Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature

Abstract

BACKGROUND There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout. OBJECTIVE To determine the clinical impact of the febuxostat-thiopurine DI. DESIGN AND SETTING Case series derived from the U.S. Food and Drug Administration Adverse EventReporting System (FAERS) and published medical literature. PATIENTS Nineteen patients who received concomitant febuxostat and either AZA or 6-MP. MEASUREMENTS Laboratory and clinical data. RESULTS Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only. LIMITATIONS Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostatthiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting. CONCLUSION Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.

Azathioprine‐induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report

“…The blood concentration of AZA is elevated when administrated with xanthine oxidase inhibitor, which is a metabolic enzyme of 6‐MP, and the adverse effects are exacerbated by the competitive drug interaction. 19 , 20 Hence, a potential risk with the co‐administration of these two drugs has been reported 21 , 22 …”

Hyperuricemia as a trigger of immune response in hypertension and chronic kidney disease

“…131 Current febuxostat labeling contraindicates concomitant administration of febuxostat with either azathioprine or 6-mercaptopurine. 132 Topiroxostat is a novel, nonpurine, selective xanthine oxidase inhibitor approved in Japan that has demonstrated a strong effect against hyperuricemia. Several reports suggest an important protective effect against progression of kidney disease and proteinuria.…”

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art

“…While allopurinol only leads to the inhibition of reduced forms of XO, febuxostat, a newer selective non-purine-based XO inhibitor, inhibits both oxidized and reduced forms and seems to have a greater potency to inhibit XO [41,42]. It seems likely that co-administration of XO inhibitors and thiopurines causes a similar metabolic shift of thiopurine metabolism, and a case series demonstrated that concomitant use is indeed associated with TGNinduced myelosuppressive adverse events [42]. Sulfasalazine and other 5-aminosalicylic acid (5-ASA) derivates, used in gram doses to treat IBD, were shown to be potent in vitro inhibitors of recombinant human TPMT [43][44][45].…”

“…Although the biological mechanism of this switch in preferential metabolism is not completely elucidated, it is suggested that TPMT is directly inhibited because of an increase in thioxanthine, which is a consequence of the inhibition of xanthine dehydrogenase by oxypurinol, the active metabolite of allopurinol [ 40 ]. While allopurinol only leads to the inhibition of reduced forms of XO, febuxostat, a newer selective non-purine-based XO inhibitor, inhibits both oxidized and reduced forms and seems to have a greater potency to inhibit XO [ 41 , 42 ]. It seems likely that co-administration of XO inhibitors and thiopurines causes a similar metabolic shift of thiopurine metabolism, and a case series demonstrated that concomitant use is indeed associated with TGN-induced myelosuppressive adverse events [ 42 ].…”