Drug Interactions between mavacamten and Nuedexta

GENERALLY AVOID: Coadministration with potent CYP450 2D6 inhibitors (e.g., quinidine, terbinafine) may significantly increase the plasma concentrations of dextromethorphan in patients who are extensive metabolizers of this isoenzyme (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). The proposed mechanism is inhibition of the CYP450 2D6-mediated O-demethylation of dextromethorphan. Studies in humans have shown an increase in systemic exposure of dextromethorphan of up to 43-fold when given concurrently with quinidine. Increased plasma concentrations increase the risk of dextromethorphan-related adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome. However, this interaction has also been used clinically, with dextromethorphan in combination with quinidine indicated by some authorities for the treatment of pseudobulbar affect. Data evaluating the impact of this interaction in patients who are poor metabolizers of CYP450 2D6 are limited; most studies include extensive metabolizers of this isoenzyme. It is expected that poor metabolizers would have elevated dextromethorphan levels without concurrent quinidine

MANAGEMENT: The combination of dextromethorphan with potent CYP450 2D6 inhibitors should be generally avoided. Some manufacturers consider the concomitant use of dextromethorphan and selective serotonin reuptake inhibitors contraindicated. If use is considered necessary, the patient should be monitored for signs of dextromethorphan adverse effects (e.g., agitation, confusion, tremor, insomnia, diarrhea, and respiratory depression) and serotonin syndrome, and advised to notify their health care professional if these adverse effects develop or worsen. Dose reduction of dextromethorphan may also be required.

MONITOR: Coadministration with mavacamten may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4, 2C9, and/or 2C19. The proposed mechanism is accelerated clearance due to induction of these isoenzymes by mavacamten. The interaction may be particularly important for sensitive substrates or those that demonstrate a narrow therapeutic index. When midazolam, a probe substrate for CYP450 3A4, was coadministered with a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) in healthy CYP450 2C19 normal metabolizers, midazolam peak plasma concentration (Cmax) decreased by 7% and systemic exposure (AUC) decreased by 13%. Following coadministration of mavacamten once daily in patients with obstructive hypertrophic cardiomyopathy (HCM), midazolam Cmax and AUC are predicted to decrease by 13% to 48% and 21% to 64%, respectively, depending on the dose of mavacamten and CYP450 2C19 phenotype. Additionally, concomitant use of mavacamten once daily in HCM patients is predicted to decrease the Cmax and AUC of repaglinide, a CYP450 2C8 and 3A4 substrate, by 12% to 39%; the Cmax and AUC of tolbutamide, a CYP450 2C9 substrate, by 33% to 65%; and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, by 48% to 67%, depending on the dose of mavacamten and CYP450 2C19 phenotype.

MANAGEMENT: Caution is advised when mavacamten is used concomitantly with drugs that are substrates of CYP450 3A4, 2C9 and/or 2C19, particularly sensitive substrates or those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mavacamten is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a CYP450 inducer like mavacamten and for any dosage adjustments that may be required.