What Is Camzyos Capsule, Gelatin Coated Used For?

• 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)].

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) and Use in Specific Populations (8.1, 8.3) ]. Initiation or up-titration of CAMZYOS in patients with LVEF <55% is not recommended. Initiation Dosage in Adult Patients The recommended starting dose is 5 mg orally once daily without regard to food; allowable subsequent doses with titrations 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 3). 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 3) for appropriate CAMZYOS dosing and monitoring schedules. If LVEF <50% while taking CAMZYOS, interrupt treatment. Follow the algorithm for Interruption (Figure 4) 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 for Adult Patients Initiation Dosage in Pediatric Patients The recommended starting dose is • • 5 mg orally once daily for pediatric patients weighing greater than or equal to 45 kg. • 2.5 mg orally once daily for pediatric patients weighing 30 kg to less than 45 kg. CAMZYOS was not studied in pediatric patients weighing less than 30 kg. CAMZYOS is taken orally once daily without regard to food; allowable subsequent doses with titrations are 1 mg, 2.5 mg, 5 mg, 10 mg, or 15 mg. The maximum recommended dose is 15 mg orally once daily. Follow the algorithms for Initiation (Figure 2) and Maintenance (Figure 3) for appropriate CAMZYOS dose adjustment and monitoring schedules in pediatric patients. If LVEF <50% while taking CAMZYOS, interrupt treatment. Follow the algorithm for Interruption (Figure 4) for guidance on interrupting, restarting, or discontinuing CAMZYOS. Figure 2: Initiation Phase for Pediatric Patients Maintenance and Interruption of Treatment in Adult and Pediatric Patients Figure 3: Maintenance Phase for Adult and Pediatric Patients Figure 4: Treatment Interruption at Any Clinic Visit if LVEF <50% for Adult and Pediatric Patients 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. image1 figure 1 figure 2 image 2 figure 3 image 3 figure 4 image 4 2.2 Concomitant Administration of Weak to Moderate CYP2C19 or Moderate to Strong CYP3A4 Inhibitors Initiate CAMZYOS at the recommended starting dosage in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor (see Figure 1 for adults and Figure 2 for pediatric patients). In patients who are on stable therapy with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor, initiate CAMZYOS at one dose below the recommended starting dose. Interrupt CAMZYOS treatment if Valsalva LVOT gradient is <20 mm Hg at Week 4 or Week 8 if the patient is on the lowest dose. Treatment may be resumed after 4 weeks at that dose once daily if LVEF is ≥50%. If treatment is resumed by 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 dose (i.e., 15 mg to 10 mg; 10 mg to 5 mg; 5 mg to 2.5 mg; or 2.5 mg to 1 mg [pediatric]). Schedule clinical and echocardiographic assessment 4 weeks after the initiation of a CYP2C19 or CYP3A4 inhibitor, and do not up-titrate to the next higher daily (mg) dose of CAMZYOS until 12 weeks later. Avoid initiation of concomitant weak to moderate CYP2C19 and moderate to strong CYP3A4 inhibitors in patients who are on the lowest recommended dose of CAMZYOS [ 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. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy.

CAMZYOS capsules contain white to off-white powder. The opaque capsule cap is imprinted with the strength, and the white opaque capsule body is imprinted with “Mava”. Available strengths include:

1. •1 mg – white cap
2. •2.5 mg – light purple cap
3. •5 mg – yellow cap
4. •10 mg – pink cap
5. •15 mg – gray cap

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)].

• 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 in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor (see Figure 1 for adults and Figure 2 for pediatric patients). Reduce dose of CAMZYOS to the next lower daily (mg) dose [i.e., 15 mg to 10 mg, 10 mg to 5 mg, 5 mg to 2.5 mg, or 2.5 mg to 1 mg (pediatric)] 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 the lowest recommended dose of CAMZYOS [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 one dose below the recommended starting dose 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 [i.e., 15 mg to 10 mg; 10 mg to 5 mg; 5 mg to 2.5 mg; or 2.5 mg to 1 mg (pediatric)] 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 the lowest recommended dose of CAMZYOS [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.