CAMZYOS (mavacamten) capsule, gelatin coated
Myokardia, Inc.

Myokardia, Inc.
CAMZYOS
mavacamten
MAVACAMTEN
MAVACAMTEN
CROSCARMELLOSE SODIUM
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
MANNITOL
SILICON DIOXIDE
FERROSOFERRIC OXIDE
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
Light purple capsule cap
hard gelatin
Mava;one;side;strength;on;other
CAMZYOS
mavacamten
MAVACAMTEN
MAVACAMTEN
CROSCARMELLOSE SODIUM
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
MANNITOL
SILICON DIOXIDE
FERROSOFERRIC OXIDE
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
capsule cap
hard gelatin
Mava;one;side;strength;on;other
CAMZYOS
mavacamten
MAVACAMTEN
MAVACAMTEN
CROSCARMELLOSE SODIUM
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
MANNITOL
SILICON DIOXIDE
FERROSOFERRIC OXIDE
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
capsule cap
hard gelatin
Mava;one;side;strength;on;other
CAMZYOS
mavacamten
MAVACAMTEN
MAVACAMTEN
CROSCARMELLOSE SODIUM
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
MANNITOL
SILICON DIOXIDE
FERROSOFERRIC OXIDE
GELATIN, UNSPECIFIED
FERRIC OXIDE RED
TITANIUM DIOXIDE
FERRIC OXIDE YELLOW
capsule cap
hard gelatin
Mava;one;side;strength;on;other

Warnings and Precautions, Heart Failure (5.1)

06/2023

Warnings and Precautions, Embryo-Fetal Toxicity (5.4)

04/2024

WARNING: RISK OF HEART FAILURE

CAMZYOS reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction [see Warnings and Precautions (5.1)].

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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

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 [see Contraindications (4) and Warnings and Precautions (5.2)]:

  • 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 CAMZYOS REMS PROGRAM [see Warnings and Precautions (5.3)].

WARNING: RISK OF HEART FAILURE

See full prescribing information for complete boxed warning.

  • CAMZYOS can cause heart failure due to systolic dysfunction. (5.1)
  • Echocardiogram assessments of left ventricular ejection fraction (LVEF) required before and during CAMZYOS use. (2.1)
  • Initiation in patients with LVEF <55% not recommended.
  •   Interrupt if LVEF <50% or if worsening clinical status. (2.1, 5.1)
  • Certain CYP450 inhibitors and inducers are contraindicated in patients taking CAMZYOS because of an increased risk of heart failure. (4, 5.2, 7)
  • CAMZYOS is available only through a restricted program called the CAMZYOS REMS Program. (5.3)

1 INDICATIONS AND USAGE

CAMZYOS® 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 a cardiac myosin inhibitor 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. (1)

2 DOSAGE AND ADMINISTRATION

Dosage must be individualized based on clinical status and echocardiographic assessment of patient response. Refer to the Full Prescribing Information for instructions (2.1)

2.1 Initiation, Maintenance, and Interruption of Treatment

Confirm absence of pregnancy and usage of effective contraception in females of reproductive potential [see Warnings and Precautions (5.4)].

Initiation or up-titration of CAMZYOS in patients with LVEF <55% is not recommended.

The recommended starting dose is 5 mg orally once daily without regard to food; allowable subsequent doses with titration are 2.5 mg, 5 mg, 10 mg, or 15 mg orally once daily. The maximum recommended dose is 15 mg orally once daily.

Patients may develop heart failure while taking CAMZYOS. Regular LVEF and Valsalva left ventricular outflow tract (LVOT) gradient assessment is required for careful titration to achieve an appropriate target Valsalva LVOT gradient, while maintaining LVEF ≥50% and avoiding heart failure symptoms (see Figure 1 and Figure 2).

Daily dosing takes weeks to reach steady-state drug levels and therapeutic effects, and genetic variation in metabolism and drug interactions can cause large differences in exposure [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

When initiating or titrating CAMZYOS, first consider LVEF then consider the Valsalva LVOT gradient and patient clinical status to guide appropriate CAMZYOS dosing. Follow the algorithms for Initiation (Figure 1) and Maintenance (Figure 2) for appropriate CAMZYOS dosing and monitoring schedules.

If LVEF <50% while taking CAMZYOS, interrupt treatment. Follow the algorithm for Interruption (Figure 3) for guidance on interrupting, restarting, or discontinuing CAMZYOS. If interrupted at 2.5 mg, either restart at 2.5 mg or discontinue permanently.

Figure 1: Initiation Phase

Fig_InitiationPhase

Figure 2: Maintenance Phase

Fig_MaintenancePhase

Figure 3: Treatment Interruption at Any Clinic Visit if LVEF <50%

Fig_TreatmentInterruption

Delay dose increases when there is intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) that may impair systolic function. Consider interruption of CAMZYOS in patients with intercurrent illness [see Warnings and Precautions (5.1)].

Missed or delayed doses

If a dose is missed, it should be taken as soon as possible, and the next scheduled dose should be taken at the usual time the following day. Exact timing of dosing during the day is not essential, but two doses should not be taken on the same day.

Swallow capsules whole. Do not break, open, or chew the capsules.

Fig_InitiationPhase
Fig_MaintenancePhase
Fig_TreatmentInterruption

2.2 Concomitant Administration of Weak CYP2C19 or Moderate CYP3A4 Inhibitors

Initiate CAMZYOS at the recommended starting dosage of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor.

Reduce dosage of CAMZYOS by one level (i.e., 15 mg 10 mg; 10 mg 5 mg; or 5 mg 2.5 mg) in patients who 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 CAMZYOS once-daily dose is not available [see Dosage and Administration (2.1), Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS

CAMZYOS is available as capsules imprinted with the strength and “Mava” in the following strengths:

  • 2.5 mg – light purple cap
  • 5 mg – yellow cap
  • 10 mg – pink cap
  • 15 mg – gray cap

Capsules: 2.5 mg, 5 mg, 10 mg, and 15 mg (3)

4 CONTRAINDICATIONS

CAMZYOS is contraindicated with concomitant use of:

  • Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors (4, 5.2)
  • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers (4, 5.2)

5 WARNINGS AND PRECAUTIONS

  • Heart Failure: Consider interruption of CAMZYOS in patients with intercurrent illness. (2.1, 5.1)
  • Drug Interactions Leading to Heart Failure or Loss of Effectiveness: Advise patients of the potential for drug interactions including with over-the-counter medications. (4, 5.2, 17)
  • Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential to use effective contraception until 4 months after the last dose. Avoid concomitant use with a combined hormonal contraceptive that contains a progestin other than norethindrone. (5.4, 7.2, 8.1, 8.3)

5.1 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 [see Clinical Trial Experience (6.1)].

Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly [see Dosage and Administration (2.1)]. 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 [see Dosage and Administration (2.1, 2.2)].

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 [see Drug Interactions (7)].

5.2 CYP450 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 [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)].

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 [see Drug Interactions (7.1), Patient Counseling Information (17)].

5.3 CAMZYOS 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 [see Warnings and Precautions (5.1, 5.2)].

Notable requirements of the CAMZYOS REMS Program include the following:

  • Prescribers must be certified by enrolling in the CAMZYOS REMS Program.
  • Patients must enroll in the CAMZYOS REMS Program and comply with ongoing monitoring requirements [see Dosage and Administration (2.1)].
  • Pharmacies must be certified by enrolling in the CAMZYOS 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.

5.4 Embryo-Fetal Toxicity

CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on findings in 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 [see Drug Interactions (7.2) and Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following adverse reaction is discussed in other sections of the labeling:

Adverse reactions occurring in >5% of patients and more commonly on CAMZYOS than on placebo were dizziness (27%) and syncope (6%). (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of CAMZYOS was evaluated in EXPLORER-HCM, a Phase 3, double-blind, randomized, placebo-controlled trial [see Clinical Studies (14)]. Of the 251 adults with obstructive HCM, 123 patients were treated with CAMZYOS 2.5-15 mg daily and 128 were treated with placebo. CAMZYOS-treated patients had a median duration of exposure of 30 weeks (range: 2-40 weeks).

Syncope (0.8%) was the only adverse drug reaction leading to discontinuation in patients receiving CAMZYOS.

Adverse reactions occurring in >5% of patients and more commonly on CAMZYOS than on placebo were dizziness (27% vs. 18%) and syncope (6% vs. 2%).

The safety of CAMZYOS in patients was further evaluated in VALOR-HCM, a Phase 3, double-blind, randomized, placebo-controlled trial [see Clinical Studies (14)]. Of the 112 adults with symptomatic obstructive HCM, 56 patients were treated with CAMZYOS 2.5-15 mg daily and 55 were treated with placebo. CAMZYOS-treated patients had a median duration of exposure of 17 weeks (range: 3-19 weeks).

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. Consistent with the mechanism of action of CAMZYOS, 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 to <50% (median 48%: range 35-49%) while on treatment. In 3 of the 7 CAMZYOS patients and 1 of the 2 placebo patients, these reductions were asymptomatic. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS [see Warnings and Precautions (5.1) ].

7 DRUG INTERACTIONS

  • Weak CYP2C19 inhibitors and moderate CYP3A4 inhibitors: May increase risk of heart failure. If initiating an inhibitor, CAMZYOS dose reduction and additional monitoring are required. (2.2, 7.1)
  • Negative inotropes: Close medical supervision and LVEF monitoring is recommended if a negative inotrope is initiated, or the dose of a negative inotrope is increased. Avoid certain combinations of negative inotropes. (7.2)

7.1 Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS

Mavacamten 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 mavacamten [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. (See Table 1)

Table 1: Established and Potentially Significant Pharmacokinetic Drug Interactions with CAMZYOS

Impact of Other Drugs on CAMZYOS

Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors

Clinical Impact

Concomitant use with a moderate to strong CYP2C19 or a strong CYP3A4 inhibitor increases mavacamten exposure, which may increase the risk of heart failure due to systolic dysfunction [see Contraindications (4), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

Prevention or Management

Concomitant use with a moderate to strong CYP2C19 inhibitor or a strong CYP3A4 inhibitor is contraindicated.

Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers

Clinical Impact

Concomitant use with a moderate to strong CYP2C19 inducer or a moderate to strong CYP3A4 inducer decreases mavacamten exposure, which may reduce CAMZYOS’ efficacy [see Clinical Pharmacology (12.3)]. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes [see Contraindications (4) and Warnings and Precautions (5.2)].

Prevention or Management

Concomitant use of a moderate to strong CYP2C19 inducer or a moderate to strong CYP3A4 inducer is contraindicated.

Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors

Clinical Impact

Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases mavacamten exposure, which may increase the risk of adverse drug reactions [see Warnings and Precautions (5.2)].

Prevention or Management

Initiate CAMZYOS at the recommended starting dosage 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. 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 [see Dosage and Administration (2.2)].

7.2 Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs

Certain CYP3A4, CYP2C9, and CYP2C19 Substrates

Mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C9, or CYP2C19 substrates may reduce plasma concentration of these drugs [see Clinical Pharmacology (12.3)]. 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 [ see Clinical Pharmacology (12.3)], 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 for 4 months after the last dose of CAMZYOS.

7.3 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 [see Warnings and Precautions (5.1)].

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female. There are no human data on the use of CAMZYOS during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The underlying maternal condition during pregnancy poses a risk to the mother and fetus (see Clinical Considerations). Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy.

In animal embryo-fetal development studies, mavacamten-related decreases in mean fetal body weight, reductions in fetal ossification of bones, and increases in post-implantation loss (early and/or late resorptions) were observed in rats and increases in visceral and skeletal malformations were observed in both rabbits and rats at dose exposures similar to that achieved at the maximum recommended human dose (MRHD) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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.

Clinical Considerations

Disease-Associated Maternal and Embryo-Fetal Risk

Obstructive HCM in pregnancy has been associated with increased risk for preterm birth.

Data

Animal Data

When mavacamten was administered orally to pregnant rats (0.3 to 1.5 mg/kg/day) during the period of organogenesis, increases in post-implantation loss, decreases in mean fetal body weight, reductions in fetal ossification of bones, and fetal malformations (visceral and skeletal) were observed in the high dose group (1.5 mg/kg/day). Visceral malformations (heart malformation in fetuses, including one total situs inversus) and increased incidences of skeletal malformations (mainly fused sternebrae) were observed at a similar exposure as in humans at the MRHD. Plasma exposure (based on area under the concentration-time curve or AUC) at the no-effect dose for embryo-fetal development in rats is 0.3 times the exposure in humans at the MRHD.

When mavacamten was administered orally to pregnant rabbits (0.6 to 2.0 mg/kg/day) during the period of organogenesis, fetal malformations (visceral and skeletal) were increased at doses of 1.2 mg/kg/day and higher, with similar plasma exposure at 1.2 mg/kg/day as in humans at the MRHD. Visceral findings consisted of malformations of the great vessels (dilatation of pulmonary trunk and/or aortic arch). Skeletal malformations consisted of higher incidences of fused sternebrae at ≥1.2 mg/kg/day. Plasma exposure (AUC) at the no-effect dose for embryo-fetal development in rabbits is 0.4 times the exposure in humans at the MRHD.

In a pre/postnatal development study, mavacamten was administered orally to pregnant rats (0.3, to 1.5 mg/kg/day) from gestation Day 6 to lactation/post-partum Day 20. No adverse effects were observed in the dams or offspring exposed daily from before birth (in utero) through lactation. The no-observed-adverse-effect level (NOAEL) was 1.5 mg/kg/day (the highest dosage level tested), with similar exposure (AUC) as in humans at the MRHD.

8.2 Lactation

Risk Summary

The presence of mavacamten in human or animal milk, the drug’s effects on the breastfed infant, and 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.

8.3 Females and Males of Reproductive Potential

Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Pregnancy Testing

Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS.

Contraception

Females

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 [see Drug Interactions (7.2)].

8.4 Pediatric Use

The safety and effectiveness of CAMZYOS have not been established in pediatric patients.

8.5 Geriatric Use

Clinical trials included 319 patients dosed with CAMZYOS, 119 of whom were 65 years of age or older (37.3%), and 25 of whom (7.8%) were age 75 years or older. Safety, effectiveness, and pharmacokinetics were similar between patients ≥65 years and younger patients.

8.6 Hepatic Impairment

No dosage adjustment is required in patients with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment. Mavacamten exposure (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function. However, no additional dose adjustment is required in patients with mild to moderate hepatic impairment with the recommended dose titration algorithm and monitoring plan. The effect of severe (Child-Pugh C) hepatic impairment is unknown [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Clinical Experience and Effects

  • Cardiovascular effects may include reduced LVEF (left ventricular ejection fraction), heart failure, hypotension, and asystole refractory to medical intervention.
  • Neurological effects may include dizziness and syncope.
  • An infant death was reported after accidental ingestion of three 15 mg capsules (45 mg).
  • An adult administered a single dose of 144 mg developed a vasovagal reaction, hypotension, and asystole, but the subject recovered.

Management

  • Discontinue CAMZYOS treatment.
  • Provide medically supportive measures to maintain hemodynamic stability and monitor left ventricular function.
  • Consider administering activated charcoal (pediatric dose is 1 g/kg; adult dose is 50 g) within 2 hours of ingestion in addition to other supportive measures. The benefit of activated charcoal is negligible after 6 hours [see Clinical Pharmacology (12.3)].
  • Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

11 DESCRIPTION

CAMZYOS capsules for oral use contain mavacamten, a cardiac myosin inhibitor.

The chemical name of mavacamten is 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidinedione. The molecular formula is C15H19N3O2, and the molecular weight is 273.33 g/mol.

The structural formula of mavacamten is:

Chemical_Structure

Mavacamten is a white to off-white powder that is practically insoluble in water and aqueous buffers at pH 2-10, sparingly soluble in methanol and ethanol, and freely soluble in DMSO and NMP.

CAMZYOS is supplied as immediate release Size 2 hard gelatin capsules, containing 2.5 mg, 5 mg, 10 mg, or 15 mg of mavacamten per capsule as active ingredient and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate (non-bovine), mannitol, and silicon dioxide. The capsule shell contains black edible ink, black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.

Chemical_Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin. Mavacamten modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. Mavacamten shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with mavacamten reduces dynamic LVOT obstruction and improves cardiac filling pressures.

12.2 Pharmacodynamics

Left Ventricular Ejection Fraction and Left Ventricular Outflow Tract Obstruction

In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the CAMZYOS group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reductions in Valsalva LVOT gradient were accompanied by decreases in LVEF, generally within the normal range. Eight weeks after discontinuation of CAMZYOS, mean LVEF and Valsalva LVOT gradients were similar to baseline.

Cardiac Structure

In EXPLORER-HCM, echocardiographic measurements of cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group (-7.4 [17.8] g/m2) versus an increase in LVMI in the placebo group (8.9 [15.3] g/m2). There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group (-7.5 [7.8] mL/m2) versus no change in the placebo group (-0.1 [8.7] mL/m2). The clinical significance of these findings is unknown.

Cardiac Biomarkers

In the EXPLORER-HCM trial [see Clinical Studies (14)], reductions in a biomarker of cardiac wall stress, NT-proBNP, were observed by Week 4 and sustained through the end of treatment. At Week 30 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]).

In the VALOR-HCM trial [see Clinical Studies (14)], a reduction in NT-proBNP was observed by Week 8 and sustained throughout treatment. At Week 16 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 67% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.33 [95% CI: 0.27, 0.42]). At Week 16 compared with baseline, a reduction in cardiac troponin I after mavacamten treatment was 47% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.53 [95% CI: 0.41, 0.70]).

The clinical significance of the NT-proBNP and troponin findings is unknown.

Cardiac Electrophysiology

In healthy volunteers receiving multiple doses of CAMZYOS, a concentration-dependent increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known.

A meta-analysis across clinical studies in HCM patients does not suggest clinically relevant increases in the QTc interval in the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with potential for QT prolongation commonly used in the HCM population. The effect of coadministration of CAMZYOS with other QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval have not been characterized.

12.3 Pharmacokinetics

Mavacamten exposure increases dose proportionally following multiple once-daily doses of 1 mg to 15 mg. At the same dose level of CAMZYOS, 170% higher exposures of mavacamten are observed in patients with HCM compared to healthy subjects. Mavacamten accumulation is approximately 100% for Cmax and approximately 600% for AUC in CYP2C19 normal metabolizers (NMs). The accumulation is dependent upon the CYP2C19 metabolism status with the largest accumulation occurring in CYP2C19 poor metabolizers (PMs). At steady-state, the peak-to-trough mavacamten plasma concentration ratio with once daily dosing is approximately 1.5.

Absorption

Mavacamten has an estimated oral bioavailability of at least 85% and median time to maximum concentration (Tmax) of 1 to 2 hours.

Effect of Food

No clinically significant differences in mavacamten AUC were observed following its administration with a high fat meal.

Distribution

Plasma protein binding of mavacamten is between 97 and 98%.

Elimination

Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten terminal half‑life is 6 to 9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days.

Metabolism

Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).

Excretion

Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of mavacamten were observed based on age (range: 18-82 years), sex, race, ethnicity, or mild (eGFR: 60 to 89 mL/min/1.73 m2) to moderate (eGFR: 30 to 59 mL/min/1.73 m2) renal impairment. The effects of severe (eGFR: 15 to 30 mL/min/1.73 m2) renal impairment and kidney failure (eGFR: <15 mL/min/1.73 m2; including patients on dialysis) are unknown.

Hepatic Impairment

Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown.

Drug Interactions

Clinical Studies and Model-Informed Approaches

Weak CYP2C19 Inhibitors: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg) once daily increased mavacamten AUCinf by 48% with no effect on Cmax in healthy CYP2C19 NMs and rapid metabolizers (RMs; e.g., *1/*17).

Moderate CYP3A4 Inhibitors: Concomitant use of mavacamten (25 mg) with verapamil sustained release (240 mg) increased mavacamten AUCinf by 16% and Cmax by 52% in intermediate metabolizers (IMs; e.g., *1/*2, *1/*3, *2/*17, *3/*17) and NMs of CYP2C19. Concomitant use of mavacamten with diltiazem in CYP2C19 PMs is predicted to increase mavacamten AUC0-24h and Cmax up to 55% and 42%, respectively.

Strong CYP3A4 Inhibitors: Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg once daily is predicted to increase mavacamten AUC0-24 and Cmax up to 130% and 90%, respectively.

Strong CYP2C19 and CYP3A4 Inducers: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten AUC0-inf and Cmax by 87% and 22%, respectively, in CYP2C19 NMs, and by 69% and 4%, respectively, in CYP2C19 PMs.

CYP3A4 Substrates: Concomitant use of a 16‑day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) decreased AUCinf and Cmax of midazolam by 13% and 7%, respectively, in healthy subjects. Following coadministration of mavacamten once daily in HCM patients at the upper end of the therapeutic range, midazolam AUCinf and Cmax are predicted to decrease up to 45% and 24%, respectively.

Certain combined oral contraceptives: No clinically significant differences in ethinyl estradiol and norethindrone exposure were observed in healthy female subjects with CYP2C19 NM phenotype following concomitant use of a combined oral contraceptive containing ethinyl estradiol and norethindrone with a 17-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 15 days). The impact of mavacamten on oral contraceptives containing other progestins is unknown.

CYP2C8 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of repaglinide, a CYP2C8 and CYP3A substrate, by up to 27% and 19%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.

CYP2C9 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of tolbutamide, a CYP2C9 substrate, by up to 54% and 23%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.

CYP2C19 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of omeprazole, a CYP2C19 substrate, by up to 48% and 17%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.

Activated Charcoal: Mavacamten AUC0-72h and AUC0-infinity was reduced by 14% and 34%, respectively, following administration of 50 g activated charcoal with sorbitol 2 hours after ingestion of a single mavacamten 15 mg dose. Administration of activated charcoal 6 hours after the mavacamten dose had minimal effect on mavacamten exposure.

In Vitro Studies

CYP Enzymes: Mavacamten does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19, or CYP3A4. Mavacamten is a CYP2B6 inducer.

Transporter Systems: Mavacamten does not inhibit P-gp, BCRP, BSEP, MATE1, MATE2-K, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), or organic anion transporters (OATs).

12.5 Pharmacogenomics

Mavacamten AUCinf increased by 241% and Cmax increased by 47% in CYP2C19 poor metabolizers (PMs) compared to normal metabolizers (NMs) following a single dose of 15 mg mavacamten. Mean half-life is prolonged in CYP2C19 PMs compared to NMs (23 days vs. 6 to 9 days, respectively).

Polymorphic CYP2C19 is the main enzyme involved in the metabolism of CAMZYOS. An individual carrying two normal function alleles is a NM (e.g., *1/*1). An individual carrying two no function alleles is a PM (e.g., *2/*2, *2/*3, *3/*3).

The prevalence of CYP2C19 poor metabolizers differs depending on ancestry. Approximately 2% of individuals of European ancestry and 4% of individuals of African ancestry are PMs; the prevalence of PMs is higher in Asian populations (e.g., approximately 13% of East Asians).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), a human in vitro lymphocyte clastogenicity assay, or a rat in vivo micronucleus assay.

There was no evidence of carcinogenicity seen in a 6-month rasH2 transgenic mouse study at mavacamten doses of up to 2.0 mg/kg/day in males and 3.0 mg/kg/day in females, or in a 2-year rat study at mavacamten doses up to 0.6 mg/kg/day. The exposure-based (AUC) safety margins in mice and rats were up to 3X or 0.2X, respectively, compared to AUC exposures in humans at the MRHD.

In reproductive toxicity studies, there was no evidence of effects of mavacamten on mating and fertility in male or female rats at doses up to 1.2 mg/kg/day, or on the viability and fertility of offspring of dams dosed up to 1.5 mg/kg/day. Plasma exposure (AUC) of mavacamten at the highest dose tested was the same as in humans at the MRHD.

13.2 Animal Toxicology and/or Pharmacology

The safety of mavacamten has been evaluated in rats and dogs at multiple dose levels (0.06 to 10 mg/kg/day) orally. Noted toxicities, including echocardiographic findings, reduction in systolic function, cardiac dilation, and death, as well as increased heart weights in rats, were consistent with mavacamten’s mechanism of action and primary pharmacological activity. Other findings included cardiac osseous metaplasia in rats and QTc prolongation in dogs. Plasma exposures (AUC) at the NOAEL in rats and dogs were 0.1 and 0.3 times, respectively, human exposure (AUC) at the MRHD.

14 CLINICAL STUDIES

EXPLORER-HCM

The efficacy of CAMZYOS was evaluated in EXPLORER-HCM (NCT-03470545) a Phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial in 251 adults with symptomatic NYHA class II and III obstructive HCM, LVEF ≥55%, and LVOT peak gradient ≥50 mmHg at rest or with provocation.

Patients on dual therapy with beta blocker and calcium channel blocker treatment or monotherapy with disopyramide or ranolazine were excluded. Patients with a known infiltrative or storage disorder causing cardiac hypertrophy that mimicked obstructive HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy, were also excluded.

Patients were randomized in a 1:1 ratio to receive either a starting dose of 5 mg of CAMZYOS or placebo once daily for 30 weeks. Treatment assignment was stratified by baseline NYHA functional class, baseline use of beta blockers, and type of ergometer (treadmill or exercise bicycle).

Groups were well matched with respect to age (mean 59 years), BMI (mean 30 kg/m2), heart rate (mean 62 bpm), blood pressure (mean 128/76 mmHg), and race (90% Caucasian). Males comprised 54% of the CAMZYOS group and 65% of the placebo group.

At baseline, approximately 73% of the randomized patients were NYHA class II and 27% were NYHA class III. The mean LVEF was 74%, and the mean Valsalva LVOT gradient was 73 mmHg. About 10% had prior septal reduction therapy, 75% were on beta blockers, 17% were on calcium channel blockers, and 14% had a history of atrial fibrillation.

All patients were initiated on CAMZYOS 5 mg (or matching placebo) once daily, and the dose was periodically adjusted to optimize patient response (decrease in LVOT gradient with Valsalva maneuver) and maintain LVEF ≥50%. The dose was also informed by plasma concentrations of CAMZYOS.

In the CAMZYOS group, at the end of treatment, 49% of patients were receiving the 5-mg dose, 33% were receiving the 10-mg dose, and 11% were receiving the 15-mg dose. Three patients temporarily interrupted their dose due to LVEF <50%, of whom two resumed treatment at the same dose and one had the dose reduced from 10 mg to 5 mg.

Primary endpoint

The primary composite functional endpoint, assessed at 30 weeks, was defined as the proportion of patients who achieved either improvement of peak oxygen consumption (pVO2) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class.

A greater proportion of patients met the primary endpoint at Week 30 in the CAMZYOS group compared to the placebo group (37% vs. 17%, respectively, p=0.0005; see Table 2).

Table 2: Primary Endpoint at 30 Weeks

CAMZYOS

n (%)

N = 123

Placebo

n (%)

N = 128

Difference

(95% CI)

p-value

Total responders

45 (37%)

22 (17%)

19% (9, 30)

0.0005

Change from baseline

pVO2 ≥1.5 mL/kg/min and

decreased NYHA

41 (33%)

18 (14%)

19% (9, 30)

Change from baseline

pVO2 ≥3 mL/kg/min and

NYHA not increased

29 (23%)

14 (11%)

13% (3, 22)

A range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. Results of the primary analysis consistently favored CAMZYOS across all subgroups analyzed (Figure 4).

Figure 4: Subgroup Analysis of the Primary Composite Functional Endpoint

Fig_SubgroupAnalysisofthePrimaryCompositeFunctionalEndpoint

The dashed vertical line represents the overall treatment effect and the solid vertical line (no effect) indicates no difference between treatment groups.
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

 

Although the benefit of mavacamten was smaller in patients on background beta blocker therapy compared to those who were not (attenuated improvement in pVO2), analyses of other secondary endpoints (symptoms, LVOT gradient) suggest that patients might benefit from mavacamten treatment regardless of beta blocker use.

Secondary endpoints

The treatment effects of CAMZYOS on LVOT obstruction, functional capacity, and health status were assessed by change from baseline through Week 30 in post-exercise LVOT peak gradient, change in pVO2, proportion of patients with improvement in NYHA class, Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) Clinical Summary Score (CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) Shortness of Breath (SoB) domain score. At Week 30, patients receiving CAMZYOS had greater improvement compared to the placebo group across all secondary endpoints (Table 3, Figure 5, Figure 6, Table 4, and Figures 7-10).

Table 3: Change from Baseline to Week 30 in Post-Exercise LVOT Gradient, pVO2, and NYHA Class

CAMZYOS

N = 123

Placebo

N = 128

Difference (95% CI)

p-value

Post-Exercise LVOT

gradient (mmHg), mean

(SD)

-47 (40)

-10 (30)

-35 (-43, -28)

<0.0001

pVO2 (mL/kg/min), mean

(SD)

1.4 (3.1)

-0.1 (3.0)

1.4 (0.6, 2.1)

<0.0006

Number (%) with NYHA

Class improved ≥1

80 (65%)

40 (31%)

34% (22%, 45%)

<0.0001

Figure 5: Cumulative Distribution of Change from Baseline to Week 30 in LVOT Peak Gradient

Fig_CumulativeDistributionofChangefromBaselinetoWeek30inLVOTPeakGradient

Figure 6: Cumulative Distribution of Change from Baseline to Week 30 in pVO2

Fig_CumulativeDistributionofChangefromBaselinetoWeek30inpVO2
Table 4: Change from Baseline to Week 30 in KCCQ-23 CSS and HCMSQ SoB Domain
The KCCQ‑23 CSS is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations.
The HCMSQ SoB domain score measures the frequency and severity of shortness of breath. The HCMSQ SoB domain score ranges from 0 to 18 with lower scores representing less shortness of breath.
Missing data were not imputed to summarize the baseline and change from baseline to Week 30 values. Difference in mean change from baseline between treatment groups was estimated using a mixed model for repeated measures.

Baseline, Mean (SD)

Change from Baseline to Week 30, Mean

(SD)

Difference,

LS Mean

(95%CI) and

p-value

CAMZYOS

Placebo

CAMZYOS

Placebo

KCCQ‑23 CSS

n=99

71 (16)

n=97

71 (19)

14 (14)

4 (14)

9 (5, 13)

p<0.0001

     KCCQ-23 TSS

71 (17)

69 (22)

12 (15)

5 (16)

     KCCQ-23 PL

70 (18)

72 (19)

15 (17)

4 (15)

HCMSQ SoB

n=108

5 (3)

n=109

5 (3)

-3 (3)

-1 (2)

-2 (-2, -1)

p<0.0001

Figure 7 shows the time course for changes in KCCQ-23 CSS. Figure 8 shows the distribution of changes from baseline to Week 30 for KCCQ-23 CSS.

Figure 7: KCCQ-23 Clinical Summary Score: Mean Change from Baseline Over Time

Fig_KCCQ-23ClinicalSummaryScoreMeanChangefromBaselineOverTime

Figure 8: KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 30

Fig_KCCQ-23ClinicalSummaryScoreCumalativeDistributionofChangefromBaselinetoWeek30

Figure 9 shows the time course for changes in HCMSQ SoB. Figure 10 shows the distribution of changes from baseline to Week 30 for HCMSQ SoB.

Figure 9: HCMSQ Shortness of Breath Domain: Mean Change from Baseline Over Time

Fig_HCMSQShortnessofBreathDomainMeanChangefromBaselineOverTime

Figure 10: HCMSQ Shortness of Breath Domain: Cumulative Distribution of Change from Baseline to Week 30

Fig_HCMSQShortnessofBreathDomainCummlativeDistributionofChangefromBaselinetoWeek30

VALOR-HCM

The efficacy of CAMZYOS was evaluated in VALOR-HCM, a Phase 3, double-blind, randomized, 16-week placebo-controlled trial in 112 patients (mean age of 60 years; 51% men; 93% ≥ NYHA class III) randomized 1:1 to receive treatment with CAMZYOS or placebo. At baseline, all patients had symptomatic obstructive HCM and were SRT eligible.

Patients with severely symptomatic drug-refractory obstructive HCM (including 33% on any combination of beta-blocker, calcium channel blocker and/or disopyramide; 20% were on disopyramide alone or in combination with other treatment), and NYHA class III/IV or class II with exertional syncope or near syncope, were included in the study. Patients were required to have LVOT peak gradient ≥50 mmHg at rest or with provocation, and LVEF ≥60%. Patients must have been referred or under active consideration within the past 12 months for SRT and actively considering scheduling the procedure.

Patients received CAMZYOS (2.5 mg, 5 mg, 10 mg, or 15 mg) or a placebo capsule once daily for 16 weeks. Dose adjustment was based on clinical echocardiogram parameters.

Primary endpoint

CAMZYOS was shown to be superior to placebo in reducing the proportion of patients who met the primary endpoint (the composite of patient decision to proceed with SRT prior to or at Week 16 or met SRT eligibility (LVOT gradient of ≥ 50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) at Week 16 (18% vs. 77%, respectively, p<0.0001; see Table 5).

Table 5: Primary Endpoint at 16 Weeks
*NYHA Class III or IV, or Class II with exertion induced syncope or near syncope and dynamic LVOT gradient at rest or with provocation (i.e., Valsalva or exercise) ≥ 50 mmHg.

CAMZYOS

n (%)

n=56

Placebo

n (%)

n=56

Treatment difference

(95% CI)

p-value

Primary efficacy composite endpoint

10 (18)

43 (77)

59%
(44%, 74%)

<0.0001

Patient decision to proceed with SRT

2 (3.6)

2 (3.6)

SRT-eligible based on guideline
criteria*

8 (14)

39 (70)

SRT status not evaluable (imputed as
meeting guideline criteria)

0

2 (3.6)

Secondary endpoints

The treatment effects of CAMZYOS on LVOT obstruction, functional capacity, and health status were assessed by change from baseline through Week 16 in post-exercise LVOT gradient, proportion of patients with improvement in NYHA class, and KCCQ-23 CSS.

Table 6: Change from Baseline to Week 16 in Secondary Endpoints
The KCCQ-23 CSS is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ-23. The CSS ranges from 0 to 100 with higher scores representing less severe symptoms and/or physical limitations.

CAMZYOS

n = 56

Placebo

n = 56

Difference

(95% CI)

p-value

Post-Exercise LVOT gradient (mmHg), mean (SD)

-39

(37)

-2

(29)

-38

(-49, -28)

<0.0001

Number (%) with NYHA Class improved ≥1

35

(63%)

12

(21%)

41%

(25%, 58%)

<0.0001

KCCQ-23 CSS, mean (SD)

10

(16)

2

(12)

9

(5, 14)

<0.0001

  •  KCCQ-23 TSS, mean (SD)

10

(16)

2

(14)

10

(5, 15)

  •  KCCQ-23 PL, mean (SD)

10

(19)

2

(17)

10

(5, 16)

Figure 11 shows the time course for changes in KCCQ-23 CSS. Figure 12 shows the distribution of changes from baseline to Week 16 for KCCQ-23 CSS.

Figure 11: KCCQ-23 Clinical Summary Score: Mean Change from Baseline Over Time

Fig_VALOR-Mean-Change

Figure 12: KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 16

Fig_VALOR-Cumm-Dist

The figure displays the cumulative percentage of patients achieving a certain level of response.

Fig_SubgroupAnalysisofthePrimaryCompositeFunctionalEndpoint
Fig_CumulativeDistributionofChangefromBaselinetoWeek30inLVOTPeakGradient
Fig_CumulativeDistributionofChangefromBaselinetoWeek30inpVO2
Fig_KCCQ-23ClinicalSummaryScoreMeanChangefromBaselineOverTime
Fig_KCCQ-23ClinicalSummaryScoreCumalativeDistributionofChangefromBaselinetoWeek30
Fig_HCMSQShortnessofBreathDomainMeanChangefromBaselineOverTime
Fig_HCMSQShortnessofBreathDomainCummlativeDistributionofChangefromBaselinetoWeek30
Fig_VALOR-Mean-Change
Fig_VALOR-Cumm-Dist

16 HOW SUPPLIED/STORAGE AND HANDLING

CAMZYOS® is supplied as immediate release Size 2 hard gelatin capsules containing 2.5 mg, 5 mg, 10 mg, or 15 mg of mavacamten. White opaque capsule bodies are imprinted with “Mava”, and the opaque cap is imprinted with the strength. The capsule contains white to off-white powder. CAMZYOS capsules are available in bottles of 30 capsules, as listed in the table below:

Strength

Capsule Cap

NDC Number

2.5 mg

Light purple

73625-111-11

5 mg

Yellow

73625-112-11

10 mg

Pink

73625-113-11

15 mg

Gray

73625-114-11

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Heart Failure

Inform patients that cardiac function monitoring must be performed using echocardiography to monitor for heart failure [see Warnings and Precautions (5.1)]. Advise patients to report any signs or symptoms of heart failure immediately to their healthcare provider.

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine) and supplements, prior to and during CAMZYOS treatment.

CAMZYOS REMS Program

CAMZYOS is available only through a restricted program called the CAMZYOS REMS Program [see Warnings and Precautions (5.3)]. Inform the patient of the following notable requirements:

CAMZYOS is only prescribed by certified healthcare providers and only dispensed from certified pharmacies participating in the program. Provide patients with the telephone number and website for information on how to obtain the product [see Warnings and Precautions (5.3) ].

Embryo-Fetal Toxicity

Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].

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 [see Drug Interactions (7.2) and Use in Specific Populations (8.3)].

Advise females who are exposed to CAMZYOS during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancies to Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.

Instructions for Taking CAMZYOS

CAMZYOS capsules should be swallowed whole. Advise patients that if they miss a dose of CAMZYOS, to take the dose as soon as possible that day and the next scheduled dose should be taken at the usual time the following day. The patient should not take two doses in the same day.

Marketed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

CAMZYOS® is a trademark of MyoKardia, Inc., a Bristol Myers Squibb company.

 

MEDICATION GUIDE

CAMZYOS ® (kam-zai-ōs)

(mavacamten)

capsules, for oral use

What is the most important information I should know about CAMZYOS?

CAMZYOS may cause serious side effects, including:

  • Heart failure, a condition where the heart cannot pump with enough force. Heart failure is a serious condition that can lead to death. You must have echocardiograms before you take your first dose and during your treatment with CAMZYOS to help your healthcare provider understand how your heart is responding to CAMZYOS. People who develop a serious infection or irregular heartbeat have a greater risk of heart failure during treatment with CAMZYOS.
  •  Tell your healthcare provider or get medical help right away if you develop new or worsening:

o shortness of breath

o swelling in your legs

o chest pain

o a racing sensation in your heart (palpitations)

o fatigue

o rapid weight gain

  • The risk of heart failure is also increased when CAMZYOS is taken with certain other medicines. Tell your healthcare provider about the medicines you take, both prescribed and obtained over-the-counter, before and during treatment with CAMZYOS.
  • Because of the serious risk of heart failure, CAMZYOS is only available through a restricted program called the CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program.
    • oYour healthcare provider must be enrolled in the CAMZYOS REMS Program in order for you to be prescribed CAMZYOS.
    • oBefore you take CAMZYOS, you must enroll in the CAMZYOS REMS Program. Talk to your healthcare provider about how to enroll in the CAMZYOS REMS Program. You will be given information about the program when you enroll.
    • oBefore you take CAMZYOS, your healthcare provider and pharmacist will make sure you understand how to take CAMZYOS safely, which will include returning for echocardiograms when advised by your healthcare provider.
  •  CAMZYOS can only be dispensed by a certified pharmacy that participates in the CAMZYOS REMS Program. Your healthcare provider can give you information on how to find a certified pharmacy. You will not be able to get CAMZYOS at a local pharmacy.
  •  
    • oIf you have questions about the CAMZYOS REMS Program, ask your healthcare provider, go to www.CAMZYOSREMS.com, or call 1-833-628-7367.

See “What are the possible side effects of CAMZYOS?” for information about side effects.

What is CAMZYOS?

CAMZYOS is a prescription medicine used to treat adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). CAMZYOS may improve your symptoms and your ability to be active. It is not known if CAMZYOS is safe and effective in children.

Before taking CAMZYOS, tell your healthcare provider about all of your medical conditions, including if you:

  • are pregnant or plan to become pregnant. CAMZYOS may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with CAMZYOS. You may also report your pregnancy by calling Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.
  •   If you are a female and able to become pregnant:
  • oYour healthcare provider will do a pregnancy test before you start treatment with CAMZYOS.
  • oYou should use effective birth control (contraception) during treatment with CAMZYOS and for 4 months after your last dose of CAMZYOS.
  • oCAMZYOS may reduce how well some hormonal birth control works. Talk to your healthcare provider about the use of effective forms of birth control during treatment with CAMZYOS.
  • are breastfeeding or plan to breastfeed. It is not known if CAMZYOS passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with CAMZYOS.

Before and during CAMZYOS treatment, tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking CAMZYOS with certain medicines or grapefruit juice may cause heart failure. Do not stop or change the dose of a medicine or start a new medicine without telling your healthcare provider.

Especially tell your healthcare provider if you:

  • Take over-the-counter medicines such as omeprazole (for example, Prilosec), esomeprazole (for example, Nexium), or cimetidine (for example, Tagamet).
  • Take other medicines to treat your obstructive HCM disease.
  • Develop an infection

How should I take CAMZYOS?

  • Take CAMZYOS exactly as your healthcare provider tells you to take it.
  • Do not change your dose of CAMZYOS without talking to your healthcare provider first.
  • Take CAMZYOS 1 time a day.
  • Swallow the capsule whole. Do not break, open, or chew the capsule.
  • If you miss a dose of CAMZYOS, take it as soon as possible and take your next dose at your regularly scheduled time the next day. Do not take 2 doses on the same day to make up for a missed dose.
  • Your healthcare provider may change your dose, temporarily stop, or permanently stop your treatment with CAMZYOS if you have certain side effects.
  • If you take too much CAMZYOS, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of CAMZYOS?

CAMZYOS may cause serious side effects, including:

  • Heart failure. See “What is the most important information I should know about CAMZYOS?”

The most common side effects of CAMZYOS include: dizziness and fainting (syncope).

These are not all of the possible side effects of CAMZYOS.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Bristol-Myers Squibb at 1-800-721-5072.

How should I store CAMZYOS?

Store CAMZYOS at room temperature between 68°F to 77°F (20°C to 25°C).

Keep CAMZYOS and all medicines out of the reach of children.

General information about the safe and effective use of CAMZYOS.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CAMZYOS for a condition for which it was not prescribed. Do not give CAMZYOS to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about CAMZYOS that is written for health professionals.

What are the ingredients in CAMZYOS?

Active ingredient: mavacamten

Inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate (non-bovine), mannitol, and silicon dioxide. The capsule contains black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.

Marketed by:

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

CAMZYOS® is a trademark of MyoKardia, Inc., a Bristol Myers Squibb company.

For more information, go to www.CAMZYOS.com or call 1-800-721-5072.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 04/2024

CAMZYOS 2.5 mg Label

NDC 73625-111-11

Rx only

CAMZYOS

(mavacamten)

capsules

2.5 mg

Dispense the enclosed Medication Guide to each patient.

Recommended Dosage: See Prescribing Information

Keep out of reach of children.

Do not use if inner seal bottle is broken or missing.

30 Capsules

Bristol Myers Squibb

2_5mgLabel
2_5mgLabel

CAMZYOS 5 mg Label

NDC 73625-112-11

Rx only

CAMZYOS

(mavacamten)

capsules

5 mg

Dispense the enclosed Medication Guide to each patient.

Recommended Dosage: See Prescribing Information

Keep out of reach of children.

Do not use if inner seal bottle is broken or missing.

30 Capsules

Bristol Myers Squibb

5mgLabel
5mgLabel

CAMZYOS 10 mg Label

NDC 73625-113-11

Rx only

CAMZYOS

(mavacamten)

capsules

10 mg

Dispense the enclosed Medication Guide to each patient.

Recommended Dosage: See Prescribing Information

Keep out of reach of children.

Do not use if inner seal bottle is broken or missing.

30 Capsules

Bristol Myers Squibb

10mgLabel
10mgLabel

CAMZYOS 15 mg Label

NDC 73625-114-11

Rx only

CAMZYOS

(mavacamten)

capsules

15 mg

Dispense the enclosed Medication Guide to each patient.

Recommended Dosage: See Prescribing Information

Keep out of reach of children.

Do not use if inner seal bottle is broken or missing.

30 Capsules

Bristol Myers Squibb

15mgLabel
15mgLabel