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.
In clinical studies, 5% of ZULRESSO-treated patients compared to 0% of placebo-treated patients experienced sedation and somnolence that required dose interruption or reduction. Loss of consciousness or altered state of consciousness was reported in 4% of ZULRESSO-treated patients compared with 0% of placebo-treated patients.
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.
Notable requirements of the ZULRESSO REMS include:
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.
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.
ZULRESSO contains brexanolone, a Schedule IV controlled substance under the Controlled Substances Act.
The efficacy of ZULRESSO in the treatment of PPD was demonstrated in two multicenter, randomized, double-blind, placebo-controlled studies (referred to as Studies 1 and 2) in women (18 to 45 years) with PPD who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode (DSM-IV) with onset of symptoms in the third trimester or within 4 weeks of delivery. Women were enrolled up to 6 months postpartum. In these studies, patients received a 60-hour continuous intravenous infusion of ZULRESSO or placebo and were then followed for 4 weeks. Study 1 (NCT02942004) included patients with severe PPD (HAM-D score ≥26), and Study 2 (NCT02942017) included patients with moderate PPD (HAM-D score of 20 to 25). A titration to the recommended target dosage of 90 mcg/kg/hour was evaluated in both studies (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 20 hours, 90 mcg/kg/hour for 28 hours, followed by a taper to 60 mcg/kg/hour for 4 hours and then 30 mcg/kg/hour for 4 hours). A titration to a target dosage of 60 mcg/kg/hour (patients received 30 mcg/kg/hour for 4 hours, 60 mcg/kg/hour for 52 hours, then 30 mcg/kg/hour for 4 hours) was also evaluated in Study 1.
The safety of ZULRESSO was evaluated across 3 clinical trials (a Phase II study, Study 1, and Study 2) in 140 women who were exposed to ZULRESSO. The Phase II study evaluated 21 women with severe PPD, 10 of whom received a dose of 90/mcg/kg/hour of ZULRESSO.
Demographic and baseline disease characteristics were generally similar across treatment groups in the pooled Studies 1 and 2. Most patients were White (63%) or Black (34%); 18% of patients identified as Hispanic or Latina; the average age of women receiving ZULRESSO was 28 years. Most patients (76%) had onset of PPD symptoms within 4 weeks after delivery, with the remainder having onset during the third trimester. Baseline oral antidepressant use was reported for 23% of patients.
The primary endpoint was the mean change from baseline in depressive symptoms as measured by the HAM-D total score at the end of the infusion (Hour 60). A pre-specified secondary efficacy endpoint was the mean change from baseline in HAM-D total score at Day 30.
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