Instructions Mexidol® FORTE 250 film-coated tablets, 40 tablets of 250 mg

1. Name of the drug

Mexidol® FORTE 250, 250 mg, film-coated tablets

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, biconvex, film-coated light pink tablets. The cross-section reveals a nearly white core.

4. Clinical data

4.1. Indications:

• The consequences of acute cerebral circulation disorders, including after transient ischemic attacks, in the subcompensation phase as preventive courses;
• Mild traumatic brain injury, consequences of traumatic brain injury;
• Encephalopathies of various origin (dyscirculatory, dysmetabolic, post-traumatic, mixed);
• Chronic cerebral ischemia;
• Vegetative dystonia syndrome;
• Mild (moderate) cognitive disorders;
• The relief of withdrawal syndrome in alcoholism with predominant neurosis-like and vegetative-vascular disorders, post-withdrawal disorders;
• Status post acute antipsychotic intoxication;
• Asthenic conditions, as well as prevention of somatic diseases induced by extreme factors and stress;
• The exposure to extreme (stressful) factors.

4.2. Dosage and administration:

Dosage mode
The drug is administered 250 mg 3 times a day.
The initial dose is 250 mg (1 tablet) 1-2 times a day, with gradual up-titration until the therapeutic is achieved. The maximum daily dose is 750 mg (3 tablets).
Duration of treatment: 2-8 weeks; for alcohol withdrawal relief: 5-7 days. The duration of the therapy course in patients with ischemic heart disease should be at least 1.5-2 months.
The course of treatment for chronic cerebral ischemia with Mexidol® FORTE 250 is recommended after completing a course of parenteral therapy with Mexidol®.
Repeated courses (as recommended by the physician) are preferably administered in spring and autumn.

Children
The safety and efficacy of Mexidol® FORTE 250 in children aged 0 to 18 have not been established.

Mode of administration
The drug is taken orally with water.

4.3. Contraindications

• Hypersensitivity to ethylmethylhydroxypyridine succinate or to any of the excipients listed in section 6.1;
• Acute liver and/or kidney dysfunction;
• Pediatric use (due to insufficient data on the drug action);
• Pregnancy, breastfeeding (due to insufficient data on the drug action);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

4.4. Special instructions and precautions for use:

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® Forte 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:

Mexidol® FORTE 250 is contraindicated during pregnancy and breastfeeding.

4.7. Effects on ability to drive and use machines

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

Summary of adverse reactions
The frequency of side effects was determined pursuant to the World Health Organization (WHO) classification: very common (≥10%), common (≥1 and <10%), uncommon (≥0.1 and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%) and unknown (frequency cannot be determined based on available data).
Immune system disorders: very rare – angioedema, urticaria.
Mental disorders: very rarely - drowsiness.
Nervous system disorders:  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 the marketing authorization of a drug in order to ensure continuous monitoring of its benefit-risk ratio. Healthcare professionals are advised to report any suspected adverse reactions of the drug through the national adverse reaction reporting systems of the Eurasian Economic Union member states.

4.9. Overdosage

Symptoms
Drowsiness, insomnia.

Treatment
Due to low toxicity, overdose is unlikely. Treatment is usually not required, symptoms disappear within a day. In the case of pronounced manifestations, supportive and symptomatic treatment should be administered.

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
The pharmacological action of Mexidol® FORTE 250 is due to its antioxidant, antihypoxant, and membrane-protective action. It inhibits lipid peroxidation, increases superoxide dismutase activity, increases the lipid-protein ratio, reduces membrane viscosity and increases membrane fluidity. Mexidol® FORTE 250 modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase), receptor complexes (benzodiazepine, gamma-aminobutyric acid (GABA), acetylcholine), which enhances their ability to bind to ligands, contributes to preserving the structural and functional organization of biomembranes, transporting neurotransmitters and improving synaptic transmission. It causes enhancement of compensatory activation of aerobic glycolysis and reduction of the inhibition rate of oxidative processes in the Krebs cycle under hypoxia with an increased content of adenosine triphosphate (ATP), creatine phosphate and activation of energy-synthesizing functions of mitochondria, as well as promotes stabilization of cell membranes..
Mexidol® FORTE 250 increases dopamine levels in the brain.

Pharmacodynamics
Mexidol® FORTE 250 is an inhibitor of free radical processes and a membrane protector with antihypoxic, stress-protective, nootropic, antiepileptic, and anxiolytic effects. The drug enhances the body’s resistance to various damaging factors in pathological conditions (hypoxia and ischemia, impaired cerebral circulation, intoxication with ethanol and antipsychotic agents). Its anti-stress action is manifested in the normalization of post-stress behavior, somatovegetative disorders, restoration of sleep-wake cycles, improvement of impaired learning and memory processes, and reduction of dystrophic and morphological changes in various brain structures. It has a hypolipidemic effect, reduces the levels of total cholesterol and low-density lipoproteins. Mexidol® FORTE 250 improves the functional state of ischemic myocardium. It preserves the integrity of morphological structures and physiological functions of ischemic myocardium. In the case of coronary insufficiency, it increases collateral blood supply to the ischemic myocardium, and helps preserve cardiomyocyte integrity and maintain their functional activity. It effectively restores myocardial contractility in cases of reversible cardiac dysfunction. The drug stabilizes membrane structures of blood cells (erythrocytes and platelets) reducing the possible 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® Forte 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® Forte 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® Forte 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® Forte 250 above the placebo. According to the results of the assessment of the secondary endpoints of the effectiveness of drugs Mexidol® and Mexidol® Forte 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. Pharmacokinetics:

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
The drug is metabolized in the liver by glucuronic conjugation. 5 metabolites have been identified: 3-oxypyridine phosphate is formed in the liver and decompounds into phosphoric acid and 3-oxypyridine by alkaline phosphatase; the 2nd metabolite is pharmacologically active, is formed in large quantities and detected in the urine 1-2 days after administration; the 3rd metabolite is excreted in large quantities with urine; the 4th and 5th metaolites are glucuronic conjugates.

Elimation
Half-life (T1/2) after oral administration is 2.0-2.6 hours. It is rapidly excreted in the urine, primarily as metabolites, with only a small amount excreted unchanged. The most intensive excretion occurs within the first 4 hours after the drug administration. The urinary excretion levels of the unchanged drug and its metabolites exhibit 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. Validity period (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 the used drug or waste obtained after the drug administration or handling

There are no special disposal requirements.

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/ .