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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

SPRAVATO® (esketamine)

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Adverse Events of SPRAVATO - Nausea and Vomiting

Last Updated: 03/25/2024

SUMMARY

Since some patients may experience nausea and vomiting after administration of SPRAVATO nasal spray, patients should be advised not to eat for at least 2 hours before administration and not to drink liquids for at least 30 minutes prior to administration.¹
In phase 2 and 3 studies for treatment-resistant depression (TRD) that included 1709 patients treated with SPRAVATO + newly initiated oral antidepressant (AD), 458 patients (26.8%) reported nausea while 177 patients (10.4%) reported vomiting.² Note: this pooled analysis was performed before the conclusion of the phase 3 studies by Reif et al,³ Zaki et al,⁴ and Chen et al,⁵ and thus, does not include those studies. Please see below for individual study results.
- During the double-blind phases of the studies, 24.5% (144/587) reported nausea in the SPRAVATO+oral AD arm compared with 5.8% (28/486) in the oral AD + placebo (PBO) arm.
- During the double-blind phases of the studies, 8.3% (49/587) reported vomiting in the SPRAVATO+oral AD arm compared with 1.2% (6/486) in the oral AD+PBO arm.
- Discontinuation of treatment due to these events was reported in <1% of patients.
A long-term, open-label, phase 3 safety study (up to 6.5 years) found that nausea and vomiting occurred in 33.6% (386/1148) and 15.9% (182/1148) of patients, respectively.⁴
Most of the adverse events (AEs) of nausea and vomiting occurred on the day of dosing and resolved the same day, with a median duration of ≤1 hour in most patients across dosing sessions.⁶
Rates of reported nausea and vomiting decreased over time.⁶
Rescue medication given to treat nausea included ondansetron 8 mg sublingually; metoclopramide 10 mg orally, intravenously, or intramuscularly; or dimenhydrinate
25 to 50 mg intravenously or intramuscularly.⁷^-⁹
- Medication was used to treat an AE of nausea and vomiting in <5% of SPRAVATO-treated patients.²
Some patients in the clinical trial program for SPRAVATO received prophylactic treatment (eg, ondansetron) for nausea as needed prior to the dosing session; no details were captured regarding the specific number of patients who used this treatment or the timeframe in which it was used prior to a SPRAVATO treatment session.¹⁰
In phase 3 studies (ASPIRE-I and ASPIRE-II) of patients with major depressive disorder and active suicidal ideation with intent, 26.9% (61/227) reported nausea in the SPRAVATO + standard of care (SOC) arm compared with 20.4% (31/225) in the SOC+PBO arm. 11.5% (26/227) reported vomiting in the SPRAVATO+SOC arm compared with 5.3% (12/225) in the SOC+PBO arm.¹¹^,¹²
In postmarketing safety data from the SPRAVATO REMS program from 5 March 2019 to 5 January 2023, based on 1580 serious adverse events reported on patient monitoring forms, nausea and vomiting were reported in 7.1% and 7.6% of patients, respectively.¹³ In an analysis of postmarketing safety data (March 2019 to first quarter 2020) from the Food and Drug Administration Adverse Event Reporting System (FAERS), nausea (75 reports) and vomiting (74 reports) were reported as expected adverse events (AEs) with a detected signal.¹⁴

CLINICAL DATA

The incidence of nausea and vomiting from phase 3 studies in TRD and major depressive disorder and active suicidal ideation with intent are described in the Table: Incidence of Nausea and Vomiting in Phase 3 Trials.

Incidence of Nausea and Vomiting in Phase 3 Trials

PHASE 3 TRIALS IN TRD AND MDSI
SHORT-TERM TRIALS IN TRD
Trial Design	Incidence of Nausea and Vomiting
Popova et al (2019)⁸ conducted a 4-week, randomized, DB, active-controlled, multinational study to compare the efficacy and safety of flexibly-dosed SPRAVATO nasal spray plus a newly initiated oral AD vs. a newly initiated oral AD plus PBO in adult patients (18-64 years) with TRD Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the DB phase following a fixed titration schedule. Study Groups 56 or 84 mg SPRAVATO+oral AD (n=114); SPRAVATO was started on day 1 at 56 mg for all Oral AD+PBO (n=109)	Nausea SPRAVATO+oral AD: 30/114 (26.1%) Oral AD+PBO: 7/109 (6.4%) Vomiting SPRAVATO+oral AD: 11/114 (9.6%) Oral AD+PBO: 2/109 (1.8%) Incidence rates were from the DB phase.
Fedgchin et al (2019)¹⁵ conducted a 4-week, randomized, DB, active-controlled, multinational study to compare the efficacy and safety of fixed-dose SPRAVATO plus a newly initiated oral AD vs. a newly initiated oral AD plus PBO in adult patients (18-64 years) with TRD Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD was initiated (see Popova et al above). Study Groups 56 mg SPRAVATO+oral AD (n=115; safety analysis set: n=115) 84 mg SPRAVATO+oral AD (n=114; safety analysis set: n=116); SPRAVATO was started on day 1 at 56 mg Oral AD+PBO (n=113; safety analysis set: 113)	Nausea 56 mg SPRAVATO+oral AD: 31/115 (27.0%) 84 mg SPRAVATO+oral AD: 37/116 (31.9%) Oral AD+PBO: 12/113 (10.6%) Vomiting 56 mg SPRAVATO+oral AD: 7/115 (6.1%) 84 mg SPRAVATO+oral AD: 14/116 (12.1%) Oral AD+PBO: 2/113 (1.8%) Incidence rates were from the DB phase.
Ochs-Ross et al (2020)¹⁶ conducted a 4-week, randomized, DB, active-controlled, multicenter study in elderly patients (≥65 years) with TRD which assessed the efficacy, safety, and tolerability of flexible doses of SPRAVATO plus a newly initiated oral AD compared with a newly initiated oral AD plus PBO. Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD was initiated (see Popova et al above). Study groups 28, 56, or 84 mg SPRAVATO+oral AD (n=72); SPRAVATO was started on day 1 at 28 mg Oral AD+PBO (n=65)	Nausea SPRAVATO+oral AD: 13/72 (18.1%) Oral AD+PBO: 3/65 (4.6%) Vomiting SPRAVATO+oral AD: 5/72 (6.9%) Oral AD+PBO: 1/65 (1.5%) Incidence rates were from the DB phase.
Chen et al (2023)⁵ conducted a randomized, DB, active-controlled, multicenter study in patients with TRD aged 18-64 years in China and the USA to evaluate the efficacy and safety of flexibly dosed (56 or 84 mg) SPRAVATO+oral AD vs oral AD+PBO after 4 weeks of treatment. Study Treatment Patients self-administered either SPRAVATO or PBO 2 times per week for 4 weeks during the DB phase under supervision of clinical staff. A new OL oral AD was initiated (see the Popova et al [2019] study above). Study Groups 56 or 84 mg SPRAVATO+oral AD (n=126); SPRAVATO was started on day 1 at 28 mg Oral AD+PBO (n=126)	Nausea SPRAVATO+oral AD: 53/126 (42.1%) Oral AD+PBO: 17/126 (13.5%) Vomiting SPRAVATO+oral AD: 23/126 (18.3%) Oral AD+PBO: 2/126 (1.6%) Incidence rates were from the DB phase.
LONG-TERM TRIALS IN TRD
Daly et al (2019)¹⁷ conducted a long-term, DB, active-controlled, randomized-withdrawal, maintenance study to assess the efficacy of flexibly-dosed SPRAVATO plus an oral AD compared with an oral AD plus PBO in delaying relapse of depressive symptoms in patients with TRD who were stable responders and remitters after an initial 16 weeks of treatment with SPRAVATO plus oral AD. Study Treatment During the induction phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization (12 weeks) and maintenance (variable duration) phases, nasal spray medication was administered weekly for the first 4 weeks, then individualized to once weekly or once every other week based on severity of depression symptoms. A new OL oral AD (duloxetine, escitalopram, sertraline, or venlafaxine XR) was administered daily for the duration of the DB phase following a fixed titration schedule during the induction phase and remaining unchanged during the maintenance phase. Study Groups 56 or 84 mg SPRAVATO+oral AD (n=152); SPRAVATO was started on day 1 at 56 mg. Oral AD+PBO (n=145).	Nausea SPRAVATO+oral AD: 25/152 (16.4%) Oral AD+PBO: 1/145 (0.7%) Vomiting SPRAVATO+oral AD: 10/152 (6.6%) Oral AD+PBO: 1/145 (0.7%) Incidence rates were from the DB phase.
Wajs et al (2020)⁹ conducted an OL, multicenter, study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of flexibly-dosed SPRAVATO nasal spray (28, 56 or 84 mg) plus a newly initiated oral AD in patients with TRD. Study Treatment During the induction phase (initial 4 weeks [IND]), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization and maintenance phases (48 weeks [OP/MA]), nasal spray medication was reduced to once weekly for the first 4 weeks, and then individualized to once weekly or once every other week based on severity of depression symptoms. A new OL oral AD was initiated (see Daly et al above). Study Groups 28, 56, or 84 mg SPRAVATO+oral AD (n=802); SPRAVATO was started on day 1 at 28 mg for patients ≥65 years and 56 mg for all other patients.	Nausea SPRAVATO+oral AD: 201/802 (25.1%) Vomiting SPRAVATO+oral AD: 87/802 (10.8%) Incidence rates were from the IND & OP/MA phases
Zaki et al (2023)⁴ conducted an OL extension study to evaluate the long-term safety and efficacy of individualized, intermittently dosed SPRAVATO+oral AD in patients with TRD. Study Treatment During the induction phase (initial 4 weeks), patients self-administered a flexible dose of SPRAVATO 2 times per week. In the OP/MA phase (variable duration), patients administered SPRAVATO once weekly, every other week, or every 4 weeks based on CGI-S and tolerability. Study Groups Starting dose of 28 mg (patients aged ≥65 years), 56 mg, or 84 mg SPRAVATO (N=1148): induction phase, n=458; OP/MA phase, n=1110 (690 were directly enrolled; 420 were continued from the induction phase).	Nausea SPRAVATO+oral AD: 386/1148 (33.6%) Vomiting SPRAVATO+oral AD: 182/1148 (15.9%)
Reif et al (2023)³ conducted an OL, 32-week, randomized, phase 3b study that evaluated the efficacy and safety of SPRAVATO vs QUE-XR in combination with ongoing oral AD (SSRI or SNRI) in the treatment of patients with TRD. Study Treatment In the treatment phase (initial 8 weeks) patients were randomized to receive flexible doses of SPRAVATO+oral AD or QUE-XR+oral AD; flexible dosing was continued for 24 weeks in the maintenance phase. SPRAVATO was administered 2 times per week during weeks 1-4, once weekly during weeks 5-8, and once weekly or every other week during weeks 9-32.¹⁸ Study Groups 56 mg or 84 mg (28 mg option for those of Japanese ancestry aged 65 to ≤74 years) SPRAVATO+oral AD (n=336; safety analysis set, n=334) 50 mg on day 1, increasing to 150-300 mg/day QUE-XR+oral AD (n=340; safety analysis set, n=336)	Nausea¹⁸ SPRAVATO+oral AD: 98/334 (29.3%) QUE-XR+oral AD: 12/336 (3.6%) Vomiting¹⁸ SPRAVATO+oral AD: 36/334 (10.8%) QUE-XR+oral AD: 5/336 (1.5%)
PHASE 3 TRIALS IN MDSI
Fu et al (2019)¹¹ conducted a DB, randomized, PBO-controlled study (ASPIRE-I) to assess the efficacy and safety of SPRAVATO 84 mg plus comprehensive SOC^a in patients with major depressive disorder and active suicidal ideation with intent. Study Treatment Patients received either SPRAVATO+SOC^a or PBO+SOC 2 times per week for 4 weeks followed by ~2 months of follow-up with SOC only. Study Groups 84 mg SPRAVATO+SOC (n=114; safety analysis set: n=113) PBO+SOC (n=112; safety analysis set: n=112)	Nausea 84 mg SPRAVATO+SOC: 23/113 (35.4%) PBO+SOC: 15/112 (13.4%) Vomiting 84 mg SPRAVATO+SOC: 8/113 (7.1%) PBO+SOC: 7/112 (6.3%) Incidence rates were from the DB phase.
Ionescu et al (2019)¹² conducted a second identically designed study (ASPIRE-II) as above. Study Groups 84 mg SPRAVATO+SOC (n=115; safety analysis set: n=114) PBO+SOC (n=115; safety analysis set: n=113)	Nausea 84 mg SPRAVATO+SOC: 38/114 (33.3%) PBO+SOC: 16/113 (14.2%) Vomiting 84 mg SPRAVATO+SOC: 18/114 (15.8%) PBO+SOC: 5/113 (4.4%) Incidence rates were from the DB phase.
Abbreviations: AD, antidepressant; CGI-S, Clinical Global Impression-Severity Scale; DB, double-blind; IND, induction; MDSI, major depressive disorder (MDD) with suicidal ideation and intent; OL, open-label; OP/MA, optimization and maintenance; PBO, placebo nasal spray; QUE-XR, quetiapine extended release; SNRI, serotonin-norepinephrine reuptake inhibitor; SOC, standard of care; SSRI, selective serotonin reuptake inhibitor; TEAE, treatment-emergent adverse event; TRD, treatment-resistant depression.^aSOC consisted of newly initiated or optimized AD along with at least 5 days of initial hospitalization and enhanced by twice-weekly intensive visits during DB phase.

Post Hoc Analyses of Tolerability Trends During Postdose Monitoring in TRD Studies

Williamson et al (2018)¹⁹ conducted a post hoc analysis of two 4-week, randomized DB SPRAVATO trials in patients with TRD.⁸^,¹⁵ The objectives of the analysis were to measure if the incidence of specific AEs, including nausea, during the first week of treatment appeared to be associated with the incidence/frequency of the same AE during week 2-4.

Of 345 patients who received SPRAVATO+AD, the incidence of nausea (reported as an AE) was 28.3% over 4 weeks of treatment. Of those patients who experienced nausea once, twice, or not at all during the first week of treatment, the table Rates of Recurrence of Nausea reports the associated proportion of patients who experienced a recurrence of nausea during the subsequent 3 weeks of treatment.

Rates of Recurrence of Nausea¹⁹

AE	4-Week Incidence	Week 1 Incidence (number of monitoring periods [0-2] AE observed)		Number of Patients with AEs in Weeks 2-4	Number of Sessions (0-6) in which an AE was experienced in Weeks 2-4
Nausea	28.3%	None - 79.7% (n=275)	→	5.5% (n=15)	1.07
		Once - 20.3% (n=70)	→	44.3% (n=31)	2.37
		Twice - 5.2% (n=18)	→	66.7% (n=12)	3.62
Abbreviations: AE, adverse event. Data sample was a combination of data from the 3 intranasal SPRAVATO groups from the fixed-dose and flexible-dose studies (n=345). The first-week incidence groups are not mutually exclusive - the “Twice” group is a subset of the “Once” group.

A similar post hoc analysis by Williamson et al (2022)²⁰ for the two long-term studies (SUSTAIN-1 and SUSTAIN-2)⁹^,¹⁷ that evaluated whether the incidence of adverse events, including nausea, during weeks 1 and 4 of treatment predicted the recurrence of nausea as a spontaneously reported AE in subsequent postdose monitoring sessions.

Nausea was reported in 14% (133/949) of patients during week 1. The more frequently nausea was reported during the first week of treatment, the higher the rate of recurrence in subsequent time periods (see Table: Rates of Nausea Recurrence According to Frequency of Nausea Occurrence in Week 1).

Rates of Nausea Recurrence According to Frequency of Nausea Occurrence in Week 1²⁰

Postdose Monitoring Period	No. of Patients	Overall Incidence (%)	None in Week 1 (%, n/N)	Once in Week 1 (%, n/N)	Twice in Week 1 (%, n/N)
Weeks 2-4	949	9.2	5.1 (42/816)	28.6 (32/112)	61.9 (13/21)
Weeks 5-8	918	4.0	1.7 (13/786)	16.1 (18/112)	30.0 (6/20)
Months 3-6	595	7.2	4.5 (23/506)	20.8 (16/77)	33.3 (4/12)
Months 6-12	595	6.7	4.9 (25/506)	18.2 (14/77)	8.3 (1/12)
n/N represents the number of patients who experienced a recurrence of nausea/number of patients who contributed data to the time period depicted in the row.

Postmarketing Safety Data

REMS Database

REMS patient monitoring forms completed by certified 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 Nausea and vomiting were reported as serious adverse events on the REMS patient monitoring forms (n=1,580) with an occurrence of 7.1% (n=112) and 7.6% (n=120), respectively. In a separate search of the SPRAVATO global medical safety database, which included AEs reported from the REMS, 2,437 AEs (out of 658,360) were reported to be serious, of which 3.6% (n=89) involved nausea and 4.4% (n=107) involved vomiting.

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.¹⁴ 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.

Nausea and vomiting were classified as expected AEs with a detected signal. Nausea was reported as an AE with 75 reports, a reporting odds ratio of 2.79 (95% CI, 2.21-3.51), and a Bayesian information component of 1.43 (95% CI, 1.05-1.71). Vomiting was reported as an AE with 74 reports, a reporting odds ratio of 4.75 (95% CI, 3.77-5.99), and a Bayesian information component of 2.17 (95% CI, 1.78-2.45). 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.¹⁴

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 01 March 2024.

References

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2	Data on File. Data on File. Esketamine. Integrated Summary of Safety- TRD. Janssen Research & Development, LLC. EDMS-ERI-155147726; 2018.
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4	Zaki N, Chen LN, Lane R, et al. Long-term safety and maintenance of response with esketamine nasal spray in treatment-resistant depression: final results of the SUSTAIN-3 study. Poster presented at: Psych Congress; September 6-10, 2023; Nashville, TN.
5	Chen X, Hou X, Bai D, et al. Efficacy and safety of flexibly dosed esketamine nasal spray plus a newly initiated oral antidepressant in adult patients with treatment-resistant depression: a randomized, double-blind, multicenter, active-controlled study conducted in China and USA. Neuropsychiatr Dis Treat. 2023;19:693-707.
6	European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP). SPRAVATO assessment report. Procedure No. EMEA/H/C/004535/0000. 2019- [cited 2024 March 12]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/spravato-epar-public-assessment-report_en.pdf.
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8	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.
9	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.
10	Data on File. Esketamine. Internal Communication.
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12	Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31.
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15	Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.
16	Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-141.
17	Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.
18	Reif A, Bitter I, Buyze J, et al. Supplement to: Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389(14):1298-1309.
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