Information Leaflet of Mexidol® solution for intravenous and intramuscular administration 50 mg/ml, 10 vials of 2 ml

1. Name of the drug

Mexidol® solution for intravenous and intramuscular administration, 50 mg/ml, 2 ml

2. Qualitative and quantitative composition

Active ingredient: ethylmethylhydroxypyridine succinate.
Each 1 ml of solution contains 50 mg of ethylmethylhydroxypyridine succinate.
A 2 ml ampoule contains 100 mg of ethylmethylhydroxypyridine succinate.
Excipients that must be included in the composition of the medicinal product: sodium metabisulfite – 0.4 mg per 1 ml of the drug (see section 4.4).
A full list of excipients is provided in section 6.1.

3. Dosage form

Solution for intravenous and intramuscular administration.
A clear, colorless or slightly yellowish liquid.

4. Clinical data

4.1. Indications:

• acute cerebral circulation disorders;
• cerebral infarction (ischemic stroke);
• 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. Dosage and administration:

Dosage regimen
Adults: the maximum daily dose should not exceed 1200 mg.
In acute cerebrovascular accidents, Mexidol® is used intravenously (IV) by drip, 200-500 mg 2-4 times a day for the first 10-14 days, then intramuscularly (IM) 200-250 mg 2-3 times a day for 2 weeks, after which a transition to oral dosage forms is recommended.
In cases of traumatic brain injury and the consequences of traumatic brain injury, Mexidol® is used intravenously by drip, 200-500 mg 2-4 times a day for 10-15 days, after which a transition to oral dosage forms is recommended.

In cases of cerebral infarction (ischemic stroke), Mexidol is administered intravenously by drip at 500 mg (10 ml) twice daily for 10 days, after which a transition to oral dosage forms at a dose of 250 mg 3 times daily for 60 days is carried out.
For cerebrovascular insufficiency in the decompensation phase, Mexidol® should be administered intravenously by jet stream or drip at a dose of 200-500 mg 1-2 times daily for 14 days. Then, intramuscularly at 100-250 mg per day for the next 2 weeks, after which a transition to oral dosage forms is recommended.
For a course of prophylaxis of cerebrovascular insufficiency, the drug is administered intramuscularly at a dose of 200-250 mg twice daily for 10-14 days, after which a transition to oral dosage forms is recommended.
For chronic cerebral ischemia , Mexidol® should be administered at a dose of 10 ml (500 mg) once daily, intravenously by drip or slow intravenous stream for 14 days, after which a transition to oral dosage forms is recommended.
For mild (moderate) cognitive impairment, Mexidol® should be administered at a dose of 10 ml (500 mg) once daily, intravenously by drip or slow intravenous stream for 14 days, after which a transition to oral dosage forms is recommended.
For anxiety disorders, the drug is administered intramuscularly at a daily dose of 100-300 mg per day for 14-30 days, after which a transition to oral dosage forms is recommended.
In acute myocardial infarction, as part of combination therapy, Mexidol® is administered intravenously or intramuscularly for 14 days against the background of traditional therapy for myocardial infarction, including nitrates, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, thrombolytics, anticoagulant and antiplatelet agents, as well as symptomatic agents as indicated.
In the first 5 days, to achieve the maximum effect, the drug is preferably administered intravenously; in the following 9 days, Mexidol® can be administered intramuscularly.
Intravenous administration of the drug is performed by drip infusion, slowly (to avoid side effects) in 0.9% sodium chloride solution or 5% dextrose (glucose) solution in a volume of 100-150 ml over 30-90 minutes. If necessary, a slow jet injection of the drug is possible for at least 5 minutes.
The drug is administered (intravenously or intramuscularly) 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, a single dose - 250 mg.
For open-angle glaucoma of various stages, as part of combination therapy, Mexidol® is administered intramuscularly at 100-300 mg per day, 1-3 times a day for 14 days.
For alcohol withdrawal syndrome, Mexidol® is administered at a dose of 200-500 mg intravenously by drip or intramuscularly 2-3 times a day for 5-7 days.
In acute intoxication with antipsychotic drugs, the drug is administered intravenously at 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 periods. The administered doses depend on the form and severity of the disease, the prevalence of the process, and the variants of the clinical course. The drug should be discontinued 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, intravenously by drip (in 0.9% sodium chloride solution) and intramuscularly. Mild necrotic pancreatitis - 100-200 mg 3 times a day intravenously by drip (in 0.9% sodium chloride solution) and intramuscularly. Moderate severity - 200 mg 3 times a day, intravenously by drip (in 0.9% sodium chloride solution). Severe cases : 800 mg pulse dose on the first day, administered twice daily; then 200-500 mg twice daily with a gradual reduction in the daily dose. Extremely severe cases : 800 mg per day initially until the symptoms of pancreatogenic shock are persistently relieved; once the condition is stabilized, 300-500 mg twice daily intravenously by drip (in 0.9% sodium chloride solution) with a gradual reduction in the daily dose.

Directions for administration:
IM or IV (jet or drip).
Mexidol® is administered slowly over 5-7 minutes by jet injection, or at a rate of 40-60 drops per minute by drip.
For instructions on preparing the medication before use, see section 6.6.

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 study
  of the drug’s action);
• pediatric use (due to insufficient data on the drug action).

4.4. Special instructions and precautions for use:

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.

Based on the results of clinical studies and post-marketing surveillance, no signals of drug-drug interactions have been identified.

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

Summary of adverse reactions
The frequency of adverse reactions 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 – anaphylactic shock, angioedema, urticaria.
Mental disorders: very rare – drowsiness.
Nervous system disorders: very rare – headache, dizziness (may be associated with an excessively high rate of administration and is short-lived).
Vascular disorders: very rare – decreased blood pressure (BP), increased blood pressure (may be associated with excessively high administration rate and is short-lived).
Respiratory, thoracic, and mediastinal disorders: very rare – dry cough, sore throat, chest discomfort, difficulty breathing (may be associated with excessively high administration rate and is short-lived).
Gastrointestinal disorders: very rare – dry mouth, nausea, unpleasant odor, metallic taste in the mouth.
Skin and subcutaneous tissue disorders: very rare – itching, rash, hyperemia.
General disorders and reactions at the injection site: very rare – sensation of warmth.

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 Pharmacodynamics:

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:
Mexidol®'s mechanism of action is due to its antihypoxic, antioxidant, and membrane-protective effects. It inhibits lipid peroxidation, increases superoxide dismutase activity, improves the lipid-protein ratio, reduces membrane viscosity, and increases membrane fluidity. It modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase) and receptor complexes (benzodiazepine, gamma-aminobutyric acid (GABA), and acetylcholine), enhancing their ligand-binding capacity, helping to maintain the structural and functional organization of biomembranes, neurotransmitter transport, and improve synaptic transmission. Mexidol® increases dopamine levels 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 Krebs cycle under hypoxic conditions with an increase in the content of adenosine triphosphate (ATP), creatine phosphate and activation of the energy-synthesizing functions of mitochondria, stabilization of cell membranes.

Pharmacodynamic effects
: It has antihypoxic, membrane-protective, nootropic, anticonvulsant, and anxiolytic effects, and increases the body's resistance to stress. The drug increases the body's resistance to the effects of major damaging factors and oxygen-dependent pathological conditions (shock, hypoxia and ischemia, cerebrovascular accidents, alcohol intoxication, and intoxication with antipsychotic drugs (neuroleptics)). It stabilizes the membrane structures of blood cells (erythrocytes and platelets) during hemolysis.
Mexidol® improves cerebral metabolism and cerebral blood flow, improves microcirculation and blood rheology, and reduces platelet aggregation. It has a hypolipidemic effect, reducing total cholesterol and low-density lipoprotein (LDL) levels.

The use of Mexidol in cerebral infarction (ischemic stroke) reduces the degree of neurological deficit and improves the recovery of neurological functions, as well as improves functional outcome and reduces disability.
Mexidol® normalizes metabolic processes in the ischemic myocardium, reduces the area of ​​necrosis, restores and improves electrical activity and myocardial contractility, increases coronary blood flow in the ischemic zone, and reduces the consequences of reperfusion syndrome in acute coronary insufficiency. It enhances the antianginal activity of nitro drugs.
Mexidol® helps preserve retinal ganglion cells and optic nerve fibers in progressive neuropathy caused by chronic ischemia and hypoxia. It improves the functional activity of the retina and optic nerve, increasing visual acuity.
It reduces enzymatic toxemia and endogenous intoxication in acute pancreatitis.

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. In the Mexidol® therapy group, a significant reduction in symptoms and functional impairment was demonstrated compared to placebo. 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 at the end of therapy 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 the end of therapy, the average value was lower in the Mexidol® group (p = 0.035). The use of Mexidol® contributed to improved functional recovery: the proportion of patients without problems with spatial mobility was significantly higher (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, and the safety profile of long-term sequential therapy with Mexidol® was comparable to placebo in patients of different age groups.
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 were randomized into 2 groups: the first group received therapy with Mexidol® at 10 ml (500 mg) once a day intravenously by drip or intravenous by slow stream for 14 days, followed by Mexidol® FORTE 250 at 1 tablet 3 times a day for the next 60 days. According to the study results, at the end of therapy, statistically significant changes in scores on the Montreal Cognitive Assessment (MoCA) were revealed when comparing the dynamics between the Mexidol®/Mexidol® FORTE 250 and Placebo 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 allows us to state the superior efficacy of Mexidol® and Mexidol® FORTE 250 over Placebo. Also, according to the study results, statistically significant changes in scores on the Montreal MoCA scale at the end of patient therapy were revealed to compare the dynamics between the groups of Mexidol® and Mexidol® FORTE 250 and Placebo during a subanalysis for all age groups, which indicates equal efficacy of Mexidol® and Mexidol® FORTE 250 in all age groups. 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 MoCA scale; 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 Vein 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 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 demonstrate the absence of significant differences between the compared groups in terms of the main safety parameters, which indicates a comparable safety profile of the studied drugs Mexidol® and Mexidol® FORTE 250 and Placebo. A subanalysis in patients of different age groups demonstrated a similar safety profile of Mexidol® + Mexidol® FORTE 250 (ethyl methylhydroxypyridine succinate) and Placebo.

A prospective, international, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Mexidol + Mexidol FORTE 250 (MIR, phase III) when used sequentially in patients in the acute and early recovery periods of ischemic stroke was conducted on 304 patients aged 40 to 75 years. Patients in the study group received therapy with Mexidol 50 mg/ml, 10 ml (500 mg) 2 times a day (1000 mg per day) intravenously by drip for 10 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.
At the end of therapy, the change in the patient's condition assessment results using the mRS scale relative to the baseline was -2.45 points in the Mexidol + Mexidol FORTE 250 group and -2.01 points in the placebo group, and this difference was statistically significant (p = 0.003). At the end of therapy, a statistically significant prevalence of the proportion of disabled patients (3 or more points on the mRS scale) was revealed in the Placebo group (28%) compared to the Mexidol + Mexidol FORTE 250 group (16%) (p = 0.016). At the same time, the proportion of patients with an assessment of 0-1 point on the mRS scale at the end of therapy was statistically significantly (p = 0.002) higher in the Mexidol + Mexidol FORTE 250 group (60%) than in the Placebo group (41%). The obtained results of the study allow us to state a higher efficacy of Mexidol + Mexidol FORTE 250 compared to Placebo in improving the functional outcome of the disease and reducing the level of disability.
Also, by the end of therapy, a statistically significant difference was recorded in terms of absolute dynamics, compared with the baseline level and on the NIHSS scale: -7.00 [-9.00; -6.00] points in the Mexidol + Mexidol FORTE 250 group and -7.00 [-8.00; -5.00] points in the Placebo group (p < 0.001). Thus, when using Mexidol + Mexidol FORTE 250, a statistically significant, more pronounced recovery of neurological functions was noted compared to Placebo. The median of absolute dynamics according to the Rivermead index in the group of patients receiving Mexidol + Mexidol FORTE 250 at the end of therapy was 10.00 [7.00; 12.00] points compared to the Placebo group – 9.00 [7.00; 11.00] points (statistically significant differences between groups at p = 0.008). According to the obtained results, the use of Mexidol in the acute and early recovery periods of ischemic stroke improves the patient’s activity and mobility, which leads to more successful rehabilitation. An additional analysis in the ITT population, including data from early termination visits, confirmed the above findings.
Statistical analysis of vital signs. SBP, DBP, HR and RR were statistically significantly normalized in both groups. Thus, no negative effect of Mexidol on the cardiovascular system was detected. A safety analysis based on adverse reaction reporting revealed no evidence of adverse drug interactions between the study drug Mexidol (parenteral and oral administration) and other medications (antihypertensive, antithrombotic, and lipid-lowering) included in the background therapy. A
statistical analysis of the incidence of adverse events, physical examination data (including vital signs), and laboratory and instrumental examination results demonstrated no significant differences between the comparison groups in terms of key safety parameters.

5.2.Pharmacokinetics:

Absorption:
Following intramuscular administration, absorption is detectable in plasma for 4 hours after administration. The time to reach maximum concentration (Tmax) is 0.45-0.5 hours. Cmax after administration of a dose of 400-500 mg is 3.5-4.0 mcg/ml.

Distribution:
Rapidly passes from the bloodstream into organs and tissues and is rapidly eliminated from the body. The drug's mean residence time (MRT) is 0.7-1.3 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 drug is excreted mainly in urine, mainly in glucuronide-conjugated form and in small amounts unchanged.

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:

• 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. Shelf life:

3 years.

6.4. Special storage precautions:

Store in a place protected from light at a temperature no higher than 25°C.

6.5. Description and content of the primary packaging

2 ml of the drug in ampoules made of colorless glass of the 1st hydrolytic class or neutral glass grade NS-3 with a break point and three marking rings (upper - yellow, middle - white, lower - red) or without marking rings.
A label made of writing paper, label paper, or self-adhesive is affixed to the ampoule, or the inscriptions on the ampoule are applied with intaglio or inkjet ink for glass products, or the inscriptions are applied by enamel printing with subsequent heat treatment.
Five ampoules are placed in a blister pack made of EP-73 polyvinyl chloride film.
For 2 ml ampoules, two or four blister packs along with instructions for medical use (insert leaflet) are placed in a cardboard pack for consumer packaging.

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.
For intravenous administration, the drug should be diluted in 100-150 ml of 0.9% sodium chloride solution or 5% dextrose (glucose) solution.

7. Marketing authorization holder

Russia

NPK PHARMASOFT LLC
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.(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

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://eec.eaeunion.org/.