Dioren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIOREN (DIOREN)

Composition:

Active substance: torasemide;

1 tablet contains 5 mg of torasemide;

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

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or almost white, round-shaped, with a flat surface, bevelled edges, and a score line.

Pharmacotherapeutic group. Diuretics. High-ceiling diuretics.

ATC code C03CA04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Torasemide acts as a saluretic 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 effect

In humans, the diuretic effect of the drug develops rapidly after intravenous administration and oral intake, reaching maximum within the first hour and 2–3 hours, respectively, and lasting up to 12 hours.

In healthy volunteers, diuresis increased in proportion to the logarithm of the drug dose within the dose range of 5 mg to 100 mg (loop diuretic activity).

Increased diuresis was observed even in cases where other diuretics (e.g., thiazide diuretics acting in the distal tubules) had already failed to produce the desired effect, such as 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. After oral administration, the antihypertensive effect of torasemide develops gradually, beginning from the first week of treatment. The maximum antihypertensive effect is achieved no later than 12 weeks. Torasemide reduces blood pressure by decreasing peripheral vascular resistance. This effect is explained by normalization of disturbed electrolyte balance, primarily due to reduction of elevated levels of free intracellular calcium ions in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely leads to decreased enhanced vascular contractility and/or reduced vascular sensitivity to endogenous vasoactive substances, such as catecholamines.

Pharmacokinetics

Absorption and distribution

After oral administration, torasemide is rapidly and almost completely absorbed; maximum serum concentration is reached within 1–2 hours after intake. Bioavailability is approximately 80–90%; under conditions of complete absorption, the maximum first-pass effect is 10–20%. Data from two studies demonstrate that food reduces the rate (dynamic component) of torasemide absorption (Cmax is reduced and time to reach maximum concentration (tmax) is prolonged), but does not affect overall absorption. Protein binding of torasemide to plasma proteins exceeds 99%; for metabolites M1, M3, and M5, it is 86%, 95%, and 97%, respectively. The 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 by oxidation of the methyl group on 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, renal clearance is approximately 10 mL/min. Approximately 80% of the dose is excreted as unchanged torasemide (24%) and its metabolites: M1 (12%), M3 (3%), M5 (41%). The main metabolite, M5, has no diuretic effect; approximately 10% of the pharmacological activity is attributed to the active metabolites M1 and M3 combined.

In renal insufficiency, total clearance and t1/2 of torasemide remain unchanged, while t1/2 of M3 and M5 is prolonged. However, the pharmacodynamic profile remains unchanged, 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 dysfunction or heart failure, 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 is unlikely.

Linearity

Torasemide and its metabolites exhibit linear, dose-dependent kinetics; that is, maximum serum concentration and area under the pharmacokinetic curve increase proportionally with dose.

Clinical characteristics.

Indications.

Essential hypertension. Treatment and prevention of recurrence of edema and/or effusions caused by heart failure.

Contraindications.

• Hypersensitivity to the active substance, to sulphonamide derivatives, or to any of the excipients of the medicinal product.
• Renal insufficiency with anuria.
• Hepatic coma or precoma.
• Arterial hypotension.
• Arrhythmia.
• Hypovolemia.
• Hyponatremia. Hypokalemia.
• Significant impairment of urination (e.g., due to benign prostatic hyperplasia).
• Breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations

Torasemide, especially in high doses, may enhance the following adverse reactions:

Otototoxic and nephrotoxic effects of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin), cytostatic agents – active platinum derivatives, as well as nephrotoxic effects of cephalosporins.

Concomitant use of torasemide and lithium preparations may increase lithium blood concentration, potentially leading to enhanced effects and increased adverse reactions of lithium.

Combinations requiring caution

Torasemide enhances the effect of other antihypertensive agents, particularly angiotensin-converting enzyme (ACE) inhibitors. Concomitant use or immediate sequential use of ACE inhibitors with torasemide may result in excessive reduction of arterial blood pressure. When torasemide is used concomitantly with digitalis preparations, potassium deficiency caused by diuretic use may lead to increased incidence or severity of adverse reactions of both agents.

Torasemide may reduce the effectiveness of antidiabetic agents.

Probenecid and nonsteroidal anti-inflammatory drugs (e.g., indomethacin, acetylsalicylic acid) may diminish the diuretic and antihypertensive effects of torasemide.

When salicylates are administered in high doses, torasemide may enhance their toxic effects on the central nervous system.

Torasemide enhances the effects of theophylline and curare-like muscle relaxants.

Laxatives, as well as mineralocorticoids and glucocorticoids, may intensify potassium loss induced by torasemide.

Torasemide may reduce the vasoconstrictive effect of catecholamines (e.g., epinephrine and norepinephrine).

Concomitant use with cholestyramine may reduce the absorption of torasemide 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);
• pathological changes in acid-base balance;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood count abnormalities (e.g., thrombocytopenia or anemia in patients without renal insufficiency);
• renal failure caused by nephrotoxic substances;
• children and adolescents (under 18 years of age).

Due to the possible increase in blood glucose concentration in patients with latent or manifest diabetes mellitus, careful monitoring of carbohydrate metabolism is required. Particular attention should be paid, especially at the beginning of treatment and in elderly patients, to the emergence of symptoms indicating electrolyte loss and hemoconcentration. During long-term use of torasemide, regular monitoring of serum electrolytes, particularly potassium, is necessary. Additionally, regular monitoring of blood glucose, uric acid, urea, creatinine, and lipid levels, as well as blood counts (erythrocytes, leukocytes, platelets), is required.

Consequences of improper use for doping purposes

When torasemide is used, positive results may occur in doping tests.

It is impossible to predict the impact of the medicinal product Diuren on health if it is used improperly, i.e., for doping purposes; in such cases, potential harm to health cannot be excluded.

Excipients

The medicinal product Diuren contains lactose; therefore, it should not be administered to patients with rare hereditary conditions of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Reliable data on the effects of torasemide in pregnant women are lacking or limited.

Information on the reproductive toxicity of torasemide comes from animal studies. Furthermore, animal studies have demonstrated that torasemide crosses the placental barrier. The medicinal product Diuren is not recommended during pregnancy, and also for women of childbearing potential who are not using contraception.

Therefore, torasemide should be used during pregnancy only under life-threatening conditions and at the lowest possible 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 cardiac or renal insufficiency, careful monitoring of electrolytes and hematocrit, as well as fetal development, is required.

Lactation period. It has not yet been established whether torasemide or its metabolites are excreted in human or animal breast milk. The risk of using the drug in 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/abandon treatment with Diuren should be made based on the benefits of breastfeeding for the child and the benefits of treatment with the drug for the woman.

Fertility. Studies on the effects of torasemide on fertility in humans have not been conducted. Animal experiments did not reveal any such effects of torasemide.

Ability to affect reaction speed when driving or operating machinery.

Even when used correctly, torasemide may alter reaction speed to such an extent that the patient's ability to drive vehicles, operate machinery, or perform work without safety backup may be impaired.

Such changes are most likely at the beginning of treatment, when the dose is increased, when switching medications, as well as when additional drugs are used or alcohol is consumed.

Dosage and Administration

Dosage

Essential Hypertension

Adults. The recommended initial dose is 2.5 mg of torasemide per day (½ tablet of Dioren, 5 mg tablets). Reduction in arterial pressure occurs gradually during the first week of treatment and reaches its maximum effect no later than 12 weeks.

If normalization of arterial pressure is not achieved after 12 weeks of treatment with 2.5 mg of torasemide daily, the daily dose may be increased to 1 tablet of Dioren, equivalent to 5 mg of torasemide. The daily dose of Dioren should not exceed 1 tablet (equivalent to 5 mg of torasemide), as no further reduction in arterial pressure is expected with higher doses.

Edema and/or Effusions due to Heart Failure

Adults. Treatment should be initiated with a dose of 5 mg of torasemide per day (1 tablet of Dioren, 5 mg tablets). This dose is usually considered a maintenance dose.

If the daily dose of 5 mg is insufficient, a daily dose of 10 mg should be administered daily. Subsequently, the daily dose of torasemide is 10 mg.

If the therapeutic effect is inadequate, the daily dose may be increased up to 20 mg of torasemide, depending on the severity of the patient's condition.

A tablet can be divided into two equal parts as follows:

hold the tablet with the index and thumb of both hands, with the score line facing upwards, and press down with the thumbs along the score line to break it.

Special Patient Groups

Elderly Patients

No specific 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"). The drug should be administered with caution in patients with hepatic insufficiency, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Administration

Tablets should be taken in the morning, swallowed with a small amount of liquid. The bioavailability of torasemide is not affected by food intake.

Duration of Treatment depends on the course of the disease. Torasemide is usually administered for a prolonged period or until edema subsides.

Children

The safety and efficacy of Dioren 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 Warnings and Precautions for Use").

Overdose.

Symptoms of Intoxication

The typical clinical picture of intoxication is unknown. In case of overdose, forced diuresis may occur, with a risk of excessive loss of fluid and electrolytes. Possible symptoms include somnolence, confusion, arterial hypotension, cardiovascular insufficiency, and gastrointestinal disturbances.

Treatment of Intoxication

No specific antidote is known. The severity of intoxication symptoms usually decreases with dose reduction or discontinuation of the drug, along with correction of fluid and electrolyte balance (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 of cardiovascular insufficiency: anti-shock positioning of the patient and, if necessary, symptomatic therapy.

Anaphylactic Shock (Emergency Measures)

At the first signs of shock (e.g., skin reactions such as urticaria or erythema, patient agitation, headache, episodes of sweating, nausea, cyanosis), the following should be done:

• ensure venous access;
• in addition to other standard emergency measures, place the patient on their back with elevated legs, ensure free air access, and administer oxygen;
• if necessary, apply intensive care measures (including administration of epinephrine, volume-replacing solutions, and glucocorticoid hormones).

Side effects

Below are the adverse reactions associated with the use of Dioren.

Frequency is defined as follows:

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 (frequency cannot be estimated due to lack of data).

Blood and lymphatic system disorders

Very rare: blood thickening, decreased platelet, erythrocyte and/or leukocyte count (see section "Special precautions").

Immune system disorders

Very rare: allergic reactions.

Metabolism and nutrition disorders

Common: exacerbation of metabolic alkalosis; hyperglycemia, hypokalemia with 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 develop, such as hypovolemia, hypokalemia and/or hyponatremia (see section "Special precautions").

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 and cardiac disorders.

Gastrointestinal disorders

Common: digestive disturbances (e.g., loss of appetite, stomach pain, nausea, vomiting, diarrhea, constipation), particularly at the beginning of treatment.

Uncommon: xerostomia.

Very rare: pancreatitis.

Hepatobiliary disorders

Common: increased blood concentration of certain liver enzymes (gamma-glutamyl transferase).

Skin and subcutaneous tissue disorders

Very rare: allergic skin reactions (e.g., pruritus, exanthema), photosensitization reactions, 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 urinary disorders (e.g., due to prostatic hyperplasia), increased urine production may lead to urinary retention and excessive bladder distension.

General disorders

Common: fatigue, weakness (especially at the beginning of treatment).

Laboratory findings

Common: increased blood concentration of uric acid and lipids (triglycerides, cholesterol) (see section "Special precautions").

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug 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.

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 blisters per carton.

Prescription status

Prescription only.

Manufacturer

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations

17 Miru Street, Kyiv, 03134, Ukraine.