Evaluation of interaction between fluconazole and an oral contraceptive in healthy women.
OBJECTIVE
To evaluate the potential pharmacokinetic interaction between 2 x 150 mg fluconazole administered once weekly and an oral contraceptive (OC) containing ethinyl estradiol and norethindrone.


METHODS
A placebo-controlled, double-masked, randomized, two-way crossover study was used to investigate the pharmacokinetic interaction between 300 mg fluconazole once weekly and the OC Ortho Novum 7/7/7 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ) in 26 healthy women, 18-36 years old. In the first cycle (28 days), subjects received OC only. In the second cycle, subjects were assigned randomly to receive OC-fluconazole or OC-placebo. In the third cycle, subjects were crossed over to the opposite treatment.


RESULTS
Data for 21 subjects who completed the study were included in the pharmacokinetic analysis; data for all 26 subjects were included in the safety analysis (26 OC only; 24 OC-fluconazole; 23 OC-placebo). Treatment with OC-fluconazole resulted in small but statistically significant increases in 0-24 hour area under the plasma concentration-time curve (AUC(0-24)) for both ethinyl estradiol (mean 24%, 95% confidence interval [CI] 18%, 31%) and norethindrone (mean 13%, 95% CI 8%, 18%) as compared with treatment with OC-placebo. Ethinyl estradiol maximum plasma concentration (C(max)) was slightly (mean 8%, 95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone C(max) was not different (95% CI -6%, 11%) between the two treatment groups. No adverse events related to treatment were seen in the fluconazole treatment group.


CONCLUSIONS
The concomitant administration of 300 mg fluconazole once weekly, twice the recommended dose for vaginal candidiasis, to women using OCs results in a slight increase in OC concentrations. Therefore, it appears that there is no threat of contraceptive failure because of concomitant fluconazole administration.
Hilbert
J
J
Clinical Pharmacology, Pfizer Global Research and Development, Pfizer, Inc., Groton, Connecticut 06340, USA. james_hilbert@groton.pfizer.com
Messig
M
M
Kuye
O
O
Friedman
H
H
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D045166:Estradiol Congeners / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics*; D006801:Humans; D008656:Mestranol / Q000493:pharmacokinetics*; D009640:Norethindrone / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D045166:Estradiol Congeners; D004997:Ethinyl Estradiol; C014715:Norinyl; D015725:Fluconazole; D008656:Mestranol; D009640:Norethindrone