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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Furosemide 20 mg Tablets BP.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20mg Furosemide Ph.Eur.

Excipient(s) with known effect:

Also contains lactose monohydrate.

For full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

Appearance: White circular tablet with a breakline on one side

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

In the treatment of oedema associated with congestive heart failure, cirrhosis of the liver, renal disease including nephrotic syndrome.

In the treatment of peripheral oedema due to mild to moderate hypertension (alone, or in combination with other antihypertensive agents in the treatment of more severe cases).

Management of oliguria due to acute or chronic renal insufficiency.

Posology and method of administration

Adults and children over 12 years:

Oedema: Initially 40mg daily in the morning; ordinarily a prompt diuresis ensues and the starting dose can then be maintained or even reduced. Diuresis lasts for approximately four hours following administration and hence the time of administration can be adjusted to suit the patient's requirements. Maintenance dose is 20mg daily or 40mg on alternate days, increased in resistant oedema to 80mg daily.

Hypertension: 20-40mg twice daily; if 40mg twice daily does not lead to a clinically satisfactory response, the addition of other antihypertensive agents, rather than an increase in the dose of furosemide should be considered.

In patients with chronic renal insufficiency, an initial daily dose of 250mg is employed. If a satisfactory diuresis is not produced then the dose may be increased in steps of 250mg at four to six hourly intervals up to a maximum daily dose of 1500mg in 24 hours. In exceptional cases, up to 2000mg in 24 hours may be given.

Children under 12 years: The oral dose for children ranges from 1-3mg/kg body weight daily up to a maximum total dose of 40mg per day.

Elderly: The usual daily dose, but caution is advised as Furosemide is excreted more slowly in the elderly. Dosage should be titrated until the required response is achieved.

Dosage adjustment may be required (see also section 4.4)

Dosage adjustment may be necessary in patients with:

•    hypoproteinaemia

•    liver congestions/dysfunction

Concomitant administration of the following with furosemide should be considered (see section 4.4):

Colestyramine and colestipol - Administer 2 to 3 hours apart

Method of administration: Oral- the tablets should be swallowed with water

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)

4.4 Special warnings and precautions for use

Hypotension and/or hypovolaemia (see also section 4.3)

These and any acid-base disturbances should be corrected before furosemide is started

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 totoxicity)

•    In moderate liver congestion dosage adjustment may be needed Caution required:

Caution needed in the following circumstances

•    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

•    patients with hypotension

Clinical monitoring requirements (see also section 4.8):

Regular monitoring for

•    blood dyscrasias. If these occur, stop furosemide immediately

•    liver damage

•    idiosyncratic reactions

In premature infants there is a risk of development of nephrocalcinosis/nephrolithiasis. Renal function must be monitored and renal ultrasonography performed.

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

The use of some diuretics is considered to be unsafe in acute porphyria, therefore caution should be exercised.

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, Angiotensin II receptor antagonists and betablockers 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 risik of ventricular arrhythmias with amisulpride or sertindole. Enhanced hypotensive effect with phenothiazines.

Anti-arrhythmics (including digoxin, amiodarone, disopyramide, flecainaide 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 QT prolongation - 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. Avoid the use of diuretics in lymecycline treatment.

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. Diuretic effect reduced by phenytoin.

Antihistamines - hypokalaemia with increased risk of cardiac toxicity.

Antifungals - increased risk of hypokalaemia with amphoterecin.

Antivirals - plasma concentrations of diuretics may be increased by antivirals (nelfinavir, ritonavir or squinavir)

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

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

Corticosteroids/ACTH - diuretic effect anatgonised (sodium retention) and increased risk of hypokalaemia.

Cytotoxics - increased risk of nephrotoxicity and ototoxicity with platinum compounds including cisplatin.

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

Dopaminergics - enhanced hypotensive effect with levodopa.

Immunomodulators - enhanced hypotensive effect with aldesleukin.

Immunosuppressive drugs - increased risk of hypokalaemia with tacrolimus

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

Oestrogens and progestogens - 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.

Methotrexate - may decrease diuretic effect. Methotrexate and other drugs that, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide. Conversely, furosemide may decrease the renal elimination of these drugs. In case of high-dose treatment (in particular, of both furosemide and the other drug), this may lead to increased serum levels and an increased risk of adverse effects due to furosemide or the concomitant medication.

Carbenoxolone - increased risk of hypokalaemia

Laxative abuse - increases the risk of potassium loss.

Liquorice - excess intake may increase the risk of hypokalaemia.

Barbiturates-Plasma concentrations of diuretics may be decreased by barbiturates.There may be an increased risk of osteomalacia when diuretics are taken in combination with phenobarbital.

4.6    Fertility, Pregnancy and lactation

The teratogenic and embryontoxic 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. Furosemide crosses the placental barrier. It must not be given during pregnancy unless the benefits to the patient outweigh the possible risks to the foetus which includes persistence of patent ductus arteriosus (see section 4.8). Treatment during pregnancy requires monitoring of foetal growth.

Furosemide passes into breast milk and may inhibit lactation. Women must not breast feed if they are treated with furosemide.

4.7    Effects on ability to drive and use machines

Reduced mental alertness and rarely dizziness and blurred vision have been reported. Patients so affected should not drive or operate machines.

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).

	Uncommon:	aplastic anaemia (necessitates withdrawal of treatment)
Blood and lymphatic system disorders:	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 (Impaired glucose tolerance in patients with diabetes

mellitus may lead to a deterioration of metabolic control, latent diabetes mellitus may become manifest) 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 (Symptoms of which include thirst, headache, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms), hyperglycaemia.
Phychiatric disorder:	Rare:	psychiatric disorder NOC
Nervous system disorders:	Rare:	paraesthesia, confusion, headache, dizziness.
Eye disorders:	Uncommon:	visual disturbance, blurred vision, yellow vision.
Ear and labyrinth disorders:	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, lightheadedness, 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

		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:	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.
Musculoskeletal and connective tissue disorders:	Uncommon:	muscle cramps, muscle weakness.
Renal and urinary disorders:	Uncommon:	reduced diuresis, urinary incontinence, urinary obstruction/ bladder outlet obstruction (in patients with hyperplasia of the prostate, bladder inability to empty, urethral stricture unspecified).
	Rare:	Nephrocalcinosis/nephrolithiasis (in preterm infants treated with Furosemide), interstitial nephritis, acutre 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 and dehydration (especially in elderly or dehydrated patients). Severe fluid depletion may lead to haemoconcentration with a tendency of thrombosis to develop.
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

The clinical picture in acute or chronic overdose depends primarily on the extent and consequences of electrolyte and fluid loss, e.g. hypovolaemia, dehydration, haemoconcentration, cardiac arrhythmias due to excessive diuresis. Symptoms of these disturbances include severe hypotension (progressing to shock), acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion. In cirrhotic patients, overdosage may precipitate hepatic coma.

Management

The drug should be discontinued. Treatment should be aimed at fluid replacement and correction of the electrolyte imbalance. Together with the prevention and treatment of serious complications resulting from such disturbances and of other effects on the body, this corrective action may necessitate general and specific intensive medical monitoring and therapeutic measures.

No specific antidote to furosemide is known. If ingestion has only just taken place, attempts may be made to limit further systematic absorption of the active ingredient by measures such as gastric lavage or those designated to reduce absorption (e.g. activated charcoal).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:

High-ceiling diuretic sulphonamide- CO3C A01

Furosemide is one of the high ceiling diuretics, a term used to denote a group of diuretics that have a distinctive action on renal tubular function. The peak diuresis is far greater than that observed with other agents. The evidence from many experimental studies suggests that furosemide acts along the entire nephron with the exception of the distal exchange site. The main site of action is the thick ascending loop of Henle where they inhibit electrolyte re-absorption. It increases renal blood flow without increasing the filtration rate. Such a change in renal haemodynamics reduces fluid and electrolyte re-absorption in the proximal tubule and may augment the initial diuretic response. Furosemide is an inhibitor of carbonic anhydrase but this activity is too weak to contribute to the proximal diuresis except when massive doses are employed. Furosemide enhances the excretion of both calcium and magnesium to an extent approximately proportional to the increase calcium re-absorption in the distal tubule. The calciuiric action of these agents is the basis for their use in symptomatic hypercalcaemia.

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 incompletely but fairly rapidly absorbed from the gastrointestinal tract. Bioavailability is about 65%. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration 6997% of activity from a radio-labelled dose is excreted in the first 4 hours after the drug is given. It has biphasic half-life in plasma with a terminal elimination phase up to about 2 hours but this is prolonged in neonates, and in patients with hepatic and renal insufficiency. It is extensively bound to plasma proteins but is rapidly secreted by the organic acid transport system of the proximal tubule. In this manner it gains access to the tubular fluid and eventually to its site of action more distally. It is mainly excreted in the urine via the kidneys (80-90%) largely unchanged, but also in the form of glucuronide and free amine metabolites. Variable amounts are also excreted in the bile and 10-15% of the activity can be recovered from the faeces. Furosemide crosses the placental barrier and is excreted in milk. Non-renal elimination is considerably increased in renal failure. The clearance of furosemide is not increased in renal failure. The clearance of furosemide is not increased by haemodialysis.

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.

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 new born, possibly due to immature tubular function.

5.3 Preclinical safety data

Not relevant.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate, magnesium stearate, sodium starch glycollate, maize starch.

6.2 Incompatibilities

None known.

6.3    Shelf life

Tablet container:    3 years

Blister:    2 years

6.4    Special precautions    for storage

Do not store above 25°C.

Keep the container tightly closed.

Store in the original container.

6.5    Nature and contents    of container

1.    Tablet container and cap (polypropylene container with low density polyethylene cap).

Pack sizes: 28, 56, 100, 250, 500 and 1000 tablets.

2.    Blister (250 pm white opaque PVC and 20 pm hard temper aluminium foil). Pack sizes: 28 and 56 tablets.

6.6 Special precautions for disposal

Not applicable.