Torasemide-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORASEMIDE-DARNITSA (TORASEMIDE-DARNITSA)

Composition:

active substance: torasemide;

1 ampoule (4 ml) of injection solution contains 20 mg of torasemide;

excipients: polyethylene glycol 400 (macrogol 400), sodium hydroxide, tromethamine, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: a clear, colorless liquid practically free from mechanical inclusions.

Pharmacotherapeutic group. Drugs affecting the cardiovascular system. Diuretics. High-ceiling diuretics. Ordinary sulfonamides. Torasemide. 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 constant for almost 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 even in cases where other diuretics, such as distally acting thiazide-type diuretics, were no longer effective, for example in renal failure. Due to this mechanism of action, torasemide leads to reduction of edema. In the case of heart failure, torasemide reduces symptoms of the disease and improves myocardial function by decreasing preload and afterload.

Pharmacokinetics.

Absorption and distribution

The plasma protein binding of torasemide is over 99%, and 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, M3, and M5 are formed through stepwise oxidation of the methyl group attached to the phenyl ring of the carboxylic acid, while metabolite M3 is formed via hydroxylation of the ring.

Metabolites M2 and M4, identified in animal experiments, were not detected in humans.

Elimination

The terminal half-life (t1/2) of torasemide and its metabolites in healthy volunteers is 3–4 hours. The 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, 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 pharmacodynamic effect. In renal failure, total clearance and t1/2 of torasemide remain unchanged, while t1/2 of M3 and M5 is prolonged. However, pharmacodynamic characteristics remain unchanged, and the severity of renal failure does not affect the duration of action. In patients with hepatic dysfunction or heart failure, the t1/2 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. Torasemide and its metabolites are practically not eliminated by hemodialysis or hemofiltration.

Linearity

The pharmacokinetics of torasemide and its metabolites are characterized by linear dependence.

This means that its maximum serum concentration and the area under the serum 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 drug is required, for example, in 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 prostatic hyperplasia. Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Combinations not recommended

Torasemide, especially at high doses, may enhance the oto- 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 adverse effects 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 digitalis preparations, potassium deficiency caused by diuretic use may lead to increased incidence and severity of 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);
• Acid-base metabolism disorders;
• Concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• Blood abnormalities such as thrombocytopenia or anemia in patients without renal insufficiency;
• Renal dysfunction caused by nephrotoxic substances;
• In children and adolescents under 18 years of age.

Since treatment with torasemide may lead to increased blood glucose concentration, 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 during treatment of elderly patients, to the emergence of symptoms of haemoconcentration and symptoms of electrolyte loss. During prolonged use of torasemide, electrolyte balance should be monitored regularly, particularly serum potassium levels. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is required. Furthermore, complete blood count (erythrocytes, leukocytes, platelets) should be monitored regularly.

Consequences of misuse (as a doping agent)

The use of torasemide may lead to a positive doping test result. The health consequences of misuse, i.e. using the drug for doping purposes, cannot be predicted and, in such cases, harm to health cannot be ruled out.

Important information about excipients

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

Use during pregnancy or breastfeeding

Pregnancy

There are no reliable data on the effects of torasemide on the human embryo or fetus. Reproductive toxicity of torasemide has been demonstrated in animal studies. Torasemide crosses the placental barrier; therefore, this medicinal product is not recommended during pregnancy or 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 lowest 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 exert 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

It has not yet been established whether torasemide passes into breast milk in animals or humans. Harm to newborns/infants from the use of this medicinal product cannot be excluded. Therefore, the use of torasemide during breastfeeding is contraindicated (see section "Contraindications"). A decision to discontinue breastfeeding or to discontinue/abandon the use of the medicinal product 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 effects of torasemide on fertility in humans have not been conducted. In animal studies, no such effects of torasemide were observed.

Ability to affect performance when driving or operating machinery

Even when used correctly, torasemide may negatively affect a patient's ability to drive or operate machinery, particularly at the beginning of treatment, when the dose is increased, when switching medications, or when concomitant therapy is initiated. Therefore, extreme caution is required when driving or operating machinery during treatment with torasemide.

Dosage and Administration

Edema and/or effusions due to heart failure

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

Acute pulmonary edema

Treatment should begin with intravenous administration of a single dose of 4 mL of the medicinal product, equivalent to 20 mg of torasemide.

Depending on the clinical response, this dose may be repeated at 30-minute intervals. The maximum daily dose of 20 mL of the medicinal product, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups

Elderly patients

Treatment of this patient group 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 intravenously, slowly. Intra-arterial administration is prohibited. Only administer the clear solution. The medicinal product 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 should be immediately disposed of according to local regulations. The medicinal product 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, since intravenous administration of torasemide is not recommended for longer than 7 days.

Children

The safety and efficacy of torasemide in children and adolescents under 18 years of age have not been established. Therefore, the medicinal product should not be used in children and adolescents under 18 years of age (see section "Special precautions for use").

Overdose

The typical symptoms of overdose are unknown. Overdose may cause profound diuresis and, consequently, 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 appropriate replacement of fluids and electrolytes (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 in case of circulatory collapse: place the patient in a supine position and, if necessary, administer symptomatic therapy.

Anaphylactic shock (emergency measures)

In case of skin reactions (urticaria or skin redness), agitation, headache, excessive sweating, nausea, cyanosis, perform venous catheterization; place the patient in a horizontal position, ensure free air access, and administer oxygen.

If necessary, further use intensive therapy measures (including administration of epinephrine, glucocorticoids, and replacement of circulating blood volume).

Adverse Reactions

All adverse reactions are listed by system organ class and frequency: 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), frequency not known (cannot be estimated from the available data).

Eye disorders: very rare – visual disturbances.

Ear and labyrinth disorders: very rare – tinnitus, hearing loss.

Gastrointestinal disorders: common – gastrointestinal disorders (e.g., loss of appetite, flatulence, stomach pain, nausea, vomiting, diarrhea, persistent constipation), particularly at the beginning of treatment; rare – xerostomia (dry mouth); very rare – pancreatitis.

Hepatobiliary disorders: common – increased concentration of certain liver enzymes (gamma-glutamyl transferase) in blood.

Renal and urinary disorders: rare – in cases of impaired micturition (e.g., due to prostate hypertrophy), increased urine formation may lead to urinary retention and excessive bladder distension.

Metabolism and nutrition disorders: 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 dose and duration of treatment, disturbances in fluid and electrolyte balance may occur, such as hypovolemia, hypokalemia and/or hyponatremia (see section "Special precautions for use").

Nervous system disorders: common – headache, dizziness (particularly at the beginning of treatment); uncommon – paresthesia; very rare – syncope, cerebral ischemia, confusion.

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.

Blood and lymphatic system disorders: very rare – hemoconcentration, thrombocytopenia, erythropenia and/or leukopenia, anemia (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.

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 (particularly at the beginning of treatment).

General disorders and administration site conditions: common – increased fatigue, general weakness (particularly at the beginning of treatment); frequency not known – local reactions after injection.

Investigations: common – increased concentration of uric acid and lipids (triglycerides, cholesterol) in blood (see section "Special precautions for use"); rare – increased concentration of urea and creatinine in blood (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of a 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 via the national reporting system.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging. Use the injection solution immediately after first opening.

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.

The medicinal product must not be mixed with other medicinal products for intravenous injection and/or infusion.

Packaging.

4 ml in a vial. 5 vials in a blister pack, 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Address of manufacturer and location of operations.

13, Borispilska Street, Kyiv, 02093, Ukraine.