Drug Interactions between Liptruzet and teriflunomide

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. The risk is thought to extend to teriflunomide, its principal active metabolite, because recommended dosages of both result in a similar range of plasma concentrations of teriflunomide. Elevated liver transaminases, hepatitis, jaundice/cholestasis, hepatic failure, and acute hepatic necrosis have been reported with the use of 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 FDA 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, acetaminophen, 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.

MANAGEMENT: Caution is advised if leflunomide or teriflunomide must be used in patients who are currently receiving or have recently received treatment with other hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice), and vice versa. Liver enzymes and bilirubin should be measured prior to initiation of leflunomide/teriflunomide 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 or teriflunomide. Patients who develop elevated serum ALT greater than three times ULN while receiving these medications 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 or teriflunomide 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.

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MONITOR: Coadministration with ezetimibe may rarely increase the risk of myopathy and serum transaminase elevations associated with HMG-CoA reductase inhibitors (i.e., statins). The mechanism of interaction is unknown. A case report describes two patients whose serum creatine kinase increased after ezetimibe was added to their statin therapy (atorvastatin and fluvastatin, respectively). One of the patients also developed myalgia and tendinopathy, which resolved promptly after withdrawal of both drugs. Statin therapy was subsequently reintroduced at the previous dosage without incident. In the other patient, serum creatine kinase returned to normal within 4 weeks after discontinuation of ezetimibe while the statin was continued. On the contrary, no cases of myopathy or tendinopathy occurred in a study of 33 hypercholesterolemic patients treated with ezetimibe and atorvastatin or simvastatin. There were also no reports of myopathy or significant increases in serum creatine kinase in a study of 32 subjects treated with ezetimibe and fluvastatin. In controlled clinical studies, the incidence of consecutive elevations (greater than 3 times the upper limit of normal) in serum transaminases was 1.3% for patients treated with ezetimibe in combination with a statin versus 0.4% for patients treated with a statin alone. These elevations were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

MANAGEMENT: Until further information is available, use of a statin in combination with ezetimibe should be approached with caution. Patients should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The drugs should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. In addition, liver function tests should be performed at initiation of therapy and according to the recommendations of the HMG-CoA reductase inhibitor.

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MONITOR: Coadministration with teriflunomide may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of the organic anion transporting polypeptide (OATP) 1B1 and 1B3 and/or breast cancer resistance protein (BCRP) transporters. The proposed mechanism, based on in vivo data, is decreased clearance due to teriflunomide-mediated inhibition of OATP 1B1/1B3 or BCRP transport proteins.

MANAGEMENT: Caution is advised if teriflunomide is used concomitantly with drugs that are substrates of OATP 1B1/1B3 and/or BCRP. Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever teriflunomide is added to or withdrawn from therapy with these drugs. Patients should be monitored for the development of adverse effects.

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