Mavacamten

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

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.

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.

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

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.

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.

There are no data from the use of mavacamten in pregnant women. Studies in animals have shown reproductive toxicity. Mavacamten is suspected to cause embryo-foetal toxicity when administered during pregnancy. Therefore, mavacamten is contraindicated during pregnancy. Mavacamten should be stopped 6 months before planning a pregnancy. 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.

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. Because of the unknown adverse effects of mavacamten in breastfed newborns/infants, women must not breast-feed during treatment with mavacamten.

Women of childbearing potential / Contraception in females

Mavacamten is contraindicated in women of childbearing potential not using effective contraception. 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, 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.

When stopping mavacamten therapy for planning a pregnancy the possible return of LVOT obstruction and symptom burden should be considered.

Fertility

No human fertility data on mavacamten are available. Studies in animals are insufficient with respect to male or female fertility.

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.

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 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 the table below 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).

Adverse reactions:

^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.

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.