Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Mavacamten reduces LVEF and may cause heart failure due to systolic dysfunction defined as symptomatic LVEF <50%. Patients with a serious intercurrent illness such as infection or arrhythmia (including atrial fibrillation or other uncontrolled tachyarrhythmia), or those undergoing major cardiac surgery may be at greater risk of systolic dysfunction and progress to heart failure (see section 4.8). New or worsening dyspnoea, chest pain, fatigue, palpitations, leg oedema or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of systolic dysfunction and should prompt an evaluation of cardiac function. LVEF should be measured prior to initiating treatment and closely monitored thereafter. Treatment interruption may be necessary to ensure that LVEF remains ≥50% (see section 4.2).
Mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4 and mostly by CYP3A4 in CYP2C19 poor metabolisers, which may lead to the following interactions (see section 4.5):
Prior to and during mavacamten treatment, the potential for interactions, including over the counter medicinal products (such as omeprazole or esomeprazole), should be considered.
The safety of concomitant use of mavacamten with disopyramide, or use of mavacamten in patients taking beta blockers in combination with verapamil or diltiazem has not been established. Therefore, patients should be closely monitored when taking these concomitant medicinal products (see section 4.5).
Based on animal studies, mavacamten is suspected to cause embryo-foetal toxicity when administered to a pregnant woman (see section 5.3). Due to risk to the foetus, CAMZYOS is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for 6 months after treatment discontinuation (see sections 4.3 and 4.6).
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
If treatment with a new negative inotrope is initiated or if the dose of a negative inotrope is increased in a patient receiving mavacamten, close medical supervision with monitoring of LVEF should be provided until stable doses and clinical response have been achieved (see section 4.2 and 4.4).
In CYP2C19 intermediate, normal, rapid and ultra-rapid metabolisers, mavacamten is primarily metabolised by CYP2C19 and to a lesser extent by CYP3A4. In CYP2C19 poor metabolisers, metabolism is mostly by CYP3A4 (see section 5.2). CYP2C19 inhibitors/inducers and CYP3A4 inhibitors/inducers may thus affect the clearance of mavacamten and increase/decrease mavacamten plasma concentration, and this will depend on the CYP2C19 phenotype.
All clinical drug-drug interaction studies mainly enrolled CYP2C19 normal metabolisers and no CYP2C19 poor metabolisers were included in the assessment of the drug-drug interaction and therefore the effect of co-administration of CYP2C19 and CYP3A4 inhibitors with mavacamten in CYP2C19 poor metabolisers is not completely certain.
Recommendations for dose modification and/or additional monitoring of patients initiating or discontinuing treatment with, or changing the dose of, concomitant medicinal products that are inhibitors of CYP2C19 or CYP3A4 or inducers of CYP2C19 or CYP3A4 are provided in table 2.
Co-administration of mavacamten with the combination of a strong CYP2C19 and a strong CYP3A4 inhibitor is contra-indicated (see section 4.3).
The effect of a moderate and strong CYP2C19 inhibitor on the PK of mavacamten was not investigated in a clinical drug-drug interaction study. The effect of a strong CYP2C19 inhibitor (e.g., ticlopidine) will be similar to the effect of the CYP2C19 poor metabolising status (see table 1). Co-administration of mavacamten with a weak CYP2C19 inhibitor (omeprazole) resulted in a 48% increase in mavacamten AUCinf with no effect on Cmax in CYP2C19 normal metabolisers. Intermittent administration of a CYP2C19 inhibitor (such as omeprazole or esomeprazole) is not recommended (see section 4.4).
Co-administration of mavacamten with a strong CYP3A4 inhibitor (itraconazole) in CYP2C19 normal metabolisers resulted in an increase in mavacamten plasma concentration of up to 59% and 40% in AUC0-24 and Cmax, respectively. Co-administration of mavacamten with a moderate CYP3A4 inhibitor (verapamil) in CYP2C19 normal metabolisers resulted in an increase in mavacamten plasma concentration of 16% and 52% in AUCinf and Cmax, respectively. This change was not considered clinically significant.
No clinical interaction studies were conducted to investigate the effect of concomitant administration with a strong CYP3A4 and CYP2C19 inducer. Co-administration of mavacamten with a strong inducer of both CYP2C19 and CYP3A4 (e.g., rifampicin) is expected to significantly affect the pharmacokinetics (PK) of mavacamten and leads to reduced efficacy and therefore co-administration with strong inducers of both CYP2C19 and CYP3A4 is not recommended. If discontinuing concomitant treatment with a strong inducer of CYP2C19 or CYP3A4 increase clinical assessments and mavacamten dose should be reduced (see section 4.2).
Table 2. Dose modification/monitoring of mavacamten with concomitant medicinal products:
| Concomitant medicinal product | CYP2C19 poor metaboliser phenotype* | CYP2C19 intermediate, normal, rapid and ultra-rapid metaboliser phenotype |
|---|---|---|
| Inhibitors | ||
| Combined use of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor | Contra-indicated (see section 4.3) | Contra-indicated (see section 4.3) |
| Strong CYP2C19 inhibitor (e.g., ticlopidine, fluconazole, fluvoxamine) | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). If CYP2C19 phenotype has not yet been determined: No adjustment of the starting dose of 2.5 mg is needed. The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). | Initiate mavacamten at a dose of 2.5 mg. The dose should be reduced from 15 mg to 5 mg and from 10 mg and 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). |
| Strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole, ketoconazole, voriconazole, ritonavir, cobicistat, ceritinib, idelalisib, tucatinib) | Contra-indicated (see section 4.3). | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). |
| Moderate CYP2C19 inhibitor (e.g., fluconazole, fluoxetine, omeprazolea) | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). If CYP2C19 phenotype has not yet been determined: No adjustment of the starting dose of 2.5 mg is needed. The dose should be reduced from 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). | No adjustment of the starting dose of 5 mg is needed. Initiating or increasing the dose of a moderate inhibitor while on mavacamten treatment: Dose should be reduced by one dose level or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). |
| Moderate CYP3A4 inhibitor (e.g., erythromycin, grapefruit juice, verapamil, diltiazem) | If on medication when starting mavacamten, no adjustment of the starting dose of 2.5 mg is needed. Initiating or increasing the dose of a moderate inhibitor while on mavacamten treatment: If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). |
| Weak CYP2C19 inhibitor (e.g., cimetidine, citalopram, omeprazolea, esomeprazole) | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). | Initiating or increasing the dose of a weak inhibitor while on mavacamten treatment: Monitor LVEF 4 weeks later, and subsequently resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). |
| Weak CYP3A4 inhibitor (e.g., cimetidine, esomeprazole, omeprazole, pantoprazole) | If on medication when starting mavacamten, no adjustment of the starting dose of 2.5 mg is needed. Initiating or increasing the dose of weak inhibitor while on mavacamten treatment: If patients are receiving a 5 mg dose of mavacamten, their dose should be reduced to 2.5 mg or if on 2.5 mg pause treatment for 4 weeks. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). | Initiating or increasing the dose of a weak inhibitor while on mavacamten treatment: No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). |
| Inducers | ||
| Strong CYP2C19 inducer and strong CYP3A4 inducer (e.g., rifampicin, apalutamide, enzalutamide, mitotane, phenytoin, carbamazepine, efavirenz, St. John’s wort) | Initiating or increasing the dose of strong inducer while on mavacamten treatment: Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient’s monitoring and titration schedule (see section 4.2). The maximum dose is 5 mg. Discontinuing or decreasing the dose of strong inducer while on mavacamten treatment: Decrease mavacamten dose from 5 mg to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). | Initiating or increasing the dose of strong inducer while on mavacamten treatment: Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient’s monitoring and titration schedule (see section 4.2). Discontinuing or decreasing the dose of strong inducer while on mavacamten treatment: Decrease mavacamten by one dose level when on doses 5 mg or higher. Maintain mavacamten dose when on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). |
| Moderate or weak CYP2C19 inducer (e.g., letermovir, norethindrone, prednisone) | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). | Initiating the dose of moderate or weak inducer while on mavacamten treatment: Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient’s monitoring and titration schedule (see section 4.2). Discontinuing a moderate or weak inducer while on mavacamten treatment: Decrease mavacamten by one dose level when on doses 5 mg or higher. Maintain mavacamten dose when on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). |
| Moderate or weak CYP3A4 inducer (e.g., phenobarbital, primidone) | Initiating or increasing the dose of moderate or weak inducer while on mavacamten treatment: Monitor LVOT gradient and LVEF 4 weeks later. Adjust mavacamten dose based on clinical assessment and then resume the patient’s monitoring and titration schedule (see section 4.2). Discontinuing or decreasing the dose of moderate or weak inducer while on mavacamten treatment: Decrease mavacamten dose to 2.5 mg or pause treatment if on 2.5 mg. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule (see section 4.2). | No dose adjustment. Monitor LVEF 4 weeks later, and then resume the patient’s monitoring and titration schedule. Adjust mavacamten dose based on clinical assessment (see section 4.2). |
* Includes patients for whom the CYP2C19 phenotype has not yet been determined. a Omeprazole is considered a weak CYP2C19 inhibitor at a dose of 20 mg once daily and a moderate CYP2C19 inhibitor at a total daily dose of 40 mg.
Mavacamten in vitro data suggest a potential induction of CYP3A4 substrates. Co-administration of a 17-day course of mavacamten at clinical relevant exposures in CYP2C19 normal, rapid and ultra-rapid metabolisers did not decrease the exposure to ethinyl oestradiol and norethindrone, which are the components of typical oral contraceptives and substrates for CYP3A4. Furthermore, co-administration of a 16-day course of mavacamten in CYP2C19 normal metabolisers, at clinical relevant exposures, resulted in a 13% decrease in midazolam plasma concentration. This change was not considered clinically significant.
CAMZYOS is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for 6 months after discontinuation of CAMZYOS, since it takes approximately 5 half-lives (approximately 45 days for CYP2C19 normal metabolisers and 115 days for CYP2C19 poor metabolisers) to eliminate mavacamten from the body after treatment discontinuation (see sections 4.4 and 5.2).
When stopping mavacamten therapy for planning a pregnancy the possible return of LVOT obstruction and symptom burden should be considered (see section 4.4).
There are no data from the use of mavacamten in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Mavacamten is suspected to cause embryo-foetal toxicity when administered during pregnancy. Therefore, CAMZYOS is contraindicated during pregnancy (see section 4.3). CAMZYOS should be stopped 6 months before planning a pregnancy (see section 4.4). If a patient becomes pregnant, mavacamten must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed.
It is unknown whether mavacamten or its metabolites are excreted in human milk. There is no information on the excretion of mavacamten or its metabolites in animal milk (see section 5.3). Because of the unknown adverse effects of mavacamten in breastfed newborns/infants, women must not breast-feed during treatment with mavacamten.
No human fertility data on mavacamten are available. Studies in animals are insufficient with respect to male or female fertility (see section 5.3).
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 or use machines if they experience dizziness.
The most commonly reported adverse reactions with mavacamten are dizziness (17%), dyspnoea (12%), systolic dysfunction (5%) and syncope (5%).
Adverse reactions reported in patients treated with mavacamten in two phase 3 studies are tabulated below. A total of 179 patients received a daily dose of either 2.5 mg, 5 mg, 10 mg or 15 mg of mavacamten. The median treatment duration for patients receiving mavacamten was 30.1 weeks (range: 1.6 to 40.3 weeks).
The adverse reactions included in table 3 are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions are presented in order of decreasing frequency and seriousness. In addition, the corresponding frequency category for each adverse reaction is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).
Table 3. Adverse reactions:
| System organ class | Adverse reaction | Frequency |
|---|---|---|
| Nervous system disorders | Dizziness | Very common |
| Syncope | Common | |
| Cardiac disorders | Systolic dysfunctiona | Common |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | Very common |
a Defined as LVEF <50% with or without symptoms.
In Phase 3 clinical studies, 5% (9/179) of patients in the mavacamten group experienced reversible reductions in LVEF <50% (median 45%: range: 35-49%) while on treatment. In 56% (5/9) of these patients, reductions were observed without other clinical manifestations. In all patients treated with mavacamten, LVEF recovered following interruption of mavacamten and they completed the study on treatment (see section 4.4).
In Phase 3 clinical studies, dyspnoea was reported in 12.3% of patients treated with mavacamten compared to 8.7% of patients on placebo. In the EXPLORER-HCM study, most (67%) of the dyspnoea events were reported after mavacamten was discontinued, with median time to onset of 2 weeks (range: 0.1-4.9) after last dose.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
