Mexidol^® FORTE 250 (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasoft Npc, LLC (Russia)

Manufactured By

ZiO-Health CJSC (Russia)

Or

Rapharma, JSC (Russia)

Contact Information

PHARMASOFT NPK LLC (Russia)

ATC Code

N07XX (Other drugs for the treatment of nervous system diseases)

Active Substance

Ethylmethylhydroxypyridine succinate

Dosage Form

Mexidol® FORTE 250

Film-coated tablets, 250 mg: 10, 20, 30, 40, 50 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex; the core on the cross-section is almost white.

Excipients: lactose monohydrate, povidone K-30, magnesium stearate.

Film coating composition hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin, iron oxide red dye, iron oxide yellow dye.

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (2) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (4) – cardboard packs.
10 pcs. – blister packs (5) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.

Clinical-Pharmacological Group

Antioxidant drug

Pharmacotherapeutic Group

Other drugs for the treatment of nervous system diseases. Other drugs for the treatment of nervous system diseases

Pharmacological Action

Mechanism of action

The mechanism of action of the drug Mexidol^® FORTE 250 is due to its antioxidant, antihypoxic, and membrane-protective effects. It inhibits lipid peroxidation, increases superoxide dismutase activity, increases the lipid-protein ratio, reduces membrane viscosity, and increases its fluidity.

Mexidol^® FORTE 250 modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase), receptor complexes (benzodiazepine, GABA, acetylcholine), which enhances their ligand-binding ability, contributes to the preservation of the structural and functional organization of biomembranes, neurotransmitter transport, and improvement of synaptic transmission. It causes an enhancement of compensatory activation of aerobic glycolysis and a reduction in the degree of inhibition of oxidative processes in the Krebs cycle under hypoxia with an increase in ATP and creatine phosphate content, activation of the energy-synthesizing functions of mitochondria, and stabilization of cell membranes.

Mexidol^® FORTE 250 increases the dopamine content in the brain.

Pharmacodynamic effects

Mexidol^® FORTE 250 is 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 in pathological conditions (hypoxia and ischemia, cerebrovascular accidents, ethanol intoxication, and antipsychotic agents). 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, and reduction of dystrophic and morphological changes in various brain structures. It has a hypolipidemic effect, reducing the content of total cholesterol and LDL. Mexidol^® FORTE 250 improves the functional state of the ischemic myocardium. It ensures the integrity of the morphological structures and physiological functions of the ischemic myocardium. Under conditions of coronary insufficiency, it increases collateral blood supply to the ischemic myocardium, promotes the preservation of cardiomyocyte integrity and the maintenance of their functional activity. It effectively restores myocardial contractility in reversible cardiac dysfunction. It stabilizes the membrane structures of blood cells (erythrocytes and platelets), reducing the likelihood of hemolysis.

Clinical efficacy and safety

An international multicenter randomized double-blind placebo-controlled phase III study (MEMO) to evaluate the efficacy and safety of sequential therapy with Mexidol^® and Mexidol^® FORTE 250 in patients with chronic cerebral ischemia was conducted with the participation of 318 patients aged 40 to 90 years. Patients in the study group received therapy with Mexidol^® 10 ml (500 mg) once/day IV drip or IV slow bolus for 14 days, followed by Mexidol^® FORTE 250 1 tablet 3 times/day for the next 60 days. Patients in the control group received placebo according to a similar scheme. According to the study results, at the end of therapy, statistically significant changes in scores on the Montreal Cognitive Assessment (MoCA) scale were revealed when comparing the dynamics in the study and control groups (p< 0.000001, t-test for independent samples). The lower limit of the 95% confidence interval for the difference in means of the primary efficacy endpoint in the Mexidol^®/Mexidol^® FORTE 250 and placebo groups was 1.51. This limit is a positive value, which allowed stating the superior efficacy of Mexidol^® and Mexidol^® FORTE 250 over placebo. According to the results of the assessment of secondary efficacy endpoints of Mexidol^® and Mexidol^® FORTE 250 during therapy, statistically significant differences compared to placebo were obtained for the following indicators: dynamics of the severity of cognitive impairment according to the Digit Symbol Substitution Test; dynamics of the severity of asthenic disorders according to the MFI-20 asthenia scale; dynamics of autonomic changes according to the Wayne questionnaire; dynamics of anxiety level according to the Beck scale; dynamics of motor changes according to the Tinetti scale; dynamics of overall 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 frequency of adverse events, laboratory test indicators, and results of physical examination demonstrate the absence of significant differences between the compared groups in the main safety indicators, which proves the safety profile of Mexidol^®, comparable to placebo.

Pharmacokinetics

Absorption

Rapidly absorbed when taken orally. C_max at doses of 400-500 mg is 3.5-4.0 µg/ml.

Distribution

Rapidly distributed in organs and tissues. The mean residence time of the drug in the body when taken orally is 4.9-5.2 h.

Metabolism

Metabolized in the liver by glucuronoconjugation. Five metabolites have been identified: 3-oxypyridine phosphate – formed in the liver and, with the participation of alkaline phosphatase, breaks down into phosphoric acid and 3-oxypyridine; the 2nd metabolite – pharmacologically active, formed in large quantities and detected in urine on days 1-2 after administration; the 3rd – excreted in large quantities in urine; the 4th and 5th – glucuronoconjugates.

Elimination

T_1/2 when taken orally is 2-2.6 h. Rapidly excreted in urine mainly as metabolites and in small amounts – unchanged. Most intensively excreted within the first 4 hours after drug intake. The indicators of excretion of the unchanged drug and metabolites in urine have individual variability.

Preclinical safety data

In preclinical data obtained from standard pharmacological safety studies, toxicity upon repeated administration, genotoxicity, carcinogenic potential, reproductive and ontogenetic toxicity, no particular harm to humans has been identified.

Indications

• Consequences of acute cerebrovascular accidents, including after transient ischemic attacks, in the subcompensation phase as preventive courses;
• Mild traumatic brain injury, consequences of traumatic brain injuries;
• Encephalopathies of various origins (dyscirculatory, dysmetabolic, post-traumatic, mixed);
• Chronic cerebral ischemia;
• Autonomic dystonia syndrome;
• Mild (moderate) cognitive disorders;
• Anxiety disorders in neurotic and neurosis-like states;
• Coronary artery disease (as part of complex therapy);
• Relief of withdrawal syndrome in alcoholism with a predominance of neurosis-like and vegetative-vascular disorders, post-withdrawal disorders;
• Conditions after acute intoxication with antipsychotic agents;
• Asthenic conditions, as well as for the prevention of the development of somatic diseases under the influence of extreme factors and loads;
• Exposure to extreme (stress) factors.

ICD codes

Dosage Regimen

The drug is taken orally at 250 mg 3 times/day, with water.

The initial dose is 250 mg (1 tab.) 1-2 times/day with a gradual increase until a therapeutic effect is achieved. The maximum daily dose is 750 mg (3 tabs.).

The duration of treatment is 2-8 weeks; for relief of alcohol withdrawal – 5-7 days. The duration of the therapy course in patients with coronary artery disease is at least 1.5-2 months.

The course of treatment for chronic cerebral ischemia with Mexidol^® FORTE 250 is recommended to be carried out after completing the course of parenteral therapy with Mexidol^®. Repeated courses (as recommended by a doctor) are preferably conducted in the spring and autumn periods.

Adverse Reactions

The frequency of side effects was determined in accordance with the WHO classification: 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 rarely – angioedema, urticaria.

Psychiatric 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.

Contraindications

• Hypersensitivity to ethylmethylhydroxypyridine succinate or any of the excipients of the drug;
• Acute liver dysfunction;
• Acute renal dysfunction;
• Pregnancy (due to insufficient study of the drug’s action);
• Breastfeeding (due to insufficient study of the drug’s action);
• Childhood (due to insufficient study of the drug’s action);
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Use in Pregnancy and Lactation

Mexidol^® FORTE 250 is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

The drug is contraindicated in acute liver dysfunction.

Use in Renal Impairment

The drug is contraindicated in acute renal dysfunction.

Pediatric Use

The use of the drug in children is contraindicated.

Special Precautions

Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take Mexidol^® FORTE 250.

Use in pediatrics

The safety and efficacy of Mexidol^® FORTE 250 in children under 18 years of age have not been established.

Effect on ability to drive vehicles and operate machinery

Caution should be exercised during the period of drug use when engaging in activities requiring rapid psychophysical reactions (driving vehicles, operating machinery, etc.).

Overdose

Symptoms drowsiness, insomnia.

Treatment due to low toxicity, overdose is unlikely. Treatment is generally not required, symptoms disappear on their own within 24 hours. In case of severe manifestations, supportive and symptomatic treatment is carried out.

Drug Interactions

Mexidol^® FORTE 250 is compatible with all drugs used to treat somatic diseases.

It enhances the action of benzodiazepine drugs, antidepressants, anxiolytics, antiparkinsonian drugs (levodopa) and anticonvulsants (carbamazepine), nitrates.

Reduces the toxic effects of ethanol.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.