Camzyos

Treatment should be initiated under the supervision of a physician experienced in the management of patients with cardiomyopathy. 4). If LVEF is < 55%, treatment should not be initiated. 6). Patients should be genotyped for Cytochrome P450 (CYP) 2C19 (CYP2C19) in order to determine appropriate mavacamten dose.

2). If treatment initiation occurs prior to determination of CYP2C19 phenotype, patients should follow dosing instructions for poor metabolisers (see figure 1 and 3 and table 1) until CYP2C19 phenotype is determined. 5 mg, 5 mg, 10 mg or 15 mg).

5 mg orally once daily. The maximum dose is 5 mg once daily. The patient should be assessed for early clinical response by left ventricular outflow tract (LVOT) gradient with Valsalva manoeuvre 4 and 8 weeks after treatment initiation (see figure 1).

CYP2C19 intermediate, normal, rapid and ultra-rapid metaboliser phenotype The recommended starting dose is 5 mg orally once daily. The maximum dose is 15 mg once daily. The patient should be assessed for early clinical response by LVOT gradient with Valsalva manoeuvre 4 and 8 weeks after treatment initiation (see figure 2).

Once an individualised maintenance dose is achieved with LVEF ≥ 55%, patients should be assessed every 6 months. For patients with LVEF 50 - < 55% regardless of Valsalva LVOT gradient, patients should be assessed every 3 months (see figure 3).

If at any visit the patient’s LVEF is < 50%, the treatment should be interrupted for 4 weeks and until LVEF returns to ≥ 50% (see figure 4). 4). , no improvement in symptoms, quality of life, exercise capacity, LVOT gradient) after 4-6 months on the maximum tolerated dose.

4 Figure 1: Treatment initiation in CYP2C19 poor metaboliser phenotype * Interrupt treatment if LVEF is < 50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50% (see figure 4). LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract Week 12*Week 4* Week 8* Valsalva LVOT gradient Valsalva LVOT gradient ≥ 20 mmHg See maintenance phase in figure 3 < 20 mmHg 1.

5 mg once daily if LVEF ≥ 50%. 2. Recheck clinical status, Valsalva LVOT gradient and LVEF in 4 weeks and maintain the current dose for the next 8 weeks unless LVEF < 50%. 5 mg once daily ≥ 20 mmHg See maintenance phase in figure 3 5 Figure 2: Treatment initiation in CYP2C19 intermediate, normal, rapid and ultra-rapid metaboliser phenotype * Interrupt treatment if LVEF is < 50% at any clinical visit; restart treatment after 4 weeks if LVEF ≥ 50% (see figure 4).

Summary of the safety profile The most commonly reported adverse reactions with mavacamten are dizziness (17%), dyspnoea (12%), systolic dysfunction (5%) and syncope (5%). Tabulated list of adverse reactions Adverse reactions reported in patients treated with mavacamten in two phase 3 studies (EXPLORER- HCM and VALOR-HCM) are tabulated below.

5 mg, 5 mg, 10 mg or 15 mg of mavacamten. 3 weeks). 15 The adverse reactions included in table 3 are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in order of decreasing frequency and seriousness.

In addition, the corresponding frequency category for each adverse reaction is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000).

Table 3:

Adverse reactions System organ class Adverse reaction Frequency Nervous system disorders Dizziness Very common Syncope Common Cardiac disorders Systolic dysfunctiona Common Respiratory, thoracic and mediastinal disorders Dyspnoea Very common a Defined as LVEF < 50% with or without symptoms.

Description of selected adverse reactions Systolic dysfunction In Phase 3 clinical studies, 5% (9/179) of patients in the mavacamten group experienced reversible reductions in LVEF < 50% (median 45%: range: 35-49%) while on treatment.

In 56% (5/9) of these patients, reductions were observed without other clinical manifestations. 4). 7% of patients on placebo. 9) after last dose. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Systolic dysfunction defined as symptomatic LVEF < 50% Mavacamten reduces LVEF and may cause heart failure due to systolic dysfunction defined as symptomatic LVEF < 50%. 8). New or worsening dyspnoea, chest pain, fatigue, palpitations, leg oedema or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of systolic dysfunction and should prompt an evaluation of cardiac function.

LVEF should be measured prior to initiating treatment and closely monitored thereafter. 2). 5): ▪ Starting or increasing the dose of a strong or moderate CYP3A4 inhibitor or any CYP2C19 inhibitor may increase risk of heart failure due to systolic dysfunction.

▪ Stopping or decreasing dose of any inhibitor of CYP3A4 or CYP2C19 may lead to a loss of therapeutic response to mavacamten. ▪ Starting a strong CYP3A4 or strong CYP2C19 inducer may lead to a loss of therapeutic response to mavacamten.

▪ Stopping a strong CYP3A4 or strong CYP2C19 inducer may increase risk of heart failure due to systolic dysfunction. Prior to and during mavacamten treatment, the potential for interactions, including over the counter medicinal products (such as omeprazole or esomeprazole), should be considered.

3). 5). 5). Concomitant use of negative inotropes The safety of concomitant use of mavacamten with disopyramide, or use of mavacamten in patients taking beta blockers in combination with verapamil or diltiazem has not been established.

5). 3). Due to risk to the foetus, CAMZYOS is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. 6). Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

1. 6). 5). 5).