Torahexal
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Torahexal2.5 mg tablets
Torahexal5 mg tablets
Torahexal10 mg tablets
Torahexal20 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Torahexal2.5 mg tablets
Each tablet contains 2.5 mg torasemide.
Torahexal5 mg tablets
Each tablet contains 5 mg torasemide.
Torahexal10 mg tablets
Each tablet contains 10 mg torasemide.
Torahexal20 mg tablets
Each tablet contains 20 mg torasemide.
Excipient with known effect: lactose
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL form
Tablet
Torahexal2.5 mg tablets
white to off-white, round tablet
Torahexal5 mg tablets
white to off-white, round tablet with break notch
The tablet can be divided into equal halves.
Torahexal10 mg tablets
white to off-white, round tablet with cross break notch
The tablet can be divided into equal halves.
Torahexal20 mg tablets
white to off-white, round tablet with cross break notch
The tablet can be divided into equal quarters.
4. Clinical particulars
Therapeutic indications
Torahexal2.5 mg/-5 mg tablets
Essential hypertension
Torahexal5 mg/- 10 mg/- 20 mg tablets
Oedema in patients with heart failure
Posology and method of administration
Posology
Torahexal 2.5 mg/-5 mg tablets – treatment of essential hypertension
Adults
The usual dose is 2.5 mg daily, preferably at breakfast time. Dose increase should not take place until 2 months after the initiation of the treatment and maximum dose is 5 mg, taken once daily.
Torahexal5 mg/- 10 mg/- 20 mg tablets – treatment of oedema in patients with heart failure
Adults
The usual dose is 5 mg orally once daily. Usually this is the maintenance dose.If necessary, the dose can be increased stepwise up to 20 mg once daily.
Older people
There are no deviating dosage recommendations for older people. However there are insufficient comparative studies between older and younger patients.
Children (< 12 years)
There is no experience with torasemide in children (see section 4.4).
Hepatic and Renal Insufficiency
There is limited information on dosage adjustments in patients with hepatic and renal insufficiency. Patients with hepatic insufficiency should be treated with some caution since plasma concentrations might be increased (see section 5.2).
Method of administration
Oral use.
The tablets should be taken in the morning, without chewing, with a small quantity of liquid.
Torasemide is usually given for long-term treatment or until disappearance of oedema.
Contraindications
Hypersensitivity to the active substance, to sulphonylureas or to any of the excipientslisted in section 6.1;
renalfailure with anuria;
hepatic coma and pre-coma;
hypotension;
lactation
hypovolaemia
Special warnings and precautions for use
Hypokalaemia, hyponatraemia and hypovolaemia must be corrected before treatment.
Disorders of micturition (e.g. benign prostatic hypertension).
Cardiac arrhythmias (e.g. sino-atrial-block, atrioventricular-block second or third degree).
On long-term treatment with torasemide, regular monitoring of the electrolyte balance, particularly serum potassium(in particular in patients with concomitant therapy with digitalis glycosides, glucocorticoids, mineralacorticoids or laxatives), glucose, uric acid, creatinine and lipids in the blood and the blood cells (red and white blood cells and platelets), is recommended.
Since an increase in blood glucose can occur, careful monitoring of the carbohydrate balance is recommended in patients with latent or manifest diabetes mellitus.
Be aware of signs of electrolyte loss and haemoconcentration, particularly at the beginning of treatment and in older patients.
Careful monitoring of patients with a tendency to hyperuricaemia and gout is recommended. Carbohydrate metabolism in latent or manifest diabetes mellitus should be monitored.
Due to insufficient experience with torasemide treatment, care should be exerted in the following conditions:
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Pathological changes of the acid-base balance,
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Concomitant treatment with lithium, aminoglycosides or cephalosporins
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Renal insufficiency due to nephrotoxic agents
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Children below 12 years
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Pathological changes of the blood cells (e.g. thrombocytopenia or anaemia in patients without renal insufficiency)
Torasemide tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
When used simultaneously with cardiac glycosides, a potassium and/or magnesium deficiency may increase sensitivity of the cardiac muscle to such medicinal products. The kaliuretic effect of mineralo-and glucocorticoids and laxatives may be increased.
The effect of antihypertensive medicinal products, in particular ACE inhibitors,given concomitantly may be potentiated.
Sequential or combined treatment, or starting a new co-medication with an ACE inhibitor may result in severe hypotension. This may be minimised by lowering the starting dose of the ACE inhibitor and/ or reducing or stopping temporarily the dose of torasemide, 2 or 3 days before treatment with the ACE inhibitor.
Torasemide may decrease arterial responsiveness to pressor agents e.g. adrenaline, noradrenaline.
Torasemide may reduce the effect of anti-diabetics.
Torasemide, especially at high doses, may potentiate the nephrotoxic and ototoxic effects of aminoglycoside antibiotics, toxicity ofcisplatin preparations and the nephrotoxic effects of cephalosporins.
Lithium serum-concentrations and cardio- and neurotoxic effects of lithium may be increased.
The action of curare-containing muscle relaxants and of theophylline can be potentiated.
Non-steroidal anti-inflammatory drugs(eg. Indomethacin) may reduce the diuretic and hypotensive effect of torasemide possibly through an inhibition of prostaglandin synthesis.
Probenecid may reduce efficacy of torasemide by inhibition of tubular secretion.
Torasemide inhibits the renal excretion of salicylates, increasing the risk for salicylate toxicity in patients receiving high doses of salicylates.
Concomitant use of torasemide and cholestyramine has not been studied in humans, but in an animal study co-administration of cholestyramine decreased absorption of oral torasemide.
4.6 Fertility, pregnancyand lactation
Pregnancy
There are no data from experience in humans of the effect of torasemide on the embryo and foetus.
Whilst studies in the rat have shown no teratogenic effect, foetal and maternal toxicity have been observed after high doses in pregnant rabbits and rats. Torasemide passes into the foetus and causes electrolyte disturbances. There is also a risk of neonatal thrombocytopenia.
Until further experience is available, torasemide should only be given during pregnancy after careful consideration of whether the benefits clearly outweigh the risks. The lowest possible dose should be used.
Breast-feeding
There is no information on the excretion of torasemide in human or animal breast milk.
The use of torasemide is therefore not recommended during breast-feeding.
Fertility
No effects on fertility have been seen in preclinical data (see section 5.3).
4.7 Effects on ability to drive and use machines
As for other medicinal productswhichproduce changes in blood pressure, patients taking torasemide should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies in particular at the beginning of the therapy, when increasing the dosage, changing the preparation or when concomitantly ingesting alcohol.
Undesirable effects
The following adverse reactions have been observed and reportedduring treatmentwith torasemide with thefollowing frequencies:Very common(≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), notknown(cannot be estimated from the available data).
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System Organ Class |
Common ≥ 1/100 to < 1/10 |
Uncommon ≥ 1/1 000 to < 1/100 |
Very Rare < 1/10 000 |
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Blood and lymphatic system disorders |
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Thrombocytopenia, erythropenia, leukopenia |
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Metabolism and nutrition disorders |
Decreased appetite, enhancement of metabolic alkalosis, disorders in the water and electrolyte balance depending on the dosage and duration of treatment, particularly e.g. hypovolaemia, hypokalaemia and/or hyponatraemia; hypokalaemia in concomitant low-potassium diet, in cases of vomiting, diarrhoea, after excessive use of laxatives as well as in patients with chronic hepatic dysfunction |
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Nervous system disorders |
Headache, vertigo, (particularly at the beginning of therapy) |
Paraesthesia |
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Eye disorders |
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Visual impairment |
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Ear and labyrinth disorders |
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Tinnitus, deafness |
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Vascular disorders |
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Thromboembolic complications, confusion, Hypotension, cardiac and central circulation disorders (including ischaemia of heart and brain) on account of haemoconcentration. These can lead to e.g. arrhythmias, angina pectoris, acute myocardial infarction or syncopes. |
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Gastrointestinal disorders |
Gastric pain, nausea, vomiting, diarrhoea, constipation (particularly at the beginning of treatment) |
Dry mouth |
Pancreatitis |
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Skin and subcutaneous tissue disorders |
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Allergic reactions (e.g. pruritus, exanthema, photosensitivity), severe skin reactions |
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Musculoskeletal and connective tissue disorders |
Muscle spasms (particularly at the beginning of therapy) |
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Renal and urinary disorders |
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In patients with impaired micturition (e.g. due to prostatic hyperplasia), increased urinary production can lead to urinary retention and overexpansion of the bladder. |
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General disorders and administration site conditions |
Headache, vertigo, Fatigue, asthenia (particularly at the beginning of therapy) |
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Investigations |
Increases in the concentration of uric acid and glucose in the blood; increase in blood fats (triglycerides, cholesterol); increase in certain liver enzyme concentrations (gamma-GT) in the blood |
Increase in the concentrations of creatinine and urea in the blood |
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Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via [the national reporting system; to be completed nationally].
4.9 Overdose
Symptoms and signs
No typical picture of intoxication is known. If overdose occurs, then there may be marked diuresis with the danger of loss of fluid and electrolytes that may lead to somnolence and confusion, hypotension, circulatory collapse. Gastrointestinal disturbances may occur.
Treatment
No specific antidote is known. Symptoms and signs of overdose require the reduction of the dose or withdrawal of torasemide, and simultaneous replacement of fluid and electrolytes.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Diuretics; Sulfonamides, plain
ATC Code: C03CA04
Pharmacodynamic effects
Torasemide is a loop diuretic. However, at low doses its pharmacodynamic profile resembles that of the thiazide class regarding the level and duration of diuresis. At higher doses, torasemide induces a brisk diuresis in a dose dependant manner with a high ceiling of effect. Torasemide has maximal diuretic activity 2-3 hours after oral administration. In healthy subjects given doses between 5 and 100 mgit has a log-proportional increase in diuretic activity.
Pharmacokinetic properties
Absorption
Torasemide is absorbed rapidly and almost completely after oral administration, and peak serum levels are reached after one to two hours. Systemic bioavailability after oral administration is 80-90%.
Serum protein binding
More than 99% of torasemide is bound to plasma proteins, while metabolites M1, M3 and M5 are bound 86%, 95% and 97%, respectively.
Distribution
The apparent distribution volume is 16 l (Vz: 16 l).
Biotransformation
Torasemide is metabolised to three metabolites, M1, M3 and M5 by stepwise oxidation, hydroxylation or ring hydroxylation. The hydroxyl-metabolites have diuretic activity. Metabolites M1 and M3 add to about 10% of the pharmacodynamic action, whereas M5 is inactive.
Elimination
The terminal half-life of torasemide and its metabolites is three to four hours in healthy subjects. Total clearance of torasemide is 40 ml/min and renal clearance about 10 ml/min. About 80% of the dose administered is excreted as torasemide and metabolites into the renal tubule - torasemide 24%, M1 12%, M3 3%, M5 41%.
In the presence of renal failure, the elimination half-life of torasemide is unchanged but the half-lives of metabolites M3 and M5 are increased. Torasemide and its metabolites are not significantly removed by hemodialysis or hemofiltration.
In patients with hepatic impairment, increases in plasma concentrations of torasemide have been observed, likely due to decreased hepatic metabolism. In patients with cardiac or hepatic failure the half-lives of torasemide and metabolite M5 are slightly increased but accumulation is unlikely (see section 4.2).
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on single dose toxicity, genotoxicity and carcinogenicity studies.
The changes observed in toxicity studies in dogs and rats at high doses are considered attributable to an excess pharmacodynamic action (diuresis). Changes observed were weight reduction, increases in creatinine and urea and renal alterations such as tubular dilatation and interstitial nephritis. All medicinal product induced changes were shown to be reversible.
Reproduction toxicology: Studies in the rat have shown no teratogenic effects, but foetal and maternal toxicity have been observed after high doses in pregnant rabbits and rats. No effects on fertility have been seen. Torasemide passes into thefoetus and causes electrolyte disturbances.
In mice torasemide showed no evidence of tumorigenic potential. In rats a statistically significant increase in renal adenomas and carcinomas was observed in the high-dose female group. This seems to have no relevance for therapeutic doses in humans.
6. PHARMACEUTICAL PARTICULARS
List of excipients
Microcrystalline cellulose
Lactose monohydrate
Magnesium stearate
Maize starch
Colloidal anhydrous silica
Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25 °C.
Nature and contents of container
The tablets are packed in PVC/PVdC/Al blister or Al/Al blister and inserted into a carton.
Pack sizes:
10, 14, 20, 28, 30, 50, 56, 100, 400 (20 x 20) tablets
Not all pack sizes may be marketed.
6.6 Special precautionsfor disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:
Date of latest renewal:
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
12/08/2013