Drug Interactions between mavacamten and Poly Hist DHC

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mavacamten. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. According to the prescribing information, mavacamten is primarily metabolized by CYP450 2C19 (74%) and to a lesser extent by CYP450 3A4 (18%) and 2C9 (8%). When mavacamten (25 mg) was coadministered with the moderate CYP450 3A4 inhibitor verapamil (sustained-release 240 mg) in intermediate and normal metabolizers of CYP450 2C19, mavacamten systemic exposure (AUC) increased by 15% and peak plasma concentration (Cmax) increased by 52%. Concomitant use of mavacamten with diltiazem, another moderate CYP450 3A4 inhibitor, in CYP450 2C19 poor metabolizers is predicted to increase mavacamten AUC and Cmax by up to 55% and 42%, respectively. Concomitant use of mavacamten (15 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily) is predicted to increase mavacamten AUC and Cmax by up to 130% and 90%, respectively. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. 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 potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Food does not affect the extent of absorption of mavacamten. No clinically significant difference in mavacamten exposure was observed following administration with a high-fat meal. However, the time to reach peak plasma concentration (Tmax) was increased by 4 hours.

MANAGEMENT: Mavacamten may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with mavacamten.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

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