1. Name of the drug

Mexidol® Fort 250, 250 mg, tablets covered with film shell

2. Qualitative and quantitative composition

Active substance: ethylmethylhydroxypyridine succinate.
1 tablet contains: ethylmethylhydroxypyridine of succinate (in terms of 100 % substance) - 250 mg.
Excipients, the presence of which must be taken into account as part of the drug: lactose monohydrate (see section 4.4).
A full list of excipients is given in section 6.1.

3. Dosage form

Tablets covered with a film shell.
Round double-shaped tablets covered with a film-pink film shell. The transverse section is almost white.

4. Clinical data

4.1. Indications for use

• The consequences of acute cerebral circulation disorders, including after transient ischemic attacks, in the subcompensation phase as preventive courses;
• Mild cranial injury, consequences of traumatic brain injuries;
• Encephalopathy of various origins (discirculatory, dysmetabolic, post-traumatic, mixed)
• chronic cerebral ischemia;
• vegetative dystonia syndrome;
• mild (moderate) cognitive disorders;
• The relief of withdrawal syndrome in alcoholism with a predominance of neurosis-like and vegetative-vascular disorders, post-withdrawal disorders;
• Condition after acute intoxication with antipsychotic drugs;
• Asthenic conditions, as well as for the prevention of the development of somatic diseases under the influence of extreme factors and loads;
• The impact of extreme (stressor) factors.

4.2. Dosing mode and method of application

Dosage mode
of 250 mg 3 times a day.
The initial dose is 250 mg (1 tablet) 1-2 times a day with a gradual increase to the therapeutic effect. The maximum daily dose is 750 mg (3 tablets).
The duration of treatment is 2-8 weeks; For stopping alcoholic withdrawal-5-7 days. The duration of the course of therapy in patients with coronary heart disease is at least 1.5-2 months.
The course of treatment of chronic brain ischemia with Mexidol® Forte 250 is recommended after completing the course of parenteral therapy with Mexidol®.
Repeated courses (on the recommendation of a doctor), it is advisable to conduct in the spring-autumn periods.

Children
safety and effectiveness of the drug Mexidol® Forte 250 in children aged 0 to 18 years are not established.

Method of administration
Orally, with water.

4.3

• hypersensitivity to ethylmethylhydroxypyridine to succinate or to any of the auxiliary substances listed in section 6.1;
• Acute liver and/or kidney dysfunction;
• children's age (due to insufficient knowledge of the drug);
• Pregnancy, breastfeeding (due to insufficient study of the drug's action);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

4.4. Special instructions and precautions while applying

Patients with rarely encountered by hereditary intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption should not take this drug.

4.5. Interaction with other drugs and other types of interaction:

Mexidol® Fort 250 is combined with all drugs used to treat somatic diseases.
Enhances the effect of benzodiazepine drugs, antidepressants, anxiolytics, antiepileptic drugs (carbamazepine) and anti -parquinsonical drugs (leftodope), nitrates. Reduces the toxic effect of ethanol.

4.6. Fertility, pregnancy and lactation

The drug Mexidol® Fort 250 is contraindicated during pregnancy and during breastfeeding.

4.7. Influence on the ability to drive vehicles and work with mechanisms

During the drug administration period, caution should be exercised when performing work requiring quick psychophysical reactions (driving vehicles, using machines, etc.).

4.8. Adverse reactions

The resume of unwanted reactions
of the frequency of side effects was determined in accordance with the classification of the World Health Organization (WHO): very often (≥ 10 %); often (≥ 1 %, but ˂ 10 %); infrequently (≥ 0.1 %, but ˂ 1 %); rarely (≥ 0.01 %, but ˂ 0.1 %); very rarely (˂ 0.01 %); The frequency is unknown (the frequency cannot be determined on the basis of the available data).
Violations of the immune system: very rarely - angioedema, urticaria.
Mental disorders: very rarely - drowsiness.
Violations of the nervous system: very rarely - headache.
Gastrointestinal disorders: very rarely-dry mouth, nausea, pain, burning and discomfort in the epigastric region, heartburn, flatulence, diarrhea.
Disorders from the skin and subcutaneous tissues: very rarely - rash, itching, hyperemia.

Reporting suspected adverse reactions
It is important to report suspected adverse reactions after registration of the medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions of the medicinal product through the national adverse reaction reporting systems of the Eurasian Economic Union member states.

4.9. Overdose

Symptoms
Drowsiness, insomnia.

Treatment
due to low toxicity overdose is unlikely. Treatment, as a rule, is not required, the symptoms disappear independently during the day. With severe manifestations, supportive and symptomatic treatment is performed.

5. Pharmacological properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: other drugs for the treatment of diseases of the nervous system. Other drugs for the treatment of diseases of the nervous system.
ATX Code: N07XX.

The mechanism of action
mechanism of action of the drug Mexidol® Forte 250 is due to its antioxidant, antihypoxic and membraneoprotective effects. It inhibits the peroxidation of lipids, increases the activity of superoxidsmutase, increases the ratio of lipid-beam, reduces the viscosity of the membrane, and increases its fluidity. Mexidol® 250 modulates the activity of membrane enzymes (calcium-dependent phosphodesturas, adenilatziclase, acetylcholineersterase), receptor complexes (benzodiazepine, gamma-amino-melting acid (GABA), acetylcholine), which enhances their ability to bind ligands, and contributes to the preservation of structural-francs zionic organization of biomembrane , transport of neurotransmitters and improving synaptic transmission. It causes an increase in the compensatory activation of aerobic glycolysis and a decrease in the degree of inhibition of oxidative processes in the Crebs cycle in conditions of hypoxia with an increase in the content of adenosine triphosphate (ATP) and creatine phosphate, activation of energy synthetic functions of mitochondria, and stabilization of cell membranes.
Mexidol® Forte 250 increases the content of dopamine in the brain.

The pharmacodynamic effects of
Mexidol® Forte 250 are an inhibitor of free radical processes, a membraneoprotector with an anti-Hipoxic, stress-prototective, nootropic, antiepiletic and anxiolytic effects. The drug increases the body's resistance to various damaging factors in pathological conditions (hypoxia and ischemia, cerebrovascular disorders, ethanol intoxication and antipsychotic agents). The anti-stress is manifested in the normalization of post-stress behavior, somatovegetative disorders, restoration of sleep-bonding cycles, impaired learning and memory processes, a decrease in dystrophic and morphological changes in various brain structures. It has a hypolipidemic effect, reduces the content of total cholesterol and low density lipoproteins. Mexidol® Fort 250 improves the functional state of ischemized myocardium. Provides the integrity of morphological structures and physiological functions of ischemic myocardium. In conditions of coronary insufficiency, it increases the collateral blood supply to ischemic myocardium, helps to maintain the integrity of cardiomyocytes and maintain their functional activity. Effectively restores myocardial contractility with reversible heart dysfunction. Stabilizes membrane structures of blood cells (red blood cells and platelets), reducing the likelihood of hemolysis.

Clinical efficiency and safety
International multicenteric randomized double-tied placebo-controlled study on evaluating the effectiveness and safety of consecutive therapy with Mexidol® and Mexidol® Forter III (MEMO) in patients with chronic brain ischemia with the participation of 318 patients aged 40 to 90 years. Patients in the studied group received therapy with Mexidol® 10 ml (500 mg) 1 time per day in/in dripped or intravenously slowly for 14 days, followed by taking Mexidol® Fort 250, 1 tablet 3 times a day for subsequent ones for subsequent ones 60 days. Patients in the control group received a placebo according to a similar scheme. Based on the results of the study, at the time of completion of therapy, patients identified statistically significant changes in points on the Montreal scale of evaluating cognitive functions (MOCA) when comparing the dynamics in the studied and control groups (P <0.000001, T-criteria for independent samples). The lower border of 95 % of the trust interval for the difference in the average main performance indicator in the groups of drugs Mexidol®/Mexidol® Fort 250 and the placebo was 1.51. This boundary is a positive value, which made it possible to state the superior effectiveness of the drugs Mexidol® and Mexidol® Fort 250 above the placebo. According to the results of the assessment of the secondary endpoints of the effectiveness of drugs Mexidol® and Mexidol® Fort 250 during therapy, statistically significant differences were obtained compared to placebo according to the following indicators: the dynamics of the severity of cognitive disturbances for the diucal replacement test; The dynamics of the severity of asthenic disorders on the asthenia scale MFI-20; the dynamics of autonomic changes according to the Wein questionnaire; dynamics of anxiety level on the Bek scale; The dynamics of motor changes on the Tinetti scale; The dynamics of the general clinical impression on the general clinical impression scale (The Clinical Global Impressions Scale); The dynamics of the quality of life of patients according to the SF-36 questionnaire (psychological component of health).
The results of a statistical analysis of the frequency of the occurrence of undesirable phenomena, laboratory analyzes, the results of a physics examination demonstrate the absence of significant differences between the compared groups in basic safety indicators, which proves the security profile of Mexidol® comparable to the placebo.

5.2. Pharmacokinetic properties

Absorption
is rapidly absorbed when oral administration. The maximum concentration (CMAX) at doses of 400-500 mg is 3.5-4.0 μg/ml. It is quickly distributed in organs and tissues.

Distribution of
the average deduction time (MRT) of the drug in the body when taking orally-4.9-5.2 hours.

Biotransformation
is metabolized in the liver by glucuronconjuging. 5 metabolites have been identified: 3-oxypyridine phosphate-is formed in the liver, with the participation of alkaline phosphatase, it breaks up into phosphoric acid and 3-oxypyridin; The 2nd metabolite is pharmacologically active, formed in large quantities and is found in the urine for 1-2 days after administration; 3rd-is displayed in large quantities in urine; 4th and 5th-Glukuronkonjugat.

Elimation
The half-life (T1/2) of the drug in case of oral administration is 2.0-2.6 hours. It is quickly excreted in the urine, mainly as metabolites, and unchanged in small amounts. It is most intensively excreted during the first 4 hours after taking the drug. The rates of excretion of unchanged drug and metabolites in the urine have individual variability.

5.3. Preclinical safety data

No specific harm to humans has been identified in preclinical data obtained from standardized studies of pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive and ontogenetic toxicity.

6. Pharmaceutical properties

6.1. List of excipients

Excipients:

• Lactose monohydrate;
• Povidon K-30;
• Magnesium stearat.
• Film shell:
• Gipromellose;
• Titanium dioxide;
• Lactose monohydrate;
• Macrogol 4000;
• Triacinin;
• The dye of iron oxide is red;
• The dye of iron oxide is yellow.

6.2. Incompatibility

Not applicable.

6.3. Expiry date (shelf life)

3 years.

6.4. Special storage precautions

Store in a place protected from the light, at a temperature not exceeding 25 ° C.

6.5. Description and content of the primary packaging

10 tablets covered with a film shell in a contour cell package from a polyvinyl chloride film and aluminum foil.
1, 2, 3, 4, 5, 6 contour cell packages along with instructions for use in a pack of cardboard.

6.6. Special precautions for disposal of used medicinal product or waste resulting from use of or handling of the medicinal product

There are no special requirements for disposal.

7. Marketing authorization holder

Russian Federation
LLC NPK "Farmasoft",
115407, city of Moscow, Shipostroynaya street, house 41, floor 1, room 12
tel/ fax: +7 (495) 626-47-55
Email: Pharmasoft@pharmasoft.ru

7.1. Representative of the Marketing Authorization Holder

Consumer claims to be sent to the address:
Russian Federation
NPK Pharmasoft
115407, city of Moscow, shipbuilding street, house 41, floor 1, room 12
tel/ fax: +7 (495) 626-47-55
Email: Pharmasoft@ Pharmasoft.ru

8. Marketing authorization number

LP-№ (000066)-(RG-RU)

9. Date of the first marketing authorization (authorization confirmation, re-authorization)

Date of the first registration: 03.06.2020

10. Text revision date

The general characteristics of the drug Mexidol® Forte 250 are available on the information portal of the Eurasian Economic Union in the Information and Communication network "Internet" http://eec.eaeunion.org/ .