Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study.

Purpose: This study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT agonist/5-HT antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women.

Methods: Healthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 μg and levonorgestrel 150 μg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were C and AUC of ethinylestradiol and levonorgestrel.

Findings: Of the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) C and AUC values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of C and AUC were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) C and AUC values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively).

Implications: Pretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46.