Version May 2024
Mavacamten reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required prior to and during treatment with mavacamten. Initiation of mavacamten in patients with LVEF <55% is not recommended. Interrupt mavacamten if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status.
Concomitant use of mavacamten with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of mavacamten is contraindicated with the following: moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors; moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers. Because of the risk of heart failure due to systolic dysfunction, mavacamten is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called CAMZYOS REMS PROGRAM.
Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction:
Note: Only initiate therapy in patients with left ventricular ejection fraction (LVEF) ≥55%. If LVEF falls to <50% at any point, interrupt therapy (see "Dosing: Adjustment for Toxicity: Adult"). Recheck LVEF regularly and at least 4 weeks after dose adjustments. Delay dose increases or consider interrupting therapy when there is a concurrent illness or arrhythmia present that may impair systolic function.
Oral:
Initiation phase:
Initial: 5 mg once daily, only if LVEF is ≥55%; further titration is based on Valsalva left ventricular outflow tract (LVOT) gradient and LVEF reassessment every 4 weeks.
Week 4 assessment: If Valsalva LVOT gradient is <20 mm Hg, reduce dose to 2.5 mg once daily. If Valsalva LVOT gradient is ≥20 mm Hg, continue 5 mg once daily.
Week 8 assessment, patients on 2.5 mg once daily: If Valsalva LVOT gradient is <20 mm Hg, interrupt therapy and reassess at week 12. If Valsalva LVOT gradient is ≥20 mm Hg, continue 2.5 mg once daily.
Week 8 assessment, patients on 5 mg once daily: If Valsalva LVOT gradient is <20 mm Hg, reduce dose to 2.5 mg once daily. If Valsalva LVOT gradient is ≥20 mm Hg, continue 5 mg once daily.
Week 12 assessment, patients who needed to interrupt therapy at week 8: If LVEF is ≥50%, restart 2.5 mg once daily and continue for the next 12 weeks unless LVEF falls <50%.
Week 12 assessment, patients on 2.5 mg or 5 mg once daily: See “Maintenance phase” below.
Maintenance phase:
LVEF <50% at any time: Interrupt therapy and see "Dosing: Adjustment for Toxicity: Adult."
LVEF 50% to 55%, regardless of Valsalva LVOT gradient: Maintain current dose and reassess in 12 weeks.
LVEF >55% and Valsalva LVOT gradient <30 mm Hg: Maintain current dose and reassess in 12 weeks.
LVEF ≥55% and Valsalva LVOT gradient ≥30 mm Hg: Increase dose to the next higher daily dosage level after being on the same dose for 12 weeks (eg, 2.5 mg once daily increased to 5 mg once daily, or 5 mg once daily increased to 10 mg once daily, or 10 mg once daily increased to 15 mg once daily). A maximum dose is not specifically noted in the prescribing information, but it does not mention titrating beyond 15 mg once daily, and the clinical trial did not titrate beyond 15 mg once daily (Olivotto 2020).
Missed dose: Take as soon as possible, then resume regular schedule; however, do not take >1 dose in the same day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR: ≥30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling; mild or moderate renal impairment had no clinically significant effect on mavacamten pharmacokinetics.
eGFR: <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Dialysis: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Mild to moderate (Child-Pugh class A or B) impairment: No dosage adjustment necessary. Exposure increased up to 220% compared to patients with normal hepatic function; however, no additional dose adjustment is required besides the recommended dose titration algorithm and monitoring plan.
Severe (Child-Pugh class C) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Dose adjustment if left ventricular ejection (LVEF) decreases from baseline:
LVEF decreases to 50% to 55% during therapy: Do not up-titrate the dose further; continue current dose and continue to monitor.
LVEF decreases to <50% during therapy: Interrupt therapy. Reassess LVEF every 4 weeks thereafter. If LVEF increase back to ≥50%, restart at the next lower daily dose (eg, previously 5 mg once daily should restart at 2.5 mg once daily, previously 10 mg once daily should restart at 5 mg once daily, previously 15 mg once daily should restart at 10 mg once daily) or if therapy was interrupted while previously on 2.5 mg once daily may restart at 2.5 mg once daily. Reassess LVEF after 4 weeks. If LVEF remains ≥50%, continue the current dose for a total of 12 weeks and proceed according to the “Maintenance phase” of dosing.
LVEF decreases to <50% twice while on 2.5 mg once daily: Stop therapy permanently.
Arrhythmia or concurrent illness that may impair systolic function occurs while on therapy: Delay dose increases or consider interrupting therapy.
Patients ≥65 years of age: Refer to adult dosing.
Mavacamten is associated with decreased left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction.
Mechanism: Dose-related; related to the pharmacologic action (Ho 2020).
Onset: Intermediate; within 4 weeks of therapy initiation (Ho 2020).
Risk factors:
• Serious intercurrent illness (eg, serious infection)
• Uncontrolled tachyarrhythmia ( eg, atrial fibrillation)
• Concomitant use with disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker
• Concomitant use with certain moderate to strong CYP2C19 and/or CYP3A4 inhibitors
• Discontinuation of certain moderate to strong CYP2C19 and/or CYP3A4 inducers
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%: Nervous system: Dizziness (27%)
1% to 10%: Cardiovascular: Decreased left ventricular ejection fraction (6%) (table 1), syncope (6%)
|
Drug (Mavacamten) |
Placebo |
Number of Patients (Mavacamten) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|
|
6% |
2% |
123 |
128 |
Reversible reduction in left ventricular ejection fraction to <50% |
Concomitant use of moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors; concomitant use of moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to mavacamten or any component of the formulation; pregnancy.
Other warnings/precautions:
• REMS program: Prescribers must be certified by enrolling in the REMS program. Patients must also enroll in the REMS program and comply with monitoring requirements. Pharmacies must be certified to dispense medication by enrolling in the REMS program.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Camzyos: 2.5 mg, 5 mg, 10 mg, 15 mg
No
Capsules (Camzyos Oral)
2.5 mg (per each): $327.69
5 mg (per each): $327.69
10 mg (per each): $327.69
15 mg (per each): $327.69
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Camzyos: 2.5 mg, 5 mg [contains gelatin (bovine), gelatin (pork)]
Camzyos: 10 mg, 15 mg
Oral: Swallow capsule whole. Do not break, open, or chew the capsule. May take with or without food.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Mavacamten may cause teratogenicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214998s001lbl.pdf#page=29, must be dispensed with this medication.
Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: Treatment of symptomatic obstructive hypertrophic cardiomyopathy (New York Heart Association [NYHA] class II to III) in adults to improve functional capacity and symptoms.
Substrate of CYP2C19 (major), CYP2C9 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Beta-Blockers: May enhance the adverse/toxic effect of Mavacamten. Specifically, negative inotropic effects may be increased. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May enhance the adverse/toxic effect of Mavacamten. Specifically, negative inotropic effects may be increased. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a non-DHP CCB. For those stable on mavacamten who are initiating a non-DHP CCB, reduce mavacamten dose by one dose level. Monitor for excessive negative inotropic effects. Risk D: Consider therapy modification
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP2C19 Inducers (Moderate): May decrease the serum concentration of Mavacamten. Risk X: Avoid combination
CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Mavacamten. Risk X: Avoid combination
CYP2C19 Inhibitors (Strong): May increase the serum concentration of Mavacamten. Risk X: Avoid combination
CYP2C19 Inhibitors (Weak): May increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a weak CYP2C19 inhibitor. For those stable on mavacamten who are initiating a weak CYP2C19 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modification
CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Mavacamten may decrease the serum concentration of CYP2C9 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Mavacamten. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Mavacamten. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Mavacamten. Management: Start mavacamten at 5 mg/day if stable on a moderate CYP3A4 inhibitor. For those stable on mavacamten who are initiating a moderate CYP3A4 inhibitor, reduce mavacamten dose by one dose level. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Mavacamten. Risk X: Avoid combination
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers): Mavacamten may decrease the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inducers). Risk C: Monitor therapy
Disopyramide: May enhance the adverse/toxic effect of Mavacamten. Specifically, negative inotropic effects may be increased. Risk X: Avoid combination
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Hormonal Contraceptives: Mavacamten may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative contraceptive that is not sensitive to CYP3A4 induction or a back-up method during coadministration, and to continue back-up contraception for 4 months after stopping mavacamten to ensure contraceptive reliability. Risk D: Consider therapy modification
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Ranolazine: May enhance the adverse/toxic effect of Mavacamten. Risk X: Avoid combination
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Treosulfan: May increase the serum concentration of CYP2C19 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation; pregnancy should be excluded prior to treatment.
Patients who may become pregnant should use effective contraception during therapy and for 4 months after the last mavacamten dose. Mavacamten may reduce the efficacy of combination hormonal contraceptives; alternative contraception or additional nonhormonal contraception may be required. Consult drug interactions database for more detailed information specific to use of mavacamten and specific contraceptives not affected by CYP450 enzyme induction.
Based on data from animal reproduction studies, in utero exposure to mavacamten may cause fetal harm.
Data collection to monitor pregnancy and infant outcomes following exposure to mavacamten is ongoing. Health care providers are encouraged to enroll patients exposed to mavacamten during pregnancy or within 4 months after the last dose in the pregnancy safety study (800-721-5072 or www.bms.com).
It is not known if mavacamten is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Signs and symptoms of heart failure; left ventricular ejection fraction prior to initiation, during dose titration (ie, 4 weeks after each dose titration), and regularly during therapy. Evaluate pregnancy status prior to use; exclude pregnancy prior to treatment initiation in patients who could become pregnant.
Mavacamten is an allosteric and reversible inhibitor selective for cardiac myosin. It modulates the number of myosin heads that cross-bridge to actin during systole or diastole. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of hypertrophic cardiomyopathy (HCM). Mavacamten promotes an energy-sparing, recruitable, super-relaxed state. In HCM patients, this reduces dynamic left ventricular outflow tract obstruction and improves cardiac filling pressures.
Protein binding: Plasma: 97% to 98%.
Metabolism: Extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).
Bioavailability: ≥85%.
Half-life elimination: CYP2C19 normal metabolizers: 6 to 9 days; CYP2C19 poor metabolizers: 23 days.
Time to peak: 1 hour; Tmax is increased to 4 hours when taken with a high-fat meal.
Excretion: Feces: 7% (1% as unchanged drug); urine: 85% (3% as unchanged drug).
Hepatic function impairment: Exposure is increased by up to 220% in patients with mild to moderate (Child-Pugh class A or B) impairment when compared to patients with normal hepatic function. The effect of severe (Child-Pugh class C) impairment is unknown.
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