ZURZUVAE Capsule Ref.[107395] Active ingredients: Zuranolone

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.

Table 1. Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric^* and Adult Patients:

^* ZURZUVAE is not approved in pediatric patients.

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)].

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)]

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.

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):

¹ Somnolence includes sedation and hypersomnia
² Dizziness includes vertigo
³ Fatigue includes asthenia
⁴ Abdominal pain includes upper abdominal pain

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):

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.

Table 4 displays clinically important drug interactions with ZURZUVAE.

Table 4. Clinically Important Drug Interactions with ZURZUVAE:

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 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 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.

Potential adverse effects of zuranolone on embryofetal development in pregnant rabbits were not adequately assessed.

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.

Risk Summary

Available data from a clinical lactation study in 14 women indicate that zuranolone is present in low levels in human milk (see Data). There are no data on the effects of zuranolone on a breastfed infant and limited data on the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZURZUVAE and any potential adverse effects on the breastfed child from ZURZUVAE or from the underlying maternal condition.

Data

A steady-state milk study was conducted in 14 healthy lactating women treated with daily oral administration of 30 mg of ZURZUVAE for 5 days. At steady state (Day 5), the calculated maximum relative infant dose for ZURZUVAE was <1%. The daily infant dose was low (approximately 0.0013 mg/kg/day), reflecting a mean relative infant dose of 0.357% compared to the maternal dose. Concentrations of ZURZUVAE in breastmilk were below the level of quantification limit (BQL) by 4-6 days after the last dose.

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)].

Contraception

Advise female patients of reproductive potential to use effective contraception during treatment with ZURZUVAE and for one week after the final dose.

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.

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.

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 contains zuranolone, a Schedule IV controlled substance under the Controlled Substances Act.

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.

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)].