Dioren

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

Composition:

Active substance: torasemide;

1 tablet contains torasemide 0.01 g (10 mg);

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

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, round-shaped, with 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; 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 persists up to 12 hours.

An increase in diuresis was observed even in cases where other diuretic agents (e.g., thiazide diuretics acting in the distal tubules) no longer produced the desired effect, 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. 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 free calcium ion activity in arterial smooth muscle cells, which has been observed in patients with arterial hypertension. This effect likely results in reduced vascular contractility and/or responsiveness to endogenous vasoconstrictive substances, such as catecholamines.

Pharmacokinetics.

Absorption and distribution

After oral administration, torasemide is rapidly and almost completely absorbed; maximum serum concentration (Cmax) 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. Plasma protein binding of torasemide exceeds 99%, while 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 of other metabolites. Metabolites M1 and M5 are formed by oxidation of the methyl group of the phenolic ring to 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, does not exhibit diuretic activity; approximately 10% of the pharmacokinetic activity is attributable 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 eliminated by hemodialysis or hemofiltration. In patients with impaired liver function or heart failure, t1/2 of torasemide and metabolite M5 is slightly prolonged, while 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.

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

Contraindications.

• Hypersensitivity to the active substance, to sulfonamide derivatives, or to any of the excipients of the medicinal product.
• Renal failure 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:

Ototoxic 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. When ACE inhibitors are administered concurrently or immediately after torasemide treatment, excessive reduction in arterial blood pressure may occur. Concomitant use of torasemide with digoxin preparations may result in potassium deficiency caused by diuretic therapy, which may lead to increased or enhanced adverse reactions of both drugs.

Torasemide may reduce the effectiveness of antidiabetic agents.

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

When treating with high-dose salicylates, 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 mineralo- 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 absorption of torasemide and, consequently, its expected efficacy.

Special precautions for use

Torasemide should not be administered in the following cases:

• gout;
• cardiac arrhythmias (e.g. sinoatrial block, second- and third-degree atrioventricular block);
• acid-base balance disorders;
• concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• blood picture 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 potential 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. With prolonged 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

Torasemide treatment may lead to positive results in doping tests.

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

Excipients

Dioren contains lactose; therefore, the drug 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 physician before taking this medication.

Use during pregnancy or breastfeeding

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

Information on reproductive toxicity of torasemide comes from animal studies. Furthermore, animal studies have demonstrated that torasemide crosses the placental barrier. Dioren is not recommended during pregnancy, and in 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 effective dose.

Diuretics are unsuitable 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, hematocrit, and fetal development is required.

Breastfeeding period. It has not yet been established whether torasemide or its metabolites are excreted in human or animal breast milk. A 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 discontinue/stop treatment with Dioren should be made taking into account 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 effects of torasemide on fertility.

Ability to influence 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 medications are used or alcohol is consumed.

Method of Administration and Dosage

Dosage

Edema and/or effusions caused by heart failure

Adults. Treatment should be initiated with a daily dose of 5 mg of torasemide, equivalent to ½ tablet of Dioren 10 mg tablets. 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 prescribed daily. Subsequently, the daily dose of torasemide is 10 mg.

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

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

Holding the tablet between the index and thumb of both hands with the dividing line facing upwards, press downwards 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 effects in younger patients 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 used with caution in patients with hepatic insufficiency, as increased plasma concentrations of torasemide may occur (see section "Pharmacokinetics").

Method of administration

Tablets should be taken in the morning 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 precautions").

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 fluid and electrolyte loss. Possible symptoms include somnolence, confusion, arterial hypotension, cardiovascular failure, 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 and concomitant restoration of fluid and electrolyte balance (monitoring should be performed).

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 of cardiovascular failure: anti-shock positioning of the patient and, if necessary, symptomatic therapy.

Anaphylactic shock (emergency measures)

Upon 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 performed:

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

Adverse reactions

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 number of platelets, erythrocytes and/or leukocytes (see section "Special precautions").

Immune system disorders

Very rare: allergic reactions.

Metabolism and nutrition disorders

Common: worsening 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), especially at the beginning of treatment.

Uncommon: xerostomia.

Very rare: pancreatitis.

Hepatobiliary disorders

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

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., with prostate 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 medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

10 tablets in a blister; 3 blisters in a 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 its business activity.

17 Myru Street, Kyiv, 03134, Ukraine.