Dioren

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

Composition:

Active substance: torasemide;

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

Excipients: sodium hydroxide, trometamol, polyethylene glycol (macrogol) 400, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, colorless liquid.

Pharmacotherapeutic group. Diuretic agents. 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 sodium and chloride ion reabsorption in the ascending limb of the loop of Henle.

Pharmacodynamic effects

In humans, the diuretic effect reaches its maximum rapidly within the first hour after intravenous administration or within 2–3 hours after oral administration, and remains consistent for approximately 12 hours. In healthy volunteers, 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 a reduction in edema. In the case 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 is greater than 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 the human body, torasemide is metabolized to form three metabolites: M1, M3, and M5. There is no evidence of other metabolites. Metabolites M1, M3, and M5 are formed through stepwise oxidation of the methyl group attached to the phenyl ring into a carboxylic acid; metabolite M3 is formed via ring hydroxylation. Metabolites M2 and M4, observed in animal experiments, have not been detected 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 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 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 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 hepatic dysfunction 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 volunteers; therefore, accumulation of torasemide and its metabolites does not occur.

Linearity

The pharmacokinetics of torasemide and its metabolites are characterized by linear kinetics. This means that its maximum plasma concentration and the area under the plasma 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 medicinal product is required, for example, in 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 retention, for example, due to prostatic hyperplasia. Breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Unrecommended combinations

Torasemide, especially in high doses, may enhance the ototoxic and nephrotoxic effects of aminoglycoside antibiotics, for example, 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 concentration in blood plasma, which may lead to enhanced effects and increased adverse effects of lithium.

Combinations requiring special caution

Torasemide enhances the effects of other antihypertensive agents, particularly angiotensin-converting enzyme (ACE) inhibitors, which may result in excessive reduction of arterial blood pressure when used concomitantly.

Concomitant use of torasemide with digoxin preparations may lead to potassium deficiency caused by diuretic use, which may result in enhanced adverse effects of both medicinal products.

Torasemide may reduce the efficacy 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 enhance their toxic effects on the central nervous system (CNS).

Torasemide may enhance the effect of theophylline, as well as the muscle-relaxant effect of curare-like medicinal products.

Laxatives, as well as mineralo- and glucocorticoids, may enhance potassium loss induced by torasemide.

Torasemide may reduce the vasoconstrictive effect of catecholamines, for example, 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);
• Pathological changes in acid-base metabolism;
• Concomitant therapy with lithium, aminoglycosides, or cephalosporins;
• Blood count 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 torasemide therapy 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 when treating elderly patients, to the emergence of symptoms indicating electrolyte loss and hemoconcentration.

During 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. Regular blood count monitoring (erythrocytes, leukocytes, platelets) is also required.

Consequences of misuse as doping

The use of torasemide may lead to a positive doping test result. The health consequences of improper use of the drug, such as for doping purposes, cannot be predicted; in such cases, potential harm to health cannot be ruled out.

Excipients

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

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. Torasemide is not recommended during pregnancy and in women of childbearing potential who are not using contraception. Due to the above, torasemide may 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 heart or renal failure, careful monitoring of electrolyte levels and hematocrit, as well as fetal development, is required.

Breastfeeding period. It is currently unknown 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 breastfeeding is contraindicated (see section "Contraindications"). The decision to discontinue breastfeeding or to discontinue/stop treatment with torasemide should be made by weighing the benefits of breastfeeding for the child against the benefits of treatment for the mother.

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 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, and when consuming alcohol. Therefore, special caution is advised when driving or operating machinery during treatment with torasemide.

Method of Administration and Dosage

Edema and/or effusions due to heart failure.

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

Acute pulmonary edema.

Treatment should begin with intravenous administration of a single dose of 4 mL of Dioren 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 Dioren, equivalent to 100 mg of torasemide, must not be exceeded.

Special patient groups

Elderly patients. Dose adjustment is not required for this patient group. However, no comparative studies on the drug's effect in young versus elderly patients have been conducted.

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

Method of administration

The injection solution must be administered slowly intravenously. Only clear, transparent solutions should be used. Intra-arterial administration is strictly prohibited! Dioren medicinal product must not be used if signs of solution degradation are present (e.g., presence of suspended particles) or if the ampoule is damaged. One ampoule is intended for single use only. Any remaining solution must be immediately disposed of according to local regulations. Dioren 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 use of torasemide is not recommended for more than 7 days.

Children.

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

Overdose.

Symptoms of intoxication

The typical clinical picture is unknown. Overdose may cause excessive diuresis, with risk of significant loss of water and electrolytes, somnolence, 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 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 of circulatory collapse: place the patient in a supine position and, if necessary, administer symptomatic therapy.

Anaphylactic shock (emergency 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 placed in a horizontal position, free air access ensured, and oxygen administered. If necessary, intensive therapy should be continued (e.g., administration of epinephrine, glucocorticoids, and replacement of circulating blood volume).

Adverse Reactions

The adverse reactions listed below may occur during treatment with the medicinal product Dioren.

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, erythrocytopenia and/or leukopenia (see section "Special precautions").

Immune system disorders. Very rare: allergic reactions. Acute, potentially life-threatening hypersensitivity reactions (anaphylactic shock) may occur with intravenous administration, requiring immediate medical intervention.

Metabolism and nutrition disorders. Common: exacerbation of metabolic alkalosis, hyperglycemia, hypokalemia (in patients on a low-potassium diet, with vomiting, diarrhea, after excessive use of laxatives, or in patients with chronic liver dysfunction). Depending on dose and duration of treatment, disturbances in water and electrolyte balance may occur, 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 or decreased hearing.

Cardiac disorders. Very rare: myocardial ischemia, arrhythmia, angina pectoris, acute myocardial infarction.

Vascular disorders. Very rare: thromboembolic complications, arterial hypotension, disturbances in coronary and central circulation.

Gastrointestinal disorders. Common: gastrointestinal disturbances such as 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 concentration of certain liver enzymes (gamma-glutamyl transferase).

Skin and subcutaneous tissue disorders. Very rare: allergic skin reactions (e.g. pruritus, exanthema), photosensitivity 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 impaired urination (e.g. due to prostate 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 precautions").
Uncommon: increased blood concentrations of urea and creatinine (see section "Special precautions").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Do not use after the expiry date stated on the packaging. The solution should be used immediately after first opening of the ampoule.

Storage conditions.

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

Keep out of reach and sight of children.

Incompatibilities.

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

Packaging. 4 ml in an ampoule made of neutral colorless glass. 5 ampoules in a cassette, one cassette per carton.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

17 Myru Street, Kyiv, 03134, Ukraine.

Date of last review.