CyclophosphamideRx

Trade Names: Cytoxan, Neosar

Synonyms: CTX, CYT, CYC  (abbreviations not recommended)

Drug Class: Cancer chemotherapeutic; alkylating agent

Preparations
Tablets: 25-  and 50 mg
Powder for injection:  500 mg; 1- and 2 g

Dose: Varies according to indication and patient response – examples  below
Oral dose: 1–3 mg/kg/day
Intravenous infusion: Dose of 500–750 mg/square m repeated monthly for 3-6 months. An alternative regimen for SLE nephritis, termed the “Euro-Lupus” regimen, is 500 mg IV every 2 weeks for a total of 6 doses followed by maintenance therapy with azathioprine or mycophenolate.  Whatever the regimen, adjust dose according to clinical response and WBC nadir and recovery. In many conditions, after an induction period of infusions for 3-6 months an alternative therapy is instituted to maintain remission.

Indications: Vasculitis, rheumatoid vasculitis, SLE with organ involvement, polymyositis/dermatomyositis refractory to treatment

Mechanism of Action: Interferes with DNA synthesis by alkylating and cross-linking DNA strands

Contraindications: Hypersensitivity to cyclophosphamide; pregnancy

Precautions: Bone marrow suppression, active infection, decrease dose in renal/hepatic impairment, avoid BCG and live virus vaccines, consider dose reduction if renal or hepatic function impaired, reliable contraception

Monitoring: Frequent monitoring of CBC and platelets is required. Nadir of WBC occurs 10–14 days after a single dose. A WBC nadir of 3,000/mm3 is sometimes used as a target for intravenous pulses. With long-term use, monitor urinalysis for blood. During and after long- term oral use, monitor for bladder cancer with urinalysis, cytology, and (if needed) cystoscopy.

Pregnancy Risk: D

Adverse Effects: Dose and duration dependent; myelosuppression (WBC more than platelets), infections (bacterial and viral infections and opportunistic organisms). Hemorrhagic cystitis is more common with daily oral regimens. Gonadal suppression and permanent infertility occur. Risk of ovarian failure is greater with oral regimens and increases in frequency with increased age of female patients. GI symptoms increase with dose. Pulmonary fibrosis, rashes, hypersensitivity, and fluid retention occur. Long-term risk of secondary malignancy (bladder, lymphoma, leukemia, and skin cancers).

Drug Interactions
Thiazide diuretics: May cause prolonged leukopenia
Immunosuppressants: Concurrent therapy increases risk of myelosuppression
and infection

Patient Instructions: Take as a single dose in the morning and drink lots of liquids to keep urine diluted. Empty bladder frequently. Report blood in urine. Avoid live virus vaccines. Regular follow-up is essential. Report any significant fever. Use reliable contraception.

Comments: Life-threatening complications may occur with cyclophosphamide treatment. Titrate dose to avoid leucopenia. Oral regimens are preferred by some for vasculitis, and the less toxic monthly intravenous regimen is generally preferred for SLE. Duration of cyclophosphamide therapy is empirical, but after disease remission, alternative drugs are substituted to maintain  remission. Premedicate with antiemetic regimen and continue antiemetic prophylaxis for 24–48 hours. Mesna may be used to protect against hemorrhagic cystitis. Consider pneumocystis prophylaxis.

Clinical Pharmacology: Good rapid oral absorption; hepatic metabolism to several active metabolites including 4-hydroxycyclophosphamide. Plasma half-life is 2–10 hours. Metabolites are eliminated in the urine. Acrolein is the urinary metabolite thought to cause hemorrhagic cystitis.

Cost: $$$$

BIBLIOGRAPHY

Langford CA. Cyclophosphamide as induction therapy for Wegener's granulomatosis and microscopic polyangiitis. Clin Exp Immunol. 2011 May;164 Suppl 1:31-4.PMID:21447129

Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res 2012;64(6):797-808. PMID:22556106