SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

SYNURETIC 50

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Amiloride hydrochloride (as dihydrate)    5.69 mg

Hydrochlorothiazide    50.00 mg

Also contains lactose (see section 6.1 for other excipients)

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Hypertension.

Congestive heart failure.

Hepatic cirrhosis with ascites where potassium depletion might be anticipated.

SYNURETIC 50 is particularly indicated in conditions where potassium balance is especially important, e.g. patients with congestive heart failure receiving digitalis.

4.2    Posology and method of administration

Tablets to be taken orally.

Adult dosage:

Hypertension:

Initially V tablet daily, increased if necessary to a maximum of 1 tablet daily.

SYNURETIC 50 may be used alone or as an adjunct to other antihypertensive drugs such as methyldopa or timolol maleate. Since SYNURETIC 50 enhances the action of these agents the dosage of the antihypertensive drugs may be to reduced to avoid an excessive drop in blood pressure. Timolol maleate and SYNURETIC 50 can be used together once daily. The majority of patients will respond to 10-20 mg timolol maleate once daily together with V tablet of SYNURETIC 50.

Congestive cardiac failure:

Initially V tablet daily, subsequently adjusted if required but not exceeding 2 tablets a day. The optimal dosage is to be determined by the diuretic response and the serum 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:

Initially 1 tablet a day, increased gradually if necessary until there is acceptive diuresis, but not exceeding 2 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 dosage may be lower than those required to initiate diuresis; dosage reduction should be attempted when the patient's weight is stabilised.

Elderly:

Dosage is the same as for adults but hyperkalaemia is more likely to occur with the adult dosage regimen and should be carefully monitored.

Children:

Not recommended for children under 18 years of age.

4.3 Contraindications

Hyperkalaemia (plasma potassium level over 5.5 mmol/l), other potassium-conserving diuretics, and 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 130qmol/l in whom serum electrolyte and blood urea levels cannot be monitored carefully and frequently;

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:

Hyperkalaemia has commonly occurred in diabetic patients on amiloride hydrochloride, especially those with chronic renal disease or pre-renal azotaemia. The status of renal function should therefore be determined before SYNURETIC 50 is given to known or suspected diabetics. SYNURETIC 50 should be discontinued before giving a glucose-tolerance test, as one patient with poorly controlled diabetes mellitus, who became severely hyperkalaemic while receiving amiloride hydrochloride, died following two repeated intravenous glucose-tolerance tests. The insulin requirement of diabetic patients may need to be changed. Diabetes mellitus which has been latent may become manifest during thiazide administration.

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. The development of acidosis may be associated with rapid increases in serum potassium.

Hyperkalaemia (serum potassium over 5.5 mmol/l):

This has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged and in diabetics.

Hyperkalemia has been reported in hospital patients with hepatic cirrhosis or congestive heart failure who had known renal involvement, were seriously ill, or were undergoing vigorous diuretic therapy. Such patients should be carefully observed for clinical, laboratory and ECG evidence of hyperkalaemia (not always associated with abnormal ECG). In renal impairment, use of potassium-conserving agents may result in rapid development of hyperkalaemia. Some deaths have been reported in this group of patients.

Should hyperkalaemia develop, SYNURETIC 50 should be discontinued immediately and, if necessary, active measures taken to reduce the serum potassium to normal.

Electrolyte imbalance and blood urea increases:

Hyponatraemia , hypomagnesia and hypochloraemia may occur, although the likelihood of hypochloraemia alkalosis is reduced with SYNURETIC 50. 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.

Reversible increases in blood urea have been reported accompanying vigorous diuresis, especially in seriously ill patients, such as those with hepatic cirrhosis with resistant oedema; serum electrolyte and blood urea levels should be carefully monitored in these patients.

SYNURETIC 50 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.

In addition, azotaemia may be precipitated or increased by hydrochlorothiazide. If increasing azotaemia and oliguria occur during treatment, SYNURETIC 50 should be discontinued.

Effects in cirrhotic patients:

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 as a result of associated aldosteronism.

Hepatic encephalopathy, manifested by tremors, confusion and coma, has been reported in patients on amiloride hydrochloride. Patients with liver disease should be observed for this complication when SYNURETIC 50 is given.

In cirrhotic patients receiving amiloride hydrochloride alone, a deepening of jaundice has occurred, 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.

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 orthostatic hypotension. The antihypertensive effect of thiazides may be enhanced in the post-sympathectomy patient.

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 not be given to patients receiving SYNCRETIC 50 as 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 50 is not recommended for use during pregnancy. Since thiazides cross the placental barrier and appear in cord blood, use where pregnancy is present or suspected requires that the benefits of the drug be weighed against possible hazards to the foetus. These hazards include foetal or neo-natal jaundice, thrombocytopenia, bone marrow depression and possibly other side effects that have occurred in the adult.

Use in lactation: although it is not known whether amiloride hydrochloride is excreted in human milk, it is known that thiazides do appear in breast milk. If the drug is deemed essential, the patient should stop nursing.

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.

The dosage of anti-hypertensive agents, especially the ganglionic blockers, may need to be reduced when SYNURETIC 50 is added to the regimen. Lithium should generally not be given to patients receiving diuretics, since the risk of lithium toxicity is very high in such patients. The possibility that the thiazides may activate or exacerbate systemic lupus erythematosus has been reported.

The antihypertensive effect of thiazides may be enhanced in the postsympathectomy patient. Thiazides may decrease serum PBI levels without signs of thyroid disturbance. Pathological changes in the parathyroid glands accompanied by hyperkalaemia and hypophosphataemia, have been reported in a few patients receiving prolonged thiazide therapy. The common complications of hyperparathyroidism have not been observed. Thiazides should be discontinued before carrying out tests for parathyroid function. Hyperuricaemia may occur, or gout may be precipitated in certain patients receiving thiazides. As with any drug, patients should be observed regularly for the possible occurrence of liver dysfunction, idiosyncratic reactions, or blood dyscrasias.

The combination of amiloride and hydrochlorothiazide is usually well tolerated. Although minor side effects are relatively common, 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 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, neutropenia.

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

Psychiatric:    Decreased libido, somnolence.

Respiratory: Cough.

Special senses:    Tinnitus, increased intro-ocular pressure.

Urogenital:    Polyuria, urinary frequency, bladder spasm.

Anaphylactic reaction, fever.

Necrotising angiitis (vasculitis, cutaneous vasculitis). Jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramp, gastric irritation.

Glucosuria, hyperglycaemia, hyperuricaemia. Photosensitivity, sialadenitis, 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 and it is not known whether the drug is dialysable.

Treatment should be symptomatic and supportive. Therapy should be discontinued and the patient watched closely. If ingestion is recent, gastric lavage should be performed. The most common signs and symptoms of overdosage with amiloride hydrochloride are dehydration and electrolyte imbalance. If hyperkalaemia occurs, active measures should be taken to reduce the plasma potassium levels.

Electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide overdosage. Blood pressure should be monitored and corrected where necessary.

If digitalis has been administered, hypokalaemia may accentuate cardiac arrhythmias.

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: It is completely absorbed from the intestinal tract, and acts within 2 hours of dosing. The biological half-life of amiloride is 6 hours. It is excreted unchanged partly in urine. Peak serum levels are reached in 4 hours.

Hydrochlorothiazide: Peak plasma concentration reached in 1.3-3 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 Purified water

6.2 Incompatibilities

None known other than those described above.

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.

These containers are of 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 tablets.

Blister packs consisting of PVC/Aluminium foil backed in which the tablets are packed in pack sizes of 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

Chelonia Healthcare Limited 11 Boumpoulinas Street,

3^rd floor, 1060 Nicosia Cyprus

8    MARKETING AUTHORISATION NUMBER(S)

PL 33414/0030

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/12/84

10    DATE OF REVISION OF THE TEXT

14/04/2008