onducted, concomitant administration of allopurinol [a xanthine oxidase inhibitor] with azathioprine or mercaptopurine has been reported to substantially increase plasma concentrations of these drugs. Because ULORIC is a xanthine oxidase 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 ULORIC drug interaction study with theophylline has been conducted, concomitant administration of theophylline with allopurinol, a xanthine oxidase inhibitor at doses ≥ 600 mg per day, has been reported to increase theophylline plasma concentrations. Because ULORIC is a xanthine oxidase inhibitor and theophylline is a low therapeutic index drug, ULORIC 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 CYP1A2, 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 ULORIC and drugs metabolized by these CYP enzymes are unlikely.
Effect of Other Drugs on ULORIC
Febuxostat is metabolized by conjugation and oxidation via multiple metabolizing enzymes. The relative contribution of each enzyme isoform is not clear. Drug interactions between ULORIC and a drug that inhibits or induces one particular enzyme isoform is in general not expected.
In Vivo Drug Interaction Studies
Colchicine: No dose adjustment is necessary for either ULORIC or colchicine when the two drugs are co-administered. Administration of ULORIC (40 mg once daily) with colchicine (0.6 mg twice daily) resulted in an increase of 12% in C and 7% in AUC of febuxostat. In addition, administration of colchicine (0.6 mg twice daily) with ULORIC (120 mg daily) resulted in less than 11% change in C or AUC of colchicine for both AM and PM doses. These changes were not considered clinically significant.
Naproxen: No dose adjustment is necessary for ULORIC or naproxen when the two drugs are co-administered. Administration of ULORIC (80 mg once daily) with naproxen (500 mg twice daily) resulted in a 28% increase in Cand a 40% increase in AUC of febuxostat. The increases were not considered clinically significant. In addition, there were no significant changes in the C or AUC of naproxen (less than 2%).
Indomethacin: No dose adjustment is necessary for either ULORIC or indomethacin when these two drugs are co-administered. Administration of ULORIC (80 mg once daily) with indomethacin (50 mg twice daily) did not result in any significant changes in C or AUC of febuxostat or indomethacin (less than 7%).
Hydrochlorothiazide: No dose adjustment is necessary for ULORIC when co-administered with hydrochlorothiazide. Administration of ULORIC (80 mg) with hydrochlorothiazide (50 mg) did not result in any clinically significant changes in C or AUC of febuxostat (less than 4%), and serum uric acid concentrations were not substantially affected.
Warfarin: No dose adjustment is necessary for warfarin when co-administered with ULORIC. Administration of ULORIC (80 mg once daily) with warfarin had no effect on the pharmacokinetics of warfarin in healthy subjects. INR a
