ZURZUVAE

1 INDICATIONS AND USAGE ZURZUVAE 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer with fat-containing food. ( 2.1 ) Recommended dosage is 50 mg orally once daily in the evening for 14 days. ( 2.1 ) Dosage may be reduced to 40 mg once daily if CNS depressant effects occur. ( 2.1 ) ZURZUVAE can be used alone or as an adjunct to oral antidepressant therapy. ( 2.1 ) Severe Hepatic Impairment: Recommended dosage is 30 mg orally once daily in the evening for 14 days. ( 2.3 , 8.6 ) Moderate or Severe Renal Impairment: Recommended dosage is 30 mg orally once daily in the evening for 14 days. ( 2.4 , 8.7 ) 2.1 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) [see Clinical Pharmacology ( 12.3 )] . 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. 2.2 Dosage Modifications for Concomitant Use with CYP3A4 Inducers or CYP3A4 Inhibitors CYP3A4 Inducers Avoid concomitant use of ZURZUVAE with CYP3A4 inducers [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]. 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 [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]. No dosage modification is recommended when ZURZUVAE is concomitantly used with a moderate CYP3A4 inhibitor. 2.3 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 [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. 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. 2.4 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 [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]. 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. 2.5 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.

3 DOSAGE FORMS AND STRENGTHS Capsules: 20 mg: light-orange cap, ivory to light-yellow body, printed with “S-217 20mg” on body of capsule in black 25 mg: light-orange cap, light-orange body, printed with “S-217 25mg” on body of capsule in black 30 mg: orange cap, light-orange body, printed with “S-217 30mg” on body of capsule in black Capsules: 20 mg, 25 mg, and 30 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities [see Warnings and Precautions ( 5.1 )] Central Nervous System Depressant Effects [see Warnings and Precautions ( 5.2 )] Suicidal Thoughts and Behavior [see Warnings and Precautions ( 5.3 )] Most common adverse reactions (incidence ≥5% and greater than placebo) were somnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-844-987-9882 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies ( 14.1 )]. 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%) [see Clinical Studies ( 14.1 )]. 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 Trea …

7 DRUG 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 )

8 USE IN SPECIFIC POPULATIONS 8.1 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 …

12.1 Mechanism of Action The mechanism of action of zuranolone in the treatment of PPD is not fully understood but is thought to be related to its positive allosteric modulation of GABA A receptors.

11 DESCRIPTION ZURZUVAE contains zuranolone, a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator. The chemical name is 1-[(3α, 5β)-3-hydroxy-3-methyl-20- oxo-19-norpregnan-21-yl]-1H-pyrazole-4-carbonitrile and it has the following chemical structure: The molecular formula of zuranolone is C 25 H 35 N 3 O 2 and the relative molecular mass is 409.57 Da. Zuranolone is a white to off-white, non-hygroscopic, crystalline solid. It is sparingly soluble in ethyl acetate, methanol, and ethanol; slightly soluble in methyl tert -butyl ether and isopropanol; soluble in tetrahydrofuran and acetone; and practically insoluble in water and n -heptane. ZURZUVAE is available in 20 mg, 25 mg, and 30 mg capsules for oral administration. Each capsule contains zuranolone as the active ingredient and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The capsule shells contain gelatin, red iron oxide, titanium dioxide, and yellow iron oxide, and are imprinted with black ink (containing ammonium hydroxide, black iron oxide, propylene glycol, and shellac glaze). Chemical Structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ZURZUVAE (zuranolone) is supplied as 20 mg, 25 mg, and 30 mg capsules as follows: Capsule Strength Capsule Colors Capsule Markings Packaging Configuration NDC 20 mg light-orange cap ivory to light-yellow body Black “S-217 20mg” on body Bottle of 14 64406-029-01 25 mg light-orange cap light-orange body Black “S-217 25mg” on body Bottle of 14 64406-030-01 Blister pack of 28 64406-030-02 30 mg orange cap light-orange body Black “S-217 30mg” on body Bottle of 14 64406-031-01 Storage Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].