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

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 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.

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.

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 [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.

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.

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 [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)].

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 [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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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)].

8.4 Pediatric Use

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

8.5 Geriatric Use

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

8.6 Hepatic Impairment

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)].

8.7 Renal Impairment

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.

9.1 Controlled Substance

ZURZUVAE contains zuranolone, a Schedule IV controlled substance.

9.2 Abuse

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.

9.3 Dependence

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 7th 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)].

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 GABAA receptors.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Zuranolone exposure (Cmax 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.

Specific Populations

Racial Groups

Black or African American participants had a 14% higher CL/F compared to participants of other races (Asian, White, or other).

Male and Female Patients, Patients with Renal Impairment, Patients with Hepatic Impairment

Exposures of zuranolone in specific populations are summarized in Figure 1 [see Dosage and Administration (2.4, 2.5) and Use in Specific Populations (8.6, 8.7)].

Figure 1 Effect of Specific Populations on the Pharmacokinetics of Zuranolone

Data shown for participants ≥65 years relative to younger participants (18 to 45 years); female participants relative to male participants; renal and hepatic impairment relative to participants with normal renal and hepatic function, respectively. Hepatic impairment: Mild (Child-Pugh Class A); moderate (Child-Pugh Class B); severe (Child-Pugh Class C). Renal impairment: Mild (eGFR 60-89 mL/min/1.73m2); moderate (eGFR 30-59 mL/min/1.73m2); severe (eGFR <30 mL/min/1.73m2 and not on dialysis). CI = confidence interval; GMR = geometric mean ratio

Drug Interaction Studies

The effect of co-administered drugs on the pharmacokinetics of zuranolone is summarized in Figure 2 [see Dosage and Administration (2.3) and Drug Interactions (7)].

Figure 2 Effect of Co-Administered Drugs on the Pharmacokinetics of Zuranolone

Data shown are zuranolone plus co-administered drug relative to zuranolone alone. CI = confidence interval; GMR = geometric mean ratio; * clinically significant drug interaction

ZURZUVAE did not affect the pharmacokinetics of alprazolam or ethanol. Increased impairment of psychomotor performance was observed when ZURZUVAE was co-administered with alprazolam or ethanol [see Warnings and Precautions (5.2) and Drug Interactions (7)].

In Vitro Studies

Enzyme systems: Zuranolone is not an inhibitor of CYP1A2, 2B6, 2C19, 2C8, 2C9, 2D6 or 3A4. Zuranolone is not an inducer for CYP1A2, CYP2B6 or CYP3A4 at the therapeutic dose range.

Transporter systems: Zuranolone is not a substrate of P-glycoprotein (P-gp), BCRP, OATP1B1 or OATP1B3. Zuranolone does not inhibit P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT2, OCT1, OCT2, MATE1, or MATE2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

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.

14.1 Postpartum Depression

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.

Baseline Demographics and Disease Characteristics

In Studies 1 and 2, the baseline demographic and disease characteristics of patients were similar between the ZURZUVAE and placebo groups. In Study 1, patients had a mean age of 30 years (range 19 to 44 years); were 70% White, 22% Black or African American, 1% Asian, and 7% were other races; and 38% were of Hispanic or Latino ethnicity. Baseline use of stable oral antidepressants was reported in 15% of patients. In Study 2, patients had a mean age of 28 years (range 18 to 44 years); were 56% White, 41% Black or African American, 1% Asian, and 2% were other races; and 23% were of Hispanic or Latino ethnicity. Baseline use of stable oral antidepressants was reported in 19% of patients.

The primary endpoint for Studies 1 and 2 was the change from baseline in depressive symptoms as measured by the HAMD-17 total score at Day 15. In these studies, patients in the ZURZUVAE groups experienced statistically significantly greater improvement on the primary endpoint compared to patients in the placebo groups, as shown in Table 5. For Study 1, the key secondary endpoints included change from baseline in HAMD-17 total score at Days 3, 28, and 45.

Table 5 Results for the Primary Endpoint: Change from Baseline in the HAMD-17 Total Score at Day 15 (Studies 1 and 2 in Women with PPD)

HAMD-17: 17-item Hamilton depression rating scale; SD: standard deviation; LS: least squares; SE: standard error; CI: confidence interval
*This capsule formulation of zuranolone is approximately equivalent to 40 mg of ZURZUVAE.
Study Number	Treatment Group	N	Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo- subtracted Difference (95% CI)
1	50 mg of ZURZUVAE	98	28.6 (2.49)	-15.6 (0.82)	-4.0 (-6.3, -1.7)
	Placebo	97	28.8 (2.34)	-11.6 (0.82)
2	Zuranolone (another capsule formulation)*	76	28.4 (2.09)	-17.8 (1.04)	-4.2 (-6.9, -1.5)
	Placebo	74	28.8 (2.32)	-13.6 (1.07)

Subgroup analyses of the primary endpoint did not suggest differences in response to 50 mg of ZURZUVAE for age, race, or BMI.

The time course of response for 50 mg ZURZUVAE compared to placebo for Study 1 is shown in Figure 3.

Figure 3 Mean Change from Baseline in HAM-D Total Score Over Time (Days) in Women with PPD in Study 1

*Both phases were double-blind.

14.2 Effects on Driving

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.

How Supplied

ZURZUVAE (zuranolone) is supplied as 20 mg, 25 mg, and 30 mg capsules as follows:

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].

Impaired Ability to Drive or Engage in Other Potentially Hazardous Activities

Inform patients that ZURZUVAE causes driving impairment. Advise patients to take ZURZUVAE in the evening. 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. Warn patients that they may not be able to assess their own ability to drive or the degree of impairment caused by ZURZUVAE [see Warnings and Precautions (5.1)].

Central Nervous System Depressant Effects

Inform patients that ZURZUVAE can cause somnolence, dizziness, sedation, and confusion. Advise patients to use caution if taking ZURZUVAE in combination with alcohol, other CNS depressants, or medications that increase the concentration of ZURZUVAE [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Drug Interactions (7)].

Suicidal Thoughts and Behavior

Advise patients to look for the emergence of suicidal thoughts and behaviors and instruct them to report such symptoms to the healthcare provider immediately [see Warnings and Precautions (5.3)].

Administration Instructions

Inform patients to take ZURZUVAE with fat-containing food [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

Instruct patients that if a daily dose is missed, the missed dose should be taken the next day as scheduled. Patients should be advised not to take extra capsules to make up for the missed dose [see Dosage and Administration (2.1, 2.5)].

Abuse, Misuse, and Physical Dependence

Advise patients that ZURZUVAE has abuse potential with associated risks of misuse, abuse, and substance use disorder including addiction and that ZURZUVAE is associated with the potential for physical dependence [see Drug Abuse and Dependence (9.2, 9.3)].

Pregnancy

Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ZURZUVAE. Advise female patients of reproductive potential to use effective contraception during treatment with ZURZUVAE and for one week after the final dose [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZURZUVAE during pregnancy [see Use in Specific Populations (8.1)].

Manufactured for:
Biogen Inc.
225 Binney Street
Cambridge, MA 02142 USA

ZURZUVAE is a trademark of Sage Therapeutics, Inc.
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