CO-TENIDONE TABLETS BP 50/12.5mg

Each tablet contains: 50mg Atenolol PhEur and 12.5mg Chlortalidone BP.

Brownish pink film-coated tablets.

Brownish pink circular, biconvex film-coated tablets impressed “C” on one face and the identifying letters “YI” on the reverse.

1) Management of hypertension.

Adults (including elderly): 1 tablet daily.

Children: There is no experience of using Co-tenidone in children; therefore it is not recommended.

Renal impairment: In patients with renal impairment a reduction in daily dose or in frequency of administration may be necessary.

For oral use.

• Co-tenidone should not be used in patients with known hypersensitivity to atenolol or chlortalidone (or to sulphonamide derived medicinal products) or any other component of the product.

• Like other beta-blocker diuretic combinations, Co-tenidone should not be used in patients with second or third degree heart block

• Cardiogenic shock

• Severe peripheral arterial circulatory disturbances

• Intermittent claudication

• It should not be used in patients with severe renal or hepatic failure.

• Sick-sinus syndrome

• Bradycardia

• Uncontrolled heart failure

• Hypotension

• Metabolic acidosis

• Untreated phaeochromocytoma

• Pregnancy and lactation

Due to its beta-blocker component:

Care should be taken when using beta-blockers in patients with poor cardiac reserve. Atenolol is contraindicated in uncontrolled heart failure (see section 4.3) but may be used in patients whose signs of failure have been adequately controlled.

It 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.

Atenolol may modify the warning signs of hypoglycaemia as tachycardia, palpitation and sweating.

Atenolol may mask the cardiovascular signs of thyrotoxicosis.

Atenolol reduces heart rate. In the rare instances when symptoms may be attributable to the slow heart rate, the dose should be reduced. In patients suffering from ischaemic heart disease, treatment should not be discontinued abruptly.

Atenolol 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 (epinephrine) used to treat the allergic reactions.

Patients with bronchospastic disease should, in general, not receive beta blockers due to a detrimental effect on airways resistance. If the use of Co-tenidone in patients with asthma or a history of obstructive airways disease is unavoidable, the risk of inducing bronchospasm should be appreciated and appropriate precautions taken. Atenolol is a beta-1-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 bronchospasm occurs, Co-tenidone should be discontinued and bronchodilator therapy (e.g. salbutamol) administered if necessary.

In patients with phaeochromocytoma Co-tenidone must be administered only after alpha-receptor blockade. Blood pressure should be monitored closely.

Caution must be exercised when using anaesthetic agents with Co-tenidone. 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 myocardial depression are best avoided.

Due to its chlortalidone component:

All patients treated with diuretics should have their fluid and electrolyte states monitored, especially the elderly, patients with potassium-losing gastrointestinal disturbances, on low potassium diets or taking cardiac glycosides for cardiac failure. Hypokalaemia, hyponatraemia or hypomagnesaemia may occur. Hypokalaemia may predispose to arrhythmias in patients receiving digitalis.

Chlortalidone may decrease glucose tolerance in diabetes. Patients should be aware of the potential for increased glucose levels. During prolonged therapy and in the initial phase of therapy, close monitoring of glycaemia is recommended and regular tests for glycosuria should be carried out.

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.

Patient information leaflets and labels will carry the following warnings:

Patient Information Leaflet: Do not take this medicine if you have a history of wheezing or asthma. Consult your doctor or pharmacist first.

Labels: Do not take this medicine if you have a history of wheezing or asthma.

Due to atenolol:

In general, beta-adrenoceptor-blocking agents should not be given concomitantly with amphetamines, ergotamine and local anaesthetic-type anti-arrhythmic agents.

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 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 (e.g., 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. Hypokalaemia can precipitate digitalis toxicity.

Aminoglycoside nephrotoxicity may be potentiated.

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, e.g. adrenaline (epinephrine), may counteract the effect of beta-blockers.

Concomitant use of prostaglandin synthetase inhibiting drugs (e.g., ibuprofen, indometacin) may decrease the hypotensive effects of beta-blockers.

Due to chlortalidone:

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.

Lithium should not be administered concurrently because lithium clearance may be significantly reduced causing lithium toxicity. Dose adjustments of lithium may therefore be necessary.

Due to the combination product:

Reduced absorption may occur if calcium or aluminium hydroxide is administered concurrently.

Concurrent administration of indometacin 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.

Concomitant therapy with dihydropyridines e.g., 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.

Both atenolol and chlortalidone cross the placenta. They also enter breast milk. Co-tenidone should not be used in pregnant or lactating women.

The use of Co-tenidone 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.

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, 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

Not known: Constipation.

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.

Musculoskeletal and connective tissue disorders:

Not known: Muscle fatigue.

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.

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. Discontinuation of therapy with a beta-blocker should be gradual.

Symptoms – cardiac insufficiency, bronchospasm, extreme bradycardia and hypotension with nausea, weakness, dizziness and disturbances of electrolyte balance.

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. 1-2mg intravenously and/or a cardiac pacemaker followed if necessary 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 glucagon occurs or if glucagon is unavailable, a beta adrenoceptor stimulant such as dobutamine 2.5-10 micrograms/kg/minute by intravenous infusion or isoprenaline 10-25 micrograms given as an infusion at a rate not exceeding 5 micrograms/minutes 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 or isoprenaline 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.

Atenolol is a cardiovascular beta-adrenoceptor antagonist with no membrane stabilising activity and no partial agonist activity.

Chlortalidone is a long acting thiazide-like diuretic.

Atenolol is a beta-adrenoceptor blocking agent which is cardioselective, its principal action being on beta-adrenergic receptors in the heart. It is without intrinsic sympathomimetic and membrane stabilising activities.

Human studies have shown that a negligible amount of atenolol crosses the blood brain barrier.

Relief of anginal symptoms is probably due to the action of atenolol in reducing cardiac rate and myocardial contractility, ie negative inotropic effect. Its mode of action in the treatment of hypertension is unclear.

Early intervention in acute myocardial infarction reduces infarct size and may decrease morbidity.

Chlorthalidone is an effective diuretic which is capable of eliminating 5-10% of the filtered load of sodium. Like most thiazide diuretics it is an inhibitor of carbonic anhydrase and it is 70 times as potent as hydrochlorthiazide in inhibiting carbonic anhydrase. Thus it has weak diuretic effects in the proximal tubule and in high doses bicarbonate excretion is increased.

The main mechanism of diuretic action is, like other thiazide diuretics, due to inhibition of sodium chloride reabsorption in the early distal tubule (cortical diluting segment) which impairs urine dilution but not concentration. Thiazide diuretics have also been suggested to cause (I) phosphodiesterase inhibition (cf. theophylline) (ii) impaired renal cell metabolism (oxidative phosphorylation) affecting the energy supply for active sodium transport and (iii) prostaglandin inhibition. The evidence for these various mechanisms is inconclusive.

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.

Chlorthalidone: 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% excreted in the faeces. No metabolites have been identified.

Not applicable.

Also contains: macrogol, magnesium stearate, maize starch, polyvidone, sodium starch glycollate, E171, E172, E341, E460, E464.

Not applicable.

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store below 25°C in a dry place.

Protect from light.

The product to be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

PL 0142/0413

12.12.2001

07/07/2010