Cyclophosphamide

Cyclophosphamide

Usual Diluents

Dilution Data

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]

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:

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:

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.

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.