Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy

Abstract

Purpose: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Methods: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination nor ethindrone 1.0 mg/ethinyl estradiol 35-μg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Results: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus- time curve over the 24-h period (AUC0.24) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p ≤ 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p ≤ 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline. Conclusions: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing ≤35 μg of ethinyl estradiol.