1. Name of the drug

Mexidol®, 125 mg, film-coated tablets

2. Qualitative and quantitative composition

Active ingredient: ethylmethylhydroxypyridine succinate.
1 tablet contains: ethylmethylhydroxypyridine succinate - 125.0 mg.
Excipients,the presence of which must be taken into account in the composition of the drug: lactose monohydrate
A full list of excipients is given in section 6.1.

3. Dosage form

Film-coated tablets.
Round, biconvex film-coated tablets, from white to white with a yellowish tint; the presence of a characteristic odor is allowed.

4. Clinical data

Indications

• The consequences of acute cerebrovascular accident, 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)
• vegetative dystonia syndrome;
• Mild cognitive disorders of atherosclerotic genesis;
• anxiety disorders in neurotic and neurosis-like states;
• Coronary heart disease as a part of complex therapy;
• 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 (stress) factors;
• Attention deficit hyperactivity disorder (ADHD) in children, including hyperactivity, attention deficit disorder, impulsivity.

4.3. Dosage regimen and method of administration

Dosage regimen
Orally 125-250 mg 3 times a day; maximum daily dose - 750 mg. Duration of treatment is 2-8 weeks; for relief of alcohol withdrawal is 5-7 days. Treatment is stopped gradually, reducing the dose over 2-3 days.
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.
Duration of the course of therapy for patients with coronary 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 periods.

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

Method of administration
Orally, with water.

4.3. Contraindications

• Individual hypersensitivity to the drug and its components listed in section 6.1;
• Acute liver and/or kidney dysfunction;
• Children under 6 years of age (due to insufficient study of the drug's action);
• 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 rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other drugs and other types of interaction

Mexidol® is compatible with all drugs used for the treatment of somatic diseases. It enhances the effects of benzodiazepines, antidepressants, anxiolytics, anticonvulsants, and anti-Parkinsonian agents. It reduces the toxic effects of ethanol.

4.6. Fertility, pregnancy and lactation

Mexidol® is contraindicated during pregnancy and 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

Summary of adverse reactions
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 %); frequency unknown (frequency cannot be determined on the basis of available data).
Immune system disorders: very rarely - 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.
Skin and subcutaneous tissue disorders: 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
Overdose is unlikely due to low toxicity. Treatment is usually not required, because symptoms disappear on their own within 24 hours. In case of severe manifestations, supportive and symptomatic treatment is carried out.

5. Pharmacological properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: antioxidant agent.
ATX Code: N07XX.

The mechanism of action
of Mexidol® is due to its antioxidant, antihypoxic and membrane-protective action. It inhibits lipid peroxidation, increases the activity of superoxide dismutase, increases the lipid-protein ratio, reduces membrane viscosity, and increases its fluidity. Mexidol® modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase), receptor complexes (benzodiazepine, 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 causes an increase in compensatory activation of aerobic glycolysis and a decrease in the degree of inhibition of oxidative processes in the Krebs cycle under hypoxic conditions with an increase in the content of ATP and creatine phosphate, activation of the energy-synthesizing functions of mitochondria, stabilization of cell membranes. Mexidol® increases the level of dopamine in the brain.

The pharmacodynamic effects
Mexidol® are an inhibitor of free radical processes, a membrane protector with antihypoxic, stress-protective, nootropic, anticonvulsant and anxiolytic effects. The drug increases the body's resistance to the effects of various damaging factors (shock, hypoxia and ischemia, cerebrovascular accidents, intoxication with alcohol and antipsychotic drugs (neuroleptics)). The anti-stress effect is manifested in the normalization of post-stress behavior, somatovegetative disorders, restoration of sleep-wake cycles, impaired learning and memory processes, reduction of dystrophic and morphological changes in various brain structures. It has a hypolipidemic effect, reduces the content of total cholesterol and low-density lipoproteins. Mexidol® improves the functional state of the ischemic myocardium. In conditions of coronary insufficiency, it increases collateral blood supply to the ischemic myocardium, helps to preserve the integrity of cardiomyocytes and maintain their functional activity. It effectively restores myocardial contractility in reversible cardiac dysfunction. It stabilizes membrane structures of blood cells (erythrocytes and platelets) during hemolysis. The drug improves metabolism and blood supply to the brain, improves microcirculation and rheological properties of blood, reduces platelet aggregation.
Mexidol® reliably reduces the severity of manifestations of attention deficit hyperactivity disorder in children aged 6-12 years: it reduces the severity of symptoms of inattention, hyperactivity/impulsivity, promotes clinical improvement. The use of the drug in ADHD helps to increase concentration and the ability to concentrate, increase perseverance, reduce signs of hyperactivity and reduce impulsivity, which helps to improve learning and social adaptation of children.
Mexidol® has an expressed antitoxic effect in withdrawal syndrome. It eliminates neurological and neurotoxic manifestations of acute alcohol intoxication, restores behavioral disorders, vegetative functions, and it is also able to relieve cognitive impairment caused by long-term ethanol administration and its withdrawal. Under the influence of Mexidol®, the effect of tranquilizing, neuroleptic, antidepressant, hypnotic and anticonvulsant drugs is enhanced, which allows to reduce their doses and reduce side effects.

Clinical efficacy and safety
A randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and safety of Mexidol® (Phase III, Epica) during long-term sequential therapy in patients with hemispheric ischemic stroke in the acute and early recovery periods was conducted involving 150 patients aged 40 to 79 years. Patients were randomized into two groups: the first group received therapy with Mexidol® 500 mg per day intravenously by drip for 10 days, followed by 1 tablet (125 mg) 3 times a day for 8 weeks. The Mexidol® therapy group showed a significant reduction in symptoms and functional disorders. While using Mexidol®, there was a significantly more expressed improvement in life activity 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); also in this group, the dynamics of the decrease in the average score on the mRS was more expressed (p = 0.023). The part of patients who have reached the recovery corresponding to 0-2 points for mRS (the 5th visit) was significantly higher in the Mexidol® therapy group compared to Placebo – 59 (96.7%) and 53 (84.1%), respectively (p = 0.039). At the end of therapy, the neurological deficit was significantly lower in the Mexidol® therapy group: while testing on the National Institutes of Health stroke scale at the 5th visit, the mean value was lower in the first group (p = 0.035). The use of Mexidol® contributed to better functional recovery: the part of patients with no problems with spatial mobility was significantly higher in the first group (p = 0.022). According to the results of the subanalysis, the effectiveness of Mexidol® on all scales used was equal in all age groups. No significant differences in the frequency of adverse reactions were found in patients of both groups.. A multicenter, double-blind, randomized, placebo-controlled, three-parallel-group clinical study with the participation of 333 patients was conducted in order 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 with different dosing regimens (MEGA).

According to the results of the assessment of the efficacy endpoints 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 scores for the inattention subscale of the SNAP-IV scale, the mean change in scores for the hyperactivity/impulsivity subscale of the SNAP-IV scale, the mean change in scores for the Conners Index of the SNAP-IV scale, the mean change in the ADHD Rating Scale IV, the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scale, and the Clinical Global Impressions Scale – Improvement (CGI-I) scale. 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 expressed 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 -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. The 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 assessed using 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, with significant improvement observed 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 a statistical analysis on the frequency of the occurrence of adverse reactions, indicators of laboratory tests, and a physically examination demonstrate the absence of significant differences between compared groups in the main safety indicators. The foregoing indicates the comparable nature of the security profiles of the studied dosing of the drug Mexidol® and Placebo.

5.2. Pharmacokinetic properties

Absorption
The drug is rapidly absorbed in case of oral administration. The maximum concentration at doses of 400-500 mg is 3.5-4.0 mcg/ml. It is quickly distributed in organs and tissues.

Distribution
The mean drug retention time in case of oral administration is 4.9-5.2 hours.

Biotransformation
The drug is metabolized in the liver by glucuronide conjugation. Five metabolites have been identified: 3-hydroxypyridine phosphate is formed in the liver and, with the participation of alkaline phosphatase, decomposes 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 one is excreted in large quantities in the urine; the 4th and 5th metabolites are glucuronide conjugates.

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 stearate;
Film coating;
Hypromellose;
Titanium dioxide;
Lactose monohydrate;
Macrogol;
Triacetin.

6.2. Incompatibility

Not applicable.

6.3. Expiry date (shelf life)

3 years.
Do not use after the expiry date stated 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 in a blister pack made of polyvinyl chloride film and aluminum foil.
1, 2, 3, 4, 5 blister packs together with instructions for use in a cardboard pack.

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

LLC "NPK Pharmasoft" Sudostroitelnaya street, 41, 1st floor, 12th office, Moscow 115407, Russia tel./ Fax: +7 (495) 626-47-55 Email: Pharmasoft@pharmasoft.ru

7.1. Representative of the Marketing Authorization Holder

Consumer claims should be sent to the address in the Russian Federation: LLC "NPK Pharmasoft" Sudostroitelnaya street, 41, 1st floor, 12th office: Moscow, 115407 Russia tel./ Fax: +7 (495) 626-47-55 Email: Pharmasoft@pharmasoft.ru

8. Marketing authorization number

ЛП-№(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 in the information and communication network "Internet" http://www.eurasancommission.org/.