Usual Adult Dose for Hypertrophic Cardiomyopathy

Starting dose: 5 mg orally once a day
Allowable subsequent doses with titration: 2.5, 5, 10, or 15 mg orally once a day

Comments:

• Patients may develop heart failure while taking this drug; regular left ventricular ejection fraction (LVEF) and Valsalva left ventricular outflow tract (LVOT) gradient assessment is needed for careful titration to achieve an appropriate target Valsalva LVOT gradient, while maintaining LVEF at least 50% and avoiding heart failure symptoms.
• When initiating or titrating this drug, LVEF should be considered first, then the Valsalva LVOT gradient and patient clinical status should be considered to guide appropriate dosing; the algorithms for INITIATION and MAINTENANCE should be followed for appropriate dosing and monitoring schedules.
• If LVEF is less than 50% during therapy, this drug should be interrupted; the algorithm for INTERRUPTION should be followed for guidance on interrupting, restarting, or discontinuing this drug. If interrupted at 2.5 mg, the patient should either restart at 2.5 mg or permanently discontinue this drug.

Use: For the treatment of patients with symptomatic New York Heart Association (NYHA) class II to III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Mild to moderate liver dysfunction (Child-Pugh A or B): No adjustment recommended.
Severe liver dysfunction (Child-Pugh C): Data not available

Dose Adjustments

INITIATION PHASE:
5 mg orally once a day

• Therapy should be initiated only if LVEF at least 55%.
• Week 4, 8, and 12: Therapy should be interrupted if LVEF less than 50% at any clinic visit; therapy should be restarted after 4 weeks if LVEF at least 50%. The algorithm for INTERRUPTION should be followed.

Week 4:

• Valsalva LVOT gradient less than 20 mmHg: Patient should be down-titrated to 2.5 mg orally once a day.
• Valsalva LVOT gradient at least 20 mmHg: Patient should be maintained at 5 mg orally once a day.

Week 8:

• If at 2.5 mg orally once a day:
• Valsalva LVOT gradient less than 20 mmHg: Drug should be withheld and patient should return at Week 12.
• Valsalva LVOT gradient at least 20 mmHg: 2.5 mg orally once a day
• If at 5 mg orally once a day:
• Valsalva LVOT gradient less than 20 mmHg: 2.5 mg orally once a day
• Valsalva LVOT gradient at least 20 mmHg: Patient should be maintained at 5 mg orally once a day.

Week 12:

• If drug was withheld: (1) Patient should be restarted on 2.5 mg if LVEF at least 50% and clinical status and echocardiogram (echo) should be rechecked in 4 weeks; (2) Patient should be maintained on the same dose for the next 8 weeks (consistent with the algorithm for MAINTENANCE) unless LVEF less than 50%.
• If at 2.5 mg orally once a day: The algorithm for MAINTENANCE should be followed.
• If at 5 mg orally once a day: The algorithm for MAINTENANCE should be followed.

MAINTENANCE PHASE:
Week 12 and every 12 weeks:

• Current dose:
• If LVEF less than 50%: Therapy should be interrupted; the algorithm for INTERRUPTION should be followed.
• If LVEF 50% to 55% (regardless of Valsalva LVOT gradient) OR LVEF greater than 55% and Valsalva LVOT gradient less than 30 mmHg: Patient should be maintained on the same dose and should follow-up 12 weeks later.
• If LVEF at least 55% and Valsalva LVOT gradient at least 30 mmHg: (1) Patient should be up-titrated to the next higher daily (mg) dose level (i.e., 2.5 to 5 mg; 5 to 10 mg; 10 to 15 mg); (2) Clinical status and echo should be rechecked in 4 weeks and patient should be maintained on the same dose for the next 8 weeks unless LVEF less than 50%; (3) Further up-titration is allowed after 12 weeks of therapy on the same dose level.

TREATMENT INTERRUPTION AT ANY CLINIC VISIT IF LVEF LESS THAN 50%:
LVEF less than 50%:

• Therapy should be interrupted; echo parameters should be rechecked every 4 weeks until LVEF at least 50%.
• LVEF at least 50%: (1) Therapy should be restarted at the next lower daily (mg) dose level (5 to 2.5 mg; 10 to 5 mg; 15 to 10 mg; if interrupted at 2.5 mg, patient should be restarted at 2.5 mg); (2) Clinical status and echo should be rechecked in 4 weeks and patient should be maintained on the same dose for the next 8 weeks unless LVEF less than 50%; (3) The algorithm for MAINTENANCE should be followed.
• Therapy should be permanently discontinued if LVEF less than 50% twice on 2.5 mg orally once a day.

Dose increases should be delayed when there is intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation, other uncontrolled tachyarrhythmia) that may impair systolic function; interruption of this drug should be considered in patients with intercurrent illness.

COADMINISTRATION OF WEAK CYP450 2C19 OR MODERATE CYP450 3A4 INHIBITORS:

• Patients who are on stable therapy with a weak CYP450 2C19 inhibitor or a moderate CYP450 3A4 inhibitor: This drug should be started at the recommended starting dosage of 5 mg orally once a day.
• Patients who start a weak CYP450 2C19 inhibitor or a moderate CYP450 3A4 inhibitor: The dosage of this drug should be reduced by 1 level (i.e., 15 to 10 mg; 10 to 5 mg; or 5 to 2.5 mg).
• Clinical and echocardiographic assessment should be scheduled 4 weeks after inhibitor initiation.
• This drug should not be up-titrated until 12 weeks after inhibitor initiation.
• Weak CYP450 2C19 and moderate CYP450 3A4 inhibitors should not be started in patients who are on stable therapy with 2.5 mg of this drug as a lower once-daily dose is not available.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for mavacamten. It includes elements to assure safe use and an implementation system. For additional information: www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:

• RISK OF HEART FAILURE: This drug reduces LVEF and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required before and during therapy. Starting this drug in patients with LVEF less than 55% is not recommended; therapy should be interrupted if LVEF is less than 50% at any visit or if the patient has heart failure symptoms or worsening clinical status. Coadministration with certain CYP450 inhibitors or stopping certain CYP450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of this drug is contraindicated with: moderate to strong CYP450 2C19 inhibitors or strong CYP450 3A4 inhibitors, and moderate to strong CYP450 2C19 inducers or moderate to strong CYP450 3A4 inducers. Because of the risk of heart failure due to systolic dysfunction, this drug is available only through a restricted program under a REMS called Camzyos REMS Program.

CONTRAINDICATIONS:

• Coadministration with moderate to strong CYP450 2C19 inhibitors or strong CYP450 3A4 inhibitors
• Coadministration with moderate to strong CYP450 2C19 inducers or moderate to strong CYP450 3A4 inducers

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Before therapy, confirm absence of pregnancy and usage of effective contraception in patients of childbearing potential.
• Do not initiate or up-titrate this drug in patients with LVEF less than 55%.
• Administer without regard to food.
• Swallow capsules whole; do not break, open, or chew the capsules.

Storage requirements:

• Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).

General:

• Daily dosing takes weeks to reach steady-state drug levels and therapeutic effects; genetic variation in metabolism and drug interactions can cause large differences in exposure.

Monitoring:

• Cardiovascular: LVEF (before and regularly during therapy)
• General: Clinical status (before and regularly during therapy)

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Immediately report any signs/symptoms of heart failure to health care provider.
• You must enroll in the program and comply with ongoing monitoring requirements.
• Patients of childbearing potential:
• Notify health care provider of a known or suspected pregnancy.
• Use effective contraception during therapy and for 4 months after the last dose.
• If using combined hormonal contraceptives (CHCs), use an alternative contraceptive method or add nonhormonal contraception; this drug may decrease the efficacy of CHCs.
• If exposed to this drug during pregnancy, you are encouraged to report your pregnancy to Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.
• If a dose is missed, take it as soon as possible that day, and then take the next scheduled dose at the usual time the following day; do not take 2 doses in the same day.