Drug Interaction Report

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of osilodrostat, which is partially metabolized by the isoenzyme. 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. Pharmacokinetic data for osilodrostat in combination with a potent CYP450 3A4 inhibitor have not been reported. Clinically, high plasma levels of osilodrostat may increase the 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: The manufacturer recommends reducing the dosage of osilodrostat by one-half during concomitant use of a potent CYP450 3A4 inhibitor. Further 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 for signs and symptoms of hypocortisolism such as nausea, vomiting, abdominal pain, loss of appetite, fatigue, dizziness, hypotension, abnormal electrolyte levels, and hypoglycemia. Decrease dosing or temporarily discontinue osilodrostat if patients experience symptoms of hypocortisolism or if urine free cortisol levels fall below the target range or there is a rapid decrease in cortisol levels. Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if patients have symptoms of adrenal insufficiency and serum or plasma cortisol levels are below target range. Osilodrostat therapy may be restarted at a lower dosage when symptoms have resolved and cortisol values are within target range. Additionally, an electrocardiogram and serum electrolyte levels should also be obtained prior to initiating osilodrostat, with ECG repeated within one week after starting treatment and periodically thereafter. Correct hypokalemia and/or hypomagnesemia before starting treatment and as indicated during treatment, as they may be risk factors for ventricular arrhythmias. If QTc interval exceeds 480 msec at any point, temporary dose reduction, interruption, or discontinuation of osilodrostat may be necessary.

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of osilodrostat, which is partially metabolized by the isoenzyme. 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. Pharmacokinetic data for osilodrostat in combination with a potent CYP450 3A4 inhibitor have not been reported. Clinically, high plasma levels of osilodrostat may increase the 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: The manufacturer recommends reducing the dosage of osilodrostat by one-half during concomitant use of a potent CYP450 3A4 inhibitor. Further 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 for signs and symptoms of hypocortisolism such as nausea, vomiting, abdominal pain, loss of appetite, fatigue, dizziness, hypotension, abnormal electrolyte levels, and hypoglycemia. Decrease dosing or temporarily discontinue osilodrostat if patients experience symptoms of hypocortisolism or if urine free cortisol levels fall below the target range or there is a rapid decrease in cortisol levels. Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if patients have symptoms of adrenal insufficiency and serum or plasma cortisol levels are below target range. Osilodrostat therapy may be restarted at a lower dosage when symptoms have resolved and cortisol values are within target range. Additionally, an electrocardiogram and serum electrolyte levels should also be obtained prior to initiating osilodrostat, with ECG repeated within one week after starting treatment and periodically thereafter. Correct hypokalemia and/or hypomagnesemia before starting treatment and as indicated during treatment, as they may be risk factors for ventricular arrhythmias. If QTc interval exceeds 480 msec at any point, temporary dose reduction, interruption, or discontinuation of osilodrostat may be necessary.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.