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Table 1 Agomelatine-induced liver injury in pre- and postmarketing clinical trials and non-interventioal studies

From: A systematic review of agomelatine-induced liver injury

Study [reference number] No. Patients enrolled Duration (weeks) Indication Liver enzymes >3X ULN Serious hepatic reactions (i.e., hepatitis, liver enzymes >10X ULN and hepatic failure) and deaths due to hepatic reaction
European clinical trials (2008) [8] 40681 up to 52 weeks All indications (Overall safety set) Ago25: 1.04%2 Ago50: 1.39%2 Pbo: 0.72% • >10X ULN: 1:1000-10 0003 1 case hepatitis4
Zajecka et al. (2010) [22,23] 511 8 MDD Ago25: 0% Ago50: 4.5% Pbo: 0% 0%
Stahl et al. (2010) [24,25] 503 8 MDD Ago25: 0.6% Ago50: 3.0% Pbo: 0.6% 0%
CAGO178A2303 [26] 503 8 MDD Ago25: 1.3% Ago50: 0.6% Par20: 0.6% Pbo: 0% 0%
Hale et al. (2010) [27] 515 8 MDD Ago25/50: 1.6%5 Flx20/40: 0.4% 0%
Kasper et al. (2010) [28] 313 6 sleep in MDD Ago25/50: 0.7%5 Ser50/100: 0% 0%
CAGO178A2301E1 (2009) [29] 329 52 MDD Ago25/50: 2.0% 0%
CAGO178A2302E1 (2009) [30] 358 52 MDD Ago25/50: 2.0% 0%
CAGO178A2303E1 (2010) [31] 334 52 MDD Ago25: 1.2%6 Ago50: 2.0%6 0%
CAGO178A2304 [32] 633 52 MDD Ago25/50: 4.6% (open-label phase) Pbo: 2.1% (double-blind continuation phase)7 0%
Calabrese et al. (2007) [33] 21 6, plus optional 46 (total 52) bipolar I disorder Ago25: N/A 0%
Olié & Kasper (2007) [34] 238 6 MDD Ago25/50 and Pbo: N/A 0%
Goodwin et al. (2009) [35] 339 34 MDD Ago25/50 and Pbo: N/A 0%
Demyttenaere et al. (2013) [36] 8628 up to 24 MDD Ago25: 1.79% Ago50: 2.61% SSRIs: 0.34% 0%
Bruno et al. (2013) [37] 15 12 Fibromyalgia Ago25: 0% 0%
Martinotti et al. (2012) [38] 60 8 MDD Ago25/50 and Vlx75/150: N/A 0%
Stein et al. (2012) [39] 477 43 GAD N/A 0%
Stein et al. (2014) [40] 412 12 GAD N/A 0%
Heun et al. (2013) [41] 222 8 MDD Ago25/50: 1.3%5 Pbo: 0% 0%
Laux and the VIVALDI Study Group (2012) [42] 3356 12 MDD Ago25/50: 0.2%8 0%
Sparshatt et al. (2013) [43] 110 12 MDD Ago25/50: -Baseline: 0.9%9 -Week 8: 0% 0%
Karaistos et al. (2013) [44] 40 16 Depression in type II diabetes Ago25/50 and Ser50/100: N/A 0%
Quera-Slava et al. (2011) [45] 138 24 MDD Ago25/50 and Esci10/20: N/A 0%
Montejo et al. (2010) [46] 92 8 healthy volunteers Ago25/50, Par20, and Pbo: N/A 0%
  1. Ago25 = 25 mg agomelatine; Ago50 = 50 mg agomelatine; Ago25/50 = entire agomelatine treatment group; Pbo = placebo; Par20 = 20 mg paroxetine, Flx20/40 = entire fluoxetine treatment group; Ser50/100 = entire sertraline treatment group; Vlx75/150 = entire venlafaxine treatment group; Esci10/20 = entire escitalopram treatment group; SSRIs: selective serotonin reuptake inhibitors; MDD = Major Depressive Disorder; GAD = Generalized Anxiety Disorder; Slp = sleep; N/A = non-vailable.
  2. 1: Number of patients receiving agomelatine; the number of patients receiving placebo is not clear.
  3. 2: Classified as a common event.
  4. 3: Classified as a rare event.
  5. 4: Case did not recover at follow-up (2.5 years after end of study).
  6. 5: Percentage calculated from safety set (i.e., enrolled patients who received at least one dose of the study treatment).
  7. 6: Percentage calculated from all treated patients enrolled in the extension phase.
  8. 7: Percentages calculated from information provided in Novartis Clinical Trial Results Database, 2010—study CAGO178A2.
  9. 304.
  10. 8: It is not mentioned by the authors if other ADs were taken concurrently.
  11. 9: Percentage calculated from information provided in the article.