Interaction between fenofibrate and warfarin.
OBJECTIVE
To determine whether the potentiation of warfarin's anticoagulation effect, which occurred in two patients, was due to an interaction with fenofibrate.


METHODS
Two patients developed significant potentiation of the anticoagulant effect of warfarin while receiving fenofibrate. In one patient we followed published guidelines to test the potential interaction, including rechallenge twice, and measurements of factors II, V, and VII and liver enzymes to ensure the authenticity of the interaction. We confirmed the interaction by noting that the international normalized ratio (INR) increased with rechallenge, the clotting factor concentrations decreased in concert with the INR, and no other laboratory or clinical factors accounted for this potentiation of the oral anticoagulant affect.


CONCLUSIONS
We previously developed criteria specifically for determining the strength of inferred causation in reports of drug interactions with oral anticoagulants; these criteria were adapted from previously described principles of causality assessment. Our observations in two patients suggest a "highly probable" potentiating interaction between fenofibrate and warfarin. Our data do not allow us to draw definitive conclusions on a mechanism of interaction, but fenofibrate is an oral antilipemic agent, similar to clofibrate, that has been described as potentiating oral anticoagulants by affecting coagulation factor synthesis, likely by altering receptor synthesis. Our finding of lower concentrations of coagulation factors suggests a similar mechanism for fenofibrate. Recent data suggest that lipid lowering is effective for primary and secondary prevention of cardiac events. One might therefore expect to see an increase in the use of the various lipid-lowering agents in patients who receive long-term anticoagulation. Our results indicate that the potential for an exaggerated anticoagulant effect occurs within 5-10 days in patients treated with fenofibrate who are receiving long-term anticoagulation with warfarin.


CONCLUSIONS
Fenofibrate potentiates the effect of warfarin. Serial monitoring of the INR, at least three times per week, is therefore strongly recommended when initiating fenofibrate therapy in patients receiving warfarin.
Department of Medicine, University of Ottawa, Ontario, Canada.
K J
KJ
Ascah
G A
GA
Rock
P S
PS
Wells
D000925:Anticoagulants / Q000009:adverse effects* / Q000627:therapeutic use; D004347:Drug Interactions; D004357:Drug Synergism; D011345:Fenofibrate / Q000009:adverse effects* / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010146:Pain / Q000139:chemically induced; D014859:Warfarin / Q000009:adverse effects* / Q000627:therapeutic use
D000925:Anticoagulants; D000960:Hypolipidemic Agents; D014859:Warfarin; D011345:Fenofibrate