Cyclophosphamide
Pronouncation: (sigh-kloe-FOSS-fuh-mide)Class: Nitrogen mustard
Trade Names:
Cytoxan
- Lyophilized powder for injection 100ߙmg
- Lyophilized powder for injection 200 mg
- Lyophilized powder for injection 500 mg
- Lyophilized powder for injection 1 g
- Lyophilized powder for injection 2 g
- Tablets 25 mg
- Tablets 50 mg
Trade Names:
Neosar
- Dry powder for injection 100 mg
- Dry powder for injection 200ߙmg
- Dry powder for injection 500 mg
- Dry powder for injection 1 g
- Dry powder for injection 2 g
Pharmacology
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Feedback for Cyclophosphamide
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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 t ½ 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 ImpairmentMetabolites may be elevated but increased toxicity has not been seen.
Indications and Usage
AdultLymphomas, multiple myeloma, leukemias, disseminated neuroblastoma, ovarian adenocarcinoma, retinoblastoma, breast carcinoma, mycosis fungoides.
ChildrenLymphomas, multiple myeloma, leukemias, disseminated neuroblastoma, ovarian adenocarcinoma, retinoblastoma, breast carcinoma, mycosis fungoides.
Unlabeled Uses
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.
Dosage and Administration
Lymphomas, Multiple Myeloma, Leukemias, Disseminated Neuroblastoma, Ovarian Adenocarcinoma, Retinoblastoma, Breast Carcinoma, Mycosis FungoidesAdults
PO/IV Dosage regimens that include cyclophosphamide are too numerous to list. Usual doses range from 500 to 1,500ߙmg/m 2 per course of therapy. In myelosuppressed patients, reduce initial loading dose by 33% to 50%.
PO 60 to 120 mg/m 2 /day for initial and maintenance therapy.
Dosage Adjustment (Hepatic Function Impairment Reduction)Adults
PO/IV If LFTs show bilirubin 3.1 to 5 mg/dL or AST greater than 180 units/L, administer 75% of dose. If bilirubin is greater than 5ߙmg/dL, no dose is to be given.
Lymphomas, Multiple Myeloma, Leukemias, Ovarian Adenocarcinoma, Retinoblastoma, Breast Carcinoma, Mycosis FungoidesChildren
PO/IV Doses are similar to those used in adult regimens and calculated based on BSA. Usual doses range from 500 to 1,500ߙmg/m 2 per course of therapy. Follow dosage adjustment guidelines recommended for adults.
PO 60 to 120 mg/m 2 /day for initial and maintenance therapy.
NeuroblastomaChildren
IV 3,000 mg/m 2 /day for 2 days or 2,000 mg/m 2 /day for 3 consecutive days.
General Advice
- 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 10ߙmL; 500 mg vial with 25 mL (20 to 25ߙmL for Cytoxan lyophilized powder); 1,000 mg vial with 50 mL; 2,000 mg vial with 100ߙmL (80 to 1,000ߙmL for Cytoxan lyophilized powder).
- Reconstituted solutions may be further diluted with: dextrose 5%, dextrose 5% with sodium chloride 0.9%, or sodium chloride 0.45%. The maximum concentration of cyclophosphamide for IV infusion is 20ߙmg/mL.
- For use in bone marrow transplantation regimens, reconstitute powder with sterile water for injection. The reconstituted 20ߙmg/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 h of preparation.
- 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.
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.
Storage/Stability
Store tablets or powder for injection at room temperature.
CytoxanSolutions prepared with bacteriostatic water for injection are stable for 48 h at room temperature or up to 28 days under refrigeration.
NeosarSolutions prepared with bacteriostatic water for injection are stable for 24 h at room temperature or up to 6 days under refrigeration.
Drug Interactions
AnticoagulantsIncreased hypoprothrombinemic effect may occur.
Barbiturates, other enzyme inducersMay increase the rate of active cyclophosphamide metabolite formation and possibly increase neutropenic effects.
Chloramphenicol, other enzyme inhibitorsMay inhibit cyclophosphamide's antineoplastic activity by decreasing rate of active metabolite formation.
DigoxinMay cause decreased serum levels of digoxin.
Oral quinolone antibioticsMay cause decreased GI absorption of quinolone antibiotics.
Succinylcholine and possibly mivacuriumProlongation of neuromuscular blockade by cyclophosphamide's inhibition of pseudocholinesterase may occur.
Laboratory Test Interactions
None well documented.
Adverse Reactions
Cardiovascular
Acute hemorrhagic myocarditis; CHF; cardiac necrosis.
Dermatologic
Alopecia; skin and fingernail hyperpigmentation; palmar-plantar erythrodysesthesia.
Endocrine
SIADH.
GI
Nausea; vomiting; diarrhea; mucositis.
Genitourinary
Hemorrhagic cystitis; amenorrhea; reversible oligospermia and azoospermia; sterility.
Hematologic
Bone marrow suppression.
Hypersensitivity
Cross-sensitivity with other alkylating agents.
Miscellaneous
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.
Hypersensitivity
Hypersensitivity reactions (type I) have occurred.
Renal Function
Use cautiously. There is no evidence indicating a need for modified dosage in these patients.
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. Cardiotoxicity has been observed in some patients receiving high doses of cyclophosphamide ranging from 120 to 270ߙmg/kg administered over a period of a few days.
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. 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 h prior to cyclophosphamide to ensure adequate urine output. Encourage patients to drink extra fluids (especially water) during the next 24 h to maintain urine output. 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 greater than 4% solutions. The use of mesna (a uroprotectant) has reduced the incidence of cyclophosphamide-induced cystitis. Cotreatment with mesna may be required to prevent hemorrhagic cystitis in patients receiving high doses of cyclophosphamide. Consider mesna prophylaxis when cyclophosphamide doses greater than 1,000ߙmg/m 2 are administered.
Hematologic
Leukopenia of less than 2,000ߙcells/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.
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
SIADH has occurred with IV doses greater than 50 mg/kg. It is both a limitation to and consequence of fluid loading. Hemorrhagic ureteritis and renal tubular necrosis have occurred.
Wound healing
May interfere with normal wound healing.
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: 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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More Cyclophosphamide resources:
cyclophosphamide oral/injection
Cyclophosphamide - Includes detailed dosage instructions.
Cyclophosphamide Drug Interactions
Rheumatoid Arthritis, Multiple Sclerosis, Prostate Cancer, Breast Cancer, Nephrotic Syndrome, Systemic Lupus Erythematosus, Non-Small Cell Lung Cancer, Ovarian Cancer, Multiple Myeloma, Organ Transplant -- Rejection Prophylaxis, Cancer, Acute Nonlymphocytic Leukemia, Chronic Myelogenous Leukemia (CML), Dermatomyositis, Non-Hodgkin's Lymphoma, Endometrial Cancer, Chronic Lymphocytic Leukemia (CLL), Bladder Cancer, Hodgkin's Lymphoma, Mycosis Fungoides, Brain Tumor, Acute Lymphocytic Leukemia, Wegener's Granulomatosus, Testicular Cancer, Cervical Cancer, Osteosarcoma, Small Cell Lung Cancer, Wilms' Tumor, Neuroblastoma, Histiocytosis, Ewing's Sarcoma, Bullous Pemphigoid, Pemphigus, Pemphigoid
