4.1. Therapeutic indications

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

4.2. Posology and method of administration

Adults

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

Special populations

Elderly

No special dosage adjustments are necessary.

Children

There is no experience of torasemide in children.

Patients with hepatic impairment

As elimination half-lives of torasemide and its metabolites in patients with mild to moderate hepatic impairment are only slightly increased, dose adjustment in these patients is not required. Special caution is required for patients with hepatic cirrhosis and ascites (see 4.4). Extreme caution is required when torasemide is administered in patients with a history of hepatic encephalopathy.

Method of administration

Torasemide tablets are intended to be administered by oral route. Tablets must be swallowed with some fluid without chewing. For convenience, the tablets should be taken in the morning.

4.3. Contraindications

Torasemide is contraindicated for patients with:-

• Hypersensitivity to the active substances, sulphonamides (“sulfa drugs”) or to any of the excipients listed in section 6.1.

• Anuria with renal failure.

• Hepatic coma until the condition is improved or corrected.

• Hypotension

• Pre-existing hypovolaemia

• Cardiac arrhythmias

• Simultaneous therapy with aminoglycosides or cephalosporins

• Renal dysfunction due to drugs which cause renal damage

4.4. Special warnings and precautions for use

Torasemide may lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required, and dose schedules have to be adjusted to the individual patient's needs. Especially at the start of the treatment and in elderly, patients must be carefully monitored.

Regular blood monitoring of the electrolyte balance, potassium values and the parameters glucose, uric acid, and creatinine should be carried out especially during long-term treatment with torasemide for signs of electrolyte and volume deficiency and haemoconcentration.

Urine retention must be corrected before or during treatment with torasemide. Extreme caution is required when torasemide is administered in patients suffering from severe urine retention. Patients with partial occlusion of the urinary tract must be closely monitored.

There is an increased risk of gout attacks with patients taking diuretics. Caution is required when torasemide is administered in patients with gout.

Carbohydrate metabolism in latent or manifest diabetes mellitus should be monitored.

In nephrotic syndrome, treatment of the primary disease should take precedence.

In patients with hepatic cirrhosis and ascites, it is recommended that diuresis with any drug be initiated in the hospital. Too rapid diuresis in such patients can precipitate severe electrolyte disturbances and hepatic coma. Extreme caution is required when torasemide is administered in patients with a history of hepatic encephalopathy. The concomitant use of an aldosterone antagonist or a potassium-sparing drug is recommended to prevent hypokalemia and metabolic alkalosis.

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.

Torasemide might cause hypokalaemia that has prominent effects on cardiac, skeletal, and intestinal muscle cells. In particular, it is a major risk factor for both ventricular and atrial arrhythmias. Therefore the potassium level of patients must be closely monitored during treatment with torasemide. Existing hypokalemia or hypokalemia developing during torasemide treatment has to be corrected.

Low levels of sodium must be corrected before or during treatment with torasemide.

Hypovolemia must be corrected before or during treatment with torasemide. Torasemide must only be given in exceptional cases to patients with hypovolemia under close monitoring.

Loop diuretics worsen existing hypotension. In case, diuretic treatment is required in hypotensive patients with oedema, hypotension must be corrected before or during treatment with torasemide

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

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 drugs. The potassium-depleting effect of mineralo- and glucocorticoids and laxatives may be increased.

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

Combination of loop diuretics with ACE inhibitors or AT2 antagonists may cause severe hypotension.

The risk of ACE-induced renal impairment may be increased.

Torasemide, especially at high doses, may potentiate the phototoxicity and nephrotoxic effects of aminoglycoside antibiotics, cytostatic platinum derivatives the nephrotoxic effects of cephalosporins, and the cardio-and neurotoxic effect of lithium. In patients receiving high doses of salicylates, salicylate toxicity may be increased. The action of anti-diabetic drugs may be reduced. Additionally, the risk of recurrent gout attacks is increased in patients taking salicylates.

Torasemide is a substrate for Cytochrome P450 CYP2C8 and CYP2C9. A mutual interaction between ligands for the same enzyme might occur. Therefore, co-medication that is also affected by these Cytochrome isoforms should be monitored closely to avoid unwanted plasma levels of these drugs. This interaction has been established for coumarin derivates. The possibility of Drug-Drug interaction may be crucial with drugs that have a narrow therapeutic range.

The antihypertensive and diuretic effects of loop diuretics appear to be reduced by NSAIDs. Diuretics may increase the risk of NSAID-induced acute renal failure.

Probenecid may reduce the diuretic effect of torasemide.

The effect of some muscle relaxants and the plasma level of theophylline may be influenced (increase or decrease possible). Monitoring of theophylline plasma levels is recommended.

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

Simultaneous use of alcohol and torasemide may cause dizziness or other related symptoms.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is insufficient data from the use of torasemide in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Torasemide should not be used during pregnancy, unless the clinical condition of the woman requires treatment with torasemide.

Breastfeeding

There is insufficient information on the excretion of torasemide in human milk. A risk to the suckling child cannot be excluded. Loop diuretics may suppress lactation. A decision should be made whether to discontinue breast-feeding or to discontinue from torasemide therapy taking into account the benefit of breast feeding for the child and the benefit of the therapy for the woman.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from available data)

The following undesirable effects were observed:

Blood and lymphatic system disorders

Frequency not known: Thrombocytopenia, Leukopenia, Anaemia

Immune system disorders

Very rare: Allergic skin reactions (eg Pruritus, Exanthema), Photosensitivity reaction

Frequency not known: Serious skin reactions (eg Stevens-Johnson syndrome, Toxic epidermal necrolysis

Metabolism and nutrition disorders

Common: Metabolic alkalosis, Fluid and electrolyte imbalance (eg Hypovolaemia, Hyponatraemia)

Nervous system disorders

Common: Headache, Dizziness

Frequency not known: Cerebral ischaemia, Parenthesia, confusional state

Eye disorders

Frequency not known: Visual impairment

Ear and labyrinth disorders

Frequency not known: tinnitus, Deafness

Cardiac disorders

Frequency not known: Acute myocardial infarction, Myocardial ischaemia, Angina pertoris, Syncope, Hypotension

Vascular disorders

Frequency not known: Embolism

Gastrointestinal disorders

Common: Gastrointestinal disorder (e.g. Loss of appetite, abdominal pain upper, Nausea, Vomiting, Diarrhoea, Constipation)

Frequency not known: Dry mouth, Pancreatitis

Hepatobiliary disorders

Uncommon: Hepatic enzyme increased (e.g. Gamma-glutamyltransferase increased)

Skin and subcutaneous tissue disorders

Very rare: Allergic skin reactions (e.g. Pruritus, Exanthema), Photosensitivity reaction

Frequency not known: Serious skin reactions (e.g. Stevens-Johnson syndrome, Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Common: Muscle spasms

Renal and urinary disorders

Uncommon: Urinary retention, Bladder dilatation

Rare: Blood urea increased, Blood creatinine increased

General disorders and administration site conditions

Common: Fatigue, Asthenia

Investigations

Uncommon: Blood uric acid increased, Blood glucose increased, Lipids increased (e.g. Blood triglycerides increased, Blood cholesterol increased)

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

Signs and symptoms of overdosage are those of excessive pharmacologic effects. If overdosage occurs, then there may be marked diuresis with the danger of loss of fluid and electrolytes which may lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. Gastrointestinal disturbances may occur.

Treatment

No specific antidote is known. No data are available to suggest physiological manoeuvres (e.g., manoeuvers to change the pH of the urine) that might accelerate elimination of torasemide and its metabolites. Torasemide is not dialyzable, so haemodialysis will not accelerate elimination. Symptoms and signs of overdosage require the reduction of the dose or withdrawal of torasemide, and simultaneous replacement of fluid and electrolytes.