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.
1 mL of the solution contains 50 mg of ethylmethylhydroxypyridine succinate.
2 mL vial contains 100 mg of ethylmethylhydroxypyridine succinate.
Main excipients: sodium metabisulfite – 0.4 mg in 1 mL of the drug (see section 4.4.).
A complete 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:

• 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;
  
• withdrawal syndrome in alcoholism with predominance
  of neurosis-like and vegetative-vascular disorders;
• acute intoxication with antipsychotic drugs;
• acute purulent-inflammatory processes of the abdominal cavity (acute necrotizing
  pancreatitis, peritonitis) as part of complex therapy.

4.2. Dosage and administration:

Dosage regimen Adults: the maximum daily dose should not exceed 1,200mg.
Acute cerebral circulation disorders: 200-500 mg of Mexidol® is administered intravenously (IV) by drop infusion 2-4 times a day for the first 10-14 days, followed by 200-250 mg intramuscularly (IM) 2-3 times a day for 2 weeks. Then it is recommended to switch to oral dosage forms.
Traumatic brain injury and its consequences: 200-500 mg of Mexidol® is administered by IV drop infusion 2-4 times a day for 10-15 days/ Then it is recommended to switch to oral dosage forms.
Dyscirculatory encephalopathy in the decompensation phase: 200-500 mg of Mexidol® is administered by IV stream or drop infusion 1-2 times a day for 14 days. Then it should be administered IM at a dose of 100-250 mg per day for the next 2 weeks. Then it is recommended to switch to oral dosage forms.
Dyscirculatory encephalopathy prevention course: the drug is administered IM at a dose of 200-250 mg 2 times a day for 10-14 days. Then it is recommended to switch to oral dosage forms.
Chronic cerebral ischemia: 10 ml (500 mg) of Mexidol® is administered by IV drop or (slow) stream infusion 1 time a day for 14 days. Then it is recommended to switch to oral dosage forms.
Mild (moderate) cognitive disorders:  10 ml (500 mg) of Mexidol® is administered by IV drop or (slow) stream infusion 1 time a day for 14 days. Then it is recommended to switch to oral dosage forms.
Anxiety disorders: the drug is administered IM at a dose of 100-300 mg 1 time a day for 14-30 days. Then it is recommended to switch to oral dosage forms.
Acute myocardial infarction as part of complex therapy: Mexidol® is administered IV or IM for 14 days in connection with conventional therapy of myocardial infarction, including nitrates, beta-blocking agents, inhibitors of angiotensin-converting enzyme (ACE), thrombolytics, anticoagulant and antiplatelet agents, as well as symptomatic agents as indicated.
To achieve the maximum effect, the drug should be administered IV within the first 5 days. During the the next 9 days, IM administrtion is possible.
IV administration is performed by drop infusion, slowly (to avoid side effects), using 100-150 ml of 0.9% sodium chloride solution or 5% dextrose (glucose) solution for 30-90 minutes. If necessary, the drug can e administered by slow stream infusion for at least 5 minutes.
Administration of the drug (IV or IM) is performed 3 times a day every 8 hours. The daily therapeutic dose is 6-9 mg/kg of the body weight per day, the single dose is 2-3 mg/kg of the body weight. The maximum daily dose should not exceed 800 mg, the maximum single dose should not exceed 250 mg.
Open-angle glaucoma of various stages as a part of complex therapy: 100-300 mg of Mexidol® is administered IM 1-3 times a day for 14 days.
Withdrawal alcohol syndrome: Mexidol® is administered at a dose of 200-500 mg by IV drop infusion or IM 2-3 times a day for 5-7 days.
Acute intoxication with antipsychotic agents: the drug is administered IV at a dose of 200-500 mg per day for 7-14 days.
Acute purulent-inflammatory processes of the abdominal cavity (acute necrotizing pancreatitis, peritonitis): the drug is administered in the first day of both preoperative and postoperative periods. The administered doses depend on the form and severity of the disease, the spread of the process, and clinical patterns. The drug should be withdrawn gradually only after achieving a sustainable positive clinical and laboratory effect.
Acute edematous (interstitial) pancreatitis: 200-500 mg of Mexidol® is administered 3 times a day by IV drop infusion (in 0.9% sodium chloride solution) and by IM injection. Necrotizing pancreatitis of mild severity: 100-200 mg 3 times a day by IV drop infusion (in 0.9% sodium chloride solution) and by IM injection.   Necrotizing pancreatitis of medium severity: 200 mg of the drug 3 times a day, by IV drop infusion (in 0.9% sodium chloride solution).   Severe necrotizing pancreatitis: pulse dosage of 800 mg on the first day using two-time mode of administration, followed by 200-500 mg 2 times a day with a gradual decrease in the daily dose.  Extremely severe necrotizing pancreatitis: 800 mg a day initially until persistent relief of manifestations of pancreatogenic shock, after stabilization of the condition, the during is taken at a dose of 300-500 mg 2 times a day by IV drop infusion (in 0.9% sodium chloride solution) with a gradual decrease in the daily dose.

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 data on the drug 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.

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

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.

Summary of adverse reactions
The frequency of adverse reactions was determined pursuant to the World Health Organization (WHO) classification: very common (≥10%), common (≥1 and <10%), uncommon (≥0.1 and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%) and unknown (frequency cannot be determined based on available data).
Immune system disorders: very rare – anaphylactic shock, angioedema, urticaria.
Mental disorders: very rarely - drowsiness.
Nervous system disorders: very rare – headache, dizziness (may be associated with an excessively high rate of administration and is short-term).
Vascular disorders: very rare – decreased blood pressure (BP), increased BP (may be associated with an excessively high rate of administration and is short-term).
Respiratory system, chest and mediastinal organs disorders: very rare – dry cough, throat congestion, chest discomfort, difficulty breathing (may be associated with an excessively high rate of administration and is short-term).
Gastrointestinal disorders: very rare – dry mouth, nausea, unpleasant odor, metallic aftertaste.
Skin and subcutaneous tissue disorders: very rare – itching, rash, hyperemia.
General disorders and reactions at the injection site: very rare – warmth sensation.

Reporting suspected adverse reactions
It is important to report suspected adverse reactions after the marketing authorization of a drug in order to ensure continuous monitoring of its benefit-risk ratio. Healthcare professionals are advised to report any suspected adverse reactions of the drug 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 usually not required, symptoms disappear within a day. In the case of pronounced manifestations, supportive and symptomatic treatment should be administered.

5. Pharmacological properties

5.1 Pharmacodynamics:

Pharmacotherapeutic group: antioxidant agent.
ATX Code: N07XX.

The pharmacological action
of Mexidol is due to its antihypoxant, antioxidant and membrane-protective action. It inhibits lipid peroxidation processes, increases superoxide dismutase activity, increases the lipid-protein ratio, reduces membrane viscosity and increases membrane fluidity. The drug 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 to preserve the structural and functional organization of biomembranes, transport neurotransmitters and improve synaptic transmission. Mexidol® increases the content of dopamine in the brain. It causes enhancement of compensatory activity of aerobic glycolysis and reduction of the inhibition rate of oxidative processes in the Krebs cycle under hypoxia with an increased content of adenosine triphosphate (ATP), creatine phosphate and activation of energy-synthesizing functions of mitochondria, as well as promotes stabilization of cell membranes.

Pharmacodynamic effects
The drug has an antihypoxic, membrane-protective, nootropic, anticonvulsant, anxiolytic effect, and increases the body’s resistance to stress. The drug increases the body’s resistance to major damaging factors and oxygen-dependent pathological conditions (shock, hypoxia and ischemia, impaired cerebral circulation, intoxication with alcohol and antipsychotic agents (neuroleptics)). It stabilizes membrane structures of blood cells (erythrocytes and platelets) in hemolysis.
Mexidol® improves cerebral metabolism and blood supply to the brain, improves microcirculation and rheological properties of blood, and reduces platelet aggregation. It has a hypolipidemic effect, reduces the levels of total cholesterol and low-density lipoproteins (LDLs).
Mexidol® normalizes metabolic processes in ischemic myocardium, reduces the necrosis area, restores and improves myocardial electrical activity and contractility, as well as increases coronary blood flow in the ischemia area and mitigates the consequences of reperfusion syndrome in acute coronary insufficiency. It increases antianginal activity of nitrates.
Mexidol® promotes preservation of 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, and increases the visual acuity.
The drug reduces enzymatic toxemia and endogenous intoxication in patients with acute pancreatitis.

The clinical performance and safety
A randomized double-blind placebo-controlled parallel-group study of efficacy and safety of Mexidol® in phase III (EPICA) in long-term sequential therapy in patients with hemispheric ischemic stroke in the acute and early recovery periods involved 150 patients aged 40 to 79. The patients were randomized into 2 groups: the first group was treated with Mexidol® 500 mg daily by IV drop infusion for 10 days followed by 1 tablet (125 mg) 3 times a day for 8 weeks. The Mexidol® group showed a significant reduction of symptoms and functional disorders, as compared with the placebo group. Mexidol® administration led to significantly more pronounced improvement of vital activity in comparison with the placebo: the average score on the Modified Rankin Scale (mRS) at the end of therapy was lower in the Mexidol® group (p = 0,04). Furthermore, this group demonstrated more pronounced dynamics of decrease in the mRS average score (p = 0.023). The proportion of the patients who achieved recovery corresponding to 0-2 points on the mRS at the end of therapy was significantly higher in the Mexidol® group in comparison with the placebo group: 59 (96,7%) and 53 (84,1%), respectively (p = 0.039). The neurological deficit at the end of therapy was significantly lower in the Mexidol® group: the testing according to the National Institute of Health Stroke Scale showed that the mean value at the end of therapy was lower in the Mexidol® group (p = 0.035). The use of Mexidol® contributed to better functional recovery: the proportion of the patients with no spatial mobility issues was significantly higher (p = 0.022). According to the subanalysis results, the efficacy of Mexidol® on all of the scales used was identical in all of the age groups. There were no significant differences in the frequency of adverse reactions in the patients of both groups, and the safety profile of long-term sequential therapy with Mexidol® was comparable to that of the placebo in the patients of different age groups.
An international multicenter randomized double-blind placebo-controlled study to evaluate the efficacy and safety of sequential therapy with Mexidol® and Mexidol® FORTE 250 in phase III (MEMO) in patients with chronic cerebral ischemia involved 318 patients aged from 40 to 90. The patients were randomized into 2 groups: the first group was treated with Mexidol® 10 ml (500 mg) daily by IV drop or stream infusion slowly for 14 days followed by Mexidol® FORTE 250 1 tablet 3 times a day for the next 60 days. According to the results of the study, statistically significant changes in scores on the Montreal Cognitive Assessment Scale (MoCA) were detected at the end of therapy when comparing the progress between the groups of Mexidol®/Mexidol® FORTE 250 and the placebo (p < 0.000001, t-test for independent samples). The lower boundary of the 95% confidence interval for the mean difference of the main efficacy index between the groups of Mexidol®/Mexidol® FORTE 250 and the placebo was 1.51. This boundary is a positive value, indicative of the superior efficacy of Mexidol® and Mexidol® FORTE 250 over the placebo. Moreover, the results of the study revealed statistically significant changes of the MoCa scores at the end of therapy by the patient for the purpose of comparison of the progress between the groups of Mexidol® and Mexidol® FORTE 250 and placebo in the subanalysis for all of the age groups, which indicates equal efficacy of Mexidol® and Mexidol® FORTE 250 in all of the age groups. According to the results of evaluating secondary endpoints of efficacy of Mexidol® and Mexidol® FORTE 250 during the therapy, statistically significant differences between the drug groups and the placebo group were obtained for the following indicators: changes in cognitive impairment severity over time on the MoCA scale; changes in cognitive impairment severity over time according to the digit symbol substitution test; changes in asthenic disorders severity over time according to the Multidimensional Fatigue Inventory MFI-20; vegetative changes over time according to the Vein’s Questionnaire; changes in the anxiety level over time according to the Beck Depression Inventory; motor changes over time according to the Tinetti test; changes in the general clinical impression over time using the Clinical Global Impressions Scale; changes in the patients’ quality of life according to the Short Form (36) Health Survey questionnaire (psychological component of health).
The results of the statistical analysis of the adverse events frequency as well as the results of laboratory tests and physical examination demonstrate the absence of significant differences between the compared groups in terms of the primary safety endpoints, which is indicative of the comparable nature of the safety profiles of Mexidol® and Mexidol® FORTE 250 and the placebo. The subanalysis performed in patients of different age groups confirmed the similar nature of safety profiles of Mexidol®+Mexidol® FORTE 250 (ethylmethylhydroxypyridine succinate) and the placebo.

5.2.Pharmacokinetics:

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
The drug is metabolized in the liver by glucuronic conjugation. 5 metabolites have been identified: 3-oxypyridine phosphate is formed in the liver and decompounds into phosphoric acid and 3-oxypyridine by alkaline phosphatase; the 2nd metabolite is pharmacologically active, is formed in large quantities and detected in the urine 1-2 days after administration; the 3rd metabolite is excreted in large quantities with urine; the 4th and 5th metaolites are glucuronic conjugates.

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. 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 is packaged into vials made of colorless glass of the 1st hydrolytic class or neutral glass of NS-3 grade with a snap-off neck and three marking rings (yellow upper ring, white middle ring, red lower ring) or without marking rings.
The vial has a label made of writing paper, or label paper, or self-adhesive paper, or is inscribed with rotogravure ink or ink for inkjet printing for glassware or using enamel printing with subsequent heat treatment.
5 vials are placed into a blister pack made of polyvinyl chloride film type EP-73.
2 or 4 blister packs of 2 ml vials are placed into a folding-box carton pack together with the patient information leaflet (package insert).

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.
When administered by infusion, 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

PHARMASOFT RESEARCH AND PRODUCTION COMPLEX LLC
Bld. 12, floor 1, 41, Sudostroitelnaya Street, 115407 Moscow, Russia  
tel./Fax: +7 495 626-47-55
Email: Pharmasoft@pharmasoft.ru

7.1 Representative of the marketing authorization holder:

Please address consumer complaints to:
in the Russian Federation:
"LLC “RESEARCH AND PRODUCTION COMPANY “PHARMASOFT”
Bld. 12, floor 1, 41, Sudostroitelnaya Street, 115407 Moscow, Russia
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 summary of product characteristics for Mexidol® is available on the information portal of the Eurasian Economic Union in the Internet information and communication network at http://eec.eaeunion.org/.