What is the recommended initiation, titration, and monitoring protocol for mavacamten (cardiac myosin inhibitor) in hypertrophic cardiomyopathy, and what alternatives are available if it is not tolerated?

Mavacamten Protocol for Hypertrophic Cardiomyopathy

Initiate mavacamten at 5 mg orally once daily in adults with symptomatic NYHA class II-III obstructive HCM who have LVEF ≥55%, then titrate every 4-12 weeks based on echocardiographic assessment of Valsalva LVOT gradient and LVEF to maintain gradient control while keeping LVEF ≥50%. 1

Initiation Requirements

Before starting mavacamten, you must confirm: 1

• LVEF ≥55% - do not initiate if LVEF <55%
• Negative pregnancy test in females of reproductive potential
• Effective contraception established (mavacamten is teratogenic and contraindicated in pregnancy)
• CYP2C19 metabolizer status determined via genetic testing to guide dosing 2, 3
• Baseline echocardiogram documenting Valsalva LVOT gradient and LVEF

The 2024 AHA/ACC guidelines recommend mavacamten as a Class 1 indication for patients with obstructive HCM who remain symptomatic despite beta-blockers or non-dihydropyridine calcium channel blockers. 4

Titration Protocol

Starting Dose

• 5 mg once daily for patients with normal CYP2C19 metabolism 1
• Take without regard to food, swallow capsules whole 1
• Available doses: 2.5 mg, 5 mg, 10 mg, 15 mg (maximum 15 mg daily) 1

Dose Adjustment Schedule

At Week 4: 1, 5, 6

• If Valsalva LVOT gradient <20 mmHg: down-titrate by one level
• If Valsalva LVOT gradient ≥20 mmHg and LVEF ≥50%: continue current dose
• If LVEF <50%: interrupt treatment (see interruption protocol below)

At Week 8: 6

• If Valsalva LVOT gradient <20 mmHg: down-titrate by one level
• If Valsalva LVOT gradient ≥20 mmHg and LVEF ≥50%: continue current dose

At Week 12 and every 12 weeks thereafter: 1, 5, 6

• If Valsalva LVOT gradient ≥30 mmHg AND LVEF ≥55%: up-titrate by one level
• If Valsalva LVOT gradient <30 mmHg: continue current dose
• If LVEF <55%: do not up-titrate
• If LVEF <50%: interrupt treatment

Real-world data shows mean time to reach maintenance dose is approximately 14 weeks, with over 50% of patients requiring dose adjustments during titration. 2

Monitoring Requirements

Echocardiographic Monitoring

Mandatory assessments at: 1

• Baseline
• Week 4
• Week 8
• Week 12
• Every 12 weeks during maintenance

Measure: 1, 5

• Valsalva LVOT gradient (primary efficacy parameter)
• LVEF (primary safety parameter)
• Resting LVOT gradient

Clinical Monitoring

Assess at each visit: 1

• NYHA functional class
• Symptoms of heart failure (dyspnea, chest pain, fatigue, palpitations, leg edema)
• NT-proBNP levels (optional but helpful - expect significant reductions with effective therapy) 2, 7

Treatment Interruption Protocol

Mandatory interruption if LVEF <50% at any visit: 8, 4, 1

1. Stop mavacamten immediately
2. Repeat echocardiogram in 4 weeks
3. If LVEF recovers to ≥50%:
   • Restart at one dose level lower than interruption dose
   • If interrupted at 2.5 mg, either restart at 2.5 mg or discontinue permanently 1
4. If LVEF remains <50%:
   • Continue interruption
   • Repeat echo in another 4 weeks
   • If LVEF does not recover, discontinue permanently 1

The 2024 AHA/ACC guidelines mandate that cardiac myosin inhibitors must be discontinued if persistent systolic dysfunction (LVEF <50%) develops. 8, 4

Drug Interactions Requiring Dose Adjustment

Contraindicated (Do Not Use): 1

• Moderate-to-strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine)
• Strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir)
• Moderate-to-strong CYP2C19 inducers (e.g., rifampin)
• Moderate-to-strong CYP3A4 inducers (e.g., carbamazepine, phenytoin)

Allowed With Dose Reduction: 1

Weak CYP2C19 inhibitors or moderate CYP3A4 inhibitors:

• Reduce mavacamten by one dose level when initiating inhibitor
• Schedule echo assessment 4 weeks after inhibitor initiation
• Do not up-titrate mavacamten until 12 weeks after inhibitor initiation
• Avoid initiating these inhibitors in patients on 2.5 mg (no lower dose available)

Special Circumstances

Intercurrent Illness or Arrhythmia

Consider interrupting mavacamten if patient develops: 1

• Serious infection
• Atrial fibrillation or uncontrolled tachyarrhythmia
• Any condition that may impair systolic function

These conditions increase risk of systolic dysfunction and heart failure. Delay dose increases during intercurrent illness. 1

Negative Inotropes

If adding other negative inotropes (verapamil, diltiazem, disopyramide): 1

• Close medical supervision required
• Frequent LVEF monitoring
• Avoid combining multiple negative inotropes when possible

Alternatives if Mavacamten Not Tolerated

If mavacamten causes persistent LVEF reduction <50% or is otherwise not tolerated, the 2024 AHA/ACC guidelines recommend: 4

1. Disopyramide (in combination with AV nodal blocking agent for rate control)
2. Septal reduction therapy (surgical myectomy or alcohol septal ablation) at experienced centers
3. Continue optimized beta-blockers or non-dihydropyridine calcium channel blockers

For patients who develop systolic dysfunction (LVEF <50%) from any cause, discontinue all negative inotropic agents and initiate guideline-directed heart failure therapy. 8

Key Safety Considerations

• REMS Program: Mavacamten is only available through the CAMZYOS REMS Program due to heart failure risk 1
• Pregnancy: Absolutely contraindicated - causes fetal harm. Females must use effective contraception until 4 months after last dose. Avoid combined hormonal contraceptives containing progestins other than norethindrone. 1
• Heart Failure Risk: Atrial fibrillation occurred in 11.5 per 100 patient-years and heart failure in 1.7 per 100 patient-years in clinical trials 7
• Treatment interruption rates: Approximately 8.7% in clinical trials, often protocol-driven due to LVEF <50% 7

The echocardiography-guided titration strategy allows identification of the lowest individualized dose needed for symptom improvement while minimizing LVEF reduction risk across all CYP2C19 metabolizer phenotypes. 5, 6