Brand Name
Camzyos
Generic Name
Mavacamten
View Brand Information FDA approval date: April 28, 2022
Classification: Cardiac Myosin Inhibitor
Form: Capsule
What is Camzyos (Mavacamten)?
CAMZYOS ® is indicated for the treatment of adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms. CAMZYOS is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy to improve functional capacity and symptoms.
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Brand Information
CAMZYOS (mavacamten)
WARNING: RISK OF HEART FAILURE
CAMZYOS 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 CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status
Concomitant use of CAMZYOS 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 CAMZYOS is contraindicated with the following
- Strong CYP2C19 inhibitors
- Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called CAMZYOS REMS PROGRAM
1INDICATIONS AND USAGE
CAMZYOS
2DOSAGE FORMS AND STRENGTHS
CAMZYOS is available as capsules imprinted with the strength and “Mava” in the following strengths:
- 2.5 mg – light purple cap
- 5 mg – yellow cap
- 10 mg – pink cap
- 15 mg – gray cap
3CONTRAINDICATIONS
CAMZYOS is contraindicated with concomitant use of:
- Strong CYP2C19 inhibitors Warnings and Precautions (5.2), Drug Interactions (7.1)]
- Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers
4ADVERSE REACTIONS
The following adverse reaction is discussed in other sections of the labeling:
- Heart failure
4.1Clinical 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
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 Phase 3, double-blind, randomized, placebo-controlled trial
There were no new adverse reactions identified in VALOR-HCM.
Effects on Systolic Function
In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Consistent with the mechanism of action of CAMZYOS, mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF to <50% (median 48%: range 35-49%) while on treatment. In 3 of the 7 CAMZYOS patients and 1 of the 2 placebo patients, these reductions were asymptomatic. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS
5OVERDOSAGE
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
- Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
6DESCRIPTION
CAMZYOS capsules for oral use contain mavacamten, a cardiac myosin inhibitor.
The chemical name of mavacamten is 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1
The structural formula of mavacamten is:
Mavacamten is a white to off-white powder that is practically insoluble in water and aqueous buffers at pH 2-10, sparingly soluble in methanol and ethanol, and freely soluble in DMSO and NMP.
CAMZYOS is supplied as immediate release Size 2 hard gelatin capsules, containing 2.5 mg, 5 mg, 10 mg, or 15 mg of mavacamten per capsule as active ingredient and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate (non-bovine), mannitol, and silicon dioxide. The capsule shell contains black edible ink, black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide.
7CLINICAL STUDIES
EXPLORER-HCM
The efficacy of CAMZYOS was evaluated in EXPLORER-HCM (NCT-03470545) a Phase 3, double-blind, randomized, placebo-controlled, multicenter, international, parallel-group trial in 251 adults with symptomatic NYHA class II and III obstructive HCM, LVEF ≥55%, and LVOT peak gradient ≥50 mmHg at rest or with provocation.
Patients on dual therapy with beta blocker and calcium channel blocker treatment or monotherapy with disopyramide or ranolazine were excluded. Patients with a known infiltrative or storage disorder causing cardiac hypertrophy that mimicked obstructive HCM, such as Fabry disease, amyloidosis, or Noonan syndrome with left ventricular hypertrophy, were also excluded.
Patients were randomized in a 1:1 ratio to receive either a starting dose of 5 mg of CAMZYOS or placebo once daily for 30 weeks. Treatment assignment was stratified by baseline NYHA functional class, baseline use of beta blockers, and type of ergometer (treadmill or exercise bicycle).
Groups were well matched with respect to age (mean 59 years), BMI (mean 30 kg/m
At baseline, approximately 73% of the randomized patients were NYHA class II and 27% were NYHA class III. The mean LVEF was 74%, and the mean Valsalva LVOT gradient was 73 mmHg. About 10% had prior septal reduction therapy, 75% were on beta blockers, 17% were on calcium channel blockers, and 14% had a history of atrial fibrillation.
All patients were initiated on CAMZYOS 5 mg (or matching placebo) once daily, and the dose was periodically adjusted to optimize patient response (decrease in LVOT gradient with Valsalva maneuver) and maintain LVEF ≥50%. The dose was also informed by plasma concentrations of CAMZYOS.
In the CAMZYOS group, at the end of treatment, 49% of patients were receiving the 5-mg dose, 33% were receiving the 10-mg dose, and 11% were receiving the 15-mg dose. Three patients temporarily interrupted their dose due to LVEF <50%, of whom two resumed treatment at the same dose and one had the dose reduced from 10 mg to 5 mg.
Primary endpoint
The primary composite functional endpoint, assessed at 30 weeks, was defined as the proportion of patients who achieved either improvement of peak oxygen consumption (pVO
A greater proportion of patients met the primary endpoint at Week 30 in the CAMZYOS group compared to the placebo group (37% vs. 17%, respectively, p=0.0005; see Table 2).
A range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. Results of the primary analysis consistently favored CAMZYOS across all subgroups analyzed (Figure 4).
Figure 4: Subgroup Analysis of the Primary Composite Functional Endpoint
The dashed vertical line represents the overall treatment effect and the solid vertical line (no effect) indicates no difference between treatment groups.
Although the benefit of mavacamten was smaller in patients on background beta blocker therapy compared to those who were not (attenuated improvement in pVO
Secondary endpoints
The treatment effects of CAMZYOS on LVOT obstruction, functional capacity, and health status were assessed by change from baseline through Week 30 in post-exercise LVOT peak gradient, change in pVO
Figure 5: Cumulative Distribution of Change from Baseline to Week 30 in LVOT Peak Gradient
Figure 6: Cumulative Distribution of Change from Baseline to Week 30 in pVO
Figure 7 shows the time course for changes in KCCQ-23 CSS. Figure 8 shows the distribution of changes from baseline to Week 30 for KCCQ-23 CSS.
Figure 7: KCCQ-23 Clinical Summary Score: Mean Change from Baseline Over Time
Figure 8: KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 30
Figure 9 shows the time course for changes in HCMSQ SoB. Figure 10 shows the distribution of changes from baseline to Week 30 for HCMSQ SoB.
Figure 9: HCMSQ Shortness of Breath Domain: Mean Change from Baseline Over Time
Figure 10: HCMSQ Shortness of Breath Domain: Cumulative Distribution of Change from Baseline to Week 30
VALOR-HCM
The efficacy of CAMZYOS was evaluated in VALOR-HCM, a Phase 3, double-blind, randomized, 16-week, placebo-controlled trial in 112 patients (mean age of 60 years; 51% men; 93% ≥NYHA class III) randomized 1:1 to receive treatment with CAMZYOS or placebo. At baseline, all patients had symptomatic obstructive HCM and were SRT eligible.
Patients with severely symptomatic drug-refractory obstructive HCM (including 33% on any combination of beta-blocker, calcium channel blocker and/or disopyramide; 20% were on disopyramide alone or in combination with other treatment), and NYHA class III/IV or class II with exertional syncope or near syncope, were included in the study. Patients were required to have LVOT peak gradient ≥50 mmHg at rest or with provocation, and LVEF ≥60%. Patients must have been referred or under active consideration within the past 12 months for SRT and actively considering scheduling the procedure.
Patients received CAMZYOS (2.5 mg, 5 mg, 10 mg, or 15 mg) or a placebo capsule once daily for 16 weeks. Dose adjustment was based on clinical echocardiogram parameters.
Primary endpoint
CAMZYOS was shown to be superior to placebo in reducing the proportion of patients who met the primary endpoint (the composite of patient decision to proceed with SRT prior to or at Week 16 or met SRT eligibility (LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) at Week 16 (18% vs. 77%, respectively, p<0.0001; see Table 5).
Secondary endpoints
The treatment effects of CAMZYOS on LVOT obstruction, functional capacity, and health status were assessed by change from baseline through Week 16 in post-exercise LVOT gradient, proportion of patients with improvement in NYHA class, and KCCQ-23 CSS.
Figure 11 shows the time course for changes in KCCQ-23 CSS. Figure 12 shows the distribution of changes from baseline to Week 16 for KCCQ-23 CSS.
Figure 11: KCCQ-23 Clinical Summary Score: Mean Change from Baseline Over Time
Figure 12: KCCQ-23 Clinical Summary Score: Cumulative Distribution of Change from Baseline to Week 16
The figure displays the cumulative percentage of patients achieving a certain level of response.
The figure displays the cumulative percentage of patients achieving a certain level of response.
8HOW SUPPLIED/STORAGE AND HANDLING
CAMZYOS
Storage
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F)
9PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Heart Failure
Inform patients that cardiac function monitoring must be performed using echocardiography to monitor for heart failure
Drug Interactions
Advise patients to inform their healthcare providers of all concomitant products, including over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine) and supplements, prior to and during CAMZYOS treatment.
CAMZYOS REMS Program
CAMZYOS is available only through a restricted program called the CAMZYOS REMS Program
- Patients must enroll in the program and comply with ongoing monitoring requirements
CAMZYOS is only prescribed by certified healthcare providers and only dispensed from certified pharmacies participating in the program. Provide patients with the telephone number and website for information on how to obtain the product
Embryo-Fetal Toxicity
Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy
Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose.
CHCs containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). 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 of CAMZYOS
Advise females who are exposed to CAMZYOS during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancies to Bristol-Myers Squibb at 1-800-721-5072 or www.bms.com.
Instructions for Taking CAMZYOS
CAMZYOS capsules should be swallowed whole. Advise patients that if they miss a dose of CAMZYOS, to take the dose as soon as possible that day and the next scheduled dose should be taken at the usual time the following day. The patient should not take two doses in the same day.
Marketed by:
CAMZYOS
10CAMZYOS 2.5 mg Label
NDC 73625-111-11
Rx only
CAMZYOS™
(mavacamten)
capsules
2.5 mg
Dispense the enclosed Medication Guide to each patient.
Recommended Dosage: See Prescribing Information
Keep out of reach of children.
Do not use if inner seal bottle is broken or missing.
30 Capsules
Bristol Myers Squibb
11CAMZYOS 5 mg Label
NDC 73625-112-11
Rx only
CAMZYOS™
(mavacamten)
capsules
5 mg
Dispense the enclosed Medication Guide to each patient.
Recommended Dosage: See Prescribing Information
Keep out of reach of children.
Do not use if inner seal bottle is broken or missing.
30 Capsules
Bristol Myers Squibb
12CAMZYOS 10 mg Label
NDC 73625-113-11
Rx only
CAMZYOS™
(mavacamten)
capsules
10 mg
Dispense the enclosed Medication Guide to each patient.
Recommended Dosage: See Prescribing Information
Keep out of reach of children.
Do not use if inner seal bottle is broken or missing.
30 Capsules
Bristol Myers Squibb
13CAMZYOS 15 mg Label
NDC 73625-114-11
Rx only
CAMZYOS™
(mavacamten)
capsules
15 mg
Dispense the enclosed Medication Guide to each patient.
Recommended Dosage: See Prescribing Information
Keep out of reach of children.
Do not use if inner seal bottle is broken or missing.
30 Capsules
Bristol Myers Squibb
