Ambría

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBRIA

Composition:

active substance: ethylmethylhydroxypyridine succinate;

1 ml of solution contains ethylmethylhydroxypyridine succinate 50.0 mg;

excipients: sodium metabisulfite (E 223), water for injections.

Pharmaceutical form. Injection solution.

Basic physical and chemical properties: colorless or pale brown solution.

Pharmacotherapeutic group. Agents affecting the nervous system. Other drugs for the treatment of central nervous system disorders.

ATC code N07X X.

Pharmacological Properties

Pharmacodynamics

The mechanism of action of the drug is determined by its antioxidant and membrane-protective effects. It inhibits lipid peroxidation, increases the activity of superoxide dismutase, improves the "lipid – protein" ratio, reduces membrane viscosity, and increases its fluidity. It modulates the activity of membrane-bound enzymes (calcium-independent phosphodiesterase, adenylate cyclase, acetylcholinesterase) and receptor complexes (benzodiazepine, gamma-aminobutyric acid (GABA), acetylcholine), thereby enhancing their ligand-binding capacity, promoting preservation of the structural and functional organization of biomembranes, neurotransmitter transport, and improving synaptic transmission. The drug increases dopamine levels in the brain. It enhances compensatory activation of aerobic glycolysis and reduces the degree of suppression of oxidative processes in the Krebs cycle under hypoxic conditions, leading to increased levels of adenosine triphosphate (ATP) and creatine phosphate, activation of mitochondrial energy-synthesizing functions, and stabilization of cellular membranes.

The medicinal product exhibits anti-hypoxic, antioxidant, membrane-protective, nootropic, anxiolytic, stress-protective, and anticonvulsant effects.

The drug enhances the body's resistance to various harmful factors and to oxygen-dependent pathological conditions [shock, hypoxia and ischemia, cerebrovascular disorders, alcohol intoxication, and intoxication with antipsychotic agents (neuroleptics)]. It improves cerebral metabolism and cerebral blood supply, microcirculation, and blood rheological properties, and reduces platelet aggregation. It stabilizes blood cell membrane structures (erythrocytes and platelets) during hemolysis. It exerts a hypolipidemic effect, reducing total cholesterol and low-density lipoprotein (LDL) levels.

Ethylmethylhydroxypyridine succinate normalizes metabolic processes in ischemic myocardium, reduces the area of necrosis, restores and improves myocardial electrical activity and contractility, increases coronary blood flow in the ischemic area, and reduces the consequences of reperfusion syndrome in acute coronary insufficiency. It enhances the antianginal activity of nitrate preparations.

Ethylmethylhydroxypyridine succinate 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 and increases visual acuity.

It reduces enzymatic toxemia and endogenous intoxication in acute pancreatitis.

Clinical Efficacy and Safety

A randomized, double-blind, placebo-controlled, parallel-group phase III clinical trial (EPICA) evaluating the efficacy and safety of ethylmethylhydroxypyridine succinate in long-term sequential therapy was conducted in 150 patients aged 40 to 79 years with hemispheric ischemic stroke in the acute and early recovery periods. Patients were randomized into two groups: the first group received ethylmethylhydroxypyridine succinate therapy at 500 mg daily administered intravenously over 10 days, followed by oral administration of 1 tablet (125 mg) three times daily for 8 weeks. In the ethylmethylhydroxypyridine succinate treatment group, a statistically significant reduction in symptoms and functional impairments was observed compared to placebo. Treatment with ethylmethylhydroxypyridine succinate resulted in a significantly greater improvement in vitality compared to placebo: at the end of therapy, the mean score on the modified Rankin Scale (mRS) was lower in the ethylmethylhydroxypyridine succinate group (p = 0.04); the group also showed a more pronounced reduction in mean mRS score over time (p = 0.023). The proportion of patients achieving recovery corresponding to 0–2 points on the mRS after completion of therapy was significantly higher in the ethylmethylhydroxypyridine succinate group compared to placebo – 59 (96.7%) versus 53 (84.1%), respectively (p = 0.039). At the end of therapy, neurological deficit was significantly lower in the ethylmethylhydroxypyridine succinate group: in the National Institutes of Health Stroke Scale (NIHSS) assessment, the mean score was lower in the treatment group (p = 0.035). Use of ethylmethylhydroxypyridine succinate promoted better functional recovery: the proportion of patients without mobility problems was significantly higher (p = 0.022). According to subgroup analysis, the efficacy of ethylmethylhydroxypyridine succinate was consistent across all age groups using all assessment scales. No statistically significant differences in the frequency of adverse reactions were observed between the two patient groups; the safety profile of long-term sequential therapy with ethylmethylhydroxypyridine succinate was comparable to that of placebo across different age groups.

Pharmacokinetics

Absorption

After intramuscular administration, the drug is detectable in blood plasma for up to 4 hours post-injection. Time to reach maximum concentration (Tmax) is 0.45–0.5 hours. Cmax following a 400–500 mg dose is 3.5–4.0 μg/mL.

Distribution

The drug rapidly transfers from the bloodstream into organs and tissues and is quickly eliminated from the body. Mean residence time (MRT) is 0.7–1.3 hours.

Biotransformation

Metabolized in the liver via glucuronidation. Five metabolites have been identified: 3-hydroxypyridine phosphate – formed in the liver, which, with the participation of alkaline phosphatase, breaks down into phosphoric acid and 3-hydroxypyridine; the second metabolite – pharmacologically active, formed in large quantities and detectable in urine 1–2 days after administration; the third – excreted in large amounts in urine; the fourth and fifth – glucuronide conjugates.

Elimination

The drug is primarily excreted in urine, mainly in glucuronidated form, and to a minor extent unchanged.

Clinical Characteristics

Indications

• Acute cerebral circulation disorders;
• Traumatic brain injury, consequences of traumatic brain injuries;
• Dyscirculatory encephalopathy;
• Chronic cerebral ischemia;
• Neurocirculatory dystonia;
• Mild cognitive impairments of atherosclerotic origin;
• Anxiety disorders in neurotic and neurosis-like conditions;
• Acute myocardial infarction (from the first day) – as part of complex therapy;
• Primary open-angle glaucoma at various stages – as part of complex therapy;
• Alcohol withdrawal syndrome with predominance of neurosis-like and

neurocirculatory disturbances – symptom control;

• Acute intoxication with antipsychotic agents;
• Acute purulent-inflammatory processes in the abdominal cavity (acute necrotic

pancreatitis, peritonitis) – as part of complex therapy.

Contraindications

• Acute hepatic or renal failure;
• Hypersensitivity to the drug;
• Pediatric age;
• Pregnancy;
• Breastfeeding period.

Interaction with other medicinal products and other types of interactions

Ambrіa enhances the effect of benzodiazepine anxiolytics, anticonvulsants (carbamazepine), and antiparkinsonian agents (levodopa). Reduces the toxic effect of ethanol.

Special precautions for use

Ambria contains sodium metabisulfite, which rarely may cause hypersensitivity reactions and bronchospasm. The drug should be used with caution in patients with diabetic retinopathy (the treatment course should not exceed 7–10 days), as the medicinal product may potentiate proliferative processes.

After completion of parenteral administration, to maintain the therapeutic effect achieved, continuation of treatment with the drug orally in the form of tablets is recommended.

Use during pregnancy or breastfeeding

Controlled clinical studies on the safety of using the drug during pregnancy or breastfeeding have not been conducted; therefore, the use of the medicinal product is contraindicated during these periods.

Ability to influence reaction rate while driving or operating machinery

During treatment, caution is required when driving vehicles or operating complex machinery, due to the possibility of adverse effects such as drowsiness, which may affect reaction speed and the ability to concentrate.

Method of Administration and Dosage

Intramuscularly or intravenously (by bolus or infusion). When administered by infusion, the medicinal product should be diluted in isotonic sodium chloride solution. For bolus administration, the drug should be injected slowly over 5–7 minutes; for infusion, at a rate of 40–60 drops per minute. The maximum daily dose should not exceed 1200 mg.

In acute cerebrovascular disorders: administer the drug intravenously by infusion at 200–500 mg 2–4 times daily during the first 10–14 days. Then switch to intramuscular administration at 200–250 mg 2–3 times daily for 2 weeks, followed by transition to oral dosage forms.

In traumatic brain injury and its sequelae: administer the drug for 10–15 days via intravenous infusion at 200–500 mg 2–4 times daily, followed by transition to oral dosage forms.

In decompensated phase of dyscirculatory encephalopathy: administer the drug intravenously either by bolus or infusion at 200–500 mg 1–2 times daily for 14 days. Then switch to intramuscular administration at 100–250 mg daily for the next 2 weeks, followed by transition to oral dosage forms.

For course prophylaxis of dyscirculatory encephalopathy: administer the drug intramuscularly at 200–250 mg twice daily for 10–14 days, followed by transition to oral dosage forms.

In chronic cerebral ischemia: administer 10 ml (500 mg) once daily by intravenous infusion or slow intravenous bolus for 14 days, followed by transition to oral dosage forms.

In mild cognitive impairment in elderly patients and anxiety disorders: administer the drug intramuscularly at a daily dose of 100–300 mg for 14–30 days, followed by transition to oral dosage forms.

In anxiety disorders: administer the drug intramuscularly at a daily dose of 100–300 mg for 14–30 days, followed by transition to oral dosage forms.

In acute myocardial infarction: administer the drug intravenously or intramuscularly for 14 days as an adjunct to standard myocardial infarction therapy, including nitrates, β-adrenoblockers, angiotensin-converting enzyme (ACE) inhibitors, thrombolytics, anticoagulants, antiplatelet agents, and symptomatic treatments as indicated. Intravenous administration is preferred during the first 5 days to achieve maximum effect; intramuscular administration may be used during the subsequent 9 days. Intravenous infusion should be performed slowly (to avoid adverse reactions) by drip infusion in 0.9% sodium chloride solution or 5% glucose solution in a volume of 100–150 ml over 30–90 minutes. If necessary, slow bolus injection may be performed over no less than 5 minutes.

The drug should be administered (intravenously or intramuscularly) three times daily, every 8 hours. The daily therapeutic dose is 6–9 mg per kg of body weight; the single dose is 2–3 mg/kg. The maximum daily dose should not exceed 800 mg; the maximum single dose should not exceed 250 mg.

In open-angle glaucoma of various stages: administer the drug as part of combination therapy intramuscularly at 100–300 mg daily, 1–3 times daily for 14 days.

In alcohol withdrawal syndrome: administer the drug at 200–500 mg intravenously or intramuscularly 2–3 times daily for 5–7 days.

In acute intoxication with antipsychotic agents: administer the drug intravenously at 200–500 mg daily for 7–14 days.

In acute purulent-inflammatory processes of the abdominal cavity (acute necrotizing pancreatitis, peritonitis): administer the drug on the first day both pre- and post-operatively. Dosage depends on the form and severity of the disease, extent of the process, and clinical presentation. Discontinuation of the drug should be gradual and only after a sustained positive clinical and laboratory response.

In acute edematous (interstitial) pancreatitis: administer 200–500 mg three times daily via intravenous infusion (in isotonic sodium chloride solution) and intramuscularly.

Mild degree of necrotizing pancreatitis: 100–200 mg three times daily via intravenous infusion (in isotonic sodium chloride solution) and intramuscularly.

Moderate severity: 200 mg three times daily via intravenous infusion (in isotonic sodium chloride solution).

Severe course: pulse-dose regimen of 800 mg on the first day with administration twice daily; thereafter, 200–500 mg twice daily with gradual reduction of the daily dose.

Very severe course: initial dose of 800 mg daily until persistent resolution of pancreatogenic shock symptoms; after stabilization of the patient's condition, administer 300–500 mg twice daily via intravenous infusion (in isotonic sodium chloride solution) with gradual dose reduction.

Children

Controlled clinical studies on the safety of the drug in children have not been conducted; therefore, the drug should not be used in this patient population.

Overdose

Symptoms

Somnolence, insomnia.

Treatment

Due to low toxicity, overdose is unlikely. Treatment is usually not required; symptoms resolve spontaneously within 24 hours. In cases of pronounced symptoms, supportive and symptomatic therapy should be administered.

Adverse Reactions

To avoid the development of adverse reactions, the dosage regimen and rate of administration of the medicinal product Ambria should be strictly followed.

The frequency of adverse reactions was determined according to 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 not known (frequency cannot be estimated from the available data).

Immune system disorders: very rare – anaphylactic shock, angioedema, urticaria; frequency not known – allergic reactions, hyperemia, possible severe hypersensitivity reactions.

Psychiatric disorders: very rare – somnolence; frequency not known – sleep disturbances, feeling of anxiety, emotional reactivity.

Nervous system disorders: very rare – headache, dizziness (may be related to excessively high infusion rate and may be transient in nature); frequency not known – coordination disorders, tremor.

Cardiac disorders: very rare – decreased/increased arterial blood pressure (may be related to excessively high infusion rate and may be transient in nature); frequency not known – palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: very rare – dry cough, throat irritation, chest discomfort, dyspnea (may be related to excessively high infusion rate and may be transient in nature); frequency not known – bronchospasm.

Gastrointestinal disorders: very rare – dry mouth, nausea, unpleasant odor sensation, metallic taste in the mouth; frequency not known – dyspeptic disorders, diarrhea.

Skin and subcutaneous tissue disorders: very rare – pruritus, rash, facial hyperemia; frequency not known – distal hyperhidrosis.

General disorders and administration site conditions: very rare – sensation of warmth; frequency not known – changes at the injection site.

During prolonged administration of the drug, the following adverse reactions may occur: flatulence, weakness, peripheral edema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities

The medicinal product must not be mixed with other medicinal products. Only use solvents specified in the instructions.

Packaging

2 ml in an ampoule, 5 ampoules in a blister pack, 2 packs in a cardboard box; 5 ml in an ampoule, 5 ampoules in a blister pack and in a cardboard box.

Prescription status

Prescription only.

Manufacturer

K.T. Rompharm Company S.R.L. / S.C. Rompharm Company S.R.L.

Manufacturer's address and location of operations

Str. Eroilor No. 1A, Otopeni city, 075100, Ilfov county, Romania – building Rompharm 1 and Rompharm 2 / Eroilor str. No 1A, Otopeni city, 075100, county Ilfov, Romania – building Rompharm 1 and Rompharm 2.