Trifas® 20 ampules

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIFAS® 20 AMPOULES (TRIFAS® 20 AMPOULES)

Composition:

Active substance: torasemide;

1 ampoule (4 ml) of injection solution contains sodium torasemide 21.262 mg (equivalent to 20 mg of torasemide);

Excipients: sodium hydroxide, trometamol, polyethylene glycol 400, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution, practically free from mechanical inclusions. pH of TRIFAS® 20 ampoules: 8.5–9.5.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Torasemide acts as a diuretic; 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 (loop diuretic activity) was observed. Increased diuresis was observed in cases where other diuretics, such as distally-acting thiazide-type diuretics, had already failed to produce the desired effect, for example in renal insufficiency. Due to this mechanism of action, torasemide leads to reduction of edema. In heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing both preload and afterload.

Pharmacokinetics

Absorption and distribution

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.

Biotransformation

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 through stepwise oxidation of the methyl group attached to the phenyl ring into a carboxylic acid; metabolite M3 is formed via ring hydroxylation. Metabolites M2 and M4, detected in animal experiments, were not identified 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, with renal clearance being 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 average proportions: torasemide – approximately 24%, metabolite M1 – approximately 12%, metabolite M3 – approximately 3%, metabolite M5 – approximately 41%. The main metabolite M5 has no diuretic activity, while the combined contribution of the active metabolites M1 and M3 accounts for approximately 10% of the total pharmacokinetic effect. 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 unaltered, and the severity of renal insufficiency does not affect the duration of action. Torasemide and its metabolites are practically not removed by hemodialysis or hemofiltration.

In patients with hepatic impairment or heart failure, the half-life of torasemide and metabolite M5 is slightly prolonged, but the amount of substance excreted in urine is nearly equal to that in healthy volunteers; therefore, accumulation of torasemide and its metabolites does not occur.

Linearity

The pharmacokinetics of torasemide and its metabolites are characterized by linear dependence. This means that its maximum plasma concentration and the area under the plasma concentration-time curve increase proportionally with dose.

Clinical characteristics.

Indications.

Treatment of edema and/or effusions caused by heart failure when intravenous administration of the medicinal product is required, for example in the case of pulmonary edema due to acute 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.

Acute urinary obstruction, for example due to benign prostatic 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 effects of platinum-containing cytostatic agents, as well as the nephrotoxic effects of cephalosporins.

Concomitant use of torasemide and lithium preparations may increase lithium plasma 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 inhibitors, which may result in excessive reduction of arterial blood pressure during concomitant use. When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by diuretic therapy may lead to increased susceptibility 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 toxic effects on the central nervous system. Torasemide may enhance the action 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.

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 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 agents;
• In children and adolescents under 18 years of age.

Since torasemide treatment may lead to increased blood glucose levels, 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 when treating elderly patients, to the emergence of symptoms of haemoconcentration and electrolyte depletion. With prolonged use of torasemide, regular monitoring of electrolyte balance, particularly serum potassium levels, is required. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is necessary. Furthermore, complete blood count (erythrocytes, leucocytes, thrombocytes) should be monitored regularly.

Consequences of misuse as doping

Use of the medicinal product Triphas® 20 ampoules may lead to a positive doping test result. The health consequences of misuse of Triphas® 20 ampoules, i.e. for doping purposes, cannot be predicted; in such cases, harm to health cannot be excluded.

Excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per ampoule, i.e. it can be considered practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking. Reproductive toxicity of torasemide has been demonstrated in animal studies. Torasemide crosses the placental barrier. Triphas® 20 ampoules are not recommended during pregnancy, nor in women of childbearing potential who are not using contraception. Due to the above, torasemide should be used during pregnancy 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 cause toxic effects on fetal development. If torasemide is used to treat pregnant women with heart failure or renal insufficiency, careful monitoring of electrolyte levels and haematocrit, as well as fetal development, is required.

Lactation period. It is currently unknown 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® 20 ampoules should be made after considering the benefits of breastfeeding for the child and the benefits of treatment with the medicinal product for the woman.

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

Ability to affect reaction speed while driving or operating machinery

Even when used correctly, torasemide may negatively affect reaction speed while 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 while driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage

Edema and/or effusions due to heart failure.

Treatment should be initiated with a single dose of 2 ml of Triphas® 20 ampoules, equivalent to 10 mg of torasemide per day. If the effect is insufficient, the single dose may be increased to 4 ml of Triphas® 20 ampoules, equivalent to 20 mg of torasemide. If the response remains inadequate, short-term therapy (for no more than 3 days) may be administered with a daily dose of 8 ml of Triphas® 20 ampoules, equivalent to 40 mg of torasemide.

Acute pulmonary edema.

Treatment should begin with intravenous administration of a single dose of 4 ml of Triphas® 20 ampoules, equivalent to 20 mg of torasemide. Depending on the response, this dose may be repeated after an interval of 30 minutes. The maximum daily dose of 20 ml of Triphas® 20 ampoules, equivalent to 100 mg of torasemide, must not be exceeded.

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 this patient group should be performed with caution, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Method of administration

The injection solution should be administered slowly intravenously. Only clear, transparent solutions should be used. Intraarterial administration is prohibited. Triphas® 20 ampoules must not be used if signs of solution decomposition are present (e.g., presence of suspended particles in the solution) or if the ampoule is damaged. Each ampoule is intended for single use only. Any unused solution should be immediately disposed of according to local legislation. Triphas® 20 ampoules must not be mixed with other medicinal products for intravenous injection and/or infusion (see section "Incompatibilities"). With prolonged use, intravenous administration should be replaced as soon as possible by oral administration, since intravenous administration of torasemide is not recommended for longer than 7 days.

Handling of single-point opening ampoules

Rotate the ampoule so that the point is on top. Tap the ampoule and shake it gently to allow the solution in the neck of the ampoule to flow down.

Rotate the ampoule so that the point is on top. Hold the ampoule at a slight angle. Break off the neck of the ampoule with a downward-directed motion.

Children. The safety and efficacy of the medicinal product Triphas® 20 ampoules 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 instructions").

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, somnolence, 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 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 in case of circulatory collapse: place the patient in a supine position and, if necessary, initiate symptomatic therapy.

Anaphylactic shock (emergency measures).

Upon the first signs of skin reactions (such as urticaria or skin redness), patient's agitation, headache, sweating, nausea, cyanosis, perform venous catheterization; place the patient in a horizontal position, ensure free access of air, administer oxygen. If necessary, further treatment should include intensive care measures (including administration of epinephrine, glucocorticoids, and blood volume replacement).

Adverse Reactions

The adverse reactions listed below may occur during treatment with the medicinal product Triphas® 20 ampoules.

The following frequency categories were used to classify the occurrence of adverse reactions:

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,
Frequency not known: cannot be estimated from the available data.

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

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 / Electrolyte imbalances. Common: exacerbation of metabolic alkalosis, hyperkalemia, hypokalemia in case of 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 occur, e.g., 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 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 skin 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: in patients with impaired micturition (e.g., due to prostatic hyperplasia), increased urine production may be accompanied by urinary retention and bladder distension.

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

Reporting suspected adverse reactions.

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

Shelf life. 3 years. After first opening of the ampoule, the solution should be used immediately.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Incompatibilities.

Triphas® 20 ampoules must not be mixed with other medicinal products intended for intravenous injection and/or infusion.

Packaging. 4 ml in an ampoule, 5 ampoules in a blister pack, contained in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.

Manufacturer's address.

Via Sette Santi 3, 50131 Florence (FI), Italy.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

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