What is the recommended use and dosage of Mavacamten (mavacamten) for treating symptomatic obstructive hypertrophic cardiomyopathy?

Mavacamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Indication and Patient Selection

Mavacamten is FDA-approved and guideline-recommended as second-line therapy for adults with symptomatic NYHA class II-III obstructive hypertrophic cardiomyopathy who remain symptomatic despite optimal first-line therapy with beta-blockers or nondihydropyridine calcium channel blockers. 1, 2, 3

• Do not initiate mavacamten in patients with LVEF <55% 3
• The drug is indicated only for obstructive HCM (LVOT gradient ≥50 mm Hg) 4
• Mavacamten is contraindicated in pregnancy due to teratogenic effects and requires confirmed absence of pregnancy and effective contraception in females of reproductive potential before initiation 1, 5, 3

Treatment Algorithm

First-Line Therapy (Must Be Tried First)

• Initiate nonvasodilating beta-blockers titrated to resting heart rate <60-65 bpm 2
• Alternative first-line: verapamil or diltiazem (up to 480 mg/day) if beta-blockers are ineffective, contraindicated, or poorly tolerated 2

Second-Line Options for Persistent Symptoms

• Add mavacamten (adult patients only) OR 1
• Add disopyramide (in combination with AV nodal blocking agent) OR 1
• Refer for septal reduction therapy at experienced centers 1

Dosing and Titration Protocol

Starting Dose

• Begin with 5 mg orally once daily without regard to food 3
• Maximum dose: 15 mg once daily 3
• Available doses for titration: 2.5 mg, 5 mg, 10 mg, or 15 mg 3

Titration Strategy

The dosing algorithm is echocardiography-guided, prioritizing LVEF monitoring first, then Valsalva LVOT gradient and clinical status 3, 6:

Initiation Phase (First 12 weeks):

• Obtain echocardiogram at weeks 4,8, and 12 3
• If LVEF ≥55% and Valsalva LVOT gradient ≥20 mm Hg: increase dose by one level 3
• If LVEF 50-54%: maintain current dose 3
• If LVEF <50%: interrupt treatment immediately 3

Maintenance Phase (After week 12):

• Obtain echocardiogram every 12 weeks 3
• Continue dose adjustments based on LVEF and LVOT gradient using same parameters 3
• Steady-state drug levels take weeks to achieve due to genetic variation in CYP2C19 metabolism 3, 6

Critical Interruption Rules

• Mandatory interruption if LVEF <50% at any visit 1, 2, 3
• Interrupt during intercurrent illness (serious infection) or uncontrolled arrhythmias (atrial fibrillation, tachyarrhythmia) that may impair systolic function 3
• Delay dose increases during intercurrent illness 3
• If interrupted at 2.5 mg, either restart at 2.5 mg or discontinue permanently 3

Expected Clinical Outcomes

Mavacamten demonstrates robust efficacy in 30-60% of patients 2, 5:

• LVOT gradient reduction: Mean reduction of 36 mm Hg in post-exercise gradient and 45-55 mm Hg in Valsalva gradient 4, 7
• Functional capacity: Mean increase of 1.4 mL/kg/min in peak oxygen consumption 4
• Symptom improvement: 34% more patients improved by ≥1 NYHA class compared to placebo (65% vs 31%) 4
• Quality of life: Significant improvement in Kansas City Cardiomyopathy Questionnaire scores (mean +9.1 points) 4
• Septal reduction therapy avoidance: 89-91% of patients avoided SRT at 56 weeks 7
• Diastolic function: Reduction in left atrial volume index (mean -7.5 mL/m²) and lateral E/e' ratio (mean -3.8) 8

Critical Safety Monitoring and Contraindications

Mandatory REMS Program

• Mavacamten is available only through a Risk Evaluation and Mitigation Strategy (REMS) program due to heart failure risk 3
• Regular echocardiographic monitoring is mandatory throughout treatment 5, 3

LVEF Reduction Risk

• 5.7% of patients develop LVEF reduction attributable to mavacamten alone 2, 5
• Up to 7-10% when considering other clinical conditions 2, 5
• In the VALOR-HCM trial, 11.1% of patients had LVEF <50%, with 2 patients having LVEF ≤30% (one death) 7
• Discontinue mavacamten permanently if persistent systolic dysfunction (LVEF <50%) develops 1

Absolute Contraindications

• Pregnancy (teratogenic effects) 1, 5, 3
• Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors 3
• Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers 3

Drug Interactions Requiring Dose Adjustment

• Weak CYP2C19 or moderate CYP3A4 inhibitors: Reduce mavacamten dose by one level (15 mg→10 mg; 10 mg→5 mg; 5 mg→2.5 mg) 3
• CYP2C19 metabolizer phenotype affects drug exposure, but the echocardiography-guided titration strategy accounts for this variability 6

Common Pitfalls to Avoid

• Do not initiate or up-titrate if LVEF <55% - this is a hard stop 3
• Do not skip scheduled echocardiograms - the entire safety profile depends on regular LVEF monitoring 3, 6
• Do not continue mavacamten if LVEF drops below 50% - interrupt immediately and follow the interruption algorithm 3
• Do not use in combination with contraindicated CYP inhibitors/inducers - this dramatically increases heart failure risk 3
• Do not use in patients with systolic dysfunction (LVEF <50%) - mavacamten must be discontinued if this develops 1
• Do not prescribe without confirming pregnancy status and contraception in females of reproductive potential 3
• Adverse events in trials were mostly mild (80%) and unrelated to drug (79%), with good overall tolerability 9