Agomelatine

Active material: Agomelatin
When ATH: N06AX22
CCF: Antidepressant
ICD-10 codes (testimony): F32, F33
When CSF: 02.02.07
Manufacturer: Servier Laboratories (France)

DOSAGE FORM, STRUCTURE AND PACKAGING

Pills, Film-coated orange-yellow, oblong, with the image of a company logo blue on one side.

Excipients: lactose monohydrate, magnesium stearate, corn starch, povidone, colloidal silicon dioxide, sodium carboxymethyl starch, stearic acid, glycerol, gipromelloza, dye iron oxide yellow, macrogol 6000, Titanium dioxide.

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

14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (7) – packs cardboard.
10 PC. – blisters (10) – packs cardboard.

Pharmacological action

Antidepressant, melatonin agonist (MT₁– and MT₂-receptors) and the serotonin antagonist (5-NT_2from-receptors).

Agomelatine is active on validated models of depression (learned helplessness test, despair test, chronic stress moderate severity), on models with heart rhythm desynchronization, as well as in experimental situations of anxiety and stress. Displaying, that agomelatine has no effect on capture monaminov and has no affinity for the α-, b-адренорецепторам, gistaminovym ryetsyeptoram, holinoreceptoram, dopaminovыm and benzodiazepinovыm receptors; This explains the lack of agomelatine typical of other antidepressants side effects on the gastrointestinal tract, sexual function and cardiovascular system.

Agomelatin, antagonistic effects due to the serotonin 5-HT_2from-receptors, increases the release of dopamine and norepinephrine, especially in the area of ​​the prefrontal cortex. In experimental studies on animal models of sleep phase syndrome inhibited (Delayed Sleep Phase Syndrome) the blind and old animals have shown, that agomelatine restores synchronization of circadian rhythms through the stimulation of melatonin receptors. When chronic stress prevents the formation of agomelatine “broken” (fragmented) sleep. In experiments on healthy volunteers, agomelatine does not disturb normal sleep patterns and has beneficial effects on sleep in patients with depression. At therapeutic doses, agomelatine prevented the development of insomnia and memory disorders after taking the drug until morning. Agomelatine is not addictive, that has been shown in a study in healthy volunteers using a visual analogue scale or the Questionnaire of the Research Center for addictions (Addiction Research Center Inventory — ARCI 49 check-list). Agomelatine is also examined for occurrence of the syndrome in patients with depression using a questionnaire, identify signs of withdrawal (Discontinuation Emergent Signs and Symptoms, ITS). Established, that withdrawal symptoms do not develop even when the dramatic treatment.

Agomelatine no effect on body weight.

During the clinical development program of agomelatine investigated its efficacy and safety against the background of major depressive disorder. In a placebo-controlled study examined the comparative 4500 patients, of which 2500 received the drug from 6 weeks to years. Agomelatine was significantly more effective than placebo, wherein the antidepressant effect occurs for 2 weeks (scatter efficiency: from 49.1% to 61% against 34.3-46.3% in the placebo group).

It was also received reliable data on the effectiveness of agomelatine in patients with more severe forms of depression (Hamilton's performance scale ≥25), comprising more than 2/3 Population. Active-controlled studies have confirmed these results.

Agomelatine has also been effective in the initially high levels of anxiety, as well as a combination of anxious and depressive disorders.

The effect of agomelatine on sexual function of patients with depression remmitiruschim course of the disease. The scale used to study the effects of the sexual sphere (Sex Effects Scale — SEXFX). It has been shown, that agomelatine does not cause sexual dysfunction, and does not affect the appearance of arousal and orgasm. Patients with depression, starting from the second week of treatment, agomelatine significantly improves the process of falling asleep, without causing subsequent inhibition day (A questionnaire was used to Leeds - Leeds Questionnaire)

Pharmacokinetics

Absorption

After oral administration, agomelatine is rapidly and well (>80%) absorbed from the gastrointestinal tract. C_max plasma achieved through 1-2 h after administration. Bioavailability of an oral therapeutic dose of about 3% and varies depending on the effect “first pass” through the liver, and individual differences in CYP1A2 activity settings.

When administered in therapeutic doses, the therapeutic drug concentration increased in proportion to dose. Eating (like usual, and high fat) It does not affect the bioavailability, or at the rate of absorption.

Distribution

V_d at steady state was about 35 l. Plasma protein binding – 95% regardless of the drug concentration, age or renal insufficiency.

Metabolism

After oral administration, agomelatine is subjected to rapid oxidation, mainly due to the CYP1A2 (90%) and CYP2C9 (10%).

The major metabolites in the form of a hydroxylated and demethylated agomelatine – not active, quickly bind and excreted in the urine.

Deduction

T_1/2 of plasma is from 1 to 2 no. Excretion is rapid. High and, primarily, metabolic clearance is around 1100 ml / min. Excretion occurs mainly via the urine (80%) and as metabolites. The amount of unchanged drug in the urine slightly. The repeated appointment of the kinetics of the drug does not change.

Pharmacokinetics in special clinical situations

The dependence of the pharmacokinetics of the age was not found.

Because patients with kidney failure are not observed significant changes in the pharmacokinetics of, special selection of doses for this category of patients is not required. When comparing the effect of the drug in healthy volunteers (matched by age, body weight and the number of cigarettes smoked) patients with mild (Class A on Child-Pugh) and moderate (Class B of Child-Pugh) degrees of hepatic failure, the latter, an increase in the duration of drug action when administered at a dose of 25 mg / day. There were no no unusual adverse reactions.

Testimony

- The treatment of major depressive disorder.

Dosage regimen

The drug is prescribed inside.

The recommended dose – 25 mg (1 tab.) 1 time / day in the evening. If necessary,, after two weeks of treatment the dose can be increased to 50 mg (2 tab.) 1 time / day in the evening.

In accordance with the WHO recommendations, depression drug therapy should be, at least, for another 6 months after the termination of a depressive episode.

Agomelatine can be taken regardless of meals. Tablets should be swallowed whole, without chewing.

When pass receiving regular doses, the next time you receive agomelatine to take the usual dose, should not increase the dose of the drug.

To improve the control of the drug on the blister, containing pills, printed Calendar.

Patients with mild to moderate hepatic insufficiency The drug is recommended to appoint a daily dose 25 mg (1 tab.).

Patients with renal insufficiency and elderly patients dose adjustment is not required.

For the cessation of treatment is not necessary to taper.

Side effect

Clinical trials included more agomelatine 4600 patients. More 2400 depressed patients received the drug in doses 25-50 mg / day. At these doses,, short-term placebo-controlled trials, the number of adverse events did not differ from those in the group, placebo. Side effects often were slightly or moderately expressed and observed in the first two weeks of treatment. Frequently observed dizziness, nausea, diarrhea, dryness of the oral mucosa, abdominal pain and itching. The incidence of headache in most cases did not differ from that in the placebo treatment. Side effects were transient and, primarily, did not require discontinuation of treatment.

When short-term placebo-controlled clinical trials, adverse reactions, It is regarded as probably related to treatment at a dose of agomelatine 25-50 mg / day, represented below.

Determination of the frequency of adverse reactions: Often (>1/10), often (> 1/100, < 1/10), sometimes (> 1/1000, <1/100); rarely (> 1/10 000 <1/1000); rarely (<1/10 000).

From the central and peripheral nervous system: often – dizziness (5.4% vs 3.1%); sometimes – paresthesia (0.9% vs 0.1%).

From the digestive system: often – nausea (7.7% vs 7.1%), dry mouth (3.3% vs 3%), diarrhea (2.9% vs 2.2%), epigastric pain (2.3% vs 1.3%); 0.5% – in patients receiving a dose of agomelatine 25-50 mg / day (vs 0.2% placebo) observed transient AST 3 times the ULN. In most cases, these parameters return to normal without treatment discontinuation

Dermatological reactions: often – itch (1.0% vs 0.5%); sometimes – dermatitis (0.5% vs 0.4%), eczema (0.2% vs 0.1%), erythematous rash (0.2% vs lack of response).

On the part of the organ of vision: sometimes – blurred vision (0.6% vs lack of response).

In a double-blind trials of agomelatine more 6 months at doses 25-50 mg / day newly detected frequency of side effects was similar to that compared to placebo. With prolonged use of the drug did not reveal any new adverse effects.

The type and frequency of adverse events did not depend on age and sex of patients.

Contraindications

- Severe hepatic impairment;

- Hypersensitivity to the drug.

Pregnancy and lactation

Minor experience with agomelatine in pregnant women has not shown any side effects on pregnancy, Health fetus or newborn. Currently, other epidemiological data on this subject is not available. In pregnancy, the drug should be used with caution in cases, when the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

Unknown, whether agomelatine is allocated with breast milk in humans. If necessary, use during lactation should stop breastfeeding.

IN experimental studies in animals have not found any direct or indirect harmful effects of the drug on pregnancy, development of an embryo or fetus, labor or postnatal development. Displaying, that agomelatine and its metabolites are excreted in the breast milk of rats.

Cautions

Not recommended simultaneous application of agomelatine with fluvoxamine, which is a potent inhibitor of CYP1A2 and 2C9 and can significantly slow down the metabolism of agomelatine.

As with other antidepressants in the treatment of, should be used with caution in patients with agomelatine or hypomanic episodes of mania in history and should stop taking the drug, If the patient developed symptoms of mania.

Agomelatine does not increase the risk of suicide. But since depression is always a risk of suicide, which may periodically occur until a stable remission, at the beginning of treatment requires very careful monitoring of patients.

When weak (Class A on Child-Pugh) and moderate (Class B of Child-Pugh) degrees of hepatic impairment, an increase in drug exposure.

Since the composition of excipients, agomelatine tablet formulation include lactose, it should not be used in patients, suffering from lactose intolerance as in the congenital form of intolerance, and when lapp lactase deficiency or malabsorption of glucose / galactose.

As with other antidepressants in the treatment of, it is not recommended to combine the drug with alcohol agomelatine.

Use in Pediatrics

We do not recommend the use of the drug in children and adolescents under the age of 18 years due to the lack of sufficient clinical data.

Overdose

In studies in healthy volunteers show, that ingestion agomelatine is well tolerated at a dose of 800 mg / day.

Agomelatine overdose cases are rare. During clinical trials is known about the dose to the reception 300 mg / day to 375 mg / day in combination with other psychotropic drugs. In all these cases are not reported any signs or symptoms of overdose.

Treatment: In case of overdose specific antidotes for agomelatine are not known. Displaying symptomatic therapy and usual for such cases monitored in specialized units.

Drug Interactions

Potential synergies

90% agomelatine is metabolized in the liver with the participation isozymes CYP1A2 and 10% – with the participation of CYP2C9 / 19. Therefore, any preparations, metabolism depends on these isoenzymes, may increase or decrease the bioavailability of agomelatine.

Fluvoxamine, which is a potent inhibitor of CYP1A2 and 2C9, can significantly slow down the metabolism of agomelatine (concurrent use is not recommended).

Paroxetine (an inhibitor of CYP1A2) and fluconazole (a potent inhibitor of CYP2C9) do not violate the pharmacokinetics of agomelatine.

It has been shown, Estrogens, moderate inhibitors of CYP1A2, enhance the effect of agomelatine.

Until, is a therapeutic drug concentration is maintained within the normal variation pharmacokinetics, the dose correction is not required. Smoking increases the effects of CYP1A2, but, as shown, only slightly reduces the duration of agomelatine. Therefore, smokers not necessary to adjust the dose.

Chance of action of agomelatine on other drugs

Agomelatine does not induce or inhibit CYP450 isozymes and therefore does not affect the action of drugs, metabolism which is associated with these isoenzymes. In healthy volunteers, agomelatine does not alter the pharmacokinetics of theophylline (CYP1А2).

Agomelatine does not change the concentration of free drug, are largely bound to plasma proteins, and, in turn, they do not affect the concentrations of agomelatine.

Between lorazepam and no agomelatine pharmacokinetic and pharmacodynamic interaction.

Between drugs lithium and agomelatine there is no pharmacokinetic and pharmacodynamic interaction.

There are no data on the use of agomelatine together with electroconvulsive therapy. Because animal studies, agomelatine showed no predisposing to seizures of properties, unwanted effects of electroconvulsive therapy in their joint application seems unlikely.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children. Special conditions for storage of the drug is not required. Shelf life – 3 year.