Drug Interactions between Akynzeo for Injection and osilodrostat

MONITOR: Osilodrostat can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a thorough QT study with 86 male and female healthy volunteers, maximum mean placebo-corrected QTcF (Fridericia corrected QT interval) increased 1.73 msec following a 10 mg dose and 25.38 msec following a 150 mg dose (up to 2.5 times the maximum recommended dosage). The predicted mean placebo-corrected QTcF change from baseline at the highest recommended dosage in clinical practice (30 mg twice daily) was estimated to be 5.3 msec, based on an interpolation of the data from the thorough QT study and population pharmacokinetic analysis. Adverse reactions of QT prolongation and clinically relevant ECG findings have also been reported in clinical studies. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if osilodrostat is used in combination with other drugs that can prolong the QT interval. An electrocardiogram (ECG) and serum electrolyte levels should be obtained prior to initiating osilodrostat therapy, 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. Some authorities suggest that a washout period be considered when switching from other treatments of Cushing's syndrome that are also known to affect the QT interval such as ketoconazole or pasireotide. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope

MONITOR: Coadministration with 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 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: Caution is advised when osilodrostat is coadministered with CYP450 3A4 inhibitors. Dosage adjustments may be required 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.