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SPRAVATO® (esketamine)
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Adverse Event of SPRAVATO - Urinary Disorders
Last Updated: 04/28/2025
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 pooled analysis of short-term treatment-resistant depression (TRD) studies (TRANSFORM-1 and 2),4
- 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
- Postmarketing safety data:
- An analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2019 to the fourth quarter of 2023 evaluating 14,606 SPRAVATO-related AEs 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
- A disproportionality analysis based on the FAERS database evaluated the urological safety profiles of SPRAVATO and ketamine compared to those of antidepressants (ADs; selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs]) and second-generation antipsychotics (SGAs). The odds of renal and urinary disorders were comparable between SPRAVATO and ketamine and SPRAVATO and SGAs, but were observed to be significantly higher when compared to ADs.10
- An analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2019 to the fourth quarter of 2023 evaluating 14,606 SPRAVATO-related AEs 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.11
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 TRD | |
| Ochs-Ross et al (2020) (TRANSFORM-3)12 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
| UTIs
|
| Long-term Clinical Trials in TRD | |
| 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
Bacterial Cystitis
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 restarted 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). | UTIs
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)13 Study Treatment14 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 Groups14
| Renal and Urinary Disorders (Nephrolithiasis)15
Severity Analysis of Treatment-Emergent Cystitis (a TEAE of Special Interest)15
|
| 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 TRD
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.9,16
Chiappini et al (2025)10 conducted an analysis of the FAERS database to evaluate the urological safety profiles of SPRAVATO and ketamine with those of ADs (SSRIs, SNRIs, and TCAs) and SGAs.
Of the 7661 AEs identified for SPRAVATO (between 2011 and 2024), 140 were related to renal and urinary disorders, including lower urinary tract symptoms (n=68 cases; comprising pollakiuria, micturition urgency, urinary incontinence, and dysuria), nephrolithiasis (n=16), bladder conditions (n=19 cases; comprising bladder pain, bladder disorder, and interstitial cystitis), urinary tract obstruction (n=19), and nonurological conditions (n=24 cases; comprising renal impairment, acute kidney injury, and renal failure).
Of the 4739 AEs identified for ketamine (between 1998-2024), 105 were related to renal and urinary disorders. The following lists some of the more frequently reported events (≥20 cases): nonurological conditions (n=133 cases; acute kidney injury, renal failure, and renal infarct were among the most frequently reported), nephrolithiasis (n=90), urinary tract disorder (n=50), urinary tract obstruction (n=49 cases; comprising hydronephrosis, urinary retention, and ureteric stenosis), lower urinary tract symptoms (n=42 cases; comprising urinary incontinence, dysuria, lower urinary tract symptoms, and pollakiuria), hematuria (n=26), and conditions involving the bladder (n=20 cases; comprising hypertonic bladder and ulcerative cystitis).
The odds of renal and urinary disorders were lower with SPRAVATO when compared with ketamine but the difference was not statistically significant (see Table: Disproportionality Assessments Related to Renal and Urinary Disorders With SPRAVATO vs Ketamine, Antidepressants, and Antipsychotics). The odds of these AEs were higher with SPRAVATO when compared to SSRIs, SNRIs, and TCAs.
| SPRAVATO vs Treatment Group | Odds of Renal and Urinary Disorders ROR (95% CI) | Odds of Renal and Urinary Disorders (Serious Cases) ROR (95% CI) |
|---|---|---|
| Ketamine | 0.82 (0.06 to -0.45) | 0.79 (0.02 to -0.49) |
| Antipsychotics | ||
| SGAsa | 1.13 (0.30 to -0.04) | 0.85 (0.01 to -0.33) |
| Antidepressants | ||
| SSRIsb | 2.05 (0.9 to 0.5) | 1.9 (0.82 to 0.45) |
| SNRIsc | 1.63 (0.7 to 0.3) | 1.46 (0.57 to 0.19) |
| TCAsd | 2.7 (1.2 to 0.8) | 2.47 (1.14 to 0.67) |
| Abbreviations: CI, confidence interval; ROR, relative odds ratio; SGA, second generation antipsychotic; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. aDrugs evaluated were quetiapine, aripiprazole, olanzapine, and risperidone. bDrugs evaluated were citalopram, escitalopram, paroxetine, fluoxetine, and sertraline. cDrugs evaluated were duloxetine and venlafaxine. dDrugs evaluated were amitriptyline and clomipramine. Note: ROR <1 indicated lower odds of renal and urinary disorders compared with the reference group; ROR >1 indicated higher odds of renal and urinary disorders compared with the reference group. | ||
Limitations of the FAERS database include inability to infer causality; passive reporting; limitations in the quality of the information received; and inability to stratify data using specific drugs, dose regimens, or administration routes, which may make direct comparison difficult. AEs associated with some formulations of ketamine may also be underreported due to its use outside healthcare supervision.10,16
Literature Search
A literature search of MEDLINE®
References
| 1 | Center for Drug Evaluation and Research. Other Review. NDA 211243 - SPRAVATO (esketamine) - Reference ID: 4398871. 2019- [cited 2025 April 22]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000OtherR.pdf |
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