Pharmacology.
Cyclophosphamide is inactive in vitro and must be enzymatically activated in the liver to yield active alkylating compounds and toxic metabolites. Cell-cycle phase nonspecific.
Administration and Adult Dosage.
IV or PO alone or in combination regimens 250-500 mg/m2 q 3-4 weeks. IV (usually) or PO in high-dose intermittent regimens (including bone marrow transplant) maximum of 40-50 mg/kg given once or over 2-5 days, repeat q 2-4 weeks-these doses are not well tolerated orally.
IV doses may be given in any convenient volume of all common IV solutions or by IV push. Continuous daily administration PO 1-5 mg/kg/day; during continuous therapy, dosage must be individualized based on patient bone marrow response.
Special Populations.
Pediatric Dosage.
IV, PO for malignancies same as adult dosage. PO for nephrotic syndrome 2.5-3 mg/kg/day for up to 8 weeks.
Geriatric Dosage.
Same as adult dosage.
Other Conditions.
No dosage alteration appears necessary in renal impairment because differences in toxicity between normals and patients with renal failure have not been reported.
Dosage Forms.
Tab 25, 50 mg; Inj 100, 200, 500 mg, 1, 2 g.
Patient Instructions.
Drink 2-3 quarts of fluids daily (1-2 quarts in smaller children) and urinate frequently; do not take oral doses at bedtime. Report any blood in the urine.
Pharmacokinetics.
Fate.
Oral absorption is 74 ± 22%. Metabolized to active compounds (including the highly toxic nonalkylating aldehyde, acrolein, and the principal alkylator, phosphoramide mustard) primarily by hepatic microsomal mixed-function oxidases. Cyclophosphamide is 13% plasma protein bound; its alkylating metabolites are 50% bound. Vd is 0.78 ± 0.57 L/kg for parent drug; Cl is 0.078 ± 0.03 L/hr/kg.10 Renal elimination accounts for 6.5 ± 4.3% of unchanged drug and 60% of metabolites,34 with a mean renal clearance of 0.66 L/hr of unchanged drug. Clearance may be reduced in obese patients. Elimination is linear over a wide range of doses.
t1⁄2.
(Serum alkylating activity) 7.5 ± 4 hr, slightly longer in patients on allopurinol or those previously exposed to cyclophosphamide; unchanged in renal dysfunction.
Adverse Reactions.
Emetic potential is moderate to high (>1 g). Nausea, vomiting, and alopecia are frequent and dose dependent. Dose-limiting toxicity is myelosuppression, with a WBC nadir of about 10 days; platelets also are suppressed, perhaps to a lesser extent. Transient, reversible blurred vision occurs frequently. The drug is locally nonirritating. Renally eliminated active metabolites occasionally cause sterile hemorrhagic cystitis, which can resolve slowly, often leading to a fibrotic, contracted bladder. Bladder epithelial changes range from minimal to frank neoplasia. An early sign of cystitis is microscopic hematuria, which can lead to hemorrhage. Prophylactic hydration is recommended. To prevent urotoxicity with high-dose regimens, administer mesna.
Acetylcysteine (Mucomyst) bladder irrigations can have antidotal activity. Rarely, bladder dysplasia can lead to bladder cancer after very high doses or with concurrent or prior bladder radiation. Cross-allergenicity with other alkylators (eg, mechlorethamine) can occur. Ovarian and testicular function can be permanently lost after high-dose, long-term therapy. Rare reactions are a high-dose fatal cardiomyopathy, “allergic” interstitial pneumonitis, and a transient condition similar to SIADH that is preventable with vigorous isotonic hydration.
Contraindications.
Previous life-threatening hypersensitivity to cyclophosphamide; marked leukopenia and thrombocytopenia; hemorrhagic cystitis; severe pulmonary toxicity caused by prior alkylator therapy.
Precautions.
Consider dosage reduction or discontinuation of drug in patients who develop infections.
Drug Interactions.
Cyclophosphamide can prolong the action of neuromuscular blocking agents. Allopurinol and cimetidine can enhance cyclophosphamide myelotoxicity.
Parameters to Monitor.
Before induction therapy, assess the patient for adequate numbers of WBCs (>3500/_L) and platelets (>120,000/_L). With long-term use, assess these counts at least monthly. Monitor closely for hematuria, especially if the patient has received a large cumulative dosage.
Notes.
Do not dilute with benzyl alcohol-preserved solutions. Diluted solution is stable for 24 hr at room temperature and 6 days under refrigeration. Widely used in hematologic and solid malignancies and as an immunosuppressant in a variety of autoimmune disorders.
