2.1 Important Considerations Prior to Initiating and During Therapy

A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the ZULRESSO infusion.

Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm. Assess for excessive sedation every 2 hours during planned, non-sleep periods [see Warnings and Precautions (5.1)].

Initiate ZULRESSO treatment early enough during the day to allow for recognition of excessive sedation [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

Administer ZULRESSO as a continuous intravenous (IV) infusion over a total of 60 hours (2.5 days) as follows:

• 0 to 4 hours: Initiate with a dosage of 30 mcg/kg/hour
• 4 to 24 hours: Increase dosage to 60 mcg/kg/hour
• 24 to 52 hours: Increase dosage to 90 mcg/kg/hour (a reduction in dosage to 60 mcg/kg/hour may be considered during this time period for patients who do not tolerate 90 mcg/kg/hour)
• 52 to 56 hours: Decrease dosage to 60 mcg/kg/hour
• 56 to 60 hours: Decrease dosage to 30 mcg/kg/hour

If excessive sedation occurs at any time during the infusion, stop the infusion until the symptoms resolve. The infusion may be resumed at the same or lower dose as clinically appropriate.

2.3 Preparation and Storage Instructions

ZULRESSO is supplied in vials as a concentrated solution that requires dilution prior to administration. After dilution, the product can be stored in infusion bags under refrigerated conditions for up to 96 hours. However, given that the diluted product can be used for only 12 hours at room temperature, each 60-hour infusion will require the preparation of at least five infusion bags.

Prepare according to the following steps using aseptic technique:

• Visually inspect the vials of ZULRESSO for particulate matter and discoloration prior to administration. ZULRESSO is a clear, colorless solution. Do not use if the solution is discolored or particulate matter is present.
• The 60-hour infusion will generally require the preparation of five infusion bags. Additional bags will be needed for patients weighing ≥ 90 kg.
• For each infusion bag:
  • Prepare and store in a polyolefin, non-DEHP, nonlatex bag, only. Dilute in the infusion bag immediately after the initial puncture of the drug product vial.
  • Withdraw 20 mL of ZULRESSO from the vial and place in the infusion bag. Dilute with 40 mL of Sterile Water for Injection, and further dilute with 40 mL of 0.9% Sodium Chloride Injection (total volume of 100 mL) to achieve a target concentration of 1 mg/mL.
  • Immediately place the infusion bag under refrigerated conditions until use.

Diluted ZULRESSO storage instructions:

• If not used immediately after dilution, store under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth.
• Each prepared bag of diluted ZULRESSO may be used for up to 12 hours of infusion time at room temperature. Discard any unused ZULRESSO after 12 hours of infusion.

2.4 Administration Instructions

ZULRESSO must be diluted before administration [see Dosage and Administration (2.3)]. The following are important administration instructions:

• Use a programmable peristaltic infusion pump to ensure accurate delivery of ZULRESSO.
• Administer ZULRESSO via a dedicated line. Do not inject other medications into the infusion bag or mix with ZULRESSO.
• Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter.
• Use a PVC, non-DEHP, nonlatex infusion set. Do not use in-line filter infusion sets.

2.5 Recommendations in Patients with End Stage Renal Disease

Avoid use of ZULRESSO in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium [see Clinical Pharmacology (12.3, 12.6)].

5.1 Excessive Sedation and Sudden Loss of Consciousness

In clinical studies in adults, ZULRESSO caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of ZULRESSO-treated patients compared to 0% of placebo-treated patients). Some adult patients were also reported to have loss of consciousness or altered state of consciousness during the ZULRESSO infusion (4% of the ZULRESSO-treated patients compared with 0% of the placebo-treated patients). Time to full recovery from loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes in clinical studies in adults. A healthy 55-year-old man participating in a cardiac repolarization study experienced severe somnolence and <1 minute of apnea while receiving two times the maximum recommended dosage of ZULRESSO (180 mcg/kg/hour).

In an open-label clinical study in 20 patients ages 15 to 17 years, one patient experienced dizziness and loss of consciousness.

All patients with loss of or altered state of consciousness recovered with dose interruption. There was no clear association between loss or alteration of consciousness and pattern or timing of dose. Not all patients who experienced a loss or alteration of consciousness reported sedation or somnolence before the episode.

During the infusion, monitor patients for sedative effects every 2 hours during planned, non-sleep periods. Immediately stop the infusion if there are signs or symptoms of excessive sedation.

After symptoms resolve, the infusion may be resumed at the same or lower dose as clinically appropriate [see Dosage and Administration (2.2)].

Immediately stop the infusion if pulse oximetry reveals hypoxia. After hypoxia, the infusion should not be resumed.

Patients should be cautioned against engaging in potentially hazardous activities requiring mental alertness, such as driving after infusion until any sedative effects of ZULRESSO have dissipated. Patients must be accompanied during interactions with their child(ren) while receiving the infusion because of the potential for excessive sedation and sudden loss of consciousness.

Concomitant use of opioids, antidepressants, or other CNS depressants such as benzodiazepines or alcohol may increase the likelihood or severity of adverse reactions related to sedation [see Drug Interactions (7.1, 7.2)].

Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS [see Warnings and Precautions (5.2)].

5.2 ZULRESSO Risk Evaluation and Mitigation Strategy (REMS)

ZULRESSO is available only through a restricted program under a REMS called the ZULRESSO REMS because excessive sedation or sudden loss of consciousness can result in serious harm [see Warnings and Precautions (5.1)].

Notable requirements of the ZULRESSO REMS include the following:

• Healthcare facilities must enroll in the program and ensure that ZULRESSO is only administered to patients who are enrolled in the ZULRESSO REMS.
• Pharmacies must be certified with the program and must only dispense ZULRESSO to healthcare facilities who are certified in the ZULRESSO REMS.
• Patients must be enrolled in the ZULRESSO REMS prior to administration of ZULRESSO.
• Wholesalers and distributors must be registered with the program and must only distribute to certified healthcare facilities and pharmacies.

Further information, including a list of certified healthcare facilities, is available at www.zulressorems.com or 1-844-472-4379.

5.3 Suicidal Thoughts and Behaviors

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.

ZULRESSO does not directly affect monoaminergic systems. Because of this and the comparatively low number of exposures to ZULRESSO, the risk of developing suicidal thoughts and behaviors with ZULRESSO is unknown. Consider changing the therapeutic regimen, including discontinuing ZULRESSO, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice.

The safety of ZULRESSO was evaluated in 140 adult patients with postpartum depression (PPD). A titration to a target dosage of 90 mcg/kg/hour was evaluated in 102 adult patients and a titration to a target dose of 60 mcg/kg/hour was evaluated in 38 adult patients [see Clinical Studies (14)]. Patients were then followed for 4 weeks.

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush (Table 2).

Adverse Reactions Leading to Discontinuation, Dosage Interruption, or Dosage Reduction

In the pooled placebo controlled-studies in adults, the incidence of patients who discontinued due to any adverse reaction was 2% of ZULRESSO-treated patients compared to 1% of placebo-treated patients. The adverse reactions leading to treatment discontinuation in ZULRESSO-treated patients were sedation-related (loss of consciousness, vertigo, syncope, and presyncope) or infusion site pain.

In the pooled placebo controlled-studies in adults, the incidence of patients who had an interruption or reduction of the dosage due to any adverse reaction was 7% of ZULRESSO-treated patients compared to 3% of placebo-treated patients. The adverse reactions leading to dose reduction or interruption in ZULRESSO-treated patients were sedation-related (loss of consciousness, syncope, somnolence, dizziness, fatigue), infusion site events, changes in blood pressure, or medication error due to infusion pump malfunction. Three ZULRESSO-treated patients who had a dosage interruption because of loss of consciousness subsequently resumed and completed treatment after resolution of symptoms; two patients who had dosage interruption because of loss of consciousness did not resume the infusion.

Table 2 presents the adverse reactions that occurred in ZULRESSO-treated adult PPD patients at a rate of at least 2% and at a higher rate than in the placebo-treated patients during the 60-hour treatment period.

Patients 15 to 17 Years

The safety of ZULRESSO was evaluated in an open-label study in patients 15 to 17 years. A titration to a target dosage of 90 mcg/kg/hour was evaluated in 20 patients with PPD. Patients were then followed for 4 weeks. Adverse reactions reported in the clinical study were generally similar to those observed in clinical studies of ZULRESSO in adults with PPD.

7.1 CNS Depressants

Concomitant use of ZULRESSO with CNS depressants (e.g., opioids, benzodiazepines) may increase the likelihood or severity of adverse reactions related to sedation [see Warnings and Precautions (5.1)].

7.2 Antidepressants

In the placebo-controlled studies, a higher percentage of ZULRESSO-treated patients who used concomitant antidepressants reported sedation-related events [see Warnings and Precautions (5.1)].

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ .

Risk Summary

Based on findings from animal studies of other drugs that enhance GABAergic inhibition, ZULRESSO may cause fetal harm. Available data from case reports with ZULRESSO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, malformations were not seen in rats or rabbits at plasma levels up to 5 and 6 times the maximum recommended human dose (MRHD), respectively. Developmental toxicities were seen in the fetuses of rats and rabbits at 5 and ≥3 times the plasma levels at the MRHD, respectively. Reproductive toxicities were seen in rabbits at ≥3 times the plasma levels at the MRHD. These effects were not seen in rats and rabbits at 2 and 1.2 times the plasma levels at the MRHD. Brexanolone administered to pregnant rats during pregnancy and lactation resulted in lower pup survival at doses which were associated with ≥2 times the plasma levels at the MRHD and a neurobehavioral deficit in female offspring at 5 times the plasma levels at the MRHD. These effects were not seen at 0.8 times and 2 times the plasma levels at the MRHD, respectively (see Data).

In published animal studies, administration of other drugs that enhance GABAergic inhibition to neonatal rats caused widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes in rats (postnatal days 0-14) corresponds to the period of brain development that takes place during the third trimester of pregnancy in humans.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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

In pregnant rats and rabbits, no malformations were seen when brexanolone was given during the period of organogenesis at continuous intravenous doses up to 60 and 30 mg/kg/day, respectively. These doses were associated with maternal plasma levels 5 and 6 times the plasma levels at the MRHD of 90 mcg/kg/hour, in rats and rabbits, respectively. In rats, a decrease in fetal body weights was seen at 60 mg/kg/day (5 times the plasma level at the MRHD). In rabbits, increased numbers of late resorptions and a decrease in fetal body weights were seen at doses equal to and greater than 15 mg/kg/day (3 times the plasma levels at the MRHD) with fewer live fetuses and a higher post implantation loss seen at 30 mg/kg/day (6 times the plasma levels at the MRHD) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain and/or body weight loss). Effects in rats and rabbits were not seen at 2 and 1.2 times the plasma levels at the MRHD, respectively.

When brexanolone was administered to pregnant rats by continuous intravenous administration at 30 and 60 mg/kg/day (2 and 5 times plasma levels at the MRHD, respectively) during the period of organogenesis and throughout pregnancy and lactation, increased numbers of dead pups and fewer live pups at birth were seen. This effect was not seen at 0.8 times the plasma levels at the MRHD. Decreased pup viability between postnatal day 0 and 4 in the presence of maternal toxicity (decreased body weight gain and food consumption during lactation) was seen at 5 times the plasma levels at the MRHD. These effects were not seen at 2 times the plasma levels at the MRHD. A neurobehavioral deficit, characterized by slower habituation in the maximal startle response in the auditory startle test, was seen in female offspring of dams dosed at 5 times the plasma levels at the MRHD. This effect was not seen at 2 times the plasma levels at the MRHD.

8.2 Lactation

Risk Summary

Available data from a lactation study in 12 adult women indicate that brexanolone is transferred to breastmilk in nursing mothers. However, the relative infant dose (RID) is low, 1% to 2% of the maternal weight-adjusted dosage (see Data). Also, as ZULRESSO has low oral bioavailability (<5%) in adults, infant exposure is expected to be low. There were no reports of effects of ZULRESSO on milk production. There are no data on the effects of ZULRESSO on a breastfed infant. Available data on the use of ZULRESSO during lactation do not suggest a significant risk of adverse reactions to breastfed infants from exposure to ZULRESSO. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZULRESSO and any potential adverse effects on the breastfed child from ZULRESSO or from the underlying maternal condition.

Data

A study was conducted in twelve healthy adult lactating women treated with intravenous ZULRESSO according to the recommended 60-hour dosing regimen (maximum dosage was 90 mcg/kg/hour). Concentrations of ZULRESSO in breast milk were at low levels (<10 ng/mL) in >95% of women by 36 hours after the end of the infusion of ZULRESSO. The calculated maximum relative infant dose for ZULRESSO during the infusion was 1% to 2%.

8.4 Pediatric Use

Safety and effectiveness of ZULRESSO for the treatment of PPD have been established in patients 15 to 17 years.

Use of ZULRESSO in this population is supported by evidence from adequate and well-controlled studies in adults with PPD, pharmacokinetic data in adults and patients 15 to 17 years, and safety data in patients 15 to 17 years [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

The safety and effectiveness of ZULRESSO in patients less than 15 years of age have not been established.

8.5 Geriatric Use

PPD is a condition associated with pregnancy; there is no geriatric experience with ZULRESSO.

8.6 Hepatic Impairment

Dosage adjustment in patients with hepatic impairment is not necessary. Modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone were observed in patients with moderate to severe hepatic impairment (Child-Pugh≥7) with no associated change in tolerability [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dosage adjustment is recommended in patients with mild (eGFR 60 to 89 mL/minute/1.73 m2), moderate (eGFR 30 to 59 mL/minute/1.73 m2) or severe (eGFR 15 to 29 mL/minute/1.73 m2) renal impairment [see Clinical Pharmacology (12.3)].

Avoid use of ZULRESSO in patients with end stage renal disease (ESRD) with eGFR of < 15 mL/minute/1.73 m2 because of the potential accumulation of the solubilizing agent, betadex sulfobutyl ether sodium [see Clinical Pharmacology (12.3, 12.6)].

9.1 Controlled Substance

ZULRESSO contains brexanolone, a Schedule IV controlled substance.

9.2 Abuse

In a human abuse potential study, 90 mcg/kg, 180 mcg/kg (two times the maximum recommended infusion rate), and 270 mcg/kg (three times the maximum recommended infusion rate) ZULRESSO infusions over a one-hour period were compared to oral alprazolam administration (1.5 mg and 3 mg). On positive subjective measures of "drug liking", "overall drug liking", "high" and "good drug effects", the 90 mcg/kg dosage produced scores that were similar to placebo. Scores on these positive subjective measures for both dosages of ZULRESSO 90 mcg/kg and 180 mcg/kg were lower than both alprazolam doses. However, the scores on the positive subjective measures for ZULRESSO 270 mcg/kg dosage were similar to those produced by both doses of alprazolam. In this study, 3% of subjects administered ZULRESSO 90 mcg/kg and 13% administered ZULRESSO 270 mcg/kg reported euphoric mood, compared to none administered placebo during the one-hour administration.

9.3 Dependence

In the PPD clinical studies conducted with ZULRESSO, end of treatment occurred through tapering. Thus, in these studies it was not possible to assess whether abrupt discontinuation of ZULRESSO produced withdrawal symptoms indicative of physical dependence. It is recommended that ZULRESSO be tapered according to the dosage recommendations, unless symptoms warrant immediate discontinuation [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

12.1 Mechanism of Action

The mechanism of action of brexanolone 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

Brexanolone potentiated GABA-mediated currents from recombinant human GABAA receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.

Brexanolone exposure-response relationships and the time course of pharmacodynamics response are unknown.

Cardiac Electrophysiology

The effect of brexanolone on the QT interval was evaluated in a Phase 1 randomized, placebo and positive controlled, double-blind, three-period crossover thorough QT study in 30 healthy adult subjects. At 1.9-times the exposure occurring at the highest recommended infusion rate (90 mcg/kg/hour), brexanolone did not prolong the QT interval to a clinically relevant extent.

12.3 Pharmacokinetics

Brexanolone exhibited dose proportional pharmacokinetics over a dosage range of 30 mcg/kg/hour to 270 mcg/kg/hour (three times the maximum recommended dosage). Mean steady state exposure at 60 mcg/kg/hour and 90 mcg/kg/hour was around 52 ng/mL and 79 ng/mL, respectively.

Distribution

The volume of distribution of brexanolone was approximately 3 L/kg, suggesting extensive distribution into tissues. Plasma protein binding was greater than 99% and is independent of plasma concentrations.

Elimination

The terminal half-life of brexanolone is approximately 9 hours. The total plasma clearance of brexanolone is approximately 1 L/h/kg.

Metabolism

Brexanolone is extensively metabolized by non-CYP based pathways via three main routes - keto-reduction (AKRs), glucuronidation (UGTs), and sulfation (SULTs). There are three major circulating metabolites that are pharmacologically inactive and do not contribute to the overall efficacy of ZULRESSO.

Excretion

Following administration of radiolabeled brexanolone, 47% was recovered in feces (primarily as metabolites) and 42% in urine (with less than 1% as unchanged brexanolone).

Specific Populations

Patients 15 to 17 years

Brexanolone pharmacokinetics were evaluated in 20 patients with PPD (15 to 17 years) and were comparable to those in adult patients with PPD.

Patients with Renal or Hepatic Impairment

No clinically significant differences in the pharmacokinetics of brexanolone were observed based on renal impairment (severe) study or hepatic impairment (mild, moderate, severe) study. The effect of end stage renal disease (ESRD, eGFR < 15 mL/minute/1.73 m2) on brexanolone pharmacokinetics is unknown. However, avoid use of ZULRESSO in patients with ESRD [see Use in Specific Populations (8.7)].

Drug Interaction Studies

No studies were conducted to evaluate the effects of other drugs on ZULRESSO.

No clinically significant differences in the pharmacokinetics of phenytoin (CYP2C9 substrate) were observed when it was used concomitantly with brexanolone.

12.6 Betadex Sulfobutyl Ether Sodium Pharmacokinetics

Betadex sulfobutyl ether sodium is a solubilizing agent in ZULRESSO. In patients with severe renal impairment (eGFR 15-29 mL/minute/1.73 m2), betadex sulfobutyl ether sodium AUCinf increased 5.5-fold and Cmax increased 1.7-fold. Avoid use of ZULRESSO in patients with ESRD [see Use in Specific Populations (8.7)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of brexanolone have not been performed.

Mutagenesis

Brexanolone was not genotoxic when tested in an in vitro microbial mutagenicity (Ames) assay, an in vitro micronucleus assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Treatment of female and male rats with brexanolone at doses equal to and greater than 30 mg/kg/day, which is associated with 2 times the plasma levels at the maximum recommended human dose (MRHD) of 90 mcg/kg/hour, caused impairment of female and male fertility and reproduction. In female rats, brexanolone was associated with decreased mating and fertility indices, an increase in number of days to mating, prolonged/irregular estrous cycles, an increase in the number of early resorptions, and post implantation loss. Reversal of effects in females was observed following a 28-day recovery period. In male rats, brexanolone was associated with decreased mating and fertility indices, decreased conception rate, lower prostate, seminal vesicle, and epididymis weight, as well as decreased sperm numbers. Impaired female and male fertility and reproduction were not observed at 0.8 times the MRHD.