Drug Interaction Report

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.

GENERALLY AVOID: Use of milnacipran in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Milnacipran alone can increase serum transaminase levels. In placebo-controlled fibromyalgia trials, increases in ALT were more frequently observed in patients treated with milnacipran 100 mg/day (6%) and 200 mg/day (7%) compared to patients treated with placebo (3%). One patient receiving milnacipran 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal (ULN) but did not exceed 10 times the ULN. Increases in AST were also more frequently observed in patients treated with milnacipran 100 mg/day (3%) and 200 mg/day (5%) than in patients treated with placebo (2%). There have been reported cases of increased liver enzymes and severe liver injury, including fulminant hepatitis, from foreign postmarketing experience with milnacipran. Significant underlying clinical conditions and/or use of multiple concomitant medications were present in the cases of severe liver injury.

MANAGEMENT: Due to the risk of liver injury, patients prescribed milnacipran should be counseled to avoid excessive use of alcohol. Milnacipran should generally not be prescribed to patients with substantial alcohol use.