Tornid rg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORNID RG (TORNID RG)

Composition:

Active substance: torasemide;

1 ml of injection solution contains torasemide calculated as 100 % dry substance – 5 mg;

Excipients: polyethylene glycol (macrogol) 400, tromethamine, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution practically free from mechanical particles. pH of torasemide: 8.5–9.5.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Torasemide acts as a diuretic; its effect is associated with inhibition of renal reabsorption of sodium and chloride ions in the ascending limb of the loop of Henle.

Pharmacodynamic effects. In humans, the diuretic effect rapidly reaches its maximum within the first 2–3 hours after intravenous and oral administration, respectively, and remains consistent for approximately 12 hours. In healthy volunteers, within the dose range of 5–100 mg, a logarithmic dose-proportional increase in diuresis was observed (loop diuretic activity). Increased diuresis was observed even in cases where other diuretics, such as distally acting thiazide-type diuretics, had already failed to produce the desired effect, for example, in renal insufficiency. Due to this mechanism of action, torasemide administration leads to reduction of edema. In heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing both preload and afterload.

Pharmacokinetics.

Absorption and distribution. Torasemide plasma protein binding exceeds 99%; metabolites M1, M3, and M5 are bound to plasma proteins by 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

Biotransformation. In the human body, torasemide is metabolized to form three metabolites—M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1 and M5 are formed by stepwise oxidation of the methyl group attached to the phenyl ring into a carboxylic acid; metabolite M3 is formed by hydroxylation of the ring. Metabolites M2 and M4, detected in animal experiments, were not identified in humans.

Elimination. The terminal half-life (t½) of torasemide and its metabolites in healthy volunteers is 3–4 hours. Total clearance of torasemide is 40 mL/min, renal clearance is approximately 10 mL/min. In healthy volunteers, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites in the following average percentages: torasemide—approximately 24%, metabolite M1—approximately 12%, metabolite M3—approximately 3%, metabolite M5—approximately 41%. The main metabolite M5 has no diuretic effect; the combined contribution of the active metabolites M1 and M3 accounts for approximately 10% of the total pharmacokinetic activity. In renal insufficiency, total clearance and t½ of torasemide remain unchanged, while t½ of M3 and M5 is prolonged. However, pharmacodynamic characteristics remain unchanged, and the severity of renal insufficiency does not affect the duration of action. Torasemide and its metabolites are hardly eliminated by hemodialysis or hemofiltration.

In patients with impaired liver function or heart failure, t½ of torasemide and metabolite M5 is slightly prolonged, but the amount of substance excreted in urine is almost equal to that in healthy volunteers; therefore, accumulation of torasemide and its metabolites does not occur.

Linearity. The pharmacokinetics of torasemide and its metabolites are characterized by linear kinetics. This means that maximum plasma concentration and area under the plasma concentration-time curve increase proportionally with dose.

Clinical characteristics.

Indications.

Treatment of edema and/or effusions caused by heart failure, when intravenous administration of the drug is required, for example, in the case of pulmonary edema due to acute heart failure.

Contraindications.

Hypersensitivity to the active substance, sulfonylurea drugs, or to any of the excipients of the medicinal product.

Renal failure with anuria.

Hepatic coma or precoma.

Arterial hypotension.

Hypovolemia.

Hyponatremia.

Hypokalemia.

Acute impairment of urination, for example due to prostatic hypertrophy. Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Combinations not recommended.

Torasemide, especially at high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics, such as kanamycin, gentamicin, tobramycin, and cytostatic agents – active platinum derivatives, as well as the nephrotoxic effects of cephalosporins.

Concomitant use of torasemide and lithium preparations may increase lithium plasma concentration, potentially leading to enhanced effects and increased adverse reactions of lithium.

Medicinal product combinations requiring caution.

Torasemide enhances the effects of other antihypertensive agents, including angiotensin-converting enzyme inhibitors, which may result in excessive reduction of arterial blood pressure during their concomitant use. When torasemide is used concomitantly with digoxin preparations, potassium deficiency caused by diuretic use may lead to increased and enhanced adverse effects of both drugs. Torasemide may reduce the effectiveness of antidiabetic agents. Probenecid and nonsteroidal anti-inflammatory drugs (e.g., indomethacin, acetylsalicylic acid) may inhibit the diuretic and antihypertensive effects of torasemide. When treating with high-dose salicylates, torasemide may increase their toxic effects on the central nervous system. Torasemide may enhance the effects of theophylline and the muscle-relaxing effects of curare-like medicinal agents. Laxatives, as well as mineralo- and glucocorticoids, may intensify potassium loss induced by torasemide. Torasemide may reduce the vasoconstrictive effects of catecholamines, such as epinephrine and norepinephrine.

Special precautions for use.

Torasemide should not be prescribed in the following cases:

• gout;
• cardiac arrhythmias, e.g. sinoatrial block, second- and third-degree atrioventricular block;
• pathological changes in acid-base metabolism;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood abnormalities, e.g. thrombocytopenia or anemia in patients without renal insufficiency;
• renal dysfunction caused by nephrotoxic substances;
• in children under 18 years of age.

Since increased blood glucose concentration may occur during treatment with torasemide, patients with latent or manifest diabetes mellitus should undergo regular monitoring of carbohydrate metabolism. Particular attention should be paid, especially at the beginning of treatment and when treating elderly patients, to the emergence of symptoms of hemoconcentration and symptoms of electrolyte loss. With prolonged use of torasemide, regular monitoring of electrolyte balance, particularly serum potassium levels, is required. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is necessary. Furthermore, regular monitoring of complete blood count (erythrocytes, leukocytes, platelets) should be performed.

Consequences of misuse as doping. Administration of the medicinal product TORNID RG, ampoules, may lead to a positive doping test result. The health consequences of incorrect use of TORNID RG, i.e. for doping purposes, cannot be predicted; in such cases, harm to health cannot be ruled out.

Excipients. This medicinal product contains less than 1 mmol of sodium (23 mg) per ampoule, i.e. it can be considered virtually sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking. Reproductive toxicity of torasemide has been demonstrated in animal experiments. Torasemide crosses the placental barrier. The medicinal product is not recommended for use in pregnant women or women of childbearing potential who are not using contraception. Therefore, torasemide should be used during pregnancy only under life-threatening conditions and at the minimum effective dose. Diuretics are not suitable for standard treatment regimens of arterial hypertension or edema in pregnant women, as they may reduce placental perfusion and cause toxic effects on fetal development. If torasemide is used to treat pregnant women with cardiac or renal insufficiency, careful monitoring of electrolyte levels and hematocrit, as well as fetal development, is required.

Lactation. It is currently unknown whether torasemide or its metabolites are excreted in breast milk in animals or humans. Risk to newborns/infants cannot be excluded. Therefore, the use of torasemide during lactation is contraindicated (see section "Contraindications"). A decision to discontinue breastfeeding or to discontinue/abandon treatment with the medicinal product should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment with the medicinal product for the woman.

Fertility. Studies on the effects of torasemide on fertility in humans have not been conducted. Animal experiments did not reveal any effect of torasemide on fertility.

Ability to affect reaction rate while driving or operating machinery.

Even when used at recommended doses, torasemide may negatively affect reaction speed while driving or operating machinery. This is particularly relevant at the beginning of treatment, during dose escalation, when switching medications, when initiating concomitant therapy, or when consuming alcohol. Therefore, caution should be exercised while using this medicinal product when driving or operating machinery.

Method of Administration and Dosage.

Edema and/or effusions due to heart failure. Treatment should be initiated with a single dose of 2 mL of TORNID RG, equivalent to 10 mg of torasemide per day. If the effect is insufficient, the single dose may be increased to 4 mL of TORNID RG, equivalent to 20 mg of torasemide. If the effect remains inadequate, short-term therapy (for no more than 3 days) with a daily dose of 8 mL of TORNID RG, equivalent to 40 mg of torasemide, may be used.

Acute pulmonary edema. Treatment should be initiated with intravenous administration of a single dose of 4 mL of TORNID RG, equivalent to 20 mg of torasemide. Depending on the response, this dose may be repeated at 30-minute intervals. The maximum daily dose of 20 mL of TORNID RG, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups.

Elderly patients. No specific dose adjustment is required. However, studies comparing the effect of the drug in younger and elderly patients have not been conducted.

Patients with hepatic impairment. Torasemide is contraindicated in patients with hepatic coma or precoma (see section "Contraindications"). Treatment in this patient group should be performed with caution, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Method of administration. The injection solution should be administered slowly intravenously. Only clear, transparent solutions should be used. Intra-arterial administration is prohibited. The medicinal product must not be used if signs of solution decomposition are present (e.g., presence of suspended particles) or if the ampoule is damaged. One ampoule is intended for single use only. Any unused solution must be immediately disposed of according to local legislation. TORNID RG must not be mixed with other medicinal products for intravenous injection and/or infusion (see section "Incompatibilities"). During prolonged treatment, intravenous administration should be replaced as soon as possible with oral administration, as intravenous administration of torasemide is not recommended for longer than 7 days.

Children. The safety and efficacy of TORNID RG in children under 18 years of age have not been established. Therefore, torasemide should not be used in this age group (see section "Special precautions for use").

Overdose.

Symptoms of intoxication. The typical clinical picture is unknown. Overdose may cause pronounced diuresis, including the risk of excessive loss of water and electrolytes, somnolence, confusion, symptomatic arterial hypotension, circulatory collapse, and gastrointestinal disturbances.

Treatment of overdose. No specific antidote is known. Symptoms of intoxication usually resolve with dose reduction or discontinuation of the drug and appropriate fluid and electrolyte replacement (monitoring is required). Torasemide is not removed from blood by hemodialysis.

Treatment in case of hypovolemia: fluid volume replacement.

Treatment in case of hypokalemia: administration of potassium supplements.

Treatment in case of circulatory collapse: place the patient in a supine position and, if necessary, initiate symptomatic therapy.

Anaphylactic shock (emergency measures). At the first signs of skin reactions (e.g., urticaria or skin redness), patient agitation, headache, excessive sweating, nausea, or cyanosis, venous catheterization should be performed; the patient should be placed in a horizontal position, free air access ensured, and oxygen administered. If necessary, further treatment should include intensive care measures (including administration of epinephrine, glucocorticoids, and circulating blood volume replacement).

Adverse Reactions

The adverse reactions listed below may occur during the use of the medicinal product TORINID RG.

The following frequency categories were used to assess the occurrence of adverse reactions: very common: ≥1/10, common: ≥1/100 to <1/10, uncommon: ≥1/1000 to <1/100, rare: ≥1/10,000 to <1/1000, very rare: <1/10,000, frequency not known: cannot be estimated from available data.

Blood and lymphatic system disorders: very rare – haemoconcentration, thrombocytopenia, erythropenia and/or leukopenia (see section "Special precautions for use").

Immune system disorders: very rare – allergic reactions. After intravenous administration, acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur, requiring immediate medical intervention.

Metabolism and nutrition disorders: common – exacerbation of metabolic alkalosis, hyperkalemia, hypokalemia in patients on a low-potassium diet, with vomiting, diarrhea, after excessive use of laxatives, and in patients with chronic liver dysfunction. Depending on dose and duration of treatment, disturbances in fluid and electrolyte balance such as hypovolemia, hypokalemia and/or hyponatremia may occur (see section "Special precautions for use").

Nervous system disorders: common – headache, dizziness (especially at the beginning of treatment); rare – paresthesia; very rare – syncope, cerebral ischemia, confusion.

Eye disorders: very rare – visual disturbances.

Ear and labyrinth disorders: very rare – tinnitus, hearing loss.

Cardiac disorders: very rare – myocardial ischemia, arrhythmia, angina pectoris, acute myocardial infarction.

Vascular disorders: very rare – thromboembolic complications, arterial hypotension, circulatory disorders in the heart and disturbances of central circulation.

Gastrointestinal disorders: common – gastrointestinal disturbances (e.g., loss of appetite, stomach pain, nausea, vomiting, diarrhea, persistent constipation), especially at the beginning of treatment; rare – xerostomia; very rare – pancreatitis.

Hepatobiliary disorders: common – increased blood concentrations of certain liver enzymes (γ-glutamyl transpeptidase).

Skin and subcutaneous tissue disorders: very rare – allergic reactions (e.g., pruritus, rash, photosensitization), severe skin reactions.

Musculoskeletal and connective tissue disorders: common – muscle cramps (especially at the beginning of treatment).

Renal and urinary disorders: rare – in patients with impaired urination (e.g., due to prostate hyperplasia), increased urine production may be accompanied by urinary retention and bladder distension.

General disorders and administration site conditions: common – increased fatigue, general weakness (especially at the beginning of treatment).

Investigations: common – increased blood concentrations of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions for use"); rare – increased blood concentrations of urea and creatinine (see section "Special precautions for use").

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Incompatibilities. The contents of the ampoules must not be mixed with other medicinal products intended for intravenous injection and/or infusion.

Packaging. 4 ml in an ampoule; 5 ampoules in a blister; 1 blister in a carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhym-Kharkiv".

Address of manufacturer and location of its operations.
36 Severyna Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.