SUMMARY

• Before SPRAVATO administration, instruct patients not to engage in potentially hazardous activities, such as driving a motor vehicle or operating machinery until the next day after a restful sleep.¹
• Somnolence was 1 of the more common treatment-emergent adverse events (TEAE) observed in phase 3 studies (see Table: TEAEs of Sedation/Somnolence and/or MOAA/S).^2-8 Sedative effects were measured by the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale. Based on the MOAA/S, onset of sedative symptoms was generally observed at approximately 15 minutes after the first dose was administered, peaking at 30-45 minutes postdose and resolving by 1 to 1.5 hours postdose.^3,4,9,10
  • The most frequently reported level of sedation in both adult and elderly patients in the treatment-resistant depression (TRD) studies was mild sedation (corresponding to a MOAA/S score of 4).⁹
  • Dose-related increases in the incidence of sedation were observed in the fixed-dose TRD study.³
• Post hoc analyses of 2 short-term and 2 long-term studies in TRD found that those who experienced somnolence or sedation during the first week of treatment with SPRAVATO+oral antidepressant (AD) were more likely to have somnolence or sedation recur during subsequent weeks.^{2,3,5,6,11,12}
• In postmarketing safety data from the Risk Evaluation and Mitigation Strategy (REMS) program from 5 March 2019 to 5 January 2023, sedation was reported in 64.4% of patients and 36.6% of treatment sessions.¹³ In an analysis of postmarketing safety data (first quarter 2019 to second quarter 2021) from the Food and Drug Administration Adverse Event Reporting System (FAERS), sedation (248 reports) and somnolence (34 reports) were reported as expected adverse events (AEs) with a detected signal.¹⁴ In another recent analysis using the FAERS database (first quarter of 2019 to the first quarter of 2023), sedation (n=567) was reported under SPRAVATO-related AEs.¹⁵
• A postmarketing evaluation of Janssen’s Global Medical Safety Database (from March 2019 through January 2023) identified 25 cases in which patients were reported to have concurrent respiratory depression AEs and sedation and/or dissociation.¹⁶ In the majority of cases, patients were using concomitant medications or had comorbidities, including anxiety disorder, obesity, alcohol abuse, and hypothyroidism (although respiratory depression cannot be attributed to these factors).
• Concomitant use with central nervous system (CNS) depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation; therefore, closely monitoring for sedation is recommended with concomitant use of SPRAVATO with CNS depressants.¹⁷

PRODUCT LABELING

• Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS.¹⁸ 
• Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session (including pulse oximetry), followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.¹⁸
• SPRAVATO may cause sedation or loss of consciousness. In some cases, patients may display diminished or less apparent breathing.¹⁸
• In clinical trials, 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (corresponding to a MOAA/s score of 0).¹⁸

BACKGROUND

The MOAA/S was used to measure treatment-emergent sedation. MOAA/S scores correlate with the levels of sedation defined by the American Society of Anesthesiologists (ASA) continuum. The level of sedation was scored on the MOAA/S 0-5 point scale⁹:

• 0=no response to painful stimulus (corresponding to ASA continuum for general anesthesia).
• 1=responds only after painful stimulus.
• 2=responds only after mild prodding or shaking.
• 3=responds only after name is called loudly and/or repeatedly.
• 4=lethargic response to name spoken in normal tone.
• 5=readily responds to name spoken in normal tone (awake; corresponding to ASA continuum for minimal sedation).

In the phase 3 program mild sedation corresponded with MOAA/S score 4, while moderate or greater sedation was defined as MOAA/S score ≤3.⁹

CLINICAL DATA

Spontaneously reported TEAEs of sedation and somnolence, as well as results based on the MOAA/S scale in the phase 3 clinical programs for TRD and Major Depressive Disorder with Acute Suicidal Ideation or Behavior (MDSI) are presented in Table: TEAEs of Sedation/Somnolence and/or MOAA/S.

Sedative effects on the MOAA/S typically showed an onset at around 15 minutes after the first dose was administered, with symptoms peaking at 30 to 45 minutes postdose and generally resolving (ie, MOAA/S score of 5) by 1 to 1.5 hours postdose.^2,3,9,10

Across all phase 2 and 3 TRD studies, the most frequently reported level of sedation in both adult and elderly subjects was mild sedation (corresponding to a MOAA/S score of 4).⁹ A total of 10 patients with TRD in the SPRAVATO+oral AD arm and 1 in the oral AD+placebo (PBO) arm had MOAA/S scores of 0 or 1 at any time point during phase 3 studies, corresponding to severe sedation. These events generally did not recur with subsequent dosing. Of the 10 patients in the SPRAVATO+oral AD arm, 2 patients with a MOAA/S score of 1 also received a concomitant benzodiazepine on the day before dosing.^9,19

Of note, in cases of reported sedation, no symptoms of respiratory distress were observed, and hemodynamic parameters (including vital signs and oxygen saturation) remained within normal limits.^9,10

• TRD studies: In total, 4 patients out of the 1599 SPRAVATO-treated patients with MOAA/S scores had a score on the MOAA/S scale of 0, ie, deeply sedated and did not respond to trapezius muscle squeeze. These events were rare, and all resolved on the dosing day without any medical intervention. In all cases, pulse oximetry was within normal range, with no evidence of respiratory depression. Of note, 1 patient was taking zopiclone (non-benzodiazepine hypnotic) every night for sleeplessness, including the nights preceding intranasal dosing days. Following the events, it was noted that SPRAVATO was discontinued in 1 patient while 1 patient received a dose decrease to 56 mg.⁹
• MDSI studies: One patient had MOAA/S scores of 0 and 1 on multiple dosing days. On those dosing days, the patient’s vital signs were within normal range, and the patient did not require medical intervention.¹⁰

Post Hoc Analysis of Tolerability Trends During Postdose Monitoring

Williamson et al (2018)¹¹ conducted a post hoc analysis of two 4-week, randomized, double-blind (DB) trials in patients with TRD.^2,3 The objectives of the analysis were to measure if the incidence of specific AEs, including sedation, during the first week of treatment appeared to be associated with the incidence/frequency of the same AEs during week 2-4, and if the duration of time until patients were determined to be discharge-ready during week 1 was associated with the subsequent duration during weeks 2-4.

As illustrated in Table: Incidence of Somnolence in Week 1 and Incidence/Frequency of Somnolence in Weeks 2-4, the incidence of AEs of somnolence was 17.3% for 345 patients who received SPRAVATO+oral AD. Most patients (88.7%) did not report somnolence during the first week. Of those patients who experienced sedation once, twice, or not at all during the first week of treatment, the table below provides data on the associated proportion of patients who experienced a recurrence of sedation during the subsequent 3 weeks of treatment.

Williamson et al (2022)¹² conducted a post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 trials to characterize the recurrence of AEs for SPRAVATO based on AEs that occurred during the early and later courses of treatment. Incidence, frequency, and severity of the most common AEs (ie, dizziness, dissociation, nausea, vertigo, increased blood pressure, and sedation) were evaluated. The patients were monitored for ≥90 minutes after SPRAVATO administration at each treatment session. This analysis included adult (aged 1864 years) patients with TRD who received SPRAVATO.

Sedation was reported in 3.8% (36/949) of patients in week 1, see Table: Rates of Sedation Recurrence According to Frequency of Sedation Occurrence in Week 1. The frequency of sedation in week 4 was more associated to later recurrence than its week 1 frequency.

On stratifying patients based on the level of sedation observed during weeks 1 and 4, the average severity during recurrent episodes was reflective of mild sedation (MOAA/S score, 3.5-4.0); 1 patient had a mean MOAA/S score of 3.25, indicating moderate sedation.

Post Hoc Analysis of MDSI studies

Fua et al (2020)²⁶ performed a post hoc analysis of patients with MDSI (pooled data from ASPIRE I AND ASPIRE II trials), which found 10.1% of patients (23/227) who had received SPRAVATO+standard of care (SOC) and 2.2% of patients (5/225) who had received PBO+SOC experienced clinician-reported sedation, with no clinician reports of severe sedation in either group. Deep sedation or a MOAA/S score ≤1 occurred in one patient who received SPRAVATO+SOC and in no patients who received PBO+SOC. Discontinuations due to sedation of any severity occurred in 0.4% of patients (1/227) who received SPRAVATO+SOC and in no patients who received PBO+SOC.

Real-world Retrospective Study

Martinotti et al (2022)²⁷ conducted a real-world retrospective, observational study (REAL-ESK) in Italy to evaluate the effectiveness and safety of SPRAVATO in 116 patients (female, 52.6%; mean age [SD], 50 [12] years) with TRD. Sedation was reported in 28.4% of patients.

Postmarketing Safety Data

REMS Database

REMS patient monitoring forms completed by certified United States (US) healthcare settings and pharmacies from 5 March 2019 to 5 January 2023 identified 34,110 patients who received at least 1 SPRAVATO treatment session and a total of 815,172 treatment sessions.¹³ Sedation was reported in 64.4% of patients and 36.6% of treatment sessions. Most reports of sedation were nonserious, and among those monitored for at least 2 hours postdose, 98.7% resolved within the patient monitoring period.

Food and Drug Administration Adverse Event Reporting System

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.²⁸ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval (March 2019 to first quarter 2020). If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into four categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs. Sedation and somnolence were reported as expected AEs with a detected signal with 173 (Reporting odds ratio [ROR]: 238.46 [95% confidence interval (CI) ¹: 202.98 to 280.15]; Bayesian information component [IC]: 7.0 [95% CI: 6.75 to 7.18] and 15 reports (ROR: 2.1 [95% CI: 1.26 to 3.48]; IC: 1.01 [0.14 to 1.61], respectively.

A similar case/non case disproportionality study was completed using FAERS from the first quarter of 2019 to the second quarter of 2021.¹⁴ Sedation was one of the most common neurological AEs reported, of which 248 cases were serious and 113 cases were nonserious. Somnolence was reported 34 times, of which 20 cases were serious and 14 cases were non-serious. A signal was detected when the lower limit of the 95% CI >1 (ROR₀₂₅). The ROR₀₂₅ for sedation and somnolence were 204.00 and 1.47, respectively.

The authors noted that the results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.²⁸ In addition, expected AEs such as sedation are solicited and reported via the REMS at every outpatient SPRAVATO treatment session triggering multiple reports in FAERS.²⁹ The authors noted that there were efforts to de-duplicate the reports, though duplicates may remain as the FAERS does not allow for patient identification.

Another analysis conducted using the FAERS database for 5061 SPRAVATO-related AEs from the first quarter of 2019 to the first quarter of 2023 reported the occurrence of 567 cases of sedation (Reporting Odds Ratio [95% CI], 161.79 [148.17-176.67]; Proportional Reporting Ratio [95% CI], 153.62 [141.26-167.06]; Bayesian Information Component [IC; the lower limit of the 95% CI for the IC], 6.82 [6.69]; Empiric Bayes Geometric Mean [EBGM; the lower limit of the 90% CI for the EBGM], 141.16 [129.27]).¹⁵

Postmarketing safety data related to respiratory depression symptoms reported with concurrent sedation and/or dissociation

An evaluation of the Janssen Global Medical Safety Database (from March 2019 through January 2023) identified 50 cases that involved patients who had clinical symptoms of respiratory depression on the day of administration, and either had respiratory rates and/or oxygen saturation levels below thresholds (≤10 breaths per minute and/or oxygen saturation ≤93%) or cases that failed to report either or both values.¹⁶ Of those cases, 25 were reported with concurrent respiratory depression AEs and sedation and/or dissociation (20/25 were serious AEs). AEs included dyspnea (13), oxygen saturation decreased (3), respiratory distress (2), respiratory rate decreased (2), apnea (1), cardio-respiratory arrest (1), hypopnea (1), respiratory abnormal (1), respiratory arrest (1), and respiratory disorder (1). Eighteen of these cases reported the patient as recovered (17) or recovering (1); 1 case not recovered; and 6 cases had 7 adverse events with unknown outcomes (1 case involved more than 1 adverse event/outcome). Ten cases reported both sedation and dissociation, 9 cases reported sedation, and 6 cases reported dissociation.

Interventions were reported in 17 cases, which included hospital/emergency room services (6), medication (3), oxygen (3), stimulation (2), cardiopulmonary resuscitation (1), rescue breathing (1) and an unspecified intervention (1). Eight cases did not document an intervention. In 9 cases, patients were ready for discharge within the 2-hour observation period. In the remaining cases, patients were assessed as not ready for discharge within the 2-hour monitoring period (13), or discharge readiness was not reported (3).¹⁶

In the majority of cases, patients were using concomitant medications or had comorbidities, including anxiety disorder, obesity, alcohol abuse, and hypothyroidism (although respiratory depression cannot be attributed to these factors).¹⁶

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 17 May 2024.