Leflunomide can potentiate the anticoagulant effect of warfarin

December 7, 2002

V Lim, I Pande.

Rheumatology Department, Nottingham City Hospital, Nottingham NG5 1PB

Correspondence to: V Lim vunroei@...

Leflunomide (Arava; Aventis Pharma) is used widely to treat inflammatory

arthritis. We report a case of a probable interaction between leflunomide

and warfarin.

A 49 year old man with resistant rheumatoid arthritis started taking

leflunomide at the recommended loading dose of 100 mg daily for three days.

His international normalised ratio had been stable for a year while he was

taking warfarin, and two days before starting treatment with leflunomide it

was 3.4. After he took the second dose of leflunomide, he developed gross

haematuria, for which he required hospital admission. His international

normalised ratio had risen to 11, and warfarin was discontinued. His

haemoglobin concentration was satisfactory and the haematuria spontaneously

resolved several hours after admission. His ratio remained raised for the

next two days, even though he had stopped taking warfarin, and he was given

1 mg of vitamin K intravenously on the third day. Twelve hours later, the

ratio decreased to 1.9 (figure), which coincided with the change to the

leflunomide maintenance dose of 20 mg daily. Subsequently he began taking

warfarin again but at a lower dose of 1 mg daily, which was sufficient to

maintain his international normalised ratio within the recommended range.

Leflunomide was considered to have caused the increase in the patient's

international normalised ratio. Such a role for leflunomide is supported by

the temporal relation to the abnormal ratio and the subsequent lower

warfarin doses required to maintain the ratio within the normal range. A

rechallenge was not possible or ethical.

Leflunomide is rapidly converted to the active metabolite A771726 by first

pass metabolism in the gut wall and liver. A771726 inhibits cytochrome

P-4502C9 and can increase the bioavailability of drugs metabolised by

cytochrome P-4502C9, such as warfarin and phenytoin. This is important as

many patients with inflammatory arthritis also take warfarin. The

interaction between leflunomide and warfarin was not detected in clinical

trials 1 2 nor is it mentioned in the British National Formulary.3 We found

no published reports of an interaction between leflunomide and warfarin.

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