title: Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding.
abstract: OBJECTIVE
  Antiepileptic drugs (AEDs) are widely used in reproductive-age women. The AED carbamazepine (CBZ) induces the hepatic cytochrome P450 system, thereby accelerating hormone metabolism. We sought to assess the pharmacodynamic effects of CBZ on breakthrough bleeding and ovulation during oral contraceptive (OC) use.
  
  
  METHODS
  A double-blind, randomized, crossover study of healthy women ages 18-35 years. Participants took an OC containing 20 μg ethinyl estradiol (EE) and 100 μg levonorgestrel (LNG) for 4 months. Concurrently, participants took 600 mg CBZ or a matching placebo for 2 months each, administered in random order. During the second month of CBZ or placebo, we measured EE and LNG levels 12 times over 24 h, ovarian follicular diameters with eight biweekly vaginal ultrasounds, weekly progesterone levels, and bleeding (using a diary).
  
  
  RESULTS
  We enrolled 25 women; 10 completed the study. Five women discontinued because of reversible CBZ side effects. Mean area under the curve (AUC) measurements were lower during CBZ use compared to placebo for EE (1,778 vs. 986 pg*h/ml, p < 0.001) and LNG (24.8 vs. 13.8 pg*h/ml, p = 0.04). Ovulation occurred in 5 of 10 CBZ cycles compared to 1 of 10 placebo cycles (p = 0.06). Three or more days of breakthrough bleeding occurred during 8 of the 10 CBZ cycles compared to 2 of the 10 placebo cycles (p = 0.07).
  
  
  CONCLUSIONS
  A commonly used dose of CBZ decreased levels of contraceptive steroids, increased breakthrough bleeding, and permitted ovulation during use of a low-dose OC. Women treated with CBZ are not adequately protected from pregnancy by low-dose OCs.
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York 10032, USA. ard4@columbia.edu
authors.forename: Anne R
authors.initials: AR
authors.lastname: Davis
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Westhoff
authors.forename: Frank Z
authors.initials: FZ
authors.lastname: Stanczyk
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002220:Carbamazepine / Q000009:adverse effects* / Q000493:pharmacokinetics; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D016912:Levonorgestrel / Q000009:adverse effects / Q000493:pharmacokinetics; D008598:Menstruation / Q000187:drug effects*; D006080:Ovarian Follicle / Q000033:anatomy & histology / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects*; D011374:Progesterone / Q000097:blood; D013256:Steroids / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003278:Contraceptives, Oral, Hormonal; D013256:Steroids; D002220:Carbamazepine; D004997:Ethinyl Estradiol; D011374:Progesterone; D016912:Levonorgestrel