Co-Tenidone 100/25 Mg Film-Coated Tablets Bp
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-tenidone 100/25 mg Film-coated Tablets BP
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains
Atenolol 100 mg
Chlortalidone 25 mg
For full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Film-coated Tablet
Co-tenidone 100/25 mg Film-coated Tablets are brownish pink, round, biconvex film-coated tablets marked CT/100 on one side and plain on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Management of hypertension.
4.2 Posology and method of administration
Co-tenidone 100/25 mg Film-coated Tablets are administered orally.
Adults:
One tablet daily.
Elderly:
One tablet daily. Older patients with hypertension who do not respond to low dose therapy with a single agent should have a satisfactory response to a single tablet daily of Co-tenidone Film-coated Tablets. Where hypertensive control is not achieved, addition of a small dose of a third agent e.g. as a vasodilator, may be appropriate.
There is no paediatric experience of using Co-tenidone therefore it is not recommended for children.
Renal impairment:
In patients with renal impairment, a reduction in daily dose or in frequency of administration may be necessary (see section 4.4).
4.3 Contraindications
Co-tenidone should not be used in patients with any of the following:
- Known hypersensitivity to either active component or any of the excipients;
- Bradycardia;
- Cardiogenic shock;
- Hypotension;
- Metabolic acidosis;
- Severe peripheral arterial circulatory disturbances;
- Second-or-third-degree heart block;
- Sick sinus syndrome;
- Untreated phaeochromocytoma;
- Uncontrolled heart failure
Co-tenidone must not be given during pregnancy or lactation.
4.4 Special warnings and precautions for use
Due to its beta-blocker component Co-tenidone Film-coated Tablets:
- 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 betai-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) 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 the tachycardia of hypoglycaemia
- may mask the signs of thyrotoxicosis.
- atenolol should be used with caution in diabetics subject to frequent episodes of hypoglycaemia since symptoms of hypoglycaemia may be masked.
- will reduce 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.
- may cause a hypersensitivity reaction including angioedema and urticaria.
-patients with psoriasis should only be given beta-blockers after careful consideration, as psoriasis may be aggravated.
Co-tenidone contains the cardioselective beta-blocker atenolol. Although cardioselective (beta1) beta-blockers may have less effect on lung function than nonselective beta-blockers, as with all beta-blockers, these should be avoided in patients with reversible obstructive airways disease, unless there are compelling clinical reasons for their use. Where such reasons exist, Co-tendione may be used with caution. Occasionally, some increase in airways resistance may occur in asthmatic patients, however, and this may usually be reversed by commonly used dosage of bronchodilators such as salbutamol or isoprenaline.
The product label will state ‘Do not take this medicine if you have a history of wheezing or asthma’.
Due to its chlortalidone component:
-hypokalaemia may occur. Measurement of potassium levels is appropriate, 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. Hypokalemia may predispose to arrhythmias in patients receiving digitalis;
-caution must be exercised in patients with severe renal failure (See section 4.2);
-impaired glucose tolerance may occur and caution must be exercised if chlortalidone is administered to patients with a known predisposition to diabetes mellitus;
- hyperuricaemia may occur. Only a minor increase in serum uric acid usually occurs but in cases of prolonged elevation, the concurrent use of a uricosuric agent will reverse the hyperuricaemia.
4.5 Interaction with other medicinal products and other forms of interaction
Combined use of beta-blockers and calcium channel blockers with negative inotropic effects e.g. verapamil, diltiazem, can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or sino-atrial or atrioventricular 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.
Concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Digitalis glycosides, in association with beta-blockers, may increase atrio-ventricular 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.
Class I anti-arrhythmic drugs (e.g.disopyramide) and amiodarone may have a potentiating effect on atrial-conduction time and induce negative inotropic effect.
Concomitant use of sympathomimetic agents, e.g. adrenaline (epinephrine), may counteract the effect of beta-blockers.
Concomitant use with insulin and oral antidiabetic drugs may lead to the intensification of the blood sugar lowering effects of these drugs.
Concomitant use of prostaglandin synthetase inhibiting drugs (e.g.ibuprofen, indomethacin) may decrease the hypotensive effects of beta-blockers.
Preparations containing lithium should not be given with diuretics because they may reduce its renal clearance.
Caution must be exercised when using anaesthetic agents with Co-tenidone Film-coated Tablets. The anaesthetist 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 mycocardial depression are best avoided.
4.6 Fertility, pregnancy and lactation
Co-tenidone must not be given during pregnancy or lactation.
4.7 Effects on ability to drive and use machines
The use of Co-tenidone is unlikely to result in any impairment of the ability of patient to drive or operate machinery, however it should be taken into account that occasionally dizziness or fatigue may occur.
4.8 Undesirable effects
Co-tenidone Film-coated Tablets are well tolerated. In clinical studies, the undesired events reported 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 (0.10.9%), rare (0.01-0.09%), very rare (<0.01%), not known (cannot be estimated from the available data):
Blood and lymphatic system disorders:
Rare: Purpura, thrombocytopenia, leucopenia (related to chlortalidone).
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
Hepatobiliary disorders:
Rare: Hepatic toxicity including intrahepatic cholestasis, pancreatitis (related to chlortalidone).
Skin and subcutaneous tissue disorders:
Rare: Alopecia, psoriasiform skin reaction, exacerbation of psoriasis, skin rashes.
Not known: Hypersensitivity reactions, including angioedema and urticaria.
Reproductive system and breast disorders:
Rare: Impotence
General disorders and administration site conditions:
Common: Fatigue
Investigations:
Common: Related to chlortalidone: 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.
Discontinuance of Co-tenidione Film-coated Tablets should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions.
4.9 Overdose
The symptoms of overdosage may include bradycardia, hypotension, 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 10 mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1-10 mg/hour depending on response. If no response to glucagon 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-adrenoceptor 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. Bronchospasm can usually be reversed by bronchodilators.
Excessive diuresis should be countered by maintaining normal fluid and electrolyte balance.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Atenolol and other diuretics -ATC Code: C07CB03.
Co-tenidone Film-coated Tablets combine the antihypertensive activity of two agents, a beta-blocker (atenolol) and a diuretic (chlortalidone).
Atenolol:
Atenolol is betai-selective (i.e. acts preferentially on betai-adrenergic receptors in the heart). Selectivity decreases with increasing dose.
Atenolol is without intrinsic sympathomimetic and membrane-stabilising activities and, as with other beta-adrenoceptor blocking drugs, has negative inotropic effects (and is therefore contraindicated in uncontrolled heart failure).
As with other beta-blockers, the mode of action in the treatment of hypertension is unclear.
It is unlikely that any additional ancillary properties possessed by S (-) atenolol, in comparison with the racemic mixture, will give rise to different therapeutic effects.
Atenolol is effective and well-tolerated in most ethnic populations. Black patients respond better to the combination of atenolol and chlortalidone, than to atenolol alone.
The combination of atenolol with thiazide-like diuretics has been shown to be compatible and generally more effective than either drug used alone.
Chlortalidone:
Chlortalidone, a monosulfonamyl diuretic, increases excretion of sodium and chloride. Natriuresis is accompanied by some loss of potassium. The mechanism by which chlortalidone reduces blood pressure is not fully known but may be related to the excretion and redistribution of body sodium.
5.2 Pharmacokinetic properties
Atenolol: Absorption of atenolol following oral dosing is consistent but incomplete (approximately 40-50%) with peak plasma concentration occurs 2-4 hours after dosing. The Atenolol blood levels are consistent and subject to little variability. There is no significant hepatic metabolism of atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. The Plasma half-life is 6 hours but this may rise in severe renal impairment since the kidney is the major route of elimination. Atenolol penetrates tissues poorly due to its low lipid solubility and its concentration in brain tissue is low. Plasma protein binding is low (approximately 3%).
Chlortalidone: Absorption of chlortalidone following oral dosing is consistent but incomplete (approximately 60%) with peak plasma concentrations occurring about 12 hours after dosing. The chlortalidone blood levels are consistent and subject to little variability. The plasma half-life is about 50 hours and the kidney is the major route of elimination. Plasma protein binding is high (approximately 75%).
Co-administration of chlortalidone and atenolol has little effect on the pharmacokinetics of either.
Co-tenidone is effective for at least 24 hours after a single oral daily dose. This simplicity of dosing facilities compliance by its acceptability to patients.
5.3 Preclinical safety data
Atenolol and chlortalidone are drugs on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the summary of product characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Maize starch
Calcium hydrogen phosphate dihydrate Microcrystalline cellulose Povidone K30
Sodium starch glycolate Type A Magnesium stearate
Film Coat:
Hypromellose (E464)
Titanium dioxide (E171)
Iron oxide red (E172)
Macrogol
Iron oxide yellow (E172)
Iron oxide black (E172)
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 to protect from light and moisture.
6.5 Nature and contents of container
Blister packs of white opaque PVC film and hard tempered aluminium foil. Pack sizes: 28, 30, 56, 60. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
None stated.
7 MARKETING AUTHORISATION HOLDER
Activase Pharmaceuticals Limited,
11 Boumpoulinas, 3rd Floor,
PC. 1060 Nicosia.
Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 28444/0100
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/04/2014
10 DATE OF REVISION OF THE TEXT
10/04/2014