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VALDOXAN Film-coated tablets (2019)

Active ingredients: Agomelatine

Pharmacodynamic properties

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

Mechanism of action

Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C 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 European Medicines Agency has deferred the obligation to submit the results of studies with agomelatine in one or more subsets of the paediatric population in the treatment of major depressive episodes (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Absorption and bioavailability

Agomelatine is rapidly and well (≥80%) absorbed after oral administration. Absolute bioavailability is low (<5% at the therapeutic oral dose) and the interindividual variability is substantial. The bioavailability is increased in women compared to men. The bioavailability is increased by intake of oral contraceptives and reduced by smoking. The peak plasma concentration is reached within 1 to 2 hours.

In the therapeutic dose-range, agomelatine systemic exposure increases proportionally with dose. At higher doses, a saturation of the first-pass effect occurs. Food intake (standard meal or high fat meal) does not modify the bioavailability or the absorption rate. The variability is increased with high fat food.

Distribution

Steady state volume of distribution is about 35 l and plasma protein binding is 95% irrespective of the concentration and is not modified with age and in patients with renal impairment but the free fraction is doubled in patients with hepatic impairment.

Biotransformation

Following oral administration, agomelatine is rapidly metabolised mainly via hepatic CYP1A2; CYP2C9 and CYP2C19 isoenzymes are also involved but with a low contribution. The major metabolites, hydroxylated and demethylated agomelatine, are not active and are rapidly conjugated and eliminated in the urine.

Elimination

Elimination is rapid, the mean plasma half-life is between 1 and 2 hours and the clearance is high (about 1,100 ml/min) and essentially metabolic.

Excretion is mainly (80%) urinary and in the form of metabolites, whereas unchanged compound recovery in urine is negligible. Kinetics are not modified after repeated administration.

Renal impairment

No relevant modification of pharmacokinetic parameters in patients with severe renal impairment has been observed (n=8, single dose of 25 mg), but caution should be exercised in patients with severe or moderate renal impairment as only limited clinical data are available in these patients (see section 4.2).

Hepatic impairment

In a specific study involving cirrhotic patients with chronic mild (Child-Pugh type A) or moderate (Child-Pugh type B) liver impairment, exposure to agomelatine 25 mg was substantially increased (70-times and 140-times, respectively), compared to matched volunteers (age, weight and smoking habit) with no liver failure (see section 4.2, 4.3 and 4.4).

Elderly

In a pharmacokinetic study in elderly patients (≥65 years), it was showed that at a dose of 25 mg the mean AUC and mean Cmax were about 4-fold and 13-fold higher for patients ≥75 years old compared to patients <75 years old. The total number of patients receiving 50 mg was too low to draw any conclusions. No dose adaptation is required in elderly patients.

Ethnic groups

There is no data on the influence of race on agomelatine pharmacokinetics.

Preclinical safety data

In mice, rats and monkeys sedative effects were observed after single and repeated administration at high doses.

In rodents, a marked induction of CYP2B and a moderate induction of CYP1A and CYP3A were seen from 125 mg/kg/day whereas in monkeys the induction was slight for CYP2B and CYP3A at 375 mg/kg/day. No hepatotoxicity was observed in rodents and monkeys in the repeat dose toxicity studies.

Agomelatine passes into the placenta and foetuses of pregnant rats.

Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility, embryofoetal development and pre- and post natal development.

A battery of in vitro and in vivo standard genotoxicity assays concludes to no mutagenic or clastogenic potential of agomelatine.

In carcinogenicity studies agomelatine induced an increase in the incidence of liver tumours in the rat and the mouse, at a dose at least 110-fold higher than the therapeutic dose. Liver tumours are most likely related to enzyme induction specific to rodents. The frequency of benign mammary fibroadenomas observed in the rat was increased with high exposures (60-fold the exposure at the therapeutic dose) but remains in the range of that of controls.

Safety pharmacology studies showed no effect of agomelatine on hERG (human Ether à-go-go Related Gene) current or on dog Purkinje cells action potential. Agomelatine did not show proconvulsive properties at ip doses up to 128 mg/kg in mice and rats.

No effect of agomelatine on juvenile animals behavioural performances, visual and reproductive function were observed. There were mild non dose dependent decreases in body weight related to the pharmacological properties and some minor effects on male reproductive tract without any impairment on reproductive performances.