SUMMARY  

• SPRAVATO nasal spray must be administered by the patient under the direct supervision of a healthcare provider. A treatment session consists of nasal administration of SPRAVATO and post-administration observation under supervision.¹
• Blood pressure (BP) should be monitored after SPRAVATO administration. Measure BP around 40 minutes post dose and subsequently as clinically warranted until values decline.² If BP remains high, promptly seek assistance from practitioners experienced in BP management.³
• Upon receiving SPRAVATO treatment, patients should avoid potentially hazardous activities requiring complete mental alertness and motor coordination, such as driving a motor vehicle or operating machinery, until the next day following a restful sleep.⁴ Patients will need to arrange transportation home following treatment with SPRAVATO.
• Post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 studies^5,6 showed that adverse events (AEs) of dizziness, dissociation, increased blood pressure, nausea, vertigo, and sedation were more likely to recur later in treatment if the AE was experienced once or twice during the first week of treatment.⁷ However, the overall recurrence of these AEs diminished over the 12-month treatment period.
• A post hoc analysis of two short-term studies in treatment-resistant depression (TRD) observed that ≥90% of patients were considered ready for discharge at 90 minutes after administration, with an additional 2-7% ready at 2 hours. Overall, AEs were consistent with the known safety profile of SPRAVATO. The most commonly occurring ongoing AEs at 2 hours after SPRAVATO dosing among patients not ready for discharge were dissociation, dizziness, vertigo, somnolence, feeling drunk, hypoesthesia, fatigue, and nausea/dysgeusia.^8-10

product labeling

• Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours (including pulse oximetry) at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting.¹¹ 
• 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).¹¹
  • For additional information or questions about the REMS program, call 1-855-382-6022 or visit www.SPRAVATOrems.com.
  • Additional resources, including patient monitoring forms can be obtained at the following link: https://www.spravatorems.com/resources.html

background

Clinical Global Assessment of Discharge Readiness (CGADR)

The CGADR was an assessment developed for use in the SPRAVATO phase 3 TRD program to assess the patient’s current clinical status and readiness for discharge from the study site. The clinician answered “Yes” or “No” to the question “Is the subject considered ready to be discharged based on their overall clinical status (e.g., sedation, BP, and other adverse events)?”

On each intranasal dosing day, the CGADR was performed at 1 hour and 1.5 hours postdose. If the response was not "Yes" at 1.5 hours postdose, the assessment was repeated every 15 minutes until a “Yes” response was achieved or until the patient was referred for appropriate medical care, if clinically indicated.⁵

Clinical data

Post Hoc Analysis of Tolerability Trends During Postdose Monitoring

Williamson et al (2022)⁷ conducted a post hoc analysis of pooled data from SUSTAIN-1 and SUSTAIN-2 trials^5,6 to characterize 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 (i.e., dizziness, dissociation, nausea, vertigo, increased blood pressure, and sedation) were evaluated.

Dizziness (20.6%), dissociation (16.7%), nausea (14.0%), vertigo (12.1%), increased blood pressure (4.3%), and sedation (3.8%) were the most common AEs during the first week of treatment and decreased with ongoing treatment over a 12-month period. Recurrence rates of AEs (based on clinician-reported AEs and standard measures of dissociation, sedation, and increased blood pressure) that were more frequent during the first week were higher later in the treatment course. Therefore, AEs that occurred twice during week 1 were more likely to recur than AEs that occurred once during week 1, which in turn, were more likely to recur than AEs that had no occurrence during week 1. Recurrence rates after week 4 appeared more like the rates seen in week 4 vs. those seen in week 1. Most AEs were mild or moderate in severity with no correlation found between initial and future severity due to a low number of patients with moderate or severe AEs.

Post Hoc Analysis of Adverse Events Affecting Readiness for Discharge From the Clinical Setting After Administration of SPRAVATO Nasal Spray

Starr et al (2019)⁸conducted a post hoc, pooled analysis of two 4-week, double-blind, placebo-controlled studies of SPRAVATO in patients with TRD⁹to describe clinical findings in patients considered not ready for discharge from clinical study sites 2 hours after administration of SPRAVATO. In the phase 3 TRD studies, patients were permitted to leave the study site 90 minutes after dosing with SPRAVATO if assessed to be clinically stable. Treatment-emergent adverse events (TEAEs) noted prior to the administration of the SPRAVATO dose or that did not resolve after dosing could be treated prophylactically or with rescue medications following dosing, if clinically warranted. The CGDAR was used to document clinical status of the patient and capture the clinician’s determination of the patient’s readiness to leave the study site. AEs that began after the dosing start time were considered to be ongoing at a specific time point if their duration extended beyond the time point or if data on the end time of the AE were missing. AEs that were considered ongoing at 90 and 120 minutes after SPRAVATO administration were summarized by discharge readiness (3 groups): 1) patients considered ready for discharge at 90 minutes after dosing; 2) patients considered ready for discharge at 2 hours after dosing; and 3) patients considered not ready for discharge at 2 hours after dosing.

Across 8 treatment sessions (n=346), ≤3.5% (n=12) were not considered ready for discharge at 2 hours after SPRAVATO dosing. The most common AEs ongoing at 90 minutes in patients remaining in the clinical setting at 2 hours after dosing were dizziness, feeling drunk, and dissociation/derealization. The most common AEs ongoing at 2 hours in the patients remaining in the clinical setting at 2 hours after dosing were nausea, feeling drunk, vertigo and dizziness.

Among patients not ready for discharge at 2 hours, the most common ongoing AEs at 2 hours after SPRAVATO dosing were vertigo, dissociation, somnolence, feeling drunk, dizziness, nausea, hypoesthesia, fatigue, and dysgeusia (Figure: Ongoing AEs Across 8 Treatment Sessions at 2 Hours After ESK Dosing in Patients Not Ready for Discharge at 2 Hours). Interventional treatment with rescue medications was allowed per protocol, but not typically required. Increases in BP were generally transient, and investigators were encouraged to use medication only in the event of elevated systolic BP ≥180 mm Hg and or diastolic BP ≥110 mm Hg. Overall, AEs across all 8 treatment sessions were consistent with the known safety profile of SPRAVATO.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENTDrug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 20 June 2024.