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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[Nationally completed name] 50 mg tablets [Nationally completed name] 100 mg tablets [Nationally completed name] 200 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg of torasemide.

Each tablet contains 100 mg of torasemide.

Each tablet contains 200 mg of torasemide.

For excipients, see section 6.1

3. PHARMACEUTICAL FORM

Tablet.

50 mg tablets: White to off-white round tablet.

100 mg tablets: White to off-white round tablet with break notch. The tablet can be divided into equal doses.

200 mg tablets: White to off-white round tablet with cross break notch on both sides. The tablet can be divided into four equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

The administration of [Nationally completed name] 50 mg/- 100 mg/- 200 mg tablets is exclusively indicated in patients with highly reduced renal function (creatinine clearance less than 20 ml/min and/or serum creatinine concentration greater than 6 mg/dl). For maintenance of residual diuresis in case of severe renal insufficiency – even on dialysis if there is a considerable residual diuresis (more than 200 ml/24 hours) – if oedemas, effusions and/or hypertension exist.

Note: [Nationally completed name] 50 mg/- 100 mg/- 200 mg tablets tablets are to be used only in case of highly impaired and not in normal renal function.

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4.2 Posology and method of administration

Posology

Adults Individual dose depending on the degree of renal function impairment. The therapy should be started with 50 mg torasemide a day. If the dose of 50 mg does not yield an adequate response, the dose may be increased to 100 mg torasemide a day and, if necessary, gradually increased thereafter to a maximum of 200 mg once daily, preferably at breakfast time. The highest daily dose to have been used in long-term treatment is 200 mg. Daily doses of 200 mg should only be used in patients with severe renal insufficiency (creatinine- clearance < 20 ml/min and/or creatinine-levels > 530 µmol/l). It should be confirmed that diuresis is at least 200ml/ 24 h.

Elderly No dose adjustments are necessary.

Hepatic insufficiency Caution should be exercised in patients with hepatic insufficiency since plasma concentrations might be increased (see section 5.2). Experience is, however, insufficient to establish general recommendations in this patient population.

Paediatric population There is no experience of use of torasemide in children below the age of 12 years.

For doses not realisable/practicable with this strength other strengths of this medicinal product are available.

Method of administration

For oral use.

4.3 Contraindications

 Hypersensitivity to the active substance and sulfonylureas or to any of the excipients listed in section 6.1  Renal insufficiency with anuria  Hepatic coma (until the improvement of this condition)  Hypotension  Hypovolaemia  Hyponatriaemia  Hypokalaemia  Severe micturition disorders (e.g. due to prostatic hyperplasia)  Normal or only moderately impaired renal function (creatinine clearance > 30 ml/min and/or serum creatinine levels < 3.5 mg/dl), since there is the risk of excessive water and electrolyte losses.  Lactation (see section 4.6)  Gout  Cardiac arrhythmias (e.g. sino-atrial-block, atrioventricular-block second or third degree)  Concomitant treatment with aminoglycosides or cephalosporins 2 | Page Sandoz Business use only Page 3 of 9 1.3.1 spc-label-pl - common-spc – 11,006 20191218 (DE/H/1772/001-002-003 – 155347 - validation) TORASEMIDE 100 MG, 200 MG, 50 MG, TABLET 721-6534.01, 721-6535.01, 721-6536.01

 Renal insufficiency due to nephrotoxic agents

4.4 Special warnings and precautions for use

Due to insufficient experience with torasemide treatment, torasemide should not be used in:  Pathological changes of the acid-base balance  Pathological changes of the blood cells (e.g. thrombocytopenia or anaemia in patients without renal insufficiency)  Creatinine clearance between 20 ml/min – 30 ml/min and/or serum creatinine levels between 3.5 mg/dl – 6 mg/dl

Micturition disorders must be corrected prior treatment start with torasemide.

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 counts (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 older patients.

In patients with arrhythmias, the administration of loop diuretics may be potentially life-threatening due to changes in electrolyte levels (potassium, sodium, calcium, and magnesium). There should be regular blood control of the electrolyte composition.

The use of [Nationally completed name] may produce positive results in doping controls. The possible health effects of using [Nationally completed name] as a doping agent cannot be predicted, severe health hazards cannot be excluded.

4.5 Interaction with other medicinal products and other forms of interaction

The following interactions of this medicinal product must be considered:

Torasemide may reduce the effect of antidiabetics.

Torasemide enhances the effect of other antihypertensive medicinal products, particularly that of ACE inhibitors. If ACE inhibitors are given in addition or directly following therapy with torasemide, the blood pressure can fall excessively. The risk of ACE-induced renal insufficiency may be increased.

Torasemide-induced hypokalaemia can enhance and increase the incidence of adverse events of concomitantly administered digitalis preparations (risk of intoxication).

Concomitant colestyramine therapy may reduce absorption and hence efficacy of orally administered torasemide.

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The action of curare-containing muscle relaxants and of theophylline can be influenced (potentiated or attenuated) by torasemide. Monitoring of serum theophylline levels is recommended.

The kaliuretic effect of mineralo-and glucocorticoids and laxatives may be increased.

In concomitant use of torasemide and lithium serum-concentrations and hence effects and adverse events of lithium may be increased.

Probenecid and anti-inflammatory agents of the NSAID type (e.g. indomethacin, propionic acid derivatives or acetylsalicylic acid) may reduce the diuretic and antihypertensive effects of torasemide. Diuretics may increase the risk of NSAID-induced renal failure.

In high dose salicylate therapy, torasemide may enhance the neurotoxic effects of salicylate. In addition, the risk of recurrent gout attacks is increased in patients taking salicylates.

Torasemide, especially at high doses, may enhance the following adverse events: Ototoxic and nephrotoxic effects of aminoglycoside antibiotics (e.g. kanamycin, gentamicin, tobramycin), cytotoxicity of platin derivatives and the nephrotoxic effects of cephalosporins.

Torasemide may reduce the vasoconstrictive effects of catecholamines (e.g. adrenalin, noradrenalin).

Torasemide is a substrate for cytochrome P450 CYP2C8 and CYP2C9. There may be an interaction between the ligands for the same enzyme. Therefore, concomitant administration of medicinal products that are also catalyzed by these cytochrome isoforms should be closely monitored to avoid undesirable serum levels of these medicinal products. This interaction has been demonstrated for coumarin derivatives. The potential for drug-drug interaction may be critical for substances with a narrow therapeutic range.

4.6 Fertility, pregnancy and lactation

Pregnancy There is insufficient clinical experience in humans on the effect of torasemide on the embryo and foetus. Animal studies have shown reproductive toxicity. In animal studies torasemide passed the placenta (see section 5.3).

Until further experience is available, torasemide must only be given during pregnancy in compelling indication. The lowest effective dose should be used.

Diuretics are not suited for routine therapy of hypertension and oedema during pregnancy, since they can impair placental perfusion and thus intrauterine growth. If, in case of cardiac or renal insufficiency, torasemide must be administered to a pregnant woman, electrolytes and haematocrit as well as foetal growth must be thoroughly monitored.

Breast-feeding There is insufficient information on whether torasemide passes into breast milk. A risk for the newborn/child can not be excluded. Loop diuretics can reduce milk production. Therefore, torasemide must not be used during breast-feeding (see section 4.3). A decision must be made as to whether breast-feeding should be interrupted or whether treatment with torasemide should be discontinued. Both the benefits of breast-feeding for the child and the benefits of the therapy for the woman should be considered.

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4.7 Effects on ability to drive and use machines

Even if used as intended, torasemide can alter reactivity to such an extent that the ability to drive, use machines or work in potentially hazardous situations is impaired. This applies in particular at the beginning of the therapy, when increasing the dose, changing the preparation, initiating additional medication or when concomitantly ingesting alcohol.

4.8 Undesirable effects

The following adverse reactions may occur during treatment with torasemide.

The following frequencies are used for the description of the occurrence of adverse reactions:

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) Not known (frequency cannot be estimated from the available data)

Blood and lymphatic system disorders: Very rare: Reduction in thrombocytes, erythrocytes and/or leukocytes.

Immune system disorders: Very rare: Allergic reactions (e.g. pruritus, exanthema, photosensitivity), severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis).

Metabolism and nutrition disorders: Common: Enhancement of metabolic alkalosis. 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 dose and duration of treatment, disorders in the water and electrolyte balance can occur, particularly e.g. hypovolaemia, hypokalaemia and/or hyponatraemia.

Nervous system disorders: Common: Headache, vertigo. Uncommon: Paraesthesia. Not known: Cerebral ischaemia, confusion.

Eye disorders: Very rare: Visual disturbances.

Ear and labyrinth disorders: Very rare: Tinnitus, hearing loss.

Cardiac disorders:

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

Vascular disorders: Very rare: Thromboembolic complications due to hemoconcentration.

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

Hepatobiliary disorders: Common: Increases in certain liver enzyme concentrations (gamma-glutamyltransferase) in the blood.

Musculoskeletal and connective tissue disorders: Common: Myospasm (particularly at the beginning of therapy).

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.

General disorders and administration site conditions: Common: Fatigue, asthenia (particularly at the beginning of therapy).

Investigations: Common: Increases in the concentration of uric acid and glucose in the blood and in blood lipids (triglycerides, cholesterol).

Effect on laboratory parameters Potassium Following administration of 2.5 mg and 5 mg torasemide over 12 to 14 weeks the mean decrease in serum concentration was 0.2 to 0.3 mM/l. The maximum average decrease was 0.39 mM/l after 6 weeks administration of 10 mg torasemide and 0.42 mM/l after 6 weeks administration of 40 mg torasemide (see section 4.4).

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 listed in Appendix V*.

[*For the printed material, please refer to the guidance of the annotated QRD template.]

4.9 Overdose

Symptoms of intoxication

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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 which may lead to somnolence and confusion, hypotension, circulatory collapse. Gastrointestinal disturbances may occur.

Treatment of intoxication No specific antidote is known. Symptoms and signs of overdose subside with the reduction of the dose or withdrawal of torasemide, and simultaneous replacement of fluid and electrolytes (control!).

Torasemide is not dialyzable; haemodialysis does not accelerate its elimination. Therapy in case of hypovolaemia: volume substitution Therapy in case of hypokalaemia: potassium substitution Therapy in case of circulatory collapse: shock positioning, if necessary, shock therapy

Immediate measures in case of anaphylactic shock: At first signs (e.g. cutaneous reactions such as urticaria or flush, restlessness, headache, extensive perspiration, nausea, cyanosis):  create venous access  besides other usual emergency measures, head-chest down position, maintain patent airways, application of oxygen  if necessary, further, even intensive care measures (including administration of adrenaline, volume substitutes, glucocorticoid) should be initiated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: High-ceiling diuretics, sulfonamides, plain, ATC code: C03CA04

Torasemide, a sulfonamide derivative, is effective through inhibition of absorption of sodium and chloride in the ascending limb of the loop of Henley. With diuresis there is increased excretion of potassium and magnesium. The onset of the diuretic effect occurs within 1 hour, the maximum effect is apparent after 2 – 3 hours and may last up to 12 hours. The maximum blood pressure-lowering effect after repeated administration is seen after up to 10 –12 weeks. Torasemide is a loop diuretic and, at the dose used for antihypertensive treatment, has a weak diuretic and saluretic effect. The blood pressure-lowering effects are not correlated with diuresis or excretion of electrolytes. In healthy volunteers, increased diuresis proportional to the logarithm of the dose (“high-ceiling activity”) was observed in the dose range 5-100 mg. Diuresis can also increase if other diuretics (e.g. distal thiazides) are no longer sufficiently effective, e.g. in case of impaired renal function. In patients with severe up to terminal chronic renal failure, torasemide causes leachate of oedema and lowering of increased arterial blood pressure.

5.2 Pharmacokinetic properties

Absorption and distribution The bioavailability of torasemide is 80-90%. Peak serum concentrations are reached after 1-2 hours and the volume of distribution is approximately 16 litres. Total clearance is approximately 40 ml/minute with renal clearance accounting for approximately 25%.

Torasemide is bound to plasma proteins at more than 99%, the metabolites M1, M3 and M5 are bound at 86%, 95% and 97%. 7 | Page Sandoz Business use only Page 8 of 9 1.3.1 spc-label-pl - common-spc – 11,006 20191218 (DE/H/1772/001-002-003 – 155347 - validation) TORASEMIDE 100 MG, 200 MG, 50 MG, TABLET 721-6534.01, 721-6535.01, 721-6536.01

Biotransformation In humans, torasemide is metabolised to the three metabolites M1, M3 and M5.

Elimination Following oral administration the half-life of torasemide is approximately 3 hours. Torasemide is eliminated by hepatic metabolism and renal excretion of the unchanged substance and its metabolites. About 80% of a dose is excreted in the form of torasemide and its metabolites by way of renal tubular secretion with the following distribution: Torasemide approx. 24 %, metabolite M1 approx. 12 %, metabolite M3 approx. 3 %, metabolite M5 approx. 41 %. The main metabolite M5 is diuretically inactive, while M1 and M3 are to some degree active.

In case of renal insufficiency, total clearance and the elimination half-life of torasemide are unchanged, but the half-life of M3 and M5 is prolonged. The duration of effect is not influenced by the severity of renal insufficiency. Torasemide and its metabolites are not significantly eliminated via haemodialysis or haemofiltration.

In patients with hepatic dysfunction or e. g. cardiac insufficiency, elevated plasma concentrations have been reported and the elimination half-lives of torasemide and metabolite M5 are slightly prolonged, but the quantities of the substance excreted in urine largely correspond to those in healthy persons.

Accumulation is not expected.

Linearity Torasemide and its metabolites are characterised by kinetics linear to the dose, i.e. maximum serum concentrations and areas under the serum level curves increase in proportion to the dose.

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 active substance induced changes were shown to be reversible.

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Microcrystalline cellulose Copovidone Crospovidone Hydrogenated castor oil Magnesium stearate Mannitol (E 421) Colloidal anhydrous silica

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6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years

6.4 Special precautions for storage Do not store above 25 °C.

6.5 Nature and contents of container The tablets are packed in alu/PVC/COC/PVDC blisters or alu/alu blisters and inserted into a carton.

50 mg tablets: Pack sizes: 10, 20, 30, 50, 60, 70, 80, 90, 100, 400 (20 x 20) tablets 100 mg tablets: Pack sizes: 10, 20, 30, 50, 60, 70, 80, 90, 100, 400 (20 x 20) tablets 200 mg tablets: Pack sizes: 10, 20, 30, 50, 100, 400 (20 x 20) tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY} Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT {MM/YYYY} [To be completed nationally]

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