Instructions for use MELITOR

Pharmacological properties of the drug Melitor

Agomelatine (N[2-(7-methoxy-1-naphthyl) ethyl]acetamide) is used to treat depressive episodes and recurrent depressive disorders. Agomelatine is a melatonergic agonist of MT1 and MT2 receptors and an antagonist of 5-HT2c receptors. Studies examining the binding of agomelatine to receptors have demonstrated that agomelatine does not affect monoamine uptake and has no affinity for α- and β-adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine does not affect the level of extracellular serotonin and increases the release of dopamine and norepinephrine specifically in the frontal cortex. The effectiveness of agomelatine has been proven in experimental studies in various validated models of depression, as well as in models with desynchronization of circadian rhythms and in modeling stress or anxiety. Experimental studies have found that agomelatine resynchronizes circadian rhythms. Agomelatine preserves sleep structure in healthy volunteers and normalizes sleep in patients with depression. In therapeutic doses, agomelatine does not impair attention and memory in healthy volunteers during the day (based on tests using a visual analogue scale and the ARCI questionnaire). When abruptly stopping treatment with agomelatine, no withdrawal syndrome is observed (based on the results of a study of patients with depression using the DESS questionnaire.) The use of agomelatine does not affect body weight (based on the results of clinical studies). The effectiveness and safety of agomelatine was proven in clinical studies involving 4600 patients with depressive episodes and recurrent depressive disorders, 2400 of whom took agomelatine. Short-term placebo-controlled studies that lasted 6-8 weeks showed statistically significant benefits of agomelatine compared to placebo (the result was assessed by the Hamilton scale (HAM-D17), total score, including symptoms of depression and sleep disturbance). The therapeutic effect (improvement of condition) was noted within 2 weeks after the start of treatment. Similar results were also found in patients with major depressive episodes (pre-treatment Hamilton Depression Severity Scale (HAM-D) ≥25). These studies reported a high percentage of patients who responded to treatment (49.1–61.5%) compared with placebo (34.3–46.3%). Several long-term (>24 weeks) comparative and active control studies have demonstrated the effectiveness of agomelatine in the treatment of patients with depressive episodes and recurrent depressive disorders with long-term use (as assessed by the Hamilton scale (HAM-D17)). Agomelatine has proven effective in treating depression in patients with high initial levels of anxiety. A special comparative study demonstrated that the likelihood of developing new cases of sexual dysfunction when taking agomelatine is lower than when treating with other antidepressants (assessment results on the SEXFX scale). A pooled analysis of ASEX studies demonstrated that agomelatine use was not associated with sexual dysfunction. In patients with depression, agomelatine significantly improved the process of falling asleep and the quality of sleep without daytime sleepiness (as measured by the LEEDS sleep quality questionnaire) from the second week of treatment. Agomelatine is rapidly and well absorbed (≥80%) after oral administration. The maximum concentration in blood plasma is achieved within 1–2 hours after taking agomelatine. Absolute bioavailability is about 3% of the therapeutic dose (individual fluctuations are possible). When agomelatine is used in recommended therapeutic doses, its concentration in the blood plasma increases in proportion to the dose. With a further increase in dose, a saturation effect of the primary passage is observed. Food intake (with a balanced diet or a high-fat diet) does not affect the bioavailability or rate of absorption of agomelatine. Plasma protein binding is 95% regardless of the concentration of the active substance; this figure does not change with age and in patients with impaired renal function. After administration, agomelatine is rapidly metabolized, mainly by the liver enzymes CYP 1A2 (90%), a small amount is metabolized by the isoenzymes CYP 2C9 and CYP 2C19 (10%). The main metabolites (in the form of hydroxylated and demethylated agomelatine) do not have pharmacological activity, are quickly conjugated and excreted in the urine. Agomelatine is characterized by rapid elimination from the body. The half-life from blood plasma averages 1–2 hours. Clearance is high (about 1100 ml/min) and is mainly associated with the excretion of metabolites. It is excreted mainly in the urine (80%) in the form of metabolites. The amount of active substance excreted in urine unchanged is insignificant. The pharmacokinetics of agomelatine does not change with prolonged use. The pharmacokinetics of agomelatine do not change in patients with severe renal impairment, so there is no need for dose adjustment. In volunteers with mild to moderate chronic liver failure, agomelatine concentrations increased significantly, so the use of the drug is contraindicated in liver diseases with impaired liver function.

Instructions for use: medications and their generics (5)

Murzaeva Irina Yurievna

Endocrinologist, Preventive Medicine Doctor

June 5, 2015

Among the drugs used to treat thyroid dysfunction, the main group consists of hormonal drugs. Selecting them for farm. The Russian market, unfortunately, is not large. And in recent years it has also decreased.

Today I want to talk about drugs for the treatment of hypothyroidism, low thyroid function. This group of drugs consists of 3 subgroups, if they are divided conventionally like this. Thyroxine (T4) preparations replace the T4 hormone, better known as L-thyroxine, which will be discussed separately later.

Triiodothyronine (T3) preparations that replace the T3 hormone - I really want to talk about it now, and group 3 - combination drugs that include T4 and T3, sometimes also iodine (at a dose of 100-200 mcg).

If with T4 drugs on the farm. The market is still fine, the drug is available, and most importantly, in different doses. Things are getting worse with T3 drugs – they simply don’t exist. For several years, T3 drugs were not sold in our country. Some of the tablets did not undergo the procedure for re-registration of the drug in Russia with regulatory organizations, while others were completely discontinued from production.

During these years, a small percentage of patients began to experience insensitivity to T4, and, accordingly, persistent hypothyroidism, which also required additional replacement with drugs containing T3. Considering the huge prevalence of thyroid pathology, the total number of people in need of T3 turned out to be quite large.

The drug T3 is also very important for children with hypothyroidism (congenital or acquired), who are actively growing and developing, especially for the “maturation” of brain cells, for the development of memory, attention, and intelligence.

T3 can also be used in the complex treatment of diffuse non-toxic goiter and multinodular goiter with nodule size less than 2 cm, after operations on the thyroid gland, with AIT in combination with hypothyroidism, with a hypertrophic form or multinodular form.

To understand the importance of T3 in the body, below is a simplified diagram of the formation of thyroid hormones.

The diagram shows that T3 is formed in the body by transition from T4, it is more active, and directly “works” at the level of tissues and target organs, also due to the fact that the ratio of T4 and T3 in the body is 1:10, then there should be 10 times more trioidthyronine, which is taken into account during treatment.

That is why, with a full replacement dose of T4 for hypothyroidism and a “normal” TSH level, malaise persists - lethargy, weakness, poor weight loss, absent-minded attention, that is, there is not enough T3 in the body.

There are drugs that can compensate for T3 deficiency in the body.

• these are preparations of liothyronine or triiodothyronine , they are not available in Russia and are not produced, but abroad they are available under the names:
• Tibon 100 mcg and 20 mcg, Sanofi,
• Triiodine Thyronine 50 mcg, Berlin Hemi (Germany),
• Cytomel 5 mcg, 24 mcg, Uhlimann-Eyrard (Switzerland).
• Cytomel 25 mcg, Merrel Dau France, Dinkel (Türkiye).
• Cyronin 25 mcg, 50 mcg, Meija (USA).
• Cytomel 5 mcg, Smif Kleim USA S Kleim French (Canada, Holland).
• Cytomel 25 mcg, S.T. Riet Belgium SK USA, SK French (Canada, Holland).
• Cytomel 50 mcg, Smith Kleim (USA).
• Linomel 25 mcg, Smith Kleim (Argentina).
• Neotiroimad 5 mcg, 25 mcg, (Portugal).
• Ro-theranine 25 mcg, 50 mcg, Robinson (USA).
• Tertoxin 25 mcg (injection solution), Glaxo (Denmark).
• Tertoxin 20 mcg, Glaxo Denmark, UK, (South Africa).
• Tibon-forte 20 mcg, 100 mcg, Hoechst (Germany).
• Tyrotardine injection 100 mcg (dry matter), Henning Berlin (Germany).
• Ti-tre 5 mcg, 20 mcg, Glaxo (Italy).
• Tiromel 25 mcg, Ibrahim (Türkiye).
• Tyranin 25 mcg, Abello (Spain)
• Triiodothyronine 20 mcg, Nycomed (Sweden).
• Triiodine Sanabo 25 mcg, Sanabo (Austria).
• Triiodine 50 50 mcg, Berlin-Chemie (Germany).
• Triiodine Leo 25 mcg, Leo (Spain).
• Cytover T3 50 mcg, Vermodje

Triiodothyronine tablets are not used on their own (there are “narrow” indications for this); in the treatment of thyroid diseases, a combination of T4 and T3 in the ratio is usually selected; they are selected only by the attending physician.

Use of the drug Melitor

Take orally, regardless of meals or during meals. The tablets should be swallowed whole with water. The recommended dose for adults is 25 mg (1 tablet) 1 time per day before bedtime. After 2 weeks, if necessary, the dose can be increased to 50 mg (2 tablets) 1 time per day before bedtime. According to WHO recommendations, treatment for depression should be continued for at least 6 months after the end of a depressive episode or recurrent depressive disorder (normalization of the condition). Discontinuation of treatment with agomelatine does not require gradual dose reduction. With sudden cessation of treatment with agomelatine, no withdrawal syndrome is observed.

Directions for use and dosage

The recommended dose of Melitor is one tablet (25 mg), which should be taken once before bedtime. Eating does not affect the effectiveness of the medicine.

After assessing the effectiveness of the therapy, after two weeks the dose can be doubled if necessary - up to 2 tablets, which are also taken before bedtime.

Liver function monitoring should be carried out:

• At the beginning of treatment;
• After six weeks (at the end of the acute phase);
• At the end of 12 and 24 weeks (at the end of the maintenance phase);
• Until the end of the treatment course - according to clinical indications.

Typically, treatment for depression is quite long and lasts at least six months. After complete disappearance of symptoms, the medication can be discontinued without gradually reducing the dosage.

Side effects of the drug Melitor

In clinical studies of agomelatine, which included 2400 patients with depressive episodes or recurrent depressive disorders, it was found that side effects were usually mild or moderate and were observed during the first 2 weeks of treatment. The most common side effects were nausea and dizziness. These side effects were usually temporary and, as a rule, did not require cessation of treatment. Side effects observed in short-term placebo-controlled clinical studies, the association of which with agomelatine in doses of 25 or 50 mg has been established or possible, are listed below by frequency of occurrence: very often (1/10); often (1/100 and ≤1/10); uncommon (1/1000 and ≤1/100); rare (1/10,000 and ≤1/1000); very rare (≤1/10,000). From the gastrointestinal tract often: nausea, dry mouth, diarrhea, pain in the epigastric region. From the nervous system: often: dizziness, increased fatigue, drowsiness, migraine; uncommon: paresthesia. Mental disorders often: anxiety; uncommon: sleep disturbances, irritability. On the part of the organ of vision: uncommon: blurred vision. From the skin and subcutaneous fat often: itching, increased sweating; uncommon: dermatitis, eczema, erythematous rash. From the laboratory test indicators: there were several cases (in 0.6% of patients) of increased activity of AST and ALT (3 times higher than the upper limit of normal) when using agomelatine at a dose of 25 or 50 mg.

Special instructions for the use of Melitor

Patients with depression should be under medical supervision, especially at the beginning of treatment. As with other antidepressants, agomelatine should be used with caution in patients with a history of mania or hypomania. If the patient develops manic symptoms, agomelatine should be discontinued. There is no association between agomelatine use and an increased risk of suicide. The risk of suicide is characteristic of depressive conditions, and it may persist until clinically significant remission is achieved. It is not recommended to prescribe agomelatine to children and adolescents under the age of 18 due to the lack of data regarding the use of the drug in this group of patients. Use with caution in elderly patients (over 65 years of age) due to limited clinical data. The drug contains lactose, so it should not be prescribed to patients with congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. As with the use of other antidepressants, the simultaneous use of agomelatine and alcohol consumption is not recommended. The drug should be prescribed with caution during pregnancy (due to the lack of clinical data). In animal experiments, no direct or indirect negative effect on the course of pregnancy, development of the embryo/fetus, influence on the period of childbirth or postnatal development was established. If agomelatine therapy is necessary, breastfeeding should be stopped. There are no clinical data on the penetration of agomelatine into breast milk. Experimental studies have shown that agomelatine and its metabolites pass into breast milk. The effect of agomelatine on an infant during breastfeeding has not been established. Agomelatine therapy does not affect the ability to drive vehicles or operate potentially dangerous machinery, but patients should be warned to exercise caution when performing such activities during treatment, especially if side effects are present.

Pharmacological action of Melitor

Agomelatine (the active component of the drug) is an agonist of melatonin and serotonin 5-HT2C receptors.

Melitor has an antidepressant effect and has positive phase shift properties, bringing the sleep phase closer by increasing the production of melatonin and lowering body temperature.

Melitor according to the instructions does not affect memory and alertness during the daytime, having a predominant effect on sleep:

• Increased slow-wave sleep;
• The time to fall asleep is reduced.

The medication does not cause changes in body weight, heart rate, blood pressure, or withdrawal symptoms. As a result of research, it has been established that Melitor is also non-addictive and has no potential for abuse.

Interactions of the drug Melitor

Drugs that interact with cytochrome P450 1A2 (CYP1A2) and CYP2C9/19 enzymes may reduce or increase the bioavailability of agomelatine, since agomelatine is predominantly metabolized by the above enzymes (90 and 10%, respectively). Drugs that interact with the above enzymes may decrease or increase the bioavailability of agomelatine. Fluvoxamine is a highly active CYP1A2 inhibitor and a moderate 2C9 inhibitor and therefore significantly inhibits the metabolism of agomelatine, resulting in a significant increase in concentrations. Therefore, the simultaneous use of agomelatine with fluvoxamine and ciprofloxacin is contraindicated. Paroxetine is a moderate CYP1A2 inhibitor. Paroxetine does not affect the pharmacokinetics of agomelatine. Fluconazole is a highly active CYP 2C9 inhibitor. Fluconazole does not affect the pharmacokinetics of agomelatine. Agomelatine does not activate or inhibit isoenzymes of the CYP 450 system, therefore agomelatine does not affect the concentration of drugs that are metabolized by CYP 450. Agomelatine does not affect the concentration in the blood serum of the free fraction of substances with a high degree of binding to plasma proteins and vice versa. There are no pharmacokinetic or pharmacodynamic interactions between agomelatine and lorazepam, as well as lithium preparations. There is no experience with the use of agomelatine concomitantly with electroconvulsive therapy. Animal experiments have shown that agomelatine does not cause seizures, so it is unlikely that the simultaneous use of electroconvulsive therapy and agomelatine would lead to clinically significant complications.

Drug interactions

Melitor should not be co-administered with CYP1A2 inhibitors such as ciprofloxacin and fluvoxamine, since this combination of drugs causes a sharp increase in the inhibitory effect of agomelatine on metabolism.

There was no significant therapeutic effect of Melitor when used simultaneously with drugs with high plasma protein binding, as well as other drugs that are most often prescribed as part of combination therapy for depression - lithium, fluconazole, benzodiazepines, paroxetine or theophylline.

Melitor overdose, symptoms and treatment

No cases of overdose have been reported. During clinical trials of the drug, there were several reports of the use of agomelatine at a dose of up to 300 mg in monotherapy or in combination with other psychotropic drugs at a dose of up to 375 mg. In these cases, no signs or symptoms of overdose were noted. There is no specific antidote. In case of overdose, medical observation of the patient’s condition in a specialized department is recommended, and symptomatic therapy is recommended if indicated.