Drug Interactions between encorafenib and osilodrostat

MONITOR CLOSELY: Coadministration with potent inducers of CYP450 3A4 and/or 2B6 may decrease the plasma concentrations of osilodrostat, which is partially metabolized by these isoenzymes. According to the product labeling, multiple CYP450 isoenzymes (CYP450 3A4, 2B6, and 2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism, and no single pathway contributes greater than 25% to the total clearance. Some of the known potent CYP450 3A4 and 2B6 inducers also induce UDP-glucuronosyltransferases. Pharmacokinetic data for osilodrostat in combination with a potent inducer of one or more of these pathways have not been reported. Reduced therapeutic efficacy of osilodrostat may occur during coadministration. On the other hand, discontinuation of a potent CYP450 3A4 and/or 2B6 inducer during treatment with osilodrostat may result in increased osilodrostat plasma concentrations and increased risk of adverse effects such as hypocortisolism (which may lead to life-threatening adrenal insufficiency), QT prolongation (which may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death), and elevated androgen and 11-deoxycorticosterone levels (the latter of which may activate mineralocorticoid receptors and cause hypokalemia, edema, and hypertension).

MANAGEMENT: An increase in the dosage of osilodrostat may be required during concomitant use of a potent CYP450 3A4 and/or 2B6 inducer. Dosage adjustments should be based on clinical response and tolerance. Patients should have regular monitoring of 24-hour urine free cortisol and serum or plasma cortisol during treatment, as well as regular evaluations of their signs and symptoms. A reduction in dosage of osilodrostat may be required if the potent CYP450 3A4 and/or 2B6 inducer is discontinued during treatment with osilodrostat.