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Drugs reference index «Cyclophosphamide»

Cyclophosphamide

Pronunciation: (SYE-kloe-FOS-fa-mide)Class: Nitrogen mustard

Trade Names:Cyclophosphamide- Tablets, oral 25 mg- Tablets, oral 50 mg- Injection, powder for solution 500 mg- Injection, powder for solution 1 g- Injection, powder for solution 2 g

Procytox (Canada)

Pharmacology

Cyclophosphamide is first hydroxylated by hepatic microsomal enzymes to the intermediate metabolites 4-hydroxycyclophosphamide and aldophosphamide. These are oxidized to the active antineoplastic alkylating compounds acrolein and phosphoramide mustard. The mechanism of action of the active metabolites is thought to involve cross-linking of DNA, which interferes with growth of susceptible neoplasms and normal tissues.

Pharmacokinetics

Absorption

Well absorbed orally. T max is 2 to 3 h for metabolites (IV dose).

Distribution

More than 75% bioavailable after oral administration. More than 60% of metabolites are bound to plasma proteins. Low protein binding for cyclophosphamide.

Metabolism

Converted to active alkylating metabolites in the liver.

Elimination

The half-life is 3 to 12 h (unchanged drug). Eliminated primarily as metabolites. 5% to 25% is excreted in urine as unchanged drug.

Special Populations

Renal Function Impairment

Metabolites may be elevated, but increased toxicity has not been seen.

Indications and Usage

Malignant diseases

Malignant lymphomas (stages III and IV of the Ann Arbor staging system); Hodgkin disease; lymphocytic lymphoma (nodular or diffuse); mixed-cell type lymphoma; histocytic lymphoma; Burkett lymphoma; multiple myeloma; chronic lymphocytic leukemia; chronic granulocytic leukemia; acute myelogenous and monocytic leukemia; acute lymphoblastic (stem cell) leukemia in children; mycosis fungoides (advanced disease); neuroblastoma (disseminated disease); adenocarcinoma of the ovary; retinoblastoma; carcinoma of the breast.

Nonmalignant diseases

Biopsy-proven minimal change nephrotic syndrome in children, but not as primary therapy.

Unlabeled Uses

Multiple sclerosis; Wegener granulomatosis; other steroid-resistant vasculidites; severe progressive rheumatoid arthritis; systemic lupus erythematosus; polyarteritis nodosa; bronchogenic, small cell lung, endometrial, prostate, and testicular carcinomas; sarcomas; bone marrow transplantation.

Contraindications

Previous hypersensitivity to the drug; continued use in severely depressed bone marrow function.

Dosage and Administration

Malignant DiseasesAdults and Children

PO 1 to 5 mg/kg daily for both initial and maintenance treatment. Adjust dosage according to evidence of antitumor activity and/or leukopenia. Total leukocyte count is an objective indicator for regulating dosage. Transient decreases in the total WBC count to 2,000 cells/mm 3 (following short courses) or more persistent reduction to 3,000 cells/mm 3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia. IV When used as the only oncolytic agent in patients with no hematologic deficiency, the initial dose is 40 to 50 mg/kg in divided doses over a period of 2 to 5 days. Alternatively, other regimens have included 10 to 15 mg/kg every 7 to 10 days or 3 to 5 mg/kg twice weekly. Adjust dosage according to evidence of antitumor activity and/or leukopenia. Total leukocyte count is an objective indicator for regulating dosage. Transient decreases in the total WBC count to 2,000 cells/mm 3 (following short courses) or more persistent reduction to 3,000 cells/mm 3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

Nonmalignant Diseases (Biopsy-Proven Minimal Change Nephrotic Syndrome in Children)Children

PO 2.5 to 3 mg/kg daily for 60 to 90 days is recommended. Oligospermia and azoospermia increase if the duration of treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility.

General Advice

  • Reduce the cyclophosphamide dose when cyclophosphamide is included in combination with cytotoxic regimens.
  • Extemporaneous liquid preparations for oral administration may be prepared by dissolving cyclophosphamide for injections in aromatic elixir, N.F.
  • Follow safe handling procedures when dispensing and discarding oral chemotherapy. Wear gloves and avoid skin exposure and inhalation of fumes.

Storage/Stability

Store tablets and vials below 77°F. The tablets will withstand brief exposure to temperatures up to 86°F. Store extemporaneous oral liquid preparation refrigerated in glass containers and use within 14 days. Constituted cyclophosphamide is stable for 24 h at room temperature or for 6 days in the refrigerator.

Drug Interactions

Anticoagulants (eg, warfarin)

Increased hypoprothrombinemic effect may occur.

Digoxin

May cause decreased serum levels of digoxin.

Doxorubicin

Doxorubicin-induced cardiotoxicity may be potentiated.

Enzyme inducers (eg, barbiturates, phenytoin)

Exposure to the active cyclophosphamide metabolites may be increased, increasing the risk of toxicity.

Enzyme inhibitors (eg, azole antifungal agents [eg, fluconazole, itraconazole], chloramphenicol)

Exposure to cyclophosphamide and its metabolites may be increased, increasing the risk of adverse reactions.

Succinylcholine and possibly mivacurium

Prolongation of neuromuscular blockade by cyclophosphamide's inhibition of pseudocholinesterase may occur.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Acute cardiac toxicity, CHF, hemopericardium, hemorrhagic myocarditis, myocardial necrosis, pericarditis.

CNS

Asthenia, malaise (postmarketing).

Dermatologic

Alopecia, nail changes, skin pigmentation, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

GI

Abdominal discomfort and pain, anorexia, diarrhea, hemorrhagic colitis, oral mucosal ulceration, nausea, vomiting.

Endocrine

SIADH.

Genitourinary

Amenorrhea associated with decreased estrogen and increased gonadotropin secretion, atypical urinary bladder epithelial cells in the urine, azoospermia, cystitis, hematuria, hemorrhagic cystitis, hemorrhagic ureteritis, impairment of fertility, oligospermia, ovarian fibrosis, renal tubular necrosis, testicular atrophy, urinary bladder fibrosis.

Hepatic

Jaundice.

Hematologic-Lymphatic

Anemia, leukopenia, neutropenia with fever, thrombocytopenia.

Hypersensitivity

Anaphylactic reactions, including death.

Respiratory

Interstitial pneumonitis, interstitial pulmonary fibrosis (postmarketing).

Miscellaneous

Infections, secondary malignancies (eg, carcinoma of the renal pelvis, secondary acute myeloid leukemia, urinary bladder malignancies).

Precautions

Monitor

Monitor hematologic profile, particularly neutrophils and platelets, regularly to determine the degree of hematopoietic suppression. Examine urine regularly for RBCs, which may precede hemorrhagic cystitis.

Pregnancy

Category D .

Lactation

Excreted in breast milk.

Elderly

Select dose with caution, usually starting at the low end of the dosing range, and adjust as necessary based on response.

Hypersensitivity

Death associated with anaphylactic reactions has been reported.

Renal Function

Use with caution; there is no consistent evidence indicating a need for dosage modification.

Hepatic Function

Use cautiously. There is no evidence indicating a need for modified dosage in these patients.

Carcinogenesis

Secondary neoplasia has developed with cyclophosphamide alone or with other antineoplastic drugs or radiation therapy. These most frequently have been urinary bladder, myeloproliferative, and lymphoproliferative malignancies.

Fertility

Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in men and women. Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women treated with cyclophosphamide.

Special Risk Patients

Give cautiously to patients with leukopenia, thrombocytopenia, tumor cell infiltration of bone marrow, previous radiation therapy, or previous cytotoxic therapy.

Adrenalectomy patients

Adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.

Cardiac toxicity

Few instances of cardiac dysfunction have occurred. No causal relationship has been established.

GU

Acute hemorrhagic cystitis may occur. Ample fluid intake and frequent voiding help to prevent cystitis. Vigorous hydration and frequent urination reduce the risk of hemorrhagic cystitis. Encourage patients to drink extra fluids to maintain urine output.

Hematologic

Leukopenia of less than 2,000 cells/mm 3 develops commonly in patients treated with an initial loading dose of the drug. Thrombocytopenia or anemia develop occasionally. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.

Immunosuppression

May cause significant suppression of immune responses. Serious, sometimes fatal infections may develop in severely immunosuppressed patients.

Oligospermia and azoospermia

Oligospermia and azoospermia increase if the duration of treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility.

Wound healing

May interfere with normal wound healing.

Overdosage

Symptoms

No information is available.

Patient Information

  • Take tablets preferably on an empty stomach. If GI upset is severe, take with food.
  • Notify health care provider if the following symptoms occur: chills, cough, fever, flank or stomach pain, joint pain, lack of menstrual flow, seizures, shortness of breath, sore throat, sores in the mouth or on the lips, unusual bleeding or bruising, unusual lumps or masses, yellow discoloration of the skin or eyes.
  • Contraceptive measures are recommended during therapy for men and women.
  • Advise patients undergoing general anesthesia to inform the anesthesiologist that they are on cyclophosphamide.

Copyright © 2009 Wolters Kluwer Health.

  • Cyclophosphamide MedFacts Consumer Leaflet (Wolters Kluwer)
  • Cyclophosphamide Prescribing Information (FDA)
  • Cyclophosphamide Detailed Consumer Information (PDR)
  • cyclophosphamide oral/injection Concise Consumer Information (Cerner Multum)
  • cyclophosphamide Oral, Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information
  • Cytoxan Prescribing Information (FDA)

See Also...

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