Camzyos Capsule, Gelatin Coated
FDA Label NDC 73625-112

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)].

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.

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 once daily without regard to food; allowable subsequent doses with titration are 2.5, 5, 10, or 15 mg 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 may 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 (Fig Initiationphase)

Figure 2. Maintenance Phase

Fig_maintenancephase (Fig Maintenancephase)

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

Fig_treatmentinterruption (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.

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 → 10 mg; 10 → 5 mg; or 5 → 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)].

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

CAMZYOS is contraindicated with concomitant use of:

• Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors [see Warnings and Precautions (5.2), Drug Interactions (7.1)]
• Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers [see Warnings and Precautions (5.2), Drug Interactions (7.1)]

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 beta blockers, or diltiazem with beta blockers as these medications and combinations were excluded from the clinical studies of CAMZYOS in obstructive HCM (EXPLORER-HCM). Concomitant use of CAMZYOS with disopyramide in combination with verapamil or diltiazem has been associated with left ventricular systolic dysfunction and heart failure symptoms in patients with obstructive HCM [see Drug Interactions (7)].

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)].

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.

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. CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method that is not affected by CYP450 enzyme induction or to add nonhormonal contraception [see Drug Interactions (7.2) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy.

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

• Heart failure [see Warnings and Precautions (5.1)]

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%).

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)].

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

Mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs [see Clinical Pharmacology (12.3)]. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce their activity.

Hormonal Contraceptives: Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of ethinyl estradiol and progestin [see Clinical Pharmacology (12.3)], which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP450 enzyme induction (e.g., intrauterine system) or add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS.

Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. In the EXPLORER-HCM trial, 119 of 123 patients who received CAMZYOS received concomitant therapy with beta blockers (n=94), verapamil (n=19), or diltiazem (n=6).

Avoid concomitant use of CAMZYOS with disopyramide in combination with verapamil or diltiazem because such use has been associated with left ventricular systolic dysfunction and heart failure symptoms [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.

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.

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.

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. Use of CAMZYOS may reduce the effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception [see Drug Interactions (7.2)].

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

Clinical trials included 263 patients dosed with CAMZYOS, 95 of whom were 65 years of age or older (36.1%), and 17 of whom (6.5%) were age 75 years or older. Safety, effectiveness, and pharmacokinetics were similar between patients ≥65 years and younger patients.

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)].

Human experience of overdose with CAMZYOS is limited. CAMZYOS has been given as a single dose of up to 144 mg in patients with HCM. One subject administered a single dose of 144 mg experienced serious adverse events including vasovagal reaction, hypotension, and asystole, but the subject recovered. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days, with 3 of 8 participants treated at the 25 mg dose level experiencing 20% or greater reductions in LVEF. An infant death was reported after accidental ingestion of three 15-mg capsules.

Systolic dysfunction is the most likely result of overdosage of CAMZYOS. Treatment of overdose with CAMZYOS consists of discontinuation of CAMZYOS treatment as well as medically supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF and management of the clinical status of the patient. Overdose in humans can be life-threatening and result in asystole refractory to any medical intervention.

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 (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, 5, 10, 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.

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.

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]). The clinical significance of these 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 QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval have not been characterized.

Mavacamten exposure increases generally dose proportionally after 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.

Absorption

Mavacamten has an estimated oral bioavailability of at least 85% and time to maximum concentration (T_max) of 1 hour.

Effect of Food

No clinically significant differences in mavacamten pharmacokinetics were observed following its administration with a high fat meal. The T_max was increased by 4 hours.

Distribution

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

Elimination

Mavacamten has a variable terminal t_1/2 that depends on CYP2C19 metabolic status. Mavacamten terminal half-life is 6-9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days. Drug accumulation occurs with an accumulation ratio of about 2-fold for C_max and about 7-fold for AUC in CYP2C19 NMs. The accumulation depends on the metabolism status for CYP2C19 with the largest accumulation observed in CYP2C19 PMs. At steady-state, the peak-to-trough plasma concentration ratio with once daily dosing is approximately 1.5.

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 AUC_inf by 48% with no effect on C_max 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 AUC_inf by 15% and C_max 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 AUC_0-24h and C_max 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 AUC_0-24 and C_max 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 AUC_0-inf and C_max 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) resulted in a 13% and 7% decrease in midazolam AUC_inf and C_max, respectively, in healthy CYP2C19 NMs. Following coadministration of mavacamten once daily in HCM patients, midazolam AUC_inf and C_max are predicted to decrease by 21 to 64% and 13 to 48%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.

CYP2C8 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and C_max of repaglinide, a CYP2C8 and CYP3A substrate, by 12 to 39 %, 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 C_max of tolbutamide, a CYP2C9 substrate, by 33 to 65%, 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 C_max of omeprazole, a CYP2C19 substrate, by 48 to 67%, depending on the dose of mavacamten and CYP2C19 phenotype.

In Vitro Studies

CYP Enzymes: Mavacamten does not inhibit CYP1A2, CYP2B6, or CYP2C8. At clinically relevant concentrations, mavacamten is not an inhibitor of 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).

Mavacamten AUC_inf increased by 241% and C_max 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. 6-9 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).

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, which resulted in exposures (AUC) that were 1.8- and 3-fold in males and females, 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.

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.

Obstructive Hypertrophic Cardiomyopathy

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 Valsalva 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 disease severity 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 mixed 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).

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 (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).

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

Fig_cumulativedistributionofchangefrombaselinetoweek30inlvotpeakgradient (Fig Cumulativedistributionofchangefrombaselinetoweek30inlvotpeakgradient)

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

Fig_cumulativedistributionofchangefrombaselinetoweek30inpvo2 (Fig Cumulativedistributionofchangefrombaselinetoweek30inpvo2)

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 (Fig Kccq 23clinicalsummaryscoremeanchangefrombaselineovertime)

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

Fig_kccq-23clinicalsummaryscorecumalativedistributionofchangefrombaselinetoweek30 (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 (Fig Hcmsqshortnessofbreathdomainmeanchangefrombaselineovertime)

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

Fig_hcmsqshortnessofbreathdomaincummlativedistributionofchangefrombaselinetoweek30 (Fig Hcmsqshortnessofbreathdomaincummlativedistributionofchangefrombaselinetoweek30)

CAMZYOS™ is supplied as immediate release Size 2 hard gelatin capsules containing 2.5, 5, 10, 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:

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].

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:

• Patients must enroll in the program and comply with ongoing monitoring requirements [see Warnings and Precautions (5.1 and 5.3)].

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. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception because CAMZYOS may decrease the efficacy of CHCs [see Drug Interactions (7.2), 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

Distributed by:

MyoKardia, Inc., a wholly-owned subsidiary of Bristol Myers Squibb

Brisbane, CA 94005

CAMZYOS is a trademark of MyoKardia, Inc., a wholly-owned subsidiary of Bristol Myers Squibb.

©2022 MyoKardia, Inc.

• 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.

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

Before and during 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

•  This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 04/2022

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 (Image 01)

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)

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 (Image 02)

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)