U.S. Full Prescribing Information, including Boxed WARNING

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For SRT-eligible patients with NYHA class II–III obstructive HCM,

In VALOR-HCM LTE, CAMZYOS® Consistently Reduced Obstruction and Reduced Symptoms (NYHA Class) Through Week 561-3

Study Design > See Select Safety Profile >

VALOR-HCM Primary Endpoint

PRIMARY ENDPOINT3,6 The primary endpoint was a composite of the proportion of patients who decided to proceed with SRT or who remained SRT-eligible at week 16. At Week 16, 18% (n=10/56) of patients taking CAMZYOS vs 77% (n=43/56) taking placebo remained guideline-eligible or chose to undergo SRT. Two patients in each group decided to proceed with SRT. The treatment difference was 59% (95% CI: 44, 74; P<0.0001). After Week 16, patients were offered the opportunity to continue in the LTE, with crossover for the patients in the placebo group to receive CAMZYOS 5 mg daily

VALOR-HCM LTE: Primary Objective – Impact on SRT

In the pivotal VALOR-HCM trial, 18% (n=10/56) of patients taking CAMZYOS and 77% (n=43/56) taking placebo met the primary composite endpoint (remained guideline eligible for SRT at Week 16 or chose to undergo SRT at or before Week 16). Two patients in each group decided to proceed with SRT.4

Interim Week 56 results

~91% of Patients Were No Longer Guideline Eligible for and Chose Not to Undergo Septal Reduction Therapy (SRT) in the Original CAMZYOS Group1

At Week 56, ~9% (n=5/56) in the original CAMZYOS group* and ~19% in the placebo-to-CAMZYOS crossover group† remained guideline eligible for or chose to proceed with SRT.1

This prespecified exploratory endpoint was not powered for significance, and statistic comparisons have not been made.

  • ‡These patients were imputed as meeting SRT criteria.2

VALOR-HCM LTE: LVOT Obstruction

In the pivotal VALOR-HCM trial, -45.2 (28.5) mean change (SD) in Valsalva LVOT gradient with CAMZYOS vs 0.4 (29.7) mmHg with placebo from baseline to Week 16.5

Interim Week 56 results

CAMZYOS Demonstrated Consistent Reductions in Valsalva LVOT Gradient Through Week 56 in the Original CAMZYOS Group1

Exploratory endpoint: Mean change in Valsalva LVOT gradient from baseline to Week 561,3

Mean Change in Valsalva LVOT gradient from Baseline to Week 56 Chart Mean Change in Valsalva LVOT gradient from Baseline to Week 56 Chart

These prespecified exploratory endpoints were not powered for significance, and statistical comparisons have not been made.

Important LVOT gradient thresholds6:

  • An LVOT peak gradient of ≥30 mmHg is indicative of obstruction
  • A resting or provoked LVOT gradient of ≥50 mmHg is the obstructive criteria for SRT in patients with drug-refractory symptoms

VALOR-HCM LTE: NYHA class

In the pivotal VALOR-HCM trial, 63% of patients (n=35/56) taking CAMZYOS improved by ≥1 NYHA class vs 21% (n=12/56) taking placebo group from baseline to Week 16. Approximately 7% of the randomized patients were NYHA class II and 93% were NYHA class III+ at baseline.4

Interim Week 56 results

CAMZYOS Demonstrated Symptom Improvement in ~93% of Patients in the Original CAMZYOS Group From Baseline to Week 561

NYHA class improvement at Week 56

At study baseline, approximately 6% of randomized patients were NYHA class II and 94% were NYHA class III+.1

This prespecified exploratory endpoint was not powered for significance, and statistical comparisons have not been made.

VALOR-HCM LTE: Patient-Reported Outcomes

In the pivotal VALOR-HCM trial, patients taking CAMZYOS (n=56) had a mean change (SD) of 10 (16) in KCCQ-23-CSS (patient-reported total symptom score and physical limitations) vs. 2 (12) for Placebo (n=56); treatment difference (95% CI): 9 (5, 14), from Baseline to Week 16.4

Interim Week 56 results

CAMZYOS Demonstrated Consistent Improvements in KCCQ-23–CSS Scores in the Original CAMZYOS Group1§

Exploratory endpoint: Mean change in KCCQ-23–CSS from baseline to Week 561,3

Mean Change in KCCQ-23 CSS from Baseline to Week 56 Chart Mean Change in KCCQ-23 CSS from Baseline to Week 56 Chart

This prespecified exploratory endpoint wasn’t powered for significance and statistical comparisons have not been made.

  • §The KCCQ-23–CSS is derived from the TSS and PL score of the KCCQ-23. The Clinical Summary Score ranges from 0 to 100, with higher scores representing less severe symptoms and/or physical limitations.4

KCCQ-23–CSS=Kansas City Cardiomyopathy Questionnaire (23-item version)–Clinical Summary Score; PL=physical limitations; TSS=total symptom score.

VALOR-HCM LTE: Cardiac Biomarker

In the pivotal VALOR-HCM trial, the proportion of geometric mean ratio of NT-proBNP between the CAMZYOS group and placebo group was 0.33 (95% CI: 0.27, 0.42) from baseline to Week 16.4

Interim Week 56 results

Change in NT-proBNP from Baseline to Week 561

Exploratory endpoint: Median change in NT-proBNP from baseline to Week 561,3

Median Change in NT-proBNP from Baseline to Week 56 Chart Median Change in NT-proBNP from Baseline to Week 56 Chart

These prespecified exploratory endpoints were not powered for significance and statistical comparisons have not been made. The clinical significance of the NT-proBNP findings is unknown.4

VALOR-HCM LTE: Cardiac Structure

Interim Week 56 results

Changes in LAVI and LVMI for Both the Original CAMZYOS Group and Crossover Group With CAMZYOS1,3

Mean Change in LAVI from Baseline to Week 56 Chart, Mean Change in LVMI from Baseline to Week 56 Chart Mean Change in LAVI from Baseline to Week 56 Chart Mean Change in LVMI from Baseline to Week 56 Chart

These prespecified exploratory endpoints were not powered for significance and statistical comparisons have not been made.

LAVI=left atrial volume index; LVMI=left ventricular mass index.

The VALOR-HCM LTE trial was designed to assess the safety and efficacy of CAMZYOS in patients who remained guideline-eligible for SRT or decided to proceed with SRT, through Week 56. Patients included those who were initially randomized to CAMZYOS (56 weeks of exposure, n=56) as well as those who were initially randomized to placebo who then crossed over to CAMZYOS starting at 5 mg at Week 16 (40 weeks of exposure, n=52).1,2*

Dose adjustments of CAMZYOS were guided by site-read echos with clinical visits occurring every 4 weeks from Weeks 16 to 32, and every 12 weeks from Weeks 32 to 56, and through the end of the study.† Treatment with CAMZYOS was temporarily interrupted if LVEF was <50%, and an LVEF <30% resulted in permanent discontinuation.1,2

  • *Two patients in the placebo group withdrew (1 each due to ineligibility and withdrawn consent) and 2 patients proceeded to SRT and did not continue into the LTE.2
  • †CAMZYOS could be down-titrated at Week 20 and up-titrated at Weeks 24 and 28 and re-evaluated every 12 weeks after Week 32.1,2
Read the VALOR-LTE reprint >

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Important Safety
Information
WARNING: RISK OF HEART FAILURE

CAMZYOSTM (mavacamten) reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction.

Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status.

Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following:

  • Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
  • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM.

CONTRAINDICATIONS

CAMZYOS is contraindicated with concomitant use of:

  • Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
  • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
WARNINGS AND PRECAUTIONS

Heart Failure

CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure.

Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function.

Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations.

Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited.

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

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

Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment.

CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program

CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following:

  • Prescribers must be certified by enrolling in the REMS Program.
  • Patients must enroll in the REMS Program and comply with ongoing monitoring requirements.
  • Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS.
  • Wholesalers and distributors must only distribute to certified pharmacies.

Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367.

Embryo-Fetal Toxicity

CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

ADVERSE REACTIONS

In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM.

Effects on Systolic Function

In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30–week treatment period. At Week 38, following an 8–week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS.

DRUG INTERACTIONS

Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS

CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS.

Impact of Other Drugs on CAMZYOS:

  • Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors: Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated.
  • Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers: Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated
  • Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors: Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available

Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs

CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C9, or CYP2C19 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used with concomitant CYP3A4, CYP2C9, or CYP2C19 substrates unless otherwise recommended in the Prescribing Information.

Certain Combined Hormonal Contraceptives (CHC): Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins, which may lead to contraceptive failure. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and 4 months after the last dose of CAMZYOS.

Drugs That Reduce Cardiac Contractility

Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited.

If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved.

SPECIFIC POPULATIONS

Pregnancy

CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or www.bms.com.

Lactation

The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition.

Females and Males of Reproductive Potential

Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

INDICATION

CAMZYOS® (mavacamten) is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

CAMZYOS is available in 2.5 mg, 5 mg, 10 mg, and 15 mg capsules.

Please see US Full Prescribing Information, including Boxed WARNING.

References:

  1. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: Week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977.
  2. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: Week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977. [supplementary appendix protocol]
  3. Desai MY, Owens A, Wolski K, et al. Myosin inhibition in patients with obstructive HCM referred for septal reduction therapy: Week 56 results of the VALOR-HCM trial. Presented at ESC 2023. Oral presentation.
  4. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  5. Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80(2):95-108. doi:10.1016/j.jacc.2022.04.048
  6. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25):e533-e631. doi:10.1161/CIR.0000000000000938
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References:

  1. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: Week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977.
  2. Desai MY, Owens A, Wolski K, et al. Mavacamten in patients with hypertrophic cardiomyopathy referred for septal reduction: Week 56 results from the VALOR-HCM randomized clinical trial. JAMA Cardiol. 2023;8(10):968-977. [supplementary appendix protocol]
  3. Desai MY, Owens A, Wolski K, et al. Myosin inhibition in patients with obstructive HCM referred for septal reduction therapy: Week 56 results of the VALOR-HCM trial. Presented at ESC 2023. Oral presentation.
  4. CAMZYOS [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  5. Desai MY, Owens A, Geske JB, et al. Myosin inhibition in patients with obstructive hypertrophic cardiomyopathy referred for septal reduction therapy. J Am Coll Cardiol. 2022;80(2):95-108. doi:10.1016/j.jacc.2022.04.048
  6. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25):e533-e631. doi:10.1161/CIR.0000000000000938
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