Drug Interactions between brexanolone and dextromethorphan / quinidine

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 CLOSELY: Coadministration with central nervous system (CNS) depressants (e.g., alcohol, benzodiazepines, opioids) or antidepressants may enhance the sedative effects of brexanolone and increase the likelihood or severity of sedation-related adverse reactions. Patients treated with brexanolone are at risk of excessive sedation or sudden loss of consciousness during administration. In clinical studies, 5% of patients receiving brexanolone infusion experienced sedation and somnolence that required dose interruption, compared to 0% of patients receiving placebo. Some patients also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% vs. 0%). All patients recovered from loss or altered state of consciousness after dose interruption, with full recovery time ranging from 15 to 60 minutes. There was no clear association between loss or alteration of consciousness and pattern or timing of dose. Not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode.

MANAGEMENT: Caution is advised during concomitant use of brexanolone with CNS depressants, antidepressants, or other agents that cause sedation. Patients should be closely monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. During the brexanolone infusion, monitor for sedative effects every 2 hours during planned, non-sleep periods, and immediately stop the infusion if there are signs or symptoms of excessive sedation. After symptoms resolve, the infusion may be resumed at the same or lower dose as clinically appropriate. If pulse oximetry reveals hypoxia, immediately stop the infusion and do not resume infusion following resolution of the hypoxia. Patients should be cautioned against driving, operating machinery, or engaging in potentially hazardous activities requiring mental alertness and motor coordination until sedative effects of brexanolone and other concomitant medications have dissipated. Patients must be accompanied during interactions with their child(ren) while receiving brexanolone because of the potential for excessive sedation and sudden loss of consciousness.