ZURANOLONE Drug Interactions: What You Need to Know

INTERACTIONS Table 4 displays clinically important drug interactions with ZURZUVAE.

Table

4 Clinically Important Drug Interactions with ZURZUVAE CNS Depressant Drugs and Alcohol Clinical Impact Due to additive pharmacological effects, the concomitant use of CNS depressant drugs, including alcohol, may increase impairment of psychomotor performance or CNS depressant effects. Management If use with another CNS depressant is unavoidable, consider dosage reduction. Caution should be used when ZURZUVAE is administered in combination with other CNS drugs or alcohol [see Warnings and Precautions ( 5.2 )] . Strong CYP3A4 Inhibitors Clinical Impact Concomitant use of ZURZUVAE with a strong CYP3A4 inhibitor increases the exposure of zuranolone [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of ZURZUVAE-associated adverse reactions.

Management

Reduce the ZURZUVAE dosage when used with a strong CYP3A4 inhibitor [see Dosage and Administration ( 2.3 )]. CYP3A4 Inducers Clinical Impact Concomitant use of ZURZUVAE with a CYP3A4 inducer decreases the exposure of zuranolone [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of ZURZUVAE.

Management

Avoid concomitant use of ZURZUVAE with CYP3A4 inducers [see Dosage and Administration ( 2.3 )].

Cns

Depressants: Concomitant use may increase impairment of psychomotor performance or CNS depressant effects. If use with another CNS depressant is unavoidable, consider dosage reduction. ( 7 ) Strong CYP3A4 Inhibitors: Concomitant use may increase the risk of ZURZUVAE-associated adverse reactions. Reduce the ZURZUVAE dosage to 30 mg orally once daily in the evening for 14 days when used concomitantly with a strong CYP3A4 inhibitor. ( 2.2 , 7 ) CYP3A4 Inducers: Concomitant use may decrease the efficacy of ZURZUVAE. Avoid concomitant use. ( 2.2 , 7 )

None. None. ( 4 )

AND PRECAUTIONS CNS Depressant Effects: ZURZUVAE can cause CNS depressant effects such as somnolence and confusion. If patients develop CNS depression, consider dosage reduction or discontinuation of ZURZUVAE. ( 5.2 )

Suicidal

Thoughts and Behavior: Consider changing the therapeutic regimen, including discontinuing ZURZUVAE, in patients whose PPD worsens, or who experience emergent suicidal thoughts and behaviors. ( 5.3 ) Embryo-fetal Toxicity: May cause fetal harm. Advise a pregnant woman of the potential risk to an infant exposed to ZURZUVAE in utero. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during ZURZUVAE treatment and for one week after the final dose. ( 5.4 , 8.1 , 8.2 , 8.3 )

5.1 Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities ZURZUVAE causes driving impairment due to central nervous system (CNS) depressant effects <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . In two driving simulation studies, the driving ability of healthy adults was impaired in a dose-dependent manner following repeat nighttime administration of 30 mg of ZURZUVAE (0.6 times the recommended dose) for five days as well as 50 mg of ZURZUVAE (recommended dose) for seven days <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . Advise patients not to drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness, such as operating machinery, until at least 12 hours after ZURZUVAE administration for the duration of the 14-day treatment course. Inform patients that they may not be able to assess their own driving competence or the degree of driving impairment caused by ZURZUVAE.

5.2 Central Nervous System Depressant Effects ZURZUVAE can cause CNS depressant effects such as somnolence and confusion.

In Study

1, 36% of patients who received 50 mg of ZURZUVAE and 6% of patients who received placebo daily developed somnolence.

In Study

2, 19% of patients who received another zuranolone capsule formulation (approximately equivalent to 40 mg of ZURZUVAE) and 11% of patients who received placebo daily developed somnolence [see Clinical Studies ( 14 )]. In each clinical study, some ZURZUVAE-treated patients developed confusional state. One of these cases was severe, and was also associated with somnolence, dizziness, and gait disturbance. A higher percentage of ZURZUVAE-treated patients, compared to placebo-treated patients, experienced somnolence, dizziness, or confusion that required dosage reduction, interruption, or discontinuation [see Adverse Reactions ( 6.1 )] . Because ZURZUVAE can cause CNS depressant effects, patients may be at higher risk of falls. Other CNS depressants such as alcohol, benzodiazepines, opioids, tricyclic antidepressants, or drugs that increase zuranolone concentration, may increase impairment of psychomotor performance or CNS depressant effects such as somnolence, cognitive impairment, and the risk of respiratory depression in ZURZUVAE-treated patients [see Drug Interactions ( 7 )] . To reduce the risk of CNS depressant effects and/or mitigate CNS depressant effects that occurs with ZURZUVAE treatment: If patients develop CNS depressant effects, consider dosage reduction or discontinuation of ZURZUVAE [see Dosage and Administration ( 2.1 )] . If use with another CNS depressant is unavoidable, consider dosage reduction. Reduce the ZURZUVAE dosage in patients taking strong CYP3A4 inhibitors [see Dosage and Administration ( 2.2 )] .

5.3 Suicidal Thoughts and Behavior In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with major depressive disorder (MDD). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 .

Table

1 Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric * and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated * ZURZUVAE is not approved in pediatric patients.

Increases

Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ZURZUVAE does not directly affect monoaminergic systems. Consider changing the therapeutic regimen, including discontinuing ZURZUVAE, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

5.4 Embryo-fetal Toxicity Based on findings from animal studies, ZURZUVAE may cause fetal harm when administered to a pregnant woman. In rat studies following exposure during gestation or throughout gestation and lactation, adverse effects on development (fetal malformations, embryofetal and offspring mortality, growth deficits) were observed. In addition, neuronal death was observed in rats exposed to zuranolone during a period of brain development that in humans begins during the third trimester of pregnancy and continues during the first few years after birth <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.2 )]</span>. Advise a pregnant woman of the potential risk to an infant exposed to ZURZUVAE in utero. Advise females of reproductive potential to use effective contraception during treatment with ZURZUVAE and for one week after the final dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.