MYQORZO Film-coated tablet Ref.[116279] Active ingredients: Aficamten

Systolic dysfunction defined as LVEF <50%

Aficamten reduces cardiac contractility and LVEF. Heart failure due to systolic dysfunction can occur in patients receiving cardiac myosin inhibitors (see section 4.8).

Patients who experience a severe intercurrent illness (e.g. serious infection) or arrhythmia (e.g. new or uncontrolled atrial fibrillation) may be at greater risk of developing systolic dysfunction and heart failure. Additional monitoring should be considered for asymptomatic LVEF reduction with intercurrent illnesses, and arrhythmias (see section 4.2).

The patient's clinical status and LVEF should be assessed prior to and regularly during treatment and the dose should be adjusted accordingly. New or worsening arrhythmia, dyspnoea, chest pain, fatigue, leg oedema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function.

Heart failure or loss of response to aficamten due to interactions

Aficamten is metabolised by CYP2C9, CYP2D6 and CYP3A enzymes. Initiation of certain medicinal products that inhibit multiple P450 pathways of aficamten elimination (e.g. fluconazole, voriconazole, fluvoxamine), and strong CYP2C9 inhibitors may lead to increased blood concentrations of aficamten, and increase the risk of heart failure due to systolic dysfunction (see sections 4.2, 4.3 and 4.5).

Discontinuation of moderate-to-strong CYP3A inducers and moderate-to-strong CYP2C9 inducers may lead to increased blood concentrations of aficamten, and increase the risk of heart failure due to systolic dysfunction. Conversely, initiation of certain medicinal products that induce P450s (e.g. rifampicin, moderate-to-strong CYP3A or CYP2C9 inducers) may lead to decreased blood concentrations of aficamten and potential loss of effectiveness (see sections 4.2, 4.3 and 4.5).

Patients should be advised of the potential for drug interactions and to inform their healthcare professional of all concomitant medicinal products prior to and during MYQORZO treatment.

Pregnancy

There is no evidence for the use of aficamten in pregnant women, and animal studies are insufficient to inform maternal or embryo-foetal risk in humans. Foetal harm cannot be ruled out (see sections 4.6 and 5.3).

Recurrence of HCM symptoms with discontinuation

Discontinuation of aficamten may result in recurrence of HCM symptoms. In SEQUOIA-HCM, cardiovascular adverse events were reported more commonly in the aficamten group compared to the placebo group with an onset during the washout period [n=23 (16.2%) versus n=9 (6.5%)], 3 had serious events of worsening HCM when stopping aficamten. Careful monitoring during discontinuation is recommended. Gradual dose reduction may attenuate the rate of symptom recurrence following treatment discontinuation (see section 4.2).

Excipient with known effect

Sodium

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

Pharmacodynamic interactions

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 (see section 4.2).

Pharmacokinetic interactions

Effect of other medicinal products on aficamten

Aficamten is primarily metabolised by CYP2C9 and, to a lesser extent by CYP2D6 and CYP3A, with minimal CYP2C19 involvement. Concomitant administration of certain medicinal products that inhibit multiple P450 pathways of aficamten elimination, strong inhibitors of CYP2C9, and moderate-to-strong inducers of CYP2C9 or CYP3A, may affect the exposure of aficamten (see Table 3).

Concomitant use contraindicated

Coadministration of aficamten with more than a single dose of fluconazole and adagrasib is contraindicated (see section 4.3). Fluconazole (400 mg once daily), which is a moderate CYP2C9, strong CYP2C19, and moderate CYP3A inhibitor) increased aficamten AUC by 278%. Adagrasib a moderate CYP2C9, strong inhibitor of CYP3A4 and moderate inhibitor of CYP2D6 is expected to result in comparable or higher increased aficamten exposures as fluconazole.

Coadministration of aficamten with medicinal products that are strong inducers of CYP3A and are also moderate CYP2C9 inducers such as rifampicin or St. John's wort (Hypericum perforatum) may result in decreased plasma concentrations of aficamten leading to loss of therapeutic effect (see section 4.3).

Concomitant use not recommended

Avoidance is recommended for strong CYP2C9 inhibitors (e.g. sulfaphenazole) (see section 4.2).

Other interactions

Interactions of aficamten and potential co-administered medicinal products are listed in Table 3 below (increase is indicated as "↑", decrease as "↓"). These interactions are based on either drug interaction studies or physiologically based pharmacokinetic predicted interactions due to the expected magnitude of interaction.

Table 3. Interactions between aficamten and other medicinal products:

Effect of aficamten on other medicinal products

Coadministration of aficamten is not expected to cause clinically significant drug-drug interactions with sensitive substrates of CYP enzymes or drug transporters.

Aficamten increased total dabigatran exposure by 26% and therefore, aficamten is not a clinically significant P-glycoprotein inhibitor.

Women of childbearing potential

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

Pregnancy

There is no evidence from the use of aficamten in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). A careful benefit/risk evaluation is required before use and during pregnancy and MYQORZO 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, see section 5.2). Monitoring of the woman should consider the circulatory adaptations to pregnancy.

Breast-feeding

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 MYQORZO therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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 (see section 5.1) with a median treatment duration of 24.1 weeks (range 3.9 to 29.4 weeks).

The adverse reactions included in Table 4 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 4. 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 (see section 4.4).

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.

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.

Not applicable.