Drug Interactions between allopurinol and azathioprine

ADJUST DOSE: Allopurinol may potentiate the pharmacologic effects of orally administered thiopurines. Severe bone marrow suppression and other toxicity have been associated with concomitant use of allopurinol and mercaptopurine (6-MP) or azathioprine, the latter of which is metabolized to 6-MP in vivo. The mechanism is thought to be allopurinol inhibition of 6-MP first-pass metabolism via hepatic or intestinal xanthine oxidase, the enzyme that catalyzes the inactivation of 6-MP. In one study, allopurinol pretreatment resulted in a nearly 500% increase in peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of oral 6-MP. No effect was observed on the pharmacokinetics of intravenous 6-MP. In a retrospective study of 24 heart and/or lung transplant patients receiving azathioprine, investigators found that 46% became leukopenic, 30% moderately anemic, and 22% thrombocytopenic within 3 months after starting allopurinol despite general compliance with thiopurine dosage reduction guidelines. Thus, decreasing the dosage by two-thirds or greater as often recommended does not abolish the risk of myelotoxicity.

MANAGEMENT: Caution is advised if allopurinol must be used concomitantly with oral thiopurines. Most authorities recommend that thiopurine dosage be reduced to approximately 1/4 to 1/3 the usual dosage, and the patient closely monitored for hematologic and other toxicity. Subsequent doses should be adjusted based on therapeutic response and appearance of adverse effects. Patients should be advised to consult their physician if they develop signs and symptoms suggestive of thiopurine toxicity such as fever, chills, sore throat, fatigue, lethargy, pallor, anorexia, jaundice, dark urine, nausea, vomiting, signs of local infection, and unusual bleeding or bruising.