Doxycycline and Estradiol: Interaction Details

a) Systemic exposure of ethinyl estradiol/etonogestrel with use of the vaginal ring contraceptive was not affected by concomitant use of doxycycline in a randomized, 2-way crossover study in healthy volunteers (n=15). Following synchronization of menstrual cycles by 21 to 28 days and a 7 day ring-free period, volunteers received the vaginal ring for 21 days with or without doxycycline 200 mg orally on day 1 then, 100 mg daily for 10 days. After a 7 day ring-free washout period, subjects crossed over to the opposite treatment arm. With administration of the vaginal ring alone, the mean AUC of ethinyl estradiol, measured at 24 hours, day 9 to 10, day 10, and day 21, was 0.638 nanograms x hr/mL, 0.538 nanograms x hr/mL, 5.51 nanograms x hr/mL, and 11.2 nanograms x hr/mL, respectively. With administration of the ring plus doxycycline, the mean AUC of ethinyl estradiol was 0.6 nanograms x hr/mL, 0.512 nanograms x hr/mL, 5.35 nanograms x hr/mL, and 10.9 nanograms x hr/mL, respectively. The AUC interaction/control ratio (ring with doxycycline to ring alone) also showed absence of drug interaction. At 24 hours, day 9 to 10, day 10, and day 21, the interaction/control ratio was 0.95, 0.92, 0.95, and 0.95, respectively. The etonogestrel plasma concentrations and interaction/control ratio demonstrated similar findings at all time points ⁶.

b) There was no significant difference in oral contraceptive (OC) failure rates among women who received OC with or without concomitant antibiotics, including tetracyclines; and the OC failure rate in both groups did not exceed a typical contraceptive failure rate of 1% to 3% in a retrospective chart review and follow-up survey. Of 356 women who received antibiotics and OC concurrently over 311.2 woman-years, 5 pregnancies occurred yielding a rate of 1.6 pregnancies per 100 woman-years or a 1.6%/year failure rate. Of 425 control patients who received OC without antibiotics for 1244.9 woman-years, 12 pregnancies occurred yielding a rate of 0.96 pregnancies per 100 woman-years or 0.96%/year failure rate. The difference in failure rate between these groups was not significant (95% CI on the difference, -0.81 to 2.1; p=0.4) and ruled out a substantial difference (greater than 2.1% per year). The women in the control group consisted of 263 women who received OC but did not concomitantly use OC with antibiotics and 162 OC users who never concomitantly used antibiotics. Among women who never concomitantly used antibiotics (n=162) over 551.2 woman-years, 7 pregnancies occurred, yielding a rate of 1.3 pregnancies per 100 woman-years or 1.3%/year failure rate ¹.

c) There was no increased risk of contraceptive failure with concomitant antibiotic use in a study of 34 patients with acne who used oral antibiotics, including tetracycline (n=17) and erythromycin (n=20), concomitantly with low-dose estrogen oral contraceptives for a total period of 71 women-years. The calculated contraceptive failure rate was 1.4 per 100 women-years for the study, which was not significantly different than an accepted and documented contraceptive failure rate of 0.27 per 100 women-years (p=0.17). Of the 34 patients, one became pregnant while using the norethindrone, ethinyl estradiol, and mestranol combination concomitantly with oral tetracycline (12 months duration of use); the patient stated that she did not miss any doses of the contraceptive combination or had any changes in her menstrual cycle. Two other patients reported menstrual irregularities; one reported spotting while using the ethinyl estradiol and ethynodiol diacetate combination concomitantly with terfenadine and minocycline treatment, and another reported heavy cramping while using the norethindrone acetate and ethinyl estradiol combination concomitantly with tetracycline. Although this study determined that there was no increased risk of contraceptive failure with concomitant antibiotic use, the data suggests that tetracycline and its derivatives may interact with low-dose estrogen contraceptives ².

d) The effect of doxycycline on serum levels of estradiol and norethindrone was studied in 24 women taking oral contraceptives. The subjects had been taking an oral contraceptive containing 1 mg norethindrone and 35 mcg ethinyl estradiol for at least 2 months prior to the study. Administration of doxycycline 100 mg daily for 7 days starting on day 14 of the 28-day cycle had no significant effect on the average serum levels of estradiol and norethindrone, however, there was substantial variability. Progesterone levels indicated that ovulation had not occurred in any of these subjects. Although no significant effect was observed in this study, antibiotics may have an effect in patients with unusually low oral contraceptive hormone levels ³.

e) A study which documented 163 cases of oral contraceptive failure in reliable pill takers found that 23% (37 cases) of these failures were associated with antibiotic use. Of these 163 cases, 6 were attributed to the use of tetracyclines, including doxycycline, minocycline, and lymecycline. The authors recommended a 7 day abstinence period or a barrier method of contraceptive following a course of antibiotics ⁵.

f) The interaction between oral contraceptives and tetracyclines has been suggested to be due to an alteration of the gut flora. The normal gut flora is thought to be responsible for the hydrolysis of the glucuronide moiety (estrogen metabolite found in the bile) to free drug. When the gut flora is altered, enterohepatic recirculation is reduced and the metabolite is simply excreted. This causes a decrease in body levels of the estrogen and reduced effectiveness ⁴.