Trigrim (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

Or

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Manufactured By

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

Akrikhin, JSC (Russia)

ATC Code

C03CA04 (Torasemide)

Active Substance

Torasemide (Rec.INN registered by WHO)

Dosage Forms

	Trigrim	Tablets 2.5 mg: 20, 30 or 60 pcs.
		Tablets 5 mg: 20, 30 or 60 pcs.
		Tablets 10 mg: 20, 30 or 60 pcs.
		Tablets 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, biconvex.

Excipients : lactose monohydrate – 44.9 mg, corn starch, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (2) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (3) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (6) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel on both sides and a score line on one side.

Excipients : lactose monohydrate – 89.8 mg, corn starch, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (2) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (3) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (6) – cardboard packs.

Tablets white or almost white, round, flat-cylindrical, with a bevel on both sides and a score line on one side.

Excipients : lactose monohydrate – 179.6 mg, corn starch, colloidal silicon dioxide, magnesium stearate.

10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (2) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (3) – cardboard packs.
10 pcs. – blister packs made of polyvinyl chloride film and printed lacquered aluminum foil (6) – cardboard packs.

Tablets from white to white with a grayish or yellowish tint, round, biconvex, with a cross-shaped score line.

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

10 pcs. – blisters made of aluminum foil and PVC film (3) – cardboard packs.

Clinical-Pharmacological Group

Diuretic

Pharmacotherapeutic Group

Diuretics; “loop” diuretics; sulfonamides

Pharmacological Action

Torasemide is a “loop” diuretic. However, at low doses, its pharmacodynamic profile acquires properties of the thiazide class of diuretics regarding the level and duration of diuresis. In higher doses, Torasemide causes a rapid dose-dependent diuresis.

The primary mechanism of action of the drug is due to the reversible binding of torasemide to the sodium/chloride/potassium co-transporter located in the apical membrane of the thick 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.

Administration of doses from 5 to 100 mg to healthy subjects led to a logarithmically proportional increase in diuretic activity.

Torasemide can be used for a long time.

Pharmacokinetics

Absorption

After oral administration, Torasemide is rapidly and almost completely absorbed from the gastrointestinal tract.

C_max of torasemide in plasma is observed 1-2 hours after oral administration after a meal.

Bioavailability is about 80-90% with minor individual variations.

Distribution

Binding to plasma proteins is more than 99%. Metabolites M1, M3 and M5 bind by 86%, 95% and 97%, respectively.

V_d is 16 L. In patients with liver cirrhosis, V_d doubles.

Metabolism

Torasemide is metabolized in the liver with the participation of cytochrome P450 isoenzymes. As a result of sequential oxidation, hydroxylation or ring hydroxylation reactions, 3 metabolites are formed – M1, M3 and M5.

The hydroxyl metabolites have diuretic activity.

Metabolites M1 and M3 add 10% of pharmacological activity, while M5 is inactive.

Excretion

T_1/2 of torasemide and its metabolites is 3-4 hours in healthy subjects. In the presence of renal failure, T_1/2 of torasemide does not change, but T_1/2 of metabolites M3 and M5 is prolonged.

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 patients with liver disorders, increased plasma concentrations of torasemide were obtained, possibly due to reduced hepatic metabolism.

In patients with cardiac or hepatic insufficiency, T_1/2 of torasemide and metabolite M5 was slightly increased, but accumulation is unlikely.

Pharmacokinetics in special clinical cases

Hepatic insufficiency. The drug is contraindicated in hepatic coma and precoma.

In hepatic insufficiency, the plasma concentration of torasemide increases due to a decrease in drug metabolism in the liver.

In patients with cardiac or hepatic insufficiency, T_1/2 of torasemide and metabolite M5 is slightly increased, drug accumulation is unlikely.

In patients with liver cirrhosis, Vd, T_1/2 and renal clearance are increased, but total clearance remains unchanged.

Chronic heart failure. In patients with decompensated chronic heart failure, hepatic and renal clearance of the drug is reduced.

In such patients, the total clearance of torasemide is 50% less than in healthy volunteers, and T_1/2 and total bioavailability are correspondingly higher.

Renal insufficiency. In patients with renal insufficiency, the renal clearance of torasemide is markedly reduced, but this does not affect the total clearance.

The diuretic effect in renal insufficiency can be achieved by using high doses.

In renal insufficiency, T_1/2 of torasemide does not change, T_1/2 of metabolites M3 and M5 increases.

Torasemide and its metabolites are slightly excreted by hemodialysis and hemofiltration.

The drug is contraindicated in renal failure with increasing azotemia.

Children. The pharmacokinetics of torasemide has not been studied.

Elderly patients. The pharmacokinetic profile of torasemide in elderly patients is similar to that in young patients, except that there is a decrease in the renal clearance of the drug due to the characteristic age-related impairment of renal function in elderly patients.

Total clearance and T1/2 do not change.

Dependence on gender and race. The influence of ethnic and racial background on the pharmacokinetics of torasemide has not been studied.

Indications

• Edema syndrome of various origins, including in chronic heart failure, diseases of the liver, lungs and kidneys;
• Arterial hypertension (used in monotherapy or in combination with other antihypertensive drugs).

ICD codes

Dosage Regimen

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

If it is necessary to take half a tablet, use a special tablet splitter.

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.

The maximum single dose is 40 mg, it is not recommended to exceed it (no experience of use). The drug is prescribed for a long period or until the edema disappears.

Congestive heart failure

5-20 mg (1/4-1 tablet with a dosage of 20 mg) once a day. If necessary, the daily dose can be gradually increased (doubling it), up to a maximum of 200 mg (10 tablets of 20 mg).

Chronic renal failure

The initial dose is 20 mg (1 tablet with a dosage of 20 mg) per day. If necessary, this dose can be gradually increased (doubling it) until an appropriate diuretic effect is achieved. The maximum daily dose is 200 mg (10 tablets of 20 mg).

Liver cirrhosis

5-10 mg (1/4-1/2 tablet) once a day. If necessary, this dose can be gradually increased (doubling it) until an appropriate diuretic effect is achieved.

No adequately controlled studies have been conducted in patients with liver disease using doses greater than 40 mg (2 tablets with a dosage of 20 mg) per day.

Primary arterial hypertension

The usual initial dose is 2.5 mg orally once a day (1 tablet with a dosage of 2.5 mg or 1/2 tablet with a dosage of 5 mg). If necessary, the dose can be increased to 5-10 mg once a day. If a dose of 10 mg does not give the desired effect, an antihypertensive drug of another group should be added to the treatment regimen. The maximum effect is achieved after approximately 12 weeks of continuous treatment.

Elderly patients

Elderly patients do not require dose adjustment.

Children

There are no data regarding the use of the drug Trigrim in children.

Adverse Reactions

The frequency of adverse effects listed below was determined according to the following (WHO classification): very common (more than 10%); common (more than 1% and less than 10%); uncommon (more than 0.1% and less than 1%); rare (more than 0.01% and less than 0.1%); very rare (less than 0.01%), including isolated reports; frequency unknown (cannot be estimated from available data).

Blood and lymphatic system disorders frequency unknown – thrombocytopenia, leukopenia, agranulocytosis, aplastic or hemolytic anemia.

Metabolism and nutrition disorders uncommon – hypercholesterolemia, hypertriglyceridemia; frequency unknown – decreased glucose tolerance (possible manifestation of latent diabetes mellitus).

Nervous system disorders common – dizziness, headache, drowsiness; uncommon – muscle cramps of the lower extremities; frequency unknown – confusion, fainting, paresthesia in the extremities (sensation of numbness, “pins and needles” and tingling).

Eye disorders frequency unknown – visual impairment.

Ear and labyrinth disorders : frequency unknown – hearing impairment, ringing in the ears and hearing loss (usually reversible) usually in patients with renal failure or hypoproteinemia (nephrotic syndrome).

Cardiac disorders uncommon – extrasystole, tachycardia, arrhythmia, palpitations, facial flushing; frequency unknown – excessive arterial hypotension, orthostatic hypotension, collapse, deep vein thrombosis, thromboembolism, hypovolemia.

Respiratory, thoracic and mediastinal disorders uncommon – nosebleeds.

Gastrointestinal disorders common – diarrhea; uncommon – abdominal pain, flatulence; frequency unknown – dry mouth, nausea, vomiting, loss of appetite, pancreatitis, dyspeptic disorders, intrahepatic cholestasis.

Renal and urinary disorders common – increased frequency of urination, polyuria, nocturia; uncommon – frequent urge to urinate; frequency unknown – oliguria, urinary retention (e.g., in patients with urinary tract obstruction), interstitial nephritis, hematuria, increased blood urea and creatinine concentrations.

Reproductive system and breast disorders frequency unknown – impaired potency.

Skin and subcutaneous tissue disorders frequency unknown – skin itching, rash, urticaria, erythema multiforme, exfoliative dermatitis, purpura, vasculitis, photosensitivity.

Musculoskeletal and connective tissue disorders frequency unknown – muscle weakness.

General disorders and administration site conditions uncommon – asthenia (exhaustion), thirst, weakness, increased fatigue, hyperactivity, nervousness.

Investigations uncommon – increased platelet count; frequency unknown – hyperglycemia, hyperuricemia, decreased red blood cell, white blood cell and platelet counts, slight increase in blood alkaline phosphatase activity, increased activity of some liver enzymes (e.g., GGT).

Electrolyte and acid-base balance disorders frequency unknown – 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 common in elderly patients), which can lead to hemoconcentration with a tendency to develop thrombosis.

Contraindications

• Hypersensitivity to torasemide or to any of the excipients included in the drug;
• Hypersensitivity to sulfonamides (sulfonamide antimicrobial agents or sulfonylurea drugs);
• Renal failure with anuria;
• Hepatic coma and precoma;
• Refractory hypokalemia;
• Refractory hyponatremia;
• Hypovolemia (with or without arterial hypotension) or dehydration;
• Severely impaired urine outflow of any etiology (including unilateral urinary tract involvement);
• Glycoside intoxication;
• Acute glomerulonephritis;
• Sinoatrial and AV block II-III degree;
• Arrhythmia;
• Decompensated aortic and mitral stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Increased central venous pressure (more than 10 mm Hg);
• Hyperuricemia;
• Children under 18 years of age (efficacy and safety not established);
• Pregnancy;
• Breastfeeding period;
• Simultaneous use of aminoglycosides and cephalosporins.

With caution

It should be prescribed with caution in arterial hypotension, stenosing atherosclerosis of cerebral arteries, hypoproteinemia, predisposition), hyperuricemia, impaired urine outflow (benign prostatic hyperplasia, urethral stricture or hydronephrosis), history of ventricular arrhythmia, acute myocardial infarction (increased risk of cardiogenic shock), with diarrhea, pancreatitis, diabetes mellitus (decreased glucose tolerance), impaired liver and/or kidney function, hepatorenal syndrome, gout, anemia, hypokalemia, hyponatremia.

Simultaneous use of cardiac glycosides, aminoglycosides or cephalosporins, corticosteroids or ACTH.

Use in Pregnancy and Lactation

Pregnancy

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

No controlled studies have been conducted on the use of torasemide in pregnant women; the drug is not recommended for use during pregnancy.

Breastfeeding period

It is not known whether Torasemide passes into breast milk. If it is necessary to use torasemide during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug is contraindicated in hepatic coma and precoma.

The drug should be prescribed with caution to patients with impaired liver function, liver cirrhosis.

Use in Renal Impairment

The drug is contraindicated in renal failure with anuria.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

Elderly patients do not require dose adjustment.

Special Precautions

Use strictly as prescribed by a doctor.

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.

Patients with hypersensitivity to sulfonamides and sulfonylurea derivatives may have cross-sensitivity to the drug Torasemide. Patients receiving high doses of the drug Torasemide for a long period, in order to avoid the development of hyponatremia, metabolic alkalosis and hypokalemia, are recommended a diet with sufficient salt content and the use of potassium preparations.

The risk of hypokalemia is greatest in patients with liver cirrhosis, severe diuresis, with insufficient intake of electrolytes with food, as well as with simultaneous treatment with corticosteroids or ACTH.

An increased risk of developing water-electrolyte imbalance is noted in patients with renal failure. During course 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, lipids, and, if necessary, carry out appropriate corrective therapy (more frequently in patients with frequent vomiting and while receiving parenteral fluids).

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

The selection of the dosing regimen for patients with ascites due to liver cirrhosis should be carried out in a hospital setting (water-electrolyte imbalance can lead to the development of hepatic coma). This category of patients requires regular monitoring of blood plasma electrolytes.

The use of the drug Torasemide can cause an exacerbation of gout. Administer with caution in gout or tendencies to increased uric acid levels.

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

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

In patients with cardiovascular diseases, especially those taking cardiac glycosides, diuretic-induced hypokalemia can cause the development of arrhythmias.

In unconscious patients, control of diuresis is necessary due to the possibility of acute urinary retention.

In case of thrombocytopenia or bone marrow function suppression, as well as skin rashes, the drug should be discontinued.

Excipients

The drug Trigrim contains lactose monohydrate. Patients with rare hereditary diseases such as galactose intolerance, lactose intolerance due to lactase deficiency, or glucose-galactose malabsorption syndrome should not take this medicine.

Influence on the ability to drive vehicles and mechanisms

At the initial stage of administration, it is not recommended to drive vehicles or operate machinery due to the possibility of dizziness.

Overdose

Symptoms excessively increased diuresis, accompanied by a decrease in blood volume and disturbance of the blood electrolyte balance, 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, administer activated charcoal. Treatment is symptomatic, reduce the dose or discontinue the drug and simultaneously replenish blood volume and parameters of water-electrolyte balance and acid-base balance under the control of serum electrolyte concentrations and hematocrit. Hemodialysis is ineffective.

Drug Interactions

Torasemide increases the concentration and risk of nephro- and ototoxic effects of cephalosporins, aminoglycosides, chloramphenicol, ethacrynic acid, antibiotics, salicylates, platinum drugs (e.g., 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 each other’s effectiveness.

The bioavailability and, consequently, the effectiveness of torasemide may be reduced during concomitant therapy with cholestyramine.

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

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

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, impairment of plasma renin activity and aldosterone excretion.

Torasemide enhances the 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 high doses of salicylates during torasemide therapy, the risk of their toxicity manifestation increases (due to competitive renal excretion).

Sequential or simultaneous use of torasemide with ACE inhibitors or angiotensin II receptor antagonists may lead to a pronounced 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 (same pathway of secretion). On the other hand, Torasemide can lead to a decrease in the renal elimination of these drugs.

Concomitant use with inhibitors of the CYP2C9 isoenzyme (e.g., amiodarone, fluconazole) may lead to an increase in the blood concentration of torasemide.

Concomitant use with inducers of CYP2C9 (e.g., rifampicin) may lead to a decrease in the blood concentration of torasemide. It is necessary to monitor blood pressure and the diuretic effect when torasemide is used concomitantly with such drugs, and also to change the dose of torasemide if necessary.

Due to the influence of torasemide on metabolism via the CYP2C9 isoenzyme, it can affect the efficacy and safety of drugs metabolized by CYP2C9, such as celecoxib, or drugs with a narrow therapeutic index, for example, warfarin or phenytoin. In such cases, it is necessary to monitor patients and adjust the dose if necessary.

With simultaneous use of cyclosporine and torasemide, the risk of developing gouty arthritis increases because cyclosporine can cause impaired renal excretion of urates, and Torasemide can cause hyperuricemia.

It has been reported that in patients at high risk of nephropathy receiving oral Torasemide, impaired renal function was observed more frequently upon administration of radiocontrast agents than in high-risk nephropathy patients who received intravenous hydration prior to radiocontrast agent administration.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

For Trigrim tablets with a dosage of 2.5 mg, 5 mg, 10 mg, the shelf life is 3 years.

For Trigrim tablets with a dosage of 20 mg, the shelf life is 2 years.

Do not use the drug 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.