Toraren

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

Composition:

Active substance: 1 tablet contains torasemide 10 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: flat cylindrical tablets with beveled edges and a score line, white or almost white in color.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

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. In humans, the diuretic effect rapidly reaches its maximum within the first 2–3 hours after intravenous and oral administration, respectively, and remains sustained for approximately 12 hours. Available data indicate that in the dose range of 5–100 mg, diuresis increases proportionally to the logarithm of the dose (loop diuretic activity). Increased diuresis has been observed even in cases where other diuretics, for example, distally-acting thiazide-type diuretics, have 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 both preload and afterload. After oral administration, the antihypertensive effect of torasemide develops gradually, beginning in the first week of treatment. The 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 levels of free intracellular calcium ions in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely reduces the heightened vascular sensitivity to endogenous vasoactive substances, such as catecholamines.

Pharmacokinetics

After oral administration, torasemide is rapidly and completely absorbed. Peak plasma concentration is reached within 1–2 hours. Bioavailability is approximately 80–90%; under conditions of complete absorption, the maximum first-pass effect is 10–20%. Food reduces the rate (dynamic component) of torasemide absorption (Cmax is reduced and tmax is increased), but does not affect total absorption. Plasma protein binding of torasemide exceeds 99%; for metabolites M1, M3, and M5, it is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L. In humans, torasemide is metabolized to form three metabolites: M1, M3, and M5. There is no evidence for the existence of other metabolites. Metabolites M1, M3, and M5 are formed by oxidation of the methyl group on the phenyl ring to a carboxylic acid; metabolite M3 is formed by ring hydroxylation. The pharmacokinetics of torasemide and its metabolites are characterized by linear kinetics. This means that maximum plasma concentration and area under the plasma concentration-time curve increase proportionally with dose. The terminal half-life (t1/2) of torasemide and its metabolites in healthy individuals is 3–4 hours. Total clearance of torasemide is 40 mL/min, with renal clearance being approximately 10 mL/min. In healthy individuals, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites in the following approximate proportions: torasemide – 24%, metabolite M1 – 12%, metabolite M3 – 3%, metabolite M5 – 41%. The main metabolite M5 has no diuretic activity, while the combined contribution of the active metabolites M1 and M3 to the overall pharmacodynamic effect is approximately 10%. In renal insufficiency, total clearance and the half-life of torasemide remain unchanged, while the half-lives of M3 and M5 are prolonged. However, pharmacodynamic characteristics remain unchanged, and the severity of renal insufficiency does not affect the duration of action. In patients with hepatic dysfunction or heart failure, the half-lives of torasemide and metabolite M5 are slightly prolonged, but the amount of substance excreted in urine is nearly identical to that in healthy individuals; therefore, accumulation of torasemide and its metabolites does not occur. Torasemide and its metabolites are practically not removed by hemodialysis or hemofiltration.

Clinical characteristics.

Indications.

Treatment and prevention of recurrences of edema and/or effusions caused by heart failure.

Contraindications.

Hypersensitivity to the active substance, sulfonylurea drugs, and excipients of the medicinal product. Renal failure with anuria. Hepatic coma or precoma. Arterial hypotension. Hypovolemia. Hyponatremia. Hypokalemia. Significant impairment of urination, e.g., due to benign prostatic hyperplasia.

Interaction with other medicinal products and other forms of interaction.

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 drugs. 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 increase their toxic effects on the central nervous system. Torasemide, especially 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 enhance the nephrotoxic effects of cephalosporins. Torasemide may enhance the effects of theophylline and the action of curare-like medicinal products. Laxatives, as well as mineralocorticoids and glucocorticoids, may intensify potassium loss induced by torasemide. Concomitant use of torasemide and lithium preparations may increase lithium plasma concentration, potentially leading to enhanced effects and increased adverse reactions of lithium. Torasemide may reduce the vasoconstrictive effects of catecholamines, such as epinephrine and norepinephrine. When used concomitantly with cholestyramine, absorption of torasemide may be reduced, and consequently, its expected efficacy diminished.

Special precautions for use.

Before initiating treatment with the medicinal product, existing hypokalemia, hyponatremia, or hypovolemia should be corrected. During prolonged use of torasemide, regular monitoring of electrolyte balance is required, particularly serum potassium levels, 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 to patients suffering from liver diseases associated with liver cirrhosis and ascites, as sudden changes in fluid and electrolyte balance may lead to hepatic encephalopathy. Treatment with torasemide (as with other diuretics) in these patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic acidosis, the drug should be prescribed together with aldosterone antagonists or potassium-sparing agents. Cases of ototoxicity (tinnitus and hearing loss) have been observed after administration of torasemide; 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 should be carefully monitored. These may manifest as dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle pain or cramps, myasthenia, hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may result in dehydration, reduced circulating blood volume, thrombosis, and embolism, particularly in elderly patients.

Patients experiencing disturbances in fluid and electrolyte balance 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 torasemide treatment, 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 emergence 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 unless sufficient clinical experience supports its use:

• Gout;
• Arrhythmias, e.g., sinoatrial block, second- and third-degree atrioventricular block;
• Acid-base metabolic disturbances;
• Concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• Blood count abnormalities, e.g., thrombocytopenia or anemia in patients without renal insufficiency;
• Renal dysfunction caused by nephrotoxic substances.

The medicinal product 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 the medicinal product Toraren may result in a positive doping test. The health consequences of misuse of Toraren, i.e., 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. Information on reproductive toxicity of torasemide is available. Torasemide crosses the placental barrier. Therefore, torasemide may be used during pregnancy only for life-threatening indications and at the lowest possible 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 electrolytes and hematocrit, as well as fetal development, is required.

Breastfeeding period. It is currently unknown whether torasemide passes into breast milk in animals or humans. The risk of using the drug in 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 effect of torasemide on fertility in humans have not been conducted.

Ability to affect reaction speed when driving vehicles or operating machinery.

Even when used correctly, torasemide may affect a patient's reaction to such an extent that it significantly impairs the ability to drive vehicles or operate machinery. This is particularly relevant at the beginning of treatment, when increasing the dose of the drug, when switching to another medication, or when concomitant therapy is prescribed. Therefore, caution is required when driving vehicles or operating machinery during treatment with torasemide.

Method of Administration and Dosage.

Adults. Treatment should be initiated with a daily dose of 5 mg of torasemide, which corresponds to ½ tablet of Toraren. This dose is generally considered a maintenance dose. To split the tablet into two equal halves, place the tablet on a hard surface and press with the thumbs on both sides of the score line, which allows for accurate division to achieve the required dose. If the daily dose of 5 mg is insufficient, a daily dose of 10 mg of torasemide should be used, as prescribed by a physician. Depending on the severity of the patient's condition, the daily dose may be increased up to 20 mg of torasemide. Tablets should be taken on an empty stomach, without chewing, and swallowed with a small amount of liquid. The bioavailability of torasemide is not affected by food intake. Toraren can usually be administered for a prolonged period or until edema symptoms subside.

Patients with hepatic insufficiency. Treatment of such patients should be performed with caution, as increased plasma concentrations of torasemide are possible.

Elderly patients. No specific dose adjustment is required. However, adequate studies comparing the drug's effects in younger and elderly patients have not been conducted.

Children and adolescents. The safety and efficacy of Toraren in children have not been established. Therefore, torasemide is contraindicated in pediatric patients.

Children. Torasemide should not be administered to children due to insufficient clinical experience.

Overdose.

Typical symptoms are unknown. Overdose may cause pronounced diuresis, including the risk of excessive loss of water and electrolytes, somnolence, amnestic syndrome (a form of consciousness disturbance), symptomatic arterial hypotension, cardiovascular insufficiency, 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 blood by hemodialysis.

Treatment in case of hypovolemia: fluid volume replacement.

Treatment in case of hypokalemia: administration of potassium supplements.

Treatment of cardiovascular insufficiency: place patient in a supine position and, if necessary, provide 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, administer oxygen. If necessary, administer epinephrine, volume-replacing solutions, and glucocorticoid hormones.

Adverse reactions.

Metabolism/electrolytes: worsening of metabolic alkalosis. Muscle cramps (especially at the beginning of treatment), indigestion, flatulence, increased frequency of urination, rash. Increased concentrations of uric acid and glucose in blood, as well as cholesterol and triglycerides. Hypokalemia may occur with concomitant potassium-free diet, vomiting, diarrhea, after excessive use of laxatives, and in patients with chronic liver dysfunction. Depending on dose and duration of treatment, disturbances of water and electrolyte balance such as hypovolemia, hypokalemia and/or hyponatremia may occur. With significant fluid and electrolyte losses due to enhanced diuresis, arterial hypotension, headache, fatigue, drowsiness may occur, especially at the beginning of treatment and in elderly patients.

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

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

Renal and urinary system: increased concentrations of creatinine and urea in blood. 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: increased concentrations of certain liver enzymes (gamma-glutamyl transpeptidase) in blood.

Immune system: allergic reactions, such as itching, exanthema, photosensitization, severe skin reactions.

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

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

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging. 10 tablets in a blister; 1, 3 or 8 blisters per carton.

Prescription category. Prescription only.

Manufacturer: JSC "KYIV VITAMIN PLANT".

Manufacturer's address and location of business activity:

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua