SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Co-amilozide 2.5/25 Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Amiloride Hydrochloride 2.5mg Hydrochlorothiazide 2 5 mg

Excipients: lactose.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Cream to very pale buff coloured, odourless, flat bevelled edge tablets, marked CZ2.5 on one face and CP on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-amilozide is indicated in patients with hypertension, congestive heart failure, or hepatic cirrhosis with ascites, in whom potassium depletion might be anticipated. Amiloride hydrochloride in co-amilozide minimises the possibility of excessive potassium loss during vigorous diuresis for long term therapy. Co-amilozide is particularly indicated in conditions where potassium balance is important, eg patients with congestive heart failure receiving digitalis.

4.2 Posology and method of administration

The rate of loss of weight and the serum electrolyte levels should determine the dosage. The most satisfactory rate of weight loss after initiation of diuresis is about 0.5-1.0 kg/day.

Hypertension: Initially one tablet given once a day. The dosage may be increased if necessary to two tablets given once a day or in divided doses.

Co-amilozide may be used alone or as an adjunct to other antihypertensive drugs, but since the antihypertensive effect of these agents may be enhanced, their dosage may need to be reduced in order to reduce the risk of an excessive drop in pressure.

Congestive heart failure: Initially one tablet a day, subsequently adjusted if required, but not exceeding four tablets a day. Optimal dosage is determined by the diuretic response and the plasma potassium level. Once 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 dose of two tablets may be increased gradually until there is an effective diuresis. Dosage should not exceed four tablets a day. A gradual weight reduction is especially desirable in cirrhotic patients to reduce the likelihood of untoward reactions associated with diuretic therapy. Maintenance dosages may be lower than those required to initiate diuresis; dosage reduction should therefore be attempted when the patient's weight is stabilised.

Elderly: Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance. The dosage should be carefully adjusted to renal function and clinical response. (See also Special Warnings & Precautions, subsections Hyperkalaemia, Electrolyte imbalance).

Children: Co-amilozide is not recommended for children under 18 years of age as safety and efficacy has not been established.

4.3 Contraindications

Hyperkalaemia other potassium-conserving diuretics; potassium supplements; potassium rich foods; concomitant treatment with spironolactone or triamterene; severe progressive renal disease, acute renal failure, diabetic nephropathy; anuria; concurrent lithium therapy; hepatic failure; hypercalcaemia; Addison's disease. Sensitivity to amiloride hydrochloride, hydrochlorothiazide or other sulphonamide derived drugs. Use of potassium conserving agents may result in rapid development of hyperkalaemia in patients with renal impairment. The safety of amiloride hydrochloride for use in children under 18 years of age has not been established. Co-amilozide should not be taken during pregnancy or lactation.

4.4 Special warnings and precautions for use

Diabetes Mellitus: Hyperkalaemia has occurred in diabetic patients on amiloride hydrochloride, especially those with pre-renal azotaemia or chronic renal disease. The status of renal function should therefore be determined before co-amilozide is given to known or suspected diabetics. Use of thiazides may aggravate diabete mellitus (see 4.8 Undesirable Effects, Endocrine subsection).

Co-amilozide should be discontinued at least three days before glucose tolerance tests are performed in patients with diabetes mellitus, especially if there is renal insufficiency or diabetic nephropathy, because of the risks of provoking severe hyperkalaemia.

Hyperkalaemia : Hyperkalaemia has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged and in diabetics. Hyperkalaemia has been reported in seriously ill hospital patients with congestive heart failure or hepatic cirrhosis who had renal impairment, or were undergoing vigorous diuretic therapy.

Such patients should be carefully observed for laboratory, clinical and ECG evidence of hyperkalaemia (which may not always be associated with an abnormal ECG). Some deaths have been reported in this group of patients. Should hyperkalaemia develop, co-amilozide should be discontinued immediately. If necessary, active measures should be taken to reduce the serum potassium to normal.

Hyperuricaemia: Use of thiazides may aggrevate gout (see 4.8 Undesirable Effects, Metabolic subsection).

Metabolic or respiratory acidosis: Potassium conserving therapy should be initiated with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, eg patients with decompensated diabetes or cardiopulmonary disease. Shifts in acid base balance alter the balance of extracellular/intracellular potassium. The development of acidosis may be associated with rapid increases in serum potassium.

Electrolyte imbalance and blood urea increases: Some patients may be particularly susceptible to hyponatraemia, including the elderly and those with severe heart failure who are very oedematous, particularly with large doses of thiazides in conjunction with restricted salt in the diet. All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy (see also 4.8 Undesirable Effects, Electrolyte Imbalance). In seriously ill patients, reversible increases in blood urea have been reported accompanying vigorous diuresis, hepatic cirrhosis, ascites and metabolic alkalosis or those with resistant oedema. Serum electrolyte and blood urea levels should be carefully monitored in these patients. Co-amilozide should be used with caution in patients with renal impairment. Special care should be taken to avoid cumulative or toxic effects due to a reduced excretion of its components (see

4.3 Contraindications). Azotaemia may be precipitated or increased by hydrochlorothiazide. Co-amilozide should be discontinued if increasing oliguria and azotaemia occurs during treatment.

Liver disease: Use with caution in hepatic impairment. As a result of associated aldosteronism, oral diuretic therapy is more frequently accompanied by adverse reactions in patients with hepatic cirrhosis and ascites because these patients are intolerant of acute shifts in electrolyte balance and because they often have pre-existing hypokalaemia (see 4.8 Undesirable Effects). Use in hepatic failure is contraindicated (see 4.3 Contraindications).

Other: Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma.

It has been reported that the thiazides may possibly activate or exacerbate systemic lupus erythematosus.

Caution should be observed in porphyria. Hydrochlorothiazide is considered unsafe for use in acute porphyrias.

Caution is required in patients with severe asthma, as hypokalaemia associated with beta₂-agonist therapy can be potentiated by concurrent use of diuretics.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Co-administration of alcohol may potentiate orthostatic hypotension.

Analgesics: Some Non-steroidal anti-inflammatory drugs (NSAIDs), notably indometacin, may attenuate the diuretic, natriuretic and antihypertensive effects of diuretics. NSAIDs increase the risk of hyperkalaemia with potassium-sparing diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs.

Anion-exchange resins: Cholestyramine and colestipol reduce absorption of thiazides and should be given at least two hours apart.

Anti-arrhythmics: Toxicity of amiodarone, disopyramide, flecainide and quinidine is increased if hypokalaemia occurs. Action of lidocaine and mexilitine is antagonised by hypokalaemia. Hypokalaemia increases risk of ventricular arrhythmias with sotalol, a beta-blocker. The anti arrhythmic activity of quinidine may be opposed by amiloride.

Antidepressants: Co-administration of tricyclic antidepressants may potentiate ortho static hypotension. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs). Possibly increased risk of hypokalaemia if thiazides given with reboxetine.

Anti diabetics: Thiazides may antagonise the hypoglycaemic effect of antidiabetics. Oral and parenteral antidiabetic drugs may require adjustment of dosage with concurrent use. Co-amilozide can act synergistically with chlorpropamide to increase the risk of hyponatraemia.

Antiepileptics There is an increased risk of hyponatraemia with carbamazepine.

Antifungals: Increased risk of hypokalaemia with concurrent use of thiazide diuretics and amphotericin. Hydrochlorothiazide may increase the plasma concentration of fluconazole.

Antigout agents: Potential for increased toxicity and hypersensitivity/allergic reactions with concomitant use of allopurinol and thiazide diuretics.

Antihistamines: Diuretic-induced hypokalaemia increases risk of ventricular arrhythmias with terfenadine.

Antihypertensives: The dosage of concurrently administered antihypertensive drugs may need to be reduced when co-amilozide is added to the regimen.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II antagonists -Enhanced hypotensive effect, risk of severe hyperkalaemia with potassium-sparing diuretics. Therefore, if concomitant use of these agents is indicated they should be used with caution and with frequent monitoring of serum potassium. Diuretic therapy should be discontinued for two to three days prior to initiation of therapy with an ACE inhibitor to reduce the likelihood of first dose hypotension.

Alpha-blockers — increased risk of first-dose hypotension with alpha-blockers such as prazosin.

Beta-blockers and calcium-channel blockers — enhanced hypotensive effect may occur.

Antipsychotics: Diuretic-induced hypokalaemia increases the risk of ventricular arrhythmias with primozide and sertindole, concurrent use should be avoided.

Barbiturates: Co-administration of barbiturates may potentiate orthostatic hypotension.

Calcium salts & Vitamins: There is a risk of hypercalcaemia with calcium salts and vitamin D. There is an increased risk of developing milk-alkali syndrome in patients given large amounts of calcium or vitamin D in combination with thiazides.

Cardiac Glycosides: Increased risk of toxicity if diuretic-induced hypokalaemia occurs.

Corticosteroids or ACTH: Increased risk of electrolyte depletion, particularly hypokalaemia, mainly with the naturally occurring corticosteroids such as cortisone and hydrocortisone. The synthetic corticosteroids have a much less marked potassium-losing effect. Fluid retention associated with corticosteroid use may antagonise the diuretic/antihypertensive effect.

Cytotoxics Diuretics increase the risk of nephrotoxicity and ototoxicity with cisplatin.

Diuretics: Increased risk of hypokalaemia with concurrent administration of other thiazides and other diuretics including acetazolamide and loop diuretics.

Dopaminergics: Potential for increased risk of amantadine toxicity in association with hydrochlorothiazide.

Hormones and other endocrine drugs: When amiloride hydrochloride is administered concomitantly with trilostane, the risk of hyperkalaemia may be increased. Thiazide diuretics may increase the risk of hypercalcaemia with toremifene. Oestrogens and progestogens antagonise diuretic effect.

Immunosuppressants: When amiloride hydrochloride is administered concomitantly with ciclosporin or tacrolimus, the risk of hyperkalaemia may be increased.

Lithium: Lithium may accumulate as a result of reduced renal clearance (see

4.3 Contraindications).

Muscle relaxants: Enhanced hypotensive effect may occur with tizanidine.

Potassium salts: Increased risk of hyperkalaemia with administration of potassium supplements (see 4.3 Contraindications).

Prostaglandins: Hypotensive effect may be potentiated by alprostadil

Sympathomimetics: increased risk of hypokalaemia with thiazide diuretics and high doses of sympathomimetics (See 4.4 Warnings and Precautions, use of beta₂-agonists in severe asthma). Pressor amines such as adrenaline may show decreased arterial responsiveness when used with co-amilozide but this reaction is not enough to preclude their therapeutic usefulness.

Ulcer-healing drugs: Fluid retention associated with carbenoxolone may cause antagonism of diuretic/antihypertensive effect. Thiazides can be used to treat the adverse side-effects of carbenoxolone, but not amiloride which may antagonise the ulcer-healing effect.

Vitamins. See under Calcium salts & Vitamins.

Drug/laboratory tests: Because thiazides may affect calcium metabolism, co-amilozide may interfere with tests for parathyroid function.

Creatinine clearance: Amiloride can block the tubular secretion of creatinine and may lead to falsely high measurements of creatinine clearance.

4.6 Pregnancy and lactation

Co-amilozide is not recommended for use during pregnancy. Thiazides appear in breast milk and cross the placental barrier, appearing in cord blood and foetal serum levels may equal those of the mother. Treatment with large doses of thiazides may suppress lactation. If use of the drug is deemed essential, the patient should stop nursing.

The use of co-amilozide where pregnancy is present or suspected must be weighed against possible hazards to the foetus. These hazards include thrombocytopenia, foetal or neonatal jaundice, foetal hypokalaemia and other possible side effects that have occurred in adult patients. Reductions in maternal blood volume could also adversely affect placental perfusion. The routine use of diuretics is not indicated in otherwise healthy pregnant women with or without mild oedema.

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Co-amilozide during breast feeding is not recommended. If Co-amilozide is used during breast feeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

Side-effects such as headache, visual disturbances, dizziness and vertigo may occur. Should these occur, the patient should be cautioned not to drive or operate machinery.

4.8 Undesirable effects

The combination of amiloride and hydrochlorothiazide is usually well tolerated and significant side effects are infrequent. No increase in the risk of adverse reactions has been seen over those of the individual components.

The reported adverse reactions of Co-amilozide, and additional side-effects of amiloride and hydrochlorothiazide alone:

Body as a whole:

Co-amilozide - Headache, weakness, fatigue, malaise, syncope.

Cardiovascular:

Co-amilozide -Arrhythmias, tachycardia, orthostatic hypotension, dizziness, vertigo, chest pain and digitalis toxicity (see 4.5 Interactions, sub-heading Cardiac Glycosides).

Dermatological:

Co-amilozide - Rash, pruritus,

Hydrochlorothiazide- Urticaria , photosensitivity, which may persist after thiazide withdrawal.

Disorders of the immune system:

Hydrochlorothiazide- Hypersensitivity reactions, anaphylactic reaction, fever, respiratory distress including pneumonitis and pulmonary oedema occur rarely (see also Dermatological side-effects above).

Electrolyte Balance:

Co-amilozide - Elevated plasma potassium levels electrolyte imbalance, gout, dehydration, and hyponatraemia. Hyponatraemia as a complication is rare, but constitutes a medical emergency as onset may be rapid. The symptoms of hyponatraemia may be non-specific and include nausea, lethargy, weakness, irritability, mental confusion, muscle cramps and anorexia, but it may be an important cause of morbidity. Severe sequelae of hyponatraemia include tonic-clonic seizures and clinical features resembling subarachnoid haemorrhage. Amiloride - Hyperkalaemia (see also 4.3 Contraindications and 4.4 Special Warnings & Precautions).

Hydrochlorothiazide- Hypokalaemia, hypochloraemic alkalosis, hyperuricaemia, the urinary excretion of calcium may be reduced and the potential for hypercalcaemia exists (use in pre-existing hypercalcaemia is contraindicated, see 4.3).

Endocrine:

Hydrochlorothiazide - Hyperglycaemia and glycosuria may occur, diabetes mellitus may be aggravated and latent diabetes may become manifest during thiazide administration. Blood-glucose concentrations should be monitored in patients taking antidiabetics, since requirements may change (see 4.5 Interactions).

Gastrointestinal:

Co-amilozide -Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain and thirst.

Amiloride - Dry mouth,

Hydrochlorothiazide'. Cramping, gastric irritation and pancreatitis. Haematological:

Amiloride- Aplastic anaemia and neutropenia.

Hydrochlorothiazide- Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura and thrombocytopenia.

Hepatic:

Amiloride - Abnormal liver function. A deepening of jaundice has occurred in cirrhotic patients receiving amiloride hydrochloride alone, but the relationship to amiloride is uncertain.

Hydrochlorothiazide -Jaundice (intrahepatic cholestatic jaundice). Encephalopathy may be precipitated by hypokalaemia in patients with preexisting liver disease.

Metabolic:

Hydrochlorothiazide- Hyperuricaemia may occur or gout may be precipitated or aggravated in patients receiving thiazides.

Nervous:

Co-amilozide - Paraesthesiae and stupor.

Psychiatric: Co-amilozide : Nervousness, mental confusion, depression and sleepiness.

Amiloride - Decreased libido and somnolence.

Hydrochlorothiazide- Restlessness.

Respiratory:

Co-amilozide -Dyspnoea.

Hydrochlorothiazide- Respiratory distress including pneumonitis, pulmonary oedema

Special senses:

Co-amilozide -Visual disturbances.

Hydrochlorothiazide- Transient blurred vision and xanthopsia.

Urogenital:

Co-amilozide —Impotence occurring early in the course of treatment (onset after 2 years unlikely) and reversible on withdrawal of treatment. Nocturia, renal dysfunction including renal failure.

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

No specific antidote is available. Supportive measures include emesis or gastric lavage. If hyperkalaemia occurs measures should be taken to reduce serum potassium levels.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Amiloride

A mild diuretic acting on distal renal tubules, increasing excretion of sodium and chloride and reducing potassium excretion.

Hydrochlorothiazide

A diuretic which acts by reducing reabsorption of electrolytes from renal tubules, thereby increasing the excretion of sodium and chloride ions and consequently of water. Potassium ions are excreted to a lesser extent. Hydrochlorothiazide also has a blood pressure lowering effect, and enhances the effects of other antihypertensive agents.

5.2 Pharmacokinetic properties Amiloride

Acts in 2 hours, completely absorbed from intestinal tract. Biological half life 6 hours, excreted unchanged partly in urine. Peak serum levels reached in 4 hours.

Hydrochlorothiazide

Peak plasma concentration reached in 1.5 to 3 hours, with diuresis lasting for 12 hours.

5.3 Preclinical safety data

Amiloride and hydrochlorothiazide have been used in clinical practice for over 20 years and have become commonly used in combination.

Lactose

Calcium phosphate dibasic Maize starch

Pregelatinised maize starch Magnesium stearate Purified water

6.2    Incompatibilities

None known.

6.3    Shelf life

30 months.

6.4    Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5    Nature and contents of container

PVC aluminium foil blister.

Polypropylene or polyethylene containers.

6.6    Special precautions for disposal

Not applicable.

MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0041

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/07/1995

10    DATE OF REVISION OF THE TEXT

05/08/2015