mavacamten 10 MG Oral Capsule [Camzyos]

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 )

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.

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 significantly reduce 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. Combined hormonal contraceptives (CHCs) containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten. However, CAMZYOS may reduce the effectiveness of certain other CHCs. 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 )] .

CONTRAINDICATIONS CAMZYOS 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 )

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.