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 was evaluated in a phase 3 study (SUSTAIN-3).¹
  • In the interim analysis, hepatic adverse events (AEs) were reported in 6.3% of patients, with 9 AEs being serious events (cholelithiasis, n=8; cholecystitis, n=1), all of which were considered by investigators as unrelated to SPRAVATO.
• 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

CLINICAL 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 at the interim data cutoff point (December 1, 2020) was 31.5 months (0-56 months).
• Most patients received SPRAVATO (84 mg, 66.4%; 56 mg, 31.0%) either weekly or every other week in combination with an oral antidepressant.
• Hepatic AEs were reported in 6.3% of patients, mostly of mild or moderate intensity.
  • The most common hepatic AEs were increased gamma glutamyl transferase level (2.1%), increased alanine aminotransferase (ALT) level (1.4%), increased aspartate aminotransferase (AST) level (1.0%), increased hepatic enzyme level (1.0%), and cholelithiasis (1.0%).
  • ALT level >3 x upper limit of normal (ULN) and total bilirubin level >2 x ULN were not observed in any patient.
  • Nine serious hepatic AEs (cholelithiasis, n=8; cholecystitis, n=1) occurred but were judged as not associated with SPRAVATO.

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.

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 25 October 2024.