camzyos

Dosage must be individualized based on clinical status and echocardiographic assessment of patient response. Refer to the Full Prescribing Information for instructions. ( 2.1 ) 2.1 Initiation, Maintenance, and Interruption of Treatment Confirm absence of pregnancy and usage of effective contraception in females of reproductive potential [see Warnings and Precautions (5.4) ] . Initiation or up-titration of CAMZYOS in patients with LVEF <55% is not recommended. 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. Patients may develop heart failure while taking CAMZYOS. Regular LVEF and Valsalva left ventricular outflow tract (LVOT) gradient assessment is required for careful titration to achieve an appropriate target Valsalva LVOT gradient, while maintaining LVEF ≥50% and avoiding heart failure symptoms (see Figure 1 and Figure 2). 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 Boxed Warning , Contraindications (4) , Warnings and Precautions (5.2) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . When initiating or titrating CAMZYOS, first consider LVEF…

The following adverse reaction is discussed in other sections of the labeling: • Heart failure [see Warnings and Precautions (5.1) ] Adverse reactions occurring in >5% of patients and more commonly on CAMZYOS than on placebo were dizziness (27%) and syncope (6%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 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 CAMZYOS was evaluated in EXPLORER-HCM, a Phase 3, double-blind, randomized, placebo-controlled trial [see Clinical Studies (14) ] . Of the 251 adults with obstructive HCM, 123 patients were treated with CAMZYOS 2.5-15 mg daily and 128 were treated with placebo. CAMZYOS-treated patients had a median duration of exposure of 30 weeks (range: 2-40 weeks). Syncope (0.8%) was the only adverse drug reaction leading to discontinuation in patients receiving CAMZYOS. Adverse reactions occurring in >5% of patients and more commonly on CAMZYOS than on placebo were dizziness (27% vs. 18%) and syncope (6% vs. 2%). The safety of CAMZYOS in patients was further evaluated in VALOR-HCM, a…

CAMZYOS is contraindicated with concomitant use of: • Strong CYP2C19 inhibitors [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] • Strong CYP2C19 inhibitors. ( 4 , 5.2 ) • Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. ( 4 , 5.2 )

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 CAMZYOS 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 Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

Weak to moderate CYP2C19 inhibitors and moderate to strong CYP3A4 inhibitors : May increase risk of heart failure. If initiating an inhibitor, CAMZYOS dose reduction and additional monitoring are required. ( 2.2 , 7.1 ) • Negative inotropes : Close medical supervision and LVEF monitoring is recommended if a negative inotrope is initiated, or the dose of a negative inotrope is increased. Avoid certain combinations of negative inotropes. ( 7.3 ) 7.1 Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS 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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . (See Table 1 ) Table 1: Established and Potentially Significant Pharmacokinetic Drug Interactions with CAMZYOS Impact of Other Drugs on CAMZYOS Strong CYP2C19 Inhibitors Clinical Impact Concomitant use with a strong CYP2C19 inhibitor increases mavacamten exposure, which may increase the risk of heart failure due to systolic dysfunction [see Contraindications (4) , Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] . Prevention or Management Concomitant use with a strong CYP2C19 inhibitor is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers Clinical Impact Concomitant use with a moderate to strong CYP2C19 inducer or a moderate to strong CYP3A4 inducer decreases mavacamten exposure, which may reduce CAMZYOS’ efficacy [see Clinical Pharmacology (12.3) ] . The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes [see Contraindications (4) and Warnings and Precautions (5.2) ] . Prevention or Management Concomitant use of a moderate to strong CYP2C19 inducer or a moderate to strong CYP3A4 inducer is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors Clinical Impact Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases mavacamten exposure, which may increase the risk of adverse drug reactions [see Warnings and Precautions (5.2) ] . Prevention or Management Initiate CAMZYOS at the recommended starting dosage of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS to the next lower daily (mg) dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available [see Dosage and Administration (2.2) ] . For short-term use (e.g., 1 week), interrupt CAMZYOS for the duration of treatment with a weak inhibitor of CYP2C19 or a moderate inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. Moderate CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors Clinical Impact Concomitant use with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor increases mavacamten exposure, which may increase the risk of adverse drug reactions [see Warnings and Precautions (5.2) ] . Discontinuing use of a moderate CYP2C19 inhibitor or strong CYP3A4 inhibitor after long-term concomitant use may decrease mavacamten exposure, which may reduce CAMZYOS’ efficacy [see Clinical Pharmacology (12.3) ] . Prevention or Management Initiate CAMZYOS at a starting dosage of 2.5 mg orally once daily in patients who are on stable therapy with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Reduce dose of CAMZYOS to the next lower daily (mg) dose level (i.e., 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg) in patients who are on CAMZYOS and intend to initiate a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Avoid initiation of concomitant moderate CYP2C19 and strong CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available [see Dosage and Administration (2.2) ] . An increase in dose of CAMZYOS may be needed if the moderate inhibitor of CYP2C19 or strong inhibitor of CYP3A4 is discontinued after long-term concomitant use. Monitor for new or worsening symptoms. For short-term use (e.g., 1 week), interrupt CAMZYOS for the duration of treatment with a moderate inhibitor of CYP2C19 or a strong inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. 7.2 Potential for CAMZYOS 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 [see Clinical Pharmacology (12.3) ]. Closely monitor when CAMZYOS is used with concomitant CYP3A4, CYP2C9 or CYP2C19 substrates unless otherwise recommended in the Prescribing Information. Certain Combined Hormonal Contraceptives Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins [ see Clinical Pharmacology (12.3) ] , which may lead to contraceptive failure. 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) during concomitant use and for 4 months after the last dose of CAMZYOS. 7.3 Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS 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 [see Warnings and Precautions (5.1) ] . 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.