Universal reference book for medicines
Product name: VALDOXAN ® (VALDOXAN ® )

Active substance: agomelatine

Type: Antidepressant

Manufacturer: Les Laboratoires Servier (France) manufactured by Les Laboratoires Servier Industrie (France) packaged and packaged Les Laboratoires Servier Industrie (France)
Composition, form of production and packaging
The film-coated tablets are
oblong, orange-yellow with a blue logo on one side.

1 tab.

agomelatine 25 mg

Excipients: lactose monohydrate - 61.84 mg, magnesium stearate - 1.3 mg, corn starch - 26 mg, povidone-K30 - 9.1 mg, silicon dioxide colloid - 0.26 mg, sodium carboxymethyl starch - 3.9 mg, stearic acid - 2.6 mg.

The composition of the film shell: glycerol - 0.19665 mg, hypromellose - 3.26871 mg, iron oxide, yellow oxide - 0.19509 mg, macrogol 6000 - 0.20872 mg, magnesium stearate 0.19665 mg, titanium dioxide 0.43418 mg.

Composition of blue paint: shellac, propylene glycol, indigo carmine, aluminum lacquer.

10 pieces.
- blisters (10) - packs of cardboard.
14 pcs.
- blisters (1) - packs of cardboard.
14 pcs.
- blisters (2) - packs of cardboard.
Packages for hospitals:

10 pieces.
- blisters (10) - packs of cardboard.
14 pcs.
- blisters (7) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Pharmacodynamics

Antidepressant, agonist melatoninergic MT 1 - and MT 2 -receptors and antagonist serotonin 5-HT 2c- receptors.

Agomelatine is active on validated depression models (test of acquired helplessness, despair test, chronic stress of moderate severity), as well as on models with desynchronization of circadian rhythms, and also in experimental situations of anxiety and stress.
It has been shown that agomelatine does not affect the capture of monoamines and has no affinity for? -,? -adrenoreceptors, histaminergic receptors, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex and does not affect the concentration of extracellular serotonin.In animal experiments with desynchronization of circadian rhythms, it was shown that agomelatine restores the synchronization of circadian rhythms by stimulating melatonin receptors.

Agomelatine helps restore normal sleep patterns, reduce body temperature and release melatonin.

The effectiveness of short-term use of agomelatine (therapy 6-8 weeks) in doses of 25-50 mg in patients with large depressive episodes is shown.

The efficacy of agomelatine in patients with more severe forms of depressive disorder is also indicated (score on the Hamilton scale of ≥25).

Agomelatine was also effective at initially high levels of anxiety, as well as in the combination of anxiety and depressive disorders.

The supporting antidepressant effect of agomelatine (with a duration of 6 months) in a dose of 25-50 mg 1 time / day was confirmed.
The results of the study confirmed the anti-relapse efficacy of agomelatine, which was evaluated before the onset of relapse (p = 0.0001). The recurrence rate in the group of patients taking agomelatine was 22%, in the placebo group - 47%.
The efficacy of agomelatine has been demonstrated in 6 of 7 clinical trials (advantage (2 studies) or comparable efficacy (4 studies)) in heterogeneous populations of adult patients with depression compared to selective serotonin reuptake inhibitors (SSRIs) / selective norepinephrine reuptake inhibitors (SSRIs ) (sertraline, escitalopram, fluoxetine, venlafaxine, or duloxetine).
The antidepressant effect was assessed on the Hamilton scale (17-point version) either as primary or as a secondary endpoint.
Agomelatine does not adversely affect care and memory; in patients with depression, agomelatine 25 mg increases the duration of the slow-sleep phase without changing the number and duration of fast-sleep phases.
Taking agomelatine in a dose of 25 mg also contributes to a faster onset of sleep with a decrease in heart rate and improved sleep quality (starting from the first week of treatment); at the same time there is no slowing down in the daytime.
Against the background of taking agomelatine, there was a tendency to decrease the frequency of sexual dysfunction (effect on excitement and orgasm).

Admission of agomelatine does not affect the heart rate and blood pressure, does not cause sexual disorders, does not cause withdrawal syndrome (even with a sharp cessation of treatment) and addiction.

The efficacy of agomelatine in a dose of 25-50 mg 1 time / day was confirmed in elderly patients (under 75 years) with depression during the 8-week clinical trial.Patients aged 75 years and older have no confirmed data on the presence of significant effect.
The tolerability of agomelatine in elderly patients is comparable to that of young patients.
In the course of a 3-week controlled study involving patients with major depressive disorder and an insufficient therapeutic effect of taking paroxetine (SSRIs) or venlafaxine (SSRIs), withdrawal from therapy with these antidepressants for treatment with agomelatine was observed.
The withdrawal syndrome appeared both after a one-stage cessation of treatment with SSRI / SSRIs previously prescribed, and with their gradual withdrawal, which could be mistaken for the low effectiveness of agomelatine at the initial stage of treatment.
The number of patients who had at least one symptom associated with withdrawal syndrome one week after the withdrawal of SSRIs / SSRIs was lower in the group with a prolonged dose reduction (gradual reduction of the SSRI / SSRI dose within 2 weeks) than in the group with a rapid decline dose (a gradual reduction in the dose of SSRIs / SSRIs within 1 week), and than with one-stage withdrawal: 56.1%, 62.6% and 79.8% of patients, respectively.

PHARMACOKINETICS

Suction

After ingestion, agomelatine quickly (? 80%) is absorbed.
C max in plasma is achieved 1-2 hours after ingestion. Absolute bioavailability after taking a therapeutic dose is low (<5%); interindividual variability is considerable. Bioavailability in women is higher than in men. Bioavailability increases with oral contraceptives and decreases with smoking.
When the drug was administered in therapeutic doses, C max increased in proportion to the dose.
When taken in higher doses, a more pronounced effect of "first passage" through the liver was noted. The intake of food (both normal and high in fat) did not affect either bioavailability or the degree of absorption. Against the background of food intake with a high fat content interindividual variability of the indicators increased.
Distribution

V d in the equilibrium state was about 35 liters.
Binding to plasma proteins is 95% regardless of drug concentration, age or presence of renal insufficiency.
In liver failure, there was a twofold increase in the free fraction of the drug.

Metabolism

After ingestion, agomelatine undergoes rapid oxidation, mainly due to CYP1A2 and CYP2C9.
Isozyme CYP2C19 is also involved in the metabolism of agomelatine, but its role is less significant.
The main metabolites in the form of hydroxylated and demethylated agomelatine are inactive, quickly bind and excreted by the kidneys.

Excretion

T 1/2 from the plasma is from 1 to 2 hours. The elimination is rapid.
The metabolic clearance is about 1100 ml / min. Excretion occurs mainly in the kidneys (80%) in the form of metabolites. The amount of unchanged drug in the urine is insignificant. With repeated administration of the drug, the kinetics does not change.
Pharmacokinetics in special clinical cases

In patients with severe renal failure with a single admission of agomelatine in a dose of 25 mg, the pharmacokinetic parameters did not change significantly.
Because of limited clinical experience, caution should be exercised in prescribing agomelatine to patients with moderate and severe renal failure.
With the appointment of agomelatine in a dose of 25 mg to patients with poorly expressed (class A on the Child-Pugh scale) and moderate (class B on the Child-Pugh scale), chronic hepatic insufficiency against a cirrhosis of the liver was noted to increase its plasma concentrations by 70 and 140 times , respectively, compared with volunteers, comparable in sex, age and attitude to smoking, but without liver failure.

In appointing agomelatine in a dose of 25 mg to elderly patients (65 years and older), it was noted that the mean AUC and mean C max were 4-fold and 13-fold, respectively, higher in patients aged 75 years and older compared with patients younger than 75 years.
The total number of patients receiving the drug at a dose of 50 mg was too low to draw any conclusions. Dose adjustment according to age is not required.
There are no data on racial differences in pharmacokinetic parameters.

INDICATIONS

- Treatment of major depressive disorder in adults.

DOSING MODE

The drug is prescribed inside.
Valdoxane ® can be taken regardless of food intake. Tablets should be swallowed whole, without chewing.
If you skip the next dose of the drug, during the next dose, take Valdoxane ® in the usual dose (do not take the missed dose of the drug).

To improve the control of taking the drug on a blister containing tablets, a calendar is printed.

The recommended dose is 25 mg (1 tab.) 1 time / day before bedtime.
In the absence of clinical dynamics after a two-week treatment, the dose may be increased to 50 mg (2 tablets of 25 mg) 1 time / day before bedtime.
The decision to increase the dose should be taken in light of the increasing risk of increased transaminase activity.
Increase the dose to 50 mg should be after assessing the benefit and risk for a particular patient and under strict control of hepatic samples.
Before starting therapy, functional liver tests should be performed in all patients.
Therapy can not be started in patients with a transaminase level more than 3 times the upper limit of the norm (see the sections "Contraindications" and "Special instructions"). During the treatment, the liver function should be monitored periodically, approximately 3 weeks later, after about 6 weeks (the end of the stopping period of therapy), approximately 12 weeks and 24 weeks (the end of the maintenance period of therapy) after the initiation of therapy, and thereafter in accordance with the clinical situation (see section "Special instructions"). If the activity of transaminases is more than 3 times higher than the upper limit of the norm, the drug should be discontinued (see the sections "Contraindications" and "Special instructions").
With increasing doses, liver function should be monitored at the same frequency as at the beginning of the drug.

Duration of treatment

Drug therapy for depression should be performed for at least 6 months until the symptoms of depression disappear completely.

Transition from SSRI / SSRI therapy to agomelatine therapy

Possible withdrawal syndrome after discontinuation of SSRI / SSRIs.

To reduce the risk of withdrawal syndrome after discontinuing treatment with previously prescribed SSRIs / SSRIs, follow the instructions for the medical use of these drugs.

The intake of agomelatine can be started from the 1 st day of a gradual reduction in the dose of SSRI / SSRI antidepressants (see the section "Pharmacodynamics").

Discontinuation of treatment

In the event of discontinuation of treatment, there is no need for a gradual dose reduction.

Elderly patients

The efficacy and safety of agomelatine (in the dose of 25-50 mg / day) is confirmed in elderly patients (under 75 years) with depression.
Patients aged 75 years and older have no confirmed data on the presence of significant effect. In this regard, Valdoxane ® should not be prescribed to patients of this age group (see sections "Special instructions" and "Pharmacological action"). Dose adjustments are not required depending on age (see section "Pharmacological action").
Patients with renal insufficiency

In patients with severe renal insufficiency no significant change in pharmacokinetic parameters was noted.
The experience of using the drug Valdoxane in large depressive episodes in patients with moderate to severe renal failure is limited. When appointing Valdoxane ® to such patients, care should be taken (see section "Special instructions").
Patients with hepatic insufficiency

Valdoxane ® is contraindicated in patients with hepatic insufficiency (see the sections "Contraindications", "Special instructions" and "Pharmacokinetics").

SIDE EFFECT

In clinical studies, Waldoxan ® received more than 7,900 patients with depression.
Side effects were most often mild or moderate and were observed in the first 2 weeks of treatment. The most common signs of nausea and dizziness. The noted side effects, as a rule, were transient and, basically, did not require the cessation of treatment.
The frequency of side effects of agomelatine is given in the following gradation: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1 / 10 000, <1/1000);
very rarely (<1/10 000), frequency, unspecified.
From the side of the central nervous system: often - headache, dizziness, drowsiness, insomnia, migraine;
infrequently, paresthesia, restless legs syndrome.
Mental disorders: often - anxiety;
infrequent - agitation and related symptoms *, such as irritability and anxiety, aggressiveness *, nightmares *, unusual dreams *; rare - mania / hypomania * (these symptoms can also be a manifestation of the underlying disease (see section "Special instructions")), hallucinations *; unspecified frequency - suicidal thoughts or suicidal behavior (see section "Special instructions").
From the gastrointestinal tract: often - nausea, diarrhea, constipation, abdominal pain, vomiting *.

On the part of the hepatobiliary system: often - increase in ALT and / or ACT activity (more than 3 times compared with IVH in 1.4% of patients with agomelatine at a dose of 25 mg per day and 2.5% of patients receiving agomelatine at a dose of 50 mg per day, compared with 0.6% for placebo in clinical trials);
rarely - hepatitis, increased activity of gamma-GGT * (more than 3 times compared with IGN), increased activity of AP * (more than 3 times compared with IGN), hepatic insufficiency * (1), jaundice *.
From the skin and subcutaneous tissue: often - sweating;
infrequently - eczema, itchy skin *, urticaria *; rarely - erythematous rash, face swelling and Quincke's edema *.
From the side of the organ of hearing: infrequently - noise in the ears.

From the side of the organ of vision: infrequently - fuzzy sight.

From the musculoskeletal system: often - pain in the back.

General disorders: often fatigue.

Data from additional examinations: rarely - weight gain, weight loss.

* - an estimate of the incidence of adverse reactions identified by spontaneous reports was made on the basis of clinical trial data.

(1) Only a few cases with a fatal outcome or liver transplantation have been reported in patients with previous risk factors for liver damage.

CONTRAINDICATIONS

- hepatic insufficiency (for example, cirrhosis or liver disease in the active phase) or an increase in the level of transaminases more than 3 times with respect to IGN (see the sections "Dosage regimen" and "Special instructions");

- simultaneous application of powerful inhibitors of the isoenzyme CYP1A2 (such as fluvoxamine, ciprofloxacin) (see section "Drug Interactions");

- Children under 18 years of age (due to lack of sufficient clinical experience).
In children and adolescents, suicidal behavior (suicide attempts and suicidal ideation) and hostility (predominantly aggressiveness, conflict behavior, irritation) were noted more frequently in comparison with the placebo group in the presence of other antidepressants;
- lactose intolerance (lactase deficiency, galactosemia and glucose-galactose malabsorption);

- Hypersensitivity to agomelatine and / or any of the excipients of the drug (see section "Composition").

Caution should be given to the drug in the treatment of major depressive episodes in patients with moderate and severe renal failure;
with simultaneous administration of agomelatine with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin); patients with manic or hypomanic episodes in the anamnesis, patients who had a history of suicidal events, as well as patients who had suicidal intent before initiating therapy.
Caution should be exercised when prescribing the drug to patients who abuse alcohol or take drugs that can cause liver dysfunction.

PREGNANCY AND LACTATION

Data on the use of agomelatine in pregnancy are absent or limited (less than 300 pregnancy outcomes).

Studies in animals have not revealed direct or indirect adverse effects on the course of pregnancy, embryo and fetus development, labor activity and postnatal development.
As a precaution, it is recommended to avoid the appointment of the drug Valdoxan ® in pregnancy.
It is not known whether agomelatine penetrates breast milk in women during lactation.
In experimental studies in animals, it has been shown that agomelatine and its metabolites penetrate into breast milk. If treatment with agomelatine is necessary, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with severe renal insufficiency no significant change in pharmacokinetic parameters was noted.
The experience of using the drug Valdoxane in large depressive episodes in patients with moderate to severe renal failure is limited. When assigning agomelatine drug to such patients, it should be
careful.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

The drug is contraindicated in hepatic insufficiency.
APPLICATION FOR CHILDREN

Is contraindicated in children younger than 18 years (due to lack of sufficient clinical experience). In children and adolescents while taking other antidepressants suicidal behavior (suicide attempts and suicidal thoughts), and hostility (predominantly aggression, conflict behavior, anger) were more frequent than in the placebo group

APPLICATION IN ELDERLY PATIENTS

The efficacy and safety of agomelatine (at a dose of 25-50 mg / day) was confirmed in elderly patients (younger than 75 years) with depression. In patients aged 75 years and over, there are no confirmed evidence of a significant effect. Therefore agomelatine ® should not be administered to patients in this age group. No dose adjustment based on age is not required.
SPECIAL INSTRUCTIONS

Monitoring of liver function tests
have been reported cases of liver injury, including liver failure (drive in exceptional cases, to death or requiring liver transplantation in patients with pre-existing liver disease risk factors), increased liver enzymes more than 10 times the upper limit of normal, hepatitis, jaundice patients treated with agomelatine ® , a Post-registration period (see. the section "Side effect"). Most of these violations occurred in the first months of treatment. The nature of liver damage represented mainly hepatocellular. As a rule, after the cessation of therapy, transaminase levels returned to normal.
Care should be taken before treatment and be closely monitored during treatment for all patients, especially those with risk factors for liver or receiving concomitant therapy with disease that can cause liver damage.
Prior to treatment
Treatment with agomelatine ® it should be administered only after careful evaluation of the ratio of expected benefit for the possible risk in patients with risk factors for liver dysfunction, such as obesity / overweight / nonalcoholic steatosis, diabetes, alcohol abuse and administration of drugs, can cause abnormal liver function.
Before therapy liver function tests should be performed in all patients, and the treatment can not be started if the level of liver enzymes ALT and / or ACT is more than 3 times the ULN (see. Section "Contraindications").
Caution must be exercised when administering the drug agomelatine ® patients with initially increased activity of transaminases (ULN above, but no more than 3 times the ULN).
Frequency of liver function tests:
- before the start of therapy;
- and further:
- about after 3 weeks
- after about 6 weeks (ending acute treatment period)
- about after 12 and 24 weeks (end of maintenance period therapy),
- in the future - in accordance with the clinical situation.
With increasing doses should monitor liver function with the same frequency as that of the start of therapy.
By increasing the activity of transaminases in the serum should be conducted repeated research for 48 h.
The course of treatment
Treatment with agomelatine ® should be stopped immediately in case:
- the appearance of the symptoms and signs of potential liver disorders (such as dark urine, discolored chair, yellowing of the skin / eye, pain in the right upper abdomen, recently introduced the constant fatigue and unexplained);
- increasing transaminase levels more than 3-fold compared with ULN.
After the cancellation of therapy with agomelatine ® should be regularly liver function tests until the normalization of transaminase levels.
Elderly patients

The effectiveness of the drug in elderly patients (75 years and older) is not installed. In this regard, should not be given agomelatine ® for patients in this age group (see. Sections "Dosage" and "Mode of action").
Elderly patients with dementia
should not assign Valdoskan ® for the treatment of major depressive episodes in elderly patients with dementia (due to lack of data on efficacy and safety of the drug in this patient group).
Patients with renal insufficiency

In patients with severe renal insufficiency, significant changes in pharmacokinetic parameters were observed. However, experience with the drug agomelatine ® in major depressive episodes in patients with moderate to severe renal insufficiency is limited. When assigning agomelatine preparation ® such patients should be cautious.
Bipolar disorder / mania / hypomania
Caution must be exercised when using the drug agomelatine ® in patients with bipolar disorder, manic or hypomanic episodes in history. When the mania symptoms should stop taking the drug.
Suicide / suicidal behavior
When depression are at increased risk of suicidal thoughts, self harm and suicide (events related to suicide). Risk persists until the distinct remission. Patients should be kept under medical supervision until improvement (may take a few weeks after initiation of therapy before the condition improves). Clinical experience suggests that the risk of suicide may increase in the early stages of the remission.
Patients with a history of events were associated with suicide, as well as patients who had suicidal ideation at baseline are at risk and during therapy should be under close medical supervision.
Results of a meta-analysis of clinical studies of antidepressants in patients with mental disorders indicate an increased risk of suicidal behavior in patients under the age of 25 in patients receiving placebo compared with antidepressants.
During treatment, patients are especially at risk should be under close medical supervision, especially at the beginning of treatment and when changing the dose. Patients (and caregivers of them) should be informed about the need for immediate treatment to the doctor when deterioration, suicidal and unusual behavior, as well as the emergence of suicidal thoughts.
Joint application with inhibitors of CYP1A2 isoenzyme
Caution must be exercised while the use of agomelatine with moderate CYP1A2 isoenzyme inhibitors (such as propranolol, enoxacin) due to the possibility of increasing the concentration of the agomelatine (see. The sections "Contra" and "Drug Interactions").
Patients with lactose intolerance
should not use the drug in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption (see section "Contraindications".).
Impact on the ability to drive vehicles and manage mechanisms

Studies on the influence of drug agomelatine ® driving ability and other mechanisms is not performed. It should be borne in mind that dizziness and sleepiness - common side effects of agomelatine.
OVERDOSE

Data on agomelatine overdose is limited.
Symptoms: drowsiness, epigastric pain, anxiety, weakness, anxiety, agitation, tension, dizziness, cyanosis, and malaise. When receiving agomelatine patient at a dose of 2450 mg of state returned to normal on their own, without any violations of the cardiovascular system, or changes in laboratory parameters.
Treatment: the specific antidotes for agomelatine are known. Symptomatic treatment and monitoring in specialized departments with subsequent observation.
DRUG INTERACTION

Potentially possible effect of other drugs
Agomelatine 90% is metabolized in the liver with cytochrome P450 1A2 (CYP1A2) and 10% using CYP2C9 / 19. Therefore, any drugs the metabolism of which depends on these isozymes may increase or decrease the bioavailability of agomelatine.
Fluvoxamine is a potent inhibitor of CYP1A2 isozyme and a moderate inhibitor of CYP2C9 isozyme and significantly slows the metabolism of agomelatine, wherein agomelatine concentration increases by about 60 (12-412) times. Therefore, the simultaneous use of agomelatine and strong inhibitors isoenzyme CYP1A2 (such as fluvoxamine, ciprofloxacin) is contraindicated.
Simultaneous administration of agomelatine and estrogen that are moderate inhibitors of isoenzyme CYP1A2, leads to an increase in the concentration of the agomelatine several times. Although the combined use of estrogen and agomelatine not accompanied by the deterioration of the profile of the therapy safety caution while appointing agomelatine with other moderate inhibitors isoenzyme CYP1A2 (such as propranolol, enoxacin) until a sufficient accumulation of clinical experience (see. The "Special instructions").
Rifampicin, both as an inducer of cytochromes involved in the metabolism of agomelatine, capable of reducing bioavailability of agomelatine. It has been shown that smoking induce isoenzyme CYP1A2, it reduces the bioavailability of agomelatine, especially in patients who abuse tobacco (? 15 cigarettes / day) (see. "Pharmacokinetics" section).
Potentially agomelatine possible influence on other drugs
In vivo agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine inhibits the isoenzyme CYP1A2 in vivo and other cytochrome P450 isozymes in vitro. Therefore, agomelatine has no effect on the concentration of drugs whose metabolism is associated with these isoenzymes.
Preparations of largely bind to plasma proteins
Agomelatine does not modify free concentrations of drugs that are highly bound to plasma proteins and, in turn, they do not affect the concentration of the agomelatine.
Other drugs
revealed the absence of a pharmacokinetic and pharmacodynamic interaction between agomelatine and drugs frequently used in the target patient population: benzodiazepines, lithium preparations, paroxetine, fluconazole and theophylline.
Alcohol
is not recommended the use of agomelatine together with alcohol.
Electroconvulsive therapy (ECT)
There are no data on the use of agomelatine together with electroconvulsive therapy (ECT). Because animal studies, agomelatine has not contributed to the seizures, adverse effects of agomelatine with ECT sharing seems unlikely.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of the reach of children.
Special conditions for the storage of the drug is required. Shelf life - 3 years. Do not use after the expiration date printed on the package.
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