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

ABSTRACT

PIP: The efficacy of combined oral contraceptives (OCs) is diminished in women taking enzyme-inducing anti-epileptic drugs such as phenytoin, phenobarbital, and carbamazepine. In preliminary in vitro studies, a new anti-epileptic drug derived from D-fructose, topiramate, produced no clinically relevant inhibitory effects on the metabolism of such drugs as barbiturates, classic neuroleptics, and tricyclic antidepressants. To assess this new drug, 12 women with documented histories of epilepsy took an OC containing 1 mg norethindrone and 35 mcg ethinyl estradiol as well as topiramate (100-400 mg every 12 hours) for 4 menstrual cycles. Serial blood samples were obtained on day 20 of the 4 cycles. None of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate. Ethinyl estradiol serum levels were reduced by an average of 30% from baseline. The mean area under the concentration-versus-time curve over the 24-hour period values for ethinyl estradiol were 18-30% lower in cycles 2-4 than the baseline cycle and mean oral serum clearance values were 14.7-33.0% higher. This compares favorably with the 40-72% reductions in progestin and estrogen levels recorded in women taking a levonorgestrel-containing OC and enzyme-inducing anti-epileptics. Although topiramate's modest interaction with OCs is not likely to interfere with contraceptive efficacy, the reduction in serum estrogen concentrations has the potential to increase the incidence of breakthrough bleeding, indicating the OC should contain at least 35 mcg of estrogen.