DRUG INTERACTIONS
Cholestyramine and Charcoal
Administration of cholestyramine or activated charcoal in patients (n=13) and volunteers (n=96) resulted in a rapid and significant decrease in plasma M1 (the active metabolite of leflunomide) concentration (see
PRECAUTIONS – General – Need for Drug Elimination).
Hepatotoxic Drugs
Increased side effects may occur when leflunomide is given concomitantly with hepatotoxic substances. This is also to be considered when leflunomide treatment is followed by such drugs without a drug elimination procedure. In a small (n=30) combination study of ARAVA with methotrexate, a 2- to 3-fold elevation in liver enzymes was seen in 5 of 30 patients. All elevations resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. A >3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both drugs and 3 after discontinuation of leflunomide. Three patients met "ACR criteria" for liver biopsy (1: Roegnik Grade I, 2: Roegnik Grade IIIa). No pharmacokinetic interaction was identified (see
CLINICAL PHARMACOLOGY).
NSAIDs
In in vitro studies, M1 was shown to cause increases ranging from 13 – 50% in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range. The clinical significance of this finding is unknown; however, there was extensive concomitant use of NSAIDs in clinical studies and no differential effect was observed.
Tolbutamide
In in vitro studies, M1 was shown to cause increases ranging from 13 – 50% in the free fraction of tolbutamide at concentrations in the clinical range. The clinical significance of this finding is unknown.
Rifampin
Following concomitant administration of a single dose of ARAVA to subjects receiving multiple doses of rifampin, M1 peak levels were increased (~40%) over those seen when ARAVA was given alone. Because of the potential for ARAVA levels to continue to increase with multiple dosing, caution should be used if patients are to be receiving both ARAVA and rifampin.
Warfarin
Increased INR (International Normalized Ratio) when ARAVA and warfarin were co-administered has been rarely reported.
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