Interactions between Corlanor and Sebetralstat

Monitor

Sebetralstat can cause concentration-dependent prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may theoretically result in additive QT effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In healthy subjects, the largest observed mean increase in corrected QT (QTc) interval was 10.4 msec (upper confidence interval 15.3 msec) after administration of a supratherapeutic dose equal to 2.5 times the maximum recommended dose. 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 their dosages.

Management

Caution is recommended if sebetralstat is used in combination with other drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms suggestive of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, or shortness of breath.

Generally avoid

Grapefruit juice may significantly increase the plasma concentrations of ivabradine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. According to the product labeling, administration with grapefruit juice (quantity unknown) resulted in an approximately twofold increase in ivabradine systemic exposure (AUC). Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

Adjust dosing interval

Food delays the absorption of ivabradine by approximately 1 hour and increases plasma exposure by 20% to 40% compared to fasting conditions.

Management

Patients treated with ivabradine should avoid or limit consumption of grapefruit or grapefruit juice. The manufacturer recommends taking ivabradine with meals to reduce variability in exposure.

Generally avoid

Coadministration with grapefruit juice may increase the plasma concentrations of sebetralstat. The mechanism is decreased clearance of sebetralstat due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The interaction has not been studied with grapefruit juice but has been reported for the strong CYP450 3A4 inhibitor, itraconazole. In clinical studies, concomitant administration with the strong CYP450 3A4 inhibitor itraconazole (200 mg once daily for 6 days) increased sebetralstat peak plasma concentration (Cmax) by 2.4-fold and systemic exposure (AUC) by 5.2-fold. Increased sebetralstat exposure may increase the risk of adverse reactions such as headache and QT prolongation. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated strong inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to sebetralstat may increase the risk and/or severity of adverse effects such as headache and QT prolongation. The use of sebetralstat alone at doses 2.5 times the maximum recommended dose has been associated with a mean increase in corrected QT (QTc) interval of 10.4 msec. Although clinical data are lacking for sebetralstat, in general, prolongation of the QT interval may increase the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

Management

Consumption of food or drinks containing grapefruit should generally be avoided during treatment with sebetralstat.