TIVORTIN® FORTE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIVORTIN® Forte (TIVORTIN Forte)

Composition:

Active substance: arginine hydrochloride;

1 ml contains 84 mg of arginine hydrochloride;

Excipient: water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear colorless or slightly yellowish-brown solution. Theoretical osmolarity – 797 mosmol/L.

Pharmacotherapeutic group. Blood 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 and acts as an active and versatile cellular regulator of numerous vital functions of the body, demonstrating important protective effects under critical conditions.

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

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

The medicinal product Tivortin® Forte serves as a substrate for NO-synthase—an enzyme that catalyzes the synthesis of nitric oxide in endotheliocytes. The drug activates guanylate cyclase and increases the level of cyclic guanosine monophosphate (cGMP) in vascular endothelium, reduces activation and adhesion of leukocytes and platelets to the vascular endothelium, inhibits the synthesis of adhesion proteins VCAM-1 and MCP-1, thereby preventing the formation and progression of atherosclerotic plaques, and suppresses the synthesis of endothelin-1, a potent vasoconstrictor and stimulator of vascular smooth muscle cell proliferation and migration. Arginine hydrochloride also inhibits the synthesis of asymmetric dimethylarginine—a powerful endogenous stimulator of oxidative stress. The drug stimulates thymus gland activity, which produces T-cells, and regulates blood glucose levels during physical exertion. It exerts an acidifying effect and promotes correction of acid-base balance.

Pharmacokinetics.

During continuous intravenous infusion, the maximum plasma concentration of arginine hydrochloride is observed 20–30 minutes after the start of administration. Arginine hydrochloride 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 manifestations of intermittent claudication, diabetic angiopathy, arterial hypertension, chronic heart failure, hypercholesterolemia, chronic obstructive pulmonary diseases, pulmonary hypertension.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

When using the medicinal product Tivortin® Forte, it should be considered 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 infusion, as the medicinal product may cause hyperkalemia.

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

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

Use with caution in patients with electrolyte metabolism disorders and kidney diseases. If symptoms of asthenia worsen during treatment with the medicinal product, therapy should be discontinued.

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

Use during pregnancy or breastfeeding.

The medicinal product crosses the placenta and therefore may be used during pregnancy only when 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 medicinal product may cause dizziness.

Method of Administration and Dosage

The medicinal product is administered intravenously by drip infusion at a rate of 5 drops per minute for the first 10–15 minutes; thereafter, the infusion rate may be increased to 15 drops per minute.

The daily dose of the drug is 50 ml of solution.

In cases of severe circulatory disturbances in central and peripheral vessels, pronounced signs of intoxication, hypoxia, and asthenic conditions, the dose of the medicinal product may be increased up to 100 ml per day.

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

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 test results.

Children

There is insufficient data regarding the use of this medicinal product in children.

Overdose

Symptoms: renal failure, hypoglycemia, metabolic acidosis.

Treatment: In case of overdose, the infusion of the medicinal product must be discontinued. Monitoring of physiological responses and maintenance of vital functions should be carried out. If necessary, administer alkalizing agents and agents to restore diuresis (diuretics), 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 blood pressure, changes in heart rhythm, chest pain.

Nervous system: headache, dizziness, feeling of fear, weakness, seizures, tremor, more frequent with exceeding the infusion rate.

Laboratory parameters: hyperkalemia.

Reporting of side effects

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as 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. 2 years.

Storage conditions.

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

Incompatibility.

The medicinal product is incompatible with thiopental.

Packaging.

50 ml in glass vials. 1 vial per cardboard box. 100 ml in glass bottles. 1 bottle per cardboard box.

Prescription category. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address and location of its business activities.

108, Kozbartska St., Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.