Co-Amilozide 2.5 Mg/25 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-amilozide 2.5mg/25mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Amiloride hydrochloride 2.5mg and hydrochlorothiazide 25mg
Excipient with known effect: Each tablet contains 40mg lactose (as lactose monohydrate)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Tablet
A slightly yellow, round, scored tablets with bevelled edge, with an approximate diameter of 7mm with the code EZ/3 on one side
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
Hypertension, congestive heart failure, or hepatic cirrhosis with ascites.
4.2 Posology and method of administration Hypertension
Initially one Co-amilozide 2.5mg/25mg tablet given once a day. If necessary an increase to two Co-amilozide 2.5mg/25mg tablets given once a day or in divided doses.
Congestive heart failure
Initially one Co-amilozide 2.5mg/25mg tablet a day, subsequently adjusted if
required, but not exceeding four Co-amilozide 2.5mg/25mg tablets a day. Optimal 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
Initiate therapy with a low dose. A single daily dose of two Co-amilozide 2.5mg/25mg tablets may be increased gradually until there is an effective diuresis. Dosage should not exceed four Co-amilozide 2.5mg/25mg 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.
Paediatric use:
Co-amilozide 2.5mg/25mg Tablets are not recommended for children under 18 years of age.
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.
4.3 Contraindications
Hypersensitivity to the active substance: amiloride hydrochloride, hydrochlorothiazide, other sulphonamide-derived drugs or to any of the excipients listed in section 6.1.
Hyperkalaemia (serum potassium over 5.5 mmol/1); other potassium-conservingdiuretics. Potassium supplementsor potassium-rich food (except in severe and/or refractory cases of hypokalaemia under careful monitoring); concomitant use with spironolactone or triamterene; anuria, acute renal failure, severe progressive renal disease, severe hepatic failure , precoma associated with hepatic cirrhosis, 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. In renal impairment, use of potassium-conserving agent may result in rapid development of hyperkalaemia. The safety of amiloride hydrochloride for use in children has not been established; Co-amilozide is therefore not recommended in children. For "Use in pregnancy and the nursing mother", see section 4.6 (Pregnancy and lactation).
4.4 Special warnings and precautions for use Diabetes mellitus:
Hyperkalaemia has commonly occurred in diabetic patients on amiloride hydrochloride, especially those with chronic renal disease or pre-renal azotaemia. The status of renal function should therefore be determined before Co-amilozide is given to known or suspected diabetics. Co-amilozide should be discontinued for at least 3days before giving a glucose-tolerance test, as one patient with poorly controlled diabetes mellitus, who became severely hyperkalaemic while receiving amiloride hydrochloride, died following two repeated intravenous glucose-tolerance tests. 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. Thiazides may impair glucose tolerance. Diabetes mellitus may be precipitated or aggravated by therapy with 'Co-amilozide' (see 4.3 'Contraindications'). Dosage adjustment of antidiabetic agents, including insulin, may be required.
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 serum potassium.
Hyperkalaemia (serum potassium level over 5.5 mmol/1):
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 known renal involvement, 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). Some deaths have been reported in this group of patients.
Treatment of hyperkalaemia: Should hyperkalaemia develop, Co-amilozide should be discontinued immediately, and if necessary, active measures taken to reduce the serum 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.
Electrolyte imbalance and blood urea increases:
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 hyponatremia, hypochloraemic alkalosis, hypokalaemia and hypomagnesaemia.
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.
Hypokalaemia may develop, especially as a result of brisk diuresis, 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. Therapy should be discontinued before carrying out tests for parathyroid function.
Any chloride deficit may be corrected by the use of ammonium chloride (except in patients with liver disease) and largely prevented by a near-normal salt intake.
Reversible increases in blood urea have been reported accompanying vigorous diuresis, especially in seriously ill patients, such as those with hepatic cirrhosis with ascites and metabolic alkalosis or those with resistant oedema; serum electrolyte and blood urea levels should be carefully monitored in these patients.
Impaired renal function:
Renal function should be monitored because the use of 'Co-amilozide' in impaired renal function
may result in the rapid development of hyperkalaemia. Thiazide diuretics become ineffective when creatinine clearance falls below 30 ml/min.
Uraemia may be precipitated or increased by hydrochlorothiazide. Co-amilozide should be used with cautions 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 during treatment, Co-amilozide should be discontinued.
Hepatic disease:
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease (see 4.3 'Contraindications'), since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Effects in cirrhotic patients:
Oral diuretic therapy is more frequently accompanied by adverse reactions in patients with hepatic cirrhosis and ascites because these patients rare intolerant of acute shifts in electrolyte balance and because they often have pre-existing hypokalemia as a result of associated aldosteronism. Hepatic encephalopathy, manifested by tremors, confusion and coma, has been reported in patients on amiloride hydrochloride. Patients with liver disease should be observed for this complication when Co-amilozide is given. In cirrhotic patients receiving amiloride hydrochloride alone, a deepening of jaundice has occurred, but the relationship to amiloride hydrochloride is uncertain.
Sensitivity reactions:
The possibility that thiazides may activate or exacerbate systemic lupus erythematosus has been reported.
Sensitivity reactions to thiazides may occur in patients with or without a history of allergy or bronchial asthma.
Metabolic
Hyperuricaemia may occur, or gout may be precipitated or aggravated, in certain patients receiving thiazides.
Calcium excretion is decreased by hydrochlorothiazide and magnesium excretion is increased.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance. Pathological changes in the parathyroid glands, accompanied by hypercalcaemia mad hypophosphataemia, have been reported in a few patients receiving prolonged thiazide therapy. The common complications of hyperparathyroidism have not been observed.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Other precautions:
As with any drug, patients should be observed regularly for the possible occurrence of liver dysfunction, idiosyncratic reactions or blood dyscrasia.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose
4.5 Interaction with other medicinal products and other forms of interaction
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.
Hydrochlorothiazide potentiates the action of other antihypertensive agents. Therefore the dosage of these agents, especially the ganglionic blockers, may need to be reduced when Co-amilozide is added to the regimen. NSAID's including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may attenuate the antihypertensive effect of antihypertensive drugs, including the diuretic, natriuretic and antihypertensive effects of diuretics. The possibility that the thiazides may activate or exacerbate systemic lupus erythematosus has been reported.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Therefore, the combination should be administered with caution in patients with compromised renal function.
Concomitant administration of NSAIDs and potassium-sparing agents, including amiloride HCl, may cause hyperkalemia, particularly in elderly patients. Therefore, when amiloride HCl is used concomitantly with NSAIDs, serum potassium levels should be carefully monitored.
Amiloride Hydrochloride
When amiloride hydrochloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist, trilostane, ciclosporin or tacrolimus, 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:
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.
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. 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.
Cholestyramine 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 gastro-intestinal tract by up to 85 and 43 %, respectively. When cholestyramine 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.
Drug/laboratory tests: Because thiazides may affect calcium metabolism, 'Co-amilozide' may interfere with tests for parathyroid function.
Hydrochlorothiazide may decrease arterial responsiveness to pressor amines such as epinephrine (adrenaline) and noradrenaline, but not enough to prevent noradrenaline being effective in therapeutic usage.
Non-depolarising muscle relaxants such as tubocurarine which may possibly interact with 'Co-amilozide' to increase muscle relaxation.
Alcohol, barbiturates and narcotics: Co-administration may potentiate orthostatic hypotension.
The antihypertensive effect of thiazides may be enhanced in the postsympathectomy patient.
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 as 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.
Hydrochlorothiazide:
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
Amiloride Hydrochloride:
It is not known whether amiloride hydrochloride is excreted in human milk. Hydrochlorothiazide:
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
Infrequently, patients may experience weakness, fatigue, dizziness, stupor and vertigo. Should any of these occur, the patient should be cautioned not to drive or operate machinery.
4.8 Undesirable effects
Although 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.
The following side effects have been reported with 'Co-amilozide':
Body as a whole: anaphylactic reaction, headache*, weakness*, fatigue, malaise, chest pain, back pain, syncope.
Cardiovascular: arrhythmias, tachycardia, digitalis toxicity, orthostatic hypotension, angina pectoris.
Digestive: anorexia*, nausea*, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding , appetite changes, abdominal fullness, flatulence, thirst, hiccups,.
Metabolic: elevated plasma potassium levels (above 5.5 mmol/l), electrolyte imbalance, hyponatraemia (see 4.4 'Special warnings and precautions for use'), gout, dehydration, symptomatic hyponatraemia.
Integumentary: rash*, pruritus, flushing, diaphoresis.
Musculoskeletal: leg ache, muscle cramps, joint pain.
Nervous: dizziness*, vertigo, paraesthesiae, stupor.
Psychiatric: insomnia, nervousness, mental confusion, depression, sleepiness, Respiratory: dyspnoea.
Special senses: bad taste, transient visual disturbance, nasal congestion.
Urogenital: impotence, dysuria, nocturia, incontinence, renal dysfunction including renal failure.
Additional side effects that have been reported with the individual components and may be potential side effects of 'Co-amilozide' are listed below:
Amiloride:
Body as a whole: neck/shoulder ache, pain in extremities.
Digestive:, abnormal liver function, activation of probable pre-existing peptic ulcer, dyspepsia, jaundice.
Integumentary: dry mouth, alopecia.
Nervous: tremors, encephalopathy.
Haematological: aplastic anaemia, neutropenia.
Cardiovascular: one patient with partial heart block developed complete heart block, palpitation.
Psychiatric: decreased libido, somnolence.
Respiratory: cough.
Special senses: tinnitus, increased intra-ocular pressure.
Urogenital: polyuria, urinary frequency, bladder spasm.
Hydrochlorothiazide:
Body as a whole: fever.
Cardiovascular: necrotising angiitis (vasculitis, cutaneous vasculitis.)
Digestive: jaundice (intrahepatic cholestatic jaundice), pancreatitis, cramping, gastric irritation.
Endocrine/Metabolic: glycoscuria, hyperglycaemia, hyperuricaemia,
hypokalaemia.
Integumentary: photosensitivity, sialadenitis, urticaria, toxic epidermal necrolysis.
Haematological: agranulocytosis, aplastic anaemia, haemolytic anaemia, leucopenia, purpura, thrombocytopenia.
Psychiatric: restlessness.
Renal: interstitial nephritis.
Respiratory: respiratory distress, including pneumonitis, pulmonary oedema. Special senses: transient blurred vision, xanthopsia.
Whenever side-effects are moderate or severe, the dosage of Co-amilozide should be reduced or therapy withdrawn.) * Side effects that have been reported most frequently during controlled clinical trials with amiloride/ hydrochlorothiazide
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 internet at www.mhra.gov.uk/yellowcard.
4.9 Overdose
No specific data are available on overdosage with ' Co-amilozide'. it is not known whether the drug is dialysable.
Treatment of overdosage: There is no specific antidote. Treatment is symptomatic and supportive. Therapy should be discontinued and the patient watched closely. If ingestion is recent, emesis should be induced or gastric lavage performed. Dehydration, electrolyte imbalance and hepatic coma are treated by the established procedures. Blood pressure should be monitored and corrected when necessary. If hyperkalaemia occurs, active measures should be taken to reduce the serum potassium levels. For respiratory impairment, oxygen or artificial respiration should be administered.
Electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration are the most common signs and symptoms of hydrochlorothiazide overdosage. 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 half-life; the plasma half-life of amiloride is about six hours.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Hydrochlorothiazide and amiloride hydrochloride are both very well known drug
substances marketed world-wide. Hydrochlorothiazide is a natriuretic, diuretic, and
antihypertensive agent. Amiloride hydrochloride is a potassium-conserving diuretic and antihypertensive agent.
5.2 Pharmacokinetic properties
Amiloride hydrochloride and Hydrochlorothiazide are well known drug substances
marketed world-wide - solely and in combination. The pharmacokinetic properties of the active substances have been studied and a number of articles have been published.
The formulation of Co-amilozide does not modify the intrinsic pharmacokinetic properties of the drug substance. A bioavailability study has demonstrated that Co-amilozide is bioequivalent with the leading equivalent product with respect to rate as well as extent of absorption of the active substances.
5.3 Preclinical safety data
Not relevant (widely used in clinical practice).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Wheat starch, Lactose monohydrate, Gelatin, Talc, Magnesium stearate.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years.
6.4 Special precautions for storage
Store below 25°C protected from light.
6.5 Nature and contents of container
Polyethylene (PE-HD) containers with polyethylene (PE-LD) closures. Containers of 28, 30, 56, 60, 100 and 500 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St Neots
Cambridgeshire
PE19 8ET
UK
MARKETING AUTHORISATION NUMBER(S)
PL 11311/0522
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 15/02/2002
10
DATE OF REVISION OF THE TEXT
21/08/2015