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.