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 [see Warnings and Precautions ( 5.1 ) ]. 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) [see Warnings and Precautions ( 5.1 ) ]. Because of these risks, ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS [see Warnings and Precautions ( 5.2 ) ]. WARNING: EXCESSIVE SEDATION AND SUDDEN LOSS OF CONSCIOUSNESS See full prescribing information for complete boxed warning. Patients are at risk of excessive sedation or sudden loss of consciousness during administration of ZULRESSO. ( 5.1 ) 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). ( 5.1 ) ZULRESSO is available only through a restricted program called the ZULRESSO REMS. ( 5.1 , 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Suicidal Thoughts and Behaviors: Consider changing the therapeutic regimen, including discontinuing ZULRESSO, in patients whose PPD becomes worse or who experience emergent suicidal thoughts and behaviors. ( 5.3 ) 5.1 Excessive Sedation and Sudden Loss of Consciousness 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 adult 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 to 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, 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 [see Dosage and Administration ( 2.2 )] . Immediately stop the infusion if pulse oximetry reveals hypoxia. After hypoxia, the infusion should not be resumed. 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 of opioids, antidepressants, or other CNS depressants such as benzodiazepines or alcohol may increase the likelihood or severity of adverse reactions related to sedation [see Drug Interactions ( 7.1 , 7.2 )] . Because of the risk of serious harm resulting from excessive sedation or sudden loss of consciousness, ZULRESSO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ZULRESSO REMS [see Warnings and Precautions ( 5.2 )] . 5.2 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 [see Warnings and Precautions ( 5.1 )] . Notable requirements of the ZULRESSO REMS include the following: 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 1-844-472-4379. 5.3 Suicidal Thoughts and Behaviors In pooled analyses of placebo-controlled trials of chronically administered antidepressant drugs (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. 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). The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric ZULRESSO is not approved in patients less than 15 years old. and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient 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.
warnings and cautions table
<table ID="table1" width="775" styleCode="Noautorules"><caption>Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric<footnote>ZULRESSO is not approved in patients less than 15 years old.</footnote> and Adult Patients</caption><col width="30%" align="center"/><col width="70%" align="center"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Age Range (years)</content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Rrule"><content styleCode="bold">Increases Compared to Placebo</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"><18</td><td styleCode="Botrule Rrule">14 additional patients</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">18-24</td><td styleCode="Botrule Rrule">5 additional patients</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Rrule"><content styleCode="bold">Decreases Compared to Placebo</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">25-64</td><td styleCode="Botrule Rrule">1 fewer patient</td></tr></tbody></table>
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Excessive Sedation and Sudden Loss of Consciousness [see Boxed Warning , Warnings and Precautions ( 5.1 )] 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. ( 6.1 ) 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZULRESSO was evaluated in 140 adult patients with postpartum depression (PPD). A titration to a target dosage of 90 mcg/kg/hour was evaluated in 102 adult patients and a titration to a target dose of 60 mcg/kg/hour was evaluated in 38 adult patients [see Clinical Studies ( 14 )] . Patients were then followed for 4 weeks. 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 ( Table 2 ). Adverse Reactions Leading to Discontinuation, Dosage Interruption, or Dosage Reduction In the pooled placebo controlled-studies in adults, 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 in adults, 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. Table 2 presents the adverse reactions that occurred in ZULRESSO-treated adult PPD patients at a rate of at least 2% and at a higher rate than in the placebo-treated patients during the 60-hour treatment period. Table 2: Adverse Reactions in Placebo-Controlled Studies in Adults with PPD Reported in ≥ 2% of ZULRESSO-Treated Patients and Greater than Placebo-Treated Patients Placebo (n=107) Maximum dosage 60 mcg/kg/hour (n=38) Maximum dosage 90 mcg/kg/hour (Recommended dosage) (n=102) Cardiac Disorders Tachycardia - - 3% Gastrointestinal Disorders Diarrhea 1% 3% 2% Dry mouth 1% 11% 3% Dyspepsia - - 2% Oropharyngeal pain - 3% 2% Nervous System Disorders Dizziness, presyncope, vertigo 7% 13% 12% Loss of consciousness - 5% 3% Sedation, somnolence 6% 21% 13% Vascular Disorders Flushing, hot flush - 5% 2% 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 PPD. 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.