ZURANOLONE: 885 Adverse Event Reports & Safety Profile

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. 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

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 )

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]</span>. 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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span>. 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 &lt;60 mL/min/1.73 m 2 ) is 30 mg orally once daily in the evening for 14 days <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )]</span>. 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.

None. None. ( 4 )

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 [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)

Adverse Reaction

Placebo (N=98) (%) 50 mg of ZURZUVAE (N=98) (%) 1 Somnolence includes sedation and hypersomnia 2 Dizziness includes vertigo 3 Fatigue includes asthenia 4 Abdominal pain includes upper abdominal pain Somnolence 1 6 36 Dizziness 2 9 13 Diarrhea 2 6 Fatigue 3 2 5 Urinary tract infection 4 5 Memory impairment 0 3 Abdominal pain 4 0 3 Tremor 0 2 Hypoesthesia 0 2 Muscle twitching 0 2 Myalgia 0 2 COVID-19 0 2 Anxiety 1 2 Rash 1 2 In Study 2, the incidence of adverse reactions that led to discontinuation in patients who received another zuranolone capsule formulation (approximately equivalent to 40 mg of ZURZUVAE) and placebo was 1% and 0%, respectively. The adverse reaction that led to treatment discontinuation was somnolence. Dosage reduction due to an adverse reaction occurred in 4% of zuranolone-treated patients. The adverse reactions that led to dosage reduction were somnolence and confusional state. The most common (≥5% and greater than placebo) adverse reactions in zuranolone-treated patients were somnolence, nasopharyngitis, dizziness, fatigue, and diarrhea.

Table

3 summarizes the adverse reactions that occurred in ≥2% of zuranolone-treated patients with PPD and at a higher incidence than in placebo-treated patients in Study 2.

Table

3 Adverse Reactions that Occurred in ≥2% of Patients with PPD Treated with Another Zuranolone Capsule Formulation * and Greater than in Patients Treated with Placebo (Study 2)

Adverse Reaction

Placebo (N=73) (%)

Another Zuranolone Capsule

Formulation * (N=78) (%) 1 Somnolence includes sedation 2 Nasopharyngitis includes upper respiratory tract infection 3 Fatigue includes lethargy * This capsule formulation of zuranolone is approximately equivalent to 40 mg of ZURZUVAE.

Somnolence

1 11 19 Nasopharyngitis 2 3 9 Dizziness 6 8 Fatigue 3 1 5 Diarrhea 3 5 Dry mouth 0 4 Sinus congestion 0 3 Toothache 0 3

AND PRECAUTIONS 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 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.2 )]</span> . 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 Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated * ZURZUVAE is not approved in pediatric patients.

Increases

Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.2 )]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

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 )