Drug Interactions between leflunomide and upadacitinib

MONITOR CLOSELY: The use of leflunomide with other immunosuppressive or myelosuppressive agents 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 hematotoxic therapy. Agents that may be significantly immuno- or myelosuppressive include antineoplastic agents, radiation, zidovudine, linezolid, some antirheumatic agents, high dosages of corticosteroids or adrenocorticotropic agents (greater than 10 mg/day to 1 mg/kg/day, whichever is less, of prednisone or equivalent for more than 2 weeks), and long-term topical or inhaled corticosteroids. 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. Due to the prolonged elimination half-life of leflunomide's active metabolite, an interaction may occur even when hematotoxic agents are initiated after the discontinuation of leflunomide. Administering a washout procedure with cholestyramine or activated charcoal helps to accelerate elimination of the active metabolite from plasma and reduce the overlap of systemic exposure to these agents.

MANAGEMENT: Close monitoring for the development of infection is recommended if leflunomide or teriflunomide is used in patients who are currently receiving or have recently received other immuno- or myelosuppressive agents, and vice versa. Platelet, white blood cell count, and hemoglobin or hematocrit should be evaluated at baseline and regularly during therapy. Patients should be advised to contact their physician if they develop signs and symptoms of infection such as fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, and pain or burning during urination. If evidence of serious 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.