cyclophosphamide
Cytoxan, Neosar

Available forms
Available by prescription only
Injection: 100-mg, 200-mg, 500-mg, 1-g, 2-g vials
Tablets: 25 mg, 50 mg

Indications and dosages
Dosages and indications may vary. Check literature for recommended protocols.
 Breast, head, neck, lung, and ovarian carcinoma; Hodgkin’s disease; chronic lymphocytic or myelocytic and acute lymphoblastic leukemia; neuroblastoma; retinoblastoma; malignant lymphomas; multiple myeloma; mycosis fungoides; sarcomas; severe rheumatoid disorders; immunosuppression after transplants. Adults: 40 to 50 mg/kg I.V. in divided doses over 2 to 5 days. Oral dosing for initial and maintenance dosage is 1 to 5 mg/kg P.O. daily.
 Polymyositis. Adults: 1 to 2 mg/kg P.O. daily.
 Rheumatoid arthritis. Adults: 1.5 to 3 mg/kg P.O. daily.
 Wegener’s granulomatosis. Adults: 1 to 2 mg/kg P.O. daily (usually administered with prednisone).
 Nephrotic syndrome in children. Children: 2.5 to 3 mg/kg P.O. daily for 60 to 90 days.
≡ Dosage adjustment. For patients with renal impairment, adjust dosage.

Pharmacodynamics
Antineoplastic action: Cytotoxic action of cyclophosphamide is mediated by its two active metabolites. These metabolites function as alkylating agents, preventing cell division by cross-linking DNA strands. This results in an imbalance of growth within the cell, leading to cell death. Cyclophosphamide also has significant immunosuppressive activity.

Pharmacokinetics
Absorption: Almost completely absorbed from the GI tract at doses of 100 mg or less. Higher doses (300 mg) are about 75% absorbed.
Distribution: Distributed throughout the body, although only minimal amounts have been found in saliva, sweat, and synovial fluid. The level in CSF is too low for treatment of meningeal leukemia. The active metabolites are about 50% bound to plasma proteins.
Metabolism: Metabolized to its active form by hepatic microsomal enzymes. The activity of these metabolites is terminated by metabolism to inactive forms.
Excretion: Eliminated primarily in urine, with 15% to 30% excreted as unchanged drug. The elimination half-life ranges from 3 to 12 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those with severe bone marrow suppression. Use cautiously in patients with impaired renal or hepatic function, leukopenia, thrombocytopenia, or malignant cell infiltration of bone marrow and in those who have recently undergone radiation therapy or chemotherapy.

Interactions
Drug-drug. Allopurinol, chloramphenicol, chloroquine, imipramine, phenothiazines, potassium iodide, vitamin A: May inhibit cyclophosphamide metabolism. Monitor patient closely.
Barbiturates, chloral hydrate, phenytoin: Increases cyclophosphamide metabolism. Use cautiously.
Corticosteroids: Inhibits cyclophosphamide metabolism, reducing its effect. Eventual dosage reduction or discontinuation of corticosteroids may increase cyclophosphamide metabolism to toxic level. Use with extreme caution.
Doxorubicin: Potentiates cardiotoxic effects. Avoid use together.
Succinylcholine: Prolongs respiratory distress and apnea. Use succinylcholine with caution or not at all.

Adverse reactions
CV: cardiotoxicity (with very high doses and with doxorubicin).
GI: anorexia, nausea, vomiting (within 6 hours), abdominal pain, stomatitis, mucositis.
GU: hemorrhagic cystitis, fertility impairment.
Hematologic: leukopenia (nadir between days 8 to 15, recovery in 17 to 28 days), thrombocytopenia, anemia.
Hepatic: hepatotoxicity.
Metabolic: increased serum uric acid levels.
Respiratory: pulmonary fibrosis (with high doses).
Skin: reversible alopecia.
Other: secondary malignant disease, anaphylaxis, hypersensitivity reactions.

Effects on lab test results
• May increase uric acid levels. May decrease pseudocholinesterase levels.
• May decrease hemoglobin, hematocrit, and WBC, RBC, and platelet counts.

Overdose and treatment
Signs and symptoms of overdose include myelosuppression, alopecia, nausea, vomiting, and anorexia.
 Treatment is generally supportive and includes antiemetics and transfusion of blood components. Drug is dialyzable.

Special considerations
• Follow institutional guidelines for safe preparation, administration, and disposal of chemotherapeutic drugs.
• Reconstitute vials with appropriate volume of bacteriostatic or sterile water for injection to give a concentration of 20 mg/ml.
• Reconstituted solution is stable 6 days if refrigerated or 24 hours at room temperature.
• Drug can be given by direct I.V. push into a running I.V. line or by infusion in normal saline solution or D₅W.
• I.M. injections shouldn’t be given when platelet counts are low.
• Higher oral doses (400 mg) may be tolerated better if divided into smaller doses.
• Administration with cold foods such as ice cream may improve toleration of oral dose.
• Push fluid (3 L daily) to prevent hemorrhagic cystitis. Some clinicians use uroprotectant agents such as mesna. Drug shouldn’t be given at bedtime, because voiding afterward is too infrequent to avoid cystitis. If hemorrhagic cystitis occurs, discontinue drug. Cystitis can occur months after therapy has been discontinued.
• Reduced drug dosage is warranted if patient is also receiving corticosteroid therapy and develops viral or bacterial infections.
• Nausea and vomiting are most common with high doses of I.V. cyclophosphamide.
• Drug has been used successfully to treat many nonmalignant conditions, for example, multiple sclerosis, because of its immunosuppressive activity.
• Drug may suppress positive reaction to Candida species, mumps, trichophytin, and tuberculin skin tests. A false-positive result for the Papanicolaou test may occur.
• Monitor uric acid, CBC, and renal and hepatic functions.
• Observe patient for hematuria and dysuria.
• Monitor for cyclophosphamide toxicity if patient’s corticosteroid therapy is discontinued.
Pregnant patients
• Advise both men and women to practice contraception while taking drug and for 4 months after because drug has teratogenic properties.
Breast-feeding patients
• Drug appears in breast milk; woman should discontinue breast-feeding because of risk of serious adverse reactions, mutagenicity, and carcinogenicity in the infant.

Patient education
• Emphasize importance of continuing drug despite nausea and vomiting.
• Tell patient to take oral form with or after a meal.
• Advise patient to report vomiting that occurs shortly after an oral dose.
• Warn patient that alopecia is likely to occur, but that it’s reversible.
• Encourage adequate fluid intake to prevent hemorrhagic cystitis and to facilitate uric acid excretion.
• Tell patient to promptly report unusual bleeding or bruising.
• Advise patient to avoid individuals with infections and to call immediately if fever, chills, or signs of infection occur.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use