VALDOXAN 25mg tablets medication leaflet

Valdoxan 25 mg film-coated tablets

Each film-coated tablet contains 25 mg of agomelatine.

Each film-coated tablet contains 61.8 mg lactose (as monohydrate)

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Orange-yellow, oblong, 9.5 mm long, 5.1 mm wide film-coated tablet.

Valdoxan is indicated for the treatment of major depressive episodes in adults.

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 to50 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 doseincrease to 50 mg should be made on an individual patient benefit/risk basis and with strict respect of

Liver Function Test monitoring.

Liver function tests should be performed in all patients before starting treatment. Treatment should notbe initiated if transaminases exceed 3 X upper limit of normal (see sections 4.3 and 4.4).

During treatment transaminases should be monitored periodically after around three weeks, six weeks(end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and thereafterwhen clinically indicated (see also section 4.4). Treatment should be discontinued if transaminasesexceed 3 X upper limit of normal (see sections 4.3 and 4.4).

When increasing the dosage, liver function tests should again be performed at the same frequency aswhen initiating treatment.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that theyare 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 a SSRI//SNRI (see section 5.1).

No dosage tapering is needed on treatment discontinuation.

The efficacy and safety of agomelatine (25 to 50mg/day) have been established in elderly depressedpatients (< 75years). No effect is documented in patients ≥75 years. Therefore, agomelatine should notbe used by patients in this age group (see sections 4.4 and 5.1). No dose adjustment is required in relationto age (see section 5.2).

No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renalimpairment has been observed. However, only limited clinical data on the use of agomelatine indepressed patients with severe or moderate renal impairment with major depressive episodes isavailable. Therefore, caution should be exercised when prescribing agomelatine to these patients.

Agomelatine is contraindicated in patients with hepatic impairment (see sections pct. 4.3, pct. 4.4 and 5.2).

Children from birth to <7 years

There is no relevant use of agomelatine in children from birth to <7 years for treatment of majordepressive episodes. No data are available.

Children and adolescents from 7 to 17 years

The safety and efficacy of agomelatine in children and adolescents aged from 7 to 17 years for treatmentof major depressive episodes have not been established. Currently available data are described insections 4.4, pct. 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

For oral use.

Valdoxan film-coated tablets may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hepatic impairment (i.e. cirrhosis or active liver disease) or transaminases exceeding 3 X upper limit ofnormal (see sections 4.2 and 4.4).

Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) (see section 4.5).

Cases of liver injury, including hepatic failure (few cases were exceptionally reported with fatal outcomeor liver transplantation in patients with hepatic risk factors), elevations of liver enzymes exceeding 10times upper limit of normal, hepatitis and jaundice have been reported in patients treated withagomelatine in the post-marketing setting (see section 4.8). Most of them occurred during the firstmonths of treatment. The pattern of liver damage is predominantly hepatocellular with increased serumtransaminases, which usually return to normal levels on cessation of agomelatine.

Caution should be exercised before starting treatment and close surveillance should be performedthroughout the treatment period in all patients, especially if hepatic injury risk factors orconcomitant medicinal products associated with risk of hepatic injury are present.

Before starting treatment

Treatment with Valdoxan should only be prescribed after careful consideration of benefit and risk inpatients with hepatic injury risk factors e.g.:

- obesity/overweight/non-alcoholic fatty liver disease, diabetes

- alcohol use disorder and /or substantial alcohol intakeand 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 inpatients with baseline values of ALT and/or AST >3 X upper limit of normal (see section 4.3). Cautionshould be exercised when Valdoxan 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 frequencyas when initiating treatment.

Any patient who develops increased serum transaminases should have his/her liver function testsrepeated within 48 hours.

During treatment period

Valdoxan treatment should be discontinued immediately if:

‐ patient develops symptoms or signs of potential liver injury (such as dark urine, lightcoloured stools, yellow skin/eyes, pain in the upper right belly, sustained new-onset andunexplained fatigue).

‐ the increase in serum transaminases exceeds 3 X upper limit of normal.

Following discontinuation of Valdoxan therapy liver function tests should be repeated until serumtransaminases return to normal.

Valdoxan is not recommended in the treatment of depression in patients under 18 years of age sincesafety and efficacy of agomelatine have not been established. In clinical trials among children andadolescents treated with other antidepressants, suicide-related behaviour (suicide attempt and suicidalthoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were morefrequently observed compared to those treated with placebo.

For agomelatine reported suicidal events were too few to make any meaningful comparison betweenagomelatine and placebo. Pooled data from clinical trials with agomelatine 25 mg have shown thatsuicidal events occurred at a higher frequency in adolescents (3.1%) compared to adults (1.2%),seesection on Suicide/suicidal thoughts below and section 4.8.

In pooled data from clinical trials hepatic adverse events were more frequently reported by adolescents(6.3%) compared to adults (1.7%).

Long-term safety data is limited. This includes long-term experience on growth, pubertal development(see section 5.1) and cognitive function.

No effect of agomelatine is documented in patients ≥75 years, therefore agomelatine should not be usedby patients in this age group (see also sections 4.2 and 5.1).

Use in elderly with dementia

Valdoxan should not be used for the treatment of major depressive episodes in elderly patients withdementia since the safety and efficacy of Valdoxan have not been established in these patients.

Bipolar disorder/ mania/hypomania

Valdoxan should be used with caution in patients with a history of bipolar disorder, mania or hypomaniaand should be discontinued if a patient develops manic symptoms (see section 4.8).

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 occurduring the first few weeks or more of treatment, patients should be closely monitored until suchimprovement occurs. It is general clinical experience that the risk of suicide may increase in the earlystages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidalideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts orsuicide 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 anincreased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25years old.

Close supervision of patients and in particular those at high risk should accompany treatment especiallyin early treatment and following dose changes. Patients (and caregivers of patients) should be alerted tothe need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes inbehaviour and to seek medical advice immediately if these symptoms present.

Combination with CYP1A2 inhibitors (see sections 4.3 and 4.5)

Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (e.g.propranolol, enoxacin) which may result in increased exposure of agomelatine.

Valdoxan contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicine.

Level of sodium

Valdoxan contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially ‘sodium-free’.

Potential interactions affecting agomelatine

Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19(10%). Medicinal products that interact with these isoenzymes may decrease or increase thebioavailability of agomelatine.

Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism ofagomelatine resulting in a 60-fold (range 12-412) increase of agomelatine exposure.

Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine,ciprofloxacin) is contraindicated.

Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several foldincreased exposure of agomelatine. While there was no specific safety signal in the 800 patients treatedin combination with oestrogens, caution should be exercised when prescribing agomelatine with othermoderate CYP1A2 inhibitors (e.g. propranolol, enoxacin) until more experience has been gained (seesection 4.4).

Rifampicin an inducer of all three cytochromes involved in the metabolism of agomelatine may decreasethe bioavailability of agomelatine.

Smoking induces CYP1A2 and has been shown to decrease the bioavailability of agomelatine,especially in heavy smokers (> 15 cigarettes/day) (see section 5.2).

Potential for agomelatine to affect other medicinal products

In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 invivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinalproducts metabolised by CYP 450.

Other medicinal products

No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which couldbe prescribed concomitantly with Valdoxan in the target population was found in phase I clinical trials:benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol

The combination of agomelatine and alcohol is not advisable.

Electroconvulsive therapy (ECT)

There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shownproconvulsant properties (see section 5.3). Therefore, clinical consequences of ECT performedconcomitantly with agomelatine treatment, are considered to be unlikely.

Interaction studies have only been performed in adults.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of agomelatinein pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect topregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of Valdoxan during pregnancy.

It is not known whether agomelatine/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of agomelatine/metabolites inmilk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be madewhether to discontinue breast-feeding or to discontinue/abstain from Valdoxan therapy taking intoaccount the benefit of breast feeding for the child and the benefit of therapy for the woman.

Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility (see section5.3).

Agomelatine has minor influence on the ability to drive and use machines.Considering that dizzinessand somnolence are common adverse reactions, patients should be cautioned about their ability todrive or operate machines.

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.

The below table gives the adverse reactions observed from adult placebo-controlled and adult 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 beencorrected for placebo.

System organ class Frequency Preferred Term

Psychiatric disorders Common Anxiety

Abnormal dreams*

Uncommon Suicidal thoughts or behaviour (see section4.4)

Agitation and related symptoms* (such asirritability and restlessness)

Aggression*

Nightmares*

Mania/hypomania*

These symptoms may also be due to theunderlying disease (see section 4.4).

Confusional state*

Rare Hallucinations*

Nervous system Very common Headachedisorders Common Dizziness

Somnolence

Insomnia

Uncommon Migraine

Paraesthesia

Restless leg syndrome*

Rare Akathisia*

Eye disorders Uncommon Blurred vision

Ear and labyrinth Uncommon Tinnitus*disorders

Gastrointestinal Common Nausea

Disorders Diarrhoea

Abdominal pain

Vomiting*

Hepato- biliary Common Increased ALT and/or AST (in clinical trials,disorders increases >3 times the upper limit of thenormal range for ALT and/or AST were seenin 1.2% of patients on agomelatine 25 mgdaily and 2.6 % on agomelatine 50 mg dailyvs. 0.5% on placebo).

Uncommon Increased gamma-glutamyltransferase*(GGT)(>3 times the upper limit of the normalrange

Rare Hepatitis

Increased alkaline phosphatase*(>3 times the upper limit of the normalrange)

Hepatic failure*(1)

Jaundice*

Skin and subcutaneous Uncommon Hyperhidrosistissue disorders Eczema

Pruritus*

Urticaria*

Rare Erythematous rash

Face oedema and angioedema*

Musculoskeletal and Common Back painconnective tissuedisorders Uncommon Myalgia*

Renal and urinary Rare Urinary retention*disorders

General disorders and Common Fatigueadministration siteconditions

Investigations Common Weight increased *

Uncommon Weight decreased*

* Frequency estimated from clinical trials for adverse reactions detected from spontaneous report(1) Few cases were exceptionally reported with fatal outcome or liver transplantation in patients withhepatic risk factors.

A total of 80 children aged 7 to less than 12 years old and 319 adolescent patients aged between 12 to17 years with moderate to severe major depressive disorder were treated with agomelatine in a double-blind, active (fluoxetine) and placebo-controlled study.

In general, the safety profile of agomelatine 25 mg in adolescents in the pivotal study (double-blindcontrolled part) was similar to that seen in adults, except for nausea which occurred at a higher frequencyin adolescents (13.3%) than in adults (6.3%).

Pooled data from clinical trials with agomelatine have shown that adverse events and serious adverseevents (all-causality) were reported with higher frequency in the adolescents than in the adults (67.2%vs 60.4% of patients who reported at least one adverse event and 10.4% versus 3.5% of the patients whoreported at least one serious adverse event).

Hepatic adverse events were reported by 6.3% of adolescents compared to adults (1.7%). Suicidal events(for instance suicidal behavior, suicide thoughts, suicide attempt and self-injury) occurred at a higherfrequency in adolescents (3.1%, 10 events reported in 6 patients) compared to adults (1.2%, 66 eventsreported in 65 patients) (see section 4.4.).

Long-term safety data for agomelatine 25 mg in adolescents is limited. This includes long-termexperience on growth, pubertal development (see section 5.1) and cognitive function.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with agomelatine overdose. Experience with agomelatine in overdose hasindicated that epigastralgia, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis ormalaise have been reported.

One person having ingested 2,450 mg agomelatine, recovered spontaneously without cardiovascular andbiological abnormalities.

No specific antidotes for agomelatine are known. Management of overdose should consist of treatmentof clinical symptoms and routine monitoring. Medical follow-up in a specialised environment isrecommended.

5 PHARMACOLOGICAL PROPERTIES

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

Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist. Binding studiesindicate 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 noinfluence on the extracellular levels of serotonin.

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

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

Clinical efficacy and safety in adults

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

Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatinein 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 tenshort-term double-blind placebo-controlled trials. Primary endpoint was change in HAMD-17 scorefrom 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 withparoxetine and fluoxetine as these comparators where added in order to ensure assay sensitivity of thetrials. 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 notallowed to increase the start dose of either agomelatine, paroxetine or fluoxetine even if the responsewas not adequate.

Efficacy was also observed in more severely depressed patients (baseline HAM-D ≥ 25) in all positiveplacebo-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 inheterogeneous populations of depressed adult patients versus SSRI/SNRI (sertraline, escitalopram,fluoxetine, venlafaxine or duloxetine) The anti-depressive effect was assessed with the HAMD-17 scoreeither as primary or secondary endpoint.

The maintenance of antidepressant efficacy was demonstrated in a relapse prevention trial. Patientsresponding to 8/10-weeks of acute treatment with open-label agomelatine 25-50 mg once daily wererandomised 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 toplacebo (p=0.0001) on the primary outcome measure, the prevention of depressive relapse, as measuredby time to relapse. The incidence of relapse during the 6-months double-blind follow up period was22% 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 ofsleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the qualityof sleep were significantly improved without daytime clumsiness as assessed by patients.

In a specific sexual dysfunction comparative trial with remitted depressed patients, there was anumerical trend (not statistically significant) towards less sexual emergent dysfunction than venlafaxinefor Sex Effects Scale (SEXFX) drive arousal or orgasm scores on agomelatine. The pooled analysis oftrials using the Arizona Sexual Experience Scale (ASEX) showed that agomelatine was not associatedwith sexual dysfunction. In healthy volunteers agomelatine preserved sexual function in comparisonwith 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 inducediscontinuation syndrome after abrupt treatment cessation.

Agomelatine has no abuse potential as measured in healthy volunteer studies on a specific visualanalogue 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 pointson HAM-D total score, the primary outcome. Responder rate analysis favoured agomelatine. Noimprovement 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 depressivedisorder and insufficiently improved with paroxetine (a SSRI) or venlafaxine (a SNRI). When treatmentwas switched from these antidepressants to agomelatine, discontinuation symptoms arose after cessationof the SSRI or SNRI treatment, either after abrupt cessation or gradual cessation of the previoustreatment. These discontinuation symptoms may be confounded with a lack of early benefit ofagomelatine.

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

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

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

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 wasa 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 Week12).

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 14.0years (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 psychoticfeatures) for 38.3%. The mean duration of current episode was 143.4 ± 153.2 days with a median of96.0 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 tolast post-baseline value for the overall population showed a difference between agomelatine 25 mgcompared 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. Themean 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-monthextension period at a agomelatine dose of 10 or 25 mg. However, this period was not designed as arelapse-prevention study and all patients received flexible doses of agomelatine. Useful data on efficacyand safety beyond 12 weeks are therefore limited.

Pubertal status was assessed by Tanner stage. Although data are limited, they do not suggest an impactof 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 changein the mean CDRS-R raw total score at the end of the short term phase was lower in absolute value inthe agomelatine 25 mg group (-17.1 ± 13.3) than in the placebo group (-19.0 ± 18.3).

Absorption and bioavailability

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

In the therapeutic dose-range, agomelatine systemic exposure increases proportionally with dose. Athigher 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.

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

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 rapidlyconjugated and eliminated in the urine.

Elimination is rapid, the mean plasma half-life is between 1 and 2 hours and the clearance is high (about1,100 ml/min) and essentially metabolic.

Excretion is mainly (80%) urinary and in the form of metabolites, whereas unchanged compoundrecovery in urine is negligible.

Kinetics are not modified after repeated administration.

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

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, pct. 4.3 and 4.4).

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

The pharmacokinetics of agomelatine was investigated in 60 children and 166 adolescents receivingdaily doses ranging from 1 to 25 mg. Most data derive from saliva concentration measurements, andplasma exposure of agomelatine in the paediatric population is to a large extent uncharacterised. As inadults, the inter-individual variability in agomelatine PK is substantial. The available paediatric datasuggest a considerable overlap with the observed exposure range in adults following a 25 mgagomelatine dose.

Ethnic groups

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

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

In rodents, a marked induction of CYP2B and a moderate induction of CYP1A and CYP3A were seenfrom 125 mg/kg/day whereas in monkeys the induction was slight for CYP2B and CYP3A at375 mg/kg/day. No hepatotoxicity was observed in rodents and monkeys in the repeat dose toxicitystudies.

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, embryofoetaldevelopment and pre- and post natal development.

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

In carcinogenicity studies agomelatine induced an increase in the incidence of liver tumours in the ratand the mouse, at a dose at least 110-fold higher than the therapeutic dose. Liver tumours are most likelyrelated to enzyme induction specific to rodents. The frequency of benign mammary fibroadenomasobserved in the rat was increased with high exposures (60-fold the exposure at the therapeutic dose) butremains 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 proconvulsiveproperties at ip doses up to 128 mg/kg in mice and rats.

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

6 PHARMACEUTICAL PARTICULARS

Lactose monohydrate

Maize starch

Povidone (K30)

Sodium starch glycolate type A

Stearic acid

Magnesium stearate

Silica, colloidal anhydrous

Hypromellose

Yellow iron oxide (E172)

Glycerol

Macrogol (6000)

Magnesium stearate

Titanium dioxide (E171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/PVC blister packed in cardboard boxes.

Calendar packs containing 14, 28, 56, 84 and 98 film-coated tablets.

Calendar packs of 100 film-coated tablets for hospital use.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Les Laboratoires Servier50, rue Carnot92284 Suresnes cedex

France

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EU/1/08/499/006

EU/1/08/499/007

EU/1/08/499/008

Date of first authorisation : 19 February 2009

Date of latest renewal : 12 December 2018

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.