Furic Drug Interactions

Xanthine Oxidase Substrate Drugs: Febuxostat is an XO inhibitor. Drug interaction studies of febuxostat with drugs that are metabolized by XO (eg, theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to toxicity. Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine or theophylline.
Cytotoxic Chemotherapy Drugs: Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of febuxostat during cytotoxic chemotherapy.
In Vivo Drug Interaction Studies: Based on drug interaction studies in healthy subjects, febuxostat does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, febuxostat may be used concomitantly with these medications.
Effect of Febuxostat on Other Drugs: Xanthine Oxidase Substrate Drugs-Azathioprine, Mercaptopurine and Theophylline: Febuxostat is an XO inhibitor. Drug interaction studies that febuxostat with drugs that are metabolizer by XO (eg, theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibitor of XO by febuxostat may cause increased plasma concentrations of these drug leading to toxicity. Febuxostat is contraindicated in patients being treated with azathioprine, mercaptopurine and theophylline.
Azathioprine and mercaptopurine undergo metabolism via 3 major metabolic pathways, 1 of which is mediated by XO. Although febuxostat drug interaction studies with azathioprine and mercaptopurine have not been conducted, concomitant administration of allopurinol (a XO inhibitor) with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because febuxostat is a XO inhibitor, it could inhibit the XO-mediated metabolism of azathioprine and mercaptopurine leading to increased plasma concentrations of azathioprine or mercaptopurine that could result in severe toxicity.
Theophylline is a CYP1A2 and XO substrate. Although no febuxostat drug interaction study with theophylline has been conducted, concomitant administration of theophylline with allopurinol, a xanthine oxidase inhibitor at doses=600 mg/day, has been reported to increase theophylline plasma concentrations. Because febuxostat is a xanthine oxidase inhibitor and theophylline is a low therapeutic index drug, febuxostat could inhibit the XO-mediated metabolism of theophylline leading to increased plasma concentrations of theophylline that could induce severe theophylline toxicity.
P450 Substrate Drugs: In vitro studies have shown that febuxostat does not inhibit P450 enzymes CPY1A2, 2C9, 2C19, 2D6 or 3A4 and it also does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 at clinically relevant concentrations. As such, pharmacokinetic interactions between febuxostat and drugs metabolized by these CYP enzymes are unlikely.
Effect of Other Drugs on Febuxostat: Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between febuxostat and a drug that inhibits or induces 1 particular enzyme isoform in general is not expected.
In Vivo Drug Interaction Studies: Colchicine: No dose adjustment is necessary for either febuxostat or colchicine when the 2 drugs are co-administered. Administration of febuxostat (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in C_max and 7% in AUC₂₄ of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with febuxostat (120 mg daily) resulted in <11% change in C_max or AUC of colchicine for both am and pm doses. These changes were not considered clinically significant.
Naproxen: No dose adjustment is necessary for febuxostat or naproxen when the two drugs are co-adminstered. Administration of febuxostat (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in C_max and a 40% increase in AUC of febuxostat. The increase were not considered clinically significant. In addition, there were no significant changes in the C_max or AUC of naproxen (<2%).
Indomethacin: No dose adjustment is necessary for either febuxostat or indomethacin when these 2 drugs are co-administered. Administration of febuxostat (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in C_max or AUC of febuxostat or indomethacin (<7%).
Hydrochlorothiazide: No dose adjustment is necessary for febuxostat when co-administered with hydrochlorothiazide. Administration of febuxostat (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in C_max or AUC of febuxostat (<4%) and serum uric acid concentrations were not substantially affected.
Warfarin: No dose adjustment is necessary for warfarin when co-administered with febuxostat. Administration of febuxostat (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. International normalized ratio (INR) and factor VII activity were also not affected by the co-administration of febuxostat.
Desipramine: Co-administration of drugs that are CYP2D6 substrates (eg, desipramine) with febuxostat are not expected to require dose adjustment. Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro and in vivo. Administration of febuxostat (120 mg once daily) with desipramine (25 mg) resulted in an increase in C_max (16%) and AUC (22%) of desipramine, which was associated with a 17% decrease in the 2-hydroxydesipramine to desipramine metabolic ratio (based on AUC).