Torasemide-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORASEMIDE-TEVA (TORASEMIDE-TEVA)

Composition:

Active substance: torasemide;

1 tablet contains 5 mg or 10 mg of torasemide;

Excipients: lactose monohydrate, corn starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round, biconvex tablets with a break line on one side and embossing 915 (for 5 mg tablets) or 916 (for 10 mg tablets) on the other side.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics. Simple sulfonamide agents. ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Torasemide is a loop diuretic that inhibits renal reabsorption of sodium and chloride ions in the ascending limb of the Henle loop. However, at low doses, the pharmacodynamic profile of torasemide in terms of the extent and duration of diuresis resembles that of thiazides. At higher doses, torasemide produces diuresis with dose-dependent intensity and a high maximum effect. Maximum diuretic activity of torasemide is achieved within 2–3 hours after oral administration. In healthy volunteers, doses ranging from 5 to 100 mg caused a logarithmic increase in diuretic activity. The antihypertensive effect of torasemide is associated with reduced peripheral vascular resistance due to decreased intracellular free Ca²⁺ activity in arterial smooth muscle cells in patients with arterial hypertension. This likely results in reduced vascular contractility and diminished response to endogenous pressor substances such as catecholamines.

Pharmacokinetics

After oral administration, torasemide is rapidly and almost completely absorbed from the gastrointestinal tract. Peak serum concentrations are reached within 1–2 hours. Systemic bioavailability after oral administration is 80–90%. Over 99% of torasemide is bound to plasma proteins, while protein binding of metabolites M1, M3, and M5 is 86%, 95%, and 97%, respectively. The volume of distribution is 16 liters. Torasemide is metabolized via stepwise oxidation, hydroxylation, or ring hydroxylation, resulting in three metabolites – M1, M3, and M5. The hydroxyl metabolites possess diuretic activity. Active metabolites M1 and M3 account for approximately 10% of the pharmacodynamic effect, while metabolite M5 is inactive.

In healthy volunteers, the terminal half-life of torasemide and its metabolites ranges from 3 to 4 hours. Total clearance of torasemide is 40 ml/min, and renal clearance is approximately 10 ml/min. Approximately 80% of the administered dose is excreted via renal tubules as torasemide and its metabolites – torasemide (24%), M1 (12%), M3 (3%), M5 (41%). In patients with impaired renal function, the half-life of torasemide remains unchanged, but the half-lives of metabolites M3 and M5 are prolonged. Hemodialysis and hemofiltration do not significantly remove torasemide and its metabolites. If increased plasma concentrations of torasemide are observed in patients with renal impairment, this is likely due to reduced hepatic metabolism. In patients with heart failure or impaired liver function, the half-life of torasemide and metabolite M5 is slightly prolonged, but accumulation is unlikely.

Clinical characteristics.

Indications.

Essential hypertension.

Edema and/or effusions caused by congestive heart failure.

Contraindications.

Hypersensitivity to torasemide, sulfonylurea, sulfonylurea derivatives, or to any of the excipients of the medicinal product.

Renal failure with anuria.

Hepatic coma and precoma.

Arterial hypotension.

Hypovolemia, hypokalemia, hyponatremia.

Pregnancy, breastfeeding.

Arrhythmia (e.g., sinoatrial block, atrioventricular block of grade II–III).

Concomitant therapy with aminoglycosides or cephalosporins.

Renal dysfunction caused by medicinal products inducing renal damage.

Urinary disorders (e.g., benign prostatic hyperplasia).

Interaction with other medicinal products and other forms of interactions.

When used concomitantly with cardiac glycosides, potassium or magnesium deficiency may increase myocardial sensitivity to these drugs. Concomitant use of torasemide with mineralocorticoids, glucocorticoids, or laxatives may enhance potassium excretion.

Torasemide enhances the effect of antihypertensive agents, particularly angiotensin-converting enzyme (ACE) inhibitors. Sequential or combined therapy, as well as initiation of a new concomitant therapy with an ACE inhibitor, may lead to severe arterial hypotension. This can be minimized by reducing the initial dose of the ACE inhibitor or by reducing the dose of or temporarily discontinuing torasemide 2 to 3 days before starting the ACE inhibitor.

Torasemide may reduce arterial sensitivity to vasoconstrictors, such as adrenaline and noradrenaline.

Torasemide may reduce the effectiveness of antidiabetic agents.

Torasemide, especially at high doses, may enhance the nephrotoxic and ototoxic effects of aminoglycoside antibiotics and etacrynic acid, particularly in patients with renal impairment, as well as the toxicity of cisplatin-containing agents and the nephrotoxic effects of cephalosporins.

An enhanced effect of theophylline and curare-based muscle relaxants is also possible.

Nonsteroidal anti-inflammatory drugs (e.g., indomethacin) may reduce the antihypertensive and diuretic effects of torasemide, likely due to inhibition of prostaglandin synthesis.

Probenecid reduces the efficacy of torasemide by inhibiting tubular secretion.

Increased serum lithium concentrations and enhanced cardiotoxic and neurotoxic effects of lithium are possible.

Torasemide inhibits renal excretion of salicylates, thereby increasing the risk of salicylate toxicity in patients receiving high salicylate doses.

When torasemide is used concomitantly with cholestyramine, absorption of torasemide may be reduced, thus weakening its effect.

Special precautions for use.

Before initiating treatment with the medicinal product, hypokalemia, hyponatremia, hypovolemia, and urinary excretion disorders should be corrected.

Renal and hepatic impairment

Limited data are available on dose adjustment in patients with impaired renal or hepatic function. Treatment should be administered with caution in patients with hepatic impairment, as increased plasma concentrations of the drug may occur. Torasemide should be used with particular caution in patients with liver diseases associated with liver cirrhosis and ascites, since sudden changes in water-electrolyte balance may lead to hepatic coma. Therapy with torasemide (as with other diuretics) in these patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic alkalosis, the drug should be administered concomitantly with aldosterone antagonists or potassium-sparing agents.

During long-term treatment with torasemide, regular monitoring of electrolyte balance (especially in patients receiving concomitant therapy with cardiac glycosides, glucocorticoids, mineralocorticoids, or laxatives), glucose, uric acid, creatinine, and blood lipids, as well as blood cells (erythrocytes, leukocytes, and platelets), is recommended.

Careful monitoring is advised in patients predisposed to hyperuricemia and gout. Blood glucose levels should be monitored in patients with latent or overt diabetes mellitus.

Due to insufficient clinical experience, torasemide is not recommended for use in the following conditions:

− pathological changes in acid-base balance;

− concomitant use of lithium;

− blood disorders (e.g., thrombocytopenia or anemia in patients without renal impairment).

Torasemide-Teva tablets contain lactose. The product should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

There are no data on the effects of torasemide on the human embryo or fetus. Although studies in rats did not reveal teratogenic effects, administration of high doses of torasemide to pregnant rabbits resulted in fetal developmental abnormalities. Torasemide crosses the placental barrier and may cause electrolyte imbalances. There is also a risk of neonatal thrombocytopenia.

Studies on the excretion of torasemide into breast milk have not been conducted. Therefore, torasemide is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

As with other medicinal products affecting blood pressure, patients receiving torasemide should avoid driving or operating machinery requiring high concentration, due to the possible occurrence of dizziness and other related symptoms. This is particularly relevant during the initial treatment period, dose escalation, or switching to other medications.

Dosage and Administration

Essential hypertension: The recommended dose of torasemide is 2.5 mg (1/2 of a 5 mg Torasemide-Teva tablet) once daily. If necessary, the dose may be increased to 5 mg daily. Doses exceeding 5 mg/day do not provide additional blood pressure reduction. The maximum antihypertensive effect is achieved after approximately 12 weeks of continuous treatment.

Edema: The usual recommended dose is 5 mg once daily. This is generally the maintenance dose. If necessary, the dose may be gradually increased up to 20 mg once daily.

Elderly patients

Use with caution, as there is insufficient information regarding the need for dose adjustment in elderly patients.

Patients with hepatic and renal impairment

Information on dose adjustment in patients with hepatic or renal impairment is limited. Torasemide should be used with caution in patients with hepatic impairment, as increased plasma concentrations of torasemide may occur.

Administration

Administer orally. Torasemide-Teva tablets should be taken in the morning, without chewing, with a small amount of liquid. The bioavailability of Torasemide-Teva is not affected by food intake. The duration of treatment depends on the course of the disease.

Children

Safety and efficacy in children have not been established; therefore, torasemide should not be prescribed to this age group.

Overdose

Symptoms: Typical symptoms of intoxication are unknown. In case of overdose, adverse reactions may be intensified (profound diuresis leading to dehydration, hypovolemia, arterial hypotension, hyponatremia, hypochloremic alkalosis, hemoconcentration, somnolence, confusion, cardiovascular insufficiency, loss of consciousness). Gastrointestinal disturbances are possible.

Treatment: There is no specific antidote. Symptoms and signs of overdose may necessitate dose reduction or discontinuation of Torasemide-Teva, along with restoration of fluid and electrolyte balance and symptomatic treatment.

Side effects.

Metabolic side effects: metabolic alkalosis, disturbances of water and electrolyte balance (especially with marked dietary salt restriction), hypokalemia (particularly in cases of insufficient dietary potassium intake, as well as in vomiting, diarrhea, frequent use of laxatives, and impaired liver function); increased levels of uric acid, glucose, and lipids in blood serum; worsening of metabolic alkalosis, hyperuricemia, hypovolemia, hyponatremia.

In cases of pronounced diuresis, especially during initial treatment and in elderly patients, symptoms and signs of electrolyte depletion and volume depletion may occur, such as headache, dizziness, arterial hypotension, weakness, drowsiness, confusion, loss of appetite, and cramps. Dose adjustment is required.

Cardiovascular system side effects: embolism, thromboembolic complications, cardiac ischemia, which may lead, in particular, to cardiac arrhythmia, angina pectoris, acute myocardial infarction, or syncope; extrasystoles, arterial hypotension, accelerated heartbeat, tachycardia.

Gastrointestinal tract side effects: gastrointestinal disturbances (e.g., loss of appetite, upper abdominal pain, stomach pain, nausea, vomiting, diarrhea, constipation, flatulence); dry mouth, pancreatitis.

Renal and urinary tract side effects: urinary retention in patients with urinary tract obstruction, urgent need to urinate, bladder distension, increased serum creatinine and urea levels.

Hepatobiliary system side effects: increased levels of certain liver enzymes, e.g., gamma-glutamyl transferase (GGT).

Blood and lymphatic system side effects: decreased number of erythrocytes, leukocytes, and platelets.

Immune system side effects: allergic skin reactions (e.g., itching, rash); severe skin reactions (e.g., Stevens–Johnson syndrome, toxic epidermal necrolysis).

Skin and subcutaneous tissue side effects: photosensitivity.

Musculoskeletal and connective tissue side effects: muscle spasms.

Nervous system side effects: headache, dizziness, weakness, cerebral ischemia, paresthesia, confusion, drowsiness, increased activity, nervousness.

Respiratory system side effects: nosebleeds.

Eye-related side effects: visual disturbances.

Ear-related side effects: tinnitus, deafness.

General side effects: increased fatigue, asthenia, thirst.

Laboratory findings: increased concentrations of uric acid, glucose, and lipids (e.g., triglycerides, cholesterol).

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister; 2 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and place of business.
Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.