Active ingredients: Agomelatine
Valdoxan 25 mg film-coated tablets
Why is Valdoxan used? What is it for?
Valdoxan contains the active substance agomelatine. It belongs to a group of medicines called antidepressants and Valdoxan has been prescribed to you to treat depression.
Valdoxan is used in adults
Depression is a persistent mood disorder that interferes with everyday life. Symptoms of depression vary from one person to another, but often include deep sadness, feelings of self-deprecation, loss of interest in favorite activities, disturbances sleep, a feeling of slowing down, feeling anxious, weight changes.
The expected benefits of Valdoxan are the reduction and gradual elimination of symptoms related to your depression.
Contraindications When Valdoxan should not be used
Do not take Valdoxan
- if you are allergic (hypersensitive) to agomelatine or any of the other ingredients of this medicine (listed in section 6),
- if the liver does not work properly (hepatic impairment),
- if you are taking fluvoxamine (another medicine used to treat depression) or ciprofloxacin (an antibiotic).
Precautions for use What you need to know before taking Valdoxan
It may be that Valdoxan is not suitable for you for some reason
- If you are taking medicines that affect liver function. Ask your doctor for advice on what medicines they are.
- If you are obese or overweight, ask your doctor for advice.
- If you are diabetic, ask your doctor for advice.
- If you have increased levels of liver enzymes before treatment, your doctor will decide if Valdoxan is suitable for you.
- If you have bipolar disorder, have had or develop manic symptoms (a period of abnormally intense excitement and emotions), talk to your doctor before you start taking the medicine or before continuing to take (see also "Possible undesirable effects "in section 4).
- If you have dementia, your doctor will make a subjective assessment to determine if taking Valdoxan is safe for you.
During treatment with Valdoxan:
What to do to avoid potential serious liver problems:
- Your doctor must make sure that your liver is working properly before starting treatment. Some patients may have increased levels of liver enzymes in their blood during treatment with Valdoxan. Therefore, constant monitoring must be performed according to the following schedule:
Based on the evaluation of these tests, your doctor will decide whether you can take or continue to use Valdoxan (see also "How to take Valdoxan" in section 3).
Look out for signs and symptoms that may indicate that your liver is not working properly.
- If you notice any of these signs and symptoms of liver problems: abnormal darkening of urine, light colored stools, yellowing of the skin / eyes, pain in the upper right abdomen, unusual tiredness (especially associated with the other symptoms listed above) , contact a doctor urgently who may advise you to stop treatment with Valdoxan.
The effect of Valdoxan is not documented in patients 75 years of age and older. Therefore, Valdoxan should not be used in these patients.
Thoughts of suicide and worsening of depression
If you are depressed you may sometimes have thoughts of harming or killing yourself. These thoughts may be heightened when you first start treatment with antidepressants, as these medicines take a period of time to be effective, usually around two weeks but sometimes even 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. Clinical trial data have shown an increased risk of suicidal behavior in young adults (aged less than 25 years) with psychiatric disorders who have been treated with an antidepressant.
Anytime you have thoughts of harming or killing yourself, 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 may ask them to tell you if they think your depression is getting worse or if they are worried about changes in your behavior.
Children and adolescents
Valdoxan is not intended for use in children and adolescents (under 18 years).
Interactions Which drugs or foods can modify the effect of Valdoxan
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
You must not take Valdoxan together with certain medicines (see also "Do not take Valdoxan" in section 2): fluvoxamine (another medicine used to treat depression) ciprofloxacin (an antibiotic) can change the expected dose of agomelatine in the blood
Tell your doctor if you are taking any of the following medicines: propranolol (a beta blocker used to treat high blood pressure), enoxacin (an antibiotic) and if you smoke more than 15 cigarettes a day.
Valdoxan with alcohol
It is not recommended to drink alcohol while being treated with Valdoxan.
Warnings It is important to know that:
Pregnancy
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Feeding time
Tell your doctor if you are breastfeeding or intend to breastfeed, as breastfeeding must be stopped if you take Valdoxan.
ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
You may feel dizzy or sleepy which may affect your ability to drive or use machines. Make sure your reactions are normal before driving or using machines.
Valdoxan contains lactose.
If your doctor has told you that you have an intolerance to some sugars, talk to him before taking Valdoxan.
Dose, Method and Time of Administration How to use Valdoxan: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose of Valdoxan is one tablet (25 mg) at bedtime. In some cases, your doctor may prescribe a higher dose (50 mg), which is two tablets to be taken together at bedtime.
In most depressed people, Valdoxan starts to act on the symptoms of depression within two weeks of starting treatment. Your doctor may continue to prescribe Valdoxan when you feel better to prevent the depression from returning. The depression should be treated for a period of time. enough of at least 6 months to ensure you get rid of symptoms.
Do not stop taking the medicine without your doctor's advice, even if you feel better.
Valdoxan is for oral use. You should swallow the tablet with a drink of water.Valdoxan can be taken with or without food.
How to switch from an antidepressant medicine (SSRI / SNRI) to Valdoxan?
If your doctor changes your previous antidepressant therapy to an SSRI or SNRI and prescribes Valdoxan, he will advise you how to stop your previous treatment when starting Valdoxan therapy.
Even if the dose of the previous antidepressant medicine is gradually reduced, you may experience withdrawal symptoms related to stopping the previous medicine for a few weeks. Withdrawal symptoms include: dizziness, numbness, sleep disturbances, agitation or anxiety, headache, nausea, malaise and tremor These effects are usually mild to moderate and disappear spontaneously within a few days.
If you start taking Valdoxan while you are reducing the dosage of the previous medicine, the possible withdrawal symptoms should not be confused with a lack of the early benefits of Valdoxan.
When starting Valdoxan, you should discuss with your doctor the best way to stop your previous antidepressant therapy.
Liver function surveillance (see also section 2):
Your doctor may order laboratory tests to check that your liver is working properly before starting treatment and then periodically during treatment, usually after 3 weeks, 6 weeks, 12 weeks and 24 weeks. are taking up to 50 mg, laboratory tests should be done when starting the new dosage and then periodically during treatment, usually after 3 weeks, 6 weeks, 12 weeks and 24 weeks. Tests will then be carried out if your doctor deems it necessary. If your liver is not functioning properly, you should not use Valdoxan.
If you have kidney problems, your doctor will carry out an individual assessment to determine if Valdoxan is safe for you.
Overdose What to do if you have taken too much Valdoxan
If you take more Valdoxan than you should
If you have taken more Valdoxan than prescribed, or if for example a child has taken the medicine by mistake, contact your doctor immediately.
Experience of overdose with Valdoxan is limited, but reported symptoms include upper stomach pain, drowsiness, 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. Take your next dose at the usual time.
The calendar printed on the blister containing the tablets will help you remember when you took your last Valdoxan tablet.
If you stop taking Valdoxan
You should talk to your doctor before you stop taking this medicine. If you think the effect of Valdoxan is too strong or too weak, talk to your doctor or pharmacist.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Valdoxan
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Most of the side effects are mild or moderate. They usually occur within the first two weeks of treatment and are usually transient.
Side effects include:
- Common side effects (may affect up to 1 in 10 people): dizziness, sleepiness, difficulty sleeping (insomnia), migraine, headache, feeling sick (nausea), diarrhea, constipation, abdominal pain, excessive sweating (hyperhidrosis) , back pain, tiredness, anxiety, increased levels of liver enzymes in the blood, vomiting.
- Uncommon side effects (may affect up to 1 in 100 people): tingling in the fingers and toes (paraesthesia), blurred vision, restless legs syndrome (a disorder characterized by an uncontrolled need to move the legs), ringing in the ears, eczema, itching, hives, agitation, irritability, restlessness, aggressive behavior, nightmares, abnormal dreams, confusion.
- Rare side effects (may affect up to 1 in 1,000 people): severe skin rash (erythematous rash), face edema (swelling) and angioedema (swelling of the face, lips, tongue and / or throat which may cause difficulty in breathing swallowing), hepatitis, yellowing of the skin or whites of the eyes (jaundice), liver failure *, mania / hypomania (see also "Warnings and precautions" in section 2), hallucinations, weight gain, weight decrease bodily.
- Other possible side effects:
Frequency not known (frequency cannot be estimated from the available data): suicidal thoughts or behavior.
* Some cases with liver transplant or fatal outcome have been reported
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister. The expiry date refers to the last day of the month.
This medicine does not require any special storage conditions
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Valdoxan contains
- The active ingredient is agomelatine. Each film-coated tablet contains 25 mg of agomelatine.
- The other ingredients are:
- lactose monohydrate, maize starch, povidone, sodium starch glycolate type A, stearic acid, magnesium stearate, anhydrous colloidal silica, hypromellose, glycerol, macrogol, yellow iron oxide (E172) and titanium dioxide (E171).
- printing ink: shellac, propylene glycol and indigo carmine aluminic lacquer (E132).
What Valdoxan looks like and contents of the pack
Valdoxan 25 mg film-coated tablets are oblong, yellow-orange, with the company logo embossed in blue on one side.
Valdoxan 25 mg tablets are available in calendar blisters. The packs contain 7, 14, 28, 42, 56, 84 or 98 tablets. Packs of 100 film-coated tablets for hospital use are also available
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
VALDOXAN 25 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 25 mg of agomelatine.
Excipient with known effects: each tablet contains 61.84 mg of lactose (as monohydrate).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet [tablet].
Orange-yellow, oblong, 9.5mm long, 5.1mm wide film-coated tablet with the company logo embossed in blue on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of major depressive episodes.
Valdoxan is indicated in adults.
04.2 Posology and method of administration
Dosage
The recommended dose is 25 mg once daily orally to be taken at bedtime.
After two weeks of treatment, if there is no improvement in symptoms, the dose can be increased to 50 mg once a day, ie two 25 mg tablets in a single intake, taken in the evening before bedtime.
The decision to increase the dose must be weighed in the light of a higher risk of transaminase elevations. Any dose increase to 50 mg should be done on the basis of the individual patient's benefit / risk ratio, following a strict control of liver function tests (LFT).
Liver function tests should be performed in all patients before starting treatment. Treatment should not be initiated if transaminases exceed 3 times the upper limit of normal (see sections 4.3 and 4.4).
During treatment, transaminases should be monitored periodically after approximately three weeks, six weeks (end of the acute phase), twelve and twenty-four weeks (end of the maintenance phase) and thereafter when clinically indicated (see also section 4.4). Treatment should be discontinued if transaminases exceed 3 times the upper limit of normal (see sections 4.3 and 4.4).
When the dosage is increased, liver function tests should be performed again with the same frequency as the initiation of treatment.
Duration of treatment
Depressed patients should be treated for a sufficient period of at least 6 months to ensure that they no longer have symptoms.
Change of therapy from an SSRI / SNRI antidepressant to agomelatine
Patients may experience withdrawal symptoms after stopping an SSRI / SNRI antidepressant.
For how to discontinue treatment in order to avoid withdrawal symptoms, the Summary of Product Characteristics of the SSRI / SNRI with which the patient is being treated should be consulted. Agomelatine can be started immediately while reducing the SSRI / SNRI dosage (see section 5.1).
Discontinuation of treatment
In case of discontinuation of the treatment a progressive reduction of the dose is not necessary.
Special populations
Elderly patients
The efficacy and safety of agomelatine (dose 25 to 50 mg / day) have been demonstrated in elderly depressed patients (dose adjustment age for age (see section 5.2).
Patients with renal impairment
No relevant changes in agomelatine pharmacokinetic parameters were observed in patients with severe renal impairment. However, only limited clinical data are available on the use of Valdoxan in depressed patients with severe or moderate renal impairment with major depressive episodes. Therefore, Valdoxan should be prescribed with caution to these patients.
Patients with hepatic impairment
Valdoxan is contraindicated in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).
Pediatric population
The safety and efficacy of Valdoxan in children 2 years of age and older for the treatment of major depressive episodes have not yet been established.
No data are available (see section 4.4).
There is no indication for a specific use of Valdoxan from birth to 2 years for the treatment of major depressive episodes.
Method of administration
For oral use.
Valdoxan film-coated tablets can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hepatic impairment (e.g., current cirrhosis or liver disease) (see sections 4.2 and 4.4) or transaminases exceeding 3 times the upper limit of normal (see sections 4.2 and 4.4).
Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) (see section 4.5).
04.4 Special warnings and appropriate precautions for use
Monitoring of liver function
Cases of hepatic injury, including hepatic impairment (some cases with fatal outcome or liver transplantation in patients with hepatic risk factors have been reported exceptionally in patients with hepatic risk factors) and enzyme elevations have been reported in patients treated with Valdoxan liver disease 10 times the upper limit of normal, hepatitis and jaundice (see section 4.8). Most of these occurred during the first months of treatment. The type of hepatic injury is essentially hepatocellular with serum transaminases usually returning to normal levels following discontinuation of Valdoxan.
Caution should be exercised before starting treatment and close surveillance should be performed throughout the treatment period in all patients, especially if risk factors for liver injury are present or if medicinal products associated with risk of liver injury are administered concomitantly. .
• Before starting the treatment
Valdoxan should only be prescribed in patients with risk factors for liver injury such as obesity / overweight / non-alcoholic fatty liver disease, diabetes, heavy alcohol intake and in patients receiving concomitant medicinal products associated with the risk of liver injury. after a "careful evaluation of the benefits and risks.
Baseline liver function tests should be performed in all patients and treatment should not be initiated in patients with baseline ALT and / or AST> 3 times the ULN (see section 4.3).
Caution should be exercised when Valdoxan is administered to patients with pre-treatment elevated transaminases (> the upper limit of the normal range and ≤ 3 times the upper limit of the normal range).
• Frequency of liver function tests
- Before the start of treatment
- then:
- after about 3 weeks
- after about 6 weeks (end of the acute phase)
- after about 12 and 24 weeks (end of the maintenance phase)
- and thereafter when clinically indicated.
When the dosage is increased, liver function tests should be performed again with the same frequency as the initiation of treatment.
Patients who develop elevated serum transaminases must repeat liver function tests within 48 hours.
• During the treatment period
Valdoxan treatment should be stopped immediately if:
- the patient develops symptoms or signs of potential liver damage (such as dark urine, light colored stools, yellowing of the skin / eyes, pain in the upper right abdomen, a feeling of prolonged and unexplained new onset fatigue.
- the increase in serum transaminases exceeds the upper limit of normal by 3 times.
Following discontinuation of Valdoxan therapy, liver function tests should be repeated until serum transaminase levels return to normal.
Use in the pediatric population
Valdoxan is not recommended for the treatment of depression in patients under the age of 18 as the safety and efficacy of Valdoxan have not been evaluated in this age group. More frequently compared to those treated with placebo suicidal behavior (suicide attempt and suicidal ideation), and hostile attitude (mainly aggressive, oppositional and anger behavior) (see section 4.2).
Elderly patients
There are no documented effects of agomelatine in patients ≥ 75 years of age, therefore agomelatine should not be used in patients in this age group (see also sections 4.2 and 5.1).
Use in elderly patients with dementia
Valdoxan should not be used to treat major depressive episodes in elderly patients with dementia, as the safety and efficacy of Valdoxan have not been evaluated in these patients.
Bipolar disorder / mania / hypomania
Valdoxan 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 (see section 4.8).
Suicide / suicidal ideation
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 or subsequent weeks of treatment, patients should be monitored closely until improvement occurs. It is general clinical experience that the risk of suicide can increase early in the healing process.
Patients with a history of suicide-related events, or who exhibit a significant degree of suicidal ideation prior to initiation of treatment, are known to be at higher risk for suicidal thoughts or suicide attempts, and should be closely monitored during treatment. A meta-analysis of clinical trials conducted with antidepressant medicinal products compared with placebo in the treatment of psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age treated with antidepressants compared to placebo.
Treatment should be associated with close surveillance of patients, particularly those at high risk, especially in the early stages of treatment and after dose changes.Patients (and caregivers) should be advised of the need to monitor for any worsening clinical picture, suicidal behaviors or thoughts, and unusual changes in behavior and to seek immediate medical attention if these symptoms occur.
Combination with CYP1A2 inhibitors (see sections 4.3 and 4.5)
Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (eg propranolol, enoxacin) which may lead to increased agomelatine exposure.
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.
04.5 Interactions with other medicinal products and other forms of interaction
Potential interactions with agomelatine
Agomelatine is mainly metabolised by cytochrome P450 1A2 (CYP1A2) (90%) and CYP2C9 / 19 (10%). Medicines that interact with these isoenzymes may reduce or increase the bioavailability of agomelatine.
Fluvoxamine, a potent inhibitor of CYP1A2 and moderate inhibitor of CYP2C9, markedly inhibits the metabolism of agomelatine, resulting in a 60-fold (range 12-412) increase in agomelatine exposure.
Therefore, co-administration of Valdoxan with potent CYP1A2 inhibitors (eg fluvoxamine, ciprofloxacin) is contraindicated.
The combination of agomelatine with estrogen (moderate inhibitors of CYP1A2) results in a several-fold increase in exposure to agomelatine. Although no specific safety-related evidence was found in the 800 patients treated in combination with estrogen, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (e.g. propranolol, enoxacin) until a more experience (see section 4.4).
Rifampicin, an inducer of all three cytochromes involved in agomelatine metabolism, may decrease the bioavailability of agomelatine.
Smoking induces CYP1A2 and has been shown to reduce the bioavailability of agomelatine, especially in heavy smokers (≥15 cigarettes / day) (see section 5.2).
Possible interactions of agomelatine with other medicinal products
In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine does not inhibit CYP1A2 either in vivo, nor the CYP450 in vitro. Therefore, agomelatine does not affect exposure to medicinal products metabolised by CYP450.
Medicinal products strongly bound to plasma proteins
Agomelatine does not change the free concentration of drugs strongly bound to plasma proteins or vice versa.
Interactions with other medicines
In phase I clinical studies, no pharmacokinetic or pharmacodynamic interactions were observed with medicinal products that could be prescribed concomitantly with Valdoxan in the target population, such as benzodiazepines, lithium, paroxetine, fluconazole and theophylline.
Alcohol
The combination of Valdoxan with alcohol is not recommended.
Electroconvulsive Therapy (ECT)
There is no experience on the combined use of agomelatine with ECT. Animal studies have shown no proconvulsant properties (see section 5.3). Therefore, clinical consequences of concomitant treatment with ECT and agomelatine are considered unlikely.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and breastfeeding
Pregnancy
Data on the use of agomelatine in pregnant women do not exist or are limited (less than 300 exposed pregnancies). Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic / fetal development, parturition or post development. -natal (see section 5.3). As a precaution, it is preferable to avoid the use of Valdoxan during pregnancy.
Feeding time
It is unknown whether agomelatine / metabolites are excreted in human milk. Available pharmacodynamic / toxicological data in animals have shown excretion of agomelatine / metabolites in milk (see section 5.3). A risk to the newborns / infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue therapy. / abstain from Valdoxan therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
Reproduction studies in rats and rabbits showed no effects of agomelatine on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
However, considering that dizziness and somnolence are common adverse reactions, patients should be advised to pay attention to their ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
In clinical trials, over 7,900 depressed patients received Valdoxan.
Adverse reactions were usually mild or moderate and occurred during the first two weeks of treatment. The most common adverse reactions were nausea and dizziness. These adverse reactions were usually transient and generally did not lead to discontinuation of therapy.
Table of adverse reactions
Adverse reactions are listed below using the following convention: very common (≥1 / 10); common (≥1 / 100,
* Frequency estimated based on clinical studies for adverse events reported from spontaneous reports
some cases with fatal outcome or liver transplantation have been exceptionally reported in patients with hepatic risk factors
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions occurring after authorization of the medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the website: www. Agenziafarmaco.gov.it/it/responsabili of the Italian Medicines Agency.
04.9 Overdose
Symptoms
Experience with agomelatine overdose is limited. Experience with agomelatine overdose has reported epigastralgia, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis or malaise. A person who ingested 2450 mg of agomelatine recovered spontaneously without cardiovascular and biological abnormalities.
Management
There are no known specific antidotes for agomelatine. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical assistance in a specialist setting is recommended.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: psychoanaleptics, other antidepressants.
ATC code: N06AX22.
Mechanism of action
Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C receptor antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and has no affinity for a, b adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine resynchronizes circadian rhythms in animal models of circadian rhythm alteration. Agomelatine increases the release of norepinephrine and dopamine particularly in the frontal cortex and has no influence on extracellular levels of serotonin.
Pharmacodynamic effects
Agomelatine showed an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with desynchronization of the circadian rhythm and in models related to stress and anxiety.
In humans, Valdoxan has positive phase shift properties; it induces a phase advancement of sleep, a decrease in body temperature and the onset of melatonin production.
Clinical efficacy and safety
The efficacy and safety of Valdoxan in major depressive episodes were studied in a clinical program including 7,900 patients treated with Valdoxan.
Ten placebo-controlled studies have been performed to investigate the short-term efficacy of Valdoxan in major depressive disorder in adults, at fixed dose and / or dose titration. At the end of treatment (beyond 6 or 8 weeks) it has been demonstrated a significant efficacy of agomelatine 25-50 mg in six out of ten of the short-term, double-blind, placebo-controlled studies. The primary endpoint was the change in HAMD-17 score from baseline. Agomelatine did not differentiate from placebo in two studies in which the active control, paroxetine or fluoxetine, showed sensitivity to the test. Agomelatine was not directly compared. with paroxetine and fluoxetine as these comparator drugs were added to ensure test sensitivity in the studies. In two other studies no conclusion could be drawn as the two active controls, paroxetine or fluoxetine, did not differentiate from placebo However, in these studies it was not possible to increase the starting dose of either agomelatine, paroxetine or fluoxetine, although the response was not sufficient.
Efficacy was also seen in patients with more severe depression (baseline HAM-D score ≥ 25) in all positive placebo-controlled studies.
Response rates were statistically significantly higher with Valdoxan than with placebo.
Superiority (2 studies) or non-inferiority (4 studies) were demonstrated in 6 of 7 efficacy studies conducted in heterogeneous populations of adult patients depressed towards SSRI / SNRI (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The antidepressant effect was assessed with the HAMD-17 score, used as a primary or secondary endpoint.
Maintenance of antidepressant efficacy was demonstrated in a relapse prevention study. Patients responding to 8/10 weeks of acute open-label treatment with 25-50 mg Valdoxan once daily were randomized to 25-50 mg. of Valdoxan once daily or placebo for an additional 6 months. Administration of Valdoxan 25-50 mg once daily demonstrated statistically significant superiority over placebo (p = 0.0001) on the primary outcome, the prevention of depressive relapses, evaluated as time to relapse. The incidence of relapses during the 6-month double-blind follow-up period was 22% for Valdoxan and 47% for placebo, respectively.
Valdoxan does not affect daytime alertness and memory in healthy volunteers. In depressed patients, treatment with Valdoxan 25 mg increased the slow wave sleep phase without changing the amount of REM sleep (Rapid Eye Movement) or REM sleep latency. Valdoxan 25 mg also induced early sleep onset and an increase in minimal heart rate. As assessed by the patients themselves, sleep onset and quality improved significantly, starting in the first week of treatment without causing daytime sleepiness.
In a specific comparative study of sexual dysfunction, conducted in patients who had achieved remission from depression, there was a tendency for a lower occurrence of sexual dysfunction attributed to Valdoxan compared to venlafaxine (statistically not significant) for arousal or arousal scores. orgasm according to the Sex Effects Scale (SEXFX). The "combined analysis of the studies using the"Arizona Sexual Experience Scale (ASEX) has shown that Valdoxan is not associated with sexual dysfunction. In healthy volunteers, Valdoxan maintains sexual function unaltered compared to paroxetine.
In clinical studies Valdoxan did not show any effect on heart rate and blood pressure.
In a study designed to evaluate withdrawal symptoms using the Discontinuation Emergent Signs and Symptoms (DESS) checklist in patients who had achieved remission from depression, Valdoxan did not induce withdrawal syndrome following sudden cessation of treatment.
Valdoxan has no potential for abuse as assessed in studies conducted in healthy volunteers using a specific visual analog scale or with the "Addiction Research Center Inventory (ARCI) for 49 voices.
An 8-week placebo-controlled study with agomelatine 25-50 mg / day in elderly depressed patients (≥ 65 years, N = 222, of whom 151 treated with agomelatine) demonstrated a statistically significant difference of 2.67 points in HAM -D total score, primary outcome. The response rate analysis is in favor of agomelatine.
However, data in very elderly patients (≥ 75 years, N = 69 of whom 48 treated with agomelatine) are limited. Tolerability of agomelatine in elderly patients is comparable to that seen in young adults.
A specific, controlled, 3-week study was conducted in patients with major depressive disorder, and with insufficient improvement during treatment with paroxetine (an SSRI) or venlafaxine (a SNRI). When treatment was switched from these antidepressants to agomelatine, withdrawal symptoms occurred after cessation of SSRI or SNRI treatment, whether abrupt or gradual discontinuation of previous treatment. These withdrawal symptoms can be confused with a lack of early agomelatine benefits.
The percentage of patients with at least one withdrawal symptom one week after stopping SSRI / SNRI treatment was lower in the long-dose taper group (gradual discontinuation of prior SSRI / SNRI over 2 weeks) than in the a short dose reduction (gradual discontinuation of the previous SSRI / SNRI in 1 week) and in the immediate replacement group (abrupt discontinuation): 56.1%, 62.6% and 79.8%, respectively.
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Valdoxan in one or more subsets of the pediatric population for the treatment of major depressive episodes (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Absorption and bioavailability
Agomelatine is well and rapidly absorbed (≥ 80%) after oral administration. Absolute bioavailability is low (oral contraceptives and decreased by smoking. Peak plasma concentration is reached within 1-2 hours.
Systemic exposure to agomelatine over the therapeutic dose range appears to increase proportionally with dose. With higher doses there is saturation of the first pass effect.
Food intake (a standard meal or a high-fat meal) does not change bioavailability or rate of absorption. Variability is increased by high-fat foods.
Distribution
The steady-state volume of distribution is approximately 35 l and plasma protein binding is 95% regardless of concentration, and does not change with age and in patients with renal dysfunction, but the free fraction is doubled in patients. with hepatic impairment.
Biotransformation
After oral administration, agomelatine is rapidly metabolised primarily by the hepatic cytochrome CYP1A2. The isoenzymes CYP2C9 and CYP2C19 are minimally involved.
The major metabolites, hydroxylated and demethylated agomelatine, are inactive 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 clearance is high (approximately 1,100 ml / min) and essentially metabolic.
The excretion is mainly urinary (80%) and consists of the metabolites, while the urinary dosage of the unchanged substance is negligible.
The kinetics are not changed after repeated administration.
Renal impairment
No significant changes in pharmacokinetic parameters were observed in patients with severe renal impairment (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 for these patients ( see section 4.2).
Hepatic impairment
In a specific study conducted in cirrhotic patients with chronic mild (Child-Pugh type A) or moderate (Child-Pugh type B) hepatic impairment, exposure to agomelatine 25 mg was significantly increased (70 and 140-fold, respectively) compared to matched volunteers (for age, weight and smoking habits) without hepatic impairment (see sections 4.2, 4.3 and 4.4).
Elderly patients
In a pharmacokinetic study in elderly patients (≥ 65 years), it was shown that at a dose of 25 mg the median AUC and median C were approximately 4-fold and 13-fold higher in patients ≥ 75 years of age than in patients. of age
Ethnic groups
No data are available on the influence of race on agomelatine pharmacokinetics.
05.3 Preclinical safety data
At high doses, sedative effects were observed in mice, rats and monkeys after single and repeated administration.
In rodents, marked induction of CYP2B and moderate induction of CYP1A and CYP3A was found starting at 125 mg / kg / day while in monkeys induction was mild for CYP2B and CYP3A at 375 mg / kg / day. of repeat dose toxicity in rodents and monkeys, no hepatotoxicity was observed.
Agomelatine passes into the placenta and fetuses of pregnant female rats.
Reproduction studies in rats and rabbits showed no effects of agomelatine on fertility, embryo / fetal development and pre- and postnatal development.
A series of standard genotoxicity assays in vitro And in vivo demonstrated the absence of mutagenic or clastogenic potential of agomelatine.
In carcinogenicity studies agomelatine induced an increased incidence of liver tumors in rats and mice at doses at least 110 times higher than the therapeutic dose. Liver tumors are most likely related to rodent-specific enzyme induction. The observed frequency of benign mammary fibroadenomas in rats increased at high doses (60 times the therapeutic dose), but remained within the control range.
Pharmacological safety studies have shown no effects of agomelatine on human Ether a-go-go Related Gene (hERG) currents or on the action potentials of canine Purkinje cells. Agomelatine did not show proconvulsant properties at ip doses up to 128 mg / kg in mice and rats.
No effects of agomelatine were observed on the behavior, reproductive and visual functions of young animals. There were small, dose-independent decreases in body weight related to pharmacological properties and some minor effects on the male reproductive tract without impaired reproductive function.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet core:
- Lactose monohydrate
- Cornstarch
- Povidone K 30
- Sodium starch glycolate type A
- Stearic acid
- Magnesium stearate
- Anhydrous colloidal silica.
Coating film:
- Hypromellose
- Yellow iron oxide (E172)
- Glycerol
- Macrogol 6000
- Magnesium stearate
- Titanium dioxide (E171).
Printing ink containing shellac, propylene glycol and indigo carmine aluminic lake (E132).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Aluminum / PVC blisters 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.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Les Laboratoires Servier
50, rue Carnot
92284 Suresnes cedex
France
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/08/499 / 001-008
039143019
039143021
039143045
039143058
039143060
039143072
039143084
A.I.C. n ° 039143033 / E - pack of 28 tablets
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19 February 2009
Date of most recent renewal: February 19, 2014
10.0 DATE OF REVISION OF THE TEXT
11/2014
