Mavacamten

Mavacamten is used for: Obstructive Hypertrophic Cardiomyopathy

Oral Obstructive Hypertrophic Cardiomyopathy Indicated for symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms Starting dose: 5 mg PO once daily Allowable subsequent doses with titration are 2.5, 5, 10, or 15 mg once daily The maximum recommended dose is 15 mg orally once daily Initiation or up-titration in patients with left ventricular ejection fraction (LVEF) <55% not recommended Hepatic impairment Mild-to-moderate (Child-Pugh A or B): No dosage adjustment required; although AUC increases, no additional dose adjustment required owing to recommended dose titration algorithm and monitoring Severe (Child-Pugh C): Unknown

Renal impairment Mild-to-moderate (eGFR 30-89 mL/min/1.73 m2): No dosage adjustment required Severe impairment and kidney failure, including patients on dialysis (eGFR <30 mL/min/1.73 m2): Unknown

May take with or without food

Coadministration with moderate-to-strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Coadministration with moderate-to-strong CYP2C19 or CYP3A4 inducers

Based on animal studies, may cause fetal toxicity when administered to pregnant females; confirm absence of pregnancy in females of reproductive potential before initiating and instruct patient on use of effective contraception. Confirm absence of pregnancy and usage of effective contraception in females of reproductive potential. Risk of heart failure (HF) Reduces left ventricular ejection fraction (LVEF) and can cause HF owing to systolic dysfunction ECG assessments of LVEF required before and during treatment Initiation in patients with LVEF <55% not recommended Interrupt dosing if LVEF <50% at any visit or if patient experiences HF symptoms or worsening clinical status

Pregnancy Based on animal data, may cause fetal harm when administered to pregnant females Human data are not available on use during pregnancy to evaluate for drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes Confirm absence of pregnancy in females of reproductive potential prior to initiation and use of effective contraception Animal studies Mavacamten-related decreases in mean fetal body weight, reductions in fetal ossification of bones, and increases in post-implantation loss (early and/or late resorptions) observed in rats and increases in visceral and skeletal malformations observed in both rabbits and rats at dose exposures like that achieved at maximum recommended human dose (MRHD) Contraception Advise females of reproductive potential to use effective contraception during treatment and for 4 months after last dose Mavacamten may reduce effectiveness of combination hormonal contraceptives; advise using an alternant contraceptive method or add nonhormonal contraception Clinical considerations Underlying maternal condition during pregnancy poses risk to mother and fetus Obstructive HCM in pregnancy associated with increased risk for preterm birth Advise pregnant females about potential risk to fetus with maternal exposure to mavacamten during pregnancy Lactation Unknown if present in human or animal milk, effects on breastfed infants, and effects on milk production Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for mavacamten and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition

Coadministration with drugs that interact with these enzymes may lead to life-threatening drug interactions (eg, heart failure) or loss of effectiveness Advise patients of potential drug interactions, including OTC medications (eg, omeprazole, esomeprazole, or cimetidine) Moderate-to-strong CYP2C19 or strong CYP3A4 inhibitors Contraindicated Coadministration with moderate-to-strong CYP2C19 inhibitors or strong CYP3A4 inhibitors increases mavacamten systemic exposure, which may increase risk of HF due to systolic dysfunction Moderate-to-strong CYP2C19 or CYP3A4 inducers Contraindicated Coadministration with moderate-to-strong CYP2C19 or CYP3A4 inducers decreases mavacamten systemic exposure, which may reduce efficacy May increase risk of adverse effects Hormonal contraceptives Use alternant contraceptive (eg, intrauterine system) not affected by CYP450 induction or add nonhormonal contraception during treatment and for 4 months after last dose Progestin and ethinyl estradiol are CYP3A4 substrates Mavacamten may decrease exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or increased breakthrough bleeding Weak CYP2C19 or moderate CYP3A4 inhibitors On stable therapy with weak CYP2C19 or moderate CYP3A4 inhibitor: Initiate at recommended 5 mg/day dose Intend to initiate weak CYP2C19 or moderate CYP3A4 inhibitor: Reduce mavacamten dose by 1 level On stable treatment with mavacamten 2.5 mg/day: Avoid initiating weak CYP2C19 or moderate CYP3A4 inhibitor (no lower mavacamten dose available) Drugs that reduce cardiac contractility Avoid coadministration Coadministration with disopyramide in combination with verapamil or diltiazem has been associated with left ventricular systolic dysfunction and HF symptoms in patients with obstructive HCM Avoid concomitant use in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited If concomitant therapy with negative inotrope initiated, or if dose of negative inotrope increased, monitor LVEF closely until stable doses and clinical response achieved

Side effects of Mavacamten : >10% Dizziness (27%) 1-10% Syncope (6%) Reduced LVEF (6%)

Selective allosteric inhibitor of cardiac myosin Modulates number of myosin heads that can enter “on actin” (power-generating) states, thus reduces probability of force-producing (systolic) and residual (diastolic) cross-bridge formation Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM Mavacamten shifts overall myosin population towards an energy-sparing, recruitable, super-relaxed state In patients with HCM, myosin inhibition with mavacamten reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures