Expiration date: 09/2027
The dosage form
is round biconvex film-coated tablets from light yellow to brownish yellow in color. Two layers are visible on the cross-section of the tablet: a white or almost white core and a film shell.
Composition
1 tablet contains:
Active ingredient: agomelatine - 25.00 mg.
Excipients: lactose monohydrate (milk sugar) - 61.84 mg, corn starch - 26.00 mg, povidone-K30 - 9.10 mg, sodium carboxymethyl starch - 3.90 mg, stearic acid - 2.60 mg, magnesium stearate - 1.30 mg, colloidal silicon dioxide - 0.26 mg. Shell composition: hypromellose - 3.00 mg, titanium dioxide - 0.82 mg, macrogol-4000 - 0.50 mg, iron oxide yellow dye - 0.18 mg.
Pharmacotherapeutic group
antidepressant
Pharmacodynamics
Agomelatine is an agonist of the melatonergic MT1 and MT2 receptors and an antagonist of the serotonin 5-HT2C receptors. Agomelatonin is an antidepressant active in validated models of depression (acquired helplessness test, despair test, moderate chronic stress), as well as in models with desynchronized circadian rhythms, as well as in experimental situations of anxiety and stress. Agomelatine has been shown to have no effect on monoamine uptake and has no affinity for alpha-, beta-adrenergic, histaminergic, cholinergic, dopaminergic, or benzodiazepine receptors.
Agomelatine enhances the release of dopamine and norepinephrine, especially in the prefrontal cortex of the brain and does not affect the concentration of extracellular serotonin. In animal experiments with desynchronization of circadian rhythms, it has been shown that agomelatin restores synchronization of circadian rhythms by stimulating melatonin receptors.
Agomelatine helps to restore the normal structure of sleep, reduce body temperature and release melatonin.
The effectiveness of short-term use of agomelatin (6-8 weeks therapy) at doses of 25-50 mg in patients with major depressive episodes has been shown.
Agomelatin has also been shown to be effective in patients with more severe forms of depressive disorder (Hamilton scale score > 25).
Agomelatine was also effective in initially high levels of anxiety, as well as in a combination of anxiety and depressive disorders.
The supportive antidepressant effect of agomelatine (with a study duration of 6 months) at a dose of 25-50 mg once a day was confirmed. The results of the study confirmed the anti-relapse efficacy of agomelatin, which was assessed by the time of onset of disease recurrence (p = 0.0001). The recurrence rate in the group of patients taking agomelatin was 22%, in the placebo group - 47%.
The efficacy of agomelatin has been demonstrated in 6 out of 7 clinical trials (predominantly 2 studies), or comparable efficacy (4 studies) in heterogeneous populations of adult patients with depression, compared with SSRIs/SSRIs (selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors) (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The antidepressant effect was assessed on the Hamilton scale (17-point version) as either the primary or secondary endpoint.
Agomelatine did not have a negative effect on mindfulness and memory; in patients with depression, agomelatine at a dose of 25 mg increased the duration of the slow-wave sleep phase without changing the number and duration of REM sleep phases. Taking agomelatine at a dose of 25 mg also promotes a faster onset of sleep with a decrease in heart rate (HR) and an improvement in sleep quality (starting from the first week of treatment); at the same time, daytime lethargy is not noted.
Against the background of the use of agomelatine, there was a tendency to decrease the frequency of sexual dysfunction (effects on arousal and orgasm).
The use of agomelatin has no effect on heart rate and blood pressure, does not cause sexual disorders, does not cause "withdrawal" syndrome (even with abrupt discontinuation of treatment) and "addictive" syndrome.
The efficacy of agomelatin at a dose of 25-50 mg once a day was confirmed in elderly patients with depression younger than 75 years during an 8-week clinical trial. There is no confirmed evidence of a significant effect in patients aged 75 years and older.
The tolerance of agomelatine in elderly patients is comparable to that in younger patients.
During a 3-week clinical trial involving patients with major depressive disorder and insufficient therapeutic effect from the use of paroxetine (SSRIs) or venlafaxine (SSRIs), a withdrawal syndrome was observed during the transition from therapy with these antidepressants to treatment with agomelatin. The "withdrawal" syndrome appeared both after the simultaneous discontinuation of treatment with previously prescribed SSRIs /SSRIs, and with their gradual withdrawal, which could be mistaken for the manifestation of low efficacy of agomelatin at the initial stage of treatment.
The number of patients who had at least one withdrawal-related symptom a week after SSRI/SSRI withdrawal was lower in the group of patients with prolonged dosage reduction (gradual dose reduction of SSRIs/SSRIs for 2 weeks) than in the group with rapid dosage reduction, or than with simultaneous withdrawal: 56.1%, 62.6% and 79.8%, respectively.
Pharmacokinetics
Absorption and bioavailability
After oral administration, agomelatin is rapidly (> 80%) absorbed.
Maximum
The concentration (Cmax) in blood plasma is reached 1-2 hours after ingestion. Absolute bioavailability after oral administration of the therapeutic dose is low (< 5%); interindividual variability is significant. Bioavailability is higher in women than in men. Bioavailability increases with the use of oral contraceptives and decreases with smoking.
When using therapeutic doses, the Cmax in blood plasma increases proportionally to the dose. When taking higher doses, there is a more pronounced effect of "primary passage" through the liver. Simultaneous intake with food (both regular and high-fat) does not affect either bioavailability or the degree of absorption. Against the background of high-fat meals, the interindividual variability of indicators increases.
Distribution
The volume of distribution in the equilibrium phase is about 35 liters.
The binding to plasma proteins is 95%, regardless of the concentration of agomelatine, age, or the presence of impaired renal function. With impaired liver function, there is a twofold increase in the free fraction of agomelatine.
Metabolism
After oral administration, agomelatine undergoes rapid oxidation, mainly due to the isoenzymes CYP1A2 and CYP2C9. The CYP2C19 isoenzyme 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, bind quickly and are excreted by the kidneys.
Withdrawal
Withdrawal is fast. The half-life from the blood plasma is from 1 to 2 hours. The metabolic clearance is about 1100 ml/min. Excretion mainly occurs by the kidneys (80%) in the form of metabolites. The amount of unchanged agomelatine in urine is insignificant. With repeated use of the drug, the kinetics does not change.
Impaired renal function
In patients with severe renal insufficiency, the pharmacokinetic parameters did not significantly change with a single dose of agomelatin 25 mg. Due to limited clinical experience, caution should be exercised when using agomelatin in patients with moderate to severe renal insufficiency.
Liver function disorders
When using agomelatin at a dose of 25 mg in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) chronic liver failure on the background of liver cirrhosis, an increase in its concentration in blood plasma was noted by 70 and 140 times, respectively, compared with healthy volunteers., comparable in gender, age, and attitude to smoking, but without liver failure.
Elderly patients
When agomelatin was administered at a dose of 25 mg to elderly patients aged 65 years and older, it was noted that the average AUC (area under the concentration-time curve) and average Cmax were 4 times and 13 times higher, respectively, in patients aged 75 years and older, compared with patients younger than 75 years old. The total number of patients receiving 50 mg of agomelatine was too low to draw any conclusions. No dose adjustment is required depending on the patient's age.
Race
Indications
Treatment of major depressive disorder in adults .
Contraindications
- Hypersensitivity to agomelatine and / or any of the excipients included in the preparation;
- Impaired liver function (for example, cirrhosis or liver disease in the active phase) or an increase in the level of transaminases by more than 3 times relative to the upper limit of normal (ULN) (see sections "Dosage and administration" and "Special instructions");
- Simultaneous use of powerful inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) (see the section "Interaction with other drugs");
- Children under 18 years of age (due to lack of sufficient clinical experience). In children and adolescents with other antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggression, conflict behavior, irritation) were more common compared with the placebo group.;
- Lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.
With caution: use in patients with moderate to severe renal
insufficiency in the treatment of major depressive episodes; with the simultaneous use of agomelatin with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin); in patients with a history of manic or hypomanic episodes; in patients with a history of suicide-related events, as well as in patients who had suicidal intentions before starting therapy.
The drug should be used with caution in patients who abuse alcohol or take medications that may cause liver dysfunction.
Use during pregnancy and lactation
Pregnancy
Data on the use of agomelatine during pregnancy are missing or limited (less than 300 pregnancy outcomes).
Animal studies have not revealed direct or indirect harmful effects on the course of pregnancy, the development of the embryo and fetus, labor and postnatal development.
As a precautionary measure, it is recommended to avoid using Agomelatin during pregnancy.
Breastfeeding period
It is unknown whether agomelatin is excreted in breast milk.
Animal experiments have shown that agomelatine and its metabolites enter the milk of lactating animals. The risk to the newborn/child cannot be excluded.
It is necessary to evaluate the importance of breastfeeding for the child and therapy for the mother and decide whether to stop breastfeeding or discontinue the use of the drug.
Fertility
Reproductive studies in rats and rabbits have not shown a significant effect of agomelatin on fertility.
Method of administration and dosage
Inside.
The drug Agomelatin can be taken regardless of the meal time. The tablet should be swallowed whole without chewing.
If you miss taking the next dose of the drug, Agomelatin is taken at the usual dose during the next dose (you should not take the missed dose). The recommended daily dose is 25 mg (1 tablet) once before bedtime. In the absence of clinical dynamics after two weeks of treatment, the dose can be increased to 50 mg (2 tablets of 25 mg) once before bedtime.
The decision to increase the dose should be made taking into account the increasing risk of increased activity of "liver" transaminases. Any increase in the dose of the drug to 50 mg should be made based on an assessment of the benefit-risk ratio for a particular patient and with strict monitoring of liver tests.
Before starting therapy, functional liver tests should be performed in all patients. Therapy cannot be initiated in patients with activity of "hepatic" transaminases more than 3 times higher than the upper limit of the norm (see sections "Contraindications", "Special instructions"). During treatment, liver function should be monitored periodically, approximately 3 weeks later, approximately 6 weeks (the end of the relief period of therapy), approximately 12 and 24 weeks (the end of the maintenance period of therapy) after the start of therapy, and thereafter in accordance with the clinical situation (see section "Special instructions"). If the activity of "hepatic" transaminases is more than 3 times higher than the ULN, Agomelatin should be discontinued (see sections "Contraindications", "Special instructions").
When increasing the dose, liver function should be monitored with the same frequency as at the beginning of taking the drug.
Duration of therapy
Drug therapy for depression should be carried out for at least 6 months until the symptoms of depression disappear completely.
Transition from SSRI/SSRI therapy to agomelatin therapy
It is possible to develop a "withdrawal syndrome" after discontinuation of treatment with previously prescribed SSRIs / SSRIs, it is necessary to follow the instructions for the medical use of these drugs.
Agomelatin can be started from day 1 of a gradual reduction in the dose of SSRI/SSRI antidepressants (see section "Pharmacodynamics").
Discontinuation of treatment
If treatment is discontinued, there is no need to gradually reduce the dose.
Special patient groups Elderly patients
The efficacy and safety of agomelatin (at a dose of 25-50 mg per day) has been confirmed in elderly patients with depression younger than 75 years. There is no confirmed evidence of a significant effect in patients 75 years of age and older. In this regard, Agomelatin should not be used in patients of this age group (see sections "Pharmacological properties", "Special instructions"). No age-related dose adjustment is required (see sections "Pharmacological properties").
Patients with impaired renal function In patients with severe renal insufficiency, there was no significant change in pharmacokinetic parameters. The experience of using agomelatin preparations in major depressive episodes in patients with moderate to severe renal insufficiency is limited. Caution should be exercised when using Agomelatin in such patients (see section "Special instructions"). Patients with impaired liver function
The use of Agomelatin in patients with impaired liver function is contraindicated (see sections "Contraindications", "Special instructions", "Pharmacokinetics").
Side effects
In clinical trials, 8,000 depressed patients received agomelatin. Side effects were most often mild or moderate and were observed in the first two weeks of therapy. The most common symptoms were headache, nausea, and dizziness. Usually, side effects were usually transient and generally did not require discontinuation of therapy.
The following are data on side effects observed in placebo-controlled and comparative clinical trials.
Side effects are systematized for each organ system depending on the frequency of occurrence using the World Health Organization classification: very common (>1/10), common (>1/100), infrequent (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000, including isolated cases), the frequency is unknown (insufficient data to estimate the frequency of development).
Disorders of the nervous system: very often - headache; often -dizziness, drowsiness, insomnia; infrequently - migraine, paresthesia, restless legs syndrome*; rarely - akathisia*.
Disorders of the gastrointestinal tract: often - nausea, diarrhea, constipation, abdominal pain, vomiting* .
Liver and biliary tract disorders: often - increased activity of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (more than 3 times higher than ULN in 1.2% of patients with agomelatine at a dose of 25 mg per day and in 2.6% of patients with agomelatine at a dose of 50 mg per day day, compared with 0.5% on placebo in clinical trials); infrequently - increased activity of y-glutamyltransferase (more than 3 times compared with ULN); rarely - hepatitis, increased alkaline phosphatase activity * (more than 3 times higher than ULN), liver failure* (1), jaundice*.
Disorders of the skin and subcutaneous tissues: infrequently - increased sweating, eczema, pruritus*, urticaria*; rarely - erythematous rash, facial edema and angioedema (angioedema)*.
Hearing disorders and labyrinthine disorders: infrequently - tinnitus*.
Visual disturbances: infrequently - blurred vision.
Musculoskeletal and connective tissue disorders: often - back pain. Disorders of the kidneys and urinary tract: rarely - urinary retention*.
General disorders and disorders at the injection site: often - increased fatigue.
Psychiatric disorders: often - anxiety, unusual dreams*; infrequently - suicidal thoughts or suicidal behavior (see section "Special instructions"), agitation and related symptoms* (such as irritability and anxiety), aggressiveness*, nightmares*, mania/hypomania* (these symptoms may be also a manifestation of the underlying disease (see section "Special instructions")), confusion*; rarely - hallucinations* .
Metabolic and nutritional disorders: often - weight gain*; infrequently - weight loss*.
* The frequency of adverse reactions identified by spontaneous reports was assessed based on the results of clinical trials.
(1) Only a few cases of death or liver transplantation have been reported in patients with pre-existing risk factors for liver damage.
Overdose
Data on agomelatine overdose are limited.
Symptoms: drowsiness, epigastric pain, restlessness, weakness, anxiety, agitation, tension, dizziness, cyanosis, malaise.
When the patient took agomelatine at a dose of 2450 mg, the condition returned to normal on its own, without disturbances from the cardiovascular system or changes in laboratory parameters.
Treatment: there is no specific antidote. Symptomatic treatment and monitoring in specialized institutions with follow-up.
Drug interaction
Potential effects of other drugs
Agomelatin is 90% metabolized in the liver with the participation of cytochrome P450 1A2 isoenzymes (CYP1A2 isoenzyme) and 10% with the help of CYP2C9/19 isoenzymes. Therefore, any drugs whose metabolism depends on these isoenzymes can increase or decrease the bioavailability of agomelatine.
Fluvoxamine is a potent inhibitor of the CYP1A2 isoenzyme and a moderate inhibitor of the CYP2C9 isoenzyme and significantly slows down the metabolism of agomelatin, while the concentration of agomelatin increases by an average of 60 (12-412) times. Therefore, the simultaneous use of agomelatine and strong inhibitors of the CYP1A2 isoenzyme (such as fluvoxamine, ciprofloxacin) is contraindicated. The simultaneous use of agomelatine and estrogens, which are moderate inhibitors of the CYP1A2 isoenzyme, leads to an increase in the concentration of agomelatine in blood plasma several times. Although the simultaneous use of agomelatine and estrogens was not accompanied by a deterioration in the safety profile of the therapy, caution should be exercised when agomelatine is co-administered with other moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) until sufficient clinical experience is gained (see section "Special instructions"). Rifampicin, as an inducer of all three isoenzymes involved in agomelatine metabolism, may reduce the bioavailability of agomelatine.
It has been shown that smoking, by inducing the CYP1A2 isoenzyme, reduces the bioavailability of agomelatine, especially in patients who abuse smoking (> 15 cigarettes per day) (see section "Pharmacokinetics").
Potential effect of agomelatin on other drugs In vivo, agomelatin does not induce cytochrome P450 isoenzymes. Agomelatin does not inhibit the CYP1A2 isoenzyme in vivo and other cytochrome P450 isoenzymes in vitro.
Therefore, agomelatin does not affect the concentration of drugs whose metabolism is associated with these isoenzymes.
Drugs that bind significantly to plasma proteins Agomelatin did not change the free concentration of drugs that bind significantly to plasma proteins and, in turn, they did not affect the concentration of agomelatin.
Other medicines
There was no pharmacodynamic or pharmacokinetic interaction between agomelatine and drugs commonly used in the target patient population: benzodiazepines, lithium preparations, paroxetine, fluconazole, and theophylline.
Ethanol (alcohol)
The use of agomelatine in combination with ethanol is not recommended.
Electroconvulsive therapy (ECT)
There is no data on the use of agomelatine simultaneously with ECT. Since agomelatine did not contribute to the development of seizures in animal experiments, the undesirable consequences of the combined use of agomelatine and ECT seem unlikely.
Special instructions
Monitoring of liver function indicators
Cases of liver damage have been reported, including liver failure (which in exceptional cases resulted in death or required liver transplantation in patients with pre-existing risk factors for liver damage), an increase in liver enzymes by more than 10 times relative to ULN, hepatitis and jaundice in patients taking agomelatin during the post-marketing period (see section "Side effect"). Most of these disorders occurred in the first months of therapy. The nature of liver damage appears to be mainly hepatocellular. As a rule, after discontinuation of treatment, transaminase levels returned to normal values.
Caution should be exercised before starting therapy and careful monitoring should be carried out during treatment for all patients, especially those with risk factors for liver disease or receiving concomitant therapy with drugs that can cause liver damage.
- Before starting therapy
Treatment with Agomelatin should be prescribed only after careful assessment of the ratio of expected benefit to possible risk in patients with risk factors for liver dysfunction, such as obesity / overweight / non-alcoholic fatty hepatosis / diabetes mellitus; alcoholism and / or alcohol abuse; the use of drugs that can cause liver dysfunction.
Before starting therapy, functional liver tests should be performed in all patients, and therapy cannot be initiated if the level of liver enzymes (ALT or AST) is more than 3 times the ULN (see "Contraindications"). Caution should be exercised when prescribing Agomelatin to patients with initially elevated transaminase activity (above the upper limit of normal, but not more than 3 times relative to the upper limit of normal).
- Frequency of functional liver tests
- Before starting therapy;
- And further: after about 3 weeks, after about 6 weeks (the end of the relief period of treatment), after about 12 and 24 weeks (the end of the maintenance period of therapy), in the future - in accordance with the clinical situation.
- When increasing the dose, liver function should be monitored with the same frequency as at the beginning of therapy.
If the activity of transaminases in the blood serum increases, a repeat study should be performed within 48 hours.
During the treatment process
Agomelatin therapy should be discontinued immediately if:
- the appearance of symptoms and signs of possible liver dysfunction (such as dark urine, discolored stools, yellow skin/eyes, pain in the right upper abdomen, recent persistent or unexplained fatigue);
- an increase in the level of transaminases by more than 3 times, compared with the ULN.
After discontinuation of the drug Agomelatin, functional liver tests should be performed regularly until the level of transaminases normalizes.
Elderly patients
The effectiveness of the drug in patients aged 75 years and older has not been established. In this regard, Agomelatin should not be prescribed to patients of this age group (see sections "Pharmacological properties", "Dosage and administration").
Elderly patients with dementia
Agomelatin should not be used to treat major depressive episodes in elderly patients with dementia (due to the lack of data on the efficacy and safety of the drug in this group of patients).
Patients with impaired renal function
No significant changes in pharmacokinetic parameters were observed in patients with severe renal insufficiency. However, the experience of using agomelatin in major depressive episodes in patients with moderate or severe renal insufficiency is limited. Caution should be exercised when prescribing Agomelatin to such patients.
Bipolar disorders/mania/hypomania
Caution should be exercised when using Agomelatin in patients with a history of bipolar disorder, manic or hypomanic episodes. If symptoms of mania appear, you should stop taking the drug (see the section "Side effect").
Suicide/suicidal behavior
People with depression have an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until a marked remission occurs.
Patients should be under medical supervision until their condition improves (it may take several weeks after the start of therapy before their condition improves). Clinical experience shows that the risk of suicide may increase in the early stages of remission.
Patients with a history of suicide-related events, as well as patients who had suicidal intentions before starting therapy, are at risk and should be under close medical supervision during therapy.
The results of a meta-analysis of clinical trials of antidepressants in patients with psychiatric disorders indicate an increased risk of suicidal behavior in patients under the age of 25 years on the background of antidepressant use compared with placebo.
During treatment, patients, especially those at risk, should be under close medical supervision, especially at the beginning of therapy and when changing the dose of the drug. Patients (and their caregivers) should be informed about the need to immediately consult a doctor in case of deterioration, suicidal and unusual behavior, as well as suicidal thoughts.
Simultaneous use with inhibitors of the CYP1A2 isoenzyme
Caution should be exercised when using agomelatin concomitantly with moderate inhibitors of the CYP1A2 isoenzyme (such as propranolol, enoxacin) due to the possibility of increasing the concentration of agomelatin in blood plasma (see sections "Contraindications", "Interaction with other drugs"). Patients with lactose intolerance should not use Agomelatin in patients with lactose intolerance: lactase deficiency, galactosemia and glucose-galactose malabsorption (see section "Contraindications").
Influence on the ability to drive vehicles, mechanisms
There have been no studies on the effect of agomelatine on the ability to drive vehicles and other mechanisms.
It should be remembered that dizziness and drowsiness are common side effects of agomelatin.
Storage temperature
from 2℃ to 25℃
