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(sigh-kloe-FOSS-fuh-mide)
Cytoxan
Lyophilized powder for injection
100 mg, 200 mg, 500 mg, 1 g, 2 g
Tablets
25 mg and 50 mg
Neosar
Dry powder for injection
100 mg, 200 mg, 500 mg, 1 g, 2 g
Class: Alkylating agent
Nitrogen mustard

 Actions 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. Cyclophosphamide is well absorbed after oral administration with a bioavailability > 75%. Plasma protein binding of unchanged drug is low, but some metabolites are > 60% bound. The drug is activated and inactivated to alkylating and nonalkylating metabolites respectively, by the P450 system in the liver. It is eliminated primarily in the form of metabolites; 5% to 25% of a dose is excreted as unchanged cyclophosphamide which has an elimination half-life of 3 to 12 hr.

 Indications

Adult

Lymphomas, multiple myeloma, leukemias, disseminated neuroblastoma, ovarian adenocarcinoma, retinoblastoma, breast carcinoma, mycosis fungoides.

Pediatric

Lymphomas, multiple myeloma, leukemias, disseminated neuroblastoma, ovarian adenocarcinoma, retinoblastoma, breast carcinoma, mycosis fungoides.

Bronchogenic, small cell lung, cervical, endometrial, prostate, and testicular carcinomas; sarcomas, bone marrow transplantation; systemic lupus erythematosus, vasculitis, rheumatoid arthritis, and other autoimmune diseases.

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

 Route/Dosage

Lymphomas, Multiple Myeloma, Leukemias, Disseminated Neuroblastoma, Ovarian Adenocarcinoma, Retinoblastoma, Breast Carcinoma, Mycosis Fungoides

ADULTS: PO/IV Dosage regimens that include cyclophosphamide are too numerous to list. Usual doses range from 500 to 1500 mg/m2 per course of therapy. In myelosuppressed patients, reduce initial loading dose by 33 to 50%.

ADULTS: PO 60 to 120 mg/m2/day for initial and maintenance therapy.

Dosage Adjustment (Hepatic Dysfunction Reduction)

ADULTS: PO/IV If LFTs show bilirubin 3.1 to 5 mg/dL or AST > 180 units/L, administer 75% of dose. If bilirubin > 5 mg/dL, no dose is to be given.

Lymphomas, Multiple Myeloma, Leukemias, Ovarian Adenocarcinoma, Retinoblastoma, Breast Carcinoma, Mycosis Fungoides

PEDIATRIC: PO/IV Doses are similar to those used in adult regimens and calculated based on body surface area (BSA). Usual doses range from 500 to 1500 mg/m2 per course of therapy. Follow dosage adjustment guidelines recommended for adults.

PEDIATRIC: PO 60 to 120 mg/m2/day for initial and maintenance therapy.

Neuroblastoma

PEDIATRIC: IV 3000 mg/m2/day for 2 days or 2000 mg/m2/day for 3 consecutive days.

Interactions

Anticoagulants

Increased hypoprothrombinemic effect may occur.

Barbiturates, other enzyme inducers

May increase the rate of active cyclophosphamide metabolite formation and possibly increase neutropenic effects.

Chloramphenicol, other enzyme inhibitors

May inhibit cyclophosphamide’s antineoplastic activity by decreasing rate of active metabolite formation.

Digoxin

May cause decreased serum levels of digoxin.

Oral quinolone antibiotics

May cause decreased GI absorption of quinolone antibiotics.

Succinylcholine, and possibly mivacurium

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

Lab Test Interferences None well documented.

 Adverse Reactions

CARDIOVASCULAR: Acute hemorrhagic myocarditis; CHF; cardiac necrosis. DERMATOLOGIC: Alopecia; skin and fingernail hyperpigmentation; palmar-plantar erythrodysesthesia. ENDOCRINE: Inappropriate antidiuretic hormone syndrome. GI: Nausea; vomiting; diarrhea; mucositis. GU: Hemorrhagic cystitis; amenorrhea; reversible oligospermia and azoospermia; sterility. HEMATOLOGIC: Bone marrow suppression. HYPERSENSITIVITY: Cross sensitivity with other alkylating agents. OTHER: Secondary malignancy; bladder carcinoma; hemorrhagic cystitis; myeloproliferative malignancy; lymphoproliferative malignancy. RENAL: Renal tubular necrosis. RESPIRATORY: Interstitial pulmonary fibrosis.

 Precautions

Pregnancy: Category D. Lactation: Cyclophosphamide is excreted in breast milk. 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. 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. Cardiac toxicity: Few instances of cardiac dysfunction have occurred. No causal relationship has been established. Cardiotoxicity has been observed in some patients receiving high doses of cyclophosphamide ranging from 120 to 270 mg/kg administered over a period of a few days. Fertility impairment: 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. GU: Acute hemorrhagic cystitis occurs in 7% to 12% of patients, although some report an occurrence of up to 40%, and is probably caused by urinary metabolites. Ample fluid intake and frequent voiding help to prevent cystitis. A formalin (37% formaldehyde solution diluted to a 1% solution) bladder instillation has successfully controlled the cystitis. Complications may occur with the 10% solution; there appears to be no additional value in using > 4% solutions. The use of mesna has reduced the incidence of cyclophosphamide-induced cystitis. Hematologic: Leukopenia of < 2000 cells/mm3 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. Hypersensitivity: Hypersensitivity reactions (type I) have occurred. Hyperuricemia: May occur because of rapid cell lysis; monitor serum uric acid. Minimize effects of hyperuricemia with hydration, urinary alkalinization, and allopurinol. Immunosuppression: May cause significant suppression of immune responses. Serious, sometimes fatal infections may develop in severely immunosuppressed patients. Renal effects: A syndrome of inappropriate antidiuretic hormone (SIADH) has occurred with IV doses > 50 mg/kg. It is both a limitation to and consequence of fluid loading. Hemorrhagic ureteritis and renal tubular necrosis have occurred. Renal/Hepatic function impairment: Use cautiously. There is no evidence indicating a need for modified dosage in these patients. Wound healing: May interfere with normal wound healing.

PATIENT CARE CONSIDERATIONS

 Administration/Storage

  • Store tablets or powder for injection at room temperature.
  • Reconstitute powder for injection with Sterile Water or Bacteriostatic Water (with parabens only) for Injection, shaking the vial to dissolve the powder.
  • Reconstitute cyclophosphamide according to the following guidelines: 100 mg vial with 5 mL diluent; 200 mg vial with 10 mL; 500 mg vial with 25 mL (20 to 25 mL for Cytoxan lyophilized powder; 1000 mg vial with 50 mL; 2000 mg vial with 100 mL (80 to 1000 mL Cytoxan lyophilized powder.
  • Reconstituted solutions may be further diluted with: 5% Dextrose, 5% Dextrose with 0.9% Sodium Chloride, or 0.45% Sodium Chloride. The maximum concentration of cyclophosphamide for IV infusion is 20 mg/mL.
  • For use in bone marrow transplantation regimens, reconstitute powder with Sterile Water for Injection. The reconstituted 20 mg/mL solution may be infused without further dilution.
  • Solutions prepared with Sterile Water for Injection are preservative-free. Discard preservative-free cyclophosphamide solutions within 24 hr of preparation.
  • Administer by oral, IV infusion, or IV/IM injection.
  • Vigorous hydration and frequent urination reduces the risk of hemorrhagic cystitis. Patients may be hydrated with 1.5 to 2 L of fluids for 3 hr prior to cyclophosphamide to ensure adequate urine output. Encourage patients to drink extra fluids (especially water) during the next 24 hr to maintain urine output.
  • Oral tablets should be taken on an empty stomach.
  • Follow safe handling procedures when dispensing and disposing oral chemotherapy. Wear gloves and avoid skin exposure and inhalation of fumes.

IV Infusion

  • Cyclophosphamide may be infused over 1 to 2 hr.

Extemporaneous Oral Solution

  • Oral solutions may be prepared from powder for injection (dry or lyophilized) by dissolving the powder in Aromatic Elixir NF to a concentration of 1 to 5 mg/mL. It is stable for up to 14 days in glass bottles under refrigeration.

Cytoxan

  • Solutions prepared with Bacteriostatic Water for Injection are stable for 48 hr at room temperature or up to 28 days under refrigeration.

Neosar

  • Solutions prepared with Bacteriostatic Water for Injection are stable for 24 hr at room temperature or up to 6 days under refrigeration.

 Assessment/Interventions

  • During treatment, monitor the patient’s hematologic profile (particularly neutrophils and platelets) regularly to determine the degree of hematopoietic suppression. Examine urine regularly for red cells which may precede hemorrhagic cystitis.

Mesna Treatment

  • Cotreatment with mesna (a uroprotectant) may be required to prevent hemorrhagic cystitis in patients receiving high doses of cyclophosphamide. Consider mesna prophylaxis when cyclophosphamide doses > 1000 mg/m2 are administered.

 Patient/Family Education

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

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