Drug Interaction Report

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.

GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

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

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of zuranolone. When administered with a low-fat meal (e.g., 400 to 500 calories, 25% fat), zuranolone peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.5- and 1.8-fold, respectively, compared to administration under fasted conditions. Zuranolone was administered with food in the premarketing study population. The efficacy of zuranolone when administered in the fasted state is unknown.

GENERALLY AVOID: Concomitant use of zuranolone with central nervous system (CNS) depressants, including alcohol, may potentiate adverse effects such as somnolence, confusion, dizziness, and gait disturbance.

MANAGEMENT: Zuranolone must be administered with fat-containing food (e.g., 400 to 1,000 calories, 25% to 50% fat) according to the manufacturer. Patients should also be advised to avoid or limit consumption of alcohol and to avoid activities requiring mental alertness such as driving or operating hazardous machinery until at least 12 hours after administration of zuranolone.