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 to conserve potassium during periods of vigorous diuresis and during long term maintenance therapy.

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

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 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 usual initial dosage is 10mg (as a single dose or 5mg twice a day). The total daily dose should not exceed 20mg (20ml) a day.

After diuresis has been achieved, the dosage may be reduced by 5mg (5ml) 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 2.5mg (2.5ml) given once a day together with the usual antihypertensive dosage of the thiazide concurrently employed. If necessary, increase to 5mg (5ml) given once a day or in divided doses.

Congestive heart failure

Initially 2.5mg (2.5ml) a day together with the usual dosage of the diuretic concurrently employed, subsequently adjusted if required, but not exceeding 10mg (10ml) 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

Initiate therapy with a low dose. A single daily dose of 5mg (5ml) plus a low dosage of the other diuretic agent may be increased gradually until there is an effective diuresis. The dosage of Amiloride Hydrochloride should not exceed 10mg (10ml) a day. Maintenance dosages may be lower than those required to initiate diuresis; dosage reduction should therefore be attempted when the patient's weight is stabilised. A gradual weight reduction is especially desirable in cirrhotic patients to reduce the likelihood of untoward reactions associated with diuretic therapy.

Children

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

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

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 extracellularintracellular 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 or 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.

Impaired Renal Function

Patients with increases in blood urea over 10mmol/l, serum creatinine over 130µmol/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 Hyperkalemia

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 Hydrochloride 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 and coma, and increased jaundice has been reported in association with diuretics, including Amiloride Hydrochloride.

Excipient Warnings

This product contains:

- Liquid maltitol (E965). Patients with rare hereditary problems of fructose should not take this medicine.

- Methyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

- Propylene glycol (E1520) 103.5mg in each 5ml. Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates.

- Ethanol. This medicine contains 3.7 mg of alcohol (ethanol) in each 5 ml. The amount in 5 ml of this medicine is equivalent to less than 1 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

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.

Hyponatraemia and hypochloraemia may occur when Amiloride is used with other diuretics (See Section 4.4 Special warnings and precautions for use).

When Amiloride Hydrochloride is administered concomitantly with an angiotensinconverting 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.

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. Therefore, when amiloride hydrochloride is used concomitantly with NSAIDs, renal function and serum potassium levels should be carefully monitored.

4.6. Pregnancy and lactation

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

It is not known whether Amiloride Hydrochloride 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

None known

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 rash are probably due to Amiloride; but other side effects are generally associated with diuresis or with the underlying condition being treated.

Body as a whole

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

Cardiovascular

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

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. Serum uric acid levels may rise during treatment with Amiloride and acute attacks of gout may be precipitated.

Nervous

Dizziness, vertigo, paraesthesiae, 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 spasm, 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.

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

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 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.