Mavacamten (Monograph)

Brand name: Camzyos
Drug class: Cardiac Drugs, Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for mavacamten to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of mavacamten and consists of the following: elements to assure safe use and implementation system. See REMS under Dosage and Administration and also see the FDA REMS page ([Web]).

Warning

Mavacamten can cause heart failure due to systolic dysfunction.
Echocardiogram assessments of left ventricular ejection fraction (LVEF) required before and during mavacamten use.
Initiation in patients with LVEF <55% not recommended.
Interrupt if LVEF <50% or if worsening clinical status.
Certain CYP-450 inhibitors and inducers are contraindicated in patients taking mavacamten because of an increased risk of heart failure.
Mavacamten is available only through a restricted program called the Camzyos REMS Program.

Introduction

Cardiac myosin inhibitor.

Uses for Mavacamten

Hypertrophic Cardiomyopathy

Treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms. Designated an orphan drug by FDA for this use.

Has been shown to decrease obstruction and improve exercise capacity, NYHA class, and health status.

Mavacamten Dosage and Administration

General

Pretreatment Screening

Obtain an echocardiogram before starting treatment. Do not initiate treatment in patients with left ventricular ejection fraction (LVEF) <55%.
Confirm absence of pregnancy and usage of effective contraception in females of reproductive potential.

Patient Monitoring

Assess echocardiogram during treatment. Interrupt treatment if LVEF <50%.
Perform regular assessments of LVEF and Valsalva left ventricular outflow tract (LVOT) gradient to guide appropriate dosing.
Monitor for symptoms of heart failure or worsening clinical status at each visit.
Monitor for changes in patient's medications to appropriately manage potential drug interactions and ensure appropriate dose adjustments.

REMS

Mavacamten is available only through a restricted distribution program called the Camzyos REMS Program. Clinicians, patients, and pharmacies must enroll in the program and complete any necessary requirements in order to prescribe, receive, and dispense the drug. Details of the program can be found on the FDA's REMS website or at [Web].

Administration

Oral Administration

Administer once daily with or without food.

Swallow capsules whole; do not open, break, chew, or crush.

Take a missed dose as soon as it is remembered; do not take 2 doses on the same day.

Dosage

Adults

Obstructive Hypertrophic Cardiomyopathy

Oral

Initiate only if left ventricular ejection (LVEF) ≥55%. Recommended initial dosage is 5 mg once daily.

Individualize dose based on clinical status and echocardiographic assessment. Titrate dosage based on LVEF and Valsalva left ventricular outflow tract (LVOT) gradient. Manufacturer states that allowable subsequent dosages are 2.5 mg, 5 mg, 10 mg, or 15 mg once daily; maximum recommended dosage is 15 mg daily.

Monitor LVEF and Valsalva LVOT regularly for careful titration to achieve an appropriate target Valsalva LVOT gradient while maintaining LVEF ≥50% and avoiding heart failure symptoms. First consider LVEF and then consider the Valsalva LVOT gradient and patient clinical status to guide initial dosage and subsequent titration.

Clinical monitoring and dose adjustments are recommended every 4 weeks for the first 12 weeks, and then every 12 weeks thereafter during maintenance phase of therapy. If treatment is interrupted at a dosage of 2.5 mg daily, either restart at 2.5 mg once daily or permanently discontinue therapy.

Delay dose increases or interrupt treatment in patients with intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or uncontrolled tachyarrhythmias) that could impair systolic function.

Table 1. Initial Dose Titration and Maintenance of Mavacamten Therapy.1
Initial Dosage	Monitoring and Dosing Instructions at Week 4	Monitoring and Dosing Instructions at Week 8	Monitoring and Dosing Instructions at Week 12 + every 12 Weeks (Maintenance)
5 mg once daily if LVEF ≥55%	LVEF <50%: interrupt treatment. Recheck ECHO every 4 weeks until LVEF ≥50%; once LVEF ≥50%, restart treatment at the next lower daily dose level (decrease from 5 to 2.5 mg, 10 to 5 mg, or 15 to 10 mg). Recheck clinical status and ECHO in 4 weeks and maintain the same dosage for the next 8 weeks unless LVEF<50%. Permanently discontinue mavacamten therapy if LVEF <50% occurs twice on a dosage of 2.5 mg daily. Valsalva LVOT <20 mm Hg: reduce to 2.5 mg once daily. Valsalva LVOT ≥20 mm Hg: maintain at 5 mg once daily.	LVEF <50%: interrupt treatment. Recheck ECHO every 4 weeks until LVEF ≥50%; once LVEF ≥50%, restart treatment at the next lower daily dose level (decrease from 5 to 2.5 mg, 10 to 5 mg, or 15 to 10 mg). Recheck clinical status and ECHO in 4 weeks and maintain the same dosage for the next 8 weeks unless LVEF<50%. Permanently discontinue mavacamten therapy if LVEF <50% occurs twice on a dosage of 2.5 mg daily. Valsalva LVOT <20 mm Hg in patients receiving 2.5 mg once daily: withhold therapy and return at week 12. Valsalva LVOT ≥20 mm Hg in patients receiving 2.5 mg once daily: continue at 2.5 mg once daily. Valsalva LVOT < 20 mm Hg in patients receiving 5 mg once daily: reduce to 2.5 mg once daily. Valsalva LVOT ≥20 mm Hg in patients receiving 5 mg once daily: continue at 5 mg once daily.	LVEF <50%: interrupt treatment. Recheck ECHO every 4 weeks until LVEF ≥50%; once LVEF ≥50%, restart treatment at the next lower daily dose level (decrease from 5 to 2.5 mg, 10 to 5 mg, or 15 to 10 mg). Recheck clinical status and ECHO in 4 weeks and maintain the same dosage for the next 8 weeks unless LVEF <50%. Permanently discontinue mavacamten therapy if LVEF <50% occurs twice on a dosage of 2.5 mg daily. If treatment was withheld at week 8 in patients with Valsalva LVOT <20 mm Hg, restart at 2.5 mg once daily as long as LVEF 50% and recheck clinical status and ECHO in 4 weeks. Maintain same dosage for the next 8 weeks consistent with maintenance treatment as described below, unless LVEF <50%. LVEF 50 to 55%, regardless of LVOT gradient OR LVEF >55% and LVOT gradient <30 mm Hg: maintain same dosage and follow up 12 weeks later. LVEF ≥55% and Valsalva LVOT gradient ≥30 mm Hg: up titrate to next dosage level (2.5 to 5 mg, 5 to 10 mg, or 10 to 15 mg). Recheck clinical status and ECHO in 4 weeks and maintain the same dosage for the next 8 weeks unless LVEF <50%. Further up-titration is allowed after 12 weeks of treatment on the same dose level.

Dosage Modification for Concomitant Administration of CYP2C19 or CYP3A4 Inhibitors

For patients on stable therapy with a weak cytochrome P450 (CYP) 2C19 or moderate CYP3A4 inhibitor, initiate mavacamten at 5 mg once daily.

For patients starting a weak CYP2C19 or moderate CYP3A4 inhibitor while taking mavacamten, reduce mavacamten dose by one dose level (i.e., reduce from 15 mg to 10 mg; 10 mg to 5 mg; 5 mg to 2.5 mg). For patients on mavacamten 2.5 mg once daily, avoid initiation of weak CYP2C19 or moderate CYP3A4 inhibitors. Check clinical status and echocardiogram 4 weeks after initiation of enzyme inhibitor and do not up-titrate mavacamten until 12 weeks after initiation of enzyme inhibitor.

Dosage Modification for Toxicity

Reduced Left Ventricular Function

If LVEF is <50%, interrupt mavacamten therapy and recheck echocardiogram every 4 weeks until LVEF is ≥50%. When LVEF increases to ≥50%, restart treatment at the next lower dose. If treatment was interrupted at 2.5 mg, restart at 2.5 mg. Recheck clinical status and echocardiogram in 4 weeks and maintain the same dose for the next 8 weeks unless LVEF is <50%. Treatment should be permanently discontinued if LVEF is <50% twice on 2.5 mg daily.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A and B): No dosage adjustment required.

Severe hepatic impairment (Child-Pugh class C): Effects unknown.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Mavacamten

Contraindications

Concomitant use of moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors. (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)
Concomitant use of moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Warnings/Precautions

Warnings

Heart Failure

Heart failure due to systolic dysfunction can occur. (See Boxed Warning.) Risk increases with intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia).

Conduct echocardiogram assessments of left ventricular ejection fraction (LVEF) before and during use.

Do not initiate if LVEF <55%.

Interrupt therapy if LVEF <50% or if worsening clinical status.

Avoid use in patients treated with disopyramide, ranolazine, verapamil with a β-adrenergic blocking agent, or diltiazem with a β-adrenergic blocking agent; concomitant use not studied. Concomitant use with disopyramide in combination with verapamil or diltiazem associated with left ventricular systolic dysfunction and heart failure symptoms.

Other Warnings and Precautions

CYP-450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness

Mavacamten primarily metabolized by CYP2C19 and CYP3A4. Concomitant use with other drugs that interact with these enzymes may lead to life-threatening interactions such as heart failure or loss of effectiveness.

Advise patients of potential drug interactions and to report use of all prescription and over-the-counter medications.

Fetal/Neonatal Morbidity and Mortality

Can cause fetal harm based on animal studies. Confirm absence of pregnancy prior to treatment and advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Specific Populations

Pregnancy

Can cause fetal harm.

Report mavacamten exposure to the Bristol Myers Squibb pregnancy registry at 1-800-721-5072 or [Web] if administered during pregnancy, or if pregnancy occurs while taking mavacamten or within 4 months after the last dose.

Lactation

Not known whether mavacamten or its metabolites are distributed into milk, affect milk production, or affect nursing infants.

Consider developmental and health benefits of breast-feeding along with mother's clinical need for mavacamten, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during mavacamten treatment and for 4 months after the last dose.

Since mavacamten can reduce the effectiveness of combined hormonal contraceptives, add a non-hormonal contraceptive (e.g., condoms), or use an alternative contraceptive not affected by CYP-450 enzyme induction (e.g., intrauterine system).

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in safety, effectiveness, and pharmacokinetics relative to younger patients.

Hepatic Impairment

Exposure increased in patients with mild to moderate hepatic impairment. No additional dose adjustment other than recommended dose titration and monitoring plan is required in patients with mild to moderate hepatic impairment.

Unknown effect of severe hepatic impairment.

Renal Impairment

No clinically significant differences in the pharmacokinetics of mavacamten were observed in patients with mild to moderate (eGFR 30–89 mL/minute per 1.73 m²) renal impairment.

Unknown effects of severe renal impairment or dialysis.

Common Adverse Effects

Adverse effects (>5%): dizziness, syncope.

Drug Interactions

Primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9.

Inducer of CYP2B6, CYP3A4, CYP2C9, and CYP2C19.

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 or drug transporters, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin exclusion (MATE1), MATE2-K, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), or organic anion transporters (OATs).

Drugs Affecting Hepatic Microsomal Enzymes

Moderate to strong CYP2C19 inhibitors (e.g., fluconazole, felbamate, fluvoxamine, esomeprazole, omeprazole, fluoxetine, voriconazole):Concomitant use contraindicated.

Strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, ketoconazole, posaconazole, ritonavir-containing products, nefazodone, itraconazole, cobicistat, nelfinavir, idelalisib): Concomitant use contraindicated.

Weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors (e.g., verapamil, diltiazem, ciprofloxacin, erythromycin, dronedarone, isoniazid, omeprazole, cimetidine):: may increase mavacamten exposure and risk of adverse effects. Dosage adjustments and additional monitoring required.

Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers (e.g., fosphenytoin, phenytoin, apalutamide, etravirine, mitotane, primidone, nafcillin, phenobarbital, rifampin, St. John's wort, efavirenz, carbamazepine, and enzalutamide:Concomitant use contraindicated.

Drugs Metabolized by Hepatic Microsomal Enzymes

Exposure and activity of CYP3A4, CYP2C9, or CYP2C19 substrates can be reduced by mavacamten. Closely monitor patients receiving mavacamten in combination with CYP3A4, CYP2C19, or CYP2C9 substrates where decreases in the plasma concentration of the substrate drug may reduce its activity.

Drugs That Reduce Cardiac Contractility

Additive negative inotropic effects with concomitant use of other drugs that reduce cardiac contractility.

Avoid concomitant use of disopyramide in combination with verapamil or diltiazem, since such use has been associated with left ventricular systolic dysfunction and symptoms of heart failure. If a negative inotrope is initiated or the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response are attained.

Specific Drugs

Drug	Interaction	Comments
Calcium-channel blocking agents (diltiazem, verapamil)	Diltiazem: Predicted increased AUC of mavacamten by 55% and peak plasma concentrations by 42% in CYP2C19 poor metabolizers Verapamil: Increased AUC of mavacamten by 15% and peak plasma concentrations by 52% in intermediate and normal CYP2C19 metabolizers	For patients on stable therapy with a moderate CYP3A4 inhibitor, initiate mavacamten at 5 mg once daily For patients starting moderate CYP3A4 inhibitor while taking mavacamten, reduce mavacamten dose by one dose level (i.e., reduce 15 mg to 10 mg; 10 mg to 5 mg; 5 mg to 2.5 mg) For patients on mavacamten 2.5 mg once daily, avoid initiation of moderate CYP3A4 inhibitors Check clinical status and echocardiogram 4 weeks after initiation of enzyme inhibitor and do not up-titrate mavacamten until 12 weeks after initiation of enzyme inhibitor
Hormonal contraceptives (ethinyl estradiol/progestin)	Possible decreased exposure of ethinyl estradiol and progestin leading to possible contraceptive failure or increase in breakthrough bleeding	Use a contraceptive method not affected by CYP enzyme induction (e.g., intrauterine system) or add nonhormonal contraception (e.g., condoms) during concomitant use and for 4 months after last dose of mavacamten
Ketoconazole	Predicted increased AUC of mavacamten up to 130% and peak plasma concentrations by 90%	Concomitant use is contraindicated
Midazolam	Decreased AUC of midazolam by 13% and peak plasma concentrations by 7% in CYP2C19 normal metabolizers In patients with HCM, predicted decrease in AUC of midazolam by 21 to 64% and decrease in peak plasma concentrations by 13 to 48% depending on mavacamten dose and CYP2C19 phenotype	Monitor for reduced efficacy of midazolam
Omeprazole	Omeprazole, a weak CYP2C19 inhibitor and CYP2C19 substrate, increased AUC of mavacamten by 48%; no effect on peak plasma concentrations in normal and rapid CYP2C19 metabolizers Predicted decrease in AUC and peak plasma concentrations of omeprazole by 48 to 67% depending on mavacamten dose and CYP2C19 phenotype	For patients on stable therapy with a weak CYP2C19 inhibitor, initiate mavacamten at 5 mg once daily For patients starting on a weak CYP2C19 inhibitor while taking mavacamten, reduce mavacamten dose by one dosage level (i.e., reduce 15 to 10 mg; 10 to 5 mg; 5 to 2.5 mg) For patients on mavacamten 2.5 mg once daily, avoid initiation of weak CYP2C19 inhibitors Check clinical status and echocardiogram 4 weeks after initiation of enzyme inhibitor and do not up-titrate mavacamten until 12 weeks after initiation of enzyme inhibitor Monitor for reduced efficacy of omeprazole
Repaglinide	Predicted decrease in AUC and peak plasma concentrations of repaglinide by 12 to 39% depending on mavacamten dose and CYP2C19 phenotype	Monitor for reduced efficacy of repaglinide
Rifampin	Predicted decreased AUC of mavacamten by 87% and peak plasma concentrations by 22% in CYP2C19 normal metabolizers and by 69% and 4%, respectively in CYP2C19 poor metabolizers	Concomitant use is contraindicated
Tolbutamide	Predicted decrease in AUC and peak plasma concentration of tolbutamide, a CYP2C9 substrate, by 33 to 65% depending on mavacamten dose and CYP2C19 phenotype	Monitor for reduced efficacy of tolbutamide

Mavacamten Pharmacokinetics

Absorption

Bioavailability

Estimated oral bioavailability at least 85%.

Peak plasma concentrations achieved in about 1 hour

Food

No clinically relevant effect on pharmacokinetics after a high fat meal; time to peak plasma concentrations increased by 4 hours.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

97–98%.

Elimination

Metabolism

Extensively metabolized; primarily through CYP2C19 and to a lesser extent through CYP3A4 and CYP2C9.

CYP2C19 poor metabolizers: AUC increased by 241% and peak plasma concentration increased by 47%.

Elimination Route

Urine: 85% (3% unchanged).

Feces: 7% (1% unchanged).

Half-life

CYP2C19 normal metabolizers: 6 to 9 days

CYP2C19 poor metabolizers: 23 days

Special Populations

Mild and moderate hepatic impairment (Child-Pugh class A and B): Exposure is increased.

Severe hepatic impairment (Child-Pugh class C): Unknown effect.

Mild to moderate renal impairment (eGFR 30–89 mL/min per 1.73 m²): No clinically significant changes in pharmacokinetics. Severe renal impairment (eGFR 15–30 mL/minute per 1.73 m²) and dialysis: Unknown effect.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted to 15–30°C).

Actions

Allosteric and reversible inhibitor selective for cardiac myosin; targets the underlying sarcomere hypercontractility of HCM.
Reduces myocardial contractility by decreasing actin-myosin cross-bridge formation.
Shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state.

Advice to Patients

Advise patients and/or their caregivers to read the FDA-approved patient labeling (Medication Guide).
Advise patients to swallow mavacamten capsules whole; do not break, crush, open, or chew the capsules.
Advise patients that if they miss a dose of mavacamten, to take the dose as soon as possible that day and to take the next scheduled dose at the usual time the following day. The patient should not take 2 doses in the same day.
Inform patients that cardiac function monitoring must be performed using echocardiography to monitor for heart failure. Advise patients to report any signs or symptoms of heart failure immediately to their healthcare provider.
Advise patients to notify their healthcare provider if they develop serious infection or arrhythmia, which may require interruption of mavacamten therapy.
Inform patients that mavacamten is available only through a restricted program called the Camzyos REMS Program. Advise patients of the need to enroll and comply with monitoring requirements of the program.
Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with mavacamten and for 4 months after the last dose. Advise patients who are using combined hormonal contraceptives to use an alternative contraceptive method or add a nonhormonal contraception because mavacamten may decrease the efficacy of combination hormonal contraceptives.
Advise females who are exposed to mavacamten during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancies to Bristol-Myers Squibb at 1-800-721-5072.
Advise patients to inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mavacamten is only available through a restricted program called the Camzyos REMS Program because of the risk of heart failure due to systolic dysfunction.