SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Furosemide 50mg/5ml Oral Solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 50mg Furosemide.

For excipients, see Section 6.1

3. PHARMACEUTICAL FORM

Oral solution.

A clear solution with odour of cherries.

4.    CLINICAL PARTICULARS

4.1    Therapeutic Indications

Furosemide 50mg/5ml Oral Solution is a diuretic recommended for use in all indications when a prompt and effective diuresis is required in patients who are unable to take solid dose forms. Indications include cardiac, pulmonary, hepatic and renal oedema, peripheral oedema due to mechanical obstruction or venous insufficiency or hypertension.

4.2 Posology and Method of Administration

Furosemide 50mg/5ml Oral Solution has an exceptionally wide therapeutic range, the effect being proportional to the dosage. Furosemide 50mg/5ml Oral Solution is best given as a single dose either daily or on alternate days.

The usual initial daily dose is 40 mg. This may require adjustment until the effective dose is achieved as a maintenance dose. In mild cases, 20 mg daily or 40 mg on alternate days may be sufficient, whereas in cases of resistant oedema, daily doses of 80 mg and above may be used as one or two daily, or intermittently. Severe cases may require gradual titration of the furosemide dosage up to 600mg daily. The recommended maximum daily dose of furosemide administration is 1,500 mg.

Elderly: The dosage recommendations for adults apply, but in the elderly, furosemide is generally eliminated more slowly. Dosage should be titrated until the required response is achieved.

Children: Oral doses for children range from 1 to 3 mg/kg body weight daily up to a maximum total dose of 40 mg/day.

Contraindications

Furosemide 50mg/5ml Oral Solution is contra-indicated in patients with hypovolaemia or dehydration, impaired renal function with a creatinine clearance below 30ml/min per 1.73m² body surface area, anuria or renal failure with anuria not responding to furosemide, renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents or renal failure associated with hepatic coma, severe hypokalaemia, severe hyponatraemia, pre-comatose and comatose states associated with hepatic encephalopathy, Addison’s disease, digitalis intoxication and breast feeding women.

Furosemide is also contra-indicated in patients taking concomitant potassium supplements or potassium sparing diuretics.

Hypersensitivity to furosemide or any of the excipients of Furosemide 50mg/5ml Oral Solution. Patients allergic to sulphonamides may show cross-sensitivity to furosemide.

This product contains liquid maltitol and should not be taken by patients with the rare hereditary problem of fructose intolerance.

4.4 Special warnings and precautions for use

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition have an increased risk of developing acute retention and require careful monitoring.

Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.

Furosemide is not recommended:

In patients at high risk of radiocontrast nephropathy - Furosemide should not be used for dieresis as part of the preventative measures against radiocontrast-induced nephropathy.

In elderly patients with dementia taking risperidone - increased mortality (see below and section 4.5)

Particular caution and/or dose reduction is necessary in:

■    elderly patients (lower initial dose as particularly susceptible to side effects - see section 4.2).

■    patients with hypotension.

■    patients who are at risk from a pronounced fall in blood pressure.

■    diabetes mellitus (latent diabetes may become manifest or the insulin requirements of diabetic patients may increase: stop furosemide before a glucose tolerance test).

■    pregnancy (see section 4.6).

■    gout (furosemide may raise uric acid levels/precipitate gout).

■    impaired hepatic function - hepatic failure and alcoholic cirrhosis particularly predispose to hypokalaemia and hypomagnesaemia (see section 4.3 and below -monitoring required).

■    impaired renal function (see section 4.3 and below - monitoring required).

■    adrenal disease (see section 4.3 - contraindication in Addison’s disease)

■    hypoproteinaemia, e.g. associated with nephrotic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Cautious dose titration is required.

■    acute hypercalcaemia (dehydration results from vomiting and diuresis - correct before giving furosemide). Treatment of hypercalcaemia with a high dose of furosemide results in fluid and electrolyte depletion - meticulous fluid replacement and correction of electrolyte required).

■    premature infants (possible development nephrocalcinosis/nephrolithiasis; renal function must be monitored and renal ultrasonography performed).

■    some diuretics have been considered unsafe in acute porphyria.

Caution should be observed in patients liable to electrolyte deficiency. Regular monitoring of serum sodium, potassium and creatinine is generally recommended during furosemide therapy; particularly close monitoring is required in patients at high risk of developing electrolyte imbalances or in case of significant additional fluid loss. Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of furosemide. Avoidance with other medicines (see also section 4.5 for other interactions):

■    concurrent NSAIDs should be avoided - if not possible diuretic effect of furosemide may be attenuated

■    ACE-inhibitors and Angiotensin II receptor antagonists - severe hypotension may occur - dose of furosemide should be reduced/stopped (3 days) before starting or increasing the dose of these

■    concurrent risperidone in elderly patients with dementia has resulted in increased mortality - no mechanism for and no consistent pattern of deaths identified (see section 4.5)

Regular monitoring is required for:

■    blood dyscrasias. If these occur, stop furosemide immediately

■    liver damage

■    idiosyncratic reactions

Laboratory and other monitoring requirements:

■    serum sodium

Particularly in the elderly or in patients liable to electrolyte deficiency.

■    serum potassium

The possibility of hypokalaemia should be taken into account, in particular in patients with cirrhosis of the liver, those receiving concomitant treatment with corticosteroids, those with an unbalanced diet and those who abuse laxatives. Regular monitoring of the potassium, and if necessary treatment with a potassium supplement, is recommended in all cases, but is essential at higher doses and in patients with impaired renal function. It is especially important in the event of concomitant treatment with digoxin, as potassium deficiency can trigger or exacerbate the symptoms of digitalis intoxication (see section 4.5). A potassium-rich diet is recommended during long-term use.

Frequent checks of the serum potassium are necessary in patients with impaired renal function and creatinine clearance below 60ml/min per 1.73m² body surface area as well as in cases where furosemide is taken in combination with certain other drugs which may lead to an increase in potassium levels (see section 4.5 and refer to section 4.8 for details of electrolyte and metabolic abnormalities).

■    renal function

Frequent BUN in the first few months of treatment, periodically thereafter. Long-term/high-dose BUN should regularly be measured. Marked diuresis can cause reversible impairment of kidney function in patients with renal dysfunction. Adequate fluid intake is necessary in such patients. Serum creatinine and urea levels tend to rise during treatment. If used in premature infants there is a risk of nephrocalcinosis/nephrolithiasis so renal function must be monitored and renal ultrasonography performed.

■    glucose

Adverse effect on carbohydrate metabolism - exacerbation of existing carbohydrate intolerance or diabetes mellitus. Regular monitoring of blood glucose levels is desirable.

■    other electrolytes

Patients with hepatic failure/alcoholic cirrhosis are particularly at risk of hypomagnesaemia (as well as hypokalaemia). During long-term therapy (especially at high doses) magnesium, calcium, chloride, bicarbonate and uric acid should be regularly measured.

This medicinal product contains ethanol 10%v/v (alcohol) -each dose contains up to 0.5ml per dose and should be used with care in those suffering from alcoholism. To be taken into account in pregnant or breast feeding women, children and high-risk groups such as patients with liver disease or epilepsy.

4.5 Interaction with other medicinal products and other forms of interaction

The dosage of concurrently administered anti-hypertensive agents may require adjustment. A marked fall in blood pressure and deterioration in renal function may be seen when ACE inhibitors are added to furosemide therapy. The dose of furosemide should be reduced for at least three days, or the drug stopped, before initiating the ACE inhibitor or increasing the dose of an ACE inhibitor.

The effects of certain drugs which have inherent anti-hypertensive effects will be potentiated with furosemide.

Antihypertensives - enhanced hypotensive effect possible with all types. Concurrent use with ACE inhibitors or Angiotensin II receptor antagonists can result in marked falls in blood pressure, furosemide should be stopped or the dose reduced before starting with an ACE-inhibitor or Angiotensin II receptor antagonists (see section 4.4). Increased risk of first dose hypotension with post-synaptic alpha-blockers (e.g. prazosin).

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

In placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone. No consistent pattern for cause of death was observed but caution should be exercised and the risks and benefits of this combination considered prior to the decision to use.

Anti-arrhythmics (including amiodarone, disopyramide, flecainide and sotalol) -risk of cardiac toxicity (because of furosemide-induced hypokalaemia). The effects of lidocaine, tocainide or mexiletine may be antagonised by furosemide.

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

Vasodilators - enhanced hypotensive effect with moxisylyte (thymoxamine) or hydralazine. Other diuretics - profound dieresis possible when furosemide given with metolazone. Increased risk of hypokalaemia with thiazides. Contraindicated with potassium sparing diuretics (e.g. amiloride spironolactone) - increased risk of hyperkalaemia (see section 4.3). concurrent use with the tetracyclines may increasing risk of rising BUN (see section 4.4 -monitoring).

Antibiotics - increased risk of ototoxicity with aminoglycosides, polymixins or vancomycin -only use concurrently if compelling reasons. Increased risk of nephrotoxicity with aminoglycosides or cefaloridine. Furosemide can decrease vancomycin serum levels after cardiac surgery. Increased risk of hyponatraemia with trimethoprim. Chelating agents -sucralfate may decrease the gastro-intestinal absorption of furosemide - the two drugs should be taken at least 2 hours apart.

Renin inhibitors - aliskiren reduces plasma concentrations of furosemide.

Nitrates - enhanced hypotensive effect.

Lithium - furosemide reduces lithium excretion with increased plasma lithium concentrations (risk of cardio- and/or neuro-toxicity). Avoid concomitant administration unless plasma levels are monitored.

NSAIDs - increased risk of nephrotoxicity (especially with pre-existing hypovolaemia/dehydration. Indomethacin and ketorolac may antagonise the effects of furosemide (avoid if possible, see section 4.4). .

Salicylates - effects may be potentiated by furosemide. Salicylic toxicity may be increased by furosemide.

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

Antidiabetics - hypoglycaemic effects antagonised by furosemide.

Antivirals - plasma concentrations of diuretics may be increased by nelfinavir, ritonavir or saquinavir.

Muscle relaxants - enhanced hypotensive effect with baclofen or tizanidine. Increased effect of curare-like muscle relaxants.

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

Cytotoxics - increased risk of nephrotoxicity and ototoxicity with platinum compounds/cisplatin given concomitantly. 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. Antihistamines - hypokalaemia with increased risk of cardiac toxicity.

Drugs that prolong QT interval - increased risk of toxicity with furosemide induced electrolyte disturbances.

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

Concomitant administration of carbamazepine or aminoglutethimide may increase the risk of hyponatraemia.

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

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

Corticosteroids - diuretic effect antagonised (sodium retention) and increased risk of hypokalaemia.

Antifungals - increased risk of hypokalaemia and nephrotoxicity with amphotericin, Potassium salts are contraindicated - increased risk of hyperkalaemia.

Sympathomimetics - increased risk of hypokalaemia with high doses of B2 sympathomimetics

Probenecid - the effects of furosemide may be reduced by probenecid and furosemide may reduce the renal clearance of probenecid.

Theophylline may cause an enhanced hypotensive effect.

Anti-metabolites - the effects of furosemide may be reduced by methotrexate and furosemide may reduce renal clearance of methotrexate.

Concomitant treatment with certain other drugs may cause an enhanced hypotensive effect e.g., and Amifostine.

Dopaminergics - enhanced hypotensive effect with levodopa.

Immunomodulators - enhanced hypotensive effect with aldeskleukin. Increased risk of hyperkalaemia with ciclosporin and tacrolimus. Increased risk of gouty arthritis with ciclosporin.

Prostaglandins such alprostadil may cause an enhanced hypotensive effect.

Progestogens (drospirenone) - increased risk of hyperkalaemia.

Oestrogens - diuretic effect antagonised.

Warfarin and clofibrate compete with furosemide in binding to serum albumin - possibly significant if this is low (e.g. nephritic syndrome).

Alcohol may cause an enhanced hypotensive effects.

Laxative abuse may increase the risk of potassium loss.

4.6 Pregnancy and Lactation

There is clinical evidence of safety of the drug in the third trimester of human pregnancy; however, furosemide crosses the placental barrier.

It must not be given during pregnancy unless there are compelling medical reasons. 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.

Effects on Ability to Drive and Use Machines

Reduced mental alertness may impair ability to drive or operate dangerous machinery.

4.8 Undesirable effects

Furosemide 50mg/5ml Oral Solution is generally well tolerated.

Eosinophilia is rare.

Occasionally, thrombocytopenia may occur. In rare cases, leucopenia and, in isolated cases, agranulocytosis and haemolytic anaemia may develop.

Aplastic anaemia and bone marrow depression have been reported as a rare complication and necessitate withdrawal of treatment.

Rarely, paraesthesiae may occur. Psychiatric disorder NOC.

Serum calcium levels may be reduced; in very rare cases tetany has been observed.

If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Risk of nephrocalcinosis / nephrolithiasis (see Tetany and reduced serum calcium and section 4.4 re monitoring).

Serum cholesterol and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months.

Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to a deterioration of metabolic control; latent diabetes mellitus may become manifest. Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephrotic syndrome) and/or when intravenous furosemide has been given too rapidly.

Furosemide may cause a reduction in 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.

Pure intra hepatic cholestasis, hepatic function abnormal, increase in liver transaminases. Isolated cases of acute pancreatitis or jaundice have been reported after long term diuretic therapy.

The incidence of allergic reactions, such as skin rashes, photosensitivity, vasculitis, fever, interstitial nephritis or shock, is very low, but when these occur treatment should be withdrawn.

Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, erythema multiforme, exfoliative dermatitis, purpura. Steven-Johnson’s syndrome, toxic epidermal necrolysis may occasionally occur.

As with other diuretics, electrolytes and water balance may be disturbed as a result of diuresis after prolonged therapy. Furosemide leads to increased excretion of sodium and chloride and consequently water. In addition excretion of other electrolytes (in particular potassium, calcium and magnesium) is increased. Symptomatic electrolyte disturbances and metabolic alkalosis may develop in the form of a gradually increasing electrolyte deficit or, e.g. where higher furosemide doses are administered to patients with normal renal function, acute severe electrolyte losses. Warning signs of electrolyte disturbances include increased thirst, headache, hypotension, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms. Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.

The diuretic action of furosemide may lead to or contribute to hypovolaemia and dehydration, especially in elderly patients. Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop.

Increased production of urine may provoke or aggravate complaints in patients with an obstruction of urinary outflow. Thus, acute retention of urine with possible secondary complications may occur for example, in patients with bladder-emptying disorders, prostatic hyperplasia or narrowing of the urethra.

Side-effects of a minor nature such as nausea, malaise or gastric upset (vomiting or diarrhoea) may occur but are not usually severe enough to necessitate withdrawal of treatment.

As with other diuretics, treatment with furosemide may lead to transitory increases in blood creatinine and urea levels. Serum levels of uric acid may increase and attacks of gout may occur.

Severe anaphylactic or anaphylactoid reactions (e.g. shock) occur rarely.

Reduced diuresis, urinary incontinence.

Hepatic encephalopathy in patients with hepatocellular insufficiency may occur.

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

Overdosing may lead to dehydration and electrolyte depletion through excessive diuresis. Severe potassium loss may lead to serious cardiac arrhythmias. 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.

Treatment of overdose consists of fluid replacement and electrolyte imbalance correction. 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 systemic 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

High-Ceiling Diuretic Sulfonamide ATC code: C03C A01 Furosemide is a loop diuretic.

5.2 Pharmacokinetic Properties

Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastro-intestinal tract. Furosemide is rapidly but incompletely absorbed (60-70%) on oral administration and its effect is largely over within four 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 four hours after the drug is given. 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.

5.3 Preclinical Safety Data

Furosemide is a widely used diuretic which has been available for over thirty years and its safety profile in man is well established.

PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Sodium hydroxide 32%w/w solution

Disodium hydrogen orthophosphate dodecahydrate

Citric acid monohydrate

Maltitol liquid

Cherry flavour

Ethanol (96%v/v)

Purified water

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

24 months unopened.

Once opened, use within 3 months.

6.4    Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5.    Nature and Contents of Container

Amber glass (type III, Ph Eur) bottle with polypropylene screw cap containing 150ml.

6.6.    Instruction for Use/Handling None.

7    MARKETING AUTHORISATION HOLDER

Focus Pharmaceuticals Ltd Capital House,

85 King William Street,

London EC4N 7BL,

United Kingdom.

8.    MARKETING AUTHORISATION NUMBER

PL 20046/0039

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/12/2005 /09/07/2010

10    DATE OF REVISION OF THE TEXT

17/06/2016