Myqorzo (aficamten)

In patients receiving stable therapy with fluconazole, voriconazole, fluvoxamine, or a strong cytochrome P-450 (CYP) 2C9 inhibitor, initiate aficamten at 5 mg once daily.

In patients discontinuing a moderate to strong CYP3A inducer, initiate aficamten at 5 mg once daily.

In patients initiating fluconazole (if used for more than 3 days) or voriconazole, reduce aficamten dose to 5 mg once daily if the patient is currently receiving a dose of 15 mg or 20 mg; avoid concomitant use in patients receiving aficamten 5 or 10 mg daily. Assess LVEF and Valsalva LVOT gradient 2 to 8 weeks after initiation of fluconazole or voriconazole and titrate the dose of aficamten according to Table 1.

In patients initiating fluvoxamine or a strong CYP2C9 inhibitor, reduce aficamten dose from 20 mg to 10 mg; from 15 mg to 5 mg; or from 10 mg to 5 mg once daily. Continue aficamten at 5 mg once daily in patients currently receiving a dosage of 5 mg daily. Assess LVEF and Valsalva LVOT gradient 2 to 8 weeks after initiation of the inhibitor and titrate the dose of aficamten according to Table 1.

In patients discontinuing stable therapy with a moderate to strong CYP3A inducer (e.g., carbamazepine), reduce aficamten dose from 20 mg to 10 mg; from 15 mg to 5 mg; or from 10 mg to 5 mg once daily. Continue aficamten at 5 mg once daily in patients currently receiving a dosage of 5 mg daily. Assess LVEF and Valsalva LVOT gradient 2 to 8 weeks after discontinuation of the inducer and titrate the dose of aficamten according to Table 1.

Aficamten is administered orally; the drug is available as film-coated tablets.

Administer aficamten once daily with or without food.

Tablets should be taken at the same time each day and swallowed whole.

If a dose of aficamten is missed, the missed dose should be taken as soon as possible on the same day. Two doses should not be taken on the same day.

Store aficamten tablets at 20-25degreesC; excursions permitted between 15-30degreesC.

No dosing information is available for this tab.

Aficamten undergoes extensive metabolism, primarily through cytochrome P-450 (CYP) 2C9, with contributions from CYP2D6, CYP2C19, and CYP3A.

At clinically relevant concentrations, aficamten is not expected to inhibit CYP1A2, 2B6, 2C8, 2C19, 2D6, or 3A4 or induce CYP1A2, 2B6, or 3A4.

Aficamten is not a sensitive substrate of drug transporters and is not expected to inhibit breast cancer resistance protein (BCRP), organic cation transporters (OCT) 2 or OCT3, organic anion transporters (OAT) 1 or OAT3, organic anion transporting polypeptides (OATP) 1B1 or OATP1B3, or multidrug and toxin extrusion proteins (MATE) 1 or MATE2-K at clinically relevant concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Aficamten/Rifampin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, and CYP2C9 substrate. Rifampin, a strong CYP3A4 inducer, strong CYP2C19 inducer, and moderate CYP2C9 inducer may induce the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent or recent use of rifampin may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of aficamten states coadministration with rifampin is contraindicated.(1)

DISCUSSION: In a study, rifampin (strong CYP3A4 inducer, strong CYP2C19 inducer, moderate CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 79%.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aficamten/Fluconazole; Voriconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, and CYP2C9 substrate. Fluconazole is a moderate CYP3A4 and CYP2C9 inhibitor and a strong CYP2C19 inhibitor. Voriconazole is a strong CYP3A4 inhibitor, a moderate CYP2C19 inhibitor, and a weak CYP2C9 inhibitor. Fluconazole and voriconazole may inhibit the metabolism of aficamten.(1-3)

CLINICAL EFFECTS: Concurrent use of fluconazole or voriconazole with aficamten is expected to increase plasma exposure of aficamten, which may increase the incidence and severity of adverse reactions to aficamten, including heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients on stable therapy with fluconazole or voriconazole, initiate aficamten at the usual 5 mg starting dose.(1) In patients currently on aficamten and starting fluconazole for more than 3 days or voriconazole: - If the patient is taking 5 mg or 10 mg of aficamten daily, avoid concomitant use. - If the patient is taking 15 mg or 20 mg of aficamten daily, reduce the dose of aficamten to 5 mg daily.(1) Schedule clinical and echocardiographic assessment 2-8 weeks after inhibitor initiation, and titrate aficamten dose based on prescribing information.(1)

DISCUSSION: Concomitant use of aficamten with fluconazole 400 mg once daily increased aficamten area-under-curve (AUC) by 278%. There was no change to aficamten exposure when coadministered with fluconazole 150 mg x 2 doses given 48 hours apart. Concomitant use of voriconazole 200 mg twice daily increase aficamten AUC by 94%.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aficamten/Fluvoxamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, CYP2C9, and CYP2D6 substrate. Fluvoxamine is a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor. Fluvoxamine may decrease the metabolism of aficamten.(1)(1)

CLINICAL EFFECTS: Concurrent use of fluvoxamine increases the plasma exposure of aficamten which may increase the incidence and severity of adverse reactions of aficamten, including heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients on stable therapy with fluvoxamine, initiate aficamten at the usual 5 mg starting dose.(1) In patients currently on aficamten and starting fluvoxamine: - If the patient is taking 5 mg of aficamten daily, continue 5 mg daily. - If the patient is taking 10 mg or 15 mg of aficamten daily, reduce the dose of aficamten to 5 mg daily. - If the patient is taking 20 mg of aficamten daily, reduce the dose of aficamten to 10 mg daily.(1) Schedule clinical and echocardiographic assessment 2-8 weeks after inhibitor initiation, and titrate aficamten dose based on prescribing information.(1)

DISCUSSION: Concomitant use of aficamten with fluvoxamine (150 mg), a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor, twice daily increased aficamten area-under-curve (AUC) by 116%.(1)

Aficamten/Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aficamten is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)

DISCUSSION: In a study, carbamazepine (moderate to strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Aficamten/Strong Cyp2c9 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, and CYP2C9 substrate. Strong CYP2C9 inhibitors may decrease the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C9 inhibitor increases plasma exposure of aficamten, which may increase the incidence and severity of adverse reactions of aficamten, including heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients on stable therapy with a strong CYP2C9 inhibitor, initiate aficamten at the usual 5 mg starting dose.(1) In patients currently on aficamten and starting a strong CYP2C9 inhibitor: - If the patient is taking 5 mg of aficamten daily, continue 5 mg daily. - If the patient is taking 10 mg or 15 mg of aficamten daily, reduce the dose of aficamten to 5 mg daily. - If the patient is taking 20 mg of aficamten daily, reduce the dose of aficamten to 10 mg daily.(1) Schedule clinical and echocardiographic assessment 2-8 weeks after inhibitor initiation, and titrate aficamten dose based on prescribing information.(1)

DISCUSSION: Concomitant use of aficamten with sulfaphenazole (2000 mg), a strong CYP2C9 inhibitor, once daily increased aficamten area-under-curve (AUC) by 113%.(1) Strong CYP2C9 inhibitors linked to this monograph include: camizestrant and sulfaphenazole.(2,3)

Aficamten/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aficamten is a CYP3A4 substrate. Strong CYP3A4 inducers may induce the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)

DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's Wort.(2,3)

*Concomtiant use of rifampin.

There are no contraindication contraindications for this drug.

• Chronic heart failure
• Infection

There are no moderate contraindications for this drug.

The most common adverse effect of aficamten in clinical studies was hypertension (8%).

There are no severe adverse reactions for this drug.

More Frequent

• Hypertension

No enhanced messaging available.

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

No data are available to assess the risks of aficamten use during pregnancy. In animal studies, aficamten caused structural malformations at exposures >=4 times the maximum recommended human dose; no adverse developmental effects occurred at 3 times the maximum recommended human dose.

Obstructive hypertrophic cardiomyopathy during pregnancy is associated with an increased risk of preterm birth.

A pregnancy safety study is available; report aficamten exposure during pregnancy or within 3 weeks after the last dose to Cytokinetics at 1-833-633-2986.

No data are available on the presence of aficamten in human milk or its effects on the breastfed infant or on milk production. Aficamten was detected in the plasma of rat pups during lactation and may be present in human milk. Consider the benefits of breastfeeding, the maternal need for aficamten, and potential adverse effects on the breastfed infant.

The manufacturer provides no specific dosage adjustment recommendation for geriatric patients.

Among aficamten-treated patients in the SEQUOIA-HCM trial, 57 (40%) were >=65 years of age, including 45 (32%) who were 65-74 years of age and 12 (8%) who were >=75 years of age. No overall differences in safety or effectiveness were observed between patients >=65 years of age and younger adults.