Expiration date: 05/2025
Structure and Composition:
Tablets, film-coated. 1 tablet contains agomelatine 25 mg.
Excipients: magnesium stearate, lactose monohydrate corn starch povidone, colloidal silicon dioxide, stearic acid, sodium carboxymethyl glycerol hypromellose dye yellow iron oxide titanium dioxide Macrogol 6000
composition of blue ink: shellac, propylene glycol, indigo carmine aluminum lacquer
Description pharmaceutical form:
Oblong tablets, film-coated, orange-yellow, with the image of the company logo blue on one side.
Pharmacokinetics:
Absorption and bioavailability
After oral administration, agomelatine rapidly (& ge80%) absorbed. Cmax in plasma achieved in 1-2 hours after ingestion. The absolute bioavailability after administration of a therapeutic dose is low (<5%) interindividual variability substantial. Bioavailability is higher for women than for men. The bioavailability is increased by intake of oral contraceptives and reduced by smoking background.
In appointing the therapeutic doses of the drug Cmax increased in proportion to the dosage. At higher doses a more pronounced effect was observed first-pass through the liver. Eating (both regular and high-fat) does not affect the bioavailability or the extent of absorption. Against the background of a meal high in interindividual variability increased fats.
Distribution
Vss was about 35 liters.
Binding to plasma proteins - 95%, regardless of the concentration of the drug, age, or renal insufficiency. When liver failure was noted a doubling of the free fraction of the drug.
Biotransformation
After oral administration, agomelatine is subjected to rapid oxidation, mainly due to the isoenzymes CYP1A2 and CYP2C9. Isozyme CYP2C19 is also involved in the metabolism of agomelatine, but its role is less significant.
The major metabolites in the form of hydroxylated and demethylated agomelatine inactive, rapidly conjugated and excreted by the kidneys.
Breeding
Excretion is rapid. T1 / 2 of plasma is from 1 to 2 hours. Metabolic clearance is about 1100 ml / min. Withdrawal takes place in the kidneys (80%) in the form of metabolites. The amount of unchanged drug in the urine is negligible. With the reappointment of the kinetics of the drug does not change.
Kidney failure
In patients with severe renal insufficiency with single dose of agomelatine 25 mg pharmacokinetic parameters were not significantly changed. Due to the limited clinical experience, caution should be exercised in the appointment of agomelatine in patients with moderate to severe renal insufficiency.
Liver failure
In the appointment of agomelatine 25 mg in patients with mild (Class A according to the classification of Child-Pugh) or moderate (Grade B for the classification of Child-Pugh), chronic liver disease on the background of cirrhosis of the liver showed an increase of its plasma concentrations of 70 and 140 times respectively, compared to volunteers matched for gender, age and attitude to smoking, but without liver failure.
Ethnicity
There are no data on racial differences in pharmacokinetic parameters.
Description of the pharmacological actions:
Agomelatine - agonist melatoninergic MT1 MT2 receptors and an antagonist of the serotonin 5-HT2C receptors.
Agomelatine is an antidepressant active on validated models of depression (learned helplessness test, despair test, chronic stress moderate severity), as well as on models with desynchronization of circadian rhythms, as well as in experimental situations of anxiety and stress. It has been shown that agomelatine has no effect on the capture of monoamines and has no affinity for the alpha, beta adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors.
Agomelatine increases the release of dopamine and norepinephrine, in particular in the area of ??the prefrontal cortex, and will not affect the concentration of extracellular serotonin. In animal experiments with simulated desynchronization of circadian rhythms, it was shown that agomelatine recovers synchronization of circadian rhythms by melatonin receptor stimulation.
Agomelatine helps to restore normal sleep patterns, decrease in body temperature and release of melatonin.
The effectiveness of short-term use of agomelatine (therapy 6-8 weeks) at doses of 25-50 mg in patients with major depressive episodes.
Also shown the efficacy of agomelatine in patients with more severe forms of depression (score on the Hamilton & ge25 scale).
Agomelatine was also effective in initially high levels of anxiety, as well as the combination of anxiety and depressive disorders.
Confirmed supporting the antidepressant effect of agomelatine (for the duration of the study 6 months) at a dose of 25-50 mg 1 time per day.
Results of the study confirmed the efficacy of anti agomelatine, which was estimated at the time to the onset of disease recurrence (p = 0,0001). The frequency of recurrence in the group of patients treated with agomelatine, was 22% in the placebo group - 47%.
Agomelatine no adverse effects on attention and memory in patients with depression, agomelatine 25mg prolong REM sleep phase without changing the number and duration of REM. Admission agomelatine 25 mg also promotes more rapid sleep onset and improve its quality (since the first week of treatment) while inhibition is not observed in the daytime.
While taking agomelatine showed a tendency to decrease in the frequency of sexual dysfunction (effects on arousal and orgasm).
Admission agomelatine has no effect on body weight, heart rate and blood pressure, does not cause sexual dysfunction, does not cause withdrawal symptoms (even with abrupt discontinuation of treatment) and addiction syndrome.
Testimony:
Treatment of major depressive disorder in adults.
Contraindications:
Hypersensitivity to agomelatine, and / or any of the excipients of the drug
hepatic insufficiency (eg cirrhosis or liver disease in the active phase) (see. "Dosage and Administration" and "Cautions")
the simultaneous use of potent inhibitors of CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see. "Interaction")
Children up to age 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 with placebo
Patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption.
Precautions: elderly patients (65 years and older) with major depressive episodes in patients with moderate to severe renal insufficiency, while the appointment of agomelatine with moderate inhibitors of isoenzyme of CYP1A2 (such as propranolol, grepafloksatsin, enoxacin), patients with a manic or hypomanic episodes in the history of the patients, a history of which there were events associated with suicide, as well as patients who had suicidal intentions prior to initiating therapy treatment of major depressive episodes in elderly patients with dementia (due to lack of data on efficacy and safety of the drug in this group patients), patients who use alcohol in large quantities or taking drugs that may cause liver dysfunction.
Application of pregnancy and breastfeeding:
Data on the use of agomelatine during pregnancy are not available.
Animal studies revealed no direct or indirect harmful effects on pregnancy, embryonic and fetal development, generic activities and postnatal development.
In appointing the drug to pregnant women should be careful.
It is not known whether agomelatine passes into breast milk in women during lactation.
In animal experiments it was shown that agomelatine and its metabolites into breast milk.
If agomelatine treatment is necessary, breast-feeding should be discontinued.
Side effect:
In clinical studies, agomelatine received more than 3,900 patients with depression.
Side effects were mostly mild or moderate and expressed observed in the first 2 weeks of treatment. The most frequently observed nausea and dizziness. Reported side effects were usually transient and generally did not require discontinuation of treatment. In some cases, difficult to distinguish between symptoms of depression and side effects of agomelatine.
The frequency of side effects of agomelatine is shown in the following grading: very common (& ge1 / 10), often (& ge1 / 100, <1/10), uncommon (& ge1 / 1000, <1/100), rarely (& ge1 / 10,000, <1 / 1000), very rare (<1/10000), unspecified frequency.
CNS: often - headache, dizziness, somnolence, insomnia, migraine rarely - paresthesia.
On the part of the digestive tract: often - nausea, diarrhea, constipation, abdominal pain.
Co Hepatobiliary system: often - increased ALT and / or AST (to more than 3 times compared to the ULN in patients receiving agomelatine in 1.3% of patients and 0.7% for placebo background), rarely - hepatitis, increased activity GGT * (more than 3 times compared to the ULN), increased ALP activity * (more than 3 times compared to the ULN).
Skin and subcutaneous tissue: often - sweating rarely - eczema, pruritus * rare - erythematous rash.
On the part of the organ of vision: rarely - blurred vision.
From the musculoskeletal system: often - back pain.
General disorders: often - fatigue.
Psychiatric disorders: often - anxiety seldom - agitation and symptoms associated with it *, such as irritability and restlessness, aggression *, nightmares *, abnormal dreams * rare - mania / hypomania *, these symptoms can also be a manifestation of the underlying disease (see. "Special instructions") hallucinations * unspecified frequency - suicidal thoughts or suicidal behavior (see "Special instructions")..
* Evaluation of the frequency of adverse reactions identified by spontaneous reports, carried out on the basis of clinical studies.
Drug Interactions:
Potentially the possible influence of other drugs. Agomelatine 90% is metabolized in the liver with the cytochrome P450 isoenzyme 1A2 (CYP1A2) and 10% - using CYP2C9 / 19. Therefore, any drugs which metabolism depends on these isoenzymes may increase or decrease the bioavailability of agomelatine.
Fluvoxamine is a potent inhibitor of CYP1A2 isoenzyme and a moderate inhibitor of CYP2C9 isoenzymes and significantly slows down the metabolism of agomelatine, with agomelatine increases the concentration of about 60 (12-412) times. Therefore, concurrent use of agomelatine and strong inhibitors of CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated. Simultaneous administration of agomelatine and estrogen that are moderate inhibitors isoenzyme CYP1A2, increases the concentration of the agomelatine several times. Although the combined use of agomelatine and estrogen was not associated with worsening of the profile of the therapy safety, caution should be exercised with concomitant administration of agomelatine with other moderate inhibitors of isoenzyme of CYP1A2 (such as propranolol, grepafloksatsin, enoxacin) until the accumulation of sufficient clinical experience (see. "Special Instructions").
Potentially the possible influence of agomelatine on other drugs. In vivo, agomelatine does not induce cytochrome P450 isoenzymes. Agomelatine inhibits the isoenzyme CYP1A2 in vivo and other isozymes of cytochrome P450 in vitro. Therefore, agomelatine has no effect on the concentration of drug whose metabolism is associated with these isoenzymes.
Drugs that bind to a large extent to plasma proteins. Agomelatine did not alter the free concentration of the drug, which is largely bound to plasma proteins and, in turn, they do not affect the concentration of the agomelatine.
Other drugs. The absence of pharmacokinetic and pharmacodynamic interaction between agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium, drugs, paroxetine, fluconazole and theophylline.
Alcohol. We do not recommend the use of agomelatine together with alcohol.
Electroconvulsive therapy (ECT). There are no data on the use of agomelatine with ECT simultaneously. Because animal studies, agomelatine has not contributed to the occurrence of seizures, adverse effects of agomelatine with ECT sharing seems unlikely.
Dosage and administration:
Inside, swallowing whole, without chewing, regardless of the meal.
Omitting receiving regular doses of the drug at the time of the next dose agomelatine is accepted in the usual dose (not to be added to take the missed dose).
To improve the control of the patient taking the drug, on the blister containing the tablets, imprinted calendar.
The recommended daily dose - 25 mg (1 tab.) Once in the evening. In the absence of clinical dynamics after two weeks of treatment dose can be increased to 50 mg (Table 2. 25 mg) once in the evening.
It is recommended to monitor liver function at initiation of therapy and periodically thereafter, 3, 6 (end of acute treatment period), 12, and 24 weeks (end of maintenance phase treatment) after the start of therapy in the future according to the clinical situation.
Depression Drug therapy should be carried out for at least 6 months for a full cessation of symptoms.
Discontinuation of treatment
Upon termination of treatment no need for a gradual reduction in the dose.
Overdose:
Data on agomelatine overdose is limited.
Symptoms: drowsiness, epigastric pain, anxiety, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise.
Upon receipt of the patient in a dose of agomelatine 2450 mg of state returned to normal on their own, without any violations by the CCC or changes in laboratory parameters.
Treatment: specific antidotes for agomelatine are unknown. Recommended symptomatic treatment and monitoring of specialized departments to follow-up.
Special instructions:
Elderly patients
The effectiveness of the drug in elderly patients (aged 65 years and older) is not installed. There are limited data on the use of the drug agomelatine in major depressive episodes in patients aged 65 years and older. In appointing the drug elderly patients should be cautious.
Patients with renal failure
In patients with severe renal failure significant change in pharmacokinetic parameters was observed. However, experience with agomelatine drug in major depressive episodes in patients with moderate to severe renal insufficiency is limited. In appointing the drug agomelatine such patients should use caution.
Bipolar disorder / mania / hypomania
Caution should be exercised when using the drug agomelatine in patients with bipolar disorder, manic or hypomanic episodes in history. When 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). The risk persists until the distinct remission. Patients should be under medical supervision until improvement (it may take several weeks after initiation of therapy before the condition improves). Clinical experience suggests that the risk of suicide may increase in the early stages of remission.
Patients with a history of events were associated with suicide, and patients who had suicidal intentions prior to initiating therapy, 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 of the need for immediate treatment to the doctor when deterioration, suicidal behavior, and unusual, as well as the emergence of suicidal thoughts.
The combined use of inhibitors of the CYP1A2 isoenzyme
Caution must be exercised with concomitant use of agomelatine with moderate inhibitors of CYP1A2 isoenzyme (such as propranolol, grepafloxacin, enoxacin) due to the possibility of increasing the concentration of the agomelatine (see. "Interaction").
