CYCLOPHOSPHAMIDE

The authors make no claims of the accuracy of the information contained herein; and these
suggested doses and/or guidelines are not a substitute for clinical judgment. Neither GlobalRPh Inc.
nor any other party involved in the preparation of this document shall be liable for any special,
consequential, or exemplary damages resulting in whole or part from any user's use of or reliance
upon this material. PLEASE READ THE DISCLAIMER CAREFULLY BEFORE ACCESSING OR USING
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USUAL DILUENTS
D5W, D5NS, D5LR, LR, 0.45NS, NS
Dilution Data

Solutions of cyclophosphamide may be injected intravenously, intramuscularly, intraperitoneally, or

intrapleurally if constituted by adding 0.9% sodium chloride solution, or they may be infused
intravenously in the diluents listed above.1
Administration:
Slow IVP (doses ≤1 gram2): Cyclophosphamide should be prepared for parenteral use by adding
0.9% sterile sodium chloride solution if injected directly.
IVPB or continuous intravenous infusion2: I.V. infusions may be administered over 1 to 24 hours.
Doses >500 mg to approximately 2 grams may be administered over 20-30 minutes.
Stability/Storage: Constituted cyclophosphamide is chemically and physically stable for 24 hours at
room temperature or for six days in the refrigerator; it does not contain any antimicrobial
preservative and thus care must be taken to assure the sterility of prepared solutions.1
Further dilutions in D5W or NS are stable for 24 hours at room temperature (25°C) and 6 days at
refrigeration2.
Alternatively3:
≤1 gram: 100 mL NS
> 1 g: 250 mL NS
High dose in BMT: 500-1000 ml NS
or 4:
[Doses ≤1 gram] [100 mL NS] [ 15 minutes]
[Doses 1000 - 2000 mg] [250mL NS] [ 30 minutes]
[Doses >2000mg] [250-500mL ] [30-60 minutes]
[High dose (2000 mg/m2 or greater)] [1000 mL NS] [over 1 to 4 hours]
Stability / Miscellaneous
PHARMACOLOGY INDICATIONS CONTRAINDICATIONS
DOSAGE AND ADMINISTRATION PREPARATION / DILUTION HOW SUPPLIED
WARNINGS/PRECAUTIONS - See package insert.
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DESCRIPTION
Cyclophosphamide for Injection, USP is a sterile white powder containing cyclophosphamide
monohydrate. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the
nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula
C7H15CI2N2O2P•H2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate.

CLINICAL PHARMACOLOGY
Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a
mixed function microsomal oxidase system. These metabolites interfere with the growth of
susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve
cross-linking of tumor cell DNA.
Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than
75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in
the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug.
Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma.
Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose.
Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent
greater than 60%. It has not been demonstrated that any single metabolite is responsible for either
the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of
cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in
such patients has not been demonstrated.

INDICATIONS AND USAGE

Malignant Diseases
Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used
concurrently or sequentially with other antineoplastic drugs. The following malignancies are often
susceptible to cyclophosphamide treatment: Malignant lymphomas (Stages III and IV of the Ann
Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell
type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic
lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis),
acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children
(cyclophosphamide given during remission is effective in prolonging its duration). Mycosis
fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary.
Retinoblastoma. Carcinoma of the breast.
Nonmalignant Disease Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:
Cyclophosphamide is useful in carefully selected cases of biopsy proven “minimal change” nephrotic
syndrome in children but should not be used as primary therapy. In children whose disease fails to
respond adequately to appropriate adrenocorticosteroid therapy or in whom the
adrenocorticosteroid therapy produces or threatens to produce intolerable side effects,
cyclophosphamide may induce a remission. Cyclophosphamide is not indicated for the nephrotic
syndrome in adults or for any other renal disease.
CONTRAINDICATIONS
Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone
marrow function. Cyclophosphamide is contraindicated in patients who have demonstrated a
previous hypersensitivity to it. See WARNINGS and PRECAUTIONS sections.
DOSAGE AND ADMINISTRATION
Treatment of Malignant Diseases Adults and Children
When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients
with no hematologic deficiency usually consists of 40 to 50 mg/kg given intravenously in divided
doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7
to 10 days or 3 to 5 mg/kg twice weekly.

Oral cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and
maintenance dosing.

Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must
be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte
count is a good, objective guide for regulating dosage. Transient decreases in the total white blood
cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000
cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no
marked granulocytopenia.
When cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce
the dose of cyclophosphamide as well as that of the other drugs.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative
differences depending upon the dialysis system being used. Patients with compromised renal
function may show some measurable changes in pharmacokinetic parameters of cyclophosphamide
metabolism, but there is no consistent evidence indicating a need for cyclophosphamide dosage
modification in patients with renal function impairment.

Treatment of Nonmalignant Diseases Biopsy Proven “Minimal Change’’ Nephrotic Syndrome in

Children
An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the
incidence of oligospermia and azoospermia increases if the duration of cyclophosphamide treatment
exceeds 60 days. Treatment beyond 90 days increases the probability of sterility.
Adrenocorticosteroid therapy may be tapered and discontinued during the course of
cyclophosphamide therapy. See PACKAGE INSERT FOR PRECAUTIONS section concerning
hematologic monitoring.

Preparation and Handling of Solutions

Parenteral drug products should be inspected visually for particulate matter and discoloration prior
to administration, whenever solution and container permit.
Cyclophosphamide should be prepared for parenteral use by adding 0.9% sterile sodium chloride
solution if injected directly.

Cyclophosphamide should be prepared for parenteral use by infusion by adding Sterile Water for
Injection, USP. Cyclophosphamide, constituted in water, is hypotonic and should not be injected
directly. Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve
immediately and completely, it is advisable to allow the vial to stand for a few minutes.
Use the quantity of diluent shown below to constitute the product:

Cyclophosphamide for Injection

Dosage Strength Contains Cyclophosphamide Monohydrate Quantity of Diluent
500 mg 534.5 mg 25 mL
1g 1069.0 mg 50 mL
2g 2138.0 mg 100 mL
Solutions of cyclophosphamide may be injected intravenously, intramuscularly, intraperitoneally, or
intrapleurally if constituted by adding 0.9% sodium chloride solution, or they may be infused
intravenously in the following:

Dextrose Injection, USP (5% dextrose)

Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sodium chloride)

5% Dextrose and Ringer’s Injection

Lactated Ringer’s Injection, USP

Sodium Chloride Injection, USP (0.45% sodium chloride)

Sodium Lactate Injection, USP (1/6 molar sodium lactate)

Constituted cyclophosphamide is chemically and physically stable for 24 hours at room temperature
or for six days in the refrigerator; it does not contain any antimicrobial preservative and thus care
must be taken to assure the sterility of prepared solutions.

The osmolarities of solutions of cyclophosphamide constituted with water and 0.9% sodium
chloride solution are found in the following table:

Cyclophosphamide and Diluent mOsm/L

5 mL water per 100 mg cyclophosphamide (anhydrous) 74
5 mL 0.9% sodium chloride solution per 100 mg cyclophosphamide (anhydrous) 374
Isotonic 0.9% sodium chloride solution has an osmolarity of 289 mOsm/L.

Cyclophosphamide solution in water is hypotonic.

Extemporaneous liquid preparations of cyclophosphamide for oral administration may be prepared

by dissolving cyclophosphamide in Aromatic Elixir, N.F.& Such preparations should be stored under
refrigeration in glass containers and used within 14 days.

HOW SUPPLIED
Cyclophosphamide for Injection, USP contains cyclophosphamide monohydrate and is supplied in
vials for single dose use.
NDC 10019-955-01 500 mg vial, carton of 1

NDC 10019-956-01 1.0 g vial, carton of 1

NDC 10019-957-01 2.0 g vial, carton of 1

Store vials at or below 25°C (77°F) [see USP Controlled Room Temperature]. During transport or
storage of cyclophosphamide vials, temperature influences can lead to melting of the active
ingredient, cyclophosphamide. Vials containing melted substance can be visually differentiated.
Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase
or in droplets in the affected vials. Do not use cyclophosphamide vials if there are signs of melting.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several
guidelines on this subject have been published.1-8 There is no general agreement that all of the
procedures recommended in the guidelines are necessary or appropriate.

Reference(s)
PRIMARY:
1) [PACKAGE INSERT DATA] : CYCLOPHOSPHAMIDE injection, powder, for solution. Baxter
Healthcare Corporation. Deerfield, IL 60015 USA. Revision Date 07/2009.
2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to
Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.
3. BC Cancer Agency Chemotherapy Preparation and Stability Chart© version 2.00. Revised Date: 1
July 2010. https://www.bccancer.bc.ca
4. Cancer care Ontario. 620 University Avenue Toronto Ontario, Canada M5G
2L7. https://www.cancercare.on.ca/
Proper handling and disposal: ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines
and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-
2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington,
D.C. 20402. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985;
253 (11): 1590-1592. National Study Commission on Cytotoxic Exposure—Recommendations for
Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study
Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences,
179 Longwood Avenue, Boston, Massachusetts 02115. Clinical Oncological Society of Australia.
Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia 1983;
1:426-428. Jones RB, et al: Safe Handling of chemotherapeutic agents: A Report from the Mount Sinai
Medical Center. CA—A Cancer Journal for Clinicians 1983; (Sept/Oct) 258-263. American Society of
Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am
J Hosp Pharm 1990; 47:1033-1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA
WORK PRACTICE GUIDELINES). Am J Health Syst Pharm 1996; 53:1669-1685.