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Torasemid Sandoz

Document: Torasemid Sandoz tablets ENG SmPC change

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCTS

Torasemid Sandoz, 2.5 mg tablets

Torasemid Sandoz, 5 mg tablets

Torasemid Sandoz, 10 mg tablets

Torasemid Sandoz, 20 mg tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Torasemid Sandoz, 2.5 mg tablets

Each tablet contains 2.5 mg torasemide.


Torasemid Sandoz, 5 mg tablets

Each tablet contains 5 mg torasemide.


Torasemid Sandoz, 10 mg tablets

Each tablet contains 10 mg torasemide.


Torasemid Sandoz, 20 mg tablets

Each tablet contains 20 mg torasemide.


For a full list of excipients, see section 6.1.


3. PHARMACEUTICAL form

Tablet


Torasemid Sandoz, 2.5 mg tablets

white to off-white, round tablet


Torasemid Sandoz, 5 mg tablets

white to off-white, round tablet with break notch

The tablet can be divided into equal halves.


Torasemid Sandoz, 10 mg tablets

white to off-white, round tablet with cross break notch

The tablet can be divided into equal halves.


Torasemid Sandoz, 20 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

Torasemid Sandoz, 2.5 mg/ - 5 mg tablets

Essential hypertension


Torasemid Sandoz, 5 mg/- 10 mg/- 20 mg tablets

Oedema in patients with heart failure


Posology and method of administration

Torasemid Sandoz, 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.


Torasemid Sandoz, 5 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.


Elderly

There are no deviating dosage recommendations for elderly. However there are insufficient comparative studies between older and younger patients.


Children (< 12 years)

There is no experience with torasemide in children (see 4.4 Special warnings and special precautions for use).


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 5.2 Pharmakokinetic properties).


Route 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 torasemide, to sulphonylureas or to any of the excipients;

Renal failure with anuria;

hepatic coma and pre-coma;

hypotension;

lactation


Special warnings and special 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 (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.


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:


The use of Torasemid Sandoz, may produce positive results in doping controls.


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 (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.


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 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.


The use of torasemide is therefore not recommended during breastfeeding.


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.


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.


Undesirable effects

The following undesirable effects can occur during therapy with Torasemid Sandoz,:


The following categories are the basis for the information on frequencies:

Very common: 10%

Common: 1% - < 10%

Uncommon: 0.1% - < 1%

Rare: 0.01% - < 0.1%

Very rare: < 0.01%

Not known: cannot be estimated from the available data


Metabolism and nutrition disorders

Common: Enhancement of metabolic alkalosis. Myospasm (particularly at the beginning of therapy). Increases in the concentration of uric acid and glucose in the blood and in blood fats (triglycerides, cholesterol). 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.


Depending on the dosage and duration of treatment, disorders in the water and electrolyte balance can occur, particularly e.g. hypovolaemia, hypokalaemia and/or hyponatraemia.


Cardiovascular disorders

Very rare: On account of haemoconcentration, thromboembolic complications, confusion, hypotension as well as cardiac and central circulation disorders (including ischaemia of heart and brain) can occur. These can lead to e.g. arrhythmias, angina pectoris, acute myocardial infarction or syncopes.


Gastrointestinal disorders

Common: Gastrointestinal disorders (e.g. inappetence, gastric pain, nausea, vomiting, diarrhoea, constipation), particularly at the beginning of treatment.

Very rare: Pancreatitis.


Renal and urinary disorders

Uncommon: Increase in the concentrations of creatinine and urea in the blood.

In patients with impaired micturition (e.g. due to prostatic hyperplasia), increased urinary production can lead to urinary retention and overexpansion of the bladder.


Hepatobiliary disorders

Common: Increase in certain liver enzyme concentrations (gamma-GT) in the blood.


Skin and subcutaneous tissue disorders

Very rare: Allergic reactions (e.g. pruritus, exanthema, photosensitivity), severe skin reactions.


Blood and lymphatic system disorders

Very rare: Reduction in thrombocytes, erythrocytes and/or leukocytes.


General disorders

Common: Headache, vertigo, fatigue, asthenia (particularly at the beginning of therapy).

Uncommon: Xerostomia, paraesthesia.

Very rare: Dysopia, tinnitus, hearing loss.


Note

Longer-term therapy with torasemide requires regular monitoring of the electrolyte balance, particularly serum potassium.


Glucose, uric acid, creatinine and lipids in the blood are to be monitored as well at regular intervals.


Since an increase in blood glucose can occur, careful monitoring of the carbohydrate balance is recommended in patients with latent or manifest diabetes mellitus.


The blood count (erythrocytes, leukocytes, thrombocytes) are also to be monitored at regular intervals.


Be aware of signs of electrolyte loss and haemoconcentration, particularly at the beginning of treatment and in elderly patients.


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: 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.


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).


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. (See 4.2 Posology and method of administration).


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.


2,5 mg, 5 mg and 20 mg tablets:

Pack sizes: 10, 14, 20, 28, 30, 50, 56, 100, 400 (20 x 20) tablets


10 mg tablets:

Pack sizes: 10, 14, 20, 28, 30, 50, 56, 98, 100, 400 (20 x 20) tablets


Not all pack sizes may be marketed.


6.6 Special Precautions for Disposal

No special requirements


7. MARKETING AUTHORISATION HOLDER

<[for Sweden only]>


Hexal AG

Industriestrasse 25

83607 Holzkirchen

Germany

Tel: +49 8024 908 0

Fax: +49 8024 908 1277


Sandoz A/S

Edvard Thomsens Vej 14

2300 Köpenhamn S

Denmark


8. MARKETING AUTHORISATION NUMBERS

<[for Sweden only]>


Torasemid Sandoz 2,5 mg tablets: 18236

Torasemid Sandoz 5 mgtablets: 18237

Torasemid Sandoz 10 mgtablets: 18238

Torasemid Sandoz 20 mgtablets: 18239



9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/07/2003


10. DATE OF REVISION OF THE TEXT

25/06/2012

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