Trigrim

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

Composition:

Active substance: torasemide;

1 tablet contains torasemide 10 mg;

Excipients: lactose monohydrate; maize starch; colloidal silicon dioxide anhydrous; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white, round, flat tablets with a score line. Diameter: 8.9–9.3 mm.

Pharmacotherapeutic group.

High-ceiling diuretics. Simple sulfonamide agents. ATC code C03CA04.

Pharmacological properties.

Pharmacodynamics.

Torasemide is a loop diuretic. However, at low doses its pharmacodynamic profile resembles that of thiazide diuretics in terms of the level and duration of diuresis. At higher doses, torasemide enhances diuresis in a dose-dependent manner, and this effect can be very pronounced.

Pharmacokinetics.

Absorption. After oral administration, torasemide is rapidly and almost completely absorbed; peak serum concentrations are reached within 1–2 hours.

Protein binding. More than 99% of torasemide is bound to plasma proteins.

Distribution. The volume of distribution of torasemide is 16 L.

Biological transformation. Torasemide is metabolized into three metabolites – M1, M3, and M5 – via stepwise oxidation, hydroxylation, and hydroxylation of the aromatic ring.

Elimination. The elimination half-life of torasemide is approximately 3–4 hours. Total clearance of torasemide is 40 ml/min, renal clearance is approximately 10 ml/min. About 80% of the administered dose is excreted as unchanged torasemide (24%) and its metabolites: M1 (12%), M3 (3%), M5 (41%). In renal insufficiency, the elimination half-life of torasemide remains unchanged, while the elimination half-lives of metabolites M3 and M5 are prolonged. Torasemide and its metabolites are practically not removed by hemodialysis or hemofiltration. In patients with impaired liver function or heart failure, the half-lives of torasemide and metabolite M5 are slightly prolonged, but accumulation of torasemide and its metabolites is unlikely.

Clinical characteristics.

Indications.

Edema due to heart failure.

Contraindications.

• Hypersensitivity to torasemide, sulfonylurea derivatives, or excipients of the medicinal product.
• Renal failure accompanied by anuria.
• Hepatic coma and precomatose state.
• Arterial hypotension.
• Pregnancy or breastfeeding period.
• Tachyarrhythmia.
• Concomitant use of aminoglycoside antibiotics or cephalosporins, or renal failure following administration of other nephrotoxic medicinal products.
• Hypovolemia.
• Hyponatremia.
• Hypokalemia.
• Significant impairment of urination, for example due to benign prostatic hyperplasia.
• Gout.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of torasemide with cardiac glycosides may increase myocardial sensitivity to these medicinal products due to potassium or magnesium deficiency. Concomitant use with mineralocorticoids, glucocorticoids, or laxatives increases the risk of potassium deficiency.

Torasemide, like other diuretics, may enhance the hypotensive effect of medicinal products when used concomitantly. Concomitant use of torasemide with ACE inhibitors may lead to hypotension. This effect can be minimized by reducing the initial dose of the ACE inhibitor and (or) decreasing the dose of torasemide 2–3 days prior to initiating ACE inhibitor therapy (or by temporarily discontinuing torasemide).

Torasemide may reduce the vasoconstrictive effects of adrenaline and noradrenaline.

Torasemide reduces the efficacy of antidiabetic agents.

The use of torasemide, especially at high doses, may enhance the nephrotoxic and ototoxic effects of aminoglycoside antibiotics (e.g., kanamycin, gentamicin, tobramycin), the toxic effects of platinum-containing agents (cisplatin), and the nephrotoxic effects of cephalosporins.

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

Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., indomethacin, propionic acid derivatives) and probenecid may reduce the diuretic and hypotensive effects of torasemide.

Concomitant use of torasemide and lithium preparations may increase lithium blood concentration, thereby enhancing its cardiotoxic and neurotoxic effects.

During therapy with high-dose salicylates, torasemide may enhance their toxic effects on the central nervous system (CNS).

Concomitant use with cholestyramine may reduce the absorption of torasemide, thereby weakening its effect.

Special precautions for use.

Before initiating treatment with the drug, existing hypokalemia, hyponatremia, or hypovolemia should be corrected, and disturbances in urine excretion should be adjusted.

During prolonged treatment with torasemide, regular monitoring of electrolyte balance is recommended, especially plasma potassium levels (particularly in patients concurrently receiving cardiac glycosides, glucocorticoids, mineralocorticoids, or laxatives), as well as blood glucose, uric acid, creatinine, and lipid levels.

Patients predisposed to hyperuricemia and gout require special monitoring.

Patients with overt or latent diabetes mellitus should have carbohydrate metabolism monitored.

Due to insufficient clinical experience, torasemide is not recommended in conditions involving pathological changes in acid-base balance; in blood picture abnormalities such as thrombocytopenia or anemia in patients without renal insufficiency; concomitant use with lithium, aminoglycosides, or cephalosporins; renal dysfunction caused by nephrotoxic agents; in children; and in elderly patients (dosing recommendations are lacking).

Torasemide should be used with particular caution in patients with liver diseases associated with liver cirrhosis and ascites, as sudden changes in water-electrolyte balance may lead to hepatic coma. Treatment with torasemide (as with other diuretics) in these patients should be conducted under hospital conditions. To prevent hypokalemia and metabolic acidosis, the drug should be administered together with aldosterone antagonists or potassium-sparing agents.

Ototoxic effects (tinnitus and hearing loss) have been observed after administration of torasemide. These effects were reversible, but a direct causal relationship with the drug has not been established.

When prescribing diuretics, clinical symptoms of electrolyte imbalance, hypovolemia, extrarenal azotemia, and other disturbances should be carefully monitored. These may manifest as dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle pain or cramps, myasthenia, hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may lead to dehydration, reduced circulating blood volume, thrombosis, and vascular embolism, particularly in elderly patients. Signs of hemoconcentration and electrolyte loss should be closely monitored, especially at the beginning of treatment and in elderly patients.

Patients experiencing disturbances in water-electrolyte balance should discontinue the drug. After resolution of adverse effects, therapy may be resumed starting with lower doses.

Regular laboratory monitoring of serum potassium and other electrolyte levels is necessary during treatment. Blood cell counts (erythrocytes, leukocytes, platelets) should also be monitored regularly.

Information on dosing in patients with renal or hepatic impairment is limited. Torasemide should be administered with caution in patients with hepatic insufficiency due to the possibility of increased plasma concentration of torasemide.

Treatment with torasemide may result in positive doping test outcomes.

The medicinal product contains lactose. If the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated during pregnancy. Reliable data on the effects of torasemide on the human embryo and fetus are lacking. Information on reproductive toxicity of torasemide is available. Torasemide crosses the placental barrier. Therefore, torasemide may 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 is currently unknown whether torasemide passes into breast milk in animals or humans. Risk to newborns/infants cannot be excluded. Therefore, the use of torasemide during breastfeeding is contraindicated. If torasemide must be used during this period, breastfeeding should be discontinued.

Fertility. Studies on the effects of torasemide on human fertility have not been conducted.

Ability to affect reaction rate when driving or operating machinery.

The drug may alter human reaction speed, reducing it during driving or operating machinery, especially when used concomitantly with alcohol. Therefore, driving or operating potentially hazardous machinery should be avoided during treatment with this drug.

Dosage and Administration.

Tablets should be taken whole, without chewing or crushing, regardless of food intake and time of day, with a small amount of liquid.

The duration of treatment depends on the course of the disease; treatment should continue until edema has resolved.

Initiate therapy with a dose of 5 mg once daily. This dose is usually considered maintenance. If a daily dose of 5 mg is insufficient, a daily dose of 10 mg should be used, administered daily. Depending on the severity of the patient's condition, the daily dose may be gradually increased up to 20 mg of torasemide (once daily).

For elderly patients, no additional dose adjustment is required.

Treatment in patients with severe hepatic impairment should be conducted with caution, as increased plasma concentrations of torasemide may occur.

Children.

There are insufficient clinical data on the safety of torasemide use in children.

Overdose.

Symptoms. There is no typical intoxication pattern. Overdose symptoms include enhanced diuresis with risk of dehydration and electrolyte loss, which may lead to somnolence and confusion, arterial hypotension, and cardiovascular failure. Gastrointestinal disturbances may also occur.

Treatment. There is no specific antidote. Depending on overdose symptoms, it is recommended to reduce the dose or discontinue torasemide and simultaneously restore fluid volume and electrolytes. 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: sitting position and, if necessary, symptomatic therapy.

Anaphylactic shock (emergency measures). At the first signs of skin reactions (such as urticaria or skin redness), patient agitation, headache, sweating, nausea, cyanosis, perform venous catheterization; place the patient in a horizontal position, ensure free air access, administer oxygen. If necessary, administer epinephrine, volume-replacement solutions, and glucocorticoid hormones.

Side effects

Side effects are classified according to their frequency of occurrence: very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1000 and < 1/100; rare ≥ 1/10000 and < 1/1000; very rare < 1/10000; not known (frequency cannot be estimated due to lack of data).

Metabolic and nutritional disorders: common – exacerbation of metabolic alkalosis; hypokalemia in patients on a diet low in potassium, with 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 fluid and electrolyte balance may occur, such as hypovolemia, hypokalemia, hyponatremia. With significant fluid and electrolyte losses due to pronounced diuresis, arterial hypotension, headache, asthenia, drowsiness, and somnolence may occur, particularly at the beginning of treatment and in elderly patients.

Cardiovascular system disorders: very rare – thrombosis, arterial hypotension, cardiac and cerebral ischemia, possibly leading to cardiac arrhythmias, angina pectoris, acute myocardial infarction, syncope.

Nervous system disorders: common – headache, dizziness (especially at the beginning of treatment); uncommon – paresthesia.

Gastrointestinal disorders: common – loss of appetite, nausea, vomiting, stomach pain, gastric discomfort, diarrhea, constipation, flatulence, mainly at the beginning of treatment; uncommon – dry mouth; very rare – pancreatitis.

Renal and urinary disorders: uncommon – in patients with urinary disorders, e.g., due to benign prostatic hyperplasia, urinary retention and excessive bladder distension may occur; urinary urgency.

Hepatobiliary disorders: common – increased plasma levels of certain liver enzymes (γ-glutamyl transpeptidase).

Blood and lymphatic system disorders: very rare – decreased platelet, erythrocyte, and/or leukocyte counts.

Skin and subcutaneous tissue disorders: very rare – allergic reactions: pruritus, rash, exanthema, photosensitivity; severe skin reactions have been reported (e.g., Stevens–Johnson syndrome, toxic epidermal necrolysis).

Eye disorders: very rare – visual disturbances.

Ear and labyrinth disorders: very rare – tinnitus, hearing loss.

Musculoskeletal and connective tissue disorders: common – muscle cramps (especially at the beginning of treatment).

General disorders: common – confusion, increased fatigue, general weakness (especially at the beginning of treatment).

Laboratory investigations: common – increased plasma concentrations of uric acid, glucose, and lipids (cholesterol, triglycerides); uncommon – possible increase in serum creatinine and urea levels.

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Pharmaceutical Works «Polpharma» S.A., Poland.

Manufacturer's address.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.