CO-TENIDONE 50/12.5 MG FILM-COATED TABLETS BP - summary of medicine characteristics

Co-tenidone 50/12.5 mg Film-coated Tablets BP

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains

Atenolol 50 mg

Chlortalidone 12.5 mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablet

Co-tenidone 50/12.5 mg Film-coated Tablets are brownish pink, round, biconvex film-coated tablets marked CT/50 on one side and plain on the other.

4.1

4.2

Management of hypertension.

Posology

Adults:

One tablet daily.

Elderly:

One tablet daily. The elderly 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 tablets. Where hypertensive control is not achieved, addition of a small dose of a third agent e.g. as a vasodilator, may be appropriate.

Paediatric population:

The use of Co-tenidone Tablets is not recommended in children. The safety and efficacy of Co-Tenidone Tablets in children has not yet been established.

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 administrated to patients with severe renal impairment (see section 4.3).

Oral use.

4.3 Contraindications

Co-tenidone should not be used in the following:

– Hypersensitivity to the active substances (or to sulphonamide derived medicinal products) or to any of the excipients listed in section 6.1;

– Bradycardia;

– Cardiogenic shock;

– Hypotension;

– Metabolic acidosis;

– Severe peripheral arterial circulatory disturbances;

– Second-or-third-degree heart block;

– Sick sinus syndrome;

– Untreated phaeochromocytoma;

– Severe renal failure;

– 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 beta1-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 warning signs of hypoglycaemia as tachycardia, palpitation and sweating.

– may mask the cardiovascular signs of thyrotoxicosis.

– 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 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 tablets should be used and utmost caution must be exercised. If increased airways resistance does occur, Co-tenidone tablets should be discontinued and bronchodilator therapy (e.g.-salbutamol) administered if necessary.

-systemic effects of oral beta-blockers may be potentiated when used concomitantly with ophthalmic beta-blockers.

– in patients with phaeochromocytoma must be administered only after alfareceptor blockade. Blood pressure should be monitored closely.

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

Due to its chlortalidone component:

– hypokalaemia and hyponatraemia may occur. Measurement of electrolyte 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. Hypokalaemia may predispose to arrhythmias in patients receiving digitalis;

-plasma electrolyte should be periodically determined in appropriate intervals to detect possible electrolyte imbalance especially hypokalaemia and hyponatraemia. -impaired glucose tolerance may occur and caution must be exercised if chlortalidone is administered to patients with a known predisposition to diabetes mellitus; 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.

– 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.

The patient information leaflet for this product will state: Do not take this medicine if you have wheezing or asthma. Talk to your doctor or pharmacist first.

– Choroidal effusion, acute myopia and secondary angle-closure glaucoma: Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

4.5 Interaction with other medicinal products and other forms of interaction Due to atenolol

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.

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

Caution must be exercised when using anaesthetic agents with Co-tenidone Film-coated Tablets.

The chlortalidone component may reduce the renal clearance of lithium leading to increased serum concentrations. Dose adjustments of lithium may therefore be necessary.

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 baclofen may increase the antihypertensive effect making dose adjustments necessary.

Concomitant therapy with dihydropyridines e.g. nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.

4.6

Co-tenidone tablets must not be given during pregnancy.

Co-tenidone tablets must not be given during lactation.

No data on fertility available.

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 to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

Tabulated list of adverse reactions

Co-tenidone tablets were well tolerated in clinical studies, the undesired events reported are usually attributable to the pharmacological actions of its components.

The following undesired events, listed by body system, have been reported with the following frequencies: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare ((>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Discontinuance of Co-tenidone tablets should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions.

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. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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: Beta-blocking agents, Atenolol and other diuretics -ATC Code: C07CB03.

Co-tenidone Film-coated Tablets combines the antihypertensive activity of two agents, a beta-blocker (atenolol) and a diuretic (chlortalidone).

Atenolol is beta1-selective (i.e. acts preferentially on beta1-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, 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 concentrations occurring 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 about 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%).

Coadministration of chlortalidone and atenolol has little effect on the pharmacokinetics of either.

Co-tenidone tablets is effective for at least 24 hours after a single oral daily dose. This simplicity of dosing facilitates 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 Prescribing Information.

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.

6.6 Special precautions for disposal

None stated.

Activase Pharmaceuticals Limited, 11 Boumpoulinas, 3rd Floor,

P.C. 1060

Nicosia.

Cyprus