The effect of rofecoxib, a highly selective cyclooxygenase (COX)-2 inhibitor, on the pharmacokinetics of ethinyl estradiol (EE) and norethindrone (NET), two common components of a combination oral contraceptive product, was examined. A double-blind, two-period crossover study was conducted in 18 healthy women who received ORTHO-NOVUM 1/35, a combination of EE (35 microg) and NET (1 mg), concurrently for 14 days with either 175 mg rofecoxib or matching placebo during two consecutive menstrual cycles. Plasma was sampled for EE, NET, sex hormone binding globulin (SHBG), and albumin. The AUC(0-24 h) geometric mean ratio (GMR: rofecoxib/placebo) with corresponding 90% confidence interval (CI) of EE and NET was 1.13 (1.06, 1.19) and 1.18 (1.13, 1.24), respectively. The Cmax GMR of EE and NET was 1.06 (0.98, 1.16) and 1.04 (0.99, 1.09), respectively. In each case, the 90% CIs satisfied the predefined bioequivalence limits of (0.80, 1.25). Measures of SHBG and albumin and routine clinical and laboratory safety parameters showed no clinically meaningful changes. The addition of rofecoxib to the oral contraceptive was not associated with any clinically important changes in EE or NET pharmacokinetics and thus would not be anticipated to influence the efficacy of this contraceptive regimen.