Torasemide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORSID® (TORSID)

Composition:

Active substance: torasemide;

1 ml of solution contains torasemide, calculated as 100 % dry substance, 5 mg;

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

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear colorless liquid, practically free from mechanical inclusions.

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 subjects, a logarithmic dose-proportional increase in diuresis (loop diuretic activity) was observed over the dose range of 5–100 mg. 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 leads to reduction of edema. In cases of heart failure, torasemide reduces disease symptoms and improves myocardial function by decreasing preload and afterload.

Pharmacokinetics

Absorption and distribution

Plasma protein binding of torasemide exceeds 99%, while 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 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 a 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 individuals is 3–4 hours. Total clearance of torasemide is 40 mL/min, with renal clearance being approximately 10 mL/min. In healthy individuals, approximately 80% of the administered dose is excreted in urine as torasemide and its metabolites, with 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 active metabolites M1 and M3 together account for approximately 10% of the total pharmacodynamic 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 stable, 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 nearly equal to that in healthy individuals; 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 the maximum plasma concentration and the area under the plasma concentration-time curve increase proportionally with the administered dose.

Preclinical safety data

In studies of pharmacological safety, chronic toxicity, mutagenicity, and carcinogenicity in animals, no data indicating an increased risk associated with the use of the drug 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 torasemide crosses the placental barrier in rats. 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 required, 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 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, such as kanamycin, gentamicin, tobramycin, and cytostatic 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 effects and increased 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 concomitant use. When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by diuretic use may lead to increased and enhanced adverse effects of both drugs. 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 effect of theophylline, as well as the muscle-relaxing effect of curare-like medicinal agents. Laxatives, as well as mineralo- and glucocorticoids, may intensify potassium loss induced by torasemide. Torasemide may reduce the vasoconstrictive effect 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, atrioventricular block of grade II and III;
• pathological changes in acid-base metabolism;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood count abnormalities, e.g. 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, carbohydrate metabolism should be monitored regularly in patients with latent or manifest diabetes mellitus. Particular attention should be paid, especially at the beginning of treatment and when treating elderly patients, to the appearance of symptoms of hemoconcentration and symptoms of electrolyte loss. 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, regular monitoring of complete blood count (erythrocytes, leukocytes, platelets) should be performed.

Consequences of misuse as doping

The use of the medicinal product Torsid® may lead to a positive doping test result. It is not possible to predict the health effects if Torsid® has been misused, i.e. used for doping purposes – in such cases, harm to health cannot be excluded.

Excipients

The minimum dose of the medicinal product is 2 ml and contains 20.0092 mmol of sodium.

One ampoule (4 ml) of this medicinal product contains 40.0184 mmol of sodium. Caution is advised when prescribing to patients on a sodium-restricted diet.

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. Torsid® is not recommended for use during pregnancy or in women of reproductive potential who are not using contraception. Therefore, torasemide should be used during pregnancy only if clearly needed and at the lowest effective dose. Diuretics are not suitable 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 electrolytes and hematocrit, as well as fetal development, is required.

Lactation period. It is currently unknown whether torasemide passes into 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/abstain from treatment with Torsid® should be made taking into account 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. In animal studies, no effect of torasemide on fertility was observed.

Ability to influence reaction speed when driving or operating machinery.

Even when used correctly, torasemide may negatively affect 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 due to heart failure.

Adults.

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

Acute pulmonary edema.

Adults.

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

Special patient groups

Elderly patients. Treatment of this patient category does not require special dose adjustment. However, no comparative studies in elderly patients versus younger patients have 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. Intraarterial administration is prohibited! Only administer the undiluted solution. Torcid® must not be used if signs of solution degradation are present (e.g., presence of particulate matter in the solution) or if the ampoule is damaged. One ampoule is intended for single use only. Any unused solution must be immediately disposed of in accordance with local legislation. Torcid® must not be mixed with other medicinal products intended for intravenous injection and/or infusion (see section "Incompatibilities"). During prolonged treatment, intravenous administration should be replaced as soon as possible with oral administration, since intravenous administration of torasemide is not recommended for longer than 7 days.

Children.

The safety and efficacy of Torcid® medicinal product 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, along with appropriate fluid and electrolyte replacement (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 supplements.

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

Anaphylactic shock (immediate 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, free access to air ensured, and oxygen administered. If necessary, further intensive therapy measures should be applied (including administration of epinephrine, glucocorticoids, and circulating blood volume replacement).

Adverse reactions.

Listed below are adverse reactions that may occur with the use of the medicinal product TORASIDE®.

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 leucopenia (see section "Special warnings and 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 electrolyte disorders. Common: exacerbation of metabolic alkalosis, hyperkalaemia, hypokalaemia when associated with a low-potassium diet, vomiting, diarrhoea, or excessive use of laxatives, as well as in patients with chronic liver dysfunction. Depending on dose and duration of treatment, disturbances in fluid and electrolyte balance such as hypovolaemia, hypokalaemia and/or hyponatraemia may occur (see section "Special warnings and 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, 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, diarrhoea, 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: in cases of impaired micturition (e.g. due to benign 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 warnings and precautions for use"). Uncommon: increased blood concentrations of urea and creatinine (see section "Special warnings and precautions for use").

Reporting 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 encouraged to 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.

Store in the original packaging at a temperature not exceeding 25°C. Do not freeze.

Keep out of reach and sight of children.

Incompatibilities. TORASIDE® must not be mixed with other medicinal products for intravenous injection and/or infusion.

Packaging.

2 ml or 4 ml in a vial; 5 vials in a carton. 5 vials in a blister; 1 blister in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.