The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin

Objective: The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokin etics of warfarin. Methods: Two single-dose (12.5 or 50 mg of rofecoxib with 25 mg or 30 mg of oral warfarin, respectively, on day 7 of each period) trials (N = 12 men) and 1 steady-state warfarin trial (25 mg rofecoxib; N = 15, 13 men and 2 wo men) were completed as two-period, randomized, balanced, crossover, double- blind designs. The prothrombin time international normalized ratio (INR) an d S(-) and R(+) warfarin enantiomers were assessed during 144 hours after t he single warfarin doses. In the steady-state warfarin trial, after the att ainment of a stable INR (1.4-1.7), the stable warfarin dose was co-administ ered with rofecoxib (25 mg) and placebo over two 21-day periods. After the dose of warfarin on day 21, INR and S(-) and R(+) warfarin were assessed du ring 24 hours. Results: Compared with placebo, rofecoxib slightly increased the INR by app roximately 5% (90% confidence interval on the geometric ratio, 1.03, 1.08) and 11% (1.04, 1.19) for the two single-dose warfarin trials with 12.5 and 50 mg of rofecoxib, respectively. In the steady-state warfarin study with 2 5 mg of rofecoxib, the INR was increased by 8% (1.02, 1.15). Rofecoxib had no significant effect (versus placebo) on the pharmacokinetics of S(-) warf arin. However, in the 3 studies, treatment with 12.5, 25, and 50 mg of rofe coxib was associated with a 27%, 38%, and 40% increase in the area under th e plasma concentration-time curve of the biologically less active R(+) warf arin. Conclusions: Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR The approximately 8% increase in INR at steady state with warfarin co-administe red with 25 mg of rofecoxib is not likely to be clinically important in mos t patients taking warfarin. However, standard monitoring of INR values shou ld be conducted when therapy with rofecoxib is initiated or changed, partic ularly in the first few days, for patients receiving warfarin.