Cyclophosphamide

Cyclophosphamide is an alkylating prodrug used in severe organ-threatening autoimmune disease, including proliferative lupus nephritis, ANCA vasculitis, neuropsychiatric lupus, systemic sclerosis lung disease and refractory inflammatory myopathy. It is gonadotoxic, bladder-toxic and carcinogenic, so cumulative dose is limited and it is used for time-limited induction.

Class. Nitrogen mustard alkylating agent, cytotoxic immunosuppressant.

Mechanism. Hepatic CYP2B6, 2C9 and 3A4 activation produces phosphoramide mustard, which cross-links DNA and kills dividing lymphocytes, and acrolein, which causes urothelial injury.

Pharmacokinetics. Oral bioavailability over 75 percent. Half-life 3 to 12 hours. Active and toxic metabolites are renally excreted, so clearance falls and toxicity rises in renal impairment.

Lupus nephritis (class III, IV or V), low dose induction.

• 500 mg intravenously every 2 weeks for 6 doses (total 3 g), followed by maintenance with azathioprine or mycophenolate.

• Loading dose: none.

• Maximum dose: 3 g cumulative in this regimen.

Lupus nephritis, high dose induction (severe or crescentic disease). 0.5 to 1 g/m2 intravenously monthly for 6 months, with the dose adjusted to the white cell nadir.

ANCA vasculitis induction (severe renal or pulmonary disease).

• Intravenous: 15 mg/kg every 2 weeks for 3 doses, then every 3 weeks, for a total of 3 to 6 months; maximum single dose 1.2 g.

• Oral: 2 mg/kg daily for 3 to 6 months, maximum 200 mg daily.

• Dose reduction with age: about 25 percent lower in patients aged over 60 years and about 40 to 50 percent lower in those over 75 years.

• Rituximab is an alternative induction option.

• Maintenance then switches to azathioprine, methotrexate, mycophenolate or rituximab.

Systemic sclerosis interstitial lung disease (specialist). 1 to 2 mg/kg daily orally for 12 months or intravenous pulses of 500 mg to 1 g/m2 monthly for 6 months.

Renal dose adjustment. eGFR 30 to 59 mL/min: reduce by about 20 to 30 percent; eGFR under 30 mL/min: reduce by about 40 percent or more and extend the interval. Haemodialysis: give after dialysis.

Protective co-prescription. Intravenous hydration with the pulse and oral fluids of 2 to 3 L daily for 24 hours afterwards, frequent bladder emptying, mesna at about 20 percent of the cyclophosphamide dose given at 0, 4 and 8 hours with intravenous pulses of 1 g or more, and morning oral dosing. Antiemetic (ondansetron). Pneumocystis prophylaxis with co-trimoxazole 480 mg daily or 960 mg three times weekly. Ovarian protection with a gonadotrophin-releasing hormone agonist before each pulse in premenopausal women.

Contraindications. Pregnancy, severe marrow suppression, active uncontrolled infection, acute urinary tract obstruction or haemorrhagic cystitis, and hypersensitivity.

Boxed-warning-level risks. Not formally boxed in many regions, but myelosuppression, haemorrhagic cystitis, bladder and haematological malignancy, infertility and teratogenicity are the dose-limiting hazards.

Adverse effects. Common: nausea, vomiting, alopecia, leucopenia with nadir at days 10 to 14, amenorrhoea. Serious: haemorrhagic cystitis, bladder cancer (rises with cumulative dose over about 25 to 36 g), cardiotoxicity at high dose, interstitial pneumonitis, SIADH hyponatraemia, premature ovarian failure and azoospermia, opportunistic infection.

Major interactions. Allopurinol (more marrow toxicity), CYP inducers such as rifampicin and phenytoin (more active metabolite), CYP inhibitors such as azole antifungals (less activation), azathioprine and other myelosuppressives, anticoagulants (monitor INR), succinylcholine (prolonged block), live vaccines (avoid), thiazide diuretics (more marrow toxicity).

Common prescribing errors. Not adjusting for renal function or age; omitting mesna and hydration; missing pneumocystis prophylaxis; exceeding cumulative dose limits.

Special groups.

• Pregnancy: contraindicated (foetal malformations and loss). Use effective contraception during and for 1 year after in women and 4 months after in men.

• Breastfeeding: avoid.

• Children: body surface area dosing; specialist only.

• Older adults: reduced dose; high infection risk.

• Kidney impairment: eGFR 30 to 59 mL/min, reduce by about 20 to 30 percent; under 30 mL/min, reduce by about 40 percent or more and extend the interval.

• Liver impairment: caution; reduced activation and clearance.

• Region: screen for tuberculosis, hepatitis B and HIV; schistosomiasis causes haematuria and bladder pathology, so exclude it before starting where prevalent.

Formulations. 50 mg tablets or capsules; intravenous vials (reconstitute with sterile water or 0.9 percent sodium chloride and infuse over 30 to 60 minutes).

Baseline. Full blood count, creatinine and eGFR, liver enzymes, urinalysis, pregnancy test, hepatitis B, C and HIV serology, and fertility counselling and preservation.

Monitoring. Full blood count at the expected nadir (day 10 to 14 after each pulse), before each pulse, and every 1 to 2 weeks on oral therapy. Urinalysis for haematuria before each dose and indefinitely afterwards. Track cumulative dose.

Hold thresholds. Neutrophils under 1.5 x 10^9/L or white cell count under 4 x 10^9/L before a pulse: delay and reduce the next dose by 20 to 25 percent. Haematuria: stop and perform cystoscopy.

Referral and escalation. Always specialist initiated. Refer for febrile neutropenia (admit, cultures, empirical intravenous antibiotics), persistent haematuria, or inadequate response at 3 months.