Mechanism of action
Cyclophosphamide has both antimitotic and immunosuppressive properties. It has a cytotoxic effect on lymphocytes. It is a nitrogen mustard analogue which is converted to the active metabolite in the body.
The dose in rheumatoid vasculitis is 1 to 3 mg/kg/day orally. In some other conditions (such as systemic lupus erythematosus—SLE), it can be administered as an intravenous pulse.
The usefulness of cyclophosphamide is limited by its toxicity. The most common, and potentially serious, adverse effect with use of cyclophosphamide is bone marrow suppression, particularly neutropenia. Even if patients tolerate cyclophosphamide well for several months, there is usually a gradual decline in the white blood cell count that eventually requires dose adjustment.
Accumulation of active metabolites can lead to haemorrhagic cystitis. Strategies for preventing haemorrhagic cystitis include adequate hydration (intake of 3 litres of water per day), taking oral doses in the morning with plenty of water, and the use of mesna at the time of intravenous administration of cyclophosphamide (see Treatment regimens for systemic vasculitis).
Other adverse effects include nausea, vomiting, malaise and alopecia. There is an increased risk of bladder cancer with long-term use. Secondary bone marrow disorders including secondary leukaemia have been reported.
Pneumocystis jiroveci (carinii) pneumonia prophylaxis (eg with sulphamethoxazole+trimethoprim) should be considered for all patients unless contraindicated by allergy. Sulphamethoxazole+trimethoprim can also contribute to marrow suppression (see Pneumocystis jiroveci (carinii) pneumonia in Antibiotic guidelines).
A protocol for full blood count monitoring (at least every 2 weeks) should be established before initiating therapy. Patients with borderline cell counts may need more frequent monitoring.Urine analysis should be performed monthly, and patients advised to report dysuria. Cystoscopy should be performed if cystitis is suspected either because of symptoms, or asymptomatic abnormality on urine analysis. If cystitis is confirmed, it is a contraindication to further use of cyclophosphamide.