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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-Amilozide Tablets 5/50mg Zido-Co 5/50

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5mg amiloride hydrochloride BP and 50mg hydrochlorothiazide BP.

3 PHARMACEUTICAL FORM

Tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-amilozide Tablets 5/50mg are indicated in patients with hypertension, congestive heart failure, hepatic cirrhosis with ascites and oedema. In hypertension co-amilozide may be used alone or in conjunction with other anti-hypertensive agents.

This product is intended for patients where potassium depletion is anticipated or might be suspected.

4.2 Posology and method of administration

Adults

Hypertension

Usually half a tablet is given once a day. Dosage may be increased to one tablet a day either as a single or divided dose.

Congestive heart failure

Half a tablet a day, adjusted if necessary but not exceeding 2 tablets a day. The optimal dose is determined by the diuresis response and plasma potassium level. Once an initial diuresis has been attained, dosage reduction should be attempted for maintenance therapy. It may be possible to give maintenance therapy on an intermittent basis.

Hepatic cirrhosis with ascites

Therapy should be initiated with a low dose. A single daily dose of one tablet may be increased until effective diuresis is achieved. Doses should not exceed 2 tablets a day. Dosage reduction to a maintenance level should be attempted once the patient’s weight has stabilised. A gradual weight reduction is desirable to reduce the likelihood of unwanted effects associated with diuretic medication.

Children:

Not recommended for children under 18 years of age as safety and efficacy has not been established.

Elderly

The dosage should be adjusted to reflect the clinical response and renal function.

Route of administration

Oral.

4.3 Contraindications

Co-amilozide Tablets 5/50mg are contraindicated if the patient:

•    Has hypersensitivity to amiloride hydrochloride, hydrochlorothiazide or other sulphonamide-derived drugs, or to any of the other ingredients of the tablets

•    Has hyperkalaemia (plasma potassium over 5.5mmol/l)

•    Is taking other potassium-conserving diuretics, or potassium supplements and potassium-rich foods

•    Is having concomitant treatment with spironolactone or triamterene

•    Has anuria

•    Has acute renal failure or severe progressive renal disease

•    Has severe hepatic failure or precoma associated with hepatic cirrhosis

•    Has Addison’s disease

•    Has hypercalcaemia

•    Is having concurrent lithium therapy

•    Has diabetic nephropathy

•    Has blood urea over 10mmol/l, diabetes mellitus, or serum creatinine over 130mmol/l where serum electrolyte and blood urea cannot be monitored carefully and frequently

Co-amilozide is not recommended for use in children under 18 years old.

4.4 Special warnings and precautions for use

Risk of Hyperkalaemia:

Hyperkalaemia has been observed in patients taking amiloride hydrochloride, especially in the elderly or hospitalised patients with hepatic cirrhosis or congestive heart failure with renal involvement, in seriously ill patients or in those undergoing vigorous diuretic treatment. In such cases, the patient should be carefully observed for clinical, laboratory or ECG evidence of hyperkalaemia. The ECG may not appear to be abnormal in all cases.

Some deaths have been reported in patients especially at risk of hyperkalaemia. If hyperkalaemia is suspected, treatment should be discontinued immediately and active measures taken to reduce the plasma potassium to normal levels.

Potassium supplements and potassium-rich foods should be avoided unless it is possible to monitor the serum potassium levels.

Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated. Dosage adjustment of antidiabetic agents, including insulin, may be required.

To minimise the risk of hyperkalaemia in patients with proven or suspected diabetes, the renal function should be assessed before co-amilozide therapy. Co-amilozide should be discontinued for at least 3 days before a glucose tolerance test.

Potassium sparing treatment should be started with caution in severely ill patients, where metabolic or respiratory acidosis may occur, (such as cardiopulmonary disease or inadequately controlled diabetes). Shifts in acid base balance alter the balance of potassium in and outside the cells; the development of acidosis may be associated with a rapid increase in plasma potassium.

Impaired renal function:

Hyperkalaemia may develop rapidly in patients with impaired renal function, which should be monitored. At creatinine levels below 30ml/min, thiazide diuretics are ineffective.

Electrolyte imbalance:

Patients should be monitored for fluid and electrolyte imbalance; hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. Warnings signs and symptoms include dry mouth, weakness, lethargy, drowsiness, restlessness, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and GI disturbances such as nausea and vomiting. If the patient is vomiting excessively or receiving parenteral fluids, serum and urine electrolytes should be determined.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance, calcium excretion is also decreased. Pathological changes in the parathyroid glands accompanied by hypercalcaemia and hypophosphataemia have been seen in a few patients receiving prolonged thiazide therapy.

Hypokalaemia:

May develop due to aggressive diuretic therapy, after prolonged therapy or if there is severe liver cirrhosis. This may sensitise or exaggerate the heart's response to digitalis toxicity.

Hyponatraemia:

Diuretic-induced hyponatraemia is usually mild and asymptomatic, although it may become severe and symptomatic. If this occurs, the patient requires prompt treatment.

Azotaemia:

Azotaemia may be precipitated or increased by hydrochlorothiazide.

In patients with impaired renal function, cumulative effects may be seen.

Co- amilozide should be discontinued if increasing azotaemia and oliguria develop.

Hepatic disease:

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease. Minor alteration of electrolyte and fluid balance may precipitate hepatic coma.

Hyperuricaemia may occur, or gout may be aggravated or precipitated in certain patients.

Increases in cholesterol and triglyceride levels may be seen.

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

4.5 Interaction with other medicinal products and other forms of interaction

Thiazides may decrease urinary calcium excretion, or may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Therapy should be discontinued before carrying out tests for parathyroid function.

Cholestyramine and colestipol reduce the absorption of thiazides and should therefore be given at least 2 hours apart.

Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by co-amilozide therapy. Dosage adjustment of antidiabetic agents including insulin may be required.

NSAIDs may reduce the diuretic effects of diuretics. However diuretics increase the risk of nephrotoxicity of NSAIDs. Indomethacin and possibly other NSAIDs may increase the risk of hyperkalaemia when taken with potassium sparing diuretics.

Co-amilozide should not be used concomitantly with spironolactone or triamterene.

The risk of hyperkalaemia and an enhanced hypotensive effect may occur if an ACE inhibitor or angiotensin-II antagonist are administered concurrently with amiloride hydrochloride. If concomitant use of these agents is desirable, frequent monitoring of serum potassium should be carried out. There is also an increased risk of hyperkalaemia if cyclosporin, potassium salts or trilostane are used concomitantly with amiloride.

Co-administration of alcohol, barbiturates or narcotics may potentiate orthostatic hypotension. There is a risk of postural hypotension when taken with tricyclic antidepressants. Other antihypertensive agents may have an additive effect; their dosages may need to be reduced (especially adrenergic blockers) when co-amilozide is added to existing therapy.

Diuretic therapy should be discontinued for 2-3 days before an ACE inhibitor is introduced to minimise the risk of a first-dose hypotensive effect. There is an increase in the risk of first dose hypotensive effects when post-synaptic alphablockers, such as prazosin, are taken comitantly with co-amilozide.

Anti-hypertensives, calcium channel blockers, alprostadil, betablockers and moxisylyte can all enhance the antihypertensive effects of co-amilozide tablets.

There is an increased risk of toxicity from cardiac glycosides and the following anti-arrythmics; amiodarone, disopyramide, flecainide and quinidine, if hypokalaemia occurs with a thiazide diuretic. The actions of lidocaine and mexiletine are antagonised by hypokalaemia.

There is an increased risk of hypokalaemia if co-amilozide tablets are taken with the following; reboxetine, amphotericin and high doses of sympathomimetics. There is also an increased risk of hypokalaemia if loop diuretics, thiazides or acetazolamide are given together.

Carbenoxolone can increase the risk of hypokalaemia whilst antagonising the diuretic effect of co-amilozide. The ulcer healing effect of carbenoxolone is antagonised by amiloride.

Corticosteroids or ACTH may intensify any thiazide induced electrolyte depletion, especially hypokalaemia and also antagonise the diuretic effect.

Hypokalaemia and other electrolyte imbalances can lead to an increase in ventricular arrhythmia when co-amilozide is taken with terfenadine, halofantrine, pimozide and sotalol.

Pressor amines, such as adrenaline, may show decreased arterial responsiveness when used with co-amilozide but the therapeutic effect may still be of use.

There is an increased risk of hypercalcaemia if thiazides are given with vitamin D, toremifene or calcium salts.

The diuretic effect of co-amilozide tablets is antagonised by oestrogen, combined oral contraceptives.

Non-depolarising muscle relaxants, such as tubocurarine, may possibly interact with co-amilozide to cause increased muscle relaxation. Other muscle relaxants such as baclofen and tizanidine may enhance the hypotensive effects of co-amilozide.

Lithium may accumulate due to reduced renal clearance.

Hydrochlorothiazide may decrease arterial responsiveness to pressor amines such as noradrenaline (norepinephrine), but not enough to preclude their therapeutic usefulness.

Cisplatin and co-amilozide can increase the risk of nephrotoxicity and ototoxicity.

Co-amilozide combined with chlorpropamide, carbemazapine or aminoglutethimide can act in synergy to increase the risk of hyponatraemia.

Hydrochlorothiazide increases plasma concentrations of fluconazole.

4.6 Fertility, pregnancy and lactation

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. Diuretics do not prevent the development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful for its treatment.

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.

Lactation:

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, confusion, dizziness and vertigo may occur. Should these occur the patient should be cautioned not to drive or operate machinery.

4.8 Undesirable effects

Although serious side effects are infrequent, minor side effects are common. They are generally associated with the underlying disease, diuresis or thiazide therapy. There is no known increased risk of side-effects due to the combination of amiloride with hydrochlorothiazide.

Although the likelihood of electrolyte imbalance is reduced with co-amilozide, careful check should be kept for such signs of fluid and electrolyte imbalance

As hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. It is particularly important to make serum and electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid or electrolyte imbalance include dryness of mouth, weakness, lethargy, drowsiness, restlessness, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting. Hyperkalaemia    has

been observed in patients receiving amiloride hydrochloride, either alone or in combination with other diuretics, particularly in the aged or in hospital patients with hepatic cirrhosis or congestive heart failure with renal involvement, who 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 an abnormal ECG).

Should hyperkalaemia develop, discontinue treatment immediately and, if necessary, take active measures to reduce the plasma potassium to normal.

Neither potassium supplements nor a potassium rich diet should be used with co-amilozide except under careful monitoring in severe and/or refractory cases of hypokalaemia. Some deaths have been reported in this group of patients.

Body as a whole: headache, weakness, fatigue, malaise, chest pain, back pain, syncope, dizziness, vertigo, stupor, paraesthesia, bad taste, visual disturbances, nasal congestion.

Cardiovascular: arrhythmias, tachycardia, digitalis toxicity, orthostaic hypotension, angina pectoris.

Gastrointestinal: anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pains, GI bleeding, changes in appetite, abdominal fullness, flatulence, thirst, hiccus.

Metabolic: elevated plasma potassium levels (above 5.5mmol/l), electrolyte imbalance, hyponaraemai (possibly sympotomatic), gout, dehydration.

Skin: rashes, pruritis, flushing, sweating.

Musculoskeletal: aching legs, muscle cramps, joint pains.

Psychiatric: insomnia, nervousness, mental confusion, depression, sleepiness. Respiratory: dyspnoea

Urogenital: impotence, Dysuria, nocturia, incontinence, renal dysfunction including renal failure.

Amiloride has been reported to cause: neck or shoulder aches or pain in the extremities, abnormal liver function, activation of pre-existing peptic ulcers, dyspepsia or jaundice, dry mouth, alopecia or sweating, tremors or encephalopathy, aplastic anaemia or neutropenia, palpitations, possible aggravation of partial heart block, decreased libido, sleepiness, cough , tinnitus or increased intra-occular pressure, polyuria, urinary frequency or bladder spasm.

Hydrochlorothiazide has been reported to cause: fever, anaphylaxsis, necrotizing angiitis, jaundice, pancreatitis, cramps, gastric irritation, glycosuria, hyperglycaemia, hyperuricaemia, photosensitivity, inflammation of the salivary glands, urticaria, agranulocytosis, aplastic anameia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia, restlessness, interstitial

nephritis, transient blurred or coloured vision, respiratory distress, including pneumonitis and pulmonary oedema

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No specific antidote is available and it is not known whether either component of co-amilozide is dialysable. Treatment should be symptomatic and supportive.

The most likely signs and symptoms are dehydration and electrolyte imbalance of amiloride overdosage.

Electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide overdosage.

Therapy should be discontinued and the patient observed. If ingestion is recent, emesis should be induced and/or gastric lavage performed. The most common signs of overdosage are dehydration and electrolyte imbalance.

Blood pressure should be monitored and corrected as necessary. In the event of hyperkalaemia, plasma potassium levels should be actively reduced. If digitalis has been administered, hypokalaemia may exaggerate cardiac arrhythmias.

The plasma half-life of amiloride is about 6 hours, and of hydrochlorothiazide about 5'A hours with a longer terminal half-life.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Hydrochlorothiazide and amiloride are both oral diuretics Amiloride hydrochloride appears to act mainly on the distal renal tubules. It increases the excretion of sodium and reduces the excretion of potassium.

Thiazides reduce the absorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. The excretion of other electrolytes notably potassium and magnesium, is also increased. The excretion of calcium is reduced. Thiazides also reduce carbonic-anhydrase activity so bicarbonate excretion is increased, but this effect is generally small compared with the effect on chloride and does not appreciably alter the pH of urine; they also reduce the glomerular filtration rate. Thiazides also have a hypotensive effect probably partly due to a reduction in peripheral resistance and enhance the effects of other antihypertensive agents. Paradoxically, they have and antidiuretic effect in patients with diabetes insipidus.

Hydrochlorothiazide slightly increases the bicarbonate excretion without appreciable alterations to the acid-base balance or the pH of the urine. It has an anti-hypertensive effect and enhances the action of other hypotensive agents.

Diuresis occurs in about two hours and lasts up to twenty-four hours.

5.2 Pharmacokinetic properties

Amiloride hydrochloride is incompletely absorbed from the gastrointestinal tract bioavailability of about 50% is reported. Food reduces the absorption. It is not significantly bound to plasma proteins and has a half-life of 6-9 hours.

It is excreted unchanged by the kidneys.

Hydrochlorothiazide is rapidly absorbed from the gastro-intestinal tract, with a bioabsorbability of 65-70%. It has a plasma half-life of about 5 hours with a terminal half-life of up to 15 hours. It is excreted unchanged by the kidneys. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

5.3 Preclinical safety data

None Known

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose, maize starch, microcrystalline cellulose, sodium starch glycollate, purified talc, magnesium stearate, sunset yellow (E110).

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years in Securitainers and 4 years in blister packs.

6.4 Special precautions for storage

Store below 25^oC. Protect from moisture and light.

6.5 Nature and contents of container

Securitainers stoppered with a polyurethane foam insert and sealed with a press cap. Pack size: 100 or 500 tablets.