Mavacamten

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. 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 [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. initiation phase Maintenance phase Treatment interruption 2.2 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 [see Dosage and Administration (2.1) , Drug Interactions (7.1) ] . 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.

6 ADVERSE REACTIONS 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) ] .

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 C max 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 (T max ) 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 t 1/2 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 m 2 ) to moderate (eGFR: 30 to 59 mL/min/1.73 m 2 ) renal impairment. The effects of severe (eGFR: 15 to 30 mL/min/1.73 m 2 ) renal impairment and kidney failure (eGFR: <15 mL/min/1.73 m 2 ; 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 16% 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 in CYP2C19 poor metabolizers 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) decreased AUC inf and C max 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 AUC inf and C max 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 C max 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 C max 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 C max of omeprazole, a CYP2C19 substrate, by up to 48% and 17%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype. Activated Charcoal: Mavacamten AUC 0-72h and AUC 0-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).