Warfarin Institute of America
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LEFLUNOMIDE INTERACTION WITH WARFARIN
Lim and Pande published the first report of an interaction between warfarin and leflunomide. (However, they state that The Committee on Safety of Medicines has over 300 similar reports.)
Their patient was a 49-year-old man who had been taking warfarin with a stable INR for one year. He had an INR of 3.4 two days before he started leflunomide. After two days of leflunomide 100 mg/day, he developed gross hematuria. His INR was then found to be 11. The warfarin was stopped, and the INR remained raised for the next two days, so he was given vitamin K 1 mg IV. This resulted in the INR dropping to 1.9 within twelve hours. It is not stated in the report if the leflunomide was continued but it is implied that it was since they state that the dose was lowered to the 20 mg maintenance dose. Warfarin was restarted at 1 mg per day (the previous warfarin dose was not stated) and this maintained the INR in the recommended range.
The authors state that leflunomide was considered to have caused the increased INR. They say that this is supported by the temporal relationship to the abnormal INR and the need for lower warfarin doses after this.
The authors state that leflunomide is converted to an active metabolite which inhibits the liver enzyme CYP450-2C9. This would be expected to raise an INR because this enzyme metabolizes warfarin.
Editor’s Notes:
I’m not sure that I agree with the statement that the temporal relationship supports the interaction. Warfarin slows production of vitamin k-dependent clotting factors. Thus a change usually takes about three days before it is manifest in the INR. The dramatic increase in the INR seems to have occurred faster than should have happened.
The authors also seem unsure of what should happen after warfarin is discontinued. They seem surprised that the INR remained high for two days after the warfarin was stopped. This is exactly what should have occurred. The average time for the INR to decrease by half is about 48 hours. If the leflunomide was continued and it inhibits CYP450 2C9, then it might be expected that the INR would take longer than 48 hours to decrease by half. If the patient had gross hematuria and the authors wanted to decrease the INR, would it not have made more sense to give the vitamin K sooner and probably held the leflunomide for one or two days?
It would also have been helpful if the published report had contained the original warfarin dosage as well as the dosage after the interaction occurred.
The official US FDA package insert says, "Increased INR (International Normalized Ratio) when ARAVA and warfarin were co-administered has been rarely reported."
With the information given, it seems prudent to check the INR within a few days after leflunomide is started. Patients should also be counseled to watch for any signs of bleeding.
References:
Lim V. Leflunomide can potentiate the anticoagulant effect of warfarin. BMJ. 2002 Dec 7;325:1333.
www.arava.com viewed on November 13, 2004.
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Last updated November 13, 2004