Fenofibrate Potentiates Warfarin Effects

Abstract

To describe 2 patients in whom the initiation of fenofibrate potentiated warfarin's anticoagulant effects. A 71-year-old white woman and an 80-year-old white woman with multiple medical conditions were both stabilized on long-term warfarin therapy. During the course of anticoagulation, both patients were prescribed fenofibrate and experienced threefold and twofold increases in international normalized ratio (INR), respectively, requiring total weekly warfarin dosage reductions of 30-40%. Before starting fenofibrate therapy, both patients' coagulation values were within the therapeutic range. When interviewed, patients and caregivers denied bleeding, bruising, changes in diet, alcohol ingestion, nonadherence with therapy, or changes in drug regimen except for the addition of fenofibrate. Upon chart review, evaluation of potentially contributory parameters, such as other changes in drug therapy, thyroid function, liver function, and drug-disease interactions, showed that these parameters remained stable and were ruled noncontributory. The addition of fenofibrate in 2 patients on stable and therapeutic doses of warfarin increased the anticoagulant response to warfarin. A clear temporal relationship with the addition of fenofibrate and the appearance of the interaction was seen. Fenofibrate is highly protein bound, with the potential to displace warfarin from its binding protein, leading to an enhanced hypoprothrombinemic effect. Fenofibrate is also a mild to moderate inhibitor of CYP2C9, the enzyme responsible for warfarin metabolism. The combination of these effects--displacement of warfarin by fenofibrate coupled with decreased metabolism of warfarin--may increase the anticoagulant response to warfarin. Using the Naranjo probability scale, these interactions were designated as probable. We suggest serial monitoring of INR and consider an empiric 20% reduction in warfarin dosage when fenofibrate is initiated, with the possibility for a greater warfarin dosage reduction based on INR results.