestinal or tions in the immediate postpartum period. Cefoxitin is one
genitourinary procedures: Infants, Children, and of the antibiotics recommended for prophylactic use prior
Adolescents: IV: 30 to 40 mg/kg administered 30 to to cesarean delivery.
60 minutes before procedure; maximum dose: Breastfeeding Considerations Very small amounts of
2,000 mg/dose (Warady [ISPD 2012])
cefoxitin are excreted in breast milk. The manufacturer
Surgical prophylaxis: Children and Adolescents: IV:
recommends that caution be exercised when administer-
40 mg/kg 60 minutes prior to procedure; may redose
ing cefoxitin to nursing women. Nondose-related effects
‘in 6 hours; maximum dose: 2,000 mg (Bratzler 2013)
could include modification of bowel flora. Cefoxitin phar-
Renal Impairment: Pediatric
macokinetics may be altered immediately postpartum.
Infants, Children, and Adolescents: Dosage adjust-
ments are not provided in the manufacturer's labeling; Contraindications Hypersensitivity to cefoxitin, any com-
however, the following guidelines have been used by ponent of the formulation, or other cephalosporins
some clinicians (Aronoff 2007); Note: Renally Warnings/Precautions Modify dosage in patients with
adjusted dose recommendations are based on doses severe renal impairment. Prolonged use may result in
of 20 to 40 mg/kg/dose every 12 hours: superinfection. Use with caution in patients with a history
GFR 230 mL/minute/1.73 m?: No adjustment of penicillin allergy, especially IgE-mediated hypersensi-
required. tivity reactions (eg, anaphylaxis, urticaria). If a hyper-
GFR 10 to 29 mL/minute/1.73 m2: 20 to 40 mg/kg/ sensitivity reaction occurs,.discontinue immediately. Use
dose every 24 hours with caution in patients with a history of seizures or
GFR <10 mL/minute/1.73 m?: 20 to 40 mg/kg/dose gastrointestinal disease (particularly colitis). Prolonged
every 48 hours use may result in fungal or bacterial superinfection, includ-
Intermittent hemodialysis: 20 to 40 mg/kg/dose every ing C. difficile-associated diarrhea (CDAD) and pseudo-
48 hours; give after dialysis on dialysis days membranous colitis; CDAD has been observed >2 months
Peritoneal dialysis (PD): 20 to 40 mg/kg/dose every postantibiotic treatment. For group A beta-hemolytic strep-
48 hours tococcal infections, antimicrobial therapy should be given
Continuous renal replacement therapy (CRRT): 20 to for at least 10 days to guard against the risk of rheumatic
40 mg/kg/dose every 12 hours fever or glomerulonephritis. In pediatric patients 23
Hepatic Impairment: Pediatric There are no dosage months of age, higher doses have been associated with
adjustments provided in the manufacturer's labeling. an increased incidence of eosinophilia and elevated AST.
’ Preparation for Administration Parenteral: Elderly patients are more likely to have decreased renal
IM: Reconstitute vial with SWFI, NS, lidocaine 0.5% or function; use care in dose selection and monitor renal
1%, or bacteriostatic water for injection to a final con- function.
centration <500 mg/mL
Adverse Reactions
IV intermittent: Further dilute reconstituted solution to a
Gastrointestinal: Diarrhea
concentration of 10 to 40 mg/mL
Rare but important or life-threatening: Anaphylaxis,
IV push: Reconstitute with SWFI to a concentration
$182 mg/mL angioedema, bone marrow depression, dyspnea, eosi-
nophilia, exacerbation of myasthenia gravis, exfoliative
Administration
Parenteral: dermatitis, fever, hemolytic anemia, hypotension,
IM: Inject deep IM into large muscle mass increased blood urea nitrogen, increased serum creati-
IV intermittent: Infuse over 20 to 60 minutes nine, increased serum transaminases, interstitial neph-
IV push: Inject direct IV over 3 to 5 minutes ritis, jaundice, leukopenia, nausea, nephrotoxicity
Monitoring Parameters CBC, prothrombin time, renal (increased; with aminoglycosides), phlebitis, prolonged
function tests; number and type of stools/day for diarrhea; prothrombin time, pruritus, pseudomembranous colitis,
signs and symptoms of hemolytic anemia; monitor for skin rash, thrombocytopenia, thrombophlebitis, toxic epi-
signs of anaphylaxis during first dose dermal necrolysis, urticaria, vomiting
Test Interactions Positive direct Coombs'. False-positive Drug Interactions
urinary glucose test using cupric sulfate (Benedict's sol- Metabolism/Transport Effects None known.
ution, Clinitest, Fehling's solution); use test based on Avoid Concomitant Use
enzymatic glucose oxidase. May cause false-positive Avoid concomitant use of CefOXitin with any of the
serum or urine creatinine with Jaffé reaction following: BCG (Intravesical); Cholera Vaccine
Additional Information Sodium content of 1000 mg: 3.5 Increased Effect/Toxicity
mEq. CefOxitin may increase the levels/effects of: Aminogly-
Dosage Forms Excipient information presented when cosides; Vitamin K Antagonists
available (limited, particularly for generics); consult spe-
cific product labeling. The levels/effects of CefOXitin may be increased by:
Solution Reconstituted, Injection: Probenecid
Cefotan: 1 g (1 ea); 2 g (1 ea) Decreased Effect
Generic: 1 g (1 ea); 2 g (1 ea); 10 g (1 €a) CefOXitin may decrease the levels/effects of: BCG
Solution Reconstituted, Intravenous: (Intravesical); BCG Vaccine (Immunization); Cholera
Generic: 1 g (1 ea); 2 g (1 ea) Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Typhoid Vaccine
@ Cefotetan Disodium see CefoTEtan on page 390
Storage/Stability Prior to reconstitution store between
2°C and 25°C (36°F and 77°F). Avoid exposure to temper-
CefOXitin (se Foxs i tin) atures >50°C (122°F). Cefoxitin tends to darken depend-
ing on storage conditions; however, product potency is not
Medication Safety Issues adversely affected.
Sound-alike/look-alike issues:
CefOXitin may be confused with ceFAZolin, cefotaxime, Reconstituted solutions of 1 g per 10 mL in sterile water
cefoTEtan, cefTAZidime, ceffRIAXone, Cytoxan for injection, bacteriostatic water for injection, sodium
Mefoxin may be confused with Lanoxin se chloride 0.9% injection, or dextrose 5% injection are stable
Brand Names: US Mefoxin [DSC] for 6 hours at room temperature or for 7 days under
Brand Names: Canada Cefoxitin For Injection refrigeration (<5°C [43°F}).
Therapeutic Category Antibiotic, Cephalosporin (Sec-
ond Generation) DUPLEX container: Store unactivated container at 20°C to
Generic Availability (US) May be product dependent 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C
(59°F to 86°F); do not freeze. Following activation, sol-
Use Treatment of susceptible lower respiratory tract, skin
and skin structure, bone and joint, genitourinary tract, ution is stable for 12 hours at room temperature and 7
sepsis, gynecologic, and intra-abdominal infections and days refrigerated.
surgical prophylaxis (FDA approved in ages 23 months Mechanism of Action Inhibits bacterial cell wall syn-
and adults); has also been used in the prophylaxis of thesis by binding to one or more of the penicillin-binding
peritonitis in patients with peritoneal catheters undergoing proteins (PBPs) which in turn inhibits the final transpepti-
gastrointestinal or genitourinary procedures dation step of peptidoglycan synthesis in bacterial cell
Pregnancy Considerations Adverse events have not walls, thus inhibiting cell wall biosynthesis. Bacteria even-
been observed in animal reproduction studies. Cefoxitin tually lyse due to ongoing activity of cell wall autolytic
crosses the placenta and reaches the cord serum and enzymes (autolysins and murein hydrolases) while cell
amniotic fluid. wall assembly is arrested.

391
CEFOXITIN

Pharmacodynamics/Kinetics (Adult data unless Administration Parenteral:

noted) IVP: Administer over 3 to 5 minutes
Distribution: Widely to body tissues and fluids including Intermittent IV infusion: Administer over 10 to 60 minutes
ascitic, pleural, synovial, bile; poorly penetrates into CSF IM: Deep IM injection into a large muscle mass such as
even with inflammation of the meninges (Landesman the upper outer quadrant of the gluteus maximus. Note:
1981) IM injection is painful and this route of administration is
Protein binding: 65% to 79% not described in the prescribing information.
Half-life elimination: Neonates and Infants (PNA: 10-53 Monitoring Parameters Renal function periodically when
days): 1.4 hours (Regazzi 1983); Adults: 41-59 minutes; used in combination with other nephrotoxic drugs; liver
prolonged with renal impairment function and hematologic function tests; number and type
Time to peak, serum: IM: Within 20-30 minutes of stools/day for diarrhea. Observe for signs and symp-
Excretion: Urine (85% as unchanged drug) toms of anaphylaxis during first dose.
Dosing Test Interactions Positive direct Coombs', false-positive
Neonatal General dosing; susceptible infection: Lim- urinary glucose test using cupric sulfate (Benedict's sol-
ited data available: IV: 90.to 100 mg/kg/day divided ution, Clinitest®, Fehling's solution), false-positive serum
every 8 hours (Regazzi 1983; Roos 1980) or urine creatinine with Jaffé reaction
Pediatric Dosage Forms Excipient information presented when
available (limited, particularly for generics); consult spe-
General dosing, susceptible infection (Red Book
cific product labeling. [DSC] = Discontinued product
[AAP 2012]): Infants, Children, and Adolescents: IM,
Solution, 4ntravenous:
IV:
_Mefoxin: 1 g(50 mL [DSC}); 2 g (50 mL [DSC})
Mild to moderate infection: 80 mg/kg/day divided
Solution Reconstituted, Injection:
every 6 to-8 hours; maximum daily dose:
Generic: 10 g (1 ea)
4,000 mg/day
Solution Reconstituted, Injection [preservative free]:
Severe infection: 160 mg/kg/day divided every 6
Generic: 10 g (1 ea)
hours; maximum daily dose: 12 g/day
Solution Reconstituted, Intravenous:
Manufacturer's labeling: Infants 23 months, Children,
Generic: 1 g (1 ea); 2 g (1 ea)
and Adolescents: 80 to 160 mg/kg/day divided every Solution Reconstituted, Intravenous [preservative free]:
4 to 6 hours; maximum daily dose: 12 g/day Generic: 1 g (1 ea); 2 g (1 ea)
Intra-abdominal infections, complicated: Infants, .
Children, and Adolescents: IV: 160 mg/kg/day divided @ Cefoxitin For Injection (Can) see CefOXitin
every 4 to 6 hours; maximum daily dose: 8 g/day on page 391
(Solomkin 2010) @ Cefoxitin Sodium see CefOXitin on page 391
Peritonitis, prophylaxis for patients receiving peri-
@ Cefoxitin Sodium/D5W see CefOXitin on page 397
toneal dialysis undergoing gastrointestinal or
genitourinary procedures: Limited data available:
Infants, Children, and Adolescents: IV: 30 to 40 mg/kg Cefpodoxime (sef pode OKS eem)
administered 30 to 60 minutes before procedure;
maximum dose: 2,000 mg/dose (Warady Medication Safety Issues
[ISPD 2012]) Sound-alike/look-alike issues:
Surgical prophylaxis: IV: Vantin may be confused with Ventolin
Manufacturer's labeling: Infants 23 months, Children, Therapeutic Category Antibiotic, Cephalosporin (Third
and Adolescents: 30 to 40 mg/kg 30 to 60 minutes Generation)
prior to initial incision, followed by 30 to 40 mg/kg Generic Availability (US) Yes
every 6 hours for up to 24 hours; maximum single Use Treatment of the following mild to moderate infections
dose: 2,000 mg caused by susceptible organisms: Acute otitis media (FDA
Alternate dosing (ASHP guidelines, endorsed by approved in 2 months to 12 years); pharyngitis or tonsillitis
IDSA): Children and Adolescents: 40 mg/kg within (FDA approved in ages 22 months and adults); acute
60 minutes prior to surgery; may repeat in 2 hours if maxillary sinusitis (FDA approved in ages 22 months
procedure is lengthy or if there is excessive blood and adults); community acquired pneumonia (FDA
loss; maximum single dose: 2,000 mg (Bratzler approved in ages 212 years and adults); acute, bacterial
2013; Red Book [AAP 2012]) exacerbation of chronic bronchitis (FDA approved in ages
212 years and adults); acute uncomplicated urethral and
Renal Impairment: Pediatric
cervical gonorrhea (FDA approved in ages 212 years and
Infants, Children, and Adolescents: The manufacturer's
adults); ano-rectal gonorrhea (FDA approved in female
labeling suggests dosing modification consistent with
patients ages 212 years and adult); uncomplicated skin
the adult recommendations. Some clinicians have
and skin structure infections (FDA approved in ages 212
used the following guidelines (Aronoff 2007); Note:
years and adults); and uncomplicated urinary tract infec-
Renally adjusted dose recommendations are based
tions (FDA approved in ages 212 years and adults)
on doses of 20 to 40 mg/kg/dose every 6 hours.
Note: CDC no longer recommends oral cephalosporins as
GFR >50 mL/minute/1.73 m?: No adjustment
a first-line agent for treatment of gonorrhea and cefpo-
required.
doxime is no longer listed as a recommended option for
GFR 30 to 50 mL/minute/1.73 m?: 20 to 40 mg/kg/ treatment (CDC 2012).
dose every 8 hours
Pregnancy Risk Factor B
GFR 10 to 29 mL/minute/1.73 m2: 20 to 40 mg/kg/
Pregnancy Considerations Teratogenic events were
dose every 12 hours
not observed in animal reproduction studies. An increase
GFR <10 mL/minute/1.73 m?: 20 to 40 mg/kg/dose in most types of birth defects was not found following first
every 24 hours trimester exposure to cephalosporins.
Intermittent hemodialysis: Moderately dialyzable
Breastfeeding Considerations Cefpodoxime is
(20% to 50%): 20 to 40 mg/kg/dose every 24 hours excreted in breast milk. The manufacturer recommends
Peritoneal dialysis (PD): 20 to 40 mg/kg/dose every discontinuing nursing or discontinuing the medication in
24 hours breastfeeding women. Nondose-related effects could
Continuous renal replacement therapy (CRRT): 20 to include modification of bowel flora.
40 mg/kg/dose every 8 hours Contraindications Hypersensitivity to cefpodoxime, any
Hepatic Impairment: Pediatric There are no dosage component of the formulation, or other cephalosporins
adjustments provided in the manufacturer's labeling. Warnings/Precautions Modify dosage in patients with
Preparation for Administration Parenteral: severe renal impairment. Prolonged use may result in
IVP: Reconstitute vials with SWF, bacteriostatic water for fungal or bacterial superinfection, including C. difficile-
injection, NS, or D5W to a final concentration of 95 associated diarrhea (CDAD) and pseudomembranous
to180 mg/mL; see manufacturer's labeling for specific colitis; CDAD has been observed >2 months postantibiotic
details. treatment. Use with caution in patients with a history of
Intermittent IV infusion: Reconstitute vials with SWFI, beta-lactam allergy, especially IgE-mediated reactions
bacteriostatic water for injection, NS, or DSW; see man- (eg, anaphylaxis, urticaria).
ufacturer’s labeling for specific details. Further dilute to a
final concentration not to exceed 40 mg/mL in NS, Ds1/4NS, Potentially significant drug-drug interactions may exist,
Ds5V2NS, DsNS, D5W, Di pW, LR, D5LR, mannitol 5% requiring dose or frequency adjustment, additional mon-
or 10%, or sodium bicarbonate 5%. In fluid restricted
itoring, and/or selection of alternative therapy.
patients, a concentration of 125 mg/mL using SWFI Benzyl alcohol and derivatives: Some dosage forms may
results in a maximum recommended osmolality for contain sodium benzoate/benzoic acid; benzoic acid (ben-
peripheral infusion (Robinson 1987) , zoate) is a metabolite of benzyl alcohol; large amounts of
IM: Reconstitute vial with 1 to 2 mL of 0.5% or 1% benzyl alcohol (299 mg/kg/day) have been associated
lidocaine (McCloskey 1979; Sonneville 1977) with a potentially fatal toxicity ("gasping syndrome") in

392
 CEFPROZIL

neonates; the "gasping syndrome" consists of metabolic Otitis media, acute: Infants and Children 2 months to
acidosis, respiratory distress, gasping respirations, CNS 12 years: Oral: 5 mg/kg/dose every 12 hours; max-
dysfunction (including convulsions, intracranial hemor- imum dose: 200 mg/dose. Variable duration of ther-
rhage), hypotension, and cardiovascular collapse (AAP apy; the manufacturer suggests 5-day course in all
["Inactive" 1997]; CDC 1982); some data suggests that patients; however, AAP guidelines recommend dura-
benzoate displaces bilirubin from protein binding sites tion based on patient age: If <2 years of age or severe
(Ahlfors 2001); avoid or use dosage forms containing symptoms (any age): 10-day course; if 2 to 5 years of
benzyl alcohol derivative with caution in neonates. See age with mild to moderate symptoms: 7-day course; if
manufacturer's labeling. 26 years of age with mild to moderate symptoms: 5- to
Adverse Reactions 7-day course (AAP [Lieberthal 2013)).
Central nervous system: Headache Pharyngitis/tonsillitis:
Dermatologic: Diaper rash, skin rash Infants 22 months and Children <12 years: Oral:
Gastrointestinal: Abdominal pain, diarrhea, nausea, vom- 5 mg/kg/dose every 12 hours for 5 to 10 days;
iting maximum dose: 100 mg/dose
Genitourinary: Vaginal infection Children 212 years and Adolescents: Oral: 100 mg
Rare but important or life-threatening: Anaphylaxis, anxi- every 12 hours for 5 to 10 days
ety, chest pain, cough, decreased appetite, dizziness,
Pneumonia, acute community-acquired:
dysgeusia, epistaxis, eye pruritus, fatigue, fever, flat-
Infants >3 months and Children <12 years: Limited
ulence, flushing, fungal skin infection, hypotension,
data available: Oral: 5 mg/kg/dose every 12 hours;
insomnia, malaise, nightmares, pruritus, pseudomem-
maximum dose: 200 mg/dose (Bradley 2015; IDSA
branous colitis, purpuric nephritis, tinnitus, vulvovaginal
[Bradley 2011])
| candidiasis, weakness, xerostomia
Children 212 years and Adolescents: Oral: 200 mg
Drug Interactions
every 12 hours for 14 days
Metabolism/Transport Effects None known.
Rhinosinusitis, acute maxillary:
Avoid Concomitant Use
Infants 22 months and Children <12 years: Oral:
Avoid concomitant use of Cefpodoxime with any of the
5 mg/kg/dose every 12 hours for 10 days; maximum
following: BCG (Intravesical); Cholera Vaccine
dose: 200 mg/dose; Note: IDSA recommends use
Increased Effect/Toxicity
in combination with clindamycin for 10 to 14 days in
Cefpodoxime may increase the levels/effects of: Amino-
patients with nontype 1 penicillin allergy, after failure
glycosides; Vitamin K Antagonists
of initial therapy or in patients at risk for antibiotic
The levels/effects of Cefpodoxime may be increased by: resistance (eg, daycare attendance, age <2 years,
Probenecid recent hospitalization, antibiotic use within the past
Decreased Effect month) (Chow 2012).
Cefpodoxime may decrease the levels/effects of: BCG Children 212 years and Adolescents: Oral: 200 mg
(Intravesical); BCG Vaccine (Immunization); Cholera every 12 hours for 10 days
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate; Skin and skin structure: Children 212 years and
Typhoid Vaccine Adolescents: Oral: 400 mg every 12 hours for 7 to
The levels/effects of Cefpodoxime may be decreased by: 14 days
Antacids; Histamine H2 Receptor Antagonists; Proton Urinary tract infection, uncomplicated: Children 212
Pump Inhibitors years and Adolescents: Oral: 100 mg every 12 hours
Food Interactions Food increases extent of absorption for 7 days
and peak concentration of tablets. Management: Take Renal Impairment: Pediatric
tablets with food. Infants 22 months, Children, and Adolescents:
Storage/Stability CrCl 230 mL/minute: No dosage adjustment necessary.
Suspension: Store at 20°C to 25°C (68°F to 77°F); after CrCl <30 mL/minute: Administer every 24 hours.
reconstitution, suspension may be stored in refrigerator Hemodialysis: Approximately 23% removed during a 3-
for 14 days. hour dialysis session. Administer dose 3 times weekly
Tablet: Store at 20°C to 25°C (68°F to 77°F); protect from after hemodialysis.
light. Hepatic Impairment: Pediatric Infants 22 months,
Mechanism of Action Inhibits bacterial cell wall syn- Children, and Adolescents: No dosage adjustment nec-
thesis by binding to one or more of the penicillin-binding essary in patients with cirrhosis.
proteins (PBPs) which in turn inhibits the final transpepti- Preparation for Administration Oral suspension:
dation step of peptidoglycan synthesis in bacterial cell Reconstitute powder for oral suspension with appropriate
walls, thus inhibiting cell wall biosynthesis. Bacteria even- amount of water as specified on the bottle. Shake vigo-
tually lyse due to ongoing activity of cell wall autolytic rously until suspended.
enzymes (autolysins and murein hydrolases) while cell Administration Oral:
wall assembly is arrested. ess Ae Tablet: Administer with food
Pharmacodynamics/Kinetics (Adult data unless Suspension: May administer with or without food; shake
noted) suspension well before use
Absorption: Rapid and well absorbed (50%); tablet AUC Monitoring Parameters Observe patient for diarrhea;
increased 21% to 33% with food with prolonged therapy, monitor renal function periodically.
Distribution: Good tissue penetration, including lung and Observe for signs and symptoms of anaphylaxis during
tonsils; penetrates into pleural fluid first dose.
Protein binding: Serum: 22% to 33%; Plasma: 21% to 29%
Test Interactions Positive direct Coombs’, false-positive
Metabolism: De-esterified in Gl tract to active metabolite,
urinary glucose test using cupric sulfate (Benedict's sol-
cefpodoxime
ution, Clinitest®, Fehling's solution), false-positive serum
Bioavailability: Oral: 50%
or urine creatinine with Jaffé reaction
Half-life elimination: ~2 to 3 hours; prolonged with renal
impairment (~10 hours for CrCl <30 mL/minute) Dosage Forms Excipient information presented when
Time to peak: Tablets: Within 2 to 3 hours; Oral suspen- available (limited, particularly for generics); consult spe-
sion: Slower in presence of food, 48% increase in Tmax cific product labeling.
Excretion: Urine (~29% to 33% as unchanged drug) in 12 Suspension Reconstituted, Oral:
hours Generic: 50 mg/5 mL (50 mL, 100 mL); 100 mg/5 mL (50
Pharmacodynamics/Kinetics: Additional Consider- mL, 100 mL)
ations Tablet, Oral:
Renal function impairment: Elimination is reduced in those Generic: 100 mg, 200 mg
with CrCl less than 50 mL/minute. i @ Cefpodoxime Proxetil see Cefpodoxime on page 392
Geriatric: The half-life is increased to about 4.2 hours.
Dosing
Pediatric Cefprozil (sef PROE zil)
General dosing, susceptible infection: Mild to mod-
erate infections: Infants, Children, and Adolescents:
Medication Safety Issues
Oral: 5 mg/kg/dose every 12 hours; usual maximum Sound-alike/look-alike issues:
dose: 200 mg/dose; however, in patients 212 years, Cefprozil may be confused with ceFAZolin, cefuroxime
higher doses (ie, 400 mg/dose) may be required for Cefzil may be confused with Ceftin
some types of infection (Bradley 2015; Red Book Brand Names: Canada Apo-Cefprozil; Auro-Cefprozil;
[AAP 2015]) Ava-Cefprozil; Cefzil; RAN-Cefprozil; Sandoz-Cefprozil
Bronchitis, bacterial exacerbation of chronic: Chil- Therapeutic Category Antibiotic, Cephalosporin (Sec-
dren 212 years and Adolescents: Oral: 200 mg every ond Generation)
12 hours for 10 days j Generic Availability (US) Yes

393
CEFPROZIL

Use Treatment of mild to moderate infections caused by Refrigerate suspension after reconstitution; discard after
susceptible organisms involving the upper respiratory tract 14 days.
and skin and skin structure (FDA approved in ages 22 Mechanism of Action Inhibits bacterial cell wall syn-
years and adults); treatment of mild to moderate acute thesis by binding to one or more of the penicillin-binding
sinusitis and otitis media (FDA approved in ages 26 proteins (PBPs) which in turn inhibits the final transpepti-
months and adults) dation step of peptidoglycan synthesis in bacterial cell
Pregnancy Risk Factor B walls, thus inhibiting cell wall biosynthesis. Bacteria even-
Pregnancy Considerations Adverse events were not tually lyse due to ongoing activity of cell wall autolytic
observed in animal reproduction studies. enzymes (autolysins and murein hydrolases) while cell
Breastfeeding Considerations Small amounts of cef- wall assembly is arrested.
prozil are excreted in breast milk. The manufacturer Pharmacodynamics/Kinetics (Adult data unless
recommends that caution be exercised when administer- noted)
ing cefprozil to nursing women. Nondose-related effects Absorption: Well absorbed (95%)
could include modification of bowel flora. Distribution: Vg: 0.23 L/kg
Contraindications Hypersensitivity to cefprozil, any com- Protein binding: ~36%
ponent of the formulation, or other cephalosporins Bioavailability: 95%
Warnings/Precautions Modify dosage in patients with Half-life elimination:
severe renal impairment. Hypersensitivity reactions have Infants and Children (6 months to 12 years): 1.5 hours
been reported; if hypersensitivity, occurs, discontinue and Adults:
institute emergency supportive measures, including air- Normal-hepatic and renal function: 1.3 hours
way management and treatment (eg, epinephrine, anti- Renal impairment: 5.2 hours
histamines and/or_corticosteroids). Use with caution in ~ Renai failure: 5.9 hours
patients with a history of penicillin allergy. Use with caution Hepatic impairment: 2 hours
in patients with a history of gastrointestinal disease, Time to peak, serum: Fasting: 1.5 hours
particularly colitis. Prolonged use may result in fungal or Excretion: Urine (~60% as unchanged drug)
bacterial superinfection, including C. difficile-associated Pharmacodynamics/Kinetics: Additional Consider-
diarrhea (CDAD) and pseudomembranous colitis; CDAD ations ‘
has been observed >2 months postantibiotic treatment. Geriatric: AUC is about 35% to 60% higher.
Potentially significant interactions may exist, requiring Dosing
dose or frequency adjustment, additional monitoring, Pediatric
and/or selection of alternative therapy. Some products General dosing, susceptible infection (Red Book
may contain phenylalanine. 2012): Infants, Children, and Adolescents: Oral: Mild
to moderate infection: 7.5 to 15 mg/kg/dose twice
Benzyl alcohol and derivatives: Some dosage forms may
daily; maximum single dose: 500 mg
contain sodium benzoate/benzoic acid; benzoic acid (ben-
Bronchitis, acute bacterial exacerbation: Adoles-
zoate) is a metabolite of benzyl! alcohol; large amounts of
cents: Oral: 500 mg every 12 hours for 10 days
benzyl alcohol (299 mg/kg/day) have been associated
Otitis media, acute: Infants 26 months and Children:
with a potentially fatal toxicity ("gasping syndrome") in
Oral: 15 mg/kg/dose every 12 hours for 10: days;
neonates; the "gasping syndrome" consists of metabolic
maximum single dose: 500 mg. Note: Cefprozil is
acidosis, respiratory distress, gasping respirations, CNS
not routinely recommended as a treatment option
dysfunction (including convulsions, intracranial hemor-
(AAP [Lieberthal 2013)).
rhage), hypotension, and cardiovascular collapse (AAP
Pharyngitis/tonsillitis: Oral:
["Inactive" 1997]; CDC, 1982). Some data suggest that
Children 22 years: 7.5 mg/kg/dose every 12 hours for
benzoate displaces bilirubin from protein-binding sites
10 days; maximum single dose: 500 mg
(Ahlfors, 2001); avoid or use dosage forms containing
Adolescents: 500 mg every 24 hours for 10 days
benzyl! alcohol derivative with caution in neonates. See
Rhinosinusitis: Oral:
manufacturer's labeling.
Infants 26 months and Children: 7.5 to 15 mg/kg/dose
Some dosage forms may contain polysorbate 80 (also every 12 hours for 10 days; maximum single dose:
known as Tweens). Hypersensitivity reactions, usually a 500 mg
delayed reaction, have been reported following exposure Adolescents: 250 to 500 mg every 12 hours for
to pharmaceutical products containing polysorbate 80 in 10 days \
certain individuals (Isaksson, 2002; Lucente 2000; Shel- Skin and skin structure infection: Oral:
ley, 1995). Thrombocytopenia, ascites, pulmonary deteri- Children 22 years: 20 mg/kg/dose once daily for 10
oration, and renal and hepatic failure have been reported days; maximum single dose: 500 mg
in premature neonates after receiving parenteral products Adolescents: 250 mg every 12 hours or 500 mg every
containing polysorbate 80 (Alade, 1986; CDC, 1984). See 12 to 24 hours for 10 days
manufacturer's labeling. Urinary tract infection: Oral: Infants and Children 2 to
Adverse Reactions 24 months: 15 mg/kg/dose twice daily for 7 to 14 days
Central nervous system: Dizziness (AAP 2011)
Dermatologic: Diaper rash, genital pruritus Renal Impairment: Pediatric
Gastrointestinal: Abdominal pain, diarrhea, nausea, vom- Infants, Children, and Adolescents: Oral:
iting Manufacturer's labeling:
Genitourinary: Vaginitis CrCl 230 mL/minute: No dosage adjustment nec-
Hepatic: Increased serum transaminases (2%) essary.
Infection: Superinfection CrCl <30 mL/minute: Reduce usual recommended
Rare but important or life-threatening: Anaphylaxis, dose by 50%.
angioedema, arthralgia, cholestatic jaundice, confusion, End-stage renal disease (ESRD) on hemodialysis:
drowsiness, eosinophilia, erythema multiforme, fever, Give dose after dialysis on dialysis days.
headache, hyperactivity, increased blood urea nitrogen, Alternative recommendations: The following recom-
increased serum creatinine, insomnia, leukopenia, pseu- mendations have been used by some clinicians
domembranous colitis, serum sickness, skin rash, Ste- (Aronoff 2007): Note: Renally adjusted dose recom-
vens-Johnson syndrome, thrombocytopenia, urticaria mendations are based on a usual dose of 30 'mg/kg/
Drug Interactions day divided every 12 hours
Metabolism/Transport Effects None known. GFR 230 mL/minute/1.73 m?: No dosage adjust-
Avoid Concomitant Use ment necessary
Avoid concomitant use of Cefprozil with any of the GFR <30 mL/minute/1.73 m2: 7.5 mg/kg/dose every
following: BCG (Intravesical); Cholera Vaccine 12 hours
Increased Effect/Toxicity Intermittent hemodialysis: ~55% is removed by
Cefprozil may increase the levels/effects of: Aminoglyco- hemodialysis; 7.5 mg/kg/dose every 12 hours;
sides; Vitamin K Antagonists administer an additional 5 mg/kg/dose after dialy-
sis session
The levels/effects of Cefprozil may be increased by: Peritoneal dialysis: 7.5 mg/kg/dose every 12 hours
Probenecid Hepatic Impairment: Pediatric Infants, Children and
Decreased Effect Adolescents: No dosage adjustment necessary
Cefprozil may decrease the levels/effects of: BCG (Intra- Preparation for Administration Oral suspension:
vesical); BCG Vaccine (Immunization); Cholera Vaccine; Reconstitute powder for oral suspension with appropriate
Lactobacillus and Estriol; Sodium Picosulfate; Typhoid amount of water as specified on the bottle. Shake vigo-
Vaccine rously until Suspended.
Food Interactions Food delays cefprozil absorption. Administration Oral: May administer with or without food;
Management: May administer with food. administer with food if stomach upset occurs; chilling
Storage/Stability Store at 20°C to 25°C (68°F to 77°F); improves flavor of suspension (do not freeze); shake
excursions permitted to 15°C to 30°C (59°F to 86°F). suspension well before use

394
 CEFTAROLINE FOSAMIL

Monitoring Parameters Evaluate renal function before Hypersensitivity: Anaphylaxis (adults), hypersensitivity
and during therapy; with prolonged therapy, monitor coag- (adults)
ulation tests, CBC, and liver function tests periodically; Renal: Renal failure (adults)
monitor for signs of anaphylaxis during first dose. Miscellaneous: Fever (adults)
Test Interactions Positive direct Coombs, false-positive Rare but important or life-threatening: Agranulocytosis
urinary glucose test using cupric sulfate (Benedict's sol- (adults), leukopenia (adults)
ution, Clinitest, Fehling's solution), but not with enzyme- Drug Interactions
based tests for glycosuria (eg, Clinistix). A false-negative Metabolism/Transport Effects None known.
reaction may occur in the ferricyanide test for blood Avoid Concomitant Use
glucose. Avoid concomitant use of Ceftaroline Fosamil with any of
Dosage Forms Excipient information presented when the following: BCG (Intravesical); Cholera Vaccine
available (limited, particularly for generics); consult spe- Increased Effect/Toxicity
cific product labeling. Ceftaroline Fosamil may increase the levels/effects of:
Suspension Reconstituted, Oral: Vitamin K Antagonists
Generic: 125 mg/5 mL (50 mL, 75 mL, 100 mL); 250 mg/
5 mL (50 mL, 75 mL, 100 mL) The levels/effects of Ceftaroline Fosamil may be
Tablet, Oral: increased by: Probenecid
Generic: 250 mg, 500 mg Decreased Effect
Ceftaroline Fosamil may decrease the levels/effects of:
BCG (Intravesical); BCG Vaccine (Immunization); Chol-
Ceftaroline Fosamil (sef Tar oh leen FOS a mil) era Vaccine; Lactobacillus and Estriol; Sodium Picosul-
Brand Names: US Teflaro fate; Typhoid Vaccine
Therapeutic Category Antibiotic, Cephalosporin (Fifth Storage/Stability Store unused vials at 25°C (77°F);
Generation) excursions permitted between 15°C and 30°C (59°F and
Generic Availability (US) No 86°F). Diluted solutions in D2.5W, /2NS, D5W, LR, or NS
Use Treatment of acute bacterial skin and skin structure (in infusion bags or Mini-Bag Plus) should be used within 6
infections (ABSSSI) caused by susceptible isolates of hours when stored at room temperature or within 24 hours
Staphylococcus aureus (including methicillin-susceptible if refrigerated at 2°C to 8°C (36°F to 46°F).
and -resistant isolates), Streptococcus pyogenes, Strep- Mechanism of Action Inhibits bacterial cell wall syn-
tococcus agalactiae, Escherichia coli, Klebsiella pneumo- thesis by binding to penicillin-binding proteins (PBPs) 1
niae, and Klebsiella oxytoca (FDA approved in ages 22 through 3. This action blocks the final transpeptidation
months and adults); treatment of community-acquired step of peptidoglycan synthesis in bacterial cell walls
pneumonia (CAP) caused by Streptococcus pneumoniae and inhibits cell wall biosynthesis. Bacteria eventually lyse
(including cases with concurrent bacteremia), Staphylo- due to ongoing activity of cell wall autolytic enzymes
coccus aureus (methicillin-susceptible isolates only), Hae- (autolysis and murein hydrolases) while cell wall assembly
mophilus influenzae, Klebsiella pneumoniae, Klebsiella is arrested. Ceftaroline has a strong affinity for PBP2a, a
oxytoca, and Escherichia coli (FDA approved in ages 22 modified PBP in MRSA, and PBP2x in S. pneumoniae,
months and adults) contributing to its spectrum of activity against these bac-
Pregnancy Considerations Adverse events have been teria.
observed in some animal reproduction studies. Pharmacodynamics/Kinetics (Adult data unless
Breastfeeding Considerations It is not known if ceftaro- noted) Note: The pharmacokinetics of ceftaroline in
line fosamil is excreted in breast milk. The manufacturer pediatric patients from 2 months to <18 years of age were
recommends that caution be exercised when administer- similar to those in adult patients.
ing ceftaroline fosamil to nursing women. Distribution: Vg: Median: 20.3 L (range: 18.3 to 21.6 L)
Contraindications Known serious hypersensitivity to cef- Protein binding: ~20%
taroline, other members of the cephalosporin class, or any Metabolism: Ceftaroline fosamil (inactive prodrug) under-
component of the formulation goes rapid conversion to bioactive ceftaroline in plasma
Warnings/Precautions Serious hypersensitivity (ana- by phosphatase enzyme; ceftaroline is hydrolyzed to
phylactic) and skin reactions have occurred with ceftaro- form inactive ceftaroline M-1 metabolite
line. Use with caution in patients with a history of penicillin, Half-life elimination: ~1.6 hours (single dose); ~2.66 hours
cephalosporin, or carbapenem allergy. Maintain clinical (multiple dose)
supervision if given to penicillin or beta-lactam allergic Time to peak: ~1 hour
patients. Seroconversion from a negative to a positive Excretion: Urine (~88%); feces (~6%)
direct Coombs’ test has been reported. Hemolytic anemia Pharmacodynamics/Kinetics: Additional Consider-
was not reported in clinical studies; however, if anemia ations
develops during or after treatment, diagnostic tests should Renal function impairment: AUC increased 52% in mod-
include a direct Coombs’ test. If drug-induced hemolytic erate renal impairment (CrCl >30 to 50 mL/minute) and
anemia is considered, discontinue the drug and institute 115% in severe renal impairment (CrCl 15 to 30 mL/
supportive care as clinically indicated. Prolonged use may
minute) as compared to patients with normal renal
result in fungal or bacterial superinfection, including C. function. Following a 4-hour hemodialysis session,
difficile-associated diarrhea (CDAD) and pseudomembra- 21.6% of a single 400 mg IV dose (administered prior
nous colitis (including fatalities); CDAD has been
to hemodialysis) was recovered in the dialysate.
observed >2 months postantibiotic treatment. Use with
Geriatric: The AUC was approximately 33% higher in
caution in patients with renal impairment (CrCl <50 mL/
elderly patients, mainly because of changes in renal
minute); dosage adjustments recommended. Potentially
function.
significant drug-drug interactions may exist, requiring
Dosing
dose or frequency adjustment, additional monitoring,
and/or selection of alternative therapy. Pediatric
Pneumonia, community acquired: Treatment dura-
Adverse Reactions The following reactions occurred in
all indicated populations unless otherwise specified. tion in patients <18 years is variable (5 to 14 days);
Cardiovascular: Bradycardia (adults), palpitations (adults), dependent on severity of infection and clinical
phlebitis (adults) response
Central nervous system: Dizziness (adults), headache Infants 22 months and Children <2 years: IV: 8 mg/kg/
(infants, children, and adolescents), insomnia (adults), dose every 8 hours
seizure (adults) Children 22 years and Adolescents <18 years:
Dermatologic: Pruritus (infants, children, and adoles- $33 kg: IV: 12 mg/kg/dose every 8 hours
cents), skin rash, urticaria (adults) >33 kg: IV: 400 mg every 8 hours or 600 mg every
Endocrine & metabolic: Hyperglycemia (adults), hyper- 12 hours
kalemia (adults), hypokalemia (adults) Adolescents 218 years: 600 mg every 12 hours for 5
Gastrointestinal: Abdominal pain (adults), constipation to 7 days
(adults), diarrhea, nausea, pseudomembranous colitis Skin and skin structure infection: Treatment duration
(adults), vomiting is variable (5 to 14 days); dependent on severity of
Hematologic & oncologic: Anemia (adults), eosinophilia infection and clinical response
(adults), neutropenia (adults), positive direct Coombs Infants 22 months and Children <2 years: IV: 8 mg/kg/
test (no evidence of hemolysis in any treatment group), dose every 8 hours
thrombocytopenia (adults) Children 22 years and Adolescents <18 years:
Hepatic: Hepatitis (adults), increased serum ALT (infants, $33 kg: IV: 12 mg/kg/dose every 8 hours
children, and adolescents), increased serum AST >33 kg: IV: 400 mg every 8 hours or 600 mg every
(infants, children; and adolescents), increased serum 12 hours
transaminases (adults) Adolescents 218 years: IV: 600 mg every 12 hours >
395
CEFTAROLINE FOSAMIL

Renal Impairment: Pediatric Breastfeeding Considerations Very small amounts of

Infants 22 months, Children and Adolescents <18 ceftazidime are present in breast milk. The manufacturer
years: Note: Renal function estimated using the recommends that caution be exercised when administer-
Schwartz equation. ing ceftazidime to’ breastfeeding women. Ceftazidime in
CrCl >50 mL/minute/1.73 m?: No adjustment nec- not absorbed when given orally; therefore, any medication
essary that is distributed to human milk should not result in
CrCl <50 mL/min/1.73 m?: There are no dosage systemic concentrations in the breastfed infant. Non-
adjustments provided in the manufacturer's labeling, dose-related effects could include modification of bowel
data is insufficient; use with caution, dosage adjust- flora.
ment may be necessary Contraindications Hypersensitivity to ceftazidime, other
Adolescents 218 years: Note: Renal function may be cephalosporins, or any component of the formulation
estimated using the Cockcroft-Gault formula for dos- Warnings/Precautions Modify dosage in patients with
age adjustment purposes. severe renal impairment. Hypersensitivity and anaphy-
CrCl >50 mL/minute: No dosage adjustment nec- laxis have been reported in patients receiving beta-lactam
essary drugs. Use caution in patients with a history of hyper-
CrCl >30 to <50 mL/minute: 400 mg every 12 hours sensitivity to penicillins or other beta-lactams; use is
CrCl 215 to <30 mL/minute: 300 mg every 12 hours contraindicated in patients with cephalosporin allergy
CrCl <15 mL/minute: 200 mg every 12 hours (according to the manufacturer). If severe hypersensitivity
ESRD patients receiving hemodialysis: Dialyzable: occurs, discontinue immediately and institute supportive
200 mg every 12 hours; dose should be given after emergency_measures. High ceftazidime levels in patients
hemodialysis on dialysis days with renal insufficiency can lead to seizures, nonconvul-
Hepatic Impairment: Pediatric There are no dosage sive status epilepticus, encephalopathy, coma, asterixis,
adjustments provided in the manufacturer's labeling (has myoclonia, and neuromuscular excitability. Adjust dosage
not been studied). However, ceftaroline is primarily based on renal function. Prolonged use may result in
renally eliminated. fungal or bacterial superinfection, including C. difficile-
Preparation for Administration Reconstitute 400 mg or associated diarrhea (CDAD) and pseudomembranous
600 mg vial with 20 mL SWFI, NS, DSW, or LR; mix colitis; CDAD has been observed >2 months postantibiotic
gently; resultant concentration is: 400 mg vial = treatment. May be associated with increased INR, espe-
20 mg/mL, and 600 mg vial = 30 mg/mL. Reconstituted cially in nutritionally-deficient patients, prolonged treat-
solution should be further diluted for lV administration in a- ment, hepatic or renal disease. Monitor INR during
compatible solution to a final concentration not to exceed treatment if patient is at risk; administer vitamin K as
12 mg/mL. Use of the same solution as used for recon- clinically indicated. Use with caution in patients with a
stitution suggested with the exception of SWFI, if SWFI history of Gl disease, especially colitis. Use with caution
was used for reconstitution, then appropriate infusion in patients with a history of seizure disorder; high levels
solutions include NS, t/2NS, D5W, D2.5W, or LR. To may increase risk of seizures.
prepare a 400 or 600 mg dose, withdraw 20 mL of diluent Adverse Reactions
from 50 mL IV infusion bag; inject the entire contents of Central nervous system: Seizure
the ceftaroline vial (also 20 mL) to achieve a total volume Dermatologic: Pruritus, skin rash
of 50 mL; resulting concentration is 12 mg/mL (600 mg Endocrine & metabolic: Increased gamma-glutamyl trans-
vial) or 8 mg/mL (400 mg vial). Color of infusion solutions ferase, increased lactate dehydrogenase
ranges from clear and light to dark yellow depending on Gastrointestinal: Diarrhea
concentration and storage conditions; potency is not Hematologic & oncologic: Agranulocytosis, eosinophilia,
affected. leukopenia, lymphocytosis, neutropenia, positive direct
Administration IV: Administer diluted solution by IV infu- Coombs test (without hemolysis), thrombocythemia,
sion over 5 to 60 minutes thrombocytopenia
Monitoring Parameters Renal function periodically; Hepatic: Increased serum alkaline phosphatase,
CBC; number and type of stools/day for diarrhea; monitor increased serum ALT, increased serum AST
for signs of anaphylaxis during first dose Hypersensitivity; Hypersensitivity reactions
Dosage Forms Excipient information presented when Local: Inflammation at injection site, injection site phlebitis
available (limited, particularly for generics); consult spe- Renal: Increased blood urea nitrogen, increased serum
cific product labeling. creatinine
Solution Reconstituted, Intravenous: Miscellaneous: Fever
Teflaro: 400 mg (1 ea); 600 mg (1 ea) Rare but important or life-threatening: Abdominal pain,
anaphylaxis (severe in rare instances, including cardio-
@ Ceftaroline Fosamil Acetate see Ceftaroline Fosamil pulmonary arrest), angioedema, candidiasis, Clostridium
on page 395 difficile associated diarrhea, dizziness, erythema multi-
forme, headache, hemolytic anemia, hyperbilirubinemia,
CefTAZidime (SEF tay zi deem) jaundice, nausea, pain at injection site, paresthesia,
renal insufficiency, Stevens-Johnson syndrome, toxic
Medication Safety Issues epidermal necrolysis, urticaria, vaginitis, vomiting
Sound-alike/look-alike issues: Drug Interactions
CefTAZidime may be confused with ceFAZolin, cefe- Metabolism/Transport Effects None known.
pime, cefoTEtan, cefOXitin, cefTRIAXone Avoid Concomitant Use
Ceptaz may be confused with Septra Avoid concomitant use of CefTAZidime with any of the
Tazicef may be confused with Tazidime following: BCG (Intravesical); Cholera Vaccine
International issues: Increased Effect/Toxicity
Ceftim [Portugal] and Ceftime [Thailand] brand names CefTAZidime may increase the levels/effects of: Amino-
for ceftazidime may be confused with Ceftin brand glycosides; Vitamin K Antagonists
name for cefuroxime [U.S., Canada]; Cefiton brand
name for cefixime [Portugal] The levels/effects of CefTAZidime may be increased by:
Brand Names: US Fortaz; Fortaz in D5W; Tazicef Probenecid
Brand Names: Canada Fortaz Decreased Effect
Therapeutic Category Antibiotic, Cephalosporin (Third CefTAZidime may decrease the levels/effects of: BCG
Generation) (Intravesical); BCG Vaccine (Immunization); Cholera
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Generic Availability (US) May be product dependent
Typhoid Vaccine
Use Treatment of susceptible infections of the respiratory
tract, urinary tract, gynecologic, skin and skin structure, The levels/effects of CefTAZidime may be decreased by:
intra-abdominal, osteomyelitis, sepsis, and meningitis Chloramphenicol (Systemic)
(FDA approved in all ages). Has also been used in treat- Storage/Stability
ment of peritonitis in patients with peritoneal catheters and Vials: Store intact vials at 20°C to 25°C (68°F to 77°F).
for the treatment of endocarditis Protect from light. Refer to manufacturer's labeling for
Pregnancy Risk Factor B specific storage instructions for reconstituted solution
Pregnancy Considerations Adverse events have not and solution further diluted for IV infusion (varies by
been observed in animal reproduction studies. Ceftazi- diluent).
dime crosses the placenta and reaches the cord serum Duplex container: Store unactivated containers at 20°C to
and amniotic fluid. An increase in most types of birth 25°C (68°F to 77°F); excursions permitted to 15°C to
defects was not found following first trimester exposure 30°C (59°F to 86°F). Protect from light. Do not freeze.
to cephalosporins. Maternal peak serum concentration is Unactivated duplex containers with foil strip removed
unchanged in the first trimester. After the first trimester, from the drug chamber must be protected from light
serum concentrations decrease by approximately 50% of and used within 7 days at room temperature. Once
those in nonpregnant patients. Renal clearance is activated, must be used within 12 hours if stored at room
increased during pregnancy. temperature or within 3 days if stored under refrigeration.

396
 CEFTIBUTEN

Premixed frozen solution: Store at -20°C (-4°F). Thawed Renal Impairment: Pediatric
solution is stable for 8 hours at room temperature or for 3 Infants, Children, and Adolescents: The manufacturer
days under refrigeration; do not refreeze. recommends decreasing dosing frequency based on
Mechanism of Action Inhibits bacterial cell wall syn- the calculated BSA-adjusted creatinine clearance.
thesis by binding to one or more of the penicillin-binding The following guidelines have been used by: some
proteins (PBPs), which in turn inhibits the final trans- clinicians (Aronoff 2007): Note: Renally adjusted
dose recommendations are based on a usual dose
peptidation step of peptidoglycan synthesis in bacterial
of 25 to 50 mg/kg/dose every 8 hours:
cell walls, thus inhibiting cell wall biosynthesis. Bacteria
GFR >50 mL/minute/1.73 m2: No adjustment required
eventually lyse due to ongoing activity of cell wall autolytic
GFR 30 to 50 mL/minute/1.73 m?: 50 mg/kg/dose
enzymes (autolysins and murein hydrolases) while cell every 12 hours
wall assembly is arrested. GFR 10 to 29 mL/minute/1.73 m?: 50 mg/kg/dose
Pharmacodynamics/Kinetics (Adult data unless every 24 hours
noted) GFR <10 mL/minute/1.73 m?: 50 mg/kg/dose every
Distribution: Widely throughout the body including bone, 48 hours
bile, skin, CSF (higher concentrations achieved when Hemodialysis: Dialyzable (50% to 100%): 50 mg/kg/
meninges are inflamed), endometrium, heart, pleural dose every 48 hours, give after dialysis on dialy-
and lymphatic fluids sis days
Protein binding: <10% Peritoneal dialysis: 50 mg/kg/dose every 48 hours
Continuous renal replacement therapy (CRRT):
Half-life elimination: 1 to 2 hours, prolonged with renal
50 mg/kg/dose every 12 hours
impairment
Hepatic Impairment: Pediatric Infants, Children and
Time to peak, serum: IM: ~1 hour
Adolescents: No adjustment required.
Excretion: Urine (80% to 90% as unchanged drug) Preparation for Administration Note: Any carbon diox-
Dosing ide bubbles that may be present in the withdrawn solution
Neonatal should be expelled prior to injection.
General dosing, susceptible infection: IM: Reconstitute the 500 mg vials with 1.5 mL or the
Manufacturer's labeling: IV: 30 mg/kg/dose every 12 1,000 mg vials with 3 mL of either SWFI, bacteriostatic
hours ‘ water for injection, or lidocaine (0.5% or 1%) to a final
Alternate dosing (Red Book [AAP 2015]): IM, IV: concentration of 280 mg/mL
Body weight <1 kg: IV:
PNA S14 days: 50 mg/kg/dose every 12 hours IVP: Reconstitute vial using SWF to a concentration of
PNA 15 to 28 days: 50 mg/kg/dose every 8 to 12 100 to 170 mg/mL; see manufacturer's labeling for
specific details.
hours
Intermittent IV infusion: Further dilute with a compatible
Body weight 1 to 2 kg:
solution (eg, D5W, NS) to a final concentration
PNA <7 days: 50 mg/kg/dose every 12 hours <40 mg/mL. In fluid-restricted patients, a concentration
PNA 8 to 28 days: 50 mg/kg/dose every 8 to 12 of 125 mg/mL using SWFI results in a maximum rec-
hours ommended osmolality for peripheral infusion (Robin-
Body weight >2 kg: son 1987).
PNA <7 days: 50 mg/kg/dose every 12 hours Administration Parenteral: Inadvertent intra-arterial
PNA 8 to 28 days: 50 mg/kg/dose every 8 hours administration may result in distal necrosis.
Meningitis (Tunkel 2004): IV: IM: Deep IM injection into a large muscle mass such as
PNA <7 days: 100 to 150 mg/kg/day divided every 8 to the upper outer quadrant of the gluteus maximus or
12 hours lateral part of the thigh.
PNA >7 days: 150 mg/kg/day divided every 8 hours IV:
IVP: Administer over 3 to 5 minutes
Pediatric
Intermittent IV infusion: Administer over 15 to 30 minutes
General dosing, susceptible infection (Red Book
Monitoring Parameters Renal function periodically when
[AAP 2015]): IM, IV: Infants, Children, and Adolescents:
used in combination with aminoglycosides; with prolonged
Mild to moderate infections: 90 to 150 mg/kg/day div- therapy also monitor hepatic and hematologic function
ided every 8 hours; maximum daily dose: periodically; number and type of stools/day for diarrhea.
3,000 mg/day Observe for signs and symptoms of anaphylaxis during
Severe infections: 200 mg/kg/day divided every 8 first dose. Monitor prothrombin time in patients at risk for
hours; maximum daily dose: 6 g/day; higher doses increased INR (nutritionally deficient patients, prolonged
(300 mg/kg/day) have been recommended for cystic treatment, hepatic or renal disease)
fibrosis patients Test Interactions Positive direct Coombs’, false-positive
Cystic fibrosis, lung infection caused by Pseudomo- urinary glucose test using cupric sulfate (Benedict's sol-
nas spp: Infants, Children, and Adolescents: IV: 150 to ution, Clinitest®, Fehling's solution), false-positive serum
200 mg/kg/day divided every 6 to 8 hours (Bradley or urine creatinine with Jaffé reaction
2017); maximum daily dose: 6 g/day; higher doses Dosage Forms Excipient information presented when
have been used: 200 to 400 mg/kg/day divided every available (limited, particularly for generics); consult spe-
cific product labeling.
6 to 8 hours; maximum daily dose: 12 g/day
Solution, Intravenous, as sodium [strength expressed as
(Zobell 2013)
base]:
Endocarditis, treatment: Children and Adolescents: IV: Fortaz in D5W: 1 g (50 mL); 2 g (50 mL)
100 to 150 mg/kg/day divided every 8 hours; maximum Tazicef: 1 g/50 mL (50 mL)
daily dose: 4,000 mg/day; use in combination with Solution Reconstituted, Injection:
gentamicin or vancomycin and gentamicin (plus rifam- Fortaz: 500 mg (1 ea);.1 g (1 ea); 2 g (1 ea); 6 g (1 ea)
pin if prosthetic material is present) depending on the Tazicef: 1 g (1 ea); 2 g (1 ea); 6 g (1 ea)
cause of infection (AHA [Baltimore 2015]) Generic: 1 g (1 ea); 2 g (1 ea); 6 g (1 ea)
Intra-abdominal infections, complicated: Infants, Solution Reconstituted, Injection [preservative free]:
Children, and Adolescents: IV: 50 mg/kg/dose every 8 Generic: 1 g (1 ea); 2 g (1 ea); 6 g (1 ea)
hours in combination with metronidazole; maximum Solution Reconstituted, Intravenous:
daily dose: 6 g/day (Solomkin 2010) — Fortaz: 1 g (1 ea); 2 g (1 ea)
Meningitis: Infants, Children, and Adolescents: IV:
Tazicef: 1 g (1 ea); 2 g (1 ea)
Generic: 1 g/50 mL (1 ea); 2 g/50 mL (1 ea)
150 mg/kg/day divided every 8 hours; maximum daily
dose: 6 g/day (Tunkel 2004) i
Peritonitis (peritoneal dialysis): Infants, Children, and Ceftibuten (sef TYE byoo ten)
Adolescents: Intraperitoneal:
Medication Safety Issues
Intermittent: 20 mg/kg/dose every 24 hours in the long
Sound-alike/look-alike issues:
dwell (ISPD [Warady 2012]); in adults, intermittent:
Cedax may be confused with Cidex
1,000 to 1,500 mg every 24 hours per exchange in
International issues:
the long dwell (26 hours) (Li 2010) Cedax [US and multiple international markets] may be
Continuous: Loading dose: 500 mg per liter of dialy- confused with Codex brand name for acetaminophen/
sate; maintenance dose: 125 mg per liter (ISPD codeine [Brazil] and Saccharomyces boulardii [Italy]
[Warady 2012]) Brand Names: US. Cedax [DSC]
Urinary tract infection: Infants and Children 2 to 24 Therapeutic Category Antibiotic, Cephalosporin (Third
months: IV: 100 to 150 mg/kg/day divided every 8 Generation)
hours (AAP 2011) ! Generic Availability (US) Yes

397
CEFTIBUTEN

Use Treatment of acute bacterial otitis media and phar- The levels/effects of Ceftibuten may be increased by:
yngitis/tonsillitis due to susceptible organisms (FDA Probenecid
approved in ages 26 months and adults); treatment of Decreased Effect
acute exacerbations of chronic bronchitis (FDA approved Ceftibuten may decrease the levels/effects of; BCG
in ages 212 years and adults) (Intravesical); BCG Vaccine (Immunization); Cholera
Pregnancy Risk Factor B Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Pregnancy Considerations Adverse events have not Typhoid Vaccine
been observed in animal reproduction studies. An
The levels/effects of Ceftibuten may be decreased by:
increase in most types of birth defects was not found Multivitamins/Minerals (with ADEK, Folate, Iron); Multi-
following first trimester exposure to cephalosporins (Crider
vitamins/Minerals (with AE, No Iron); Zinc Salts
2009).
Storage/Stability Store at 2°C to 25°C (36°F to 77°F).
Breastfeeding Considerations Ceftibuten was not Reconstituted suspension is stable for 14 days when
detectable in milk after a single 200 mg dose (limit of refrigerated at 2°C to 8°C (36°F to 46°F).
detection: 1 mcg/mL) (Barr 1991). It is not known if it
Mechanism of Action Inhibits bacterial cell wall syn-
would be detectable after a.400 mg dose or multiple
thesis by binding to one or more of the penicillin-binding
doses. The manufacturer recommends that caution be
proteins (PBPs) which in turn inhibits the final transpepti-
exercised when administering ceftibuten to nursing
dation step of peptidoglycan synthesis in bacterial cell
women.
walls, thus inhibiting cell wall biosynthesis. Bacteria even-
Contraindications Hypersensitivity to ceftibuten, other tually lyse_due to ongoing activity of cell wall autolytic
cephalosporins, or any component of the formulation. enzymes (autolysins and murein hydrolases) while cell
Warnings/Precautions Use with caution in patients with wall assembly is arrested.
renal impairment; modify dosage in moderate to severe
Pharmacodynamics/Kinetics (Adult data unless
impairment and in hemodialysis patients. Prolonged use
noted)
may result in fungal or bacterial superinfection, including
Absorption: Rapid; food decreases peak concentrations,
C. difficile-associated diarrhea (CDAD) and pseudomem-
delays Tmax, and lowers AUC
branous colitis; CDAD has been observed >2 months
Distribution: Distributes into middle ear fluid, bronchial
postantibiotic treatment. Use with caution in patients with
secretions, and sputum; Vg: Children: 0.5 L/kg; Adults:
a history of colitis and other gastrointestinal diseases. Use
0.21 L/kg
with caution in patients with a history of penicillin allergy; if
Protein binding: 65%
a hypersensitivity reaction occur, discontinue therapy and
Bioavailability: 75% to 90% (Owens 1997)
institute supportive emergency measures. Potentially sig-
Half-life elimination: Children: 2 hours; Adults: 2.4 hours;
nificant drug-drug interactions may exist, requiring dose or
CrCl 30 to 49 mL/minute: 7.1 hours; CrCl 5 to 29 mL/
frequency adjustment, additional monitoring, and/or selec-
minute: 13.4 hours; CrC] <5 mL/minute: 22.3 hours
tion of alternative therapy.
Time to peak: 2 to 2.6 hours
Some formulations may contain sucrose. Excretion: Urine (~56%); feces (39%)
Pharmacodynamics/Kinetics: Additional Consider-
Benzyl alcohol and derivatives: Some dosage forms may
ations
contain sodium benzoate/benzoic acid; benzoic acid (ben-
Renal function impairment: Clearance is decreased and
zoate) is a metabolite of benzyl alcohol; large amounts of
half-life is increased.
benzyl alcohol (299 mg/kg/day) have been associated
with a potentially fatal toxicity ("gasping syndrome") in
Dosing
neonates; the "gasping syndrome" consists of metabolic Pediatric
acidosis, respiratory distress, gasping respirations, CNS General dosing, susceptible infection; mild to mod-
dysfunction (including convulsions, intracranial hemor- erate: Infants, Children, and Adolescents: Oral:
rhage), hypotension, and cardiovascular collapse (AAP 9 mg/kg/dose once daily; maximum dose: 400 mg/
["Inactive" 1997]; CDC 1982); some data suggests that dose (Red Book [AAP 2015])
benzoate displaces bilirubin from protein binding sites Bronchitis, chronic; acute bacterial exacerbations:
(Ahlfors 2001); avoid or use dosage forms containing Children 212 years and Adolescents: Oral: 400 mg
benzyl alcohol derivative with caution in neonates. See once daily for 10 days
manufacturer’s labeling. Otitis media, acute: Note: Ceftibuten is not a recom-
mended treatment option in the AAP guidelines (Lie-
Polysorbate 80: Some dosage forms may contain poly- berthal 2013).
sorbate 80 (also known as Tweens). Hypersensitivity Infants 26 months and Children <12 years: Oral:
reactions, usually a delayed reaction, have been reported 9 mg/kg/dose once daily for 10 days; maximum
following exposure to pharmaceutical products containing dose: 400 mg/dose
polysorbate 80 in certain individuals (Isaksson 2002; Children 212 years and Adolescents: Oral: 400 mg
Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, once daily for 10 days
pulmonary deterioration, and renal and hepatic failure Pharyngitis/tonsillitis: Note: Ceftibuten is not a rec-
have been reported in premature neonates after receiving ommended treatment option in the IDSA guidelines
parenteral products containing polysorbate 80 (Alade, (Shulman 2012).
1986; CDC 1984). See manufacturer’s labeling. Infants 26 months and Children <12 years: Oral:
Warnings: Additional Pediatric Considerations May 9 mg/kg/dose once daily for 10 days; maximum
cause diarrhea; incidence is higher in younger pediatric dose: 400 mg/dose
patients (8% in patients s2 years; 2% in patients >2 Children 212 years and Adolescents: Oral: 400 mg
years). once daily for 10 days
Adverse Reactions Renal Impairment: Pediatric
Central nervous system: Dizziness, headache Infants 26 months, Children, and Adolescents:
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, CrCl 250 mL/minute: No adjustment needed.
loose stools, nausea, vomiting CrCl 30 to 49 mL/minute: 4.5 mg/kg (maximum dose:
Hematologic & oncologic: Change in platelet count 200 mg/dose) every 24 hours
(increase), decreased hemoglobin, eosinophilia, CrCl 5 to 29 mL/minute: 2.25 mg/kg (maximum dose:
Hepatic: Increased serum ALT, increased serum bilirubin 100 mg/dose) every 24 hours
Renal: Increased blood urea nitrogen End-stage renal disease on intermittent hemodialysis
Rare but important or life-threatening: Agitation, anorexia, (2 or 3 times weekly): Dialyzable; 65% removed by a
aphasia, candidiasis, constipation, dehydration, diaper 2- to 4-hour hemodialysis session: Administer
rash, drowsiness, dysgeusia, dyspnea, dysuria, eructa- 9 mg/kg (maximum dose: 400 mg/dose) after hemo-
tion, fatigue, fever, flatulence, hematuria, hyperkinesia, dialysis
increased serum alkaline phosphatase, increased serum Hepatic Impairment: Pediatric There are no dosage
AST, increased serum creatinine, insomnia, irritability, adjustments provided in the manufacturer’s labeling.
jaundice, leukopenia, melena, nasal congestion, pares- Preparation for Administration Oral suspension:
thesia, pruritus, pseudomembranous colitis, psychosis, Reconstitute powder for oral suspension with appropriate
rigors, serum sickness, skin rash, Stevens-Johnson syn- amount of water as specified on the bottle. Shake vigo-
drome, stridor, thrombocytopenia, toxic epidermal nec- rously until suspended.
rolysis, urticaria, vaginitis, xerostomia Administration
Drug Interactions Oral:
Metabolism/Transport Effects None known. Capsule: Administer without regard to food.
Avoid Concomitant Use Suspension: Shake suspension well before use. Admin-
Avoid concomitant use of Ceftibuten with any of the ister 2 hours before or 1 hour after meals.
following: BCG (Intravesical); Cholera Vaccine Monitoring Parameters Observe for signs and symp-
Increased Effect/Toxicity toms of anaphylaxis during first dose; with prolonged
Ceftibuten may increase the levels/effects of: Amino- therapy, monitor renal, hepatic, and hematologic function
glycosides; Vitamin K Antagonists periodically; number and type of stools/day for diarrhea

398
 CEFTRIAXONE

Test Interactions Positive direct Coombs', false-positive those who are premature since ceftriaxone is reported to
urinary glucose test using cupric sulfate (Benedict's sol- displace bilirubin from albumin binding sites; concomitant
ution, Clinitest®, Fehling's solution), false-positive serum use with intravenous calcium-containing solutions/prod-
or urine creatinine with Jaffé reaction ucts in neonates ($28 days); IV use of ceftriaxone solu-
Dosage Forms Excipient information presented when tions containing lidocaine.
available (limited, particularly for generics); consult spe- Warnings/Precautions Serious and sometimes fatal
cific product labeling. [DSC] = Discontinued product hypersensitivity has been reported. Use caution in
Capsule, Oral: patients with a history of any allergy (particularly drugs),
Cedax: 400 mg [DSC] [contains butylparaben, edetate penicillin allergy or beta-lactam sensitivity. If severe hyper-
calcium disodium, methylparaben, propylparaben] sensitivity occurs, discontinue immediately and institute
Generic: 400 mg [DSC] supportive emergency measures.
Suspension Reconstituted, Oral:
Cedax: 90 mg/5 mL (60 mL [DSC], 90 mL [DSC], 120 mL Gall bladder pseudolithiasis has been reported, possibly
[DSC]) [contains polysorbate 80, sodium benzoate] due to ceftriaxone-calcium precipitates; probability more
Cedax: 180 mg/5 mL (30 mL [DSC], 60 mL [DSC}) likely in pediatric patients; discontinue in patients who
[contains sodium benzoate; cherry flavor] develop signs and symptoms of gallbladder disease.
Generic: 180 mg/5 mL (60 mL [DSC]) Secondary to biliary obstruction, pancreatitis has been
reported rarely. Most patients had biliary stasis or sludge
® Ceftin [DSC] see Cefuroxime on page 402 risk factors (eg, preceding major surgery, sever illness,
® Ceftin (Can) see Cefuroxime on page 402 TPN). Use with caution in patients with a history of Gl
disease, especially colitis. Severe cases (including some
fatalities) of immune-related hemolytic anemia have been
CefTRIAXone (er trye AKS one) reported in patients receiving cephalosporins, including
ceftriaxone. Prolonged use may result in fungal or bacte-
Medication Safety Issues rial superinfection, including C. difficile-associated diar-
Sound-alike/look-alike issues:
rhea (CDAD) and pseudomembranous colitis; CDAD has
CefTRIAXone may be confused with ceFAZolin, cefoTE-
been observed >2 months postantibiotic treatment.
tan, cefOXitin, cefTAZidime, Cetraxal
Rocephin may be confused with Roferon Potentially’ significant interactions may exist, requiring
Related Information dose or frequency adjustment, additional monitoring,
Relative Infant Dose on page 2207 and/or selection of alternative therapy. May be associated
Brand Names: US Rocephin [DSC] with increased INR (rarely), especially in nutritionally-
Brand Names: Canada Ceftriaxone for Injection; Cef- deficient patients, prolonged treatment, hepatic or renal
_ triaxone for Injection USP; Ceftriaxone Sodium for Injec- disease. Monitor INR during treatment if patient has
tion; Ceftriaxone Sodium for Injection BP impaired synthesis or low stores of vitamin K; supplemen-
Therapeutic Category Antibiotic, Cephalosporin (Third tation may be needed if clinically indicated.
Generation) No adjustment is generally necessary in patients with
Generic Availability (US) Yes renal impairment; use with caution in patients with con-
Use Treatment of sepsis, meningitis, infections of the lower current hepatic dysfunction and significant renal disease,
respiratory tract, acute bacterial otitis media, skin and skin dosage should not exceed 2 g/day. Use extreme caution
structure, bone and joint, intra-abdominal and urinary tract in neonates due to risk of hyperbilirubinemia, particularly
due to susceptible organisms (FDA approved in infants, in premature infants (contraindicated in hyperbilirubinemic
children, adolescents, and adults); surgical prophylaxis neonates and neonates <41 weeks postmenstrual age).
(FDA approved in adults); documented or suspected Ceftriaxone may complex with calcium causing precipita-
uncomplicated gonococcal infection or pelvic inflamma- tion. Fatal lung and kidney damage associated with cal-
tory disease (FDA approved for adults); has also been cium-ceftriaxone precipitates has been observed in
used for the treatment of endocarditis, Lyme disease, premature and term neonates. Do not reconstitute, admix,
acute bacterial rhinosinusitis, salmonellosis, shigellosis, or coadminister with calcium-containing solutions, even
syphilis, and typhoid fever and prophylaxis of peritonitis via separate infusion lines/sites or at different times in
in patients undergoing invasive dental procedures any neonatal: patient. Ceftriaxone should not be diluted
Pregnancy Risk Factor B or administered simultaneously with any calcium-contain-
Pregnancy Considerations Adverse events have not ing solution via a Y-site in any patient. However, ceftriax-
been observed in animal reproduction studies. Ceftriax- one and calcium-containing solution may be administered
one crosses the placenta. Pregnancy was found to influ- sequentially of one another for use in patients other than
ence the single dose pharmacokinetics of ceftriaxone neonates if infusion lines are thoroughly flushed, with a
when administered prior to delivery (Popovié 2007). The compatible fluid, between infusions.
pharmacokinetics of ceftriaxone following multiple doses Adverse Reactions
in the third trimester are similar to those of nonpregnant Dermatologic: Skin rash, skin tightness (IM)
patients (Bourget Fernandez 1993). Ceftriaxone is recom- Gastrointestinal: Diarrhea
mended for use in pregnant women for the treatment of Hematologic & oncologic: Eosinophilia, leukopenia,
gonococcal infections, Lyme disease, and may be used in thrombocythemia
certain situations prior to vaginal delivery in women at high Hepatic: Increased serum transaminases
risk for endocarditis (consult current guidelines) (ACOG Local: Induration at injection site (incidence higher with
120, 2011; CDC [Workowski 2015]; Wormser 2006). IM), pain at injection site, tenderness at injection site,
Breastfeeding Considerations Ceftriaxone is excreted warm sensation at injection site (IM)
into breast milk. Renal: Increased blood urea nitrogen
The relative infant dose (RID) of ceftriaxone is 1.2% to Rare but important or life-threatening: Abdominal pain,
2.4% when calculated using the highest breast milk con- acute generalized exanthematous pustulosis, acute
centration located and compared to a therapeutic infant renal failure (post-renal), agranulocytosis, allergic der-
dose of 50 to 100 mg/kg/day. In general, breastfeeding is matitis, anaphylactoid reaction, anaphylaxis, anemia,
considered acceptable when the relative infant dose is basophilia, blood coagulation disorder, bronchospasm,
<10% (Anderson 2016; Ito 2000). Using the highest milk candidiasis, casts in urine, choledocholithiasis, choleli-
concentration (7.89 mcg/mL), the estimated daily infant thiasis, clostridium difficile associated diarrhea, colitis,
dose via breast milk is 1.2 mg/kg/day. This milk concen- decreased prothrombin time, dysgeusia, dyspepsia,
tration was obtained following a maternal dose of ceftriax- edema, epistaxis, erythema multiforme, fever, flushing,
one 2 g/day on postpartum day 2 (day 7 of antimicrobial gallbladder sludge, glossitis, glycosuria, granulocytope-
therapy) (Bourget 1993). nia, headache, hematuria, hemolytic anemia, hypersen-
sitivity pneumonitis, increased monocytes, increased
The elimination half-life in breast milk following adminis- serum alkaline phosphatase, increased serum bilirubin,
tration of a single dose of ceftriaxone 1 g was 12.8 hours increased serum creatinine, jaundice, kernicterus, leuko-
and: 17.3 hours with lV and IM administration, respectively cytosis, lymphocytopenia, lymphocytosis, nephrolithia-
(Kafetzis 1983). sis, neutropenia, oliguria, palpitations, pancreatitis,
In general, antibiotics that are present in breast milk may phlebitis, prolonged prothrombin time, pseudomembra-
cause nondose-related modification of bowel flora. Mon- nous colitis, seizure, serum sickness, Stevens-Johnson
itor infants for GI disturbances (WHO 2002). Ceftriaxone is syndrome, stomatitis, thrombocytopenia, toxic epidermal
considered compatible with breastfeeding when used in necrolysis, ureteral obstruction, urogenital fungal infec-
usual recommended doses (WHO 2002). The manufac- tion, urolithiasis, vaginitis
turer recommends that caution be exercised when admin- Drug Interactions
istering ceftriaxone to nursing women. Metabolism/Transport Effects None known.
Contraindications
)Hypersensitivity to ceftriaxone, any Avoid Concomitant Use
component of the formulation, or other cephalosporins; Avoid concomitant use of CeffR/AXone with any of the
do not use in hyperbilirubinemic neonates, particularly following: BCG (Intravesical); Cholera Vaccine
 CEFTRIAXONE

4 Increased Effect/Toxicity
CefTRIAXone may increase the levels/effects of: Amino-
Ophthalmia neonatorum: IM, IV: 25 to 50 mg/kg as a
single dose; maximum dose: 125 mg/dose; Note:
glycosides; Vitamin K Antagonists May also be used for prophylaxis if erythromycin
ointment is not available. i
The levels/effects of CeffRIAXone may be increased by: Meningitis, nen-gonococcal: Limited data available,
Calcium Salts (Intravenous); Probenecid; Ringer's Injec-
dose not established: Note: In neonates, current IDSA
tion (Lactated)
guidelines suggest cefotaxime as the preferred non-
Decreased Effect pseudomonal third-generation cephalosporin; no cef-
CefTRIAXone may decrease the levels/effects of: BCG triaxone dosing is provided in the guidelines (IDSA
(Intravesical); BCG Vaccine (Immunization); Cholera [Tunkel 2004]). Dosing based on an open-label pro-
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
spective trial of 71 patients (age range: PNA 14 days to
Typhoid Vaccine
15 years) which included 26 patients diagnosed with
Storage/Stability meningitis and a pharmacokinetic analysis of 20 neo-
Powder for injection: Prior to reconstitution, store at $25°C nates and infants (n=12 neonates; including six with
($77°F). Protect from light. PNA <14 days) with sepsis or meningitis; both trials
Premixed solution (manufacturer premixed): Store at reported adequate CSF penetration and favorable
-20°C; once thawed, solutions are stable for 3 days at
response (Martin 1984; Yogev 1986). IV:
25°C (77°F) or for 21 days at 5°C (41°F). Do not
PNA <14 days: 50 mg/kg/dose once daily
refreeze.
PNA 214 days: 100 mg/kg for one dose, followed by 80
Stability of reconstituted solutions:
to-100 mg/kg/dose once daily
10 to 40 mg/mL: Reconstituted in D5W, Dj W, NS, or
Pediatric :
SWFI: Stable for 2 days at room temperature of 25°C
General dosing, susceptible infection (Red Book
(77°F) or for 10 days when refrigerated at 4°C (39°F).
[AAP 2015]): Infants, Children, and Adolescents: IM,
Stable for 26 weeks when frozen at -20°C when recon-
IV:
stituted with DSW or NS. Once thawed (at room tem-
Mild to moderate infection: 50 to 75 mg/kg/dose once
perature), solutions are stable for 2 days at room
daily; maximum daily dose: 1,000 mg/day
temperature of 25°C (77°F) or for 10 days when
Severe infection: 100 mg/kg/day divided every 12 to
refrigerated at 4°C (39°F); does not apply to manufac-
24 hours; maximum daily dose: 4,000 mg/day
turer's premixed bags. Do not refreeze. If D5NS or Ds/2NS
Chancroid: Infants, Children, and Adolescents: IM:
are used, solutions are only stable for 2 days at of
25°C (778 P): 50 mg/kg as a single dose; maxirnum dose: 250 mg/
100 mg/mL: dose (Red Book [AAP 2015])
Reconstituted in DSW, SWFI, or NS: Stable for 2 days Endocarditis, bacterial (non-gonococcal):
at room temperature of 25°C (77°F) or for 10 days Prophylaxis for dental and upper respiratory proce-
when refrigerated at 4°C (39°F). dures (patients allergic to penicillins and/or unable to
Reconstituted in lidocaine 1% solution or bacteriostatic take oral): Infants, Children, and Adolescents: IM,
water: Stable for 24 hours at room temperature of IV: 50 mg/kg 30 to 60 minutes prior to procedure;
25°C (77°F) or for 10 days when refrigerated at maximum dose: 1,000 mg/dose (Red Book [AAP
4°C (39°F). 2015]; Wilson 2007). Note: AHA guidelines. (Balti-
250 to 350 mg/mL: Reconstituted in D5W, NS, lidocaine more 2015) limit the use of prophylactic antibiotics to
1% solution, bacteriostatic water, or SWFI: Stable for patients at the highest risk for infective endocarditis
24 hours at room temperature of 25°C (77°F) or for 3 (IE) or adverse outcomes (eg, prosthetic heart
days when refrigerated at 4°C (39°F). valves, patients with previous IE, unrepaired cya-
Mechanism of Action Inhibits bacterial cell wall syn- notic congenital heart disease, repaired congenital
thesis by binding to one or more of the penicillin-binding heart disease with prosthetic material or device
proteins (PBPs) which in turn inhibits the final transpepti- during first 6 months after procedure, repaired con-
dation step of peptidoglycan synthesis in bacterial cell genital heart disease with residual defects at the site
walls, thus inhibiting cell wall biosynthesis. Bacteria even- or adjacent to site of prosthetic patch or device, and
tually lyse due to ongoing activity of cell wall autolytic heart transplant recipients with cardiac valvul-
enzymes (autolysins and murein hydrolases) while cell opathy).
wall assembly is arrested. Treatment: Children and Adolescents: IV: 100 mg/kg/
Pharmacodynamics/Kinetics (Adult data unless day divided every 12 hours or 80 mg/kg/dose every
noted) 24 hours; maximum daily dose: 4,000 mg/day, daily
Absorption: IM: Well absorbed doses over 2,000 mg should be divided into 2
Distribution: Widely throughout the body including gall- doses; treat for at least 4 weeks; longer durations
bladder, lungs, bone, bile, CSF (higher concentrations may be necessary; may use in combination with
achieved when meninges are inflamed); V4: other antibiotics based on organism (AHA [Baltimore
Neonates: 0.34 to 0.55 L/kg (Richards 1984) 2015])
Infants and Children: 0.3 to 0.4 L/kg (Richards 1984) Enteric infection, bacteria, empiric therapy pending
Adults: ~6 to 14 L diagnostic studies (HIV-exposed/-positive): Ado-
Protein binding: 85% to 95% lescents: IV: 1,000 mg every 24 hours (HHS [Ol adult]
Half-life elimination: 2015)
Neonates (Martin 1984): 1 to 4 days: 16 hours; 9 to 30 Gonococcal infections, treatment:
days: 9 hours Bacteremia (CDC [Workowski 2015]):
Children (age not specified): 4.1 to 6.6 hours Infants and Children weighing <45 kg: IM, IV:
(Richards 1984) 50 mg/kg/dose once daily for 7 days; maximum
Adults: Normal renal and hepatic function: ~5 to 9 hours dose: 1,000 mg/dose
Adults: Renal impairment (mild-to-severe): ~12 to 16 Children weighing >45 kg and Adolescents: IM, IV:
hours 1,000 mg once daily for 7 days
Time to peak, serum: IM: 2 to 3 hours Epididymitis, acute: Adolescents: IM: 250 mg in a
Excretion: Urine (33% to 67% as unchanged drug); feces single dose in combination with doxycycline (CDC
(as inactive drug) [Workowski 2015])
Dosing Uncomplicated cervicitis, pharyngitis, proctitis, ure-
Neonatal Note: Use cefotaxime in place of ceftriaxone if thritis, and vulvovaginitis (CDC [Workowski 2015]):
hyperbilirubinemia is present or if patient is receiving Infants and Children weighing $45 kg: IM, IV: 25 to
calcium-containing intravenous solutions. 50 mg/kg as a single dose; maximum dose:
General dosing, susceptible infection (Red Book 125 mg/dose
[AAP 2015]): IM, IV: 50 mg/kg/dose every 24 hours Children weighing >45 kg and Adolescents: IM:
Gonococcal infections (CDC [Workowski 2015]): Note: 250 mg as a single dose in combination with single
Administer cautiously to hyperbilirubinemic neonates, oral dose of azithromycin
especially those born premature; alternative agent may Disseminated infection (arthritis or arthritis-dermatitis
be necessary. syndrome) (CDC [Workowski 2015]):
Prophylaxis, asymptomatic neonates born to mothers Infants and Children: IM, IV: 50 mg/kg/dose. once
with gonococcal infection: IM, IV: 25 to 50 mg/kg as a daily for 7 days; maximum dose: 1,000 mg/dose
single dose; maximum dose: 125 mg/dose Adolescents: IM, |V: 1,000 mg once daily for 7 days;
Treatment: use in combination with a single oral dose of
Disseminated infection (including sepsis, arthritis, and azithromycin
meningitis)/Scalp abscess: |M, |V: 25 to 50 mg/kg/ Conjunctivitis: Adolescents: IM: 1,000 mg in a single
dose every 24 hours for 7 days, up to 10 to 14 days if dose in combination with a single oral dose of
meningitis is documented azithromycin (CDC [Workowski 2015])

400
 CEFTRIAXONE

Meningitis: Salmonellosis: Note: Salmonella in healthy patients

Infants and Children weighing <45 kg: IV, IM: typically does not require antibiotic treatment as it
50 mg/kg/day divided every 12 to 24 hours for 10 generally resolves in 5 to 7 days (CDC 2015).
to 14 days; maximum daily dose: 2,000 mg/day; Infants <6 months of age or Infants, Children, and
use in combination with oral erythromycin (Red Adolescents who have severe infection, prostheses,
Book [AAP 2015]) valvular heart disease, severe atherosclerosis,
Children weighing 245 kg and Adolescents: IV: malignancy, or uremia: Non-typhi species diarrhea:
1,000 to. 2,000 mg every 12 to 24 hours for 10 to IM, IV: 100 mg/kg/day divided every 12 to 24 hours
14 days; use in combination with a single dose of for 14 days; or longer if relapsing. Note: Not recom-
oral azithromycin (CDC [Workowski 2015]; Red mended for routine use (Guerrant 2001).
Book [AAP 2015]) HIV-exposed/-positive: Adolescents: IV: 1,000 mg
- Endocarditis: every 24 hours; duration dependent upon CD4
Infants and Children weighing <45 kg: IV, IM: counts and presence of bacteremia (HHS [Ol
50 mg/kg/day divided every 12 to 24 hours for at adult 2015])
least 28 days; maximum daily dose: 2,000 mg/day; If CD4 count 2200 cells/mm3: 7 to 14 days; if
use in combination with oral erythromycin (Red bacteremia present: At least 14 days; longer dura-
Book [AAP 2015]) tions if bacteremia or if infection is complicated
Children weighing 245 kg and Adolescents: IV: If CD4 count <200 cells/mm®: 2 to 6 weeks
1,000 to 2,000 mg every 12 to 24 hours for at least Shigellosis: Infants, Children, and Adolescents: IM, IV:
28 days; use in combination with a single dose of 50 to 100 mg/kg/dose once daily; maximum daily
azithromycin (CDC [Workowski 2015]; Red Book dose: 4,000 mg/day; usual duration 5 days; may
[AAP 2015]) shorten duration to 2 days if clinical response good
Intra-abdominal infection, complicated: Infants, and no extraintestinal involvement (Red Book [AAP
Children, and Adolescents: IV: 50 to 75 mg/kg/day 2015]; WHO 2005)
divided every 12 to 24 hours; maximum daily dose: Skin/skin structure infections: Infants, Children, and
2,000 mg/day (IDSA [Solomkin 2010]) Adolescents: IM, IV: 50 to 75 mg/kg/day in 1 to 2
Lyme disease, neurologic involvement, persistent/ divided doses; maximum daily dose: 2,000 mg/day
recurrent arthritis, heart block, or carditis: Infants, S. pneumoniae infection, invasive (Red Book [AAP
Children, and Adolescents: IV: 50 to 75 mg/kg/dose 2015]): Infants, Children, and Adolescents: IV:
once daily; maximum dose: 2,000 mg/dose; duration CNS infection: 100 mg/kg/day divided every 12
dependent on symptoms and response (AAN [Hal- hours; maximum daily dose: 4,000 mg/day
perin 2007]; IDSA [Wormser 2006]) Non-CNS infection: 50 to 75 mg/kg/day divided every
Meningitis: Infants, Children, and Adolescents: IM, IV: 12 to 24 hours; maximum daily dose: 1,000 mg/day
Loading dose of 100 mg/kg may be administered at Surgical prophylaxis: Children and Adolescents: IV:
the start of therapy; maximum dose: 4,000 mg/dose 50 to 75 mg/kg within 60 minutes prior to the proce-
Manufacturer's labeling: 100 mg/kg/day divided every dure; maximum dose: 2,000 mg/dose (ASHP/IDSA
12 to 24 hours for 7 to 14 days; maximum daily [Bratzler 2013])
dose: 4,000 mg/day Syphilis: Note: Not considered first-line therapy and
IDSA guidelines (IDSA [Tunkel 2004]): 80 to use should be reserved for special circumstances with
100 mg/kg/day divided every 12 to 24 hours; max- close monitoring and follow-up:
imum daily dose: 4,000 mg/day Congenital syphilis, treatment (CDC [Workowski
Meningococcal infection, chemoprophylaxis for 2015]): Note: There is insufficient data regarding
high-risk contacts (close exposure to patients the use of ceftriaxone for treatment of congenital
with invasive meningococcal disease) (Red Book syphilis (penicillin is recommended); use should be
[AAP 2015]): reserved for situations of penicillin shortage.
Infants, Children, and Adolescents <15 years: IM: Infants 230 days: IM, IV: 75 mg/kg/dose once daily
125 mg in a single dose for 10 to 14 days
Adolescents 215 years: IM: 250 mg in a single dose Children: IM, IV: 100 mg/kg/dose once daily for 10 to
Otitis media, acute (AAP [Lieberthal 2013]; Red Book 14 days
[AAP 2015]): Infants, Children, and Adolescents: Postexposure prophylaxis (HIV-exposed/-positive):
Acute bacterial: IM, IV: 50 mg/kg in a single dose; Adolescents: IM, IV: 1,000 mg once daily for 8 to
maximum dose: 1,000 mg/dose 10 days (HHS [O! adult 2015])
Persistent or relapsing: IM, IV: 50 mg/kg/dose once Treatment:
daily for 3 days; maximum dose: 1,000 mg/dose Early syphilis (independent of HIV status): Adoles-
Peritonitis (peritoneal dialysis), prophylaxis for cents: IM, IV: 1,000 to 2,000 mg once daily for 10
patients receiving peritoneal dialysis who require to 14 days; optimal dose and duration have not
dental procedures: Infants, Children, and Adoles- been defined (CDC [Workowski 2015]; HHS [Ol
cents: IM, IV: 50 mg/kg administered 30 to 60 minutes adult 2015))
before dental procedure; maximum dose: 1,000 mg/ Neurosyphillis, otic, ocular disease (HIV-exposed/-
dose (ISPD [Warady 2012]) positive; penicillin-allergic): Adolescents: IM, IV:
Pneumonia: Community-acquired (CAP): (IDSA/PIDS 2,000 mg once daily for 10 to 14 days (CDC [Work-
[Bradley 2011]): Infants >3 months, Children, and owski 2015). Note: Penicillin desensitization is the
Adolescents: IV: 50 to 100 mg/kg/day divided every preferred approach; use shouldbe reserved when
12 to 24 hours; maximum daily dose: 2,000 mg/day; desensitization is not feasible (HHS [Ol
higher maximum daily doses as high as 4,000 mg/ adult 2015)).
day have been recommended for HIV-exposed/-pos- Typhoid fever: Infants, Children, and Adolescents: IV:
itive patients (HHS [Ol pediatric 2013]). Note: May 80 mg/kg/dose once daily for 14 days (Stephens
consider addition of vancomycin or clindamycin to 2002). Note: Ceftriaxone is reserved for patients
empiric therapy if community-acquired MRSA sus- who have failed oral therapy or who have severe
pected. Use the higher end of the range for penicil- disease, intestinal complications, or obtundation and
lin-resistant S. pneumoniae; in children 25 years, a cannot take oral medications.
macrolide antibiotic should be added if atypical pneu- Urinary tract infections: IM, IV:
monia cannot be ruled out; preferred in patients not Infants and Children 2 to 24 months: 50 to 75 mg/kg/
fully immunized for H. influenzae type b and S. dose once daily (AAP 2011; Bradley. 2016)
pneumoniae, or significant local resistance to penicil- Children >24 months and Adolescents: 50 mg/kg/
lin in invasive pneumococcal strains. dose once daily; maximum dose: 2,000 mg/dose
Prophylaxis against sexually transmitted diseases (Bradley 2016)
following sexual assault (CDC [Workowski 2015]): Renal Impairment: Pediatric
Adolescents: IM: 250 mg as a single dose in combi- No dosage adjustment is generally necessary in renal
nation with azithromycin and metronidazole (or tini- impairment; Note: If concurrent renal and hepatic
dazole) dysfunction, a reduced maximum daily dose should
Rhinosinusitis, acute bacterial: be considered; in adults a maximum daily dose
Ambulatory patients: Children and Adolescents: IM, $2,000 mg/day is suggested.
IV: 50 mg/kg as a single dose; maximum dose: Poorly dialyzed; no supplemental dose or dosage
2,000 mg/dose; use for patients who are unable to adjustment necessary, including patients on intermit-
tolerate oral medication, or unlikely to be adherent to tent hemodialysis, peritoneal dialysis, or continuous
the initial doses of antibiotic (AAP [Wald 2013]) renal replacement therapy (eg, CVVHD) (Aron-
Severe infection requiring hospitalization: Infants, off 2007)
Children, and Adolescents: IV: 50 mg/kg/day: div- Hepatic Impairment: Pediatric No adjustment is gen-
ided every 12 hours for 10 to 14 days; maximum erally necessary in hepatic impairment; Note: If concur-
daily dose: 2,000 mg/day (IDSA [Chow 2012]) rent renal and hepatic dysfunction, a reduced maximum >
401
CEFTRIAXONE

daily dose should be considered; in adults a maximum Brand Names: Canada Apo-Cefuroxime; Auro-Cefurox-
daily dose <2,000 mg/day is suggested. ime; Ceftin; Cefuroxime For Injection; Cefuroxime For
Preparation for Administration Parenteral: Do not Injection, USP; PRO-Cefuroxime; ratio-Cefuroxime
reconstitute with calcium-containing solutions. Therapeutic Category Antibiotic, Cephalosporin (Sec-
IM: Vials should be reconstituted with appropriate volume ond Generation) f
of diluent (including D5W, NS, SWFI, bacteriostatic Generic Availability (US) May be product dependent
water, or 1% lidocaine) to make a final concentration of Use
250 mg/mL or 350 mg/mL; more dilute concentrations Oral suspension: Treatment of mild to moderate suscep-
(100 mg/mL) can be used if needed; see manufacturer's tible infections including pharyngitis/tonsillitis, acute bac-
labeling for specific detail. terial maxillary sinusitis, acute bacterial otitis media, and
IV: Reconstitute powder for injection to a concentration of impetigo (All indications: FDA approved in ages 3
~100 mg/mL with an appropriate IV diluent (including months to 12 years)
SWFI, D5W, D10W, NS); see manufacturer's labeling Oral tablet: Treatment of mild to moderate susceptible
for specific details. Further dilute dose in compatible infections including acute bacterial otitis media (FDA
solution (eg, DSW or NS) to a final concentration not to approved in pediatric patients [age not specified] and
exceed 40 mg/mL. adults), acute bacterial maxillary sinusitis (FDA approved
Administration Parenteral: Do not coadminister with cal- in pediatric patients [age not specified] and adults), acute
cium-containing solutions. bacterial exacerbations of chronic bronchitis (FDA
IM: Administer IM injections deep into a large approved in ages 213 years and adults); pharyngitis/
muscle mass tonsillitis (FDA approved in ages 213 years and adults);
Intermittent IV infusion: Administer over 30 minutes; urinary tract (uncomplicated) (FDA approved in ages 213
years and adults), skin and soft tissue (uncomplicated)
shorter infusion times (15 minutes) have been reported
(FDA approved in ages 213 years and adults), urethral
(Yogev 1986)
and endocervical gonorrhea (uncomplicated) (FDA
IVP: Administration over 2 to 4 minutes has been reported
approved in ages 213 years and adults), and early Lyme
in pediatric patients >11 years and adults primarily in the
disease (FDA approved in ages 213 years and adults)
outpatient setting (Baumgartner 1983; Garrelts 1988;
Parenteral: Treatment susceptible infections involving the
Poole 1999) and over 5 minutes in pediatric patients
lower respiratory tract, urinary tract, skin and skin struc-
ages newborn to 15 years with meningitis (Grubbauer
ture, sepsis, uncomplicated and disseminated gonor-
1990; Martin 1984). Rapid IVP injection over 5 minutes
rhea, and bone and joints (FDA approved in ages 23
of a 2,000 mg dose resulted in tachycardia, restless- months and adults); meningitis (FDA approved in pedia-
ness, diaphoresis, and palpitations in an adult patient tric patients 23 months); surgical prophylaxis (FDA
(Lossos 1994). IV push administration in young infants approved in adults)
may also have been a contributing factor in risk of Note: Although FDA approved for the treatment of men-
cardiopulmonary events occurring from interactions ingitis in pediatric patients and uncomplicated and dis-
between ceftriaxone and calcium (Bradley 2009). seminated gonococcal infections in adolescents and
Monitoring Parameters CBC with differential, platelet adults, cefuroxime is no longer recommended for these
count, PT, renal and hepatic function tests periodically; indications. In pediatric clinical trials, the use of cefurox-
number and type of stools/day for diarrhea; observe for ime has been found to be inferior to third-generation
signs and symptoms of anaphylaxis cephalosporins (eg, ceftriaxone) in the treatment of
Test Interactions Positive direct Coombs’, false-positive bacterial meningitis. Therefore, cefuroxime is NOT rec-
urinary glucose test using nonenzymatic methods, false- ommended for the treatment of bacterial meningitis
positive galactosemia tests. (IDSA [Tunkel 2004]). Due to widespread resistance,
Additional Information Rocephin contains 3.6 mEq cefuroxime should NOT be used for treatment of gonor-
sodium per gram of ceftriaxone. rhea (CDC [Workowski 2015]).
Dosage Forms Excipient information presented when Pregnancy Risk Factor B
available (limited, particularly for generics); consult spe- Pregnancy Considerations Adverse events were not
cific product labeling. [DSC] = Discontinued product observed in animal reproduction studies. Cefuroxime
Solution, Intravenous: crosses the placenta and reaches the cord serum and
Generic: 20 mg/mL (50 mL); 40 mg/mL (50 mL) amniotic fluid. Placental transfer is decreased in the
Solution Reconstituted, Injection: presence of oligohydramnios. Several studies have failed
Rocephin: 500 mg (1 ea [DSC]); 1 g (1 ea [DSC]) to identify an increased teratogenic risk to the fetus
Generic: 250 mg (1 ea); 500 mg (1 ea); 1 g (1 ea); 2.9 (1 following maternal cefuroxime use.
ea); 100 g (1 ea) During pregnancy, mean plasma concentrations of cefur-
Solution Reconstituted, Injection [preservative free]: oxime are 50% lower, the AUC is 25% lower, and the
Generic: 250 mg (1 ea); 500 mg (1 ea); 1g (1 ea); 2g plasma half-life is shorter than nonpregnant values. At
(1 ea) term, plasma half-life is similar to nonpregnant values
Solution Reconstituted, Intravenous: and peak maternal concentrations after IM administration
Generic: 1 g (1 ea); 2 g (1 ea); 10 g (1 ea) are slightly decreased. Pregnancy does not alter the
Solution Reconstituted, Intravenous [preservative free]: volume of distribution. Cefuroxime is one of the antibiotics
Generic: 10 g (1 ea) recommended for prophylactic use prior to cesarean
delivery.
@ Ceftriaxone for Injection (Can) see CeffRIAXone
Breastfeeding Considerations Cefuroxime is present in
on page 399
breast milk.
@ Ceftriaxone for Injection USP (Can) see CeffRIAXone
on page 399 The relative infant dose (RID) of cefuroxime is 0.5% when
calculated using the highest breast milk concentration
® Ceftriaxone Sodium see CeffRIAXone on page 399 located and compared to an oral infant therapeutic dose
@ Ceftriaxone Sodium for Injection (Can) see CefTRIAX- of 30 mg/kg/day. In general, breastfeeding is considered
one on page 399 acceptable when the RID is <10% (Anderson 2016; Ito
@ Ceftriaxone Sodium for Injection BP (Can) see Cef- 2000). Using the highest milk concentration (1.05
TRIAXone on page 399 mcg/mL), the estimated daily infant dose via breast milk
is 0.158 mg/kg/day. This milk concentration was obtained
0.5 to 1.5 hours following maternal administration of oral
Cefuroxime (se fyoor OKS eem) cefuroxime axetil 500 mg (Vree 1990).
Medication Safety Issues Diarrhea has been reported in breastfeeding infants
Sound-alike/look-alike issues: exposed to cefuroxime (Benyami 2005). In general, anti-
Cefuroxime may be confused with cefotaxime, cefprozil, biotics that are present in breast milk may cause nondose-
deferoxamine related modification of bowel flora. Monitor infants for Gl
Ceftin may be confused with Cefzil, Cipro disturbances, such as thrush and diarrhea (WHO 2002).
Zinacef may be confused with Zithromax Recommendations for use in breastfeeding women vary
International issues: by manufacturer; however, beta-lactam antibiotics are
Ceftin [US, Canada] may be confused with Cefiton brand generally considered compatible with breastfeeding when
name for cefixime [Portugal]; Ceftim brand name for used in usual recommended doses; cefuroxime was not
ceftazidime [Portugal]; Ceftime brand name for ceftazi- specifically included within this report (WHO 2002).
dime [Thailand] Contraindications Hypersensitivity to cefuroxime, any
Related Information component of the formulation, or other beta-lactam anti-
Oral Medications That Should Not Be Crushed or Altered bacterial drugs (eg, penicillins and cephalosporins)
on page 2217 ) Warnings/Precautions Serious and occasionally severe
Brand Names: US Ceftin [DSC]; Zinacef in Sterile Water or fatal hypersensitivity (anaphylactic) reactions have
[DSC]; Zinacef [DSC] been reported in patients receiving beta-lactam drugs.
 CEFUROXIME

Before initiating therapy, carefully investigate previous Decreased Effect

penicillin, cephalosporin, or other allergen hypersensitivity. Cefuroxime may decrease the levels/effects of: BCG
Use caution if given to a patient with a penicillin or other (Intravesical); BCG Vaccine (Immunization); Cholera
beta-lactam allergy because cross sensitivity among beta- Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
lactam antibacterial drugs has been established. If an Typhoid Vaccine
allergic reaction occurs, discontinue and institute appro-
priate therapy. Modify dosage in patients with severe renal The levels/effects of Cefuroxime may be decreased by:
Antacids; Histamine H2 Receptor Antagonists; Proton
impairment. Use with caution in patients with ahistory of
Pump Inhibitors
penicillin allergy, especially IgE-mediated reactions (eg,
anaphylaxis, urticaria). Prolonged use may result in fungal Food Interactions Bioavailability is increased with food;
cefuroxime serum levels may be increased if taken with
or bacterial superinfection, including C. difficile-associated
food or dairy products. Clinical and bacteriologic
diarrhea (CDAD) and pseudomembranous colitis; CDAD
responses were independent of food intake in clinical
has been observed >2 months postantibiotic treatment.
trials. Management: Administer tablet without regard to
Use with caution in patients with a history of colitis. Use
meals; suspension must be administered with food.
with caution in patients with a history of seizure disorder;
cephalosporins have been associated with seizure activity, Storage/Stability
particularly in patients with renal impairment not receiving
Injection: Store intact vials at 15°C to 30°C (59°F to 86°F);
dose adjustments. Discontinue if seizures occur. May be protect from light. Reconstituted solution is stable for 24
associated with increased INR, especially in nutritionally hours at room temperature and 48 hours when refriger-
ated. IV infusion in NS or D5W solution is stable for 24
deficient patients, prolonged treatment, hepatic or renal
hours at room temperature, 7 days when refrigerated, or
disease. Tablets and oral suspension are not bioequiva-
26 weeks when frozen. After freezing, thawed solution is
lent (do not substitute on a mg-per-mg basis). Tablets
stable for 24 hours at room’ temperature or 21 days when
should not be crushed or chewed due to a strong, persis-
refrigerated.
tent bitter taste. Patients unable to swallow whole tablets
Duplex container: Store unactivated units at 20°C to 25°C
should be prescribed the oral suspension. Potentially
(68°F to 77°F). Unactivated units with foil strip removed
significant drug-drug interactions may exist, requiring
from the drug chamber must be protected from light and
dose or frequency adjustment, additional monitoring,
used within 7 days. Once activated, may be stored for up
and/or selection of alternative therapy.
to 24 hours at room temperature or for 7 days under
Benzyl alcohol and derivatives: Some dosage forms may refrigeration. Do not freeze.
contain sodium benzoate/benzoic acid; benzoic acid (ben- TwistVial vials: Joined, but not activated, vials are stable
Zoate) is a metabolite of benzyl alcohol; large amounts of for 14 days. Once activated, stable for 24 hours at room
benzyl alcohol (299 mg/kg/day) have been associated temperature and 7 days refrigerated. Do not freeze.
with a potentially fatal toxicity ("gasping syndrome") in Premix Galaxy plastic containers: Store frozen at -20°C.
neonates; the "gasping syndrome" consists of metabolic Thaw container at room temperature or under refriger-
acidosis, respiratory distress, gasping respirations, CNS ation; do not force thaw. Thawed solution is stable for 24
dysfunction (including convulsions, intracranial hemor- hours at room temperature and 28 days refrigerated; do
rhage), hypotension, and cardiovascular collapse (AAP not refreeze.
["Inactive" 1997]; CDC 1982); some data suggests that Oral suspension: Prior to reconstitution, store at 2°C to
benzoate displaces bilirubin from protein binding sites 30°C (36°F to 86°F). Reconstituted suspension is stable
(Ahlfors 2001); avoid or use dosage forms containing for 10 days at 2°C to 8°C (36°F to 46°F).
benzyl alcohol derivative with caution in neonates. See Tablet: Store at 15°C to 30°C (59°F to 86°F).
manufacturer’s labeling. Mechanism of Action Inhibits bacterial cell wall syn-
thesis by binding to one or more of the penicillin-binding
Phenylalanine: Some products may contain phenyla- proteins (PBPs) which in turn inhibits the final transpepti-
lanine. dation step of peptidoglycan synthesis in bacterial cell
Adverse Reactions walls, thus inhibiting cell wall biosynthesis. Bacteria even-
Cardiovascular: Local thrombophlebitis tually lyse due to ongoing activity of cell wall autolytic
Dermatologic: Diaper rash (children) enzymes (autolysins and murein hydrolases) while cell
Endocrine & metabolic: Increased lactate dehydrogenase wall assembly is arrested.
Gastrointestinal: Diarrhea (duration-dependent), nausea Pharmacodynamics/Kinetics (Adult data unless
and vomiting, unpleasant taste noted)
Genitourinary: Vaginitis Absorption: Oral tablet: Increases with food
Hematologic: Decreased hematocrit, decreased hemoglo- Distribution: Widely to body tissues and fluids including
bin, eosinophilia bronchial secretions, synovial and pericardial fluid, kid-
Hepatic: Increased serum alkaline phosphatase, neys, heart, liver, bone and bile; crosses blood-brain
increased serum transaminases barrier; therapeutic concentrations achieved in CSF
Immunologic: Jarisch-Herxheimer reaction even when meninges are not inflamed
Rare but important or life-threatening: Anaphylaxis, Protein binding: 33% to 50%
angioedema, anorexia, brain disease, candidiasis, chest Metabolism: Cefuroxime axetil (oral) is hydrolyzed in the
tightness, cholestasis, Clostridium difficile associated intestinal mucosa and blood to cefuroxime
diarrhea, colitis, decreased creatinine clearance, drug Bioavailability: Tablet: Fasting: 37%; Following food: 52%;
fever, dyspepsia, dysuria, erythema, erythema multi- cefuroxime axetil suspension is less bioavailable than
forme, gastrointestinal hemorrhage, gastrointestinal the tablet (91% of the AUC for tablets)
infection, glossitis, headache, hearing loss, hemolytic Half-life elimination:
anemia, hepatitis, hyperactivity, hyperbilirubinemia, Premature neonates:
hypersensitivity, hypersensitivity angiitis, increased PNA s3 days: Median: 5.8 hours (de Louvois 1982)
blood urea nitrogen, increased liver enzymes, increased PNA 28 days: Median: 1.6-3.8 hours (de Louvois 1982)
serum creatinine, increased thirst, interstitial nephritis, Children and Adolescents: 1.4-1.9 hours
irritability, joint swelling, leukopenia, muscle cramps, Adults: ~1 to 2 hours; prolonged with renal impairment
muscle rigidity, muscle spasm (neck), neutropenia, oral Time to peak, serum: IM: ~15 to 60 minutes; IV: 2 to 3
mucosa ulcer, pancytopenia, positive direct Coombs minutes; Oral: Children: ~3 to 4 hours; Adults: ~2 to 3
test, prolonged prothrombin time, pseudomembranous hours
colitis, renal insufficiency, renal pain, seizure, serum Excretion: Urine (66% to 100% as unchanged drug)
sickness-like reaction, sialorrhea, sinusitis, Stevens- Dosing
Johnson syndrome, swollen tongue, tachycardia, throm- Neonatal
bocytopenia (rare), toxic epidermal necrolysis, trismus, General dosing, susceptible infection: IM, IV (Red
upper respiratory tract infection, urethral bleeding, ure- Book [AAP 2015]):
thral pain, urinary’ tract infection, vaginal discharge,
vaginal irritation, viral infection, vulvovaginal candidiasis,
_ vulvovaginal pruritus
Body Postnatal
Drug Interactions : Weight Age
Metabolism/Transport Effects None known. $14 days 50 mg/kg/dose every 12 hours
Avoid Concomitant Use <1 kg
15 to 28 days | 50 mg/kg/dose every 8 to 12 hours
Avoid concomitant use of Cefuroxime with any of the
following: BCG (Intravesical); Cholera Vaccine; Hista- 4 to 2k 50 _mg/kg/dose every 12 hours
)
mine H2 Receptor Antagonists; Proton Pump Inhibitors o 8 to 28 days | 50 mg/kg/dose every 8 to 12 hours
Increased Effect/Toxicity 50 mg/kg/dose every 12 hours
Cefuroxime may increase the levels/effects of: Amino- >2 kg
8 to 28 days 50 mg/kg/dose every 8 hours
glycosides; Vitamin K Antagonists
The levels/effects/ofCefuroxime may be increased by:
Probenecid

403
CEFUROXIME

Pediatric Note: Cefuroxime axetil film-coated tablets and Renal Impairment: Pediatric
oral suspension are not bioequivalent and are not sub- Infants, Children, and Adolescents:
stitutable on a mg/mg basis. Oral: There are no dosage adjustments provided in
General dosing, susceptible infection (Red Book the manufacturer's labeling; however, the following
[AAP 2015]): Infants, Children, and Adolescents: adjustments have been reported in the literature
Mild to moderate infection: (Aronoff 2007): Note: Renally adjusted dose recom-
mendations are based on doses of 30 mg/kg/day
Oral: 20 to 30 mg/kg/day divided twice daily; max-
divided every 12 hours:
imum dose: 500 mg/dose
GFR 230 mL/minute/1.73 m?: No adjustment
IM, IV: 75 to 100 mg/kg/day divided in 3 doses;
required
maximum dose: 1,500 mg/dose
GFR 10 to 29 mL/minute/1.73 m?: Administer
Severe infection: IM, IV: 100 to 200 mg/kg/day div- 15 mg/kg/dose every 12 hours
ided in 3 to 4 doses; maximum dose: 1,500 mg/dose GFR <10 mL/minute/1.73 m2: Administer 15 mg/kg/
Bone and joint infection: Infants 23 months, Children, dose every 24 hours
and Adolescents: IM, IV: 50 mg/kg/dose every 8 Intermittent hemodialysis: Administer 15 mg/kg/
hours; maximum dose: 1,500 mg/dose. Note: Upon dose every 24 hours
completion of parenteral therapy follow with oral anti- Peritoneal dialysis (PD): Administer 15 mg/kg/dose
biotic therapy if indicated. every 24 hours
Bronchitis, chronic; acute exacerbations: Adoles- IV: The manufacturer's labeling recommends
cents: Oral tablets: 250 to 500 mg every 12 hours decreasing the frequency similar to adult recom-
for 10 days mendations. The following guidelines have been
Impetigo: Infants 23 months and Children: Oral sus- used by some clinicians (Aronoff 2007). Note:
pension: 15 mg/kg/dose twice daily for 10 days; max- Renally adjusted dose recommendations are based
on doses of 75 to 150 mg/kg/day divided every 8
imum dose: 500 mg/dose
hours.
Intra-abdominal infection complicated, community-
GFR 230 mL/minute/1.73 m?: No adjustment
acquired: Infants, Children, and Adolescents: IV:
required .
150 mg/kg/day in divided doses every 6 to 8 hours; GFR 10 to 29 mL/minute/1.73 m2: Administer 25 to
maximum dose: 1,500 mg/dose (IDSA [Solo- 50 mg/kg/dose every 12 hours
mkin 2010)) GFR <10 mL/minute/1.73 m?:, Administer 25 to
Lyme disease: Infants, Children, and Adolescents: 50 mg/kg/dose every 24 hours
Acrodermatitis chronica atrophicans: Oral: 15 mg/kg/ Intermittent hemodialysis: Administer 25 to
dose every 12 hours for 21 days; maximum dose: 50 mg/kg/dose every 24 hours
500 mg/dose (Wormser 2006) Peritoneal dialysis (PD): Administer 25 to 50 mg/kg/
Early localized disease: Oral: 15 mg/kg/dose every 12 dose every 24 hours
hours for 14 days; maximum dose: 500 mg/dose Continuous renal replacement therapy (CRRT):
(Red Book [AAP 2015]; Wormser 2006) Administer 25 to 50 mg/kg/dose every 8 hours
Late disease (arthritis): Oral: 15 mg/kg/dose every 12 Hepatic Impairment: Pediatric There are no dosage
hours for 28 days; maximum dose: 500 mg/dose adjustments provided in the manufacturer's labeling.
(Wormser 2006) Preparation for Administration
Otitis media, acute: Infants 23 months and Children: Oral suspension: Reconstitute powder for oral suspension
Oral suspension: 15 mg/kg/dose twice daily for 10 with appropriate amount of water as specified on the
bottle. Shake vigorously until suspended.
days; maximum dose: 500 mg/dose
Parenteral:
Oral tablet (patients able to swallow tablet whole):
IM: Dilute 750 mg vial with 3 mL SWEFI; resultant sus-
250 mg twice daily for 10 days
pension with a concentration of 225 mg/mL
Note: AAP recommends variable duration of therapy Intermittent IV infusion: Further dilute reconstituted sol-
depending on age: If 6 months to 2 years of age or ution to a final concentration <30 mg/mL; in fluid
severe symptoms (any age): 10-day course; if 2 to 5 restricted patients, dilution with SWFI to a concentra-
years of age with mild to moderate symptoms: 7-day tion of 137 mg/mL results in a maximum recommended
course; if 26 years of age with mild to moderate osmolality for peripheral infusion (Robinson 1987)
symptoms: 5- to 7-day course (AAP [Lieber- IVP: Reconstitute vial to a final concentration of 90 or
thal 2013]) 95 mg/mL (per manufacturer), some centers have used
Pharyngitis/tonsillitis: a final concentration of 100 mg/mL.
Infants 23 months and Children: Oral suspension: Administration
10 mg/kg/dose twice daily for 10 days; maximum Oral: Cefuroxime axetil suspension must be administered
dose: 250 mg/dose with food; shake suspension well before use; tablets may
Adolescents: Oral tablets: 250 mg twice daily for be administered with or without food; administer with
10 days food to decrease GI upset; avoid crushing the tablet
Pneumonia, bacterial (HIV-exposed/-positive): due to its bitter taste
Parenteral:
Infants and Children: IV: 35 to 50 mg/kg/dose 3 times
IM: Inject deep IM into large muscle mass, such as
daily; maximum dose: 2,000 mg/dose (HHS [Ol
gluteus or lateral part of thigh
pediatric 2016])
Intermittent IV infusion: Administer over 15 to 30 minutes
Sinusitis: IVP: Administer over 3 to 5 minutes
Infants 23 months and Children: Monitoring Parameters With prolonged therapy, monitor
Oral suspension: 15 mg/kg/dose twice daily for 10 renal, hepatic, and hematologic function periodically; num-
days; maximum dose: 500 mg/dose ber and type of stools/day for diarrhea; and prothrombin
Oral tablet (for patients able to swallow tablet time. Observe for signs and symptoms of anaphylaxis
whole): 250 mg twice daily for 10 days during first dose.
Adolescents: Oral tablet: 250 mg twice daily for Test Interactions Positive direct Coombs’, false-positive
10 days urinary glucose test using cupric sulfate (Benedict's sol-
Skin and skin structure infections, uncomplicated: ution, Clinitest®, Fehling's solution); false-negative may
Adolescents: Oral tablet: 250 to 500 mg twice daily for occur with ferricyanide test. Glucose oxidase or hexoki-
10 days nase-based methods should be used.
Surgical prophylaxis: Children and Adolescents: IV: Dosage Forms Excipient information presented when
50 mg/kg within 60 minutes prior to procedure; may available (limited, particularly for generics); consult spe-
repeat dose in 4 hours if procedure is lengthy or if cific product labeling. [DSC] = Discontinued product
there is excessive blood loss; maximum dose: Solution, Intravenous, as sodium [strength expressed as
base]:
1,500 mg/dose (Bratzler 2013)
Zinacef in Sterile Water: 1.5 g (50 mL [DSC])
Urinary tract infection, uncomplicated:
Solution, Intravitreal, as sodium [strength expressed as
Infants and Children 2 to 24 months: Oral suspension:
base]:
10 to 15 mg/kg/dose twice daily (AAP 2011) Generic: 10 mg/mL in NaCl 0.9% (1 mL)
Children >24 months: Moderate to severe disease Solution Reconstituted, Injection, as sodium [strength
(possible pyelonephritis): Oral suspension: 20 to expressed as base]:
30 mg/kg/day divided twice daily; maximum dose: Zinacef: 750 mg (1 ea [DSC]); 1.5 g (1 ea [DSC]); 7.5 g
500 mg/dose (Bradley 2017) (1 ea [DSC})
Adolescents: Oral tablet: 250 mg twice daily for 7 to Generic: 750 mg (1 ea); 1.5 g (1 ea [DSC}); 7.5 g (1 ea);
10 days 75 g (1 ea [DSC}]); 225 g (1 ea [DSC})

404
 CELECOXIB

Solution Reconstituted, Intravenous, as sodium [strength dose via breast milk of 0.05 mg/kg/day. This milk concen-
expressed as base]: tration was obtained following maternal administration of
Zinacef: 750 mg (1 ea [DSC]); 1.5 g (1 ea [DSC)) celecoxib 200 mg as a single oral dose to six postpartum
Generic: 1.5 g (1 ea); 7:5. g (1 ea [DSC}]) women (Gardiner 2006). In one study, the half-life of
Solution Reconstituted, Intravenous, as sodium [strength celecoxib in breast milk was calculated to be 4 to 6.5
expressed as base, preservative free]: hours (Knoppert 2003). Peak concentrations occurred
Generic: 1.5 g (1 ea) between 2’and 4 hours in breast milk (Gardner 2006; Hale
Suspension Reconstituted, Oral, as axetil [strength 2004).
expressed as base]:
Ceftin: 125 mg/5 mL (100 mL [DSC]); 250 mg/5 mL (50 Adverse events were not observed in two breastfeeding
mL. [DSC], 100 mL [DSC}]) [contains aspartame; tutti- infants, 17 and 22 months of age. In general, NSAIDs may
frutti flavor] be used in postpartum women who wish to breastfeed
Tablet, Oral, as axetil [strength expressed as base]: (Montgomery 2012); however, use should be avoided in
Ceftin: 250 mg [DSC], 500 mg [DSC] women breastfeeding infants with platelet dysfunction or
Generic: 250 mg, 500 mg thrombocytopenia (Bloor 2013; Sammaritano 2014).
Although other agents are preferred, celecoxib is consid-
@ Cefuroxime Axetil see Cefuroxime on page 402 ered acceptable for short-term use (Montgomery 2012).
@ Cefuroxime For Injection (Can) see Cefuroxime According to the manufacturer, the decision to breastfeed
on page 402 during therapy should consider the risk of infant exposure,
® Cefuroxime For Injection, USP (Can) see Cefuroxime the benefits of breastfeeding to the infant, and benefits of
on page 402 treatment to the mother.
Contraindications Hypersensitivity to celecoxib, sulfona-
® Cefuroxime Sodium see Cefuroxime on page 402
mides, aspirin, other NSAIDs, or any component of the
@ Cefzil see Cefprozil on page 393 formulation; patients who have experienced asthma, urti-
@ CeleBREX see Celecoxib on page 405 caria, or allergic-type reactions after taking aspirin or other
@ Celebrex (Can) see Celecoxib on page 405 NSAIDs; use in the setting of CABG surgery.
Note: Although the FDA approved product labeling states
this medication is contraindicated with other sulfona-
Celecoxib (se le KoKs ib) mide-containing drug classes, the scientific basis of this
statement has been challenged. See "Warnings/Precau-
Medication Safety Issues
tions" for more detail.
Sound-alike/look-alike issues:
CeleBREX may be confused with CelexXA, Cerebyx, Canadian labeling: Additional contraindications (not in US
Cervarix, Clarinex labeling): Pregnancy (third trimester); women who are
Brand Names: US CeleBREX breastfeeding; severe, uncontrolled heart failure; active
Brand Names: Canada Celebrex gastrointestinal ulcer (gastric, duodenal, peptic); active
Therapeutic Category Nonsteroidal Anti-inflammatory gastrointestinal bleeding; inflammatory bowel disease;
Drug (NSAID), COX-2 Selective cerebrovascular bleeding; severe liver impairment or
Generic Availability (US) Yes active hepatic disease; severe renal impairment (CrCl
Use Relief of signs and symptoms of juvenile idiopathic <30 mL/minute) or deteriorating renal disease; known
arthritis (JIA) (FDA approved in ages 22 years weighing hyperkalemia; use in patients <18 years of age
210 kg); relief of sign and symptoms of osteoarthritis, adult Warnings/Precautions [US Boxed Warning]: NSAIDs
rheumatoid arthritis, and ankylosing spondylitis (FDA cause an increased risk of serious (and potentially
approved in adults); management of acute pain (FDA fatal) adverse cardiovascular thrombotic events,
approved in adults); treatment of primary dysmenorrhea including MI and stroke. Risk may occur early during
(FDA approved in adults) treatment and may increase with duration of use.
Medication Guide Available Yes Relative risk appears to be similar in those with and
Pregnancy Risk Factor C (prior to 30 weeks gestation)/ without known cardiovascular disease or risk factors for
D (230 weeks gestation) cardiovascular disease; however, absolute incidence of
Pregnancy Considerations Birth defects have been cardiovascular events (which may occur early during treat-
observed following in utero NSAID exposure in some ment) was higher in patients with known cardiovascular
studies, however data is conflicting (Bloor 2013). Non- disease or risk factors. New onset hypertension or exac-
teratogenic effects, including prenatal constriction of the erbation of hypertension may occur (NSAIDs may also
ductus arteriosus, persistent pulmonary hypertension of impair response to ACE inhibitors, thiazide diuretics, or
the newborn, oligohydramnios, necrotizing enterocolitis, loop diuretics); may contribute to cardiovascular events;
renal dysfunction or failure, and intracranial hemorrhage monitor blood pressure; use with caution in patients with
have been observed in the fetus/neonate following in utero hypertension. May cause sodium and fluid retention, use
NSAID exposure. In addition, non-closure of-the ductus with caution in patients with edema. Avoid use in patients
arteriosus postnatally may occur and be resistant to with heart failure (ACCF/AHA [Yancy 2013]). Avoid use in
medical management (Bermas 2014; Bloor 2013). patients with recent MI unless benefits outweigh risk of
Because NSAIDs may cause premature closure of the cardiovascular thrombotic events. Long-term cardiovascu-
ductus arteriosus, product labeling for celecoxib specifi- lar risk in children has not been evaluated. Use the lowest
cally states use should be avoided starting at 30 weeks' effective dose for the shortest duration of time, consistent
gestation. with individual patient goals, to reduce risk of cardiovas-
Use of NSAIDs can be considered for the treatment of cular events; alternate therapies should be considered for
mild rheumatoid arthritis flares in pregnant women, how- patients at high risk.
ever use should be minimized or avoided early and late in [US Boxed Warning]: Celecoxib is contraindicated in
pregnancy (Bermas 2014; Saavedra Salinas 2015). Some the setting of coronary artery bypass graft surgery
guidelines recommend avoiding use of selective Cox-2 (CABG). Risk of Ml and stroke may be increased with use
inhibitors completely during pregnancy due to limited data following CABG surgery.
(Flint 2016).
[US Boxed Warning]: NSAIDs cause an increased risk
The chronic use of NSAIDs in women of reproductive age of serious gastrointestinal inflammation, ulceration,
may be associated with infertility that is reversible upon bleeding, and perforation (may be fatal); elderly
discontinuation of the medication. Consider discontinuing patients and patients with history of peptic ulcer
use in women having difficulty conceiving or those under-
disease and/or GI bleeding are at greater risk for
going investigation of fertility. The use of NSAIDs close to
serious GI events. These events may occur at any
conception may be associated with an increased risk of
time during therapy and without warning. Avoid use
miscarriage (Bermas 2014; Bloor 20713).
in patients with active Gl bleeding. Use caution. with a
Breastfeeding Considerations
history of GI ulcers, concurrent therapy known to increase
Celecoxib is present in breast milk.
the risk of GI bleeding (eg, aspirin, anticoagulants and/or
The relative infant dose (RID) of celecoxib is 1.7% when corticosteroids, selective serotonin reuptake inhibitors),
calculated using the highest breast milk concentration smoking, use of alcohol, or in the elderly or debilitated
located and compared to a weight-adjusted maternal dose patients. Use the lowest effective dose for the shortest
of 200 mg/day. duration of time, consistent with individual patient goals, to
reduce risk of Gl adverse events; alternate therapies
In general, breastfeeding is considered acceptable when
should be considered for patients at high risk. When used
the RID of a medication is <10% (Anderson 2016;
concomitantly with aspirin, a substantial increase in the
Ito 2000).
risk of gastrointestinal complications (eg, ulcer) occurs;
The RID of celecoxib was calculated using a milk concen- concomitant gastroprotective therapy (eg, proton pump
tration of 330 ng/mL, providing an estimated daily infant inhibitors) is recommended (Bhatt 2008).

405
CELECOXIB

NSAIDs may cause serious skin adverse events including needed to determine if carriers of the CYP2C9*3 allele are
exfoliative dermatitis, Stevens-Johnson syndrome (SJS), at increased risk for cardiovascular toxicity or dose related
and toxic epidermal necrolysis (TEN); may occur without adverse effects of celecoxib, especially with long-term,
warning and in patients without prior known sulfa allergy. high-dose use of the drug (Stempak 2005). Long-term
Anaphylactoid reactions may occur, even without prior (>6 months) cardiovascular toxicity in children and ado-
exposure; patients with "aspirin triad" (bronchial asthma, lescents has not been studied.
aspirin intolerance, rhinitis) may be at increased risk. Adverse Reactions
Contraindicated in patients who have experienced an Cardiovascular: Peripheral edema
anaphylactic reaction with NSAID or aspirin therapy. The Dermatologic: Acute generalized exanthematous pustulo-
manufacturer's labeling states to not administer to patients sis, exfoliative dermatitis
with aspirin-sensitive asthma due to severe and potentially Gastrointestinal: Abdominal pain, diarrhea, dyspepsia,
fatal bronchospasm that has been reported in such flatulence, gastroesophageal reflux disease, gastrointes-
patients having received aspirin and the potential for cross tinal perforation, gastrointestinal ulcer, Gl inflammation,
reactivity with other NSAIDs. The manufacturer also intestinal perforation, vomiting
states to use with caution in patients with other forms of Hepatic: Increased liver enzymes (<3x ULN)
asthma. However, in patients with known aspirin-exacer- Hypersensitivity: Anaphylaxis
bated respiratory disease (AERD), the use of celecoxib Immunologic: DRESS syndrome
initiated at a low dose with gradual titration in patients with Renal: Nephrolithiasis
stable, mild to moderate persistent asthma has been used Respiratory: Dyspnea, local. alveolar osteitis (post oral
without incident (Morales 2013). surgery patients), pharyngitis, rhinitis, sinusitis, upper
respiratory tract infection
Use with caution in patients with decreased hepatic (dos-
Miscellaneous: Accidental injury
age adjustments are recommended for moderate hepatic
Rare but important or life-threatening: Acute renal failure,
impairment; not recommended for patients with severe
ageusia, agranulocytosis, albuminuria, alopecia, ana-
hepatic impairment) or renal function. Transaminase ele-
phylactoid reaction, anemia, angina pectoris, angioe-
vations have been reported with use; closely monitor
dema, anorexia, anosmia, anxiety, aplastic anemia,
patients with any abnormal LFT. Rare (sometimes fatal),
arthralgia, aseptic meningitis, ataxia, bronchitis, bron-
severe hepatic reactions (eg, fulminant hepatitis, hepatic
chospasm, bronchospasm (aggravated), cellulitis, cere-
necrosis, hepatic failure) have occurred with NSAID use,
brovascular accident, chest pain, cholelithiasis, colitis
rarely; discontinue if signs or symptoms of liver disease
(with bleeding), constipation, contact dermatitis, coro-
develop, if systemic manifestations occur, or with persis-
nary artery disease, cough, cyst, cyst (NOS), cystitis,
tent or worsening abnormal hepatic function tests. NSAID
deafness, decreased hemoglobin, deep vein thrombosis,
use may compromise existing renal function; dose-
depression, dermatitis, diaphoresis, diverticulitis, drowsi-
dependent decreases in prostaglandin synthesis may
ness, dysphagia, dysuria, ecchymoses, edema, epis-
result from NSAID use, causing a reduction in renal blood
taxis, eructation, erythema multiforme, erythematous
flow which may cause renal decompensation (usually
rash, esophageal perforation, esophagitis, exacerbation
reversible). Patients with impaired renal function, dehy-
of hypertension, facial edema, fatigue, fever, flu-like
dration, hypovolemia, heart failure, liver dysfunction, those
symptoms, gangrene of skin or other tissue, gastritis,
taking diuretics, ACE inhibitors, angiotensin II receptor
gastroenteritis, gastroesophageal reflux disease, gastro-
blockers, and the elderly are at greater risk for renal
intestinal hemorrhage, hematuria, hemorrhoids, hepatic
toxicity. Rehydrate patient before starting therapy; monitor
failure, hepatic necrosis, hepatitis, hiatal hernia, hot
renal function closely. Avoid use in patients with advanced
flash, hypercholesterolemia, hyperglycemia, hypersensi-
renal disease; discontinue use with persistent or worsen-
tivity exacerbation, hypersensitivity reaction, hypertonia,
ing abnormal renal function tests. Long-term NSAID use
hypoesthesia, hypoglycemia, hypokalemia, hyponatre-
may result in renal papillary necrosis.
mia, increased appetite, increased blood urea nitrogen,
Use with caution in patients with known or suspected increased creatine phosphokinase, increased nonprotein
deficiency of cytochrome P450 isoenzyme 2C9; poor nitrogen, increased serum alkaline phosphatase, inter-
metabolizers may have higher plasma levels due to stitial nephritis, intestinal obstruction, intracranial hemor-
reduced metabolism; consider reduced initial doses. Alter- rhage, jaundice, laryngitis, leg cramps, leukopenia,
nate therapies should be considered in patients with JIA maculopapular rash, melena, migraine, myalgia, myo-
who are poor metabolizers of CYP2CQ9. cardial infarction, nervousness, osteoarthritis, pain, pal-
pitations, pancreatitis, pancytopenia, paresthesia,
Anemia may occur with use; monitor hemoglobin or hem- peripheral pain, pneumonia, pruritus, pulmonary embo-
atocrit in patients on long-term treatment. Celecoxib does lism, skin changes, skin photosensitivity, Stevens-John-
not affect PT, PTT or platelet counts; does not inhibit
son syndrome, stomatitis, syncope, synovitis,
platelet aggregation at approved doses. Potentially sig- tachycardia, tendonitis, tenesmus, thrombocythemia,
nificant drug-drug interactions may exist, requiring dose or thrombocytopenia, thrombophlebitis, tinnitus, toxic epi-
frequency adjustment, additional monitoring, and/or selec- dermal necrolysis, urinary frequency, urticaria, vasculitis,
tion of alternative therapy. ventricular fibrillation, vertigo, weight gain, xeroderma,
Use with caution in pediatric patients with systemic-onset xerostomia
juvenile idiopathic arthritis (JIA); serious adverse reac- Drug Interactions
tions, including disseminated intravascular coagulation, Metabolism/Transport Effects Substrate of CYP2C9
may occur. (major), CYP3A4 (minor); Note: Assignment of Major/
Minor substrate status based on clinically relevant drug
Sulfonamide ("sulfa") allergy: The FDA-approved product interaction potential; Inhibits CYP2D6 (weak)
labeling for many medications containing a sulfonamide Avoid Concomitant Use
chemical group includes a broad contraindication in
Avoid concomitant use of Celecoxib with any of the
patients with a prior allergic reaction to sulfonamides.
following: Acemetacin; Aminolevulinic Acid (Systemic);
There is a potential for cross-reactivity between members
Dexibuprofen; Dexketoprofen; Floctafenine; Ketorolac
of a specific class (eg, two antibiotic sulfonamides). How-
(Nasal); Ketorolac (Systemic); Macimorelin; Mecamyl-
ever, concerns for cross-reactivity have previously
amine; Mifamurtide; Morniflumate; Nonsteroidal Anti-
extended to all compounds containing the sulfonamide
Inflammatory Agents; Nonsteroidal Anti-Inflammatory
structure (SO2NH2). An expanded understanding of aller-
Agents (COX-2 Selective); Omacetaxine; Pelubiprofen;
gic mechanisms indicates cross-reactivity between anti-
Phenylbutazone; Talniflumate; Tenoxicam; Zaltoprofen
biotic sulfonamides and nonantibiotic sulfonamides may
Increased Effect/Toxicity
not occur or at the very least this potential is extremely low
Celecoxib may increase the levels/effects of: 5-Amino-
(Brackett 2004; Johnson 2005; Slatore 2004; Tornero
salicylic Acid Derivatives; Ajmaline; Aliskiren; Aminogly-
2004). In particular, mechanisms of cross-reaction due
cosides; Aminolevulinic Acid (Systemic); Aminolevulinic
to antibody production (anaphylaxis) are unlikely to occur
Acid (Topical); Anticoagulants; ARIPiprazole; Bisphosph-
with nonantibiotic sulfonamides. T-cell-mediated (type IV)
onate Derivatives; CycloSPORINE (Systemic); Defera-
reactions (eg, maculopapular rash) are less well under-
sirox; Desmopressin; Dexibuprofen; Digoxin;
stood and it is not possible to completely exclude this
Drospirenone; Eplerenone; Estrogen Derivatives; Halo-
potential based on current insights. In cases where prior
peridol; Lithium; Mecamylamine; Methotrexate; Nonster-
reactions were severe (Stevens-Johnson syndrome/TEN),
oidal Anti-Inflammatory Agents (COX-2 Selective);
some clinicians choose to avoid exposure to these
Omacetaxine; Perhexiline; Porfimer; Potassium-Sparing
classes.
Diuretics; PRALAtrexate; Prilocaine; Quinolones;
Warnings: Additional Pediatric Considerations Con-
Sodium Nitrite; Tacrolimus (Systemic); Tenofovir Prod-
sider alternate therapy in JIA patients who are identified to
ucts; Tolperisone; Triflusal; Vancomycin; Verteporfin;
be CYP2C9 poor metabolizers. In a small pediatric study
Vitamin K Antagonists
(n=4), the AUC of celecoxib was ~10 times higher in a
child who was homozygous for CYP2C9*3, compared to The levels/effects of Celecoxib may be increased by:
children who were homozygous for the *1 allele (n=2) or Acemetacin; Alcohol (Ethyl); Angiotensin Il Receptor
who had the CYP2C9*1/*2 genotype; further studies are Blockers; Angiotensin-Converting Enzyme Inhibitors;

406
 CENTRUROIDES IMMUNE F(AB’)2 (EQUINE)

Aspirin; Ceritinib; Corticosteroids (Systemic); Cyclo- Renal Impairment: Pediatric Children 22 years and
SPORINE (Systemic); CYP2C9 Inhibitors (Moderate); Adolescents:
Dapsone (Topical); Dexketoprofen; Felbinac; Floctafe- Baseline:
nine; Herbs (Anticoagulant/Antiplatelet Properties); Mild or moderate impairment: There are no dosage
Ketorolac (Nasal); Ketorolac (Systemic); Loop Diuretics; adjustments provided in the manufacturer's labeling;
Lumacaftor; MiFEPRIStone; Morniflumate; Naftazone; however, since <1% of the drug is excreted in the
Nitric Oxide; Nonsteroidal Anti-Inflammatory Agents; urine, dosage adjustment is not necessary (Davies
Pelubiprofen; Phenylbutazone; Probenecid; Selective 2000). Based on unpublished data, AUC was ~40%
Serotonin Reuptake Inhibitors; Sodium Phosphates; Tal- lower in adult patients with chronic renal insufficiency
(GFR 35 to 60 mL/minute) compared with subjects
niflumate; Tenoxicam; Tetracaine (Topical); Thiazide and
with normal renal function due to a higher apparent
Thiazide-Like Diuretics; Tolperisone; Tricyclic Antide-
clearance.
pressants (Tertiary Amine); Triflusal; Zaltoprofen
Severe impairment: Use is not recommended.
Decreased Effect Advanced renal disease: Use is not recommended;
Celecoxib may decrease the levels/effects of: Aliskiren; however, if celecoxib treatment cannot be avoided,
Angiotensin || Receptor Blockers; Angiotensin-Convert- monitor renal function closely.
ing Enzyme Inhibitors; Beta-Blockers; Eplerenone; During therapy: Abnormal renal function tests (persistent
HydrALAZINE; Loop Diuretics; Macimorelin; Mifamur- or worsening): Discontinue use.
tide; Potassium-Sparing Diuretics; Prostaglandins (Oph- Hepatic Impairment: Pediatric
» thalmic); Selective Serotonin Reuptake Inhibitors; Children 22 years and Adolescents:
Thiazide and Thiazide-Like Diuretics Moderate hepatic impatient (Child-Pugh Class B):
Reduce dose by 50%; monitor closely
The levels/effects of Celecoxib may be decreased by:
Severe hepatic impairment (Child-Pugh Class C): Use
Bile Acid Sequestrants; CYP2C9 Inducers (Moderate); is not recommended; has not been studied
Dabrafenib; Enzalutamide; Lumacaftor; Rifapentine Administration Lower doses (up to 200 mg twice daily)
Food Interactions Peak concentrations are delayed and may be administered without regard to meals (may admin-
AUC is increased by 10% to 20% when taken with a high- ister with food to reduce Gl upset); larger doses should be
fat meal. Management: Administer without regard to administered with food to improve absorption. Capsules
meals. é may be swallowed whole or the entire contents emptied
Storage/Stability Store at 20°C to 25°C (68°F to 77°F); onto a teaspoon of cool or room temperature applesauce
excursions permitted to 15°C to 30°C (59°F to 86°F). and ingested immediately with water. The sprinkled con-
Mechanism of Action Inhibits prostaglandin synthesis tents of the capsule on applesauce may be stored under
by decreasing the activity of the enzyme, cyclooxygenase- refrigeration for up to 6 hours.
2 (COX-2), which results in decreased formation of pros- Monitoring Parameters CBC; blood chemistry profile;
taglandin precursors; has antipyretic, analgesic, and anti- occult blood loss; periodic liver function tests; renal func-
inflammatory properties. Celecoxib does not inhibit cyclo- tion (urine output, serum BUN and creatinine); monitor
oxygenase-1 (COX-1) at therapeutic concentrations. efficacy (eg, in arthritic conditions: Pain, range of motion,
grip strength, mobility, inflammation); observe for weight
Pharmacodynamics/Kinetics (Adult data unless
gain, edema; observe for bleeding, bruising; evaluate Gl
noted) effects (abdominal pain, bleeding, dyspepsia); blood pres-
Absorption: Prolonged due to low solubility sure (baseline and throughout therapy); cardiac ischemia
Distribution: Vg (apparent): Children and Adolescents in patients with a recent MI (avoid use in patients with a
~7-16 years (steady-state): 8.3 + 5.8 L/kg (Stempak recent MI unless the benefits are expected to outweigh the
2002); Adults: ~400 L risk of recurrent CV thrombotic events)
Protein binding: ~97% primarily to albumin; binds to JIA: Monitor for development of abnormal coagulation
alpha,-acid glycoprotein to a lesser extent tests in patients with systemic-onset JIA
Metabolism: Hepatic via CYP2C9; forms inactive metab- Dosage Forms Excipient information presented when
olites (a primary alcohol, corresponding carboxylic acid, available (limited, particularly for generics); consult spe-
and its glucuronide conjugate) cific product labeling.
Bioavailability: Absolute: Unknown Capsule, Oral:
Half-life elimination: Children and Adolescents ~7-16 CeleBREX: 50 mg, 100 mg, 200 mg, 400 mg
years (steady-state): 6 + 2.7 hours (range: 3-10 hours) Generic: 50 mg, 100 mg, 200 mg, 400 mg
(Stempak 2002); Adults: ~11 hours (fasted) @ Celestoderm V (Can) see Betamethasone (Topical)
Time to peak: Children: Median: 3 hours (range: 1-5.8 on page 269
hours) (Stempak 2002); Adults: ~3 hours
@ Celestoderm V/2 (Can) see Betamethasone (Topical)
Excretion: Feces (~57% as metabolites, <3% as
on page 269
unchanged drug); urine (27% as metabolites, <3% as
unchanged drug); primary metabolites in feces and Celestone Soluspan see Betamethasone (Systemic)
urine: Carboxylic acid metabolite (73% of dose); low on page 267
amounts of glucuronide metabolite appear in urine @ CeleXA see Citalopram on page 461
Pharmacodynamics/Kinetics: Additional Consider- @ Celexa (Can) see Citalopram on page 461
ations CellCept see Mycophenolate on page 1413
Renal function impairment: AUC is approximately 40% ® CellCept Intravenous see Mycophenolate
lower in patients with a CrCl of 35 to 60 mL/minute. on page 1413
Hepatic function impairment: AUC is increased approx-
@ CellCept I.V. (Can) see Mycophenolate on page 1413
imately 40% in patients with mild impairment and 180%
in patients with moderate impairment. ® Cell Culture Inactivated Influenza Vaccine, Quadriva-
Pediatric: The AUC and C,,2x following administration of a lent [Flucelvax Quadrivalent] see Influenza Virus Vac-
cine (Inactivated) on page 1073
capsule contents sprinkled on applesauce were reported
to be similar as administration of an intact capsule @ Celontin see Methsuximide on page 1339
(Krishnaswami 2012). @ Celontin® (Can) see Methsuximide on page 1339
Geriatric: Cmax is 40% higher and AUC is 50% higher. Celsentri (Can) see Maraviroc on page 1274
Race: AUC is approximately 40% higher in black com-
Cemill [OTC] see Ascorbic Acid on page 186
pared with white patients.
Dosing @ Cemill SR [OTC] see Ascorbic Acid on page 186
Pediatric , @ Centany see Mupirocin on page 1412
Juvenile idiopathic arthritis (JIA): Note: Use the low- @ Centany AT see Mupirocin on page 1412
est effective dose for the shortest duration of time, @ Centruroides Immune FAB2 (Equine) see Centruroides
consistent with individual patient goals. Immune F(ab’)2 (Equine) on page 407
Children 22 years and Adolescents:
210 kg to $25 kg: Oral: 50 mg twice daily
>25 kg: Oral: 100 mg twice daily Centruroides Immune F(ab’). (Equine)
(sen tra ROY dez i MYUN fab too E kwine)
Dosing adjustment in poor metabolizers of CYP2C9
substrates: Use with caution in patients who are Brand Names: US Anascorp
known or suspected poor metabolizers of cytochrome Therapeutic Category Antivenin
P450 isoenzyme 2C9 substrates. Generic Availability (US) No
Children 22 years and Adolescents: Consider alternate Use Treatment of scorpion envenomation in patients with
therapy in JIA patients who are poor metabolizers; clinical signs of envenomation (FDA approved in ages of
experience in adult patients suggests dosing neonates through adults)
adjustment. Pregnancy Risk Factor C >
407
 CENTRUROIDES \MMUNE F(AB’)2 (EQUINE)

4 Pregnancy Considerations Animal reproduction studies Hepatic Impairment: Pediatric There are no dosage
have not been conducted. In general, medications used as adjustments provided in manufacturer's labeling.
antidotes should take into consideration the health and Preparation for Administration IV: Reconstitute each
prognosis of the mother; antidotes should be administered vial with 5 mL NS; gently swirl to mix. Dilute dose (eg, 1 to
to pregnant women if there is a clear indication for use and 3 vials) with NS to a total volume of 50 mL. Inspect diluted
should not be withheld because of fears of teratogenicity solution; do not use if it contains particulate matter or is
(Bailey 2003). Pregnant women experiencing symptoms discolored or turbid.
refractory to reasonable doses of opioids or other sys- Administration |V: Administer over 10, minutes; others
temic effects which pose a danger to the patient or fetus have reported beginning infusion slower at 25 to 50 mL/
should be considered for antivenom therapy (Brown hour and then double the rate every 5 minutes as tolerated
2013). (Tuuri 2011); monitor for return of symptoms of enveno-
Breastfeeding Considerations It is not known if this mation and repeat as needed. Medications (eg, epinephr-
product is excreted into breast milk. The manufacturer ine, corticosteroids, diphenhydramine) and equipment for
recommends caution be used if administered to a nursing resuscitation should be readily available in case of hyper-
woman. *. sensitivity reactions. IM administration should generally be
Contraindications There are no contraindications listed avoided since the time to peak blood concentration may
within the manufacturer’s labeling. be prolonged with this route of administration (Tuuri 2011;
Warnings/Precautions Derived from equine (horse) Vasquez 2010). If unable to obtain intravenous access,
immune globulin F(ab’) fragments; anaphylaxis and ana- intraosseous (full dose) and intramuscular (single vial
phylactoid reactions are possible, especially in patients dose) administration have been reported in a neonate
with known allergies to horse protein. However, due to the and-a 16 month old child (Hiller 2010).
lower protein content, purity, and absence of the immuno- Monitoring Parameters Signs and symptoms of enve-
genic Fc portion of the immunoglobulin, serious adverse nomation (eg, opsoclonus, involuntary muscle movement,
events are uncommon; in a prospective study (n=1,534), slurred speech, paresthesias, respiratory distress, saliva-
the incidence of acute antivenom reactions and type 3 tion, frothy sputum, vomiting); signs and symptoms of
hypersensitivity reactions (eg, urticaria, dyspnea); follow-
immune reactions was 0.2% (n=3) and 0.5% (n=8),
up visits for signs and symptoms of serum sickness (eg,
respectively (Boyer 2013). Patients who have had pre-
arthralgia, fever, myalgia, rash)
vious treatment with Centruroides immune F(ab’). or other
equine-derived antivenom/antitoxin may be at a higher- Additional Information Each vial of Centruroides
immune F(ab’). (equine) contains <120 mg total protein
risk for acute hypersensitivity reactions. In patients who
and 2150 LD50 (mouse) neutralizing units.
develop an anaphylactic reaction, discontinue the infusion
and administer emergency care. Immediate treatment (eg,
Dosage Forms Excipient information presented when
epinephrine 1 mg/mL, corticosteroids, diphenhydramine) available (limited, particularly for generics); consult spe-
cific product labeling.
should be available. In addition, delayed serum sickness
Solution Reconstituted, Intravenous [preservative free]:
may occur, usually within 2 weeks; monitor patients with
Anascorp: (1 ea)
follow-up visits for signs and symptoms (eg, arthralgia,
fever, myalgia, rash). @ Cepacol Dual Relief [OTC] [DSC] see Benzocaine
Product of equine (horse) plasma; may potentially contain on page 257
infectious agents (eg, viruses) which could transmit dis- @ Cepacol INSTAMAX [OTC] see Benzocaine
ease. May contain small amounts of cresol resulting from on page 257
the manufacturing process; local reactions and myalgias @ Cepacol Sensations Hydra [OTC] [DSC] see Benzo-
may occur. caine on page 257
Adverse Reactions @ Cepacol Sensations Warming [OTC] [DSC] see Ben-
Central nervous system: Fatigue, headache, lethargy zocaine on page 257
Dermatologic: Pruritus, skin rash
Gastrointestinal: Diarrhea, nausea, vomiting
Miscellaneous: Fever Cephalexin (sef a LEks in)
Neuromuscular & skeletal: Myalgia
Respiratory: Cough, rhinorrhea Medication Safety Issues
Rare but important or life-threatening: Aspiration, ataxia, Sound-alike/look-alike issues:
chest tightness, hypersensitivity, hypoxia, ocular edema,
Cephalexin may be confused with cefaclor, ceFAZolin,
ciprofloxacin
palpitations, pneumonia, respiratory distress, serum
Keflex may be confused with Keppra, Valtrex
sickness (delayed)
Drug Interactions Related Information
Relative Infant Dose on page 2207
Metabolism/Transport Effects None known.
Avoid Concomitant Use There are no known interac-
Brand Names: US Daxbia; Keflex
tions where it is recommended to avoid concomitant use.
Brand Names: Canada Apo-Cephalex; Dom-Cepha-
lexin; Keflex; PMS-Cephalexin; Teva-Cephalexin
Increased Effect/Toxicity There are no known signifi-
Therapeutic Category Antibiotic, Cephalosporin (First
cant interactions involving an increase in effect.
Generation)
Decreased Effect There are no known significant inter-
Generic Availability (US) Yes
actions involving a decrease in effect.
Use Treatment of susceptible bacterial infections, including
Storage/Stability Store unused vials at room temperature
acute otitis media and infections of the respiratory tract,
of 25°C (77°F); excursions permitted up to 40°C (104°F);
skin and skin structure, bone, and genitourinary tract (FDA
do not freeze. Discard partially used vials.
approved in pediatric patients [age not specified] and
Mechanism of Action Contains venom-specific F(ab’). adults); has also been used as alternate therapy for
fragments of IgG which bind and neutralize venom toxins;
endocarditis prophylaxis
thereby helping to remove the toxin from the target tissue
Pregnancy Risk Factor B
and eliminate it from the body.
Pregnancy Considerations Adverse events were not
Pharmacodynamics/Kinetics (Adult data unless observed in animal reproduction studies. Cephalexin
noted) crosses the placenta and produces therapeutic concen-
Onset: Time to resolution of symptoms: Adults: 1.91 + 1.4 trations in the fetal circulation and amniotic fluid (Creatsas
hours; Children: 1.28 + 0.8 hours; >95% of all patients 1980). Peak concentrations in pregnant patients are sim-
will experience resolution of symptoms within 4 hours ilar to those in nonpregnant patients. Prolonged labor may
Distribution: Vgss: 13.6 L + 5.4 L decrease oral absorption (Griffith 1983; Paterson 1972).
Half-life, elimination: 159 + 57 hours Breastfeeding Considerations Cephalexin is excreted
Dosing in breast milk.
Neonatal Scorpion envenomation: lV: Initial: 3 vials
(~$360 mg total protein and 2450 LD50 [mouse] neutral- The relative infant dose (RID) of cephalexin is 0.13% to
izing units) initiated as soon as possible after scorpion 0.52% when compared to an infant therapeutic dose of 25
sting; may administer additional vials in 1-vial increments to 100 mg/kg/day. In general, breastfeeding is considered
every 30 to 60 minutes as needed acceptable when the relative infant dose is <10%; when
Pediatric Scorpion envenomation: Infants, Children, an RID is >25% breastfeeding should generally be
and Adolescents: IV: Initial: 3 vials (~<360 mg total avoided (Anderson 2016; Ito 2000). Using a milk concen-
protein and 2450 LD50 [mouse] neutralizing units) ini- tration of 0.85 mcg/mL, the estimated daily infant dose via
tiated as soon as possible after scorpion sting; may
breast milk is 0.13 mg/kg/day. This milk concentration was
administer additional vials in 1-vial increments every 30 obtained following a single maternal dose of cephalexin
1,000 mg orally on the third postpartum day (Kafet-
to,60 minutes as needed; typical reported dosage range:
zis 1981).
1 to 5 vials (Boyer 2013)
Renal Impairment: Pediatric There are no dosage The mean peak milk concentration occurred 4 to 5 hours
adjustments provided in manufacturer's labeling. after the dose (Kafetzis 1981). Slightly higher

408
 CEPHALEXIN

concentrations of cephalexin were detected in the breast proteins (PBPs) which in turn inhibits the final transpepti-
milk of a lactating woman also administered probenecid dation step of peptidoglycan synthesis in bacterial cell
and cephalexin for 216 days (Ilett 2006). walls, thus inhibiting cell wall biosynthesis. Bacteria even-
tually lyse due to ongoing activity of cell wall autolytic
Diarrhea has been reported in breastfeeding infants (Ilett
enzymes (autolysins and murein hydrolases) while cell
2006; Ito 1993). In general, antibiotics that are present in
wall assembly is arrested.
breast milk may cause nondose-related modification of
bowel flora. Monitor infants for GI disturbances
Pharmacodynamics/Kinetics (Adult data unless
(WHO 2002). noted)
Absorption: Rapid (90%); delayed in young children and
When an antibiotic is needed, cephalexin may be used to may be decreased up to 50% in neonates
treat mastitis in breastfeeding women allergic to preferred Distribution: Widely into most body tissues and fluids,
agents (Amir 2014; Berens 2015). The manufacturer including gallbladder, liver, kidneys, bone, sputum, bile,
recommends that caution be exercised when administer- and pleural and synovial fluids; CSF penetration is poor
ing cephalexin to nursing women. Protein binding: 6% to 15%
Contraindications Hypersensitivity to cephalexin, other Half-life elimination: Neonates: 5 hours; Children 3-12
cephalosporins, or any component of the formulation months: 2.5 hours; Adults: 0.5 to 1.2 hours (prolonged
Warnings/Precautions Allergic reactions (eg, rash, urti- with renal impairment)
caria, angioedema, anaphylaxis, erythema multiforme, Time to peak, serum: ~1 hour
Stevens-Johnson syndrome, toxic epidermal necrolysis Excretion: Urine (80% to 100% as unchanged drug) within
[TEN]) have been reported. If an allergic reaction occurs, 8 hours
discontinue immediately and institute appropriate treat- Dosing
| ment. Use with caution in patients with a history of seizure Pediatric
disorder; high levels, particularly in the presence of renal General dosing, susceptible infection: Infants, Chil-
impairment, may increase risk of seizures. Modify dosage dren, and Adolescents:
in patients with severe renal impairment. Use with caution Mild to moderate infection: Oral: 25 to 50 mg/kg/day
in patients with a history of penicillin allergy, especially divided every 6 or 12 hours; maximum daily dose:
IgE-mediated reactions (eg, anaphylaxis, urticaria). Pos- 2,000 mg/day (Red Book [AAP 2015])
itive direct Coombs tests and acute intravascular hemol- Severe infection: Oral: 75 to 100 mg/kg/day divided
ysis has been reported. If anemia develops during or after every 6 to 8 hours; maximum daily dose: 4,000 mg/
therapy, discontinue use and work up for drug-induced day (Bradley, 2015; Red Book [AAP 2015])
hemolytic anemia. Prolonged use may result in fungal or Catheter (peritoneal dialysis); exit-site or tunnel
bacterial superinfection, including C. difficile-associated infection: Limited data available: Infants, Children,
diarrhea (CDAD) and pseudomembranous colitis; CDAD and Adolescents: Oral: 10 to 20.mg/kg/day once daily
has been observed >2 months postantibiotic treatment. or divided into 2 doses; maximum dose: 1,000 mg/
May be associated with increased INR, especially in nutri- dose (Warady [ISPD] 2012)
tionally-deficient patients, prolonged treatment, hepatic or Pharyngitis/tonsillitis (group A streptococcal):
renal disease. Potentially significant interactions may Manufacturer's labeling: Note: Experts recommend
exist, requiring dose or frequency adjustment, additional dosing on the higher end of the presented range
monitoring, and/or selection of alternative therapy. (IDSA [Shulman 2012])
Adverse Reactions Children and Adolescents <15 years: Oral: 25 to
Central nervous system: Agitation, confusion, dizziness, 50 mg/kg/day divided every 12 hours; maximum
fatigue, hallucination, headache dose: 500 mg/dose
Dermatologic: Erythema multiforme (rare), genital pruritus, Adolescents 215 years: Oral: 500 mg every 12
skin rash, Stevens-Johnson syndrome (rare), toxic epi- hours
dermal necrolysis (rare), urticaria Alternate dosing: IDSA recommendation: Infants,
Gastrointestinal: Abdominal pain, diarrhea, dyspepsia, Children, and Adolescents: Oral: 20 mg/kg/dose
gastritis, nausea (rare), pseudomembranous colitis, twice daily for 10 days, maximum dose: 500 mg/
vomiting (rare) dose (IDSA [Shulman 2012])
Genitourinary: Genital candidiasis, vaginal discharge, Impetigo (staphylococcus or streptococcus):
vaginitis Infants, Children, and Adolescents: Oral: 25 to
Hematologic & oncologic: Eosinophilia, hemolytic anemia, 50 mg/kg/day divided every 6 or 8 hours; maximum
neutropenia, thrombocytopenia dose: 250 mg/dose; continue for at least 7 days, full
Hepatic: Cholestatic jaundice (rare), hepatitis (transient, duration dependent upon clinical response (IDSA
rare), increased serum ALT, increased serum AST [Stevens 2014])
Hypersensitivity: Anaphylaxis, angioedema, hypersensi- Otitis media, acute (AOM): Infants and Children: Oral:
tivity reaction 75 to 100 mg/kg/day divided every 6 hours; maximum
Neuromuscular & skeletal: Arthralgia, arthritis, arthropathy dose not established for AOM; usual maximum adult
Renal: Interstitial nephritis (rare) - dose for mild to moderate infections: 500 mg/dose
Drug Interactions and for severe infections: 1,000 mg/dose. Note:
Metabolism/Transport Effects None known. Cephalexin is not routinely recommended as an
Avoid Concomitant Use empiric treatment option (AAP [Lieberthal 2013)).
Avoid concomitant use of Cephalexin with any of the Skin and skin structure aHipations (eg, cellulitis,
following: BCG (intravesical); Cholera Vaccine erysipelas):
Increased Effect/Toxicity Manufacturer's labeling:
Cephalexin may increase the levels/effects of: MetFOR- Infants, Children, and Adolescents $15 years: Oral:
MIN; Vitamin K Antagonists 25 to 50 mg/kg/day divided every 12 hours, max-
imum dose: 500 mg/dose; for B-hemolytic strepto-
The levels/effects of Cephalexin may be increased by:
Probenecid coccal infections, a duration of 10 days is
suggested
Decreased Effect
Adolescents >15 years: 500 mg every 12 hours
Cephalexin may decrease the levels/effects of: BCG
Alternate dosing: IDSA recommendations: Infants,
(Intravesical); BCG. Vaccine (Immunization); Cholera
Children, and Adolescents: Oral: 25 to 50 mg/kg/
Vaccine; Lactobacillus and Estriol; Sodium Picosulfate;
Typhoid Vaccine day divided every-6 hours; maximum dose:
500 mg/dose; continue for at least 5 days or longer
The levels/effects of Cephalexin may be decreased by: depending upon clinical response (IDSA [Ste-
Multivitamins/Minerals (with ADEK, Folate, Iron); Multi- vens 2014])
vitamins/Minerals (with AE, No Iron); Sucroferric Oxy- Endocarditis; prophylaxis (dental, oral, or respira-
hydroxide; Zinc Salts tory tract procedures): Infants, Children, and Ado-
Food Interactions Peak antibiotic serum BanGEnOStON |is lescents: Oral: 50 mg/kg administered 30 to 60
lowered and delayed, but total drug absorbed is not minutes prior to procedure; maximum dose:
affected. Cephalexin serum levels may be decreased if 2,000 mg/dose (AHA [Wilson 2007]). Note: American
taken with food. Management: Administer without regard Heart Association (AHA) guidelines now recommend
to food. prophylaxis only in patients undergoing invasive pro-
Storage/Stability cedures and in whom underlying cardiac conditions
Capsule: Store at 25°C (77°F); excursions permitted to may predispose to a higher risk of adverse outcomes
15°C to 30°C (59°F to 86°F). should infection occur (AHA [Wilson 2007]).
Powder for oral suspension: Store at 20°C to 25°C (68°F Pneumonia, community-acquired: S. aureus
to 77°F). a after reconstitution; discard after (methicillin-susceptible), mild infection or step-
14 days. down therapy: Infants >3 months, Children, and
Tablet: Store at 20°C to 25°C (68°F to 77°F). Adolescents: Oral: 75 to 100 mg/kg/day in 3 to 4
Mechanism of Action Inhibits bacterial cell wall syn- divided doses; maximum daily dose: 4,000 mg/day
thesis by binding to one or more of the penicillin-binding (IDSA/PIDS [Bradley 2011]) b
409
 CEPHALEXIN

< Urinary tract infection, treatment: Oral:

Infants and Children 2 months to 2 years: Empiric
type 2 (CLN2, or tripeptidy! peptidase 1 [TPP1] deficiency)
(FDA approved in pediatric patients >3 years of age)
therapy in febrile patients: 50 to 100 mg/kg/day Pregnancy Considerations Animal reproduction studies
divided every 6 hours for 7 to 14 days (AAP 2011) have not been conducted with cerliponase alfa.
Adolescents >15 years: Uncomplicated cystitis: Breastfeeding Considerations It is not known if cerli-
500 mg every 12 hours for 7 to 14 days ponase alfa is present in breast milk. According to the
Osteoarticular infection (eg, septic arthritis, osteo- manufacturer, the decision to breastfeed during therapy
myelitis); step-down therapy: Infants, Children, and should consider the risk of infant exposure, the benefits of
Adolescents: Oral: 100 mg/kg/day divided every 6 to breastfeeding to the infant, and benefits of treatment to the
8 hours; maximum daily dose: 4,000 mg/day; dura- mother.
tion of therapy variable, dependent upon clinical Contraindications Acute intraventricular access device-
response and typically extensive (weeks of therapy); related complications (eg, leakage, device failure, device-
compliance should be monitored (Bradley 2015; Red
related infection); ventriculoperitoneal shunts
Book [AAP 2015]); a small (n=11) prospective, open-
Warnings/Precautions Hypotension has been reported
label pharmacokinetic study reported a median dose
up to 8 hours after the completion of cerliponase alfa
of 40 mg/kg/dose every 8 hours (mean age: 7 years;
infusion; monitor vital signs. Use with caution in patients
range: 1 to 16 years; dose range: 19 to 51 mg/kg/
with a history of bradycardia, conduction disorder, or
dose every 8 hours) maintained serum concentrations
structural heart disease; monitor EKG during infusion.
long enough to meet the pharmacokinetic/pharmaco-
dynamic target for efficacy (T>MIC 240%) (Autmiz- Complications can occur with intraventricular access devi-
guine 2013) ces. Device-related infections have been reported with
Renal Impairment: Pediatric cerliponase alfa and may be subclinical. Administer using
Infants, Children, and Adolescents: There are no rec- aseptic technique to minimize infection. Monitor access
ommendations in the manufacturer's labeling; the point skin integrity and send CSF samples routinely for
following adjustments have been recommended signs of infection. Management of infection may include
(Aronoff 2007). Note: Renally adjusted dose recom- antibiotic treatment and device replacement before
mendations are based on doses of 25 to 50 mg/kg/ resumption of therapy. Monitor the device for signs of
day divided every 6 hours: Oral: leakage or device failure. Material degradation of the
CrCl >50 mL/minute/1.73 m?: No adjustment nec- intraventricular access device reservoir may occur with
essary prolonged use (2105 perforations), requiring replacement
CrCl 30 to 50 mL/minute/1.73 m2: 5 to 10 mg/kg/dose of the device.
every 8 hours (maximum dose: 500 mg/dose)
Hypersensitivity reactions, including pyrexia, vomiting,
CrCl 10 to 29 mL/minute/1.73 m: 5 to 10 mg/kg/dose
pleocytosis and irritability, have been reported in patients,
every 12 hours (maximum dose: 500 mg/dose)
during and up to 24 hours after completion of cerliponase
CrCl <10 mL/minute/1.73 m?: 5 to 10 mg/kg/dose
alfa infusion. Pretreat with antihistamines with or without
every 24 hours (maximum dose: 500 mg/dose)
antipyretics or corticosteroids 30 to 60 minutes prior to
Intermittent hemodialysis: 5 to 10 mg/kg/dose every
start of infusion.
24 hours after dialysis (maximum dose:
500 mg/dose) Administer cerliponase alfa by FDA-approved infusion
Peritoneal dialysis: 5 to 10 mg/kg/dose every 24 pump system via intraventricular implanted catheter
hours (maximum dose: 500 mg/dose) access (consult prescribing information for device details);
Hepatic Impairment: Pediatric There are no dosing health care providers should be experienced with intra-
adjustments provided in the manufacturer's labeling. ventricular drug administration.
Preparation for Administration Oral: Powder for oral Adverse Reactions
suspension: Reconstitute powder for oral suspension with Cardiovascular: Bradycardia, ECG abnormality, hypoten-
appropriate amount of water as specified on the bottle. sion
Shake vigorously until suspended. Central nervous system: Abnormal cerebrospinal fluid
Administration Oral: Shake suspension well before use. (pleocytosis), abnormal proteins in cerebrospinal fluid
Take without regard to food. If Gl distress, may take with (more common with decreased proteins), headache,
food. Give around-the-clock to promote less variation in irritability, jitterines, seizure
peak and trough serum levels.
Gastrointestinal: Vomiting
Monitoring Parameters With prolonged therapy, monitor Hematologic & oncologic: Hematoma
renal, hepatic, and hematologic function periodically; mon-
Hypersensitivity: Hypersensitivity reaction (not consistent
itor for signs of anaphylaxis with first few doses; number
with classic immune mediated hypersensitivity; included
and type of stools/day for diarrhea
pyrexia with vomiting, pleocytosis, irritability)
Test Interactions Positive direct Coombs’, false-positive
Immunologic: Antibody development
urinary glucose test using cupric sulfate (Benedict's sol-
Local: Catheter infection
ution, Clinitest®, Fehling's solution), false-positive serum
Miscellaneous: Fever
or urine creatinine with Jaffé reaction, false-positive uri-
Rare but important or life-threatening: Hypoxia
nary proteins and steroids
Drug Interactions
Dosage Forms Excipient information presented when
Metabolism/Transport Effects None known.
available (limited, particularly for generics); consult spe-
Avoid Concomitant Use There are no known interac-
cific product labeling.
tions where itis recommended to avoid concomitant use.
Capsule, Oral:
Increased Effect/Toxicity There are no known signifi-
Daxbia: 333 mg [contains brilliant blue fcf (fd&c blue #1),
cant interactions involving an increase in effect.
fd&c yellow #10 (quinoline yellow), fd&c yellow #6
(sunset yellow)]
Decreased Effect There are no known significant inter-
Keflex: 250 mg, 500 mg, 750 mg [contains brilliant blue
actions involving a decrease in effect.
fef (fd&c blue #1), fd&c yellow #10 (quinoline yellow), Storage/Stability Store cerliponase alfa injection and
fd&c yellow #6 (sunset yellow)] intraventricular electrolytes injection upright in a freezer
Generic: 250 mg, 500 mg, 750 mg at -25°C to -15°C (-13°F to 5°F) in original carton and
Suspension Reconstituted, Oral: protect from light. Store administration kit in original carton
Generic: 125 mg/5 mL (100 mL, 200 mL); 250 mg/5 mL separately from cerliponase alfa. Do not freeze kit. Thaw
(100 mL, 200 mL) cerliponase alfa and intraventricular electrolytes vials at
Tablet, Oral: room temperature for approximately. 60 minutes. Prefera-
Generic: 250 mg, 500 mg bly, administer immediately after thawing. May store
thawed vials at 2°C to 8°C (36°F to 46°F) for 24 hours.
@ Cephalexin Monohydrate see Cephalexin on page 408 Use product held in labeled syringes immediately. If not
@ Ceprotin see Protein C Concentrate (Human) used immediately, store in syringes at 2°C to. 8°C (36°F to
on page 1709 46°F) and use within 4 hours. Vials are single use only.
Cerebyx see Fosphenytoin on page 924 Mechanism of Action
Cerliponase alfa is a proenzyme that, once activated,
@ Cerezyme see Imiglucerase on page 1050 cleaves tripeptides from the N-terminus of proteins. This
leads to the breakdown of lysosomal storage materials
Cerliponase Alfa (ser Lip oh nase AL fa) that otherwise accumulate in patients with late infantile
neuronal ceroid lipofuscinosis type 2 (CLN2), leading to
Brand Names: US Brineura progressive decline in motor function.
Therapeutic Category Hydrolytic Lysosomal N-terminal Intraventricular electrolytes (included in the administration
Tripeptidy! Peptidase kit) are used to flush the infusion line, port needle, and
Generic Availability (US) No intraventricular access device in order to fully administer
Use To delay the loss of ambulation in symptomatic cerliponase alfa and maintain patency of the intraven-
patients with late infantile neuronal ceroid lipofuscinosis tricular access device.
 CETIRIZINE (SYSTEMIC)

Pharmacodynamics/Kinetics (Adult data unless [OTC]; ZyrTEC Allergy [OTC]; ZyrTEC Childrens Allergy
noted) [OTC]; ZyrTEC Childrens Hives Relief [OTC] [DSC]; Zyr-
Distribution: Pediatric patients 23 years: Vsgs: CSF: TEC Hives Relief [OTC] [DSC]
Median range: 186 to 245 mL; with repeat dosing, Brand Names: Canada Aller-Relief [OTC]; Apo-Cetiri-
volume was observed to decrease zine [OTC]; Extra Strength Allergy Relief [OTC]; PMS-
Metabolism: Degraded via peptide hydrolysis Cetirizine; Reactine; Reactine [OTC]
Half-life elimination: CSF: 6.2 to 7.7 hours Therapeutic Category Antihistamine
Time to peak: Pediatric patients 23 years: CSF: Median Generic Availability (US) May be product dependent
range: 4.3 to 4.5 hours after start of infusion; Plasma: Use
Median range: 12 to 12.3 hours after start of infusion Prescription products: Oral syrup: Relief of symptoms
Dosing associated with perennial allergic rhinitis (FDA approved
Pediatric Note: Pretreat with antihistamines with or with- in ages 6 to 23 months); treatment of the uncomplicated
out antipyretics or corticosteroids 30 to 60 minutes prior skin manifestations of chronic idiopathic urticaria (FDA
to start of infusion. approved in ages 6 months to 5 years)
Neuronal ceroid lipofuscinosis type 2: Children 23 OTC products: Relief of symptoms of hay fever or other
years and Adolescents: Intraventricular: 300 mg (10 respiratory allergies, relief of symptoms of common cold
mL) once every other week infused via implanted (OTC products: oral syrup: FDA approved in ages 22
reservoir and infusion device specific for cerliponase years and adults; tablets: FDA approved in ages 26
alfa; begin therapy (first dose) 5 to 7 days after device years and adults). Note: Approved ages and uses for
implantation. Following cerliponase alfa infusion, generic products may vary; consult labeling for specific
administer 2 mL intraventricular electrolytes (included information.
| in administration kit). Pregnancy Considerations Maternal use of cetirizine
Renal Impairment: Pediatric Children 23 years and has not been associated with an increased risk of major
Adolescents: There are no dosage adjustments provided malformations. Cetirizine may be used for the treatment of
in the manufacturer's labeling. rhinitis and urticaria during pregnancy (NAEPP 2005;
Hepatic Impairment: Pediatric Children 23 years and Wallace 2008; Zuberbier 2014).
Adolescents: There are no dosage adjustments provided Breastfeeding Considerations Cetirizine is present in
in the manufacturer's labeling. breast milk.
Preparation for Administration Thaw cerliponase alfa
and intraventricular electrolyte vials at room temperature Drowsiness and irritability have been reported in breastfed
for approximately 60 minutes. Do not shake or refreeze infants exposed to antihistamines (Ito 1993). In general,
vials; do not dilute cerliponase alfa or mix with any other second generation antihistamines (eg, cetirizine) are less
drug. Cerliponase alfa may contain thin translucent fibers sedating as compared to their first generation counter-
or opaque particles. Intraventricular electrolytes may con- parts. If a breastfed infant is exposed to a second gen-
tain particles, which appear during the thawing period but eration antihistamine via breast milk, they should be
should dissolve when the solution reaches room temper- monitored for irritability, jitteriness, or drowsiness (But-
ature. ler 2014).
Administration Intraventricular: For intraventricular use When treatment with an antihistamine is needed in breast-
only; administer to the intraventricular space by infusion feeding women, second generation antihistamines are
pump via a surgically implanted reservoir and catheter. preferred (Butler 2014; Powell 2015; Zuberier 2014).
Use a 0.2 micron inline filter (provided in kit) and infuse at
2.5 mL/hour (4 hours total). After completion of dose, Antihistamines may decrease maternal serum prolactin
administer intraventricular electrolytes (included in admin- concentrations when administered prior to the establish-
istration kit) at 2.5 mL/hour. See prescribing information ment of nursing (Messinis 1985).
for details on intraventricular infusion. Contraindications Hypersensitivity to cetirizine, hydrox-
Monitoring Parameters Vital signs (blood pressure, yzine, or any component of the formulation
heart rate) prior to start of infusion, periodically. during Warnings/Precautions Cetirizine should be used cau-
infusion and postinfusion; skin integrity (prior to infusion); tiously in patients with hepatic or renal impairment; con-
routine CSF samples (to detect subclinical device infec- sider dosage adjustment in patients with renal impairment.
tions); in patients with cardiac abnormalities, ECG during Use with caution in elderly patients; may be more sensitive
infusion, and every 6 months in patients without cardiac to adverse effects. May cause drowsiness; use caution
abnormalities performing tasks which require alertness (eg, operating
Dosage Forms Excipient information presented when machinery or driving). Potentially significant drug-drug
available (limited, particularly for generics); consult spe- interactions may exist, requiring dose or frequency adjust-
cific product labeling. ment, additional monitoring, and/or selection of alternative
Solution, Intraventric [preservative free]: therapy. Effects may be potentiated when used with other
Brineura: 150 mg/5 mL (1 ea) sedative drugs or ethanol.
Warnings: Additional Pediatric Considerations
@ Cerubidine see DAUNOrubicin (Conventional) Safety and efficacy for the use of cough and cold products
on page 576 in pediatric patients <4 years of age is limited; the AAP
@ Cervarix (Can) see Papillomavirus (Types 16, 18) Vac- warns against the use of these products for respiratory
cine (Human, Recombinant) on page 1557 illnesses in this age group. Serious adverse effects includ-
@ C.E.S. see Estrogens (Conjugated/Equine, Systemic) ing death have been reported. Many of these products
on page 783 contain multiple active ingredients, increasing the risk of
accidental overdose when used with other products. The
@ C.E.S. see Estrogens (Conjugated/Equine, Topical) FDA notes that there are no approved OTC uses for these
on page 787 products in pediatric patients <2 years of age. Health care
@ Cesamet see Nabilone on page 1417 providers are reminded to ask caregivers about the use of
Cetafen [OTC] see Acetaminophen on page 37 OTC cough and cold products in order to avoid exposure
to multiple medications containing the same ingredient
® Cetafen Extra [OTC] see Acetaminophen on page 37
(AAP 2012; FDA 2008).
Some dosage forms may contain propylene glycol; in
Cetirizine (Systemic) (se TI ra zeen)
neonates large amounts of propylene glycol delivered
Medication Safety Issues orally, intravenously (eg, >3,000 mg/day), or topically
Sound-alike/look-alike issues: have been associated with potentially fatal toxicities which
Cetirizine may be confused with sertraline, stavudine can include metabolic acidosis, seizures, renal failure, and
ZyrTEC may be confused with Lipitor, Serax, Xanax, CNS depression; toxicities have also been reported in
Zantac, Zerit, Zocor, ZyPREXA, ZyrTEC-D children and adults including hyperosmolality, lactic acido-
ZyrTEC (cetirizine) may be confused with ZyrTEC Itchy sis, seizures and respiratory depression; use caution
Eye (ketotifen) (AAP 1997; Shehab 2009).
International issues: Drug Interactions
Benadryl international brand name for cetirizine [Great Metabolism/Transport Effects Substrate of CYP3A4
Britain, Phillipines], but also the brand name for acri- (minor), P-glycoprotein/ABCB1; Note: Assignment of
vastine and pseudoephedrine [Great Britain] and sev- Major/Minor substrate status based on clinically relevant
eral products containing diphenhydramine [U.S., drug interaction potential
Canada] Avoid Concomitant Use
Brand Names: US All Day Allergy Childrens [OTC]; All Avoid concomitant use of Cetirizine (Systemic) with any
Day Allergy [OTC]; Cetirizine HCI Allergy Child [OTC]; of the following: Aclidinium; Azelastine (Nasal); Bromper-
Cetirizine HCI Childrens Alrgy [OTC]; Cetirizine HCI Child- idol; Cimetropium; Eluxadoline; Glycopyrrolate (Oral
rens [OTC]; Cetirizine HCl Hives Relief [OTC]; Good- Inhalation); Ipratropium (Oral Inhalation); Levosulpiride;
Sense All Day Allergy [OTC]; ZyrTEC Allergy Childrens Orphenadrine; Oxatomide; Oxomemazine; Paraldehyde; »
411
CETIRIZINE (SYSTEMIC)

Potassium Chloride; Potassium Citrate; Thalidomide; GFR <10 mL/minute/1.73 m?: Not recommended.
Tiotropium; Umeclidinium Intermittent hemodialysis or peritoneal dialysis:
Increased Effect/Toxicity Decrease dose by 50%.
Cetirizine (Systemic) may increase the levels/effects of: Hepatic Impairment: Pediatric There are no dosage
AbobotulinumtoxinA; Alcohol (Ethyl); Amezinium; Anti- adjustments provided in manufacturer's labeling.
cholinergic Agents; Azelastine (Nasal); Blonanserin; Administration Oral: Administer without regard to food
Buprenorphine; Cimetropium; CNS Depressants; Elux- Chewable tablet: Chew tablet before swallowing; may be
adoline; Flunitrazepam; Glucagon; Glycopyrrolate (Oral taken with or without water.
Inhalation); HYDROcodone; Methotrimeprazine; Metyro- Dissolving tablet: Allow tablet to melt in mouth; may be
SINE; Mirabegron; Mirtazapine; OnabotulinumtoxinA; taken with our without water.
Opioid Analgesics; Orphenadrine; OxyCODONE; Paral-
Test Interactions May cause false-positive serum TCA
dehyde; Pilsicainide; Piribedil; Potassium Chloride;
screen. May suppress the wheal and flare reactions to
Potassium Citrate; Pramipexole; Ramosetron; Rimabo-
skin test antigens.
tulinumtoxinB; ROPINIRole; Rotigotine; Selective Sero-
tonin Reuptake Inhibitors; Suvorexant; Thalidomide; Dosage Forms Excipient information presented when
Thiazide and Thiazide-Like- Diuretics; Tiotropium; Top- available (limited, particularly for generics); consult spe-
iramate; Zolpidem cific product labeling. [DSC] = Discontinued product
Capsule, Oral, as hydrochloride:
The levels/effects of Cetirizine (Systemic) may be ZyrTEC Allergy: 10 mg
increased by: Aclidinium; Amantadine; Brimonidine (Top- Solution, Oral, as hydrochloride:
ical); Bromopride; Bromperidol; Cannabis; Chloral All Day Allergy Childrens: 5 mg/5 mL (118 mL [DSC})
Betaine; Chlormethiazole; Chlorpbhenesin Carbamate; [contains methylparaben, propylene glycol, propyl-
Dimethindene (Topical); Doxylamine; Dronabinol; Dro- paraben]
peridol; HydrOXYzine; Ipratropium (Oral Inhalation); All Day Allergy Childrens: 5 mg/5 mL (118 mL) [dye free,
Kava Kava; Lofexidine; Lumacaftor; Magnesium Sulfate; gluten free; contains methylparaben, propylene glycol,
Methotrimeprazine; Mianserin; Minocycline; Nabilone; propylparaben; grape flavor]
Oxatomide; Oxomemazine; Perampanel; P-glycopro- Cetirizine HCI Allergy Child: 5 mg/5 mL (120 mL) [alco-
tein/ABCB1 Inhibitors; Pilsicainide; Pramlintide; Ranola- hol free, dye free, gluten free, sugar free; contains
zine; Rufinamide; Sodium Oxybate; Tapentadol; methylparaben, propylene glycol, propylparaben; grape
Tetrahydrocannabinol; Trimeprazine; Umeclidinium flavor]
Decreased Effect Cetirizine HCI Allergy Child: 5 mg/5 mL (120 mL) [alco-
Cetirizine (Systemic) may decrease the levels/effects of: hol free, sugar free; contains methylparaben, propylene
Acetylcholinesterase Inhibitors; Amifampridine; Benzyl- glycol, propylparaben]
penicilloy! Polylysine; Betahistine; Gastrointestinal Cetirizine HCI Childrens: 5 mg/5 mL (118 mL) [contains
Agents (Prokinetic); Hyaluronidase; |topride; Levosulpir- methylparaben, propylene glycol, propylparaben]
ide; Nitroglycerin; Pitolisant; Secretin Cetirizine HCI Childrens Alrgy: 5 mg/5 mL (118 mL, 120
mL) [contains methylparaben, propylene glycol, propyl-
The levels/effects of Cetirizine (Systemic) may be
paraben; grape flavor] ,
decreased by: Acetylcholinesterase Inhibitors; Amifam-
pridine; Amphetamines; Lumacaftor; P-glycoprotein/
Cetirizine HCI Hives Relief: 5 mg/5 mL (120 mL) [alcohol
free, sugar free; contains methylparaben, propylene
ABCB1 Inducers
glycol, propylparaben; grape flavor]
Food Interactions Cetirizine's absorption and maximal
GoodSense All Day Allergy: 5 mg/5 mL (118 mL) [dye
concentration are reduced when taken with food. Manage-
free, gluten free, sugar free; contains propylene glycol,
ment: May be taken without regard to meals.
sodium benzoate, sorbitol]
Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
ZyrTEC Childrens Allergy: 5 mg/5 mL (118 mL [DSC)})
excursions are permitted between 15°C and 30°C (59°F
[contains methylparaben, propylene glycol, propyl-
and 86°F).
paraben]
Mechanism of Action Competes with histamine for H,-
ZyrTEC Childrens Allergy: 5 mg/5 mL (5 mL [DSC], 118
receptor sites on effector cells in the gastrointestinal tract,
mL) [dye free, sugar free; contains propylene glycol,
blood vessels, and respiratory tract
sodium benzoate]
Pharmacodynamics/Kinetics (Adult data unless ZyrTEC Childrens Allergy: 5 mg/5 mL (118 mL [DSC})
noted) [dye free, sugar free; contains propylene glycol, sodium
Onset of action: Suppression of skin wheal and flare: 0.7 benzoate; bubble-gum flavor]
hours (Simons 1999) ZyrTEC Childrens Allergy: 5 mg/5 mL (118 mL) [dye free,
Duration of action: Suppression of skin wheal and flare: sugar free; contains propylene glycol, sodium ben-
224 hours (Simons 1999) zoate; grape flavor]
Absorption: Rapid Generic: 5 mg/5 mL (120 mL, 473 mL, 480 mL)
Distribution: Children: 0.7 L/kg; Adults: 0.56 L/kg Syrup, Oral, as hydrochloride:
(Simons 1999) ZyrTEC Childrens Hives Relief: 5 mg/5 mL (118
Protein binding, plasma: Mean: 93% mL [DSC]) :
Metabolism: Limited hepatic Tablet, Oral, as hydrochloride:
Half-life elimination: Children: 6.2 hours; Adults: 8 hours All Day Allergy: 10 mg
Time to peak, serum: 1 hour GoodSense All Day Allergy: 10 mg [contains corn starch,
Excretion: Urine (70%; 50% as unchanged drug); fd&c blue #1 aluminum lake]
feces (10%) ZyrTEC Allergy: 10 mg
Dosing ZyrTEC Hives Relief: 10 mg [DSC]
Pediatric Generic: 5 mg, 10 mg
Chronic urticaria: Oral: Tablet Chewable, Oral, as hydrochloride:
Infants 6 to <12 months: 2.5 mg once daily All Day Allergy Childrens: 10 mg [DSC] [tutti-frutti flavor]
Children 12 to 23 months: Initial; 2.5 mg once daily; Cetirizine HC! Childrens: 5 mg, 10 mg [contains aspar-
dosage may be increased to 2.5 mg twice daily tame, fd&c yellow #6 aluminum lake]
Children 2 to 5 years: Initial: 2.5 mg once daily; ZyrTEC Childrens Allergy: 5 mg [DSC]
dosage may be increased to 2.5 mg twice daily or ZyrTEC Childrens Allergy: 10 mg [DSC] [contains fd&c
5 mg once daily; maximum daily dose: 5 mg/day blue #2 aluminum lake]
Allergic rhinitis; perennial: Oral: Generic: 5 mg, 10 mg
Infants 6 to <12 months: 2.5 mg once daily Tablet Disintegrating, Oral, as hydrochloride:
Children 12 to 23 months: Initial: 2.5 mg once daily; ZyrTEC Allergy: 10 mg
dosage may be increased to 2.5 mg twice daily ZyrTEC Allergy Childrens: 10 mg [DSC]
Allergic symptoms, hay fever: ZyrTEC Allergy Childrens: 10 mg [citrus flavor]
Children 2 to 5 years: Initial: 2.5 mg once daily;
dosage may be increased to 2.5 mg twice daily or
5 mg once daily; maximum daily dose: 5 mg/day @ Cetirizine HCI Allergy Child [OTC] see Cetirizine (Sys-
Children 26 years and Adolescents: 5 to 10 mg once temic) on page 411
daily @ Cetirizine HCl Childrens [OTC] see Cetirizine (Sys-
Renal Impairment: Pediatric temic) on page 411
There are no dosage adjustments provided in the man- @ Cetirizine HCI Childrens Alrgy [OTC] see Cetirizine
ufacturer's labeling; however, the following adjustments (Systemic) on page 411
have been recommended (Aronoff 2007):
Cetirizine HCI Hives Relief [OTC] see Cetirizine (Sys-
Infants, Children, and Adolescents:
temic) on page 411
GFR 230 mL/minute/1.73 m?: No dosage adjustment
necessary. @ Cetirizine Hydrochloride see Cetirizine (Systemic)
GFR 10 to 29 mL/minute/1.73 m?: Decrease dose on page 411
by 50%. @ Cetraxal see Ciprofloxacin (Otic) on page 453

412
 CHARCOAL, ACTIVATED

@ Cetylev see Acetylcysteine on page 48 been shown to reduce morbidity or mortality (Vale 1999).
@ CFDN see Cefdinir on page 382 It may be considered if a patient has ingested a life-
threatening amount of carbamazepine, dapsone, pheno-
@ CG see Chorionic Gonadotropin (Human) on page 439
barbital, quinine, or theophylline, although no controlled
@ CGP 33101 see Rufinamide on page 1793 studies have demonstrated clinical benefit.
@ CGP-57148B see Imatinib on page 1046
Benzyl alcohol and derivatives: Some dosage forms may
CGS-20267 see Letrozole on page 1187 contain sodium benzoate/benzoic acid; benzoic acid (ben-
@ ch14.18 see Dinutuximab on page 650 zoate) is a metabolite of benzyl alcohol; large amounts of
@ Charac-25 [OTC] (Can) see Charcoal, Activated benzyl alcohol (299 mg/kg/day) have been associated
on page 413 with a potentially fatal toxicity ("gasping syndrome") in
neonates; the "gasping syndrome" consists of metabolic
@ Charac-50 [OTC] (Can) see Charcoal, Activated
acidosis, respiratory distress, gasping respirations, CNS
on page 413
dysfunction (including convulsions, intracranial hemor-
@ Charactol-25 [OTC] (Can) see Charcoal, Activated rhage), hypotension, and cardiovascular collapse (AAP
on page 413 ["Inactive" 1997]; CDC 1982); some data suggests that
@ Charactol-50 [OTC] (Can) see Charcoal, Activated benzoate displaces bilirubin from protein binding sites
on page 413 (Ahlfors 2001); avoid or use dosage forms containing
benzyl alcohol derivative with caution in neonates. See
manufacturer's labeling.
Charcoal, Activated (CHAR kole AK tiv ay ted)
Some dosage forms may contain propylene glycol; large
Medication Safety Issues amounts are potentially toxic and have been associated
Sound-alike/look-alike issues: hyperosmolality, lactic acidosis, seizures and respiratory
~ Actidose may be confused with Actos depression; use caution (AAP ["Inactive" 1997]; Zar 2007).
Related Information Capsules and tablets should not be used for the treatment
Oral Medications That Should Not Be Crushed or Altered of poisoning.
on page 2217 Warnings: Additional Pediatric Considerations
Brand Names: US Actidose-Aqua [OTC]; Actidose/Sor- Excessive amounts of activated charcoal with sorbitol
bitol [OTC]; Char-Flo with Sorbitol [OTC]; EZ Char [OTC]; may cause hypernatremic dehydration in pediatric
Kerr Insta-Char in Sorbitol [OTC]; Kerr Insta-Char [OTC] patients (Farley 1986); use is not recommended in infants
Brand Names: Canada Charac-25 [OTC]; Charac-50 <1 year of age. Aspiration may cause tracheal obstruction
[OTC]; Charactol-25 [OTC]; Charactol-50 [OTC]; Charco- in infants but usually not a major problem in adults.
dote Susp [OTC]; Charcodote TFS [OTC]; Charcodote- Aspiration pneumonitis, bronchiolitis obliterans, and
Aqueous Sus; Premium Activated Charcoal [OTC] ARDS have been reported following aspiration of char-
Therapeutic Category Antidiarrheal; Antidote, Adsorb- coal; however, these problems may be due to the aspira-
ent; Antiflatulent tion of gastric contents and not charcoal per se.
Generic Availability (US) May be product dependent
Some dosage forms may contain propylene glycol; in
Use Emergency treatment in poisoning by drugs and
neonates large amounts of propylene glycol delivered
chemicals (FDA approved in all ages); repetitive doses
orally, intravenously (eg, >3,000 mg/day), or topically
for GI dialysis in drug overdose to enhance the elimination
of certain drugs (theophylline, phenobarbital, carbamaze- have been associated with potentially fatal toxicities which
can include metabolic acidosis, seizures, renal failure, and
pine, dapsone, quinine) (FDA approved in all ages)
CNS depression; toxicities have also been reported in
Pregnancy Considerations Activated charcoal is not
children and adults including hyperosmolality, lactic acido-
absorbed systemically following oral administration. Use
sis, seizures and respiratory depression; use caution
during pregnancy is not expected to result in significant
exposure to the fetus. In general, medications used as
(AAP 1997; Shehab 2009).
antidotes should take into consideration the health and Some products contain fructose or sorbitol and should not
prognosis of the mother; antidotes should be administered be administered to patients with a rare autosomal reces-
to pregnant women if there is a clear indication for use and sive genetic intolerance to fructose.
should not be withheld because of fears of teratogenicity Adverse Reactions
(Bailey 2003). Gastrointestinal: Abdominal distention, appendicitis, con-
Breastfeeding Considerations Activated charcoal is stipation, dental discoloration (black; temporary), fecal
not absorbed systemically following oral administration. discoloration (black), intestinal obstruction, mouth discol-
Breastfeeding is not expected to result in significant oration (black; temporary), vomiting
exposure to a nursing child. Ophthalmic: Corneal abrasion (with direct contact)
Contraindications There are no absolute contraindica- Respiratory: Aspiration, respiratory failure
tions listed within the manufacturer’s labeling. Drug Interactions
Note: The American Academy. of Clinical Toxicology Metabolism/Transport Effects None known.
(AACT) and European Association of Poisons Centres Avoid Concomitant Use There are no known interac-
and Clinical Toxicologists (EAPCCT) consider the follow- tions where it is recommended to avoid concomitant use.
ing to be contraindications to the use of charcoal (Chyka Increased Effect/Toxicity There are no known signifi-
2005; Vale 1999): Presence of intestinal obstruction or Gl cant interactions involving an increase in effect.
tract not anatomically intact; patients at risk of Gl hemor- Decreased Effect
rhage or perforation; patients with an unprotected airway Charcoal, Activated may decrease the levels/effects of:
(eg, CNS depression without intubation); if use would Leflunomide; Teriflunomide
increase the risk and severity of aspiration Food Interactions The addition of some flavoring agents
Warnings/Precautions Charcoal may cause vomiting; (eg, milk, ice cream, sherbet, marmalade) are known to
the risk appears to be greater when charcoal is adminis- reduce the adsorptive capacity, and therefore the efficacy,
tered with sorbitol (Chyka 2005). IV antiemetics may be of activated charcoal and should be avoided in preference
required to reduce the risk of vomiting or to control to activated charcoal-water slurries; nevertheless, these
vomiting to facilitate administration (Vale 1999). Due to flavoring agents do not completely compromise the effec-
the risk of vomiting, avoid the use of charcoal in hydro- tiveness of activated charcoal and may be necessary in
carbon and caustic ingestions. Use caution with some circumstances (eg, administration in pediatric
decreased peristalsis. Some products may contain sorbi- patients) to enhance compliance (Cooney 1995; Dagnone
tol. Coadministration of a cathartic is not recommended; 2002).
cathartics (eg, sorbitol, mannitol, magnesium sulfate) Storage/Stability Adsorbs gases from air, store in a
have not been demonstrated to change patient outcome closed container.
and have no role in the management of the poisoned Mechanism of Action Adsorbs toxic substances, thus
patient. Cathartics subject the patient to the risk of devel- inhibiting Gl absorption and preventing systemic toxicity.
oping significant fluid and electrolyte abnormalities (AACT Administration of multiple doses of charcoal may interrupt
2004a). Do not use products containing sorbitol in persons enteroenteric, enterohepatic, and enterogastric circulation
with a genetic intolerance to fructose or in patients who of some drugs; may also adsorb any unabsorbed drug
are dehydrated; may cause excessive diarrhea. Ipecac which remains in the gut.
should not be administered routinely in the management Pharmacodynamics/Kinetics (Adult data unless
of poisoned patients (AACT 2004b).
noted)
Not effective in the treatment of poisonings due to the Note: In studies using adult human volunteers: Mean
ingestion of low molecular weight compounds such as reduction in drug absorption following a single dose of
cyanide, iron, ethanol, methanol, or lithium. Most effective 250g activated charcoal (AACT [Chyka 2005)}):
when administered within 30-60 minutes of ingestion. Given within 30 minutes after ingestion: 47.3% reduction
Based on experimental and clinical studies, multidose Given at 60 minutes after ingestion: 40.07% reduction
activated charcoal, in most acute poisonings, has not Given at 120 minutes after ingestion: 16.5% reduction

413
CHARCOAL, ACTIVATED

Given at 180 minutes after ingestion: 21.13% reduction A policy statement by the American Academy of Pediatrics
Given at 240 minutes after ingestion: 32.5% reduction states that it is currently premature to recommend the
Absorption: Not absorbed from the GI tract routine administration of activated charcoal as a home
Excretion: Feces (as charcoal) treatment strategy for poisonings (AAP 2003).
Dosing Dosage Forms Excipient information presented when
Pediatric available (limited, particularly for generics); consult spe-
Acute poisoning: Oral, NG: cific product labeling.
Single dose: Charcoal in water: Liquid, Oral:
Age-directed dosing: Note: Although dosing by body Actidose-Aqua: 15 g/72 mL (72 mL); 25 g/120 mL (120
weight in children (0.5 to 1 g/kg) is recommended by mL); 50 g/240 mL (240 mL) [sweet flavor]
several resources, there are no data or scientific Actidose/Sorbitol: 25 g/120 mL (120 mL); 50 9/240 mL
rationale to support this recommendation (240 mL) [sweet flavor]
(Chyka 2005). Kerr Insta-Char: 25 g/120 mL (120 mL); 50 g/240 mL
Infants <1 year: (240 mL) [contains fd&c red #40, methylparaben
Manufacturer's labeling (Actidose-Aqua): 1 g/kg sodium, propylene glycol, propylparaben sodium,
AACT recommendation (Chyka 2005): 10 to 25 g sodium benzoate; cherry flavor]
Children 1 to 12 years: Kerr Insta-Char: 50 g/240 mL (240 mL) [contains propy-
Manufacturer's labeling: lene glycol]
Actidose-Aqua: 25 to 50 g Kerr Insta-Char in Sorbitol: 25 g/120 mL (120 mL); 50 g/
Kerr Insta-Char (Aqueous): Weight 216 kg: 1 to 240 mL (240 mL) [contains fd&c red #40, methylpar-
aben-sodium, propylene glycol, propylparaben sodium,
2 g/kg or 15 to 30g
sodium benzoate; cherry flavor]
AACT recommendation (Chyka 2005): 25 to 50 g
Suspension, Oral:
Adolescents:
Char-Flo with Sorbitol: 25 g (120 mL)
Manufacturer's labeling:
Suspension Reconstituted, Oral:
Actidose-Aqua: 50 to 100 g
EZ Char: 25 g (1 ea) [contains bentonite]
Kerr Insta-Char (Aqueous): Weight 232 kg: 1 to
2 g/kg or 50 to 100 g @ Charcodote-Aqueous Sus (Can) see Charcoal, Acti-
AACT recommendation (Chyka 2005): 25 to 100 g vated on page 413
Single dose: Charcoal with sorbitol; Note: Use of oral
Charcodote Susp [OTC] (Can) see Charcoal, Activated
charcoal with sorbitol as part of a multiple dose on page 413 \
activated charcoal regimen is not recommended
(AACT [Vale 1999]); however, a single dose may be @ Charcodote TFS [OTC] (Can) see Charcoal, Activated
used to produce catharsis (AACT 2004): on page 413
Infants <1 year: Not recommended @ Char-Flo with Sorbitol [OTC] see Charcoal, Activated
Children 1 to 12 years (Actidose with Sorbitol): on page 413
Weight 16 to <32 kg: 25g @ Chemet see Succimer on page 1867
Weight 232 kg: 25 to 50 g @ Chenodal see Chenodiol on page 414
Adolescents:
Actidose with Sorbitol: 50 g @ Chenodeoxycholic Acid see Chenodiol on page 414
Kerr Insta-Char in Sorbitol: Weight 232 kg: 1 to 2 g/
kg or 50 to 100 g Chenodiol (kee noe DYE ole)
Multiple dose: Charcoal in water (doses are repeated
until clinical observations of toxicity subside and Brand Names: US Chenodal
serum drug concentrations have returned to a sub- Therapeutic Category Bile Acid
therapeutic range or until the development of absent Generic Availability (US) No
bowel sounds or ileus); Note: Reserve for life threat- Use Oral dissolution of radiolucent cholesterol gallstones in
ening ingestions of carbamazepine, dapsone, pheno- well-opacifying gallbladders in patients who are not can-
barbital, quinine, or theophylline (AACT 1999). didates for surgery due to systemic disease or age (FDA
Manufacturer's labeling (Actidose-Aqua): approved in adults); has also been used for lipid storage
Infants <1 year: 1 g/kg every 4 to 6 hours diseases, including cerebrotendinous xanthomatosis, Zell-
Children 1 to 12 years: 25 to 50 g every 4 to 6 hours weger syndrome, and other susceptible bile acid biosyn-
Adolescents: 50 to 100 g every 4 to 6 hours thesis defects which result in low chenodeoxycholic acid
Administration Oral: Administer as soon as possible after concentrations
ingestion, preferably within 1 hour for greatest effect. Prescribing and Access Restrictions Prescriptions
Shake well before use; may be mixed with chocolate syrup are only dispensed by Dohmen Life Science Services
or orange juice to increase palatability. Manufacturer's Chenodal Total Care Program which may be contacted
labeling for Actidose Aqua and Actidose with sorbitol at 866-758-7068.
recommends avoiding adding chemicals, syrups, or dairy Pregnancy Risk Factor X
products. Pregnancy Considerations Use is contraindicated in
women who are or can become pregnant. Adverse events
Instruct patient to drink slowly, rapid administration may
were observed in some animal reproduction studies.
increase frequency of vomiting; if patient has persistent
Breastfeeding Considerations It is not known if cheno-
vomiting, multiple doses may be administered as a con-
diol is excreted in breast milk. The manufacturer recom-
tinuous enteral infusion
mends that caution be exercised when administering
Monitoring Parameters Check for presence of bowel chenodiol to nursing women.
sounds before administration. Fluid status, sorbitol intake,
Contraindications Known hepatocyte dysfunction or bile
number of stools, electrolytes if increase in stools or
ductal abnormalities (eg, intrahepatic cholestasis, primary
diarrhea occurs; continually assess for active bowel biliary cirrhosis, sclerosing cholangitis); use in a patient
sounds in patients receiving multiple dose activated char- with a gallbladder confirmed as nonvisualizing after two
coal consecutive single doses of dye; radiopaque stones; gall-
Additional Information The Position Paper on single stone complications or compelling reasons for gallbladder
dose activated charcoal by The American Academy of surgery (eg, unremitting acute cholecystitis, cholangitis,
Clinical Toxicology and The European Association of biliary obstruction, gallstone pancreatitis, biliary gastro-
Poisons Centres and Clinical Toxicologists (Chyka 2005) intestinal fistula); use in pregnancy or in women who
does not advocate routine use of single dose activated can become pregnant.
charcoal in the treatment of poisoned patients. Scientific Warnings/Precautions Drug-induced liver toxicity may
literature supports the use of activated charcoal within 1 occur (dose-related); close monitoring of serum amino-
hour of toxin ingestion, when it will be more likely to transferase levels recommended during therapy. Amino-
produce benefit. Studies in volunteers demonstrate that transferase elevations >3 times ULN have been reported;
the effectiveness of activated charcoal decreases as the prompt discontinuation recommended. Transaminase lev-
time of administration after toxin ingestion increases. els usually return to normal after chenodiol is withheld.
Therefore, this publication states that activated charcoal Temporarily withhold therapy for transient transaminase
may be considered up to 1 hour following ingestion of a elevations of 1.5 to 3 times ULN. Biochemical and histo-
potentially toxic amount of poison. In addition, the use of logic chronic active hepatitis has been reported (rare case
activated charcoal may be considered greater than 1 hour reports), although a causal relationship to chenodiol could
following ingestion, since the potential benefit cannot be not be determined. Avoid in patients with preexisting
excluded. Furthermore, based on current literature, the hepatic impairment or elevated liver enzymes; use contra-
routine administration of a cathartic with activated char- indicated in patients with known hepatocyte dysfunction or
coal is not recommended; when cathartics are used, only bile ductal abnormalities. Dose-related diarrhea com-
a single dose should be administered so as to decrease monly occurs (up to 40% of patients); may occur at any
adverse effects (AACT 2004). time, but is most common during treatment initiation.

414
 CHENODIOL

Diarrhea is usually mild and does not interfere with Inborn errors of bile acid biosynthesis: Very limited
therapy; however, diarrhea may be severe and a tempo- data available: Oral: Infants, Children and Adoles-
rary dosage reduction or discontinuation may be required. cents: Note: Due to the rarity of the disease states,
Antidiarrneal agents may be of benefit in some patients. data is limited to small case series and case reports.
Epidemiologic studies have suggested that bile acids may Adjust dose based upon targeted bile acid or biosyn-
increase the risk of colon cancer. Evidence is weak and thesis intermediate compound concentrations. Com-
conflicting; however, a potential link between bile acids bination therapy with ursodeoxycholic acid (urosdiol)
and colon cancer cannot be ruled out. dependent on specific deficiency, and phenotypic
[US Boxed Warning]: Due to the hepatotoxicity poten- presentation of syndrome.
tial, poor response rate in certain subgroups, and an Cerebrotendinous xanthomatosis: \nitial: 10 to
increased rate of cholecystectomy necessary in other 15 mg/kg/day divided 1 to 3 times daily; in adoles-
subgroups, chenodiol is not an appropriate treatment cents, a fixed dose of 750 mg/day has also been
for many patients with gallstones. Use should be reported (Beringer 2010; Kaufman 2012; Setchell
reserved to carefully selected patients; treatment 2006; van Heijst 1998)
must be accompanied with liver function monitoring. Steroid dehydrogenase or reductase. deficiencies
Studies have shown dissolution rates are higher in (susceptible): Usual initial range: 5 to 10 mg/kg/
patients with small (<15 mm in diameter), radiolucent, day divided once or twice daily; higher initial doses
and/or floatable stones. Radiopaque (calcified or partially of 11 to 18 mg/kg/day have also been reported; a
calcified) stones and bile pigment stones do not respond maintenance dose of 5 mg/kg/day was the most
to bile acid dissolution therapy. Response to therapy frequently reported and initiated once targeted bile
should be monitored with oral cholecystograms or ultra- acid normalized orstabilized (depending upon the
sonograms at 6- to 9-month intervals. Complete dissolu- syndrome) (Clayton 1996; Clayton 2011; Ichimiya
tion should then be confirmed by a repeat test 1 to 3 1990; Riello 2010)
months after continued therapy. If partial dissolution is
Peroxisome deficiency, including Zellweger syn-
not observed by 9 to 12 months, complete dissolution is
drome: Oral: 100 to 250 mg/day or 5 mg/kg/day
unlikely, If no response is observed by 18 months, therapy
have been used (Maeda 2002; Setchell 1992)
should be discontinued; safety beyond 24 months of use
has not been established. Recurrence of gallstones may Renal Impairment: Pediatric There are no dosage
occur within 5 years in approximately 50% of patients; adjustments provided in manufacturer's labeling.
serial cholecystograms or ultrasonograms are recom- Hepatic Impairment: Pediatric Use extreme caution;
mended to monitor for recurrence. Prophylactic doses contraindicated for use in presence of known hepatocyte
have not been established and reduced doses cannot dysfunction or bile duct abnormalities.
be recommended. Long-term consequences of repeated Administration May be taken without regard to meals.
courses or chenodiol are not known. Potentially significant Monitoring Parameters Serum aminotransferase levels
drug-drug interactions may exist, requiring dose or fre- (monthly for first 3 months, then every 3 months during
quency. adjustment, additional monitoring, and/or selec- therapy); serum cholesterol (every 6 months); for gall-
tion of alternative therapy. stone dissolution: Oral cholecystograms and/or ultrasono-
Adverse Reactions grams (6-9 month intervals for response to therapy);
Endocrine & metabolic: Increased LDL cholesterol, dissolutions of stones should be confirmed 1-3 months
increased serum cholesterol (total) later; for bile acid biosynthesis defects: Targeted bile acids
Gastrointestinal: Diarrhea (30% to 40%; severe diarrhea or intermediate product concentrations from either serum
that requires dose reduction: 10% to 15%), biliary colic, or blood should be measured (as appropriate) (Clatyon
abdominal cramps, abdominal pain, anorexia, constipa- 2011; Setchell, 2006)
tion, dyspepsia, flatulence, heartburn, nausea, vomiting Dosage Forms Excipient information presented when
Hematologic & oncologic: Leukopenia
available (limited, particularly for generics); consult spe-
Hepatic: Increased serum transaminases (230%; >3 x
cific product labeling.
ULN: 2% to 3%)
Tablet, Oral:
Drug Interactions
Chenodal: 250 mg
Metabolism/Transport Effects None known.
Avoid Concomitant Use There are no known interac- @ Cheracol D [OTC] see Guaifenesin and Dextromethor-
tions where it is recommended to avoid concomitant use. phan on page 967
Increased Effect/Toxicity @ Cheracol Plus [OTC] see Guaifenesin and Dextrome-
Chenodiol may increase the levels/effects of: Vitamin K
thorphan on page 967
Antagonists
Decreased Effect e Cheratussin see GuaiFENesin on page 964
The levels/effects of Chenodiol may be decreased by: 5 Cheratussin AC see Guaifenesin and Codeine
Aluminum Hydroxide; Bile Acid Sequestrants; Estrogen on page 965
Derivatives; Fibric Acid Derivatives S Chew-C [OTC] see Ascorbic Acid on page 186
Storage/Stability Store at 20°C to 20°C (68°F to 77°F).
oa CHG see Chlorhexidine Gluconate (Topical) on page 421
Mechanism of Action Chenodiol (chenodeoxycholic
acid) is a naturally occurring human bile acid, normally e Chickenpox vaccine see Measles, Mumps, Rubella, and
constituting one-third of the total bile acid pool. In patients Varicella Virus Vaccine on page 1279
with cholesterol gallstones, chenodiol is believed to sup- Sa Chickenpox Vaccine see Varicella Virus Vaccine
press hepatic synthesis of cholesterol and cholic acid, and on page 2039
inhibit biliary cholesterol secretion, which leads to
Chiggerex [OTC] [DSC] see Benzocaine on page 257
increased production of cholesterol unsaturated bile
thereby allowing for dissolution of gallstones. Chiggertox [OTC] [DSC] see Benzocaine on page 257
Pharmacodynamics/Kinetics (Adult data unless Childrens Advil [OTC] see Ibuprofen on page 1034
noted) ¢ Children's Advil Cold (Can) see Pseudoephedrine and
¢$¢¢
Absorption: Rapid, almost completely absorbed in prox-
Ibuprofen on page 1714
imal small intestine (Crosignani 1996)
Distribution: Vg: ~1600 L (Crosignani 1996) Childrens Loratadine [OTC] see Loratadine
Metabolism: Converted hepatically to taurine and glycine on page 1247
conjugates and secreted in bile; extensive first-pass Childrens Motrin [OTC] see Ibuprofen on page 1034
hepatic clearance; undergoes enterohepatic circulation; Childrens Motrin Jr Strength [OTC] [DSC] see Ibupro-
further metabolized in colon by bacteria to lithocholic
fen on page 1034
acid; small portion of lithocholate is absorbed and con-
verted to sulfolithocholyl conjugates in the liver Childrens Silfedrine [OTC] see Pseudoephedrine
Half-life: ~45 hours (Crosignani 1996) on page 1712
Excretion: Feces (~80%, as lithocholate) Children’s Advil (Can) see Ibuprofen on page 1034
Dosing of Children’s Europrofen (Can) see lbuprofen
Pediatric on page 1034
Gallstone dissolution: Limited data available: Oral:
Children 212 years and Adolescents: 15 mg/kg/day S4 Children’s Motion Sickness Liquid [OTC] (Can) see
divided 3 times daily with meals; dosing based on DimenhyDRINATE on page 646
reported experience in three obese pediatric patients ChiRhoStim see Secretin on page 1811
(age range:12 to 13 years); Note: Not first-line @ Chloditan see Mitotane on page 1385
therapy due to frequent side effect (increased LFT,
diarrhea) and other therapeutic options available Chlodithane see Mitotane on page 1385
(Podda 1982) @ Chioral see Chloral Hydrate on page 416

415
CHLORAL HYDRATE

doses), hallucinations, hangover effect, malaise, night-

Chloral Hydrate (kior al HYE crate) mares, paradoxical excitation, somnambulism, vertigo
Dermatologic: Skin rash (including erythema, eczematoid
Medication Safety Issues dermatitis, urticaria, scarlatiniform exanthems)
High alert medication: !
Endocrine & metabolic: Acute porphyria, ketonuria
The Institute for Safe Medication Practices (ISMP) Gastrointestinal: Diarrhea, flatulence, gastric irritation,
includes this medication (for sedation of children) nausea, vomiting
among its list of drugs which have a heightened risk Hematologic & oncologic: Acute porphyria, eosinophilia,
of causing significant patient harm when used in error. leukopenia
Geriatric Patients: High-Risk Medication: Ophthalmic: Allergic conjunctivitis, blepharoptosis, kerato-
Beers criteria: Based on pharmacologic class concerns conjunctivitis
for hypnotics in the Beers Criteria, chloral hydrate may Otic: Increased middle ear pressure (infants and children)
be a potentially inappropriate medication to be avoided Respiratory: Airway obstruction (young children), laryng-
in patients 65 years and older (independent of diag- eal edema (children)
nosis or condition); tolerance occurs within 10 days and Miscellaneous: Drug tolerance
risk of overdose with doses only 3 times the recom- Drug Interactions
mended dose (Beers Criteria [AGS 2012; AGS 2015]) Metabolism/Transport Effects None known.
Brand Names: Canada Chloral Hydrate-Odan; PMS- Avoid Concomitant Use
Chloral Hydrate Avoid concomitant use of Chloral Hydrate with any of the
Therapeutic Category Hypnotic; Sedative following: Azelastine (Nasal); Bromperidol; Furosemide;
Generic Availability (US) No Orphenadrine; Oxomemazine; Paraldehyde; Sodium
Use Sedative/hypnotic for surgeries and diagnostic proce- Oxybate; Thalidomide
dures or EEG evaluations in children and adults. Sedative Increased Effect/Toxicity
for mechanically-ventilated infants, children, and adoles- Chloral Hydrate may increase the levels/effects of: Alco-
cents. Note: Within the US, there are no longer any FDA- hol (Ethyl); Azelastine (Nasal); Blonanserin; Buprenor-
approved commercially-available preparations. phine; CNS Depressants; Flunitrazepam;
Pregnancy Considerations Animal reproduction studies HYDROcodone; Methotrimeprazine; MetyroSINE; Mirta-
have not been conducted. Chloral hydrate crosses the zapine; Opioid Analgesics; Orphenadrine; OxyCO-
placenta, and long-term use may lead to withdrawal DONE; Paraldehyde; Piribedil; Pramipexole;
symptoms in the neonate. ROPINIRole; Rotigotine; Selective Serotonin Reuptake
Breastfeeding Considerations Chloral hydrate is Inhibitors; Sodium Oxybate; Suvorexant; Thalidomide;
excreted in breast milk; use by breastfeeding women Vitamin K Antagonists; Zolpidem
may cause sedation in the infant. The levels/effects of Chloral Hydrate may be increased
Contraindications Hypersensitivity to chloral hydrate or by; Brimonidine (Topical); Bromopride; Bromperidol;
any component of the formulation; marked hepatic or renal Cannabis; Chlormethiazole; Chlorphenesin Carbamate;
impairment Dimethindene (Topical); Doxylamine; Dronabinol; Dro-
Warnings/Precautions May cause CNS depression, peridol; Furosemide; HydrOXYzine; Kava Kava; Lofex-
which may impair physical or mental abilities; patients idine; Magnesium Sulfate; Melatonin;
must be cautioned about performing tasks that require Methotrimeprazine; Minocycline; Nabilone; Oxomema-
mental alertness (eg, operating machinery or driving). zine; Perampanel; Rufinamide; Tapentadol; Tetrahydro-
Use with caution in patients with porphyria, cardiac dis- cannabinol; Trimeprazine
ease, gastrointestinal disease, or respiratory disorders. Decreased Effect There are no known significant inter-
Excessive sedation or other adverse effects may be more actions involving a decrease in effect.
likely to occur in elderly patients; avoid use in older adults. Storage/Stability Store syrup at controlled room temper-
Life-threatening respiratory obstruction and deaths have ature in a light-resistant, airtight container; protect from
been reported with use in children; use with extreme freezing.
caution. Prolonged use in neonates is associated with Mechanism of Action Central nervous system depres-
direct hyperbilirubinemia (active metabolite [TCE] com- sant effects are due to its active metabolite trichloroetha-
petes with bilirubin for glucuronide conjugation in the nol, mechanism unknown
liver). Potentially significant drug-drug interactions may Pharmacodynamics/Kinetics (Adult data unless
exist, requiring dose or frequency adjustment, additional noted)
monitoring, and/or selection of alternative therapy. Onset of action: 15 to 30 minutes (Krauss 2006)
Duration: 1 to 2 hours (Krauss 2006)
Benzyl alcohol and derivatives: Some dosage forms may
Absorption: Oral: Well absorbed
contain sodium benzoate/benzoic acid; benzoic acid (ben-
Protein binding: Trichloroethanol: 35% to 40%; trichloro-
zoate) is a metabolite of benzyl! alcohol; large amounts of
acetic acid: ~94% (may compete with bilirubin for albu-
benzyl alcohol (299 mg/kg/day) have been associated
min binding sites)
with a potentially fatal toxicity ("gasping syndrome") in
Metabolism: Rapidly metabolized in the liver by alcohol
neonates; the "gasping syndrome" consists of metabolic
dehydrogenase to trichloroethanol (active metabolite);
acidosis, respiratory distress, gasping respirations, CNS
trichloroethanol undergoes glucuronidation in the liver;
dysfunction (including convulsions, intracranial hemor-
variable amounts hepatically and renally to trichloro-
rhage), hypotension, and cardiovascular collapse (AAP
acetic acid (inactive)
{"Inactive" 1997]; CDC 1982); some data suggests that
Half-life elimination:
benzoate displaces bilirubin from protein binding sites Chloral hydrate (Mayer 1991):
(Ahlfors 2001); avoid or use dosage forms containing Preterm infants (postmenstrual age [PMA] 31 to 37
benzyl! alcohol derivative with caution in neonates. See weeks): 1.01 + 0.97 hours
manufacturer’s labeling. Term infants (PMA 38 to 42 weeks): 3.01 + 5.81 hours
Warnings: Additional Pediatric Considerations Children and Adolescents <14 years: 9.68 + 7.73 hours
Deaths and permanent neurologic injury from respiratory Active metabolite (trichloroethanol) (Mayers 1991):
compromise have been reported in children sedated with Preterm infants (PMA 31 to 37 weeks): 39.82 + 14.27
chloral hydrate; respiratory obstruction may occur in chil- hours
dren with tonsillar and adenoidal hypertrophy, obstructive Term infants (PMA 38 to 42 weeks): 27.8 + 21.32 hours
sleep apnea, and Leigh's encephalopathy, and in ASA Children and Adolescents <14 years: 9.674 1.72 hours
class Ill children; depressed levels of consciousness Adults: 8 to 12 hours (Fuhrman 2011)
may occur; chloral hydrate should not be administered Trichloroacetic acid: Adults: 67 hours (Furhman 2011)
for sedation by nonmedical personnel or in a nonsuper- Excretion: Urine (as metabolites); feces (small amounts)
vised medical environment; sedation with chloral hydrate Dosing
requires careful patient monitoring (Coté 2000). Animal Neonatal Sedation, procedural (eg, echocardiogram
studies suggest that chloral hydrate may depress the or EEG): Limited data available: Oral: 25 to 50 mg/kg/
genioglossus muscle and other airway-maintaining dose once prior to procedure (Fuhrman 2011; Krauss
muscles in patients who are already at risk for life-threat- 2006; Rudolph 1996)
ening airway obstruction (eg, obstructive sleep apnea); Pediatric
alternative sedative agents should be considered for these Sedation, mechanically-ventilated patients: Very
patients (Hershenson 1984). limited data available: Infants, Children, and Adoles-
Adverse Reactions cents: Oral: Initial: 8 to 25 mg/kg/dose every 6 to 8
Cardiovascular: Atrial arrhythmia, depression of myocar- hours; titrate to effect based on patient response up to
dial contractility, hypotension, shortening of refractory 50 mg/kg/dose every 6 hours; maximum dose:
periods, torsades de pointes, ventricular arrhythmia 1,000 mg/dose (AHFS 1993; Parkinson 1997). Dos-
Central nervous system: Abnormal gait, ataxia, confusion, ing based on randomized control trial of 44 patients
delirium, dizziness, drowsiness, drug dependence (phys- (age range: 1 day to 15 years) that compared con-
ical and psychological; with prolonged use or large tinuous infusion midazolam (n=20) to promethazine

416
 CHLORAMBUCIL

plus chloral hydrate (n=23) at dose of 25 mg/kg/dose Contraindications Hypersensitivity to chlorambucil or

every 6 hours for sedation in ventilated patients. If any component of the formulation; hypersensitivity to
sedation unsatisfactory, doses could be increased up other alkylating agents (may have cross-hypersensitivity);
to 50 mg/kg/dose every 6 hours. The total number of prior (demonstrated) resistance to chlorambucil
satisfactory sedation assessments was significantly Canadian labeling: Additional contraindications (not in US
higher in the chloral hydrate/promethazine group labeling): Use within 4 weeks of a full course of radiation
(61%) compared to the midazolam group (48%) (Par- or chemotherapy
kinson 1997). Warnings/Precautions Seizures have been observed;
Sedation, procedural (eg, echocardiogram or EEG): use with caution in patients with seizure disorder or head
Limited data available: Infants and Children (best trauma; history of nephrotic syndrome and high pulse
results in children <3 years): Oral: 25 to 100 mg/kg/ doses are at higher risk of seizures. [U.S. Boxed Warn-
dose 30 minutes prior to procedure; maximum dose ing]: May cause severe bone marrow suppression;
1,000 mg/dose; may repeat after 30 minutes with 25 neutropenia may be severe. Reduce initial dosage if
to 50 mg/kg/dose if necessary. Maximum total dose: patient has received myelosuppressive or radiation ther-
100 mg/kg/procedure or 2,000 mg/procedure (Heist- apy within the previous 4 weeks, or has a depressed
ein 2006; Krauss 2006; Napoli 1996; Wheeler 2001). baseline leukocyte or platelet count. Irreversible bone
Note: Although dosing may be used in adolescent marrow damage may occur with total doses approaching
patients, use in these patients is not common; older 6.5 mg/kg. Progressive lymphopenia may develop (recov-
children and adolescent patients may not require ery is generally rapid after discontinuation). Avoid admin-
sedation for echocardiogram and other agents used istration of live vaccines to immunocompromised patients.
for EEG. Rare instances of severe skin reactions (eg, erythema
Renal Impairment: Pediatric There are no dosage multiforme, Stevens-Johnson syndrome, toxic epidermal
_ adjustments provided in the manufacturer's labeling. necrolysis) have been reported; discontinue promptly if
Use is contraindicated in patients with marked renal skin reaction occurs.
impairment. Chlorambucil is primarily metabolized in the liver. Dosage
Dialysis: Dialyzable reductions should be considered in patients with hepatic
Hepatic Impairment: Pediatric There are no dosage impairment. [U.S. Boxed Warning]: Affects human fer-
adjustments provided in the manufacturer's labeling. Use tility; carcinogenic in humans and probably muta-
is contraindicated in patients with marked hepatic impair- genic and teratogenic as well; chromosomal damage
ment. has been documented. Reversible and irreversible sterility
Administration Oral: Minimize unpleasant taste and gas- (when administered to prepubertal and pubertal males),
tric irritation by administering with water, infant formula, azoospermia (in adult males) and amenorrhea (in
fruit juice, or ginger ale. females) have been observed. [U.S. Boxed Warning]:
Monitoring Parameters Level of sedation; vital signs, Carcinogenic; acute myelocytic leukemia and secondary
heart rhythm (with long-term use), and Oz saturation. malignancies may be associated with chronic therapy.
Test Interactions May interfere with copper sulfate tests Duration of treatment and higher cumulative doses are
for glycosuria or with fluorometric urine catecholamine and associated with a higher risk for development of leukemia.
urinary 17-hydroxycorticosteroid tests. Potentially significant drug-drug interactions may exist,
Product Availability Not available in the US requiring dose or frequency adjustment, additional mon-
itoring, and/or selection of alternative therapy.
® Chioral Hydrate-Odan (Can) see Chloral Hydrate Adverse Reactions
on page 416 Central nervous system: Drug fever, peripheral neuro-
pathy
Dermatologic: Allergic skin reaction, skin rash, urticaria
Chlorambucil (kor am byoo sil)
Endocrine & metabolic: Amenorrhea
Medication Safety Issues Gastrointestinal: Diarrhea (infrequent), nausea (infre-
Sound-alike/look-alike issues: quent), oral mucosa ulcer (infrequent), vomiting (infre-
Chlorambucil may be confused with Chloromycetin quent)
Leukeran may be confused with Alkeran, leucovorin, Genitourinary: Azoospermia, cystitis (sterile), infertility
Leukine, Myleran Hematologic & oncologic: Anemia, bone marrow depres-
High alert medication: sion, bone marrow failure (irreversible), leukemia (sec-
This medication is in a class the Institute for Safe ondary), leukopenia, lymphocytopenia, malignant
Medication Practices (ISMP) includes among its list of neoplasm (secondary), neutropenia (onset: 3 weeks;
drug classes which have a heightened risk of causing recovery: 10 days after last dose), pancytopenia, throm-
significant patient harm when used in error. bocytopenia
Hepatic: Hepatotoxicity, jaundice
Related Information
Hypersensitivity: Angioedema, hypersensitivity reaction
Oral Medications That Should Not Be Grushed-or Altered
Respiratory: Interstitial pneumonitis, pulmonary fibrosis
on page 2217
Miscellaneous: Fever
Brand Names: US Leukeran’ Rare but important or life-threatening: Agitation, ataxia,
Brand Names: Canada Leukeran confusion, erythema multiforme, flaccid paralysis, seiz-
Therapeutic Category Antineoplastic Agent, Alkylating ure (focal/generalized), hallucination, muscle twitching,
Agent; Antineoplastic Agent, Alkylating Agent (Nitrogen myoclonus, SIADH (syndrome of inappropriate antidiu-
Mustard) retic hormone secretion), Stevens-Johnson syndrome,
Generic Availability (US) No toxic epidermal necrolysis, tremor
Use Treatment of chronic lymphocytic leukemia (CLL), Drug Interactions
Hodgkin's and. non-Hodgkin's lymphoma (FDA approved Metabolism/Transport Effects None known.
in adults); has also been used in the treatment of neph- Avoid Concomitant Use
rotic syndrome (unresponsive to conventional therapy) Avoid concomitant use of Chlorambucil with any of the
and Waldenstrém's macroglobulinemia following: BCG (\Intravesical); Deferiprone; Dipyrone;
Pregnancy Risk Factor D Natalizumab; Pimecrolimus; Tacrolimus (Topical); Vac-
Pregnancy Considerations Animal reproduction studies cines (Live)
have demonstrated teratogenicity. Chlorambucil crosses Increased Effect/Toxicity
the human placenta. Following exposure during the first Chlorambucil may increase the levels/effects of: Barici-
trimester, case reports have noted adverse renal effects tinib; CloZAPine; Deferiprone; Fingolimod; Leflunomide;
(unilateral agenesis). Women of childbearing potential Natalizumab; Tofacitinib; Vaccines (Live)
should avoid becoming pregnant while receiving treat-
ment. [U.S. Boxed Warning]: Affects human fertility;
The levels/effects of Chlorambucil may be increased by:
Chloramphenicol (Ophthalmic); Denosumab; Dipyrone;
probably mutagenic and teratogenic as well; chromo-
Ocrelizumab; Palifermin; Pimecrolimus; Promazine;
somal damage has been documented. Reversible and
Roflumilast; Tacrolimus (Topical); Trastuzumab
irreversible sterility (when administered to prepubertal
and pubertal males), azoospermia (in adult males) and
Decreased Effect
Chlorambucil may decrease the levels/effects of: BCG
amenorrhea (in females) have been observed. Fibrosis,
(Intravesical); Coccidioides immitis Skin Test; Lenogras-
vasculitis and depletion of primordial follicles have been
tim; Lipegfilgrastim; Nivolumab; Pidotimod; Sipuleucel-T;
noted on autopsy of the ovaries.
Tertomotide; Vaccines (Inactivated); Vaccines (Live)
Breastfeeding Considerations It is not known if chlor-
ambucil is excreted in breast milk. Due to the potential for The levels/effects of Chlorambucil may be decreased by:
serious adverse reactions in the nursing infant, the deci- Echinacea
sion to discontinue chlorambucil or to discontinue breast- Food Interactions Absorption is decreased when admin-
feeding should take into account the benefits of treatment istered with food. Management: Administer preferably on
to the mother. an empty stomach.
CHLORAMBUCIL

Hazardous Drugs Handling Considerations Dosage Forms Excipient information presented when
Hazardous agent (NIOSH 2016 [group 1}). available (limited, particularly for generics); consult spe-
cific product labeling.
Use appropriate precautions for receiving, handling, Tablet, Oral: d ;
administration, and disposal. Gloves (single) should be Leukeran: 2 mg
worn during receiving, unpacking, and placing in storage. Extemporaneous Preparations A 2 mg/mL oral sus-
NIOSH recommends single gloving for administration of pension may be prepared with tablets. Crush sixty 2 mg
intact tablets or capsules. If manipulating tablets/capsules tablets in a mortar and reduce to a fine powder. Add small
(eg, to prepare an oral suspension), NIOSH recommends portions of methylcellulose 1% and mix to a uniform paste
(total methylcellulose: 30 mL); mix while adding simple
double gloving, a protective gown, and preparation in a
syrup in incremental proportions to almost 60 mL; transfer
controlled device; if not prepared in a controlled device,
to a graduated cylinder, rinse mortar and pestle with
respiratory and eye/face protection as well as ventilated
simple syrup, and add quantity of vehicle sufficient to
engineering controls are recommended. NIOSH recom-
make 60 mL. Transfer contents of graduated cylinder to
mends double gloving, a protective gown, and (if there is a
an amber prescription bottle. Label "shake well", "refriger-
potential for vomit or spit up) 6ye/face protection for ate", and "protect from light". Stable for 7 days refriger-
administration of an oral liquid/feeding tube administration ated.
(NIOSH 2016). Dressman JB and Poust RI. Stability of Allopurinol and of Five Antineo-
Storage/Stability Store in refrigerator at 2°C to 8°C (36°F plastics in Suspension. Am J Hosp Pharm. 1983;40(4):616-618.
to 46°F). Nahata MC, Pai-VB, and Hipple TF. Pediatric Drug Formulations, Sth
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
Mechanism of Action Alkylating agent; interferes with
DNA replication and RNA transcription by alkylation and @ Chlorambucilum see Chlorambucil on page 417
cross-linking the strands of DNA @ Chloraminophene see Chlorambucil on page 417
Pharmacodynamics/Kinetics (Adult data unless
noted)
Absorption: Rapid and complete (>70%) from Gl tract; Chloramphenicol (Systemic)
(klor am FEN i kole) :
reduced with food
Distribution: Vg: ~0.3 L/kg Medication Safety Issues
Protein binding: ~99%; primarily to albumin Sound-alike/look-alike issues:
Metabolism: Hepatic (extensively); primarily to active Chloromycetin may be confused with chlorambucil,
metabolite, phenylacetic acid mustard Chlor-Trimeton
Half-life elimination: ~1.5 hours; Phenylacetic acid mus- Brand Names: Canada Chloromycetin; Chloromycetin
tard: ~1.8 hours Succinate; Diochloram; Pentamycetin
Time to peak, plasma: Within 1 hour; Phenylacetic acid Therapeutic Category Antibiotic, Miscellaneous
mustard: Within 1.9 + 0.7 hours Generic Availability (US) Yes
Excretion: Urine (~20% to 60% within 24 hours, primarily Use Treatment of serious infections caused by susceptible
as inactive metabolites, <1% as unchanged drug or organisms [eg, Salmonella, rickettsia, H. influenza (men-
phenylacetic acid mustard) ingitis), or cystic fibrosis pathogens] when less toxic drugs
Dosing are ineffective (ie, resistance) or contraindicated (FDA
Pediatric Note: For oncologic uses, dosing and fre- approved in all ages)
quency may vary by protocol and/or treatment phase; Pregnancy Risk Factor C
refer to specific protocol. Pregnancy Considerations Animal reproduction studies
Hodgkin lymphoma: Limited data available: Infants 27 have not been conducted. Chloramphenicol crosses the
months, Children, and Adolescents: ChIVPP regimen: placenta producing cord concentrations approaching
Oral: 6 mg/m?/day on days 1 to 14 of a 28-day cycle maternal serum concentrations. An increased risk of ter-
for 6 to 10 cycles in combination with vinblastine, atogenic effects has not been associated with the use of
procarbazine, and prednisolone (Atra 2002; Capra chloramphenicol in pregnancy (Czeizel 2000; Heinonen
2007; Hall 2007; Stoneham 2007) 1977). "Gray Syndrome" has occurred in premature
Nephrotic syndrome; frequently relapsing steroid- infants and newborns receiving chloramphenicol. Chlor-
amphenicol may be used as an alternative agent for the
sensitive: Limited data available: Children and Ado-
treatment of Rocky Mountain spotted fever in pregnant
lescents: Oral: 0.1 to 0.2 mg/kg/day once daily for 8
women although caution should be used when adminis-
weeks (maximum cumulative dose: 11.2 mg/kg)
tration occurs during the third trimester (CDC [Biggs
(Baluarte 1978; Hodson 2010; KDIGO 2012); Note:
2016)).
Chlorambucil is not a preferred agent due to a higher
Breastfeeding Considerations
incidence of adverse effects with no greater efficacy
Chloramphenicol and its inactive metabolites are present
(Gipson 2009). in breast milk.
Dosing adjustment for toxicity: The presented dosing Chloramphenicol is well absorbed following oral adminis-
adjustments are based on experience in adult patients; tration; however, metabolism and excretion are highly
specific recommendations for pediatric patients are variable in infants and children. The half-life is also
limited. Refer to specific protocol for management. significantly prolonged in low birth weight infants (Powell
Adult: 1982). Due to the potential for serious adverse reactions
Skin reactions: Discontinue treatment in the breastfed: infant, the manufacturer recommends a
Hematologic: decision be made to discontinue breastfeeding or to
WBC or platelets below normal: Reduce dose discontinue the drug, taking into account the importance
Severely depressed WBC or platelet counts: Dis- of treatment to the mother. Other sources recommended
continue avoiding use while breastfeeding, especially young
Persistently low neutrophil or platelet counts or infants (<34 weeks postconceptual age or <1 month of
peripheral lymphocytosis: May be suggestive of age) or when unusually large doses are needed (Atkin-
bone marrow infiltration; if infiltration confirmed, son 1988; Matsuda 1984; Plomp 1983; WHO 2002). In
do not exceed 0.1 mg/kg/day in adults general, antibiotics that are present in breast milk may
Concurrent or within 4 weeks (before or after) of cause non-dose-related modification of bowel flora.
chemotherapy/radiotherapy: Initiate treatment cau- Infants exposed to chloramphenicol from breast milk
tiously; reduce dose; monitor closely. should be monitored for GI disturbances, hemolysis
Renal Impairment: Pediatric There are no dosage and jaundice (WHO 2002).
adjustments provided in manufacturer's labeling; how- Contraindications Hypersensitivity to chloramphenicol or
any component of the formulation; treatment of trivial or
ever, based on experience in adult patients, renal elim-
viral infections; bacterial prophylaxis
ination of unchanged chlorambucil and active metabolite
(phenylacetic acid mustard) is minimal and renal impair-
Warnings/Precautions
Use in premature and full-term neonates has resulted in
ment is not likely to affect elimination.
"gray syndrome" characterized by cyanosis, abdominal
Hepatic Impairment: Pediatric Chlorambucil under-
distention (with or without emesis), vasomotor collapse
goes extensive hepatic metabolism. Although dosage
(often with irregular respiration), and death; progression of
reduction should be considered in patients with hepatic
symptoms is rapid; prompt termination of therapy
impairment, there are no dosage adjustments provided required. Reaction may result from drug accumulation
in the manufacturer's labeling (data is insufficient). caused by immature hepatic or renal function in neonates
Administration Oral: May be administered as a single and infants. Use with caution and reduce dose with renal
daily dose; preferably on an empty stomach. or hepatic impairment and monitor serum concentrations.
Monitoring Parameters Liver function tests, CBC with Use with caution in patients with glucose 6-phosphate
differential (weekly, with WBC monitored weekly during dehydrogenase deficiency. [US Boxed Warning]: Seri-
the first 3 to 6 weeks of treatment) ous and fatal blood dyscrasias (aplastic anemia,

418
 CHLORAMPHENICOL (SYSTEMIC)

hypoplastic anemia, thrombocytopenia, and granulo- Chloramphenicol succinate: Hydrolyzed in the liver, kid-
cytopenia) have occurred after both short-term and ney, and lungs to chloramphenicol (active)
prolonged therapy; do not use for minor infections or (Ambrose 1984)
when less potentially toxic agents are effective. Mon- Bioavailability:
itor CBC frequently in all patients; discontinue if evi- Chloramphenicol: Oral: ~80% (Ambrose 1984)
dence of myelosuppression. Irreversible bone marrow Chloramphenicol succinate: IV: ~70%; highly variable,
suppression may occur weeks or months after therapy. dependent upon rate and extent of metabolism to
Avoid prolonged or repeated courses of treatment. Pro- chloramphenicol (Ambrose 1984)
longed use may result in fungal or bacterial superinfection, Half-life elimination:
including C. difficile-associated diarrhea (CDAD) and Neonates: 1 to 2 days: 24 hours; 10 to 16. days: 10 hours
pseudomembranous colitis; CDAD has been observed Chloramphenicol: Infants: Significantly prolonged
>2 months postantibiotic treatment. Potentially significant (Powell 1982); Children 4 to 6 hours; Adults: ~4 hours
drug-drug interactions may exist, requiring dose or fre- (Ambrose 1984)
quency adjustment, additional monitoring, and/or selec- Hepatic disease: Prolonged (Ambrose 1984)
tion of alternative therapy. Excretion: Urine (~30% as unchanged chloramphenicol
Adverse Reactions succinate in adults, 6% to 80% in children; 5% to 15%
Central nervous system: Confusion, delirium, depression, as chloramphenicol) (Ambrose 1984; Powell 1982)
headache Dosing
Dermatologic: Skin rash, urticaria Neonatal Note: Follow serum concentrations closely to
Gastrointestinal: Diarrhea, enterocolitis, glossitis, nausea, monitor for toxicity and efficacy in neonates due to
stomatitis, vomiting variability in metabolism; use should be restricted to
Hematologic & oncologic: Aplastic anemia, bone marrow treatment of serious infections caused by susceptible
depression, granulocytopenia, hypoplastic anemia, pan- organisms when less toxic drugs are ineffective (ie,
cytopenia, thrombocytopenia resistance) or contraindicated.
Hypersensitivity: Anaphylaxis, angioedema, hypersensi- Meningitis (Tunkel, 2004): IV: Note: Treat for a mini-
tivity reaction mum of 21 days; use smaller doses and longer inter-
Ophthalmic: Optic neuritis vals for neonates <2 kg:
Miscellaneous: Drug toxicity (Gray syndrome), fever PNA <7 days: 25 mg/kg/dose every 24 hours
Drug Interactions ¢ PNA 8-28 days: 25 mg/kg/dose every 12 hours or
Metabolism/Transport Effects Inhibits CYP2C9 50 mg/kg/dose every 24 hours
(weak) Severe infection: IV:
Avoid Concomitant Use Weight-based dosing: Limited data available (Prober,
Avoid concomitant use of Chloramphenicol (Systemic) 1990):
with any of the following: BCG (Intravesical); Cholera Patient weight:
Vaccine; Deferiprone; Dipyrone <1200 g: 22 mg/kg/dose every 24 hours
Increased Effect/Toxicity 1200-2000 g: 25 mg/kg/dose every 24 hours
Chloramphenicol (Systemic) may increase the levels/ Age-based dosing: Limited data available:
Premature neonate or term neonate with PNA <7
effects of: Alcohol (Ethyl); Barbiturates; Carbocisteine;
days: Dosing regimens variable: 25 mg/kg/dose
CloZAPine; CycloSPORINE (Systemic); Deferiprone;
every 24 hours or initiation with a loading dose of
Fosphenytoin; Phenytoin; Sulfonylureas; Tacrolimus
20 mg/kg followed in 12 hours by a maintenance
(Systemic); Vitamin K Antagonists; Voriconazole
regimen of 12.5 mg/kg/dose every 12 hours (Rajch-
The levels/effects of Chloramphenicol (Systemic) may got, 1982; Rajchgot, 1983; Weiss, 1960)
be increased by: Chloramphenicol (Ophthalmic); Dipyr- Term neonate with PNA >7 days: Dosing regimens
one; Fosphenytoin; Phenytoin; Promazine variable: 25 mg/kg/dose every 12 hours or
Decreased Effect 12.5 mg/kg/dose every 6 hours (Rajchgot, 1983;
Chloramphenicol (Systemic) may decrease the levels/ Weiss, 1960)
effects of: BCG (intravesical); BCG Vaccine (Immuniza- Manufacturer's labeling: Note: Frequency recom-
tion); CefTAZidime; Cholera Vaccine; Lactobacillus and mended by the manufacturer for this age group is
Estriol; Sodium Picosulfate; Typhoid Vaccine; Vitamin higher than other expert recommendations, which
B12 generally recommend no more frequent than every
12 hours; monitor serum concentrations closely.
The levels/effects of Chloramphenicol (Systemic) may Preterm infants: 6.25 mg/kg/dose every 6 hours
be decreased by: Barbiturates; Fosphenytoin; Pheny- Term infants:
toin; RifAMPin PNA <14 days: 6.25 mg/kg/dose every 6 hours
Hazardous Drugs Handling Considerations PNA 214 days: 12.5 mg/kg/dose every 6 hours
Hazardous agent (NIOSH 2016 [group 2]). Pediatric
Use appropriate precautions for receiving, handling, Note: Follow serum concentrations closely to monitor for
administration, and disposal. Gloves (single) should be toxicity. Use should be restricted to treatment of serious
worn during receiving, unpacking, and placing in storage. infections when less toxic drugs are ineffective (ie,
resistance) or contraindicated.
NIOSH recommends double gloving, a protective gown, Meningitis: Infants, Children, and Adolescents: IV:
ventilated engineering controls (a class || biological safety 18.75-25 mg/kg/dose every 6 hours (Bradley, 2012;
cabinet or a compounding aseptic containment isolator), Kliegman, 2011; Tunkel, 2004)
and closed system transfer devices (CSTDs) for prepara- Severe infections: Infants, Children, and Adolescents:
tion. Double gloving, a gown, and (if dosage form allows) IV:
CSTDs are required during administration (NIOSH 2016). Manufacturer's labeling: 12.5 mg/kg/dose every 6
Assess risk to determine appropriate containment strategy hours; in some cases higher doses up to
(USP-NF 2017). 25 mg/kg/dose every 6 hours may be required;
Storage/Stability Store intact vials at 20°C to 25°C (68°F higher doses should be promptly decreased
to 77°F). when able
Mechanism of Action Reversibly binds to 50S ribosomal Alternate dosing: 12.5-25 mg/kg/dose every 6 hours;
subunits of susceptible organisms preventing amino acids maximum daily dose: 4000 mg/day (AAP, 2012)
from being transferred to growing peptide chains thus Renal Impairment: Pediatric All patients: Use with
inhibiting protein synthesis caution; monitor serum concentrations.
Pharmacodynamics/Kinetics (Adult data unless Hepatic Impairment: Pediatric All patients: Use with
noted) caution; monitor serum concentrations.
Distribution: To most tissues and body fluids (Ambrose Preparation for Administration
1984); good CSF and brain penetration Parenteral: Should not be administered IM; has been
CSF concentration with uninflamed meninges: 21% to shown to be ineffective.
50% of plasma concentration IV push: Reconstitute with 10 mL SWFI or D5W for a
CSF concentration with inflamed meninges: 45% to 89% concentration of 100 mg/mL
of plasma concentration Intermittent IV infusion: Further dilute in D5W to a final
Chloramphenicol: Vg: 0.6 to 1 L/kg (Ambrose 1984) concentration not to exceed 20 mg/mL (Klaus 1998); in
Chloramphenicol succinate: Vy: 0.2 to 3.1 L/kg neonates, a higher maximum concentration of
(Ambrose 1984) 25 mg/mL has been used (Prober 1990; Rajch-
Protein binding: Chloramphenicol: ~60%; decreased with got 1983)
hepatic or renal dysfunction and 30% to 40% in newborn Administration
infants (Ambrose 1984) Parenteral:
Metabolism: } IV push: Administer over at least 1 minute
Chloramphenicol: Hepatic to metabolites (inactive) Intermittent IV infusion: Infuse over 30 to 60 minutes
(Ambrose 1984) (Klaus 1998). In neonates, some centers have >
419
CHLORAMPHENICOL (SYSTEMIC)

administered as an intermittent IV infusion over 15 Periodontal chip: Infectious events (eg, abscesses, cellu-
minutes (Prober 1990) litis) have been observed rarely with adjunctive chip place-
Monitoring Parameters CBC with differential and plate- ment post scaling and-root planing; use with caution in
let counts (baseline and every 2 days during therapy), patients with periodontal disease and concomitant dis-
serum iron level, iron-binding capacity, periodic liver and eases potentially decreasing immune status (eg, diabetes,
renal function tests, serum drug concentration cancer). Use in acute periodontal abscess pocket is not
Reference Range recommended.
Therapeutic concentrations: Warnings: Additional Pediatric Considerations
Pediatric: Some dosage forms may contain propylene glycol; in
Peak: Neonates: 15 to 25 mcg/mL (Muhall 1983); neonates large amounts of propylene glycol delivered
Infants, Children, and Adolescents: 15 to 30 mcg/mL orally, intravenously (eg, >3,000 mg/day), or topically
(Balbi 2004; Coakley 1992; Long 2012) have been associated with potentially fatal toxicities which
Trough: 5 to 15 mcg/mL can include metabolic acidosis, seizures, renal failure, and
Adult: CNS depression; toxicities have also been reported in
Peak: 10 to 20 mcg/mL (Ambrose 1984; Hammet- children and adults including hyperosmolality, lactic acido-
Stabler 1998) sis, seizures, and respiratory depression; use caution
Trough: 5 to 10 mcg/mL (Ambrose 1984) (AAP 1997; Shehab 2009).
Timing of serum samples: Draw peak concentrations 0.5 Adverse Reactions
to 1.5 hours after completion of IV dose; and trough Dermatologic: Cellulitis
immediately before next dose (Hammet-Stabler 1998) Gastrointestinal: Apnthous stomatitis, dental discoloration
Additional Information Sodium content of 1 g injection: (with oral rinse), dental discomfort, gingival hyperplasia,
2.25 mEq increased tartar formation, mouth discoloration,
Dosage Forms Excipient information presented when toothache
available (limited, particularly for generics); consult spe- Infection: Abscess
cific product labeling. Neuromuscular & skeletal: Arthritis, tendonitis
Solution Reconstituted, Intravenous: Respiratory: Bronchitis, pharyngitis, sinusitis, upper respi-
Generic: 1 g (1 ea) ratory tract infection :
Rare but important or life-threatening: Coated tongue,
@ ChlioraPrep One Step [OTC] [DSC] see Chlorhexidine desquamation, dysgeusia, erythema, geographic
Gluconate (Topical) on page 427 tongue, gingivitis, glossitis, hyperkeratosis, hypersensi-
@ Chlorbutinum see Chlorambucil on page 417 tivity reaction, hypoesthesia, mouth irritation, oral lesion,
oral mucosa ulcer, paresthesia, parotid gland enlarge-
@ Chlorethazine see Mechlorethamine (Systemic)
ment, sialadenitis, stomatitis, tongue changes (short
on page 1284
frenum), tongue edema, tongue irritation, trauma, xero-
@ Chlorethazine Mustard see Mechlorethamine (Sys- stomia
temic) on page 1284 Drug Interactions
Metabolism/Transport Effects None known.
Chlorhexidine Gluconate (Oral) Avoid Concomitant Use There are no known interac-
(klor HEKS i deen GLOO koe nate) tions where it is recommended to avoid concomitant use.
Increased Effect/Toxicity There are no known signifi-
Medication Safety Issues cant interactions involving an increase in effect.
Sound-alike/look-alike issues: Decreased Effect There are no known significant inter-
Peridex may be confused with Precedex actions involving a decrease in effect.
Brand Names: US Peridex; Periogard Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
Brand Names: Canada GUM Paroex; ORO-Clense; excursions permitted to 15°C to 30°C (59°F to 86°F).
Perichlor; Peridex Oral Rinse; Periogard Mechanism of Action Chlorhexidine has activity against
Therapeutic Category Antibiotic, Oral Rinse; Antibiotic, gram-positive and gram-negative organisms, facultative
Topical anaerobes, aerobes, and yeast; it is both bacteriostatic
Generic Availability (US) Yes and bactericidal, depending on its concentration. The
Use bactericidal effect of chlorhexidine is a result of the binding
Oral rinse: Treatment of gingivitis (FDA approved in of this cationic molecule to negatively charged bacterial
adults) cell walls and extramicrobial complexes. At low concen-
Periodontal chip: Adjunctive therapy to reduce pocket trations, this causes an alteration of bacterial cell osmotic
depth in patients with periodontitis (FDA approved in equilibrium and leakage of potassium and phosphorous
adults) resulting in a bacteriostatic effect. At high concentrations
Pregnancy Risk Factor B/C (manufacturer specific) of chlorhexidine, the cytoplasmic contents of the bacterial
Pregnancy Considerations Adverse events have not cell precipitate and result in cell death.
been observed in animal reproduction studies following Pharmacodynamics/Kinetics (Adult data unless
use of the oral rinse; use of periodontal chip has not been noted)
studied. Chlorhexidine oral rinse is poorly absorbed from Absorption:
the GI tract. Oral rinse: ~30% retained in the oral cavity following
Breastfeeding Considerations It is not known if chlo- rinsing and slowly released into oral fluids; poorly
rhexidine is excreted in breast milk. The manufacturer absorbed from Gl tract. After oral administration appli-
recommends that caution be exercised when administer- cation, serum concentrations are not detectable in
ing chlorhexidine oral rinse to nursing women. However, plasma 12 hours after dose.
oral rinse is not intended for ingestion; patient should Periodontal chip: Chlorhexidine released from chip in a
expectorate after rinsing. biphasic manner: ~40% within initial 24 hours, then
Contraindications Hypersensitivity to chlorhexidine or remainder released linearly over 7 to 10 days; no
any component of the formulation detectable urine or plasma levels measured following
Warnings/Precautions Serious allergic reactions, includ- insertion of 4 chips under clinical conditions
ing anaphylaxis, have been reported with use. Duration of action: Serum concentrations: Detectable
levels are not present in the plasma 12 hours after
Oral rinse: Staining of oral surfaces (teeth, tooth restora- administration
tions, dorsum of tongue) may occur; patients exhibited a Excretion: Oral rinse: Feces (~90%); Urine (<1%)
measurable increase of staining in the facial anterior after Dosing
six months of therapy that is more pronounced when there
Pediatric Gingivitis: Limited data available: Children 28
is a heavy accumulation of unremoved plaque. Stain does
years and Adolescents: Oral: Oral rinse (0.12%): Swish
not adversely affect health of the gingivae or other oral
15 mL (one capful) for 30 seconds after toothbrushing,
tissues, and most stain can be removed from most tooth
then expectorate; repeat twice daily (morning and eve-
surfaces by dental prophylaxis. Because removal may not
ning) (de la Rosa 1998)
be possible, patients with anterior facial restorations with
Renal Impairment: Pediatric There are no dosage
rough surfaces or margins should be advised of the
adjustments provided in the manufacturer's labeling.
potential permanency of the stain. An increase in supra-
Hepatic Impairment: Pediatric There are no dosage
gingival calculus has been observed with use; it is not
adjustments provided in the manufacturer's labeling.
known if the incidence of subgingival calculus is
Administration
increased. Dental prophylaxis to remove calculus deposits
should be performed at least every 6 months. May alter
Oral rinse: Swish rinse and expectorate after rinsing; do
taste perception during use; has rarely been associated not swallow. Use in the morning and evening after
with permanent taste alteration. brushing teeth. Following administration, do not rinse
with water or other mouthwashes, brush teeth, or eat
Effect on periodontitis has not been determined; has not immediately.
been tested in patients with acute necrotizing ulcerative Periodontal chip: Adults: Periodontal pocket should be
gingivitis. isolated and surrounding area dried prior to chip
 CHLORHEXIDINE GLUCONATE (TOPICAL)

insertion. The chip should be grasped using forceps with normal saline to remove excess disinfectant after proce-
the rounded edges away from the forceps. The chip dures may help avoid chemical burns (Eichenwald 2017;
should be inserted into ‘the ‘periodontal pocket to its Nuntnarumit 2013). Several studies have noted detectable
maximum depth. It may be maneuvered into position serum concentrations in neonates after chlorhexidine
using the tips of the forceps or a flat instrument. Patients exposure; no correlation between serum concentration
should avoid dental floss at the site of periodontal chip and GA, birth weight, or PNA was identified; the clinical
insertion for 10 days after placement because flossing significance is undetermined (Chapman 2013; Garland
might dislodge the chip. The chip biodegrades com- 2009).
pletely and does not need to be removed. Adverse Reactions
Monitoring Parameters Topical: Monitor for redness/skin Dermatologic: Allergic sensitization, erythema, hypersen-
irritation especially in infants <2 months sitivity reaction, rough skin, xeroderma
Dosage Forms Excipient information presented when Rare but important or life-threatening: Anaphylaxis (Health
available (limited, particularly for generics); consult spe- Canada May 2016), dyspnea, facial edema, nasal con-
cific product labeling. gestion
Solution, Mouth/Throat: Drug Interactions
Peridex: 0.12% (118 mL, 1893 mL) [contains alcohol, Metabolism/Transport Effects None known.
usp, brilliant blue fcf (fd&c blue #1), saccharin sodium;
Avoid Concomitant Use There are no known interac-
mint flavor] tions where it is recommended to avoid concomitant use.
Periogard: 0.12% (473 mL) [mint flavor]
Generic: 0.12% (15 mL, 118 mL, 473 mL)
Increased Effect/Toxicity There are no known signifi-
cant interactions involving an increase in effect.
Decreased Effect There are no known significant inter-
Chlorhexidine Gluconate (Topical) actions involving a decrease in effect.
(klor HEKS i deen GLOO koe nate) Storage/Stability Store at room temperature. Alcohol-
Brand Names: US Antiseptic Skin Cleanser [OTC]; containing topical products are flammable; keep away
Betasept Surgical Scrub [OTC]; ChloraPrep One Step from flames or fire.
[OTC] [DSC]; Dyna-Hex 2 [OTC]; Hibiclens [OTC]; Hibistat Mechanism of Action Chlorhexidine has activity against
[OTC] [DSC]; Tegaderm CHG Dressing [OTC] gram-positive and gram-negative organisms, facultative
Therapeutic Category Antibiotic, Oral Rinse; Antibiotic, anaerobes, aerobes, and yeast; it is both bacteriostatic
Topical 3 and bactericidal, depending on its concentration. The
Generic Availability (US) May be product dependent bactericidal effect of chlorhexidine is a result of the binding
Use Topical: Skin cleanser for preoperative skin prepara- of this cationic molecule to negatively charged bacterial
tion, prior to injection; skin wound and general skin cell walls and extramicrobial complexes. At low concen-
cleanser for patients (FDA approved in pediatric patients trations, this causes an alteration of bacterial cell osmotic
[age not specified] and adults); surgical scrub and anti- equilibrium and leakage of potassium and phosphorous
septic hand rinse for health care personnel (FDA resulting in a bacteriostatic effect. At high concentrations
approved in adults). Note: Indications vary by product; of chlorhexidine, the cytoplasmic contents of the bacterial
refer to specific product labeling for details. cell precipitate and result in cell death.
Pregnancy Considerations No reports of adverse Pharmacodynamics/Kinetics (Adult data unless
effects in newborns have been reported, even though noted) Absorption: Topical: Neonates: Detectable serum
chlorhexidine is commonly used during labor and in the concentrations have been noted following topical chlo-
neonate. Moreover, only very small amounts of disinfec- rhexidine administration (Chapman 2013; Cowen 1979;
tant reach the maternal circulation and the fetus. Garland 2009)
Breastfeeding Considerations It is not known if chlo- Dosing
rhexidine is excreted in breast milk. Neonatal
Contraindications Hypersensitivity to chlorhexidine or Skin cleanser, procedural (eg, phleobotomy, central
any component of the formulation line placement [PICC, UAC], line maintenance
Warnings/Precautions Serious allergic reactions, includ- care): Note: Guidelines for pediatric patients and
ing anaphylaxis, have been reported with use. For topical adults recommend using a >0.5% chlorhexidine prep-
use only. Keep out of eyes, ears, and the mouth; if contact aration in alcohol; however, no recommendations are
occurs, rinse with cold water immediately; permanent eye provided for neonates and infants <2 months (IDSA
injury may result if agent enters and remains in the eye. [O’Grady 2011]). NICU specific recommendations sug-
Deafness has been reported following instillation in the gest no preferred agent, but advise against using
middle ear through perforated ear drums. Avoid applying tincture of iodine (AAP [Polin 2012]); most neonatal
to wounds that involve more than the superficial skin studies have used a 2% chlorhexidine and alcohol
layers. Avoid repeated use as general skin cleansing of preparation (Chapman 2013; Garland 2009; O’Connor
large surfaces (unless necessary for condition). Not for 2016); a few studies have used a 0.5% chlorhexidine
preoperative preparation of face or head;-avoid contact concentration (Garland 1995; Garland 1996). It is rec-
with meninges (do not use on lumbar puncture sites). ommended to use chlorhexidine-containing products
Avoid applying to genital areas; generalized allergic reac- with care in this population due to potential risk of
tions, irritation, and sensitivity have been reported. Sol- dermal irritation or chemical burns.
utions may be flammable (products may contain alcohol); Premature or term neonates with body weight >1.5 kg
avoid exposure to open flame and/or ignition source (eg, and PNA >7 days: Limited data available: Topical:
electrocautery) until completely dry; avoid application to Cleanse site with chlorhexidine product for ~30 sec-
hairy areas which may significantly delay drying time. Use onds, allow to dry (~30 to 60 seconds) prior to line
with caution in children <2 months of age due to potential insertion, dressing application or lab draw (Chapman
for increased absorption, and risk of irritation or chemical
2013; Garland 1995; Garland 2009; O’Connor 2016).
burns. May cause staining of fabrics (brown stain) due to a
Note: Minimal age and weight variable; use has been
chemical reaction between chlorhexidine gluconate bound
evaluated in ELBW neonates with GA as young as 24
to fabric and chlorine (if sufficient chlorine is present from
weeks and birth weight as low as 630 g (Chapman
certain laundry detergents used during laundering proc-
2013); some studies suggest, however, an increased
ess). When used as a topical antiseptic, improper use may
risk of skin irritation and burns with decreased matur-
lead to product contamination. Although infrequent, prod-
ity and bodyweight (AAP [Polin 2010]; Garland 1996;
uct contamination has been associated with reports of
Garland 2009; Tamma 2010); risk versus benefit must
localized and systemic infections. To reduce the risk of
infection, ensure antiseptic products are used according to be weighed prior to use in neonates.
the labeled instructions; avoid diluting products after open- Pediatric
ing; and apply single-use containers only one time to one Skin cleanser for preoperative skin preparation, skin
patient and discard any unused solution (FDA Drug Safety wound and general skin cleanser for patients: Top-
Communication, 2013). ical:
Warnings: Additional Pediatric Considerations Infants <2 months: Note: It is recommended to use with
Although topical chlorhexidine is widely used in many care in this population due to potential risk of dermal
NICUs as a skin cleanser prior to procedures (eg, central irritation or chemical burns. Expert suggestions are
venous line placement/care) (Tamma 2010), data is lack- variable depending upon site and clinical scenario.
ing to support use in premature infants. Manufacturer's Not all products may be appropriate for use in this
labeling recommends using with caution in premature population; refer to product specific labeling. Some
neonates and infants <2 months of age as chlorhexi- experience in neonatal patients applicable to this
dine-containing products may cause irritation or chemical patient population (Garland 2009; Tamma 2010).
burns. A survey,of US NICU chlorhexidine use reports Preoperative skin preparation: Solution: Apply liber-
dermal burns occurring more frequently in neonates with ally to surgical site and swab for at least 2 minutes.
birth weight <1,500 g (Tamma’ 2010). If used for neonatal Dry with sterile towel. Repeat procedure (swab for
dermal site cleansing, some suggest using sterile water or additional 2 minutes and dry with sterile towel). p
421
 CHLORHEXIDINE GLUCONATE (TOPICAL)
é
< Wound care and general skin cleansing: Rinse area nerve blocks including |umbar and caudal epidural
with water, then apply the minimum amount of blocks (FDA approved in adults)
chlorhexidine necessary to cover skin or wound area Limitations of use: Do not use chloroprocaine with or
and wash gently. Rinse again thoroughly. without preservatives. for subarachnoid administration.
Infants 22 months, Children, and Adolescents: Topical Do not use chloroprocaine with preservatives for lumbar
solution: or caudal epidural anesthesia.
Preoperative skin preparation: Solution: Apply liber- Pregnancy Risk Factor C
ally to surgical site and swab for at least 2 minutes. Pregnancy Considerations Animal reproduction studies
Dry with sterile towel. Repeat procedure (swab for have not been conducted. Local anesthetics rapidly cross
additional 2 minutes and dry with sterile towel). the placenta and may cause varying degrees of maternal,
Wound care and general skin cleansing: Rinse area fetal, and neonatal toxicity. Close maternal and fetal
with water, then apply the minimum amount of monitoring (heart rate and electronic fetal monitoring
chlorhexidine necessary to cover skin or wound area advised) are required during obstetrical use.. Maternal
and wash gently. Rinse again thoroughly. hypotension has resulted from regional anesthesia. Posi-
Renal Impairment: Pediatric There are no dosage tioning the patient on her left side and elevating the legs
adjustments provided in the manufacturer's labeling. may help. Epidural, paracervical, or pudendal anesthesia
Hepatic Impairment: Pediatric There are no dosage may alter the forces of parturition through changes in
adjustments provided in the manufacturer's labeling. uterine contractility or maternal expulsive efforts. The
Administration Topical: Keep out of eyes, ears, and use of some local anesthetic drugs during labor and
mouth. Do not routinely apply to wounds which involve delivery may diminish muscle strength and tone for the
more than superficial layers of skin. Avoid contact with first day or two of life. Administration as a paracervical
meninges (ie, do not use on lumbar puncture. sites). block is not recommended with toxemia of pregnancy,
Solutions may be flammable (may contain alcohol); con- fetal distress, or prematurity. Administration of a para-
sult specific product labeling to determine if product may cervical block early in pregnancy has resulted in maternal
be used with electrocautery procedures; if product can be seizures and cardiovascular collapse. Fetal bradycardia
used near an ignition source (eg, cautery, laser), avoid and acidosis also have been reported. Fetal depression
exposure to open flame and/or ignition source until com- has occurred following unintended fetal intracranial injec-
pletely dry; avoid application to hairy areas which may tion while administering a paracervical and/or pudendal
significantly delay drying time. When using the ChloraPrep block.
applicator, do not touch sponge. Hold applicator sponge Breastfeeding Considerations It is not known if chlor-
down and pinch wings of applicator once to activate ampul oprocaine is present in breast milk. According to the
and release antiseptic. manufacturer, the decision to continue or discontinue
Monitoring Parameters Topical: Monitor for redness/skin breastfeeding during therapy should take into account
irritation especially in infants <2 months the risk of infant exposure, the benefits of breastfeeding
to the infant, and benefits of treatment to the mother.
Test Interactions If chlorhexidine is used as a disinfectant
before midstream urine collection, a false-positive urine Contraindications
protein may result (when using dipstick method based Hypersensitivity to chloroprocaine, other para aminoben-
upon a pH indicator color change). zoic acid (PABA) ester type anesthetics, or any compo-
Dosage Forms Excipient information presented when nent of the formulation.
Additional contraindications described in the Clorotekal
available (limited, particularly for generics); consult spe-
labeling (clinically, some may be applicable to other
cific product labeling. [DSC] = Discontinued product
products): Contraindications specific to spinal anesthe-
Liquid, External:
sia (eg, decompensated cardiac insufficiency, hypovole-
Betasept Surgical Scrub: 4% (118 mL, 237 mL, 473 mL,
mic, shock, coagulopathy); |V regional anesthesia;
946 mL, 3780 mL [DSC})
serious cardiac conduction problems; local infection at
Hibiclens: 4% (15 mL, 118 mL, 236 mL, 473 mL, 946 mL,
the site of proposed lumbar puncture; septicemia.
3790 mL) [contains fd&c red #40, isopropyl alcohol]
Generic: 2% (118 mL); 4% (118 mL, 237 mL, 473 mL, Warnings/Precautions Local anesthetics, at high sys-
temic concentrations, are commonly associated with
946 mL, 3800 mL)
hypotension and bradycardia especially with inadvertent
Miscellaneous, External:
intravascular administration. Perform preventive meas-
Hibistat: 0.5% (50 ea [DSC]) [contains isopropyl! alcohol]
ures (eg, limiting cumulative dose, use ultrasound or direct
Tegaderm CHG Dressing: (Dressing) (1 ea)
visualization for catheter placement). Careful and constant
Pad, External:
monitoring of the patient's cardiovascular vital signs
Generic: 2% (2 ea, 6 ea)
should be done during and following each local anesthetic
Solution, External:
injection (Cox 2003; Dickerson 2014). In the event of
Antiseptic Skin Cleanser: 4% (118 mL, 237 mL) [dye
cardiovascular collapse and/or severe CNS toxicity, treat-
free; contains isopropyl! alcohol]
ment in accordance with the American Society of Regional
ChloraPrep One Step: 2% (3 mL [DSC], 10.5 mL [DSC])
Anesthesia and Pain Medicine’s Checklist for Treatment of
[latex free]
Local Anesthetic Toxicity is recommended (Neal [ASRA
Dyna-Hex 2: 2% (473 mL) [contains isopropy! alcohol]
2012)).
@ Chliormeprazine see Prochlorperazine on page 1686 Use with caution in patients with severe hepatic impair-
@ 2-Chlorodeoxyadenosine see Cladribine on page 465 ment or severe renal impairment. Use with caution in
@ Chloromag [DSC] see Magnesium Chloride patients with cardiovascular disease, including severe
on page 1263 hypertension, hypotension, heart block, and severe car-
diac decompensation. Use with caution in patients with
@ Chloromycetin (Can) see Chloramphenicol (Systemic)
genetic deficiency of plasma cholinesterase. Use with
on page 4718
caution in the elderly, debilitated, acutely ill and pediatric
@ Chloromycetin Succinate (Can) see Chloramphenicol patients. Use with extreme caution in patients with myas-
(Systemic) on page 418 thenia gravis; may cause significant weakness (Haroutiu-
nian 2009).
Chloroprocaine (kior oh PROE kane) Intravascular injections should be avoided. Continuous
intra-articular infusion of local anesthetics after arthro-
Medication Safety Issues
scopic or other surgical procedures is not an approved
Sound-alike/look-alike issues:
use; chondrolysis (primarily in the shoulder joint) has
Nesacaine may be confused with Neptazane
occurred following infusion, with some cases requiring
High alert medication:
arthroplasty or shoulder replacement. For epidural (thora-
The Institute for Safe Medication Practices (ISMP) cic, lumbar, or caudal) and intrathecal/spinal administra-
includes this medication (epidural administration) tion, do not use solutions containing preservatives.
among its list of drug classes which have a heightened Use extreme caution in patients with spinal deformities,
risk of causing significant patient harm when used in neurologic disease, septicemia, and severe hypertension
error. when used for thoracic, lumbar, and caudal epidural
Brand Names: US Nesacaine; Nesacaine-MPF administration. With intrathecal/spinal administration, neu-
Therapeutic Category Local Anesthetic, Injectable rologic damage may occur after anesthesia (eg, pares-
Generic Availability (US) Yes thesia, loss of sensitivity, motor weakness, paralysis,
Use cauda equina syndrome); symptoms may persist and
Nesacaine 1% and 2%: Production of local anesthesia by may be permanent; carefully evaluate patients with under-
local infiltration and peripheral nerve block techniques lying neuromuscular disorders while considering risk vs.
(FDA approved in children and adults) benefit prior to treatment. Use with caution or avoid
Nesacaine-MPF 2% and 3%: Production of local anes- epidural or intrathecal/spinal administration in patients
thesia by infiltration and peripheral nerve block (FDA with bleeding disorders (congenital or acquired) and
approved in children and adults); production of central severe anemia (Horlocker 2010). Clorotekal (a product

422
 CHLOROPROCAINE

with specific FDA approval for intrathecal/spinal adminis- Mechanism of Action Chloroprocaine is an ester-type
tration) is contraindicated in patients with serious cardiac local anesthetic, which stabilizes the neuronal membranes
conduction abnormalities, local infection at proposed lum- and prevents initiation and transmission of nerve impulses
bar puncture site, or septicemia; contraindications to intra- thereby affecting local anesthetic actions. Chloroprocaine
thecal/spinal anesthesia should be taken into reversibly prevents generation and conduction of electrical
consideration. impulses in neurons by decreasing the transient increase
in permeability to sodium. The differential sensitivity gen-
Careful and constant monitoring of the patient's state of
erally depends on the size of the fiber; small fibers are
consciousness should be done following each local anes-
more sensitive than larger fibers and require a longer
thetic injection; at such times, restlessness, anxiety, tinni-
period for recovery. Sensory pain fibers are usually
tus, dizziness, blurred vision, tremors, depression, or
blocked first, followed by fibers that transmit sensations
drowsiness may be early warning signs of CNS toxicity.
of temperature, touch, and deep pressure. High concen-
Use extreme caution in patients with existing neurological
trations block sympathetic somatic sensory and somatic
disease. Seizures due to systemic toxicity leading to
motor fibers. The spread of anesthesia depends upon the
cardiac arrest have also been reported, presumably fol-
distribution of the solution. This is primarily dependent on
lowing unintentional intravascular injection. In the event of the volume of drug injected.
cardiovascular collapse and/or severe CNS toxicity, treat-
Pharmacodynamics/Kinetics (Adult data unless
ment in accordance with the American Society of Regional
noted)
Anesthesia and Pain Medicine’s Checklist for Treatment of
Onset of action: 6 to 12 minutes
Local Anesthetic Toxicity is recommended (Neal
Duration (patient, type of block, concentration, and
[ASRA 2012]).
method of anesthesia dependent): Up to 60 minutes
Local anesthetics have been associated with rare occur- Distribution: Vy: Depends upon route of administration;
rences of sudden respiratory arrest. Careful and constant high concentrations found in highly perfused organs
monitoring of the patient's respiratory (adequacy of ven- such as liver, lungs, heart, and brain
tilation) vital signs should be done following each local Metabolism: Rapidly hydrolyzed by plasma enzymes to 2-
anesthetic injection. chloro-4-aminobenzoic acid and beta-diethylaminoetha-
nol (80% conjugated before elimination)
Potentially significant drug-drug interactions may exist, Half-life elimination: In vitro, plasma: Neonates: 43 +°2
requiring dose or frequency adjustment, additional mon- seconds; Adults: 21 + 2 seconds (males), 25 + 1 second
itoring, and/or selection of alternative therapy. (females)
Adverse Reactions- Excretion: Urine (minimal as unchanged drug in urine;
Cardiovascular: Bradycardia, hypotension, syncope, ven- metabolites: Chloro-aminobenzoic acid and beta-dieth-
tricular arrhythmia ylaminoethanol primarily excreted unchanged)
Central nervous system: Anxiety, dizziness, headache, Pharmacodynamics/Kinetics: Additional Consider-
increased body temperature, loss of consciousness, ations
procedural pain, restlessness Hepatic function impairment: Pharmacokinetic parameters
Dermatologic: Diaphoresis, erythema, pruritus, urticaria can be significantly altered.
Endocrine & metabolic: Hyperglycemia Geriatric: Pharmacokinetic parameters can be signifi-
Gastrointestinal: Nausea cantly altered.
Hypersensitivity: Anaphylactoid reaction, angioedema, Dosing
hypersensitivity reaction Pediatric Dose varies with procedure, desired depth, and
Local: Injection site pain duration of anesthesia, desired muscle relaxation, vas-
Neuromuscular & skeletal: Chondrolysis (continuous intra- cularity of tissues, physical condition, and age of patient.
articular administration) The smallest dose and concentration required to pro-
Ophthalmic: Blurred vision duce the desired effect should be used. Decrease dose
Otic: Tinnitus in debilitated patients and patients with cardiac disease.
Respiratory: Laryngeal edema, respiratory arrest, Anesthesia, local injectable and peripheral nerve
sneezing block: Children >3 years and Adolescents: Maximum
Rare but important or life-threatening: Akathisia, anaphy- dose without epinephrine: 11 mg/kg; for infiltration,
laxis, arachnoiditis, auditory impairment, back pain, concentrations of 0.5% to 1% are recommended; for
burning sensation, cardiac arrhythmia, cardiac insuffi- nerve block, concentrations of 1% to 1.5% are recom-
ciency, cardiac arrest, cauda equine syndrome, diplopia, mended
drowsiness, dysesthesia, dyspnea, erythema multi- Renal Impairment: Pediatric There are no dosage
forme, fecal incontinence, feeling hot, groin pain, hyper- adjustments provided in the manufacturer's labeling.
tension, hypoesthesia, limb pain, localized numbness Use with caution due to increased risk of adverse effects.
(perineal; causing sexual dysfunction), malaise, motor Hepatic Impairment: Pediatric There are no specific
dysfunction, myocardial depression, myoclonus, oral dosage adjustments provided in the manufacturer's
hypoesthesia, oral paresthesia, paresthesia, peripheral labeling; however, dosage should be reduced. Use with
neuropathy, photophobia, presyncope, prolonged emer- caution due to increased risk of adverse effects.
gency from anesthesia, respiratory arrest, respiratory Preparation for Administration Parenteral: Dilute with
depression, seizure, sexual disorder, speech disturb- NS. To prepare 1:200,000 epinephrine-chloroprocaine
ance, spinal cord injury, tachycardia, tremor, urinary HCI injection, add 0.1 mL of a 1 mg/mL epinephrine
incontinence, urinary retention, visual disturbance, vom- injection to 20 mL of preservative-free chloroprocaine.
iting Administration Parenteral: Administer locally as a single
Drug Interactions injection or continuously through an indwelling catheter.
Metabolism/Transport Effects None known. Avoid rapid injection. Do not use for subarachnoid admin-
Avoid Concomitant Use istration. Intravascular injections should be avoided; aspi-
Avoid concomitant use of Chloroprocaine with any of the ration should be performed prior to administration; the
following: Bupivacaine (Liposomal) needle must be repositioned until no return of blood can
Increased Effect/Toxicity be elicited by aspiration; however, absence of blood in the
Chloroprocaine may increase the levels/effects of: syringe does not guarantee that intravascular injection has
Alpha-/Beta-Agonists; Bupivacaine (Liposomal); Ergot been avoided.
Derivatives; Neuromuscular-Blocking Agents; Phenyl- Monitoring Parameters Blood pressure, heart rate, res-
ephrine (Systemic) piration, signs of CNS toxicity (lightheadedness, dizzi-
ness, tinnitus, restlessness, tremors, twitching,
The levels/effects of Chloroprocaine may be increased
drowsiness, circumoral paresthesia)
by: Hyaluronidase
Product Availability Clorotekal: FDA approved Septem-
Decreased Effect 2
ber 2017; anticipated availability is currently unknown.
Chloroprocaine may decrease the levels/effects of: Sul-
Dosage Forms Excipient information presented when
fonamide Antibiotics; Technetium Tc 99m Tilmanocept
available (limited, particularly for generics); consult spe-
Storage/Stability Store at 20°C to 25°C (68°F to 77°F) in
cific product labeling.
original container; protect from freezing. Protect from light. Solution, Injection, as hydrochloride:
Discard Clorotekal and Nesacaine-MPF following single Nesacaine: 1% (30 mL); 2% (30 mL) [contains disodium
use. Solution in vials may become discolored with pro- edta, methylparaben]
longed exposure to light; do not administer discolored
Solution, Injection, as hydrochloride [preservative free]:
solutions. Crystals of chloroprocaine may develop when Nesacaine-MPF: 2% (20 mL); 3% (20 mL) [methylpar-
exposed to !ow temperatures; when the vial is returned to aben free]
room temperature, the crystals will redissolve with shak- Generic: 2% (20 mL); 3% (20 mL)
ing; do not use solutions that contain undissolved matter.
Do not heat before use; do not autoclave. Use immedi- @ Chloroprocaine Hydrochloride see Chloroprocaine
ately after initial puncture of vial or after ampule opening. on page 422

423
CHLOROQUINE

associated with hemolysis and renal impairment. Use with

Chloroquine (KLOR oh kwin) caution in patients with preexisting auditory damage;
discontinue immediately if hearing defects are noted.
Medication Safety Issues Cases of cardiomyopathy resulting in cardiac failure
International issues: (sometimes fatal) have been reported during long term
Aralen [U.S., Mexico] may be confused with Paralen therapy at high doses. Monitor for signs and symptoms of
brand name for acetaminophen [Czech Republic] cardiomyopathy; discontinue if cardiomyopathy develops.
Brand Names: US Aralen [DSC] Consider chronic toxicity and discontinue chloroquine if
Brand Names: Canada Aralen conduction disorders (bundle branch block/AV block) are
Therapeutic Category Amebicide; Antimalarial Agent diagnosed. QT prolongation, torsades de pointe, and
Generic Availability (US) Yes ventricular arrhythmias (some fatal) have been reported;
Use Suppression (prophylaxis) and treatment of disease risk’ is increased with high doses. Use with caution in
caused by susceptible malaria species (FDA approved in patients with cardiac disease, history of ventricular
pediatric patients [age not specified] and adults); treat- arrhythmias, uncorrected hypokalemia and/or hypomag-
ment of extraintestinal amebiasis (FDA approved in nesemia, or bradycardia, and during concomitant admin-
adults) i istration with QT interval prolonging agents due to
Pregnancy Considerations In animal reproduction stud- potential for QT prolongation. In a scientific statement
ies, drug accumulated in fetal ocular tissues and remained from the American Heart Association, chloroquine has
for several months following drug elimination from the rest been determined to be an agent that may either cause
of the body. Chloroquine and its metabolites cross the direct myocardial toxicity or exacerbate underlying myo-
placenta and. can be detected in the cord blood and urine cardial dysfunction (magnitude: major) (AHA [Page
of the newborn infant (Akintonwa 1988; Essien 1982; Law 2016]). Rare hematologic reactions including agranulocy-
2008). In one study, chloroquine and its metabolites were tosis, aplastic anemia, neutropenia, pancytopenia, and
measurable in the cord blood 89 days (mean) after the last thrombocytopenia; monitor CBC during prolonged ther-
maternal dose (Law 2008). apy. Consider discontinuation if severe blood disorders
Malaria infection in pregnant women may be more severe occur that are unrelated to disease. Acute extrapyramidal
than in nonpregnant women and has a high risk of disorders may occur, usually resolving after discontinua-
maternal and perinatal morbidity and mortality. Therefore, tion of therapy and/or symptomatic treatment. Severe
pregnant women and women who are likely to become hypoglycemia, including loss of consciousness, has been
pregnant are advised to avoid travel to malaria-risk areas. reported in patients treated with or without antidiabetic
Chloroquine is recommended for the treatment of preg- agents. Counsel patients about risk of hypoglycemia and
nant women for uncomplicated malaria in chloroquine- associated signs and symptoms. Skeletal muscle myopa-
sensitive regions; when caused by chloroquine-sensitive thy or neuromyopathy, leading to progressive weakness
P. vivax or P. ovale, pregnant women should be main- and atrophy of proximal muscle groups have been
tained on chloroquine prophylaxis for the duration of their reported; muscle strength (especially proximal muscles)
pregnancy (refer to current guidelines) (CDC 2013). should be assessed periodically during prolonged therapy;
Breastfeeding Considerations Chloroquine and its discontinue therapy if weakness occurs. Potentially sig-
metabolite can be detected in breast milk. Per product nificant drug-drug interactions may exist, requiring dose or
labeling, 11 lactating women with malaria were given a frequency adjustment, additional monitoring, and/or selec-
single oral dose of chloroquine 600 mg. The maximum tion of alternative therapy.
daily dose to the breastfeeding infant was calculated to be Although the manufacturer’s labeling recommends chlor-
0.7% of the maternal dose. Additional information has oquine be used with caution in patients with G6PD defi-
been published and results are variable. In one study, ciency due to a potential for hemolytic anemia, there is
the relative dose to the nursing infant was calculated to limited data to support this risk. Many experts consider
be 2.3% (chloroquine) and 1%: (metabolite) of the weight- chloroquine, when given in usual therapeutic doses to
adjusted maternal dose with the samples obtained a WHO Class || and Ill G6PD deficient patients, to probably
median of 17 days after the last dose. Women in this
be safe (Cappellini 2008; Glader 2017; Luzzatto 2016;
study received chloroquine phosphate 750 mg daily for 3
Youngster 2010). Safety in Class | G6PD deficiency (ie,
days. This report also provides data from other studies,
severe form of the deficiency associated with chronic
listing relative infant doses of chloroquine ranging from
hemolytic anemia) is generally unknown (Glader 2017).
0.9% to 9.5% of the maternal dose (Law 2008). Due to the
In a trial conducted in West Africa involving 74 G6PD
potential for serious adverse reactions in the nursing
deficient patients (predominantly Class Ill deficiency),
infant, the manufacturer recommends a decision be made
there were no cases of hemolysis reported following
whether to discontinue nursing or to discontinue the drug,
exposure to usual doses of chloroquine (Mandi 2005). In
taking into account the importance of treatment to the
addition, the ACR Rheumatology guidelines do not men-
mother. Other sources consider the amount of chloroquine
tion the need to evaluate G6PD levels prior to initiation of
exposure to the nursing infant to be safe when normal
therapy (Singh 2015).
maternal doses for malaria are used. However, the
amount of chloroquine obtained by a nursing infant from Chloroquine is not effective against chloroquine- or
breast milk would not provide adequate protection if hydroxychloroquine-resistant strains of Plasmodium spe-
therapy for malaria in the infant is needed (CDC 2018). cies. Chloroquine resistance is widespread in P. falcipa-
Contraindications Hypersensitivity to chloroquine, 4- rum and is reported in P. vivax. Prior to initiation of
aminoquinoline compounds, or any component of the chloroquine for prophylaxis, it should be determined if
formulation; the presence of retinal or visual field changes chloroquine is appropriate for use in the region to be
of any etiology (when used for indications other than acute visited; do not use for malaria prophylaxis in areas where
malaria) chloroquine resistance occurs. Patients should be treated
Warnings/Precautions Retinal toxicity, potentially caus- with another antimalarial if patient is infected with a
ing irreversible retinopathy, is predominantly associated resistant strain of plasmodia. Chloroquine does not pre-
with high daily doses and a duration of >5 years of use of vent relapses in patients with vivax or malariae ovale
chloroquine or hydroxychloroquine. Other major risk fac- malaria (not effective against exoerythrocytic forms); addi-
tors include concurrent tamoxifen use, renal impairment, tional treatment with an antimalarial effective against
lower body weight, and potentially the presence of mac- these forms (eg, an 8-aminoquinoline) is required for the
ular disease. Risk is most accurately assessed on the treatment of infections with P. vivax and P. ovale; will not
basis of duration of use relative to daily dose/body weight prevent vivax or malariae infection when administered as
(Marmor [AAO 2016]; Melles 2014). Based on these risks, a prophylactic. Also consult current CDC guidelines for
the American Academy of Ophthalmology (AAO) recom- treatment recommendations. Do not use for the treatment
mends not exceeding a daily chloroquine phosphate dos- of complicated malaria (high-grade parasitemia and/or
age of 2.3 mg/kg using actual body weight. Previous complications [eg, cerebral malaria, acute renal failure]).
recommendations to use ideal body weight are no longer Adverse Reactions
advised; very thin patients in particular were at increased
Cardiovascular: Atrioventricular block, bundle branch
risk for retinal toxicity using this practice. Current AAO
block, cardiac arrhythmia, cardiomyopathy, ECG
guidelines do not specifically address dosing in obese
changes (including prolonged QRS and QTc intervals,
patients. AAO also recommends baseline screening for
T-wave inversion, or depression), hypotension, torsades
retinal toxicity and annual screening beginning after 5
de pointes, ventricular fibrillation, ventricular tachycardia
years of use (or sooner if major risk factors are present)
Central nervous system: Agitation, anxiety, confusion,
(Marmor [AAO 2016)}).
decreased deep tendon reflex, delirium, depression,
Use with caution in patients with hepatic impairment, extrapyramidal reaction (dystonia, dyskinesia, protrusion
alcoholism or in conjunction with hepatotoxic drugs. May of the tongue, torticollis), hallucination, headache,
exacerbate psoriasis or porphyria. Use caution in patients insomnia, motor dysfunction (sensorimotor disorder),
with seizure disorders. Use caution in G6PD deficiency; 4- personality changes, polyneuropathy, psychosis, seiz-
aminoquinolines such as chloroquine has been ure, suicidal tendencies

424
 CHLOROQUINE

Dermatologic: Alopecia, bleaching of hair, blue gray skin Metabolism: Partially hepatic to main metabolite, desethyl-
pigmentation, erythema multiforme, exacerbation of chloroquine
psoriasis, exfoliative dermatitis, lichen planus, pleomor- Half-life: 3-5 days
phic rash, pruritus, skin photosensitivity, Stevens-John- Time to peak serum concentration: Oral: Within 1-2 hours
son syndrome, toxic epidermal necrolysis, urticaria Excretion: Urine (~70%; ~35% as unchanged drug); acid-
Endocrine & metabolic: Hypoglycemia ification of urine increases elimination; small amounts of
Gastrointestinal: Abdominal cramps, anorexia, diarrhea, drug may be present in urine months following discontin-
nausea, vomiting uation of therapy
Hematologic & oncologic: Agranulocytosis (reversible), Dosing
aplastic anemia, hemolytic anemia (in G6PD-deficient Pediatric
patients), neutropenia, pancytopenia, thrombocytopenia Note: Dosage expressed as chloroquine phosphate.
Hepatic: Hepatitis, increased liver enzymes Chloroquine phosphate 16.6 mg is equivalent to 10 mg
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, chloroquine base.
angioedema Malaria:
Immunologic: DRESS syndrome Chemoprophylaxis: Infants, Children, and Adoles-
Neuromuscular & skeletal: Myopathy, neuromuscular dis- cents: Oral: 8.3 mg/kg chloroquine phosphate once
ease, proximal myopathy weekly on the same day each week; maximum
Ophthalmic: Accommodation disturbances, blurred vision, dose: 500 mg chloroquine phosphate/dose. Begin
corneal opacity (reversible), macular degeneration (may 1 to 2 weeks prior to exposure; continue while in
be irreversible), maculopathy (may be irreversible), noc- endemic area and continue for at least 4 weeks after
turnal amblyopia, retinopathy (including irreversible leaving endemic area (CDC 2014); if suppressive
changes in some patients’ long-term or high-dose ther- therapy is delayed, double the initial loading dose
apy), transient scotomata, visual field defects (16.6 mg/kg, up to 1,000 mg chloroquine phos-
‘Otic: Deafness (nerve), hearing loss (risk increased in phate) and administer in 2 divided doses 6 hours
patients with preexisting auditory damage), tinnitus apart; continue for 8 weeks after leaving
Drug Interactions endemic area
Metabolism/Transport Effects Substrate of CYP2D6 Treatment, acute attack, uncomplicated: Infants, Chil-
(major), CYP3A4 (major); Note: Assignment of Major/ dren, and Adolescents: Oral: Initial 16.6 mg/kg
Minor substrate status based on clinically relevant drug chloroquine phosphate (maximum initial dose:
interaction potential : 1,000 mg chloroquine phosphate); followed by
Avoid Concomitant Use 8.3 mg/kg chloroquine phosphate (maximum dose:
Avoid concomitant use of Chloroquine with any of the 500 mg chloroquine phosphate/dose) administered
following: Agalsidase Alfa; Agalsidase Beta; Artemether; at 6, 24, and 48 hours after initial dose for a total of4
Conivaptan; Fusidic Acid (Systemic); Hydroxychloro- doses (CDC 2013)
Extraintestinal amebiasis, liver abscess: Children
quine; Idelalisib; Lumefantrine; Macimorelin; Mefloquine;
and Adolescents: Limited data available: Oral:
MiFEPRIStone; Probucol; Promazine; QTc-Prolonging
16.6 mg/kg chloroquine phosphate/dose once daily
Agents (Highest Risk); Vinflunine
in combination with metronidazole or tinidazole for
Increased Effect/Toxicity
21 days followed by paromomycin or iodoquinol:;
Chloroquine may increase the levels/effects of: Antipsy-
maximum dose: 1,000 mg chloroquine phosphate/
chotic Agents (Phenothiazines); Beta-Blockers; Cardiac
dose (Bradley 2015; Seidel 1984; Tony 1992)
Glycosides; Dapsone (Systemic); Dapsone (Topical);
Renal Impairment: Pediatric There are:no dosage
Hypoglycemia-Associated Agents; Lumefantrine; Meflo-
adjustments provided in the manufacturer’s labeling; in
quine; Perhexiline; Prilocaine; Primaquine; QTc-Prolong-
adult patients, dosage adjustment suggested.
ing Agents (Highest Risk); QTc-Prolonging Agents
Hepatic Impairment: Pediatric There are no dosage
(Moderate Risk); Sodium Nitrite
adjustments provided in the manufacturer's labeling; use
The levels/effects of Chloroquine may be increased by: with caution.
Abiraterone Acetate; Androgens; Antidiabetic Agents; Administration Oral: Administer with meals to decrease
Aprepitant; Artemether; Asunaprevir; Cimetidine; Coni- GI upset; chloroquine phosphate tablets have also been
vaptan; CYP2D6 Inhibitors (Moderate); CYP2D6 Inhib- mixed with chocolate syrup or enclosed in gelatin capsu-
itors (Strong); CYP3A4 Inhibitors (Moderate); CYP3A4 les to mask the bitter taste
Inhibitors (Strong); Dapsone (Systemic); Fosaprepitant; Monitoring Parameters Periodic CBC, examination for
Fosnetupitant; Fusidic Acid (Systemic); Herbs (Hypogly- muscular weakness, and ophthalmologic examination
cemic Properties); Hydroxychloroquine; Idelalisib; Imati- (visual acuity, slit-lamp, fundoscopic, and visual field tests)
nib; Macimorelin; Mefloquine; MiFEPRIStone; in patients receiving prolonged therapy
Monoamine Oxidase Inhibitors; Netupitant; Nitric Oxide; Dosage Forms Excipient information presented when
Palbociclib; Panobinostat; Peginterferon Alfa-2b; Pegvi- available (limited, particularly for generics); consult spe-
somant; Perhexiline; Probucol; Promazine; Prothiona- cific product labeling. [DSC] = Discontinued product
mide; QTc-Prolonging Agents (Indeterminate Risk and Tablet, Oral, as phosphate:
Risk Modifying); Quinolones; Salicylates; Selective Sero- Aralen: 500 mg [equivalent to chloroquine base
tonin Reuptake Inhibitors; Simeprevir; Stiripentol; 300 mg] [DSC]
Tamoxifen; Tetracaine (Topical); Vinflunine; Xipamide Generic: 250 mg [equivalent to chloroquine base
Decreased Effect 150 mg], 500 mg [equivalent to chloroquine base
Chloroquine may decrease the levels/effects of: Agalsi- 300 mg]
dase Alfa; Agalsidase Beta; Ampicillin; Bacampicillin; Extemporaneous Preparations
Praziquantel; Rabies Vaccine 16.67 mg chloroquine PHOSPHATE/mL (equivalent to
10 mg chloroquine BASE/mL) Oral Suspension
The levels/effects of Chloroquine may be decreased by: (ASHP Standard Concentration) (ASHP 2017)
Antacids; Bosentan; CYP3A4 Inducers (Moderate); A 16.67 mg chloroquine PHOSPHATE/mL oral suspen-
CYP3A4 Inducers (Strong); Dabrafenib; Deferasirox; sion (equivalent to 10 mg chloroquine BASE/mL) may be
Enzalutamide; Kaolin; Lanthanum; Mitotane; Peginter- made from tablets. Crush two 500 mg chloroquine
feron Alfa-2b; Pitolisant; Quinolones; Sarilumab; Siltux- PHOSPHATE tablets (equivalent to 300 mg BASE/tab-
imab; St John's Wort; Tocilizumab let) in a mortar and reduce to a fine powder. Add a small
Storage/Stability Store at 25°C (77°F); excursions are amount of sterile water for irrigation, USP and mix to a
permitted between 15°C and 30°C (59°F and 86°F); uniform paste; mix while adding cherry syrup in incre-
protect from light: : mental proportions to almost 60 mL; transfer to a
Mechanism of Action Binds to and inhibits DNA and calibrated amber glass bottle, rinse mortar with cherry
RNA polymerase; interferes with metabolism and hemo- syrup, and add sufficient quantity of cherry syrup to
globin utilization by parasites; inhibits prostaglandin make 60 mL. Label "shake well." Stable for 4 weeks
effects; chloroquine concentrates within parasite acid when stored at room temperature or refrigerated (Mir-
vesicles and raises internal pH resulting in inhibition of ochnick 1994).
parasite growth; may involve aggregates of ferriprotopor- Mirochnick M, Barnett E, Clark DF, McNamara E, Cabral H. Stability of
phyrin IX acting as chloroquine receptors causing mem- chloroquine in an extemporaneously prepared suspension stored at
brane damage; may also interfere with nucleoprotein three temperatures. Pediatr Infect Dis J. 1994;13(9):827-828.
synthesis 15 mg chloroquine PHOSPHATE/mL (equivalent to
Pharmacodynamics/Kinetics (Adult data unless 9 mg chloroquine BASE/mL) Oral Suspension
noted) A 15 mg chloroquine PHOSPHATE/mL oral suspension
Absorption: Rapid and almost complete (equivalent to 9 mg chloroquine BASE/mL) may be
Distribution: Widely in body tissues including eyes, heart, made from tablets and a 1:1 mixture of Ora-Sweet and
kidneys, liver, leukocytes, and lungs where retention is Ora-Plus. Crush three 500 mg chloroquine PHOS-
prolonged PHATE tablets (equivalent to 300 mg BASE/tablet) in a
Protein binding: ~55% mortar and reduce to a fine powder. Add 15 mL of the »
425
 CHLOROQUINE

4 vehicle and mix to a uniform paste; mix while adding the

vehicle in incremental proportions to almost 100 mL;
hypochloremic alkalosis, hyponatremia, hypomagnese-
mia) can occur. Use with caution in severe hepatic dys-
transfer to a calibrated bottle, rinse mortar with vehicle, function; hepatic encephalopathy can be caused by
and add quantity of vehicle sufficient to make 100 mL. electrolyte disturbances. Gout can be precipitate in certain
Label "shake well before using" and "protect from light". patients with a history of gout, a familial predisposition to
Stable for up to 60 days when stored in the dark at room gout, or chronic renal failure. Use caution in patients with
temperature or refrigerated (preferred). diabetes; may see a change in glucose control. Can cause
Allen LV Jr, Erickson MA 3rd. Stability of Alprazolam, Chloroquine SLE exacerbation or activation. Use with caution in
Phosphate, Cisapride, Enalapril Maleate, and Hydralazine Hydro-
chloride in Extemporaneously Compounded Oral Liquids. Am J
patients with moderate or high cholesterol concentrations.
Health Syst Pharm. 1998;55(18):1915-1920. Photosensitization may occur. Correct hypokalemia
before initiating therapy. Thiazide diuretics may decrease
@ Chloroquine Phosphate see Chloroquine on page 424 renal calcium excretion; consider avoiding use in patients
with hypercalcemia. Concomitant ethanol use may
Chlorothiazide (klor oh THYE a zide) increase the risk of orthostatic hypotension. If given the
morning of surgery, chlorothiazide may render the patient
Medication Safety Issues volume depleted and blood pressure may be labile during
Geriatric Patients: High-Risk Medication: general anesthesia. Avoid use of diuretics for treatment of
Beers Criteria: Diuretics (chlorothiazide) are identified in elevated blood pressure in patients with primary adrenal
the Beers Criteria as potentially inappropriate medica- insufficiency (Addison disease). Adjustment of glucocorti-
tions to be used with caution in patients 65 years and coid/mineralocorticoid therapy and/or use of other antihy-
older due to the potential to cause or exacerbate pertensive agents is preferred to treat hypertension
syndrome of inappropriate antidiuretic hormone secre- (Bornstein 2016; Inder 2015).
tion (SIADH) or hyponatremia; monitor sodium concen-
tration closely when initiating or adjusting the dose in Benzyl alcohol and derivatives: Some dosage forms may
older adults (Beers Criteria [AGS 2015]). contain sodium benzoate/benzoic acid; benzoic acid (ben-
International issues: Zoate) is a metabolite of benzyl alcohol; large amounts of
Diuril [US] may be confused with Duorol brand name for benzyl! alcohol (299 mg/kg/day) have been associated
acetaminophen [Spain] with a potentially fatal toxicity ("gasping syndrome”) in
Brand Names: US _Diuril; Sodium Diuril neonates; the "gasping syndrome" consists of metabolic
Therapeutic Category Antihypertensive Agent; Diuretic, acidosis, respiratory distress, gasping respirations, CNS
Thiazide dysfunction (including convulsions, intracranial hemor-
Generic Availability (US) May be product dependent rhage), hypotension, and cardiovascular collapse (AAP
Use ["Inactive" 1997]; CDC, 1982); some data suggests that
Oral: Suspension, tablets: Treatment of edema due to benzoate displaces bilirubin from protein binding sites
heart failure, hepatic cirrhosis, and estrogen or cortico- (Ahlfors, 2001); avoid or use dosage forms containing
steroid therapy (FDA approved in infants, children, and benzyl alcohol derivative with caution in neonates. See
adults); treatment of various forms of renal dysfunction, manufacturer's labeling.
including nephrotic syndrome, acute glomerulonephritis,
Sulfonamide ("sulfa") allergy: The FDA-approved product
and chronic renal failure (FDA approved in infants,
labeling for many medications containing a sulfonamide
children, and adults); management of hypertension
either alone or in combination with other antihyperten- chemical group includes a broad contraindication in
sive agents (FDA approved in infants, children, and patients with a prior allergic reaction to sulfonamides.
adults); has also been used for bronchopulmonary dys- There is a potential for cross-reactivity between members
plasia (BPD) and central diabetes insipidus of infancy; of a specific class (eg, two antibiotic sulfonamides). How-
Note: Use in pregnancy should be reserved for those ever, concerns for cross-reactivity have previously
cases causing extreme discomfort and unrelieved by extended to all compounds containing the sulfonamide
rest; should not be routinely used during pregnancy structure (SO2NH2). An expanded understanding of aller-
Parenteral: Treatment of edema due to heart failure, gic mechanisms indicates cross-reactivity between anti-
hepatic cirrhosis, and estrogen or corticosteroid therapy biotic sulfonamides and nonantibiotic sulfonamides may
(FDA approved in adults); treatment of various forms of not occur or at the very least this potential is extremely low
renal dysfunction including nephrotic syndrome, acute (Brackett 2004; Johnson 2005; Slatore 2004; Tornero
glomerulonephritis, and chronic renal failure (FDA 2004). In particular, mechanisms of cross-reaction due
approved in adults); has also been used for bronchopul- to antibody production (anaphylaxis) are unlikely to occur
monary dysplasia (BPD); Note: Use in pregnancy should with nonantibiotic sulfonamides. T-cell-mediated (type IV)
be reserved for those cases causing extreme discomfort reactions (eg, maculopapular rash) are less well under-
and unrelieved by rest; should not be routinely used stood and it is not possible to completely exclude this
during pregnancy potential based on current insights. In cases where prior
Pregnancy Risk Factor C reactions were severe (Stevens-Johnson syndrome/TEN),
Pregnancy Considerations Adverse events were not some clinicians choose to avoid exposure to these
observed in animal reproduction studies; however, studies classes.
were not complete. Chlorothiazide crosses the placenta Adverse Reactions
and is found in cord blood. Maternal use may cause may Cardiovascular: Hypotension, necrotizing angiitis, ortho-
cause fetal or neonatal jaundice, thrombocytopenia, or static hypotension
other adverse events observed in adults. Use of thiazide Central nervous system: Dizziness, headache, paresthe-
diuretics to treat edema during normal pregnancies is not sia, restlessness, vertigo
appropriate; use may be considered when edema is due Dermatologic: Alopecia, erythema multiforme, exfoliative
to pathologic causes (as in the nonpregnant patient); dermatitis, skin photosensitivity, skin rash, Stevens-
monitor. Untreated chronic maternal hypertension is asso- Johnson syndrome, toxic epidermal necrolysis, urticaria
ciated with adverse events in the fetus, infant, and mother
Endocrine & metabolic: Glycosuria, hypercalcemia, hyper-
(ACOG, 2013). Women who required thiazide diuretics for
glycemia, hyperuricemia, hypochloremic alkalosis, hypo-
the treatment of hypertension prior to pregnancy may
kalemia, hypomagnesemia, hyponatremia, increased
continue their use (ACOG, 2013).
serum cholesterol, increased serum triglycerides
Breastfeeding Considerations Chlorothiazide is
Gastrointestinal: Abdominal cramps, anorexia, constipa-
present in breast milk. Due to the potential for serious
tion, diarrhea, gastric irritation, nausea, pancreatitis,
adverse reactions in the breastfeeding infant, the manu-
sialadenitis, vomiting
facturer recommends a decision be made whether to
discontinue breastfeeding or to discontinue the drug, Genitourinary: Hematuria (IV), impotence
taking into account the importance of treatment to the Hematologic & oncologic: Agranulocytosis, aplastic ane-
mother. Diuretics have the potential to decrease milk mia, hemolytic anemia, leukopenia, purpura, thrombocy-
volume and suppress lactation. topenia
Contraindications Hypersensitivity to chlorothiazide, any Hepatic: Jaundice
component of the formulation or sulfonamide-derived Hypersensitivity: Anaphylaxis
drugs; anuria Neuromuscular & skeletal: Muscle spasm, systemic lupus
Note: Although the FDA approved product labeling states erythematosus, weakness
this medication is contraindicated with other sulfona- Ophthalmic: Blurred vision, xanthopsia
mide-containing drug classes, the scientific basis of this Renal: Interstitial nephritis, renal failure, renal insufficiency
statement has been challenged. See "Warnings/Precau- Respiratory: Pneumonitis, pulmonary edema, respiratory
tions" for more detail. distress
Warnings/Precautions Hypersensitivity reactions may Miscellaneous: Fever
occur. Use with caution in severe renal disease. Electro- Drug Interactions
lyte disturbances (hypercalcemia, hypokalemia, Metabolism/Transport Effects None known.

426
 CHLOROTHIAZIDE

Avoid Concomitant Use Pediatric

Avoid concomitant use of Chlorothiazide with any of the Note: Although the manufacturer states that IV and oral
following: Aminolevulinic Acid (Systemic); Bromperidol; dosing are equivalent; some clinicians use lower IV
Dofetilide; Levosulpiride; Mecamylamine; Promazine doses due to the poor oral absorption.
Increased Effect/Toxicity Edema (diuresis), heart failure, hypertension:
Chlorothiazide may increase the levels/effects of: Ajma- Infants, Children, and Adolescents:
line; Allopurinol; Amifostine; Aminolevulinic Acid (Sys- Oral: 10 to 40 mg/kg/day in 1 or 2 divided doses (AAP
temic); Aminolevulinic Acid (Topical); Angiotensin- [Flynn 2017]; Hobbins 1981; Stewart 2011)
Converting Enzyme Inhibitors; Antipsychotic Agents
Maximum daily doses:
(Second Generation [Atypical]); Bromperidol; Calcium
Infants and Children <2 years: 375 mg/day
Salts; CarBAMazepine; Cardiac Glycosides; Cyclophos-
phamide; Diazoxide; Dofetilide; DULoxetine; Hypoten-
Children 22 years: 1,000 mg/day
sion-Associated Agents; lvabradine; Levodopa; Adolescents: 2,000 mg/day
Levosulpiride; Lithium; Mecamylamine; Multivitamins/ IV: Limited data available: 5 to 10 mg/kg/day in div-
Minerals (with ADEK, Folate, Iron); Multivitamins/Miner- ided doses once or twice daily (Costello 2007); in
als (with AE, No Iron); Neuromuscular-Blocking Agents some cases, doses up to 20 mg/kg/day have been
(Nondepolarizing); Nitroprusside; Nonsteroidal Anti- used; maximum dose: 500 mg/dose (Moffett 2017)
Inflammatory Agents; OXcarbazepine; Pholcodine; Por- Diabetes insipidus (central): Limited data available:
fimer; Promazine; Sodium Phosphates; Topiramate; Tor- Infants: Oral: Initial: 10 mg/kg/day in 2 divided doses;
emifene; Verteporfin; Vitamin D Analogs may need to titrate dose to target urine osmolality:
100 to 150 mOsm/L; an effective dosing range of 5 to
The levels/effects of Chlorothiazide may be increased
by: Alcohol (Ethyl); Alfuzosin; Anticholinergic Agents; 10 mg/kg/dose twice, or three times daily has been
_ Barbiturates; Benperidol; Beta2-Agonists; Brigatinib; Bri- suggested (Al Nofal 2015; Rivkees 2007; Sperl-
monidine (Topical); Corticosteroids (Orally Inhaled); Cor- ing 2014)
ticosteroids (Systemic); Dexketoprofen; Diacerein; Renal Impairment: Pediatric Infants, Children, and
Diazoxide; Herbs (Hypotensive Properties); |pragliflozin; Adolescents: CrCl <10 mL/minute: Avoid use. Ineffective
Licorice; Lormetazepam; Molsidomine; Multivitamins/ with CrCl <30 mL/minute unless in combination with a
Fluoride (with ADE); Naftopidil; Nicergoline; Nicorandil; loop diuretic (Aronoff 2007).
Obinutuzumab; Opioid Analgesics; Pentoxifylline; Phos- Hepatic Impairment: Pediatric There are no dosage
phodiesterase 5 Inhibitors; Prostacyclin Analogues; Qui- adjustments provided in manufacturer’s labeling; use
nagolide; Reboxetine; Selective Serotonin Reuptake with caution.
Inhibitors
Preparation for Administration Parenteral: Reconsti-
Decreased Effect tute with 18 mL SWFI to provide a concentration of
Chlorothiazide may decrease the levels/effects of: Anti-
28 mg/mL. May be further diluted with dextrose or sodium
diabetic Agents
chloride solutions.
The levels/effects of Chlorothiazide may be decreased Administration
by: Amphetamines; Bile Acid Sequestrants; Brigatinib; Oral: Administer with food; administer early in day to avoid
Bromperidol; Herbs (Hypertensive Properties); Methyl- nocturia; if multiple daily dosing, the last dose should not
phenidate; Nonsteroidal Anti-Inflammatory Agents; be administered later than 6:00 pm unless instructed
Opioid Analgesics; Yohimbine otherwise. Shake suspension well before use.
Food Interactions Chlorothiazide serum levels may be Parenteral: Administer by direct IV infusion over 3 to 5
increased if taken with food. Management: Administer
minutes or further dilute and infuse over 30 minutes.
without regard to food.
Avoid extravasation of parenteral solution since it is
Storage/Stability
extremely irritating to tissues. Do not administer via IM
Powder for injection: Prior to reconstitution, store between
or SubQ route.
2°C to 25°C (36°F to 77°F). The manufacturer's labeling
recommends any unused reconstituted solution be dis- Monitoring Parameters Serum electrolytes, BUN, crea-
carded. Precipitation will occur in <24 hours in pH <7.4. tinine, blood pressure, fluid balance, body weight
Suspension, tablets: Store at room temperature 15°C to Test Interactions May interfere with tests for parathyroid
30°C (59°F to 86°F). Protect from freezing. function; may lead to false-negative aldosterone/renin
Mechanism of Action Inhibits sodium and chloride reab- ratio (ARR) (Funder 2016)
sorption in the distal tubules causing increased excretion Dosage Forms Excipient information presented when
of sodium, chloride, and water resulting in diuresis. Loss of available (limited, particularly for generics); consult spe-
potassium, hydrogen ions, magnesium, phosphate, and cific product labeling.
bicarbonate also occurs. Solution Reconstituted, Intravenous, as sodium [strength
Pharmacodynamics/Kinetics (Adult data unless expressed as base]:
noted) , : : Sodium Diuril: 500 mg (1 ea)
Onset of action: Diuresis: Oral: Within 2 hours; IV: 15 Generic: 500 mg (1 ea)
minutes Solution Reconstituted, Intravenous, as sodium [strength
Peak effect: Oral: ~4 hours; IV: 30 minutes expressed as base, preservative free]:
Duration of diuretic action: Oral: ~6 to 12 hours; IV: 2
Generic: 500 mg (1 ea)
hours
Suspension, Oral:
Absorption: Oral: Poor
Diuril: 250 mg/5 mL (237 mL) [contains alcohol, usp,
Metabolism: Not metabolized
Bioavailability: 9% to 56%; dose-dependent benzoic acid, fd&c yellow #10 (quinoline yellow), meth-
Half-life elimination: 45 to 120 minutes ylparaben, propylparaben, saccharin sodium]
Excretion: Urine (10% to 15% [oral], 96% [IV] as Tablet, Oral:
unchanged drug) Generic: 250 mg, 500 mg
Dosing Extemporaneous Preparations A 50 mg/mL oral sus-
Neonatal pension may be made with tablets. Crush ten 500 mg
Edema, heart failure, bronchopulmonary dysplasia: chlorothiazide tablets in a mortar and reduce to a fine
Limited data available; Note: Although the manufac- powder; mix with a small amount of glycerin to form a
turer states that IV and oral dosing are equivalent, uniform paste. Add 2 g carboxymethylcellulose gel (mix
some clinicians use lower IV doses due to poor oral 2 g carboxymethylcellulose with 5 to 10 mL water to form
absorption. t ~ a paste; add 40 mL water and heat to 60°C with moderate
Oral: 10 to 40 mg/kg/day in 2 divided doses (Hobbins stirring until dissolution occurs; cool and allow to stand for
1981; Stewart 2011) 5 1 to 2 hours to form a clear gel). Dissolve 500 mg citric
IV: 5 to 10 mg/kg/day in 2 divided doses (Costello acid in 5 mL water and add to chlorothiazide carboxyme-
2007; Eichenwald 2017); doses up to 20 mg/kg/day
thylcellulose mixture with 0.1% parabens. Add a quantity
have been used (Moffett 2017)
of purified water sufficient to make 100 mL (Nahata,
Hyperinsulinemia hypoglycemia, congenital hyper-
2004). Label "shake well" and "refrigerate". Stable for 30
insulinism (adjunct therapy): Limited data available:
Oral: 7 to 10 mg/kg/day in 2 divided doses in combi- days.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th
nation with diazoxide (Aynsley-Green 2000; Hussain
ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
2004; Kapoor 2009)
Diabetes insipidus (central): Limited data available: @ Chlorothiazide Sodium see Chlorothiazide
Oral: Initial: 10 mg/kg/day in 2 divided doses; may need on page 426
to titrate doseto target urine osmolality: 100 to 150
@ Chlorphen [OTC] [DSC] see Chlorpheniramine
mOsm/L; an effective dosing range of 5 to 10 mg/kg/
dose twice or three times daily has been suggested (Al on page 428
Nofal 2015; Rivkees 2007; Sperling 2014) @ Chlorphenamine see Chlorpheniramine on page 428

427
CHLORPHENIRAMINE

hemorrhage), hypotension, and cardiovascular collapse

Chlorpheniramine (kior fen iR a meen) (AAP ["Inactive" 1997]; CDC, 1982); some data suggests
that benzoate displaces bilirubin from protein binding sites
Medication Safety Issues (Ahlfors, 2001); aveid or use dosage forms containing
Sound-alike/look-alike issues: benzyl alcohol derivative with caution in neonates,’ See
Chlor-Trimeton may be confused with Chloromycetin manufacturer’s labeling.
Geriatric Patients: High-Risk Medication: Warnings: Additional Pediatric Considerations
Beers Criteria: Chlorpheniramine, a first-generation anti- Safety and efficacy for the use of cough and cold products
histamine, is identified in the Beers Criteria as a poten- in pediatric patients <4 years of age is limited; the AAP
tially inappropriate medication to be avoided in patients warns against the use of these products for respiratory
65 years and older (independent of diagnosis or con- illnesses in this age group. Serious adverse effects includ-
dition) because of its potent anticholinergic properties ing death have been reported. Many of these products
resulting in increased risk of confusion, dry mouth, contain multiple active ingredients, increasing the risk of
constipation, and other anticholinergic effects or tox- accidental overdose when used with other products. The
icity; use should also be avoided because of reduced FDA notes that there are no approved OTC uses for these
clearance with advanced agevand tolerance associated products in pediatric patients <2 years of age. Health care
with use as a hypnotic (Beers Criteria [AGS 2015)). providers are reminded to ask caregivers about the use of
Pharmacy Quality Alliance (PQA): Chlorpheniramine, as OTC cough and cold products in order to avoid exposure
a single agent or as part of a combination (excludes to multiple medications containing the same ingredient
OTC products), is identified as a high-risk medication in (AAP 2012; FDA 2008).
patients 65 years and older on the PQA's Use of High-
Risk Medications in the Elderly (HRM) performance Some dosage forms may contain propylene glycol; in
measure, a safety measure used by the Centers for neonates large amounts of propylene glycol delivered
Medicare and Medicaid Services (CMS) for Medicare orally, intravenously (eg, >3,000 mg/day), or topically
plans. have been associated with potentially fatal toxicities which
can include metabolic acidosis, seizures, renal failure, and
Related Information
CNS depression; toxicities have also been reported in
Oral Medications That Should Not Be Crushed or Altered
children and adults including hyperosmolality, lactic acido-
on page 2217
sis, seizures and respiratory depression; use caution
Brand Names: US Aller-Chlor [OTC]; Allergy-Time
(AAP. 1997; Shehab 2009).
[OTC]; Chlor-Trimeton Allergy [OTC]; Chlor-Trimeton
Adverse Reactions
[OTC]; Chlorphen [OTC] [DSC]; Ed Chlorped Jr [OTC];
Central nervous system: Dizziness, drowsiness (slight to
Ed ChlorPed [OTC]; Ed-Chlortan [OTC] [DSC]; Pharbech-
moderate), excitability, fatigue, headache, nervousness
lor [OTC]
Endocrine & metabolic: Weight gain
Brand Names: Canada Chlor-Tripolon®; Novo-Pheniram
Gastrointestinal: Abdominal pain, diarrhea, increased
Therapeutic Category Antihistamine appetite, nausea, xerostomia
Generic Availability (US) May be product dependent Genitourinary: Urinary retention
Use Perennial and seasonal allergic rhinitis and other Neuromuscular & skeletal: Arthralgia, weakness
allergic symptoms including urticaria (OTC products: Ophthalmic: Diplopia
Liquid: FDA approved in ages 22 years and adults); Renal: Polyuria
tablets [immediate release]: FDA approved in ages 26 Respiratory: Pharyngitis, thickening of bronchial secre-
years and adults; tablets [extended release: 12 hours]: tions
FDA approved in ages 212 years and adults); Note: Drug Interactions
Approved uses for generic products may vary; consult Metabolism/Transport Effects Substrate of CYP2D6
labeling for specific information. (major), CYP3A4 (minor); Note: Assignment of Major/
Pregnancy Considerations. Maternal chlorpheniramine Minor substrate status based on clinically relevant drug
use has generally not resulted in an increased risk of birth interaction potential
defects (Aselton 1985; Gilboa 2009; Heinonen 1977; Jick Avoid Concomitant Use
1981). Antihistamines may be used for the treatment of Avoid concomitant use of Chlorpheniramine with any of
rhinitis, urticaria, and pruritus with rash in pregnant women the following: Aclidinium; Azelastine (Nasal); Bromper-
(although second generation antihistamines may be pre- idol; Cimetropium; Eluxadoline; Glycopyrrolate (Oral
ferred) (Angier 2010; Murase 2014; Wallace 2008; Inhalation); Ipratropium (Oral Inhalation); Levosulpiride;
Zuberbier 2014). Antihistamines are not recommended Orphenadrine; Oxatomide; Oxomemazine; Paraldehyde;
for treatment of pruritus associated with intrahepatic cho- Potassium Chloride; Potassium Citrate; Thalidomide;
lestasis in pregnancy (Ambros-Rudolph 2011; Kremer Tiotropium; Umeclidinium
2011). Increased Effect/Toxicity
Breastfeeding Considerations Chlorpheniramine is Chlorpheniramine may increase the levels/effects of:
excreted into breast milk. In general, first generation AbobotulinumtoxinA; Alcohol (Ethyl); Amezinium; Anti-
antihistamines should be used with caution in breastfeed- cholinergic Agents; Azelastine (Nasal); Blonanserin;
ing women and nursing infants should be monitored for Buprenorphine; Cimetropium; CNS Depressants; Elux-
irritability or drowsiness. Second generation antihist- adoline; Flunitrazepam; Fosphenytoin-Phenytoin; Gluca-
amines are preferred (Butler 2014). Antihistamines may gon; Glycopyrrolate (Oral Inhalation); HYDROcodone;
temporarily decrease maternal serum prolactin concen- Methotrimeprazine; MetyroSINE; Mirabegron; Mirtaza-
trations when administered prior to the establishment of pine; OnabotulinumtoxinA; Opioid Analgesics; Orphena-
nursing (Messinis 1985). drine; OxyCODONE; Paraldehyde; Perhexiline; Piribedil;
Contraindications Hypersensitivity to chlorpheniramine Potassium Chloride; Potassium Citrate; Pramipexole;
maleate or any component of the formulation; narrow- Ramosetron; RimabotulinumtoxinB; ROPINIRole; Roti-
angle glaucoma; bladder neck obstruction; symptomatic gotine; Selective Serotonin Reuptake Inhibitors; Suvor-
prostate hypertrophy; during acute asthmatic attacks; exant; Thalidomide; Thiazide and Thiazide-Like
stenosing peptic ulcer; pyloroduodenal obstruction. Avoid Diuretics; Thioridazine; Tiotropium; Topiramate; Zolpi-
use in premature and term newborns due to possible dem
association with SIDS.
OTC labeling: When used for self-medication, do not use The levels/effects of Chlorpheniramine may be
to make a child sleep increased by: Abiraterone Acetate; Aclidinium; Ajmaline;
Warnings/Precautions Causes sedation, caution must Amantadine; Asunaprevir; Brimonidine (Topical); Bro-
mopride; Bromperidol; Cannabis; Chloral Betaine; Chlor-
be used in performing tasks that require alertness (eg,
methiazole; Chlorphenesin Carbamate; Cobicistat;
operating machinery, driving). Sedative effects of CNS
depressants or ethanol are potentiated. Use with caution CYP2D6 Inhibitors (Moderate); CYP2D6 Inhibitors
in patients with urinary tract obstruction, symptomatic
(Strong); Darunavir; Dimethindene (Topical); Doxyl-
prostatic hyperplasia, thyroid dysfunction, increased intra-
amine; Dronabinol; Droperidol; HydrOXYzine; Imatinib;
Ipratropium (Oral Inhalation); Kava Kava; Lofexidine;
ocular pressure, and cardiovascular disease (including
Lumefantrine; Magnesium Sulfate; Methotrimeprazine;
hypertension and ischemic heart disease). Antihistamines
Mianserin; Minocycline; Nabilone; Oxatomide; Oxome-
may cause excitation in young children. Not for OTC use
mazine; Panobinostat; Peginterferon Alfa-2b; Perampa-
in children <2 years of age.
nel; Perhexiline; Pramlintide; QuiININE; Rufinamide;
Benzyl alcohol and derivatives: Some dosage forms may Sodium Oxybate; Tapentadol; Tetrahydrocannabinol;
contain sodium benzoate/benzoic acid; benzoic acid (ben- Thioridazine; Trimeprazine; Umeclidinium
zoate) is a metabolite of benzyl alcohol; large amounts of Decreased Effect
benzyl alcohol (299 mg/kg/day) have been associated Chlorpheniramine may decrease the levels/effects of:
with a potentially fatal toxicity ("gasping syndrome") in Acetylcholinesterase Inhibitors; Amifampridine; Benzyl-
neonates; the "gasping syndrome" consists of metabolic penicilloyl Polylysine; Betahistine; Gastrointestinal
acidosis, respiratory distress, gasping respirations, CNS Agents (Prokinetic); Hyaluronidase; Itopride; Levosulpir-
dysfunction (including convulsions, intracranial ide; Nitroglycerin; Pitolisant; Secretin

428
 CHLORPROMAZINE

The levels/effects of Chlorpheniramine may be @ Chlorpheniramine Maleate and Hydrocodone Bitar-

decreased by: Acetylcholinesterase Inhibitors; Amifam- trate see Hydrocodone and Chlorpheniramine
pridine; Amphetamines; Peginterferon Alfa-2b on page 1005
Storage/Stability Protect from light.
Mechanism of Action Competes with histamine for H;- ChlorproMAZINE (klor PROE ma zeen)
receptor sites on effector cells in the gastrointestinal tract,
blood vessels, and respiratory tract Medication Safety Issues
Pharmacodynamics/Kinetics (Adult data unless Sound-alike/look-alike issues:
noted) ChlorproMAZINE may be confused with chlordiazePOX-
Note: Data from chlorpheniramine maleate: IDE, chlorproPAMIDE, clomiPRAMINE, prochlorpera-
Distribution: V4: Children and Adolescents 6 to 16 years: 7 zine, promethazine
+ 2.8 L/kg (Simons 1982); Adults: 6-12 L/kg (Paton 1985) Thorazine may be confused with thiamine, thioridazine
Protein binding: 33% (range: 29% to 37%) (Martinez- Geriatric Patients: High-Risk Medication:
Gomez 2007) Beers Criteria: Antipsychotics are identified in the Beers
Metabolism: Hepatic via CYP450 enzymes (including Criteria as potentially inappropriate medications to be
CYP2D6 and other unidentified enzymes) to active and avoided in patients 65 years and older with dementia
inactive metabolites; significant first-pass effect because of an increased risk of mortality, cerebrovas-
(Sharma 2003) cular accidents (stroke), and a greater rate of cognitive
Half-life elimination: Serum: Children and Adolescents 6 to decline with use; avoid antipsychotics for behavioral
16 years: 13.1 + 6.6 hours (range: 6.3 to 23.1 hours) problems associated with dementia or delirium unless
(Simons, 1982); Adults: 14-24 hours (Paton 1985) alternative nonpharmacologic therapies have failed
Time to peak: Children and Adolescents 6 to 16 years: and patient may harm self or others. Antipsychotics
- Oral: 2.5 + 1.5 hours (range: 1 to 6 hours) (Simons like chlorpromazine may have anticholinergic proper-
1982); Adults: 2-3 hours (Sharma 2003) ties. Use may be appropriate in geriatric patients with
Excretion: Urine (Sharma 2003) schizophrenia, bipolar disorder, or for short-term use as
an antiemetic during chemotherapy. In addition, anti-
Dosing
psychotics should be used with caution in older adults
Pediatric
because of their potential to cause or exacerbate
Allergic symptoms, cube rhinitis: Oral: Chlorphe-
syndrome of inappropriate antidiuretic hormone secre-
niramine maleate:
tion (SIADH) or hyponatremia; monitor sodium closely
Immediate release (oral figuia: tablets):
with initiation or dosage adjustments in older adults
Children 2 to <6 years: 1 mg every 4 to 6 hours;
(Beers Criteria [AGS 2015)).
maximum daily dose: 6 mg/day
Related Information
Children 6 to 11 years: 2 mg every 4 to 6 hours;
Prochlorperazine on page 1686
maximum daily dose: 12 mg/day
Brand Names: Canada Chlorpromazine Hydrochloride
Children 212 years and Adolescents: 4 mg every 4 to
Inj
6 hours; maximum daily dose: 24 mg/day
Therapeutic Category Antiemetic; Antipsychotic Agent,
Extended Release: Children 212 years and Adoles-
Typical, Phenothiazine; First Generation (Typical) Antipsy-
cents: 12 mg every 12 hours; maximum dose:
chotic; Phenothiazine Derivative
24 mg in 24 hours
Generic Availability (US) Yes
Renal Impairment: Pediatric There are no dosage
Use Treatment of nausea and vomiting (FDA approved in
adjustments provided in manufacturer's labeling.
ages 6 months to 12 years and adults), restlessness and
Hepatic Impairment: Pediatric There are no dosage
apprehension prior to surgery (FDA approved in ages 6
adjustments provided in manufacturer's labeling; how-
months to 12 years and adults), severe behavioral prob-
ever, chlorpheniramine is metabolized via the liver;
lems in children displayed by combativeness and/or explo-
therefore, a dose adjustment may be necessary. sive hyperexcitable behavior and in short-term treatment
Administration Oral: May be administered with food or of hyperactive children (FDA approved in ages 1-12
water. Timed release oral forms are to be swallowed years); adjunct in the treatment of tetanus (Parenteral
whole, not crushed or chewed. only: FDA approved in ages 6 months to 12 years and
Test Interactions May suppress the wheal and flare adults); schizophrenia (FDA approved in adults), psy-
reactions to skin test antigens. chotic disorders (FDA approved in adults), mania (FDA
Dosage Forms Excipient information presented when approved in adults), acute intermittent porphyria (FDA
available (limited, particularly for generics); consult spe- approved in adults), intractable hiccups (FDA approved
cific product labeling. [DSC] = Discontinued product in adults); has also been used in management of Tour-
Liquid, Oral, as maleate: ette's syndrome, neonatal abstinence syndrome, and
Ed ChlorPed: 2 mg/mL (60 mL) [contains fd&c red #40, cyclic vomiting syndrome (prevention); management of
propylene glycol, saccharin sodium, sodium benzoate; chemotherapy-induced nausea and vomiting (CINV);
cotton candy flavor] ; treatment of delirium
Syrup, Oral, as maleate: Pregnancy Considerations Embryotoxicity was
Aller-Chlor: 2 mg/5 mL (120 mL [DSC]) [contains alco- observed in animal reproduction studies. Jaundice or
hol, usp, fd&c yellow #6 (sunset yellow), menthol, hyper- or hyporeflexia have been reported in newborn
methylparaben, propylene glycol, propylparaben] infants following maternal use of phenothiazines. Antipsy-
Chlor-Trimeton: 2 mg/5 mL (120 mL) [contains alco- chotic use during the third trimester of pregnancy has a
hol, usp] risk for abnormal muscle movements (extrapyramidal
Ed Chlorped Jr: 2 mg/5 mL (118 mL, 473 mL) [alcohol symptoms [EPS]) and withdrawal symptoms in newborns
free, sugar free; contains fd&c red #40, methylparaben, following delivery. Symptoms in the newborn may include
propylene glycol, propylparaben; cherry flavor] agitation, feeding disorder, hypertonia, hypotonia, respira-
Tablet, Oral, as maleate: tory distress, somnolence, and tremor; these effects may
Aller-Chlor: 4 mg [DSC] [contains fd&c yellow #10 alu- be self-limiting or require hospitalization.
minum lake] Breastfeeding Considerations Chlorpromazine and its
Aller-Chlor: 4 mg [scored; contains fd&c yellow #10 metabolites have been detected in breast milk; concen-
aluminum lake] trations in the milk do not correlate with those in the
Allergy-Time: 4 mg [contains fd&c yellow #10 alumi- mother and may be higher than what is in the maternal
num lake] plasma.
Chlor-Trimeton: 4 mg-[scored] Contraindications Hypersensitivity to phenothiazines
Chlorphen: 4 mg [DSC] [contains fd&c yellow #10 ee (cross-reactivity between phenothiazines may occur);
noline yellow)] | concomitant use with large amounts of CNS depressants
Ed-Chlortan: 4 mg [DSC] [scored; contains fd&c yellow (alcohol, barbiturates, opioids, etc); comatose states
#10 aluminum lake] Warnings/Precautions [US Boxed Warning]: Elderly
Pharbechlor: 4 mg patients with dementia-related psychosis treated with
Generic: 4 mg antipsychotics are at an increased risk of death com-
Tablet Extended Release, Oral, as maleate: pared to placebo. Most deaths appeared to be either
Chlor-Trimeton Allergy: 12 mg [contains fd&c blue #2 cardiovascular (eg, heart failure, sudden death) or infec-
aluminum lake, fd&c yellow #10 aluminum lake, fd&c tious (eg, pneumonia) in nature. Use with caution in
yellow #6 aluminum lake] patients with Lewy body dementia or Parkinson disease
Chlor-Trimeton Allergy: 12 mg [contains fd&c yellow #6 dementia due to greater risk of adverse effects, increased
(sunset yellow), fd&c yellow #6 aluminum lake] sensitivity to extrapyramidal effects, and association with
Generic: 12 mg irreversible cognitive decompensation or death. The APA
recommends giving preference to second generation anti-
¢ Chlorpheniramine Maleate see Chlorpheniramine psychotics over first generation antipsychotics’ such as
on page 428 chlorpromazine in elderly patients with dementia-related >
429
 CHLORPROMAZINE

psychosis due to a potentially greater risk of harm relative dose or frequency adjustment, additional monitoring, and/
EE,
to second generation antipsychotics (APA [Reus 2016)]). or selection of alternative therapy.
Chlorpromazine is not approved for the treatment of
When discontinuing antipsychotic therapy, the American
dementia-related psychosis. Use with caution in
Psychiatric Association (APA), Canadian Psychiatric
patients with predisposition to seizures, severe cardiac
Association (CPA), and World Federation of Societies of
disease, or hepatic or renal disease. Use caution in
Biological Psychiatry (WFSBP) guidelines recommend
respiratory disease (eg, severe asthma, emphysema)
gradually tapering antipsychotics to avoid physical with-
due to potential for CNS effects.
drawal symptoms, including anorexia, anxiety, diaphore-
Leukopenia, neutropenia, and agranulocytosis (some- sis, diarrhea, dizziness, dyskinesia, headache, myalgia,
times fatal) have been reported in clinical trials and nausea, paresthesia, restlessness, tremulousness, and
postmarketing reports with antipsychotic use; presence vomiting (APA [Lehman 2004]; CPA [Addington 2005];
of risk factors (eg, preexisting low WBC or history of Lambert 2007; WFSBP [Hasan 2012]). The risk of with-
drug-induced leuko/neutropenia) should prompt periodic drawal symptoms is highest following abrupt discontinua-
blood count assessment. Discontinue therapy at first signs tion of highly anti-cholinergic or dopaminergic
of blood dyscrasias or if absolute neutrophil count antipsychotics (Cerovecki 2013). Additional factors such
<1000/mm*. as duration of antipsychotic exposure, the indication for
use, medication half-life, and risk for relapse should be
Antipsychotic use has been associated with esophageal
considered. In schizophrenia, there is no reliable indicator
dysmotility and aspiration; risk increases with age. Use
to differentiate the minority who will not from the majority
with caution in patients at risk for aspiration pneumonia
who will-relapse with drug discontinuation. However,
(ie, Alzheimer disease), particularly in patients >75 years
studies in which the medication of well-stabilized patients
(Herzig 2017; Maddalena 2004). Because chlorpromazine
were discontinued indicate that 75% of patients relapse
can suppress the cough reflex, aspiration of vomit is
within 6 to 24 months. Indefinite maintenance antipsy-
possible. Use associated with increased prolactin levels;
chotic medication is generally recommended, and espe-
clinical significance of hyperprolactinemia in patients with
cially for patients who have had multiple prior episodes or
breast cancer or other prolactin-dependent tumors is
2 episodes within 5 years (APA [Lehman 2004)).
unknown. Impaired core body temperature regulation
Warnings: Additional Pediatric Considerations EPS
may occur; caution with strenuous exercise, heat expo-
occurring with chlorpromazine should be differentiated
sure, dehydration, and concomitant medication possess-
from possible CNS syndromes which may also cause
ing anticholinergic effects. May alter cardiac conduction;
vomiting (eg, Reye’s syndrome, encephalopathy); avoid
life-threatening arrhythmias have occurred with therapeu-
use in pediatric patients whose clinical presentation is
tic doses of neuroleptics. May cause QT prolongation and
suggestive of Reye's syndrome.
subsequent torsade de pointes; avoid use in patients with
Adverse Reactions
diagnosed or suspected congenital long QT syndrome.
Cardiovascular: ECG abnormality (nonspecific QT
Use with caution in patients at risk of hypotension (ortho- changes), orthostatic hypotension, tachycardia
stasis is common) or those who would tolerate transient Central nervous system: Akathisia, dizziness, drowsiness,
hypotensive episodes (cerebrovascular disease, cardio- dystonia, neuroleptic malignant syndrome, parkinsonian-
vascular disease, or other medications which may predis- like syndrome, seizure, tardive dyskinesia
pose). Significant hypotension may occur, particularly with Dermatologic: Dermatitis, skin photosensitivity, skin pig-
parenteral administration. Injection contains sulfites. mentation (slate gray)
Endocrine & metabolic: Amenorrhea, gynecomastia,
Use with caution in patients with decreased gastrointesti-
hyperglycemia, hypoglycemia
nal motility, urinary retention, BPH, or xerostomia. Relative
Gastrointestinal: Constipation, nausea, xerostomia
to other neuroleptics, chlorpromazine has a moderate
Genitourinary: Breast engorgement, ejaculatory disorder,
potency of cholinergic blockade. May cause pigmentary
false positive pregnancy test, impotence, lactation, uri-
retinopathy, and lenticular and corneal deposits, particu-
nary retention
larly with prolonged therapy. Mild urticarial-type rash or
Hematologic & oncologic: Agranulocytosis, aplastic ane-
photosensitivity may occur; avoid undue exposure to the
mia, eosinophilia, hemolytic anemia, immune thrombo-
sun. More severe reactions, including exfoliative dermati-
cytopenia, leukopenia
tis, have been reported occasionally. Avoid use in patients
Hepatic: Jaundice
with signs/symptoms suggestive of Reye syndrome.
Ophthalmic: Blurred vision, corneal changes, epithelial
May cause extrapyramidal symptoms (EPS), including keratopathy, retinitis pigmentosa
pseudoparkinsonism, acute dystonic reactions, akathisia, Drug Interactions
and tardive dyskinesia. Risk of dystonia (and probably Metabolism/Transport Effects Substrate of CYP1A2
other EPS) may be greater with increased doses, use of (minor), CYP2D6 (major), CYP3A4 (minor); Note:
conventional antipsychotics, males, and younger patients. Assignment of Major/Minor substrate status based on
Factors associated with greater vulnerability to tardive clinically relevant drug interaction potential
dyskinesia include older in age, female gender combined Avoid Concomitant Use
with postmenopausal status, Parkinson disease, pseudo- Avoid concomitant use of ChlorproMAZINE with any of
parkinsonism symptoms, affective disorders (particularly the following: Aclidinium; Aminolevulinic Acid (Systemic);
major depressive disorder), concurrent medical disorders Amisulpride; Azelastine (Nasal); Bromopride; Bromper-
such as diabetes, previous brain damage, alcoholism, idol; Cimetropium; Dronedarone; Eluxadoline; Glycopyr-
poor treatment response, and use of high doses of anti- rolate (Oral Inhalation); Hydroxychloroquine; Ipratropium
psychotics (APA [Lehman]2004]; Soares-Weisner 2007). (Oral Inhalation); Levosulpiride; Macimorelin; Metoclo-
Consider therapy discontinuation with signs/symptoms of pramide; MiFEPRIStone; Orphenadrine; Oxatomide;
tardive dyskinesia. May cause neuroleptic malignant syn- Oxomemazine; Paraldehyde; Piribedil; Potassium Chlor-
drome (NMS). ide; Potassium Citrate; Probucol; Promazine; QTc-Pro-
longing Agents (Highest Risk); Saquinavir; Sulpiride;
May cause CNS depression, which may impair physical or
Thalidomide; Tiotropium; Umeclidinium; Vinflunine
mental abilities; patients must be cautioned about per-
forming tasks that require mental alertness (eg, operating
Increased Effect/Toxicity
machinery or driving). May increase the risk for falls due to
ChlorproMAZINE may increase the levels/effects of:
AbobotulinumtoxinA; Alcohol (Ethyl); Amifostine; Amino-
somnolence, orthostatic hypotension and motor or sen-
levulinic Acid (Systemic); Aminolevulinic Acid (Topical);
sory instability. Complete fall risk assessments at baseline
Amisulpride; Anticholinergic Agents; Antipsychotic
and periodically during treatment in patients with dis-
eases, conditions, or on medications that may increase
Agents (Second Generation [Atypical]); Azelastine
fall risk.
(Nasal); Beta-Blockers; Blonanserin; Bromperidol;
Buprenorphine; Cimetropium; CNS Depressants; Des-
Some dosage forms may contain sodium benzoate/ben- mopressin; Dronedarone; DULoxetine; Eluxadoline; Flu-
zoic acid; benzoic acid (benzoate) is a metabolite of nitrazepam; Glucagon; Glycopyrrolate (Oral Inhalation);
benzyl alcohol; large amounts of benzyl alcohol Haloperidol; HYDROcodone; Hypotension-Associated
(299 mg/kg/day) have been associated with a potentially Agents; lohexol; lomeprol; lopamidol; Mequitazine;
fatal toxicity ("gasping syndrome") in neonates; the "gasp- Methotrimeprazine; Methylphenidate; MetyroSINE; Mir-
ing syndrome" consists of metabolic acidosis, respiratory abegron; Mirtazapine; Nitroprusside; Onabotulinumtox-
distress, gasping respirations, CNS dysfunction (including inA; Opioid Analgesics; Orphenadrine; OxyCODONE;
convulsions, intracranial hemorrhage), hypotension, and Paraldehyde; Perhexiline; Pholcodine; Porfimer; Potas-
cardiovascular collapse (AAP ["Inactive" 1997]; CDC sium Chloride; Potassium Citrate; QTc-Prolonging
1982); some data suggests that benzoate displaces bilir- Agents (Highest Risk); QTc-Prolonging Agents (Moder-
ubin from protein binding sites (Ahifors 2001); avoid or use ate Risk); Ramosetron; RimabotulinumtoxinB; Saquina-
dosage forms containing benzyl alcohol derivative with vir; Selective Serotonin Reuptake Inhibitors; Serotonin
caution in neonates. See manufacturer's labeling. Poten- Modulators; Serotonin Reuptake Inhibitor/Antagonists;
tially significant drug-drug interactions may exist, requiring Sulpiride; Suvorexant; Thalidomide; Thiazide and

430
 CHLORPROMAZINE

Thiazide-Like Diuretics; Thiopental; Tiotropium; Topira- Pediatric

mate; Valproate Products; Verteporfin; Zolpidem Behavior problems; severe: Note: Begin with low
doses and gradually titrate as needed to lowest
The levels/effects of ChlorproMAZINE may be increased
effective dose; route of administration should be
by: Abiraterone Acetate; Acetylcholinesterase Inhibitors
determined by severity of symptoms.
(Central); Aclidinium; Alfuzosin; Amifampridine; Antima-
Infants 26 months, Children, and Adolescents weigh-
larial Agents; Asunaprevir; Barbiturates; Beta-Blockers;
ing $45.5 kg:
Blood Pressure Lowering Agents; Brimonidine (Topical);
Oral: Initial: 0.55 mg/kg/dose every 4 to 6 hours as
Bromopride; Bromperidol; Cannabis; Chloral Betaine;
needed; may titrate as required; in severe cases,
Chlormethiazole; Chlorphenesin Carbamate; Cobicistat;
higher doses may be required (50 to 100 mg/day);
CYP2D6 Inhibitors (Moderate); CYP2D6 Inhibitors
in older children, higher daily doses (200 mg/day
(Strong); Darunavir; Diazoxide; Dimethindene (Topical);
or higher) may be necessary; maximum daily dose:
Doxylamine; Dronabinol; Droperidol; Haloperidol; Herbs
500 mg/day; daily doses >500 mg have not been
(Hypotensive Properties); Hydroxychloroquine; HydrOX-
shown to further improve behavior in pediatric
Yzine; Imatinib; Ipratropium (Oral Inhalation); Kava
patients with severe mental impairment
Kava; Lithium; Lormetazepam; Macimorelin; Magnesium
IM, IV: Initial: 0.55 mg/kg/dose every 6 to 8 hours as
Sulfate; Methotrimeprazine; Methylphenidate; Metoclo-
needed; may titrate as required in severe cases
pramide; MetyroSINE; Mianserin; MiFEPRIStone; Mino- (Kliegman 2007)
cycline; Molsidomine; Nabilone; Naftopidil; Nicergoline;
Maximum recommended daily doses:
Nicorandil; Obinutuzumab; Oxatomide; Oxomemazine;
Children <5 years or weighing <22.7 kg:
Panobinostat; Peginterferon Alfa-2b; Pentoxifylline; Per- 40 mg/day
ampanel; Perhexiline; Phosphodiesterase 5 Inhibitors; Children 25 years and Adolescents or weighing
Pramlintide; Probucol; Promazine; Prostacyclin Ana-
22.7 to 45.5 kg: 75 mg/day
-logues; QTc-Prolonging Agents (Indeterminate Risk Adolescents weighing >45.5 kg:
and Risk Modifying); Quinagolide; Rufinamide; Serotonin Oral: Range: 30 to 800 mg/day in 2 to 4 divided
Modulators; Serotonin Reuptake Inhibitor/Antagonists; doses, initiate at lower doses and titrate as
Sodium Oxybate; Tapentadol; Tetrahydrocannabinol; Tri- needed; usual dose is 200 mg/day
meprazine; Umeclidinium; Vinflunine; Xipamide IM, IV: 25 mg initially, may repeat (25 to 50 mg) in 1
Decreased Effect to 4 hours, gradually increase to a maximum of
ChlorproMAZINE may decrease the levels/effects of: 400 mg/dose every 4 to 6 hours until patient con-
Acetylcholinesterase Inhibitors; Amifampridine; Amphet- trolled; usual dose 200 to 800 mg/day (Klieg-
amines; Anti-Parkinson Agents (Dopamine Agonist); man 2007)
Gastrointestinal Agents (Prokinetic); Guanethidine; Itopr- Nausea and vomiting, treatment (non-CINV):
ide; Levosulpiride; Nitroglycerin; Piribedil; Quinagolide; Infants 26 months, Children, and Adolescents weigh-
Secretin ing $45.5 kg: Oral, IM, IV: 0.55 mg/kg/dose every 6
The levels/effects of ChlorproMAZINE may be to 8 hours as needed; in severe cases, higher doses
decreased by: Acetylcholinesterase Inhibitors; Amifam- may be needed
pridine; Antacids; Anti-Parkinson Agents (Dopamine Usual maximum daily dose: IM, IV:
Agonist); Bromperidol; Lithium; Peginterferon Alfa-2b; Children <5 years or weighing <22.7 kg:
Piribedil 40 mg/day
Storage/Stability Children 25 years and Adolescents or weighing
22.7 to 45.5 kg: 75 mg/day
Oral: Store at 20°C to 25°C (68°F to 77°F); protect from
light and moisture.
Adolescents weighing >45.5 kg:
Oral: 10 to 25 mg every 4 to 6 hours as needed
Injection solution: Store at 20°C to 25°C (68°F to 77°F);
IM, IV: Initial: 25 mg; if tolerated (no hypotension),
excursions permitted to 15°C to 30°C (59°F to 86°F).
then may give 25 to 50 mg every 4 to 6 hours as
Protect from light and freezing. A slightly yellowed sol-
needed
ution does not indicate potency loss, but a markedly
Chemotherapy-induced nausea and vomiting
discolored solution should be discarded.
(CINV); prevention: Infants 26 months, Children,
Mechanism of Action Chlorpromazine is an aliphatic
and Adolescents: IV: Initial: 0.5 mg/kg/dose every 6
phenothiazine antipsychotic which blocks postsynaptic
hours; if not controlled, may increase up to 1 mg/kg/
mesolimbic dopaminergic receptors in the brain; exhibits
dose; monitor for sedation, maximum dose: 50 mg;
a strong alpha-adrenergic blocking effect and depresses
recommended in situations where corticosteroids are
the release of hypothalamic and hypophyseal hormones;
contraindicated (Dupuis 2013)
believed to depress the reticular activating system, thus
Cyclic vomiting syndrome; abortive therapy: Infants
affecting basal metabolism, body temperature, wakeful-
26 months, Children, and Adolescents: IV: 0.5 to
ness, vasomotor tone, and emesis
1 mg/kg/dose every 6 hours; maximum dose:
Pharmacodynamics/Kinetics (Adult data unless 50 mg; in combination with diphenhydramine (for
noted) ARTI possible dystonic reactions) (Li 2008)
Onset of action: IM: 15 minutes; Oral: 30 to 60 minutes; Delirium, ICU associated: Limited data available (Sil-
Antipsychotic effects: Gradual, may take up to several ver 2010): Infants 26 months, Children, and Adoles-
weeks; Maximum antipsychotic effect: 6 weeks to 6 cents:
months Oral: 2.5 to 6 mg/kg/day divided every 4 to 6 hours
Duration: Oral: 4 to 6 hours Maximum daily dose:
Absorption: Oral: Rapid and virtually complete; large first- Children <5 years: 50 mg/day
pass effect due to metabolism during absorption in the Children >5 years and Adolescents: 200 mg/day
GI mucosa IM: 2.5 to 4 mg/kg/day divided every 6 to 8 hours;
Distribution: Widely distributed into most body tissues and maximum daily dose: 40 mg/day
fluids; crosses blood-brain barrier Preoperative sedation, anxiety: Infants 26 months,
Va: IV (Yeung 1993): Children, and Adolescents:
Single dose: Mean: 15.7 L/kg (range: 9.03 to 37.1 L/kg) Oral: 0.55 mg/kg/dose once 2 to 3 hours before
Steady state: Mean: 8.38 L/kg (range: 5.08 to 14 L/kg) surgery; maximum dose: 50 mg
Protein binding: 92% to 97% IM: 0.55 mg/kg/dose once 1 to 2 hours before sur-
Metabolism: Extensively hepatic by demethylation (fol- gery; maximum dose: 25 mg
lowed by glucuronide conjugation) and amine oxidation Tetanus:
to active and inactive metabolites - Infants 26 months, Children, and Adolescents weigh-
Bioavailability: Oral: ~32% ing $45.5 kg: IM, IV: 0.55 mg/kg/dose every 6 to 8
Half-life, biphasic: Initial: Children: 1.1 hours; Adults: ~2 hours; in severe cases higher doses may be needed
hours; Terminal: Children: 7.7 hours; Adults: ~30 hours Usual maximum daily dose:
Excretion: Urine (<1% as unchanged drug) within 24 Children <5 years or weighing <22.7 kg:
hours 40 mg/day
Dosing Children 25 years and Adolescents or weighing
Neonatal Neonatal abstinence syndrome (withdrawal 22.7 to 45.5. kg: 75 mg/day
from maternal opioid use; controls CNS and gastro- Adolescents weighing 245.5 kg: IM, IV: 25 to 50 mg
intestinal symptoms): Limited data available: IM: Initial: every 6 to 8 hours; begin with low dose and increase
0.55 mg/kg/dose given every 6 hours; change to oral gradually based upon patient response
after ~4 days, decrease dose gradually over 2 to 3 Discontinuation of pyschosis/severe behavior ther-
weeks. Note: Chlorpromazine is rarely used for neonatal apy: Infants 26 months, Children, and Adolescents:
abstinence syndrome due to adverse effects such as The manufacturer and American Academy of Child
hypothermia, cerebellar dysfunction, decreased seizure and Adolescent Psychiatry (AACAP), American Psychi-
threshold, and eosinophilia; other agents are preferred atric Association (APA), Canadian Psychiatric Associ-
(AAP Committee on Drugs 1998; Hudak 2012). ation (CPA), National Institute for Health and Care

431
CHLORPROMAZINE

Excellence (NICE), and World Federation of Societies secretion (SIADH) or hyponatremia; monitor sodium
of Biological Psychiatry (WFSBP) guidelines recom- concentration closely when initiating or adjusting the
mend gradually tapering antipsychotics to avoid with- dose in older adults (Beers Criteria [AGS 2015)).
drawal symptoms and minimize the risk of relapse Brand Names: Canada Apo-Chlorthalidone
(AACAP [McClellan 2007]; APA [Lehman 2004]; Cer- Therapeutic Category Diuretic, Thiazide
ovecki 2013; CPA 2005; NICE 2013; WFSBP [Hasan Generic Availability (US) Yes
2012]); risk for withdrawal symptoms may be highest Use Treatment of edema due to heart failure; hepatic
with highly anticholinergic or dopaminergic antipsy- cirrhosis; estrogen or corticosteroid therapy; various forms
chotics (Cerovecki 2013). When stopping antipsychotic of renal dysfunction, including nephrotic syndrome, acute
therapy in patients with schizophrenia, the CPA guide- glomerulonephritis, and chronic renal failure (FDA
lines recommend a gradual taper over 6 to 24 months approved in adults); management of hypertension either
and the APA guidelines recommend reducing the dose alone or in combination with other antihypertensive agents
by 10% each month (APA [Lehman 2004]; CPA 2005). (FDA approved in adults)
Continuing antiparkinsonism agents for a brief period Pregnancy Risk Factor B
after discontinuation may prevent withdrawal symp- Pregnancy Considerations Adverse events have not
toms (Cerovecki 2013). When switching antipsychotics, been observed in animal reproduction studies. Chlorthali-
three strategies have been suggested: Cross-titration done crosses the placenta and can be detected in cord
(gradually discontinuing the first antipsychotic while blood. Maternal use may cause fetal or neonatal jaundice,
gradually increasing the new antipsychotic), overlap thrombocytopenia, or other adverse events observed in
and taper (maintaining the dose of the first antipsy- adults. Use of-thiazide diuretics to treat edema during
chotic while gradually increasing the new antipsychotic, normal pregnancies is not appropriate; use may be con-
then tapering the first antipsychotic), and abrupt sidered when edema is due to pathologic causes (as in
change (abruptly discontinuing the first antipsychotic the nonpregnant patient); monitor. Untreated chronic
and either increasing the new antipsychotic gradually maternal hypertension is associated with adverse events
or starting it at a treatment dose). Evidence supporting in the fetus, infant, and mother. Women who require
ideal switch strategies and taper rates is limited and thiazide diuretics for the treatment of hypertension prior
results are conflicting (Cerovecki 2013; Reming- to pregnancy may continue their use (ACOG 2013).
ton 2005). Breastfeeding Considerations Thiazides are present in
Renal Impairment: Pediatric There are no dosage breast milk. Due to the potential. for serious adverse
adjustments provided in the manufacturer's labeling; reactions in the breastfeeding infant, the manufacturer
use with caution. Not dialyzable (0 to 5%). recommends a decision be made whether to discontinue
Hepatic Impairment: Pediatric There are no dosage breastfeeding or to discontinue the drug, taking into
adjustments provided in the manufacturer's labeling; use account the importance of treatment to the mother. Diu-
with caution. retics have the potential to decrease milk volume and
Preparation for Administration Parenteral: suppress lactation.
Direct IV injection: Dilute with NS to a maximum concen- Contraindications Hypersensitivity to chlorthalidone,
tration of 1 mg/mL. other sulfonamide-derived drugs, or any component of
IV: For treatment of intractable hiccups the manufacturer the formulation; anuria
recommends diluting 25 to 50 mg of chlorpromazine in Note: Although the FDA approved product labeling states
500 to 1,000 mL NS. this medication is contraindicated with other sulfona-
Administration mide-containing drug classes, the scientific basis of this
Oral: Administer with water, food, or milk to decrease Gl statement has been challenged. See "Warnings/Precau-
upset; brown precipitate may occur when chlorproma- tions" for more detail.
zine is mixed with caffeine-containing liquids Documentation of allergenic cross-reactivity for drugs
Parenteral: Do not administer.SubQ (tissue damage and thiazide-type diuretics is limited. However, because of
irritation may occur); for direct IV injection, administer similarities in chemical structure and/or pharmacologic
diluted solution slow IV at a rate not to exceed actions, the possibility of cross-sensitivity cannot be
0.5 mg/minute in children and 1 mg/minute in adults. ruled out with certainty.
For the treatment of intractable hiccups, infuse as a slow Warnings/Precautions Hypokalemia, hypochloremic
IV infusion. To reduce the risk of hypotension, patients alkalosis, hypomagnesemia, and hyponatremia may
receiving IV chlorpromazine must remain lying down occur. Development of electrolyte disturbances can be
during and for 30 minutes after the injection. Note: Avoid minimized when used in combination with other electrolyte
skin contact with solution; may cause contact dermatitis. sparing antihypertensives (eg, ACE inhibitors or angioten-
Monitoring Parameters Vital signs (especially with sin receptor blockers) (Sica 2011). In certain patients, gout
parenteral use); lipid profile, fasting blood glucose/ can be precipitated; risk may be increased with doses
HgbA,.; BMI; mental status; abnormal involuntary move- 225 mg (in hydrochlorothiazide equivalents) (Gurwitz
ment scale (AIMS); extrapyramidal symptoms (EPS); CBC 1997). Hypersensitivity reactions may occur; risk is
in patients with risk factors for leukopenia/neutropenia; increased in patients with a history of allergy or bronchial
periodic eye exam with prolonged therapy asthma. Photosensitization may occur. Use with caution in
Reference Range Relationship of plasma concentration patients with prediabetes, diabetes mellitus, or severe
to clinical response is not well established hepatic impairment; in progressive or severe hepatic
Therapeutic: 50 to 300 ng/mL (SI: 157 to 942 nmol/L) disease, avoid electrolyte and acid/base imbalances that
Toxic: >750 ng/mL (SI: >2355 nmol/L) might lead to hepatic encephalopathy. Cumulative effects
Test Interactions False-positives for phenylketonuria, may develop, including azotemia, in patients with impaired
amylase, uroporphyrins, urobilinogen. May cause false- renal function. Avoid in severe renal disease (ineffective).
positive pregnancy test. May interfere with urine detection Thiazide diuretics may decrease renal calcium excretion;
of amphetamine/methamphetamine and methadone consider avoiding use in patients with hypercalcemia, Use
(false-positives). with caution in moderate or high cholesterol concentra-
Dosage Forms Excipient information presented when tions and in patients with (correct potassium before initiat-
available (limited, particularly for generics); consult spe- ing therapy). Thiazide diuretics reduce calcium excretion;
cific product labeling. pathologic changes in the parathyroid glands with hyper-
Solution, Injection, as hydrochloride: calcemia and hypophosphatemia have been observed
Generic: 25 mg/mL (1 mL); 50 mg/2 mL (2 mL) with prolonged use; should be discontinued prior to testing
Tablet, Oral, as hydrochloride: for parathyroid function. May cause SLE exacerbation or
Generic: 10 mg, 25 mg, 50 mg, 100 mg, 200 mg activation. If given the morning of surgery, thiazide diu-
retics may render the patient volume depleted and blood
@ Chlorpromazine HCI see ChlorproMAZINE on page 429 pressure may be labile during general anesthesia. Avoid
@ Chlorpromazine Hydrochloride see ChlorproMAZINE use of diuretics for treatment of elevated blood pressure in
on page 429 patients with primary adrenal insufficiency (Addison dis-
@ Chlorpromazine Hydrochloride Inj (Can) see Chlorpro- ease). Adjustment of glucocorticoid/mineralocorticoid ther-
MAZINE on page 429 apy and/or use of other antihypertensive agents is
preferred to treat hypertension (Bornstein 2016; Inder
2015). Potentially significant interactions may exist, requir-
Chlorthalidone (kior THAL i done) ing dose or frequency adjustment, additional monitoring,
and/or selection of alternative therapy.
Medication Safety Issues
Geriatric Patients: High-Risk Medication: Sulfonamide ("sulfa") allergy: The FDA-approved product
Beers Criteria: Diuretics (chlorthalidone) are identified in labeling for many medications containing a sulfonamide
the Beers Criteria as potentially inappropriate medica- chemical group includes a broad contraindication in
tions to be used with caution in patients 65 years and patients with a prior allergic reaction to sulfonamides.
older because of the potential to cause or exacerbate There is a potential for cross-reactivity between members
syndrome of inappropriate antidiuretic hormone of a specific class (eg, two antibiotic sulfonamides).

432
 CHLORZOXAZONE

However, concerns for cross-reactivity have previously Renal Impairment: Pediatric There are no dosage
extended to all compounds containing the sulfonamide adjustments provided in the manufacturer's labeling;
structure (SO2NH2). An expanded understanding of aller- based on experience in adult patients, use is contra-
gic mechanisms indicates cross-reactivity between anti- indicated with anuria and considered ineffective in
biotic sulfonamides and nonantibiotic sulfonamides may patients with CrCl <10 mL/minute (Aronoff 2007).
not occur or at the very least this potential is extremely low Hepatic Impairment: Pediatric There are no dosage
(Brackett 2004; Johnson 2005; Slatore 2004; Tornero adjustments provided in the manufacturer's labeling; use
2004). In particular, mechanisms of cross-reaction due with caution.
to antibody production (anaphylaxis) are unlikely to occur Administration Oral: Administer in the morning with food
with nonantibiotic sulfonamides. T-cell-mediated (type IV)
Monitoring Parameters Serum electrolytes, BUN, crea-
reactions (eg, maculopapular rash) are less well under-
tinine, blood pressure, fluid balance, body weight
stood and it is not possible to completely exclude this
Test Interactions May decrease serum protein bound
potential based on current insights. In cases where prior
iodine without signs of thyroid disturbance; may lead to
reactions were severe (Stevens-Johnson syndrome/TEN),
false-negative aldosterone/renin ratio (ARR) (Funder
some clinicians choose to avoid exposure to these
classes.
2016)
Adverse Reactions Dosage Forms Excipient information presented when
Dermatologic: Skin photosensitivity available (limited, particularly for generics); consult spe-
Endocrine & metabolic: Hypokalemia cific product labeling. [DSC] = Discontinued product
Gastrointestinal: Anorexia, dyspepsia Tablet, Oral:
Rare but important or life-threatening: Agranulocytosis, Generic: 25 mg, 50 mg, 100 mg [DSC]
aplastic anemia, cholecystitis, diabetes mellitus, gout, @ Chior-Trimeton [OTC] see Chlorpheniramine
hypercalcemia, hyperglycemia, hypersensitivity reaction, on page 428
~hypochloremic alkalosis, hyponatremia, leukopenia,
necrotizing angiitis, orthostatic hypotension, pancreatitis, @ Chlor-Trimeton Allergy [OTC] see Chlorpheniramine
renal insufficiency, thrombocytopenia, toxic epidermal on page 428
necrolysis, vasculitis, xanthopsia ¢@ Chlor-Tripolon® (Can) see Chlorpheniramine
Drug Interactions on page 428
Metabolism/Transport Effects None known. @ Chlor-Tripolon ND (Can) see Loratadine and Pseudoe-
Avoid Concomitant Use 3 phedrine on page 1249
Avoid concomitant use of Chlorthalidone with any of the
following: Aminolevulinic Acid (Systemic); Bromperidol;
Dofetilide; Levosulpiride; Mecamylamine; Promazine Chlorzoxazone (kior ZOKS a zone)
Increased Effect/Toxicity Medication Safety Issues
Chlorthalidone may increase the levels/effects of: Ajma-
Geriatric Patients: High-Risk Medication:
line; Allopurinol; Amifostine; Aminolevulinic Acid (Sys-
Beers Criteria: Chlorzoxazone is identified in the Beers
temic); Aminolevulinic Acid (Topical); Angiotensin-
Criteria as a potentially inappropriate medication to be
Converting Enzyme Inhibitors; Antipsychotic Agents
avoided in patients 65 years and older (independent of
(Second Generation [Atypical]); Bromperidol; Calcium
diagnosis or condition) because most muscle relaxants
Salts; CarBAMazepine; Cardiac Glycosides; Cyclophos-
are poorly tolerated by older adults because of anti-
phamide; Diazoxide; Dofetilide; DULoxetine; Hypoten-
sion-Associated Agents; lvabradine; Levodopa;
cholinergic effects caused by some muscle relaxants,
risk of sedation, and an increased risk of fracture. In
Levosulpiride; Lithium; Mecamylamine; Multivitamins/
Minerals (with ADEK, Folate, Iron); Multivitamins/Miner- addition, efficacy is questionable at doses tolerated by
als (with AE, No Iron); Neuromuscular-Blocking Agents geriatric patients (Beers Criteria [AGS 2015)).
(Nondepolarizing); Nitroprusside; Nonsteroidal Anti- Pharmacy Quality Alliance (PQA): Chlorzoxazone (as a
Inflammatory Agents; OXcarbazepine; Pholcodine; Por- single agent or as part of a combination product) is
fimer; Promazine; Sodium Phosphates; Topiramate; Tor- identified as a high-risk medication in patients 65 years
emifene; Verteporfin; Vitamin D Analogs and older on the PQA's Use of High-Risk Medications
in the Elderly (HRM) performance measure, a safety
The levels/effects of Chlorthalidone may be increased measure used by the Centers for Medicare and Med-
by: Alcohol (Ethyl); Alfuzosin; Anticholinergic Agents; icaid Services (CMS) for Medicare plans.
Barbiturates; Benperidol; Beta2-Agonists; Brigatinib; Bri- Brand Names: US Lorzone; Parafon Forte DSC [DSC]
monidine (Topical); Corticosteroids (Orally Inhaled); Cor- Therapeutic Category Skeletal Muscle Relaxant, Non-
ticosteroids (Systemic); Dexketoprofen; Diacerein; paralytic
Diazoxide; Herbs (Hypotensive Properties); Ipragliflozin;
Generic Availability (US) Yes
Licorice; Lormetazepam; Molsidomine; Multivitamins/
Use Adjunct to rest, physical therapy, and other measures
Fluoride (with ADE); Naftopidil; Nicergoline; Nicorandil;
for the relief of discomfort associated with acute, painful
Obinutuzumab; Opioid Analgesics; Pentoxifylline; Phos-
phodiesterase 5 Inhibitors; Prostacyclin Analogues; Qui- musculoskeletal conditions (FDA approved in adults)
nagolide; Reboxetine; Selective Serotonin Reuptake Pregnancy Considerations Animal reproduction studies
Inhibitors have not been conducted.
Decreased Effect Contraindications Hypersensitivity to chlorzoxazone or
Chlorthalidone may decrease the levels/effects of: Anti- any component of the formulation
diabetic Agents Warnings/Precautions Rare, serious (including fatal)
idiosyncratic and unpredictable hepatocellular toxicity
The levels/effects of Chlorthalidone may be decreased has been reported with use. Discontinue immediately if
by: Amphetamines; Bile Acid Sequestrants; Brigatinib; early signs/symptoms of hepatic toxicity arise (eg, fever,
Bromperidol; Herbs (Hypertensive Properties); Methyl- rash, anorexia, nausea, vomiting, fatigue, right upper
phenidate; Nonsteroidal Anti-Inflammatory Agents; quadrant pain, dark urine, or jaundice). Also discontinue
Opioid Analgesics; Yohimbine if elevated liver enzymes (eg, AST, ALT, alkaline phospha-
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). tase, bilirubin) develop. May cause CNS depression,
Protect from light. which may impair physical or mental abilities; patients
Mechanism of Action Sulfonamide-derived diuretic that must be cautioned about performing tasks that require
inhibits sodium and chloride reabsorption in the cortical- mental alertness (eg, operating machinery or driving).
diluting segment of the ascending loop of Henle Use caution in patients with known allergies or a history
Pharmacodynamics/Kinetics (Adult data unless of allergic reactions to drugs; if sensitivity (itching, red-
noted) ness, urticaria) occurs, discontinue therapy. Potentially
Onset of action: ~2.6 hours; Peak effect: 2 to 6 hours significant interactions may exist, requiring dose or fre-
(Carter 2004) quency adjustment, additional monitoring, and/or selec-
Duration: Single dose: 24 to 48 hours; Long-term dosing: tion of alternative therapy.
48 to 72 hours (Carter 2004)
Protein binding: ~75% (58% to albumin) Some dosage forms may contain sodium benzoate/ben-
Metabolism: Hepatic zoic acid; benzoic acid (benzoate) is a metabolite of
Half-life elimination: Single dose: 40 hours; Long-term benzyl alcohol; large amounts of benzyl alcohol
dosing: 45 to 60 hours (Carter 2004); may be prolonged (299 mg/kg/day) have been associated with a potentially
with renal impairment fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Excretion: Urine (primarily as unchanged drug) ing syndrome" consists of metabolic acidosis, respiratory
Dosing distress, gasping respirations, CNS dysfunction (including
Pediatric Hypertension: Children and Adolescents: convulsions, intracranial hemorrhage), hypotension and
Oral: Initial: 0.3 mg/kg/dose once daily; may titrate up cardiovascular collapse (AAP 1997; CDC 1982); some
to a maximum daily dose: 2 mg/kg/day or 50 mg/day data suggests that benzoate displaces bilirubin from pro-
(NHBPEP 2004; NHLBI 2011) tein binding sites (Ahlfors 2001); avoid or use dosage >
433
 CHLORZOXAZONE

é forms containing benzyl alcohol derivative with caution in

neonates. See manufacturer's labeling. Cholecalciferol (kole e kal SI fer ole)
Adverse Reactions
Central nervous system: Dizziness, drowsiness, malaise,
Medication Safety |ssues
!
Sound-alike/look-alike issues:
paradoxical central nervous system stimulation
Cholecalciferol may be confused with alfacalcidol, ergo-
Genitourinary: Urine discoloration
calciferol
Rare but important or life-threatening: Allergic skin rash,
Administration issues:
anaphylaxis (very rare), angioedema (very rare), ecchy-
Liquid vitamin D preparations have the potential for
moses, gastrointestinal hemorrhage, hepatotoxicity,
dosing errors when administered to infants. Droppers
petechia
should be clearly marked to easily provide 400 interna-
Drug Interactions tional units. For products intended for infants, the FDA
Metabolism/Transport Effects Substrate of CYP1A2 recommends that accompanying droppers deliver no
(minor), CYP2A6 (minor), CYP2D6 (minor), CYP2E1 more than 400 international units per dose.
(minor), CYP3A4 (minor); Note: Assignment of Major/ Brand Names: US Aqueous Vitamin D [OTC]; Bio-D-
Minor substrate status based.on clinically relevant drug Mulsion Forte [OTC] [DSC]; Bio-D-Mulsion [OTC] [DSC];
interaction potential; Inhibits CYP3A4 (weak) BProtected Pedia D-Vite [OTC]; D-3-5 [OTC]; D-Vi-Sol
Avoid Concomitant Use [OTC]; D-Vita [OTC] [DSC]; D3 Vitamin [OTC]; D3-50
Avoid concomitant use of Chlorzoxazone with any of the [OTC]; Decara [OTC]; Delta D3 [OTC]; Dialyvite Vitamin
following: Azelastine (Nasal); Bromperidol; Orphena- D 5000 [OTC]; Dialyvite Vitamin D3 Max [OTC]; Pronu-
drine; Oxomemazine; Paraldehyde; Pimozide; Thalido- trients VitaminsD3 [OTC]; Vitamin D3 Super Strength
mide : [OTC]; Vitamin D3 Ultra Potency [OTC]
Increased Effect/Toxicity Brand Names: Canada D-Vi-Sol
Chlorzoxazone may increase the levels/effects of: Alco- Therapeutic Category Nutritional Supplement; Vitamin D
hol (Ethyl); ARIPiprazole; Azelastine (Nasal); Blonan- Analog; Vitamin, Fat Soluble
serin; Buprenorphine; CNS Depressants; Dofetilide; Generic Availability (US) Yes
Flibanserin; Flunitrazepam; HYDROcodone; Lomitapide; Use Prevention and treatment of vitamin D deficiency and/
Methotrimeprazine; MetyroSINE; Mirtazapine; NiMODi- or rickets; dietary supplement (FDA approved in all ages)
pine; Opioid Analgesics; Orphenadrine; OxyCODONE; Pregnancy Considerations The cholecalciferol metab-
Paraldehyde; Pimozide; Piribedil; Pramipexole; ROPI- olite, 25(OH)D, crosses the placenta; maternal serum
NIRole; Rotigotine; Selective Serotonin Reuptake Inhib- concentrations correlate with fetal concentrations at birth
itors; Suvorexant; Thalidomide; Zolpidem (Misra 2008; Wagner 2008). Vitamin D requirements are
the same in pregnant and nonpregnant females (l1OM
The levels/effects of Chlorzoxazone may be increased 2011).
by: Brimonidine (Topical); Bromopride; Bromperidol;
Cannabis; Chlormethiazole; Chlorphenesin Carbamate; Vitamin D deficiency in a pregnant woman may lead to a
Dimethindene (Topical); Disulfiram; Doxylamine; Drona- vitamin D deficiency in the neonate (Misra 2008; Wagner
binol; Droperidol; HydrOXYzine; Isoniazid; Kava Kava; 2008). Serum 25(OH)D concentrations should be meas-
Lofexidine; Magnesium Sulfate; Methotrimeprazine; Min- ured in pregnant women considered to be at increased
ocycline; Nabilone; Oxomemazine; Perampanel; Rufina-
risk of deficiency (ACOG 2011). The amount of vitamin D
mide; Sodium Oxybate; Tapentadol; Tetra-
contained in prenatal vitamins may not be adequate to
treat a deficiency during pregnancy; although larger doses
hydrocannabinol; Tolperisone; Trimeprazine
may be needed, current guidelines recommend a total of
Decreased Effect
1,000 to 2,000 units/day until more safety data is available
The levels/effects of Chlorzoxazone may be decreased
(ACOG 2011; Holick 2011). In women not at risk for
by: |soniazid : deficiency, doses larger than the RDA should be avoided
Storage/Stability Store at 20°C to 25°C (68°F to 77°F). during pregnancy (ACOG 2011).
Mechanism of Action Centrally acting agent; acts on the Breastfeeding Considerations The 25(OH)D metabo-
spinal cord and subcortical areas of the brain to inhibit lite can be detected in breast milk. Small quantities of
polysynaptic reflex arcs involved in causing and maintain- vitamin D are found in breast milk following normal
ing skeletal muscle spasms maternal exposure via sunlight and diet. Maternal vitamin
Pharmacodynamics/Kinetics (Adult data unless D requirements are the same for nursing and non-nursing
noted) women. However, the amount of vitamin D in breast milk
Onset of action: Within 1 hour (Desiraju 1983) does not correlate with serum concentrations in the infant.
Duration: Up to 6 hours (Desiraju 1983) In addition, premature infants, infants born to vitamin D
Absorption: Rapid (Desiraju 1983) deficient mothers, dark skinned children, children living at
Metabolism: Extensively hepatic via glucuronidation high latitudes, and exclusively breast-fed infants and
Half-life elimination: ~1 hour (Desiraju 1983) children may be at increased risk for vitamin D deficiency.
Time to peak: ~1 to 2 hours Therefore, vitamin D supplementation is recommended in
Excretion: Urine (predominately as conjugates; <1% as all infants who are partially or exclusively breast fed (IOM
unchanged drug) 2011; Misra 2008; Wagner 2008).
Dosing Contraindications
Pediatric Muscle spasm: Limited data available, effi- OTC labeling: Replesta products only: When used for self-
cacy results variable (Losin 1966); Note: Chlorzoxazone medication, do not use if you have hypercalcemia,
primary hyperparathyroidism, sarcoidosis, hypervitami-
not a routine treatment option for management of spas-
nosis D, Williams syndrome, or are pregnant.
ticity in pediatric patients (eg, cerebral palsy); use has
Documentation of allergenic cross-reactivity for vitamin D
been replaced by newer, more effective agents (Delgado
is limited. However, because of similarities in chemical
2010):
structure and/or pharmacologic actions, the possibility of
Children and Adolescents: 20 mg/kg/day in 3 to 4 div-
cross-sensitivity cannot be ruled out with certainty.
ided doses; dosing based on generally recognized
Warnings/Precautions Vitamin D toxicity may occur with
expert recommendations; published pediatric trial data
excessive doses; symptoms may include nausea, vomit-
is lacking; in reported experience, initial dose range: ing, loss of appetite, constipation, dehydration, fatigue,
125 to 250 mg 3 times daily (Berman 1964, Berman irritability, confusion, weakness and/or weight loss;
1964a, Darienzo 1966, Kliegman 2007, Losin 1966); patients with hepatic and/or renal disease may be at
maximum dose: 750 mg/dose greater risk. Adults with a BMI >30 kg/m? are at high risk
Renal Impairment: Pediatric There are no dosage for vitamin D deficiency due to storage of vitamin D in
adjustments provided in the manufacturer’s labeling. adipose tissue. Doses higher than the RDA may be
Hepatic Impairment: Pediatric There are no dosage required, but must be carefully monitored to avoid toxicity
adjustments provided in the manufacturer’s labeling. (Holick 2011). Potentially significant drug-drug interactions
Administration Oral: Administer with or without food may exist, requiring dose or frequency adjustment, addi-
Monitoring Parameters Periodic liver function tests tional monitoring, and/or selection of alternative therapy.
Dosage Forms Excipient information presented when Some dosage forms may contain sodium benzoate/ben-
available (limited, particularly for generics); consult spe- zoic acid; benzoic acid (benzoate) is a metabolite of
cific product labeling. [DSC] = Discontinued product benzyl alcohol; large amounts of benzyl alcohol
Tablet, Oral: (299 mg/kg/day) have been associated with a potentially
Lorzone: 375 mg [contains sodium benzoate] fatal toxicity ("gasping syndrome") in neonates; the "gasp-
Lorzone: 750 mg [scored; contains sodium benzoate] ing syndrome" consists of metabolic acidosis, respiratory
Parafon Forte DSC: 500 mg [DSC] [scored; contains distress, gasping respirations, CNS dysfunction (including
brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quino- convulsions, intracranial hemorrhage), hypotension and
line yellow), sodium benzoate] cardiovascular collapse (AAP 1997; CDC 1982); some
Generic: 250 mg, 500 mg data suggests that benzoate displaces bilirubin from

434
 CHOLECALCIFEROL

protein binding sites (Ahlfors 2001); avoid or use dosage suggested (Golden 2014); some organizations suggest
forms containing benzy! alcohol derivative with caution in a serum 25(OH)D level >30 ng/mL should be used for
neonates. all patients (Holick 2011).
Pediatric
Some dosage forms may contain polysorbate 80 (also
Adequate intake (Al): Oral: Infants: 400 units/day
known as Tweens). Hypersensitivity reactions, usually a
(IOM 2011)
delayed reaction, have been reported following exposure
Recommended Daily Allowance (RDA): Oral: Chil-
to pharmaceutical products containing polysorbate 80 in
dren and Adolescents: 600 units/day (IOM 2011)
certain individuals (Isaksson 2002; Lucente 2000; Shelley
Vitamin D deficiency, prevention (Wagner 2008):
1995). Thrombocytopenia, ascites, pulmonary deteriora-
Oral:
tion, and renal and hepatic failure have been reported in
Breast-fed infants (fully or partially): Oral: 400 units/
premature neonates after receiving parenteral products
day beginning in the first few days of life. Continue
containing polysorbate 80 (Alade 1986; CDC 1984).
supplementation until infant is weaned to 21,000
Some dosage forms may contain propylene glycol; large mL/day or 1 qt/day of vitamin D-fortified formula or
amounts are potentially toxic and have been associated whole milk (after 12 months of age)
hyperosmolality, lactic acidosis, seizures and respiratory Formula-fed infants ingesting <1,000 mL of vitamin D-
depression; use caution (AAP 1997; Zar 2007). See fortified formula: Oral: 400 units/day
manufacturer’s labeling. Children and Adolescents without adequate intake:
Warnings: Additional Pediatric Considerations Oral: 400 units/day. Note: Children with increased
Some dosage forms may contain propylene glycol; in risk of vitamin D deficiency (chronic fat malabsorp-
neonates large amounts of propylene glyco! delivered tion, maintained on chronic antiseizure medica-
| orally, intravenously (eg, >3,000 mg/day), or topically tions): Higher doses may be required; use
have been associated with potentially fatal toxicities which laboratory testing [25(OH)D, PTH, bone mineral
can include metabolic acidosis, seizures, renal failure, and status] to evaluate
CNS depression; toxicities have also been reported in Vitamin D deficiency, treatment: Oral: Note: In addi-
children and adults including hyperosmolality, lactic acido- tion to calcium and phosphorus supplementation
sis, seizures and respiratory depression; use caution (Holick 2011; Golden 2014):
(AAP, 1997; Shehab, 2009). Infants: Oral: 2,000 units daily or 50,000 units once
Adverse Reactions No adverse reactions listed in the weekly for 6 weeks to achieve a serum 25(OH)D
manufacturer's labeling. . level >20 ng/mL; followed by a maintenance dose of
Drug Interactions 400 to 1,000 units daily. Note: For patients at high
Metabolism/Transport Effects None known. tisk of fractures a serum 25(OH)D level >30 ng/mL
Avoid Concomitant Use : has been suggested (Golden 2014); some organ-
Avoid concomitant use of Cholecalciferol with any of the izations suggest a serum 25(OH)D level >30 ng/mL
following: Aluminum Hydroxide; Multivitamins/Fluoride should be used for all patients (Holick 2011).
(with ADE); Multivitamins/Minerals (with ADEK, Folate, Children and Adolescents: Oral: 2,000 units daily or
Iron); Sucralfate; Vitamin D Analogs 50,000 units once weekly for 6 to 8 weeks to achieve
Increased Effect/Toxicity serum 25(OH)D level >20 ng/mL; followed by a
Cholecalciferol may increase the levels/effects of: Alu- maintenance dose of 600 to 1,000 units daily. Note:
minum Hydroxide; Cardiac Glycosides; Sucralfate; Vita- For patients at high risk of fractures a serum 25(OH)
min D Analogs D level >30 ng/mL has been suggested (Golden
2014); some organizations suggest a serum 25
The levels/effects of Cholecalciferol may be increased (OH)D level >30 ng/mL should be used for all
by: Calcium Salts; Danazol; Multivitamins/Fluoride (with patients (Holick 2011).
ADE); Multivitamins/Minerals (with ADEK, Folate, Iron); Children and Adolescents with increased risk of vita-
Thiazide and Thiazide-Like Diuretics min D deficiency (chronic fat malabsorption, main-
Decreased Effect tained on chronic antiseizure medications,
The levels/effects of Cholecalciferol may be decreased glucocorticoids, HIV medications and antifungals
by: Bile Acid Sequestrants; Mineral Oil; Orlistat such as ketoconazole, obesity): Higher doses (2 to
Storage/Stability Store at 15°C to 30°C (59°F to 86°F); 3 times higher) may be required; doses of at least
do not freeze. Protect from light. 6,000 to 10,000 units daily until serum 25(OH)D
Mechanism of Action Cholecalciferol (vitamin D3) is a level >30 ng/mL, followed by a maintenance dose
provitamin. The active metabolite, 1,25-dihydroxyvitamin of 3,000 to 6,000 units daily have been suggested
D (calcitriol), stimulates calcium and phosphate absorp- (Holick 2011).
tion from the small intestine, promotes secretion of cal- Note: If poor compliance, single high-dose adminis-
cium from bone to blood; promotes renal tubule phosphate tration (100,000 to 600,000 units over 1 to 5 days)
resorption (IOM 2011) followed by maintenance dosing; intermittently
Pharmacodynamics/Kinetics (Adult data-unless repeating (usually every 3 months) may be needed
noted) if poor compliance continues with maintenance dos-
Absorption: Absorbed in the small intestine; fat soluble; ing (Misra 2008)
requires bile (IOM 2011) Vitamin D insufficiency or deficiency associated
Metabolism: Inactive until hydroxylated hepatically to 25- with CKD (stages 2-5, 5D), treatment; serum 25
hydroxyvitamin D [25(OH)D; calcifediol] then renally to hydroxyvitamin D [25(OH)D] level $30 ng/mL
the active metabolite 1,25-dihydroxyvitamin D (calcitriol) (KDOQI Guidelines 2009): Oral:
(JOM 2011) Serum 25(OH)D level 16 to 30 ng/mL: Infants, Chil-
Half-life, circulating: 25(OH)D: 2 to 3 weeks; 1,25-dihy- dren, and Adolescents: 2,000 units/day for 3 months
droxyvitamin D: ~4 hours (Holick 2011) or 50,000 units every month for 3 months
Excretion: Feces (1OM 2011) Serum 25(OH)D level 5 to 15 ng/mL: Infants, Chil-
Dosing dren, and Adolescents: 4,000 units/day for 12 weeks
Neonatal or 50,000 units every other week for 12 weeks
Adequate intake (Al): Oral: 400 units/day (IOM 2011) Serum 25(OH)D level <5 ng/mL: Infants, Children,
Vitamin D deficiency, prevention: and Adolescents: 8,000 units/day for 4 weeks then
Premature neonates: 4,000 units/day for 2-months for total therapy of 3
AAP recommendations (Abrams 2013): Oral: months or 50,000 units/week for 4 weeks followed
$1.5 kg: 200 units/day by 50,000 units 2 times/month for a total therapy of 3
>1.5 kg: 200 units/day; increase dose to 400 units/ months
day when tolerating full enteral nutrition; maximum Maintenance dose [once repletion accomplished;
daily dose: 1,000 units/day i serum 25(OH)D level >30 ng/mL]: Infants, Children,
Alternate dosing: Neonates <1 kg: Oral: 150 to 400 and Adolescents: 200 to 1,000 units/day
units/kg/day (Greer 2000) Vitamin D Deficiency in cystic fibrosis, prevention
Term neonates: Breast-fed (fully or partially): Oral: 400 and treatment: Oral:
units/day beginning in the first few days of life; con- CF guidelines (Tangricha [CF Foundation] 2012):
tinue supplementation until infant is weaned to 21,000 Recommended inital daily intake to maintain serum
mL/day vitamin D-fortified formula (Golden 2014; 25(OH)D level 230 ng/mL:
Wagner 2008) Infants: Oral: 400 to 500 units/day
Vitamin D deficiency, treatment: Oral: Note: In addi- Children $10 years: Oral: 800 to 1,000 units/day
tion to calcium and phosphorus supplementation: 2,000 Children >10 years and Adolescents: Oral: 800 to
units daily or 50,000 units once weekly for 6 weeks to 2,000 units/day
achieve a serum 25(OH)D level >20 ng/mL; followed by Dosing adjustment for serum 25(OH)D level
a maintenance dose of 400 to 1,000 units daily (Golden between 20 to 30 ng/mL and patient adherence
2014; Holick 2011). Note: For patients at high risk of established (Step 1 increase):
fractures a serum 25(OH)D level >30 ng/mL has been Infants: Oral: 800 to 1,000 units/day

435
CHOLECALCIFEROL

Children <10 years: Oral: 1,600 to 3,000 units/day Decara: 50,000 units [contains fd&c yellow #10 (quino-
Children >10 years and Adolescents: Oral: 1,600 line yellow), fd&c yellow #6 (sunset yellow), soy-
to 6,000 units/day bean oil]
Dosing adjustment for serum 25(OH)D level <20 ng/ Dialyvite Vitamin D’5000: 5000 units
mL or persistently between 20 to 30 ng/mL and Pronutrients Vitamin D3: 1000 units [contains ‘soy-
patient adherence established (Step 2 increase): bean oil]
Infants: Increase up to a maximum 2,000 units/day Generic: 10,000 units, 50,000 units
Children $10. years: Increase to a maximum of Capsule, Oral [preservative free]:
4,000 units/day D-3-5: 5000 units [dairy free, dye free, egg free, gluten
Children >10 years and Adolescents: Increase to a free, no artificial color(s), nut free, soy free, sugar free,
maximum of 10,000 units/day wheat free, yeast free]
Alternate dosing (Hall 2010): D3-50: 50,000 units [dairy free, egg free, fish derivative
Initial dose: Serum 25(OH)D level $30 ng/mL free, gluten free, kosher certified, no artificial color(s),
Infants: Oral: 8,000 units/week nut free, soy free, sugar free, wheat free, yeast free}
Children and Adolescents: Oral: 800 units/day Generic: 1000 units, 2000 units, 5000 units, 10,000 units
Medium-dose regimen:*Serum 25(OH)D level Liquid, Oral:
remains <30 ng/mL and patient compliance estab- Aqueous Vitamin D: 400 units/mL (50 mL) [gluten free,
lished lactose free, sugar free; contains methylparaben, poly-
Infants and Children <5 years: Oral: 12,000 units/ sorbate 80]
week for 12 weeks Bio-D-Mulsion: 400. units/0.03 mL (30 mL [DSC]) [con-
Children 25 years and Adolescents: Oral: 50,000 tains sesame oil]
units/week for 12 weeks Bio-D-Mulsion Forte: 2000 units/0.03 mL (30 mL [DSC])
High-dose regimen: Repeat 25(OH)D level remains [contains sesame oil]
$30 ng/mL and patient compliance established BProtected Pedia D-Vite: 400 units/mL (50 mL) [alcohol
Infants and Children <5 years: Oral: 12,000 units free, sugar free; contains polysorbate 80, propylene
twice weekly for 12 weeks glycol, sodium benzoate; cherry flavor]
Children 25 years and Adolescents: Oral: 50,000 D-Vi-Sol: 400 units/mL (50 mL) [gluten free, lactose free,
units twice weekly for 12 weeks sugar free; contains polysorbate 80]
Renal Impairment: Pediatric There are no dosage D-Vita: 400 units/mL (50 mL [DSC}) [alcohol free, gluten
adjustments provided in the manufacturer's labeling; free, lactose free, sugar free; contains polysorbate 80,
however, cholecalciferol is not renally eliminated to a propylene glycol, sodium benzoate; fruit flavor]
significant extent and dosage adjustment is not neces- D3 Vitamin: 400 units/mL (50 mL) [contains polysorbate
sary. 80, sodium benzoate]
Hepatic Impairment: Pediatric There are no dosage Generic: 400 units/mL (50 mL, 52.5 mL)
adjustments provided in the manufacturer's labeling. Liquid, Oral [preservative free]:
Administration May be administered without regard to Generic: 5000 units/mL (52.5 mL)
meals; for oral liquid, use accompanying dropper for Tablet, Oral:
dosage measurements Delta D3: 400 units [gelatin free, gluten free, lactose free,
Monitoring Parameters Children at increased risk of no artificial color(s), no artificial flavor(s), starch free,
vitamin D deficiency (chronic fat malabsorption, chronic sugar free, yeast free]
antiseizure medication use) require serum 25(OH)D, PTH, Dialyvite Vitamin D3 Max: 50,000 units [scored]
and bone-mineral status to evaluate. If vitamin D supple- Vitamin D3 Super Strength: 2000 units [gluten free]
Vitamin D3 Ultra Potency: 50,000 units
ment is required, then 25(OH)D levels should be repeated
at 3-month intervals until normal. PTH and bone mineral- Generic: 400. units, 1000 units, 2000 units, 3000 units,
5000 units
status should be monitored every 6 months until normal.
Tablet, Oral [preservative free]:
Chronic kidney disease: Monitor serum 25(OH)D, cor- Generic: 400 units, 1000 units, 2000 units, 5000 units
rected total calcium and phosphorus levels 1 month Tablet Chewable, Oral:
following initiation of therapy, every 3 months during Generic: 400 units
therapy and with any Vitamin D dose change; alkaline
phosphatase, BUN
Reference Range Vitamin D status may be determined by Cholestyramine Resin (koe LES teer a meen REZ in)
serum 25(OH)D levels (Misra 2008): Brand Names: US Prevalite; Questran; Questran Light
Severe deficiency: $5 ng/mL (12.5 nmol/L) Brand Names: Canada Novo-Cholamine; Novo-Chol-
Deficiency: 15 ng/mL (37.5 nmol/L) amine Light; Olestyr; PMS-Cholestyramine; Questran;
Insufficiency: 15 to 20 ng/mL (37.5 to 50 nmol/L) Questran Light Sugar Free; ZYM-Cholestyramine-Light;
Sufficiency: 20 to 100 ng/mL (50 to 250 nmol/L)* ZYM-Cholestyramine-Regular
Excess: >100 ng/mL (250 nmol/L)**
Therapeutic Category Antilipemic Agent, Bile Acid
Intoxication: 150 ng/mL (375 nmol/L) Sequestrant
“Based on adult data a level of >32 ng/mL (80 nmol/L) is
Generic Availability (US) Yes
desirable
Use Adjunct in the management of primary hypercholester-
*“Arbitrary designation
olemia (FDA approved in adults); pruritus associated with
Target serum 25(OH)D: >30 ng/mL
elevated levels of bile acids (FDA approved in adults); has
Additional Information 1 mcg cholecalcifero!l provides
also been used to manage diarrhea associated with
40 units of vitamin D activity
excess fecal bile acids; applied topically to treat diaper
Biological potency may be greater with cholecalciferol dermatitis and as a skin-protectant around enterostomy
(vitamin D3) compared to ergocalciferol (vitamin D2). fistula sites.
Chronic kidney disease (CKD) (KDIGO, 2013; KDOQI, Pregnancy Risk Factor C
2002): Children 22 years, Adolescents, and Adults: Pregnancy Considerations
GFR <60 mL/minute/1.73 m? or kidney damage for 23 Lipid concentrations increase during pregnancy as
months; stages of CKD are described below: required for normal fetal development. When increases
CKD Stage 1: Kidney damage with normal or increased are greater than expected, supervised dietary interven-
GFR; GFR >90 mL/minute/1.73 m2 tion should be initiated. Bile acid sequestrants are rec-
CKD Stage 2: Kidney damage with mild decrease in ommended when treatment is needed (Avis 2009;
GFR; GFR 60 to 89 mL/minute/1.73 m? Jacobson 2015).
CKD Stage 3: Moderate decrease in GFR; GFR 30 to 59 Cholestyramine is not absorbed systemically, but may
mL/minute/1.73 m2 interfere with maternal vitamin absorption; therefore,
CKD Stage 4: Severe decrease in GFR; GFR 15 to 29 regular prenatal supplementation may not be adequate.
mL/minute/1.73 m2 Breastfeeding Considerations
CKD Stage 5: Kidney failure; GFR <15 mL/minute/1.73 Due to lack of systemic absorption, cholestyramine is not
m? or dialysis expected to be present in breast milk.
Dosage Forms Excipient information presented when When treatment for hypercholesterolemia in breastfeeding
available (limited, particularly for generics); consult spe- women is needed, therapy with bile acid sequestrants
cific product labeling. [DSC] = Discontinued product may be considered (Jacobson 2015; NICE 2008). How-
Capsule, Oral: ever, because use may interfere with maternal vitamin
D3-50: 50,000 units [dairy free, egg free, fish derivative absorption, the manufacturer recommends caution be
free, gluten free, kosher certified, no artificial color(s), used if administered to breastfeeding women.
nut free, soy free, sugar free, wheat free, yeast free] Contraindications Hypersensitivity to bile acid seques-
Decara: 10,000 units [contains fd&c yellow #10 alumi- tering resins or any component of the formulation; com-
num lake, fd&c yellow #6 aluminum lake, gelatin plete biliary obstruction
(bovine)} Warnings/Precautions Secondary causes of hyperlipi-
Decara: 25,000 units [contains soybean oil] demia should be ruled out prior to therapy. Bile acid

436
 CHOLESTYRAMINE RESIN

sequestrants should not be used in patients with baseline Storage/Stability Store at 20°C to 25°C (68°F to 77°F);
fasting triglyceride levels 2300 mg/dL or type Ill hyper- excursions permitted to 15°C to 30°C (59°F to 86°F).
lipoproteinemia since severe triglyceride elevations may Mechanism of Action Forms a nonabsorbable complex
occur. Use bile acid sequestrants with caution in patients with bile acids in the intestine, releasing chloride ions in
with triglyceride levels 250 to 299 mg/dL and evaluate a the process; inhibits enterohepatic reuptake of intestinal
fasting lipid panel in 4 to 6 weeks after initiation; discon- bile salts and thereby increases the fecal loss of bile salt-
tinue use if triglycerides are >400 mg/dL (Stone 2013). bound low density lipoprotein cholesterol
Use caution in patients with renal impairment. Not to be Pharmacodynamics/Kinetics (Adult data unless
taken simultaneously with many other medicines noted)
(decreased absorption). Treat any diseases contributing Onset of action: Peak effect: 21 days
to hypercholesterolemia first. Use with caution in patients Absorption: None
susceptible to fat-soluble vitamin deficiencies. Absorption Excretion: Feces (as insoluble complex with bile acids)
of fat soluble vitamins A, D, E, and K and folic acid may be Dosing
decreased; patients should take vitamins 24 hours before Neonatal Diaper dermatitis: Limited data available: Top-
cholestyramine. Chronic use may be associated with ical: Apply to affected area with each diaper change;
bleeding problems (especially in high doses); may be Note: Product not commercially available; may be pre-
prevented with use of oral vitamin K therapy. May produce pared as an extemporaneously compounded ointment or
or exacérbate constipation problems; fecal impaction may paste in Aquaphor; usual concentration: 5% to 10%;
occur; initiate therapy at a reduced dose in patients with a although higher concentrations (up to 20%) have been
history of constipation. Hemorrhoids may be worsened. compounded; some centers have also used petrolatum
Some products may contain phenylalanine. as the base for compounding (White 2003; Williams
, Warnings: Additional Pediatric Considerations With 2011) .
prolonged use, may potentially cause hypochloremic Pediatric
acidosis due to the exchange of organic anions for chlor- Diaper dermatitis: Limited data available: Topical:
ide; risk may be higher in younger and smaller patients; Infants and Children: Apply to affected area with each
growth failure and malnutrition may occur in these patients diaper change; Note: Product not commercially avail-
(ASPEN Core Curriculum, 2010). Prolonged exposure to able; may be prepared as an extemporaneously com-
tooth enamel may result in discoloration or erosion; pounded ointment or paste in Aquaphor® or
patients should be instructed to avoid sipping or slowly polyethylene glycol; usual concentration 5% to 10%;
swallowing cholestyramine doses and to maintain good although higher concentrations (up to 20%) have
dental hygiene practices. May increase serum triglyceride been compounded; some centers have also used
concentrations; in a trial of children and adolescents (>10 petrolatum as the base for compounding (Preckshot
years of age); the serum triglycerides increased 6% to 9% 2001; White 2003; Williams 2011)
from baseline (not statistically significant) (McCrindle, Dyslipidemia: Limited data available: Oral: Note: Dos-
1997). ages are expressed in terms of anhydrous resin:
Adverse Reactions Age-directed (fixed-dosing): Children 26 years and
Cardiovascular: Edema, syncope Adolescents: Initial 2 to 4 g/day for 1 week, then
Central nervous system: Anxiety, dizziness, drowsiness, increase as tolerated to 8 g/day; children <10 years
fatigue, headache, neuralgia, paresthesia, vertigo of age may only tolerate daily dose of 4 g (McCrindle
Dermatologic: Perianal skin irritation, skin irritation, skin 2007; Sprecher 1996; Tonstad 1996); lipid-lowering
rash, urticaria effects are better if dose is administered as a single
Endocrine & metabolic: Hyperchloremic metabolic acido- daily dose with the evening meal (single daily morn-
sis (children), increased libido, weight gain, weight loss ing doses are less effective); if patients cannot
Gastrointestinal: Abdominal pain, anorexia, biliary colic, tolerate once daily dosing, the total daily dose may
constipation, dental bleeding, dental caries, dental dis- be divided into 2 doses and administered with the
coloration, diarrhea, diverticulitis, duodenal ulcer with morning and evening meals; may also be adminis-
hemorrhage, dysgeusia, dysphagia, eructation, flatu- tered in 3 divided doses daily (Daniels 2002); doses
lence, gallbladder calcification, gastric ulcer, gastrointes- >8 g/day may not provide additional significant cho-
tinal hemorrhage, hemorrhoidal bleeding, hiccups, lesterol-lowering effects, but may increase adverse
intestinal obstruction (rare), melena, nausea, pancreati- effects (Sprecher 1996)
tis, rectal pain, steatorrhea, tongue irritation, tooth Weight-directed dosing: Children and Adolescents:
enamel damage (dental erosion), vomiting 240 mg/kg/day in 3 divided doses; titrate to effect,
Genitourinary: Diuresis, dysuria, hematuria maximum daily dose: 8 g/day
Hematologic & oncologic: Adenopathy, anemia, brui