Brexanolone is currently the only medication approved by the US FDA for the treatment of postpartum depression (PPD) in patients ≥15 years. Brexanolone is available commercially only through a restricted program (ZULRESSO® Risk Evaluation and Mitigation Strategy; REMS) due to risk of excessive sedation or sudden loss of consciousness during administration.
The aim of this analysis was to assess the postmarketing safety of brexanolone in adults with PPD.
The cumulative postmarketing adverse event (AE) listing from spontaneous and solicited individual case safety reports (ICSRs) received from March 19, 2019, through December 18, 2021, was analyzed. Clinical trial ICSRs were excluded. Reported AEs were classified as serious or nonserious as defined by FDA seriousness criteria and as listed or unlisted based on Table 2.0 within section 6 “Adverse Reactions” of the current brexanolone FDA-approved US Prescribing Information (PI).
Overall, 499 patients received brexanolone in this postmarketing surveillance analysis between June 2019 and December 2021 (postmarketing setting). There were 137 ICSRs with 396 total AEs: 15 serious unlisted, 2 serious listed, 346 nonserious unlisted, and 33 nonserious listed. In total, two serious and one nonserious listed excessive sedation AEs were reported—all resolved by stopping infusion and did not require any treatment; no loss of consciousness AEs were received.
Results from postmarketing surveillance data analysis are consistent with the safety profile of brexanolone for the treatment of PPD as described in the FDA-approved PI. No new safety concerns or new aspects of known risks requiring an update to the FDA-approved PI were identified.
Postpartum depression (PPD) is a common mood disorder affecting approximately 10%–15% of women in the US who give birth.
Brexanolone is the first and only medication approved by the US FDA for the treatment of PPD in patients 15 years and older.
In published brexanolone (60 and 90 μg/kg/h) clinical trials, the most common adverse reactions included sedation/somnolence (15% [21/140 total patients]), dizziness/presyncope/vertigo (12% [17/140]), dry mouth (5% [7/140]), loss of consciousness (3.6% [5/140]), and flushing/hot flush (2.9% [4/140]).
This postmarketing surveillance report evaluating brexanolone adverse events from March 19, 2019, through December 18, 2021, demonstrated that the rates of excessive sedation and loss of consciousness were lower than what was observed in clinical trials. Furthermore, the clinically observed severity was consistent with the events observed in completed clinical trials, with no new safety signals identified.
Postpartum depression (PPD) is a common mood disorder, occurring in 10%–15% of women giving birth in the US [1,2,3]. As a disabling condition for the mother, PPD may contribute to poor developmental outcomes in children . According to the American Psychiatric Association, the standard-of-care therapies for PPD—including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, and atypical antidepressants—may be effective, but the evidence supporting long-term efficacy and safety is inconclusive [4,5,6,7]. Furthermore, standard-of-care therapies are often associated with adverse events (AEs), such as increased suicidal thoughts, cardiovascular AEs, weight gain/loss, sexual dysfunction, and loss of appetite . Therefore, there is an unmet need for novel treatments designed to treat PPD .
Brexanolone (ZULRESSO®, Sage Therapeutics, Inc., Cambridge, MA, USA), a neuroactive steroid and positive allosteric modulator of γ-aminobutyric acid receptor type A, is the only medication approved by the US Food and Drug Administration (FDA) specifically for the treatment of PPD in patients 15 years and older [9,10,11]. Brexanolone, administered as a continuous intravenous infusion over 60 hours with a titration regimen up to 90 μg/kg/h, was approved by the FDA in March 2019 and became commercially available in June 2019 . In pivotal phase II and phase III clinical trials for brexanolone, the most common AEs (≥5% incidence across trials) included sedation/somnolence (15%), dizziness/presyncope/vertigo (12%), and dry mouth (5%) [9,10,11]. Meltzer-Brody and colleagues reported that brexanolone may cause excessive sedation in some adults patients (4%) . In addition, in clinical trials, some patients reported events of sudden loss of consciousness or altered state of consciousness (4%) during the brexanolone infusion [9,10,11]. Due to these risks, in the postmarketing environment, brexanolone is available only through the ZULRESSO® Risk Evaluation and Mitigation Strategy (REMS) program [1, 11,12,13].
A REMS program is a drug safety program that the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks . Designed to reinforce safe drug use, REMS programs focus on informing, educating, and/or reinforcing actions to reduce the frequency and/or severity of AEs. As such, the ZULRESSO® REMS program is a safety program to manage the risk of serious harm resulting from excessive sedation and sudden loss of consciousness during brexanolone infusion. It consists of a certified enrollment program for dispensing pharmacies and healthcare settings, enrolled patients in a registry, and administration of brexanolone to patients only in a medically supervised healthcare setting that provides monitoring while brexanolone is being administered . Patients enrolled in the program are prescribed a single continuous 60-h infusion of brexanolone for each episode of PPD at a certified healthcare facility (e.g. hospital or infusion center). Following completion of the infusion and a postinfusion assessment, which includes ensuring any sedative effects have dissipated, patients are then released from the healthcare facility.
Of note, on June 16, 2022, following the initial approval of brexanolone, the indication was extended to include patients 15–17 years by the FDA. Findings from this patient population are not part of this postmarketing surveillance data analysis as the data cut-off date for this analysis was December 18, 2021. In this manuscript, we present the postmarketing surveillance safety data analysis for brexanolone in adults 18 years and older with PPD, with primary focus on excessive sedation and loss of consciousness as defined in the ZULRESSO® REMS.
Brexanolone is only available through the ZULRESSO® REMS program and must be administered at certified healthcare facilities enrolled in the program via certified pharmacies and to patients enrolled in the ZULRESSO® REMS program. Brexanolone is administered in a medically supervised healthcare setting that provides continuous monitoring of the patient. It is administered as a single, continuous, 60-h (2.5 days) intravenous infusion via a dedicated line and programmable peristaltic pump with continuous pulse oximetry (0–4 h: initiate with a dose of 30 μg/kg/h; 4–24 h: increase dose to 60 μg/kg/h; 24–52 hours: increase dose to 90 μg/kg/h [a reduction in dosage to 60 μg/kg/h may be considered during this time period for patients who do not tolerate 90 μg/kg/h]; 52–56 h: decrease dose to 60 μg/kg/h; 56–60 hours: decrease dose to 30 μg/kg/h). A single 60-h infusion of brexanolone is prescribed for each episode of PPD after delivery. For example, a woman who develops PPD after a pregnancy (first, second, or third pregnancy) may receive brexanolone for each episode of PPD with consecutive pregnancy(ies) as appropriate. For additional information regarding dosage and administration, please refer to the brexanolone FDA-approved US Prescribing Information (PI) .
A Global Safety Database was used for collection of individual case safety reports (ICSRs) for brexanolone from the postmarketing setting. A postmarketing AE listing from spontaneous and solicited ICSRs received from March 19, 2019, through December 18, 2021, was used for the analysis. Any AE information received voluntarily or in an unsolicited manner was considered a spontaneous report. Any AE information received from patients (or healthcare professionals) when contacted by the REMS patient services team directly to learn about their brexanolone infusion experience was considered solicited. The Medical Dictionary for Regulatory Activities (MedDRA®) version 24.1 in effect at the data cut-off was used for the coding of AEs, and AEs were broken down according to MedDRA® system organ class (SOC) and preferred term (PT). This is a postmarketing analysis, and ICSRs from clinical trials were excluded.
For the purpose of this report, AEs were classified as listed if included in Table 2.0 within section 6 of the current brexanolone FDA-approved US PI, and as unlisted if not included in Table 2.0. Serious AEs were defined in line with the FDA seriousness criteria as any AE that leads to death, a life-threatening occurrence, an inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly, and any other medically significant event that may jeopardize the patient and may require medical or surgical intervention to prevent one of the other outcomes [15, 16].
Based on the ZULRESSO® REMS program, as of December 18, 2021, a total of 499 patients with PPD received treatment with brexanolone in this postmarketing surveillance analysis since it became commercially available in June 2019 . Overall, 137 ICSRs with a total of 396 AEs were received, with all 137 ICSRs representing postmarketing use only (Table 1 and Supplemental Table 1, see Electronic Supplementary Material [ESM]); of these, 50 were solicited and 87 were spontaneous reports.
Overall, there were 15 serious unlisted AEs; the majority (80%, 12/15) were in the psychiatric disorder SOC and represented symptoms of psychiatric disorders (n = 12), including suicidal ideation (n = 4), homicidal ideation (n = 2), and abnormal behavior, agitation, anxiety disorder, panic disorder, perinatal depression, and psychotic disorder (n = 1 each). The remaining three serious unlisted events were in SOCs of nervous system disorders (n = 1; seizure), respiratory disorders (n = 1; hypoxia), and general disorder/administration site conditions (n = 1; condition aggravated; Table 2).
The two serious listed AEs were both excessive sedation (PT: Sedation complication). A 30-year-old patient receiving brexanolone 90 μg/kg/h experienced dizziness followed by excessive sedation within 2 h. The sedation resolved after immediately stopping the brexanolone infusion, with no additional treatment needed. The infusion was not restarted, and the total infusion time was approximately 50 h. Although the infusion was not restarted, treatment was reported as successful, with favorable results. The second excessive sedation event occurred in a 22-year-old patient who drifted off to sleep and was not easily arousable. The event occurred while the infusion was at 60 μg/kg/h, and 10 h following the administration of promethazine hydrochloride. The infusion was immediately stopped and not restarted (total time of infusion was approximately 24 h). The patient woke up 50 min later and was conversational with no memory loss and felt as if she had been sleeping. The event was assessed as possibly related to brexanolone, noting concomitant treatment with promethazine as a potential confounding factor. Both events were deemed medically significant.
Of the 346 nonserious unlisted AEs, the most frequently reported were in the following SOCs: Injury/poisoning and procedural complications (n = 95; 27%), Psychiatric disorders (n = 94; 27%), General disorders and administration site conditions (n = 87; 25%), Nervous system disorders (n = 23; 7%), and Investigations (n = 11; 3%). The reported nonserious listed AEs (n = 33) were in the following SOCs: Nervous system disorders (n = 24; 73%), Vascular disorders (n = 4; 12%), Gastrointestinal disorders (n = 2; 6%), and Ear and labyrinth disorders, Investigations, and Injury/poisoning and procedural complications (all three n = 1; 3%). A single excessive sedation event presented in the Injury/poisoning and procedural complications SOC, and it was assessed as nonserious. The 32-year-old patient experienced worsening of migraine followed by excessive sedation. At the time of the event, approximately 30 hours into the infusion, the brexanolone infusion dose was 90 μg/kg/h. The infusion was stopped and restarted 2.5 hours after the initial onset of sedation complication and completed without the recurrence of excessive sedation.
The FDA REMS program was developed to ensure that drugs with serious safety concerns are safely administered and to reinforce the overall safe use of certain medications . The rapid onset of action and positive response to brexanolone makes it unique compared with other antidepressants such as SSRIs that may require 4–6 weeks for a response in patients with PPD [10, 17]. The analysis of postmarketing safety data from March 19, 2019, to December 18, 2021, did not identify any new safety risks or new aspects of known risks of excessive sedation or loss of consciousness. The three reported events of excessive sedation were similar in nature and severity to previously reported events of excessive sedation, and there were no reports of loss of consciousness from postmarketing sources [9,10,11]. In this postmarketing surveillance data analysis, excessive sedation and loss of consciousness when receiving brexanolone occurred at lower rates (< 1% [3/499] and 0% [0/499] of patients, respectively) than those reported in completed clinical trials [9,10,11]. The cumulative postmarketing data supports safety of brexanolone for the treatment of PPD. Notably, the majority of AEs reported during the postmarketing surveillance period were nonserious events.
Based on the assessment of the available cumulative safety data from this postmarketing surveillance data analysis, there was insufficient evidence of a causal relationship between brexanolone and the 15 serious and 346 nonserious unlisted events. These unlisted events did not represent a new adverse drug reaction for brexanolone nor a new aspect of a known risk; rather, these events were considered to be attributed to the signs and symptoms of the underlying PPD, concomitant medications, and/or the medical history of the patients. As such, based on a comprehensive analysis of these unlisted serious/nonserious AEs and insufficient evidence of a clear causal relationship between brexanolone and these unlisted events, an update to the current US PI was not warranted .
In this report of postmarketing data, the majority of the ICSRs were spontaneously reported. It is important to note that spontaneous reporting has inherent limitations, such as underreporting, variability in data reported, lack of information on precise timing of drug exposure in relation to the occurrence of AEs (the time to onset of the AE), and the role of other drugs that were used concomitantly with brexanolone when the AE occurred cannot be completely ruled out. As such, the results of our analysis must be interpreted in the context of these limitations.
Of note, after the cut-off date of this analysis, on June 16, 2022, based on results of a completed phase III, multicenter study (CHICKADEE; NCT 03665038), which evaluated the safety profile, tolerability, and pharmacokinetics of brexanolone in the treatment of adolescent patients (aged 15–17 years) with PPD, approval to extend the indication of brexanolone to include patients 15 years and older diagnosed with PPD was received from the FDA , and the ZULRESSO® REMS program was expanded accordingly.
Overall, there were no new safety concerns, new aspects of known safety risks, or trends identified related to the benefit–risk profile of brexanolone. When brexanolone is used according to the approved labeling, the benefits remain favorable for patients 18 years and older with PPD . This postmarketing surveillance report of brexanolone shows that the rates of excessive sedation and loss of consciousness were lower in the postmarketing setting, with comparable severity observed clinically compared with the completed clinical trials, and no new safety signals were detected [9, 10]. This report supports the safety profile of brexanolone for the treatment of adults with PPD [9, 10].
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This postmarketing surveillance analysis was funded by Sage Therapeutics, Inc. Medical writing support was provided by Alexander Milliken, PhD, of AlphaBioCom, a Red Nucleus company.
This surveillance program was funded by Sage Therapeutics, Inc.
Conflict of Interest
SG and ES are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. VD was an employee of Sage Therapeutics, Inc., at the time of this report, and may hold stock and/or stock options.
Consent to Participate
All patients reviewed the ZULRESSO® Patient Information Guide and enrolled in the REMS program by completing the Patient Enrollment Form with a healthcare provider.
Consent for Publication
Availability of Data and Material
The data that support the findings of this postmarketing surveillance program are available from the corresponding author upon reasonable request.
All authors contributed to data interpretation and writing of the manuscript. All authors approved the final draft for submission.
Affiliation at the time the analysis was conducted.
Below is the link to the electronic supplementary material.
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Garafola, S., Shiferaw, E. & Dev, V. Safety of Brexanolone in Adults with Postpartum Depression: Postmarketing Surveillance Data. Drugs - Real World Outcomes 10, 351–356 (2023). https://doi.org/10.1007/s40801-023-00372-4