1. Name Of The Medicinal Product
Furosemide 10mg/ml Solution for Injection or Infusion
2. Qualitative And Quantitative Composition
Each ml contains 10mg of furosemide.
Each 2ml ampoule contains 20mg of furosemide.
Each 25ml vial contains 250mg of furosemide.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection or infusion
The solution is colourless or almost colourless.
4. Clinical Particulars
4.1 Therapeutic Indications
Furosemide 10mg/ml Injection is a diuretic indicated for use when a prompt and effective diuresis is required. The intravenous formulation is appropriate for use in emergencies or when oral therapy is precluded. Indications include cardiac, pulmonary, hepatic and renal oedema.
4.2 Posology And Method Of Administration
Route of administration: intramuscular or intravenous use.
Adults
Intravenous furosemide must be injected or infused slowly; a rate of 4 mg per minute must not be exceeded. In patients with severe impairment of renal function (serum creatinine>5 mg/dl), it is recommended that an infusion rate of 2.5 mg per minute is not exceeded.
Intramuscular administration must be restricted to exceptional cases where neither oral nor intravenous administration are feasible. It must be noted that intramuscular injection is not suitable for the treatment of acute conditions such as pulmonary oedema.
To achieve optimum efficacy and suppress counter-regulation, a continuous furosemide infusion is generally to be preferred to repeated bolus injections. Where continuous furosemide infusion is not feasible for follow-up treatment after one or several acute bolus doses, a follow-up regimen with low doses given at short intervals (approximately four hours) is to be preferred to a regimen with higher bolus doses at longer intervals.
Doses of 20 to 50 mg intramuscularly or intravenously may be given initially. If larger doses are required, they should be given by 20 mg increments and not given more often than every two hours. If doses greater than 50 mg are required it is recommended that they be given by slow intravenous infusion. 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: Parenteral doses for children range from 0.5 to 1.5 mg/kg body weight daily up to a maximum total daily dose of 20 mg.
4.3 Contraindications
Furosemide 10mg/ml Injection is contra-indicated in patients with hypovolaemia or dehydration, 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 and pre-comatose and comatose states associated with hepatic encephalopathy.
Hypersensitivity to furosemide or any of the excipients of Furosemide 10mg/ml Injection. Patients allergic to sulphonamides may show cross-sensitivity to furosemide.
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.
Steps should be taken to correct hypovolaemia before commencing therapy in oliguria.
Caution is required in patients with liver failure, porphyria, pancreatitis or a history of pancreatitis, systemic lupus erythematosus or a history of systemic lupus erythematosus or severe asthma (hypokalaemia associated with beta2-agonist therapy can be potentiated by the concurrent use of diuretics). The insulin requirements of diabetic patients may increase on treatment with furosemide and latent diabetes may become manifest.
Particularly careful monitoring is necessary in:
• patients with hypotension – correct before use
• patients who are at risk from a pronounced fall in blood pressure
• patients with gout
• patients with hepatorenal syndrome
• patients with hypoproteinaemia, e.g. associated with nephrotic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Cautious dose titration is required.
• premature infants and neonates (possible development of nephrocalcinosis /nephrolithiasis in association with increased calcium excretion during long-term furosemide treatment; renal function must be monitored and renal ultrasonography performed)
Caution should be observed in patients liable to electrolyte deficiency such as the elderly. The risk of hypokalaemia is increased in patients with severe or congestive heart failure, hepatic cirrhosis or hyperaldosteronism. 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. Possibility of hypocalcaemic tetany in hypoparathyroid patients.
Prolonged treatment with furosemide can lead to thiamine deficiency, particularly in congestive heart failure or the elderly.
This medicinal product contains 0.26mmol of sodium in a 2ml ampoule and 3.25mmol of sodium in a 25ml vial. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Alcohol: Enhanced hypotensive effect. Orthostatic hypotension, associated with diuretics, may be enhanced.
Aldesleukin: Enhanced hypotensive effect.
Anaesthetics, general: Enhanced hypotensive effects.
Anion-exchange resins: Colestyramine and colestipol markedly reduce the absorption of furosemide. Administer two to three hours apart.
Anti-arrhythmics: Toxicity of amiodarone, disopyramide, flecainide and quinidine is increased if hypokalaemia occurs. Action of lidocaine and mexilitine is antagonised by hypokalaemia. Hypokalaemia increases risk of ventricular arrhythmias with sotalol, a beta-blocker.
Antibacterials: Furosemide may enhance the toxicity of nephrotoxic antibiotics including some cephalosporins. It can enhance the ototoxicity of aminoglycoside antibiotics, vancomycin and other ototoxic agents. Since this may lead to permanent damage, these drugs must only be used with furosemide if there are compelling medical reasons.
Anticoagulants: Reduced anticoagulant effect when furosemide used concomitantly with warfarin.
Antidepressants: Increased risk of postural hypotension with tricyclic antidepressants. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs). Increase risk of hypokalaemia when furosemide and reboxetine are used concomitantly.
Antidiabetics: The hypoglycaemic effect is antagonised by loop diuretics.
Antiepileptics: Increased risk of hyponatraemia with concomitant carbamazepine. The diuretic effect of furosemide has been shown to be substantially reduced by concomitant phenytoin therapy.
Antifungals: Increased risk of hypokalaemia with loop diuretics and amphotericin.
Anti-gout: Probenecid has been shown to reduce the renal clearance of furosemide and may increase, decrease or have no effect on the overall diuresis.
Antihistamines: Hypokalaemia increases risk of ventricular arrhythmias with terfenadine.
Antihypertensives: Furosemide enhances the hypotensive action of other antihypertensive drugs, including beta-blockers, calcium-channel blockers and hydralazine. The dosage of currently administered antihypertensive agents may require adjustment. There is an increase risk of first-dose hypotension with alpha blockers such as prazosin or angiotensin-converting enzyme (ACE) inhibitors such as captopril. Particular care should be taken with ACE inhibitors and angiotensin-II antagonists, since combination with furosemide can result in marked reduction in blood pressure. The dose of furosemide should be reduced for at least three days, or the drug stopped, before initiating or increasing the dose of an ACE inhibitor. Long term intensive treatment with captopril can enhance the natriuretic response to furosemide.
Antipsychotics: Hypokalaemia increases risk of ventricular arrhythmias with primozide and sertindole, concurrent use should be avoided. Enhanced hypotensive effect with phenothiazines.
Anxiolytics and hypnotics: Administration of chloral hydrate followed by intravenous furosemide may result in a syndrome of hot flushes, sweating, tachycardia and hypertension.
Cardiac Glycosides: Increased risk of toxicity if hypokalaemia occurs.
Corticosteroids: There is increased risk of hypokalaemia particularly with the naturally occurring corticosteroids such as cortisone and hydrocortisone. The synthetic corticosteroids have a much less marked potassium-losing effect. Fluid retention associated with corticosteroid use may cause antagonism of diuretic/antihypertensive effect.
Cytotoxics: There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of cisplatin may be enhanced if furosemide is not given in low doses (e.g. 40mg in patients with normal renal function) and with positive fluid balance when used to achieve forced dieresis during cisplatin treatment.
Diuretics: Increased risk of hypokalaemia with other loop diuretics and other diuretics, including acetazolamide and thiazides. Severe electrolyte disturbances may occur in patients given metolazone concurrently with furosemide.
Dompaminergics: Enhanced hypotensive effect with levodopa.
Laxatives: Prolonged use may increase the risk of developing hypokalaemia.
Lithium: In common with other diuretics, serum lithium levels may be increased when lithium is given concomitantly with furosemide, resulting in increased lithium toxicity. Therefore, it is recommended that lithium levels are carefully monitored and where necessary the lithium dosage is adjusted in patients receiving this combination.
Muscle relaxants: Enhanced hypotensive effect may occur with tizanidine; effects of curare-type muscle relaxants may be potentiated.
Nicotine: Nicotine inhibits diuresis and diminishes the diuretic effect of furosemide.
Nitrates: Enhanced hypotensive effect.
Non-steroidal anti-inflammatory agents (NSAIDs): Certain non-steroidal anti-inflammatory agents (e.g. indometacin, ketorolac) may attenuate the action of furosemide and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Enhanced nephrotoxicity of NSAIDs.
Prostaglandins: Hypotensive effect may be potentiated by alprostadil.
Sympathomimetics: There is an increased risk of hypokalaemia with high doses of β2-sympathomimetics. Effects of pressor amines may be attenuated.
Theophylline: Risk of hypokalaemia may be increased; effects of theophylline may be potentiated.
Ulcer healing drugs: carbenoxolone and liquorice may increase risk of hypokalaemia. Fluid retention associated with carbenoxolone may cause antagonism of diuretic/antihypertensive effect. Ranitidine causes a moderate increase in the bioavailability of furosemide.
4.6 Pregnancy And Lactation
Animal teratology studies indicate that furosemide may cause foetal abnormalities. 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. Furosemide is not recommended 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
Furosemide 10mg/ml Injection is generally well tolerated.
The most common side-effect is fluid and electrolyte imbalance including hyponatraemia, hypokalaemia, hypochloraemic alkalosis, hypotension and increased calcium excretion.
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.
Increased calcium excretion in infants and new-borns has been associated with reports of decreased bone mineral content, rickets, fractures and renal calcification. Hypocalcaemic tetany has also been reported in hypoparathyroid patients. Nephrocalcinosis / Nephrolithiasis may develop in premature infants.
Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.
Thiamine deficiency with prolonged treatment, particularly in congestive heart failure and the elderly.
Furosemide may cause hyperuricaemia and precipitate attacks of gout in some patients.
Serum cholesterol and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months.
Other side effects are relatively uncommon and include the following:
Cardiovascular: 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 hypotension. 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.
Disorders of the ear: tinnitus and deafness, although usually transitory, may occur in rare cases, (usually with large parenteral doses and rapid administration or in patients with hypoproteinaemia or renal impairment. Rarely deafness may be permanent, particularly if furosemide has been given to patients taking other ototoxic drugs.
Disorders of the eye: Blurred vision, yellow vision.
Disorders of the immune system: Hypersensitivity reactions, that may include skin rashes, photosensitivity, vasculitis, fever, urticaria and interstitial nephritis occur rarely but when these occur treatment should be withdrawn. Severe anaphylaxis or anaphylactoid reactions (e.g with shock) may also occur rarely and necessitate immediate withdrawal of furosemide treatment.
Endocrine: Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to a deterioration of metabolic control with hyperglycaemia and glycosuria; latent diabetes mellitus may also become manifest.
Gastrointestinal: side-effects of a minor nature such as nausea, or gastric upset (vomiting and diarrhoea) may occur but are not usually severe enough to necessitate withdrawal or treatment. Pancreatitis is more common at high doses.
Haematopoietic: In rare cases, thrombocytopenia, leucopenia, agranulocytosis, eosinophilia, aplastic anaemia or haemolytic anaemia may develop. Bone marrow depression necessitates withdrawal of treatment.
Hepatobiliary: In isolated cases, intrahepatic cholestasis, an increase in liver transaminases, or cholestatic jaundice has been reported.
Neonatal: If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus.
Nervous system: Syncope.
Neurological: Rarely, paraesthesiae may occur.
Renal/urinary: 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. As with other diuretics, treatment with furosemide may lead to transitory increases in blood creatinine and urea levels.
Skin: Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, and other rashes. Rarely these may be severe and may include purpura and exfoliative dermatitis and bullous lesions such as erythema multiforme and pemphigoid.
General disorders and administration site conditions: malaise.
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.
Treatment:
Treatment should therefore 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 systemic absorption of the active ingredient by measures such as those designed to reduce absorption (e.g. activated charcoal).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 Henle with a complex effect on renal circulation. Blood-flow is diverted from the juxta-medullary region to the outer cortex. The principle renal action of furosemide is to inhibit active chloride transport in the thick ascending limb. Re-absorption of sodium chloride from the nephron is reduced and a hypotonic or isotonic urine produced. It has been established that prostaglandin (PG) biosynthesis and the renin-angiotensin system are affected by furosemide administration and that furosemide alters the renal permeability of the glomerulus to serum proteins.
5.2 Pharmacokinetic Properties
Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastrointestinal tract. Furosemide is rapidly but incompletely absorbed (60-70%) on oral administration and its effect is largely over within 4 hours. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration, 69-97% of activity from a radio-labelled dose is excreted in the first 4 hours after the drug is given. Furosemide is bound to plasma albumin and little biotransformation takes place. Furosemide is mainly eliminated via the kidneys (80-90%); a small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces.
In renal/ hepatic impairment
Where liver disease is present, biliary elimination is reduced up to 50%. Renal impairment has little effect on the elimination rate of furosemide, but less than 20% residual renal function increases the elimination time.
The elderly
The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.
New born
A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.
5.3 Preclinical Safety Data
Not applicable.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Sodium hydroxide
Water for injections
6.2 Incompatibilities
Furosemide may precipitate out of solution in fluids of low pH (e.g. dextrose solutions).
6.3 Shelf Life
Three years
6.4 Special Precautions For Storage
Store in the original package
6.5 Nature And Contents Of Container
20 mg in 2ml
Type I amber coloured glass ampoule of 3ml capacity. Each pack contains 1, 5 or 10 ampoules*.
250 mg in 25ml
Type I amber coloured glass vial (25ml capacity) sealed with a bromobutyl stopper, aluminium overseal and polypropylene flip-off cap. Each pack contains 1, 5 or 10 vials*.
*Not all pack sizes may be marketed
6.6 Special Precautions For Disposal And Other Handling
From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately.
For single use only.
Furosemide 10mg/ml Injection solution should not be mixed with any other drugs in the injection bottle.
Intravenous furosemide must be injected or infused slowly; a rate of 4 mg per minute must not be exceeded. In patients with severe impairment of renal function (serum creatinine>5 mg/dl), it is recommended that an infusion rate of 2.5 mg per minute is not exceeded.
7. Marketing Authorisation Holder
Wockhardt UK Limited
Ash Road North
Wrexham
LL13 9UF
UK
8. Marketing Authorisation Number(S)
20mg in 2ml: PL 29831/0098
250mg in 25ml: PL 29831/0201
9. Date Of First Authorisation/Renewal Of The Authorisation
01/05/2007
10. Date Of Revision Of The Text
21/02/2011
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