SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Amiloride 5 mg Tablets BP

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5.7mg Amiloride Hydrochloride Dihydrate equivalent to 5.0mg anhydrous Amiloride Hydrochloride.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Off white to creamy white, round, flat, uncoated tablets with beveled edges and debossed with "C" and "G" on either side of breakline and another side is plain.

4.1    Therapeutic indications

Potassium- conserving agent;diuretic.

Although Amiloride Hydrochloride may be used alone, its principal indication is as concurrent therapy with thiazides or more potent diuretics in order to conserve potassium during periods of vigorous diuresis and during long-term maintenance therapy.

In congestive heart failure,Amiloride Hydrochloride may be effective alone, but its principal indication is for concomitant use in patients receiving thiazides or more potent diuretic agents.

In hypertension, it is used as an adjunct to prolonged therapy with thiazides and similar agents to prevent potassium depletion.

In hepatic cirrhosis with ascites,. Amiloride Hydrochloride 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 while maintaining a more balanced serum electrolyte    pattern.

4.2    Posology and method of administration

Adults

Amiloride Hydrochloride alone.The initial dosage is 10 mg (as a single dose or 5mg twice a day). The total daily dose should not exceed 20mg (4 tablets) per day. After diuresis has been achieved, the dosage may be reduced by 5mg increments to the least amount required.

Amiloride Hydrochloride with other diuretic therapy

When Amiloride is used with a diuretic which is given on an intermittent basis, it should be given at the same time as the diuretic.

Hypertension

Usually half ‘Amiloride’ tablet (2.5mg) given once a day together with the usual antihypertensive dosage of the thiazide concurrently employed. If necessary, increase to 5mg (one ‘Amiloride’ tablet) given once a day or in divided doses.

Congestive heart failure

Initially half ‘Amiloride’ tablet (2.5mg) a day together with the usual dosage of the diuretic concurrently employed, subsequently adjusted if required, but not exceeding two ‘Amiloride’ tablets (10mg) a day. Optimal dosage is determined by diuretic response and the plasma potassium level. Once an initial diuresis has been achieved, reduction in dosage may be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.

Hepatic cirrhosis with ascites

Treatment should be started with a low dose of Amiloride, i.e. 5mg (1 tablet), plus a low dosage of the other diuretic agent. If necessary, dosage of both agents may be increased gradually until there is effective diuresis.

The dosage of Amiloride should not exceed two ‘Amiloride’ tablets (10 mg) a day. Maintenance dosages may be lower than those required to initiate diuresis; reduction in the daily dosage should therefore be attempted when the patient's weight is stabilised. Gradual weight reduction in cirrhotic patients is especially desirable to reduce the likelihood of untoward reactions associated with diuretic therapy.

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.

Children:

The use of Amiloride in children under 18 years of age is not recommended as safety and efficacy have not been established.

4.3 Contraindications

Hyperkalaemia (plasma potassium over 5.5mmol/l), other potassium conserving agents or potassium supplements (see precautions); Addison’s disease; anuria, acute renal failure, severe progressive renal disease, diabetic nephropathy (see Precautions); prior sensitivity to this product.. Safety for use in children is not established. See also ‘Use in pregnancy’ and ‘Use in the breast feeding mother’.

4.4 Special warnings and precautions for use

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 hydrochloride should be discontinued for at least three days before a glucose tolerance test.

Metabolic or Respiratory 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 or 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 receiving Amiloride Hydrochloride, alone or with other diuretics, These patients should be observed carefully for clinical, laboratory and ECG evidence of hyperkalaemia.

Some deaths have been reported in this group of patients, Hyperkalaemia has been noted particularly in the elderly and in hospital patients with hepatic cirrhosis or cardiac oedema who have known renal involvement who were seriously ill, or 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 l0 mmol/l, serum creatinine over 130 pmol/l, or with diabetes mellitus, should not receive Amiloride Hydrochloride 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 hydrochloride 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 Hydrochloride 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.

In patients with pre-existing severe liver disease, hepatic encephalopathy manifested by tremors, confusion, coma and increased jaundice, has been reported in association with diuretics, including Amiloride hydrochloride.

4.5 Interaction with other medicinal products and other forms of interaction

Antipsychotics:

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

Antidiabetic agents:

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

Ulcer-healing agents:

Amiloride antagonises the ulcer healing effect of carbenoxolone. Immunosuppressants:

Increased risk of hyperkalaemia with cyclosporin and tacrolimus. Antihypertensives:

An enhanced hypotensive effect (which can be extreme) can occur with antihypertensives, including ACE inhibitors, angiotensin-II antagonists, calcium channel blockers, beta blockers or alpha blockers (increased risk of first dose hypotension). When Amiloride Hydrochloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, trilostrane, ciclosporin or tacrolimus, the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.

There is an increased risk of ventricular arrhythmias with sotalol.

Analgesics:

The concomitant administration of Amiloride and NSAIDs may lead to an increased risk of nephrotoxicity, an antagonism of the diuretic effect and possibly an increased risk of hyperkalaemia, particularly in elderly patients. Indomethacin and possibly other NSAIDs increase the risk of hyperkalaemia with potassium sparing diuretics. Indomethacin and ketorolac antagonise the diuretic effect. Therefore when amiloride hydrochloride is used concomitantly with NSAIDs, renal function and serum potassium levels should be carefully monitored.

Alcohol:

Postural hypotension associated with diuretic therapy may be enhanced. Antiarrhythmics:

The antiarrhythmic activity of quinidine can be opposed by amiloride. Antidepressants:

Increased risk of postural hypotension with tricyclics. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs).

Antiepileptics:

Increased risk of hyponatraemia with carbamazepine.

Antihistamines:

Electrolyte imbalance increases the risk of ventricular arrhythmias with terfenadine.

Corticosteroids:

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

Hormones and other endocrine drugs:

Combined oral contraceptives and oestrogens may antagonise the diuretic effect. There is an increased risk of hyperkalaemia with trilostane.

Muscle relaxants:

Enhanced hypotensive effect with baclofen and tizanidine.

Prostaglandins:

Hypotensive effect may be potentiated by alprostadil.

Potassium conserving agents, potassium supplements:

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

Laboratory value alterations:

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

Hyponatraemia and hypochloraemia may occur when Amiloride is used with other diuretics (see section 4.4 special warnings and precautions for use).

4.6 Pregnancy and lactation

Pregnancy

Because clinical experience is limited, Amiloride is not recommended for use during pregnancy. The potential benefits of the drug must be weighed against possible hazards to a foetus if it is administered to women of child bearing age.

It has been found that the routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated because they may be associated with hypovolaemia, increased blood viscosity and decreased placental perfusion. Foetal and neonatal jaundice, foetal bone marrow depression and thrombocytopenia have also been described.

Lactation

It is not known whether Amiloride is excreted in human milk. Because many drugs are excreted by this route and because there is a risk that it might take this route of excretion and that it might then cause serious side effects in the breast feeding infant, the mother should either stop breast feeding or stop taking the drug. The decision depends on 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 Hydrochloride is normally well tolerated, although minor side effects are reported relatively frequently. Except for hyperkalaemia, significant side effects are infrequent. Nausea, anorexia, abdominal pain, flatulence and mild skin rashes have been reported and are probably related to Amiloride: but other side effects are generally associated with diuresis, or with the underlying disease being treated.

Body as a whole: Headache, weakness, fatigue, back pain, chest pain, neck/shoulder ache, pain in extremities.

Cardiovascular: Angina pectoris, orthostatic hypotension, arrhythmias, palpitation, one patient with a partial heart block developed complete heart block.

Digestive: Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, jaundice, thirst, dyspepsia, flatulence.

Metabolism and nutrition disorders

Elevated plasma potassium levels above 5.5mmol/l, hyponatraemia. Serum uric acid levels may rise during treatment with Amiloride and acute attacks of gout may be precipitated.

Integumentary : Pruritus, rash, dryness of mouth, alopecia.

Musculoskeletal: Muscle cramps, joint pain.

Nervous: Dizziness, vertigo, paraesthesia, tremors, encephalopathy.

Psychiatric: Nervousness, mental confusion, insomnia, decreased libido, depression, somnolence.

Respiratory : Cough, dyspnoea.

Special senses: Nasal congestion, visual disturbances, increased intra ocular pressure, tinnitus.

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

Reactions in which no causal 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 had deepened, but the drug relationship is uncertain.

4.9 Overdose

No data are 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 procedures. 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 should be 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other Potassium sparing agents,

ATC code: C03DB01

Amiloride has mild diuretic and anti-hypertensive activity. It acts primarily in the distal renal tubules and does not require aldosterone for its action..

Amiloride is a mild natriuretic which does not initiate a concomitant decrease in potassium levels. The mechanism of action includes 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 Na+ ions and H+ ions. A combination of the Amiloride with a benzothiadazine diuretic will cause less magnesium excretion than the diuretic alone.

5.2 Pharmacokinetic properties

Amiloride is incompletely absorbed from the gastro-intestinal tract, only about 50% is recovered unchanged in the urine following an oral dose. The drug is not metabolised and can, therefore, be useful in patients with liver disease.

Peak plasma concentrations are reached in about 3-4 hours after oral administration and the plasma half-life is in the range of 6-9 hours.

In a 70Kg man, the distribution volume is about 5L/Kg, suggesting that the drug is widely distributed in the tissues. Amiloride appears to be weakly bound to plasma proteins as determined by electrophoretic and gel filtration studies. It is not known whether the drug is excreted in breast milk, although studies have shown the presence of Amiloride in the breast milk of rats.

Amiloride is excreted unchanged in the urine. In two studies in which single doses of 14C-Amiloride were used, approximately 50% was recovered in urine and 40% in the faeces within 72 hours. In radioactive studies, peak plasma levels of 38 - 40pg/L were seen three to four hours after a single 20mg oral dose. These low plasma levels are thought to be due to extravascular distribution as evidenced by the large volume of distribution.

In man, the calculate renal clearance of Amiloride exceed in the glomerular filtration, suggesting that there is a tubular secretory pathway. Renal clearance of the drug does not appear to be affected by probenecid, pH of the urine or urinary flow rate.

5.3 Preclinical safety data

None stated

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Dibasic calcium phosphate dihydrate

Pregelatinised starch

Maize starch

Magnesium stearate

Sodium starch glycolate

6.2    Incompatibilities

Not Applicable

6.3    Shelf life

24 Months

6.4    Special precautions for storage

Tablet containers: Do not store above 25°C. Keep in the original container. Keep the container tightly closed.

Blister packs: Do not store above 25°C. Store in the original package in order to protect from light.

6.5    Nature and contents of container Container pack:

High density polystyrene with polythene lids and/or polypropylene containers with polypropylene or polythene lids and polyurethane/polythene inserts.

Pack sizes: 100 and 500 tablets

Blister pack:

20 micron hard-tempered aluminium foil, coated on the dull side with 6-7 GSM heat-seal lacquer and printed on the bright side; 250 micron rigid, green PVC Pharmaceutical Grade.

Pack sizes: 28 and 84 tablets 1 x 28 tablets Calendar Pack in a carton 3 x 28 tablets Calendar Packs in a carton

Blister pack:

PVC/PVDC Opaque white (250/90)/Plain Aluminium foil 0.025MM Pack size: 28 tablets

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable

7    MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited Sage house, 319 Pinner Road North Harrow, Middlesex, HA1 4HF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20075/0031

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/02/2009

10    DATE OF REVISION OF THE TEXT

02/11/2011