4.1. Therapeutic indications

Mavacamten BMS 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).

4.2. Posology and method of administration

Treatment should be initiated under the supervision of a physician experienced in the management of patients with cardiomyopathy.

Before treatment initiation, patients' left ventricular ejection fraction (LVEF) should be assessed by echocardiography (see section 4.4). If LVEF is < 55%, treatment should not be initiated.

Before initiation of treatment, women of childbearing potential must have a negative pregnancy test (see sections 4.4 and 4.6).

Patients should be genotyped for Cytochrome P450 (CYP) 2C19 (CYP2C19) in order to determine appropriate mavacamten dose. Patients with CYP2C19 poor metaboliser phenotype may have increased mavacamten exposures (up to 3 times) that can lead to increased risk of systolic dysfunction compared to normal metabolisers (see sections 4.4 and 5.2). 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.

Posology

The dose range is 2.5 mg to 15 mg (either 2.5 mg, 5 mg, 10 mg or 15 mg).

CYP2C19 poor metaboliser phenotype

The recommended starting dose is 2.5 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).

In patients experiencing an intercurrent illness such as serious infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia) which may impair systolic function, LVEF assessment is recommended, and dose increases are not recommended until intercurrent illness is resolved (see section 4.4).

Consideration should be given to discontinue treatment in patients who have shown no response (e.g., no improvement in symptoms, quality of life, exercise capacity, LVOT gradient) after 4‑6 months on the maximum tolerated dose.

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

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).

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Figure 3: Maintenance phase

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Figure 4: Treatment interruption at any clinic visit if LVEF < 50%

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract

Dose modification with concomitant medicinal products

For concomitant treatment with inhibitors and inducers of CYP2C19 or CYP3A4, follow the steps shown in table 1 (see also section 4.5).

Table 1: Dose modification of mavacamten with concomitant medicinal products

Concomitant medicinal product

CYP2C19 poor metaboliser phenotype*

CYP2C19 intermediate, normal, rapid and ultra‑rapid phenotype

Inhibitors

Combined use of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor

Contra-indicated (see section 4.3).

Contra-indicated (see section 4.3).

Strong CYP2C19 inhibitor

No dose adjustment (see section 4.5).

If CYP2C19 phenotype has not yet been determined:

No adjustment of the starting dose of 2.5 mg is needed.

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg (see section 4.5).

Initiate mavacamten at a dose of 2.5 mg.

The dose should be reduced from 15 mg to 5 mg and from 10 mg and 5 mg to 2.5 mg or pause treatment if on 2.5 mg (see section 4.5).

Strong CYP3A4 inhibitor

Contra-indicated (see section 4.3).

No dose adjustment (see section 4.5).

Moderate CYP2C19 inhibitor

No dose adjustment.

If CYP2C19 phenotype has not yet been determined:

No adjustment of the starting dose of 2.5 mg is needed.

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg (see section 4.5).

No adjustment of the starting dose of 5 mg is needed.

The dose should be reduced by one dose level or pause treatment if on 2.5 mg (see section 4.5).

Moderate or weak CYP3A4 inhibitor

No adjustment of the starting dose of 2.5 mg is needed. If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg (see section 4.5).

No dose adjustment (see section 4.5).

Inducers

Discontinuing or decreasing the dose of strong CYP2C19 inducer and strong CYP3A4 inducer

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg (see section 4.5).

The dose should be reduced by one dose level when on doses 5 mg or higher when discontinuing or decreasing the dose of strong inducers while on mavacamten (see section 4.5).

No dose adjustment when on 2.5 mg.

Discontinuing or decreasing the dose of moderate or weak CYP3A4 inducer

Decrease mavacamten dose to 2.5 mg or pause treatment if on 2.5 mg (see section 4.5).

No dose adjustment (see section 4.5).

* includes patients for whom the CYP2C19 phenotype has not yet been determined.

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. Two doses should not be taken on the same day.

Special populations

Elderly

No dose adjustment to the standard dose and titration scheme is required for patients aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment to the standard dose and titration scheme is required for patients with mild (estimated glomerular filtration rate [eGFR] 60‑89 mL/min/1.73m2) to moderate (eGFR 30‑59 mL/min/1.73m2) renal impairment. No dose recommendation can be made for patients with severe (eGFR < 30 mL/min/1.73m2) renal impairment because mavacamten has not been studied in patients with severe renal impairment (see section 5.2).

Hepatic impairment

The mavacamten starting dose should be 2.5 mg in all patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment since mavacamten exposure is likely to be increased (see section 5.2). No dose recommendation can be made for patients with severe hepatic impairment (Child-Pugh class C) because mavacamten has not been studied in patients with severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of mavacamten in children and adolescents below 18 years have not been established. No data are available.

Mavacamten should not be used in children less than 12 years because of potential safety concerns.

Method of administration

For oral use.

Treatment should be taken once daily with or without meals at about the same time each day. The capsule should be swallowed whole with water.

4.3. Contraindications

▪ 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).

4.4. Special warnings and precautions for use

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).

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 that are inhibitors or inducers of CYP2C19 or CYP3A4 (see sections 4.2 and 4.5). Intermittent administration of these medicinal products is not recommended (see section 4.5).

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. Therefore, patients should be closely monitored when taking these concomitant medicinal products (see section 4.5).

Embryo-foetal toxicity

Based on animal studies, mavacamten is suspected to cause embryo-foetal toxicity when administered to a pregnant woman (see section 5.3). Due to risk to the foetus, Mavacamten BMS is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for 6 months after treatment discontinuation (see sections 4.3 and 4.6).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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).

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 strong CYP3A4 inhibitor (itraconazole) in CYP2C19 normal metabolisers is expected to result in an increase in mavacamten plasma concentration of up to 59% and 40% in AUC0‑24 and Cmax, respectively.

Co‑administration of mavacamten with a moderate CYP3A4 inhibitor (verapamil) in CYP2C19 normal metabolisers resulted in an increase in mavacamten plasma concentration of 16% and 52% in AUCinf and Cmax, respectively. This change was not considered clinically significant.

CYP2C19 and CYP3A4 inducers

No clinical interaction studies were conducted to investigate the effect of concomitant administration with a strong CYP3A4 and CYP2C19 inducer. Co‑administration of mavacamten with a strong inducer of both CYP2C19 and CYP3A4 (e.g., rifampicin) is expected to significantly affect the pharmacokinetics (PK) of mavacamten and leads to reduced efficacy and therefore co‑administration with strong inducers of both CYP2C19 and CYP3A4 is not recommended. If discontinuing concomitant treatment with a strong inducer of CYP2C19 or CYP3A4 increase clinical assessments and mavacamten dose should be reduced (see section 4.2).

Table 2: Dose modification/monitoring of mavacamten with concomitant medicinal products

Concomitant medicinal product

CYP2C19 poor metaboliser phenotype*

CYP2C19 intermediate, normal, rapid and ultra‑rapid metaboliser phenotype

Inhibitors

Combined use of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor

Contra‑indicated (see section 4.3)

Contra‑indicated (see section 4.3)

Strong CYP2C19 inhibitor (e.g., ticlopidine, fluconazolea, fluvoxamine)

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

If CYP2C19 phenotype has not yet been determined:

No adjustment of the starting dose of 2.5 mg is needed.

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg.

Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Initiate mavacamten at a dose of 2.5 mg.

The dose should be reduced from 15 mg to 5 mg and from 10 mg and 5 mg to 2.5 mg or pause treatment if on 2.5 mg.

Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, voriconazole, ritonavir, cobicistat, ceritinib, idelalisib, tucatinib)

Contra‑indicated (see section 4.3)

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Moderate CYP2C19 inhibitor (e.g., fluconazolea, fluoxetine, omeprazoleb)

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

If CYP2C19 phenotype has not yet been determined:

No adjustment of the starting dose of 2.5 mg is needed.

The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

No adjustment of the starting dose of 5 mg is needed.

Initiating or increasing the dose of a moderate inhibitor while on mavacamten treatment:

Dose should be reduced by one dose level or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Moderate CYP3A4 inhibitor (e.g., erythromycin, grapefruit juice, verapamil, diltiazem)

If on medication when starting mavacamten, no adjustment of the starting dose of 2.5 mg is needed.

Initiating or increasing the dose of a moderate inhibitor while on mavacamten treatment:

If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks.

Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Weak CYP2C19 inhibitor (e.g., cimetidine, citalopram, omeprazoleb, esomeprazole)

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

Initiating or increasing the dose of a weak inhibitor while on mavacamten treatment:

Monitor LVEF 4 weeks later, and subsequently resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

Weak CYP3A4 inhibitor (e.g., cimetidine, esomeprazole, omeprazole, pantoprazole)

If on medication when starting mavacamten, no adjustment of the starting dose of 2.5 mg is needed.

Initiating or increasing the dose of weak inhibitor while on mavacamten treatment:

If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks.

Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Initiating or increasing the dose of a weak inhibitor while on mavacamten treatment:

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

Inducers

Strong CYP2C19 inducer and strong CYP3A4 inducer (e.g., rifampicin, apalutamide, enzalutamide, mitotane, phenytoin, carbamazepine, efavirenz, St. John's wort)

Initiating or increasing the dose of strong inducer while on mavacamten treatment:

Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient's monitoring and titration schedule (see section 4.2). The maximum dose is 5 mg.

Discontinuing or decreasing the dose of strong inducer while on mavacamten treatment:

Decrease mavacamten dose from 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Initiating or increasing the dose of strong inducer while on mavacamten treatment:

Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient's monitoring and titration schedule (see section 4.2).

Discontinuing or decreasing the dose of strong inducer while on mavacamten treatment:

Decrease mavacamten by one dose level when on doses 5 mg or higher. Maintain mavacamten dose when on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

Moderate or weak CYP2C19 inducer (e.g., letermovir, norethindrone, prednisone)

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

Initiating the dose of moderate or weak inducer while on mavacamten treatment:

Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient's monitoring and titration schedule (see section 4.2).

Discontinuing a moderate or weak inducer while on mavacamten treatment:

Decrease mavacamten by one dose level when on doses 5 mg or higher. Maintain mavacamten dose when on 2.5 mg.

Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

Moderate or weak CYP3A4 inducer (e.g., phenobarbital, primidone)

Initiating or increasing the dose of moderate or weak inducer while on mavacamten treatment:

Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient's monitoring and titration schedule (see section 4.2).

Discontinuing or decreasing the dose of moderate or weak inducer while on mavacamten treatment:

Decrease mavacamten dose to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule (see section 4.2).

No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient's monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2).

* Includes patients for whom the CYP2C19 phenotype has not yet been determined.

a Fluconazole is considered a strong CYP2C19 inhibitor at a dose of 100 mg and above once daily and a moderate CYP2C19 inhibitor at a total daily dose of 50 mg or lower.

b Omeprazole is considered a weak CYP2C19 inhibitor at a dose of 20 mg once daily and a moderate CYP2C19 inhibitor at a total daily dose of 40 mg.

Effect of mavacamten on other medicinal products

Mavacamten in vitro data suggest a potential induction of CYP3A4. Co‑administration of a 17‑day course of mavacamten at clinical relevant exposures in CYP2C19 normal, rapid and ultra‑rapid metabolisers did not decrease the exposure to ethinyl oestradiol and norethindrone, which are the components of typical oral contraceptives and substrates for CYP3A4. Furthermore, co‑administration of a 16‑day course of mavacamten in CYP2C19 normal metabolisers, at clinical relevant exposures, resulted in a 13% decrease in midazolam plasma concentration. This change was not considered clinically significant.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in females

Mavacamten BMS 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 Mavacamten BMS, 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, Mavacamten BMS is contraindicated during pregnancy (see section 4.3). Mavacamten BMS 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).

4.7. Effects on ability to drive and use machines

Mavacamten has minor influence on the ability to drive and use machines. Dizziness may occur during use of mavacamten. Patients should be advised not to drive or use machines if they experience dizziness.

4.8. Undesirable effects

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).

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. 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 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Human experience of overdose with mavacamten is limited. Mavacamten has been given as a single dose of up to 144 mg in patients with HCM. There was one serious adverse reaction of vasovagal reaction, hypotension, and asystole lasting 38 seconds reported at that dose. In healthy subjects, doses of up to 25 mg have been administered for up to 25 days. A reduction of LVEF by 20% or greater was experienced in 3 out of 8 participants treated at the 25 mg dose level. Systolic dysfunction is the most likely result of overdose of mavacamten. If warranted, treatment of overdose with mavacamten consists of discontinuation of mavacamten treatment as well as medically supportive measures to maintain hemodynamic status (e.g. initiation of inotropic support with adrenergic agents), including close monitoring of vital signs and LVEF and management of the clinical status of the patient.

In healthy subjects fasted overnight, administration of activated charcoal 2 hours (approximately tmax) after ingestion of a 15 mg dose of mavacamten reduced absorption as expressed by AUC0-72 by 14%. The fraction of mavacamten dose absorbed (AUC0-inf) was reduced by 34%. Administration of activated charcoal 6 hours after the mavacamten dose had minimal effect on mavacamten exposure and elimination. Thus, early administration (prior to or as soon after tmax as possible) of activated charcoal may be considered in the management of mavacamten overdose or accidental ingestion. Under fed conditions, activated charcoal may still be effective beyond 2‑hour post mavacamten dose because of the delayed tmax (see section 5.2).