SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

SYNURETIC 25/Co-Amilozide 2.5/25 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Amiloride hydrochloride (as dihydrate)    2.85 mg

Hydrochlorothiazide    25.00 mg

Also contains lactose (see section 6.1 for other excipients)

3 PHARMACEUTICAL FORM

Tablet

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, e.g. patients with congestive heart failure receiving digitalis.

Co-Amilozide usually provides satisfactory diuresis with diminished potassium loss and less risk of metabolic alkalosis in hepatic cirrhosis with ascites.

4.2 Posology and method of administration

Tablets to be taken orally.

Dosage:

Dosage is determined against rate of loss of weight and serum electrolyte level. The most satisfactory rate of weight loss after initiation of diuresis is about 0.50 - 1.0 kg/day.

Adults:

Hypertension: Initially 1 tablet daily, increased if necessary to a maximum of 2 tablets daily.

Co-Amilozide may be used alone or as an adjunct to other antihypertensive drugs, but if used as an adjunct the dosage of antihypertensive drugs may have to be reduced to avoid an excessive drop in blood pressure, as Co-Amilozide enhances the action of these drugs. Reports indicate that Co-Amilozide can be used with Beta-Blockers on a once daily basis.

Congestive Heart Failure: Initially 1 tablet a day, increased if necessary to a maximum of 4 tablets daily. The diuretic response and the serum potassium level will determine the optimal dosage. After 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: Initially 2 tablets a day. Dosage should be increased gradually if necessary until there is effective diuresis. Do not exceed 4 tablets a day. A gradual weight reduction is desirable to reduce the likelihood of untoward reactions associated with diuretic therapy. Maintenance dosage may be lower than that required to initiate diuresis. When the patient's weight is stabilised a reduction in dosage should be attempted.

Elderly:

Co-Amilozide should be used with particular caution in elderly patients because of the susceptibility to electrolyte imbalance.

Children:

Co-Amilozide is not recommended for children under 18 years of age.

4.3 Contraindications

Hyperkalaemia (plasma potassium over 5.5 mmol/l), other potassium-conserving diuretics, potassium supplements or potassium-rich foods;

Severe progressive renal disease; acute renal failure; severe progressive renal disease; diabetic nephropathy or anuria.

Use of potassium-conserving agent may result in rapid development of hyperkalaemia in patients with renal impairment.

Hypercalcaemia;

Patients with blood urea over 10 mmol/l or serum creatinine over 130 gmol/l in whom serum electrolyte and blood urea levels cannot be monitored frequently and carefully.

Hepatic failure; precoma associated with hepatic cirrhosis;

Addison's disease;

Concurrent lithium therapy;

Concomitant treatment with spironolactone or triamterene;

Sensitivity to amiloride hydrochloride, hydrochlorothiazide or other sulphonamide derived drugs.

The safety of amiloride hydrochloride for use in children has not been established. Therefore Co-Amilozide is not recommended for children under 18 years of age.

4.4 Special warnings and precautions for use

Increases in cholesterol and triglycerides may be associated with thiazide diuretic therapy.

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

Diabetes mellitus:

Hyperkaelemia 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.

Co-Amilozide should be discontinued before giving a glucose-tolerance test. One patient with poorly controlled diabetes mellitus became severely hyperkalaemic while receiving amiloride hydrochloride and died following two repeated intravenous glucose-tolerance tests.

The insulin requirements of diabetic patients may need to be changed. Latent diabetes mellitus may become manifest during thiazide administration. Metabolic or respiratory acidosis:

Potassium-conserving therapy should be initiated with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, e.g. 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. Hyperkalaemia (serum potassium level over 5.5 mmol/l):

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 known renal involvement, 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.

Electrolyte imbalance and blood urea increases:

Hypochloraemia, hypomagnesia and hyponatraemia may occur, although the likelihood of hypochloraemic alkalosis is reduced with Co-Amilozide. Any chloride deficit may be corrected by the use of ammonium chloride (except in patients with liver disease), and is largely prevented by a near-normal salt intake. In seriously ill patients, reversible increases in blood urea have been reported accompanying vigorous diuresis, hepatic cirrhosis, ascites and metabolic alkalosis or in 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.

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

Effects in cirrhotic patients:

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.

Hepatic encephalopathy, manifested by confusion, tremors and coma, have been reported in patients on amiloride hydrochloride. Patients with liver disease should be observed for this complication when Co-Amilozide is given.

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

Other side effects:

Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Combinations of headache, weakness, chest or back pain, fever, malaise and fatigue have been reported.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

The action of other antihypertensive agents is potentiated by diuretics (amiloride, hydrochlorothiazide.) The dosage of these agents, especially ACE inhibitors, angiotensin-II antagonists and adrenergic blockers, may need to be reduced when Co-Amilozide is added to the regimen.

The hypotensive effects of Alprostadil, Aldeslukin, Baclofen, Levodopa, Tizanidine, anxyolytics and hypnotics, MAOIs, phenothioazines and general anaesthetics are also enhanced by diuretics.

Orthostatic hypotension can be potentiated by alcohol, tricyclic antidepressants, barbiturates and narcotics with thiazides.

The risk of hyperkalaemia may be increased when potassium sparing diuretics are administered concurrently with:

ACE inhibitors or angiotensin-II antagonists. If concomitant use of these agents is indicated caution should be exercised and frequent monitoring of serum potassium instituted.

Ciclosporin or tacrolimus.

Potassium supplements

There is an increased risk of hypokalaemia if thiazides are given with:

amphotericin, theophylline, other diuretics, high doses of sympathomimetrics and possibly reboxetine.

Hypokalaemia caused by diuretics increases the risk of:

cardiac toxicity with anti-arrhythmics and cardiac glycosides ventricular arrhythmias with amisulpride, pimozide, sertindole and sotalol. Hypokalaemia or other electrolyte imbalance increases the risk of ventricular arrhythmias with terfenadine.

Corticosteroids or ACTH may increase electrolyte depletion, particularly potassium.

Co-amilozide can act synergistically with chlorpropramide or carbamazepine to increase the risk of hyponatraemia.

There is increased risk of hypercalcaemia when calcium salts, vitamin D or toremifene are taken with thiazides.

In some patients, the administration of a non-steroidal anti-inflammatory drug (NSAID) can reduce the diuretic, natriuretic, and antihypertensive effects of potassium-sparing and thiazide diuretics. There is also the risk of decreased renal function and hyperkalaemia - particularly in elderly patients. Therefore, when co-amilozide and NSAIDS are used concomitantly, renal function and serum potassium levels should be monitored.

Lithium should generally not be given to patients receiving diuretics, since the risk of lithium toxicity is very high in such patients.

There is an increased risk of nephrotoxicity and ototoxicity with cisplatin. Hydrochlorothiazide may decrease arterial responsiveness to pressor amines such as noradrenaline, but not enough to prevent them being effective in therapeutic usage.

Responsiveness to skeletal muscle relaxants (e.g. tubocurarine) may be increased with thiazides.

Amiloride antagonises the ulcer healing effect of carbenoxolone. Hydrochlorothiazide increases the plasma concentration of fluconazole.

The anion-exchange resins colestyramine and colestipol reduce the absorbance of thiazides and should be given at least 4 hours apart.

Oestrogens and combined oral contraceptives antagonise the diuretic effect of Co-amilozide.

4.6 Pregnancy and lactation

SYNURETIC 25 is not recommended for use during pregnancy. Thiazides appear in breast milk and cross the placental barrier appearing in cord blood.

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 neo-natal jaundice, and other possible side-effects that have occurred in adult patients. The routine use of diuretics is not indicated in otherwise healthy pregnant women with or without mild oedema.

4.7 Effects on ability to drive and use machines

If affected by weakness, fatigue, dizziness, stupor or vertigo the patient should be advised against driving or operating machinery.

4.8 Undesirable effects

Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. Combinations of headache, weakness, chest or back pain, fever, malaise and fatigue have been reported.

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

The combination of amiloride and hydrochlorothiazide is usually well tolerated and significant side-effects are infrequent. Reported side effects are generally associated with diuresis, thiazide therapy or with the underlying disease.

No increase in the risk of adverse reactions has been seen over those of the individual components.

The reported adverse reactions of the combination:

Headache, weakness, fatigue, malaise, chest pain, back pain, syncope.

Arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension and angina pectoris.

Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, appetite changes, abdominal fullness, flatulence, thirst and hiccups.

Elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia, gout, dehydration, symptomatic hyponatraemia.

Rash, pruritus, flushing, diaphoresis.

Leg ache, muscle cramps and joint pain.

Dizziness, vertigo, paraesthesiae and stupor.

Insomnia, nervousness, mental confusion, depression and sleepiness.

Dyspnoea.

Bad taste, visual disturbance, nasal congestion.

Impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure.

The reported side effects of amiloride:

Body as a whole: Neck/shoulder ache, pain in extremities.

Abnormal liver function, activation of probable preexisting peptic ulcer, dyspepsia, jaundice.

Dry mouth, alopecia, diaphoresis.

Tremors, encephalopathy.

Aplastic anaemia and neutropenia.

One patient with partial heart block developed complete heart block, palpitation.

Decreased libido, somnolence.

Cough.

Tinnitus, increased intro-ocular pressure.

Polyuria, urinary frequency, bladder spasm.

The reported side effects of hydrochlorothiazide:

Body as a whole: Anaphylactic reaction, fever.

Cardiovascular:    Necrotising angiitis (vasculitis, cutaneous vasculitis).

Digestive:    Jaundice (intrahepatic cholestatic jaundice), pancreatitis,

cramp, gastric irritation.

Endocrine/Metabolic: Glucosuria, hyperglycaemia and hyperuricaemia. Integumentary:    Photosensitivity, sialadenitis and urticaria.

Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia.

Restlessness.

Interstitial nephritis.

Respiratory distress including pneumonitis, pulmonary oedema.

Transient blurred vision, xanthopsia.

4.9 Overdose

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

The most common signs and symptoms of over dosage with amiloride hydrochloride and / or hydrochlorothiazide are dehydration and electrolyte imbalance.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Amiloride: 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 slightly 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 concentrations reached in 1.5-3 hours with diuresis lasting for 12 hours.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Calcium hydrogen phosphate Pregelatinised maize starch Sodium starch glycollate Maize starch Magnesium stearate

6.2 Incompatibilities

None known other than those described above.

6.3 Shelf life

24 months for all packs.

6.4    Special precautions for storage

Store in a well-closed container in a dry place, below 25°C. Protect from light. Keep out of the reach of children.

Store below 25°C in a dry place in well closed containers.

6.5    Nature and contents of container

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

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 tablets.

PVC/Aluminium foil blister packs.

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 250, 500, 560 & 1000 tablets.

6.6    Special precautions for disposal

No special instructions

7    MARKETING AUTHORISATION HOLDER

Cheliona Healthcare Limited

Boumpoulinas 11, 3 ^rd floor

Nicosia

Cyprus

P C 1060

Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0031

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

27/03/1991

10 DATE OF REVISION OF THE TEXT