Zido-Co Tablets 5/50
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS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.
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.
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.
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.
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
Co-Amilozide Tablets are not recommend unless it is considered that the benefits to the mother outweigh the risks to the foetus or infant.
Diuretic use in pregnant women may be associated with hypovolaemia, increased blood viscosity or decreased placental perfusion. Diuretics do not prevent toxaemia developing and there is not satisfactory evidence of their usefulness.
Thiazides cross the placental barrier and are detectable in cord blood. The possible risks to the foetus include foetal or neonatal jaundice, thrombocytopenia and bone marrow depression.
Thiazides are detectable in breast milk; although it is not known whether amiloride hydrochloride is excreted into breast milk, it is advisable to cease breast feeding if co-amilozide is prescribed.
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
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.
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/ hours with a longer terminal half-life.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Hydrochlorothiazide and amiloride are both oral diuretics which act by reducing reabsorption of electrolytes from the renal tubules thereby increasing the excretion of sodium and chloride ions and consequently of water. Hydrochlorothiazide also increases the excretion of potassium ions while amiloride has the opposite effect and has been found to diminish the kaluretic effects of other diuretics, i.e. hydrochlorothiazide in this combination.
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 25oC. 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.
Aluminium/PVC blisters in cardboard cartons. Pack size: 28, 50 or 100 tablets.
6.6 Special precautions for disposal
None given.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited Unit G4,
Riverside Industrial Estate,
Riverside Way,
Dartford DA1 5BS UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0018
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1st January 2000
10 DATE OF REVISION OF THE TEXT
05/06/2012