Malignant Diseases

CYTOXAN (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 CYTOXAN (cyclophosphamide) treatment:

1. 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.
2. Multiple myeloma.
3. 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 (CYTOXAN (cyclophosphamide) given during remission is effective in prolonging its duration).
4. Mycosis fungoides (advanced disease).
5. Neuroblastoma (disseminated disease).
6. Adenocarcinoma of the ovary.
7. Retinoblastoma.
8. Carcinoma of the breast.

Nonmalignant Disease

Biopsy Proven "Minimal Change" Nephrotic Syndrome in Children

CYTOXAN (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, CYTOXAN (cyclophosphamide) may induce a remission. CYTOXAN (cyclophosphamide) is not indicated for the nephrotic syndrome in adults or for any other renal disease.

Treatment of Malignant Diseases

Adults and Children

When used as the only oncolytic drug therapy, the initial course of CYTOXAN (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 CYTOXAN (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 CYTOXAN (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 CYTOXAN (cyclophosphamide) is included in combined cytotoxic regimens, it may be necessary to reduce the dose of CYTOXAN (cyclophosphamide) as well as that of the other drugs.

CYTOXAN (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 CYTOXAN (cyclophosphamide) metabolism, but there is no consistent evidence indicating a need for CYTOXAN (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 CYTOXAN (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 CYTOXAN therapy. See PRECAUTIONS 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.

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:

For Direct Injection

CYTOXAN (cyclophosphamide) should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution. Solutions of CYTOXAN (cyclophosphamide) may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally if constituted by adding 0.9% sterile sodium chloride solution.

For Infusion

CYTOXAN (cyclophosphamide) may be prepared for parenteral use by infusion using any of the following methods:

1. CYTOXAN (cyclophosphamide) constituted with 0.9% sterile sodium chloride may be infused without further dilution.
2. CYTOXAN (cyclophosphamide) constituted with 0.9% sterile sodium chloride may be infused following further dilution in the following:
   Dextrose Injection, USP (5% dextrose)
   Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
   5% Dextrose and Ringer's Injection
   Lactated Ringer's Injection, USP
   Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
   Sodium Lactate Injection, USP (1/6 molar sodium lactate)
3. CYTOXAN (cyclophosphamide) sterile powder may be prepared for parenteral use by infusion by adding Sterile Water for Injection, USP. CYTOXAN (cyclophosphamide) , constituted in water, is hypotonic and should not be injected directly. Prior to infusion, solutions of CYTOXAN (cyclophosphamide) sterile powder constituted in Sterile Water for Injection, USP must be further diluted in one of the following:
   Dextrose Injection, USP (5% dextrose)
   Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
   5% Dextrose and Ringer's Injection
   Lactated Ringer's Injection, USP
   Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
   Sodium Lactate Injection, USP (1/6 molar sodium lactate)

Stability of Constituted Parenteral Solutions

CYTOXAN (cyclophosphamide) (prepared for either direct injection or infusion) 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 CYTOXAN (cyclophosphamide) constituted with water and 0.9% sterile sodium chloride solution are found in the following table:

Isotonic 0.9% sterile sodium chloride solution has an osmolarity of 289 mOsm/L.

For Oral Administration

Extemporaneous liquid preparations of CYTOXAN (cyclophosphamide) for oral administration may be prepared by dissolving CYTOXAN (cyclophosphamide) in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.

CYTOXAN® (cyclophosphamide for injection, USP) contains cyclophosphamide monohydrate and is supplied in vials for single-dose use. CYTOXAN (cyclophosphamide for injection, USP). U.S. Patent No. 4,537,883

NDC 0015-0502-41.......................500 mg vial, carton of 1
NDC 0015-0505-41.......................1.0 g vial, carton of 1
NDC 0015-0506-41.......................2.0 g vial, carton of 1

Store vials at or below 77° F (25° C). During transport or storage of CYTOXAN (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 CYTOXAN (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.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing CYTOXAN (cyclophosphamide) sterile powder for injection. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.

2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621.

3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253: 1590-1592.

4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust.1983;1:426-428.

6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin.1983;33:258-263.

7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm.1990;47:1033-1049.

8. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health- Syst Pharm.1996;53:1669-1685.

Vials Manufactured by: Baxter Healthcare Corporation Deerfield, Illinois 60015 USA. Vials Distributed: Bristol-Myers Squibb Company Princeton, New Jersey 08543. Revised September 2005. FDA Rev date: 11/7/2003

Last reviewed on RxList: 10/25/2010
This monograph has been modified to include the generic and brand name in many instances.