About ZULRESSO

ZULRESSO safety profile

Learn about the safety profile of ZULRESSO® (brexanolone) and consider if it may be right for your patients.

Excessive sedation and sudden loss of consciousness1

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 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 15-60 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

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.

Caution patients

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

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.

ZULRESSO REMS1

ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the ZULRESSO REMS because excessive sedation or sudden loss of consciousness can result in serious harm.

See notable requirements of the ZULRESSO REMS

Suicidal thoughts and behaviors1

Risk with antidepressants

In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (selective serotonin reuptake inhibitors [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.

Variation in risk

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).

Considerations for ZULRESSO

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.

ZULRESSO adverse reactions1

Adverse reactions reported in ≥2% of ZULRESSO-treated adult patients and greater than in placebo-treated patients during the 60-hour treatment period

Chart representing exposure to Zulresso in 140 patients across 3 studies

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 postpartum depression. 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.

The data described in the table reflect exposure to ZULRESSO in 140 adult patients across 3 studies.1-3

Most common adverse reactions

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.

Discontinuation

In the pooled placebo-controlled studies, 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.

Interruption or reduction

In the pooled placebo-controlled studies, 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.

Use in specific populations

Pregnancy: Based on findings from animal studies of other drugs that enhance GABAergic inhibition, ZULRESSO may cause fetal harm.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including ZULRESSO, 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/

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.

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

Renal Impairment: 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.

Breastfeeding considerations1

There are no data on the effects of ZULRESSO on a breastfed infant.

Lactation study information

  1. A study was conducted in 12 healthy adult lactating women treated with intravenous ZULRESSO according to the recommended 60-hour dosing regimen (maximum dosage was 90 mcg/kg/hour)
  2. The study indicated that brexanolone is transferred to breastmilk in nursing mothers
  3. 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
  4. The calculated maximum relative infant dose for ZULRESSO during the infusion is 1% to 2% of the maternal weight-adjusted dosage

Risk considerations

  1. ZULRESSO has low oral bioavailability (<5%) in adults; therefore, infant exposure is expected to be low
  2. Available data on the use of ZULRESSO during lactation do not suggest a significant risk of adverse events to breastfed infants from exposure to ZULRESSO
  3. 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

Discuss the potential benefits and risks of breastfeeding during the infusion with your patients.

INDICATION

ZULRESSO® is indicated for the treatment of postpartum depression (PPD) in patients 15 years and older

ZULRESSO IMPORTANT SAFETY INFORMATION

WARNING: EXCESSIVE SEDATION AND SUDDEN LOSS OF CONSCIOUSNESS

Patients treated with ZULRESSO are at risk of excessive sedation or sudden loss of consciousness during administration.

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).

Because of these risks, ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS.

WARNINGS AND PRECAUTIONS

Excessive Sedation and Sudden Loss of Consciousness

In clinical studies in adults, 5% of ZULRESSO-treated patients compared to 0% of placebo-treated patients experienced sedation and somnolence that required dose interruption or reduction during the infusion. Loss of consciousness or altered state of consciousness was reported in 4% of ZULRESSO-treated patients compared with 0% of placebo-treated during the infusion.

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

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.

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. 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.

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.

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.

Notable requirements of the ZULRESSO REMS include:

  • 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 call 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 include 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).

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. If depression becomes worse or patients experience emergent suicidal thoughts and behaviors, consider changing the therapeutic regimen, including discontinuing ZULRESSO.

Adverse Reactions

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.

Adverse reactions reported in an open-label study in patients 15 to 17 years were generally similar to those observed in clinical studies of ZULRESSO in adults with PPD.

Use in Specific Populations

  • Pregnancy: Based on findings from animal studies of other drugs that enhance GABAergic inhibition, ZULRESSO may cause fetal harm
  • Lactation: Brexanolone is transferred to breastmilk in nursing mothers. There are no data on the effects of ZULRESSO on a breastfed infant. 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
  • Pediatric Use: The safety and effectiveness of ZULRESSO for the treatment of PPD have been established in patients 15 to 17 years. The safety and effectiveness of ZULRESSO in patients less than 15 years of age have not been established
  • Renal Impairment: No dosage adjustment is recommended in patients with mild, moderate, or severe renal impairment. Avoid use of ZULRESSO in patients with end stage renal disease (ESRD)

Controlled Substance

ZULRESSO contains brexanolone, a Schedule IV controlled substance.

To report SUSPECTED ADVERSE REACTIONS, contact Sage Therapeutics, Inc. at 1-844-4-SAGERX (1-844-472-4379) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying full Prescribing Information including Boxed Warning.

INDICATION
ZULRESSO® is indicated for the treatment of postpartum depression in patients 15 years and older.

IMPORTANT SAFETY INFORMATION
WARNING: EXCESSIVE SEDATION AND SUDDEN LOSS OF CONSCIOUSNESS
Patients treated with ZULRESSO are at risk of excessive sedation or sudden loss of consciousness during administration.
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).
Because of these risks, ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS.

References

  1. ZULRESSO Prescribing Information. Cambridge, MA: Sage Therapeutics, Inc.; 6/2022.
  2. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018;392(10152):1058-1070.
  3. Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390(10093):480-489.