Zurzuvae zuranolone 25 mg Capsule, 28-count — NDC 64406-030-02 (Billing 64406-0030-02)

12 CLINICAL PHARMACOLOGY

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

12.2Pharmacodynamics Cardiac Electrophysiology At 2 times the maximum recommended dose, ZURZUVAE does not cause clinically significant QTc interval prolongation. Psychomotor Performance with Alcohol or Alprazolam Co-administration of repeated 50 mg daily doses of ZURZUVAE with alcohol or alprazolam led to impairment in psychomotor performance [see Warnings and Precautions ( 5.2 ), and Drug Interactions ( 7 )].

12.3Pharmacokinetics 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. Absorption Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (T max ).

The absolute bioavailability of ZURZUVAE was not evaluated. Effect of Food Following administration of 30 mg of ZURZUVAE to healthy subjects, the C max increased by approximately 3.5-fold and the AUC last increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The C max increased by approximately 4.3-fold and the AUC last increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions.

The T max was not impacted by food. Distribution The volume of distribution of zuranolone following oral administration is greater than 500 L. The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58.

Plasma protein binding is greater than 99.5%. Elimination The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in an adult population. The mean apparent clearance (CL/F) of zuranolone is 33 L/h.

Metabolism Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone. Excretion Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.

Specific Populations Male and Female, Racial or Ethnic Groups, and Age No clinically meaningful differences in pharmacokinetics of zuranolone were observed based on age (18-81 years), sex, or race. Exposures of zuranolone in specific populations are summarized in Figure 1 [see Dosage and Administration ( 2.4 , 2.5 )] . Patients with Renal Impairment and Patients with Hepatic Impairment Exposures of zuranolone in patients with renal impairment and patients with hepatic impairment 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 AUC = area under the concentration-time curve; CI = confidence interval; C max = maximum observed concentration; GMR = geometric mean ratio. The bar represents the 90% CI.

The symbol is the GMR. Data shown for elderly participants (≥65 years of age) are relative to younger participants (18 to 45 years of age). Data shown for female participants are relative to male participants.

Data shown for hepatic impairment are relative to participants with normal hepatic function. Data shown for renal impairment are relative to participants with normal renal function. Figure 1 Drug Interaction Studies Clinical Studies and Model-Informed Approaches The effect of co-administered drugs on the pharmacokinetics of zuranolone is summ… [Excerpted — this section continues on DailyMed.]

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

12.3Pharmacokinetics 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. Absorption Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours (T max ).

The absolute bioavailability of ZURZUVAE was not evaluated. Effect of Food Following administration of 30 mg of ZURZUVAE to healthy subjects, the C max increased by approximately 3.5-fold and the AUC last increased by approximately 1.8-fold with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The C max increased by approximately 4.3-fold and the AUC last increased by approximately 2-fold with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions.

The T max was not impacted by food. Distribution The volume of distribution of zuranolone following oral administration is greater than 500 L. The mean blood-to-plasma concentration ratio ranged from 0.54 to 0.58.

Plasma protein binding is greater than 99.5%. Elimination The terminal half-life of zuranolone is approximately 19.7 to 24.6 hours in an adult population. The mean apparent clearance (CL/F) of zuranolone is 33 L/h.

Metabolism Zuranolone undergoes extensive metabolism, with CYP3A4 identified as a primary enzyme involved. There were no circulating human metabolites greater than 10% of total drug-related materials and none are considered to contribute to the therapeutic effects of zuranolone. Excretion Following oral administration of radiolabeled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in feces as metabolites with less than 2% as unchanged zuranolone.

Specific Populations Male and Female, Racial or Ethnic Groups, and Age No clinically meaningful differences in pharmacokinetics of zuranolone were observed based on age (18-81 years), sex, or race. Exposures of zuranolone in specific populations are summarized in Figure 1 [see Dosage and Administration ( 2.4 , 2.5 )] . Patients with Renal Impairment and Patients with Hepatic Impairment Exposures of zuranolone in patients with renal impairment and patients with hepatic impairment 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 AUC = area under the concentration-time curve; CI = confidence interval; C max = maximum observed concentration; GMR = geometric mean ratio. The bar represents the 90% CI.

The symbol is the GMR. Data shown for elderly participants (≥65 years of age) are relative to younger participants (18 to 45 years of age). Data shown for female participants are relative to male participants.

Data shown for hepatic impairment are relative to participants with normal hepatic function. Data shown for renal impairment are relative to participants with normal renal function. Figure 1 Drug Interaction Studies Clinical Studies and Model-Informed Approaches 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 )] .

CNS Depressant Drugs and Alcohol Concomitant administration of alprazolam or ethanol did not alter the pharmacokinetics of zuranolone as summarized in Figure 2 . ZURZUVAE did not affect the pharmacokinetics of alprazolam or ethanol. Figure 2.

Effect of Co-Administered Drugs on the Pharmacokinetics of Zuranolone AUC = area under the concentration-time curve; CI = confidence interval; C max = maximum observed concentration; GMR = geometric mean ratio. The bar represents the 90% CI. The symbol is the GMR.

Figure 2 In Vitro Studies Enzyme systems:… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology At 2 times the maximum recommended dose, ZURZUVAE does not cause clinically significant QTc interval prolongation. Psychomotor Performance with Alcohol or Alprazolam Co-administration of repeated 50 mg daily doses of ZURZUVAE with alcohol or alprazolam led to impairment in psychomotor performance [see Warnings and Precautions ( 5.2 ), and Drug Interactions ( 7 )].

14 CLINICAL STUDIES

14.1Postpartum 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. Figure 3

14.2Effects 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. Study 3 In Study 3, 50 mg of ZURZUVAE was administered for 6 consecutive nigh… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Oral administration of zuranolone in a 26-week carcinogenicity study in transgenic mice (0, 10, 30, or 100 mg/kg/day), and in a 104-week carcinogenicity study in rats (0, 2, 6, or 20 mg/kg/day in males and 0, 0.2, 0.6, or 1.5 mg/kg/day in females) was not associated with increases in tumors in either species. Plasma exposures (AUC) in rats at the highest dose tested were approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 50 mg.

Mutagenesis Zuranolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosome aberration assay in Chinese hamster ovary cells, and an in vivo bone marrow micronucleus assay in rats. Impairment of Fertility Oral administration of zuranolone (0, 3, 10, or 30 mg/kg/day) to male rats prior to and during mating with untreated females resulted in increased post-implantation loss and a corresponding decrease in the number of viable embryos at the high dose, which was also paternally toxic.

There were no adverse effects on fertility or sperm parameters. Adverse effects on reproduction were not observed when males were remated after a 6-week treatment-free period. The no effect dose (10 mg/kg/day) for male reproductive toxicity was associated with a plasma zuranolone exposure (AUC) of approximately 4 times the human exposure at the MRHD.

Oral administration of zuranolone (0, 1, 3, or 10 mg/kg/day) to female rats prior to and throughout mating and continuing through early gestation resulted in disruption of estrous cyclicity at the high dose, but there were no adverse effects on fertility or early embryonic development. The no-effect dose (3 mg/kg/day) for female reproductive toxicity was associated with exposures approximately 4 times that in humans at the MRHD.

13.2Animal Toxicology and/or Pharmacology Death was observed in 1 dog 4 days after repeat dosing with 2.5 mg/kg/day for 9 months was stopped. Death/euthanasia in 2 dogs was also observed 2 to 4 days after dosing with 2.5 mg/kg/day for 14 days was stopped. Convulsions were observed in 1 dog 3 days after repeat dosing with 2.5 mg/kg/day 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.