Torasemide-darnitsa

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

Composition:

Active substance: torasemide;

One tablet contains torasemide 5 mg or 10 mg;

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

Medicinal form. Tablets.

Main physico-chemical properties: tablets are white or almost white, elongated in shape, with a score line and bevel on both sides.

Pharmacotherapeutic group. Drugs affecting the cardiovascular system. Diuretic agents. High-ceiling diuretics. Ordinary sulfonamides. Torasemide. ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Torasemide acts as a saluretic; its action is associated with inhibition of renal sodium and chloride ion reabsorption 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 parenteral and oral administration, respectively, and remains constant for approximately 12 hours. In healthy subjects, within 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, were no longer effective, for example in renal insufficiency. Due to this mechanism of action, torasemide promotes reduction of edema. In cases of heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing pre- and afterload. After oral administration, the antihypertensive effect of torasemide develops gradually, beginning in 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 levels of free calcium ions in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely reduces increased vascular sensitivity to endogenous vasoactive substances, such as catecholamines.

Pharmacokinetics

Absorption and Distribution

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 prolonged), but does not affect total absorption. Binding of torasemide to plasma proteins exceeds 99%; binding of metabolites M1, M3, and M5 is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

Biotransformation

In humans, torasemide is metabolized to form three metabolites: M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1, M3, and M5 are formed by oxidation of the methyl group on the phenyl ring to carboxylic acid; metabolite M3 is formed by hydroxylation of the 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 individuals is 3–4 hours. Total clearance of torasemide is 40 mL/min, renal clearance is 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 effect, while the combined contribution of active metabolites M1 and M3 accounts for approximately 10% of the total pharmacodynamic effect. In renal insufficiency, total clearance and elimination 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 excreted in urine is nearly equal to that in healthy individuals; therefore, accumulation of torasemide and its metabolites does not occur. Torasemide and its metabolites are practically not eliminated by hemodialysis or hemofiltration.

Linearity

Torasemide and its metabolites exhibit dose-dependent linear kinetics. This means that maximum plasma concentration and area under the pharmacokinetic curve increase proportionally with dose.

Clinical characteristics.

Indications.

Dosage of 5 mg: essential hypertension.

Dosage of 5 mg and 10 mg: treatment and prevention of recurrence of edema and/or effusions caused by heart failure.

Contraindications.

• Hypersensitivity to the active substance, to sulfonylurea drugs, or to any of the excipients of the medicinal product Torasemide-Darnitsia.
• Renal failure with anuria.
• Hepatic coma or precoma.
• Arterial hypotension.
• Hypovolemia.
• Hyponatremia.
• Hypokalemia.
• Arrhythmia.
• Significant impairment of urination, for example due to prostatic hyperplasia.
• Pediatric age (under 18 years).
• Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Not recommended combinations

Torasemide, especially in high doses, may enhance the ototoxic and nephrotoxic adverse reactions of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin), cytostatic agents — active platinum derivatives, as well as the nephrotoxic effects of cephalosporins.

Concomitant use of torasemide and lithium preparations may increase lithium blood concentration, potentially leading to enhanced effects and adverse reactions of lithium.

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 during their concomitant use.

When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by diuretic use may lead to enhanced 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 salicylates at high doses, torasemide may enhance their toxic effects on the central nervous system.

Torasemide may enhance the effect of theophylline, as well as the muscle-relaxing effects of curare-like medicinal products.

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 absorption of torasemide and, consequently, its expected efficacy.

Special precautions for use.

Before initiating treatment with the medicinal product, any existing hypokalemia, hyponatremia, or hypovolemia should 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 cirrhosis and ascites, as sudden changes in fluid and electrolyte balance may precipitate hepatic coma. Treatment with torasemide (as well as other diuretics) in such patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic acidosis, the drug should be co-administered with potassium-sparing agents or aldosterone antagonists. Cases of ototoxicity (tinnitus and hearing loss) have been reported 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 should be carefully monitored. These may manifest as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, myasthenia, hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may lead to dehydration, reduced circulating blood volume, thrombosis, and embolism, particularly in elderly patients.

If disturbances in fluid and electrolyte balance occur, the drug should be discontinued and therapy resumed only after resolution of adverse effects, 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. At the beginning of treatment in elderly patients, particular attention should be paid to symptoms of electrolyte loss and hemoconcentration.

Torasemide should not be prescribed in the following conditions and disorders if sufficient clinical experience with its use is lacking: gout; 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; age under 18 years.

Excipients.

Torasemide-Darnitsia contains lactose; therefore, patients with diagnosed sugar intolerances, as well as those with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, should consult a physician before taking this medicinal product.

Use of torasemide may lead to a positive doping test result and may worsen health status.

Use during pregnancy or breastfeeding.

Pregnancy. There are no reliable data on the effects of torasemide on the human embryo, fetus, or pregnant woman. Reproductive toxicity of torasemide has been demonstrated in animal studies. Torasemide crosses the placental barrier. Therefore, torasemide is not recommended during pregnancy, and in women of childbearing potential who are not using contraception. Use during pregnancy is permissible only under life-threatening conditions and at the minimum 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 exert toxic effects on fetal development. If torasemide is used to treat pregnant women with heart failure or renal insufficiency, careful monitoring of electrolytes, hematocrit, and fetal development is required.

Breastfeeding period. It is currently unknown whether torasemide passes into human or animal breast milk. A 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. The decision to discontinue breastfeeding or to stop/abstain from using Torasemide-Darnitsia should be based on the benefits of breastfeeding for the child and the benefits of treatment for the woman.

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 affect reaction speed when driving 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 or operate machinery or perform hazardous work without safeguards. This is particularly relevant at the beginning of treatment, when increasing the dose, when switching medications, or when concomitant therapy is prescribed, as well as during concomitant alcohol consumption. Therefore, extreme caution is required when driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage.

Dosage of 5 mg.

Essential hypertension. Treatment should be initiated with ½ tablet of Torasemide-Darnitsia 5 mg once daily, equivalent to 2.5 mg of torasemide. Reduction in blood pressure occurs gradually, already within the first week of treatment, and reaches its maximum effect no later than 12 weeks. If normalization of blood pressure is not achieved after 12 weeks of treatment with a daily dose of 2.5 mg of torasemide, the daily dose may be increased to 5 mg of torasemide. Additional reduction in blood pressure may be expected with dose escalation, particularly in cases of initially high blood pressure or impaired renal function. The recommended daily dose should not be exceeded, as no further reduction in blood pressure is anticipated.

Dosage of 5 mg and 10 mg.

Edema and/or effusions. Treatment is initiated with 1 tablet daily of 5 mg or ½ tablet of Torasemide-Darnitsia 10 mg. This dose is usually considered maintenance therapy. If a daily dose of 5 mg is insufficient, 2 tablets of 5 mg or 1 tablet of 10 mg should be administered daily, taken every day. 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 in the morning, without chewing, and swallowed with a small amount of liquid. The duration of treatment depends on the course of the disease. The bioavailability of torasemide is not affected by food intake. Torasemide-Darnitsia should generally be administered for a prolonged period or until edema symptoms have sufficiently decreased.

Recommendations for tablet splitting. Tablets can be easily divided into two halves (a score line is present on both sides), allowing for the administration of the required dose. Place the tablet on a hard surface, then press with the thumbs on both sides of the score line. This ensures easy tablet splitting.

Special patient groups.

Patients with impaired liver function. Treatment of such patients should be performed with caution, as increased plasma concentrations of torasemide may occur. Torasemide is contraindicated in patients with hepatic coma or precoma.

Elderly patients. No specific dose adjustment is required. However, comparative studies between elderly and younger patients are lacking.

Children.

The safety and efficacy of Torasemide-Darnitsia in children and adolescents (under 18 years of age) have not been established. Therefore, torasemide should not be used in children and adolescents (under 18 years of age).

Overdose.

Symptoms of intoxication.

Typical symptoms are unknown. Overdose may cause pronounced diuresis, including 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, discontinuation of the drug, and appropriate replacement of fluids and electrolytes (monitoring is required!). 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 of cardiovascular insufficiency: 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, sweating, nausea, or cyanosis:

• perform venous catheterization;
• in addition to other emergency measures, place the patient in a horizontal position, ensure free air access, and administer oxygen;
• if necessary, administer epinephrine, volume-replacing solutions, and glucocorticoid hormones.

Adverse Reactions

To assess the frequency of adverse events, the following classification was used: 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; unknown: frequency cannot be estimated due to lack of data.

Eye disorders: very rare: visual disturbances.

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

Gastrointestinal disorders: common: gastrointestinal disturbances (especially at the beginning of treatment), including loss of appetite, flatulence, stomach pain, nausea, vomiting, diarrhea, constipation; uncommon: xerostomia; rare: pancreatitis.

Hepatobiliary disorders: common: increased blood concentration of certain liver enzymes (gamma-glutamyl transferase).

Renal and urinary disorders: uncommon: increased blood creatinine and urea levels, urinary frequency. In patients with urinary disorders (e.g., due to prostate hyperplasia), increased urine production may lead to urinary retention and excessive bladder distension.

Metabolism and nutritional disorders: common: intensification of metabolic alkalosis. Muscle cramps (especially at the beginning of treatment). Increased blood levels of uric acid, glucose, cholesterol, and triglycerides. Hyperglycemia, hypokalemia (with concomitant low-potassium diet) in cases of vomiting, diarrhea, excessive use of laxatives, and in patients with chronic liver dysfunction. Depending on dosage and duration of treatment, disturbances in fluid and electrolyte balance may occur, e.g., hypovolemia, hypokalemia, and/or hyponatremia. With significant fluid and electrolyte loss due to enhanced diuresis, arterial hypotension, headache, asthenia, drowsiness may occur, especially at the beginning of treatment and in elderly patients.

Nervous system disorders: common: headache, dizziness (especially at the beginning of treatment); uncommon: paresthesia; rare: syncope, cerebral ischemia, confusion.

Cardiac and vascular disorders: rare: thromboembolic complications, confusion, arterial hypotension, and circulatory and cardiac disorders, including myocardial and cerebral ischemia, which may lead, for example, to arrhythmia, angina pectoris, acute myocardial infarction, syncope due to hemoconcentration.

Blood and lymphatic system disorders: rare: blood viscosity increase, decreased platelet, erythrocyte, and/or leukocyte counts.

Immune system disorders: rare: hypersensitivity reactions, including pruritus, exanthema, photosensitization, severe skin reactions (rash).

Skin and subcutaneous tissue disorders: rare: allergic skin reactions (e.g., pruritus, exanthema), photosensitization reactions, severe skin reactions.

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

General disorders: common: headache, dizziness, fatigue, general weakness (especially at the beginning of treatment); uncommon: dry mouth, unpleasant sensations in extremities (paresthesia).

Laboratory findings: common: increased blood levels of uric acid and lipids (triglycerides, cholesterol); uncommon: increased blood urea and creatinine levels.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

5 mg tablets: 10 tablets in a blister pack; 3 blisters per carton.

10 mg tablets: 10 tablets in a blister pack; 3 or 10 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska St., Kyiv, 02093, Ukraine.