Co-Amilozide Tablets Bp 5/50mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-amilozide Tablets BP 5/50 mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5.68 mg amiloride hydrochloride as the dihydrate and 50 mg hydrochlorothiazide.
For excipients see section 6.1
3. PHARMACEUTICAL FORM
Tablet.
Appearance
Pale peach, flat bevelled edge tablets with the RX on one face, breakline and tablet code 237 on reverse.
‘The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses’.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Co-amilozide Tablets are indicated for the treatment of hypertension, congestive heart failure or hepatic cirrhosis with ascites in whom potassium depletion might be anticipated. The presence of amiloride hydrochloride minimises the likelihood of excessive potassium loss during vigorous diuresis for long term therapy. The combination is particularly indicated in conditions where potassium balance is especially important, e.g. in patients with congestive heart failure receiving digitalis.
4.2 Posology and method of administration
The rate of loss of weight and the serum electrolyte levels should determine the dosage. The most satisfactory rate of weight loss after initiation of diuresis is about 0.5 to 1.0 kg per day.
Hypertension: Initially one tablet given once a day. The dosage may be increased if necessary to two tablets given once a day or in divided doses.
Co-amilozide may be used alone or as an adjunct to other antihypertensive drugs, but since the antihypertensive effect of these agents may be enhanced; their dosage may need to be reduced in order to reduce the risk of an excessive drop in pressure.
Congestive heart failure: Initially one tablet a day, subsequently adjusted if required, but not exceeding 4 tablets per day. Optimum dosage is determined by the diuretic response and the plasma 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 one tablet a day, subsequently adjusted if required, but not exceeding four tablets per day. A gradual weight reduction is especially desirable in cirrhotic patients, to reduce the likelihood of untoward reactions associated with diuretic therapy. Maintenance dosages may be lower than those required to initiate diuresis;
dosage reduction should therefore be attempted when the patient’s weight is stabilised.
Use in the elderly: Particular caution is needed in the elderly because of their susceptibility to electrolyte imbalance; the dosage should be carefully adjusted to renal function and clinical response. (See also Special Warnings & Precautions, subsections Hyperkalaemia, Electrolyte imbalance).
Children: Not recommended for children under 18 years of age as safety and efficacy has not been established.
Method of administration: Oral; swallow the tablets with water.
4.3 Contraindications
Hyperkalaemia (plasma potassium over 5.5 mmol/l); other potassium- conserving diuretics. Potassium supplements or potassium-rich food (except in severe and/or refractory cases of hypokalaemia under careful monitoring); concomitant treatment with spironolactone or triamterene; anuria; acute renal failure, severe progressive renal disease; severe hepatic failure; Addison’s disease; hypercalcaemia; concurrent lithium therapy; diabetic nephropathy; patients with blood urea over 10 mmol/l, patients with diabetes mellitus or those with serum creatinine over 130 pmol/l in whom serum electrolyte and blood urea levels cannot be monitored carefully and frequently; prior sensitivity to amiloride hydrochloride or hydrochlorothiazide. In renal impairment, use of potassium-conserving agent may result in rapid development of hyperkalaemia. Sensitivity to amiloride hydrochloride, hydrochlorothiazide or other sulphonamide derived drugs. Amiloride hydrochloride and hydrochlorothiazide tablets are not recommended for use in children. The safety of amiloride hydrochloride for use in children under 18 years of age has not been established. Co-amilozide should not be taken during pregnancy or lactation.
4.4 Special warnings and precautions for use
Use 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. Renal function should be monitored. If increasing azotaemia and oliguria occur, treatment should be discontinued.
Diabetes mellitus: Hyperkalaemia has commonly occurred in diabetic patients on amiloride hydrochloride. The status of renal function should therefore be determined before use in known or suspected diabetics. The dosage of insulin or oral hypoglycaemic agents for diabetic patients may need to be changed. Diabetes mellitus which has been latent may become manifest during thiazide administration.
Co-amilozide should be discontinued at least three days before glucose tolerance tests are performed in patients with diabetes mellitus, especially if there is renal insufficiency or diabetic nephropathy, because of the risks of provoking severe hyperkalaemia.
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, and the development of acidosis may be associated with rapid increases in plasma potassium.
Hyperkalaemia: This has been observed in patients receiving amiloride hydrochloride, either alone or with other diuretics, particularly in the aged, in diabetics, and in hospital patients with hepatic cirrhosis or congestive heart failure who had 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 an abnormal ECG). Should hyperkalaemia develop, discontinue treatment immediately, and if necessary, take active measures to reduce the plasma potassium to normal.
Electrolyte imbalance and blood urea increases: Hyponatraemia and hypochloraemia may occur. Hypochloraemic alkalosis may also occur, but its likelihood is reduced by the presence of amiloride in the combination of amiloride hydrochloride and hydrochlorothiazide. Reversible increases in blood urea have been reported accompanying vigorous diuresis, especially in seriously ill patients, such as those with hepatic cirrhosis with acites and metabolic acidosis or those with resistant oedema; plasma electrolyte and blood urea levels should be carefully monitored in these patients. All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy (see also 4.8 Undesirable Effects, Electrolyte Imbalance).
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 to acute shifts in electrolyte balance, and because they often have pre-existing hypokalaemia as a result of associated aldosteronism. Use in hepatic failure is contraindicated (see 4.3 Contraindications). Hepatic encephalopathy, manifested by tremors, confusion and coma, has been reported in patients on amiloride hydrochloride alone. Patients with liver disease on this preparation should be observed for this complication. In cirrhotic patients receiving amiloride hydrochloride alone, a deepening of jaundice has occurred but the relationship to amiloride is uncertain.
Sensitivity reactions: Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma. The possibility that thiazides may activate or exacerbate systemic lupus erythematosus has been reported.
Caution should be observed in porphyria. Hydrochlorothiazide is considered unsafe for use in acute porphyrias.
Metabolic and endocrine effects: Thiazides may decrease serum PBI levels without signs of thyroid disturbance. Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid glands accompanied by hypercalcaemia and hypophosphataemia have been seen in few patients receiving prolonged thiazide therapy. However, the common complications of hyperparathyroidism have not been observed. Therapy should be discontinued before carrying out tests for parathyroid function. Hyperuricaemia may occur, or gout may be precipitated or aggravated in certain patients receiving thiazides.
Caution is required in patients with severe asthma, as hypokalaemia associated with beta2-agonist therapy can be potentiated by concurrent use of diuretics.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.
4.5
Interaction with other medicinal products and other forms of interaction
Hydrochlorothiazide potentiates the action of other antihypertensive drugs. Therefore the dosage of these agents, especially the adrenergic blockers, may need to be reduced when this preparation is added to the regimen. The antihypertensive effect of thiazides may be enhanced in the post-sympathectomy patient. Hydrochlorothiazide may decrease arterial responsiveness to noradrenaline, but not enough to prevent noradrenaline being effective in therapeutic dosage.
Analgesics: Non steroidal anti-inflammatory drugs may attenuate the antihypertensive effect of thiazide diuretics. NSAIDs increase the risk of hyperkalaemia with potassiumsparing diuretics. Diuretics may increase the risk of nephrotoxicity of NSAIDs. Thiazide-containing drugs may increase the responsiveness to tubocurarine.
Anion-exchange resins: Cholestyramine and colestipol reduce absorption of thiazides and should be given at least two hours apart.
Anti-arrhythmics: Toxicity of amiodarone, disopyramide, flecainide and quinidine is increased if hypokalaemia occurs. Action of lidocaine and mexilitine is antagonised by hypokalaemia. Hypokalaemia increases risk of ventricular arrhythmias with sotalol, a beta-blocker. The antiarrhythmic activity of quinidine may be opposed by amiloride.
Antidepressants: Co-administration of tricyclic antidepressants may potentiate ortho static hypotension. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs). Possibly increased risk of hypokalaemia if thiazides given with reboxetine.
Antidiabetics: Thiazides may antagonise the hypoglycaemic effect of antidiabetics. Oral and parenteral antidiabetic drugs may require adjustment of dosage with concurrent use. Co-amilozide can act synergistically with chlorpropamide to increase the risk of hyponatraemia.
Antiepileptics There is an increased risk of hyponatraemia with carbamazepine.
Antifungals: Increased risk of hypokalaemia with concurrent use of thiazide diuretics and amphotericin. Hydrochlorothiazide may increase the plasma concentration of fluconazole.
Antigout agents: Potential for increased toxicity and hypersensitivity/allergic reactions with concomitant use of allopurinol and thiazide diuretics.
Antihistamines: Diuretic-induced hypokalaemia increases risk of ventricular arrhythmias with terfenadine.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II antagonists -Enhanced hypotensive effect, risk of severe hyperkalaemia with potassium-sparing diuretics.
Therefore, if concomitant use of these agents is indicated they should be used with caution and with frequent monitoring of serum potassium. Diuretic therapy should be discontinued for two to three days prior to initiation of therapy with an ACE inhibitor to reduce the likelihood of first dose hypotension.
Alpha-blockers — increased risk of first-dose hypotension with alpha-blockers such as prazosin.
Beta-blockers and calcium-channel blockers — enhanced hypotensive effect may occur.
Antipsychotics: Diuretic-induced hypokalaemia increases the risk of ventricular arrhythmias with primozide and sertindole, concurrent use should be avoided.
Barbiturates: Co-administration of barbiturates may potentiate orthostatic hypotension.
Calcium salts & Vitamins: There is a risk of hypercalcaemia with calcium salts and vitamin D. There is an increased risk of developing milk-alkali syndrome in patients given large amounts of calcium or vitamin D in combination with thiazides.
Cardiac Glycosides: Increased risk of toxicity if diuretic-induced hypokalaemia occurs.
Corticosteroids or ACTH: Increased risk of electrolyte depletion, particularly hypokalaemia, mainly with the naturally occurring corticosteroids such as cortisone and hydrocortisone. The synthetic corticosteroids have a much less marked potassium-losing effect. Fluid retention associated with corticosteroid use may antagonise the diuretic/antihypertensive effect.
Cytotoxics Diuretics increase the risk of nephrotoxicity and ototoxicity with cisplatin.
Diuretics: Increased risk of hypokalaemia with concurrent administration of other thiazides and other diuretics including acetazolamide and loop diuretics.
Dopaminergics: Potential for increased risk of amantadine toxicity in association with hydrochlorothiazide.
Hormones and other endocrine drugs: When amiloride hydrochloride is administered concomitantly with trilostane, the risk of hyperkalaemia may be increased. Thiazide diuretics may increase the risk of hypercalcaemia with toremifene. Oestrogens and progestogens antagonise diuretic effect.
Immunosuppressants: When amiloride hydrochloride is administered concomitantly with ciclosporin or tacrolimus, the risk of hyperkalaemia may be increased.
Lithium: Lithium may accumulate as a result of reduced renal clearance (see 4.3 Contraindications).
Muscle relaxants: Enhanced hypotensive effect may occur with tizanidine.
Potassium salts: Increased risk of hyperkalaemia with administration of potassium supplements (see 4.3 Contraindications).
Prostaglandins: Hypotensive effect may be potentiated by alprostadil.
Sympathomimetics: increased risk of hypokalaemia with thiazide diuretics and high doses of sympathomimetics (See 4.4 Warnings and Precautions, use of beta2-agonists in severe asthma). Pressor amines such as adrenaline may show decreased arterial responsiveness when used with co-amilozide but this reaction is not enough to preclude their therapeutic usefulness.
Ulcer-healing drugs: Fluid retention associated with carbenoxolone may cause antagonism of diuretic/antihypertensive effect. Thiazides can be used to treat the adverse side-effects of carbenoxolone, but not amiloride which may antagonise the ulcer-healing effect.
Drug/laboratory tests: Because thiazides may affect calcium metabolism, coamilozide may interfere with tests for parathyroid function.
Creatinine clearance: Amiloride can block the tubular secretion of creatinine and may lead to falsely high measurements of creatinine clearance.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates and narcotics.
4.6 Fertility, Pregnancy and lactation
Pregnancy:
Co-amilozide is not recommended for use during pregnancy. 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.
The use of co-amilozide where pregnancy is present or suspected must be weighed against possible hazards to the foetus. These hazards include foetal or neonatal jaundice, foetal hypokalaemia 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.
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 Tablets during breast feeding is not recommended. If use of the drug is deemed essential, the patient should stop nursing. If Co-amilozide Tablets is used during breast feeding, doses should be kept as low as possible.
4.7 Effects on ability to drive and use machines
This drug may cause drowsiness, headache, visual disturbances, dizziness, and vertigo. The patient should not drive or operate machinery until the drug has been shown not to affect physical or mental ability.
4.8 Undesirable effects
The combination of amiloride and hydrochlorothiazide is usually well tolerated and significant side effects are infrequent. No increase in the risk of adverse reactions has been seen over those of the individual components.
Thrombocytopenia and bone marrow depression have been reported.
The reported adverse reactions of the combination:
Body as a whole: Headache, weakness, fatigue, malaise, syncope.
Cardiovascular: Arrhythmias, tachycardia, digitalis, toxicity (see 4.5 Interactions, subheading Cardiac Glycosides), orthostatic hypotension and angina pectoris, dizziness, vertigo, chest pain;.
Digestive: Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, gastrointestinal bleeding, appetite changes, abdominal fullness, flatulence, thirst and hiccups.
Metabolic: Elevated plasma potassium levels (above 5.5 mmol/l), gout, hyponatraemia and dehydration. Hyponatraemia as a complication is rare, but constitutes a medical emergency as onset may be rapid The symptoms of hyponatraemia may be non-specific and include nausea, lethargy, weakness, irritability, mental confusion, muscle cramps and anorexia, but it may be an important cause of morbidity. Severe sequelae of hyponatraemia include tonic-clonic seizures and clinical features resembling subarachnoid haemorrhage.
Integumentary: Rash, pruritis and flushing.
Musculoskeletal: Leg ache, muscle cramps and joint pain.
Nervous: Dizziness, vertigo, paraesthesiae and stupor.
Psychiatric: Insomnia, nervousness, mental confusion, depression and sleepiness.
Respiratory: Dyspnoea.
Special senses: Bad taste, visual disturbance and nasal congestion.
Urogenital: dysuria, nocturia, renal dysfunction including renal failure and incontinence. Impotence occurring early in the course of treatment (onset after 2 years unlikely) and reversible on withdrawal of treatment.
Side effects of amiloride:
Digestive: Abnormal liver function. Activation of probable pre-existing peptic ulcer. Hyperkalaemia (see also 4.3 Contraindications and 4.4 Special Warnings & Precautions). Encephalopathy may be precipitated by hypokalaemia in patients with pre-existing liver disease.
Integumentary: Dry mouth.
Haematological: Aplastic anaemia and neutropenia.
Sexual disorders: Decreased libido and somnolence Side effects of hydrochlorothiazide:
Body as a whole: Anaphylactic reaction, fever, respiratory distress including pneumonitis and pulmonary oedema occur rarely.
Cardiovascular: Necrotising angitis (vasculitis, cutaneous vasculitis). Digestive:
Jaundice (intrahepatic cholestatic jaundice) and pancreatitis.
Endocrine/metabolic: Glycosuria, hyperglycaemia and hyperuricaemia. Diabetes mellitus may be aggravated and latent diabetes may become manifest during thiazide administration. Blood-glucose concentrations should be monitored in patients taking antidiabetics, since requirements may change (see 4.5 Interactions). Hypokalaemia, hypochloraemic alkalosis, hyperuricaemia, the urinary excretion of calcium may be reduced and the potential for hypercalcaemia exists (use in preexisting hypercalcaemia is contraindicated, see 4.3).
Integumentary: Photosensitivity, sialdenitis and urticaria.
Psychiatric: Restlessness.
Respiratory: Respiratory distress including pneumonitis.
Special senses: Transient blurred vision and xanthopsia.
Haematological: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura and thrombocytopenia.
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 the Yellow Card Scheme at: www.mhra.gov .uk/yellowcard
4.9 Overdose
No specific data is available in humans. 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, emesis should be induced and/or gastric lavage 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. The plasma half-life of hydrochlorothiazide is 5.6 hours with a subsequent longer terminal phase; the plasma half-life of amiloride is about six hours.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Amiloride hydrochloride: Amiloride is a pyrazinoylguanidine, with moderate natriuretic activity, though its major importance lies in its effect on potassium excretion. The drug interferes with transport in the late segments of the nephron. It induces a modest increase in the excretion of sodium mostly accompanied by chloride as the anion. Under ordinary circumstances there is little change in the excretion of potassium, although sometimes there is a slight increase. However, when excretion of potassium is high because of increased intake, administration of another diuretic, or an excess of mineralocorticoid, amiloride causes a sharp decrease in its excretion. The primary action is to inhibit the electrogenic entry of sodium. Because of the interruption of the electrogenic sodium transport by amiloride the electrical potential across the tubular epithelium falls. The reduction or elimination of this potential which is one of the driving forces for the secretion of potassium is probably the basis of the potassium-sparing effect.
Hydrochlorothiazide: Thiazides act directly on the kidney to increase the excretion of sodium chloride and of an accompanying volume of water; they also increase excretion of potassium. The thiazides vary widely in their potency as carbonic anhydrase inhibitors. The major site of action of thiazides is the distal tubule. The maximal rate of sodium excretion induced by thiazides is modest relative to that achievable with other types of diuretics. This is attributable to the fact that about 90% of filtered sodium is reabsorbed before the tubular fluid reaches the site of action of the thiazides. Unlike some other natriuretic agents, the thiazides decrease the renal excretion of calcium as a result of a direct action on the distal tubule. Thiazides tend to produce less distortion of the composition of the extra cellular fluid than do other diuretic agents.
5.2 Pharmacokinetic properties
Amiloride hydrochloride: About 50% of an oral dose is absorbed. Amiloride is not bound to plasma proteins, nor is it metabolised. It is secreted in the proximal tubule. Amiloride may also cause slight alkalisation of urine, due to hydrogen secretion inhibition. The most serious toxic effect is hyperkalaemia.
Hydrochlorothiazide: Hydrochlorothiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. It has been estimated to have a plasma half-life of about 3 or 4 hours with a subsequent longer terminal phase; its biological half-life is up to about 12 hours. It appears to be preferentially bound to red blood cells. It is excreted unchanged in the urine. Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.
5.3 Preclinical safety data
Amiloride and hydrochlorothiazide have been used in clinical practice for over 20 years and have become commonly used in combination.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate , calcium hydrogen phosphate dihydrate, maize starch, talc, sodium starch glycollate, magnesium stearate and lake sunset yellow.
6.2 Incompatibilities
Not applicable.
6.3
Shelf life
4 years for securitainer and 3 years for blister packs.
6.4 Special precautions for storage
Polypropylene tubes: None
Blister packs: Do not store blisters above 25oC
6.5 Nature and contents of container
Polypropylene tubes fitted with low density polyethylene caps.
Pack sizes: 28, 100, 250, 500 and 1000 tablets.
Blister packs made up of 0.25mm PVC foil and 0.02mm Al. Foil. Pack sizes: 28, 30 tablets.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Special Concept Development (UK) Limited,
Unit 1-7 Colonial Way,
Watford, Hertfordshire,
WD24 4YR United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 36722/0036
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22 April 2002
10 DATE OF REVISION OF THE TEXT
29/12/2015