Diutor®

INSTRUCTIONS for medical use of the medicinal product Diutor® (Diutor)

Composition:

Active substance: torasemide;

1 ml of injection solution contains 5 mg of anhydrous torasemide;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Diuretics. High-ceiling diuretics. Simple sulfonamides. Torasemide.

ATC code C03CA04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Torasemide acts as a saluretic; 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 constant 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, for example, distally-acting thiazide-type diuretics, had already failed to produce the desired effect, such as in renal insufficiency. Due to this mechanism of action, torasemide leads to reduction of edema. In cases of heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing preload and afterload.

Pharmacokinetics.

Absorption and distribution. Binding of torasemide to plasma proteins exceeds 99%, while binding of metabolites M1, M3, and M5 is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

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

Elimination. The terminal half-life (t1/2) of torasemide and its metabolites in healthy volunteers is 3–4 hours. Total clearance of torasemide is 40 mL/min, with renal clearance being approximately 10 mL/min. In healthy volunteers, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites, with the following average percentage distribution: torasemide—approximately 24%, metabolite M1—approximately 12%, metabolite M3—approximately 3%, metabolite M5—approximately 41%. The main metabolite M5 has no diuretic activity, while the combined contribution of active metabolites M1 and M3 accounts for approximately 10% of the total pharmacokinetic effect. In renal insufficiency, total clearance and t1/2 of torasemide remain unchanged, while t1/2 of M3 and M5 is prolonged. However, pharmacodynamic characteristics remain unchanged, and the severity of renal insufficiency does not affect the duration of action. In patients with impaired liver function or heart failure, t1/2 of torasemide and metabolite M5 is slightly prolonged, but the amount of substance excreted in urine is nearly equal to that in healthy individuals; therefore, accumulation of torasemide and its metabolites does not occur. Torasemide and its metabolites are poorly eliminated by hemodialysis and hemofiltration.

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

Preclinical safety data.

In studies of pharmacological safety, chronic toxicity, mutagenicity, and carcinogenicity in animals, no data indicating increased risk of the drug in humans were obtained. In reproductive toxicity studies in animals, no teratogenic effects of the drug were observed. However, in pregnant rabbits and rats administered high doses of the drug, signs of fetal toxicity and maternal toxicity were observed. It has been noted that in rats, torasemide crosses the placental barrier. The drug had no effect on fertility.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the active substance, sulphonilurea 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 urinary obstruction, for example due to prostate hyperplasia;
• breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

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 effect 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.

Combinations of medicinal products requiring caution. Torasemide enhances the effects of other antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, which may result in excessive reduction of arterial blood pressure when used concomitantly. When torasemide is used concomitantly with digoxin preparations, potassium deficiency caused by torasemide may lead to increased incidence and severity of 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 enhance their toxic effects on the central nervous system. Torasemide may enhance the action 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 action 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 count abnormalities, such as thrombocytopenia or anemia in patients without renal insufficiency;
• Renal dysfunction caused by nephrotoxic substances;
• In children and adolescents under 18 years of age.

Since torasemide treatment may lead to increased blood glucose levels, 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. During 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, complete blood count (erythrocytes, leukocytes, platelets) should be monitored regularly.

Consequences of misuse as a doping agent

The use of the medicinal product Diuver® may lead to a positive result in doping tests. It is impossible to predict the health effects when Diuver® is misused, i.e., used for doping purposes; in such cases, potential harm to health cannot be excluded.

Excipients

The medicinal product contains less than 1 mmol (20 mg)/dose of sodium, i.e., it is nearly 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 studies. Torasemide crosses the placental barrier. The medicinal product Diuver® is not recommended during pregnancy and in women of childbearing potential who do not use contraception. Due to the above, torasemide should be used during pregnancy only under life-threatening indications 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 heart or renal failure, careful monitoring of electrolytes and hematocrit, as well as fetal development, is required.

Lactation period. It is currently unknown whether torasemide or its metabolites are excreted in breast milk in animals or humans. The risk of using the drug in newborns/infants cannot be excluded. Therefore, the use of torasemide during lactation is contraindicated. The decision to discontinue breastfeeding or to discontinue/stop treatment with Diuver® should be made by considering the benefits of breastfeeding for the child and the benefits of treatment for the woman.

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

Ability to affect reaction speed when driving or operating machinery.

Even when used correctly, torasemide may negatively affect reaction speed when driving or operating machinery. This primarily applies to the initial phase of treatment, periods of dose escalation, drug substitution, initiation of concomitant therapy, and alcohol consumption. Therefore, extreme caution is required when driving or operating machinery during torasemide treatment.

Method of Administration and Dosage

Adults

Edema and/or effusions due to heart failure

Treatment should be initiated with a single dose of 2 mL of Diutor® medicinal product, equivalent to 10 mg of torasemide per day. If the effect is insufficient, the single dose may be increased to 4 mL of Diutor® medicinal product, 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 Diutor® medicinal product, equivalent to 40 mg of torasemide, may be used.

Acute pulmonary edema

Treatment should begin with intravenous administration of a single dose of 4 mL of Diutor® medicinal product, equivalent to 20 mg of torasemide. Depending on the effect, this dose may be repeated at 30-minute intervals. The maximum daily dose of 20 mL of Diutor® medicinal product, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups

Elderly patients. Dose adjustment is not required. However, studies comparing the drug's effects in younger and elderly patients have not been conducted.

Patients with hepatic impairment. Torasemide is contraindicated in patients with hepatic coma or precoma. Treatment in these patients should be performed with caution, as increased plasma concentrations of torasemide may occur.

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 Diutor® must not be used if signs of solution decomposition are present (e.g., presence of suspended particles in the solution) or if the ampoule is damaged. One ampoule is intended for single use only. Any remaining solution must be immediately disposed of according to local regulations. Diutor® must not be mixed with other medicinal products for intravenous injection and/or infusion (see section "Incompatibilities"). With prolonged use, intravenous administration should be replaced as soon as possible with oral administration, since intravenous administration of torasemide is not recommended for more than 7 days.

Children

Safety and efficacy of the drug in children and adolescents under 18 years of age have not been studied. Torasemide should not be used in children and adolescents under 18 years of age due to lack of sufficient clinical experience.

Overdose

Typical symptoms are unknown. Overdose may cause pronounced diuresis, including risk of excessive loss of water and electrolytes, somnolence, amnestic syndrome (a form of consciousness disturbance), 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, along with appropriate fluid and electrolyte replacement (monitoring 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 of circulatory collapse: place patient in a supine position and, if necessary, administer 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 intensive therapy should be initiated (including administration of epinephrine, glucocorticoids, and replacement of circulating blood volume).

Adverse reactions.

Adverse reactions are listed by MedDRA system organ class with the following frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 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.

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 with concomitant low-potassium diet, vomiting, diarrhea, excessive use of laxatives, and in patients with chronic liver dysfunction. Depending on dosage and duration of treatment, disturbances in water-electrolyte balance such as hypovolemia, hypokalemia and/or hyponatremia may occur.

Nervous system disorders. Common: headache, dizziness (especially at the beginning of treatment). Uncommon: 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, as well as 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. Uncommon: xerostomia. Very rare: pancreatitis.

Hepatobiliary disorders. Common: increased concentration of certain liver enzymes (gamma-glutamyl transferase) in blood.

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. Uncommon: with impaired urination (e.g., due to benign prostatic hyperplasia), increased urine formation 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 concentrations of uric acid and lipids (triglycerides, cholesterol) in blood. Uncommon: increased concentrations of urea and creatinine in blood.

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

Shelf life.

2 years. After first opening of the ampoule, the solution should be used immediately.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

The medicinal product Diutor® must not be mixed with other medicinal products for intravenous injection and/or infusion.

Packaging.

4 ml in ampoules, 5 ampoules (5×1) in a cassette with the instruction for medical use in a cardboard box.

Prescription status.

Prescription only.

Manufacturers.

Private Joint Stock Company "Lekhim-Kharkiv" (responsible for manufacturing and batch control/testing, excluding batch release).

LLC NPF "MIKROKHIM" (responsible for batch release, excluding batch control/testing).

Manufacturer addresses and sites of operations.

Ukraine, 61115, Kharkiv region, Kharkiv, 36 Severina Pototskogo Street.

Ukraine, 01013, Kyiv, 5 Budynstustrii Street.

Marketing authorization holder.

LLC NPF "MIKROKHIM".

Address of the marketing authorization holder.

Ukraine, 01013, Kyiv, 5 Budynstustrii Street.

You can report an adverse event associated with the use of the medicinal product Diutor® through the pharmacovigilance system of LLC NPF "MIKROKHIM" by calling +38(050) 309-83-54 (24/7) or via the link: https://microkhim.com.ua/farmakonaglyad.