Co-Tenidone 100/25mg Film- Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-tenidone 100/25mg Film- Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Atenolol 100mg Chlortalidone 25.00mg
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Brownish pink, round, biconvex film-coated tablets marked CTE 100 on one side and CP on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Management of hypertension in patients whose blood pressure is not adequately controlled on atenolol or chlortalidone alone.
4.2 Posology and method of administration
Posology
Adults:
One tablet daily containing 50mg atenolol and 12.5mg chlorthalidone. If appropriate, the dose of atenolol and chlorthalidone can be reduced by using the lower strength combination tablet.
Elderly:
One tablet daily.
Children and adolescents (< 18 years):
There is no experience of using Totaretic in children. Therefore it is not recommended.
Renal impairment:
Due to the properties of the chlortalidone component, Co-tenidone has reduced efficacy in the presence of renal insufficiency. This fixed dose combination should thus not be administered to patients with severe renal impairment (see section 4.3).
Hepatic impairment:
Dose adjustments are not required in patients with hepatic impairment.
Method of administration Oral administration.
4.3 Contraindications
Totaretic should not be used in patients any of the following:
• known hypersensitivity to atenololor chlortalidone (or to sulphonamide derived medicinal products) or any other component of the product.
• second or third degree heart block,
• sick-sinus syndrome
• bradycardia
• uncontrolled heart failure
• cardiogenic shock or intermittent claudication.
• hypotension
• severe peripheral arterial circulatory disturbances
• severe renal or hepatic failure.
• metabolic acidosis
• untreated phaeochromocytoma
• pregnancy and lactation
Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers, they should be avoided in patients with reversible obstructive airways disease unless there are compelling reasons for their use.
4.4 Special warnings and precautions for use
Due to its beta-blocker component:
• although contra-indicated in uncontrolled heart failure (see section 4.3) may be used in patients whose signs of heart failure have been controlled. Caution must be exercised in patients whose cardiac reserve is poor.
• may increase the number and duration of angina attacks in patients with Prinzmetal’s angina due to unopposed alpha receptor mediated coronary artery vasoconstriction. Atenolol is a beta-1 selective beta-blocker; consequently the use of Co-tenidone may be considered although utmost caution must be exercised.
• although contraindicated in severe peripheral arterial circulatory disturbances (see section 4.3) Co-tenidone may also aggravate less severe peripheral arterial circulatory disturbances.
• due to its negative effect on conduction time, caution must be exercised if it is given to patients with first degree heart block.
• may modify warning signs of hypoglycaemia as tachycardia, palpitation and sweating.
• may mask the cardiovascular signs of thyrotoxicosis.
• will reduces heart rate, as a result of its pharmacological action. In the rare instances when a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced.
• Should not be discontinued abruptly in patients suffering from ischaemic heart disease.
• may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.
• patients with bronchospastic disease should, in general, not receive beta blockers due to increasing in airways resistance.
Atenolol is a beta1-selective beta-blocker, however this selectivity is not absolute. Therefore the lowest possible dose of Co-tenidone should be used and utmost caution must be exercised. If increased airways resistance does occur, Co-tenidone should be discontinued and bronchodilator therapy (eg salbutamol) administered if necessary.
• in patients with pheochromocytoma Co-tenidone must be administered only after alfa-receptor blockade. Blood pressure should be monitored closely.
• caution must be exercised when using anaesthetic agents with Co-tenidone. The anesthetist should be informed and the choice of anaesthetic should be an agent with as little negative inotropic activity as possible. Use of beta-blockers with anaesthetic drugs may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided.
Due to its chlortalidone component:
• Hypokalaemia or hypomagnesaemia may occur. Measurement of electrolytes is recommended, especially in the older patient, those receiving digitalis preparations for cardiac failure, those taking an abnormal (low in potassium) diet or those suffering from gastrointestinal complaints. Hypokalaemia may predispose to arrhythmias in patients receiving digitalis.
• Because chlortalidone may impair glucose tolerance_diabetic patients should be aware of the potential for increased glucose levels. Close monitoring of glycaemia is recommended in the initial phase of therapy and in prolonged therapy test for glucosuria should be carried out at regular intervals.
• in patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma.
• Co-tenidone should be used with caution in patients with a predisposition to uricaemia or gout since chlortalidone may cause a rise in serum uric acid levels. Prolonged elevation can be corrected by the use of a uricosuric agent.
The product label will state 'Do not take this medicine if you have a history of wheezing or asthma'
4.5 Interaction with other medicinal products and other forms of interaction Due to atenolol:
In general, beta-adrenoceptor-blocking agents should not be given concomitantly with adrenaline, amphetamines, sympathomimetic amines, ergotamine and clonidine. Reduced absorption may occur if calcium or aluminium hydroxide is administered concurrently.
Combined use of beta-blockers and calcium channel blockers with negative inotropic effects eg, verapamil, diltiazem can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.
Class I anti-arrhythmic drugs (eg, disopyramide) and amiodarone may have potentiating effect on atrial-conduction time and induce negative inotropic effect.
Digitalis glycosides, in association with beta-blockers, may increase atrioventricular conduction time.
Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
Concomitant use of sympathomimetic agents, eg adrenaline, may counteract the effect of beta-blockers.
Concomitant use of prostaglandin synthetase inhibiting drugs (eg, ibuprofen, indomethacin) may decrease the hypotensive effects of beta-blockers.
Due to chlortalidone:
The chlortalidone component may reduce the renal clearance of lithium leading to increased serum concentrations. Dose adjustments of lithium may therefore be necessary.
Like other thiazide diuretics, chlortalidone may potentiate bone marrow suppression caused by cancer chemotherapy and may impair the control of diabetes mellitus by diet and oral hypoglycaemic agents. Hypokalaemia may precipitate digitalis toxicity.
Due to the combination product:
Concomitant therapy with dihydropyridines eg, nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Concomitant use of baclofen may increase the antihypertensive effect making dose adjustments necessary.
Aminoglycoside nephrotoxicity may be potentiated. Concurrent administration of indomethacin can reduce the hypotensive effects of both atenolol and chlortalidone.
Care should be taken when using anaesthetic agents with Co-tenidone; hypokalaemia can prolong the effects of tubocurarine. Also the choice of anaesthetic should be an agent with as little negative inotropic activity as possible.
4.6 Pregnancy and lactation
Both atenolol and chlortalidone cross the placenta and enter the breast milk. Totaretic should not be used in pregnant or lactating women.
4.7 Effects on ability to drive and use machines
The use of Totaretic is unlikely to result in any impairment of the ability to drive or operate machinery as there are only rare reports of beta-adrenoceptor blocking drugs causing symptomatic hypotension and bradycardia.
4.8 Undesirable effects
In clinical studies, the possible adverse reactions are usually attributable to the pharmacological actions of its components.
The following undesirable effects, listed by body system, have been reported with the following frequencies: Very common (>10%), common (1-9.9%), uncommon (0.1-0.9%), rare (0.01-0-09%), very rare (<0.01%), not known (cannot be estimated from available data):
Blood and lymphatic system disorders:
Rare: Purpura, thrombocytopenia, neutropenia, hyponatraemia and leucopenia (related to chlorthalidone).
Psychiatric disorders:
Uncommon: Sleep disturbances of the type noted with other beta-blockers. Rare: Mood changes, nightmares, confusion, psychoses and hallucinations.
Nervous system disorders:
Rare: Dizziness, headache, paraesthesia.
Eye disorders:
Rare: Dry eyes, visual disturbances.
Cardiac disorders:
Common: Bradycardia
Rare: Heart failure deterioration, precipitation of heart block.
Vascular disorders:
Common: Cold extremities.
Rare: Postural hypotension which may be associated with syncope, intermittent claudication may be increased if already present, in susceptible patients Raynaud’s phenomenon.
Respiratory, thoracic and mediastinal disorders:
Rare: Bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints.
Gastrointestinal disorders:
Common: Gastrointestinal disturbances (including nausea related to
chlortalidone).
Rare: Dry mouth.
Not known: Constipation
Hepatobiliary disorders:
Rare: Hepatic toxicity including intrahepatic cholestasis, pancreatitis (related to chlorthalidone).
Skin and subcutaneous tissue disorders:
Rare: Alopecia, psoriasiform skin reaction, exacerbation of psoriasis, skin rashes.
Musculoskeletal and connective tissue disorders:
Not known: Lupus-like syndrome
Reproductive system and breast disorders:
Rare: Impotence.
General disorders and administration site conditions:
Common: Fatigue.
Investigations:
Common (related to chlorthalidone): Hyperuricaemia, hyponatraemia, hypokalaemia, impaired glucose tolerance.
Uncommon: Elevations of transaminase levels.
Very rare: An increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear.
Discontinuation of Co-tenidone should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions.
Withdrawal of the drug should be considered if any such reaction is not otherwise explicable. Discontinuation of therapy with a beta-blocker should be gradual.
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
The symptoms of overdosage may include bradycardia and hypotension with nausea, weakness, dizziness, disturbances of electrolyte balance, acute cardiac insufficiency and bronchospasm.
General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock. The possible use of haemodialysis or haemoperfusion may be considered.
Excessive bradycardia may be countered by atropine 1-2 mg intravenously and/or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10mg/hour depending on response. If no response to glucagons occurs or if glucagon is unavailable, a beta adrenoceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/minute by intravenous infusion may be given. Dobutamine, because of its positive inotropic effects could be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta-blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.
Any risk of hypotension occurring following the use of beta adrenoceptor agonists will be reduced by the use of the more selective agent, dobutamine.
Bronchospasm can usually be reversed by bronchodilators.
Excessive diuresis should be countered by maintaining normal fluid and electrolyte balance.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Beta-blocking agents, selective, and other diuretics, ATC code: C07C B03.
Atenolol is a cardiovascular beta-adrenoceptor antagonist with no membrane stabilising activity and no partial agonist activity.
Chlorthalidone is a long-acting thiazide-like diuretic.
5.2 Pharmacokinetic properties
Atenolol: After an oral dose about 50% is absorbed. Peak serum concentration occurs 2-4 hours after administration. Atenolol is poorly protein bound. Plasma half life is 6-8 hours but can rise to 140 hours in severe renal impairment. There is no liver metabolism. 90% of absorbed drug is excreted unchanged in the urine. The remainder is metabolised either by hydroxylation or by conjugation with glucuronic acid or is excreted in the bile.
Atenolol crossed the placenta and enters the breast milk.
Chlortalidone: After an oral dose about 65% is absorbed. Peak serum levels are reached 2-6 hours after administration. Most of the absorbed dose (98%) is bound to red cell carbonic anhydrase. The plasma half life is 50-90 hours during long term treatment 30-60% of the dose is excreted unchanged in the urine and up to 10% is excreted in the faeces. No metabolites have been identified.
5.3 Preclinical safety data
None stated.
6.1 List of excipients
Maize starch
Calcium hydrogen phosphate Microcrystalline cellulose (PH101)
Povidone K30 Sodium starch glycollate Magnesium stearate Purified water
Film Coat
Opadry OY-6954
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Blister packs of white opaque PVC film (250 micron) and hard tempered aluminium foil (20 micron). Pack sizes: 28, 30, 56, 60.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None stated.
MARKETING AUTHORISATION HOLDER
7
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0056
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/06/2007
10 DATE OF REVISION OF THE TEXT
21/03/2016