These Highlights Do Not Include All The Information Needed To Use Zurzuvae Safely And Effectively. See Full Prescribing Information For Zurzuvae.

CYP3A4 Inducers

Avoid concomitant use of ZURZUVAE with CYP3A4 inducers [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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].

PRINCIPAL DISPLAY PANEL - 30 mg Bottle Carton

NDC 64406-031-01

Rx Only

ZURZUVAE™

CIV

(zuranolone) capsules

30 mg

For oral use

Attention: Dispense

with accompanying

Medication Guide.

14 Capsules

Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with ZURZUVAE.

In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of ZURZUVAE (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, nondependent individuals with a history of recreational CNS depressant use. The study demonstrated that ZURZUVAE has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures of “drug liking,” “overall drug liking,” “take drug again,” “high,” and “good drug effects.” In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with ZURZUVAE use.

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.

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 C₂₅H₃₅N₃O₂ and the relative molecular mass is 409.57.

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).

ZURZUVAE may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7^th day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence with zuranolone. These adverse reactions were mild-to-moderate in severity.

The risk for developing physical dependence and a subsequent withdrawal syndrome upon abrupt ZURZUVAE discontinuation for individuals who take a higher than recommended dosage and/or use ZURZUVAE for a longer duration than recommended [see Dosage and Administration (2.1)] has not been evaluated in clinical studies. However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose [see Nonclinical Toxicology (13.2)].

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

PPD is a condition associated with pregnancy; there is no geriatric experience with ZURZUVAE in patients with PPD.

None.

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)]

Table 4 displays clinically important drug interactions with ZURZUVAE.

Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/min/1.73 m²) and severe (eGFR 15 to 29 mL/min/1.73 m²) renal impairment [see Clinical Pharmacology (12.3)].

The recommended ZURZUVAE dosage in patients with moderate and severe renal impairment is lower than those with normal renal function [see Dosage and Administration (2.4)]. The recommended dosage in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m²) is the same as those in patients with normal renal function. ZURZUVAE has not been studied in patients with eGFR of < 15 mL/min/1.73 m² or patients requiring dialysis.

Zuranolone exposure (C_max and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times of the recommended dosage of ZURZUVAE) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of ZURZUVAE resulted in accumulation of approximately 1.5-fold in systemic exposures and steady state was achieved in 3 to 5 days.

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.

Exposure to zuranolone was increased in patients with severe hepatic impairment. The recommended ZURZUVAE dosage in patients with severe hepatic impairment (Child-Pugh C) is lower than patients with normal hepatic function [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

The recommended ZURZUVAE dosage in patients with mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B) is the same as those with normal hepatic function [see Clinical Pharmacology (12.3)].

ZURZUVAE is indicated for the treatment of postpartum depression (PPD) in adults.

Two randomized, double-blind, placebo- and active-controlled, four-way crossover studies (Study 3 and Study 4) evaluated the effects of nighttime ZURZUVAE administration on next-morning driving performance, 9 hours after dosing, using a computer-based driving simulation.

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.

ZURZUVAE contains zuranolone, a Schedule IV controlled substance.

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 [see Use in Specific Populations (8.1, 8.2)].

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 [see Use in Specific Populations (8.1, 8.3)].

The efficacy of ZURZUVAE for the treatment of postpartum depression (PPD) in adults was demonstrated in two randomized, placebo-controlled, double-blind, multicenter studies (Study 1, NCT04442503 and Study 2, NCT02978326) in women with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-5) with onset of symptoms in the third trimester or within 4 weeks of delivery. In these studies, concomitant use of existing oral antidepressants was allowed for patients taking a stable dose of oral antidepressant for at least 30 days before baseline. These studies included patients with HAMD-17 scores ≥ 26 at baseline.

In Study 1, patients received 50 mg of ZURZUVAE (N=98) or placebo (N=97) once daily in the evening with fat-containing food for 14 days, with the option to reduce the dosage based on tolerability to 40 mg once daily of ZURZUVAE or placebo. The patients were followed for a minimum of 4 weeks after the 14-day treatment course.

In Study 2, patients received another zuranolone capsule formulation (approximately equivalent to 40 mg of ZURZUVAE) (N=76) or placebo (N=74) once daily in the evening with food for 14 days. The patients were followed for a minimum of 4 weeks after the 14-day treatment course.

• 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)

• 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)

Capsules:

• 20 mg: light-orange cap, ivory to light-yellow body, printed with “S-217 20 mg” on body of capsule in black
• 25 mg: light-orange cap, light-orange body, printed with “S-217 25 mg” on body of capsule in black
• 30 mg: orange cap, light-orange body, printed with “S-217 30 mg” on body of capsule in black

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 [Clinical Studies (14.1)]. The studies included adult patients age 18 to 44 years diagnosed with PPD.

Across PPD clinical studies at all doses studied (Studies 1 and 2), serious adverse reactions included confusional state (1%) [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 14% 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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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.

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.

Death was observed in 1 dog four days after repeat dosing with 2.5 mg/kg for 9 months was stopped. Death/euthanasia in 2 dogs was also observed 2 to 4 days after dosing with 2.5 mg/kg for 14 days was stopped. Convulsions were observed in 1 dog three days after repeat dosing with 2.5 mg/kg for 14 days was stopped. Plasma exposure (AUC) at the no-effect dose in dogs was approximately 3 times the human exposure at the MRHD.

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.

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)].

Based on animal studies, ZURZUVAE may cause embryo-fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

The recommended dosage of ZURZUVAE in patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²) 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 m²) is the same as those in patients with normal renal function.

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.

ZURZUVAE causes driving impairment due to central nervous system (CNS) depressant effects [see Warnings and Precautions (5.2)]. 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 [see Clinical Studies (14.2)].

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.

ZURZUVAE causes driving impairment due to central nervous system (CNS) depressant effects [see Warnings and Precautions (5.1, 5.2)] .

Advise patients not to drive or engage in other potentially hazardous activities 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 [see Warnings and Precautions (5.1)] .

CYP3A4 Inducers

Avoid concomitant use of ZURZUVAE with CYP3A4 inducers [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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].

PRINCIPAL DISPLAY PANEL - 30 mg Bottle Carton

NDC 64406-031-01

Rx Only

ZURZUVAE™

CIV

(zuranolone) capsules

30 mg

For oral use

Attention: Dispense

with accompanying

Medication Guide.

14 Capsules

Zuranolone has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction. Abuse is the intentional non-therapeutic use of a drug, even once, for its desired psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Individuals with a history of drug abuse or substance use disorders may be at a greater risk of these outcomes with ZURZUVAE.

In a human abuse potential study, single oral doses of 30 mg, 60 mg, and 90 mg of ZURZUVAE (0.6 times, 1.2 times, and 1.8 times the recommended daily dose, respectively) were compared to single oral doses of alprazolam (1.5 mg and 3 mg) and placebo in healthy, nondependent individuals with a history of recreational CNS depressant use. The study demonstrated that ZURZUVAE has dose-dependent abuse potential comparable to alprazolam and greater abuse potential than placebo on positive subjective measures of “drug liking,” “overall drug liking,” “take drug again,” “high,” and “good drug effects.” In the human abuse potential study, dose-dependent, abuse-related adverse reactions, including euphoric mood, feeling drunk, and somnolence, were reported with ZURZUVAE use.

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.

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 C₂₅H₃₅N₃O₂ and the relative molecular mass is 409.57.

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).

ZURZUVAE may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Adverse reactions reported upon discontinuation of zuranolone in healthy subjects who received 50 mg of zuranolone for 5 to 7 days (on the 7^th day subjects received 50 mg or 100 mg ) included: insomnia, palpitations, decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. These adverse reactions indicate a potential for physical dependence with zuranolone. These adverse reactions were mild-to-moderate in severity.

The risk for developing physical dependence and a subsequent withdrawal syndrome upon abrupt ZURZUVAE discontinuation for individuals who take a higher than recommended dosage and/or use ZURZUVAE for a longer duration than recommended [see Dosage and Administration (2.1)] has not been evaluated in clinical studies. However, convulsions were observed in a dog upon abrupt zuranolone discontinuation after dogs were administered zuranolone for 14 days at doses that produced exposures higher than the maximum recommended human dose [see Nonclinical Toxicology (13.2)].

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

PPD is a condition associated with pregnancy; there is no geriatric experience with ZURZUVAE in patients with PPD.

None.

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)]

Table 4 displays clinically important drug interactions with ZURZUVAE.

Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/min/1.73 m²) and severe (eGFR 15 to 29 mL/min/1.73 m²) renal impairment [see Clinical Pharmacology (12.3)].

The recommended ZURZUVAE dosage in patients with moderate and severe renal impairment is lower than those with normal renal function [see Dosage and Administration (2.4)]. The recommended dosage in patients with mild renal impairment (eGFR 60 to 89 mL/min/1.73 m²) is the same as those in patients with normal renal function. ZURZUVAE has not been studied in patients with eGFR of < 15 mL/min/1.73 m² or patients requiring dialysis.

Zuranolone exposure (C_max and AUC) increased approximately dose proportionally with doses ranging from 30 mg to 60 mg (1.2 times of the recommended dosage of ZURZUVAE) with a moderate-fat meal (700 calories; 30% fat). Once-daily administration of ZURZUVAE resulted in accumulation of approximately 1.5-fold in systemic exposures and steady state was achieved in 3 to 5 days.

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.

Exposure to zuranolone was increased in patients with severe hepatic impairment. The recommended ZURZUVAE dosage in patients with severe hepatic impairment (Child-Pugh C) is lower than patients with normal hepatic function [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

The recommended ZURZUVAE dosage in patients with mild or moderate hepatic impairment (Child-Pugh A or Child-Pugh B) is the same as those with normal hepatic function [see Clinical Pharmacology (12.3)].

ZURZUVAE is indicated for the treatment of postpartum depression (PPD) in adults.

Two randomized, double-blind, placebo- and active-controlled, four-way crossover studies (Study 3 and Study 4) evaluated the effects of nighttime ZURZUVAE administration on next-morning driving performance, 9 hours after dosing, using a computer-based driving simulation.

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.

ZURZUVAE contains zuranolone, a Schedule IV controlled substance.

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 [see Use in Specific Populations (8.1, 8.2)].

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 [see Use in Specific Populations (8.1, 8.3)].

The efficacy of ZURZUVAE for the treatment of postpartum depression (PPD) in adults was demonstrated in two randomized, placebo-controlled, double-blind, multicenter studies (Study 1, NCT04442503 and Study 2, NCT02978326) in women with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-5) with onset of symptoms in the third trimester or within 4 weeks of delivery. In these studies, concomitant use of existing oral antidepressants was allowed for patients taking a stable dose of oral antidepressant for at least 30 days before baseline. These studies included patients with HAMD-17 scores ≥ 26 at baseline.

In Study 1, patients received 50 mg of ZURZUVAE (N=98) or placebo (N=97) once daily in the evening with fat-containing food for 14 days, with the option to reduce the dosage based on tolerability to 40 mg once daily of ZURZUVAE or placebo. The patients were followed for a minimum of 4 weeks after the 14-day treatment course.

In Study 2, patients received another zuranolone capsule formulation (approximately equivalent to 40 mg of ZURZUVAE) (N=76) or placebo (N=74) once daily in the evening with food for 14 days. The patients were followed for a minimum of 4 weeks after the 14-day treatment course.

• 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)

• 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)

Capsules:

• 20 mg: light-orange cap, ivory to light-yellow body, printed with “S-217 20 mg” on body of capsule in black
• 25 mg: light-orange cap, light-orange body, printed with “S-217 25 mg” on body of capsule in black
• 30 mg: orange cap, light-orange body, printed with “S-217 30 mg” on body of capsule in black

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 [Clinical Studies (14.1)]. The studies included adult patients age 18 to 44 years diagnosed with PPD.

Across PPD clinical studies at all doses studied (Studies 1 and 2), serious adverse reactions included confusional state (1%) [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 14% 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.

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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.

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.

Death was observed in 1 dog four days after repeat dosing with 2.5 mg/kg for 9 months was stopped. Death/euthanasia in 2 dogs was also observed 2 to 4 days after dosing with 2.5 mg/kg for 14 days was stopped. Convulsions were observed in 1 dog three days after repeat dosing with 2.5 mg/kg for 14 days was stopped. Plasma exposure (AUC) at the no-effect dose in dogs was approximately 3 times the human exposure at the MRHD.

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.

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)].

Based on animal studies, ZURZUVAE may cause embryo-fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

The recommended dosage of ZURZUVAE in patients with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²) 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 m²) is the same as those in patients with normal renal function.

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.

ZURZUVAE causes driving impairment due to central nervous system (CNS) depressant effects [see Warnings and Precautions (5.2)]. 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 [see Clinical Studies (14.2)].

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.

ZURZUVAE causes driving impairment due to central nervous system (CNS) depressant effects [see Warnings and Precautions (5.1, 5.2)] .

Advise patients not to drive or engage in other potentially hazardous activities 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 [see Warnings and Precautions (5.1)] .