Вальдоксан®

General characteristics. Structure:

Active agent агомелатин 25 mg.
Excipients: lactoses monohydrate of 61,84 mg, magnesium stearate of 1,3 mg, starch of corn 26,0 mg,
povidone of 9,1 mg, silicon dioxide of colloid 0,26 mg, carboxymethylstarch of sodium of 3,9 mg, stearic acid of 2,6 mg.
Film cover: глицерол 0,19665 mg, gipromelloza of 3,26871 mg, dye ferrous oxide of yellow 0,19509 mg, macrogoal of 6000 0,20872 mg, magnesium stearate of 0,91665 mg, titanium dioxide of 0,43418 mg.
The drawing of a logo of firm on a tablet is put with blue paint which part are shellac, propylene glycol, indigo carmine a varnish aluminum.
Description
Oblong tablets, film coated, orange-yellow color with the image of a logo of firm of blue color on one party.

Pharmacological properties:

Agomelatin - an agonist of melatoninergichesky receptors of MT1 and MT2 and the antagonist of serotoninovy 5-HT2C-receptors. Agomelatin represents antidepressant, active on validirovanny models of a depression (the test of the acquired helplessness, the test of despair, a chronic stress of moderate expressiveness), as well as on models with desynchronization of circadian rhythms, and also in experimental situations of alarm and
stress. It was shown what агомелатин does not influence capture of monoamines and has no affinity to alpha, beta and adrenergic, gistaminergichesky, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatin strengthens release of dopamine and noradrenaline, in particular in prefrontal cortex of a brain and does not influence concentration of extracellular serotonin. In animal experiments with simulated with desynchronization of circadian rhythms it was shown what агомелатин recovers synchronization of circadian rhythms by means of stimulation of melatoninovy receptors. Agomelatin promotes recovery of normal structure of a dream, decrease in body temperature and release of melatonin. Efficiency of short-term use of an agomelatin (therapy of 6-8 weeks) in doses of 25-50 mg at patients with big depressive episodes is shown. Efficiency of use of an agomelatin for patients with more severe forms of depressive frustration is also shown (assessment on Hamilton scale ≥ 25). Agomelatin was also effective at initially high levels of alarm, as well as at a combination of alarming and depressive frustration. The supporting antidepressive effect of an agomelatin (lasting research of 6 months) in a dose of 25-50 mg is confirmed once a day. Results of a research confirmed antirecurrent efficiency of an agomelatin which was estimated on time before a disease recurrence (p = 0,0001). Frequency of development of a recurrence in group of the patients accepting агомелатин made 22%, in group of placebo – 47%. Agomelatin does not make negative impact on attentiveness and memory, at patients with a depression агомелатин in a dose of 25 mg increases duration of a phase of a slow dream without change of quantity and duration of phases of a REM sleep. Reception of an agomelatin in a dose of 25 mg also promotes more bystry approach of a dream and improvement of its quality (since first week of treatment) and to decrease in heart rate; at the same time block is not noted in the afternoon. Against the background of reception of an agomelatin the tendency to decrease in frequency of sexual dysfunction (influence on excitement and an orgasm) is noted. Reception of an agomelatin does not exert impact on body weight, heart rate and arterial pressure, does not cause sexual disturbances, does not cause a syndrome of "cancellation" (even at the sharp termination of treatment) and a syndrome of "accustoming".

Pharmacokinetics. Absorption and bioavailability
After intake агомелатин quickly (≥ 80%) it is soaked up. The peak of concentration in plasma is reached in 1-2 hours after intake. Absolute bioavailability after reception of a therapeutic dose low (<5%); interindividual variability considerable. Bioavailability at women is higher, than at men. Bioavailability increases against the background of reception of oral contraceptives and decreases against the background of smoking.
At purpose of therapeutic doses the maximum concentration of drug increased in proportion to a dosage. At reception of higher doses more expressed effect of the first passing through a liver was noted. Meal (as usual, and with the high content of fats) did not influence neither bioavailability, nor extent of absorption. Against the background of meal with the high content of fats interindividual variability of indicators increased.
Distribution
Distribution volume in an equilibrium phase made about 35 l.
Linkng with proteins of plasma – 95% irrespective of concentration of drug, age or existence of a renal failure. At a liver failure double increase in free fraction of drug was noted.
Biotransformation
After intake агомелатин is exposed to bystry oxidation, generally at the expense of isoenzymes of CYP1A2 and CYP 2C9. CYP2C19 isoenzyme also participates in metabolism of an agomelatin, however its role is less significant.
The main metabolites in the form of a hydroxylated and demetilirovanny agomelatin are inactive, communicate quickly and removed by kidneys.
Removal
Removal happens quickly. Plasma elimination half-life makes from 1 to 2 hours. The metabolic clearance makes about 1100 ml/min. Removal happens generally kidneys (80%) in the form of metabolites. Amount of not changed drug in
to urine it is insignificant. At repeated purpose of drug the kinetics does not change. Renal failure
At patients with a heavy renal failure at a single dose of an agomelatin in a dose of 25 mg pharmacokinetic parameters significantly did not change. Because of limited clinical experience patients should be careful at purpose of an agomelatin with the moderated and expressed renal failure.
Liver failure
At purpose of an agomelatin in a dose of 25 mg to patients with poorly expressed (a class A on classification of Chayld-Pyyu) and moderated (a class B on classification of Chayld-Pyyu) the chronic liver failure against the background of cirrhosis noted increase in its concentration in plasma in 70 and 140 times, respectively, in comparison with the volunteers comparable on a sex, age and attitude towards smoking, but without liver failure.
Race
There are no data on racial distinctions of pharmacokinetic parameters.

Indications to use:

Treatment of big depressive frustration at adults.

Route of administration and doses:

Inside. It is possible to take a pill of the drug Valdoksan® irrespective of reception a pishchi.itabletka it is necessary to swallow entirely, without chewing. At the admission of reception of the next dose of drug, during the following reception of Valdoksan® is accepted in a usual dose (it is not necessary to accept the passed dose). For improvement of control by the patient of administration of drug, on the blister containing tablets the calendar is printed. The recommended daily dose – 25 mg (1 tablet) once in the evening. At absence
clinical dynamics after two-week treatment the dose can be increased to 50 mg (2 tablets on 25 mg) once in the evening. It is recommended to control function of a liver at the beginning of therapy and then periodically, in 3 weeks, in 6 weeks (the end of the stopping therapy period), 12 weeks and 24
weeks (the end of the supporting therapy period) later began therapies, and further according to a clinical situation. Medicinal therapy of a depression has to be carried out, at least, within 6 months for complete cessation of symptoms. The termination of treatment in case of the termination of treatment is not present need for a gradual dose decline.

Features of use:

Patients of advanced age
Efficiency of use of drug for elderly patients (at the age of 65 years is also more senior) is not established. There are limited data on use of the drug Valdoksan® at big depressive episodes for patients at the age of 65 years and are more senior. At purpose of drug patients of advanced age should be careful (see the section "Special Instructions").
Patients with a renal failure
At patients with a heavy renal failure of significant change of pharmacokinetic parameters it was not noted. However experience of use of the drug Valdoksan® at big depressive episodes at patients with average and heavy degree of a renal failure is limited. At purpose of the drug Valdoksan® such patients should be careful.
Bipolar frustration / mania/hypomania
It is necessary to be careful at use of the drug Valdoksan® for patients with bipolar disorders, maniacal or hypomaniacal episodes in the anamnesis. At emergence of symptoms of a mania it is necessary to stop administration of drug.
Suicide / suicide behavior
At a depression the risk of suicide thoughts, self-damages and a suicide (the events connected with a suicide) is increased. The risk remains before clear remission. Patients have to be under medical observation up to improvement of a state (after the beginning of therapy there can pass several weeks before the state improves). Clinical experience demonstrates that the risk of a suicide can increase at early stages of approach of remission. Patients in whose anamnesis there were events connected with a suicide and also the patients who had suicide intentions prior to therapy treat risk group and during performing therapy have to be under fixed medical observation.
Results of meta-analysis of clinical trials of antidepressants at patients with mental disorders demonstrate the increased risk of suicide behavior at patients aged up to 25 years against the background of reception of antidepressants in comparison with placebo. During treatment the patients who are especially belonging to risk group have to be under fixed medical observation, especially at the beginning of therapy and at change of a dose of drug. Patients (and the persons which are carrying out care of them) have to be informed on need of the immediate address to the doctor at an aggravation of symptoms, suicide and unusual behavior, and also at emergence of suicide thoughts. Combined use with inhibitors of an isoenzyme CYP1A2 It is necessary to be careful at simultaneous use of an agomelatin with moderate inhibitors of an isoenzyme CYP1A2 (such as propranolol, грепафлоксацин, эноксацин) because of a possibility of increase in concentration of an agomelatin
(see the section "Interaction with Other Medicines and Other Types of Interaction").
Increase in activity of transaminases in blood serum
In researches against the background of administration of drug of Valdoksan®, especially in a dose of 50 mg, increase in activity of transaminases in blood serum was noted (more than by 3 times in comparison with the upper bound of norm) (see the section "Side effect"). As a rule, after the therapy termination these indicators were returned to normal values. It is recommended to control function of a liver at the beginning of therapy and then periodically, in 3 weeks, in 6 weeks (the end of the stopping therapy period), 12 weeks and 24 weeks (the end of the supporting therapy period) later began therapies, and further according to a clinical situation. At increase in activity of transaminases in blood serum it is necessary to conduct a repeated research within 48 hours. If activity of transaminases more than by 3 times exceeds the upper bound of norm, administration of drug should be stopped. Further it is regularly necessary to control a functional condition of a liver before normalization
activities of transaminases. It is necessary to be careful at purpose of the drug Valdoksan® to patients with a superactivity of transaminases prior to therapy (above the upper bound of norm, but no more than by 3 times of rather upper bound of norm). At development of symptoms of an abnormal liver function it is necessary to carry out functional hepatic tests. Taking into account datas of laboratory and a clinical picture it is necessary to make the decision on the termination or continuation of therapy by the drug Valdoksan®.
At development of jaundice it is necessary to stop therapy. It is necessary to be careful at purpose of the drug Valdoksan® to patients with risk factors of development of abnormal liver functions, such as obesity / excess weight / not alcoholic fatty dystrophy of a liver, to the patients taking alcohol in significant amounts or accepting the drugs capable to cause an abnormal liver function.

Side effects:

In clinical trials of Valdoksan® more than 3900 patients with a depression received. Side effects most often were slightly or are moderately expressed and were observed in the first two weeks of treatment. Nausea and dizziness were most often noted. Noted side effects, as a rule, were passing and, generally did not demand the treatment termination. In some cases it is difficult to differentiate symptoms of depressive frustration and side effects of therapy agomelatiny. Frequency of side effects of an agomelatin is specified in a type of the following gradation: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000, <1/100), is rare (≥1/10000, <1/1000); very seldom (<1/10000), not specified frequency.
From the central nervous system
Often: headache, dizziness, drowsiness, sleeplessness, migraine.
Infrequently: paresthesias.
From digestive tract
Often: nausea, diarrhea, lock, abdominal pain.
Co of the party of gepatobiliarny system
Often: increase in activity of ALT and/or nuclear heating plant (more than by 3 times in comparison with the upper bound of norm against the background of reception of an agomelatin at 1,3% of patients and at 0,7% against the background of placebo).
Seldom: hepatitis, increase in activity of a γ-glutamiltransferaza * (gamma GGT) (more than by 3 times in comparison with the upper bound of norm), increase in activity of an alkaline phosphatase * (more than by 3 times in comparison with the upper bound of norm).
From skin and hypodermic cellulose
Often: perspiration.
Infrequently: eczema, skin зуд*.
Seldom: erythematic rash.
From an organ of sight
Infrequently: indistinct sight.
From a musculoskeletal system
Often: dorsodynia.
General frustration
Often: fatigue.
Mental disorders
Often: alarm.
Infrequently: agitation and related symptoms *, such as irritability and concern, aggression *, nightmares *, unusual сновидения*.
Seldom: mania / гипомания*. The specified symptoms can be also manifestation of a basic disease (see the section "Special Instructions").
Галлюцинации*.
Not specified frequency: suicide thoughts or suicide behavior (see the section "Special Instructions").
* Assessment of frequency of the undesirable reactions revealed according to spontaneous messages is carried out on the basis of these clinical trials.

Interaction with other medicines:

Potentially possible influence of other medicines
Agomelatin for 90% is metabolized in a liver with participation of P450 1A2 cytochrome (CYP1A2) and for 10% – by means of CYP2C9/19. Therefore any drugs which metabolism depends on these isoenzymes can increase or reduce bioavailability of an agomelatin. Fluvoksamin, is strong inhibitor of an isoenzyme CYP1A2 and moderate inhibitor of an isoenzyme CYP2C9 and significantly slows down metabolism of an agomelatin, at the same time concentration of an agomelatin increases approximately in 60 (12 - 412) times. Therefore
simultaneous use of an agomelatin and strong inhibitors of an isoenzyme CYP1A2 (such as флувоксамин, ciprofloxacin) it is contraindicated. Co-administration of an agomelatin and estrogen which are moderate inhibitors of an isoenzyme CYP1A2 leads to increase in concentration of an agomelatin several times. Though the combined use of an agomelatin and estrogen was not followed by deterioration in a profile of safety of the carried-out therapy, it is necessary to be careful at co-administration of an agomelatin with other moderate inhibitors of an isoenzyme CYP1A2 (such as propranolol, грепафлоксацин, эноксацин) before accumulation of sufficient clinical experience (see the section "Special Instructions"). Potentially possible influence of an agomelatin on other In vivo medicines агомелатин does not induce P450 cytochrome isoenzymes. Agomelatin does not inhibit an isoenzyme of CYP1A2 in vivo and other isoenzymes of P450 in vitro cytochrome. Therefore агомелатин does not influence concentration of medicines which metabolism is connected with these isoenzymes. The drugs substantially contacting proteins of plasma Agomelatin did not change free concentration of drugs which substantially contact proteins of plasma and, in turn, they did not influence concentration of an agomelatin.
Other medicines
Lack of pharmacokinetic and pharmakodinamichesky interaction of an agomelatin and the drugs which are often applied in target population of patients is revealed: benzodiazepines, drugs of lithium, paroksetin, flukonazol and theophylline.
Alcohol
Use of an agomelatin together with alcohol is not recommended.
Electroconvulsive therapy (EST)
There are no data on use of an agomelatin along with EST. As in animal experiments агомелатин did not promote developing of spasms, undesirable effects of sharing of an agomelatin and EST are represented improbable.

Contraindications:

- Hypersensitivity to an agomelatin and/or any of drug excipients.
- A liver failure (for example, cirrhosis or a disease of a liver in an active phase) (see the sections "Route of Administration and Doses" and "Special Instructions").
- Simultaneous use of powerful inhibitors of an isoenzyme of CYP1A2 (such, as флувоксамин, ciprofloxacin) (see the section "Interaction with Other Medicines and Other Types of Interaction").
- Children's age up to 18 years (due to the lack of sufficient experience of a clinical use). Children and teenagers against the background of reception of other antidepressants have a suicide behavior (attempts of a suicide and suicide thoughts) and hostility (preferential aggression, conflict behavior, irritation) were noted more often in comparison with group of placebo.
It is not necessary to use drug at patients with a lactose intolerance: lactose intolerance, galactosemia and glyukozo-galaktozny malabsorption.
WITH CARE:
Patients of advanced age (65 years are also more senior), at big depressive episodes at patients with the moderated and expressed renal failure, at co-administration of an agomelatin with moderate inhibitors of an isoenzyme CYP1A2 (such as propranolol, грепафлоксацин, эноксацин), patients with maniacal or hypomaniacal episodes in the anamnesis, patients in whose anamnesis there were events connected with a suicide and also the patients who had suicide intentions prior to therapy; treatment of big depressive episodes at elderly patients with dementia (due to the lack of data on efficiency and safety of use of drug for this group of patients).
It is necessary to be careful at purpose of drug to the patients taking alcohol in significant amounts or accepting the drugs capable to cause an abnormal liver function.

PREGNANCY AND PERIOD OF FEEDING BY THE BREAST
Data on use of an agomelatin during pregnancy are absent.
Researches on animals did not reveal straight lines or the mediated harmful effects on the course of pregnancy, development of an embryo and fruit, patrimonial activity and post-natal development. At purpose of drug pregnant women should be careful. It is unknown whether gets агомелатин into breast milk at women in the period of a lactation. In experiments on animals it was shown that агомелатин and its metabolites get into breast milk. If treatment agomelatiny is necessary, breastfeeding should be stopped.

Overdose:

Data on overdose of an agomelatin are limited.
Symptoms: drowsiness, pain in epigastriums, concern, weakness, alarm, agitation, tension, dizziness, cyanosis, an indisposition.
At reception by the patient of an agomelatin in a dose of 2450 mg the state was normalized independently, without disturbances from cardiovascular system or change of laboratory indicators.
Treatment
Specific antidotes for an agomelatin are not known. A symptomatic treatment and monitoring in specialized departments with the subsequent observation.

Storage conditions:

Special storage conditions are not required. To store in places, unavailable to children. PERIOD OF VALIDITY
3 years. NOT to APPLY AFTER the TERMINATION of the PERIOD OF VALIDITY SPECIFIED by NAUPAKOVKE.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 25 mg.
On 14 tablets in the blister (PVC / Is scarlet). On 1, 2, 7 blisters with the instruction on a medical use in a pack cardboard.
On 10 tablets in the blister (PVC / Is scarlet). On 10 blisters with the instruction on a medical use in a pack cardboard.
When packaging (packaging) at the Russian enterprise LLC Serdiks:
On 14 tablets in the blister (PVC / Is scarlet). On 1, 2 blisters with the instruction on a medical use in a pack cardboard.
On 10 tablets in the blister (PVC / Is scarlet). On 10 blisters with instructions on a medical use in a pack cardboard.
Packaging for hospitals:
On 14 tablets in the blister (PVC / Is scarlet). On 7 blisters with the instruction on a medical use in a pack cardboard.