Feburic Drug Interactions

Mercaptopurine/azathioprine: On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. Drug interaction studies of febuxostat with drugs (except theophylline) that are metabolized by XO have not been performed in humans.
Modelling and simulation analysis of data from a pre-clinical study in rats indicates that, in case of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see Precautions and Pharmacology: Toxicology: Preclinical safety data under Actions).
Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted. In the Tumor Lysis Syndrome pivotal trial febuxostat 120 mg daily was administered to patients undergoing several chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drug-disease interactions were not explored during this study. Therefore, possible interactions with any concomitantly administered cytotoxic drug cannot be ruled out.
Rosiglitazone/CYP2C8 substrates: Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, co-administration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds.
Theophylline: An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline.
Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly.
No data is available for febuxostat 120 mg.
Naproxen and other inhibitors of glucuronidation: Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t_1/2 26%). In clinical studies the use of naproxen or other NSAIDs/COX-2 inhibitors was not related to any clinically significant increase in adverse events.
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.
Inducers of glucuronidation: Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat. Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation. Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.
Colchicine/indomethacin/hydrochlorothiazide/warfarin: Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat. Administration of febuxostat (80 mg or 120 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR and Factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine/CYP2D6 substrates: Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro. In a study in healthy subjects, 120 mg Feburic QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo. Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.
Antacids: Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed. Therefore, febuxostat may be taken without regard to antacid use.