Trifas® 10 ampoules

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

Composition:

Active substance: torasemide;

1 ampoule (2 ml) of injection solution contains sodium torasemide 10.631 mg (equivalent to 10 mg of torasemide);

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution practically free from mechanical particles. pH of Trifas® 10 ampoules: 8.5 – 9.5.

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, a logarithmic dose-proportional increase in diuresis was observed over the dose range of 5–100 mg (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 disease symptoms and improves myocardial function by decreasing preload and afterload.

Pharmacokinetics

Absorption and distribution

Protein binding of torasemide to plasma proteins exceeds 99%, while metabolites M1, M3, and M5 are bound at 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 for the existence of other metabolites. Metabolites M1 and M5 are formed through stepwise oxidation of the methyl group attached to the phenyl ring into carboxylic acid, while 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, about 80% of the administered dose is excreted in urine as torasemide and its metabolites, with the following average percentage distribution: torasemide – approximately 24%, metabolite M1 – approximately 12%, metabolite M3 – approximately 3%, metabolite M5 – approximately 41%. The main metabolite M5 has no diuretic effect, while the combined contribution of the active metabolites M1 and M3 accounts for approximately 10% of the total pharmacokinetic activity. In renal insufficiency, total clearance and the half-life of torasemide remain unchanged, while the half-life of M3 and M5 is prolonged. However, pharmacodynamic characteristics remain 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 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 almost 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 kinetics. This means that the maximum plasma concentration and the area under the plasma concentration-time curve increase proportionally with the dose.

Preclinical safety data

In studies of pharmacological safety, chronic toxicity, mutagenicity, and carcinogenicity in animals, no data indicating an increased risk with use in humans were obtained. In reproductive toxicity studies in animals, no teratogenic effects of the drug were observed. However, in pregnant rabbits and rats administered high doses of the drug, signs of fetal toxicity and maternal toxicity were observed. It has been noted that in rats, torasemide crosses the placental barrier. The drug had no effect on fertility.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance, sulphonilurea 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 prostatic hypertrophy. Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Combinations not recommended

Torasemide, especially at high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics, such as kanamycin, gentamicin, tobramycin, and cytostatic agents – active platinum derivatives, 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.

Medicinal product 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 their concomitant use. When torasemide is used concomitantly with digoxin preparations, potassium deficiency caused by diuretic use may lead to increased incidence 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 effects of theophylline and the muscle-relaxing effects of curare-like medicinal agents. Laxatives, as well as mineralo- 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);
• pathological changes in acid-base metabolism;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood count abnormalities, such as thrombocytopenia or anemia in patients without renal impairment;
• renal dysfunction caused by nephrotoxic substances;
• in children and adolescents under 18 years of age.

Since increased blood glucose concentration may occur during torasemide treatment, patients with latent or overt 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 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 recommended. Furthermore, complete blood count (erythrocytes, leucocytes, thrombocytes) should be monitored regularly.

Consequences of improper use as doping

Use of the medicinal product Trifas® 10 ampoules may lead to a positive doping test result. The health consequences of improper use of Trifas® 10 ampoules, i.e. for doping purposes, cannot be predicted; in such cases, harm to health cannot be ruled out.

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. Trifas® 10 ampoules are not recommended during pregnancy, nor for women of childbearing potential who are not using contraception. Therefore, torasemide should be used during pregnancy only if strictly indicated and at the lowest effective dose. Diuretics are not suitable for standard treatment 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 or renal failure, careful monitoring of electrolyte levels and haematocrit, as well as fetal development, is required.

Lactation. 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"). A decision on whether to discontinue breastfeeding or to discontinue/stop treatment with Trifas® 10 ampoules should be made, taking into account the benefits of breastfeeding for the child and 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 adverse effects of torasemide on fertility.

Effects on ability to drive and use machines.

Even when used correctly, torasemide may impair the ability to react quickly 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 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 single dose of 2 mL of the medicinal product Triphas® 10 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® 10 ampoules, equivalent to 20 mg of torasemide. If the effect remains insufficient, short-term therapy (for no more than 3 days) may be administered with a daily dose of 8 mL of Triphas® 10 ampoules, equivalent to 40 mg of torasemide.

Acute pulmonary edema.

Adults.

Treatment should begin with intravenous administration of a single dose of 4 mL of the medicinal product Triphas® 10 ampoules, equivalent to 20 mg of torasemide. Depending on the effect, this dose may be repeated at 30-minute intervals. The maximum daily dose of 20 mL of Triphas® 10 ampoules, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups

Elderly patients. No special dose adjustment is required. However, studies comparing the drug's effect 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 intravenously, slowly. Only clear, transparent solutions should be administered.

Intraarterial administration is prohibited. Triphas® 10 ampoules must not be used if signs of solution degradation 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 remaining solution must be immediately disposed of according to local legislation. Triphas® 10 ampoules must not be mixed with other medicinal products for intravenous injection and/or infusion (see section "Incompatibilities"). During prolonged treatment, intravenous administration should be replaced as soon as possible with oral administration, as intravenous use of torasemide is not recommended for longer than 7 days.

Handling single-point opening ampoules.

Filing of ampoules is not required.

Children.

The safety and efficacy of the medicinal product Triphas® 10 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 precautions for use").

Overdose.

Symptoms of intoxication

The typical symptomatology 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 medicinal product and with appropriate replacement of fluids and electrolytes (monitoring 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 preparations.

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

Anaphylactic shock (emergency measures).

At the first signs of skin reactions (such as urticaria or skin redness), patient 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 therapy measures (including administration of epinephrine, glucocorticoids, and replacement of circulating blood volume).

Adverse Reactions

The adverse reactions listed below may occur during treatment with the medicinal product Trifas® 10 ampoules.

The following frequency categories were used to classify adverse reactions:

Very common: ≥ 1/10,
Common: ≥ 1/100 to < 1/10,
Uncommon: ≥ 1/1000 to < 1/100,
Rare: ≥ 1/10,000 to < 1/1000,
Very rare: < 1/10,000,
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. Acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur after intravenous administration, requiring immediate medical intervention.

Metabolism and nutrition disorders. Common: exacerbation of metabolic alkalosis, hyperkalaemia, hypokalaemia in patients on a low-potassium diet, with vomiting, diarrhoea, or after excessive use of laxatives, as well as in patients with chronic liver dysfunction. Depending on dose and duration of treatment, disturbances in water and electrolyte balance may occur, such as hypovolaemia, hypokalaemia and/or hyponatraemia (see section "Special precautions for use").

Nervous system disorders. Common: headache, dizziness (especially at the beginning of treatment). Uncommon: paraesthesia. Very rare: syncope, cerebral ischaemia, confusion.

Eye disorders. Very rare: visual disturbances.

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

Cardiac disorders. Very rare: myocardial ischaemia, arrhythmia, angina pectoris, acute myocardial infarction.

Vascular disorders. Very rare: thromboembolic complications, arterial hypotension, disturbances in coronary circulation, and disturbances in central circulation.

Gastrointestinal disorders. Common: gastrointestinal disturbances (e.g. loss of appetite, stomach pain, nausea, vomiting, diarrhoea, persistent constipation), particularly 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 hypertrophy), 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 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 are required to report any suspected adverse reactions.

Shelf life. 3 years. Do not use the medicinal product after the expiry date stated on the packaging. The solution should be used immediately after opening the ampoule.

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

Incompatibilities. Trifas® 10 ampoules must not be mixed with other medicinal products intended for intravenous injection and/or infusion.

Packaging. 2 ml in an ampoule, 5 ampoules in a blister pack, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

A. Menarini Manufacturing Logistics and Services S.r.l.
Via Sette Santi 3, 50131 Florence (FI), Italy.

Marketing Authorisation Holder.

Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.