Drug Interactions between osilodrostat and propafenone

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