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.

Pralidoxime and other drugs within the family of compounds called oximes, such as obidoxime, may potentiate the pharmacologic effects of atropine. Signs of atropinization such as flushing, mydriasis, tachycardia, and dry mouth and nose may occur earlier than expected during coadministration with pralidoxime relative to administration of atropine alone, particularly if the total dose of atropine has been large and the administration of pralidoxime was delayed. Clinicians should be aware of the potential interaction and monitor patients as appropriate. Pralidoxime may be used in conjunction with atropine in the treatment of organophosphate insecticide poisoning and nerve agent poisoning in terrorism or chemical warfare.

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.

GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.