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Pharmacological properties

mechanism of action. agomelatine is a melatonergic agonist of mt1 and mt2 receptors and an antagonist of 5-ht2c receptors. studies in which the binding of agomelatine to receptors was studied showed that agomelatine does not affect the uptake of monoamines and does not have affinity for α- and β-adrenergic, histaminergic, cholinergic, dopaminergic, benzodiazepine receptors.

Agomelatine resynchronizes circadian rhythms, according to experimental studies in animals with circadian rhythm disorders.

Agomelatine increases the release of dopamine and norepinephrine specifically in the frontal cortex and does not affect extracellular serotonin levels.

Pharmacodynamic effects. Agomelatine in experimental studies (in animals) showed an antidepressant effect on validated models of depression (test of hopelessness, despair, chronic mild stress), as well as on models with circadian rhythm desynchronization and models related to stress and anxiety.

When used in humans, Melitor resynchronizes circadian rhythms; it restores the phase of sleep, leads to a decrease in body temperature and promotes the secretion of melatonin.

Clinical efficacy and safety. The efficacy and safety of Melitor in the treatment of major depressive episodes was investigated in a clinical program involving 7900 patients treated with Melitor.

In 6 short-term, double-blind, placebo-controlled studies evaluating the effectiveness of Melitor in treating large depressive episodes of adult patients, agglomeatin in doses of 25-50 mg at the end of therapy (for 6-8 weeks) showed statistically significant efficacy compared with placebo. According to the results of the assessment on the HAMD-17 scale, changes in the value of the primary endpoint indicator compared with the initial level were noted.

The efficacy of Melitor was also demonstrated in patients with more severe depression (initial HAMD score ≥25) according to the results of all positive placebo-controlled studies.

The response to treatment with the use of the drug Melitor was statistically significantly higher compared with placebo.

6 out of 7 studies examining the effectiveness of Melitor in heterogeneous populations of adult patients with depression showed higher (2 studies) or similar efficacy (4 studies) of the latter compared to a selective serotonin reuptake inhibitor / selective serotonin-norepinephrine reuptake inhibitor (SSRI / SSRI) (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The antidepressant effect was evaluated on a HAMD-17 scale (primary or secondary endpoints).

The long-term antidepressant efficacy of agomelatine was demonstrated in a study investigating the prevention of relapses. According to the results of the impact on the primary endpoint — the prevention of the onset of depression relapse, which was measured by the time before the onset of relapse, Melitor at a dose of 25–50 mg / day showed a statistically significant advantage compared with placebo (p = 0.0001). The frequency of occurrence of relapse during 6 months of double-blind observation was 22 and 47%, respectively, for agomelatine and placebo.

The drug does not affect the daily care and memory of healthy volunteers. In patients with depression, treatment with Melitor prolonged the phase of slow wave sleep without affecting the phase or latent period of REM sleep. Melitor 25 mg also reduces the time to sleep (facilitates falling asleep) and achieving a minimum heart rate. From the 1st week of treatment, an acceleration of falling asleep and an improvement in sleep quality without disturbances in daytime activity (according to patients) were noted.

A pooled analysis of studies on the ASEX (Arizona Sexual Experience Scale) rating scale showed that Melitor was not associated with sexual dysfunction. In healthy volunteers, Melitor retained sexual function compared to paroxetine.

Melitor does not affect heart rate and blood pressure (according to the results of clinical studies).

In a study planned to study withdrawal symptoms using the DESS questionnaire (Discontinuation Emergent Signs and Symptoms), in patients with depression in remission, Melitor did not cause withdrawal symptoms after the therapy was suddenly stopped.

Melitor does not cause dependence in healthy volunteers according to test results using a visual-analogue scale or an ARCI questionnaire (Addiction Research Center Inventory) of 49 questions.

A placebo-controlled study of the use of agomelatine at a dose of 25-50 mg / day for 8 weeks with elderly patients with depression (≥65 years old, n = 222, 151 of whom used agomelatine) showed a statistically significant difference of 2.67 points in total HAM-D scale (primary endpoint). The level of response to treatment was positive for agomelatine. In the group of patients aged ≥75 years (n = 69, 48 of whom used agomelatine), no reliable results were obtained on improving the condition. Agomelatine tolerance in elderly patients was similar to that observed in adult patients younger in age.

A special, controlled, 3-week study was conducted with patients with major depressive disorders who did not achieve significant improvement with paroxetine (SSRIs) or venlafaxine (SSRIs). When these patients were transferred to agomelatine treatment, regardless of whether the previous therapy was terminated abruptly or gradually, withdrawal symptoms occurred. These symptoms may erroneously be regarded as a failure of the early effect of agomelatine.

The proportion of patients with at least one withdrawal symptom within 1 week after discontinuation of the SSRI / SSRI group antidepressants was less in the group of patients with a prolonged dose reduction (gradual termination of the previous antidepressant drugs within 2 weeks) than in the group of patients with a short-term dose reduction (gradual cessation of the previous administration of antidepressants within 1 week) and a group of patients with a sharp change in treatment (abrupt cessation of administration): 56.1; 62.6 and 79.8%, respectively.

Pharmacokinetics Absorption and bioavailability. Agomelatine is rapidly and well absorbed (≥80%) after oral administration. Cmax in blood plasma is achieved within 1-2 hours after taking agomelatine. Absolute bioavailability is low (5%) when administered orally in a therapeutic dose, individual fluctuations can be significant.

Bioavailability in women compared with men is higher. Bioavailability increases with the use of oral contraceptives and decreases in smokers.

When used in therapeutic doses, the concentration of agomelatine increases in proportion to the increase in dose. When used in higher doses, the effect of saturation with the first dose occurs.

Eating (regular or high fat) does not affect bioavailability or absorption.

When eating foods high in fat, the likelihood of concentration fluctuations increases.

Distribution in tissues. The volume of distribution in equilibrium is about 35 l; binding to plasma proteins - 95%, regardless of the concentration of the active substance. This indicator does not change with age, and even in patients with impaired renal function, but the concentration of the free fraction doubles in patients with impaired liver function.

Biotransformation. After use, agomelatine is rapidly metabolized, mainly by the hepatic enzymes CYP 1A2; isoenzymes CYP 2C9 and CYP 2C19 are also involved in metabolism, but their contribution is very small. The main metabolites in the form of hydroxylated and dimethylated agomelatine are inactive, quickly conjugated and excreted in the urine.

Excretion is fast, T½ from plasma, an average of 1-2 hours. The clearance is high (about 1,100 ml / min) and is mainly associated with the excretion of metabolites.It is excreted mainly in urine (80%) in the form of metabolites. The amount excreted in the urine of the active substance in unchanged form is negligible. Pharmacokinetics does not change after repeated use.

Patients with impaired renal function. Significant changes in the pharmacokinetic parameters of agomelatine were not observed in patients with severe impaired renal function (n = 8, a single dose of 25 mg), but patients with impaired renal function of severe or moderate degree should be prescribed with caution due to the limited amount of clinical data on the use of drug in patients of this group (see. APPLICATION).

Patients with impaired liver function. A special study involving patients with cirrhosis of the liver, chronic impaired liver function of mild or moderate severity (type A and B according to the Child-Pugh classification) showed an increase in the concentration of agomelatine, which was used at a dose of 25 mg (70 and 140 times, respectively), compared with volunteers with appropriate age, body weight and smoking habit without impaired liver function (see APPLICATION, CONTRAINDICATIONS and SPECIAL INSTRUCTIONS).

Elderly patients. A pharmacokinetic study involving elderly patients (≥65 years old) showed that with a dose of 25 mg, the average values ​​of AUC and Cmax were approximately 4 and 13 times higher in patients aged ≥75 years compared with patients aged 75 years. It is impossible to evaluate the pharmacokinetics of agomelatine when used at a dose of 50 mg in this population due to insufficient data. Elderly patients do not require dose adjustment.

Ethnic groups. There are no data on the pharmacokinetics of agomelatine depending on race.

Indications

Treatment of major depressive episodes in adults.

Application

For oral use.

Melitor, film-coated tablets can be used regardless of food intake.

Dosage. The recommended dose is 1 tablet of 25 mg once a day before bedtime.

If 2 weeks after the start of therapy, the improvement in the clinical condition is insufficient, the dose can be increased to 50 mg once a day, that is, 2 tablets of 25 mg, which must be taken at bedtime.

In deciding whether to increase the dose, the increased risk of increased transaminases should be considered. Increasing the dose to 50 mg must be carried out individually for each patient after evaluating the benefit / risk indicator with mandatory liver tests.

All patients must undergo liver tests before starting treatment. Treatment should not be started if the level of transaminases in the blood plasma exceeds the norm by 3 times (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS).

During treatment, it is necessary to periodically monitor the level of transaminases in the blood plasma: after about 3 weeks, 6 weeks (end of the active phase), after 12 and 24 weeks (end of the phase of maintenance therapy), and then when it is clinically necessary (see SPECIAL INSTRUCTIONS). Treatment should be discontinued if an increase in plasma transaminases reaches 3 times the normal level (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS).

With an increase in dose, hepatic tests should be carried out again with the same frequency as at the beginning of treatment.

Duration of treatment. Patients with depression should be treated for at least 6 months to ensure that the symptoms of depression have disappeared.

Transition from SSRIs antidepressant therapy / serotonin and norepinephrine reuptake inhibitors (IZSN) to agomelatine. Patients may experience withdrawal symptoms after discontinuation of the SSRI / SSRI antidepressant group.In order to avoid the appearance of these symptoms, it is necessary to take into account the recommendations for discontinuing treatment, which are contained in the instructions of the drug used by the patient. Agomelatine therapy can be started immediately in parallel with a reduction in the dose of an antidepressant (see Pharmacodynamics).

Discontinuation of treatment. Upon termination of treatment, there is no need for a gradual dose reduction.

Special patient groups

Elderly patients. The safety and effectiveness of agomelatine (25–50 mg / day) have been proven for elderly patients with depression (75 years). In the group of patients aged ≥75 years, no reliable results were obtained. Therefore, patients of this age group are not recommended to use agomelatine (see SPECIAL INSTRUCTIONS and Pharmacodynamics). There is no need for dose adjustment depending on age (see Pharmacokinetics).

Patients with impaired renal function. Significant changes in the pharmacokinetic parameters of agomelatine were not observed in patients with severe impaired renal function. However, the amount of clinical data regarding the use of Melitor in patients with severe or moderate renal impairment is limited. Therefore, such patients should be prescribed Melitor with caution.

Patients with impaired liver function. The use of the drug Melitor is contraindicated in patients with impaired liver function (see CONTRAINDICATIONS, SPECIAL INDICATIONS and Pharmacokinetics).

Contraindications

Hypersensitivity to the active substance or any auxiliary substance of the drug;

  • impaired liver function (cirrhosis of the liver or the active phase of liver disease) or an increase in the level of transaminases by more than 3 times compared with the upper limit of the norm (see APPLICATION and SPECIAL INSTRUCTIONS);
  • use in combination with highly active CYP 1A2 inhibitors (ciprofloxacin, fluvoxamine) (see INTERACTIONS).

Side effects

Security Profile Summary. in clinical trials, melitor was used in more than 8,000 depressed patients. adverse reactions usually occurred during the first 2 weeks of treatment and were mild or moderate. the most common adverse reactions were headache, nausea, and dizziness. these adverse reactions were usually temporary and, as a rule, did not lead to discontinuation of therapy.

List of adverse reactions

The following table contains adverse reactions identified during placebo-controlled clinical trials and studies using active control.

Adverse reactions are indicated with such a frequency of occurrence: very often (≥1 / 10); often (from ≥1 / 100 to 1/10); infrequently (from ≥1 / 1000 to 1/100); rarely (from ≥1 / 10,000 to 1/1000); very rarely (1/10 000); the frequency is unknown (cannot be determined from the available data). The frequency has not been adjusted for the placebo group.

Organ System Classification Frequency Adverse reaction
From the psyche Often Anxiety
Unusual Dreams *
Infrequently Suicidal thoughts or behavior (see SPECIAL INSTRUCTIONS)
Agitation and its associated symptoms * (such as irritability and anxiety)
Aggressiveness*
Nightmares *
Mania / hypomania *

These symptoms may be due to the disease (see SPECIAL INSTRUCTIONS)

Confusion *
Rarely Hallucinations *
From the nervous system Often Headache
Often Dizziness
Drowsiness
Insomnia
Infrequently Migraine
Paresthesia
Restless Leg Syndrome *
Rarely Akathisia *
On the part of the organ of vision Infrequently Blurred vision
On the part of the organ of hearing and the vestibular apparatus Infrequently Tinnitus*
From the gastrointestinal tract Often Nausea
Diarrhea
Constipation
Abdominal pain
Vomiting *
From the hepatobiliary system Often An increase in the level of AlAT and / or AsAT (in clinical studies, an increase in the level of AlAT and / or AsAT by more than 3 times from the upper limit of the norm was observed in 1.2% of patients receiving agomelatine at a dose of 25 mg / day, and in 2.6% patients receiving agomelatine at a dose of 50 mg / day, compared with 0.5% of patients receiving placebo)
Infrequently Increased levels of gamma-glutamyltransferase * (GGT) (more than 3 times from the upper limit of normal)
Rarely Hepatitis
Increased alkaline phosphatase * (more than 3 times from the upper limit of normal)
Liver failure*(1)
Jaundice*
On the part of the skin and subcutaneous tissue Infrequently Hyperhidrosis
Eczema
Itching *
Hives*
Rarely Erythematous rashes
Facial edema and angioedema *
From the musculoskeletal system and connective tissue Often Backache
From the urinary system Rarely Urinary retention *
General disorders and reactions at the injection site Often Fatigue
Laboratory Results Often Weight gain *
Infrequently Weight loss *

* The frequency of manifestations of adverse reactions identified using spontaneous messages, calculated according to clinical studies.

(1)Isolated lethal cases or cases of liver transplantation have been reported in patients with risk factors for impaired liver function.

Suspect Report

Tags: Agomelatine