ZULRESSO safety information.

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Not an actual patient.

Safety

ZULRESSO safety information1

Adverse reactions reported in ≥2% of ZULRESSO-treated patients and greater than in placebo-treated patients

Safety profile across 3 studies
  ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) PLACEBO (n=107)
Cardiac disorders
Tachycardia 3%
Gastrointestinal disorders
Diarrhea 2% 3% 1%
Dry mouth 3% 11% 1%
Dyspepsia 2%
Oropharyngeal pain 2% 3%
Nervous system disorders
Dizziness, presyncope, vertigo 12% 13% 7%
Loss of consciousness 3% 5%
Sedation, somnolence 13% 21% 6%
Vascular disorders
Flushing, hot flush 2% 5%

Tachycardia

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 3%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38)
PLACEBO (n=107)

Diarrhea

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 2%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 3%
PLACEBO (n=107) 1%

Dry mouth

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 3%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 11%
PLACEBO (n=107) 1%

Dyspepsia

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 2%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38)
PLACEBO (n=107)

Oropharyngeal pain

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 2%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 3%
PLACEBO (n=107)

Dizziness, presyncope, vertigo

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 12%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 13%
PLACEBO (n=107) 7%

Loss of consciousness

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 3%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 5%
PLACEBO (n=107)

Sedation, somnolence

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 13%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 21%
PLACEBO (n=107) 6%

Flushing, hot flush

ZULRESSO Maximum dosage 90 mcg/kg/hour (n=102) 2%
ZULRESSO Maximum dosage 60 mcg/kg/hour (n=38) 5%
PLACEBO (n=107)

The data described in the table reflect exposure to ZULRESSO in 140 patients across 3 studies.1,2

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.

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.

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.

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: The safety and effectiveness of ZULRESSO in pediatric patients 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.

Warnings and Precautions

Excessive sedation and sudden loss of consciousness1

In clinical studies, 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 (LOC) 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 to 60 minutes. 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 REMS called the ZULRESSO REMS because excessive sedation or sudden loss of consciousness can result in serious harm.

Suicidal thoughts and behaviors1

Risk in antidepressants

In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (SSRls 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.

Breastfeeding considerations

Breastfeeding considerations1

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

Lactation study information

  • 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)
  • The study indicated that brexanolone is transferred to breastmilk in nursing mothers
  • 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
  • The calculated maximum relative infant dose for ZULRESSO during the infusion is 1% to 2% of the maternal weight-adjusted dosage

Risk considerations

  • ZULRESSO has low oral bioavailability (<5%) in adults; therefore, infant exposure is expected to be low
  • 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
  • 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