Brexanolone is a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator for the treatment of postpartum depression in adult and pediatric patients 15 years and older. Brexanolone is an analog of allopregnanolone, an endogenous steroid hormone metabolite that increases during pregnancy and then declines abruptly after birth. In some women, this decline is thought to trigger depression and anxiety. Patients, treating healthcare facilities, wholesalers, distributors, and dispensing pharmacies of brexanolone must be enrolled in the Zulresso REMS monitoring program due to the risk of excessive sedation or loss of consciousness. A healthcare provider must be available on site to continuously monitor the patient, and intervene as necessary, for the duration of the 60-hour intravenous infusion. Patients must be monitored for hypoxia with continuous pulse oximetry and assessed for excessive sedation every 2 hours during planned, non-sleep periods throughout the infusion duration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Intravenous Administration
Brexanolone Infusion Preparation:
-The vials are available as a concentrated solution that requires dilution before administration.
-Visually inspect each vial, which should be a clear, colorless solution, for particulate matter and discoloration before administration. Do not use discolored vials or vials with particulate matter.
-Generally, 5 infusion bags will be required for the 60-hour infusion; additional bags will be needed for patients weighing 90 kg or more.
-Prepare and store in a polyolefin, non-DEHP, nonlatex bag only. Do not use in-line filter infusion sets.
-Dilute in the infusion bag immediately after the initial puncture of the vial.
-Withdraw 20 mL of brexanolone 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.
Brexanolone Administration Instructions:
-Administer as a continuous intravenous infusion over a total of 60 hours (2.5 days) via a dedicated line. Do not inject other medications into the infusion bag or mix with brexanolone.
-Use a programmable peristaltic infusion pump to ensure accurate drug delivery.
-Fully prime infusion administration sets with admixture before inserting into the pump and connecting to the venous catheter.
-A healthcare provider must be available on site to continuously monitor the patient, and intervene if needed, for the duration of the infusion.
-Monitor patients for hypoxia using continuous pulse oximetry equipped with an alarm throughout the infusion. If hypoxia occurs, discontinue treatment and do not re-initiate.
-Initiate treatment early enough during the day to allow for recognition of excessive sedation.
-Assess for excessive sedation every 2 hours during planned, non-sleep periods. Discontinue infusion if excessive sedation occurs; may re-start infusion when symptoms resolve, at the same or lower dose.
Brexanolone Reconstituted Storage Instructions:
-After the product is diluted, it can be stored in infusion bags under refrigerated conditions for up to 96 hours. Prolonged storage at room temperature may support adventitious microbial growth.
-Each diluted product can be used for up to 12 hours of infusion time at room temperature. Discard any unused brexanolone after 12 hours of infusion.
During clinical trials in adults with postpartum depression, the following centrally-mediated (CNS) effects occurred in at least 2% of brexanolone-treated patients and more frequently than in placebo-treated patients: dizziness/presyncope/vertigo (12% to 13%), loss of consciousness (3% to 5%), and drowsiness/sedation/somnolence (13% to 21%). In an open-label clinical study of 20 adolescents aged 15 to 17 years, 1 patient (5%) developed dizziness and loss of consciousness. Adverse reactions leading to treatment discontinuation or dose reduction in brexanolone-treated patients were frequently related to sedation (loss of consciousness, fatigue, vertigo, syncope, and presyncope). Due to these risks, patients must be accompanied during interactions with their child(ren) while receiving the infusion and should be monitored for sedative effects every 2 hours during planned, non-sleep periods during the infusion. Treatment with brexanolone should be stopped immediately if there are signs or symptoms of excessive sedation or if the pulse oximetry reveals hypoxia. If clinically indicated, the infusion may be restarted at the same or a reduced dose after symptoms of sedation resolve; however, after a hypoxic episode, the infusion should not be resumed. Time to full recovery from a loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes. There was no clear association between loss or alteration of consciousness and pattern or timing of dose, and not all patients reported sedation or somnolence before the event. Of 5 brexanolone-treated adult patients who had a dose interruption due to loss of consciousness, 3 patients subsequently resumed and completed treatment after symptom resolution and 2 patients did not.
During clinical trials in adults with postpartum depression, the following adverse gastrointestinal (GI) effects occurred in at least 2% of brexanolone-treated patients and more frequently than in placebo-treated patients: diarrhea (2% to 3%), xerostomia (3% to 11%), dyspepsia (up to 2%), and oropharyngeal pain (2% to 3%).
During clinical trials in adults with postpartum depression, the following cardiac or vascular disorders occurred in at least 2% of brexanolone-treated patients and more frequently than in placebo-treated patients: sinus tachycardia (up to 3%) and flushing/hot flush (2% to 5%). A change in blood pressure was among the adverse reactions leading to treatment discontinuation or dose reduction in brexanolone-treated patients. In a cardiac electrophysiology study, brexanolone did not prolong the QT interval to a clinically relevant extent.
A pooled analysis of placebo-controlled trials including approximately 77,000 adults and 4,500 pediatric patients showed that the incidence of suicidal thoughts and behaviors in pediatric patients and young adults (up to 24 years of age) was greater than in placebo-treated patients for most antidepressants studied (SSRIs and others). These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients 65 years and older. Because brexanolone does not directly affect monoaminergic systems and there is a low number of exposures to brexanolone, the risk of suicidal ideation is unknown. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation before treatment have an increased risk for suicidal ideation or attempts and should be closely monitored. Consider changing the therapeutic regimen, including discontinuation of brexanolone, in patients with worsening depression or emergent suicidality.
During clinical trials in adults with postpartum depression, injection site reaction (e.g., injection site pain) was among the adverse reactions leading to discontinuation of treatment; however, the exact frequency was not specified. In a pooled analysis of clinical trials, the incidence of patients who discontinued treatment with brexanolone due to any adverse effect was 2% versus 1% of placebo-treated patients.
Brexanolone may carry a risk for abuse and dependence. In the postpartum depression clinical studies conducted with brexanolone, the end of the treatment infusion occurred through tapering. Thus, in these studies it was not possible to assess whether abrupt discontinuation of the drug produced withdrawal symptoms indicative of physiological dependence. It is recommended that brexanolone be tapered as in the product label, unless symptoms warrant immediate discontinuation. In a human abuse potential study, 90 mcg/kg, 180 mcg/kg (2 times the maximum recommended infusion rate), and 270 mcg/kg (3 times the maximum recommended infusion rate) brexanolone infusions over a 1-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 90 mcg/kg and 180 mcg/kg were lower than both alprazolam doses. However, the scores on the positive subjective measures for brexanolone 270 mcg/kg dosage were similar to those produced by both doses of alprazolam. In this study, 3% of subjects administered brexanolone 90 mcg/kg and 13% administered 270 mcg/kg reported euphoric mood (euphoria), compared to none administered placebo during the 1-hour administration.
Brexanolone is available only through the Zulresso risk Evaluation and Mitigation Strategy (Zulresso REMS) program because of the risks of serious adverse outcomes including excessive sedation or sudden loss/alteration of consciousness. Brexanolone administration requires a specialized care setting (i.e., healthcare settings must be certified in the REMS program). Additional requirements include the following: all patients must be enrolled in the Zulresso REMS program before receiving brexanolone, pharmacies must be certified in the REMS program and must only dispense brexanolone to healthcare settings that are certified in the program, and wholesalers and distributors must be registered in the REMS program and must only distribute to certified healthcare facilities and pharmacies. For further information, including a list of certified healthcare facilities, visit www.zulressorems.com or call 1-844-472-4379.
Brexanolone is available only through a specialized monitoring program because of the risks of serious adverse outcomes from sedation or sudden loss of consciousness. Due to these risks, patients must be accompanied during interactions with their child(ren) while receiving brexanolone treatment regimens. Monitor treated patients for sedative effects every 2 hours during planned, non-sleep periods during the infusion. Stop treatment with brexanolone immediately if there are signs or symptoms of excessive sedation or if the pulse oximetry reveals hypoxia/hypoxemia. If clinically indicated, the infusion may be restarted at the same or a reduced dose after symptoms of sedation resolve; however, after a hypoxic episode, the infusion should not be resumed. CNS depression ranging from sedation (5%) to loss/altered state of consciousness (4%) occurred during clinical trial evaluation. Time to full recovery from loss or altered state of consciousness, after dose interruption, ranged from 15 to 60 minutes. There was no clear association between loss or alteration of consciousness and pattern or timing of dose, and not all patients reported sedation or somnolence before the event. Advise patients to avoid activities requiring coordination and concentration, such as driving or operating machinery or engaging in other potentially hazardous activities requiring complete mental alertness and motor coordination until any CNS depressant effects have dissipated. Patients receiving brexanolone should be closely monitored since coadministration with other CNS depressants may increase the incidence or severity of sedation. Patients should be instructed to avoid ethanol ingestion during treatment.
Brexanolone should be avoided in patients with end-stage renal disease (ESRD) or renal failure (i.e., eGFR less than 15 mL/minute/1.73 m2) because of the potential accumulation of betadex sulfobutyl ether sodium, a solubilizing agent in the formulation.
A pooled analysis of placebo-controlled trials including approximately 77,000 adults and 4,500 pediatric patients showed that the incidence of suicidal thoughts and behaviors in pediatric patients and young adults (up to 24 years of age) was greater than in placebo-treated patients for most antidepressants studied (SSRIs and others). Because brexanolone does not directly affect monoaminergic systems and there is a low number of exposures to brexanolone, the risk of suicidal ideation is unknown. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation before treatment have an increased risk for suicidal ideation or attempts and should be closely monitored. Consider changing the therapeutic regimen, including the discontinuation of brexanolone, in patients with worsening depression or emergent suicidality.
Patients should be advised that brexanolone can be abused or lead to physical dependence. Brexanolone should be tapered according to the dosage recommendations unless symptoms warrant abrupt discontinuation. In a human abuse potential study, 3% of subjects receiving the recommended maximum infusion dose of 90 mcg/kg and 13% of subjects receiving three times the recommended maximum (i.e., 270 mcg/kg) reported a euphoric mood compared to no patients receiving placebo during the one-hour administration. During clinical trials for postpartum depression, it was not possible to assess withdrawal due to physical dependence because the dose was tapered at the end of treatment.
Available human data regarding the use of brexanolone during pregnancy is limited to case reports and insufficient to determine any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Results from some animal reproductive studies using doses exceeding the maximum recommended human dose (MRHD) of brexanolone showed fetal harm, including fetal developmental toxicity, maternal toxicity, lower pup survival, and neurobehavioral deficits in female offspring. In animal studies assessing other drugs that enhance GABAergic transmission, drug administration to neonatal rats caused widespread apoptotic neurodegeneration in the developing brain. The window of vulnerability to these changes (postnatal days 0 to 14) corresponds to the period of brain development that occurs during the third trimester of human pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to assist patients to register by contacting the National Pregnancy Registry for Antidepressants online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-844-405-6185.
Available data on the use of brexanolone during breast-feeding do not suggest a significant risk of adverse reactions to breastfed infants from exposure to brexanolone. Data from a lactation study in 12 adult women who received intravenous brexanolone according to the recommended 60-hour dosing regimen indicate that brexanolone is transferred to breastmilk in nursing mothers, with a maximum relative infant dose of 1% to 2% of the maternal weight-adjusted dosage during the infusion. Concentrations of brexanolone in breastmilk were at low levels (less than 10 ng/mL) in more than 95% of the women by 36 hours after the end of the infusion. Because brexanolone has a low oral bioavailability of less than 5% in adults, infant exposure is expected to be low. There are no reports of effects of brexanolone on milk production, and there are no formal data on effects of brexanolone on a breastfed infant. The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for brexanolone and any potential adverse effects on the breastfed child from the drug or the underlying maternal condition.
For the treatment of postpartum depression:
Intravenous dosage:
Adults: 30 mcg/kg/hour continuous IV infusion for hours 0 to 4, followed by 60 mcg/kg/hour continuous IV infusion for hours 4 to 24, followed by 90 mcg/kg/hour continuous IV infusion for hours 24 to 52, followed by 60 mcg/kg/hour continuous IV infusion for hours 52 to 56, and followed by 30 mcg/kg/hour continuous IV infusion for hours 56 to 60. May reduce dose to 60 mcg/kg/hour for hours 24 to 52 for persons who do not tolerate 90 mcg/kg/hour. Stop the infusion if excessive sedation; may resume at the same or lower dose as appropriate once symptoms resolve.
Adolescents 15 to 17 years: 30 mcg/kg/hour continuous IV infusion for hours 0 to 4, followed by 60 mcg/kg/hour continuous IV infusion for hours 4 to 24, followed by 90 mcg/kg/hour continuous IV infusion for hours 24 to 52, followed by 60 mcg/kg/hour continuous IV infusion for hours 52 to 56, and followed by 30 mcg/kg/hour continuous IV infusion for hours 56 to 60. May reduce dose to 60 mcg/kg/hour for hours 24 to 52 for persons who do not tolerate 90 mcg/kg/hour. Stop the infusion if excessive sedation; may resume at the same or lower dose as appropriate once symptoms resolve.
Maximum Dosage Limits:
-Adults
90 mcg/kg/hour IV for up to 28 hours of the 60-hour infusion.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
15 years and older: 90 mcg/kg/hour IV for up to 28 hours of the 60-hour infusion.
Less than 15 years: Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Dosage adjustments are not required in patients with any degree of hepatic impairment.
Patients with Renal Impairment Dosing
eGFR 15 mL/minute/1.73m2 and higher: No dosage adjustments required.
eGFR less than 15 mL/minute/1.73 m2: Avoid use due to potential accumulation of betadex sulfobutyl ether sodium, a solubilizing agent.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Acetaminophen; Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Acetaminophen; Oxycodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Alfentanil: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Alprazolam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Belladonna; Opium: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Benzodiazepines: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Celecoxib; Tramadol: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Chlordiazepoxide: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Chlordiazepoxide; Amitriptyline: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Chlordiazepoxide; Clidinium: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Clonazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Clorazepate: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Codeine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Codeine; Guaifenesin: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Codeine; Promethazine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Diazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Estazolam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Fentanyl: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Flurazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Homatropine; Hydrocodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Hydrocodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Hydromorphone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Ibuprofen; Oxycodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Levorphanol: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Lorazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Meperidine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Methadone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Midazolam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Morphine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Morphine; Naltrexone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Oliceridine: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Opiate Agonists: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Oxazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Oxycodone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Oxymorphone: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Quazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Remifentanil: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Remimazolam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Sufentanil: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Tapentadol: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Temazepam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Tramadol: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Tramadol; Acetaminophen: (Moderate) Concomitant use of brexanolone with CNS depressants like the opiate agonists may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Triazolam: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
According to the manufacturer, the mechanism by which brexanolone treats postpartum depression is not fully known but is thought to be related to its positive allosteric modulation of gamma-aminobutyric acid-A (GABA-A) receptors. GABA is a major inhibitory neurotransmitter in the brain. Research conducted at the National Institute of Mental Health (NIMH) indicates that the concentration of allopregnanolone, a metabolite of the endogenous steroid hormone progesterone, increases during pregnancy reaching peak concentrations during the third trimester, then abruptly declines after birth. This decline is thought to trigger the development of depression and anxiety in some women postpartum. Brexanolone is an exogenously produced analog of allopregnanolone.
Brexanolone is administered as an intravenous infusion. The mean steady-state exposures at 60 mcg/kg/hour and 90 mcg/kg/hour were about 52 ng/mL and 79 mg/mL, respectively. The volume of distribution is about 3 L/kg, suggesting extensive distribution into tissues. The drug is highly protein bound (greater than 99%) and is independent of plasma concentrations. Brexanolone is extensively metabolized by non-CYP pathways including keto-reduction, glucuronidation, and sulfation. The 3 major metabolites are pharmacologically inactive. The brexanolone exposure-response relationship and the time course of pharmacodynamic response are unknown. The terminal half-life is about 9 hours. Brexanolone is excreted primarily as metabolites in feces (47%) and urine (42%). Less than 1% of the drug is excreted as unchanged brexanolone.
Affected cytochrome P450 isoenzymes: None
-Route-Specific Pharmacokinetics
Intravenous Route
Dose-proportional pharmacokinetics occur within the recommended dose range.
-Special Populations
Hepatic Impairment
In one hepatic impairment study, no clinically significant differences in the pharmacokinetics of brexanolone were observed based on hepatic function ranging from mild to severe impairment. There were modest increases in exposure to unbound brexanolone and modest decreases in exposure to total brexanolone in patients with moderate to severe hepatic impairment (Child-Pugh score of 7 or higher) with no associated change in tolerability.
Renal Impairment
In one study, no clinically significant differences in the pharmacokinetics of brexanolone were observed in patients with severe impairment. Betadex sulfobutyl ether sodium is a solubilizing agent in the brexanolone injectable formulation. In patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73m2), the AUC and maximum concentration (Cmax) of betadex sulfobutyl ether sodium increased 5.5-fold and 1.7-fold, respectively. Because the pharmacokinetic effects of end-stage renal disease (ESRD) on brexanolone have not been studied and increased systemic exposure to the solubilizing agent betadex sulfobutyl ether occurs in the presence of ESRD, brexanolone should be avoided in patients with ESRD.
Pediatrics
In a clinical study of 20 adolescents aged 15 to 17 years and a diagnosis of postpartum depression, pharmacokinetics were comparable to adult patients receiving brexanolone. The use of brexanolone in patients younger than 15 years old has not been evaluated.