Pharmacological properties
Pharmacodynamics. Torsemide acts as a saluretic, its action is associated with inhibition of renal absorption of sodium and chlorine ions in the ascending part of the loop of Henle. In humans, the diuretic effect quickly reaches its maximum within the first 2-3 hours after intravenous and oral administration, respectively, and remains constant for almost 12 hours. In healthy volunteers, a dose-proportional increase in diuresis (loop diuretic activity) was observed in the dose range of 5-100 mg. An increase in diuresis was recorded even in cases where other diuretics, such as distally acting effective thiazide diuretics, no longer had the desired effect, for example, in renal failure. Due to this mechanism of action, torasemide leads to a decrease in edema. In heart failure, torasemide reduces the manifestations of the disease and improves myocardial function by reducing pre- and afterload. After oral administration, the antihypertensive effect of torasemide develops gradually, starting from the 1st week after the start of treatment. The maximum antihypertensive effect is achieved no later than 12 weeks. Torasemide reduces HBP by reducing OPSS. This effect is explained by the normalization of disturbed electrolyte balance mainly by reducing the increased activity of free calcium ions in the muscle cells of arterial vessels, which is found in patients with AG. This effect probably reduces the increased susceptibility of vessels to endogenous vasopressor substances, such as catecholamines.
Pharmacokinetics. After oral administration, torasemide is rapidly and completely absorbed. C max in blood plasma is achieved within 1-2 hours. Bioavailability is 80-90%; provided that absorption is complete, the maximum value of the first-pass effect is 10-20%. Food reduces the rate (dynamic component) of torasemide absorption (C max decreases and the time to reach C max - t max increases), but does not affect total absorption. Binding of torasemide to plasma proteins is more than 99%, metabolites M1, M3, and M5 - 86; 95 and 97%, respectively. The volume of distribution (Vz) is 16 l. In humans, torasemide is metabolized to form three metabolites M1, M3, and M5. There is no evidence of the existence of other metabolites. Metabolites M1, M3 and M5 are formed as a result of oxidation of the methyl group located on the phenyl ring to carboxylic acid, metabolite M3 is formed as a result of hydroxylation of the ring. Metabolites M2 and M4, detected in animal studies, have not been observed in humans. The pharmacokinetics of torasemide and its metabolites are characterized by a linear relationship. This means that its C max in blood plasma and AUC increase in proportion to the dose. The final T ½ of torasemide and its metabolites in healthy people is 3-4 hours. The total clearance of torasemide reaches 40 ml/min, renal clearance is approximately 10 ml/min. In healthy subjects, approximately 80% of the administered dose is excreted as torasemide and its metabolites in the following percentage ratio: torasemide - approximately 24%, metabolite M1 - approximately 12%, metabolite M3 - approximately 3%, metabolite M5 - approximately 41%. The main metabolite M5 has no diuretic effect, and the active metabolites M1 and M3 together account for approximately 10% of the total pharmacodynamic action. In renal failure, the total clearance and T ½ of torasemide do not change, and T ½ of M3 and M5 are prolonged. However, the pharmacodynamic characteristics remain unchanged, and the severity of renal failure does not affect the duration of action. In patients with impaired liver function or heart failure, T ½ of torasemide and the metabolite M5 are slightly prolonged, and the amount of substance excreted in the urine is almost completely equal to the amount excreted in healthy people, so the accumulation of torasemide and its metabolites does not occur. Torasemide and its metabolites are practically not removed by hemodialysis and hemofiltration.
Indication
Essential ag. treatment and prevention of recurrence of edema and/or effusions due to heart failure.
Trifas 20 ampoules. Treatment of edema and/or effusions caused by heart failure, if intravenous administration of the drug is necessary, for example in the case of pulmonary edema due to acute heart failure.
Trifas 200 is indicated exclusively for patients with significant deterioration of renal function (creatinine clearance 20 ml/min and/or plasma creatinine concentration 6 ml/dl). To maintain residual diuresis in severe renal failure, as well as in hemodialysis conditions in the presence of at least some residual diuresis (200 ml within 24 hours), if there is edema, effusion and/or increased blood pressure.
Application
Edema and/or effusions. Treatment begins with 1 tablet of Trifas Cor or ½ tablet of Trifas 10 per day, which is 5 mg of torasemide. Usually this dose is considered maintenance. If the daily dose of 5 mg is not enough, then 10 mg of torasemide should be used, which is prescribed daily. Depending on the severity of the patient's condition, the daily dose may be increased to 20 mg of torasemide.
Tablets should be taken in the morning, without chewing, with a small amount of liquid. The duration of treatment is determined based on the course of the disease. The bioavailability of torasemide does not depend on food intake.
Recommendations for dividing the tablet. The tablets can be easily divided into two halves (the dividing risk is on one side), which ensures the possibility of obtaining the required dose. Place the tablet on a hard surface. Then press with your thumbs to the right and left of the dividing risk. This ensures easy division of the tablet.
The dosage of Trifas 200 tablets is set individually depending on the severity of renal failure. Treatment should begin with the use of ¼ tablet of Trifas 200 per day, which is equivalent to 50 mg of torasemide. In case of insufficient urination, the dose can be increased to ½ tablet of Trifas 200, which corresponds to 100 mg of torasemide. The maximum daily dose is 1 tablet of Trifas 200, which is equivalent to 200 mg of torasemide. The tablets are easily divided into 2 or 4 parts due to the scores on them. The tablets are taken in the morning, without chewing, and washed down with a small amount of liquid.
Trifas 20 ampoules
Adults. Treatment should begin with a single dose of 2 ml of Trifas 20 ampoules, equivalent to 10 mg of torasemide per day. If the effect is insufficient, the single dose can be increased to 4 ml of Trifas 20 ampoules, equivalent to 20 mg of torasemide. If the effect is still insufficient, short-term (no more than 3 days) therapy with a daily dose of 8 ml of Trifas 20 ampoules, equivalent to 40 mg of torasemide, can be used.
Acute pulmonary edema. Treatment should be initiated with a single dose of 4 ml of Trifas 20 ampoules, equivalent to 20 mg of torasemide. Depending on the effect, the dose can be repeated at 30-minute intervals. The maximum daily dose of 20 ml of Trifas 20 ampoules, equivalent to 100 mg of torasemide, must not be exceeded.
Injection solution should be administered intravenously slowly. Do not administer the solution intravenously! Only administer pure solution. With prolonged use, administration should be replaced with oral administration as soon as possible, since intravenous administration of the drug is not recommended for 7 days.
Note: Handling ampoules that open at one point. No need to dust the ampoules.
Patients with impaired liver function. Treatment of such patients should be carried out with caution, as an increase in the concentration of torasemide in the blood plasma is possible.
Elderly patients. No special dose adjustment is required. Unfortunately, adequate studies comparing treatment in elderly and young patients are lacking.
Contraindication
Hypersensitivity to torasemide, sulfonylurea compounds and other components of the drug; arterial hypotension; renal failure with anuria; hepatic coma or precoma; hypovolemia, hyponatremia, hypokalemia; arrhythmia; severe urination disorders (for example, due to prostatic hypertrophy); breastfeeding period.
The drug Trifas 200 can be additionally prescribed in normal or moderate renal failure (creatinine clearance 30 ml/min and/or plasma creatinine concentration 3.5 mg/dl) due to the risk of excessive loss of water and electrolytes.
Side effects
The following frequency of side effects was used to assess their occurrence: 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); unknown (cannot be estimated from the available data).
Metabolism / electrolytes: often - intensification of metabolic alkalosis, muscle spasms (especially at the beginning of treatment), increased concentration of uric acid and glucose in the blood plasma, as well as cholesterol and triglycerides, hypokalemia with concomitant low-calorie diet, vomiting, diarrhea, after excessive use of laxatives, as well as with chronic liver dysfunction. Depending on the dosage and duration of treatment, disturbances of water and electrolyte balance are possible, such as hypovolemia, hypokalemia and / or hyponatremia.
Cardiovascular system: very rarely - due to possible blood thickening, thromboembolic complications, confusion, hypotension, as well as circulatory and cardiac disorders, including ischemic disorders of the heart and brain, which can lead to arrhythmia, angina pectoris, acute myocardial infarction, syncope, may occur.
Digestive system: often - various disorders of the digestive tract (especially at the beginning of treatment), such as lack of appetite, stomach pain, nausea, vomiting, diarrhea, constipation, flatulence; very rarely - pancreatitis.
Kidneys and urinary tract: sometimes - an increase in the concentration of creatinine and urea in the blood plasma. In case of impaired urination (for example, with prostatic hypertrophy), increased urine production can lead to its retention and overstretching of the bladder. Urge to urinate.
On the part of the immune system: very rarely - allergic reactions, such as itching, rash, photosensitivity, severe skin reactions, rash.
Blood system: very rarely - a decrease in the number of platelets, erythrocytes and / or leukocytes.
General manifestations: often - headache, dizziness, fatigue, general weakness (especially at the beginning of treatment); sometimes - dry mouth, unpleasant sensations in the extremities (paresthesia); very rarely - visual impairment, tinnitus, hearing loss. With significant fluid and electrolyte losses due to increased urination, arterial hypotension, headache, asthenia, drowsiness may occur, especially at the beginning of treatment and in elderly patients; unknown - local reactions after injections.
Special instructions
Before starting the drug, it is necessary to eliminate existing hypokalemia, hyponatremia, or hypovolemia.
With prolonged use of torasemide, regular monitoring of electrolyte balance is necessary (especially in patients who are simultaneously using digitalis glycosides, corticosteroids, mineralocorticoids or laxatives), including potassium in the blood plasma.
Torasemide should be used with extreme caution in patients with liver disease accompanied by cirrhosis and ascites, as sudden changes in water and electrolyte balance can lead to hepatic coma. Therapy with torasemide (as well as other diuretics) in patients of this group should be carried out in a hospital setting. To prevent hypokalemia and metabolic acidosis, the drug should be prescribed with aldosterone antagonists or drugs that promote potassium retention in the body. After using the drug, cases of ototoxicity (tinnitus and hearing loss) were noted, which were reversible, but a direct connection with the use of the drug has not been established.
When prescribing diuretics, it is necessary to carefully monitor clinical symptoms of electrolyte imbalance, hypovolemia, extrarenal azotemia and other disorders, which may manifest as dry mouth, thirst, weakness, lethargy, drowsiness, agitation, muscle pain or cramps, myasthenia gravis, hypotension, oliguria, tachycardia, nausea, vomiting. Excessive diuresis can cause dehydration, lead to a decrease in circulating blood volume, thrombosis and embolism, especially in elderly patients.
Patients with water and electrolyte imbalance should discontinue use of the drug and resume therapy, starting with lower doses, after the undesirable effects have resolved.
In addition, it is necessary to regularly monitor the level of glucose, uric acid, creatinine and lipids in the blood. Due to the fact that during treatment with a diuretic, blood glucose levels may increase, patients with latent and existing diabetes mellitus require careful monitoring of carbohydrate metabolism. Regular monitoring of the blood picture (erythrocytes, leukocytes, platelets) is also necessary. At the beginning of treatment in elderly patients, special attention should be paid to the appearance of symptoms of electrolyte loss and blood thickening.
Due to the lack of sufficient clinical experience, torasemide should not be prescribed for the following diseases and conditions: Gout. Arrhythmia, such as sinoatrial block, AV block II and III degree. Pathological changes in acid-base metabolism. Concomitant therapy with lithium, aminoglycosides or cephalosporins. Pathological changes in the blood count, such as thrombocytopenia or anemia in patients without renal failure. Impaired renal function caused by nephrotoxic substances. The drug contains lactose, therefore it should not be prescribed to patients with hereditary lactase deficiency, galactose intolerance or impaired glucose / galactose metabolism. Trifas 200 is not used for creatinine clearance 20-30 ml / min and / or plasma creatinine concentration 3.5-6 mg / dl.
The use of Trifas may cause a positive result in a doping test and deterioration of health.
Pregnancy and breast-feeding. Pregnancy. There are no reliable data on the effect of torasemide on the human embryo and fetus.
Animal experiments have shown reproductive toxicity of torasemide. Torasemide crosses the placental barrier. In connection with the above, torasemide is used during pregnancy only when absolutely necessary and in the lowest possible effective dose. Diuretics are not suitable for the standard treatment regimen for hypertension or edema in pregnant women, since they can reduce the perfusion of the placental barrier and thereby slow down the intrauterine development of the fetus. If torasemide is used to treat pregnant women with heart failure or impaired renal function, careful monitoring of electrolytes and hematocrit, as well as fetal development, is necessary.
Breastfeeding. It is currently not known whether torasemide is excreted in human or animal breast milk. A risk to the newborn/infants cannot be excluded. Therefore, the use of the drug during breastfeeding is contraindicated. If it is necessary to use torasemide during this period, breastfeeding should be discontinued.
Children. The drug is not used in children due to the lack of sufficient clinical experience.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Even when used properly, torasemide may affect the patient's reaction to such an extent that it will cause a significant negative impact on the ability to drive vehicles or other mechanisms or perform work without safety precautions. This mainly applies to cases such as the start of treatment, increasing the dose of the drug, replacing the drug or when prescribing concomitant therapy. Therefore, during the use of the drug, it is necessary to be very careful when driving vehicles or other mechanisms.
Interactions
Torasemide enhances the effect of other antihypertensive agents, in particular ACE inhibitors. With their simultaneous use, excessive reduction in blood pressure is possible. With simultaneous use of torasemide with digitalis drugs, potassium deficiency caused by a diuretic can lead to increased side effects of both drugs. Torasemide may reduce the effectiveness of antidiabetic agents. Probenecid and non-steroidal anti-inflammatory drugs (e.g. indomethacin, acetylsalicylic acid) may reduce the diuretic and hypotensive effect of torasemide. When treated with salicylates in high doses, torasemide may enhance their toxic effect on the central nervous system. Torasemide, especially in high doses, may enhance the oto- and nephrotoxic effects of aminoglycoside antibiotics (e.g. kanamycin, gentamicin, tobramycin) and cytostatics - platinum derivatives, as well as the nephrotoxic effect of cephalosporins. Torsemide may enhance the effect of theophylline and curare-like muscle relaxants. Laxatives, as well as mineralocorticoids and glucocorticoids may increase the possible loss of potassium caused by torasemide. With the simultaneous use of torasemide and lithium preparations, the concentration of lithium in the blood may increase with an increase in its action and side effects. Torsemide may weaken the vasoconstrictor effect of catecholamines, such as adrenaline and noradrenaline. With simultaneous use with cholestyramine, the absorption of torasemide and, accordingly, its effectiveness may decrease.
Overdose
Typical symptoms are unknown. Overdose may result in a marked increase in diuresis, including an increased risk of severe water and electrolyte loss, drowsiness, amentia syndrome (a form of impaired consciousness), symptomatic arterial hypotension, cardiovascular failure and gastrointestinal disorders.
Treatment: there is no specific antidote. Symptoms of intoxication usually disappear when the dose is reduced and the drug is discontinued and with appropriate fluid and electrolyte replacement (monitoring is necessary!). Torasemide is not removed from the blood by hemodialysis. Treatment of hypovolemia: fluid replacement. Therapy of hypokalemia: administration of potassium preparations. Treatment of cardiovascular failure: patient lying down with legs elevated and, if necessary, symptomatic therapy.
Anaphylactic shock (emergency measures): at the first appearance of skin reactions (such as urticaria or redness of the skin), the patient's agitated state, headache, hyperhidrosis, nausea, cyanosis, a vein catheterization is performed; the patient is brought to a horizontal position, free air intake is ensured, oxygen is prescribed. If necessary, adrenaline, substituting solutions, and corticosteroids are administered.
Storage conditions
Does not require special storage conditions.
Trifas 200, Trifas 20 ampoules. Store at a temperature not exceeding 25 °C.
