ICWCNS, Basel, and if1.P.A.S. SA, Stubio, Switzerland Summary: Purpose: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.Methods: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mglday) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 p,g ethinylestradiol (EE) and 250 tJ-g levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle.Results: Compared with placebo, areas under the plasma concentration curves (AUC,,,,, geometric means) decreased by 47% for both EE (from 1,677 to 886 pgWml; p < 0.01) and LN(from 137 to 73 ngWml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < O.Ol), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p i 0.01).Conclusions: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.

The effect of fluvoxamine on the pharmacokinetics of diazepam and metabolically derived N-desmethyl-diazepam was investigated in eight healthy volunteers. Each subject received a single oral dose of diazepam (10 mg) in a control session and on the fourth day of a 16-day treatment with fluvoxamine maleate (100 to 150 mg daily). Compared with the control session, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/ml, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (from 0.40 to 0.14 ml/min/kg; p < 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p < 0.01). Although peak plasma N-desmethyldiazepam levels were similar in the two sessions, the time required for the metabolite to reach a peak was longer during fluvoxamine intake than in the control session (206 versus 62 hours; p < 0.01). N-Desmethyldiazepam area under the plasma concentration-time curve values were also significantly increased during fluvoxamine treatment. These data suggest that fluvoxamine inhibits the biotransformation of diazepam and its active N-demethylated metabolite. The magnitude of this interaction is likely to have considerable clinical significance.