AFICAMTEN

Brand names: MYQORZO

Boxed warning

WARNING: RISK OF HEART FAILURE MYQORZO reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction [see Warnings and Precautions (5.1) ]. Echocardiogram assessments are required prior to and during treatment with MYQORZO to monitor for systolic dysfunction. Initiation of MYQORZO in patients with LVEF <55% is not recommended. Decrease the dose of MYQORZO if LVEF is <50% and ≥40% [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . Interrupt the dose of MYQORZO if LVEF <40% or if the patient experiences heart failure symptoms or worsening clinical status due to systolic dysfunction [see Dosage and Administration (2.2) ]. Because of the risk of heart failure due to systolic dysfunction, MYQORZO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the MYQORZO REMS Program [see Warnings and Precautions (5.2) ]. WARNING: RISK OF HEART FAILURE See full prescribing information for complete boxed warning. MYQORZO can cause heart failure due to systolic dysfunction. ( 5.1 ) Echocardiogram assessments of left ventricular ejection fraction (LVEF) are required before and during MYQORZO use. ( 2.1 ) Initiation in patients with left ventricular ejection fraction (LVEF) <55% is not recommended. ( 2.1 ) Decrease dose if LVEF <50% and ≥40%. Interrupt dosing if LVEF <40% or if worsening clinical status. ( 2.2 ) MYQORZO is available only through a restricted program called the MYQORZO REMS Program. ( 5.2 )

Warnings

5 WARNINGS AND PRECAUTIONS Risk of Heart Failure : Consider decreasing dose or dose interruption in patients with serious intercurrent illness. ( 2.2 , 5.1 ) Drug Interactions Leading to Increased Risk of Heart Failure or Loss of Effectiveness: Advise patients of the potential for drug interactions. ( 2.3 , 5.3 , 17 ) 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) ] .

Contraindications

4 CONTRAINDICATIONS MYQORZO is contraindicated with concomitant use of rifampin [see Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Rifampin ( 4 )

Overdose

10 OVERDOSAGE Clinical Experience and Effects There have been no reports of overdose with MYQORZO. Cardiovascular effects of overdose may include reduced LVEF, heart failure, and hypotension. Signs and symptoms of heart failure such as dyspnea, fatigue, leg edema, or elevations in NT-proBNP should prompt an evaluation of cardiac function [see Warnings and Precautions (5.1) ]. Management Discontinue MYQORZO treatment. Provide medically supportive measures to maintain hemodynamic stability and monitor left ventricular function. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

Drug interactions

7 DRUG INTERACTIONS Drugs that inhibit multiple pathways of MYQORZO elimination, strong CYP2C9 inhibitors, or moderate-to-strong CYP3A inducers may increase risk of heart failure. MYQORZO dose reduction and additional monitoring may be required when initiating or discontinuing these drugs. ( 2.3 , 7.1 ) 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 Inhibitors of Multiple CYPs Fluvoxamine Clinical Impact Fluvoxamine is a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor. Coadministration of fluvoxamine is predicted to increase aficamten exposure, which may increase the risk of developing heart failure due to systolic dysfunction. Prevention or Management Initiate MYQORZO at 5 mg in patients on stable therapy with fluvoxamine. In patients who are on MYQORZO treatment and intend to initiate fluvoxamine: Reduce dose of MYQORZO (i.e., 20 mg to 10 mg, 15 mg to 5 mg, or 10 mg to 5 mg) or continue 5 mg [see Dosage and Administration (2.3) ] . Fluconazole or Voriconazole Clinical Impact Fluconazole is a moderate CYP2C9 inhibitor, moderate CYP3A inhibitor, and strong CYP2C19 inhibitor. Voriconazole is a strong CYP3A inhibitor, moderate CYP2C19 inhibitor, and weak CYP2C9 inhibitor. Coadministration with fluconazole is observed, and voriconazole is predicted, to increase aficamten exposure, which may increase the risk of developing heart failure due to systolic dysfunction [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate MYQORZO at 5 mg in patients on stable therapy with fluconazole or voriconazole. In patients currently receiving MYQORZO who intend to initiate fluconazole (if used more than 3 days) or voriconazole: Reduce dose of MYQORZO to 5 mg if they are currently receiving MYQORZO 15 mg or 20 mg. Avoid concomitant use if currently receiving MYQORZO 5 mg or 10 mg [see Dosage and Administration (2.3) ] . Strong CYP2C9 inhibitors Clinical Impact Coadministration with a strong CYP2C9 inhibitor is predicted to increase the exposure of aficamten, which may increase the risk of developing heart failure due to systolic dysfunction [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate MYQORZO at 5 mg in patients who are on stable therapy with a strong CYP2C9 inhibitor. In patients who are on MYQORZO treatment and intend to initiate a strong CYP2C9 inhibitor: Reduce dose of MYQORZO (i.e., 20 mg to 10 mg, 15 mg to 5 mg, or 10 mg to 5 mg) or continue 5 mg [see Dosage and administration (2.3) ]. CYP Inducers Rifampin Clinical Impact Rifampin is a strong CYP3A inducer, strong CYP2C19 inducer, and moderate CYP2C9 inducer. Coadministration of rifampin decreases aficamten exposure, which may reduce the effectiveness of MYQORZO [see Contraindications (4) and Clinical Pharmacology (12.3) ]. Prevention of Management Concomitant use with rifampin is contraindicated. Other moderate-to-strong CYP3A inducers Clinical Impact Concomitant use with a moderate to strong CYP3A inducer decreases aficamten exposure, which may reduce MYQORZO effectiveness [see Clinical Pharmacology (12.3) ] . The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers. Prevention or Management In patients who intend to discontinue a moderate to strong CYP3A Inducer: Reduce dose of MYQORZO (20 mg to 10 mg; 15 mg to 5 mg; 10 mg to 5 mg) or continue 5 mg [see Dosage and Administration (2.3) ].

Uses

1 INDICATIONS AND USAGE MYQORZO is indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms. MYQORZO is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms. ( 1 )

Dosage forms & strengths

TABLET, FILM COATED

AFICAMTEN 5 mg/1 AFICAMTEN 10 mg/1 AFICAMTEN 15 mg/1 AFICAMTEN 20 mg/1

2 DOSAGE AND ADMINISTRATION Recommended starting dose is 5 mg orally once daily. ( 2.1 ) Dosage is individualized based on echocardiographic assessments and clinical status. Refer to Full Prescribing Information for instructions on dosage modification. ( 2.1 , 2.2 ) 2.1 Evaluation Before and During Use of MYQORZO Initiation or up-titration of MYQORZO in patients with LVEF <55% is not recommended. Patients may develop heart failure while taking MYQORZO. Regular LVEF and Valsalva left ventricular outflow tract gradient (LVOT-G) assessment is needed for titration to achieve an appropriate target Valsalva LVOT-G, while maintaining LVEF ≥50% and avoiding heart failure symptoms. 2.2 Recommended Dosage and Administration The recommended starting dose of MYQORZO is 5 mg orally once daily. Increase the dose every 2 to 8 weeks by 5 mg until a maintenance dose or the maximum recommended dose of 20 mg once daily is achieved. The maintenance dose of MYQORZO is individualized based on the patient's LVEF and LVOT-G. Recommendations for dosing based on LVEF and LVOT-G criteria are provided in Table 1. Table 1: Dose Adjustment of MYQORZO LVEF Valsalva LVOT-G Dose Adjustment ≥55% ≥30 mmHg Increase dose by 5 mg (up to the maximum dose of 20 mg once daily) ≥55% <30 mmHg Maintain Dose <55% and ≥50% Any Maintain Dose <50% and ≥40% Any Decrease dose by 5 mg Decrease dose as follows: 20 mg to 15 mg; 15 mg to 10 mg; 10 mg to 5 mg If already on 5 mg, interrupt treatment for at least 7 days <40% Any Interrupt treatment for at least 7 days Perform an echocardiographic assessment 2 to 8 weeks after initiation of treatment or any dose adjustment (e.g., due to LVEF and LVOT-G criteria or drug interaction). After a treatment interruption due to low LVEF, resume treatment, no earlier than 7 days, when LVEF ≥55% and re-initiate dose titration at the starting dose of 5 mg (see Table 1 ). After the maintenance dose has been established, assess LVEF and Valsalva LVOT-G every 6 months, or every 3 months in patients with LVEF <55% to ≥50%. Consider monitoring LVEF and adjust the dose per Table 1 as needed, in patients with an intercurrent illness (e.g., severe infection or COVID-19), new arrhythmia (e.g., new or uncontrolled atrial fibrillation or other uncontrolled tachyarrhythmia) or any other conditions that may impair systolic function. Do not increase the dose until the intercurrent illness or new arrhythmia has resolved or stabilized. MYQORZO should be taken once daily with or without meals at about the same time every day. Swallow tablets whole. 2.3 Dosage Modifications for Drug Interactions Initiate MYQORZO at the recommended starting dose of 5 mg once daily in patients who are on stable therapy with fluconazole, voriconazole, fluvoxamine, strong CYP2C9 inhibitors, or in patients discontinuing a moderate to strong CYP3A inducer. Concomitant Administration with Fluconazole or Voriconazole In patients who initiate fluconazole (if used for more than 3 days) or voriconazole, reduce the dose of MYQORZO to 5 mg if they are currently receiving 15 mg or 20 mg. Avoid concomitant use if patients are currently receiving MYQORZO 5 mg or 10 mg. Assess LVEF and LVOT-G 2 to 8 weeks after initiation of fluconazole or voriconazole and titrate the dose of MYQORZO according to Table 1 [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Concomitant Administration with Fluvoxamine or Strong CYP2C9 Inhibitors In patients who initiate fluvoxamine or a strong CYP2C9 inhibitor, reduce the dose of MYQORZO (20 mg to 10 mg; 15 mg to 5 mg; 10 mg to 5 mg). For patients currently receiving MYQORZO 5 mg, maintain the 5 mg dose. Assess LVEF and LVOT-G 2 to 8 weeks after inhibitor initiation and titrate the dose of MYQORZO according to Table 1 [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) and Drug Interactions (7.1) ] . Concomitant Administration with Moderate to Strong CYP3A Inducers In patients who are on stable therapy with moderate to strong CYP3A inducers (e.g., carbamazepine), when discontinuing these medications, reduce the dose of MYQORZO (20 mg to 10 mg; 15 mg to 5 mg; 10 mg to 5 mg). For patients currently receiving MYQORZO 5 mg, maintain the 5 mg dose. Assess LVEF and LVOT-G 2 to 8 weeks after inducer discontinuation and titrate the dose of MYQORZO according to Table 1 [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) and Drug Interactions (7.1) ]. 2.4 Missed Dose If a dose is missed, it should be taken as soon as possible on the same day. The next scheduled dose should be taken at the usual time the following day. Two doses of MYQORZO should not be taken on the same day.

All identified pills

Side effects

6 ADVERSE REACTIONS The following adverse reaction is discussed in other sections of labeling: Heart Failure [see Warnings and Precautions (5.1) ] The most common adverse reaction was hypertension (8%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cytokinetics at 1-833-633-2986 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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.

Official source

DailyMed