Drug Interactions between leflunomide and rifampin

MONITOR CLOSELY: The recent, concomitant, or subsequent use (without the recommended leflunomide washout period or procedure) of other agents known to induce hepatotoxicity may potentiate the risk of liver injury associated with leflunomide. Elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis have been reported with leflunomide. Liver enzyme elevations were generally mild (2 times the upper limit of normal or less) and resolved while continuing treatment. Marked elevations (greater than 3-fold ULN) occurred infrequently and reversed with dose reduction or discontinuation of treatment in most cases. However, fatalities associated with severe liver injury have also been reported rarely. A 2009 review of leflunomide adverse event reports by the U.S. Food and Drug Administration identified 49 cases of severe liver injury, including 14 cases of fatal liver failure, between August 2002 and May 2009. An additional five patients required a liver transplant and nine patients experienced a life-threatening event. In this review, concomitant use of other hepatotoxic drugs and preexisting liver disease were associated with the greatest risk for liver injury during leflunomide treatment. Specifically, 46 of the 49 patients were also taking other medications that have been associated with liver injury including methotrexate, TNF-alfa blockers, hydroxychloroquine, paracetamol, nonsteroidal anti-inflammatory drugs and statins, and 14 patients had preexisting liver disease such as active or chronic hepatitis and/or a history of alcohol abuse. The estimated duration of leflunomide exposure before onset of severe liver injury ranged from 9 days to 6 years, with the majority occurring within the first 6 to 12 months of treatment.

Pharmacokinetically, coadministration of leflunomide with rifampin may increase the plasma concentrations of M1, the active metabolite of leflunomide that is responsible for essentially all of its activity in vivo. When a single dose of leflunomide was administered to subjects receiving multiple doses of rifampin, the peak plasma levels of M1 were increased by approximately 40% compared to administration of leflunomide alone. The mechanism has not been described, but may involve rifampin induction of leflunomide metabolism via hepatic CYP450 isoenzymes. Due to the long half-life of M1, levels may continue to increase with multiple dosing of leflunomide.

MANAGEMENT: Caution is advised if leflunomide is used in combination with rifampin. The potential for increased risk of leflunomide toxicities including peripheral neuropathy, immunosuppression, bone marrow suppression, and hepatotoxicity should be considered. Liver enzymes and bilirubin should be measured prior to initiation of leflunomide therapy and at least monthly for the first six months of treatment and every 6 to 8 weeks thereafter. Patients with preexisting liver disease or elevated baseline liver enzymes (i.e., ALT greater than two times ULN) should not receive leflunomide. Patients who develop elevated serum ALT greater than three times ULN while receiving leflunomide should discontinue treatment and be given washout procedures with cholestyramine or activated charcoal to accelerate elimination of leflunomide's active metabolite from plasma, which otherwise may take up to two years. Follow-up monitoring should be conducted at least weekly until the ALT value is within normal range, and washout procedures repeated as necessary. All patients treated with leflunomide should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.