Information for Healthcare Professionals: Intravenous
Promethazine and Severe Tissue Injury, Including
Gangrene
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onforHeathcareProfessionals/ucm182169.htm
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[09/16/2009] FDA is requiring a Boxed Warning for promethazine hydrochloride injection, USP products
to better communicate the risks of severe tissue injury associated with administration of this drug.
Perivascular extravasation, unintentional intra-arterial injection and intraneuronal or perineuronal
infiltration of the drug may result in irritation and tissue damage, including gangrene. The Boxed
Warning will remind practitioners that due to the risks of intravenous injection, the preferred route of
administration is deep intramuscular injection and that subcutaneous injection is contraindicated.
This action is based on FDAs analysis of post-marketing reports of severe tissue injury, including
gangrene, requiring amputation following intravenous administration of promethazine as well as FDAs
review of the current prescribing information for these products. FDA has determined that the
presentation, organization, and content of the prescribing information should be revised to more
effectively communicate the risk of severe tissue injury following intravenous administration.
In addition to the Boxed Warning, FDA is requiring a revision to the Dosage and Administration section
to increase the visibility and accessibility of specific recommendations for the maximum concentration
(25 mg per mL) and rate of administration (25 mg per minute) when intravenous administration of
promethazine is required.
FDA is requiring the changes to the prescribing information under the authorities granted to FDA by the
Food and Drug Administration Amendments Act (FDAAA) of 2007.
Promethazine hydrochloride injection, USP is approved for a variety of uses including allergic reactions,
sedation, motion sickness, nausea, and vomiting associated with anesthesia and surgery, and as an
adjunct to analgesics for control of postoperative pain.
This information reflects FDAs current analysis of data available to FDA concerning this drug. FDA intends to
update this sheet when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA
MedWatch program using the contact information at the bottom of this page.
Considerations for Healthcare Professionals:
Intravenous administration of promethazine can cause severe tissue injury, including gangrene, requiring
fasciotomy, skin graft, and/or amputation
Severe tissue injury can occur from perivascular extravasation, unintentional intra-arterial injection, and
intraneuronal or perineuronal infiltration
Deep intramuscular injection is the preferred way to administer promethazine hydrochloride injection,
USP products
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Intra-arterial and subcutaneous administration of promethazine are contraindicated
Promethazine hydrochloride injection, USP is available in two strengths, 25 mg/mL and 50 mg/mL
The 50 mg/mL promethazine hydrochloride injection, USP product is for deep intramuscular injection only
The 25 mg/mL promethazine hydrochloride injection, USP product may be administered by deep
intramuscular injection or intravenous injection (see maximum dosage and rate below)
If intravenous administration of promethazine is required, the maximum recommended concentration is 25
mg per mL and the maximum recommended rate of administration is 25 mg per minute through the tubing
of an intravenous infusion set known to be functioning properly
Be alert for signs and symptoms of potential tissue injury including burning or pain at the site of injection,
phlebitis, swelling, and blistering
Injections should be stopped immediately if a patient complains of pain during injection
Inform patients that side effects may occur immediately while receiving the injection or may develop hours
to days after an injection
Refer to the prescribing information for additional information on warnings, contraindications, adverse
events, and dosage and administration of promethazine hydrochloride injection, USP products
Promethazine should not be used in patients less than 2 years of age due to the risk of fatal respiratory
depression
Information for Patients:
Discuss any concerns you may have about the risks and benefits of promethazine with a health care
professional
Pay close attention for any signs or symptoms of adverse events including burning or pain at the injection
site, redness, swelling, and blistering, and report these symptoms immediately
Understand that side effects may occur immediately while receiving a promethazine injection or may
develop hours to days after an injection
Background and Data Summary:
Promethazine was previously sold under the brand name Phenergan Injection but this formulation has been
discontinued by Wyeth Pharmaceuticals, Inc. Currently multiple generic formulations of promethazine
hydrochloride injection, USP are marketed in the United States.
FDA has been aware of the risks of perivascular extravasation and inadvertent intra-arterial administration
causing severe tissue injury that are associated with intravenous administration of promethazine, and
communicated these risks to healthcare professionals and consumers in the December 2006 and February 2008
FDA Patient Safety News (see links to previous communications below). Furthermore, the current prescribing
information for promethazine hydrochloride injection, USP products contains information regarding the risk of
intra-arterial injection and severe tissue injury, including gangrene. Despite the previous safety communications
and the current prescribing information, cases of severe tissue injury following intravenous administration of
promethazine continue to be reported to FDA.
FDA reviewed the published literature and post-marketing adverse event reports submitted to FDAs Adverse
Event Reporting System (AERS) from 1969 to 2009 and identified cases of gangrene requiring amputation
associated with intravenous administration of promethazine. The most common amputations involved the fingers
and hands. Numerous other cases of injection reactions such as injection site pain, redness, phlebitis, cyanosis,
swelling, blistering, necrosis, and nerve damage were also found.
Additionally, FDAs review of the current prescribing information for these products found that the warnings for
gangrene and intra-arterial injection were present, but their organization and presentation in the labeling could
be improved to better convey the risk information. Therefore, based on the above case reports and conclusions
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from the prescribing information review, FDA is requiring manufacturers of these products to revise the labeling
for promethazine, including addition of a Boxed Warning describing the risk of severe tissue injury, including
gangrene, requiring amputation following intravenous administration of promethazine.
Related Information
Promethazine HCl (marketed as Phenergan) Information
Severe Tissue Injury with IV Promethazine (December 2006)
Issued 2/2008
Severe Tissue Injury with IV Promethazine
Issued 12/2006
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