Contraindications of Concomitant Use of Azathioprine and Allopurinol on Drug Package Inserts: Case Study and Comparison of New and Existing Issues of Novel Xanthine Oxidase Inhibitor

Abstract

Background/Methods: Allopurinol, a xanthine oxidase inhibitor, inhibits the metabolism of the active metabolite 6-mercaptopurine (6-MP) of azathioprine. An increased blood concentration of 6-MP results in severe myelosuppression. The package insert of febuxostat and topiroxostat states that the concomitant use of azathioprine is contraindicated, but that of allopurinol states that it may be used with caution. Based on our own case study, we demonstrated the risk of concomitant use, and investigated the inconsistent descriptions of interactions between azathioprine and uric acid synthesis inhibitors on package inserts.

Case: We report a patient with a markedly decreased renal function who was administered allopurinol, being administered azathioprine (75 mg/day) at 20 years after renal transplantation. Allopurinol was reduced to 50 mg/day. The dose of azathioprine was reduced to 50 mg/day. However, this regime resulted in prominent pancytopenia, which resolved after allopurinol was discontinued.

Results/Discussion: Although the contraindication of the concomitant use of azathioprine and febuxostat or topiroxostat is based on allopurinol being the base drug, allopurinol itself is not a contraindication. The explanation for the inconsistent descriptions of interactions between azathioprine and xanthine oxidase inhibitors on package inserts is not supported by the evidence.

An interaction that increases blood levels of nucleic acid antimetabolites, such as that of 5-FU and sorivudine, is a very dangerous and causes myelosuppression. The accumulation of the active metabolite oxypurinol of allopurinol also occurred in patients with an impaired renal function, including the present patient, which additionally increases the blood concentration of 6-MP. Thus, the concomitant use of azathioprine and allopurinol should be contraindicated, particularly in patients with an impaired renal function.