Co-Amilofruse 5/40
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Co-Amilofruse 5/40
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Amiloride Hydrochloride Dihydrate Ph. Eur. 5.70 mg
Anhydrous content 5.00 mg
Furosemide Ph. Eur. 40.00 mg
Also contains E110 (Sunset yellow aluminium lake)
For excipients see section 6.1
3 PHARMACEUTICAL FORM
Tablet (coloured), to be taken orally.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Co-amilofrose is a potassium sparing diuretic indicated where a prompt diuresis is required. It is of particular value in conditions where potassium conservation is important: oedema, congestive cardiac failure, nephrosis, cortico-steroid therapy, oestrogen therapy and for ascites associated with cirrhosis.
4.2 Posology and method of administration
Adults
One tablet which should be taken in the morning but may be increased to two tablets.
Elderly The dosage should be adjusted according to the therapeutic response.
Children Not recommended for use in children.
Co-amilofruse tablets are best taken first thing in the morning, swallowed with a little milk or water.
4.3 Contraindications
Co-amilofruse is contraindicated in patients with an impaired renal function and a creatinine clearance below 30ml/min per 1.73 m2 body surface area, anuria or acute renal failure with anuria not responding to furosemide, severe progressive renal disease (as a result of poisoning by nephrotoxic or hepatotoxic agents or renal failure associated with hepatic coma), hyperkalaemia (serum potassium >5.3 mol/litre), severe hypokalaemia, severe hyponatraemia, Addison's disease, electrolyte imbalance, pre-comatose states associated with cirrhosis, concomitant potassium supplements or potassium-sparing diuretics, and breast-feeding women.
It is contraindicated in patients with hypovolaemia or dehydration (with or without accompanying hypotension).
Known sensitivity to Furosemide, Amiloride or any of the excipients of the product.
Co-Amilofruse is contra-indicated in children and adolescents under 18 years of age as safety in this age group has not yet been established.
4.4 Special warnings and precautions for use
Warnings: Hyperkalaemia has been observed in patients receiving amiloride hydrochloride. Because angiotensin converting enzyme inhibitors may elevate serum potassium level, particularly in the presence of renal impairment, combination with Co-Amilofruse should be avoided in elderly patients, or in others in whom renal function may be compromised. Should it be deemed essential to use Co-Amilofruse, then the clinical condition and serum electrolytes must be carefully and continuously monitored.
Furosemide may cause latent diabetes to become active. It may be necessary to increase the dose of hypoglycaemic agents in diabetic patients. Amiloride should be used with caution in diabetes mellitus. Co-Amilofruse should be discontinued before a glucose tolerance test is undertaken.
Patients with impairment of micturition or with prostatic hypertrophy have an increased risk of developing acute urinary retention during diuretic therapy and require careful monitoring. Patients with hypoproteinaemia, e.g., associated with nephrotic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Caution dose titration is required.
Serum uric acid levels may rise during treatment with Co-Amilofruse, precipitating acute attacks of gout.
Bone marrow depression may occur necessitating withdrawal of the product. The haematopoietic state should be regularly monitored.
Precautions: Patients require regular supervision, with monitoring of fluid and electrolyte states, to avoid excessive loss of fluids.
Co-Amilofruse should be used with particular caution in elderly patients or those with potential obstruction of the urinary tract or disorders rendering electrolyte balance precarious.
Caution should be observed in patients liable to electrolyte deficiency, particularly in patients at high risk of developing electrolyte imbalances. Hyponatraemia, hypochloraemia and raised blood urea nitrogen may occur during vigorous diuresis, especially in seriously ill patients. Therefore careful monitoring of serum electrolytes, creatinine, glucose and urea should be undertaken in these patients. Vigorous diuresis with loop diuretics may induce acute hypotension therefore rapid reduction of plasma volume should be avoided. Correct hypovolaemia before using in oliguria. This may require temporary discontinuation of Co-amilofruse.
Furosemide should be used with caution in hypotension, liver failure, prostate enlargement and porphyria.
In patients who are at high risk for radiocontrast nephropathy, furosemide is not recommended for diuresis as part of the preventative measures against radiocontrast-induced nephropathy.
Co-amilofruse tablets contain sunset yellow dye (E110), which can cause allergic reactions including asthma. Allergy is more common in people who are allergic to aspirin.
4.5 Interaction with other medicinal products and other forms of interaction
The dosage of concurrently administered cardiac glycosides, diuretics, lithium, nondepolarising muscle relaxants or antihypertensive agents or other drugs with blood-pressure lowering potential may require adjustment during treatment with Co-Amilofruse.
Before a glucose tolerance test is undertaken, Co-Amilofruse should be discontinued.
Cephaloridine nephrotoxicity may be increased with the concomitant administration of potent diuretics such as Co-Amilofruse. Regular monitoring of fluid and electrolyte states should be undertaken to avoid excessive loss of fluid.
Co-amilofruse and sucralfate must not be taken within 2 hours of each other because sucralfate decreases the absorption of furosemide from the intestine and so reduces its effect.
Certain non-steroidal anti-inflammatory agents (e.g. indometacin, acetylsalicylic acid) may attenuate the action of Co-amilofruse and may cause renal failure in cases of preexisting hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide. Co-amilofruse may sometimes attenuate the effects of other drugs (e.g. the effects of anti-diabetics and of pressor amines) and sometimes potentiate them (e.g. the effects of salicylates, theophylline, lithium and curare-type muscle relaxants).
Interactions have also been reported with ototoxic antibiotics. Furosemide may potentiate the ototoxicity of aminoglycosides and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with co-amilofruse if there are compelling medical reasons.
There is an increased risk of otoxicity when loop diuretics are given with certain antibacterial drugs e.g., polymyxins and vancomycin.
In cases of concomitant glucocorticoids, corticosteroids, carbenoxolone, liquorice, B2 sympathomimetics in large amounts, acetazolamide, reboxetine and amphotericin therapy, or abuse of laxatives, the risk of an increased potassium loss should be borne in mind. Hypokalaemia caused by diuretics
• increases the risk of ventricular arrhythmias with sertindole, pimozide, amisulpride and sotalol
• increases cardiac toxicity with antiarrhythmic drugs such as amiodarone, quinidine, flecainide and disopyramide
• antagonises action of lidocaine and mexiletine.
ACE inhibitors or angiotensin II receptor antagonists should not be used in combination with Co-amilofruse as serum potassium levels may be increased. A marked fall in blood pressure and deterioration in renal function have also been reported. The dose of Co-amilofruse should be reduced for at least three days, or the drug stopped, before initiating the ACE inhibitor or angiotensin II receptor antagonist or increasing their dose.
There is an increased risk of hypotensive effect with: Alprostadil, adrenergic neurone blockers, alcohol, aldesleukin, alpha- & beta- blockers, general anaesthetics, anxiolytics & hypnotics, MAOIs, phenothiazines, levodopa, nitrates, calcium-channel blockers, moxisylyte, baclofen and tizanidine.
There is an increased risk of postural hypotension when diuretics are given with tricyclic antidepressants.
The hypoglycaemic effect of antidiabetic drugs may be antagonised by Furosemide.
There is increased risk of hyperkalaemia with concomitant intake of amiloride with ciclosporin, trilostane, drospirenone, potassium salts, with drugs that reduce potassium excretion, with nonsteroidal anti-inflammatory drugs or with tacrolimus.
There is increased risk of nephrotoxicity and ototoxicity with cisplatin. 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 diuresis during cisplatin treatment.
Amiloride may cause raised blood digoxin levels. Some electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) may increase the toxicity of certain other drugs (e.g. digitalis preparations and drugs inducing QT interval prolongation syndrome).
Attenuation of the effect of co-amilofruse may occur following concurrent administration of phenytoin.
Concomitant administration of chlorpropamide, carbamazepine or aminoglutethimide may increase the risk of hyponatraemia.
Probenecid, methotrexate and other drugs, which, like furosemide, undergo significant renal tubular secretion, may reduce the effect of co-amilofruse. Conversely, furosemide may decrease 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.
Concomitant administration of furosemide with chloral or triclofos may displace thyroid hormone from binding sites.
Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis.
Ketorolac, corticosteroids, oestrogens and combined oral contraceptives may antagonise the diuretic effect of co-amilofruse.
4.6 Pregnancy and lactation
The safety of Co-Amilofruse during pregnancy and lactation has not been established. Therefore it is not recommended for use during pregnancy and must be avoided during breast-feeding.
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
Side effects include: Nausea, vomiting, diarrhoea, gastric upset, constipation, malaise, parasthesia, dry mouth, dizziness, weakness, muscle cramp, headache, visual changes and confusion.
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.
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 in patients with bladderemptying disorders, prostatic hyperplasia or narrowing of the urethra.
As with other diuretics, electrolytes and water balance may be disturbed as a result of diuresis after prolonged therapy. Hyponatraemia, hypomagnesaemia, hypochloraemic alkalosis, increased calcium excretion, reduced serum calcium levels, hypokalaemia may occur. However, as treatment is continued, the serum potassium concentration may increase due to the later onset of action of amiloride, especially in patients with impaired renal function.
Hypotension and rarely hyperglycaemia have also been reported.
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.
Hypersensitivity reactions are rare but include interstitial nephritis.
If photosensitivity, skin rashes, pruritis, or severe anaphylactic or anaphylactoid reactions (shock) occur, treatment should be withdrawn.
Rarely, minor psychiatric disturbances, and disturbances of liver function tests and ototoxicity may occur.
Tinnitus and deafness have occurred but usually with large parenteral doses and rapid administration, and in renal impairment.
Treatment with Co-Amilofruse is occasionally complicated by bone marrow depression necessitating withdrawal of the product.
Agranulocytosis, thrombocytopenia, leucopenia, aplastic anaemia and haemolytic anaemia have also been reported.
Serum cholesterol and triglyceride levels may rise during treatment.
Hyperuricaemia may occur, possibly precipitating attacks of gout. Cholestatic jaundice and pancreatitis have also occurred.
4.9 Overdose
Emesis should be induced or gastric lavage performed. Correction of any electrolyte imbalance, particularly hyperkalaemia and reversing dehydration. Treatment is symptomatic and supportive. The presence of hyperkalaemia necessitates appropriate measures to reduce serum potassium.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
The Furosemide component acts on the medullary portion of the ascending loop of Henle to inhibit sodium and chloride re-absorption. Furosemide reduces the excretion of uric acid and causes an increased loss of potassium in the urine.
The Amiloride component acts primarily in the distal tubule as a mild naturetic which does not initiate a co-comitant decrease in potassium level. The mechanism of action involves inhibition of the electrogenic entry of sodium, thus causing a fall in the electrical potential across the tubular epithelium. Since this potential is one of the main causes of the secretion of potassium, this mechanism is likely to be the basis of the potassium sparing effect. By blocking the sodium channels Amiloride may also reduce exchange of sodium and hydrogen ions.
5.2 Pharmacokinetic properties
Furosemide component - food intake reduces the bio-availability by about 30%. There appears to be no pre-systemic metabolism and the mean bioavailability is about 52%. In plasma it is extensively bound to proteins, mainly albumen. The volume of distribution ranges between 170-270 ml/kg. The plasma half-life of the drug is 45-60 minutes. There is a correlation between the serum concentration of Furosemide and its diuretic effect and also between the diuretic effect and urine concentration. Furosemide is partly metabolised to and is excreted as a glucuronide in serum and bile.
Amiloride component - is incompletely absorbed (about 50%) from the gastrointestinal tract and about 50% is recovered unchanged in the urine after an oral dose. The drug is not metabolised. After an oral dose peak plasma is reached in about 3-4 hours. When taken on an empty stomach the drug acts in 2 hours, with peak plasma at about 6-10 hours.
The plasma half-life is 6-9 hours. Amiloride is weakly bound to plasma proteins. About 50% of an oral dose is excreted unchanged in the urine in the first 24-72 hours. About 40% of the dose is excreted in the faeces.
5.3 Preclinical safety data
There are no clinically relevant preclinical safety data.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline Cellulose
Crospovidone
Povidone
E110 (Sunset yellow aluminium lake, 20% dye content approx.) Magnesium Stearate
Incompatibilities
6.2
None known.
6.3 Shelf life
As packaged for sale: Two years.
6.4 Special precautions for storage
Store below 25°C in a dry place. Protect from light.
Keep out of reach of children.
6.5 Nature and contents of container
i) PVC/aluminium foil blister strips composed of 250 micron rigid white opaque pharmaceutical grade PVC and 20 micron hard tempered aluminium foil of standard purity, with clear heat-seal coating on the dull side, printed on the bright side.
Blister strips enclosed in cartons containing 28 or 56 tablets.
ii) Polypropylene tablet containers of 28, 56, 100 and 500 tablets with polyethylene closures to pharmaceutical standards, void space within the container being filled with polyethylene wadding.
6.6 Special precautions for disposal
No special precautions.
7 MARKETING AUTHORISATION HOLDER
Cheliona Healthcare Limited Boumpoulinas 11, 3 rd floor Nicosia Cyprus
P C 1060 Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 33414/0029
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28 November 1996
10 DATE OF REVISION OF THE TEXT
15/04/2008