Zurzuvae Drug Information

is indicated for the treatment of postpartum depression (PPD) in adults. ZURZUVAE is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adults.

Recommended Dosage

The recommended dosage of ZURZUVAE is 50 mg taken orally once daily in the evening for 14 days. Administer ZURZUVAE with fat-containing food (e.g., 400 to 1,000 calories, 25% to 50% fat) . If patients experience CNS depressant effects within the 14-day period, consider reducing the dosage to 40 mg once daily in the evening within the 14-day period. ZURZUVAE can be used alone or as an adjunct to oral antidepressant therapy.

The safety and effectiveness of ZURZUVAE use beyond 14 days in a single treatment course have not been established.

Dosage Modifications for

Concomitant Use with CYP3A4 Inducers or CYP3A4 Inhibitors CYP3A4 Inducers Avoid concomitant use of ZURZUVAE with CYP3A4 inducers. CYP3A4 Inhibitors Reduce the ZURZUVAE dosage to 30 mg orally once daily in the evening for 14 days when used concomitantly with a strong CYP3A4 inhibitor. No dosage modification is recommended when ZURZUVAE is concomitantly used with a moderate CYP3A4 inhibitor.

Recommended Dosage in Patients with Hepatic Impairment

The recommended dosage of ZURZUVAE in patients with severe hepatic impairment (Child-Pugh C) is 30 mg orally once daily in the evening for 14 days. The recommended dosage in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment is the same as those in patients with normal hepatic function.

Recommended Dosage in Patients with Renal Impairment

The recommended dosage of ZURZUVAE in patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m 2 ) is 30 mg orally once daily in the evening for 14 days. The recommended dosage in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m 2 ) is the same as those in patients with normal renal function.

Recommendations Regarding a Missed Dose

If a ZURZUVAE evening dose is missed, take the next dose at the regular time the following evening. Do not take extra capsules on the same day to make up for the missed dose. Continue taking ZURZUVAE once daily until the remainder of the 14-day treatment course is completed.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ZURZUVAE for the treatment of postpartum depression (PPD) was evaluated in two placebo-controlled clinical studies in 347 women with PPD treated with 50 mg of ZURZUVAE (Study 1), or with another zuranolone capsule formulation approximately equivalent to 40 mg of ZURZUVAE (Study 2) once daily for 14 days. The studies included adult patients 18 to 44 years of age diagnosed with PPD. Across PPD clinical studies at all doses studied (Studies 1 and 2), serious adverse reactions included confusional state (1%). In Study 1, the incidence of adverse reactions that led to discontinuation in patients treated with 50 mg of ZURZUVAE and placebo was 2% and 1%, respectively.

The most common adverse reaction leading to treatment discontinuation in ZURZUVAE-treated patients was somnolence. Dosage reduction due to an adverse reaction occurred in 16% of ZURZUVAE-treated patients. The most common adverse reactions leading to dosage reduction in ZURZUVAE-treated patients were somnolence (10%) and dizziness (6%). The most common adverse reactions (≥5% and greater than placebo) in ZURZUVAE-treated patients were somnolence, dizziness, diarrhea, fatigue, and urinary tract infection.

Table 2 summarizes the adverse reactions that occurred in ≥2% of patients with PPD treated with 50 mg of ZURZUVAE and at a higher incidence than in patients who received placebo in Study 1. Table 2. Adverse Reactions that Occurred in ≥2% of Patients with PPD Treated with 50 mg of ZURZUVAE and Greater than in Patients Treated with Placebo (Study 1) Adverse Reaction Placebo (N=98) (%) 50 mg of ZURZUVAE (N=98) (%) 1 Somnolence includes sedation and hypersomnia 2 Dizziness includes vertigo 3 Fatigue includes asthenia 4 Abdominal pain includes upper abdominal pain Somnolence 1 6 36 Dizziness 2 9 13 Diarrhea 2 6 Fatigue 3 2 5 Urinary tract infection 4 5 Memory impairment 0 3 Abdominal pain 4 0 3 Tremor 0 2 Hypoesthesia 0 2 Muscle twitching 0 2 Myalgia 0 2 COVID-19 0 2 Anxiety 1 2 Rash 1 2 In Study 2, the incidence of adverse reactions that led to discontinuation in patients who received another zuranolone capsule formulation (approximately equivalent to 40 mg of ZURZUVAE) and placebo was 1% and 0%, respectively. The adverse reaction that led to treatment discontinuation was somnolence. Dosage reduction due to an adverse reaction occurred in 4% of zuranolone-treated patients.

The adverse reactions that led to dosage reduction were somnolence and confusional state. The most common (≥5% and greater than placebo) adverse reactions in zuranolone-treated patients were somnolence, nasopharyngitis, dizziness, fatigue, and diarrhea. Table 3 summarizes the adverse reactions that occurred in ≥2% of zuranolone-treated patients with PPD and at a higher incidence than in placebo-treated patients in Study 2. Table 3. Adverse Reactions that Occurred in ≥2% of Patients with PPD Treated with Another Zuranolone Capsule Formulation * and Greater than in Patients Treated with Placebo (Study 2) Adverse Reaction Placebo (N=73) (%) Another Zuranolone Capsule Formulation * (N=78) (%) 1 Somnolence includes sedation 2 Nasopharyngitis includes upper respiratory tract infection 3 Fatigue includes lethargy * This capsule formulation of zuranolone is approximately equivalent to 40 mg of ZURZUVAE. Somnolence 1 11 19 Nasopharyngitis 2 3 9 Dizziness 6 8 Fatigue 3 1 5 Diarrhea 3 5 Dry mouth 0 4 Sinus congestion 0 3 Toothache 0 3

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 . Strong CYP3A4 Inhibitors Clinical Impact Concomitant use of ZURZUVAE with a strong CYP3A4 inhibitor increases the exposure of zuranolone , which may increase the risk of ZURZUVAE-associated adverse reactions.

Management Reduce the ZURZUVAE dosage when used with a strong CYP3A4 inhibitor. CYP3A4 Inducers Clinical Impact Concomitant use of ZURZUVAE with a CYP3A4 inducer decreases the exposure of zuranolone , which may reduce the efficacy of ZURZUVAE. Management Avoid concomitant use of ZURZUVAE with CYP3A4 inducers. 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. 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.

CYP3A4 Inducers: Concomitant use may decrease the efficacy of ZURZUVAE. Avoid concomitant use.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including ZURZUVAE, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ Risk Summary Based on findings from animal studies, ZURZUVAE may cause fetal harm. Advise pregnant women of the potential risk to a fetus.

Available data on ZURZUVAE use in pregnant women from the clinical development program are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animals, oral administration of zuranolone to pregnant rats during organogenesis resulted in developmental toxicity, including embryofetal death and fetal malformations, with a no observed adverse effect level (NOAEL) associated with maternal plasma exposures 7 times greater than in humans at the maximum recommended human dose (MRHD) of 50 mg. Oral administration of zuranolone to pregnant mice resulted in developmental toxicity, including decreased fetal body weight, reduced skeletal ossification, and fetal malformations with a NOAEL associated with a maternal plasma exposure similar to that in humans at the MRHD. Oral administration of zuranolone to rats during pregnancy and lactation resulted in developmental toxicity in the offspring, including, perinatal mortality, at maternal exposures similar to that in humans at the MRHD. Developmental toxicity was observed at doses that were also maternally toxic.

Neuronal death was observed in rats exposed to zuranolone during a period of brain development that begins during the third trimester of pregnancy in humans and continues up to a few years after birth. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Oral administration of zuranolone (0, 2.5, 7.5, or 22.5 mg/kg/day) to pregnant rats during organogenesis resulted in increased incidences of fetal malformations, reductions in embryofetal survival, and reduced fetal body weights as well as maternal mortality and sedation at the highest dose. The no effect dose (7.5 mg/kg/day) for adverse effects on embryofetal development was associated with maternal exposures (AUC) approximately 7 times that in humans at the MRHD of 50 mg.

Oral administration of zuranolone (0, 30, 100, or 300 mg/kg/day) to pregnant mice during organogenesis resulted in maternal dose-dependent sedation which was severe at 300 mg/kg/day. Adverse reduced body weight in the pregnant dams occurred at 300 mg/kg/day, which was associated with incomplete or no skeletal ossification in the pups. There was an increased incidence of malformations (e.g., cleft palate) at 100 mg/kg/day (4 times the AUC exposure at the MRHD). The NOAEL for embryofetal development was 30 mg/kg/day with maternal exposures (AUC) approximately 1.5 times that in humans at the MRHD. Oral administration of zuranolone (0, 1, 4, or 10 mg/kg/day) to rats throughout pregnancy and into lactation resulted in increased perinatal mortality and persistent bodyweight reductions in the offspring at the mid and high doses, which also produced maternal mortality and adverse clinical signs.

The no-effect dose (1 mg/kg/day) for adverse effects on pre- and postnatal development in rats was associated with maternal exposures (AUC) approximately 2 times that in the humans at the MRHD. Oral administration of a single dose of zuranolone (0, 2.5, or 7.5 mg/kg) to rats on postnatal Day 7 resulted in increased apoptotic neurodegeneration in the brain at the highest dose tested. The no-effect dose (2.5 mg/kg) was associated with plasma exposures (AUC) comparable to that in humans at the MRHD. Brain development on PND 7 in rats corresponds to a period of brain development that begins during the third trimester of pregnancy in humans and continue up to a few years after birth.

Pediatric Use The safety and effectiveness of ZURZUVAE in pediatric patients have not been established.

There was a case of intentional overdose with ZURZUVAE reported during premarketing clinical trials. The patient took 330 mg (6.5 times the maximum recommended dose) of ZURZUVAE and was reported to be in an altered state of consciousness. The event resolved the next day, following treatment with intravenous fluids.

Overdosage with ZURZUVAE may result in excessive CNS depressant effects such as somnolence and disturbance in consciousness. There is no specific antidote for ZURZUVAE overdosage. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.