Drug Interactions between amoxicillin / clarithromycin / omeprazole and mavacamten

CONTRAINDICATED: Coadministration with moderate to potent inhibitors of CYP450 2C19 or potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of mavacamten. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. 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%). In healthy CYP450 2C19 normal and rapid metabolizers, concomitant use of mavacamten (15 mg) with the weak CYP450 2C19 inhibitor omeprazole (20 mg) once daily increased mavacamten systemic exposure (AUC) by 48% but had no effect on peak plasma concentration (Cmax). Potent inhibitors such as fluconazole, fluoxetine, fluvoxamine, or ticlopidine may be expected to increase mavacamten exposure to a significantly greater extent, although data are currently lacking. 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.

MANAGEMENT: Concomitant use of mavacamten with moderate to potent CYP450 2C19 inhibitors or potent CYP450 3A4 inhibitors is considered contraindicated.

ADJUST DOSE: Coadministration with inhibitors of CYP450 2C19 or CYP450 3A4 may increase the plasma concentrations of mavacamten. Because mavacamten reduces systolic contraction and left ventricular ejection fraction, increased exposure may potentiate the risk of heart failure. 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%). In healthy CYP450 2C19 normal and rapid metabolizers, concomitant use of mavacamten (15 mg) with the weak CYP450 2C19 inhibitor omeprazole (20 mg) once daily increased mavacamten systemic exposure (AUC) by 48% but had no effect on peak plasma concentration (Cmax). 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 AUC increased by 16% and 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.

MANAGEMENT: The prescribing information suggests initiating mavacamten at the recommended starting dosage of 5 mg orally once daily in patients who are on stable therapy with a weak CYP450 2C19 inhibitor or a moderate CYP450 3A4 inhibitor. Conversely, when initiating the inhibitor in patients already receiving mavacamten, the prescribing information recommends reducing the dosage of mavacamten by one level (i.e., 15 to 10 mg; 10 to 5 mg; or 5 to 2.5 mg) and scheduling a clinical and echocardiographic assessment 4 weeks after inhibitor initiation. The dosage of mavacamten should not be titrated upwards until 12 weeks after inhibitor initiation. In patients who are on stable treatment with mavacamten 2.5 mg once daily, initiation of concomitant weak CYP450 2C19 or moderate CYP450 3A4 inhibitors should be avoided because a lower dose of mavacamten is not available.

MONITOR CLOSELY: Coadministration with mavacamten may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4, 2C9, and/or 2C19. The proposed mechanism is accelerated clearance due to induction of these isoenzymes by mavacamten. The interaction may be particularly important for sensitive substrates or those that demonstrate a narrow therapeutic index. When midazolam, a probe substrate for CYP450 3A4, was coadministered with a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) in healthy CYP450 2C19 normal metabolizers, midazolam peak plasma concentration (Cmax) decreased by 7% and systemic exposure (AUC) decreased by 13%. Following coadministration of mavacamten once daily in patients with obstructive hypertrophic cardiomyopathy (HCM), midazolam Cmax and AUC are predicted to decrease by 13% to 48% and 21% to 64%, respectively, depending on the dose of mavacamten and CYP450 2C19 phenotype. Additionally, concomitant use of mavacamten once daily in HCM patients is predicted to decrease the Cmax and AUC of repaglinide, a CYP450 2C8 and 3A4 substrate, by 12% to 39%; the Cmax and AUC of tolbutamide, a CYP450 2C9 substrate, by 33% to 65%; and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, by 48% to 67%, depending on the dose of mavacamten and CYP450 2C19 phenotype.

MANAGEMENT: Caution is advised when mavacamten is used concomitantly with drugs that are substrates of CYP450 3A4, 2C9 and/or 2C19, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mavacamten is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a CYP450 inducer like mavacamten and for any dosage adjustments that may be required.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.