Torasemide sandoz®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORASEMIDE SANDOZ® (TORASEMIDE SANDOZ®)

Composition:

Active substance: anhydrous torasemide;

One tablet contains 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, or 200 mg of anhydrous torasemide;

Excipients:

Tablets of 5 mg, 10 mg, or 20 mg – lactose monohydrate, maize starch, colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate;

Tablets of 50 mg, 100 mg, or 200 mg – colloidal anhydrous silicon dioxide, microcrystalline cellulose, magnesium stearate, mannitol (E 421), copovidone, crospovidone, hydrogenated castor oil.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Tablets of 5 mg: round white or almost white tablets with a score line;

Tablets of 10 mg and 20 mg: round white or almost white tablets with a cross-score;

Tablets of 50 mg: round white or almost white tablets without a score;

Tablets of 100 mg: round white or almost white tablets with a score on both sides;

Tablets of 200 mg: round white or almost white tablets with a cross-score on both sides.

Pharmacotherapeutic group.

High-ceiling diuretics. Simple sulfonamide agents. ATC code C03CA04.

Pharmacological properties.

Pharmacodynamics.

Torasemide is a loop diuretic; at low doses used for antihypertensive treatment, it exhibits weak diuretic and saluretic effects. At higher doses, torasemide induces enhanced diuresis in a dose-dependent manner. Torasemide reaches maximum diuretic activity 2–3 hours after oral administration.

Pharmacokinetics.

After oral administration, torasemide is rapidly and almost completely absorbed; maximum serum concentration is achieved within 1–2 hours after intake. Systemic bioavailability is 80–90%. Protein binding of torasemide to plasma proteins exceeds 99%, while for metabolites M1, M3, and M5 it is 86%, 95%, and 97%, respectively. The volume of distribution is 16 L. Torasemide is metabolized via oxidation and hydroxylation, forming three metabolites: M1, M3, and M5. Metabolite M5 is pharmacologically inactive, while metabolites M1 and M3 account for approximately 10% of the drug's pharmacological activity. The terminal half-life (t1/2) of torasemide and its metabolites is 3–4 hours in healthy individuals. Total clearance of torasemide is 40 mL/min, renal clearance is approximately 10 mL/min. About 80% of the administered dose is excreted as unchanged torasemide (24%) and its metabolites: M1 (12%), M3 (3%), M5 (41%). In renal insufficiency, the elimination half-life of torasemide remains unchanged, while the elimination half-lives of metabolites M3 and M5 are prolonged. Torasemide and its metabolites are practically not removed by hemodialysis or hemofiltration. In patients with impaired liver function or heart failure, the half-lives of torasemide and metabolite M5 are slightly prolonged, but accumulation of torasemide and its metabolites is unlikely.

Clinical characteristics.

Indications.

5 mg tablets – arterial hypertension.

5 mg, 10 mg, or 20 mg tablets – edema associated with heart failure.

50 mg, 100 mg, or 200 mg tablets – edema, elevated arterial pressure in severe renal failure (creatinine clearance less than 20 mL/min) in the presence of any residual diuresis (more than 200 mL over 24 hours), including in patients undergoing hemodialysis.

Contraindications.

Hypersensitivity to torasemide, to sulfonamide derivatives, or to any of the excipients. Renal failure with anuria, hepatic coma or precoma, arterial hypotension, arrhythmia. Hypovolemia, hyponatremia, hypokalemia. Significant impairment of urination, for example, due to benign prostatic hyperplasia. Gout. Concomitant use with aminoglycosides or cephalosporins. Renal failure caused by nephrotoxic substances.

Interaction with other medicinal products and other forms of interaction.

When torasemide is used concomitantly with cardiac glycosides, the myocardial sensitivity to these drugs may increase due to potassium or magnesium deficiency. Concomitant use with mineralocorticoids, glucocorticoids, or laxatives increases the risk of potassium deficiency.

Torasemide enhances the effect of other antihypertensive medicinal products, particularly angiotensin-converting enzyme (ACE) inhibitors. Concomitant use with ACE inhibitors may lead to severe hypotension. This can be prevented by reducing the initial dose of the ACE inhibitor or by reducing the dose of torasemide 2–3 days prior to starting ACE inhibitor therapy.

Torasemide may reduce the vasoconstrictive effects of adrenaline and noradrenaline.

Torasemide reduces the effectiveness of antidiabetic agents.

Torasemide, especially in high doses, may potentiate the nephrotoxic and ototoxic effects of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin), the toxic effects of platinum-containing agents, and the nephrotoxic effects of cephalosporins.

Torasemide enhances the effects of theophylline and curare-like muscle relaxants.

Probenecid and nonsteroidal anti-inflammatory drugs (e.g., indomethacin, propionic acid derivatives) reduce the diuretic and antihypertensive effects of torasemide.

When used concomitantly with lithium preparations, torasemide may increase lithium blood concentration and enhance its cardiotoxic and neurotoxic effects.

When salicylates are administered in high doses, torasemide may enhance their toxic effects on the central nervous system.

When used concomitantly with cholestyramine, the absorption of torasemide may be reduced, resulting in diminished efficacy.

Special precautions for use.

Before initiating therapy with this drug, existing hypokalemia, hyponatremia, or hypovolemia should be corrected, and urinary excretion must be restored.

During prolonged treatment with torasemide, regular monitoring of electrolyte balance is recommended, especially plasma potassium levels (particularly in patients concurrently receiving cardiac glycosides, glucocorticoids, mineralocorticoids, or laxatives), as well as blood glucose, uric acid, creatinine, and lipid levels.

Patients predisposed to hyperuricemia and gout require special monitoring.

Patients with overt or latent diabetes mellitus should have carbohydrate metabolism monitored.

Due to insufficient clinical experience, torasemide is not recommended for use in conditions involving pathological disturbances of acid-base balance; in blood picture abnormalities such as thrombocytopenia or anemia in patients without renal insufficiency; concomitantly with lithium, aminoglycosides, or cephalosporins; in renal dysfunction caused by nephrotoxic agents; in children; or in elderly patients (dosage recommendations are lacking).

Torasemide should be used with particular caution in patients with liver disease associated with cirrhosis and ascites, as sudden changes in fluid and electrolyte balance may precipitate hepatic coma. Therapy with torasemide (as with other diuretics) in such patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic acidosis, the drug should be co-administered with aldosterone antagonists or potassium-sparing agents.

Ototoxic effects (tinnitus and hearing loss) have been observed after torasemide administration; these effects were reversible, but a direct causal relationship with the drug has not been established.

When prescribing diuretics, clinical signs of electrolyte imbalance, hypovolemia, extrarenal azotemia, and other disturbances should be carefully monitored. These may manifest as dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle pain or cramps, myasthenia, hypotension, oliguria, tachycardia, nausea, or vomiting. Excessive diuresis may lead to dehydration, reduced circulating blood volume, thrombosis, and vascular embolism, particularly in elderly patients. Signs of hemoconcentration and electrolyte loss should be closely observed, especially at the beginning of treatment and in elderly patients.

In patients experiencing disturbances of water-electrolyte balance, drug administration should be discontinued and therapy resumed only after resolution of adverse effects, starting with lower doses.

Regular laboratory monitoring of serum potassium and other electrolytes is necessary during treatment. Blood cell counts (erythrocytes, leukocytes, platelets) should also be monitored regularly.

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

Torasemide may cause positive results in doping tests.

Tablets of 5 mg, 10 mg, or 20 mg contain lactose. If a patient has known sugar intolerance, consultation with a physician is advised before taking this medication. The drug is contraindicated in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Tablets of 50 mg, 100 mg, or 200 mg contain hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide on the human embryo or fetus are lacking. Information on reproductive toxicity of torasemide is available. Torasemide crosses the placental barrier. Therefore, torasemide should be used during pregnancy only if absolutely necessary 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 cardiac or renal insufficiency, careful monitoring of electrolytes, hematocrit, and fetal development is essential.

Breastfeeding period. It is currently unknown whether torasemide is excreted in human or animal breast milk. Risk to newborns/infants cannot be excluded. Therefore, the use of torasemide during breastfeeding is contraindicated. If torasemide must be used during this period, breastfeeding should be discontinued.

Fertility. Studies on the effects of torasemide on human fertility have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Until individual response to torasemide is established, caution should be exercised when driving vehicles or engaging in other potentially hazardous activities requiring high concentration and rapid psychomotor reactions.

Dosage and Administration

The tablets should be taken in the morning, without chewing, with a small amount of liquid.

The duration of treatment depends on the course of the disease; in case of heart failure, treatment should continue until edema has resolved.

Arterial hypertension. The recommended dose for adults is 2.5 mg once daily (the 5 mg tablets have a score line and can be divided into equal 2.5 mg doses). If blood pressure has not normalized after two months of therapy with 2.5 mg of torasemide daily, the dose may be increased to 5 mg (once daily). Maximum effect is usually achieved within 3 months after initiation of treatment. Doses exceeding 5 mg do not enhance the antihypertensive effect.

Edema. Initiate therapy with a dose of 5 mg once daily. This dose is usually considered as maintenance. If the daily dose of 5 mg is insufficient, a daily dose of 10 mg should be administered daily. Depending on the severity of the patient's condition, the daily dose may be gradually increased up to 20 mg of torasemide (once daily).

Cirrhosis of the liver. The initial total dose is 5–10 mg once daily, used concomitantly with aldosterone antagonist agents or potassium-sparing diuretics. If the desired diuretic effect is not achieved, the dose should be doubled (10–20 mg daily) until the desired effect is attained.

Chronic renal insufficiency. The dose should be individually determined and depends on the degree of renal impairment. If a daily dose of 20 mg is insufficient, it may be increased to 50 mg of torasemide once daily, and if necessary, gradually increased up to the maximum dose of 200 mg once daily. The maximum daily dose of 200 mg should be prescribed only to patients with severe renal impairment (creatinine clearance < 20 mL/min), including during hemodialysis, provided that diuresis is at least 200 mL/24 hours.

Patients with hepatic insufficiency. Treatment of such patients should be performed with caution due to the potential for increased plasma concentrations of torasemide.

Elderly patients. No special dose adjustment is required.

Children.

The drug should not be used in children due to lack of data.

Overdose.

Symptoms. The typical clinical picture is unknown. In case of overdose, forced diuresis may occur, with risk of excessive fluid and electrolyte loss. Possible symptoms include somnolence, confusion, arterial hypotension, cardiovascular insufficiency, and gastrointestinal disturbances.

Treatment. There is no specific antidote. Depending on overdose symptoms, dose reduction or discontinuation of the drug is recommended. Measures should be taken to restore fluid and electrolyte balance. 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 cardiovascular insufficiency: sitting position and, if necessary, symptomatic therapy.

Anaphylactic shock (emergency measures). At the first signs of skin reactions (e.g., urticaria or skin redness), patient agitation, headache, sweating, nausea, cyanosis, perform venous catheterization; place the patient in a horizontal position, ensure free air access, and administer oxygen. If necessary, administer epinephrine, volume-expanding solutions, and glucocorticoid hormones.

Side effects

Adverse reactions are classified according to their frequency: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; very rare < 1/10,000; not known (frequency cannot be estimated due to lack of data).

Metabolism and nutrition disorders: common – worsening of metabolic alkalosis; hypokalemia in patients on a low-potassium diet, with vomiting, diarrhea, after excessive use of laxatives, or in patients with chronic liver dysfunction. Depending on dose and duration of treatment, disturbances in water and electrolyte balance may occur, such as hypovolemia, hypokalemia, hyponatremia. Arterial hypotension, headache, asthenia, drowsiness may occur due to significant fluid and electrolyte loss resulting from enhanced diuresis, particularly at the beginning of treatment and in elderly patients.

Cardiovascular system disorders: very rare – thrombosis, arterial hypotension, cardiac and cerebral ischemia, potentially leading to cardiac arrhythmias, angina pectoris, acute myocardial infarction, syncope.

Nervous system disorders: common – headache, dizziness (especially at the beginning of treatment); uncommon – paresthesia.

Gastrointestinal disorders: common – loss of appetite, nausea, vomiting, stomach pain, gastric discomfort and diarrhea, constipation, flatulence, mainly at the beginning of treatment; uncommon – dry mouth; very rare – pancreatitis.

Renal and urinary disorders: uncommon – in patients with urinary disturbances, e.g. due to benign prostatic hyperplasia, urinary retention and excessive bladder distension may occur; increased urge to urinate.

Hepatobiliary disorders: common – increased plasma levels of certain liver enzymes (γ-glutamyl transferase).

Blood and lymphatic system disorders: very rare – decreased platelet, erythrocyte and/or leukocyte counts.

Skin and subcutaneous tissue disorders: very rare – allergic reactions (e.g. pruritus, rash, exanthema, photosensitivity); severe skin reactions have been reported (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis).

Eye disorders: very rare – visual disturbances.

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

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

General disorders: common – confusion, increased fatigue, general weakness (especially at the beginning of treatment).

Laboratory findings: common – increased plasma concentrations of uric acid, glucose, and lipids (cholesterol, triglycerides); uncommon – possible increase in serum creatinine and urea levels.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 2 (10 × 2) or 10 (10 × 10) blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Solutas Pharma GmbH (complete manufacturing cycle).

Manufacturer's location and address of manufacturing site.

Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Manufacturer.

1. Lek S.A.

Manufacturer's location and address of manufacturing site.

Podlipie Street 16, Strzyżów, 39-179, Poland (complete manufacturing cycle).

Domaniewska 50C, Warsaw, 02-672, Poland (primary and secondary packaging, batch release).