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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 Event of SPRAVATO – Urinary Disorders

Last Updated: 01/15/2025

Summary

In clinical trials of SPRAVATO, a higher rate of lower urinary tract symptoms (pollakiuria [abnormally frequent urination], dysuria, micturition urgency, nocturia, and cystitis) were reported in SPRAVATO-treated patients than in placebo.¹ No cases of treatment-related interstitial cystitis were observed in long-term trials (up to 6.5 years) of SPRAVATO.²^,³
- In a pooled analysis of short-term treatment-resistant depression (TRD) studies (TRANSFORM-1 and 2),⁴^,⁵ pollakiuria occurred in 3% of patients treated with SPRAVATO + oral antidepressant (AD; n=11/346) vs 0.5% of patients treated with placebo + oral AD (n=1/222).¹
- In a pooled analysis of short-term major depressive disorder with acute suicidal ideation or behavior studies (ASPIRE-I AND II),⁶^,⁷ pollakiuria (including micturition urgency) occurred in 2% of patients treated with SPRAVATO + oral AD (n=5/227) vs 1% of patients treated with placebo (n=2/225).¹
In a retrospective analysis of real-world clinical practice in France (ESKALE study) in 157 patients with moderate to severe TRD who were treated with SPRAVATO, adverse events (AEs) related to renal and urinary disorders were reported in 1 patient (0.6%).⁸
An analysis of postmarketing safety data (first quarter of 2019 to the fourth quarter of 2023) evaluating 14,606 SPRAVATO-related AEs from the Food and Drug Administration Adverse Event Reporting System (FAERS) database reported 159 (1.1%) cases related to renal and urinary disorders. The analysis identified 5 cases of interstitial cystitis among the top 50 AEs. Limitations of the database prohibit the inference of causality due to incomplete information in reporting.⁹

PRODUCT Labeling

Monitor for urinary tract and bladder symptoms during the course of treatment with SPRAVATO and refer to an appropriate healthcare provider as clinically warranted.¹⁰

CLINICAL DATA

Additional study-specific data on AEs related to renal and urinary disorders from phase 3 clinical trials are provided in the table below.

Study/Study Design	Rates of Urinary Disorders
Short-Term Clinical Trials in Treatment-Resistant Depression
Ochs-Ross et al (2020) (TRANSFORM-3)¹¹ 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. 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)	Urinary Tract Infections SPRAVATO+oral AD: 8.3% (n=6/72) Oral AD+PBO: 1.5% (n=1/65)
Long-Term Clinical Trials in Treatment-Resistant Depression
Wajs et al (2020) (SUSTAIN-2)² conducted an OL, multicenter, study to evaluate the long-term (up to 1 year of exposure) safety, tolerability and efficacy of flexibly-dosed SPRAVATO (28, 56, or 84 mg) plus a newly initiated oral AD in patients with TRD. Study Treatment During the induction phase (initial 4 weeks), patients self-administered either SPRAVATO or PBO 2 times per week. In the optimization and maintenance phases (48 weeks), 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. 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.	A total of 136 patients (17%) reported TEAEs related to renal and urinary disorders. Most were considered mild to moderate in severity and resolved within 2 weeks. Cystitis SPRAVATO+oral AD: 0.6% (n=5/802; all cases resolved while continuing SPRAVATO treatment) Bacterial Cystitis SPRAVATO+oral AD: 0.1% (n=1/802) 4/136 patients had 6 serious TEAEs (pyelonephritis, acute pyelonephritis, and tubulointerstitial nephritis, UTI); however, none resulted in discontinuation, and none were due to esketamine according to investigators. 1 patient experienced urinary retention, which led to temporary discontinuation of treatment but was re-started 4 days later after it resolved. This was assessed by investigators as doubtfully related to SPRAVATO. Another patient had moderate pollakiuria, which required a dose reduction from 84 mg to 56 mg and resolved within 5 days (assessed as probably drug-related). There was another who discontinued due to urinary incontinence. No cases of interstitial or ulcerative cystitis occurred during the study.
Zaki et al (2023) (SUSTAIN-3)³ conducted an OLE study to evaluate the long-term (up to 6.5 years) safety and efficacy of individualized, intermittently-dosed SPRAVATO plus a newly initiated 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 optimization/maintenance phase (variable duration), patients were administered SPRAVATO weekly, every other week, or every 4 weeks based on the assessment of CGI-S rating and tolerability. Study Groups Starting SPRAVATO dose of 28 mg (patients aged ≥65 years), 56 mg, or 84 mg (N=1148): induction phase, n=458; optimization/ maintenance phase, n=1110 (690 directly enrolled; 420 continued from the induction phase).	Urinary Tract Infections SPRAVATO+oral AD: 15.8% (n=181/1148) There were no cases of treatment-related interstitial or ulcerative cystitis. Other renal disorder-related AEs (≥1%) included dysuria (3.0%), cystitis (2.4%), pollakiuria (2.4%), nephrolithiasis (1.7%), micturition urgency (1.5%), urinary incontinence (1.5%), and hematuria (1.3%).
Reif et al (2023)¹² 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) for the treatment of patients with TRD. Study Treatment¹³ In the initial treatment phase (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. Study Groups¹³ SPRAVATO 56 mg on day 1, then 56 mg or 84 mg from day 4 + oral AD (patients aged 65 to ≤74 years or adults of Japanese ancestry started on 28 mg on day 1, then 28 mg, 56 mg, or 84 mg on day 4) (n=334) QUE-XR 50 mg on day 1, increasing to 150-300 mg/day + oral AD (n=336)	Renal and Urinary Disorders (Nephrolithiasis)¹⁴: SPRAVATO+oral AD: 1/334 (0.3%) QUE-XR+oral AD: 0/336 (0.0%) Severity Analysis of Treatment-Emergent Cystitis (a TEAE of Special Interest)¹⁴: SPRAVATO+oral AD: 1 (0.3%) mild case of cystitis, 1 (0.3%) moderate case of pollakiuria, and no cases of dysuria QUE-XR+oral AD: 2 (0.6%) moderate cases of cystitis, and 1 (0.3%) mild case each of pollakiuria and dysuria
Abbreviations: AD, antidepressant; AE, adverse event; CGI-S, Clinical Global Impression-Severity Scale; DB, double-blind; OL, open-label; OLE, open-label extension; PBO, placebo nasal spray; QUE-XR, quetiapine extended release; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TEAE, treatment-emergent adverse event; TRD, treatment-resistant depression; UTI, urinary tract infection.

Real-world Study in Treatment-Resistant Depression

Samalin et al (2024)⁸ conducted a real-world, multicenter, retrospective study in France (ESKALE study) in adult (≥18 years old) patients (N=157) with moderate to severe TRD (defined as non-responsive to ≥2 oral ADs) who initiated SPRAVATO from October 2019 to July 2021. Data was collected over 12 months following SPRAVATO initiation, up to June 2022. During the study period, 1 patient (0.6%) reported AEs related to renal and urinary disorders.

postmarketing safety data

Liu et al (2024)⁹ conducted an analysis of the FAERS database between the first quarter of 2019 and the fourth quarter of 2023. A total of 14,606 AEs were reported for SPRAVATO, of which 159 (1.1%) cases were related to renal and urinary disorders. The analysis identified interstitial cystitis (5 cases) among the top 50 AEs (reporting odds ratio, 17.14 [95% confidence interval (CI): 7.10-41.37]; proportional reporting ratio, 17.12 [95% CI: 7.10-41.32]; and empirical Bayes geometric mean [EBGM], 16.96 [the lower limit of the 90% CI for the EBGM: 7.02]). Limitations of the FAERS database include the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate the incidence rates of the events.⁹^,¹⁵

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 10 December 2024.

References

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1	Center for Drug Evaluation and Research. Other Review. NDA 211243 - SPRAVATO (esketamine) - Reference ID: 4398871. 2019- [cited 2024 December 10]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000OtherR.pdf
2	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.
3	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.
4	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.
5	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.
6	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.
7	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.
8	Samalin L, Mekaoui L, Rothärmel M, et al. Use of esketamine nasal spray in patients with treatment-resistant depression in routine practice: a real-world French study. Dépress Anxiety. 2024;(1):7262794.
9	Liu R, Liu C, Feng D, et al. Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database. Front Pharmacol. 2024;15:1414703.
10	SPRAVATO (esketamine) nasal spray [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc;https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/SPRAVATO-pi.pdf
11	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.
12	Reif A, Bitter I, Buyze J, et al. Esketamine nasal spray versus quetiapine for treatment-resistant depression. N Engl J Med. 2023;389(14):1298-1309.
13	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.
14	McIntyre RS, Bitter I, Buyze J. Supplement to: Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression. Eur Neuropsychopharmacol. 2024;85:58-65.
15	FDA Adverse Event Reporting System (FAERS) Public Dashboard. Accessed 2024-12-10. Available via: https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard