Mavacamten interactions with other
medicinal products¹

Pharmacodynamic interactions¹

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.

Pharmacokinetic interactions¹

Effect of other medicinal products on mavacamten

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. 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.

Strong CYP2C19 plus strong CYP3A4 inhibitors

Co-administration of mavacamten with the combination of a strong CYP2C19 and a strong CYP3A4 inhibitor is contraindicated.

CYP2C19 inhibitors

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.

Co-administration of mavacamten with a weak CYP2C19 inhibitor (omeprazole) resulted in a 48% increase in mavacamten AUC_inf  with no effect on C_max in CYP2C19 normal metabolisers.

Intermittent administration of a CYP2C19 inhibitor (such as omeprazole or esomeprazole) is not recommended.

CYP3A4 inhibitors

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 AUC_0-24 and C_max,  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 AUC_inf and C_max,  respectively. This change was not considered clinically significant.

CYP2C19 and CYP3A4 inducers

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 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.

Effect of mavacamten on other medicinal products

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.