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1 NAME OF THE MEDICINAL PRODUCT

Co-amilozide 5mg/50mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablets.

A flat, pale peach bevelled edged tablet bisected on one side, embossed ‘BL’ on the other.

The tablet can be divided into equal halves

4.1    Therapeutic indications

Potassium-conserving diuretic and antihypertensive.

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. The presence of amiloride hydrochloride minimises the likelihood of potassium loss during vigorous diuresis for long term maintenance therapy. The combination is therefore indicated especially in conditions where potassium balance is particularly important.

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. Maintenance doses may be lower than those required to initiate diuresis; 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,, blood electrolytes and diuretic response. The elderly are more likely to experience hyperkalaemia since renal reserve may be reduced.

Route of administration

For oral administration

4.3 Contraindications

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

•    Has known 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 5.5 mmol/l)

•    is taking other potassium conserving diuretics or potassium supplements

or potassium-rich food (except in severe and/or refractory cases of hypokalaemia under careful monitoring

•    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

•    has diabetic nephropathy

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

• In renal impairment, use of a potassium-conserving agent may result in rapid development of hyperkalaemia.

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

4.4 Special warnings and precautions for use

To minimise the risk of hyperkalaemia in patients with proven or suspected diabetes, the renal function should be assessed before co-amilozide therapy.

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 diabetic or suspected diabetic patients, the status of renal function should be determined before initiating therapy with co-amilozide. 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.

These tablets contain lactose and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.

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.

Elderly:

The elderly are more likely to be at risk of hyperkalaemia, while taking this medicine. Electrolyte imbalance:

Patients should be monitored for fluid and electrolyte imbalance; hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. If the patient is vomiting excessively or is being given IV fluids, electrolyte monitoring is necessary. 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. Hyponatraemia may lead to grand mal seizures. Careful monitoring of serum electrolytes and blood urea levels should therefore be carried out when amiloride is given with oral diuretics to such patients. Reports suggest that patients with preexisting severe liver disease treated with diuretics including amiloride hydrochloride, may experience hepatic encephalopathy, manifested by tremors, confusion and coma, and increased jaundice.

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. Therapy should be discontinued before carrying out tests for parathyroid function.

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

Co-amilozide should not be used concomitantly with spironolactone or triamterene. Hydrochlorothiazide potentiates the actions of other antihypertensive drugs; therefore the dosage of these agents, especially the adrenergic blockers, may need to be reduced when this product is added to the regimen.

Therapy should be discontinued before carrying out tests for parathyroid function.

NSAIDs may attenuate the diuretic natriuretic and antihypertensive effects of diuretics. Coadministration of alcohol, barbiturates or narcotics may potentiate orthostatic hypotension.

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. If concomitant use is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum electrolytes.

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

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

Non-depolarising muscle relaxants, such as tubocurarine, may possibly interact with co-amilozide to cause increased muscle relaxation. The antihypertensive effect of thiazides may be enhanced in the post-sympathectomy patient.

Lithium should not generally be given with diuretics because they reduce renal clearanceand add a high risk of lithium toxicity.

Co-amilozide can act synergistically with chlorphropramide and lead to an increased risk of hyponatraemia.

4.6 Fertility, pregnancy and lactation

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.

Although it is not known whether amiloride is excreted in human milk, 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 dizziness, confusion, visual disturbances and drowsiness have been reported. Patients should be warned that if affected they should not drive, operate machinery or take part in activities where these could put themselves or others at risk.

4.8 Undesirable effects

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 that if the patient is vomiting excessively or is being given IV fluids electrolytes should be monitored.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, in hospital patients with hepatic cirrhosis or congestive heart failure with renal involvement, who were seriously ill, or were undergoing vigorous diuretic therapy and the “aged” are at particular risk of hyperkalemia. 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.

Apart from hyperkalaemia, 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.

General disorders: anaphylactic reaction, headache, weakness, fatigue, malaise, chest pain, back pain, syncope, neck/shoulder ache, pain in extremities.

Cardiac disorders: arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris necrotising angiitis (vasculitis, cutaneous vasculitis) and palpitation.

Gastrointestinal disorders: anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pains, abnormal liver function, dyspepsia, jaundice (intrahepatic cholestatic jaundice),gastric irritation, GI bleeding, changes in appetite, abdominal fullness, flatulence, thirst, hiccups and pancreatitis.

Metabolism and Nutrition disorders: elevated plasma potassium levels electrolyte imbalance, hyponatraemia, gout, dehydration, glycosuria, hyperglycaemia and hyperuricaemia

Blood and lymphatic system disorders: agranulocytosis, aplastic anaemia, haemolitic anaemia, leucopenia, neutropenia, purpura and thrombocytopenia.

Skin and subcutaneous tissue disorders: alopecia, diaphoresis, dry mouth, photosensitivity, rash, pruritus, flushing, sialadenitis and urticaria.

Nervous system disorders: dizziness, encephalopathy, paraesthesia, stupor, tremors, vertigo.

Musculoskeletal and connective tissue disorders: aching legs, muscle cramps, joint pains.

Psychiatric disorders: decreased libido, insomnia, nervousness, mental confusion, depression, sleepiness, restlessness and somnolence

Respiratory, thoracic and mediastinal disorders: dyspnoea, cough and respiratory distress, including pneumonitis, pulmonary oedema

Special senses: bad taste, increased intra-ocular pressure, nasal congestion, tinnitus, visual disturbance and xanthopsia.

Renal and urinary disorders: bladder spasm, interstitial nephritis, impotence, dysuria, nocturia, polyuria, incontinence, renal dysfunction including renal failure and urinary frequency.

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.

Features

Nausea, vomiting and diarrhoea and increased micturition (with polyuria and thirst). In extreme cases there may be depletion of intravascular volume, hypotension and peripheral circulatory failure. Hypokalaemia may develop if diuretics.

Management

•    Oral activated charcoal to adults/children who have taken substantial amounts within 1 hour.

•    Observe for 6 hours after ingestion

•    Check U&Es particularly if significant diuresis has occurred.

•    Oral potassium supplements if indicated.

•    Intravenous fluid and electrolyte replacement is only necessary if shock is present.

•    Other measures as indicated by the patient’s clinical condition.

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

In the event of hyperkalaemia, plasma potassium levels should be actively reduced. If digitalis has been administered, hypokalaemia may exaggerate cardiac arrhythmias.

5.1 Pharmacodynamic properties

ATC Code: C03EA01 - Hydrochlorothiazide and potassium-sparing agents

Amiloride hydrochloride is a weak diuretic with potassium-sparing properties. Hydrochlorothiazide is a thiazide diuretic.

Amiloride hydrochloride appears to act mainly on the distal renal tubules. It increases the excretion of sodium and reduces the excretion of potassium.

Thiazides act by reducing 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.

5.2 Pharmacokinetic properties

Amiloride hydrochloride is incompletely absorbed from the gastrointestinal tract bioavailability of about 50% is reported. Food reduces the absorption. Peak serum concentrations are achieved about 3-4 hours after administration by mouth. It is excreted unchanged in the urine.

Amiloride has been estimated to have a serum half-life of 6-9 hours.

Hydrochlorothiazide is rapidly absorbed from the gastro-intestinal tract, with a bioabsorbability of 65-70%. It has a plasma half-life of about 3-4 hours with a subsequent longer terminal phase, its biological half-life of up to 15 hours. It is excreted unchanged in the urine. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

5.3 Preclinical safety data

None Known

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

Not applicable

6.3 Shelf life

5 years in Securitainers 4 years in Al/PVC blister packs.

6.4 Special precautions for storage

Do not store above 25^oC. Store in original package, to protect from light and moisture.

Securitaniers: Keep the container tightly closed.

Blisters: Keep the blister in the outer carton.

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.

Aluminium/PVC blisters in cardboard cartons. Pack size: 28, 50 or 100 tablets.