Diuver (Tablets) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

Manufactured By

Pliva Hrvatska, d.o.o. (Croatia)

Or

R-Pharm Novoselki LLC (Russia)

Contact Information

TEVA (Israel)

ATC Code

C03CA04 (Torasemide)

Active Substance

Torasemide (Rec.INN registered by WHO)

Dosage Forms

	Diuver	Tablets 5 mg: 20 or 60 pcs.
		Tablets 10 mg: 20 or 60 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex with a bevel, with a score on one side and an engraving “915” on the other side.

Excipients: lactose monohydrate – 58.44 mg, corn starch – 14.56 mg, sodium carboxymethyl starch – 0.8 mg, colloidal anhydrous silicon dioxide – 0.6 mg, magnesium stearate – 0.6 mg.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Tablets white or almost white, round, biconvex with a bevel, with a score on one side and an engraving “916” on the other side.

Excipients: lactose monohydrate – 116.88 mg, corn starch – 29.12 mg, sodium carboxymethyl starch – 1.6 mg, colloidal anhydrous silicon dioxide – 1.2 mg, magnesium stearate – 1.2 mg.

10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Diuretic

Pharmacotherapeutic Group

Diuretic agent

Pharmacological Action

Pharmacodynamics

“Loop” diuretic. The main mechanism of action of the drug is due to the reversible binding of torasemide to the Na⁺/Cl^–/K⁺ cotransporter located in the apical membrane of the thick segment of the ascending limb of the loop of Henle. As a result, the reabsorption of sodium ions is reduced or completely inhibited, and the osmotic pressure of the intracellular fluid and water reabsorption are reduced. It blocks aldosterone receptors in the myocardium, reduces fibrosis and improves the diastolic function of the myocardium.

Torasemide causes hypokalemia to a lesser extent than furosemide, while exhibiting greater activity and its action is more prolonged.

The maximum diuretic effect develops 2-3 hours after oral administration of the drug.

The use of torasemide is the most justified choice for long-term therapy.

Pharmacokinetics

After oral administration, Torasemide is rapidly and almost completely absorbed from the gastrointestinal tract. C_max of torasemide in plasma is reached 1-2 hours after oral administration after a meal. Bioavailability is 80-90% with minor individual variations.

The diuretic effect lasts up to 18 hours, which facilitates the tolerability of therapy due to the absence of very frequent urination in the first hours after oral administration of the drug, which limits patient activity.

Binding to plasma proteins is more than 99%. The apparent V_d is 16 L.

It is metabolized in the liver with the participation of cytochrome P450 isoenzymes. As a result of sequential reactions of oxidation, hydroxylation, or ring hydroxylation, 3 metabolites (M1, M3, and M5) are formed, the binding of which to plasma proteins is 86%, 95%, and 97%, respectively.

T_1/2 of torasemide and its metabolites is 3-4 hours and does not change in chronic renal failure. Total clearance is 40 ml/min, renal clearance is 10 ml/min.

On average, about 83% of the administered dose is excreted by the kidneys: unchanged (24%) and mainly as inactive metabolites (M1 – 12%, M3 – 3%, M5 – 41%).

In renal failure, the T_1/2 of torasemide does not change, the T_1/2 of metabolites M3 and M5 increases. Torasemide and its metabolites are excreted insignificantly by hemodialysis and hemofiltration.

In hepatic insufficiency, the concentration of torasemide in the blood plasma increases due to a decrease in the metabolism of the drug in the liver. In patients with cardiac or hepatic insufficiency, the T_1/2 of torasemide and metabolite M5 is slightly increased, accumulation of the drug is unlikely.

Indications

• Edema syndrome of various origins, including in chronic heart failure, diseases of the liver, lungs, and kidneys;
• Arterial hypertension.

ICD codes

Dosage Regimen

The drug is taken orally once a day after breakfast, with a small amount of water.

Edema syndrome of various origins, including in chronic heart failure, diseases of the liver, lungs, and kidneys

The therapeutic dose is 5 mg once a day. If necessary, the dose should be gradually increased to 20-40 mg once a day, in some cases – up to 200 mg/day. The drug is prescribed for a long period or until the edema disappears.

Arterial hypertension

The initial dose is 2.5 mg (1/2 tab. 5 mg) once a day. If necessary, the dose can be increased to 5 mg once a day.

Elderly patients do not require dose adjustment.

Adverse Reactions

From the water-electrolyte and acid-base balance: hyponatremia, hypochloremia, hypokalemia, hypomagnesemia, hypocalcemia, metabolic alkalosis. Symptoms indicating the development of electrolyte and acid-base balance disorders may include headache, confusion, convulsions, tetany, muscle weakness, heart rhythm disturbances, and dyspeptic disorders; hypovolemia and dehydration (more often in elderly patients), which can lead to hemoconcentration with a tendency to develop thrombosis.

From the cardiovascular system: excessive decrease in blood pressure, orthostatic hypotension, collapse, tachycardia, arrhythmias, decrease in circulating blood volume.

From metabolism: hypercholesterolemia, hypertriglyceridemia; transient increase in the concentration of creatinine and urea in the blood; increase in the concentration of uric acid in the blood, which can cause or enhance the manifestations of gout; decreased glucose tolerance (possible manifestation of latent diabetes mellitus).

From the urinary system: oliguria, acute urinary retention (for example, with prostatic hyperplasia, narrowing of the urethra, hydronephrosis); interstitial nephritis, hematuria, decreased potency.

From the digestive system: nausea, vomiting, diarrhea, intrahepatic cholestasis, increased activity of liver enzymes, acute pancreatitis.

From the central nervous system and hearing organ: hearing impairment, usually reversible, and/or tinnitus, especially in patients with renal insufficiency or hypoproteinemia (nephrotic syndrome), paresthesia.

From the skin: skin itching, urticaria, other types of rash or bullous skin lesions, erythema multiforme, exfoliative dermatitis, purpura, fever, vasculitis, eosinophilia, photosensitivity; severe anaphylactic or anaphylactoid reactions up to shock, which to date have been described only after intravenous administration.

From the peripheral blood: thrombocytopenia, leukopenia, agranulocytosis, aplastic or hemolytic anemia.

Contraindications

• Hypersensitivity to torasemide and other components of the drug;
• Allergy to sulfonamides (sulfonamide antimicrobial agents or sulfonylurea drugs);
• Renal failure with anuria;
• Hepatic coma and precoma;
• Severe hypokalemia;
• Severe hyponatremia;
• Hypovolemia (with or without arterial hypotension) or dehydration;
• Severely expressed disturbances of urine outflow of any etiology (including unilateral damage to the urinary tract);
• Glycoside intoxication;
• Acute glomerulonephritis;
• Decompensated aortic and mitral stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Increased central venous pressure (more than 10 mm Hg);
• Hyperuricemia;
• Age under 18 years;
• Lactation period;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution

Arterial hypotension, stenosing atherosclerosis of cerebral arteries, hypoproteinemia, predisposition to hyperuricemia, impaired urine outflow (benign prostatic hyperplasia, narrowing of the urethra or hydronephrosis), history of ventricular arrhythmia, acute myocardial infarction (increased risk of cardiogenic shock), diarrhea, pancreatitis, diabetes mellitus (decreased glucose tolerance), hepatorenal syndrome, gout, anemia, pregnancy.

Use in Pregnancy and Lactation

During pregnancy, Diuver can be used only if the benefit to the mother outweighs the possible potential risk to the fetus, only under the supervision of a doctor, and only in minimal doses.

Torasemide does not have a teratogenic effect or fetotoxicity, penetrates the placental barrier, causing disturbances in water-electrolyte metabolism and thrombocytopenia in the fetus.

It is not known whether Torasemide is excreted in breast milk. If it is necessary to use the drug Diuver during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug is contraindicated in hepatic coma and precomatose state.

Use in Renal Impairment

The drug is contraindicated in renal failure with increasing azotemia.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety have not been established).

Geriatric Use

Elderly patients do not require special dose selection.

Special Precautions

Use strictly as prescribed by a doctor.

Patients with hypersensitivity to sulfonamides and sulfonylurea derivatives may have cross-sensitivity to the drug Diuver.

Patients receiving high doses of the drug Diuver for a long period, to avoid the development of hyponatremia, metabolic alkalosis, and hypokalemia, are recommended a diet with sufficient salt content and the use of potassium preparations.

An increased risk of developing water-electrolyte balance disorders is noted in patients with renal failure. During the course of treatment, it is necessary to periodically monitor the concentration of electrolytes in the blood plasma (including sodium, calcium, potassium, magnesium), acid-base status, residual nitrogen, creatinine, uric acid, and, if necessary, carry out appropriate corrective therapy (more frequently in patients with frequent vomiting and against the background of parenterally administered fluids).

If azotemia and oliguria appear or increase in patients with severe progressive kidney diseases, it is recommended to suspend treatment.

Selection of the dosage regimen in patients with ascites due to liver cirrhosis should be carried out in a hospital setting (disturbances in water-electrolyte balance can lead to the development of hepatic coma). This category of patients is shown regular monitoring of blood plasma electrolytes.

In patients with diabetes mellitus or reduced glucose tolerance, periodic monitoring of blood and urine glucose concentration is required.

In unconscious patients, with prostatic hyperplasia, narrowing of the ureters, control of diuresis is necessary due to the possibility of acute urinary retention.

Influence on the ability to drive vehicles and mechanisms

During the treatment period, patients should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms excessively increased diuresis, accompanied by a decrease in circulating blood volume and a violation of the electrolyte balance of the blood, followed by a pronounced decrease in blood pressure, drowsiness, confusion, collapse; gastrointestinal disorders are possible.

Treatment there is no specific antidote. Induce vomiting, perform gastric lavage, prescribe activated charcoal. Treatment is symptomatic, reduce the dose or discontinue the drug and simultaneously replenish the circulating blood volume and indicators of water-electrolyte balance and acid-base balance under the control of serum electrolyte concentrations, hematocrit. Hemodialysis is ineffective.

Drug Interactions

Torasemide increases the concentration and risk of nephro- and ototoxic action of cephalosporins, aminoglycosides, chloramphenicol, ethacrynic acid, cisplatin, amphotericin B (due to competitive renal excretion).

Torasemide increases the effectiveness of diazoxide and theophylline, reduces the effectiveness of hypoglycemic agents, allopurinol.

Pressor amines and Torasemide mutually reduce effectiveness.

Drugs that block tubular secretion increase the concentration of torasemide in the blood serum.

With simultaneous use of corticosteroids, amphotericin B, the risk of hypokalemia increases, with cardiac glycosides – the risk of glycoside intoxication increases due to hypokalemia (for high- and low-polar) and prolongation of T_1/2 (for low-polar).

Torasemide reduces the renal clearance of lithium preparations and increases the likelihood of intoxication.

NSAIDs, sucralfate reduce the diuretic effect due to inhibition of prostaglandin synthesis, impaired plasma renin activity, and aldosterone excretion.

Torasemide enhances the hypotensive effect of antihypertensive agents, the neuromuscular blockade of depolarizing muscle relaxants (suxamethonium) and weakens the effect of non-depolarizing muscle relaxants (tubocurarine).

With simultaneous intake of salicylates in high doses against the background of torasemide therapy, the risk of manifestation of their toxicity increases (due to competitive renal excretion).

Sequential or simultaneous use of torasemide with ACE inhibitors or angiotensin II receptor antagonists may lead to a strong decrease in blood pressure. This can be avoided by reducing the dose of torasemide or temporarily discontinuing it.

With simultaneous use with probenecid or methotrexate, a decrease in the effectiveness of torasemide is possible (the same secretion pathway). On the other hand, Torasemide can lead to a decrease in the renal elimination of these drugs.

With simultaneous use of cyclosporine and torasemide, the risk of developing gouty arthritis increases due to the fact that cyclosporine can cause impaired excretion of urates by the kidneys, and Torasemide – hyperuricemia.

It has been reported that in patients at high risk of nephropathy receiving Torasemide orally, when contrast agents were administered, impaired renal function was observed more often than in patients at high risk of nephropathy who received intravenous hydration before the administration of contrast agents.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F).

Keep out of reach of children!

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.