Mavacamten

7 DRUG INTERACTIONS • 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.

8.1 Pregnancy Risk Summary Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female. There are no human data on the use of CAMZYOS during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The underlying maternal condition during pregnancy poses a risk to the mother and fetus (see Clinical Considerations ) . Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy.

In animal embryo-fetal development 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) were observed in rats and increases in visceral and skeletal malformations were observed in both rabbits and rats at dose exposures similar to that achieved at the maximum recommended human dose (MRHD) (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com. Clinical Considerations Disease-Associated Maternal and Embryo-Fetal Risk Obstructive HCM in pregnancy has been associated with increased risk for preterm birth.

Data Animal Data When mavacamten was administered orally to pregnant rats (0.3 to 1.5 mg/kg/day) during the period of organogenesis, increases in post-implantation loss, decreases in mean fetal body weight, reductions in fetal ossification of bones, and fetal malformations (visceral and skeletal) were observed in the high dose group (1.5 mg/kg/day). Visceral malformations (heart malformation in fetuses, including one total situs inversus) and increased incidences of skeletal malformations (mainly fused sternebrae) were observed at a similar exposure as in humans at the MRHD.

Plasma exposure (based on area under the concentration-time curve or AUC) at the no-effect dose for embryo-fetal development in rats is 0.3 times the exposure in humans at the MRHD. When…