Class: Antidepressants, Miscellaneous
Chemical Name: 1-[(3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone
Molecular Formula: C21H34O2
CAS Number: 128-20-1
Warning: Excessive Sedation and Sudden Loss of Consciousness
See full prescribing information for complete boxed warning.
Patients are at risk of excessive sedation or sudden loss of consciousness during administration of brexanolone.
Because of the risk of serious harm, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring. Patients must be accompanied during interactions with their child(ren).
Brexanolone is available only through a restricted program called the Zulresso REMS.
Risk Evaluation and Mitigation Strategy (REMS):
FDA approved a REMS for brexanolone to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of brexanolone and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.
Brexanolone is an antidepressant.
Uses for Brexanolone
Brexanolone has the following uses:
Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator indicated for the treatment of postpartum depression (PPD) in adults.
Brexanolone Dosage and Administration
Brexanolone is available in the following dosage form(s) and strength(s):
Injection: 100 mg/20 mL (5 mg/mL) single-dose vial.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Dosage and Administration
A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the infusion.
Administered as a continuous intravenous infusion over 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 (alternatively consider a dosage of 60 mcg/kg/hour for those 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.
Dilution required prior to administration.
Cautions for Brexanolone
Excessive Sedation and Sudden Loss of Consciousness
In clinical studies, brexanolone caused sedation and somnolence that required dose interruption or reduction in some patients during the infusion (5% of brexanolone-treated patients compared to 0% of placebo-treated patients). Some patients were also reported to have loss of consciousness or altered state of consciousness during the brexanolone infusion (4% of the brexanolone-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. 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 brexanolone (180 mcg/kg/hour). 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.
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 brexanolone 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.
Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, brexanolone is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Zulresso REMS.
Brexanolone 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.
Notable requirements of the Zulresso REMS include the following:
Healthcare facilities must enroll in the program and ensure that brexanolone is only administered to patients who are enrolled in the Zulresso REMS.
Pharmacies must be certified with the program and must only dispense brexanolone to healthcare facilities who are certified in the Zulresso REMS.
Patients must be enrolled in the Zulresso REMS prior to administration of brexanolone.
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.
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.
Brexanolone is not approved in pediatric patients.
Age Range (years)
Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated
Increases Compared to Placebo
14 additional patients
5 additional patients
Decreases Compared to Placebo
1 fewer patient
Brexanolone does not directly affect monoaminergic systems. Because of this and the comparatively low number of exposures to brexanolone, the risk of developing suicidal thoughts and behaviors with brexanolone is unknown. Consider changing the therapeutic regimen, including discontinuing brexanolone, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.
Pregnancy Exposure: 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 [Web]/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary: Based on findings from animal studies of other drugs that enhance GABAergic inhibition, brexanolone may cause fetal harm. There are no available data on brexanolone use in pregnant women to determine 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.
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.
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.
Risk Summary: Available data from a lactation study in 12 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. Also, as brexanolone has low oral bioavailability (<5%) in adults, infant exposure is expected to be low. There were no reports of effects of brexanolone on milk production. There are no data on the effects of brexanolone on a breastfed infant. Available data on the use of brexanolone during lactation do not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for brexanolone and any potential adverse effects on the breastfed child from brexanolone or from the underlying maternal condition.
Data: A study was conducted in twelve healthy adult lactating women treated with intravenous brexanolone according to the recommended 60-hour dosing regimen (maximum dosage was 90 mcg/kg/hour). Concentrations of brexanolone in breast milk were at low levels (<10 ng/mL) in >95% of women by 36 hours after the end of the infusion of brexanolone. The calculated maximum relative infant dose for brexanolone during the infusion was 1% to 2%.
The safety and effectiveness of brexanolone in pediatric patients have not been established.
PPD is a condition associated with pregnancy; there is no geriatric experience with brexanolone.
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.
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.
Avoid use of brexanolone 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.
Common Adverse Effects
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.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Please see product labeling for drug interaction information.
Mechanism of Action
The mechanism of action of brexanolone in the treatment of PPD in adults is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors.
Advice to Patients
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
Patients may experience loss of consciousness or altered state of consciousness during the brexanolone infusion. Advise patients to report signs of excessive sedation that may occur during the infusion. Patients must not be the primary caregiver of dependents and must be accompanied during interactions with their child(ren).
Brexanolone is available only through a restricted program called the Zulresso REMS.
Inform the patient of the following notable requirements: (1) patients must be enrolled in the Zulresso REMS Program prior to administration and (2) patients must be monitored during administration of brexanolone and report any signs and symptoms of excessive sedation to a healthcare provider.
Advise patients that brexanolone can be abused or lead to dependence.
Caution patients that opioids or other CNS depressants, such as benzodiazepines, taken in combination with brexanolone may increase the severity of sedative effects.
Advise patients and caregivers to look for the emergence of suicidal thoughts and behavior and instruct them to report such symptoms to the healthcare provider.
Advise women to notify their healthcare provider if they could possibly be pregnant prior to therapy with brexanolone. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to brexanolone during pregnancy.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Brexanolone is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.
Distribution of brexanolone is restricted. (See Brexanolone REMS, in Cautions.)
For injection concentrate, for IV infusion
Sage Therapeutics Inc.
AHFS Drug Information. © Copyright 2022, Selected Revisions June 24, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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