Symptoms
There is limited experience with agomelatine overdose. Experience with agomelatine in overdose has indicated that epigastralgia, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis or malaise have been reported.
One person having ingested 2450 mg agomelatine, recovered spontaneously without cardiovascular and biological abnormalities.
Management
No specific antidotes for agomelatine are known. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical follow-up in a specialised environment is recommended.
Hepatic impairment (i.e. cirrhosis or active liver disease) or transaminases exceeding 3 X upper limit of normal.
Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin).
Not applicable.
Summary of the safety profile
In clinical trials, more than 8.000 depressed patients have received Мелитор.
Adverse reactions were usually mild or moderate and occurred within the first two weeks of treatment. The most common adverse reactions were headache, nausea and dizziness.
These adverse reactions were usually transient and did not generally lead to cessation of therapy.
Tabulated list of adverse reactions
The below table gives the adverse reactions observed from placebo-controlled and active-controlled clinical trials.
Adverse reactions are listed below using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The frequencies have not been corrected for placebo.
| System organ class | Frequency | Preferred Term |
| Psychiatric disorders | Common | Anxiety |
| Abnormal dreams* | ||
| Uncommon | Suicidal thoughts or behaviour | |
| Agitation and related symptoms* (such as irritability and restlessness) | ||
| Aggression* | ||
| Nightmares* | ||
| Mania/hypomania* These symptoms may also be due to the underlying disease. | ||
| Confusional state* | ||
| Rare | Hallucinations* | |
| Nervous system disorders | Very common | Headache |
| Common | Dizziness | |
| Somnolence | ||
| Insomnia | ||
| Uncommon | Migraine | |
| Paraesthesia | ||
| Restless leg syndrome* | ||
| Rare | Akathisia* | |
| Eyes disorders | Uncommon | Blurred vision |
| Ear and vestibular system disorders | Uncommon | Tinnitus* |
| Gastrointestinal Disorders | Common | Nausea |
| Diarrhoea | ||
| Constipation | ||
| Abdominal pain | ||
| Vomiting* | ||
| Hepato- biliary disorders | Common | Increased ALAT and/or ASAT (in clinical trials, increases >3 times the upper limit of the normal range for ALAT and/or ASAT were seen in 1.2% of patients on agomelatine 25 mg daily and 2.6% on agomelatine 50 mg daily vs. 0.5% on placebo). |
| Uncommon | Increased gamma-glutamyltransferase* (GGT) (>3 times the upper limit of the normal range) | |
| Rare | Hepatitis | |
| Increased alkaline phosphatase* (>3 times the upper limit of the normal range) | ||
| Hepatic failure* (1) | ||
| Jaundice* | ||
| Skin and subcutaneous tissue disorders | Uncommon | Hyperhidrosis |
| Eczema | ||
| Pruritus* | ||
| Urticaria* | ||
| Rare | Erythematous rash | |
| Face oedema and angioedema* | ||
| Musculoskeletal and connective tissue disorders | Common | Back pain |
| Renal and urinary disorders | Rare | Urinary retention* |
| General disorders and administration site conditions | Common | Fatigue |
| Investigations | Common | Weight increased* |
| Uncommon | Weight decreased* |
* Frequency estimated from clinical trials for adverse events detected from spontaneous report
(1) Few cases were exceptionally reported with fatal outcome or liver transplantation in patients with hepatic risk factors.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard
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.
Treatment of major depressive episodes.
Мелитор is indicated in adults.
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, Мелитор 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 Мелитор in major depressive episodes have been studied in a clinical programme including 7,900 patients treated with Мелитор.
Ten placebo-controlled trials have been performed to investigate the short term efficacy of Мелитор 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 were 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 Мелитор 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 Мелитор 25-50 mg once daily were randomised to either Мелитор 25-50 mg once daily or placebo for further 6-months. Мелитор 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 Мелитор and placebo, respectively.
Мелитор does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with Мелитор 25 mg increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. Мелитор 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 Мелитор. The pooled analysis of trials using the Arizona Sexual Experience Scale (ASEX) showed that Мелитор was not associated with sexual dysfunction. In healthy volunteers Мелитор preserved sexual function in comparison with paroxetine.
Мелитор 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, Мелитор did not induce discontinuation syndrome after abrupt treatment cessation.
Мелитор 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
).
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.
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.
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.
Monitoring of liver function
Cases of liver injury, including hepatic failure (few cases were exceptionally reported with fatal outcome or liver transplantation in patients with hepatic risk factors), elevations of liver enzymes exceeding 10 times upper limit of normal, hepatitis and jaundice have been reported in patients treated with Мелитор in the post-marketing setting. Most of them occurred during the first months of treatment. The pattern of liver damage is predominantly hepatocellular with serum transaminases which usually return to normal levels on cessation of Мелитор.
Caution should be exercised before starting treatment and close surveillance should be performed throughout the treatment period in all patients, especially if hepatic injury risk factors or concomitant medicinal products associated with risk of hepatic injury are present.
- Before starting treatment
Treatment with Мелитор should only be prescribed after careful consideration of benefit and risk in patients with hepatic injury risk factors e.g.:
- obesity/overweight/non-alcoholic fatty liver disease, diabetes
- alcohol use disorder and /or substantial alcohol intake
and in patients receiving concomitant medicinal products associated with risk of hepatic injury.
Baseline liver function tests should be undertaken in all patients and treatment should not be initiated in patients with baseline values of ALT and/or AST >3 X upper limit of normal. Caution should be exercised when Мелитор is administered to patients with pretreatment elevated transaminases (> the upper limit of the normal ranges and ≤3 times the upper limit of the normal range).
| - Frequency of liver function tests - before starting treatment - and then: - after around 3 weeks, - after around 6 weeks (end of acute phase), - after around 12 and 24 weeks (end of maintenance phase) - and thereafter when clinically indicated. - When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment. Any patient who develops increased serum transaminases should have his/her liver function tests repeated within 48 hours. |
- During treatment period
Мелитор treatment should be discontinued immediately if:
†patient develops symptoms or signs of potential liver injury (such as dark urine, light coloured stools, yellow skin/eyes, pain in the upper right belly, sustained new-onset and unexplained fatigue).
†the increase in serum transaminases exceeds 3 X upper limit of normal.
Following discontinuation of Мелитор therapy liver function tests should be repeated until serum transaminases return to normal.
Use in paediatric population
Мелитор is not recommended in the treatment of depression in patients under 18 years of age since safety and efficacy of Мелитор have not been established in this age group. In clinical trials among children and adolescents treated with other antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed compared to those treated with placebo.
Older people
No effect of agomelatine is documented in patients >75 years, therefore agomelatine should not be used by patients in this age group (see also sections 4.2 and 5.1).
Use in older people with dementia
Мелитор should not be used for the treatment of major depressive episodes in elderly patients with dementia since the safety and efficacy of Мелитор have not been established in these patients.
Bipolar disorder/ mania / hypomania
Мелитор should be used with caution in patients with a history of bipolar disorder, mania or hypomania and should be discontinued if a patient develops manic symptoms.
Suicide/suicidal thoughts
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Combination with CYP1A2 inhibitors
Caution should be exercised when prescribing Мелитор with moderate CYP1A2 inhibitors (e.g. propranolol, enoxacin) which may result in increased exposure of agomelatine.
Lactose intolerance
Мелитор contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No studies on the effects on the ability to drive and use machines have been performed.
However, considering that dizziness and somnolence are common adverse reactions patients should be cautioned about their ability to drive a car or operate machinery.
Posology
The recommended dose is 25 mg once daily taken orally at bedtime.
After two weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily, i.e. two 25 mg tablets, taken together at bedtime.
Decision of dose increase has to be balanced with a higher risk of transaminases elevation. Any dose increase to 50 mg should be made on an individual patient benefit/risk basis and with strict respect of LFT monitoring.
Liver function tests should be performed in all patients before starting treatment. Treatment should not be initiated if transaminases exceed 3 X upper limit of normal.
). Treatment should be discontinued if transaminases exceed 3 X upper limit of normal.
When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment.
Treatment duration
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free of symptoms.
Switching therapy from SSRI/SNRI antidepressant to agomelatine
Patients may experience discontinuation symptoms after cessation from an SSRI/SNRI antidepressant.
The SmPC of the actual SSRI/SNRI should be consulted on how to withdraw the treatment to avoid this. Agomelatine can be started immediately while tapering the dosage of an SSRI/SNRI.
Treatment discontinuation
No dosage tapering is needed on treatment discontinuation.
Special populations
Elderly
The efficacy and safety of agomelatine (25 to 50mg/day) have been established in elderly depressed patients (<75years). No effect is documented in patients >75 years. Therefore agomelatine should not be used by patients in this age group. No dose adjustment is required in relation to age.
Renal impairment
No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on the use of Мелитор in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing Мелитор to these patients.
Hepatic impairment
Мелитор is contraindicated in patients with hepatic impairment.
Paediatric population
The safety and efficacy of Мелитор in children from 2 years onwards for treatment of major depressive episodes have not yet been established. No data are available.
There is no relevant use of Мелитор in children from birth to 2 years for treatment of major depressive episodes.
Method of administration
For oral use.
Мелитор film-coated tablets may be taken with or without food.
No special requirements for disposal.
