Furosemide 20 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Furosemide 20mg Tablets BP.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20 mg furosemide.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White, circular, flat bevel-edged tablets. Engraving: 1B2: plain with breakline or plain: plain with breakline.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Furosemide 20 mg Tablets are indicated for the treatment of oedema states and hypertension.
4.2 Posology and method of administration
For oral administration.
The tablets should be swallowed with water.
It is recommended that furosemide tablets are taken on an empty stomach, and with plenty of liquid.
Adults: The usual initial dosage is 40 mg (two tablets daily). This may require adjustment on an individual basis until the effective dose is achieved. 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. Severe cases may require gradual titration of the furosemide dosage up to 600 mg daily. The recommended maximum daily dose of furosemide is 1,000 mg.
Hypertension: In mild to moderate hypertension the usual dose is 40 mg furosemide once daily.
In severe cases up to 60 mg furosemide per day. In case of insufficient response combination with non-diuretic anti-hypertensives is recommended.
Children: The oral dose for children ranges from 1 - 3 mg/kg body weight daily. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose up to a maximum total dose of 40 mg per day.
Elderly: The usual adult dose, but caution is advised as furosemide is excreted more slowly in the elderly.The dose should be titrated until a satisfactory response is achieved.
In case of renal insufficiency less furosemide will reach the renal tubules.
An increase of dose may be necessary to obtain the same diuretic effect.
No dosage adjustment is needed for patients with mild hepatic impairment; however the dosage may require adjustment in cases of moderate to severe hepatic impairment.
4.3 Contraindications
• Electrolyte deficiency
• Anuria or renal failure with anuria not responding to furosemide
• Renal failure as a result of poisoning by hepatotoxic or nephrotoxic agents
• Renal failure associated with hepatic coma
• Severe hypokalaemia
• Severe hyponatraemia
• Pre-comatose states or coma due to hepatic encephalopathy
• Breast-feeding women
• Hypovolaemia or dehydration (with or without accompanying hypotension)
• Hypersensitivity to furosemide or any of the excipients of furosemide 20 mg Tablets
• Patients allergic to sulphonamides or sulphonamides derivatives may show cross-sensitivity between furosemide and sulphonamides.
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. Use with care in elderly patients.
Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.
Particularly careful monitoring is necessary in:
• Patients with hypotension.
• Patients who are at risk from a sudden, unexpected or pronounced fall in blood pressure (e.g. patients with cerebrovascular disorders or coronary heart disease)
• Patients with hepatorenal syndrome.
• Urinary tract obstruction (e.g. prostate hypertrophy, hydronephrosis, ureteral stenosis).
• Patients where latent diabetes may become manifest or the insulin requirements of diabetic patients may increase.
• Use with caution in patients with a history of gout Serum uric acid levels tend to rise during treatment with furosemide and an acute attack of gout may occasionally be precipitated. This may require temporary discontinuation of furosemide.
• Patients with hypoproteinaemia, e.g. associated with nephrotic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Careful dosage titration is required.
• Premature infants (possible development of nephrocalcinosis/nephrolithiasis; renal function must be monitored and renal ultrasonography performed). In premature infants with respiratory distress syndrome, diuretic treatment with furosemide during the first weeks of life can increase the risk of persistent ductus arteriosus Botalli.
• Hepatic cirrhosis and concomitant renal impairment,
Serum cholesterol and triglyceride levels may rise during furosemide treatment but will usually return to normal within six months.
Caution should be observed in patients liable to electrolyte deficiency.Regular checks of serum sodium, potassium, calcium, bicarbonate, urea, uric acid, creatinine and blood glucose levels are 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 (e.g. owing to acute hypercalcaemia, vomiting, diarrhoea or intense sweating). Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of furosemide.
The weight loss resulting from increased urine excretion should not exceed 1 kg/day independently from the degree of urine excretion.
The dose should be adjusted with caution in patients with nephrotic syndrome owing to the increased risk of adverse events.
Increases in blood glucose and alterations in glucose tolerance tests have been observed, and rarely, precipitation of diabetes mellitus has been reported.
During long term treatment with furosemide, a potassium rich diet is always indicated (e.g. potatoes, bananas, tomatoes, spinach, dry fruits). Sometimes a medicinal substitution of potassium is recommended. In other cases (i.e. liver cirrhosis), it is indicated to prevent hypokalemia and metabolic alkalosis by administering a potassium sparing agent.
In case of renal insufficiency less furosemide will reach the renal tubules. An increase of dose may be necessary to obtain the same diuretic effect.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The duration of administration depends on the nature and the severity of the disease.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on furosemide
Certain non-steroidal anti-inflammatory agents (e.g. indomethacin, acetylsalicylic acid) may attenuate the action of furosemide and may cause acute renal failure in patients with pre-existing hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide.
Effect offurosemide on other medicinal products
Furosemide may potentiate the action of concurrently administered cardiac glycosides, diuretics, anti-hypertensive agents, or other drugs with blood-pressurelowering potential, the dosage of which may need to be reduced.
Cardiac glycosides
In concurrent treatment with cardiac glycosides, it should be taken into account that if hypokalaemia and/or hypomagnesaemia develop during therapy with furosemide, the sensitivity of the myocardium towards cardiac glycosides is increased. There is an increased risk of ventricular arrhythmias (including torsades de pointes) when medicinal products that may cause prolongation of the QT interval (e.g. terfenadine, some antiarrhythmics of classes I and III) are used concomitantly, and in the presence of electrolyte imbalance.
Anti-hypertensive agents:
The dosage of concurrently administered antihypertensive agents may require adjustment.
ACE inhibitors:
A marked fall in blood pressure should be expected on concomitant administration of furosemide with other antihypertensives, diuretics or agents with the potential to decrease the blood pressure.The effects of other antihypertensives can be potentiated by concomitant administration of furosemide. Massive reduction in blood pressure to the point of shock in extreme cases and worsening of renal function (acute renal failure in isolated cases) have been reported when angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) were administered, or for the first time at high dosage (first dose hypotension). If possible, furosemide therapy should be temporarily discontinued (or the furosemide dosage should be reduced) for three days before therapy with an ACE inhibitor is initiated or the dose of an ACE inhibitor is increased.
Nephrotoxic antibiotics:
The toxic effects of nephrotoxic antibiotics (e.g. cephaloridine, aminoglycosides, cephalosporins, polymyxins) may be increased by concomitant administration of potent diuretics such as furosemide.
Ototoxic antibiotics:
Furosemide may potentiate the ototoxicity of aminoglycosides (e.g.kanamycin, gentamicin, tobramycin) and other ototoxic medicinal products. Since this may lead to irreversible damage, these medicinal products must only be used with furosemide if there are compelling medical reasons.
Non-steroidal anti-inflammatory agents:
Patients receiving high doses of salicylates concomitantly with furosemide, as in rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal excretory sites.
Lithium:
As with other diuretics, concomitant administration of lithium may lead to increased serum lithium levels, resulting in increased lithium toxicity. The combination of furosemide and lithium leads to reduced lithium excretion and consequently to an increase in the cardio- and neurotoxic effects of lithium.
Therefore, it is recommended that lithium levels are carefully monitored in patients requiring such combined treatment and where necessary the lithium dosage is adjusted in patients receiving this combination.
Others:
Sucralfate and oral furosemide must not be taken within two hours of each other because sucralfate decreases the absorption of furosemide from the intestine and so reduces its effect.
Furosemide may sometimes attenuate the effects of some drugs e.g. antidiabetics and pressor amines (e.g. epinephrine, norepinephrine), and sometimes potentiate the effects of others e.g. salicylates, theophylline and curare-type muscle relaxants.
There is a risk of ototoxic effects if furosemide and cisplatin are given together. In addition, 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.
Attenuation of the effect of furosemide may occur following concurrent administration of phenytoin.
Concomitant administration of aminoglutethimide or carbamazepine may increase the risk of hyponatraemia.
Corticosteroids administered concurrently may cause sodium retention.
Carbenoxolone, corticosteroids, liquorice, f>2 sympathomimetics in large amounts, and prolonged use of laxatives, amphotericin and reboxetine may increase the risk of developing hypokalaemia.
Some electrolyte disturbances (e.g. hypomagnesaemia, hypokalaemia) may increase the toxicity of certain other drugs (e.g. drugs inducing QT interval prolongation syndrome and digitalis preparations).
Methotrexate, probenecid, and other drugs which, like furosemide, undergo significant renal tubular secretion may reduce the effect of furosemide.
Conversely, furosemide may decrease the renal elimination of these drugs. In case of high-dose treatment (in particular, of both furosemide and the other drugs) this may lead to increased serum levels and an increased risk of adverse effects due to furosemide or the concomitant medication.
4.6 Fertility, Pregnancy and Lactation
Furosemide should only be used during pregnancy for short periods if absolutely necessary, as it crosses the placenta.
Diuretics are not routinely indicated for the treatment of hypertension and oedema in pregnancy since they reduce placental perfusion and consequently intra-uterine growth.
Results of animal work, in general, show no hazardous effect of furosemide in pregnancy.
The teratogenic and embryotoxic potential of furosemide in humans is unknown. Furosemide should not be used during pregnancy unless it is clearly necessary or there are compelling medical reasons (for example such as in the case of maternal congestive heart failure) and the benefits to the mother outweigh the possible risk to the foetus. There is clinical evidence of safety of the drug in the third trimester of human pregnancy; however, furosemide crosses placental barrier and can therefore cause increased diuresis of the foetus.
Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
In pregnancy furosemide should only be used on advice of a physician and should only be used if the oedema is not related to the pregnancy. Treatment of oedema and hypertension caused by pregnancy with diuretics is not advisable in general as the physiological hypovolaemia may be enhanced and the placental perfusion may be lowered . Treatment during pregnancy requires monitoring of foetal growth.
If use of furosemide is essential for the treatment of cardiac or renal insufficiency during pregnancy, careful monitoring of electrolytes, haematocrit and foetal growth is essential. Possible displacement of bilirubin from the albumin binding and thus elevated risk of nuclear icterus in hyperbilirubinaemia is discussed for furosemide.
Furosemide may compromise placental perfusion by reducing maternal blood volume.
Furosemide passes the placenta and reaches 100% of the maternal serum concentration in cord blood. No malformations in humans which might be associated with exposure to furosemide have been reported to date. However, there is insufficient experience to allow a concluding evaluation of a potential damaging effect in the embryo/foetus. In utero urinary production can be stimulated in the foetus. Urolithiasis has been observed after treatment of premature infants with furosemide.
Furosemide passes into breast milk and may inhibit lactation. Women must not breast feed if they are treated with Furosemide. If necessary, breastfeeding should be discontinued (see also section 4.3 "Contraindications").
4.7 Effects on ability to drive and use machines
Furosemide has minor or moderate influence on the ability to drive and use machines. It may elicit diverse individual reactions which might impair the ability to drive and use machines, especially at the beginning therapy, on increasing the dose or changing the treatment and in association with alcohol. Reduced mental alertness may impair the ability to drive or operate machinery.
4.8 Undesirable effects
Furosemide is generally well tolerated.
The evaluation of adverse reactions is based on the following definition of frequency:
The frequencies of adverse events are ranked according to the following: 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), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
Uncommon: thrombocytopenia Rare: eosinophilia, leukopenia
Very rare: haemolytic anaemia, aplastic anaemia, agranulocytosis
Bone marrow depression has been reported as a rare complication and necessitates withdrawal of treatment.
Immune system disorders
Uncommon: pruritus, dermal and mucosal reactions (see skin and subcutaneous tissue disorders)
Rare: severe anaphylactic and anaphylactoid reactions such as anaphylactic shock (for treatment see section 4.9)
The incidence of allergic reactions such as skin rashes, photosensitivity or shock is low, but when these occur treatment should be withdrawn. Mucous membrane and skin reactions may occasionally occur, e.g. urticaria, itching, bullous lesions or other rashes.
Endocrine disorders
Glucose tolerance may decrease during treatment with furosemide, and hyperglycaemia may occur. In patients with diabetes mellitus this may lead to a deterioration of metabolic control. Latent diabetes may become manifest.
Metabolism and nutrition disorders
Common: Impairment of electrolyte and fluid balance as a consequence of increased electrolyte excretion are commonly observed during therapy with furosemide. Regular monitoring of serum electrolytes (especially potassium, sodium and calcium) is therefore indicated.
Possible development of electrolyte disorders is influenced by underlying disorders (e.g. hepatocirrhosis, heart failure), concomitant medication (see section 4.5 "Interaction with other medicinal products and other forms of interaction") and nutrition.
As with other diuretics, water balance and electrolytes may be disturbed as a result of diuresis after prolonged therapy. Furosemide leads to an increased excretion of chloride and sodium and consequently water. In addition, excretion of other electrolytes (in particular calcium, potassium and magnesium) is increased. Symptomatic electrolyte disturbances and metabolic alkalosis may develop in the form of gradually increasing electrolyte deficit or, e.g. where higher furosemide doses are administered to patients with normal renal function, acute severe electrolyte losses. Existing metabolic alkalosis may be exacerbated, as a result of electrolyte and fluid losses during treatment with furosemide. Warning signs of electrolyte disturbances included increased thirst, headache, hypotension, muscle cramps, confusion, muscle weakness, tetany, 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.
As a result of increased renal sodium losses, hyponatraemia with corresponding symptoms may occur, particularly if the supply of sodium chloride is restricted. Commonly observed symptoms of sodium deficiency are apathy, systremma, inappetence, asthenia, somnolence, vomiting and confusion.
Particularly when the supply of potassium is concomitantly reduced and/or extrarenal potassium losses are increased (e.g. in vomiting or chronic diarrhoea), hypokalaemia may occur as a result of increased renal potassium losses. This is manifested as neuromuscular (myasthenia, paraesthesia, pareses), intestinal (vomiting, constipation, meteorism), renal (polyuria, polydipsia) and cardiac (impaired paced setting and conduction disorders) symptoms. Severe potassium losses may lead to paralytic ileus or disturbed consciousness, with coma in extreme cases.
Increased renal calcium losses (Serum calcium levels may be reduced; in very rare cases tetany has been observed) can lead to hypocalcaemia, which may induce tetania in rare cases.
In patients with increased renal magnesium losses, tetania or cardiac arrhythmia were observed in rare cases as a consequence of hypomagnesaemia.
As with other sulphonamide-based diuretics, hyperuricaemia occurs commonly during furosemide therapy. This may lead to acute episodes of gout in predisposed patients. Rarely, clinical gout may be precipitated.
Serum levels of cholesterol and triglycerides may be elevated during furosemide treatment but during prolonged therapy these usually return to normal within six months.
Nervous system disorders Rare: paraesthesia
Rare: On account of the ototoxic effects of furosemide, hearing disorders and / or, tinnitus (dysacusis and/or syrigmus (tinnitus aurium)) can occur, but this is reversible in the majority of cases. This undesirable effect is particularly associated with too rapid i.v. injection, predominantly in patients with coexisting renal insufficiency or renal failure or hypoproteinaemia (e.g. in nephrotic syndrome).
Vacular disorders
In excessive diuresis, circulatory complaints may occur, particularly in elderly patients and in children. These are predominantly manifested as headache, vertigo, dysopia, xerostomia and thirst, hypotension and orthostatic dysregulation. The diuretic action of furosemide may contribute or lead to dehydration and hypovolaemia especially in elderly patients. Dehydration and as a consequence of hypovolaemia, circulatory collapse and haemoconcentration may occur as a result of excessive diuresis. As a result of haemoconcentration, there may be an increased risk of thrombosis, particularly in elderly patients.
Rare: vasculitis
Furosemide may cause a reduction in blood pressure, which if pronounced may cause signs and symptoms such as light-headedness, sensations of pressure in the head, impairment of concentration and reactions, dizziness, headache, weakness, drowsiness, disorders of vision, dry mouth, orthostatic intolerance.
Gastrointestinal disorders
Rare: gastrointestinal complaints (e.g. nausea, vomiting, diarrhoea)
Very rare: acute pancreatitis
Reported side effects include gastric upset.
Hepato-biliary disorders
Very rare: intrahepatic cholestasis, increase in hepatic transaminases
Skin and subcutaneous tissue disorders
Uncommon: pruritus, dermal and mucosal reactions (e.g. bullous exanthema, urticaria, purpura, erythema multiforme, exfoliative dermatitis, photosensitivity)
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis
Pregnancy, puerperium and perinatal conditions
If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus. Nephrocalcinosis/nephrolithiasis has been reported in premature infants.
Renal and urinary disorders
As with other diuretics, transient rises in blood creatinine and urea levels have been reported.
Increased production of urine may aggravate or provoke complaints in patients with an obstruction of urinary outflow. Acute retention of urine with possible secondary complications may occur for example in patients with prostatic hyperplasia, bladderemptying disorders or narrowing of the urethra.
Rare: renal inflammation (interstitial nephritis)
General disorders
Rare: fever Malaise
4.9 Overdose
Overdose may lead to hypotension, orthostatic regulation disorders, electrolyte disorders (hypokalaemia, hyponatraemia, hypochloraemia) or alkalosis. Severe fluid loss may result in marked hypovolaemia, dehydration, circulatory collapse and haemoconcentration with risk of thrombosis. Delirium may occur with rapid fluid and electrolyte loss. Anaphylactic shock (symptoms: perspiration, nausea, cyanosis, severe hypotension, loss of consciousness, coma) may rarely develop.
The clinical picture in chronic or acute overdose depends primarily on the consequences and extent of electrolyte and fluid loss, e.g. dehydration, hypovolaemia, cardiac arrhythmias due to excessive diuresis and haemoconcentration. Symptoms of these disturbances include severe hypotension (progressing to shock), thrombosis, acute renal failure, delirious states, apathy, confusion and flaccid paralysis.
Treatment
Furosemide must be immediately discontinued in the event of overdose or on development of signs of hypovolaemia (hypotension, orthostatic regulation disorders).
Primary poison management measures (induced vomiting, gastric lavage) and measures to reduce absorption (medicinal charcoal) should be taken if the overdose is recent.
In severe cases, vital signs must be monitored and the fluid, electrolyte and acid-base balance, blood glucose and renally excreted substances repeatedly evaluated, and any necessary corrective measures taken.
In patients with micturition disorders (e.g. prostate hypertrophy), an unobstructed flow of urine must be maintained, as a sudden flux of urine could lead to anuria with over-extension of the bladder
Treatment of hypovolaemia: volume expansion Treatment of hypokalaemia: potassium substitution
Treatment of circulatory collapse: shock position, if necessary, shock therapy
Dehydration and electrolyte depletion should be corrected. 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).
Immediate treatment measures in case of anaphylactic shock (at the first signs e.g. cutaneous reactions such as urticaria or flush, agitation, restlessness, headache, sudden, excessive perspiration, nausea, cyanosis):
• create a venous access
• maintain circulation
• in addition to other common emergency measures, head-chest down position, ensure airways are clear, maintain patient’s airway, administration of oxygen
• if necessary, initiate further - possibly also intensive care - measures (among others administration of epinephrine, volume replacement, glucocorticoids).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: ATC Code: C03C A01 (high-ceiling diuretics, sulphonamides, plain).
Furosemide is a potent, short and rapid-acting loop diuretic.
Furosemide is one of the high ceiling diuretics, a term used to denote a group of diuretics that have a distinctive action on renal tubular function. The peak diuresis is far greater than that observed with other agents. The main site of action is the thick ascending loop of Henle where they inhibit electrolyte reabsorption. It increases renal blood flow without increasing the filtration rate. Such a change in renal haemodynamics reduces fluid and electrolyte re-absorption in the proximal tubule and may augment the initial diuretic response. Furosemide is an inhibitor of carbonic anhydrase but this activity is too weak to contribute to a proximal diuresis except when massive doses are employed. Furosemide enhances the excretion of both calcium and magnesium to an extent approximately proportional to the increase in sodium excretion. Unlike the thiazides, high ceiling diuretics do not increase calcium re-absorption in the distal tubule. The calciuric action of these agents is the basis for their use in symptomatic hypercalcaemia.
It inhibits the re-absorption ofof Na+/2Cl-/K+ in the ascending part of Henle's loop by blocking the ion carrier for these ions. The fractional sodium excretion can amount to 35% of the glomerularly filtrated sodium. Increased sodium excretion leads secondarily to increased urinary excretion and to increased distal-tubular K+-secretion attributable to osmotically bound water. The excretion of Ca2+ and Mg2+ ions is also increased. Besides the losses of the above-mentioned electrolytes, excretion of uric acid may be reduced, and a shift of the acid-base balance towards metabolic alkalosis may occur.
Furosemide interrupts the tubuloglomerular feedback mechanism at the macula densa, so that the saluretic efficacy is not attenuated.
Furosemide leads to dose-dependent stimulation of the renin-angiotensin-aldosterone system. In case of cardiac insufficiency, furosemide leads to an acute reduction of the cardiac preload through dilatation of the venous capacitance vessels. This early
vascular effect seems to be mediated through prostaglandins and requires sufficient renal function with activation of the renin-angiotensin-aldosterone system as well as intact prostaglandin synthesis.
Furosemide has an antihypertensive effect as a consequence of increased excretion of sodium chloride and reduced responsiveness of vascular smooth muscle cells to vasoconstrictive stimuli, and a reduction in blood volume.
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 from the gastrointestinal tract and its effect is largely over within four hours. 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. It is extensively bound to plasma proteins but is rapidly secreted by the organic acid transport system of the proximal tubule. In this manner it gains access to the tubular fluid and eventually to its site of action more distally. Furosemide is bound to plasma albumin and little biotransformation takes place. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration, 69-97% of activity from a radiolabelled dose is excreted in the first 4 hours after the furosemide is given. Furosemide is mainly eliminated via the kidneys (80-90%); a small fraction of the dose undergoes biliary elimination and Variable amounts are also excreted in the bile (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. 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.
a) 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 Tablets, but less than 20% residual renal function increases the elimination time.
b) The Elderly
The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.
c) Newborn
A sustained diuretic effect is seen, possibly due to immature tubular function.
5.3 Preclinical safety data
Acute oral toxicity was low in all species tested. Chronic toxicity studies in the rat and dog led to renal alterations (among others fibrous degeneration and renal calcification).
In vitro and in vivo tests of genetic toxicology did not reveal any clinically relevant evidence of a genotoxic potential of furosemide.
Long-term studies in mice and rats did not yield any relevant evidence of a tumorigenic potential.
In studies of reproductive toxicology in foetal rats, a reduced number of differentiated glomeruli, skeletal anomalies of the scapulae, humerus and ribs (induced by hypokalaemia), as well as hydronephrosis occurred in foetal mice and rabbits after administration of high doses.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Magnesium stearate Sodium starch glycolate Maize starch Starch paste.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years: Tablet container.
2 years: Blister pack.
6.4 Special Precautions for Storage
Do not store above 25°C.
Tablet container: Store in the original container. Keep the container tightly closed.
Blister pack: Store in the original package. Keep container in the outer
carton.
6.5 Nature and Contents of Container
Polypropylene containers with low density polyethylene caps in packs of 28, 56, 100, 250, 500 or 1000 tablets.
250pm white opaque PVC film with 20pm hard temper aluminium foil blister strips in packs of 28 or 56 tablets.
Not all pack sizes may be marketed.
6.6 Instructions for Use/Handling
Not applicable.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road, Hampden Park
Eastbourne, East Sussex, BN22 9AG
8. MARKETING AUTHORISATION NUMBER
PL 00289/0417
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/07/2009
10 DATE OF REVISION OF THE TEXT
02/12/2011