TIVARGIN-N

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIVARGIN-N (TIVARGIN-N)

Composition:

active substance: L-arginini hydrochloridum;

1 ml contains 42 mg of arginine hydrochloride (in 100 ml there are 20 mmol of arginine and 20 mmol of chlorides);

excipient: water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish-brown liquid.

Pharmacotherapeutic group. Plasma substitutes and perfusion solutions. Additional solutions for intravenous administration. Amino acids. Arginine hydrochloride.

ATC code B05X B01.

Pharmacological Properties

Pharmacodynamics

Arginine (α-amino-δ-guanidinovaleric acid) is an amino acid belonging to the class of conditionally essential amino acids. It acts as an active and versatile cellular regulator of numerous vital functions in the body and exhibits significant protective effects under critical conditions.

Arginine demonstrates anti-hypoxic, membrane-stabilizing, cytoprotective, antioxidant, free radical-scavenging, and detoxifying activities. It acts as an active regulator of intermediary metabolism and energy supply processes and plays a role in maintaining hormonal balance in the body. It is known that arginine increases blood levels of insulin, glucagon, growth hormone, and prolactin. It participates in the synthesis of proline, polyamines, and agmatine, and is involved in fibrinogenolysis and spermatogenesis. It exerts membrane-depolarizing effects.

Arginine is one of the main substrates in the urea cycle for urea synthesis in the liver. The drug's hypoammonemic effect is achieved by enhancing the conversion of ammonia into urea. It exerts hepatoprotective effects due to its antioxidant, anti-hypoxic, and membrane-stabilizing properties and positively influences energy supply processes in hepatocytes.

Arginine serves as a substrate for nitric oxide synthase (NOS), the enzyme that catalyzes the production of nitric oxide (NO) in endothelial cells. The drug activates guanylate cyclase and increases levels of cyclic guanosine monophosphate (cGMP) in vascular endothelium, thereby reducing leukocyte and platelet activation and adhesion to the vascular endothelium. It suppresses the synthesis of adhesion proteins VCAM-1 and MCP-1, thus preventing the formation and progression of atherosclerotic plaques. It also inhibits the synthesis of endothelin-1, a potent vasoconstrictor and stimulator of vascular smooth muscle cell proliferation and migration. Arginine further inhibits the synthesis of asymmetric dimethylarginine (ADMA), a powerful endogenous inducer of oxidative stress. The drug stimulates thymus gland activity, which produces T-cells, and helps regulate blood glucose levels during physical exertion. It exerts an acidifying effect and contributes to the correction of acid-base balance.

Pharmacokinetics

During continuous intravenous infusion, the maximum plasma concentration of arginine hydrochloride is reached within 20–30 minutes after the start of administration. Arginine crosses the placental barrier, is filtered in the renal glomeruli, but is almost completely reabsorbed in the renal tubules.

Clinical characteristics.

Indications.

Metabolic alkalosis, hyperammonemia, atherosclerosis of heart and cerebral vessels, peripheral vascular atherosclerosis including intermittent claudication, diabetic angiopathy, arterial hypertension, chronic heart failure, hypercholesterolemia, chronic obstructive pulmonary diseases, pulmonary hypertension, fetal growth retardation, and preeclampsia − as part of complex therapy.

Contraindications.

Hypersensitivity to the drug. Severe renal function impairment, hyperchloremic acidosis; history of allergic reactions; use of potassium-sparing diuretics, as well as spironolactone. Myocardial infarction (including history of).

Interaction with other medicinal products and other forms of interaction.

When using the medicinal product Tivargin-N, it should be taken into account that it may cause pronounced and persistent hyperkalemia against the background of renal insufficiency in patients who are taking or have taken spironolactone. Prior use of potassium-sparing diuretics may also lead to increased blood potassium concentration. Concomitant use with aminophylline may increase insulin levels in the blood.

Arginine is incompatible with thiopental.

Special precautions for use.

In patients with renal insufficiency, urine output and plasma potassium levels should be checked before starting the infusion, as the medicinal product may cause hyperkalemia.

The drug should be used with caution in patients with endocrine gland dysfunction. Arginine may stimulate insulin and growth hormone secretion.

If dry mouth occurs, blood glucose levels should be checked.

Caution is advised in patients with electrolyte metabolism disorders and kidney diseases. If symptoms of asthenia worsen during treatment, therapy should be discontinued.

The drug should be used with caution in patients with angina pectoris.

Use during pregnancy or breastfeeding.

The drug crosses the placenta and therefore may be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

There are no data available on the use of the medicinal product during breastfeeding.

Ability to affect reaction speed while driving or operating machinery.

Caution should be exercised when driving or operating machinery, as the drug may cause dizziness.

Method of Administration and Dosage.

The drug is administered intravenously by drip infusion at a rate of 10 drops per minute for the first 10–15 minutes; thereafter, the infusion rate may be increased to 30 drops per minute.

The daily dose of the drug is 100 ml of solution.

In cases of severe circulatory disturbances in central and peripheral vessels, pronounced signs of intoxication, hypoxia, and asthenic conditions, the dose may be increased up to 200 ml per day.

The maximum infusion rate of the solution should not exceed 20 mmol/hour.

For children under 12 years of age, the dose is 5–10 ml per kg of body weight per day.

For the treatment of metabolic alkalosis, the dose can be calculated as follows:

Arginine hydrochloride (mmol)

______________________________________ × 0.3 × body weight (kg)

Base excess (Be) (mmol/L)

Infusion should begin with half of the calculated dose. Any additional correction should be performed after obtaining updated acid-base balance results.

Children.

The drug is indicated for children aged 3 years and older.

Overdose.

Symptoms: renal failure, hypoglycemia, metabolic acidosis.

Treatment. In case of overdose, infusion of the drug must be discontinued. Monitoring of physiological responses and supportive therapy to maintain vital functions should be conducted. If necessary, administer alkalinizing agents and diuretics (saluretics), as well as electrolyte solutions (0.9% sodium chloride solution, 5% glucose solution). Treatment is symptomatic.

Side effects.

General disorders: hyperthermia, feeling of warmth, malaise.

Musculoskeletal system: joint pain.

Gastrointestinal tract: dry mouth, nausea, vomiting.

Skin and subcutaneous tissue: injection site reactions, including hyperemia, itching sensation, skin pallor, up to acrocyanosis.

Immune system: anaphylactic shock, hypersensitivity reactions, including rash, urticaria, angioneurotic edema.

Respiratory system, thoracic organs and mediastinum: dyspnea.

Cardiovascular system: fluctuations in arterial pressure, changes in heart rhythm, chest pain.

Nervous system: headache, dizziness, fear sensation, weakness, seizures, tremor, more frequently when infusion rate exceeds recommended.

Laboratory findings: hyperkalemia.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

The product is incompatible with thiopental.

Packaging.

100 ml or 200 ml in bottles.

1 bottle per pack or 10 bottles per box.

Prescription category.

Prescription only.

Manufacturer.

VIOSEAR S.A. PARENTERAL SOLUTIONS INDUSTRY.

LLC "PHARMASEL".

Manufacturer's address and location of its business activity.

9th km National Road Trikala-Larissa, Taxiarhis Trikala, 42100, Greece.

Ukraine, 07408, Kyiv region, Brovary district, village Kvitneve, Prorizna Street, 3.