Trifas® cor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIFAS® COR (TRIFAS® COR)

Composition:

Active substance: torasemide;

1 tablet contains 5 mg of torasemide;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, round, slightly biconvex tablets with a score line on one side for division.

Pharmacotherapeutic group. Diuretic agents. High-ceiling diuretics.

ATC Code: C03CA04.

Pharmacological properties.

Pharmacodynamics

Mechanism of action.

Torasemide acts as a saluretic; its action is associated with inhibition of renal reabsorption of sodium and chloride ions in the ascending limb of Henle's loop.

Pharmacodynamic effect.

In humans, the diuretic effect of the drug develops quite rapidly after intravenous administration and oral intake, reaching maximum within the first hour and 2–3 hours, respectively, and lasting up to 12 hours.

In healthy volunteers, urine output increased proportionally to the logarithm of the drug dose within the dose range of 5 mg to 100 mg (loop diuretic activity).

Increased diuresis was observed even in cases where other diuretics (e.g., thiazide diuretics acting on distal tubules) were no longer effective, for example, in renal insufficiency. Due to this mechanism of action, torasemide leads to reduction of edema. In heart failure, torasemide reduces symptoms of the disease and improves myocardial function by decreasing preload and afterload. After oral administration, the antihypertensive effect of torasemide develops gradually, starting from the first week of treatment. Maximum antihypertensive effect is achieved no later than 12 weeks. Torasemide reduces blood pressure by decreasing peripheral vascular resistance. This effect is explained by normalization of disturbed electrolyte balance, primarily due to reduction of elevated free intracellular calcium ion activity in arterial smooth muscle cells, as observed in patients with arterial hypertension. This effect likely causes reduced vascular contractility and/or reduced responsiveness to endogenous vasoactive substances, such as catecholamines.

Pharmacokinetics.

Absorption and distribution.

After oral administration, torasemide is rapidly and almost completely absorbed; maximum plasma concentration is reached within 1–2 hours after intake. Bioavailability is approximately 80–90%; under conditions of complete absorption, the maximum first-pass effect is 10–20%. Data from two studies demonstrate that food reduces the rate (dynamic component) of torasemide absorption (Cmax is reduced and tmax is increased), but does not affect total absorption. Protein binding of torasemide to plasma proteins exceeds 99%; for metabolites M1, M3, and M5, it is 86%, 95%, and 97%, respectively. The 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 for the existence of other metabolites. Metabolites M1 and M5 are formed by oxidation of the methyl group of the phenolic ring to carboxylic acid. Metabolite M3 is formed by hydroxylation of the phenolic ring. Metabolites M2 and M4, detected in animal studies, have not been found in humans.

Elimination.

The terminal half-life (t1/2) of torasemide and its metabolites in healthy volunteers is 3–4 hours. Total clearance of torasemide is 40 mL/min, renal clearance is approximately 10 mL/min. Approximately 80% of the dose is excreted as unchanged torasemide (24%) and its metabolites: M1 (12%), M3 (3%), M5 (41%). The main metabolite M5 has no diuretic effect; approximately 10% of the pharmacokinetic activity is attributed to the combined active metabolites M1 and M3.

In renal insufficiency, total clearance and half-life of torasemide remain unchanged, while the half-life of metabolites M3 and M5 is prolonged. However, the pharmacodynamic profile remains unchanged, and the severity of renal insufficiency does not affect the duration of action.

Torasemide and its metabolites are practically not eliminated 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 the amount of substance excreted in urine is almost equal to that in healthy individuals; therefore, accumulation of torasemide and its metabolites is unlikely.

Linearity.

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

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 sulfonylurea 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 (e.g., due to prostatic hyperplasia).
• Breastfeeding period.

Interaction with other medicinal products and other forms of interactions.

Unrecommended combinations.

Torasemide, especially in high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin), cytostatic platinum-containing agents, 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 increased adverse reactions of lithium.

Combinations requiring caution.

Torasemide enhances the effects of other antihypertensive agents, particularly angiotensin-converting enzyme (ACE) inhibitors. When ACE inhibitors are administered concurrently or immediately after torasemide treatment, excessive reduction in arterial blood pressure may occur. Concomitant use of torasemide with digitalis preparations may result in potassium deficiency induced by the diuretic, potentially leading to increased incidence or severity of adverse reactions of both agents.

Torasemide may reduce the effectiveness of antidiabetic agents.

Probenecid and nonsteroidal anti-inflammatory drugs (e.g., indomethacin, acetylsalicylic acid) may diminish the diuretic and antihypertensive effects of torasemide.

High-dose salicylate therapy may have its toxic effects on the central nervous system potentiated by torasemide.

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

Laxatives, as well as mineralo- and glucocorticoids, may intensify potassium loss induced by torasemide.

Torasemide may reduce the vasoconstrictive effects of catecholamines (e.g., epinephrine and norepinephrine).

Concomitant use with cholestyramine may reduce torasemide absorption and, consequently, its effectiveness.

Special precautions for use.

Torasemide should not be prescribed in the following cases:

• Gout;
• Cardiac arrhythmias (e.g., sinoatrial block, second- and third-degree atrioventricular block);
• Pathological changes in acid-base balance;
• Concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• Blood count abnormalities (e.g., thrombocytopenia or anemia in patients without renal insufficiency);
• Renal failure caused by nephrotoxic substances;
• Children and adolescents (patients under 18 years of age).

Due to the possible increase in blood glucose concentration in patients with latent or manifest diabetes mellitus, careful monitoring of carbohydrate metabolism is required. Particular attention should be paid, especially at the beginning of treatment and in elderly patients, to the emergence of symptoms indicating electrolyte loss and hemoconcentration. During prolonged use of torasemide, regular monitoring of electrolyte balance, particularly serum potassium levels, is necessary. Regular monitoring of blood glucose, uric acid, urea, creatinine, and lipid levels, as well as blood counts (erythrocytes, leukocytes, platelets), is also required.

Consequences of improper use as doping.

When using the medicine Triphas® Cor, there may be positive results in doping tests.

It is impossible to predict the health effects if Triphas® Cor is misused, i.e., used as a doping agent; in such a case, potential harm to health cannot be excluded.

Excipients.

The medicinal product Triphas® Cor contains lactose; therefore, it should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking or limited.

There is information on reproductive toxicity of torasemide obtained from animal studies. Animal studies have demonstrated that torasemide crosses the placental barrier. Triphas® Cor is not recommended during pregnancy, or for women of childbearing potential who are not using contraception.

Torasemide may be used during pregnancy only if strictly indicated 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 cardiac or renal insufficiency, careful monitoring of electrolyte levels, hematocrit, and fetal development is required.

Breastfeeding period. It has not yet been established whether torasemide or its metabolites are excreted in human or animal breast milk. Risk to newborns/infants cannot be excluded. Therefore, the use of torasemide during lactation is contraindicated (see section “Contraindications”). The decision to discontinue breastfeeding or to discontinue/abort treatment with Triphas® Cor should be made after considering the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Fertility. Studies on the effect of torasemide on fertility in humans have not been conducted. Animal experiments did not reveal any effect of torasemide on fertility.

Ability to affect reaction speed when driving or operating machinery.

Even when used correctly, torasemide may alter reaction speed to such an extent that patients may experience reduced ability to participate in road traffic, operate machinery, or perform work without safety support.

Such effects are most likely at the beginning of treatment, when increasing the dose, when switching medications, when additional drugs are prescribed, or when alcohol is consumed.

Administration and Dosage.

Dosage.

Essential Hypertension.

Adults. The recommended starting dose is 2.5 mg once daily (½ tablet of Trifas® Cor). Reduction of blood pressure occurs gradually during the first week of treatment and reaches its maximum effect no later than 12 weeks.

If blood pressure normalization is not achieved after 12 weeks of daily treatment with 2.5 mg of torasemide, the daily dose may be increased to 1 tablet of Trifas® Cor, equivalent to 5 mg of torasemide. The daily dose of Trifas® Cor should not exceed 1 tablet (equivalent to 5 mg of torasemide), as no further reduction in blood pressure is expected with higher doses.

Edema and/or effusions due to heart failure.

Adults. Initiate therapy with a dose of 5 mg once daily (1 tablet of Trifas® Cor). This dose is usually considered as the maintenance dose.

The tablet can be split into two halves as follows:

hold the tablet between the index and thumb of both hands with the score line facing upwards, and press downwards with both thumbs along the break line to split the tablet.

If the daily dose of 5 mg is insufficient, the daily dose may be increased to 10 mg, administered daily. If necessary, the daily dose of torasemide may be further increased up to 20 mg, depending on the severity of the clinical condition.

Special Patient Groups.

Elderly Patients.

No specific dose adjustment is required. However, adequate studies comparing treatment in elderly and younger patients are lacking.

Patients with Hepatic Impairment.

Torasemide is contraindicated in patients with hepatic coma or precoma (see section "Contraindications"). The drug should be administered with caution in patients with hepatic insufficiency, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Administration Method.

Tablets should be taken in the morning with a small amount of liquid. The bioavailability of torasemide is not affected by food intake.

Children.

The safety and efficacy of Trifas® Cor 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 (see section "Special Precautions").

Overdose.

Symptoms of intoxication.

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

Treatment of intoxication.

No specific antidote is known. The severity of intoxication symptoms usually decreases with dose reduction or discontinuation of the drug, along with restoration of fluid and electrolyte balance (monitoring 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 insufficiency: anti-shock positioning of the patient and, if necessary, symptomatic therapy.

Anaphylactic shock (immediate measures):

Upon the first signs of shock (e.g., skin reactions such as urticaria or skin redness, patient agitation, headache, episodes of sweating, nausea, cyanosis), the following steps should be taken:

• ensure venous access;
• in addition to other standard emergency measures, place the patient in a supine position with elevated legs, ensure free access to air, and administer oxygen(!);
• if necessary, apply intensive therapy measures (including administration of epinephrine, volume-replacing solutions, and glucocorticoid hormones).

Adverse Reactions

The adverse reactions associated with the use of Triphas® Cor are listed below.

Frequency is defined as follows:

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: frequency cannot be estimated from the available data.

Blood and lymphatic system disorders

Very rare: blood thickening, decreased number of platelets, red blood cells and/or white blood cells (see section "Special precautions for use").

Immune system disorders

Very rare: allergic reactions.

Metabolism and nutrition disorders

Common: exacerbation of metabolic alkalosis; hyperglycemia, hypokalemia in concomitant low-potassium diet, vomiting, diarrhea, after excessive use of laxatives, as well as in patients with chronic liver dysfunction. Depending on dosage and duration of treatment, disturbances in water and electrolyte balance may develop, such as hypovolemia, hypokalemia and/or hyponatremia (see section "Special precautions for use").

Nervous system disorders

Common: headache, dizziness (especially at the beginning of treatment).

Uncommon: paresthesia.

Very rare: syncope, cerebral ischemia, confusion.

Eye disorders

Very rare: visual disturbances.

Ear and labyrinth disorders

Very rare: tinnitus, hearing loss.

Cardiac disorders

Very rare: myocardial ischemia, arrhythmia, angina pectoris, acute myocardial infarction.

Vascular disorders

Very rare: thromboembolic complications, arterial hypotension, as well as circulatory and cardiac disorders.

Gastrointestinal disorders

Common: gastrointestinal disturbances (e.g., loss of appetite, stomach pain, nausea, vomiting, diarrhea, constipation), especially at the beginning of treatment.

Uncommon: xerostomia.

Very rare: pancreatitis.

Hepatobiliary disorders

Common: increased blood concentration of certain liver enzymes (gamma-glutamyltransferase).

Skin and subcutaneous tissue disorders

Very 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).

Renal and urinary disorders

Uncommon: in patients with impaired micturition (e.g., due to benign prostatic hyperplasia), increased urine production may lead to urinary retention and excessive bladder distension.

General disorders

Common: fatigue, weakness (especially at the beginning of treatment).

Laboratory findings

Common: increased blood concentration of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions for use").

Uncommon: increased blood concentration of urea and creatinine (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

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

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BERLIN-CHEMIE AG

Manufacturer's address.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.