Drug interactions of Mavacamten

1. Potential for Other Drugs to Affect Mavacamten Plasma Concentrations

Mavacamten is primarily metabolized by CYP2C19, with a smaller fraction metabolized by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19, as well as moderate to strong inhibitors or inducers of CYP3A4, may affect mavacamten exposure.

Established and Potentially Significant Pharmacokinetic Drug Interactions

Strong CYP2C19 Inhibitors

Clinical Impact: Concomitant use with strong CYP2C19 inhibitors increases mavacamten exposure, which may raise the risk of heart failure due to systolic dysfunction.Prevention or Management: Concomitant use with strong CYP2C19 inhibitors is prohibited.

Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers

Clinical Impact: Concomitant use with moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers decreases mavacamten exposure, which may reduce the therapeutic efficacy of mavacamten. Discontinuation of these inducers, as enzyme induction returns to baseline, may increase the risk of heart failure due to systolic dysfunction.Prevention or Management: Concomitant use with moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers is prohibited.

Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors

Clinical Impact: Concomitant use with weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors increases mavacamten exposure, which may elevate the risk of adverse drug reactions.Prevention or Management:

For patients on stable therapy with weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors, initiate mavacamten at the recommended starting dose of 5 mg orally once daily.

For patients receiving mavacamten who plan to initiate weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors, downtitrate mavacamten to the next lower daily dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg).

Avoid initiating concomitant weak CYP2C19 inhibitors and moderate CYP3A4 inhibitors in patients on stable mavacamten 2.5 mg daily, as no lower dose is available.

For short-term use (e.g., 1 week), interrupt mavacamten treatment during the course of weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor therapy. Mavacamten may be restarted immediately at the previous dose following discontinuation of the concomitant treatment.

Moderate CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors

Clinical Impact: Concomitant use with moderate CYP2C19 inhibitors or strong CYP3A4 inhibitors increases mavacamten exposure, which may elevate the risk of adverse drug reactions. Discontinuation of moderate CYP2C19 inhibitors or strong CYP3A4 inhibitors after long-term concomitant use may decrease mavacamten exposure, which may reduce the therapeutic efficacy of mavacamten.Prevention or Management:

For patients on stable therapy with moderate CYP2C19 inhibitors or strong CYP3A4 inhibitors, initiate mavacamten at a starting dose of 2.5 mg orally once daily.

For patients receiving mavacamten who plan to initiate moderate CYP2C19 inhibitors or strong CYP3A4 inhibitors, downtitrate mavacamten to the next lower daily dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg).

Avoid initiating concomitant moderate CYP2C19 inhibitors and strong CYP3A4 inhibitors in patients on stable mavacamten 2.5 mg daily, as no lower dose is available.

If moderate CYP2C19 inhibitors or strong CYP3A4 inhibitors are discontinued after long-term concomitant use, an increase in mavacamten dose may be required. Monitor for new or worsening symptoms.

For short-term use (e.g., 1 week), interrupt mavacamten treatment during the course of moderate CYP2C19 inhibitor or strong CYP3A4 inhibitor therapy. Mavacamten may be restarted immediately at the previous dose following discontinuation of the concomitant treatment.

2. Potential for Mavacamten to Affect Plasma Concentrations of Other Drugs

Certain CYP3A4, CYP2C9, and CYP2C19 Substrates

Mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with substrates of CYP3A4, CYP2C9, or CYP2C19 may decrease the plasma concentrations of these drugs. Unless otherwise recommended in the prescribing information, close monitoring is required when mavacamten is used concomitantly with CYP3A4, CYP2C9, or CYP2C19 substrates.

Certain Combined Hormonal Contraceptives

Progestogens and ethinyl estradiol are CYP3A4 substrates. Concomitant use with mavacamten may decrease the exposure of certain progestogens, which may result in contraceptive failure.

Combined hormonal contraceptives containing the combination of ethinyl estradiol and norethindrone may be used concomitantly with mavacamten.

For other combined hormonal contraceptives, advise patients to add a non-hormonal contraceptive method (e.g., condoms) or use an alternative contraceptive method not affected by CYP450 enzyme induction (e.g., intrauterine contraceptive system) during the concomitant use period and for 4 months after the last dose of mavacamten.

3. Drugs That Reduce Myocardial Contractility

Mavacamten is expected to have an additive negative inotropic effect when used with other drugs that reduce myocardial contractility. Concomitant use of mavacamten is not recommended in patients taking disopyramide, ranolazine, verapamil combined with beta-blockers, or diltiazem combined with beta-blockers. These drugs and drug combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms, and clinical experience with such combinations is limited.

If concomitant therapy with negative inotropic drugs is initiated, or the dose of a negative inotropic drug is increased, closely monitor left ventricular ejection fraction (LVEF) until a stable dose and clinical response are achieved.

FDA，2025.04