VALDOXAN Film-coated tablet Ref.[6100] Active ingredients: Agomelatine

Pharmacotherapeutic group: Psychoanaleptics, other antidepressants
ATC-code: N06AX22

Mechanism of action

Agomelatine is a melatonergic agonist (MT₁ and MT₂ receptors) and 5-HT_2C antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.

Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin.

Pharmacodynamic effects

Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety.

In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

Clinical efficacy and safety

The efficacy and safety of agomelatine in major depressive episodes have been studied in a clinical programme including 7,900 patients treated with agomelatine.

Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder in adults, with fixed dose and/or dose up-titration. At the end of treatment (over 6 or 8 weeks), significant efficacy of agomelatine 25-50 mg was demonstrated in 6 out of the ten short-term double-blind placebo-controlled trials. Primary endpoint was change in HAMD-17 score from baseline. Agomelatine failed to differentiate from placebo in two trials where the active control, paroxetine or fluoxetine showed assay sensitivity. Agomelatine was not compared directly with paroxetine and fluoxetine as these comparators where added in order to ensure assay sensitivity of the trials. In two other trials, it was not possible to draw any conclusions because the active controls, paroxetine or fluoxetine, failed to differentiate from placebo. However, in these studies it was not allowed to increase the start dose of either agomelatine, paroxetine or fluoxetine even if the response was not adequate.

Efficacy was also observed in more severely depressed patients (baseline HAM-D ≥25) in all positive placebo-controlled trials.

Response rates were statistically significantly higher with agomelatine compared with placebo.

Superiority (2 trials) or non-inferiority (4 trials) has been shown in six out of seven efficacy trials in heterogeneous populations of depressed adult patients versus SSRI/SNRI (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine) The anti-depressive effect was assessed with the HAMD-17 score either as primary or secondary endpoint.

The maintenance of antidepressant efficacy was demonstrated in a relapse prevention trial. Patients responding to 8/10-weeks of acute treatment with open-label agomelatine 25-50 mg once daily were randomised to either agomelatine 25-50 mg once daily or placebo for further 6-months.

Agomelatine 25-50 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.0001) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow up period was 22% and 47% for agomelatine and placebo, respectively.

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with agomelatine 25 mg increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Agomelatine 25 mg also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.

In a specific sexual dysfunction comparative trial with remitted depressed patients, there was a numerical trend (not statistically significant) towards less sexual emergent dysfunction than venlafaxine for Sex Effects Scale (SEXFX) drive arousal or orgasm scores on agomelatine. The pooled analysis of trials using the Arizona Sexual Experience Scale (ASEX) showed that agomelatine was not associated with sexual dysfunction. In healthy volunteers agomelatine preserved sexual function in comparison with paroxetine.

Agomelatine had neutral effect on heart rate and blood pressure in clinical trials.

In a trial designed to assess discontinuation symptoms by the Discontinuation Emergent Signs and Symptoms (DESS) check-list in patients with remitted depression, agomelatine did not induce discontinuation syndrome after abrupt treatment cessation.

Agomelatine has no abuse potential as measured in healthy volunteer studies on a specific visual analogue scale or the Addiction Research Center Inventory (ARCI) 49 check-list.

A placebo-controlled 8-week trial of agomelatine 25-50mg/day in elderly depressed patients (≥ 65 years, N=222, of which 151 on agomelatine) demonstrated a statistically significant difference of 2.67 points on HAM-D total score, the primary outcome. Responder rate analysis favoured agomelatine. No improvement was observed in very elderly patients (≥75 years, N= 69, of which 48 on agomelatine). Tolerability of agomelatine in elderly patients was comparable to that seen in the younger adults.

A specific controlled, 3-week trial has been conducted in patients suffering from major depressive disorder and insufficiently improved with paroxetine (a SSRI) or venlafaxine (a SNRI). When treatment was switched from these antidepressants to agomelatine, discontinuation symptoms arose after cessation of the SSRI or SNRI treatment, either after abrupt cessation or gradual cessation of the previous treatment. These discontinuation symptoms may be confounded with a lack of early benefit of agomelatine.

The percentage of patients with at least one discontinuation symptom one week after the SSRI/SNRI treatment stop, was lower in the long tapering group (gradual cessation of the previous SSRI/SNRI within 2 weeks) than in the short tapering group (gradual cessation of the previous SSRI/SNRI within 1 week) and in the abrupt substitution group (abrupt cessation): 56.1%, 62.6 % and 79.8% respectively.

Paediatric population

The efficacy and safety of two doses (10 mg and 25 mg) of agomelatine for the treatment of moderate to severe major depressive episodes, if depression is unresponsive to psychological therapy alone, were assessed in a 12-week, randomized, double-blind, and placebo-controlled, parallel groups, study (see section 4.2). Fluoxetine (10 mg/day with potential adjustment to 20 mg/day) was added to ensure assay sensitivity.

Patients (N=400; whereof 80 children from 7 to less than 12 years and 320 adolescents from 12 to 17 years) with moderate to severe depression according to DSM IV were randomised to receive agomelatine 10 mg (N=102 whereof 81 were adolescents), agomelatine 25 mg (N= 95 whereof 76 were adolescents), placebo (N=103 whereof 82 were adolescents) and fluoxetine (N= 100 whereof 81 were adolescents).

The patients were to be non-responders to psychosocial therapy before inclusion. During the double-blind period psychosocial counselling was given once a month (Week 4, 8 and 12).

The primary endpoint was the adjusted difference in baseline to Week 12 in the Children's Depression Rating Scale – Revised (CDRS-R) raw total score, using a 3-way ANCOVA. A raw score of ≥45 was a prerequisite for enrolment. The CDRS-R was performed at the selection visit, at inclusion (Week 0) and thereafter at each visit (i.e., in the double-blind period: Week 1, Week 2, Week 4, Week 8 and Week 12).

Main secondary efficacy endpoints were Clinical Global Impression – Severity of Illness (CGI-S), Improvement (CGI-I) scales and Adolescent Depression Rating Scale (ADRS) total score.

The majority of the patients in the overall population were female (62.5%) with a median age of 14.0 years (range: 7, 17). Most of the patients had their first episode of depression (71.5%). According to DSM-IV-TR criteria the episode was diagnosed as moderate for 61.8% and severe (without psychotic features) for 38.3%. The mean duration of current episode was 143.4 ± 153.2 days with a median of 96.0 days (range from 29 to 1463 days).

Regarding comorbidities, around 6% patients in the overall population had generalised anxiety disorder, 7% had social anxiety disorder and 2% separation anxiety disorder.

The results for the primary endpoint CDRS-R raw score expressed in terms of change from baseline to last post-baseline value for the overall population showed a difference between agomelatine 25 mg compared to placebo of 4.22; 95%CI [0.63; 7.82]. For the adolescent subset the estimated between- group difference was 5.22; 95%CI [1.03; 9.40] for agomelatine 25 mg compared to placebo. For the secondary endpoints Clinical Global Impression – Severity of Illness (CGI-S) and Improvement (CGI-I) scales no statistically significant differences were observed between any of the groups. The mean difference between the agomelatine 25 mg group and the placebo group in ADRS-score was 4.07, 95% CI [0.68; 7.46].

After the 12-week double-blind period, patients could continue in an optional open-label 21-month extension period at a agomelatine dose of 10 or 25 mg. However, this period was not designed as a relapse-prevention study and all patients received flexible doses of agomelatine. Useful data on efficacy and safety beyond 12 weeks are therefore limited.

Pubertal status was assessed by Tanner stage. Although data are limited, they do not suggest an impact of agomelatine on Tanner stage development (see section 4.8).

For further information on safety, please refer to sections 4.4 and 4.8.

There is only limited data on safety and efficacy in the children subgroup (age range from 7-11 years; in total 80 patients) due to a very limited number of patients (see section 4.2). In the children, the change in the mean CDRS-R raw total score at the end of the short term phase was lower in absolute value in the agomelatine 25 mg group (-17.1 ± 13.3) than in the placebo group (-19.0 ± 18.3).