Drug Interactions between fingolimod and leflunomide

MONITOR CLOSELY: The use of leflunomide with other immunosuppressive agents such as fingolimod may increase the risk of infections. 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. Serious infections including sepsis, as well as opportunistic infections like Pneumocystis jiroveci pneumonia, pulmonary and extrapulmonary tuberculosis, and aspergillosis have been reported with the use of leflunomide, particularly in patients on concomitant immunosuppressive therapy. Rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have also occurred with leflunomide alone, but were most frequent in the presence of concomitant or recent use of methotrexate or other myelotoxic agents. No specific data are available regarding use in combination with fingolimod, an agent that causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, fingolimod produces a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values, or less than 200 to 500 cells/mcL in some study patients. In addition, a mild decrease in the neutrophil count to approximately 80% of baseline occurs during chronic therapy. Serious infections requiring admission to hospital have been reported. Decreased lymphocyte counts persist during daily dosing and generally return to baseline within 1 to 2 months after stopping the medication.

MONITOR CLOSELY: The concomitant or sequential 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 leflunomide. Liver enzyme elevations were generally mild (2-fold ULN 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. However, fatalities associated with severe liver injury have also been reported rarely. Most cases occurred within six months of therapy and in a setting of multiple risk factors including preexisting liver disease and concomitant use of other hepatotoxins. No specific data are available regarding use in combination with fingolimod. Elevations in liver transaminases exceeding 3 times ULN have been reported in association with fingolimod use, and some patients have experienced recurrence upon rechallenge. The majority of cases occurred within 6 to 9 months of starting treatment. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod.

MANAGEMENT: Close monitoring is recommended if leflunomide or teriflunomide is used in patients who are currently receiving or have recently received other immunosuppressive and hepatotoxic agents, and vice versa. Due to the prolonged elimination half-life of leflunomide's active metabolite, an interaction may occur even when these agents are initiated after the discontinuation of treatment with leflunomide or teriflunomide. Liver enzymes, bilirubin, platelet, white blood cell count, and hemoglobin or hematocrit should be evaluated at baseline and regularly during therapy. If evidence of serious hepatotoxicity (i.e., ALT elevation greater than 3-fold ULN or persistent elevations between 2- and 3-fold ULN despite dose reduction), infection, or bone marrow suppression occurs, treatment should be stopped, and cholestyramine or charcoal administered to accelerate elimination of leflunomide's active metabolite from plasma, which otherwise may take up to two years. Similarly, recent complete blood count and transaminase and bilirubin levels (i.e., within last 6 months) should be available before initiating treatment with fingolimod. If a serious infection or significant liver injury develops, treatment should be suspended and the benefits and risks reassessed prior to restarting treatment. Because fingolimod remains in the blood for up to two months after the last dose, continued monitoring is recommended throughout this period. Patients should be advised to seek medical attention if they develop an infection or experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, light colored stools, and jaundice.