Torasemide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Torsid® (Torsid)

Composition:

active substance: torasemide;

1 tablet contains 5 mg or 10 mg of torasemide, calculated as 100% substance;

excipients: lactose monohydrate, pregelatinized starch, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets with flat surface, scored and beveled edge, white or almost white in color.

Pharmacotherapeutic group.

Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties.

Pharmacodynamics.

The main mechanism of diuretic action is due to reversible binding to the Na+/2Cl-/K+ cotransporter in the apical segment of the loop of Henle, resulting in reduced or completely inhibited renal reabsorption of sodium and chloride ions in the ascending limb of the loop of Henle, decreased osmotic pressure of tubular fluid, and reduced water reabsorption. Within the dose range of 5–100 mg, the increase in diuresis is proportional to the logarithm of the dose. Enhanced diuresis occurs even in cases where other diuretic agents (e.g., thiazides) are no longer sufficiently effective, such as in impaired renal function.

Reduces edema and exerts an antihypertensive effect, which is due to decreased peripheral vascular resistance resulting from reduced intracellular free calcium levels in arterial smooth muscle cells and normalization of disturbed electrolyte balance. Consequently, vascular contractility and response to endogenous pressor substances, particularly catecholamines, are diminished. Improves cardiac function by reducing both preload and afterload. After oral administration, maximum diuretic effect occurs within 1–3 hours, and the diuretic effect lasts for approximately 12 hours. The antihypertensive effect of torasemide develops gradually during the first week and reaches its maximum no later than 12 weeks.

Pharmacokinetics.

After oral administration, it is rapidly and almost completely absorbed from the gastrointestinal tract. Maximum plasma concentration is observed within 1–2 hours. Plasma protein binding of torasemide exceeds 99%, while for metabolites M1, M3, and M5 it is 86%, 95%, and 97%, respectively. Bioavailability is approximately 80%, with minimal individual variations, and is not affected by food intake. Metabolism occurs in the liver via the cytochrome P450 system, forming metabolites (M1, M3, and M5). The main metabolite M5 does not exhibit diuretic activity; the active metabolites M1 and M3 together account for approximately 10% of the pharmacodynamic effect. The elimination half-life of torasemide and its metabolites in healthy volunteers is 3–4 hours. Approximately 83% of the administered dose is excreted via renal tubules: 24% unchanged and the remainder as metabolites (M1 – 12%, M3 – 3%, M5 – 41%). Total clearance is 40 mL/min, and renal clearance is approximately 10 mL/min. In renal impairment, total clearance and the elimination half-life of torasemide remain unchanged, while the half-lives of metabolites M3 and M5 are prolonged. However, pharmacodynamic characteristics remain unaltered, and the severity of renal impairment does not affect the duration of action. In patients with hepatic dysfunction or heart failure, the elimination half-lives of torasemide and metabolite M5 are only slightly prolonged, with no accumulation of torasemide or its metabolites observed.

Clinical characteristics.

Indications.

Essential hypertension. Treatment and prevention of recurrence of edema and/or effusions caused by heart failure.

Contraindications.

Hypersensitivity to the active substance, to sulfonamide drugs, and to excipients of the medicinal product. Renal insufficiency with anuria. Hepatic coma or precoma. Arterial hypotension. Hypovolemia. Hyponatremia. Hypokalemia. Significant impairment of urination, for example, due to prostatic hyperplasia. Lactation period.

Interaction with other medicinal products and other types of interactions.

Torasemide enhances the effect of other antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, which may cause excessive reduction of arterial pressure when used concomitantly. When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by diuretic use may lead to increased or enhanced adverse effects of both agents. Torasemide may reduce the efficacy 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, particularly at high doses, may enhance the ototoxic and nephrotoxic effects of ethacrynic acid and aminoglycoside antibiotics, such as kanamycin, gentamicin, tobramycin, and cytostatic agents – active platinum derivatives, as well as the nephrotoxic effects of cephalosporins. Torasemide may enhance the effect of theophylline and the action of curare-like medicinal agents. Laxatives, as well as mineralocorticoids and glucocorticoids, may intensify potassium loss induced by torasemide. Concomitant use of torasemide and lithium preparations may increase lithium concentration in blood plasma, potentially leading to enhanced effects and increased adverse reactions of lithium. 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.

Before initiating treatment with the drug, existing hypokalemia, hyponatremia, or hypovolemia must be corrected. During prolonged use of torasemide, regular monitoring of electrolyte balance, particularly serum potassium levels, is required, especially in patients concurrently receiving cardiac glycosides, glucocorticoids, mineralocorticoids, or laxatives. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is necessary. Torasemide should be administered with particular caution in patients with liver disease associated with liver cirrhosis and ascites, as sudden changes in fluid and electrolyte balance may precipitate hepatic coma. Therapy with torasemide (as well as other diuretics) in these 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. Cases of ototoxicity (tinnitus and hearing loss) have been observed after torasemide administration; these effects were reversible, although 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—such as dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle pain or cramps, myasthenia, hypotension, oliguria, tachycardia, nausea, and vomiting—must be carefully monitored. Excessive diuresis may lead to dehydration, reduction in circulating blood volume, thrombosis, and embolism, particularly in elderly patients.

Patients who develop fluid and electrolyte imbalances should discontinue the drug; after resolution of adverse effects, therapy may be resumed starting with lower doses.

Since increased blood glucose levels may occur during treatment with torasemide, careful monitoring of carbohydrate metabolism is required in patients with latent or overt diabetes mellitus. Blood parameters (erythrocytes, leukocytes, platelets) should also be monitored regularly. Particular attention should be paid to the onset of symptoms of electrolyte loss and hemoconcentration, especially at the beginning of treatment in elderly patients.

Torasemide should not be prescribed in the following conditions and disorders if there is insufficient clinical experience:
gout; 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, e.g., thrombocytopenia or anemia in patients without renal insufficiency; kidney dysfunction caused by nephrotoxic substances.

The drug contains lactose; therefore, it should not be administered to patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use of Torasemide tablets (Torcid®) may lead to a positive result in doping tests. The health consequences of misuse of Torasemide tablets, e.g., for doping purposes, cannot be predicted, and in such cases, potential harm to health cannot be excluded.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide on the human embryo and fetus are lacking. Reproductive toxicity of torasemide has been demonstrated in animal studies. Torasemide crosses the placental barrier. Therefore, torasemide may be used during pregnancy only if strictly indicated 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, hematocrit, and fetal development is required.

Breastfeeding period. It is currently unknown whether torasemide passes into human or animal breast milk. The risk of administering the drug to newborns/infants cannot be excluded. Therefore, the use of torasemide during breastfeeding is contraindicated. If torasemide use is necessary during this period, breastfeeding should be discontinued.

Fertility.

Studies on the effects of torasemide on human fertility 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 affect a patient's reaction to an extent that significantly impairs the ability to drive a vehicle or operate machinery. This is particularly relevant at the beginning of treatment, when increasing the dose, when switching medications, or when concomitant therapy is prescribed. Therefore, caution is required when driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage.

Adults.

Take orally once daily in the morning after food, without chewing, with a small amount of liquid. The dosage and duration of treatment should be determined individually, taking into account the indications, efficacy, and tolerability of therapy.

Essential hypertension. The usual dose is 2.5 mg of Torzide®. If blood pressure normalization is not achieved after 12 weeks of treatment with 2.5 mg daily, the dose may be increased to 5 mg. Further dose escalation is not recommended, as it will not lead to additional reduction in arterial pressure.

Edema or effusions: the initial dose is 5 mg of Torzide® daily. This dose is usually considered maintenance. If the daily dose of 5 mg is insufficient, administer 10 mg of torasemide daily. The dose may be increased, depending on the severity of the disease, up to 20 mg of the drug daily.

Hepatic insufficiency. Treatment of such patients should be carried out with caution, as increased plasma concentrations of torasemide are possible.

Elderly patients. No special dose adjustment is required. Adequate studies comparing treatment in elderly and younger patients are lacking.

Children.

Torasemide should not be used in children due to lack of sufficient clinical experience.

Overdose.

The typical symptoms are unknown. Overdose may cause pronounced diuresis, including risk of excessive loss of water and electrolytes, drowsiness, amnestic syndrome (a form of consciousness disturbance), symptomatic arterial hypotension, cardiovascular failure, 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 replacement of fluids and electrolytes (monitoring of blood electrolyte levels 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 of cardiovascular failure: supine positioning of the patient 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, venous catheterization should be performed; place the patient in a horizontal position, ensure free air access, and administer oxygen. If necessary, administer epinephrine, volume-replacement solutions, and glucocorticoid hormones.

Side effects

The following frequency categories were used to assess side effects: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10000 to < 1/1000; very rare: < 1/10000. Not known: cannot be estimated from available data.

Metabolism/electrolytes. Common: exacerbation of metabolic alkalosis. Muscle cramps (especially at the beginning of treatment), indigestion, flatulence, increased frequency of urination, skin rash. Increased blood concentrations of uric acid and glucose, as well as cholesterol and triglycerides. Hypokalemia may occur in patients on a potassium-deficient 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 water and electrolyte balance may occur, such as hypovolemia, hypokalemia and/or hyponatremia. With significant fluid and electrolyte loss due to enhanced diuresis, arterial hypotension, headache, fatigue, and drowsiness may occur, particularly at the beginning of treatment and in elderly patients.

Cardiovascular system. Very rare: thromboembolic complications may occur due to possible hemoconcentration, as well as confusion, arterial hypotension, circulatory and cardiac disorders, including myocardial and cerebral ischemia, which may lead, for example, to arrhythmia, angina pectoris, acute myocardial infarction, syncope.

Gastrointestinal system. Common: gastrointestinal disturbances (especially at the beginning of treatment), including loss of appetite, stomach pain, nausea, vomiting, diarrhea, constipation. Very rare: pancreatitis.

Renal and urinary system. Uncommon: increased blood concentrations of creatinine and urea. In patients with impaired urination (e.g., due to prostatic hyperplasia), increased urine production may lead to urinary retention and excessive bladder distension.

Hepatic system. Common: increased blood concentrations of certain liver enzymes (gamma-glutamyl transferase).

Immune system. Very rare: allergic reactions, such as pruritus, exanthema, photosensitization, severe skin reactions.

Blood and lymphatic system. Very rare: decreased platelet, erythrocyte, and/or leukocyte counts as a result of hemoconcentration.

General and administration site reactions. Common: headache, dizziness, increased fatigue, general weakness (especially at the beginning of treatment). Uncommon: dry mouth, unpleasant sensations in extremities (paresthesia). Very rare: visual disturbances, tinnitus, hearing loss, deafness.

Shelf life.

5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

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

Keep out of reach of children.

Packaging.

5 mg tablets. 10 tablets in a blister. 1 or 3 blisters per carton.

10 mg tablets. 10 tablets in a blister. 1, 3, or 9 blisters per carton.

Prescription category.

Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.