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SPRAVATO® (esketamine)
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SPRAVATO - Serious Adverse Event - Death
Last Updated: 05/29/2024
SUMMARY
- A total of 15 deaths were reported in the SPRAVATO clinical trial program for treatment-resistant depression (TRD) and the clinical trial program for major depressive disorder (MDD) in patients with active suicidal ideation and intent.1
- 5 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. One death was due to COVID-19-related pneumonia, 2 deaths due to COVID-19 infection, 2 deaths due to pneumonia, and 2 deaths due to unknown causes.1-5
- Three deaths in the SPRAVATO TRD development program were due to suicides, all occurring during open-label treatment. After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO.6
-10 - Adeath by 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
, 11 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 2023, 147 deaths were reported, of which 47 were due to suicide.12 - 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 due to suicide.13
CLINICAL trial DATA
Details of the deaths during SPRAVATO clinical trials can be found in the Table: Serious Adverse Events of Death. There were a total of 4 deaths by suicide. 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.7
Table: Serious Adverse Events of Death presents additional details regarding the deaths.
| 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.15 | Not related |
| SUSTAIN-2 (TRD; phase 3, up to 1 year, 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.9 | Doubtful |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, 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.1,5 | Doubtful |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, 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.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 66; male | Died from COVID-19-related pneumonia 13 days after the last dose of SPRAVATO 84 mg.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 62; male | Died from pneumonia on day 1279 of treatment 13 days after the last dose of SPRAVATO 84 mg.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 60; male | Died from COVID-19 infection on day 1062 of treatment 24 days after the last dose of SPRAVATO 84 mg.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 60; male | Died from COVID-19 infection on day 1149 of treatment 15 days after the last dose of SPRAVATO 84 mg.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 58; male | Cause of death was unknown. The patient was found dead on day 1245 of treatment 8 days after the last dose of SPRAVATO 56 mg. The homeowner who reported the death to the investigator stated that the death was not a suicide. The investigator confirmed the patient was divorced and lived alone for some time, without active contact with his family. Prior to his death, the patient was drinking more, his diabetes was poorly controlled, and his depressed mood and suicidal ideation were not improving.5 | Not related |
| SUSTAIN-3 (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 66; female | Died from pneumonia on day 1968 of treatment 65 days after the last dose of SPRAVATO 28 mg.5 | Not related |
| ESCAPE-TRD (TRD; phase 3, up to 6.5 years, open-label safety extension trial) | 55; female | Cause of death was unknown. The patient died on the day of her last SPRAVATO 84 mg dose (day 64 of treatment). She had a medical history of hypertension and Type 2 diabetes. Her clinician cited pulmonary thromboembolism as a probable cause of death with hypertension as a risk factor.16 | Not related |
| Deaths due to suicide | |||
| SYNAPSE (TRD; Phase 2 Adjunctive Trial) | 41; male | Died due to 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.17 | 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.9 Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide.7,17 | Not related |
| SUSTAIN-3 (TRD; long-term, open-label safety extension trial) | 48; male | Died due to 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.17 | Not related |
| ASPIRE-1 (MDD with active suicidal ideation and intent; phase 3, short-term, double-blind trial) | 53; female | Died due to 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.3,11 | Not related |
| Abbreviations: COVID-19, coronavirus disease; MDD, major depressive disorder; TRD, treatment-resistant depression. | |||
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 2023.12 There were a total of 147 cases reporting 160 fatal events. Of the 147 cases, 136 reported only 1 fatal event which included 67 deaths not otherwise specified, 45 deaths by suicide, 3 overdose, 2 COVID-19 infection, 2 road traffic accidents, and 1 death each due aortic aneurysm, arteriosclerosis, Candida infection, cerebrovascular accident, diabetes mellitus, drug abuse, electrolyte imbalance, failure to thrive, hepatic cirrhosis, intestinal obstruction, intestinal perforation, multimorbidity, myocardial infarction, neoplasm malignant, post procedural complication, pulmonary embolism, and sepsis. Eleven remaining fatal cases reported more than 1 fatal event: Cardiac disorder, sepsis, and COVID-19; cardiovascular disorder, multiple organ dysfunction syndrome, and cerebrovascular accident; toxicity to various agents and accidental overdose; hip fracture and gall; hallucination auditory and death by suicide; pneumonia and multiple organ dysfunction syndrome; toxicity to various agents and death by suicide; suspected suicide and alcohol use; overdose and brain injury; organ failure and COVID-19; and substance abuse and accidental overdose. The majority of deaths were assessed by Global Medical Safety as not related to SPRAVATO treatment.12
An analysis was conducted using the FAERS (March 2019 to March 2020) to identify relevant safety signals for SPRAVATO.13 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 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.13 Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).18
Literature Search
A literature search of MEDLINE®
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. Accessed 2024-04-12. https://public4.pagefreezer.com/browse/FDA/04-03-2022T19:30/https:/www.fda.gov/media/121379/download |
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