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Valdoxan

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Summary for the public


What is Valdoxan?

Valdoxan is a medicine that contains the active substance agomelatine. It is available as orange-yellow, oblong tablets (25 mg).


What is Valdoxan used for?

Valdoxan is used to treat major depression in adults. Major depression is a condition in which patients have mood disturbances that interfere with their everyday life. Symptoms often include deep sadness, feelings of worthlessness, loss of interest in favourite activities, sleep disturbances, a feeling of being slowed down, feelings of anxiety and changes in weight.

The medicine can only be obtained with a prescription.


How is Valdoxan used?

The recommended dose of Valdoxan is one tablet once a day, taken at bedtime with or without food. If there is no improvement in symptoms after two weeks, the doctor may increase the dose to two tablets taken together at bedtime. Patients with depression should be treated for at least six months to make sure that they are free of symptoms.

The patient’s liver should be checked with blood tests when treatment starts, and then after around six, 12 and 24 weeks of treatment The liver should also be checked if the patient develops symptoms that could indicate liver problems. Treatment should be interrupted in patients with abnormal liver enzyme levels in the blood. Blood tests should then be repeated until the liver enzymes have returned to normal levels.

Because a benefit of Valdoxan has not been shown clearly in patients aged over 65 years, it should be used with caution in this age group. It should also be used with caution in patients with moderate or severe kidney problems. It must not be used in patients who have liver problems.


How does Valdoxan work?

The active substance in Valdoxan, agomelatine, is an antidepressant. It works in two ways, both by stimulating the MT1 and MT2 receptors, which are normally activated by melatonin, and also by blocking the 5-HT2C receptors, which are normally activated by the neurotransmitter 5-hydroxytryptamine (also called serotonin). This is thought to lead to increases in the levels of dopamine and noradrenaline between nerve cells in the areas of the brain that are involved in the control of mood. This is believed to help relieve the symptoms of depression. Valdoxan might also help to normalise the patient’s sleep patterns.


How has Valdoxan been studied?

The effects of Valdoxan were first tested in experimental models before being studied in humans.

Valdoxan has been compared with placebo (a dummy treatment) in five main short-term studies involving a total of 1,893 adults with major depression. Three of these studies included some patients treated with other antidepressants, either fluoxetine or paroxetine, as an ‘active comparator’. The active comparator groups were included to check that the study was able to measure the effectiveness of medicines in treating depression. The main measure of effectiveness in these five studies was the change in symptoms after six weeks, as measured on a standard scale for depression called the Hamilton Depression Rating Scale (HAM-D). The company also presented the results of a further study comparing Valdoxan with sertraline (another antidepressant).

Two other main studies compared the ability of Valdoxan and placebo to prevent symptoms returning in 706 patients whose depression had already been controlled with Valdoxan. The main measure of effectiveness was the number of patients whose symptoms returned during 24 to 26 weeks of treatment.


What benefit has Valdoxan shown during the studies?

In the short-term studies, Valdoxan was seen to be more effective than placebo in the two studies where no active comparator was used. In the other three studies, which did include an active comparator, there were no differences in scores between the patients taking Valdoxan and those taking placebo. However, no effect of fluoxetine or paroxetine was seen in two of these studies, making the results difficult to interpret. The additional study showed that agomelatine was more effective than sertraline, with a difference in HAM-D scores of 1.68 after six weeks.

In the first of the long-term studies, there was no difference between Valdoxan and placebo in preventing symptoms returning during 26 weeks of treatment. However, the second study showed that symptoms returned in 21% of the patients taking Valdoxan over 24 weeks (34 out of 165), compared with 41% of the patients taking placebo (72 out of 174).


What is the risk associated with Valdoxan?

The most common side effects with Valdoxan (seen in between 1 and 10 patients in 100) are headache, dizziness, somnolence (sleepiness), insomnia (difficulty sleeping), migraine, nausea (feeling sick), diarrhoea, constipation, upper abdominal pain (tummy ache), hyperhidrosis (excessive sweating), back pain, fatigue (tiredness), increases in liver enzymes and anxiety. Most side effects were mild or moderate in intensity and happened within the first two weeks of treatment. Some of these side effects may be linked to the patient’s depression rather than Valdoxan itself. For the full list of all side effects reported with Valdoxan, see the Package Leaflet.

Valdoxan should not be used in people who may be hypersensitive (allergic) to agomelatine or any of the other ingredients. It must not be used in patients who have problems with their liver, such as cirrhosis (scarring of the liver) or active liver disease. It must also not be used in patients who are taking medicines that slow down the breakdown of Valdoxan in the body, such as fluvoxamine (another antidepressant) and ciprofloxacin (an antibiotic).

Valdoxan should not be used in elderly patients with dementia.


Why has Valdoxan been approved?

The Committee for Medicinal Products for Human Use (CHMP) noted that Valdoxan’s benefits in terms of treating depression might be lower than seen with other antidepressants. However, since the medicine has a new mode of action, few side effects and a different safety profile to existing antidepressants, the Committee concluded that Valdoxan could be a valuable treatment for some patients as long as their liver function is tested frequently. Therefore, the CHMP decided that Valdoxan’s benefits are greater than its risks for the treatment of major depressive episodes in adults. The Committee recommended that Valdoxan be given marketing authorisation.


Which measures are being taken to ensure the safe use of Valdoxan?

The company that makes Valdoxan will supply educational material for prescribers of Valdoxan when it is launched. This material will explain the safety of the medicine, particularly its possible effects on the liver and its interactions with other medicines.


Other information about Valdoxan

The European Commission granted a marketing authorisation valid throughout the European Union for Valdoxan to Les Laboratoires Servier on 19 February 2009.

Authorisation details
Name: Valdoxan
EMEA Product number: EMEA/H/C/000915
Active substance: agomelatine
INN or common name: agomelatine
Therapeutic area: Depressive Disorder, Major
ATC Code: N06AX22
Marketing Authorisation Holder: Les Laboratoires Servier
Revision: 3
Date of issue of Market Authorisation valid throughout the European Union: 19/02/2009
Contact address:
Les Laboratoires Servier
22, rue Garnier
F-92200 Neuilly-sur-Seine
France



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1
NAME OF THE MEDICINAL PRODUCT
Valdoxan 25 mg film-coated tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 25 mg of agomelatine.
Excipient: lactose monohydrate 61.84 mg
For a full list of excipients, see section 6.1.
3
PHARMACEUTICAL FORM
Film-coated tablet [tablet].
Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side.
4
CLINICAL PARTICULARS
4.1
Therapeutic indications
Treatment of major depressive episodes in adults
Valdoxan is indicated in adults.
4.2
Posology and method of administration
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.
Liver function tests should be performed in all patients : at initiation of treatment, and then
periodically after around six weeks (end of acute phase), twelve weeks and twenty four weeks (end of
maintenance phase) and thereafter when clinically indicated (see also section 4.4).
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that
they are free of symptoms.
Valdoxan tablets may be taken with or without food.
Paediatric population :
The safety and efficacy of Valdoxan in children aged below 18 years have not been established. No
data are available. (see section 4.4).
Elderly patients:
Efficacy has not been clearly demonstrated in the elderly ( 65 years). Only limited clinical data is
available on the use of Valdoxan in elderly patients  65 years old with major depressive episodes.
Therefore, caution should be exercised when prescribing Valdoxan to these patients (see section 4.4).
Patients with 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 Valdoxan in
2
depressed patients with severe or moderate renal impairment with major depressive episodes is
available. Therefore, caution should be exercised when prescribing Valdoxan to these patients.
Patients with hepatic impairment:
Valdoxan is contraindicated in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).
Treatment discontinuation:
No dosage tapering is needed on treatment discontinuation.
Method of administration:
Valdoxan tablets may be taken with or without food.
4.3
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Hepatic impairment (i.e. cirrhosis or active liver disease) (see sections 4.2 and 4.4).
Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) (see section 4.5).
4.4
Special warnings and precautions for use
Use in paediatric population : :
Valdoxan is not recommended in the treatment of depression in patients under 18 years of age since
safety and efficacy of Valdoxan 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 (see section 4.2).
Use in elderly patients with dementia:
Valdoxan should not be used for the treatment of major depressive episodes in elderly patients with
dementia since the safety and efficacy of Valdoxan have not been established in these patients.
Mania / Hypomania:
Valdoxan should be used with caution in patients with a history of mania or hypomania and 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 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 (see sections 4.3 and 4.5)
Combination with potent CYP1A2 inhibitors is contraindicated. Caution should be exercised when
prescribing Valdoxan with moderate CYP1A2 inhibitors ( e.g. propranolol, grepafloxacine, enoxacine)
which may result in increased exposure of agomelatine.
3
Increased serum transaminases:
In clinical studies, elevations of serum transaminases (>3 times the upper limit of the normal range)
have been observed in patients treated with Valdoxan particularly on a 50 mg dose (see section 4.8).
When Valdoxan was discontinued in these patients, the serum transaminases usually returned to
normal levels. Liver function tests should be performed in all patients: at initiation of treatment and
then periodically after around six weeks (end of acute phase), after around twelve and twenty four
weeks (end of maintenance phase) and thereafter when clinically indicated. Any patient who develops
increased serum transaminases should have his/her liver function tests repeated within 48 hours.
Therapy should be discontinued if the increase in serum transaminases exceeds 3X upper limit of
normal and liver function tests should be performed regularly until serum transaminases return to
normal.
If any patient develops symptoms suggesting hepatic dysfunction liver function tests should be
performed. The decision whether to continue the patient on therapy with Valdoxan should be guided
by clinical judgement pending laboratory evaluations. If jaundice is observed therapy should be
discontinued.
Caution should be exercised when Valdoxan is administered to patients with obesity/overweight/non-
alcoholic fatty liver disease or to patients who consume substantial quantities of alcohol or are treated
with medicinal products associated with risk of hepatic injury.
Lactose intolerance:
Valdoxan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
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 the
bioavailability of agomelatine.
Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of
agomelatine 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 fold
increased exposure of agomelatine. While there was no specific safety signal in the 800 patients
treated in combination with oestrogens, caution should be exercised when prescribing agomelatine
with other moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacine, enoxacine) until more
experience has been gained (see section 4.4).
Potential for agomelatine to affect other medicinal products:
In vivo , agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in
vivo nor the other CYP450 in vitro . Therefore, agomelatine will not modify exposure to medicinal
products metabolised by CYP 450.
Medicinal products highly bound to plasma protein:
Agomelatine does not modify free concentrations of medicinal products highly bound to plasma
proteins or vice versa .
Other medicinal products:
No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which
could be 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 Valdoxan and alcohol is not advisable.
Electroconvulsive therapy (ECT):
4
There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shown
proconvulsant properties (see section 5.3). Therefore, clinical consequences of ECT concomitant
treatment with Valdoxan are considered to be unlikely.
Paediatric population
Interaction studies have only been performed in adults.
4.6
Fertility, pregnancy and lactation
Fertility
Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility.(see section
5.3).
Pregnancy
Reproduction studies in the rat and the rabbit showed no effect of agomelatine on embryofoetal
development and pre- and post natal development. (see section 5.3).
For agomelatine, no clinical data on exposed pregnancies are available. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition
or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant
women.
Breast-feeding
It is not known whether agomelatine is excreted into human milk. Agomelatine or its metabolites are
excreted in the milk of lactating rats. Potential effects of agomelatine on the breast-feeding infant have
not been established. If treatment with Valdoxan is considered necessary, breastfeeding should be
discontinued.
4.7
Effects on ability to drive and use machines
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.
4.8
Undesirable effects
In clinical trials, over 3,900 depressed patients have received Valdoxan.
Adverse reactions were usually mild or moderate and occurred within the first two weeks of treatment.
The most common adverse reactions were nausea and dizziness.
These adverse reactions were usually transient and did not generally lead to cessation of therapy.
Depressed patients display a number of symptoms that are associated with the illness itself. It is
therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which
are a result of treatment with Valdoxan.
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.
Nervous system disorders:
Common: headache, dizziness, somnolence, insomnia, migraine
Uncommon: paraesthesia
Psychiatric disorders:
Common: anxiety
Frequency not known:
Suicidal thoughts or behaviour (see section 4.4),
Mania/hypomania. These symptoms may also be due to the underlying disease (see section 4.4),
Agitation and related symptoms (as irritability and restlessness)
5
Eye disorders:
Uncommon: blurred vision
Gastrointestinal disorders:
Common: nausea, diarrhoea, constipation, upper abdominal pain
Skin and subcutaneous tissue disorders
Common: hyperhidrosis
Uncommon: eczema
Rare: erythematous rash
Frequency not known : pruritus
Musculoskeletal and connective tissue disorders
Common: back pain
General disorders and administration site conditions:
Common: fatigue
Hepato-biliary disorders:
Common: increases (>3 times the upper limit of the normal range) in ALAT and/or ASAT (i.e. 1.1%
on agomelatine 25/50 mg vs. 0.7% on placebo).
Rare: hepatitis
4.9
Overdose
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. 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.
5
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Other antidepressants, ATC-code: NO6AX22
Mechanism of action
Agomelatine is a melatonergic agonist (MT 1 and MT 2 receptors) and 5-HT 2C antagonist. Binding
studies indicate that agomelatine has no effect on monoamine uptake and no affinity for , 
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, Valdoxan has positive phase shifting properties; it induces a phase advance of sleep, body
temperature decline and melatonin onset.
6
Clinical efficacy and safety
The efficacy and safety of Valdoxan in major depressive episodes have been studied in a clinical
programme including 5,800 patients of whom 3,900 were treated with Valdoxan.
Six placebo controlled trials have been performed to investigate the short term efficacy of Valdoxan in
major depressive disorder: two flexible dose studies and four fixed dose studies. At the end of
treatment (over 6 or 8 weeks), significant efficacy of agomelatine 25-50 mg was demonstrated in 3 of
the six short-term double-blind placebo-controlled studies. Agomelatine failed to differentiate from
placebo in one study where the active control fluoxetine showed assay sensitivity. In two other studies,
it was not possible to draw any conclusions because the active controls, paroxetine and fluoxetine,
failed to differentiate from placebo.
Efficacy was also observed in more severely depressed patients (baseline HAM-D  25) in all positive
placebo-controlled studies.
Response rates were statistically significantly higher with Valdoxan compared with placebo.
The maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. Patients
responding to 8/10-weeks of acute treatment with open-label Valdoxan 25-50 mg once daily were
randomised to either Valdoxan 25-50 mg once daily or placebo for further 6-months. Valdoxan 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
Valdoxan and placebo, respectively.
Valdoxan does not alter daytime vigilance and memory in healthy volunteers. In depressed patients,
treatment with Valdoxan 25 mg increased slow wave sleep without modification of REM (Rapid Eye
Movement) sleep amount or REM latency. Valdoxan 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 study 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 Valdoxan. The pooled
analysis of studies using the Arizona Sexual Experience Scale (ASEX) showed that Valdoxan was not
associated with sexual dysfunction. In healthy volunteers Valdoxan preserved sexual function in
comparison with paroxetine.
Valdoxan had neutral effect on body weight, heart rate and blood pressure in clinical studies.
In a study designed to assess discontinuation symptoms by the Discontinuation Emergent Signs and
Symptoms (DESS) check-list in patients with remitted depression, Valdoxan did not induce
discontinuation syndrome after abrupt treatment cessation.
Valdoxan 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.
5.2
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.
7
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).
Ethnic groups:
There is no data on the influence of race on agomelatine pharmacokinetics.
5.3
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.
8
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.
6
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Tablet core:
Lactose monohydrate
Maize starch
Povidone
Sodium starch glycolate type A
Stearic acid
Magnesium stearate
Silica, colloidal anhydrous
Film-coating:
Hypromellose
Yellow iron oxide (E172)
Glycerol
Macrogol
Magnesium stearate
Titanium dioxide (E171)
Printing ink containing shellac, propylene glycol and indigotine (E132) aluminium lake.
6.2
Incompatibilities
Not applicable.
6.3
Shelf life
3 years.
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
Aluminium/PVC blister packed in cardboard boxes (calendar).
Packs containing 7, 14, 28, 42, 56, 84 and 98 film-coated tablets.
Packs of 100 film-coated tablets for hospital use.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22, rue Garnier
F-92200 Neuilly-sur-Seine
9
France
8
MARKETING AUTHORISATION NUMBER(S)
EU/1/08/499/001-008
9
DATE OF THE FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
19/02/2009
10
DATE OF REVISION OF THE TEXT
MM/YYYY
Detailed information on this medicinal product is available on the website of the European Medicines
10
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE
FOR BATCH RELEASE
11
B. CONDITIONS OF THE MARKETING AUTHORISATION
A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Les Laboratoires Servier Industrie, 905, route de Saran - 45520 Gidy, France
Servier (Ireland) Industries Ltd, Gorey Road - Arklow - Co. Wicklow, Ireland
Przedsiebiorstwo Farmaceutyczne ANPHARM S.A., ul. Annopol 6B - 03-236 Warszawa, Poland
The printed package leaflet of the medicinal product must state the name and address of the manufacturer
responsible for the release of the concerned batch.
B CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to medical prescription
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE
USE OF THE MEDICINAL PRODUCT
The Marketing Authorisation Holder (MAH) shall ensure that, at launch, all healthcare professionals who
are experienced to prescribe/use Valdoxan are provided with educational materials containing the
following:
As described in the RMP, additional risk minimisation activity including educational material will be
provided to prescribers.
Objectives of agomelatine Educational Plan:
The prescriber educational material about Valdoxan / Thymanax will be focused on:
- The potential risks of agomelatine
- Transaminases Elevations
- Interactions with potent CYP 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin).
- Guidance for hepatic function screening (Need to perform liver function tests in all patients: at initiation
of treatment, and then periodically after around six weeks (end of acute phase), twelve weeks and twenty
four weeks (end of maintenance phase) and thereafter when clinically indicated;
- Guidance in case of clinical symptoms or liver function tests abnormality;
- Caution to be exercised when therapy is administered to patients who consume substantial quantities of
alcohol or who are treated with medicinal products associated with risk of hepatic injury;
- Contra-indication in patients with hepatic impairment (i.e. cirrhosis or active liver disease);
- Contra-indication in patients receiving concomitantly potent CYP1A2 inhibitors.
12
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the Marketing
Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in the version 6.0 of the Risk Management Plan (RMP) presented in
the module 1.8.2 of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
when new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
at the request of the European Medicines Agency
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton
1.
NAME OF THE MEDICINAL PRODUCT
Valdoxan 25 mg film-coated tablets
Agomelatine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 25 mg of agomelatine.
3.
LIST OF EXCIPIENTS
Contains lactose.
See package leaflet for further information.
4.
PHARMACEUTICAL FORM AND CONTENTS
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
42 film-coated tablets
56 film-coated tablets
84 film-coated tablets
98 film-coated tablets
100 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
16
 
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22, rue Garnier
F-92200 Neuilly-sur-Seine
France
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/499/001
[EU/1/08/499/002]
[EU/1/08/499/003]
[EU/1/08/499/004]
[EU/1/08/499/005]
[EU/1/08/499/006]
[EU/1/08/499/007]
[EU/1/08/499/008]
13. BATCH NUMBER
Batch {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Valdoxan 25 mg
17
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
NAME OF THE MEDICINAL PRODUCT
Valdoxan 25 mg tablets
Agomelatine
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot{number}
5.
OTHER
MON
TUE
WED
THU
FRI
SAT
SUN
18
 
B. PACKAGE LEAFLET
19
PACKAGE LEAFLET: INFORMATION FOR THE USER
Valdoxan 25 mg film-coated tablets
Agomelatine
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
In this leaflet:
1.
What Valdoxan is and what it is used for
2.
Before you take Valdoxan
4.
Possible side effects
5
How to store Valdoxan
6.
Further information
1.
WHAT VALDOXAN IS AND WHAT IT IS USED FOR
Valdoxan belongs to a group of medicines called antidepressants and you have been given Valdoxan to
treat your depression.
Depression is a continuing disturbance of mood that interferes with everyday life. The symptoms of
depression vary from one person to another, but often include deep sadness, feelings of worthlessness, loss
of interest in favourite activities, sleep disturbances, feeling of being slowed down, feelings of anxiety,
changes in weight.
2.
BEFORE YOU TAKE VALDOXAN
Do not take Valdoxan
-
if you are allergic (hypersensitive) to agomelatine or any of the other ingredients of Valdoxan (see
What Valdoxan contains’ in section 6).
-
if you are taking fluvoxamine (another medicine used in the treatment of depression) or
ciprofloxacin (an antibiotic).
-
if your liver does not work properly (hepatic impairment).
Take special care with Valdoxan
There could be some reasons why Valdoxan may not be suitable for you:
-
If you have already experienced or if you develop manic symptoms (a period of abnormally high
excitability and emotions) talk to your doctor before you start taking this medicine or before you
continue with this medicine (see also under “ Possible side effects ” in section 4).
-
If you are taking medicine known to affect the liver. Ask your doctor for advice on which medicine
that is.
-
If you are presenting with obesity or overweight, ask your doctor for advice.
20
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take Valdoxan
-
Some patients may get increased levels of liver enzymes in their blood during treatment with
Valdoxan. Your doctor will therefore run laboratory tests to check that your liver is working
properly at the initiation of the treatment and then periodically during treatment. Based on the
evaluation of these tests the doctor will decide whether you should continue using Valdoxan or not
(see also under “ How to take Valdoxan ” in section 3).
Valdoxan is not intended for use in children and adolescents (under 18 years old).
Thoughts of suicide and worsening of your depression
If you are depressed you can sometimes have thoughts of harming or killing yourself. These may be
increased when first starting antidepressants, since these medicines all take time to work, usually about
two weeks but sometimes longer.
You may be more likely to think like this:
- if you have previously had thoughts about killing or harming yourself.
- if you are a young adult. Information from clinical trials has shown an increased risk of suicidal
behaviour in young adults (aged less than 25 years) with psychiatric conditions who were being treated
with an antidepressant.
If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital
straight away.
You may find it helpful to tell a relative or close friend that you are depressed and ask them to read this
leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are
worried about changes in your behaviour.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
You should not take Valdoxan together with certain medicines (see also under “ Do not take Valdoxan ” in
section 2): fluvoxamine (another medicine used in the treatment of depression), ciprofloxacin (an
antibiotic).
Taking Valdoxan with food and drink
Valdoxan can be taken with or without food.
It is not advisable to drink alcohol while you are being treated with Valdoxan.
Pregnancy
Talk to your doctor if you become pregnant (or plan to become pregnant) while you are taking Valdoxan.
Ask your doctor or pharmacist for advice before taking any medicine.
Breast-feeding
Talk to your doctor if you are breast-feeding or intending to breast-feed as breastfeeding should be
discontinued if you take Valdoxan.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
You might experience dizziness or sleepiness which could affect your ability to drive or operate
machinery. Make sure that your reactions are normal before driving or operating machines.
21
If you are suffering from dementia, your doctor will make an individual evaluation of whether it is
safe for you to take Valdoxan.
Important information about some of the ingredients of Valdoxan
This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, talk to your doctor before taking Valdoxan.
3.
HOW TO TAKE VALDOXAN
Always take Valdoxan exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The recommended dose of Valdoxan is one tablet (25 mg) at bedtime. In some cases, your doctor may
prescribe a higher dose (50 mg), i.e. two tablets to be taken together at bedtime.
Valdoxan starts to act on symptoms of depression in most depressed people within two weeks of starting
treatment. Your doctor may continue to give you Valdoxan when you are feeling better to prevent your
depression from returning.
Do not stop taking your medicine without the advice of your doctor even if you feel better.
Valdoxan is for oral use. You should swallow your tablet with a drink of water. Valdoxan can be taken
with or without food.
Your doctor will run laboratory tests to check that your liver is working properly at the initiation of
treatment and then periodically during treatment, usually after 6 weeks, 12 weeks and 24 weeks.
Thereafter tests will be taken if the doctor finds it necessary.
You must not use Valdoxan if your liver does not work properly.
If you have trouble with your kidneys, your doctor will make an individual evaluation of whether it is safe
for you to take Valdoxan.
If you take more Valdoxan than you should
If you have taken more Valdoxan than you should, or if for example a child has taken medicine by
accident, contact your doctor immediately.
The experience of overdoses with Valdoxan is limited but reported symptoms include pain in the upper
part of the stomach , somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis or malaise.
If you forget to take Valdoxan
Do not take a double dose to make up for a forgotten dose. Just carry on with the next dose at the usual
time.
The calendar printed on the blister containing the tablets should help you remembering when you last took
a tablet of Valdoxan.
If you have any further questions on the use of this product, please ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Valdoxan can cause side effects, although not everybody gets them.
22
Most side effects are mild or moderate. They usually occur within the first two weeks of the treatment and
are usually temporary.
The frequency of possible side effects listed below is defined using the following system:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data)
These side effects include:
-
Common side effects : dizziness, sleepiness (somnolence), difficulty in sleeping (insomnia),
migraine, headache, feeling sick (nausea), diarrhoea, constipation, upper abdominal pain, excessive
sweating (hyperhidrosis), back pain, tiredness, anxiety, increased levels of liver enzymes in your
blood.
-
Uncommon side effects : pins and needles in the fingers and toes (paraesthesia), blurred vision and
eczema.
-
Other possible side effects :
Frequency not known : suicidal thoughts or behaviour, mania/hypomania (see also under “ Take
special care with Valdoxan ” in section 2), agitation , irritability, restlessness and pruritus.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE VALDOXAN
Keep out of the reach and sight of children.
Do not use Valdoxan after the expiry date which is stated on the carton and blister. The expiry date refers
to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Valdoxan contains
-
The active substance is agomelatine. Each tablet contains 25 mg of agomelatine.
-
The other ingredients are:
tablet core: lactose monohydrate, maize starch, povidone, sodium starch glycolate type A,
stearic acid, magnesium stearate, colloidal anhydrous silica.
tablet film-coating: hypromellose, glycerol, macrogol, magnesium stearate, yellow iron
oxide (E172) and titanium dioxide (E171).
printing ink : shellac, propylene glycol and indigotine (E132) aluminium lake
23
-
Rare side effects : serious skin eruption (erythematous rash), hepatitis.
What Valdoxan looks like and contents of the pack
Valdoxan 25 mg film-coated tablets are oblong, orange-yellow with a blue imprint of ‘company logo’
on one side.
Valdoxan 25 mg film-coated tablets are available in calendar blisters. Packs contain 7, 14, 28, 42, 56, 84
or 98 tablets. Packs of 100 film-coated tablets are also available for hospital use.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer:
Marketing Authorisation Holder
Les Laboratoires Servier
22, rue Garnier
92200 Neuilly sur Seine - France
Manufacturer
Les Laboratoires Servier Industrie
905, route de Saran
45520 Gidy
France
Servier (Ireland) Industries Ltd
Gorey road
Arklow – Co. Wicklow – Ireland
and
Anpharm Przedsiebiorstwo Farmaceutyczne S.A.
03-236 Warszawa
ul. Annopol 6B
Poland
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.A. Servier Benelux N.V.
Tel: +32 (0)2 529 43 11
Luxembourg/Luxemburg
S.A. Servier Benelux N.V.
Tel: +32 (0)2 529 43 11
България
Сервие Медикал ЕООД
Тел.: +359 2 921 57 00
Magyarország
Servier Hungaria Kft.
Tel: +36 1 238 7799
Česká republika
Servier s.r.o.
Tel: +420 222 118 111
Malta
GALEPHARMA Ltd
Tel: +(356) 21 247 082
Danmark
Servier Danmark A/S
Tlf: +45 36 44 22 60
Nederland
Servier Nederland Farma B.V.
Tel: +31 (0)71 5246700
Deutschland
Norge
24
Servier Deutschland GmbH
Tel: +49 (0)89 57095 01
Servier Danmark A/S
Tlf: +45 36 44 22 60
Eesti
CentralPharmaCommunications OÜ
Tel:+ 372 640 0007
Österreich
Servier Austria GmbH
Tel: +43 (1) 524 39 99
Eλλάδα
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ
Τηλ: +30 210 939 1000
Polska
Servier Polska Sp. z o.o.
Tel: +48 (0) 22 594 90 00
España
Laboratorios Servier S.L.
Tel: +34 91 748 96 30
Portugal
Servier Portugal, Lda
Tel.: +351 21 312 20 00
France
Les Laboratoires Servier
Tel: +33 (0)1 55 72 60 00
România
Servier Pharma SRL
Tel: +4 021 528 52 80
Ireland
Servier Laboratories (Ireland) Ltd.
Tel: +353 (0)1 663 8110
Slovenija
Servier Pharma, d. o. o.,
Tel.: +386 (0)1 563 48 11
Ísland
Servier Laboratories
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Servier Slovensko spol. s r.o.
Tel.:+421 (2) 5920 41 11
Italia
Servier Italia S.p.A.
Tel: +39 (06) 669081
Suomi/Finland
Servier Finland Oy
Puh/Tel: +358 (0)9 279 80 80
Κύπρος
Χ.Α.Παπαέλληνας & Σία Λτδ
Τηλ: +357 22741741
Sverige
Servier Sverige AB
Tel : +46 (8)5 225 08 00
Latvija
SIA Servier Latvia
Tel: +371 67502039
United Kingdom
Servier Laboratories Ltd
Tel: +44 (0)1 753 666409
Lietuva
UAB “SERVIER PHARMA”
Tel: +370 (5) 2 63 86 28
This leaflet was last approved in {date}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web site
25


Source: European Medicines Agency



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