Camzyos Drug Information

® 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.

Initiation, Maintenance, and Interruption of Treatment Confirm absence of pregnancy and usage

of effective contraception in females of reproductive potential . 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 . When initiating or titrating CAMZYOS, first consider LVEF then consider the Valsalva LVOT gradient and patient clinical status to guide appropriate CAMZYOS dosing. Assessment of post-exercise LVOT gradient may be considered in symptomatic patients with normal or near normal Valsalva gradients (approximately 30 mmHg) prior to initiating treatment with CAMZYOS. 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 Figure 2: Maintenance Phase Figure 3: Treatment Interruption at Any Clinic Visit if LVEF <50% 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 . 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. initiation phase Maintenance phase Treatment interruption

Concomitant

Administration of Weak to Moderate CYP2C19 or Moderate to Strong 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 (see Figure 1). In patients who are on stable therapy with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor, initiate CAMZYOS at 2.5 mg orally once daily. Interrupt CAMZYOS treatment if Valsalva LVOT gradient is <20 mm Hg at Week 4 or Week 8. Treatment may be resumed after 4 weeks at 2.5 mg once daily if LVEF is ≥50%. If treatment is resumed at Week 12, recheck clinical status, Valsalva LVOT gradient and LVEF in 4 weeks, and maintain the current dose for the next 8 weeks unless LVEF is <50%. In patients who initiate a weak to moderate CYP2C19 inhibitor or a moderate to strong CYP3A4 inhibitor, reduce dosage of CAMZYOS to the next lower daily (mg) dose level (i.e., 15 mg to 10 mg; 10 mg to 5 mg; or 5 mg to 2.5 mg). Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate to the next higher daily (mg) dose level of CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak to moderate CYP2C19 and moderate to strong 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 . For short-term use (e.g., 1 week), interrupt CAMZYOS for the duration of treatment with a weak to moderate inhibitor of CYP2C19 or a moderate to strong inhibitor of CYP3A4. Mavacamten may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy.

• The following adverse reaction is discussed in other sections of the labeling:
• Heart failure [see Warnings and Precautions (5.1) ] 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) ] .

• Weak to moderate CYP2C19 inhibitors and moderate to strong 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. ( 7.3 ) 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 Strong CYP2C19 Inhibitors Clinical Impact Concomitant use with a strong CYP2C19 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 strong CYP2C19 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 to the next lower daily (mg) dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg 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) ] . For short-term use (e.g., 1 week), interrupt CAMZYOS for the duration of treatment with a weak inhibitor of CYP2C19 or a moderate inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. Moderate CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors Clinical Impact Concomitant use with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor increases mavacamten exposure, which may increase the risk of adverse drug reactions [see Warnings and Precautions (5.2) ] . Discontinuing use of a moderate CYP2C19 inhibitor or strong CYP3A4 inhibitor after long-term concomitant use may decrease mavacamten exposure, which may reduce CAMZYOS’ efficacy [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate CAMZYOS at a starting dosage of 2.5 mg orally once daily in patients who are on stable therapy with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Reduce dose of CAMZYOS to the next lower daily (mg) dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg) in patients who are on CAMZYOS and intend to initiate a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Avoid initiation of concomitant moderate CYP2C19 and strong 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) ] . An increase in dose of CAMZYOS may be needed if the moderate inhibitor of CYP2C19 or strong inhibitor of CYP3A4 is discontinued after long-term concomitant use. Monitor for new or worsening symptoms. For short-term use (e.g., 1 week), interrupt CAMZYOS for the duration of treatment with a moderate inhibitor of CYP2C19 or a strong inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. 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 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. Combined hormonal contraceptives (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) or use an alternative contraceptive method that is not affected by CYP450 enzyme induction (e.g., intrauterine system) 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.

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.

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

• is contraindicated with concomitant use of:
• Strong CYP2C19 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) ]
• Strong CYP2C19 inhibitors. ( 4 , 5.2 )
• Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. ( 4 , 5.2 )

• 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.