SPRAVATO - Hepatic Adverse Events and Use in Patients with Hepatic Impairment

SUMMARY

• The long-term safety and efficacy of intermittently dosed SPRAVATO nasal spray used in combination with an oral antidepressant in patients (N=1148) with treatment-resistant depression (TRD) was evaluated in a phase 3 study (SUSTAIN-3).¹
  • Hepatic adverse events (AEs) were reported in 7.9% of participants, the most common were increased gamma-glutamyl transferase (GGT; 2.5%), increased alanine aminotransferase (ALT; 1.9%), increased hepatic enzyme levels (1.6%), hepatic steatosis (1.5%), cholelithiasis (1.4%), and increased aspartate aminotransferase (AST; 1.3%). Few AE-related treatment discontinuations were noted (0.1%), and the incidence of AEs did not increase over time.  
• The pharmacokinetics and safety of esketamine nasal spray in patients with hepatic impairment were evaluated in a phase 1 study.²
  • The mean esketamine area under the curve (AUC) and half-life (t_1/2) values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function.
• Patients treated with SPRAVATO with moderate hepatic impairment likely need to be monitored for adverse reactions for a longer period of time.³
• SPRAVATO has not been studied in patients with severe hepatic impairment (Child Pugh class C). Use in this population is not recommended.⁴
• A real-world study investigates liver enzyme trajectories (AST, ALT, alkaline phosphate [ALP], and bilirubin) in 74 adults with TRD receiving either IV ketamine or SPRAVATO. No clinically meaningful changes in enzyme trajectories were observed. Three patients experienced elevations ≥2× Upper Limit of Normal (ULN). None of these cases were considered attributable to the treatment.⁵

CLINICAL trial DATA

Phase 3 Study

The long-term safety and efficacy of SPRAVATO nasal spray used in combination with an oral antidepressant was evaluated in an open-label, multicenter, long-term extension study (SUSTAIN-3) in patients with treatment-resistant depression (N=1148). These patients were previously enrolled in one of 6 phase 3 studies.¹

• SUSTAIN-3 had an induction phase (4 weeks; if applicable) followed by an optimization/maintenance phase (variable duration).
  • In the induction phase, 458 patients self-administered a 28 mg (starting dose age ≥65 years), 56 mg, or 84 mg dose of SPRAVATO (under medical supervision) twice weekly for 4 weeks.
  • In the optimization/maintenance phase, 1110 patients received intermittent doses of SPRAVATO individualized based on the severity of each patient’s depression.

Results

• Mean (range) exposure to SPRAVATO nasal spray was 42.9 months (0-79 months), with a total exposure of 3777 cumulative patient-years.
• Most patients received SPRAVATO (84 mg, 64.4%; 56 mg, 33.0%) either weekly or every 4 week in combination with an oral antidepressant.
• Hepatic AEs were reported in 7.9% of patients.
  • The most common hepatic AEs were increased GGT level (2.5%), increased ALT level (1.9%), increased hepatic enzyme levels (1.6%), hepatic steatosis (1.5%), cholelithiasis (1.4%), and increased AST level (1.3%).
  • The occurrence of hepatic AEs did not increase over time.
  • Few participants (0.1%) discontinued SPRAVATO due to hepatic AEs.

Phase 1 Study

The pharmacokinetics and safety of a single dose of esketamine 28 mg was evaluated in an open-label, single-dose, parallel group study in subjects with varying stages of hepatic impairment and in healthy subjects (N=24).²

• Patients were assigned to 3 cohorts based on hepatic impairment:
  • Cohort 1 (n=8): moderate hepatic impairment (Child-Pugh score of 7 to 9; Class B)
  • Cohort 2 (n=8): mild hepatic impairment (Child-Pugh score of 5 to 6; Class A)
  • Cohort 3 (n=8): normal hepatic function and no evidence of liver damage
• The use of esketamine in patients with severe hepatic impairment was not studied.

Results

• Mean total esketamine maximum concentration (C_max) and AUC were similar in patients with mild hepatic impairment compared to subjects with normal hepatic function.
• In patients with moderate hepatic impairment, total esketamine C_max was ~8% higher compared to patients with normal hepatic function, and AUC_∞ was 103% higher.
• Noresketamine C_max was approximately 44% lower and AUC_∞ was 25% higher in patients with moderate hepatic impairment compared with patients with normal hepatic function.
• The mean t_1/2 of esketamine in patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment was 16.5 hours (h), 13.1 h, and 18.7 h, respectively.
• Eight (33.3%) of 24 patients reported at least 1 treatment-emergent AE (TEAE). The most frequently reported TEAEs were dizziness and nasal crusting (n=2, each). Most TEAEs reported by patients were classified as mild and transient, and resolved.

Real-World Data

Singh et al (2026)⁵ conducted a secondary analysis of a real-world, retrospective historical cohort of 74 adults with TRD⁶ to characterize the hepatic safety profile of repeated or long-term use of IV ketamine (n=58) and SPRAVATO (n=16).

Study Design/Methods

• Patients with severe hepatic disease (eg, cirrhosis) were excluded.
• Participants received either IV racemic ketamine 0.5 mg/kg or SPRAVATO (56 or 84 mg) and continued their existing psychotropic medications.
• The acute treatment phase consisted of 3 to 6 IV ketamine or 8 SPRAVATO sessions. Maintenance treatment was offered to patients demonstrating at least partial response (≥25% reduction in Quick Inventory of Depressive Symptomatology, 16-item self-report version [QIDS-SR16] score from baseline) or clinically significant subjective improvement. After initial response, patients transitioned to once weekly administration for 4 weeks, then underwent gradual reductions or increases in dosing frequency depending on treatment response.
• The primary endpoint evaluated changes in liver enzymes (AST, ALT, ALP, and bilirubin) over the course of treatment. The secondary outcome assessed the incidence of clinically significant elevations, defined as values ≥2× the ULN.

Results

• No statistically significant changes in liver enzyme trajectories were observed for any marker at the time of IV ketamine or SPRAVATO initiation.
  • ALP exhibited a modest pretreatment decline followed by a slight increase post initiation (P=0.19).
  • ALT and AST levels showed mild increases around the time of initiation that subsequently plateaued (P=0.06 and P=0.12, respectively).
  • Bilirubin levels were relatively stable during the observation period (P=0.74).
• Liver enzyme levels remained stable after treatment initiation, as indicated by post initiation slope estimates showing <0.3% change per month in either direction across all markers (monthly ratios: ALP, 1.001; ALT, 0.999; AST, 0.999; bilirubin, 0.997; all P≥0.35).
• Paired pre/post ~3-month analysis showed no significant changes in ALP, ALT, AST, or bilirubin levels (all P>0.05).
• Among those with liver enzyme data available during treatment or within 3 months of treatment discontinuation (n=51), clinically significant liver enzyme elevations occurred in 3 patients (6%). In all 3 cases, other medical factors were identified including alcohol use, myalgias, and preexisting hepatic steatosis, suggesting the elevations were unlikely to be attributable to treatment.

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 12 August 2026.