Trifas® 10

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIFAS® 10 (TRIFAS® 10)

Composition:

Active ingredient: torasemide

1 tablet contains torasemide 10 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white-colored, round, flat tablets with bevelled edges and a score line on one side. The tablet can be divided into two equal parts.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

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.

Pharmacodynamic effects

In humans, the diuretic effect rapidly reaches its maximum within the first 2–3 hours after intravenous and oral administration, respectively, and remains consistent for approximately 12 hours. In healthy volunteers, within the dose range of 5–100 mg, a logarithmic dose-proportional increase in diuresis was observed (loop diuretic activity). Increased diuresis was observed 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 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 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.

Presumably, this effect reduces increased contractility and/or vascular responsiveness to endogenous vasoconstrictive substances, such as catecholamines.

Pharmacokinetics.

Absorption and distribution

After oral administration, torasemide is rapidly and almost completely absorbed. Peak plasma concentration is reached within 1–2 hours. Bioavailability is approximately 80–90%. Under conditions of complete absorption, the maximum value of the first-pass effect through the liver does not exceed 10–20%. According to data from two studies, food reduces the rate (dynamic component) of torasemide absorption (Cmax decreases and tmax increases) but does not affect total absorption. Protein binding of torasemide to plasma proteins exceeds 99%, while for its metabolites M1, M3, and M5, it is 86%, 95%, and 97%, respectively. The apparent volume of distribution (Vz) is 16 L.

Metabolism

In humans, torasemide is metabolized to form three metabolites: M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1 and M5 are formed by stepwise 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, and renal clearance is approximately 10 mL/min. In healthy volunteers, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites in the following proportions:

torasemide – approximately 24%, metabolite M1 – approximately 12%, metabolite M3 – approximately 3%, metabolite M5 – approximately 41%. The main metabolite M5 has no diuretic effect. The combined contribution of active metabolites M1 and M3 to the overall pharmacokinetic effect is approximately 10%. In renal insufficiency, total clearance and half-life of torasemide remain unchanged, while the half-life of M3 and M5 is prolonged. However, the pharmacodynamic profile remains unchanged. The severity of renal insufficiency does not affect the duration of action. Torasemide and its metabolites are practically not eliminated during hemodialysis or hemofiltration. In patients with hepatic impairment or heart failure, the half-life of torasemide and metabolite M5 is slightly prolonged. The ratio of unchanged torasemide to its metabolites excreted in urine is practically unchanged compared to healthy volunteers. Therefore, accumulation of torasemide and its metabolites does not occur.

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.

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

Contraindications.

Hypersensitivity to the active substance, sulfonylurea drugs, or to any of the excipients of the medicinal product.

Renal failure with anuria.

Hepatic coma or precoma.

Arterial hypotension.

Hypovolemia.

Hyponatremia.

Hypokalemia.

Significant impairment of urination, for example, due to prostate hyperplasia. Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended

Torasemide, especially at high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin) and nephrotoxic chemotherapeutic agents – active platinum derivatives, as well as the nephrotoxic effect of cephalosporins. Concomitant use of torasemide and lithium preparations may increase lithium plasma concentration, potentially leading to enhanced lithium effects and adverse reactions.

Medicinal product combinations requiring caution

Torasemide potentiates the effects of other antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, which may result in excessive reduction of arterial blood pressure during concomitant use. When torasemide is used concomitantly with digitalis preparations, potassium deficiency induced by diuretic therapy may lead to increased and 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 high-dose salicylates, torasemide may increase their neurotoxic effects on the central nervous system. Torasemide may enhance the effects of theophylline and the muscle-relaxing effects of curare-like medicinal products. Laxatives, as well as mineralocorticoids and glucocorticoids, may intensify potassium loss induced by torasemide. Torasemide may reduce the vasoconstrictive effects of catecholamines, such as epinephrine and norepinephrine. Concomitant use with cholestyramine may reduce torasemide absorption and, consequently, its expected efficacy.

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);
• acid-base metabolic disorders;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood count abnormalities, such as thrombocytopenia or anemia in patients without renal insufficiency;
• kidney dysfunction caused by nephrotoxic substances;
• in children and adolescents under 18 years of age.

Since increased blood glucose concentration may occur during treatment with torasemide, patients with latent or manifest diabetes mellitus should undergo regular monitoring of carbohydrate metabolism. Particular attention should be paid, especially at the beginning of treatment and in elderly patients, to the appearance of symptoms of hemoconcentration and symptoms of electrolyte loss. Regular monitoring of electrolyte balance, particularly serum potassium levels, is required during prolonged use of torasemide. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is recommended. Furthermore, regular monitoring of complete blood count (erythrocytes, leukocytes, platelets) should be performed.

Consequences of improper use as doping

The use of the medicinal product Triphas® 10 may lead to a positive doping test result. It is impossible to predict the health consequences if Triphas® 10 is used improperly, i.e. for doping purposes – in such cases, harm to health cannot be excluded.

Excipients

Triphas® 10 contains lactose; therefore, patients with rare hereditary disorders such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking. Information on reproductive toxicity of torasemide is available. Torasemide crosses the placental barrier. Triphas® 10 is not recommended during pregnancy, or in women of reproductive potential who are not using contraceptive measures. Therefore, torasemide should be used during pregnancy only under life-threatening indications and at the lowest effective dose. Diuretics are not appropriate for standard treatment regimens of arterial hypertension or edema in pregnancy, 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 and hematocrit, as well as fetal development, is necessary.

Lactation period. It has not yet been established whether torasemide or its metabolites are excreted in breast milk in animals or humans. 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 stop/abandon treatment with Triphas® 10 should be made by weighing the benefits of breastfeeding for the child against the benefits of treatment for the mother.

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

Ability to affect reaction speed when driving or operating machinery.

Even when used appropriately, torasemide may impair reaction speed when driving or operating machinery. This is particularly relevant at the beginning of treatment, during dose escalation, when switching medications, during concomitant therapy, or when consuming alcohol. Therefore, special caution should be exercised when driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage

Edema and/or effusions caused by heart failure.

Adults.

Treatment should be initiated with a daily dose of 5 mg of torasemide, equivalent to ½ tablet of Triphas® 10. This dose is usually considered a maintenance dose.

The tablet can be divided into two parts as follows:

Hold the tablet with the index and thumb of both hands, with the score line facing upwards. Press downwards with the thumbs along the score line to break the tablet.

If the daily dose of 5 mg is insufficient, a daily dose of 10 mg of torasemide should be prescribed. Depending on the severity of the patient's condition, the daily dose may be increased up to 20 mg per day.

Special patient groups

Elderly patients. No specific dose adjustment is required. However, comparative studies on the effect of the drug in younger and elderly patients have not been conducted.

Patients with hepatic impairment. Torasemide is contraindicated in patients with hepatic coma or precoma (see section "Contraindications"). Treatment in these patients should be performed with caution, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Method of administration

Tablets should be taken on an empty stomach, swallowed with a small amount of liquid. The bioavailability of torasemide is not affected by food intake.

Triphas® 10 is usually administered for a prolonged period or until edema subsides.

Children.

The safety and efficacy of Triphas® 10 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 for use").

Overdose.

Symptoms of intoxication. The typical clinical picture is unknown. Overdose may cause pronounced diuresis, including the risk of excessive loss of water and electrolytes, drowsiness, confusion, symptomatic arterial hypotension, circulatory collapse, 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 replacement of fluids and electrolytes (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 in case of circulatory collapse: place the patient in a supine position and, if necessary, administer 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, venous catheterization should be performed; the patient should be placed in a horizontal position with legs elevated, free air access ensured, and oxygen administered. If necessary, further intensive therapy should be initiated (including administration of epinephrine, glucocorticoids, and circulating blood volume replacement).

Side effects

The following adverse reactions may occur during treatment with the medicinal product Triphas® 10.

The frequency of adverse reactions is categorized as follows:

Very common: ≥1/10;
Common: ≥1/100 to <1/10;
Uncommon: ≥1/1,000 to <1/100;
Rare: ≥1/10,000 to <1/1,000;
Very rare: <1/10,000.
Not known: cannot be estimated from available data.

Blood and lymphatic system disorders. Very rare: haemoconcentration, thrombocytopenia, erythropenia and/or leukopenia (see section "Special precautions and warnings").

Immune system disorders. Very rare: allergic reactions. After intravenous administration, acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur, requiring immediate medical intervention.

Metabolism and nutrition disorders / Electrolytes. Common: exacerbation of metabolic alkalosis, hyperkalemia, hypokalemia in patients on a low-potassium diet, with vomiting, diarrhea, after 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, such as hypovolemia, hypokalemia and/or hyponatremia (see section "Special precautions and warnings").

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, circulatory disorders in the heart, and disturbances of central circulation.

Gastrointestinal disorders. Common: gastrointestinal disturbances (e.g. loss of appetite, stomach pain, nausea, vomiting, diarrhea, persistent constipation), especially at the beginning of treatment. Uncommon: xerostomia. Very rare: pancreatitis.

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

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

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

Renal and urinary disorders. Uncommon: increased urine production may be accompanied by urinary retention and bladder distension in patients with impaired micturition (e.g. due to prostate hyperplasia).

General disorders and administration site conditions. Common: increased fatigue, general weakness (especially at the beginning of treatment).

Investigations. Common: increased blood concentrations of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions and warnings").
Uncommon: increased blood concentrations of urea and creatinine (see section "Special precautions and warnings").

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

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

Packaging. 10 tablets in a blister; 3, 5 or 10 blisters per 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