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Pharmacodynamic properties Pharmacotherapeutic group: Loop diuretic/saluretic Torasemide has a saluretic effect due to inhibition of re-absorption of renal sodium and chloride in the ascending limb of the loop of Henle. In humans, the onset of diuretic effect is quick following IV and oral administration; maximum effect is reached within one hour or after 2 to 3 hours and may last up to 12 hours. In healthy subjects given doses between 5 and 100 mg, a log-proportional increase in diuretic activity (high ceiling activity) was observed. Increased diuresis can also occur when other diuretics (e.g. distal acting thiazide) are no longer fully effective, e.g. in the presence of impaired renal function. These properties enable torasemide to flush out oedema. In the treatment of heart failure, torasemide improves symptoms and improves conditions for the cardiac muscle by reducing the preload and afterload. The anti-hypertensive effect following oral administration of torasemide begins in the first week of treatment while the maximum anti-hypertensive effect is usually reached after about 12 weeks at the latest. Torasemide reduces the blood pressure by reducing peripheral resistance. This effect is attributed to the normalisation of an electrolyte imbalance, and in particular to the reduction of increased free Ca2+ ion activity in the cells of the arterial vascular muscle, which is typical for hypertension. This probably reduces the increased contractility or responsiveness of the vessels to the autologous pressor substances, such as catecholamines. Pharmacokinetic properties  Absorption and distribution Torasemide is absorbed rapidly and almost completely after oral administration, and peak serum levels are reached after one to two hours. Bioavailability is approx. 80 - 90 % and the first-pass effect is 10 - 20 % assuming that absorption is complete. The data from two studies both reveal that after food intake the absorption rate (timedependent) of torasemide is reduced (lower Cmax and raised tmax values) but the whole absorption of torasemide is not affected after food intake. More than 99% of torasemide is bound to plasma proteins, while metabolites M1, M3 and M5 are bound at 86%, 95% and 97% respectively. The apparent distribution volume is 16 l. Metabolism In humans, torasemide is metabolised to the three metabolites M1, M3 and M5. There is no evidence of the occurrence of further metabolites. The metabolites M1 and M5 are created by phased oxidation of the methyl group of the phenyl ring to carboxylic acid, and metabolite M3 by ring hydroxylation. The metabolites M2 and M4 that were found in animal experiments could not be detected in humans. Torasemide and its metabolites are characterised by dose-linear kinetics, i.e. maximum serum concentrations and areas under the serum level curves increase in proportion to the dose. Elimination The terminal half-life (t1/2) of torasemide and its metabolites is three to four hours in healthy persons. Total clearance of torasemide is 40 ml/min with renal clearance accounting for about 10 ml/min. In healthy subjects, about 80% of the dose administered is excreted in the form of torasemide and its metabolites in urine with the following mean percentage distribution: Torasemide approx. 24%, metabolite M1 approx. 12%, metabolite M3 approx. 3%, metabolite M5 approx. 41%. The principal metabolite M5 is inactive as a diuretic, while the active metabolites M1 and M3 together make up about 10% of the pharmacodynamic action. In the presence of renal failure, total clearance and the elimination half-life of torasemide remain unchanged, but the half-lives of metabolites M3 and M5 are prolonged. However, the pharmacodynamic behaviour remains unchanged and the duration of effect is not influenced by the severity of renal failure. Torasemide and its metabolites are not significantly eliminated by haemodialysis or haemofiltration. In patients with liver dysfunction or heart failure, the elimination half-lives of torasemide and metabolite M5 are slightly prolonged, but the quantities of the substance excreted in urine  largely correspond to those in healthy persons. Accumulation of torasemide and its metabolites is therefore not to be expected. Preclinical safety data Animal experiments revealed no evidence of increased risk for use in humans based on safety pharmacology, chronic toxicity, mutagenicity and carcinogenicity. Reproductive toxicology studies in the rat have revealed no teratogenic effects. However foetal and maternal toxicity have been observed after high doses in pregnant rabbits and rats. Torasemide was shown to cross the placental barrier in rats. No effects on fertility have been observed.

Pharmaceutically active ingredient 1 tablet contains 5 mg of torasemide. Other ingredients Lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silica.

Toras-Denk 10 is a diuretic and anti-hypertensive agent and belongs to a group of medications known as the loop diuretics. Toras-Denk 10 is used for the treatment and prevention of recurrent cardiac oedema and/or effusions associated with heart failure.

Toras-Denk 5 is not allowed in case of hypersensitivity to the active ingredient torasemide, sulfonyl ureas, or any of. the other ingredients of Toras-Denk 5.  in cases of renal failure associated with anuria. coma or hepatic precoma. hypotension. hypovolaemia. hyponatraemia, hypokalaemia. in cases of urinary outflow obstruction (caused for example by abnormal prostate enlargement). if you are breastfeeding.

The following adverse drug reactions may occur in association with Toras-Denk 10. The frequencies of adverse drug reactions are ranked according to the following: Very common: >10% Common: > 1% - <10% Uncommon: > 0.1% - <1% Rare: > 0.01% - <0.1% Very rare: < 0.01% including individual cases Metabolism / electrolyte Common: Reinforcementof metabolic alkalosis. Muscle cramps (particularly at the commencement of treatment). Increase in serum levels of uric acid and glucose as well as lipids (triglyceride, cholesterol). Hypokalaemia if a low potassium diet is being taken, in cases of vomiting, diarrhoea, excessive use of laxatives as well as in patients with chronic liver dysfunction. Depending on the dosage and duration of treatment, there may be disturbances of salt and water balance, particularly hypovolaemia, hypokalaemia and/or hyponatraemia. Cardiovascular system Very rare: Thromboembolic complications, confusion, hypotension as well as cardiac and cerebral circulatory disturbances (including cardiac and cerebral ischemia) can occur due to haemoconcentration. These in turn may cause arrhythmias, angina pectoris, acute heart attack or syncope. Gastrointestinal tract Common: Gastrointestinal complaints (e.g. reduced appetite, stomach ache, nausea,vomiting, diarrhoea, constipation) particularly at the beginning of treatment. Very rare: Pancreatitis. Kidneys and urinary tract Uncommon: Increase in serum urea and creatinine. Increased production of urine may provoke urinary retention and bladder strain in patients with urinary outflow obstruction (e.g. due to prostate hypertrophy). Liver Common: Elevation of certain liver enzymes (gamma-GT). Skin, allergic reactions Very rare: Allergic reactions (such as pruritis, exanthema, photosensitivity), severe skin reactions. Blood and haematopoietic system Very rare: Reduction in thrombocytes, erythrocytes and/or leukocytes. General Common: Headaches, dizziness, fatigue, weakness (particularly at the commencement of treatment). Uncommon: Xerostomia, paraesthesia. Very rare: Visual impairment, tinnitus, hearing loss. Note: Regular monitoring of electrolytes, in particular serum potassium, is recommended during long-term treatment with torasemide. Glucose, uric acid, creatinine and blood lipids should also be checked regularly. As blood glucose levels may increase, careful monitoring of carbohydrate metabolism is recommended in patients suffering from latent or manifest diabetes. The blood count (erythrocytes, leukocytes, thrombocytes) should also be checked at regular intervals. Particularly at the beginning of treatment and in elderly patients one should look out for signs of electrolyte loss and haemoconcentration.

The following interactions of this drug have to be observed: Torasemide potentiates the effect of other anti-hypertensive agents, particularly the effect of ACE inhibitors. If ACE inhibitors are given concomitantly or after treatment with torasemide, excessive hypotension may occur. Potassium deficiency caused by torasemide may increase and potentiate the adverse drug reactions of digitalis preparations given concomitantly. Torasemide may attenuate the effect of anti-diabetic agents. Probenecid and non-steroidal anti-inflammatory drugs may reduce the diuretic and antihypertensive effect of torasemide. The toxic effect of high doses of salicylate (analgesic and anti-rheumatic drug) on the central nervous system may be potentiated by torasemide. Particularly when taken in high doses, torasemide may cause intensification of the following adverse drug reactions: The ototoxic and nephrotoxic effects of amionglycoside antibiotics (e.g. kanamycin, gentamycin, tobramycin), of cytostatic acting platinum derivatives as well as nephrotoxic effects of cephalosporins. Torasemide may potentiate the effect of theophylline as well as the effect of curare-type muscle relaxants. Laxatives as well as mineralocorticoids and glucocorticoids may potentiate hypokalaemia caused by Torasemide. Serum lithium levels and the cardiotoxic and nephrotoxic effects of lithium may be increased when lithium is given concomitantly with Torasemide. Torasemide may reduce the vasoconstrictive effect of catecholamins, e.g. adrenaline,  noradrenaline. Concomitant colestyramine treatment may reduce the gastrointestinal absorption of oral torasemide and thus reduce its effect.

Symptoms of intoxication No typical clinical picture for intoxication is known. Overdose may be associated with excessive diuresis with the danger of loss of electrolytes and fluids. Somnolence, delirious states, symptomatic hypotension, circulatory collapse and gastrointestinal symptoms may occur. Treatment of intoxication No specific antidote is known. The symptoms of intoxication usually recede upon reduction of the dose or withdrawal of torasemide and simultaneous replacement of fluids and electrolytes (monitoring!). Torasemide is not dialysable and haemodialysis would therefore not speed up its elimination. Treatment of hypovolaemia: Fluid replacement. Treatment of hypokalaemia: Potassium replacement. Treatment of circulatory collapse: Shock position and, if necessary, treatment for shock.  Emergency measures in case of anaphylactic shock: at the first signs (e.g. cutaneous reactions, such as urticaria or flush, restlessness, headache, sweating, nausea, cyanosis). • Insert an IV line: • In addition to the other usual emergency measures, lay the person on their back with their legs slightly elevated, keep airway open and administer oxygen!. • If necessary, further - intensive care - measures should be taken (among other things, administration of adrenaline, fluid replacement preparation, glucocorticoid).

The treatment is commenced with 5 mg torasemide a day. This dose is usually the maintenance dose. If the usual dose does not yield an adequate response, the dose can be increased to up to 20 mg torasemide a day depending upon the severity of the illness. Treatment with 10 mg torasemide a day is indicated when the usual dose of 5 mg torasemide a day does not yield an adequate response. In such cases, 10 mg torasemide a day can be taken. If required, the dose can be increased to up to 20 mg torasemide a day depending upon the severity of the illness. Elderly patients: No dosage adjustments are necessary in elderly patients. However, comparative studies comparing older and younger patients are not available. Patients with liver failure: Caution should be exercised in patients suffering from liver failure since serum torasemide levels might be increased . Children under 12 years of age: There are no data available on the use of torasemide in children under 12 years of age. Torasemide should therefore not be used in children. The tablets should be swallowed whole with a small quantity of liquid in the morning. The biological availability of torasemide is not dependant upon food intake. Torasemide is generally given as long-term treatment or until the oedema recedes.

Store below 25°C. Do not use after the expiry date. Keep out of reach of children.