Co-Amilozide 5/50mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-amilozide 5/50mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5.68 mg Amiloride Hydrochloride (equivalent to 5mg anhydrous Amiloride hydrochloride) and 50 mg Hydrochlorothiazide.
Excipients with known effect: Lactose Monohydrate
For other excipients see 6.1
3. PHARMACEUTICAL FORM
Tablet.
Pale peach, circular flat bevelled edge tablets with the company logo ‘PV’ on one face and the tablet code A / 550 with a breakline on the reverse.
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 and oedema in whom potassium depletion might be anticipated. The presence of amiloride hydrochloride minimizes the likelihood of excessive potassium loss during vigorous diuresis for long term therapy. The combination is particularly indicated in conditions where potassium balance in 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: Usually half a Co-Amilozide tablet given once a day. If necessary, increase to a maximum of one tablet daily or in divided doses.
Congestive heart failure: Initially half a Co-amilozide tablet a day, subsequently adjusted if required, but not exceeding 2 tablets a day. Optimal dosage is determined by the diuretic response and the plasma potassium level. Once an initial dieresis has been achieved, reduction in dosage may be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.
Hepatic cirrhosis with ascites: Initiate therapy with a low dose. A single daily dose of one Co-Amilozide tablet may be increased gradually until there is an effective diuresis. Dosage should not exceed two tablets a day. Maintenance dosages may be lower than those required to initiate diuresis; dosage reduction should therefore be attempted when the patient’s weight is stabilised. A gradual weight reduction is especially desirable in cirrhotic patients to reduce the likelihood of untoward reactions associated with diuretic therapy.
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.
Paediatric use: Co- Amilozide is not recommended for children under 18 years as safety and efficacy have not been established (see 4.3 Contra-indications)
Method of administration: Oral; swallow the tablets with water.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 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); anuria; acute renal failure, severe progressive renal disease; severe hepatic failure or precoma associated with hepatic cirrhosis; Addison’s disease; hypercalcaemia; concurrent lithium therapy; concomitant treatment with spironolactone or triamterene, 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 or other sulphonamide derived drugs. In renal impairment, use of potassium-conserving agent may result in rapid development of hyperkalaemia. Amiloride hydrochloride and hydrochlorothiazide tablets are not recommended for use in children.
4.4 Special warnings and precautions for use
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).
Neither potassium supplements nor potassium rich diet should be used with co-amilozide tablets except under careful monitoring in serve and /or refractory cases of hypokalaemia.
Some deaths have been reported in this group of patients.
Should hyperkalaemia develop, discontinue treatment immediately, and if necessary, take active measures to reduce the plasma potassium to normal.
Impaired renal function: Renal function should be monitored because of the use of co-amilozide in impaired renal function may result in rapid development of hyperkalaemia. Thiazide diuretics become ineffective when creatinine levels fall below 30ml/minute.
Electrolyte imbalance: Although the likelihood of electrolyte imbalance is reduced by co-amilozide careful check should be kept for such signs of fluid and electrolyte imbalance as hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia. Electrolyte imbalance is also more likely when other diuretics are co-administered. It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid or electrolyte imbalance include: dryness of the mouth, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
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.
Hypokalaemia may develop, especially as a result of brisk dieresis, after prolonged therapy or when severe cirrhosis is present. Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).
Diuretic- induced hyponatraemia is usually mild and asymptomatic. It may become severe and symptomatic in a few patients who will then require immediate attention and appropriate treatment.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. 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.
Azotaemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotaemia or oligouria develops during treatment of renal disease, co-amilozide tablets should be discontinued.
Thiazides may decrease serum plasma bound iodine (PBI) levels without signs of thyroid disturbance.
Raised blood urea may be precipitated or aggravated by hydrochlorothiazide, especially in very ill patients such as those with hepatic cirrhosis with ascites and metabolic alkalosis or those with resistant oedema. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotaemia and oliguria develop during treatment of renal disease, co-amilozide tablets should be discontinued.
The anti-hypertensive effect of thiazides may be enhanced in patients who have had sympathectomy.
Hepatic Disease: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease (see contra-indications), since minor alterations of fluid and electrolyte balance may precipiptate hepatic coma.
Metabolic: Hyperuricaemia may occur, or gout may be precipitated or aggravated, in certain patients receiving thiazides. Thiazides may impair glucose intolerance. Diabetes mellitus may be precipitated or aggravated by therapy with co-amilozide tablets (See contraindications). Dosage adjustment of antidiabetic agents, including insulin, may be required.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
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 tablets. Therapy should be discontinued at least three days before giving a glucose tolerance test. 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 patients with inadequately controlled 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.
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.
This product contains lactose. 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
Ciclosporin: Increased risk of nephrotoxicity and hyperkalaemia when coadministered with co-amilozide.
Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Refer to the prescribing information for lithium preparations before use of such preparations.
Non-Steroidal Anti-inflammatory Drugs: Non-steroidal anti-inflammatory drugs
(NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of antihypertensive drugs, including the diuretic, natriuretic and antihypertensive effects of diuretics. In some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of diuretics. Concomitant administration of non-steroidal anti-inflammatory drugs (NASIDs) and potassium-sparing agents, including amiloride hydrochloride, may cause hyperkalaemia and renal failure, particularly in elderly patients. Therefore when amiloride hydrochloride is used concomitantly with NSAIDs, renal function and serum potassium levels should be carefully monitored.
Amiloride Hydrochloride:
When amiloride hydrochloride is administered concomitantly with an ACE inhibitor, angiotensin II antagonist, trilostane, cyclosporin, tacrolimus supplements or potassium rich food (see section 4.3 contraindications), the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Hydrochlorothiazide:
When given concurrently, the following drugs may interact with thiazide diuretics:
Alcohol, barbiturates or narcotics: Co-administration may potentiate orthostatic hypotension.
Oral and parenteral antidiabetic drugs: Antidiabetic drugs may require adjustment of dosage with concurrent use. Co-amilozide tablets can act synergistically with chlorpropamide to increase the risk of hyponatraemia.
Other antihypertensive drugs: May have an additive effect. Therefore the dosage of these agents, especially adrenergic-blockers, may need to be reduced when co-amilozide is added to the regimen, eg. spironolactone or triamterene. Diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with an ACE inhibitor to reduce the likelihood of first dose hypotension.
If diuretic therapy with co-amilozide is reintroduced because of demonstrated hypokalaemia the combination should be used with caution and electrolytes carefully monitored.
There is increased risk of hypokalaemia with concurrent use of thiazide diuretics and theophylline, amphotericin, reboxetine or loop diuretics.
Potentially serious hypokalaemia may result from beta2-adrenoreceptor stimulant therapy, and caution is advised if initiating co-amilozide therapy in severely asthmatic patients. Monitoring of serum potassium is recommended.
There is an increased risk of hypercalcaemia if thiazide diuretics are administered with vitamin D, calcium salts or toremifene.
Concomitant use with carbamazepine may increase the risk of hyponatraemia.
Allopurinol
Thiazide diuretics may cause predisposition to allopurinol hypersensitivity reactions.
Fluconazole
Hydrochlorothiazide increases plasma levels of fluconazole Although no dose adjustment of fluconazole is generally required the prescriber should be aware of this interaction.
Colestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43% respectively. When colestyramine is given 4 hours after the hydrochlorothiazide, the absorption of hydrochlorothiazide is reduced by 30% to 35%.
Corticosteroids or ACTH: May intensify any thiazide-induced electrolyte depletion, particularly hypokalaemia.
Pressor amines such as epinephrine (adrenaline): May show decreased arterial responsiveness when used with co-amilozide but this reaction is not enough to preclude their therapeutic usefulness.
Non-depolarising muscle relaxants such as tubocurarine: May possibly interact with co-amilozide to increase muscle relaxation
Drug/Laboratory tests: Because thiazides may affect calcium metabolism, co-amilozide tablets may interfere with tests for parathyroid function.
Thiazides, even when administered with amiloride, may cause hypokalaemia. If hypokalaemia is present, the following interactions are possible and potentially hazardous:
Lignocaine: Hypokalaemia inhibits the activity of lignocaine Flecainide, disopyramide: Increased risk of cardiotoxicity Amisulpiride, atomoxetine, pimozide, sertindole, sotalol: Increased risk of ventricular arrhythmia.
Neither potassium supplements nor a potassium-rich diet should be used with co-amilozide tablets except under careful monitoring in severe and/or refractory cases of hypokalaemia.
4.6 Fertility, pregnancy and lactation
Use in pregnancy:
The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated, because they are 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, bone marrow depression 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.
Since thiazides cross the placental 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 neonatal jaundice, thrombocytopenia, bone marrow depression, and possibly other side effects that have occurred in the adult.
Use in breast-feeding mothers:
Although it is not known whether amiloride hydrochloride is excreted in human milk, it is known that thiazides do appear in breast 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 use of the drug combination is deemed essential, the patient should stop breast-feeding or doses should be kept as low as possible.
4.7 Effects on ability to drive and use machines
This drug may cause dizziness, confusion, visual disturbances and drowsiness. 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.
Careful check should be kept for signs of fluid and electrolyte imbalance as hyponatraemia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia (see section 4). 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.
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.
The reported adverse reactions of the combination are:
General disorders: Headache, weakness, fatigue, malaise, syncope chest pain and back pain.
Cardiac disorders: Arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension and angina pectoris.
Gastrointestinal disorders: Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, cramping, dyspepsia, gastric irritation, gastrointestinal bleeding, appetite changes, abdominal fullness, flatulence, thirst and hiccups.
Metabolism and Nutrition disorders: Elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia, (see Special warning and precautions for use) gout, dehydration, symptomatic hyponatraemia.
Skin and subcutaneous tissue disorders: Rash, pruritis, diaphoresis and flushing.
Musculoskeletal and connective tissue disorders: Leg ache, muscle cramps, back pain and joint pain.
Nervous system disorders: Dizziness, vertigo, paraesthesiae and stupor, bad taste, headache, syncope.
Psychiatric disorders: Insomnia, nervousness, mental confusion, decreased libido, depression and sleepiness.
Respiratory, thoracic and mediastinal disorders: Dyspnoea, nasal congestion, pulmonary oedema.
Eye disorders: visual disturbance
Renal and urinary disorders: Impotence, dysuria, nocturia and incontinence, renal dysfunction including renal failure and urinary frequency.
The reported side effects of amiloride:
Musculoskeletal and connective tissue disorders: Neck/shoulder ache, pain in extremities.
Cardiac disorders: One patient with partial heart block developed complete heart block, palpitation.
Gastrointestinal disorders: Abnormal liver function. Activation of probable pre-existing peptic ulcer, dyspepsia, jaundice.
Skin and subcutaneous tissue disorders: Dry mouth, alopecia.
Blood and lymphatic system disorders: Aplastic anaemia and neutropenia.
Nervous system disorders: Tremors, encephalopathy.
Psychiatric disorders: Decreased libido, somnolence.
Respiratory, thoracic and mediastinal disorders: Cough.
Ear and labyrinth disorders: Tinnitus, increased intra-ocular pressure.
Renal and urinary disorders: Polyuria, urinary frequency, bladder spasm.
The reported side effects of hydrochlorothiazide:
Immune system disorders: Anaphylactic reaction and fever.
Cardiac disorders: Necrotising angitis (vasculitis, cutaneous vasculitis).
Gastrointestinal disorders: Jaundice (intrahepatic cholestatic jaundice) pancreatitis, cramping and gastric irritation.
Endocrine disorders: Glycosuria, hyperglycaemia, hypercalcaemia, hypokalaemia, hypochloraemic alkalosis, hypomagnesaemia and hyperuricaemia.
Skin and subcutaneous tissue disorders: Photosensitivity, sialdenitis and urticaria, toxic epidermal necrolysis.
Blood and lymphatic system disorders: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura and thrombocytopenia.
Respiratory, thoracic and mediastinal disorders: Respiratory distress including pneumonitis, pulmonary oedema.
Eye disorders: Transient blurred vision and xanthopsia.
Renal and urinary disorders: Interstitial nephritis.
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
ATC code: C03EA01
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
No data of relevance to the prescriber, which is additional to that included in other sections of the SPC.
List of Excipients
6.1.
Lactose monohydrate, calcium hydrogen phosphate (dihydrate), maize starch, talc, sodium starch glycolate, magnesium stearate, sunset yellow (E 110)
6.2. Incompatibilities
None known.
6.3. Shelf Life
4 years.
6.4. Special Precautions for Storage
None.
6.5. Nature and Contents of Container
Polypropylene tablet container
Pack sizes: 28, 100, 250, 500 and 1000 tablets.
6.6. Instructions for Use and Handling
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Pharmvit Limited, 177 Bilton Road, Perivale, Greenford, Middlesex,
UB6 8UJ
United Kingdom.
8 MARKETING AUTHORISATION NUMBER(S)
PL 04556/0041
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18th May 2005
10 DATE OF REVISION OF THE TEXT
08/09/2016