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ORIGINAL RESEARCH |
From Clinical Pharmacology, Pfizer Global Research and Development, Pfizer, Inc., Groton, Connecticut; and Biometrics, Central Research-NY, Pfizer, Inc., New York, New York.
Address reprint requests to: James Hilbert, PhD, Pfizer, Inc., MS 8260-2, Eastern Point Road, Groton, CT 06340; E-mail: james_hilbert{at}groton.pfizer.com.
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ABSTRACT |
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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 (AUC0–24) 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 (Cmax) was slightly (mean 8%,95% CI 2%, 15%) though statistically significantly higher for OC-fluconazole treatment as compared with OC-placebo treatment. Norethindrone Cmax 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.
CONCLUSION: 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.
Although much of the popularity of oral contraceptives (OCs) can be attributed to reliability when used as directed, there have been reports of therapeutic failure (breakthrough bleeding or unexpected pregnancy) attributed to drug interactions with OCs. A number of drugs have lowered the concentrations of OCs, including rifampicin,1,2 anticonvulsants,1 troglitazone,3 ritonavir,4 the 5-lipoxygenase inhibitor ABT-761,5 and broadspectrum antibiotics.1 The most likely reason for OC concentration decreases was induction of metabolism,2,5 or interference of enterohepatic recirculation of OCs by ABT-761,5 or antibiotics.2 The interactions involving enhanced metabolism of ethinyl estradiol by enzyme inducers such as rifampin and phenobarbital are of definite clinical relevance.1,6 With the introduction and widespread use of low-dose and triphasic preparations, concern for loss of contraceptive potency by concomitant drugs that affect OC pharmacokinetics has heightened.6
Single-dose fluconazole therapy is now recognized as a safe, convenient, and highly effective treatment for vaginal candidiasis.7 The prevalence of vaginal candidiasis peaks in women during the childbearing ages of 15–35 years,8,9 so many OC users may require concomitant single-dose fluconazole therapy for vaginal candidiasis.
Previous studies indicated fluconazole does not lower OC serum concentrations and would not likely cause OC failure. In a pilot study,10 single and multiple doses of fluconazole 50 mg had no effect on the ethinyl estradiol and levonorgestrel pharmacokinetics in ten women taking OCs. In a second study in 25 women taking ethinyl estradiol-levonorgestrel, there was a significant increase in the mean area under the concentration time curve (AUC) of ethinyl estradiol (40%) and levonorgestrel (24%) after dosing of fluconazole 200 mg for 10 days (data on file, Pfizer, Inc.). These studies, however, both measured the effect of multiple daily doses of fluconazole on only a single dose of OC and used an older immunoassay with higher variability and less specificity than the assay used in the current study.
A third study11 evaluated concomitant administration of a single 150-mg dose of fluconazole during a low-dose OC cycle in women. It showed statistically significant increases in maximum serum concentration and AUC of ethinyl estradiol compared with OC alone in subjects receiving either Ortho-Novum 7/7/7 or Triphasil (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ). However, it did not evaluate the effect of fluconazole on the progestin in these OCs.
The purpose of this investigation was to further evaluate the potential pharmacokinetic interaction between fluconazole at twice the recommended dose for vaginal candidiasis (300 mg) and both ethinyl estradiol and norethindrone in an OC using an assay that is more sensitive and specific than used in previous studies.
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MATERIALS AND METHODS |
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Subjects with a history of clinically significant breakthrough bleeding (one to two times per month), habitual tobacco or nicotine use within 3 months of screening, concomitant drug therapy of any type, or those who had altered their intake of vitamin C were excluded from the study.
Fluconazole (Diflucan) 150-mg tablets and matching placebo tablets were supplied by Pfizer, Inc. (New York,NY). Ortho Novum 7/7/7 was supplied by Ortho-Mc-Neil Pharmaceutical, Inc. (Raritan, NJ).
The study was conducted over three cycles of OC treatment. Each cycle consisted of 21 days of active OC tablets followed by 7 days of placebo OC tablets. During the first 28-day cycle, subjects received OC treatment only. Double-blind treatment began during the second cycle, when subjects were assigned to one of two treatment groups according to a computer-generated randomization schedule (block size = 2). Treatment with fluconazole or matching placebo was started on day 28 of the previous cycle (day 1 of each cycle was considered to be the first day of OC treatment). During the third cycle, subjects were crossed over to receive the other treatment (ie, fluconazole or placebo).
On day 1 of each cycle, subjects reported to the clinic for predose laboratory testing and took the first dose of OC after breakfast. On days 2–14, subjects took their OC as outpatients, except for days 7 and 14 of the last two cycles, when subjects received either fluconazole or fluconazole placebo at the clinic. When not at the clinic, subjects recorded the time of breakfast, the time of OC dosing, abnormal bleeding, and adverse effects. Subjects were instructed to avoid grapefruit, grapefruit juice, and tonic water and to follow as closely as possible eating and dosing times established on day 1. On days 15–20, subjects reported to the clinic only for breakfast and OC dosing. On day 21, subjects received their daily OC dose as well as their weekly fluconazole or fluconazole placebo. Blood samples for analysis of ethinyl estradiol and norethindrone were then collected. On day 22, subjects received their daily OC placebo dose at the clinic, and then took the remaining OC placebos as outpatients on days 23–27. Subjects returned on day 28 for their weekly fluconazole or fluconazole placebo.
Ethinyl estradiol and norethindrone concentrations were determined using a validated gas chromatographic assay with chemical derivatization and mass spectral detection at PPD Pharmaco, Inc. (Richmond, VA). Fluconazole concentrations were determined using a validated high-performance liquid chromatography assay using ultraviolet detection at MDS Harris Labs (Lincoln, NE).
Cmax of ethinyl estradiol and norethindrone were estimated directly from experimental data. Time of Cmax (Tmax) was defined as the time of the first occurrence of Cmax. The area under the plasma ethinyl estradiol ornorethindrone concentration versus time curve over the 24-hour dosing interval at steady state (AUC0–24) was estimated using linear trapezoidal approximations.
The primary analysis was the comparison of OC plus fluconazole versus OC plus placebo for AUC0–24 and Cmax. Natural log-transformed AUC0–24 and Cmax values were analyzed using an analysis of variance model containing sequence, subject within sequence, period, and treatment effect by the SAS GLM (SAS Institute, Cary, NC) procedure. The sequence effect was tested using the mean square of subject within sequence as the error term, whereas the period effect was tested using the within-subject mean square error as the error term. Safety data were summarized.
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RESULTS |
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There was a 24% mean increase in the OC plus fluconazole group compared with the OC plus placebogroup (P < .001, 95% CI 18%, 31%) in the AUC0–24 for ethinyl estradiol (Table 1
, Figure 1). All individual subjects’ AUC values were greater after fluconazole treatment. Mean AUC0–24 for ethinyl estradiol during OC-only treatment was not different from that during treatment with OC plus placebo. The 8% mean difference in the Cmax value between OC plus fluconazole andOC plus placebo was statistically significant (P = .01, 95% CI 2%, 15%), but the difference between OC plus fluconazole and OC only was not (95% CI -9%, 7%).
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, Figure 2). After placebo, all individual subjects’ AUC values were either greater or within 95% of the AUC after fluconazole. The mean orethindrone AUC0–24 value after OC alone was not different from that after OC plus placebo (95% CI 5%,4%). There was no significant difference in Cmax value between fluconazole and placebo (95% CI -6%, 11%) or between fluconazole and OC only (95% CI -14%, 4%). There were no statistically significant sequence (ie, carryover) effects.
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) to assess when fluconazole had reached a steady state. Values for individual subjects ranged from 50 to 429 ng/mL, except for one subject’s concentrations on day 28 of fluconazole administration (day 21 of the cycle in which she received fluconazole). This value was 6430 ng/mL and was excluded from mean calculations. There were no trends in the individual fluconazole trough data, suggesting fluconazole concentrations were at steady state by the second weekly fluconazole dose.
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DISCUSSION |
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Because there was no decrease in ethinyl estradiol or orethindrone Cmax and AUC, there appears to be nothreat of OC failure with concomitant fluconazole administration. Furthermore, the dose studied was double the dose approved for vaginal candidiasis, and given once weekly, instead of as a single dose. Therefore, any factor not studied in this trial (eg, concomitant medication), which might increase fluconazole concentrations, is not likely to have an effect in the general population taking fluconazole for vaginal candidiasis.
Concern has been expressed that drug interactions that lower contraceptive steroid concentrations are significant in only a small population of women.2 Results from this study showed that all subjects exhibited an increase in ethinyl estradiol AUC0–24 and either an increase or insignificant decrease in norethindrone AUC0–24 after fluconazole administration compared with placebo administration. Although the number of women included in this study was relatively small, there was a clear trend indicating fluconazole did not lower OC concentrations and hence efficacy of OCs in any of the women studied.
A possible explanation for the increase in ethinyl estradiol and norethindrone concentrations is the inhibition of cytochrome P4503A4 by fluconazole because it has been shown to increase concentrations of several drugs metabolized by cytochrome P4503A4.13,14 However, the effect on ethinyl estradiol and norethindrone is relatively modest, most likely because the primary route of metabolism for these compounds is glucuronidation and sulfation, rather than Cytochrome P450 oxidation.5 Thus, ascorbic acid, which is believed to inhibit ethinyl estradiol sulfation, was reported to increase ethinyl estradiol plasma concentrations to a greater extent than fluconazole did in the present study.1
In recent years, some evidence has been found to associate an increased risk of venous thromboembolism with an increase in ethinyl estradiol concentration, particularly in carriers of the coagulation factor V Leiden mutation.15 However, this appears to be most associated with older, high-dose OCs and/or smoking status of women taking OCs.15,16 There are no data to suggest that the increases seen in this study are associated with any increased risk.
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Footnotes |
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This work was supported by Pfizer, Inc. Pfizer contracted with PRACS Institute, Ltd., Fargo, ND, a Contract Research Organization under the direction of Dr. J. Carlson, to conduct the study. The authors are all Pfizer employees and own stock and/or stock options in the company.
Received November 17, 2000. Received in revised form March 8, 2001. Accepted April 12, 2001.
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REFERENCES |
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2. Weisberg E. Interactions between oral contraceptives and antifungals/antibacterials. Is contraceptive failure the result? Clin Pharmacokinet 1999;36:309–13.[Medline]
3. Loi CM, Stern R, Koup JR, Vassos AB, Knowlton P, Sedman AJ. Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent. J Clin Pharmacol 1999;39: 410–7.[Abstract]
4. Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol 1998;46:111–6.[Medline]
5. Wong SL, O’Dea RF, Dube LM, Awni WM. Effects of ABT-761, a novel 5-lipoxygenase inhibitor, on the pharmacokinetics of a single dose of ethinyl estradiol and levonorgestrel in healthy female volunteers. J Clin Pharmacol 1998;38:342–8.
6. Shenfield GM. Oral contraceptives: Are drug interactions of clinical significance? Drug Saf 1993;9:21–37.[Medline]
7. Perry CM, Whittington R, McTavish D. Fluconazole: An update of its antimicrobial activity, pharmacokinetic properties, and therapeutic use in vaginal candidiasis. Drugs 1995;49:984–1006.[Medline]
8. Eckert LO, Hawes SE, Stevens CE, Koutsky LA, Eschenbach DA, Holmes KK. Vulvovaginal candidiasis: Clinical manifestations, risk factors, management algorithm. Obstet Gynecol 1998;92:757–65.[Abstract]
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11. Sinofsky FE, Pasquale SA. The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives. Am J Obstet Gynecol 1998;178:300–4.[Medline]
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13. Honig PK, Worham DC, Zamani K, Mullin JC, ConnerDP. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993;53: 630–6.[Medline]
14. Diflucan [package insert]. New York, NY: Pfizer, Inc., 1999.
15. Sherif K. Benefits and risks of oral contraceptives. Am J Obstet Gynecol 1999;180:343S–8S.[Medline]
16. Castelli WP. Cardiovascular disease: Pathogenesis, epidemiology, and risk among users of oral contraceptives who smoke. Am J Obstet Gynecol 1999;180:349S–56S.
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