MYQORZO Film-coated tablet Ref.[116119] Active ingredients: Aficamten

5.1 Heart Failure

MYQORZO reduces cardiac contractility, which can reduce LVEF and cause heart failure.

Patients who experience a serious 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 [see Clinical Trial Experience (6.1)]. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional monitoring considerations [see Dosage and Administration (2.2)].

Assess the patient's clinical status and LVEF prior to and regularly during treatment and adjust the MYQORZO dose accordingly [see Dosage and Administration (2.3)]. New or worsening arrhythmia, dyspnea, chest pain, fatigue, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should prompt an evaluation of cardiac function.

Initiation of MYQORZO in patients with LVEF <55% is not recommended.

5.2 MYQORZO REMS Program

MYQORZO is available only through a restricted program called the MYQORZO REMS Program, because of the risk of heart failure due to systolic dysfunction [see Warnings and Precautions (5.1)].

Notable requirements of the MYQORZO REMS Program include the following:

• Prescribers must be certified by enrolling in the MYQORZO REMS Program.
• Patients must enroll in the MYQORZO REMS Program and comply with ongoing monitoring requirements [see Dosage and Administration (2.1)].
• Pharmacies must be certified by enrolling in the MYQORZO REMS Program and must only dispense to patients who are authorized to receive MYQORZO.
• Wholesalers and distributors must only distribute to certified pharmacies.

Further information is available at www.MYQORZOREMS.com or by telephone at 1-844-285-7367.

5.3 Cytochrome P450 Interactions Leading to Heart Failure or Loss of Effectiveness

MYQORZO is metabolized primarily by CYP2C9, and to a lesser extent by CYP3A, CYP2D6, and CYP2C19 enzymes. Initiation of medications that inhibit multiple P450 pathways of MYQORZO elimination (e.g., fluconazole, voriconazole, fluvoxamine) or strong CYP2C9 inhibitors, and discontinuation of moderate-to-strong CYP3A inducers may lead to increased blood concentrations of aficamten and increase the risk of heart failure due to systolic dysfunction [see Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7.1)]. Conversely, initiation of medications that induce P450 pathways of MYQORZO (e.g., rifampin, moderate-to-strong CYP3A inducers) may lead to decreased blood concentrations of aficamten and potential loss of effectiveness [see Contraindications (4) and Drug Interactions (7.1)]. Assess LVEF 2 to 8 weeks after initiation of such inhibitors or after discontinuation of such inducers and adjust the dose of MYQORZO accordingly [see Dosage and Administration (2.3)].

Advise patients of the potential for drug interactions. Advise patients to inform their healthcare provider of all concomitant medications prior to and during MYQORZO treatment [see Drug Interactions (7.1) and Patient Counseling Information (17)].

The following adverse reaction is discussed in other sections of labeling:

• Heart Failure [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of MYQORZO was evaluated in SEQUOIA-HCM, a phase 3, randomized, double-blind, placebo-controlled study [see Clinical Studies (14)]. Of the 282 adults with oHCM, 142 patients received daily doses of MYQORZO (initiated at 5 mg and titrated up to a maximum dose of 20 mg) and 140 patients received placebo. The median treatment duration for patients receiving MYQORZO was ~24 weeks (range 4 to 29 weeks).

Hypertension (8% vs. 2%) was the only adverse reaction occurring in >5% of patients and more commonly on MYQORZO than on placebo.

Eligible oHCM patients were able to participate in an ongoing, open-label, single-arm, long-term safety study (FOREST-HCM). Based on available data, the safety profile of MYQORZO in FOREST-HCM was similar to that observed in SEQUOIA-HCM.

Effects on Systolic Function

In SEQUOIA-HCM, the mean (SD) resting LVEF at baseline was 75% (6) in both treatment groups. Consistent with the mechanism of action of MYQORZO, LS mean (SE) change from baseline in LVEF was -7% (0.6) in the MYQORZO group and -2% (0.6) in the placebo group at the end of the 24-week treatment period. Four weeks after the end of treatment, mean LVEF was similar between the MYQORZO and placebo groups. During the 24-week treatment period, 5 (4%) patients in the MYQORZO group and 1 (1%) patient in the placebo group experienced a reversible reduction in LVEF to <50% (median LVEF: 47%; range 34% - 49% for these 5 patients in the MYQORZO group). Reductions in LVEF to <50% did not require treatment interruption and were not associated with clinical heart failure [see Warnings and Precautions (5.1)].

Effects on Blood Pressure

In SEQUOIA-HCM, the mean (SD) systolic/diastolic blood pressure (SBP/DBP) at baseline was 125(16)/75(11) mmHg for patients in the MYQORZO group and 126(16)/74(11) mmHg in the placebo group. There was a greater mean change from baseline in SBP/DBP (SD) in the MYQORZO group compared to the placebo group at the end of the 24-week treatment period [2(13)/3(8) mmHg and -3(14)/-1(9) mmHg, respectively]. Four weeks after the end of treatment, the mean SBP/DBP was similar between the MYQORZO and placebo groups. In SEQUOIA-HCM, SBP ≥160 mmHg was observed in approximately 16% of patients in the MYQORZO group and 8% of patients in the placebo group. MYQORZO-associated increases in blood pressure are consistent with relief of LVOT obstruction and improved cardiac output.

7.1. Potential for Other Drugs to Affect Plasma Concentrations of MYQORZO

Aficamten is primarily metabolized by CYP2C9 and, to a lesser extent by CYP3A, CYP2D6, and CYP2C19. Concomitant administration of drugs that inhibit multiple P450 pathways of aficamten elimination, strong inhibitors of CYP2C9, and moderate-to-strong inducers of CYP3A, may affect the exposure of aficamten [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)] (see Table 2).

Table 2. Established and Potentially Significant Pharmacokinetic Drug-Drug Interactions with MYQORZO:

Risk Summary

There are no available data on the use of MYQORZO during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The underlying maternal condition during pregnancy poses a risk to the mother and fetus (see Clinical Considerations). In embryo-fetal and pre- and postnatal development studies, when pregnant rats were administered aficamten during the period of organogenesis, aficamten increased the incidence of structural malformations at exposures ≥4-times the maximum recommended human dose (MRHD) of 20 mg based on free area under the concentration curve (AUC). No adverse effects on development were seen at 3-times the MRHD exposure (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There is a pregnancy safety study for MYQORZO. If MYQORZO is administered during pregnancy, or if a patient becomes pregnant while receiving MYQORZO or within 3 weeks after the last dose of MYQORZO, healthcare providers should report MYQORZO exposure by contacting Cytokinetics, Inc. at 1-833-633-2986.

Clinical Considerations

Disease-Associated Maternal and Embryo-Fetal Risk

Obstructive HCM in pregnancy has been associated with increased risk for preterm birth.

Data

Animal Data

Aficamten given to pregnant rats (2, 6 and 9 mg/kg/day) during the period of organogenesis was associated with increased external fetal malformations (kinked tail) at aficamten exposures 5-times the clinical exposures at the MRHD based on free AUC, with uncertain human relevance. Increased post-implantation loss (early and late resorptions) and decreased mean fetal body weight occurred in the presence of significant maternal toxicity at exposures 5-times the clinical exposures at the MRHD. No adverse effects on embryofetal development were observed at 6 mg/kg/day, representing 3-times the clinical exposure at the MRHD.

Pregnant rabbits given aficamten (5, 10 and 20/15 mg/kg/day) during the period of embryofetal organogenesis showed a numerical increase in post-implantation loss (late resorptions) and fetuses with cardiac malformations at 10 mg/kg/day. However, no increase in malformations was observed at the high dose of 20/15 mg/kg/day, a dose that caused significant maternal toxicity (leading to dose reduction from 20 to 15 mg/kg/day during the study) at clinically relevant exposures.

Pregnant rats given aficamten (0.5, 1.5, 6 mg/kg/day) during embryofetal organogenesis through offspring weaning in a pre- and postnatal development study had reduced offspring viability at the 6 mg/kg/day in the presence of maternal toxicity, at 4-times the clinical exposure at the MRHD based on free AUC. An increased number of offspring with bent tails was also observed at the 6 mg/kg/day. No adverse maternal toxicity or developmental effects occurred at 1.5 mg/kg/day, which corresponds to clinical exposure at the MRHD. Aficamten did not affect neurobehavioral parameters, sexual maturation, or reproductive function of the offspring at any dose.

Risk Summary

There are no data on the presence of aficamten in human milk, the effects on the breastfed infant, or the effects on milk production. Aficamten was detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for MYQORZO and any potential adverse effects on the breastfed infant from MYQORZO or from the underlying maternal condition.

The safety and effectiveness of MYQORZO in pediatric patients have not been established.

There were 57 (40%) MYQORZO-treated patients, aged 65 years and older, in SEQUOIA-HCM [see Clinical Studies (14)]. Of the total number of MYQORZO-treated patients in SEQUOIA-HCM, 45 (32%) patients were 65 to 74 years of age, and 12 (8%) patients were 75 years of age and older.

No overall differences in safety or effectiveness of MYQORZO have been observed between patients 65 years of age and older and younger adult patients.