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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-Amilofruse 5mg/40mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Furosemide 40.00mg

Amiloride Hydrochloride (Dihydrate) 5.68mg

For excipients see 6.1

3 PHARMACEUTICAL FORM

Tablet for oral use.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Co-Amilofruse is indicated where a prompt diuresis is required especially in conditions where potassium conservation is important: congestive cardiac failure, nephrosis, fluid retention due to corticosteroid or oestrogen therapy and ascites associated with cirrhosis.

4.2    Posology and method of administration

The starting dose is usually 40/5mg, subsequent dosage being adjusted to suit the needs of the patient.

Adults:

Children:

Not indicated for children under 18 years of age.

Elderly:

The dosage should be adjusted according to diuretic response. Serum electrolytes and urea should be carefully monitored.

4.3    Contraindications

Co-amilofruse is contraindicated in the following circumstances

•    Hypersensitivity to furosemide and/or amiloride, any of the product’s excipients, sulphonamides, sulphonamide derivatives

•    Anuria and impaired renal function (creatinine clearance below 30mL/min per 1.73 m² body surface area) severe progressive renal disease, and renal failure resulting from poisoning by nephrotoxic and/or hepatotoxic agents

•    Electrolyte disturbances (see also section 4.4)

•    severe hyponatraemia

•    severe hypokalaemia or hyperkalaemia (plasma potassium over 5.5 mmol/L)

•    dehydration

•    hypotension

•    Concomitant potassium supplements or other potassium sparing diuretics

•    Pre-coma/coma associated with hepatic cirrhosis

•    Addison’s disease

•    Digitalis intoxication (see also section 4.5)

•    Breast-feeding women (see section 4.6)

•    in children under 18 years of age, as safety in this age group has not been established.

4.4    Special warnings and precautions for use

Hypotension, hypovolaemia and/or dehydration (see also section 4.3)

These and any acid-base disturbances should be corrected before furosemide is started. If these occur during treatment, temporary discontinuation of furosemide infusion may be required.

Diabetes mellitus

To minimize the risk of hyperkalaemia in known or suspected diabetic patients, renal function should be determined before treatment is started. Amiloride should be discontinued at least days before a glucose tolerance test

(risk of provoking severe hyperkalaemia). Furosemide can cause latent diabetes to become overt and insulin requirements in established diabetes to increase).

Hyperkalaemia

•    Noted in patients on amiloride alone and in combination with other diuretics (see below monitoring required)

•    Noted in patients on amiloride in combination with angiotensinconverting enzyme inhibitors

•    Particularly occurs in the elderly, in patients with cirrhosis (see also section 4.3) and/or cardiac oedema who are known to have renal involvement, who are seriously ill or are undergoing vigorous diuretic therapy

•    Potassium conserving agents or diet rich in potassium should not be combined with amiloride (see section 4.3)

•    In renal impairment potassium-sparing agents may result in rapid development of hyperkalaemia. Patients with a creatinine clearance of below 60mL/min per 1.73m body surface area (blood urea over 10mmol/L: serum creatinine over 130 micromol/L) or with diabetes mellitus (see also above) should not receive amiloride without frequent monitoring (see below).

•    If hyperkalaemia develops, amiloride should be stopped immediately (and if necessary, active measures to reduce potassium levels taken)

Not recommended:

Furosemide is not recommended for use as diuresis as part of the preventative measures against radiocontrast-induced nephropathy in patients who are at high risk of developing this condition.

Dose titration/adjustment (see section 4.2)

•    Furosemide should be stopped (or dose reduced) before starting an ACE-inhibitor

•    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 (see also section 4.3)

Thiamine deficiency

Prolonged treatment with furosemide can lead to thiamine deficiency, particularly in congestive heart failure or the elderly.

Caution required:

Caution needed in the following circumstances

•    impaired hepatic function, liver failure (see sections 4.2 & 4.3 and below - monitoring required)

•    impaired renal function and hepato-renal syndrome (see section 4.3 and below -monitoring required)

•    patients (particularly those who are seriously ill) at risk of metabolic or respiratory acidosis (shifts in acid-base balance alter the balance of intra-and extracellular potassium: acidosis may be associated with rapid increases in plasma potassium)

•    elderly patients (see section 4.2: increased risk of thiamine deficiency see below)

•    difficulty with micturition/potential obstruction in the urinary tract including prostatic hypertrophy (increased risk of acute retention).

•    patients at risk of pronounced falls in blood pressure

•    patients at particular risk of hypokalaemia (severe or congestive heart failure: hepatic cirrhosis with ascites - see also section 4.3: hyperaldosteroidism - see also section 4.3)

•    patients with resistant oedema who are taking diuretics

•    gout (increased risk of hyperuricaemia)

•    pancreatititis/history of pancreatitis (increased risk of recurrence/exacerbation with high doses - see also section 4.8)

•    Systemic lupus erythematosus (SLE)/or a history of SLE (potential activation/ aggravation of SLE)

•    patients with hypoparathyroidism (risk of hypocalcaemic tetany)

•    premature infants may develop nephrocalcinosis/nephrolithiasis (see below - monitoring required)

•    porhyria (although furosemide is probably non-porphyrogenic: amiloride considered “safe” in acute porphyria)

Caution with other medicines (also see section 4.5)

•    Risperidone (use in elderly patients with dementia):

In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97 years) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 7096 years) or furosemide alone (4.1%; mean age 80 years, range 67-90 years). Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or cotreatment with other potent diuretics should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be avoided in elderly patients with dementia.

•    Beta2-agonists (asthma)

Hypokalaemia associated with beta2-agonists can be potentiated by furosemide.

Clinical monitoring requirements (see also section 4.8):

Regular monitoring for

•    blood dyscrasias. If these occur, stop furosemide immediately

•    liver damage

•    idiosyncratic reactions In infants there is a risk of

•    development of nephrocalcinosis/nephrolithiasis in premature infants. Renal function must be monitored and renal ultrasonography performed.

•    persistence of patent ductus arteriosus

Laboratory monitoring requirements:

•    renal function in patients with diabetes mellitus - prior to treatment start (risk of hyperkalaemia)

•    potassium in all patients and ECG monitoring in those at risk of hyperkalaemia (see above)

•    other serum electrolytes (particularly sodium, indicators of acid-base disturbances) with replacement as appropriate (especially in patients suffering from excessive vomiting and diarrhoea)

•    frequent BUN/creatinine in first few months of treatment, periodically thereafter

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

•    treatment should be discontinued at least 3 days before a glucose tolerance test (risk of severe hyperkalaemia)

Sugar intolerance

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Enhanced hypotensive effect. Orthostatic hypotension associated with diuretic therapy may be enhanced.

Aldesleukin: Enhanced hypotensive effect.

Anaesthetics, general: Enhanced hypotensive effect.

Anion-exchange resins: Colestyramine and colestipol markedly reduce the absorption of furosemide. Administer 2 to 3 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. Amiloride can antagonise the effects of quinidine.

Antibacterials: Furosemide may enhance the toxicity of nephritic antibiotics including some cephaloporins. Furosemide may potentiate the ototoxicity of anminoglycosides, 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). Increased risk of hypokalaemia when furosemide and reboxetine used concomitantly.

Antidiabetic agents: The hypoglycaemic effect is antagonised by loop diuretics. Hyponatraemia has rarely been reported when chlorpropamide was given with a potassium-sparing diuretic.

Antiepileptics: Increased risk of hyponatraemia with concomitant carbamazepine. The diuretic effect to furosemide has been shown to be substantially reduced by concomitant phenytoin therapy.

Antifungals: Increased risk of ototoxicity and nephrotoxicity with concurrent use of parenteral 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 dieresis. High-dose treatment with furosemide and probenecid may lead to increased serum levels (increased risk of adverse effects).

Antihistamines: Hypokalaemia increases risk of ventricular arrhythmias with terfenadine

Antihypertensives: Furosemide and amiloride enhances the hypotensive action of other antihypertensive drugs, including ACE-inhibitors, angiotensin-II antagonists, beta-blockers, calcium-channel blockers and hydralazine. In addition, amiloride increases the risk of hyperkalaemia with angiotensin-II antagonists (frequent monitoring of serum potassium required). The dosage of concurrently administered antihypertensive agents may require adjustment. There is an increased 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 when initiating or increasing their dose in concomitant therapy with furosemide/amiloride since combination can result in marked reduction in blood pressure and deterioration in renal function. The dose of both should be reduced for at least three days, or the drug stopped, before initiating or increasing the dose of an ACE inhibitor or angiotensin-II receptor antagonist.

Long term intensive treatment with captopril can enhance the natriuretic response to furosemide.

Antipsychotics: Hypokalaemia increases risk of ventricular arrhythmias with pimozide and sertindole, concurrent use should be avoided. Enhanced hypotensive effect with phenothiazines. Risperidone: Caution should be exercised and the risks and benefits of the combination or co-treatment with furosemide or with other potent diuretics should be considered prior to the decision to use. See section 4.4 Special warnings and precautions for use regarding increased mortality in elderly patients with dementia concomitantly receiving risperidone.

Cardiac Glycosides: Increased risk of toxicity if hypokalaemia or hypomagnesaemia occurs. The cardiac glycoside dosage may require adjustment as a more pronounced fall in blood pressure must be anticipated if given concomitantly with furosemide. Amiloride may raise serum digoxin levels.

Corticosteroids: The increased risk of hypokalaemia occurs 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. Concomitant administration of corticosteroids may cause sodium retention.

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 does (e.g. 40mg in patients with normal renal function) and with positive fluid balance when used to achieve forced dieresis during cisplatin treatment. Methotrexate may reduce the effects of Co-amilofruse (significant renal tubular secretion). High-dose treatment with furosemide and methotrexate may lead to increased serum levels and an increased risk of adverse effects.

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. The dosage of concurrently administered diuretics may require adjustment as a more pronounced fall in blood pressure must be anticipated if given concomitantly with furosemide.

Dompaminergics: Enhanced hypotensive effect with levodopa.

Hormones and other endocrine drugs: Combined oral contraceptives and oestrogens may antagonise the diuretic effect. There is an increased risk of hyperkalaemia when amiloride is used concomitantly with trilostane.

Immunosuppressants: Ciclosporin: Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis and nephrotoxicity.

Concurrent use of increases the risk of hyperkalaemia with ciclosporin and tacrolimus.

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 diuretics, resulting in increased lithium toxicity, including increased risk of cardiotoxic and neurotoxic effects. 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 and baclofen; effects of curare-type muscle relaxants may be potentiated.

Nephrotoxic drugs: Effects on renal function may be increased by furosemide

Nicotine: Nicotine inhibits diuresis and diminishes the diuretic effect of furosemide.

Nitrates: Enhanced hypotensive effect

Nonsteroidal anti-inflammatory agents (NSAIDs): Certain NSAIDs (e.g. indometacin, ketoralac, acetylsalicylic acid), may attenuate the diuretic effect of furosemide and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration—Concurrent Co-amilofruse may result in enhanced salicylate toxicity or nephrotoxicity of NSAIDs. When amiloride is used concurrently with NSAIDs renal function and serum potassium should be closely monitored as it may increase the risk of hyperkalaemia (particularly in the elderly).

Potassium conserving agents, potassium supplements: When amiloride is administered with potassium agents or potassium supplements, there is an increased risk of hyperkalaemia (see 4.3 Contraindications).

Prostaglandins: Hypotensive effect may be potentiated by alprostadil.

Sympathomimetics: There is an increased risk of hypokalaemia with high doses of p2- sympathomimetics. Effects of pressor amines may be attenuated.

Theophylline: Risk of hypokalaemia may be increased; effects of theophylline may be potentiated.

Ulcer-healing drugs and other GI protective drugs: Carbenoloxone and liquorice may increase risk of hypokalaemia. Fluid retention associated with carbenoxolone may cause antagonism of diuretic/antihypertensive effect. Amiloride antagonises the ulcer-healing effect of carbenoxolone. Ranitidine causes a moderate increase in the bioavailability of furosemide. Sucralfate may delay GI absorption of furosemide; administer at least 2 hours apart.

4.6 Pregnancy and lactation

Pregnancy

Co-amilofruse must not be used during pregnancy unless there are compelling medical reasons.

In humans-There is clinical evidence of the safety of the furosemide drug in the third trimeseter of human pregnancy; however, furosemide crosses the placental barrier and animal teratology studies indicate it can cause fetal abnormalities.

As a potent diuretic Co-amilofuse will reduce maternal blood volume and increased blood viscosity, and could compromise placental perfusion. If treatment is considered essential, fetal growth should be monitored.

Amiloride has been associated with fetal and neonatal jaundice, fetal bone marrow depression and thrombocytopenia

Lactation

Furosemide is not recommended in nursing mothers as it passes into breast milk and it may inhibit lactation. It is not known whether amiloride passes into breast milk.

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

Metabolism and nutrition disorders: The most common side-effect is fluid and electrolyte imbalance. Electrolyte balance: Effects on electrolyte balance e.g. hyperkalaemia (particularly in elderly patients, diabetics and patients with renal impairment), and hyponatraemia, hypochloraemic alkalosis, hypotension and increased calcium excretion.

As with other diuretics, electrolyte and water balance may be disturbed as a result of diuresis after prolonged therapy. Furosemide leads to an 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, for example, where higher furosemide doses are administered to patients with normal renal function, acute severe electrolyte losses. Warning signs of electrolyte disturbances include dry mouth, thirst, headache, hypotension, drowsiness, confusion, muscle cramps, muscle weakness, tetany, weakness, disorders of cardiac rhythm and gastrointestinal symptoms. Rises in blood-urea-nitrogen concentrations may occur with amiloride. Blood uric acid levels (Furosemide) may cause hyperuricaemia which may precipitate attacks of gout in some patients.

Thiamine deficiency with prolonged treatment particularly in congestive heart failure and the elderly. Increased calcium excretion in infants and new-borns has been associated with reports of decreased bone mineral content, rickets, fractures and renal calcification. Hypocalcaemia 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.

Serum cholesterol and triglyceride levels may rise during furosemide treatment.

During long term therapy they will usually return to normal within six months

Nervous system disorders: Rarely, paraesthesiae may occur, encephalopathy.

Ear and labyrinth disorders: Tinnitus and deafness occur rarely and are usually associated with large and/or rapidly administered parenteral doses, or in patients with hypoproteinaemia or renal impairment. They are usually transient but deafness may be permanent, particularly if furosemide is used concurrently with other ototoxic drugs.

Eye Disorders: visual changes, blurred vision, yellow vision.

Cardiac disorders: angina pectoris, arrhythmia, palpitations

Vascular disorders: 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, syncope, weakness, disorders of vision, dry mouth, and postural 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.

Immune system disorders: 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 co-amilofruse treatment.

Endocrine disorders: 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 may become manifest. Blood glucose concentrations should be monitored in patients taking antidiabetics, since requirements may change

Respiratory, thoracic and mediastinal disorders: Dyspnoea, cough

Gastrointestinal disorders: side-effects of a minor nature including nausea, or gastric upset (vomiting and diarrhoea) may occur but are not usually severe enough to necessitate withdrawal of treatment). Pancreatitis is more common at high doses. Abdominal pain, and constipation may occur.

Blood and lymphatic system disorders: In rare cases, thrombocytopenia, leucopenia, agranulocytosis, eosinophilia, aplastic anaemia or haemolytic anaemia may develop. Bone marrow depression, necessitates withdrawal of treatment.

Hepatobiliary disorders: In isolated cases, disturbances in liver function tests, intrahepatic cholestasis, an increase in liver transaminases, or cholestatic jaundice have been reported. Hepatic encephalopathy in patients with hepatocellular insufficiency may occur.

Psychiatric disorders: Minor psychiatric disturbances are a rare complication. Decreased libido has been reported with amiloride.

Skin and subcutaneous tissue disorders: Skin rashes and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, alopecia and other rashes. Rarely these may be severe and may include, purpura and exfoliative dermatitis and bullous lesions such as erythems multiforme and pemphigoid

Renal /and urinary disorders: 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.

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.

Reproductive system and breast disorders: Impotence

General disorders and administration site conditions: malaise

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Toxicity

More than a few tablets could cause marked symptoms particularly in the elderly.

Toxicity of amiloride in overdose may result from diuresis and or potassium retention. Effects such as hyperkalaemia and hyponatraemia have occurred following chronic therapeutic dosing (particularly in the elderly and those with renal insufficiency and/or diabetes).

Toxicity offurosemide is principally associated with fluid and electrolyte loss. e.g. hypovolaemia, dehydration, haemoconcentration, cardiac arrhythmias due to excessive diuresis.

Features

May cause fluid depletion and electrolyte disturbances eg hypo- or hyperkalaemia, hypo- or hypernatraemia and in severe cases renal failure. Symptoms of these disturbances can also include severe hypotension (progressing to shock), acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion

Management

•    Benefits of gastric decontamination uncertain - consider activated charcoal (50g for adults: 1g/Kg for children) if patient presents within 1 hour of taking more than 2mg/Kg of furosemide.

•    Observe for a minimum of 4 hours post-ingestion

•    Check U&Es and creatinine, and repeat in patients with significant diuresis or cardiovascular features.

•    Monitor ECG in symptomatic patients or those with hyperkalaemia

•    Treat hypotension (see below)

Hypotension

•    Correct hypotension (raise foot of bed: adequate fluids/crystalloids)

•    Patients with fluid-resistant hypotension can deteriorate extremely rapidly and should be managed by experienced physicians and should be referred as soon as possible to the local critical care team/intensive care unit.

•    If inotropes and/or vasopressors are required they should only be used by an experienced physician.

•    If severe hypotension persists advice should be sought from appropriate National Poisons Information Service

Other effects

•    Treat brady- and tachyarrhythmias appropriately

•    Treat severe hyperkalaemia conventionally (calcium gluconate: calcium chloride: insulin and dextrose)

•    Other measures as indicated by the patient’s condition.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Furosemide is a potent loop diuretic with a rapid action. Its effects are evident within one hour when administered orally, lasting four to six hours, and onset five minutes after intravenous injection, persisting for up to two hours. It has been reported to exert inhibiting effects on electrolyte reabsorption in the proximal and distal renal tubules, and in the ascending loop of Henle. Excretion of sodium, potassium and chloride ions is increased and water excretion enhanced.

Amiloride hydrochloride is a mild diuretic, which appears to act mainly on the distal renal tubules. It takes effect about two hours after oral administration and persists for up to 24 hours. The full effect may be delayed until after several days of treatment.

It increases the excretion of sodium and chloride and reduces the excretion of potassium. Amiloride adds to the natriuretic but diminishes the kaliuretic effects of other diuretics and is used as an adjunct to furosemide to conserve potassium.

5.2 Pharmacokinetic properties

Furosemide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It has a biphasic half-life in the plasma with a terminal elimination phase that has been estimated to range up to one and a half-hours. It is up to 99% bound to plasma proteins, and is mainly excreted in the urine, largely unchanged, but also in the form of the glucuronide and free amine metabolites. Variable amounts are also excreted in bile, non-renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in milk.

Amiloride is incompletely absorbed from the gastrointestinal tract; peak serum concentrations are achieved about three to four hours after oral administration. It is excreted unchanged in the urine, and animal studies have shown little evidence of any biliary excretion. Amiloride has been estimated to have a serum half-life of about six hours.

5.3 Preclinical safety data

There are no pre-clinical data of any relevance to the prescriber, which are additional to those already included in other sections.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose powder

Microcrystalline Cellulose

15005 Dispersed Sunset Yellow FCF Lake

Povidone K30

Sodium Starch Glycollate

Magnesium Stearate

Purified Water

6.2 Incompatibilities None known.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Opaque white blister packs manufactured from UPVC and aluminium foil containing 28, 30, 56, or 60 tablets.

Polypropylene or polyethylene tablet containers with a lid containing 500 tablets.