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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 Amiloride Hydrochloride, equivalent to anhydrous amiloride hydrochloride 5 mg

Also contains lactose. For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Flat cream coloured bevelled tablets, odourless. Engraved MP48 on one side and scored on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Potassium conserving diuretic.

While Amiloride Hydrochloride may be used independently, its main indication is for concurrent therapy with either thiazides or more potent diuretics in order to conserve potassium during episodes of vigorous diuresis and during long-term maintenance therapy.

(i)    Congestive heart failure, primarily for concurrent use in patients receiving thiazides or more potent diuretic agents.

(ii)    Hypertension, as an adjunctive agent.

(iii)    Hepatic cirrhosis with ascites and oedema.

4.2 Posology and method of administration

Amiloride Hydrochloride 5 mg Tablets are taken by mouth.

Adults:

The initial dosage should be 10 mg either as a single dose or 5 mg twice a day. This may be increased if necessary, but must not exceed 20 mg (4 tablets) per day. After diuresis has been achieved, the dosage may be reduced to the least amount required (by 5 mg increments).

Congestive heart failure:

Amiloride Hydrochloride may be started at a dosage of 2.5 mg (% tablet) a day, together with the usual dosage of other diuretic agents. If diuresis is not achieved with minimal dosage of both agents, the dosage of both may be gradually increased, but that of Amiloride Hydrochloride should not exceed 10 mg (2 tablets) a day. Once diuresis has been achieved, reduction in dosage of both agents may be attempted for maintenance therapy. The dosage of both agents should be determined by the diuretic response and the plasma potassium level.

Hypertension

Amiloride Hydrochloride is given at a dosage of 2.5 mg to 10 mg (% to 2 tablets) a day, together with the usual antihypertensive dosage of thiazides.

Hepatic cirrhosis with ascites

Treatment should be started with a small dose of Amiloride Hydrochloride, i.e. 5 mg (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 Hydrochloride should not exceed 10 mg (2 tablets) a day. Maintenance doses 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.

Elderly:

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

Children:

The use of Amiloride Hydrochloride is not recommended in children.

4.3 Contraindications

Hyperkalaemia (plasma potassium over 5.5 mmol/l). Other potassium-conserving agents or potassium supplements; anuria, acute renal failure, severe progressive renal disease, diabetic nephropathy. Sensitivity to Amiloride Hydrochloride and to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Diabetes Mellitus:

To minimise the risk of hypokalaemia in known or suspected diabetic patients, the status of renal function should be determined before initiating therapy. Amiloride Hydrochloride should be discontinued 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 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 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 Hydrochloride except in severe and/or refractory cases of hypokalaemia. If the combination is used, plasma potassium levels must be continuously monitored.

It is also important to bear in mind that administration of a potassium-sparing diuretic to a patient receiving an ACE inhibitor or an angiotensin-II receptor antagonist can cause severe hyperkalaemia.

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 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.

Electrolyte imbalance and 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 Hydrochloride is given with oral 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.

Hepatic encephalopathy has been reported in patients with pre-existing severe liver disease.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorbtion should not take Amiloride Hydrochloride.

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 Hydrochloride can act synergistically with chlorpropamide to increase the risk of hyponatraemia. There is also an increased risk of hyponatraemia when diuretics are given with carbamazepine.

There is an increased risk of hyperkalaemia with ciclosporin and the hormone antagonist trilostane; likewise with potassium salts.

There is a risk of decreased renal function and the development of hyperkalaemia with NSAIDs (e.g. indometacin). Concomitant use with platinum compounds may increase the risk of nephrotoxicity and ototoxicity.

The risk of hyperkalaemia may be increased when Amiloride Hydrochloride is administered concomitantly with ACE inhibitors, angio-tensin-converting enzyme inhibitors, drospirenone, trilostane or tacrolimus. Accordingly, when concomitant use of these agents is indicated, because of demonstrated hypokalaemia, frequent monitoring of serum potassium should be instituted and caution should be exercised with the use of these agents. Hypokalaemia caused by diuretics increases the risk of ventricular arrhythmias with amisulpride, pimozide and sertindole.

Concurrent administration of ACE inhibitors, adrenergic neurone blockers, alcohol, aldesleukin, alpha blockers, alprostadil, general aneasthsia, angiotensin-II receptor antagonists, anxiolytics & hypnotics, baclofen, beta blockers, calcium channel blockers, clonidine, diazoxide, hydralazine, levodopa, MAOIs, methyldopa, minoxidil, moxisylyte, moxonidine, nitrates, nitroprusside, phenothiazines or tizanidine may enhance the hypotensive effect.

There is an increased risk of postural hypotension when diuretics are given with antidepressants, tricyclic.

Corticosteroids, ketorolac and oestrogens antagonise diuretic effect of diuretics.

4.6 Fertility, Pregnancy and lactation

Amiloride Hydrochloride 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 childbearing age.

It has been found that the routine use of diuretics in otherwise healthy pregnancy 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 depression and thrombocytopenia have also been described.

Nursing Mothers: It is not known whether Amiloride Hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in the nursing infant a decision should be made whether the mother should stop nursing or whether she should stop taking the drug.

4.7 Effects on ability to drive and use machines

None stated.

4.8 Undesirable effects

Nausea/anorexia, abdominal pain, flatulence and mild skin rashes have been reported and are probably related to Amiloride Hydrochloride. Other adverse experiences that have been reported with Amiloride Hydrochloride are generally those known to be 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, heartburn, flatulence.

Metabolic:

Hyperkalaemia (plasma potassium levels over 5.5 mmo1/l).

Integumentary:

Pruritus, rash, dryness of mouth, alopecia.

Musculoskeletal:

Muscle cramps, joint pain.

Nervous:

Dizziness, vertigo, paraesthesia, tremor, 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, urinary frequency.

Unknown causal relationship:

Other reactions have been reported but occurred under circumstances where a causal relationship could not be excluded. These rare observations are listed to serve as alerting information.

In reactions where no causal relationship could be found were activation of likely preexisting peptic ulcer, aplastic anaemia, neutropenia and abnormal liver function tests. In some cirrhotic patients jaundice associated with the underlying disease has deepened, but the drug relationship is not certain.

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 Yellow Card Scheme [www.mhra.gov.uk/yellowcard].

4.9 Overdose

It is not known whether the drug is dialysable. Dehydration and electrolyte imbalance should be treated by established procedures. Amiloride Hydrochloride should be stopped and the patient observed closely. No specific antidote is available. Gastric lavage should be performed if of recent ingestion. Treatment is symptomatic and supportive. Plasma potassium levels should be reduced if hyperkalaemia occurs.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other Potassium sparing agents ATC code: C03DB01

Amiloride Hydrochloride takes effect about two hours after administration by mouth and its diuretic action persists for about 24 hours. It acts mainly on the distal renal tubules. It increases the excretion of sodium and chloride and reduces the excretion of potassium.

Amiloride Hydrochloride enhances the natiuretic and diminishes the kaliuretic effects of other diuretics.

5.2 Pharmacokinetic properties

Amiloride Hydrochloride is completely absorbed from the gastro-intestinal tract. Biological half-life in the circulation is about six hours. It is excreted unchanged in the urine.

Peak serum concentrations are reached in about four hours after a dose. About half of a dose is excreted unchanged in the urine within 72 hours.

Preclinical safety data

No relevant information additional to that contained elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Calcium hydrogen phosphate dihydrate Maize starch, pregelatinised Maize starch Magnesium stearate

6.2 Incompatibilities

None stated.

6.3 Shelf life

2 years

6.4 Special precautions for storage

a)    Containers: Do not store above 25°C. Keep the container tightly closed. Store in the original container.

b)    Strips: Do not store above 25 °C. Store in the original package. Keep in the outer carton.

6.5 Nature and contents of container

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

PVC / Aluminium foil strips. 250 micron pharmaceutical grade green PVC and 20 micron hard-tempered aluminium foil coated on the dull side with 6-7 gsm heat seal lacquer and printed on the bright side.

Containers and Strips of 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 tablets.