Instructions for Mexidol®, tablets coated with a film shell 125 mg No. 30

1. Name of the drug

Mexidol®, 125 mg, film-coated tablets

2. Qualitative and quantitative composition

Active ingredient: ethylmethylhydroxypyridine succinate.
Each tablet contains: ethylmethylhydroxypyridine succinate – 125.0 mg.
Excipients that must be included in the composition of the medicinal product include: lactose monohydrate.
A full list of excipients is provided in section 6.1.

3. Dosage form

Film-coated tablets.
Round, biconvex, film-coated tablets, white to off-white with a yellowish tint, may have a characteristic odor.

4. Clinical data

Indications

• Consequences of acute cerebral circulation disorders, including those after transient ischemic attacks, in the subcompensation phase as prophylactic courses;
• Mild traumatic brain injury, consequences of traumatic brain injury;
• Encephalopathies of various origin (dyscirculatory, dysmetabolic, post-traumatic, mixed);
• Vegetative dystonia syndrome;
• Mild cognitive disorders of atherosclerotic origin;
• Anxiety disorders in neurotic and neurosis-like states;
• Ischemic heart disease as part of complex therapy;
• 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;
• Exposure to extreme (stressful) factors;
• Attention deficit hyperactivity disorder (ADHD) in children, including hyperactivity, disorder of attention, and impulsiveness.

4.3. Dosage regimen and method of administration

Dosage regimen:
Orally 125-250 mg 3 times a day; maximum daily dose is 750 mg. Duration of treatment is 2-8 weeks; for relief of alcohol withdrawal - 5-7 days. Treatment is discontinued gradually, reducing the dose over 2-3 days.
The initial dose is 125-250 mg (1-2 tablets) 1-2 times a day with a gradual increase until a therapeutic effect is achieved.
For the treatment of the consequences of acute cerebrovascular accidents, including after transient ischemic attacks, tablets are prescribed after a course of the drug in the form of a solution for intravenous and intramuscular administration.
The duration of the course of therapy in patients with ischemic heart disease is at least 1.5-2 months. Repeated courses (as recommended by a doctor) are preferably carried out in the spring and autumn.

Children
For attention deficit hyperactivity disorder (ADHD) in children, including hyperactivity, attention deficit, impulsivity: 125 mg 2 times a day for 6 weeks.

Directions for use:
Take orally with water.

4.3. Contraindications

• Individual hypersensitivity to the drug or any of its components listed in section 6.1;
• Acute liver and/or kidney dysfunction;
• Pediatric use in children of up to 6 years of age (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 rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

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

Mexidol® is compatible with all drugs used to treat somatic diseases. It enhances the effects of benzodiazepines, antidepressants, anxiolytics, anticonvulsants, and anti-Parkinsonian drugs. The drug reduces the toxic effects of ethyl alcohol.

4.6. Fertility, pregnancy and lactation:

Mexidol® 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. Pharmacology

Pharmacotherapeutic group: antioxidant agent.
ATX code: N07XX.

Mechanism of action:
Mexidol®'s mechanism of action is due to its antioxidant, antihypoxic, and membrane-protective effects. It inhibits lipid peroxidation, increases superoxide dismutase activity, improves the lipid-protein ratio, reduces membrane viscosity, and increases membrane fluidity. Mexidol® modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase) and receptor complexes (benzodiazepine, GABA, and acetylcholine), enhancing their ligand-binding capacity, helping to maintain the structural and functional organization of biomembranes, neurotransmitter transport, and improved 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 ATP and creatine phosphate levels, activating the energy-synthesizing functions of mitochondria, and stabilizing cell membranes.
Mexidol® increases dopamine levels in the brain.

Pharmacodynamic effects:
Mexidol® is a free-radical inhibitor and membrane protector with antihypoxic, stress-protective, nootropic, anticonvulsant, and anxiolytic effects. It increases the body's resistance to various damaging factors (shock, hypoxia and ischemia, cerebrovascular accidents, alcohol intoxication, and antipsychotic drug (neuroleptic) intoxication). 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® improves the functional state of ischemic myocardium. In conditions of coronary insufficiency, Mexidol® increases collateral blood flow to the ischemic myocardium, helps maintain the integrity of cardiomyocytes and support their functional activity. It effectively restores myocardial contractility in reversible cardiac dysfunction. It stabilizes the membrane structures of blood cells (erythrocytes and platelets) during hemolysis. The drug improves metabolism and blood flow to the brain, improves microcirculation and blood rheology, and reduces platelet aggregation.
Mexidol® significantly reduces the severity of attention deficit hyperactivity disorder in children aged 6-12 years: it reduces the severity of symptoms of inattention, hyperactivity/impulsivity, and promotes clinical improvement. Use of the drug in ADHD helps improve concentration and focus, improve perseverance, reduce signs of hyperactivity, and decrease impulsivity, which contributes to improved learning and social adaptation in children.
Mexidol® has a pronounced antitoxic effect in withdrawal syndrome. It eliminates the neurological and neurotoxic manifestations of acute alcohol intoxication, restores behavioral disorders and autonomic functions, and can also alleviate cognitive impairment caused by prolonged ethanol use and withdrawal. Mexidol® enhances the effects of tranquilizers, neuroleptics, antidepressants, hypnotics, and anticonvulsants, allowing for lower dosages and reduced side effects.

Clinical Efficacy and Safety
A randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and safety of Mexidol® in long-term sequential therapy in patients with hemispheric ischemic stroke in the acute and early recovery periods was conducted in 150 patients aged 40 to 79 years. Patients were randomized into 2 groups: the first group received Mexidol® therapy at a dose of 500 mg per day intravenously by drip for 10 days, followed by 1 tablet (125 mg) 3 times a day for 8 weeks. A significant reduction in symptoms and functional impairment was demonstrated in the Mexidol® therapy group. With the use of Mexidol®, a significantly more pronounced improvement in vital functions was observed compared to placebo: at the end of therapy, the average score on the modified Rankin Scale (mRS) was lower in the Mexidol® group (p = 0.04); the dynamics of the average score decrease on the mRS was also more pronounced in this group (p = 0.023). The proportion of patients who achieved recovery corresponding to 0-2 points on the mRS (visit 5) was significantly higher in the Mexidol® group compared to placebo - 59 (96.7%) and 53 (84.1%), respectively (p = 0.039). At the end of therapy, neurological deficit was significantly lower in the Mexidol® group: when testing on the National Institutes of Health stroke scale at visit 5, the average value was lower in the first group (p = 0.035). The use of Mexidol® contributed to improved functional recovery: the proportion of patients without spatial mobility problems was significantly higher in the first group (p = 0.022). According to the results of a subanalysis, the effectiveness of Mexidol® across all scales used was equal in all age groups. No significant differences in the frequency of adverse reactions were found in patients in both groups.
A multicenter, double-blind, randomized, placebo-controlled clinical trial in three parallel groups to evaluate the efficacy and safety of Mexidol® film-coated tablets, 125 mg, in the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-12 years using various dosing regimens (MEGA) was conducted in 333 patients.
Based on the results of the efficacy endpoint assessment at the end of 6 weeks of therapy, statistically significant changes were obtained in the total score for the inattention and hyperactivity/impulsivity subscales of the SNAP-IV scale, the mean change in the scores for the inattention subscale of the SNAP-IV scale, the mean change in the scores for the hyperactivity/impulsivity subscale of the SNAP-IV scale, the mean change in the scores for the Conners Index of the SNAP-IV scale, the mean change in the value of the ADHD Rating Scale IV, the assessment for the Clinical Global Impressions of ADHD severity (CGI-ADHD-S), and the assessment for the Clinical Global Impressions Scale – Improvement (CGI-I). The superior efficacy of Mexidol® over placebo was proven.
According to the study results, statistically significant changes in the total score for the inattention and hyperactivity/impulsivity subscales of the SNAP-IV scale after 6 weeks of therapy were revealed in all three study groups (p < 0.05). Moreover, between the Mexidol®+Placebo and Placebo groups, as well as between the Mexidol® and Placebo groups, there were pronounced statistically significant differences (for the PP population: p = 0.000308 and p = 0.000024, respectively; for the FAS population: p = 0.000198 and p = 0.000024, respectively). The upper limit of the 95% confidence interval for the difference in the means of the primary efficacy indicator in the Mexidol®+Placebo and Placebo groups was -1.22 in the PP population and -1.33 in the FAS population; In the Mexidol® and Placebo groups, it was -3.25 in the PP population and -3.36 in the FAS population.
For the FAS population of all patients included in the study, the upper limit of the 95% confidence interval is a negative value, which allows us to state the superior efficacy of Mexidol® over Placebo. Analysis for the PP population confirms this conclusion.
According to the assessment of the severity of ADHD using the Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S), 66 patients in the Mexidol® group (59.46%), 34 patients in the Mexidol®+Placebo group (30.63%), and 25 patients in the Placebo group (22.52%) had a score of 3 or less at the end of therapy. When evaluating the Clinical Global Impressions Scale – Improvement (CGI-I), improvement was observed in 95 (85.59%) subjects in the Mexidol® group, 84 (75.68%) subjects in the Mexidol®+Placebo group, and 50 (45.05%) subjects in the Placebo group, while significant improvement was noted in 45 (40.54%) subjects in the Mexidol® group, 20 (18.02%) subjects in the Mexidol®+Placebo group, and 10 (9.01%) subjects in the Placebo group. Statistically significant differences were found between the groups (Pearson χ2 test, p < 0.000001).
The results of statistical analysis of the incidence of AEs, laboratory test parameters, and physical examination demonstrate the absence of significant differences between the compared groups in terms of the main safety parameters. The above indicates a comparable nature of the safety profiles of the studied dosage regimens of Mexidol® and Placebo.

5.2. Pharmacokinetics:

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

Distribution
The average retention time of the drug in the body when taken orally 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 and, with the participation of alkaline phosphatase, decomposed 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;
Povidone K-30;
Magnesium stearate;
Film coating:
Hypromellose;
Titanium dioxide;
Lactose monohydrate;
Macrogol;
Triacetin.

6.2. Incompatibility:

Not applicable.

6.3. Validity period (shelf life)

3 years.
Do not use after the expiration date printed on the package.

6.4. Special storage precautions:

Store in a dark place at a temperature not exceeding 25°C.
Keep out of reach of children.

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, or 5 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

Russia
LLC "NPK "PHARMASOFT"
115407, Moscow, Sudostroitelnaya St., 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:
In the Russian Federation:
NPK PHARMASOFT LLC
115407, Moscow, Sudostroitelnaya St., 41, floor 1, office 12
Tel./Fax: +7 (495) 626-47-55
E-mail: pharmasoft@pharmasoft.ru

8. Marketing authorization number

ЛП-No.(000086)-(РГ-RU)

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

Date of the first registration: 10/30/2020

10. Text revision date

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