SUMMARY

• During the double-blind phases of 3 short-term, phase 3 studies^1-3 of SPRAVATO nasal spray plus oral antidepressant (SPRAVATO+AD) vs antidepressant plus placebo (AD+PBO) in patients with treatment-resistant depression (TRD) and 1 short-term, double-blind, phase 2 study⁴ of adjunctive SPRAVATO in TRD, the incidence of treatment-emergent adverse events (TEAEs) of falls was 0.4% (2/502 patients) for SPRAVATO+AD vs 0.3% (1/341 patients) for AD+PBO. One patient in the double-blind phases had a fall occur on a dosing day.⁵
• During the open-label phases of a phase 2 study,⁴ a maintenance-of-effect study⁶ (direct entry patients from induction and optimization), and a long-term safety study,^7,8 the incidence of TEAEs of falls in the SPRAVATO+AD group was 0.6% (8/1,335). One patient in the open-label phases had a fall occur on a dosing day.⁵
  • In the post hoc analysis of SUSTAIN-2, comparing the long-term efficacy and safety of SPRAVATO+AD between younger (18-64 years) and older (≥65 years) patients with TRD, the incidence of TEAEs of falls in younger vs older patients was 0.3% (2/624) vs 0.6% (1/155) during the induction phase and 0.2% (1/477) vs 0.8% (1/126) during the optimization/maintenance phase.⁸
• During the follow-up phases of all 6 studies,^1-3,4,6,7 the incidence of falls in the SPRAVATO+AD group vs AD+PBO group was 0.2% (2/977 patients) vs 0%, respectively.⁵
• No cases of falls were reported on SPRAVATO dosing days in phase 3 studies of patients with major depressive disorder and active suicidal ideation with intent.^9,10
• Thirteen reports of fall appeared in an analysis of post-marketing safety data from the Food and Drug Administration Adverse Event Reporting System (FAERS).¹¹

CLINICAL TRIAL DATA

During clinical trials, 2 patients had a fall occur on a dosing day.

• A 66-year-old female patient on SPRAVATO 28 mg plus escitalopram 10 mg in the short-term elderly study had a fall approximately 2.5 hours after SPRAVATO dosing. The fall was reported as a mild, nonserious adverse event (AE) not considered related to SPRAVATO.^5,12,13
• A 56-year-old female patient on SPRAVATO 56 mg plus venlafaxine XR 225 mg experienced a fall 7.5 hours after dosing on day 183. The patient reported an AE of somnolence 15 minutes after the dose, resolving at 45 minutes. The patient was discharged at 1.5 hours after the dose. The patient accidentally slipped and fell while doing housework and suffered a right fibula fracture. The investigator did not consider the incident to be related to SPRAVATO or venlafaxine XR 225 mg as the patient did not experience any symptoms prior to the fall. The fracture resolved on day 267.⁵

Postmarketing Safety Data

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹¹ 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 vs non-cases, then this was considered a disproportionality signal. AEs were classified into 4 categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

Falls were more likely to be reported as serious AEs.¹¹ There were 13 reports of fall without a detected signal, a reporting odds ratio of 1.04 (95% confidence interval [CI], 0.6 to 1.79), and a Bayesian information component of 0.05 (95% CI, -0.89 to 0.69). 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.

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 13 December 2024.