MYQORZO

WARNING: RISK OF HEART FAILURE MYQORZO reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction [see Warnings and Precautions (5.1) ]. Echocardiogram assessments are required prior to and during treatment with MYQORZO to monitor for systolic dysfunction. Initiation of MYQORZO in patients with LVEF <55% is not recommended. Decrease the dose of MYQORZO if LVEF is <50% and ≥40% [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . Interrupt the dose of MYQORZO if LVEF <40% or if the patient experiences heart failure symptoms or worsening clinical status due to systolic dysfunction [see Dosage and Administration (2.2) ]. Because of the risk of heart failure due to systolic dysfunction, MYQORZO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the MYQORZO REMS Program [see Warnings and Precautions (5.2) ]. WARNING: RISK OF HEART FAILURE See full prescribing information for complete boxed warning. MYQORZO can cause heart failure due to systolic dysfunction. ( 5.1 ) Echocardiogram assessments of left ventricular ejection fraction (LVEF) are required before and during MYQORZO use. ( 2.1 ) Initiation in patients with left ventricular ejection fraction (LVEF) <55% is not recommended. ( 2.1 ) Decrease dose if LVEF <50% and ≥40%. Interrupt dosing if LVEF <40% or if worsening clinical status. ( 2.2 ) MYQORZO is available only through a restricted program called the MYQORZO REMS Program. ( 5.2 )

5 WARNINGS AND PRECAUTIONS Risk of Heart Failure : Consider decreasing dose or dose interruption in patients with serious intercurrent illness. ( 2.2 , 5.1 ) Drug Interactions Leading to Increased Risk of Heart Failure or Loss of Effectiveness: Advise patients of the potential for drug interactions. ( 2.3 , 5.3 , 17 ) 5.1 Heart Failure MYQORZO reduces cardiac contractility, which can reduce LVEF and cause heart failure. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., new or uncontrolled atrial fibrillation) may be at greater risk of developing systolic dysfunction and heart failure [see Clinical Trial Experience (6.1) ] . Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional monitoring considerations [see Dosage and Administration (2.2) ]. Assess the patient's clinical status and LVEF prior to and regularly during treatment and adjust the MYQORZO dose accordingly [see Dosage and Administration (2.3) ]. New or worsening arrhythmia, dyspnea, chest pain, fatigue, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should prompt an evaluation of cardiac function. Initiation of MYQORZO in patients with LVEF <55% is not recommended. 5.2 MYQORZO REMS Program MYQORZO is available only through a restricted program called the MYQORZO REMS Program, because of the risk of heart failure due to systolic dysfunction [see Warnings and Precautions (5.1) ]. Notable requirements of the MYQORZO REMS Program include the following: Prescribers must be certified by enrolling in the MYQORZO REMS Program. Patients must enroll in the MYQORZO REMS Program and comply with ongoing monitoring requirements [see Dosage and Administration (2.1) ]. Pharmacies must be certified by enrolling in the MYQORZO REMS Program and must only dispense to patients who are authorized to receive MYQORZO. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.MYQORZOREMS.com or by telephone at 1-844-285-7367. 5.3 Cytochrome P450 Interactions Leading to Heart Failure or Loss of Effectiveness MYQORZO is metabolized primarily by CYP2C9, and to a lesser extent by CYP3A, CYP2D6, and CYP2C19 enzymes. Initiation of medications that inhibit multiple P450 pathways of MYQORZO elimination (e.g., fluconazole, voriconazole, fluvoxamine) or strong CYP2C9 inhibitors, and discontinuation of moderate-to-strong CYP3A inducers may lead to increased blood concentrations of aficamten and increase the risk of heart failure due to systolic dysfunction [see Contraindications (4) , Warnings and Precautions (5.1) , and Drug Interactions (7.1) ] . Conversely, initiation of medications that induce P450 pathways of MYQORZO (e.g., rifampin, moderate-to-strong CYP3A inducers) may lead to decreased blood concentrations of aficamten and potential loss of effectiveness [see Contraindications (4) and Drug Interactions (7.1) ] . Assess LVEF 2 to 8 weeks after initiation of such inhibitors or after discontinuation of such inducers and adjust the dose of MYQORZO accordingly [see Dosage and Administration (2.3) ] . Advise patients of the potential for drug interactions. Advise patients to inform their healthcare provider of all concomitant medications prior to and during MYQORZO treatment [see Drug Interactions (7.1) and Patient Counseling Information (17) ] .

6 ADVERSE REACTIONS The following adverse reaction is discussed in other sections of labeling: Heart Failure [see Warnings and Precautions (5.1) ] The most common adverse reaction was hypertension (8%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cytokinetics at 1-833-633-2986 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 MYQORZO was evaluated in SEQUOIA-HCM, a phase 3, randomized, double-blind, placebo-controlled study [see Clinical Studies (14) ] . Of the 282 adults with oHCM, 142 patients received daily doses of MYQORZO (initiated at 5 mg and titrated up to a maximum dose of 20 mg) and 140 patients received placebo. The median treatment duration for patients receiving MYQORZO was ~24 weeks (range 4 to 29 weeks). Hypertension (8% vs. 2%) was the only adverse reaction occurring in >5% of patients and more commonly on MYQORZO than on placebo. Eligible oHCM patients were able to participate in an ongoing, open-label, single-arm, long-term safety study (FOREST-HCM). Based on available data, the safety profile of MYQORZO in FOREST-HCM was similar to that observed in SEQUOIA-HCM. Effects on Systolic Function In SEQUOIA-HCM, the mean (SD) resting LVEF at baseline was 75% (6) in both treatment groups. Consistent with the mechanism of action of MYQORZO, LS mean (SE) change from baseline in LVEF was -7% (0.6) in the MYQORZO group and -2% (0.6) in the placebo group at the end of the 24-week treatment period. Four weeks after the end of treatment, mean LVEF was similar between the MYQORZO and placebo groups. During the 24-week treatment period, 5 (4%) patients in the MYQORZO group and 1 (1%) patient in the placebo group experienced a reversible reduction in LVEF to <50% (median LVEF: 47%; range 34% - 49% for these 5 patients in the MYQORZO group). Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure [see Warnings and Precautions (5.1) ] . Effects on Blood Pressure In SEQUOIA-HCM, the mean (SD) systolic/diastolic blood pressure (SBP/DBP) at baseline was 125(16)/75(11) mmHg for patients in the MYQORZO group and 126(16)/74(11) mmHg in the placebo group. There was a greater mean change from baseline in SBP/DBP (SD) in the MYQORZO group compared to the placebo group at the end of the 24-week treatment period [2(13)/3(8) mmHg and -3(14)/-1(9) mmHg, respectively]. Four weeks after the end of treatment, the mean SBP/DBP was similar between the MYQORZO and placebo groups. In SEQUOIA-HCM, SBP ≥160 mmHg was observed in approximately 16% of patients in the MYQORZO group and 8% of patients in the placebo group. MYQORZO-associated increases in blood pressure are consistent with relief of LVOT obstruction and improved cardiac output.