Drug Interactions between ivacaftor / lumacaftor 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.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. The interaction occurs to a greater extent when ivacaftor is administered as monotherapy than when administered in combination with lumacaftor, a potent CYP450 3A4 inducer. In study subjects, ivacaftor systemic exposure (AUC) increased by 8.5-fold when it was administered concomitantly with the potent CYP450 3A4 inhibitor ketoconazole and by 3-fold with the moderate CYP450 3A4 inhibitor fluconazole. By contrast, when lumacaftor/ivacaftor was coadministered with the potent CYP450 3A4 inhibitor itraconazole, ivacaftor peak plasma concentration (Cmax) and AUC increased by an average of 3.7- and 4.3-fold, respectively, and when coadministered with the moderate CYP450 3A4 inhibitor ciprofloxacin, ivacaftor Cmax and AUC increased by just 29% each.

MANAGEMENT: Caution is advised if ivacaftor is used with CYP450 3A4 inhibitors. A dosage adjustment for ivacaftor may be required if undue adverse effects occur.

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