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 ingredient: ethylmethylhydroxypyridine succinate.
1 tablet contains: ethylmethylhydroxypyridine succinate (based on 100% substance) – 250 mg.
Excipients that must be taken into account in the composition of the medicinal product: lactose monohydrate (see section 4.4).
A full list of excipients is provided in section 6.1.

3. Dosage form

Film-coated tablets.
Round, biconvex, light pink film-coated tablets. The core is off-white when cross-sectioned.

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 regimen:
250 mg 3 times daily.
The initial dose is 250 mg (1 tablet) 1-2 times daily with a gradual increase to the therapeutic effect. The maximum daily dose is 750 mg (3 tablets).
Duration of treatment is 2-8 weeks; for the relief of alcohol withdrawal - 5-7 days. The duration of the course of therapy in patients with coronary artery disease is at least 1.5-2 months.
A course of treatment for chronic cerebral ischemia with Mexidol® FORTE 250 is recommended after completion of a course of parenteral therapy with Mexidol®.
Repeat courses (as recommended by a physician) are preferably carried out in the spring and autumn.

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

Directions for use:
Take 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 compatible with all medications used to treat somatic diseases.
It enhances the effects of benzodiazepines, antidepressants, anxiolytics, antiepileptic drugs (carbamazepine), antiparkinsonian drugs (levodopa), and nitrates. It reduces the toxic effects 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 in accordance with the classification of the World Health Organization (WHO): very common (≥ 10%); common (≥ 1%, but ˂ 10%); uncommon (≥ 0.1%, but ˂ 1%); rare (≥ 0.01%, but ˂ 0.1%); very rare (˂ 0.01%); frequency unknown (frequency cannot be estimated from the available data).
Immune system disorders: very rare – angioedema, urticaria.
Mental disorders: very rare – drowsiness.
Nervous system disorders: very rare – headache.
Gastrointestinal disorders: very rare – dry mouth, nausea, pain, burning and discomfort in the epigastric region, heartburn, flatulence, diarrhea.
Skin and subcutaneous tissue disorders: very rare – rash, itching, hyperemia.

Reporting suspected adverse reactions
is important after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions to the medicinal product 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 generally not required; symptoms resolve spontaneously within 24 hours. In cases of severe symptoms, supportive and symptomatic treatment is 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.

Mechanism of action
The mechanism of action of Mexidol® FORTE 250 is due to its antioxidant, antihypoxic, and membrane-protective effects. It inhibits lipid peroxidation, increases superoxide dismutase activity, raises 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, helps maintain the structural and functional organization of biomembranes, transport neurotransmitters, and improve synaptic transmission. It increases compensatory activation of aerobic glycolysis and reduces the degree of suppression of oxidative processes in the Krebs cycle under hypoxic conditions, increasing adenosine triphosphate (ATP) and creatine phosphate levels, activating the energy-synthesizing functions of mitochondria, and stabilizing cell membranes.
Mexidol® FORTE 250 increases dopamine levels in the brain.

Pharmacodynamic effects:
Mexidol® FORTE 250 is a free-radical inhibitor and membrane protector with antihypoxic, stress-protective, nootropic, antiepileptic, and anxiolytic effects. It increases the body's resistance to various damaging factors in pathological conditions (hypoxia and ischemia, cerebrovascular accidents, ethanol intoxication, and antipsychotic medications). Its anti-stress effect normalizes post-stress behavior, somatovegetative disorders, restores sleep-wake cycles, disrupts learning and memory processes, and reduces degenerative and morphological changes in various brain structures. It has a hypolipidemic effect, reducing total cholesterol and low-density lipoprotein levels. Mexidol® FORTE 250 improves the functional state of ischemic myocardium. Maintains the integrity of the morphological structures and physiological functions of the ischemic myocardium. In conditions of coronary insufficiency, it increases collateral blood flow to the ischemic myocardium, helping to preserve the integrity of cardiomyocytes and maintain their functional activity. It effectively restores myocardial contractility in reversible cardiac dysfunction. It stabilizes the membrane structures of blood cells (erythrocytes and platelets), reducing the likelihood of hemolysis.

Clinical efficacy and safety
An international, multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of sequential therapy with Mexidol® and Mexidol® FORTE 250 (MEMO) in patients with chronic cerebral ischemia was conducted on 318 patients aged 40 to 90 years. Patients in the study group received therapy with Mexidol® 10 ml (500 mg) once a day intravenously by drip or intravenous by slow stream for 14 days, followed by Mexidol® FORTE 250 1 tablet 3 times a day for the next 60 days. Patients in the control group received placebo according to a similar scheme. According to the study results, at the end of therapy, statistically significant changes in the Montreal Cognitive Assessment (MoCA) scores were revealed in patients when comparing the dynamics in the study and control groups (p < 0.000001, t-test for independent samples). The lower limit of the 95% confidence interval for the difference in the means of the primary efficacy indicator in the Mexidol®/Mexidol® FORTE 250 and placebo groups was 1.51. This limit is a positive value, which made it possible to state the superior efficacy of Mexidol® and Mexidol® FORTE 250 over placebo. Based on the results of the assessment of secondary endpoints of the efficacy of Mexidol® and Mexidol® FORTE 250 during therapy, statistically significant differences were obtained compared to placebo for the following indicators: dynamics of the severity of cognitive impairment according to the digital symbol substitution test; Dynamics of the severity of asthenic disorders according to the MFI-20 asthenia scale; Dynamics of autonomic changes according to the Wein questionnaire; Dynamics of the anxiety level according to the Beck scale; Dynamics of motor changes according to the Tinetti scale; Dynamics of the global clinical impression according to the Clinical Global Impressions Scale; Dynamics of the patients' quality of life according to the SF-36 questionnaire (psychological component of health).
The results of the statistical analysis of the incidence of adverse events, laboratory test results, and physical examination results demonstrate the absence of significant differences between the compared groups in the main safety indicators, which confirms the safety profile of Mexidol®, comparable to placebo.

5.2. Pharmacokinetics:

Absorption:
Rapidly absorbed after oral administration. The maximum concentration (Cmax) at doses of 400-500 mg is 3.5-4.0 mcg/ml. Rapidly distributed throughout organs and tissues.

Distribution
The mean residence time (MRT) of the drug in the body after oral administration is 4.9-5.2 hours.

Biotransformation:
Metabolized in the liver by glucuronide conjugation. Five metabolites have been identified: 3-hydroxypyridine phosphate – formed in the liver, with the participation of alkaline phosphatase, it breaks down into phosphoric acid and 3-hydroxypyridine; the 2nd metabolite is pharmacologically active, formed in large quantities and detected in urine 1-2 days after administration; the 3rd is excreted in large quantities in the urine; the 4th and 5th are glucuronide conjugates.

Elimination:
The half-life (T1/2) after oral administration is 2.0-2.6 hours. It is rapidly excreted in the urine, primarily as metabolites and to a small extent unchanged. Elimination is most extensive within the first 4 hours after administration. Rates of urinary excretion of unchanged drug and metabolites vary among individuals.

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 film-coated tablets per blister pack made of PVC film and aluminum foil.
1, 2, 3, 4, 5, or 6 blister packs along with instructions for use are packaged in a cardboard box.

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,
NPK PHARMASOFT LLC,
115407, Moscow, Sudostroitelnaya Street, Building 41, Floor 1, Office 12
Tel./Fax: +7 (495) 626-47-55
E-mail: pharmasoft@pharmasoft.ru

7.1. Representative of the Marketing Authorization Holder

Consumer complaints should be sent to the following address:
Russian Federation,
NPK PHARMASOFT LLC,
115407, Moscow, Sudostroitelnaya Street, Building 41, Floor 1, Office 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

General characteristics of the medicinal product Mexidol® FORTE 250 are available on the information portal of the Eurasian Economic Union on the Internet information and communication network http://eec.eaeunion.org/.