Drug Interactions between leflunomide and letrozole / ribociclib

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 immuno- or myelosuppressive 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.

MONITOR CLOSELY: The recent, 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 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. 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.

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. Patients should be advised to seek medical attention if they develop signs and symptoms of infection (e.g., fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, pain or burning during urination) or hepatotoxicity (e.g., fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, jaundice).

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MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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