- Approval Id
- b7a66c96c2071eb5
- Drug Approval Emc Name
- Furosemide 20 mg Tablet
- Drug Name
- Furosemide 20 mg Tablet
- Company Name
- Tillomed Laboratories Ltd
- Company Address
- 220 Butterfield, Great Marlings, Luton, LU2 8DL, UK
- Company Website
- http://www.tillomed.com/
- Company Telephone
- +44 (0)1480 402 400
- Company Medical Info Direct Line
- +44 (0)1480 402 400 [option 2]
- Company Medical Info Email
- Medical.Information@Tillomed.com
- Company Customer Care Direct Line
- +44 (0)1480 402 400 [option 1]
- Company Stock Availability
- +44 (0)1480 402 400 [option 1]
- Atc Code
- C03CA01
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Tillomed Laboratories Ltd
220 Butterfield, Great Marlings
Luton
LU2 8DL
United Kingdom.
- Authorisation Number
- PL 11311/0710
- Authorisation Date
- 18/03/2021
- Instruction Authorisation Holder
- Tillomed Laboratories Ltd
220 Butterfield, Great Marlings
Luton
LU2 8DL
United Kingdom.
- Instruction Authorisation Number
- PL 11311/0710
- Instruction Authorisation Date
- 18/03/2021
- Instruction Composition
- Each tablet contains 20mg Furosemide.
For a full list of excipients, see section 6.1.
- Instruction Dosage Form
- Tablet.
\*Appearance\*
A white, circular, flat, bevelled-edge tablet marked with FIL/F20 on one side and plain on other. Tablet diameter 6mm.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Furosemide is a potent diuretic with a rapid action. Indications for furosemide include:
The treatment of oedema associated with congestive heart failure, cirrhosis of the liver, renal disease including nephrotic syndrome.
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.4.2 Posology and method of administration
Posology
\*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 1,500mg in 24 hours. In exceptional cases up to 2,000mg in 24 hours may be given.
\*Children under 12 years:\*
From 1-3mg/kg body weight daily, up to a maximum total dose of 40mg per day.
\*Elderly:\*
Generally eliminated more slowly. 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 congestion/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:
For oral administration.4.3 Contraindications
Furosemide is contraindicated in the following circumstances:
• Hypersensitivity to furosemide, any of the 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 hypokalaemia, severe hyponatraemia, 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 section 4.5)
• Breast-feeding women (see section 4.6)4.4 Special warnings and precautions for use
Hypotension and hypovolaemia (see section 4.3).
These and any acid-base disturbance should be corrected before furosemide is started.
Symptomatic hypotension leading to dizziness, fainting or loss of consciousness can occur in patients treated with furosemide, particularly in the elderly, patients on other medications which can cause hypotension and patients with other medical conditions that are risks for hypotension.
Dose titration/adjustment (see section 4.2)
• Patients with hypoproteinaemia (such as that associated with the nephrotic 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 sections 4.2 and 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
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
Patients with rare hereditary problems of galactose intolerance, total 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 alpha blockers e.g. 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, flecainide 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 (e.g. 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. Diuretic effect reduced by phenytoin.
Antihistamines – hypokalaemia with increased risk of cardiac toxicity.
Antifungals – increased risk of hypokalaemia with amphotericin.
Anxiolytics and hypnotics – enhanced hypotensive effect. Chloral or triclofos 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) and increased 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. The effects of curare may be enhanced by furosemide.
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.
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 risk to the foetus which includes persistence of patent ductus arteriosus (section 4.8).
Furosemide may pass into the breast milk or may inhibit lactation, it should therefore 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).
Listed below are side effects, which have been associated with the administration of furosemide.
\*\*Blood and lymphatic System disorders\*\*
Uncommon\*\*\*:\*\*\* Thrombocytopenia.
Rare: Leucopenia, eosinophilia, and bone marrow depression (necessitates withdrawal of treatment). The haemopoietic status should therefore be regularly monitored.
Very rare: Agranulocytosis, aplastic anaemia or haemolytic anaemia.
\*\*Nervous system disorders\*\*
Rare: Paraesthesia, hyperosmolar coma.
Not known: Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension).
\*\*Cardiovascular disorders\*\*
Uncommon: Cardiac arrhythmias
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.
\*\*Ear and labyrinth disorders\*\*
Uncommon: Deafness (sometimes irreversible).
Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome) and/or when intravenous furosemide has been given too rapidly.
\*\*Endocrine disorders\*\*
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.
\*\*Eye disorders\*\*
Uncommon: Visual disturbance.
\*\*Hepatobiliary disorders\*\*
In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.
Hepatic encephalopathy in patients with hepatocellular insufficiency may occur (see Section 4.3).
\*\*General disorders and administration site conditions\*\*
Uncommon: Fatigue.
Rare: Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely, fever, malaise.
\*\*Vascular disorders\*\*
Rare: Vasculitis.
\*\*Gastrointestinal disorders\*\*
Uncommon: Dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhoea, constipation.
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.
Rare: Acute pancreatitis.
\*\*Metabolism and nutritional disorders\*\*
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 increase excretion of water. In addition, excretion of other electrolytes (in particular potassium, calcium and magnesium) is increased. Metabolic acidosis can also occur. The risk of this abnormality increases at higher dosages and is influenced by the underlying disorder (e.g. cirrhosis of the liver, heart failure), concomitant medication (see section 4.5) and diet. 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.
Symptoms of electrolyte imbalance depend on the type of disturbance:
Sodium deficiency can occur; this can manifest itself in the form of confusion, muscle cramps, muscle weakness, loss of appetite, dizziness, drowsiness and vomiting.
Potassium deficiency manifests itself in neuromuscular symptoms (muscular weakness, paralysis), intestinal symptoms (vomiting, constipation, meterorism), renal symptoms (polyuria) or cardiac symptoms. Severe potassium depletion can result in paralytic ileus or confusion, which can result in coma.
Magnesium and calcium deficiency result very rarely in tetany and heart rhythm disturbances.
Serum calcium levels may be reduced; in very rare cases tetany has been observed.
Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.
Serum cholesterol (reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol) and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months.
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.
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.
\*\*Musculoskeletal, connective tissue and bone disorders\*\*
Muscle spasm has been reported.
\*\*Skin and subcutaneous tissue disorders\*\*
Uncommon: Photosensitivity
Rare: Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, fever, hypersensitivity to light, exsudative erythema multiforme (Lyell's syndrome and Stevens-Johnson syndrome), bullous exanthema, exfoliative dermatitis, purpura, AGEP (Acute Generalised Exanthematous Pustulosis) and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
Not known: Bullous pemphigoid
\*\*Renal and urinary disorders\*\*
Uncommon: Serum creatinine and urea levels can be temporarily elevated during treatment with furosemide.
Rare: Interstitial nephritis, acute renal failure.
Increased urine production, urinary incontinence, can be caused or symptoms can be exacerbated in patients with urinary tract obstruction. Acute urine retention, possibly accompanied by complications, can occur for example in patients with bladder disorders, prostatic hyperplasia or narrowing of the urethra.
\*\*Pregnancy, puerperium and perinatal conditions\*\*
In premature infants with respiratory distress syndrome, administration of furosemide tablets in the initial weeks after birth entails an increased risk of a persistent patent ductus arteriosus.
In premature infants, furosemide can be precipitated as nephrocalcinosis/kidney stones.
Rare complications may include minor psychiatric disturbances.
\*\*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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.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.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiovascular apparatus. Antihypertensives. Diuretics, Diuretics of loop
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 protein.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 from the gastrointestinal tract (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. Bioavailability is about 65%\*.\* It has a 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. 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.
It is mainly excreted in the urine largely unchanged, but also in the form of glucuronide and free amine metabolites. Variable amounts are also excreted in the bile. 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 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.
The elderly
The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present. Newborn A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.5.3 Preclinical safety data
Not relevant.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Lactose monohydrate
Magnesium stearate
Sodium starch glycollate
Maize starch
Starch paste 15%6.2 Incompatibilities
Not applicable.6.3 Shelf life
Tablet container: 5 Years
Blister: 2 Years6.4 Special precautions for storage
Tablet container: Do not store above 25°C. Store in the original container. Keep the container tightly closed.
Blister: Do not store above 25°C. Store in the original package.6.5 Nature and contents of container
Tablet container and cap (polypropylene container with low density polyethylene cap)
Pack sizes: 28, 56, 100, 250, 500 and 1000 tablets.
Blister (250 µm white opaque PVC and 25 µm hard temper aluminium foil).
Pack sizes: 28 and 56 tablets.6.6 Special precautions for disposal and other handling
Not applicable.
- Instruction Content
- ## Composition
Each tablet contains 20mg Furosemide.
For a full list of excipients, see section 6.1.
## Pharmaceutical Form
Tablet.
\*Appearance\*
A white, circular, flat, bevelled-edge tablet marked with FIL/F20 on one side and plain on other. Tablet diameter 6mm.
## Clinical Particulars
4.1 Therapeutic indications
Furosemide is a potent diuretic with a rapid action. Indications for furosemide include:
The treatment of oedema associated with congestive heart failure, cirrhosis of the liver, renal disease including nephrotic syndrome.
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.4.2 Posology and method of administration
Posology
\*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 1,500mg in 24 hours. In exceptional cases up to 2,000mg in 24 hours may be given.
\*Children under 12 years:\*
From 1-3mg/kg body weight daily, up to a maximum total dose of 40mg per day.
\*Elderly:\*
Generally eliminated more slowly. 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 congestion/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:
For oral administration.4.3 Contraindications
Furosemide is contraindicated in the following circumstances:
• Hypersensitivity to furosemide, any of the 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 hypokalaemia, severe hyponatraemia, 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 section 4.5)
• Breast-feeding women (see section 4.6)4.4 Special warnings and precautions for use
Hypotension and hypovolaemia (see section 4.3).
These and any acid-base disturbance should be corrected before furosemide is started.
Symptomatic hypotension leading to dizziness, fainting or loss of consciousness can occur in patients treated with furosemide, particularly in the elderly, patients on other medications which can cause hypotension and patients with other medical conditions that are risks for hypotension.
Dose titration/adjustment (see section 4.2)
• Patients with hypoproteinaemia (such as that associated with the nephrotic 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 sections 4.2 and 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
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
Patients with rare hereditary problems of galactose intolerance, total 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 alpha blockers e.g. 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, flecainide 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 (e.g. 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. Diuretic effect reduced by phenytoin.
Antihistamines – hypokalaemia with increased risk of cardiac toxicity.
Antifungals – increased risk of hypokalaemia with amphotericin.
Anxiolytics and hypnotics – enhanced hypotensive effect. Chloral or triclofos 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) and increased 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. The effects of curare may be enhanced by furosemide.
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.
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 risk to the foetus which includes persistence of patent ductus arteriosus (section 4.8).
Furosemide may pass into the breast milk or may inhibit lactation, it should therefore 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).
Listed below are side effects, which have been associated with the administration of furosemide.
\*\*Blood and lymphatic System disorders\*\*
Uncommon\*\*\*:\*\*\* Thrombocytopenia.
Rare: Leucopenia, eosinophilia, and bone marrow depression (necessitates withdrawal of treatment). The haemopoietic status should therefore be regularly monitored.
Very rare: Agranulocytosis, aplastic anaemia or haemolytic anaemia.
\*\*Nervous system disorders\*\*
Rare: Paraesthesia, hyperosmolar coma.
Not known: Dizziness, fainting and loss of consciousness (caused by symptomatic hypotension).
\*\*Cardiovascular disorders\*\*
Uncommon: Cardiac arrhythmias
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.
\*\*Ear and labyrinth disorders\*\*
Uncommon: Deafness (sometimes irreversible).
Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome) and/or when intravenous furosemide has been given too rapidly.
\*\*Endocrine disorders\*\*
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.
\*\*Eye disorders\*\*
Uncommon: Visual disturbance.
\*\*Hepatobiliary disorders\*\*
In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.
Hepatic encephalopathy in patients with hepatocellular insufficiency may occur (see Section 4.3).
\*\*General disorders and administration site conditions\*\*
Uncommon: Fatigue.
Rare: Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely, fever, malaise.
\*\*Vascular disorders\*\*
Rare: Vasculitis.
\*\*Gastrointestinal disorders\*\*
Uncommon: Dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhoea, constipation.
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.
Rare: Acute pancreatitis.
\*\*Metabolism and nutritional disorders\*\*
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 increase excretion of water. In addition, excretion of other electrolytes (in particular potassium, calcium and magnesium) is increased. Metabolic acidosis can also occur. The risk of this abnormality increases at higher dosages and is influenced by the underlying disorder (e.g. cirrhosis of the liver, heart failure), concomitant medication (see section 4.5) and diet. 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.
Symptoms of electrolyte imbalance depend on the type of disturbance:
Sodium deficiency can occur; this can manifest itself in the form of confusion, muscle cramps, muscle weakness, loss of appetite, dizziness, drowsiness and vomiting.
Potassium deficiency manifests itself in neuromuscular symptoms (muscular weakness, paralysis), intestinal symptoms (vomiting, constipation, meterorism), renal symptoms (polyuria) or cardiac symptoms. Severe potassium depletion can result in paralytic ileus or confusion, which can result in coma.
Magnesium and calcium deficiency result very rarely in tetany and heart rhythm disturbances.
Serum calcium levels may be reduced; in very rare cases tetany has been observed.
Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.
Serum cholesterol (reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol) and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months.
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.
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.
\*\*Musculoskeletal, connective tissue and bone disorders\*\*
Muscle spasm has been reported.
\*\*Skin and subcutaneous tissue disorders\*\*
Uncommon: Photosensitivity
Rare: Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, fever, hypersensitivity to light, exsudative erythema multiforme (Lyell's syndrome and Stevens-Johnson syndrome), bullous exanthema, exfoliative dermatitis, purpura, AGEP (Acute Generalised Exanthematous Pustulosis) and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
Not known: Bullous pemphigoid
\*\*Renal and urinary disorders\*\*
Uncommon: Serum creatinine and urea levels can be temporarily elevated during treatment with furosemide.
Rare: Interstitial nephritis, acute renal failure.
Increased urine production, urinary incontinence, can be caused or symptoms can be exacerbated in patients with urinary tract obstruction. Acute urine retention, possibly accompanied by complications, can occur for example in patients with bladder disorders, prostatic hyperplasia or narrowing of the urethra.
\*\*Pregnancy, puerperium and perinatal conditions\*\*
In premature infants with respiratory distress syndrome, administration of furosemide tablets in the initial weeks after birth entails an increased risk of a persistent patent ductus arteriosus.
In premature infants, furosemide can be precipitated as nephrocalcinosis/kidney stones.
Rare complications may include minor psychiatric disturbances.
\*\*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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.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.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiovascular apparatus. Antihypertensives. Diuretics, Diuretics of loop
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 protein.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 from the gastrointestinal tract (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. Bioavailability is about 65%\*.\* It has a 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. 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.
It is mainly excreted in the urine largely unchanged, but also in the form of glucuronide and free amine metabolites. Variable amounts are also excreted in the bile. 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 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.
The elderly
The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present. Newborn A sustained diuretic effect is seen in the newborn, 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
Starch paste 15%6.2 Incompatibilities
Not applicable.6.3 Shelf life
Tablet container: 5 Years
Blister: 2 Years6.4 Special precautions for storage
Tablet container: Do not store above 25°C. Store in the original container. Keep the container tightly closed.
Blister: Do not store above 25°C. Store in the original package.6.5 Nature and contents of container
Tablet container and cap (polypropylene container with low density polyethylene cap)
Pack sizes: 28, 56, 100, 250, 500 and 1000 tablets.
Blister (250 µm white opaque PVC and 25 µm hard temper aluminium foil).
Pack sizes: 28 and 56 tablets.6.6 Special precautions for disposal and other handling
Not applicable.
