Camzyos · 4.3 Contraindications · 1

HOS-099701 · has-adverse-reaction-information · PDF-Seite 14

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. A total of 179 patients received a daily dose of either 2.5 mg, 5 mg, 10 mg or 15 mg of mavacamten. The median treatment duration for patients receiving mavacamten was 30.1 weeks (range: 1.6 to 40.3 weeks). 14 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 Dizziness Very common Nervous system disorders Syncope Common Cardiac disorders Systolic dysfunctiona Common Respiratory, thoracic and Dyspnoea Very common mediastinal disorders 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. In all patients treated with mavacamten, LVEF recovered following interruption of mavacamten and they completed the study on treatment (see section 4.4). Dyspnoea In Phase 3 clinical studies, dyspnoea was reported in 12.3% of patients treated with mavacamten compared to 8.7% of patients on placebo. In the EXPLORER-HCM study, most (67%) of the dyspnoea events were reported after mavacamten was discontinued, with median time to onset of 2 weeks (range: 0.1-4.9) after last dose. Reporting of suspected adverse reactions Reporting suspected adverse reaction

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HOS-099697 · has-contraindication-information · PDF-Seite 8

▪ Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. ▪ During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6). ▪ Concomitant treatment with strong CYP3A4 inhibitors in patients with CYP2C19 poor metaboliser phenotype and undetermined CYP2C19 phenotype (see sections 4.2, 4.4 and 4.5). ▪ Concomitant treatment with the combination of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor (see section 4.5).

HOS-099696 · has-indication-information · PDF-Seite 3

CAMZYOS is indicated for the treatment of symptomatic (New York Heart Association, NYHA, class II-III) obstructive hypertrophic cardiomyopathy (oHCM) in adult patients (see section 5.1).

HOS-099699 · has-interaction-information · PDF-Seite 9

Pharmacodynamic interactions If treatment with a new negative inotrope is initiated or if the dose of a negative inotrope is increased in a patient receiving mavacamten, close medical supervision with monitoring of LVEF should be provided until stable doses and clinical response have been achieved (see sections 4.2 and 4.4). 9 Pharmacokinetic interactions Effect of other medicinal products on mavacamten In CYP2C19 intermediate, normal, rapid and ultra-rapid metabolisers, mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4. In CYP2C19 poor metabolisers, metabolism is mostly by CYP3A4 (see section 5.2). CYP2C19 inhibitors/inducers and CYP3A4 inhibitors/inducers may thus affect the clearance of mavacamten and increase/decrease mavacamten plasma concentration, and this will depend on the CYP2C19 phenotype. All clinical drug-drug interaction studies mainly enrolled CYP2C19 normal metabolisers and no CYP2C19 poor metabolisers were included in the assessment of the drug-drug interaction and therefore the effect of co-administration of CYP2C19 and CYP3A4 inhibitors with mavacamten in CYP2C19 poor metabolisers is not completely certain. Recommendations for dose modification and/or additional monitoring of patients initiating or discontinuing treatment with, or changing the dose of, concomitant medicinal products that are inhibitors of CYP2C19 or CYP3A4 or inducers of CYP2C19 or CYP3A4 are provided in table 2. Strong CYP2C19 plus strong CYP3A4 inhibitors Co-administration of mavacamten with the combination of a strong CYP2C19 and a strong CYP3A4 inhibitor is contra-indicated (see section 4.3). CYP2C19 inhibitors The effect of a moderate and strong CYP2C19 inhibitor on the PK of mavacamten was not investigated in a clinical drug-drug interaction study. The effect of a strong CYP2C19 inhibitor (e.g., ticlopidine) will be similar to the effect of the CYP2C19 poor metabolising status (see table 1). Co-administration of mavacamten with a weak CYP2C19 inhibitor (omeprazole) resulted in a 48% increase in mavacamten AUCinf with no effect on Cmax in CYP2C19 normal metabolisers. Intermittent administration of a CYP2C19 inhibitor (such as omeprazole or esomeprazole) is not recommended (see section 4.4). CYP3A4 inhibitors The effect of strong CYP3A4 inhibitors on the PK of mavacamten was not investigated in a clinical drug-drug interaction study. Co-administration of mavacamten with a str

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HOS-099700 · has-pregnancy-information · PDF-Seite 14

Women of childbearing potential / Contraception in females CAMZYOS is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for 6 months after discontinuation of CAMZYOS, since it takes approximately 5 half-lives (approximately 45 days for CYP2C19 normal metabolisers and 115 days for CYP2C19 poor metabolisers) to eliminate mavacamten from the body after treatment discontinuation (see sections 4.4 and 5.2). When stopping mavacamten therapy for planning a pregnancy the possible return of LVOT obstruction and symptom burden should be considered (see section 4.4). Pregnancy There are no data from the use of mavacamten in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Mavacamten is suspected to cause embryo-foetal toxicity when administered during pregnancy. Therefore, CAMZYOS is contraindicated during pregnancy (see section 4.3). CAMZYOS should be stopped 6 months before planning a pregnancy (see section 4.4). If a patient becomes pregnant, mavacamten must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed. Breast-feeding It is unknown whether mavacamten or its metabolites are excreted in human milk. There is no information on the excretion of mavacamten or its metabolites in animal milk (see section 5.3). Because of the unknown adverse effects of mavacamten in breastfed newborns/infants, women must not breast-feed during treatment with mavacamten. Fertility No human fertility data on mavacamten are available. Studies in animals are insufficient with respect to male or female fertility (see section 5.3).

HOS-099698 · has-warning-information · PDF-Seite 8

Systolic dysfunction defined as symptomatic LVEF < 50% Mavacamten reduces LVEF and may cause heart failure due to systolic dysfunction defined as symptomatic LVEF < 50%. Patients with a serious intercurrent illness such as infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia), or those undergoing major cardiac surgery may be at greater risk of systolic dysfunction and progress to heart failure (see section 4.8). 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. Treatment interruption may be necessary to ensure that LVEF remains ≥ 50% (see section 4.2). 8 Heart failure risk or loss of response to mavacamten due to interactions Mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4 and mostly by CYP3A4 in CYP2C19 poor metabolisers, which may lead to the following interactions (see section 4.5): ▪ 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. ▪ Concomitant treatment with strong CYP3A4 inhibitors in patients with CYP2C19 poor metaboliser phenotype and undetermined CYP2C19 phenotype is contraindicated (see section 4.3). ▪ Concomitant treatment with the combination of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor is contraindicated (see section 4.3) ▪ Dose adjustment of mavacamten and/or close monitoring may be required in patients initiating or discontinuing treatment with, or changing the dose of concomitant medicinal products tha

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