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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amiloride Hydrochloride 5 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5.68 mg amiloride hydrochloride equivalent to 5 mg amiloride hydrochloride anhydrous.

For a full list of excipients, please refer to section 6.1.

3.    PHARMACEUTICAL FORM

Tablet

Yellow, flat, bevel-edge tablets, engraved 1A5 or BERK 1A5 on one side and plain on the reverse.

4.1. Therapeutic indications

Amiloride is a potassium sparing diuretic.

Although amiloride may be used alone, its principal use is as concurrent therapy with thiazides or more potent diuretics to conserve potassium during periods of vigorous diuresis and during long term therapy.

Hypertension: Amiloride is used as an adjunct in prolonged therapy with thiazides and similar agents to prevent potassium depletion.

Congestive heart failure: Amiloride may be effective alone, but again its principal indication is for the concomitant use in patients receiving thiazides or more potent diuretic agents.

Hepatic cirrhosis with ascites: Amiloride usually provides adequate diuresis, with diminished potassium loss and less risk of metabolic alkalosis, when used alone. It may be used with more potent diuretics when a greater diuresis is required, whilst still maintaining a more balanced serum electrolyte pattern.

4.2 Posology and method of administration

For oral administration.

Amiloride alone: The usual initial dose is 10 mg daily or 5 mg twice daily, adjusted according to response. The total daily dose should not exceed 20 mg per day. After diuresis has been achieved, the dosage may be reduced by 5 mg increments to the lowest effective dose.

With other diuretics: When used with a diuretic given on an intermittent basis, amiloride should be given at the same time.

Hypertension: 5 or 10 mg a day, together with the usual antihypertensive dose of the thiazide concurrently employed. It is not usually necessary to exceed 10 mg a day of amiloride; certainly not more than 20 mg (4 tablets) a day should be administered.

Congestive heart failure: Initially, 5 or 10 mg (1 or 2 tablets) a day, together with the usual dose of the diuretic concurrently employed. If diuresis is not achieved with minimal dosage of both agents, the dosage of both may be gradually increased, but that of amiloride must not exceed 20 mg (4 tablets) a day. Once diuresis has been achieved, reduction of both agents may be attempted for maintenance therapy. The dosage of both drugs is determined by the diuresis and the level of plasma potassium.

Hepatic cirrhosis with ascites: Treatment should be started with a small dose of amiloride i.e. 5 mg plus a low dosage of the other diuretic agent. If necessary, dosage of both agents may be increased gradually.

The dosage of amiloride should not exceed 20 mg (4 tablets) a day. Maintenance doses may be lower than those required to achieve diuresis; therefore a reduction in the daily dose should be attempted when the patient's weight is stabilised.

Children under 18 years

Amiloride tablets should not be used in children.

The Elderly

The elderly are more susceptible to electrolyte imbalance and are more likely to experience hyperkalaemia since renal reserve may be reduced. The dosage should be carefully adjusted according to renal function, blood electrolytes and diuretic response.

4.3 Contraindications

Amiloride tablets are contra-indicated in hyperkalaemia (plasma potassium over 5.5 mmol/l); prior sensitivity to amiloride; anuria, acute renal failure, severe progressive renal disease and    diabetic nephropathy (see section 4.4). They should also not be

used with other potassium conserving agents or potassium supplements (see section 4.4). Safety for use in children under 18 years of age is not established.

4.4 Special warnings and precautions for use

Amiloride should be given with caution to elderly patients, patients likely to develop acidosis, patients with diabetes mellitus and those with impaired hepatic or renal function

Diabetes mellitus: To minimise the risk of hyperkalaemia in known or suspected diabetic patients, the status of renal function should be determined before initiating therapy. Amiloride should be discontinued for at least 3 days before a glucose tolerance test.

Respiratory or metabolic acidosis: Potassium-conserving therapy should be initiated only with caution in severely ill patients in whom metabolic or respiratory acidosis may occur e.g. patients with cardiopulmonary disease of decompensated diabetes. Shifts in acid-base balance alter the balance of extracellular-intracellular potassium, and the development of acidosis may be associated with rapid increases in plasma potassium.

Hyperkalaemia: This has been observed in patients taking amiloride alone or with other diuretics or angiotensin-converting enzyme inhibitors. These patients should be observed carefully for clinical, laboratory and ECG evidence for hyperkalaemia.

Some deaths have been reported in this group of patients. Hyperkalaemia has been noted particularly in the elderly and in patients with hepatic cirrhosis or cardiac oedema who have known renal involvement, who were seriously ill, or who were undergoing vigorous diuretic therapy.

Neither potassium-conserving agents nor a diet rich in potassium should be used with amiloride except in severe and/or refractory cases of hypokalaemia. If the combination is used, plasma potassium levels must be continuously monitored.

Impaired renal function: Patients with increases in blood urea over 10 mmol/l, serum creatinine over 130 pmol/l, or with diabetes mellitus, should not receive amiloride without careful, frequent monitoring of serum electrolytes and blood urea levels. In renal impairment, use of a potassium-conserving agent may result in rapid development of hyperkalaemia.

Treatment of hyperkalaemia: If hyperkalaemia occurs, amiloride should be discontinued immediately and, if necessary, active measures taken to reduce the plasma potassium level.

Electrolyte imbalance and reversible blood urea increases: Hyponatraemia and hypochloraemia may occur when amiloride is used with other diuretics. Reversible increases in blood urea levels have been reported accompanying vigorous diuresis, especially when diuretics were used in seriously ill patients, such as those with hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant oedema. Careful monitoring of serum electrolytes and blood urea levels should therefore be carried out when amiloride is given with other diuretics to such patients.

Cirrhotic patients: Oral diuretic therapy is more frequently accompanied by side effects in patients with hepatic cirrhosis with or without ascites, because these patients are intolerant of acute shifts in electrolyte balance, and because they often already have hypokalaemia as a result of associated aldosteronism. Patients should receive careful, frequent monitoring of serum electrolytes and blood urea levels

In patients with pre-existing severe liver disease, hepatic encephalopathy (manifested by tremors, confusion, and coma), and increased jaundice, have been reported in association with diuretics, including amiloride.

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 medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Lithium should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity.

When combined with thiazide diuretics, amiloride can act synergistically with chlorpropamide to increase the risk of hyponatraemia.

When amiloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated because of hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

Concomitant administration of non-steroidal anti-inflammatory drugs (NSAIDs) and potassium-sparing agents, including amiloride, may cause hyperkalaemia and renal failure, particularly in elderly patients. Therefore, if used concomitantly, renal function    and serum potassium levels should be carefully monitored.

Indomethacin and ketorolac antagonise the diuretic effect.

An enhanced hypotensive effect (which can be extreme) can result if taking antihypertensives, including ACE inhibitors, angiotensin-II antagonists, calcium channel blockers, beta blockers or alpha blockers (increased risk of first dose hypotension). There is an increased risk of first-dose hypotensive effect of postsynaptic alpha-blockers such as prazosin. With ACE inhibitors and angiotensin-II antagonists there is also an increased risk of hyperkalaemia.

Hypokalaemia increases the risk of ventricular arrhythmias with pimozide or thioridazine. Concomitant use should be avoided.

An enhanced hypotensive effect can result if taking beta-blockers. Hypokalaemia can cause an increase in the risk of ventricular arrhythmias when taking sotalol.

An enhanced hypotensive effect can occur if taking calcium channel blockers.

If ciclosporin and potassium-sparing diuretics are taken together there is an increased risk of hyperkalaemia.

Trilostane increases the risk of hyperkalaemia in patients taking potassium-sparing diuretics.

An enhanced hypotensive effect can occur if moxisylyte is taken with diuretics.

An enhanced hypotensive effect can occur if baclofen or tizanidine are taken with diuretics.

Oestrogens and combined oral contraceptives antagonise the diuretic effect; possible hyperkalaemia can occur with trilostane, drospirenone and spironolactone or other potassium-sparing diuretics.

There is an increased risk of hyperkalaemia when potassium-sparing diuretics are taken with potassium salts.

There is an increased risk of hyperkalaemia when potassium-sparing diuretics are taken with ciclosporin and tacrolimus.

An enhanced hypotensive effect can occur if alprostadil is taken.

Cardiac toxicity of amiodarone, disopyramide, flecainide, and quinidine increased if hypokalaemia occurs; the action of lidocaine and mexiletine can be antagonised by hypokalaemia.

The antiarrhythmic activity of quinidine can be opposed by amiloride.

There is an increased risk of nephrotoxicity and ototoxicity with cisplatin.

Postural hypotension associated with diuretic therapy may be enhanced by alcohol.

There is an increased risk of postural hypotension with tricyclics, and an enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs).

There is an increased risk of hyponatraemia with carbamazepine.

Fluid retention associated with corticosteroid use may antagonise the diuretic/antihypertensive response.

Amiloride antagonises the ulcer-healing effect of carbenoxolone.

Amiloride blocks the tubular secretion of creatinine, leading to falsely high measurements of creatinine clearance.

4.6. Pregnancy and lactation

Because clinical experience is limited, use of amiloride in pregnancy is not recommended. The use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated as they may be associated with hypervolaemia, increased viscosity and decreased placental perfusion. Foetal and neonatal jaundice, foetal bone marrow depression and thrombocytopenia have also been described. The potential benefits of the drug must be weighed against the possible hazards to the foetus if administered to women of child bearing age.

It is not known whether amiloride is excreted in human milk. Many drugs are excreted by this route and there is a risk that amiloride excreted this way could cause serious side-effects to the breast-feeding baby. Therefore, the mother should either stop breast-feeding or stop taking the drug. The decision depends upon the importance of the drug to the mother.

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

Amiloride is usually well tolerated although minor side effects are reported fairly frequently. Except for hyperkalaemia, significant side effects are infrequent. Nausea/anorexia, abdominal pain, flatulence and mild skin rash are probably due to amiloride but other side effects are generally associated with diuresis or with the underlying disease being treated.

Headache, weakness, fatigue, back pain, chest pain, neck/shoulder pain, pain in the extremities.

Angina pectoris, orthostatic hypotension, arrhythmias, palpitation, one patient with partial heart block developed total heart block whilst taking amiloride.

Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, jaundice, thirst, dyspepsia, flatulence, abnormal liver function.

Elevated potassium plasma levels above 5.5 mmol/l, hyponatraemia.

Pruritus, rash, dryness of mouth, alopecia.

Muscle cramps, joint pain.

Dizziness, vertigo, paraesthesia, tremors, encephalopathy.

Nervousness, insomnia, decreased libido, depression, somnolence, mental confusion or minor psychiatric changes may occur.

Cough, dyspnoea.

Nasal congestion, visual disturbances, increased intra-ocular pressure, tinnitus.

Impotence, polyuria, dysuria, bladder spasms, frequency of micturition.

Reactions whilst taking amiloride to which no casual relationship could be established were: activation of probable pre-existing peptic ulcer, aplastic anaemia, neutropenia and abnormal liver function tests. In a few cirrhotic patients, jaundice associated with the underlying disease has deepened, but the relationship with amiloride is uncertain.

4.9. Overdose

No data is available and it is not known whether the drug is dialysable.

The most likely signs and symptoms are dehydration and electrolyte imbalance which should be treated by established methods. Therapy should be discontinued and the patient observed closely. No specific antidote is available. If ingestion is recent, emesis should be induced or gastric lavage

performed. Treatment is symptomatic and supportive. If hyperkalaemia occurs, active measures should be taken to reduce plasma potassium levels.

The plasma half-life of amiloride is about six hours.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC Code: CO3D B01 Other potassium-sparing agents.

Amiloride is a pyrazinoylguanidine derivative which acts as a mild potassium-sparing diuretic. It appears to act mainly on the distal renal tubules. Amiloride interferes with transport of electrolytes in the nephron. As electrogenic sodium transport is interrupted the electrical potential across the tubular epithelium falls. The reduction or elimination of this potential, which is one of the driving forces for secretion of potassium, is probably the basis of the potassium-sparing effect. It is described as potassium-sparing as it increases the excretion of sodium and chloride, but decreases excretion of potassium. Unlike spironolactone, amiloride does not act by inhibiting aldosterone. Amiloride does not inhibit carbonic anhydrase. It takes effect about 2 hours after administration by mouth and its diuretic action has been reported to persist for about 24 hours. The full effect may be delayed until after several days of treatment.

Amiloride adds to the natriuretic but diminishes the kaliuretic effects of other diuretics and is mainly used as an adjunct to the thiazides, frusemide and similar diuretics.

5.2    Pharmacokinetic properties

Amiloride is incompletely absorbed from the gastro-intestinal tract (approximately 50% is absorbed) and bioavailability is reduced by food.

Peak serum concentrations are achieved about three to four hours after oral administration.

It is not bound to plasma proteins and has an apparent volume of distribution greater than body water. Amiloride is not metabolised and is excreted unchanged from the kidneys.

Amiloride is secreted in the proximal tubule of the kidney and excreted in the urine unchanged.

The half life of amiloride is about 6 hours.

Preclinical safety data

Preclinical information has not been included because the safety profile of amiloride has been established after many years of clinical use. Please refer to section 4.

6.1. List of excipients

Lactose monohydrate Maize starch

Microcrystalline cellulose

Sodium starch glycolate (Type A) (E576)

Talc (E553b)

Magnesium stearate (E572)

Silica colloidal anhydrous

6.2.    Incompatibilities

Lithium should not be given with diuretics, as they reduce its renal clearance and add a high risk of lithium toxicity.

6.3.    Shelf life

36 months.

6.4.    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5.    Nature and contents of container

HDPE or polypropylene containers with caps in packs of 100 and 500 tablets.

PVdC coated PVC film with hard temper aluminium foil blister strips in packs of 7, 10, 12, 14, 21, 28, 30, 56, 60, 84, 90, 100,110, 112, 120, 150, 160, 168 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

MARKETING AUTHORISATION NUMBER(S)

PL 00289/0727

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/05/1986 / 24/01/2005

10 DATE OF REVISION OF THE TEXT

09/11/2010