Cyclophosphamide

Pronunciation

Pronunciation: SYE-kloe-FOS-fa-mide
Class: Nitrogen mustard, Alkylating agent

Trade Names

Cyclophosphamide
- Tablets 25 mg
- Tablets 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.

Slideshow: Flashback: FDA Drug Approvals 2013

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. Dosage adjustment required in severe renal impairment.

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; Burkitt 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.

Nephrotic syndrome

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

Unlabeled Uses

Multiple sclerosis; Wegener granulomatosis; other steroid-resistant vasculitis; severe progressive rheumatoid arthritis; SLE; polyarteritis nodosa; bronchogenic, small cell lung, endometrial, prostate, and testicular carcinomas; sarcomas; hematopoietic stem cell transplantation (HSCT).

Contraindications

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

Dosage and Administration

Malignant Diseases
Adults and Children PO

1 to 5 mg/kg daily for both initial and maintenance treatment.

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.

Dosage adjustment

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.

Nephrotic Syndrome (Biopsy-Proven Minimal Change)
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.

Severe Renal Function Impairment

Dosage reduction to 75% of the usual dosage may be necessary in patients with severe renal failure (CrCl 0 to 10 mL/min). After hemodialysis, some clinicians recommend supplementing with 50% of the original dose.

Hepatic Function Impairment

For patients with bilirubin of 3.1 to 5 mg/dL or AST more than 180 units/L, administer 75% of the usual dosage. Do not give to patients with bilirubin more than 5 mg/dL.

General Advice

  • Administer tablets on an empty stomach.
  • Injection may be administered by IV injection, IV infusion (over 1 to 2 h), IM, intraperitoneally, or intrapleurally.
  • 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 injection in aromatic elixir, N.F, to a concentration of 1 to 5 mg/mL.
  • 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

Allopurinol

The myelosuppressive effects of cyclophosphamide may be enhanced, possibly increasing the risk of bleeding or infection. Monitor hematologic function. If an interaction is suspected, it may be necessary to discontinue allopurinol.

Anticoagulants (eg, warfarin)

Increased hypoprothrombinemic effect may occur. Monitor coagulation parameters during and after cyclophosphamide therapy. Adjust the warfarin dose as needed.

Chloramphenicol

Cyclophosphamide half-life may be increased and metabolite concentrations may be decreased. Use an alternative antibiotic if possible.

Digoxin

May cause decreased serum levels of digoxin. Monitor digoxin serum concentrations and the clinical response of the patient. Adjust the digoxin dose as needed.

Doxorubicin

Doxorubicin-induced cardiotoxicity may be potentiated. Use with caution. Monitor for symptoms of cardiotoxicity.

Enzyme inducers (eg, barbiturates [eg, phenobarbital], phenytoin)

Exposure to the active cyclophosphamide metabolites may be increased, increasing the risk of toxicity. If administration cannot be avoided, consider reducing the initial dose of cyclophosphamide and monitoring the concentration of the 4-hydroxycyclophosphamide metabolite as a guide to cyclophosphamide dosing. Valproic acid derivatives or gabapentin may be alternatives to the use of phenytoin.

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

Exposure to cyclophosphamide and its metabolites may be increased, increasing the risk of adverse reactions. Closely monitor for cyclophosphamide adverse reactions. Adjust the cyclophosphamide dose as needed to minimize toxicity.

Pentostatin

Additive or synergistic toxicity. Respiratory distress, hypotension, hypothermia, confusion, and death may occur after the coadministration of pentostatin and cyclophosphamide. Avoid coadministration if possible.

Quinolones (eg, ciprofloxacin)

The antimicrobial effects of quinolones may be decreased. Monitor the clinical response of the patient, and adjust the quinolone dose as needed.

Succinylcholine

Prolongation of neuromuscular blockade by cyclophosphamide's inhibition of pseudocholinesterase may occur. Prolonged respiratory depression with extended periods of apnea may occur. Use with caution. If this combination is used, prior measurement of plasma cholinesterase activity with close monitoring of neuromuscular function and appropriate adjustment of succinylcholine dosage is recommended.

Thiazide diuretics

Antineoplastic-induced leukopenia may be prolonged. Monitor hematologic function. Use with caution.

Trastuzumab

The risk of trastuzumab-induced cardiac dysfunction may be increased by coadministration of cyclophosphamide. Close clinical monitoring for signs of cardiac dysfunction is indicated when trastuzumab and cyclophosphamide are coadministered.

Tumor necrosis factor (TNF)–blocking agents (eg, etanercept)

The incidence of noncutaneous solid malignancies may be increased in patients receiving TNF–blocking agents with cyclophosphamide. Coadministration is not recommended.

Vaccines, live

The risk of live vaccine–induced adverse reactions may be increased by coadministration of cyclophosphamide. The use of live vaccines in patients receiving cyclophosphamide should be deferred.

Adverse Reactions

Cardiovascular

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

CNS

Asthenia, malaise (postmarketing).

Dermatologic

Alopecia (common); nail changes, skin pigmentation, skin rash; Stevens-Johnson syndrome, TEN (postmarketing).

Endocrine

SIADH.

GI

Nausea and vomiting (common); abdominal discomfort or pain, anorexia, diarrhea, hemorrhagic colitis, oral mucosal ulceration, nausea, vomiting.

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, sterility, testicular atrophy, urinary bladder fibrosis.

Hepatic

Jaundice.

Hematologic-Lymphatic

Anemia, leukopenia, neutropenia with or without fever, thrombocytopenia.

Hypersensitivity

Anaphylactic reactions, including death.

Respiratory

Interstitial pneumonitis, interstitial pulmonary fibrosis (postmarketing).

Miscellaneous

Secondary malignancies (eg, urinary bladder, myeloproliferative, or lymphoproliferative malignancies; carcinoma of the renal pelvis).

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 . Contraindicated during the first trimester.

Lactation

Excreted in breast milk. Contraindicated in breast-feeding.

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 malignancies have developed with cyclophosphamide alone or with other antineoplastic drugs or radiation therapy. These most frequently have been urinary bladder, myeloproliferative, and lymphoproliferative malignancies. In some cases, the second malignancy developed several years after the discontinuation of cyclophosphamide.

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

Administer with caution 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 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. Rarely, this may be severe and even fatal. Urinary bladder fibrosis may also develop with or without accompanying cystitis. 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

  • Advise patients to take tablets preferably on an empty stomach. If GI upset is severe, advise patients to take with food.
  • Advise patients to notify health care provider if the following symptoms occur: blood in urine or painful/frequent urination, chills, cough, fever, flank or stomach pain, lack of menstrual flow, severe nausea or vomiting, shortness of breath, sore throat, unusual bleeding or bruising, unusual lumps or masses, yellow discoloration of the skin or eyes.
  • Recommend contraceptive measures during therapy for men and women.
  • Advise patients that irreversible sterility may develop.
  • Advise women not to breast-feed.
  • Advise patients to drink extra fluids and void frequently.
  • Advise patients undergoing general anesthesia to inform the anesthesiologist of treatment with cyclophosphamide.

Copyright © 2009 Wolters Kluwer Health.

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