Co-tenidone 100/25 mg Tablets

Summary of Product Characteristics Updated 13-Sep-2018 | Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)

1. Name of the medicinal product

Co-tenidone 100/25 mg Tablets

2. Qualitative and quantitative composition

Atenolol 100 mg

Chlortalidone 25 mg

For excipients, see 6.1

3. Pharmaceutical form

Film-coated tablet

Round, white, half scored, film-coated tablets.

4. Clinical particulars
4.1 Therapeutic indications

For the management of hypertension.

4.2 Posology and method of administration

For oral administration.

Adults: One tablet daily.

Most patients should have a satisfactory response to one tablet daily. There is little or no further fall in blood pressure with increase in dose and therefore where control of hypertension is not achieved, the addition of a low dose of a third drug eg. a vasodilator, can be used.

Elderly: Dose requirements are normally lower in the elderly.

Children: There is no paediatric experience with Co-Tenidone tablets, therefore this preparation is not recommended for children.

Patients with impaired renal function:

Due to the properties of the chlortalidone component, Co-Tenidone tablets 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).

4.3 Contraindications

Hypersensitivity to atenolol, chlortalidone or any of the other tablet ingredients.

Patients with bradycardia; second or third degree heart block; cardiogenic shock; hypotension; severe peripheral arterial disease; sick sinus syndrome; phaeochromocytoma (unless used concomitantly with an alpha-blocker); metabolic acidosis or uncontrolled heart failure.

During pregnancy and lactation.

Refractory hypokalaemia, hyponatraemia or hypercalcaemia.

Symptomatic hyperuricaemia.

Addison's disease.

Severe renal failure.

4.4 Special warnings and precautions for use

Due to the active ingredient, atenolol:

May be used with caution in patients with heart failure which has been controlled (contra-indicated in uncontrolled heart failure, see Section 4.3).

Caution must be exercised in patients whose cardiac reserve is poor.

Extreme caution is required in patients with Prinzmetal's angina as the number and duration of attacks may increase due to unopposed alpha receptor mediated coronary artery vasoconstriction. Atenolol is a beta1-selective beta-blocker; consequently the use of Co-Tenidone tablets may be considered although utmost caution must be exercised.

May aggravate less severe peripheral arterial disease (contra-indicated in severe peripheral arterial disease, see Section 4.3).

Caution is required when given to patients with first degree heart block.

In patients with portal hypertension, there is a risk of deterioration in liver function when administered beta-blockers.

Beta-blockers may unmask myasthenia gravis or potentiate a myasthenic condition.

May mask the symptoms of hypoglycaemia and hyperthyroidism. May modify warning signs of hypoglycaemia as tachycardia, palpitation and sweating.

May mask the cardiovascular signs of thyrotoxicosis.

On rare occasions atenolol may reduce the heart rate; should this occur the dose may need to be reduced.

Do not discontinue suddenly 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.

Due to its negative effect on conduction time, caution must be exercised if it is given to patients with first-degree heart block.

Cardioselective (beta1) beta-adrenoceptor blocking drugs such as atenolol may have less effect on lung function than non-selective beta-adrenoceptor blocking drugs, however, as with all beta-adrenoceptor blocking drugs Co-tenidone should be avoided in patients with reversible obstructive airways disease, unless there are compelling clinical reasons for its use. Where such reasons exist Co-tenidone 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.

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 alfa-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.

The patient information leaflet for this product states the following warning:

“If you have ever had asthma or wheezing, you should not take this medicine unless you have discussed these symptoms with the prescribing doctor.”

Due to the active ingredient, Chlortalidone:

Caution is required in patients with renal impairment (see Section 4.2) or patients with severe hepatic impairment.

Plasma electrolyte should be periodically determined in appropriate intervals to detect possible electrolyte imbalance especially hypokalaemia and hyponatraemia.

Hyperuricaemia may occur although this is normally only a minor increase in the serum uric acid level. Should a prolonged increase occur the administration of a uricosuric drug at the same time might be appropriate to reverse the hyperuricaemia.

As hypokalaemia may occur blood potassium levels may need to be monitored, particularly in the following patients: the elderly, those taking a low potassium diet, those receiving treatment with digitalis preparations for cardiac failure or if suffering from gastrointestinal problems. In patients receiving digitalis, hypokalaemia may predispose to arrhythmias.

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.

Impaired glucose tolerance may occur and 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.

Caution is required in patients with a known pre-disposition to diabetes mellitus, as glucose intolerance may occur.

4.5 Interaction with other medicinal products and other forms of interaction

Calcium channel blockers with negative inotropic effects e.g. verapamil, diltiazem: combined use with beta-adrenoceptor blocking drugs can enhance these effects especially in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular conduction abnormalities. Severe hypotension, bradycardia and cardiac failure may occur. Neither the beta-adrenoceptor blocking drugs nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

Class 1 antiarrhythmic agents (e.g. disopyramide) and amiodarone may have a potentiating effect on atrial-conduction time and induce negative inotropic effect.

Clonidine: beta-adrenoceptor blocking drugs may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are co-administered, the beta-adrenoceptor blocking drug should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenoceptor blocking drug therapy, the introduction of beta-adrenoceptor blocking drugs should be delayed for several days after clonidine administration has stopped.

Dihydropyridines e.g. nifedipine: concomitant treatment 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.

Digitalis glycosides: may increase AV block and bradycardia if given with beta-adrenoceptor blocking drugs.

Insulin and oral antidiabetic drugs: concomitant use may lead to an enhanced hypoglycaemic effect.

Prostaglandin synthetase inhibiting drugs eg. ibuprofen and indometacin: concomitant use may decrease the antihypertensive effects of beta-adrenoceptor blocking drugs.

Preparations containing lithium should not be given with diuretics because they may reduce its renal clearance.

Sympathomimetic agents, eg. adrenaline: concomitant use may cause severe hypertension; counteracts the effect of beta-adrenoceptor blocking drugs.

Caution must be exercised when using anaesthetic agents with Co-tenidone tablets (see section 4.4)

4.6 Pregnancy and lactation

Do not give during pregnancy and lactation.

4.7 Effects on ability to drive and use machines

It is unlikely that any impairment in the ability of patients to drive or operate machinery will occur, however occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

Co-tenidone is normally 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 (0.1-0.9%), rare (0.01-0.09%), very rare (<0.01%), not known (cannot be estimated from the available data):

Blood and the lymphatic system disorders:

Rare: leucopenia (related to chlortalidone); purpura; thrombocytopenia.

Psychiatric disorders:

Uncommon: sleep disturbances of the type noted with other beta blockers.

Rare: confusion; mood changes; nightmares; psychoses and hallucinations.

Nervous system disorders:

Rare: dizziness; headache; paraesthesia.

Eye disorders:

Rare: disturbances in vision; dry eyes.

Cardiac disorders:

Common: bradycardia.

Rare: deterioration of heart failure; 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; Raynaud's phenomenon in susceptible patients.

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.

Hepato-biliary disorders:

Rare: hepatic toxicity including intrahepatic cholestasis; pancreatitis (related to chlortalidone).

Skin and subcutaneous tissue disorders:

Rare: alopecia; psoriasiform skin reactions; 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: elevation 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-tenidone” 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 at: www.mhra.gov.uk/yellowcard

4.9 Overdose

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

Treatment should include close monitoring, treatment in an intensive care unit, gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract. Plasma or plasma substitutes may be used to treat hypotension and shock. Haemodialysis or haemoperfusion may be considered.

Excessive bradycardia may be treated with atropine (1- 2 mg) intravenously and/or a cardiac pacemaker, followed if necessary 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 the response. If the patient is unresponsive to glucagon or this is not available, a beta-adrenoceptor stimulant such as an intravenous infusion of dobutamine (2.5 to 10 µg/kg/minute) may be given.

Dobutamine, because of its positive inotropic effect, could also 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-blocker 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

Should bronchospasm occur this can usually be reversed by bronchodilators and excessive diuresis should be prevented by maintaining normal fluid and electrolyte balance.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Atenolol is a cardioselective beta blocker. It has great affinity for beta1-adrenergic receptors in the heart although selectivity decreases with increases in dose. Atenolol does not possess intrinsic sympathomimetic and membrane stabilizing activities and as with other beta-adrenoceptor blocking drugs, has negative inotropic effects (therefore contra-indicated in uncontrolled heart failure). As with other beta-adrenoceptor blocking drugs, the method 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.

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.

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.

5.2 Pharmacokinetic properties

Following oral administration approximately 40-50% of atenolol is absorped with peak plasma concentrations reached 2-4 hours after dosing. The atenolol blood levels are consistent and subject to little variability. There is little or no hepatic metabolism of atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. The plasma half life is about 6-7 hours but this may rise in severe renal impairment since the kidney is the major route of elimination. Atenolol has low lipid solubility and only small concentrations are reported in brain tissue. Atenolol crosses the placenta and is distributed into breast milk where concentrations are higher than in maternal plasma have been reported. Plasma binding is low (approximately 3%).

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.

A single dose of Co-tenidone 50/12.5 mg is effective for at least 24 hours.

5.3 Preclinical safety data

No data of relevance which is additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Magnesium Carbonate, Heavy

Maize Starch

Sodium Laurilsulfate

Gelatin

Magnesium Stearate

Coating:

Hypromellose

Titanium Dioxide E171

Ethylcellulose

Diethyl phthalate

6.2 Incompatibilities

None known.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

Al/PVC blister containing 28, 56, 84, 112, 140, 168, 196, 224, 252 or 280 tablets enclosed within a carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Special Concept Development (UK) Ltd

Units 1-7 Colonial Way

Watford

Hertfordshire

WD24 4YR

8. Marketing authorisation number(s)

PL 36722/0006

9. Date of first authorisation/renewal of the authorisation

19 November 2003 / 10 June 2009

10. Date of revision of the text

28/08/2015

Company Contact Details
Sigma Pharmaceuticals PLC (Special Concept Development / RxFarma)
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http://www.sigmaplc.co.uk

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