SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Teva Torasemide 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg of torasemide.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablet

White to off white, oval shaped tablet, scored and debossed “9” and “3” on each side of the score; on the other side debossed “7127”.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential hypertension; oedema due to congestive heart failure; hepatic, pulmonary or renal oedema.

4.2. Posology and Method of Administration

Adults

Essential hypertension: A dose of 2.5 mg torasemide p.o. once daily is recommended. If necessary, the dose may be increased to 5 mg once daily. Studies suggest that doses above 5 mg daily will not lead to further reduction in blood pressure. The maximum effect is exhibited after approximately 12 weeks of continuous treatment.

Oedema: The usual dose is 5 mg p.o. once daily. If necessary, the dose can be increased stepwise up to 20 mg once daily. In individual cases, as much as 40 mg torasemide/day has been administered.

Elderly

No special dosage adjustments are necessary.

Children

There is no experience of torasemide in children.

4.3. Contraindications

Renal failure with anuria; hepatic coma and pre-coma; hypotension; pregnancy and lactation; hypersensitivity to torasemide and sulphonylureas; cardiac arrhythmias, simultaneous therapy with aminoglycosides or cephalosporins, or renal dysfunction due to drugs which cause renal damage.

4.4. Special warnings and precautions for use

Hypokalaemia, hyponatraemia, hypovolaemia and disorders of micturition must be corrected before treatment.

On long-term treatment with torasemide, regular monitoring of the electrolyte balance, glucose, uric acid, creatinine and lipids in the blood, 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.

As for other drugs which produce changes in blood pressure, patients taking torasemide should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

Patients with rare hereditary problems of glucose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicine.

4.5. Interactions with other Medicaments 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 drugs. The kaliuretic effect of mineralo-and glucocorticoids and laxatives may be increased.

As with other diuretics, the effect of antihypertensive drugs given concomitantly may be potentiated.

Torasemide, especially at high doses, may potentiate the toxicity of aminoglycoside antibiotics, cisplatin preparations, the nephrotoxic effects of cephalosporins, and the cardio-and neurotoxic effect of lithium. The action of curare-containing muscle relaxants and of theophylline can be potentiated. In patients receiving high doses of salicylates, salicylate toxicity may be increased. The action of anti-diabetic drugs may be reduced.

Sequential or combined treatment, or starting a new co-medication with an ACE inhibitor may result in transient hypotension. This may be minimised by lowering the starting dose of the ACE inhibitor and/or reducing or stopping temporarily the dose of torasemide. Torasemide may decrease arterial responsiveness to pressor agents e.g. adrenaline, noradrenaline.

Non-steroidal anti-inflammatory drugs (e.g Indometacin) and probenecid may reduce the diuretic and hypotensive effect of torasemide.

Concomitant use of torasemide and colestyramine has not been studied in humans, but in an animal study coadministration of colestyramine decreased absorption of oral torasemide.

4.6. 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, malformed foetuses have been observed after high doses in pregnant rabbits. No studies have been conducted on excretion in breast milk. Consequently, torasemide is contra-indicated in pregnancy and lactation.

4.7. Effects on Ability to Drive and Use Machines

As for other drugs which produce changes in blood pressure, patients taking torasemide should be warned not to drive or operate machinery if they experience dizziness or related symptoms.

4.8. Undesirable Effects

Related to diuretic action

As with other diuretics, depending on the dosage and duration of treatment, there may be disturbances of water and electrolyte balance, especially with markedly limited salt intake.

Hypokalaemia (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); raised serum uric acid, gamma GT, glucose or lipids; aggravation of metabolic acidosis. Raised serum urea and creatinine; dryness of the mouth.

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 acid, glucose and lipids can occur.

There may be aggravation of metabolic alkalosis.

Cardiovascular system

In isolated cases, thromboembolic complications and circulatory disturbances due to

haemoconcentration may occur.

Gastro-Intestinal system

Patients may experience gastro-intestinal symptoms.

Pancreatitis has been reported in isolated cases.

Renal and Urinary system

In patients with urinary outflow obstruction, retention of urine may be precipitated.

Raised serum urea and creatinine may occur.

Liver

Increases in certain liver enzymes, e.g. gamma-GT.

Haematology

Isolated cases of decreases in red and white blood cells and platelets have been reported.

Skin/allergy

In isolated cases, there may be allergic reactions, such as pruritis, rash and photosensitivity.

Nervous system:

Isolated reports of visual disturbance.

Tinnitus and hearing loss have occurred in isolated cases.

Rarely, limb paraesthesia has been reported.

Others:

Dry mouth.

4.9. Overdose

Symptoms and signs

No typical picture of intoxication is known. If overdosage occurs, then there may be marked diuresis with the danger of loss of fluid and electrolytes which may lead to somnolence and confusion, hypotension, circulatory collapse. Gastrointestinal disturbances may occur.

Treatment

No specific antidote is known. Symptoms and signs of overdosage require the reduction of the dose or withdrawal of torasemide, and simultaneous replacement of fluid and electrolytes.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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.

5.2. Pharmacokinetic Properties

Absorption

Torasemide is absorbed rapidly and almost completely after oral administration, and peak serum levels are reached after 1-2 hours.

Serum protein binding

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

Distribution

The apparent distribution volume is 16 litres.

Metabolism

Torasemide is metabolised to three metabolites, M1, M3 and M5 by stepwise oxidation, hydroxylation or ring hydroxylation.

Elimination

The terminal half-life of torasemide and its metabolites is 3-4 hours in healthy subjects. Total clearance of torasemide is 40ml/min and renal clearance about 10ml/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, elimination half-life of torasemide is unchanged.

5.3. Preclinical Safety Data

Acute toxicity

Very low toxicity.

Chronic toxicity

The changes observed in toxicity studies in dogs and rats at high doses are 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 drug induced changes were shown to be reversible.

Teratogenicity

Reproduction toxicology studies in the rat have shown no teratogenic effect, but malformed foetuses have been observed after high doses in pregnant rabbits. No effects on fertility have been seen.

Torasemide showed no mutagenic potential. Carcinogenicity studies in rats and mice showed no tumorigenic potential.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Lactose anhydrous

Crospovidone

Povidone

Microcrystalline cellulose Magnesium stearate

6.2. Incompatibilities

Not applicable.

6.3. Shelf life

3 years.

Special precautions for storage

No special precautions required.

6.5.    Nature and contents of container

Aluminium-aluminium PVC blisters containing 20, 28, 30, 50, 100, 400 (20 x 20)¹ tablets.

Not all pack sizes may be marketed.

6.6.    Instruction for use and handling

Not applicable.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Ltd

Brampton Road, Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 00289/0447

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12 August 2003

10 DATE OF REVISION OF THE TEXT

15/09/2008

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Hospital packs