Effect of Topiramate or Carbamazepine on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Healthy Obese and Nonobese Female Subjects

Abstract

Summary:Purpose: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure.Methods: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m 2 . The BMI of the remaining four groups was Յ27 kg/m 2 .Results: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. Conclusions: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.

Dose‐dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by Topiramate

“…The pharmacokinetics of norethindrone remained unchanged. In contrast, a recent study found that TPM at doses of 50-200 mg/day did not significantly affect the clearance of either ethinyl estradiol or norethindrone (3). Thus it appears that the effect of TPM on ethinyl estradiol level may be related to the TPM dose.…”

Conversion from enzyme-inducing antiepileptic drugs to topiramate: Effects on lipids and c-reactive protein

“…This is clinically relevant, since TPM has been found to induce the metabolism of oral contraceptive hormones at high doses, but not at low doses (Rosenfeld et al, 1997;Doose et al, 2003), making it unclear whether its effects on the CYP450 system are dose-dependent, enzyme-specific, or both. It is noteworthy that the single patient in the study who was switched to highdose TPM (300mg daily), and who had one of the higher TPM levels in the patient cohort, nonetheless had a drop of 37mg/dL in TC, suggesting that the drug may not affect the cholesterol synthetic pathways even at high doses.…”

“…TPM induces at least some CYP450 enzymes at high doses (Rosenfeld et al, 1997), but there is no evidence of any CYP450 induction when it is used at low to moderate doses (Doose et al, 2003). Its effects on lipids relative to those of other AEDs have not been studied but are pertinent to the care of patients who are chronically treated with the drug.…”

The Impact of Epilepsy on Reproductive Functions

“…In women with epilepsy failure rates of oral contraceptives may increase to 6% depending on the antiepileptic drug they are taking (Morell, 1996). Drugs such as phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), oxcarbazepine (OXC) at doses above 600 mg daily and topiramate (TPM) at doses above 200 mg (Doose et al, 2003) may cause induction of hepatic cytochrome P450, reducing the effects of contraceptives to block ovulation. VPA and felbamate (FBM) inhibit the hepatic microsomal system and do not reduce, and can even increase, the levels of the steroid hormones of oral contraceptives.…”