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Probable Drug Interaction Between Warfarin and Hormonal Contraceptives

Assistant Professor, College of Pharmacy, University of Tennessee, Knoxville Campus, Knoxville, TN

Alexander B Guirguis, PharmD BCPS

Assistant Professor, College of Pharmacy, University of Tennessee, Knoxville Campus

Anita Airee, PharmD

Assistant Professor, College of Pharmacy, University of Tennessee, Knoxville Campus

Diana Cobb, MD

University of Tennessee Medical Center, Alcoa, TN

Reprints: Dr. Zingone, University of Tennessee College of Pharmacy, Knoxville Campus, 1920 Alcoa Hwy., Box 117, Knoxville, TN 37920, fax 865/974-2022, mzingone{at}uthsc.edu

OBJECTIVE: To report a single patient case that presented with a probable drug interaction between warfarin and 3 methods of hormonal contraceptives, as assessed by the Horn Interaction Probability Scale.

CASE SUMMARY: A 33-year-old female patient required long-term anticoagulation following an aortic valve replacement. While taking warfarin (38.5 mg weekly), she transitioned from a monophasic combined oral contraceptive (ethinyl estradiol plus norethindrone) to an implantable progestin-only contraceptive (etonogestrel) on the advice of her cardiologist. Nineteen days following etonogestrel implant insertion, her international normalized ratio (INR) decreased to 1.8 and required a 55.8% warfarin dose increase (resulting dose of 60 mg weekly). Within 10 months, the patient elected to have the implant removed due to vaginal bleeding. Nine days following removal of etonogestrel, she experienced a transient INR increase to 6.5. Her INR returned to within goal range after her warfarin dose was decreased to 55.5 mg weekly. After using barrier methods of contraception for 48 days, she initiated an oral progestin-only contraceptive (norethindrone). Further warfarin dose adjustments were made, resulting in a weekly warfarin dose of 53.5 mg. Thirty-nine days after initiation of oral norethindrone, she elected to discontinue use due to vaginal bleeding and no longer uses hormonal contraceptive methods. No further adjustments to her warfarin dose were warranted.

DISCUSSION: The increased warfarin requirement observed in this patient may have been a result of multiple factors. Based on a literature review, we hypothesize that the predominant mechanism of interaction was ethinyl estradiol inhibition of CYP1A2 and 2C19.

CONCLUSIONS: We recommend that further in vivo studies be completed to definitively identify the mechanism of the interaction. It is necessary to intensify warfarin monitoring upon initiation or alteration of hormonal contraceptives.

Key Words: anticoagulation, desogestrel, drug interaction, ethinyl estradiol, etonogestrel, hormonal contraception, norethindrone, progesterone, progestin, warfarin

Published Online, November 24, 2009. www.theannals.com, DOI 10.1345/aph.1M382