CAMZYOS

/ Bristol Myers Squibb (Israel) Ltd.

The recommended starting dose is 5 mg orally once daily without regard to food; allowable subsequent doses with titration are 2.5 mg, 5 mg, 10 mg, or 15 mg orally once daily. The maximum recommended dose is 15 mg orally once daily.
Daily dosing takes weeks to reach steady-state drug levels and therapeutic effects, and genetic variation in metabolism and drug interactions can cause large differences in exposure.
See prescribing information for full details

Treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

* Hypersensitivity to mavacamten or to any of the excipients
* Concomitant use with moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors
* Concomitant use with moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers

Heart Failure
This medical product reduces systolic contraction and can cause heart failure or significantly reduce ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure.
Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the mavacamten dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, 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. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations.
Initiation of mavacamten in patients with LVEF <55% is not recommended.
CYP450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness
Mavacamten is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of mavacamten and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness.
Embryo-Fetal Toxicity
Mavacamten may cause fetal toxicity when administered to a pregnant female, based on findings in animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with mavacamten and for 4 months after the last dose. Combined hormonal contraceptives (CHCs) containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten. However, mavacamten may reduce the effectiveness of certain other CHCs. If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose.
See prescribing information for full details.

Adverse reactions occurring in >5% of patients and more commonly on mavacamten than on placebo were dizziness (27% vs. 18%) and syncope (6% vs. 2%).
See prescribing information for full details.

Potential for Other Drugs to Affect Plasma Concentrations of mavacamten
Mavacamten is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of mavacamten.
Potential for mavacamten to Affect Plasma Concentrations of Other Drugs
Certain CYP3A4, CYP2C9, and CYP2C19 Substrates
Mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C9, or CYP2C19 substrates may reduce plasma concentration of these drugs.
Certain Combined Hormonal Contraceptives
Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of mavacamten may decrease exposures of certain progestins, which may lead to contraceptive failure. Combined hormonal contraceptives (CHCs) containing a combination of ethinyl estradiol and norethindrone. Combined hormonal contraceptives (CHCs) containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) or use an alternative contraceptive method that is not affected by CYP450 enzyme induction (e.g., intrauterine system).
Drugs That Reduce Cardiac Contractility
Expect additive negative inotropic effects of mavacamten and other drugs that reduce cardiac contractility.
Avoid concomitant use of mavacamten in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved.

Pregnancy: The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Obstructive HCM in pregnancy has been associated with increased risk for preterm birth.
Confirm absence of pregnancy in females of reproductive potential prior to initiation of this medical procut.
Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used. However, mavacamten may reduce the effectiveness of certain other CHCs. If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) or use an alternative contraceptive method during concomitant use and for 4 months after the last dose.
Lactation: The presence of mavacamten in human or animal milk, the drug’s effects on the breastfed infant, and the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mavacamten and any potential adverse effects on the breastfed child from mavacamten or from the underlying maternal condition.

Clinical Experience and Effects
• Cardiovascular effects may include reduced LVEF (left ventricular ejection fraction), heart failure, hypotension, and asystole refractory to medical intervention.
• Neurological effects may include dizziness and syncope.
• An infant death was reported after accidental ingestion of three 15 mg capsules (45 mg).
• An adult administered a single dose of 144 mg developed a vasovagal reaction, hypotension, and asystole, but the subject recovered.
Management
Discontinue treatment.
• Provide medically supportive measures to maintain hemodynamic stability and monitor left ventricular function.
• Consider administering activated charcoal (pediatric dose is 1 g/kg; adult dose is 50 g) within 2 hours of ingestion in addition to other supportive measures. The benefit of activated charcoal is negligible after 6 hours [see Clinical Pharmacology (12.3)].
• Consider contacting the Israel Poison Information Center (RAMBAM Medical Center, 04-7771900) or a medical toxicologist for additional overdose management recommendations.

Effects on ability to drive and use machines
Mavacamten has minor influence on the ability to drive and use machines. Dizziness may occur during use of mavacamten. Patients should be advised not to drive for use machines if they experience dizziness.