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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Diuresal 500mg Tablets Furosemide Tablets BP 500mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains furosemide BP 500 mg.

3    PHARMACEUTICAL FORM

Tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Indicated in oliguria due to renal failure.

4.2    Posology and method of administration

Adults:

Initially 250mg daily; if necessary larger doses increasing in steps of 250mg may be given every 4 to 6 hours to a maximum of a single dose of 2g.

Elderly:

Furosemide is generally eliminated more slowly in the elderly. The dosage should be titrated until the required response is achieved.

Children:

No recommended dose.

Method of administration: Oral.

4.3. Contraindications

Furosemide is contraindicated in the following circumstances:

•    Hypersensitivity to furosemide, any of its excipients, sulphonamides, sulphonamide derivatives/amiloride

•    Anuria and impaired renal function (creatinine clearance below 30mL/min per 1.73 m2 body surface area) and renal failure resulting from poisoning by nephrotoxic and/or hepatotoxic agents

•    Electrolyte disturbances (severe hyponatraemia: severe hypokalaemia), dehydration and/or hypotension (see section 4.4)

•    Concomitant potassium supplements or potassium sparing diuretics (see section 4.5)

•    Pre-coma/coma associated with hepatic cirrhosis

•    Addison's disease

•    Digitalis intoxication (see also section 4.5)

•    Breast-feeding women (see section 4.6)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

Furosemide tablets 500mg should not be given to patients with normal renal function.

4.4 Special warnings and precautions for use

Hypotension and/or hypovolaemia (see also section 4.3)

Where indicated, steps should be taken to correct hypotension, hypovolaemia and any acid-base disturbances before commencing therapy.

Furosemide may cause hypokalaemia and hyponatraemia.

Increased calcium excretion may occur with patients on furosemide therapy. Latent

diabetes may become manifest or the insulin requirements of diabetic patients may increase.

Caution should be observed in patients liable to electrolyte deficiency. Hyperuricaemia may occur, and (in rare cases) clinical gout.

There may be aggravation of metabolic acidosis.

Dose titration/adjustment (see section 4.2). Patients with hypoproteinaemia (such as that associated with the nephotic syndrome) require careful dose titration (reduced furosemide effect: increased risk of ototoxicity)

•    In moderate liver congestion dosage adjustment may be needed

Caution required:

Caution needed in the following circumstances

•    impaired hepatic function (see section below - monitoring required)

•    impaired renal function and hepato-renal syndrome (see section 4.3 and below -monitoring required)

•    elderly patients

•    difficulty with micturition/potential obstruction in the urinary tract including prostatic hypertrophy (increased risk of acute retention).

•    gout (increased risk of hyperuricaemia)

•    patients at risk of pronounced falls in blood pressure

Clinical monitoring requirements (see also section 4.8):

Regular monitoring for

•    blood dyscrasias. If these occur, stop furosemide immediately

•    liver damage

•    idiosyncratic reactions

Laboratory monitoring requirements:

•    frequent BUN in first few months of treatment, periodically thereafter

•    Serum creatinine and urea levels tend to rise during treatment

•    Serum cholesterol and triglycerides may rise but usually return to normal within 6 months of starting furosemide

Other alterations in lab values

•    Furosemide should be discontinued before a glucose tolerance test

4.5 Interaction with other medicinal products and other forms of interaction

Antihypertensives - enhanced hypotensive effect possible with all types. Concurrent use with ACEinhibitors can result in marked falls in blood pressure. Furosemide should be stopped or the dose reduced before starting an ACE-inhibitor. There is a risk of a first-dose effect with post-synaptic alphablockers eg prazosin.

Antipsychotics - furosemide-induced hypokalaemia increases the risk of cardiac toxicity. Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with amisulpride or sertindole. Enhanced hypotensive effect with phenothiazines.

Anti-arrhythmics (including amiodarone, disopyramide, flecanaide and sotalol) - risk of cardiac toxicity (because of furosemide-induced hypokalaemia). The effects of lidocaine, tocainide or mexiletine may be antagonised by furosemide. Hypokalaemia or other electrolyte imbalance may increase the risk of ventricular arrhythmias with terfenadine, pimozide, thioridazine.

Drugs associated with QTprolongation - cardiac toxicity may be increased by furosemide-induced hypokalaemia and/or hypomagnesaemia.

Cardiac glycosides - hypokalaemia and electrolyte disturbances (including magnesium) increases the risk of cardiac toxicity.

Vasodilators - enhanced hypotensive effect with moxisylyte (thymoxamine) or hydralazine.

Renin inhibitors - aliskiren reduces plasma concentrations of furosemide.

Nitrates - enhanced hypotensive effect.

Lithium - Furosemide reduces lithium excretion with increased plasma lithium concentrations (risk of toxicity). Avoid concomitant administration unless plasma levels are monitored.

Chelating agents - sucralfate may decrease the gastro-intestinal absorption of furosemide - the 2 drugs should be taken at least 2 hours apart.

Lipid regulating drugs - Bile acid sequestrants (eg colestyramine: colestipol) -reduced absorption of furosemide - administer 2 to 3 hours apart.

NSAIDs - increased risk of nephrotoxicity (especially if there is hypovolaemia). Indometacin and ketorolac may antagonise the effects of furosemide.

Salicylates - effects may be potentiated by furosemide.

Antibiotics - increased risk of ototoxicity with aminoglycosides, polymixins or vancomycin. Increased risk of nephrotoxicity with aminoglycosides or cefaloridine. Furosemide can decrease vancomycin serum levels after cardiac surgery.

Antidepressants - enhanced hypotensive effect with MAOIs. Increased risk of postural hypotension with TCAs (tricyclic antidepressants). Possible increased risk of hypokalaemia with reboxetine.

Antidiabetics - hypoglycaemic effects antagonised by furosemide.

Insulin - requirements may be increased (see section 4.4).

Antiepileptics - increased risk of hyponatraemia with carbamazepine or aminoglutethimide. Diuretic effect reduced by phenytoin.

Antihistamines - hypokalaemia with increased risk of cardiac toxicity.

Antifungals - increased risk of hypokalaemia with amphoterecin.

Anxiolytics and hypnotics - enhanced hypotensive effect. Chloral hydrate or triclorfos may displace thyroid hormone from binding site.

CNS stimulants (drugs used for ADHD) - hypokalaemia increases the risk of ventricular arrhythmias.

Corticosteroids - diuretic effect antagonised (sodium retention), exacerbate potassium loss and increase risk of hypokalaemia.

Cytotoxics - increased risk of nephrotoxicity and ototoxicity with platinum compounds. There is a risk of ototoxic effects with the concomitant administration of cisplatin. In addition, nephrotoxicity of cisplatin may be enhanced if furosemide is not given in low doses (e.g. 40 mg in patients with normal renal function) and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

Other diuretics - profound diuresis possible when furosemide given with metolazone. Increased risk of hypokalaemia with thiazides.

Dopaminergics - enhanced hypotensive effect with levodopa.

Immunomodulators - enhanced hypotensive effect with aldesleukin.

Muscle relaxants - enhanced hypotensive effect with baclofen or tizanidine (see also Anaesthetic agents below - curare).

Oestrogens andprogestogens - diuretic effect antagonized.

Prostaglandins - enhanced hypotensive effect with alprostadil.

Sympathomimetics - increased risk of hypokalaemia with high doses of beta2 sympathomimetics (such as bambuterol, femoterol, salbutamol, salmeterol and terbutaline).

Theophylline - enhanced hypotensive effect.

Probenecid - reduced renal clearance of furosemide and decreased diuretic effect.

Anaesthetic agents - general anaesthetic agents may enhance the hypotensive effects of furosemide. The effects of curare may be enhanced by furosemide.

Alcohol - enhanced hypotensive effect.

Laxative abuse - increases the risk of potassium loss.

Liquorice - excess intake may increase the risk of hypokalaemia.

Carbenoxolone may increase the risk of developing hypokalaemia.

4.6. Fertility, pregnancy and lactation

The teratogenic and embryotoxic potential of furosemide in humans is unknown. There is little evidence of safety of high-dose furosemide in human pregnancy, although the results of animal work, in general, show no hazardous effects. The drug should not be used in pregnant women unless the benefits to the patient outweigh the possible risks to the foetus which includes persistence of patent ductus arteriosus (section 4.8). It may inhibit lactation and should be used with caution in nursing mothers.

4.7 Effects on ability to drive and use machines

Reduced alertness may impair ability to drive or operate machinery.

4.8 Undesirable effects

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); Frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Rare: bone marrow depression (withdrawal required), eosinophilia, leucopenia.

Frequency not known: aplastic anaemia, haemolytic anaemia, agranulocytosis, thrombocytopenia, vasculitis.

Metabolism and nutritional disorders:

Frequency not known: aggravated pre-existing metabolic alkalosis (in decompensated cirrhosis of the liver), fluid and electrolyte disturbances (hyponatraemia, hypokalaemia, hypomagnesaemia, hypochloraemic alkalosis), thirst, gout, hyperglycaemia, hypotension, hyperuricaemia, increases in serum cholesterol and triglyceride levels (see 4.4), reduced serum calcium levels and nephrocalcinosis in premature infants.

Nervous system disorders:

Rare: tetany, paraesthesia.

Frequency not known: headache, dizziness, confusion.

Eye disorders:

Frequency not known: blurred vision, yellow vision.

Ear and labyrinth disorders:

Frequency not known: tinnitus and reversible deafness (usually with large parenteral doses, rapid administration and in renal impairment).

Cardiac disorders:

Frequency not known: Hypotension, orthostatic intolerance, arrhythmias, increased risk or persistence of patent ductus arteriosus in premature infants.

Gastrointestinal disorders:

Frequency not known: Acute pancreatitis (in long-term diuretic treatment, including furosemide), nausea and gastro-intestinal disturbances.

Hepatobiliary disorders:

Frequency not known: intrahepatic cholestasis (jaundice).

Skin and subcutaneous tissue disorders:

Rare: exfoliative dermatitis, pruritus, photosensitivity, toxic epidermal necrolysis.

Frequency not known: allergic reactions, such as skin rashes, various forms of dermatitis including urticaria, bullous lesions, erythema multiforme, purpura. When these occur treatment should be withdrawn.

Musculoskeletal and connective tissue disorders:

Frequency not known: muscle cramps, weakness.

Renal and urinary disorders:

Rare: renal failure.

Frequency not known: interstitial nephritis, acute retention of urine.

General disorders and administration site conditions:

Rare: severe anaphylactoid or anaphylactic reactions (e.g. with shock).

Frequency not known: hypovolaemia, malaise, fever.

4.9. Overdose

Dehydration and electrolyte depletion will be caused, by excessive diuresis. Fluid replacement and correction of electrolyte imbalance will be necessary.

The drug should be discontinued and electrolyte and water replacement instituted immediately; adjustment should be on the basis of careful monitoring.

In cirrhotic patients, overdosage may precipitate hepatic coma.

5.1 Pharmacodynamic properties

Furosemide is a potent diuretic with rapid action. Its effects are evident within 30 minutes to 1 hour after oral dosage, and last for 4 to 6 hours. Furosemide inhibits the reabsorption of electrolytes in the ascending limb of the Loop of Henle and in the distal renal tubules. It may also have a direct effect in the proximal tubules. Excretion of sodium, potassium and chloride ions is increased and water excretion enhanced. It has no significant effect on carbonic anhydrase.

5.2 Pharmacokinetic properties

Furosemide is incompletely but fairly rapidly absorbed from the gastrointestinal tract; bioavailability has been reported to be about 60% to 70% but is reduced in renal failure. It has a biphasic half-life in the plasma with a terminal elimination phase that has been estimated to range up to about 1/ hours although it is prolonged in renal and hepatic insufficiency. It is up to 99% bound to plasma proteins and is mainly excreted in the urine, largely unchanged. Variable amounts are also excreted in the bile, non-renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in milk.

5.3 Preclinical safety data

Not required.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Starch

Certolake tartrazine Magnesium stearate Primojel

Colloidal silicon dioxide.

6.2 Incompatibilities

None reported.