Doxycycline/hormonal contraceptives/warfarin interaction
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INR fluctuations and vaginal bleeding (first report of an interaction between warfarin and ethinylestradiol/norethisterone, and warfarin and etonogestrel): case report A 33-year-old woman experienced INR fluctuations and vaginal bleeding during long-term anticoagulation with warfarin, and treatment with hormonal contraceptives; doxycycline was considered a possible co-factor for INR fluctuations. The woman had undergone aortic valve replacement in 1998, and had since been receiving warfarin 38.5 mg/week (historical dose 42 mg/week). Due to her increased thrombosis risk, her daily ethinylestradiol/norethisterone 0.02mg/1mg oral contraceptive, which she had received for an unspecified duration, was replaced with an etonogestrel subdermal implant [dosage not stated]. Her INR reached a nadir of 1.8 after 19 days of etonogestrel therapy, requiring a 55.8% increase of her warfarin dosage (to 60 mg/week) to reach her target INR of 2.5–3.5. Ten months after etonogestrel initiation, she decided to remove the implant due to frequent menstrual bleeding [time to reaction onset not stated]. The woman received a 10-day course of prophylactic doxycycline 100 mg/day, and the implant was removed 1 day after treatment completion. Her INR increased to 4.3 immediately after implant removal and to 6.5 after nine days, but returned to target range after her warfarin dose was decreased. She did not use any hormonal contraceptives for 48 days, and her warfarin dose was titrated to 55.5mg during this time. She then began receiving oral norethisterone 0.35 mg/day, and her warfarin dose stabilised at 53.5 mg/week. However, she discontinued norethisterone therapy after 39 days due to persistence of frequent menstrual bleeding [time to reaction onset not stated]. She subsequently elected to avoid hormonal methods of contraception, and no further warfarin dosage adjustments were required [outcome of vaginal bleeding not stated]. Assessment using the Horn Interaction Probability Scale indicated a probably drug interaction between hormonal contraception and warfarin. Author comment: "There was one identified confounding drug interaction that may have contributed to fluctuations in the INR at the time of hormonal contraceptive changes, as she had taken doxycycline prior to removal of the etonogestrel implant. . . We hypothesized that multiple mechanisms of interaction may have occurred, but the predominant interaction observed is likely due to inhibition of CYP1A2 and 2C19 by ethinyl estradiol." Zingone MM, et al. Probable drug interaction between warfarin and hormonal contraceptives. Annals of Pharmacotherapy 43: 2096-2102, No. 12, Dec 2009. 803006720 Available from: URL: http://dx.doi.org/10.1345/aph.1M382 - USA
» Editorial comment: A search of AdisBase, Medline and Embase did not reveal any previous case reports involving an interaction between warfarin and etonogestrel, ethinylestradiol/ norethisterone. The WHO ADR database did not contain any reports associated with the concomitant use of warfarin and ethinylestradiol/norethisterone o
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