Aficamten

Avoidance is recommended for strong CYP2C9 inhibitors (e.g. sulfaphenazole).

Avoid concomitant administration. If coadministration cannot be avoided, reduce the dose of aficamten to 5 mg and assess LVEF and LVOT-G every 4 to 8 weeks until a new maintenance dose of aficamten in presence of the inhibitor has been reached.

Any moderate-to-strong CYP2C9 or CYP3A inducer (e.g. carbamazepine)

Initiating aficamten while on stable medicinal product treatmen: Initiate aficamten at the recommended starting dose of 5 mg once daily.

Initiating medicinal product while on stable aficamten treatment: No dose adjustment needed.

Discontinuing medicinal product while on stable aficamten treatment: Reduce dose of aficamten from 20 mg to 10 mg, from 15 mg to 5 mg, from 10 mg to 5 mg. No dose adjustment is required for patients currently receiving 5 mg of aficamten.

Assess LVEF and LVOT-G, and dose titrate/monitor according to the following table.

Dose adjustment of aficamten:

¹ Dose decrease as follows: from 20 mg to 15 mg; from 15 mg to 10 mg; from 10 mg to 5 mg

No dose recommendation can be made for patients with severe (eGFR <30 mL/min) renal impairment because aficamten has not been studied in patients with severe renal impairment.

No dose recommendation can be made for patients with severe hepatic impairment (Child-Pugh class C) because aficamten has not been studied in patients with severe hepatic impairment.

If a treatment with negative inotrope effect, such as non-dihydropyridine calcium channel blockers or disopyramide, is initiated, or if the dose of a medicinal product with negative inotrope effect is increased in a patient receiving aficamten, close medical supervision and monitoring of LVEF should be provided until stable doses and clinical response have been achieved.

There is no evidence from the use of aficamten in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. A careful benefit/risk evaluation is required before use and during pregnancy and aficamten should not be used during pregnancy unless the clinical condition of the woman requires treatment with aficamten.

Based on the mode of action of aficamten, a negative inotropic effect on the foetal heart cannot be ruled out. If a woman is treated with aficamten during pregnancy, regular foetal echocardiography (e.g. every 2 weeks) is recommended. Dose reduction or discontinuation of aficamten should be considered if any sign of foetal cardiac dysfunction is observed, also considering the maternal half-life of aficamten (approximately 3.3 days). Monitoring of the woman should consider the circulatory adaptations to pregnancy.

It is unknown whether aficamten/metabolites are excreted in human milk. There is insufficient information on the excretion of aficamten/metabolites in animal milk and a risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aficamten therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment.

Fertility

No human fertility data on aficamten are available. No effects on fertility were observed in animal studies.

Aficamten has minor influence on the ability to drive and use machines. Dizziness may occur during use of aficamten. 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 observed with aficamten are dizziness (4.2%), systolic dysfunction defined as LVEF < 50% (3.5%), palpitations (7%) and hypertension (7.7%).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on all-cause adverse events frequencies of 142 patients exposed to aficamten in SEQUOIA-HCM study with a median treatment duration of 24.1 weeks (range 3.9 to 29.4 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:

¹ Defined as LVEF <50% with or without symptoms.

Description of selected adverse reactions

Systolic dysfunction

In SEQUOIA-HCM study, during the 24-week treatment period, 3.5% patients in the aficamten group experienced a reversible dose related reduction in LVEF to <50% (median 47%; range 34% to 49%). One patient in the aficamten group experienced an asymptomatic LVEF <40%. Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure.

Effects on blood pressure

In SEQUOIA-HCM, adverse events of hypertension were reported more commonly in the aficamten group compared with the placebo group (7.7% versus 2.1%). The mean increases of blood pressure associated with aficamten treatment were 2.3 mmHg for systolic blood pressure, and 3.1 mmHg for diastolic blood pressure. Most reports of hypertension were in patients with a history of hypertension, and all reports were non-serious and mild or moderate in severity. Aficamten-associated increases in blood pressure are thought to be a consequence of relief of LVOT obstruction with improved cardiac output.