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SPRAVATO®

(esketamine)


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SPRAVATO® (esketamine)

Medical Information

SPRAVATO - Serious Adverse Event - Death

Last Updated: 05/23/2023

SUMMARY  

  • A total of 9 deaths were reported in the SPRAVATO clinical trial program for treatment-resistant depression (TRD) (including in an ongoing phase 3, open-label, safety extension study) and the clinical trial program for major depressive disorder (MDD) in patients with active suicidal ideation and intent.1-3  Study investigators assessed these deaths as either unrelated or doubtfully related to SPRAVATO.
    • Four of the deaths that occurred in the TRD development program were due to cardiovascular events or physical trauma resulting from accidents.1, 2 One death was due to COVID-19-related pneumonia.4
    • Three deaths in the SPRAVATO TRD development program were completed suicides, all occurring during open-label treatment. The suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22–1.00) completed suicides per 100 patient-years reported in a meta-analysis of patients with TRD.5, 6 After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO.
    • Adeath due to a completed suicide was reported in a patient previously treated with SPRAVATO in the follow-up phase of a trial in patients with MDD with active suicidal ideation and intent.3
  • In postmarketing safety data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) and the SPRAVATO global medical safety databases from 5 March 2019 to 5 January 2022, 62 deaths were reported, of which 17 were completed suicides.7
  • In another analysis of postmarketing safety data (March 2019 to first quarter 2020) using the Food and Drug Administration Adverse Event Reporting System (FAERS), 22 deaths were identified, of which half were completed suicides.8

CLINICAL trial DATA

In the 6 completed Phase 2 and 3 TRD studies, 4 deaths were reported in 1,708 subjects receiving SPRAVATO (611 patient-years of exposure6; 1 during double-blind treatment and 3 during open-label treatment).9 No deaths were reported in these studies among the 486 subjects who received oral AD + placebo (108 patient-years of exposure). In an ongoing long-term, open-label safety extension study (SUSTAIN-3), 4 deaths were reported in SPRAVATO-treated subjects.1, 4, 9 Of the 452 patients in the clinical program for MDD in patients with active suicidal ideation and intent, 1 death was reported in a patient previously treated with SPRAVATO during the follow-up phase.3 Additional details can be found in the Table: Serious Adverse Events of Death.

Although death by suicide is always tragic, in the SPRAVATO TRD development program, the suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22–1.00) completed suicides per 100 patient-years reported in a different study in a TRD population.5, 6  After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO. Additionally, safety data was reviewed every 6 months by an Independent Data Monitoring Committee (IDMC) to ensure the continuing safety of the patients enrolled in the phase 3 trials.10, 11

Table: Serious Adverse Events of Death presents additional details regarding the deaths.1


Serious Adverse Events of Death
Study
Age (years) /Gender
Narrative
Investigator’s Assessment of Relationship to SPRAVATO
TRANSFORM-2 (TRD; phase 3, short-term, double-blind trial)
41; male
Experienced multiple injuries following a road traffic accident on day 16 of the double-blind phase (approximately 28 hours after receiving the last dose of SPRAVATO 84 mg) and subsequently died.12
Not related
SUSTAIN-2 (TRD; phase 3, long-term, open label safety trial)
60; male
Died from acute cardiac and respiratory failure on day 113 of treatment with SPRAVATO 56 mg (event reported 5 days after last dose). Patient had medical history of hypertension and vein surgery.13
Doubtful
SUSTAIN-3
(TRD; ongoing, long-term, open-label safety extension trial)
73; female
Died from myocardial infarction 6 days after a dose of SPRAVATO 84 mg. Patient had medical history of controlled hypertension and hyperlipidemia.1, 4
Doubtful
SUSTAIN-3
(TRD; ongoing, long-term, open-label safety extension trial)
59; male
Died from accidental polytrauma to the head, abdomen, and brain due to being hit by an automobile while riding a bicycle. Patient died on day 364 of the optimization/maintenance phase, 6 days after the last dose of SPRAVATO 56 mg.4
Not related
SUSTAIN-3
(TRD; ongoing, long-term, open-label safety extension trial)
66; male
Died from COVID-19-related pneumonia 13 days after the last dose of SPRAVATO 84 mg.4
Not related
SUSTAIN-2 (TRD; phase 3, long-term, open label safety trial)
55; female
Died as a result of suicide (i.e., overdosed with zolpidem and oxazepam) on day 188, 12 days after receiving the last dose of SPRAVATO 84 mg.13 Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide.9, 10
Not related
SYNAPSE (TRD; Phase 2 Adjunctive Trial)
41; male
Died due to a completed suicide on day 45, 20 days after receiving the last dose of study medication during the follow-up phase of the study. During the 2- week double-blind treatment phase, the patient was in the placebo/ SPRAVATO 14-mg group, and during the OL phase he received 4 doses of SPRAVATO 56 mg.9
Not related
SUSTAIN-3
(TRD; ongoing, long-term, open-label safety extension trial)
48; male
Died due to a completed suicide on day 26 of the induction phase. The patient had been receiving SPRAVATO 84 mg with the last dose administered 4 days prior to the event.9
Not related
ASPIRE-1
(MDD with active suicidal ideation and intent; phase 3, short-term, double-blind trial)
53; female
Died due to a completed suicide during the follow-up phase. The last dose of SPRAVATO 84 mg was received 3 days prior to the event. The investigator considered MDD, TRD with chronic passive and active suicidal ideation, and a history of 5 suicide attempts as the risk    factors.3, 14
Not related
Abbreviations: COVID-19, coronavirus disease; MDD, major depressive disorder; TRD, treatment-resistant depression.

postmarketing safety data

REMS Database

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies and a separate SPRAVATO global medical safety database (which includes AEs reported from the REMS and other sources) from 5 March 2019 to 5 January 2022.7 There were a total of 62 cases reporting 66 fatal events. Fatalities consisted of: 17 completed suicides, 26 deaths not otherwise specified, 2 road traffic accidents, 2 myocardial infarctions, and 1 fatal case each for intestinal perforation, failure to thrive, fall [hip fracture], overdose, drug abuse, postprocedural complication, cardiovascular disorder/cerebrovascular accident/multiple organ dysfunction syndrome, multiple organ dysfunction syndrome/pneumonia, COVID-19 infection, pulmonary embolism, diabetes mellitus, aortic aneurysm, neoplasm malignant, Candida infection, and sepsis.

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.8 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. 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.

There was a total of 2,274 SPRAVATO-related AEs in 962 patients with 389 serious AEs, including 22 deaths. The causes of death involved completed suicide (n=11); death not specified (n=4); road traffic accident (n=2); pulmonary embolism, myocardial infarction, multimorbidity, intestinal perforation, and electrolyte imbalance/decreased blood glucose (1 each). 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.8 Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).15

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 12 May 2023.

References

1 Popova V. Safety. Janssen Presentations - Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee February 12, 2019. https://public4.pagefreezer.com/browse/FDA/04-03-2022T19:30/https:/www.fda.gov/media/121379/download.
2 (CHMP) Commitee for Medicinal Products for Human Use. SPRAVATO assessment report. Procedure No. EMEA/H/C/004535/0000. European Medicines Agency (EMA); November 2019. https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf. Accessed May 23, 2023.
3 Fu DJ,  Ionescu DF,  Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191.
4 Data on File. Esketamine. Abbreviated Interim Clinical Study Report 54135419TRD3008. Janssen Research & Development, LLC.  EDMS-RIM-87913. December 2020.
5 Bergfeld IO,  Mantione M,  Figee M, et al. Treatment-resistant depression and suicidality. J Affect Discord. 2018;235:362-367.
6 Drevets W,  Singh JB, Hough D et al. Letter to the editor: Comment on a word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(10):856-857.
7 Naranjo RR,  Doherty T,  Nuamah I, et al. Real-world use of esketamine nasal spray for treatment-resisant depression at 34 months: characterizing healthcare settings, prescribers, pharmacies, patients, and key safety data. Poster presented at: Psych Congress Elevate; June 3-5, 2022; Las Vegas, NV.
8 Gastaldon C,  Raschi E,  Kane JM, et al. Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system. Psychother Psychosom. 2021;90(1):41-48.
9 Data on File. Esketamine. Integrated Summary of Safety - TRD. Janssen Research & Development, LLC. EDMS-ERI-155147726. 2018.
10 Data on File. Esketamine. Clinical Study Report ESKETINTRD3004. Janssen Research & Development, LLC.  EDMS-ERI-146551506. 2018.
11 Data on File. Esketamine. TRANSFORM-2 Clinical Study Report ESKETINTRD3002. Janssen Research & Development, LLC.  EDMS-ERI-139094789. 2018.
12 Popova V,  Daly EJ,  Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.
13 Wajs E,  Aluisio L,  Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891.
14 Data on File. Esketamine. Clinical Study Report 54135419SUI3001. Janssen Research & Development, LLC.  EDMS-ERI-187180494. 2019.
15 Doherty T,  Daly EJ,  Miller J, et al. Letter to the editor: Comments to Drs. Gastaldon, Raschi, Kane, Barbui, and Schoretsanitis. Psychother Psychosom. 2020;90:138-139.