Drug Interactions between Nuedexta and zuranolone

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.

GENERALLY AVOID: Coadministration with central nervous system (CNS) depressants (e.g., alcohol, benzodiazepines, opioids) or antidepressants may enhance the sedative effect of zuranolone and increase the likelihood or severity of sedation-related adverse reactions. Zuranolone may cause CNS depressant effects such as somnolence, confusion, dizziness, and gait disturbance. In clinical trials, somnolence, dizziness, or confusion were reported at a higher percentage in patients treated with zuranolone compared to placebo which required a dosage reduction of zuranolone, treatment interruption, or cessation. One clinical study reported somnolence in 36% of patients treated with 50 mg zuranolone compared to 6% of patients treated with placebo.

MANAGEMENT: Concomitant use of zuranolone with CNS depressants should generally be avoided. Caution and close monitoring of CNS depressant effects is recommended if concomitant use of zuranolone with CNS depressants, antidepressants, or other agents that can cause sedation is required. If coadministration with another CNS depressant is considered unavoidable or if the patient experiences CNS depressant adverse effects within the 14 days treatment course, a dose reduction to 40 mg once daily for the remainder of the course is recommended. Patients should also be cautioned against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until at least 12 hours after administration of zuranolone.