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Document: spc-doc_PL 40147-0041 change

• spc-doc_PL 00289-0185
• spc-doc_PL 40147-0041

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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, hypovolaemia), 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 or encephalopathy

•    Addison's disease

•    Digitalis intoxication (see also section 4.5)

•    Breast-feeding women (see section 4.6)

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.

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

Particular caution and/or dose reduction required

• Symptomatic hypotension leading to dizziness, fainting or loss of

consciousness can occur in patients treated with furosemide, particularly the elderly, patients on other medications which can cause hypotension and patients with other medical conditions that are risks for hypotension.

•    impaired hepatic function (see sections 4.2 & 4.3 and below -monitoring required)

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

•    diabetes mellitus (latent diabetes may become overt: insulin requirements in established diabetes may increase)

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 electrolytes with replacement as appropriate

Other alterations in lab values

•    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

•    Furosemide should be discontinued before a glucose tolerance test

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

Antihypertensives - enhanced hypotensive effect possible with all types. Concurrent use with ACE inhibitors 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. Furosemide may interact with ACE inhibitors causing impaired renal function.

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.

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. In patients with dehydration or hypovolaemia, NSAIDs may cause acute renal insufficiency.

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.

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.

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 mental alertness may impair ability to drive or operate dangerous 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).

	category
Blood and lymphatic system disorders:	Uncommon:	aplastic anaemia
	Rare:	bone marrow depression (necessitates withdrawal of treatment), eosinophilia, leucopenia.
	Very rare:	haemolytic anaemia, agranulocytosis, thrombocytopenia, vasculitis.
Metabolism and nutritional disorders:	Very common:	dehydration, hyponatraemia, hypochloremic metabolic alkalosis, hypocalcaemia, hypomagnesemia (incidences of the last three are reduced by triamterene), nephrocalcinosis in infants
	Common:	Hypovolaemia, hypochloraemia
	Uncommon:	impaired glucose tolerance (by hypokalaemia) hyperuricaemia, gout, reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol, elevation of serum triglycerides, hyperglycaemia
	Very rare:	tetany
	Frequency not known:	aggravated pre-existing metabolic alkalosis (in decompensated cirrhosis of the liver), fluid and electrolyte disturbances, hyperglycaemia.
Psychiatric disorder:	Rare:	psychiatric disorder NOC
Nervous system disorders:	Rare:	paraesthesia, confusion, dizziness, headache,
	Not known:	dizziness, fainting and loss of consciousness (caused by symptomatic hypotension)
Eye disorders:	Uncommon:	visual disturbance, blurred vision, yellow vision
Ear and labyrinth disorders:	Uncommon:	deafness (sometimes irreversible)
	Rare:	tinnitus and reversible or irreversible loss of hearing (although usually transitory, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome)
Cardiac disorders:	Uncommon:	orthostatic intolerance, cardiac arrhythmias, increased risk or persistence of patent ductus arteriosus in premature infants.
Vascular disorders:	Very common:	decreased blood pressure, (which, if pronounced may cause signs and symptoms

		such as impairment of concentration and reactions, light-headedness, sensations of pressure in the head, headache, dizziness, drowsiness, weakness, disorders of vision, dry mouth, orthostatic intolerance).
	Uncommon:	hypotension, hypovolaemia
	Rare:	vasculitis, thrombosis, shock
Gastrointestinal disorders:	Uncommon:	dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhoea, constipation
	Rare:	acute pancreatitis (in long-term diuretic treatment, including furosemide).
Hepatobiliary disorders:	Rare:	pure intrahepatic cholestasis (jaundice), hepatic function abnormal.
Skin and subcutaneous tissue disorders:	Uncommon:	acute generalised exanthematous pustulosis (AGEP)
	Rare:	rash, pruritus, photosensitivity, toxic epidermal necrolysis.
	Frequency not known:	urticaria, erythema multiforme, purpura, exfoliative dermatitis, itching, allergic reactions, such as skin rashes, various forms of dermatitis including urticaria, bullous lesions. When these occur treatment should be withdrawn. DRESS (Drug rash with eosinophilia and systemic symptoms)
Musculoskeletal and connective tissue disorders:	Uncommon:	muscle cramps, muscle weakness.
Renal and urinary disorders:	Uncommon:	reduced diuresis, urinary incontinence, urinary obstruction (in patients with hyperplasia of the prostate, bladder inability to empty, urethral stricture unspecified).
	Rare:	nephrocalcinosis (in pre-term infants treated with Furosemide), interstitial nephritis, acute renal failure.
Congenital, familial and genetic disorders:	Rare:	patent ductus arteriosus
General disorders and administration site conditions:	Uncommon:	Fatigue
	Rare:	malaise, fever, severe anaphylactoid or anaphylactic reactions (e.g. with shock).

	Frequency not known:	hypovolaemia,
Investigations:	Common:	creatinine increased, blood urea increased
	Rare:	Transaminases increased, blood

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 include dehydration, electrolyte depletion and hypotension due to excessive diuresis. In cirrhotic patients, overdosage may precipitate hepatic coma.

Treatment should be aimed at fluid replacement and correction of the electrolyte imbalance. The drug should be discontinued and electrolyte and water replacement instituted immediately; adjustment should be on the basis of careful monitoring.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC code: CO3C A01

The evidence from many experimental studies suggests that furosemide acts along the entire nephron with the exception of the distal exchange site. The main effect is on the ascending limb of the loop of Henley with a complex effect on renal circulation. Blood-flow is diverted from the juxta-medullary region to the outer cortex.

The principle renal action of furosemide is to inhibit active chloride transport in the thick ascending limb. Re-absorption of sodium chloride from the nephron is reduced and a hypotonic or isotonic urine produced.

It has been established that prostaglandin (PG) biosynthesis and the renin-angiotensin system are affected by furosemide administration and that furosemide alters the renal permeability of the glomerulus to serum proteins.

5.2 Pharmacokinetic properties

Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastrointestinal tract. Furosemide is rapidly but incompletely absorbed (60-70%) on oral administration and its effect is largely over within 4 hours. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration 69-97% of activity from a radio-labelled dose is excreted in the first 4 hours after the drug is given. Furosemide is bound to plasma albumin and little biotransformation takes place. Furosemide is mainly eliminated via the kidneys (80-90%); a small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces.

In renal/ hepatic impairment

Where liver disease is present, biliary elimination is reduced up to 50%. Renal impairment has little effect on the elimination rate of furosemide, but less than 20% residual renal function increases the elimination time.

The elderly

The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.

New born

A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.

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.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Store in a cool dry place and protect from light.