Torasemide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORASEMIDE (TORASEMIDE)

Composition:

Active substance: torasemide;

1 tablet contains 10 mg of torasemide;

Excipients: lactose monohydrate, maize starch, colloidal silicon dioxide anhydrous, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round-shaped tablets with flat upper and lower surfaces, beveled edges, and a score line on one side.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Torasemide acts as a diuretic, and 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 stable for approximately 12 hours. In healthy volunteers, over 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 leads to reduction of edema. In heart failure, torasemide reduces symptoms of the disease and improves myocardial function by decreasing both preload and afterload.

After oral administration, the antihypertensive effect of torasemide develops gradually, starting from the first week of treatment. Maximum antihypertensive effect is achieved no later than 12 weeks. Torasemide reduces blood pressure by decreasing total peripheral vascular resistance. This effect is explained by normalization of disturbed electrolyte balance, primarily due to reduction of elevated free intracellular calcium ion activity in arterial smooth muscle cells, which has been observed in patients with arterial hypertension.

Likely, this effect reduces increased vascular contractility and/or vascular responsiveness to endogenous vasoactive substances such as catecholamines.

Pharmacokinetics

Absorption and distribution

After oral administration, torasemide is rapidly and almost completely absorbed. Maximum serum concentration (Cmax) is reached within 1–2 hours. Bioavailability is approximately 80–90%. Under conditions of complete absorption, the maximum first-pass hepatic effect does not exceed 10–20%. According to data from two studies, food decreases the rate (dynamic component) of torasemide absorption (Cmax is reduced and tmax is prolonged), but does not affect total absorption. Protein binding of torasemide to plasma proteins exceeds 99%, while for its metabolites M1, M3, and M5, it is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

Metabolism

In humans, torasemide is metabolized to form three metabolites – M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1 and M5 are formed through stepwise oxidation of the methyl group of the phenolic ring to a carboxylic acid. Metabolite M3 is formed by hydroxylation of the phenolic ring. Metabolites M2 and M4, detected in animal studies, have not been identified in humans.

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, and 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 approximate proportions:

torasemide – approximately 24%, metabolite M1 – approximately 12%, metabolite M3 – approximately 3%, metabolite M5 – approximately 41%. The main metabolite M5 has no diuretic activity. The combined contribution of the active metabolites M1 and M3 to the overall pharmacokinetic effect is approximately 10%. In renal insufficiency, total clearance and t1/2 of torasemide remain unchanged, while the elimination half-life of M3 and M5 is prolonged. However, the pharmacodynamic profile remains unchanged. The severity of renal insufficiency does not affect duration of action. Torasemide and its metabolites are poorly removed by hemodialysis and hemofiltration. In patients with hepatic dysfunction or heart failure, the t1/2 of torasemide and metabolite M5 is slightly prolonged. The ratio of unchanged torasemide to its metabolites excreted in urine is almost identical to that in healthy volunteers. Therefore, accumulation of torasemide and its metabolites does not occur.

Linearity

Torasemide and its metabolites exhibit dose-dependent linear kinetics. This means that Cmax and the area under the pharmacokinetic curve (AUC) increase proportionally with dose.

Clinical characteristics.

Indications.

Treatment and prevention of relapses of edema and/or effusions caused by 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.

Significant impairment of urination, for example due to prostate hyperplasia. Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended

Torasemide, especially in 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 lithium effects and adverse reactions.

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. Concomitant use of torasemide with digitalis preparations may lead to potassium deficiency caused by diuretic use, thereby increasing the risk and severity of adverse effects of both medicinal products. 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. Concomitant use with cholestyramine may reduce torasemide absorption and, consequently, its expected efficacy.

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);
• Acid-base metabolism disorders;
• 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 glucose concentration in blood may increase during torasemide therapy, 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 haemoconcentration 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, leucocytes, thrombocytes) should be performed.

Consequences of misuse as a doping agent

The use of the medicinal product Torasemide may lead to a positive doping test result. The health consequences of misuse of Torasemide as a doping agent cannot be predicted, and in such cases harm to health cannot be excluded.

Excipients

The medicinal product Torasemide contains lactose; therefore, patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking. Information regarding reproductive toxicity of torasemide is available. Torasemide crosses the placental barrier. Torasemide is not recommended during pregnancy and in women of childbearing potential who are not using contraceptive measures. Therefore, torasemide should be used during pregnancy only under life-threatening indications and at the lowest 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 failure or renal failure, careful monitoring of electrolyte levels and haematocrit, as well as fetal development, is required.

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

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 influence reaction speed when driving or operating machinery

Even when used correctly, torasemide may negatively affect reaction speed when driving or operating machinery. This is particularly relevant at the beginning of treatment, during dose escalation, when switching medications, during concomitant therapy, and when consuming alcohol. Therefore, special caution should be exercised when driving or operating machinery during treatment with torasemide.

Dosage and Administration

Edema and/or effusions due to heart failure

Adults

Treatment should be initiated with a daily dose of 5 mg of torasemide, equivalent to ½ tablet of Torasemide. This dose is generally considered to be the maintenance dose.

The tablet can be divided into two parts as follows:

Hold the tablet with the index and thumb of both hands, with the score line facing upwards. Press down with the thumbs along the score line to break the tablet.

If the daily dose of 5 mg is insufficient, a daily dose of 10 mg of torasemide should be administered. Depending on the severity of the patient's condition, the daily dose may be increased up to 20 mg per day.

Special patient groups

Elderly patients. No special dose adjustment is required. However, comparative studies of the drug's effect in young 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").

Administration method

Tablets should be taken on an empty stomach with a small amount of liquid. The bioavailability of torasemide is not affected by food intake.

The medicinal product Torasemide is usually administered for a prolonged period or until edema symptoms have subsided.

Children.

The safety and efficacy of Torasemide in children and adolescents under 18 years of age have not been established; therefore, it 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, along with appropriate fluid and electrolyte replacement (serum electrolyte levels should be monitored). Torasemide is not removed from the 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 with legs elevated, free air access ensured, and oxygen administered. If necessary, further treatment should include intensive care measures (including administration of epinephrine, glucocorticoids, and replacement of circulating blood volume).

Side effects

The following adverse reactions may occur during the use of the medicinal product Torasemide.

The frequency of adverse reactions is defined as follows:

Very common: ≥1/10;
Common: ≥1/100 to <1/10;
Uncommon: ≥1/1,000 to <1/100;
Rare: ≥1/10,000 to <1/1,000;
Very rare: <1/10,000;
Frequency not known: cannot be estimated from the available data.

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

Immune system disorders. Very rare: allergic reactions, e.g. pruritus, exanthema, photosensitization, severe skin reactions, rash.

Metabolism and nutrition disorders. Common: worsening of metabolic alkalosis, hyperkalaemia, hypokalaemia in case of concomitant low-potassium diet, vomiting, diarrhoea, excessive use of laxatives, as well as in patients with chronic liver dysfunction. Depending on dosage and duration of treatment, disturbances of water and electrolyte balance such as hypovolaemia, hypokalaemia and/or hyponatraemia may occur (see section "Special precautions for use").

Nervous system disorders. Common: headache, dizziness (especially at the beginning of treatment). Uncommon: paraesthesia. Very rare: syncope, cerebral ischaemia, confusion.

Eye disorders. Very rare: visual disturbances.

Ear and labyrinth disorders. Very rare: tinnitus, hearing loss.

Cardiac disorders. Very rare: myocardial ischaemia, arrhythmia, angina pectoris, acute myocardial infarction, 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, diarrhoea, 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: in case of impaired micturition (e.g. due to prostatic hypertrophy), increased urine production may be accompanied by urinary retention and bladder distension.

General disorders. Common: headache, dizziness, increased fatigue, general weakness (especially at the beginning of treatment). Uncommon: dry mouth, unpleasant sensations in the limbs (paraesthesia). Very rare: visual disturbances, tinnitus, hearing loss.

Investigations. Common: increased concentrations of uric acid and lipids (triglycerides, cholesterol) in blood (see section "Special precautions for use").
Uncommon: increased concentrations of urea and creatinine in blood (see section "Special precautions for use").

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister; 3 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's address and location of manufacturing activity.

16 Barvinkova Street, Lubny, Poltava region, 37500, Ukraine.