1. Name of the drug

Mexidol®, a solution for intravenous and intramuscular administration, 50 mg/ml, 5 ml

2. Qualitative and quantitative composition

Active substance: ethylmethylhydroxypyridine succinate.
Each 1 ml of the solution contains 50 mg of ethylmethydroxypyridine of succinate.
The ampoule 5 ml contains 250 mg of ethylmethylhydroxypyridine of succinate.
Excipients, the presence of which must be taken into account as part of the drug: sodium metabisulfite - 0.4 mg in 1 ml of the drug (see section 4.4.).
A full list of excipients is given in section 6.1.

3. Dosage form

Solution for intravenous and intramuscular administration.
Transparent colorless or slightly yellowish liquid.

4. Clinical data

4.1. Indications for use

• acute cerebral circulation disorders;
• traumatic brain injury, consequences of traumatic brain injury;
• dyscirculatory encephalopathy;
• chronic cerebral ischemia;
• vegetative dystonia syndrome;
• mild (moderate) cognitive disorders;
• anxiety disorders in neurotic and neurosis-like states;
• acute myocardial infarction (from the first day) as part of complex therapy;
• primary open -angle glaucoma of various stages, as part of complex therapy;
• relief of withdrawal syndrome in alcoholism with a predominance of neurosis-like and vegetative-vascular disorders;
• acute intoxication with antipsychotic drugs;
• Acute purulent-inflammatory processes of the abdominal cavity (acute necrotic pancreatitis, peritonitis) as part of complex therapy.

4.2. Dosing mode and method of application

Adult dosing mode the maximum daily dose should not exceed 1200 mg.
In acute cerebrovascular circulation, Mexidol® is used in the first 10-14 days intravenously (iv) a drop of 200-500 mg 2-4 times a day, then intramuscularly (iv/m) 200-250 mg 2-3 times a A day for 2 weeks, after which the transition to the reception of oral dosage forms is recommended.
In craniocre injury and the consequences of traumatic brain injuries, Mexidol® is used for 10-15 days in/in a drop of 200-500 mg 2-4 times a day, after which the transition to the reception of oral dosage forms is recommended.
In case of discirculatory encephalopathy in the Mexidol® decompensation phase, I should be prescribed in a slope or drop at a dose of 200-500 mg 1-2 times a day for 14 days. Then, in/m of 100-250 mg per day over the next 2 weeks, after which the transition to the reception of oral dosage forms is recommended.
For a course prevention of discirculatory encephalopathy, the drug is administered in/m at a dose of 200-250 mg 2 times a day for 10-14 days, after which the transition to taking oral dosage forms is recommended.
In case of chronic ischemia of the brain of Mexidol®, 10 ml (500 mg) should be prescribed 1 time per day in drip or ivs in the jet slowly for 14 days, after which the transition to the reception of oral dosage forms is recommended.
With mild (moderate) cognitive disorders, Mexidol® should be prescribed 10 ml (500 mg) once a day in/in drip or/in jet slowly for 14 days, after which the transition to the intake of oral dosage forms is recommended.
In case of anxiety disorders, the drug is used in/m in a daily dose of 100-300 mg per day for 14-30 days, after which the transition to the intake of oral dosage forms is recommended.
In acute myocardial infarction as part of complex therapy, Mexidol® is introduced in/in or/m for 14 days against the background of traditional therapy of myocardial infarction, including nitrates, beta-blockers, angiotensin-rising enzyme inhibitors, thrombolytics, anticoagulant and anti-alarms, antico-cargo and anti as well as symptomatic agents according to indications.
In the first 5 days, to achieve the maximum effect, it is advisable to administer the drug, in the next 9 days, Mexidol® can be administered in/m.
Intravenous administration of the drug is carried out by drip infusion, slowly (in order to avoid side effects) with a 0.9 % sodium solution of chloride or a 5 % dextrose solution (glucose) in a volume of 100-150 ml for 30-90 minutes. If necessary, a slow jet administration of the drug lasting at least 5 minutes is possible.
The introduction of the drug (intravenous or intramuscular) is carried out 3 times a day every 8 hours. The daily therapeutic dose is 6-9 mg/kg of body weight per day, a single dose is 2-3 mg/kg of body weight. The maximum daily dose should not exceed 800 mg, one -time - 250 mg.
With open-angle glaucoma of various stages as part of complex therapy, Mexidol® is introduced in/m a day per day, 1-3 times a day for 14 days.
With withdrawal alcohol syndrome, Mexidol® is introduced at a dose of 200-500 mg iv/in drip or/m 2-3 times a day for 5-7 days.
With acute intoxication with antipsychotic agents, the drug is administered in/in a dose of 200-500 mg per day for 7-14 days.
In acute purulent-inflammatory processes of the abdominal cavity (acute necrotic pancreatitis, peritonitis), the drug is prescribed on the first day both in the preoperative and postoperative period. The injected doses depend on the form and severity of the disease, the prevalence of the process, and options for the clinical course. The cancellation of the drug should be carried out gradually only after a stable positive clinical and laboratory effect.
In acute edematous (interstitial) pancreatitis, Mexidol® is prescribed at 200-500 mg 3 times a day, V/V drip (in a 0.9 % sodium chloride solution) and/m. The mild severity of necrotic pancreatitis is 100-200 mg 3 times a day in/in drip (in a 0.9 % sodium chloride solution) and/m. The average severity is 200 mg 3 times a day, iv drip (in a 0.9 % sodium solution of chloride). Heavy current -in a pulse-dosage of 800 mg on the first day, with a double administration mode; Further, 200-500 mg 2 times a day with a gradual decrease in the daily dose. An extremely severe course -in the initial dosage of 800 mg per day before the resistant stopping of pancreatogenic shock manifestations, to stabilize the condition of 300-500 mg 2 times a day in/in drip (in a 0.9 % sodium chloride solution) with a gradual decrease in the daily dosage.

Mode of administration
IM or IV (by drop or stream infusion).
Stream infusion of Mexidol® is performed slowly for 5-7 minutes, and drop infusion of the drug is performed at a rate of 40-60 drops per minute.
See section 6.6 for instructions on how to prepare the drug before use.

4.3. Contraindications

• hypersensitivity to ethylmethylhydroxypyridine succinate or to any of the excipients listed in section 6.1;
• acute renal failure;
• acute hepatic failure;
• pregnancy, breastfeeding (due to insufficient knowledge of the drug);
• pediatric use (due to insufficient data on the drug action).

4.4. Special instructions and precautions while applying

In individual cases, especially in predisposed patients with bronchial asthma with hypersensitivity to sulfites, development of severe hypersensitivity reactions and bronchospasm is possible.

4.5. Interaction with other drugs and other types of interaction

The drug enhances the effects of benzodiazepine anxiolytics, anticonvulsants (carbamazepine) and antiparkinsonian agents (levodopa). The drug reduces the toxic effects of ethyl alcohol.

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

Safety profile summary
To avoid the occurrence of adverse reactions, it is recommended to follow the dosage regimen and the rate of the drug administration.

The resume of unwanted reactions
The frequency of unwanted reactions 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 - anaphylactic shock, angioedema, urticaria.
Mental disorders: very rarely - drowsiness.
Violations of the nervous system: very rarely - headache, dizziness (may be associated with an excessively high speed of administration and is short -term).
Visual disorders: very rarely - lowering blood pressure (blood pressure), increased blood pressure (may be associated with an excessively high speed of administration and is short -term).
Violations of the respiratory system, the organs of the chest and mediastinum: very rarely - dry cough, sore throat, discomfort in the chest, difficulty breathing (may be associated with an excessively high rate of administration and is short -term).
Gastrointestinal disorders: very rarely-dry mouth, nausea, a feeling of unpleasant odor, a metallic taste in the mouth.
Disorders from the skin and subcutaneous tissues: very rarely - itching, rash, hyperemia.
General violations and reactions at the place of administration: very rarely - a feeling of heat.

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

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. Farmacological properties

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: antioxidant agent.
ATX Code: N07XX.

The mechanism of action
Mexol® action mechanism is due to its antihyplance, antioxidant and membraneoprotective effects. It inhibits the processes of lipid peroxidation, increases the activity of superoxidsmutase, increases the ratio of lipid beam, reduces the viscosity of the membrane, and increases its fluidity. The activity of membrane enzymes (calcium-dependent phosphodesturas, adenilatcyclase, acetylcholinesturaz), receptor complexes (benzodiazepin, gamma-aminobatic acid (GABA), acetylcholine), which enhances their ability to bind the structural and functional organization of biomemubin, is modulating manditors and improvement of synaptic programs. Mexidol® increases the content of dopamine in the brain. It causes an increase in the compensatory activity 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), creatine phosphate and activation of energy synthetic functions of mitochondria, stabilization of cell membranes.

Pharmacodynamic effects
have antihypoxic, membrane, nootropic, anticonvulsant, anxiolytic effects, and increases the body's resistance to stress. The drug increases the resistance of the body to the effects of the main damaging factors, to oxygen -dependent pathological conditions (shock, hypoxia and ischemia, cerebrovascular impairment, alcohol intoxication and antipsychotic drugs (antipsychotics)). Stabilizes membrane structures of blood cells (red blood cells and platelets) for hemolysis.
Mexidol® improves brain metabolism and blood supply to the brain, improves microcirculation and rheological properties of blood, reduces platelet aggregation. It has a hypolipidemic effect, reduces the level of total cholesterol and low density lipoproteins (LDL).
Mexidol® normalizes metabolic processes in ischemized myocardium, reduces the necrosis zone, restores and improves the electrical activity and contractility of myocardium, and also increases coronary blood flow in the ischemia zone, reduces the consequences of reperfusion syndrome with acute coronary insufficiency. Increases the antianginal activity of nitrophe -prescription.
Mexidol® helps to preserve ganglion cells of the retina and optic nerve fibers with progressive neuropathy, the causes of which are chronic ischemia and hypoxia. Improves the functional activity of the retina and optic nerve, increasing visual acuity.
Reduces enzymatic toxemia and endogenous intoxication in acute pancreatitis.

The clinical efficiency and safety
randomized double-blind, a clanbo-controlled in parallel groups, the study of the efficiency and safety of the drug Mexidol® Phase III (Epica) with prolonged sequential therapy in patients with hemispheric ischemic strokes in acute and early recovery periods was carried out with the participation of 150 patients aged 40 up to 79 years. Patients were randomized in 2 groups: the first group received therapy with Mexidol® at 500 mg per day in/V for 10 days with the subsequent administration of 1 tablet (125 mg) 3 times a day for 8 weeks. The Mexidol® therapy group shows a significant decrease in symptoms and functional disorders compared to placebo. When using the drug Mexidol®, a reliably more pronounced improvement in vital functions was noted compared to placebo: at the time of the end of the therapy, the average score on the modified Rankin scale (MSHR) was lower in the Mexidol® (P = 0.04) drug; Also in this group there was a more pronounced dynamics of reducing the average score in MSHR (p = 0.023). The proportion of patients who have reached the recovery corresponding to 0-2 points for MSHR upon completion of therapy was reliably higher in the Mexidol® preparation group compared to placebo-59 (96.7 %) and 53 (84.1 %), respectively (p = 0.039). At the time of the end of the therapy, the neurological deficiency was reliably lower in the therapy group Mexidol®: when testing on a stroke scale of the National Institute for Health at the time of the end of therapy, the average value was lower in the therapy group Mexidol® (p = 0.035). The use of Mexidol® contributed to better functional recovery: the proportion of patients with the lack of problems with movement in space was significantly higher (p = 0.022). According to the results of subanalysis, the effectiveness of the drug Mexidol® for all the scales used was equal in all age groups. There were no reliable differences in the frequency of unwanted reactions in patients of both groups, the safety profile of prolonged consistent therapy with Mexidol® was comparable to placebo in patients of various age groups.
International multicenter randomized dual-blind-controlled study on evaluating the effectiveness and safety of sequential therapy with Mexidol® and Mexidol® Forter III (MEMO) in patients with chronic brain ischemia was carried out with the participation of 318 patients aged 40 to 90 years. Patients were randomized in 2 groups: the first group received the therapy with Mexidol® at 10 ml (500 mg) once a day in/in drip or intravenously slowly for 14 days with the subsequent reception of Mexidol® 1 tablet 3 times per 3 times per. day for the next 60 days. 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 cognitive assessment (MOCA) when comparing the dynamics between groups of drugs Mexidol®/Mexidol® Forter 250 and placebo (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 allows us to state the superior effectiveness of the drugs Mexidol® and Mexidol® Forte 250 above the placebo. Also, according to the results of the study, statistically significant changes in points on the Monual MOCA scale at the stage of completion of therapy by the patient were detected to compare the dynamics between groups of drugs Mexidol® and Mexidol® Forte 250 and placebo during subanalysis for all age groups, which indicates equal efficiency of Mexidol® preparations and Mexidol® Fort 250 in all age groups. Based on 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 the placebo according to the following indicators: the dynamics of the severity of cognitive disorders on the MOCA scale; the dynamics of the severity of cognitive disorders on the test of the replacement of digital characters; 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, and physically examinations demonstrate the absence of significant differences between the compared groups by the main safety indicators, which indicates a comparable nature of the safety profiles of the studied drugs Mexidol® and Mexidol® Forte 250 and the placebo. When conducting subanalysis in patients of various age groups, the similar nature of the safety profiles of drugs Mexidol®+Mexidol® Forte 250 (ethylmethylhydroxypyridine succinate) and placebo was proved.

5.2. Pharmacokinetic properties

Absorption
When administered intramuscularly, the drug is detected in blood plasma within 4 h after administration. The time-to-peak-concentration Tmax is 0.45-0.5 h. Cmax at an administration dose of 400-500 mg is 3.5-4.0 µg/mL.

Distribution
The drug rapidly exits the blood stream into organs and tissues and is rapidly eliminated from the body. The mean residence time of the drug (MRT) is 0.7-1.3 h.

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 drug is excreted mainly with urine, typically in the glucuronic conjugated form and in insignificant amounts in the unchanged form.

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. The list of auxiliary substances:

• Sodium metabisulfite;
• Water for injection.

6.2. Incompatibility

This drug should not be mixed with other drugs except those listed in section 6.6.

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

5 ml of the drug into ampoules made of colorless glass of the 1st hydrolytic class or neutral glass of the NS-3 brand with a fault point and three marking rings (upper-yellow, medium-white, lower-red) or without marking rings.
A label of pussy paper, or etiquette, or self -adhesive paper, or inscriptions on the ampoule, is applied to the ampoule are applied with a paint for deep or jet printing for glass products or applied with the method of printing by enamel with subsequent heat treatment.
5 ampoules are invested in a contour cell package from a polyvinyl chloride type EP-73.
For ampoules of 5 ml-1 or 2 contour cell packages along with the instructions for medical use (leaf-liner) in a pack of cardboard for consumer containers.

6.6. Special precautions for disposal of the used drug or waste obtained after the drug administration or handling

There are no special requirements for disposal.
In case of infusion method of administration, the drug should be diluted in 100-150 ml of a 0.9 % sodium chloride solution or 5 % dextrose solution (glucose).

7. Marketing authorization holder

Russia

LLC NPK "Pharmasoft"
115407, Moscow, ul. Shipbuilding, d. 41, floor 1, pom. 12
tel./ Fax: +7 (495) 626-47-55
Email: Pharmasoft@pharmasoft.ru

7.1. Representative of the holder of the registration certificate:

Consumer claims to be sent to the address:
in the Russian Federation:
NPK Farmasoft LLC,
115407, Moscow, st. Shipbuilding, d. 41, floor 1, pom. 12.
Tel./ Fax: +7 (495) 626-47-55
Email: Pharmasoft@pharmasoft.ru

8. Marketing authorization number

ЛП-No.(000107)-(РГ-RU)

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

Date of the first marketing authorization: December 29, 2020.

10. Text revision date

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