Carmin

Approved Indications:

• Obstructive Hypertrophic Cardiomyopathy (oHCM):
  Mavacamten is indicated for the treatment of adults with symptomatic (NYHA Class II–III) obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms.

Clinically Accepted Off-Label / Investigational Uses:

• Non-obstructive HCM (under investigation):
  Being studied for non-obstructive hypertrophic cardiomyopathy, but not yet an approved indication.
• Heart failure with preserved ejection fraction (HFpEF):
  Currently under research for potential benefit in HFpEF, particularly with diastolic dysfunction.

Route: Oral, with or without food.

Adults:

• Starting Dose:
  5 mg orally once daily.
• Titration:
  Dose can be adjusted (up to 15 mg or down to 2.5 mg once daily) based on clinical response, echocardiographic assessments (LVOT gradient), and LVEF.
  Echocardiogram required at baseline and every 4 weeks during titration.
• Maintenance Dose:
  Typically 5–15 mg once daily, individualized to patient response.

Elderly (≥65 years):

• No dosage adjustment required, but monitor cardiac function closely due to age-related changes.

Renal Impairment:

• Mild to moderate impairment (eGFR ≥30 mL/min/1.73 m²): No dosage adjustment needed.
• Severe impairment: Use with caution due to limited data.

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment necessary.
• Moderate (Child-Pugh B): Use with caution.
• Severe (Child-Pugh C): Not recommended.

Pediatric Use:

• Safety and efficacy not established in patients under 18 years.

Monitoring:

• Echocardiogram every 4 weeks during initiation and titration.
• Discontinue if LVEF <50%.

Mavacamten is a selective cardiac myosin inhibitor that modulates the ATPase activity of β-cardiac myosin, the motor protein responsible for cardiac muscle contraction. In hypertrophic cardiomyopathy, excessive myosin-actin cross-bridge formation leads to hypercontractility, myocardial stiffness, and left ventricular outflow tract (LVOT) obstruction. By reducing the number of actin-myosin cross-bridges, mavacamten decreases cardiac muscle contractility and relieves LVOT obstruction, improving diastolic filling and symptoms. This action helps normalize left ventricular ejection and reduces cardiac wall stress.

• Absorption: Rapidly absorbed; peak plasma concentrations (Tmax) occur ~1 hour post-dose.
• Bioavailability: ~85%
• Distribution: Extensive tissue distribution; volume of distribution ~6.6 L/kg.
• Protein Binding: ~97–98%
• Metabolism: Primarily via CYP2C19, with minor contributions from CYP3A4 and CYP2C9.
• Half-life: Approximately 6–9 days.
• Steady State: Achieved within 6 weeks.
• Excretion: ~85% eliminated via feces (major) and urine (minor), mostly as metabolites.

• Pregnancy:
  Based on animal studies, mavacamten may cause embryo-fetal toxicity (e.g., cardiac malformations). Use is contraindicated during pregnancy. Women of reproductive potential must use effective contraception during treatment and for 4 months after the last dose.
• Lactation:
  It is unknown if mavacamten is excreted in human milk. Due to potential for serious adverse effects in nursing infants, breastfeeding is not recommended during treatment and for 4 months after the last dose.

• Primary Class: Cardiac Myosin Inhibitor
• Subclass: Selective allosteric modulator of β-cardiac myosin ATPase

• Known hypersensitivity to mavacamten or any excipients
• Left Ventricular Ejection Fraction (LVEF) <55%
• Pregnancy
• Concurrent use with moderate to strong CYP2C19 or CYP3A4 inhibitors or inducers (during initiation or dose adjustment)

• Heart Failure Risk:
  May cause systolic dysfunction or heart failure due to excessive reduction in contractility. Discontinue if LVEF falls below 50%.
• Drug Interaction Risk:
  Strong CYP2C19 or CYP3A4 inhibitors/inducers may dangerously alter serum levels. Use is contraindicated with these during titration.
• Monitoring Requirements:
  Regular echocardiographic monitoring (baseline and every 4 weeks during titration, then periodically).
• Pregnancy Risk:
  Can cause fetal harm. Pregnancy testing and contraception are required.
• REMS Program:
  Mavacamten is available only through a Risk Evaluation and Mitigation Strategy (REMS) due to the risk of systolic dysfunction.

Common Adverse Effects:

• Dizziness
• Syncope
• Fatigue
• Hypotension
• Headache

Serious Adverse Effects:

• Heart failure with reduced ejection fraction (LVEF <50%)
• Cardiogenic syncope
• Sustained arrhythmias (rare)

Dose-Dependent:

• Cardiac-related side effects (e.g., systolic dysfunction) are dose-related and reversible with dose reduction or discontinuation.

Onset:

• Typically within the first 4–12 weeks during titration.

Major Drug Interactions:

• CYP2C19 Inhibitors (e.g., fluvoxamine, omeprazole): Increase mavacamten levels—contraindicated during initiation/titration.
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Increase mavacamten exposure—contraindicated during initiation/titration.
• CYP2C19/3A4 Inducers (e.g., rifampin, carbamazepine): Decrease mavacamten efficacy—avoid use.
• Beta-blockers or Calcium Channel Blockers: May potentiate negative inotropic effects—monitor closely.

Enzyme Systems Involved:
Primarily CYP2C19 (major), with contributions from CYP3A4 and CYP2C9.

• FDA Approval (2022):
  Mavacamten was FDA approved for symptomatic oHCM based on the EXPLORER-HCM trial, showing improved exercise capacity and functional class.
• REMS Enrollment (Ongoing):
  Prescribers and pharmacies must enroll in REMS due to the potential for systolic dysfunction and need for echocardiographic monitoring.
• Guideline Integration (AHA/ACC 2023):
  Considered as a second-line option for symptomatic oHCM not controlled with beta-blockers, non-dihydropyridine CCBs, or disopyramide.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C.
• Humidity and Light: Store in a dry place; protect from excessive moisture. No special light protection required.
• Handling Instructions:
• Keep in original container.
• Keep out of reach of children.
• Do not crush or chew capsules.