Leflunomide and Warfarin Interaction: Case Report and Review of the Literature

Abstract

A 61-year-old Caucasian woman receiving long-term anticoagulation with warfarin for recurrent thromboembolism and atrial fibrillation was found to have an elevated international normalized ratio (INR) after she started leflunomide therapy for rheumatoid arthritis. Her INR had been stable for 4 months before this event. The patient required an overall decrease of 22% in her weekly warfarin dose to maintain a therapeutic INR within the goal range of 2.0-3.0 after adding leflunomide therapy. A comprehensive PubMed/MEDLINE search was conducted to identify literature addressing the potential interaction between warfarin and leflunomide. Evidence describing the interaction and its potential mechanism was limited to one published case report and to in vitro data, respectively. Our case report provides additional support that such an interaction exists and that it was at least partly responsible for the subsequent increase in the patient's INR. Therefore, continued evaluation and documentation of this potential drug interaction is imperative. To reduce the risk of adverse effects related to excessive anticoagulation with the start of leflunomide in patients taking warfarin, clinicians should increase their frequency of INR monitoring and adjust the warfarin dosage accordingly to maintain therapeutic anticoagulation.

Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis

“…The observed frequencies of DHODH 40AA genotype were similar to those reported in the International HapMap project for healthy Caucasian population (24.8% and 28.3%) and were higher than in Han Chinese and Japanese populations (6.7% and 11.1%, http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs = 3213422, accessed 23 April 2009). With the exception of case reports of leflunomide-induced ADRs in CYP2C9*3/*3 genotype carriers,5 – 7 CYP1A2*1F allele is the only genetic factor reported to be associated with leflunomide toxicity so far 3. However, we observed no significant association of DHODH 40AA genotype and CYP2C9*3 allele combination with leflunomide ADRs (p = 0.977).…”

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

“…[1108] Although CYP2C9 was not reported to be involved in leflunomide metabolism, CYP2C9*3/*3 genotype has been associated with leflunomide drug interactions and toxicity. In two case reports, patients with rheumatoid arthritis carrying the CYP2C9*3/*3 genotype that were on ongoing warfarin therapy developed severe bleeding when cotreated with leflunomide [1109,1110].…”

A Challenging Decision to Anticoagulate in an Older Adult with Rheumatoid Arthritis

“…A similar case was reported in a 61‐year‐old woman diagnosed with RA, recurrent thromboembolism, and atrial fibrillation. Hepatic CYP2C9 is the primary enzyme responsible for warfarin metabolism and the possible explanation for this life‐threatening drug–drug interaction . Effective treatment of leflunomide‐induced interstitial lung disease using cholestyramine washout therapy has been reported.…”