About ZULRESSO

How ZULRESSO is thought to work

The mechanism of action of brexanolone in the treatment of postpartum depression is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors.1

ZULRESSO® contains brexanolone, a neuroactive steroid gama-aminobutyric acid (GABA) A receptor positive modulator

ZULRESSO works differently

ZULRESSO does not directly affect monoaminergic systems. Positive allosteric modulators of the GABAA receptor enhance the response of naturally occurring GABA by binding to the receptor and increasing neuronal inhibition by GABA.1-3

Pharmacodynamics

Brexanolone potentiates GABA-mediated currents from recombinant human GABAA receptors in mammalian cells expressing α1β2γ2 receptor subunits, α4β3δ receptor subunits, and α6β3δ receptor subunits.1

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. Reddy DS, Estes WA. Clinical potential of neurosteroids for CNS disorders. Trends Pharmacol Sci. 2016;37(7):543-561.
  3. Carver CM, Reddy DS. Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology (Berl). 2013;230(2):151-188.