Torasemide 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Torasemide 5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each torasemide tablet contains 5 mg torasemide.
Excipients with known effect:
Each 5 mg tablet contains 58.44 mg lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
Torasemide 5 mg Tablets are white to almost-white, round, biconvex tablets with a break line on one side and embossing 915 on the other side. They are 6mm in diameter.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Oedema due to congestive heart failure.
4.2 Posology and method of administration
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 is no information on dosage adjustments in older people. Experience is insufficient, however, to establish general recommendations.
Paediatric population
There is no experience with torasemide in children.
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.
4.3 Contraindications
Hypersensitivity to torasemide, to sulphonylureas or to any of the excipients;
renal failure with anuria;
hepatic coma and pre-coma;
hypotension;
lactation
4.4 Special warnings and precautions for use
Hypokalaemia, hyponatraemia and hypovolaemia must be corrected before treatment.
Disorders of micturition (e.g. Benign Prostatic Hyperplasia).
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 (in particular in patients with concomitant therapy with digitalis glycosides, glucocorticoids, mineralocorticoids or laxatives), glucose, uric acid, creatinine and lipids in the blood and the blood cells (red and white blood cells and platelets), is recommended.
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:
- Pathological changes of the acid-base balance,
- Concomitant treatment with lithium, aminoglycosides or cephalosporins
- Renal insufficiency due to nephrotoxic agents
- Children below 12 years.
- 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 of cisplatin preparations and the nephrotoxic effects of cephalosporins.
The action of curare-containing muscle relaxants and of theophylline can be potentiated.
Non-steroidal anti-inflammatory drugs (e.g. 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.
Lithium serum-concentrations and cardio- and neurotoxic effects of lithium may be increased.
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, pregnancy and lactation
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.
There is no information on the excretion of torasemide in human or animal breast milk.
Torasemide should not be used during breast-feeding.
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 effective dose should be used.
4.7 Effects on ability to drive and use machines
As for other medicinal products that produce 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.
4.8 Undesirable effects
Metabolism and nutrition disorders:
Depending on the dosage and duration of treatment, there may be disturbances of water and electrolyte balance, especially with markedly limited salt intake. Hypokalaemia may occur (especially if a low potassium diet is being taken, or if vomiting, diarrhoea, or excessive use of laxatives takes place, or in cases of hepatic failure).
Symptoms and signs of electrolyte and volume depletion, such as headache, dizziness, hypotension, weakness, drowsiness, confusional states, loss of appetite and cramps, can occur if diuresis is marked, especially at the start of treatment and in elderly patients. Dose adjustment may be necessary.
Raised serum uric acid, glucose and lipids can occur.
There may be aggravation of metabolic alkalosis.
Cardiac disorders/ Vascular disorders:
In isolated cases, thromboembolic complications and cardiac and central nervous system circulatory disturbances due to haemoconcentration (including cardiac and cerebral ischemia) may occur, leading to e.g. cardiac arrhythmias, angina pectoris, acute myocardial infarction or syncope.
Gastrointestinal disorders:
Patients may experience gastro-intestinal symptoms, e.g. loss of appetite, pain in the stomach, nausea, vomiting, diarrhoea, constipation.
Pancreatitis has been reported in isolated cases.
Renal and urinary disorders:
In patients with urinary outflow obstruction, retention of urine may be precipitated. Raised serum urea and creatinine may occur.
Hepato-biliary disorders: Increases in certain liver enzymes, eg. gamma-GT.
Blood and the lymphatic system disorders: Isolated cases of decreases in red and white blood cells and platelets have been reported.
Skin and subcutaneous tissue disorders:
In isolated cases, there may be allergic reactions, such as pruritis, rash and photosensitivity. Very rarely severe skin reactions may occur.
Nervous system disorders:
Common: Headache, dizziness, tiredness, weakness.
Isolated reports of visual disturbance.
Tinnitus and hearing loss have occurred in isolated cases.
Rarely, limb paraesthesia has been reported.
General disorders:
Dry mouth.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
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, high-ceiling diuretics, sulfonamides, plain ATC Code: C03 CA 04
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 100mg it has a log-proportional increase in diuretic activity.
5.2 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 litres (Vz: 16 l).
Metabolism: 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.
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 the foetus 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
6.1 List of excipients
Lactose monohydrate Maize starch
Sodium starch glycolate Type A Silica colloidal anhydrous Magnesium stearate
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C
6.5 Nature and contents of container
PVC /PVDC //Al blisters containing 14, 28, 30, 50, 100 or 112 tablets. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
PLIVA Pharma Limited Ridings Point Whistler Drive Castleford
West Yorkshire WF10 5HX
8 MARKETING AUTHORISATION NUMBER(S)
PL 10622/0098
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/01/2008
10 DATE OF REVISION OF THE TEXT
24/10/2013