Toradiv

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TORADIV (TORADIV)

Composition:

Active substance: torasemide;

1 tablet contains 10 mg of torasemide;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round tablets with a monoscore on one side for division.

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 constant for approximately 12 hours. In healthy volunteers, within the dose range of 5–100 mg, an increase in diuresis proportional to the logarithm of the dose 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 heart failure, torasemide reduces symptoms and improves myocardial function by decreasing preload and afterload.

After oral administration, the antihypertensive effect of torasemide develops gradually, beginning in 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 free intracellular calcium ion activity in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely reduces the increased vascular sensitivity to endogenous vasoconstrictive substances, such as catecholamines.

Pharmacokinetics.

Absorption and distribution

After oral administration, torasemide is rapidly and almost completely absorbed. Maximum plasma concentration (Cmax) is reached within 1–2 hours. Bioavailability is approximately 80–90%; under conditions of complete absorption, the maximum first-pass effect in the liver does not exceed 10–20%. According to data from two studies, food reduces the rate (kinetic component) of torasemide absorption (Cmax decreases and time to reach maximum concentration (tmax) increases), but does not affect total absorption. Torasemide binding to plasma proteins exceeds 99%; binding to metabolites M1, M3, and M5 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 oxidation of the methyl group of the phenolic ring to a 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. The main metabolite M5 has no diuretic effect, while active metabolites M1 and M3 together account for approximately 10% of the pharmacokinetic activity. 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, t1/2 of torasemide and metabolite M5 is slightly prolonged, but the amount of substance excreted in urine corresponds to that in healthy individuals; therefore, accumulation of torasemide and its metabolites is not expected. Torasemide and its metabolites are poorly eliminated during hemodialysis and hemofiltration.

Linearity

Torasemide and its metabolites exhibit dose-dependent linear kinetics. This means that Cmax and the area under the pharmacokinetic curve (AUC) increase proportionally with dose.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the active substance, to other 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.

Breast-feeding period.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended

Torasemide, especially in high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics, such as kanamycin, gentamicin, tobramycin, and platinum-derived 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 lithium effects and adverse reactions.

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 digoxin preparations, potassium deficiency caused by diuretic use may lead to increased or enhanced adverse effects of both drugs.

Torasemide may reduce the effectiveness of antidiabetic agents.

Probenecid and nonsteroidal anti-inflammatory drugs 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 agents.

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

Since increased blood glucose levels 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 to signs of hemoconcentration and electrolyte depletion, especially at the beginning of treatment and when treating elderly patients. During prolonged use of torasemide, regular monitoring of electrolyte balance, especially serum potassium levels, is required. Additionally, regular monitoring of blood glucose, uric acid, creatinine, and lipid levels is necessary. Complete blood count (erythrocytes, leukocytes, thrombocytes) should also be monitored regularly.

Consequences of misuse as a doping agent

The use of torasemide tablets may lead to a positive doping test result. Health effects of improper use of torasemide, such as for doping purposes, cannot be predicted, and in such cases harm to health cannot be ruled out.

Excipients

This medicinal product contains lactose. Therefore, patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication.

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; therefore, its use during pregnancy is not recommended, nor is it recommended in women of childbearing potential who are not using contraception. Thus, torasemide should only be used during pregnancy if absolutely necessary 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 cardiac or renal insufficiency, careful monitoring of electrolyte levels, hematocrit, and fetal development is required.

Lactation. It has not yet been established whether torasemide or its metabolites are excreted in breast milk in humans or animals. 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/abort treatment with torasemide 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. Animal studies did not reveal any adverse effects of torasemide on fertility.

Ability to affect reaction speed when driving or operating machinery

Even when used correctly, torasemide may significantly impair the ability to drive or operate machinery. This is particularly relevant at the beginning of treatment, when the dose is increased, when switching medications, when concomitant therapy is initiated, or when alcohol is consumed. Therefore, caution should be exercised when driving or operating machinery during treatment with torasemide.

Dosage and Administration

Edema and/or effusions due to heart failure

Adults

Treatment should be initiated with a daily dose of 5 mg of torasemide, which corresponds to ½ tablet of Toradiv. This dose is generally considered a maintenance dose.

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

Special patient groups

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

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

Route of administration

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

Toradiv is usually administered for a prolonged period or until edema symptoms subside.

Children

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

Overdose

Symptoms of intoxication. The typical clinical picture is unknown. Overdose may cause pronounced diuresis, including risk of excessive loss of water and electrolytes, somnolence, confusion, symptomatic arterial hypotension, circulatory collapse, and gastrointestinal disturbances.

Treatment of overdose. There is no known specific antidote. Symptoms of intoxication usually resolve with dose reduction or discontinuation of the drug, along with appropriate fluid and electrolyte replacement (serum electrolyte levels should be monitored). Torasemide is not effectively 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 patient in a sitting position; symptomatic therapy should be administered if necessary.

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

Side effects.

The following classification of frequency was used to assess adverse reactions:

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.

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. Common: intensification of metabolic alkalosis; hyperkalemia, hypokalemia with concomitant low-potassium diet, vomiting, diarrhea, 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 such as hypovolemia, hypokalemia and/or hyponatremia may occur (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, 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 levels 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 urination (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 levels of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions for use").
Uncommon: increased blood urea and creatinine levels (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any possible adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister, 3 or 9 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

LLC " FARMEX GROUP".

Manufacturer's address and place of business.

100 Shevchenka St., Boryspil, Kyiv Oblast, 08301, Ukraine.