This information is intended for use by health professionals

1. Name of the medicinal product

ATENOLOL TABLETS BP 25mg

2. Qualitative and quantitative composition

Each tablet contains 25mg Atenolol PhEur.

3. Pharmaceutical form

Film-coated tablets.

White, circular, biconvex film-coated tablets impressed “A” on one side and “I” on the other side of a score line on one face, plain on the reverse.

The tablet can be divided into equal halves.

4. Clinical particulars
4.1 Therapeutic indications

For the treatment of:

• Hypertension

• Chronic stable angina pectoris

• Supraventricular arrhythmias:

- paroxysmal supraventricular tachycardia (in therapeutic or prophylactic treatment)

- atrial fibrillation and atrial flutter: in case of inadequate response to maximum dosages of cardiac glycosides; in cases where cardiac glycosides may be contraindicated or may be associated with an unfavorable risk/benefit ratio

• Ventricular arrhythmias:

- ventricular extrasystoles (prophylactic or therapeutic treatment), if the extrasystoles are the result of increased sympathetic activity

- ventricular tachycardias and ventricular fibrillation (prophylactic treatment), especially when the ventricular abnormality is the result of elevated sympathetic activity

• Secondary prevention after acute myocardial infarction

4.2 Posology and method of administration

Posology

The dosage should be determined on an individual basis. It is recommended to start with the lowest possible dosage so that heart failure, bradycardia and bronchial symptoms are noticed timely. This is especially important in elderly. Further adaptation should be done gradually (e.g., once a week) under controlled conditions or based on the clinical effect.

Adults and children over 12 years:

Hypertension: A starting dose of 25mg is recommended. The usual maintenance dosage in hypertension is one tablet (50-100mg) daily. The maximum effect will be reached after 1-2 weeks. If further improvement of the blood pressure is desired, atenolol may be combined with another anti-hypertensive e.g.: a diuretic.

Angina pectoris: 50-100mg daily, depending on the clinical effect, in order to obtain a heartbeat in rest of 55-60 beats per minute. Increasing the dose above 100mg daily does not generally lead to an increased antianginous effect. If desired the dosage of 100mg daily can be divided in two dosages.

Dysrhythmias: Initially controlled intravenously. A suitable oral maintenance dosage is 50-100mg daily, given as a single dose.

Secondary prevention after myocardial infarction: Initially controlled intravenously, followed by 50mg orally about 10 minutes after the intravenous dose provided no adverse effects occur. This should be followed by a further 50mg orally 12 hours later. Maintenance dose is 100mg daily in 1-2 dosages for 6 days or until discharge from hospital.

The Elderly: Dosage requirements may be reduced, especially in patients with impaired renal function. Dosage should be titrated according to clinical effect.

Children under 12 years: Atenolol is not recommended for use in children under 12 years of age.

Impaired renal function: Atenolol is excreted via the kidneys, therefore the dosage will need to be adjusted in severe renal conditions.

GFR (mL/min/1,73 m2 BSA)

Recommended daily dose atenolol (mg/day)

>35

No dose adjustment necessary

15-35

25-50 (or 50-100 every second day)

<15

25-50 every second day

In haemodialysis a 50mg tablet is administered after each dialysis. The administration should be done in hospital since sudden decrease of the arterial pressure may occur.

Decreased hepatic function: No dose adjustment is necessary.

Method of Administration

For oral administration.

4.3 Contraindications

Atenolol, as with other beta-blockers, should not be used in patients with any of the following:

• Second or third degree heart block

• Cardiogenic shock

• Uncontrolled heart failure

• Sick sinus syndrome (including sino-atrial block)

• Untreated phaeochromocytoma

• Metabolic acidosis

• Bradycardia (less than 45-50 beats per minute)

• Hypotension

• Hypersensitivity to atenolol or any of the excipients

• Severe peripheral circulatory disturbances.

• Concomitant intravenous use of verapamil or diltiazem

• Severe asthma and severe chronic obstructive pulmonary disease such as airway obstructions

4.4 Special warnings and precautions for use

Heart Failure: care must be exercised in patients with heart failure because of the negative inotropic effects of atenolol. Such patients should be well controlled on digitalis before therapy commences. Close monitoring for progressive failure is essential. Similarly, care must be taken with patients with poor cardiac reserve.

Ischaemic Heart disease: especially in patients with ischaemic heart disease, treatment should not be discontinued suddenly. The dosage should be gradually reduced, i.e. over 1-2 weeks, if necessary at the same time initiating replacement therapy, to prevent exacerbation of angina pectoris. In addition, hypertension and arrhythmias may develop. Furthermore, there is a risk of myocardial infarction and sudden death.

Untreated Congestive Heart disease: beta-blockers should not be used in such patients. The condition should be stabilised first.

First Degree Heart Block: due to its negative effect on conduction time, beta-blockers should only be given with caution to such patients.

Bradycardia: beta-blockers may induce bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, the dosage should be reduced.

Prinzmetal's anginal: Atenolol may increase the number and duration of anginal attacks in patients with Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery vasoconstriction. For these patients atenolol should only be used with the utmost care.

Peripheral Circulatory Disease: In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta-blockers should be used with great caution as aggravation of these disorders may occur. Severe peripheral circulatory disorders are a contra-indication (see section 4.3).

Respiratory disorders: In patients with chronic obstructive pulmonary disorders, airway obstructions may be aggravated. Therefore, atenolol should only be used for these patients with the utmost care.

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.

Renal impairment: In patients with impaired renal function, the dose should be adjusted to reduced glomerular filtration rate (see section 4.2).

Treated phaeochromocytoma: Atenolol should be used with blood pressure monitoring in patients with treated pheochromocytoma.

Diabetics: the symptoms of hypoglycaemia may be masked by atenolol, in particular tachycardia. Diabetic patients should be warned that this 'warning sign' may not occur.

Insulin sensitivity may be reduced in patients treated with atenolol.

Thyrotoxicosis: Beta-blockade may mask cardiovascular signs of thyrotoxicosis.

Allergies: Atenolol may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Atenolol may reduce the efficacy of the usual dose of adrenaline (epinephrine) used to treat allergic reactions.

Hypersensitivity: atenolol may cause a hypersensitivity reaction including angio-oedema and urticaria (see section 4.8).Psoriasis: patients with anamnestically known psoriasis should take beta-blockers only after careful consideration.

Elderly: these patients should be treated with caution, starting with a lower dosage but tolerance is usually good in the elderly (see section 4.2).

Surgery: When a patient is scheduled for surgery, and it has been decided to interrupt beta-blockade, therapy should be discontinued for at least 24 hours. Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, however the risk of hypotension may be increased as well.

If treatment is continued, caution should be observed with the use of certain anaesthetic drugs. The patient may be protected against vagal reactions by intravenous administration of atropine.

4.5 Interaction with other medicinal products and other forms of interaction

• Alcohol – concomitant use with alcohol may lead to an enhanced hypotensive effect.

• Alpha blockers – some patients experience acute postural hypotension, tachycardia and palpitations when they start to take certain alpha blockers (e.g. prazosin, alfuzosin, and terazosin), this can be exacerbated if they are already taking a beta-blocker. It is recommended that they should start with a low dose of these alpha blockers, and the first dose should be taken just before they go to bed. Patients should be warned about the possibility of postural hypotension and how to manage it (lay down, raise legs and get up slowly). When adding a beta-blocker to an alpha blocker it may be advisable to decrease the dose of the alpha blocker and re-titrate as necessary.

Anaesthetic drugs: Attenuation of the reflex tachycardia and increase the risk of hypotension. Continuation of beta-blockades reduces the risk of arrhythmia during induction and intubation. The anaesthesiologist should be informed when the patient is receiving a beta-blocking agent. Anaesthetic agents causing myocardial depression, such as cyclopropane and trichlorethylene, lidocaine, procainamide and beta-adrenoceptor stimulants such as noradrenaline (norepinephrine) are best avoided. Class I anti-arrhythmic drugs (e.g. disopyramide, quinidine) and amiodarone: May have potentiating effect on atrial-conduction time and induce a negative inotropic effect. Insulin and oral antidiabetic drugs: May intensify the blood sugar lowering effects of these drugs (especially non-selective beta-blockers).Beta-adrenergic blockade may prevent the appearance of signs of hypoglycaemia (tachycardia).

Baclofen: Causes an increased antihypertensive activity.

Contrast media, iodinated: Atenolol may impede the compensatory cardiovascular reactions associated with hypotension or shock induced by iodated contrast products.

• Calcium channel blockers – concomitant administration of dihydropyridine derivatives (e.g. nifedipine), may increase the risk of hypotension, and in patients with latent cardiac insufficiency, treatment with beta-blocking agents may lead to cardiac failure. Beta-adrenoceptor blocking drugs should be used with caution in combination with verapamil and to a lesser extent diltiazem in patients with impaired ventricular function, and not at all in patients with conduction abnormalities due to the negative influence on contractility and auriculo-ventricular conduction. May result in severe hypotension, bradycardia and cardiac failure.

• Cardiac glycosides - digitalis glycosides in association with beta-blockers may increase auriculo-ventricular conduction time.

Clonidine: Beta-blockers increase the risk of rebound hypertension. 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.Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. indometacin) may reduce the hypotensive effect of beta-blockers.

• Beta-sympathomimetic agents (e.g. isoprenaline, dobutamine) – combination with atenolol may reduce effects of both agents.

Sympathicomimetic agents (e.g. adrenaline (epinephrine)): May counteract the effect of atenolol.

Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as well as other antihypertensive agents: May increase the bloodpressure lowering effect and/or risk of bradycardia.

Ampicillin:May reduce the bioavailability of atenolol. Therefore the physician should watch for evidence of altered atenolol response especially when large doses of ampicillin are administered concomitantly

4.6 Pregnancy and lactation

Pregnancy

There are no adequate data from the use of atenolol in pregnant women to determine its potential harmfulness. Atenolol crosses the placental barrier and appears in the cord blood.

Animal studies showed no teratogenicity or foetotoxic effects after systemic administration in the therapeutic dose range.

Administration of atenolol in pregnancy has been associated with reduced foetal growth.

On the basis of its pharmacological properties, adverse effects may occur in the foetus and newborn infant, if used in the second and third trimesters (especially hypoglycaemia, hypotension and bradycardia). Beta-blockers reduce placental perfusion. Because of lack of experience, administration of atenolol during pregnancy is not recommended.

Lactation

Atenolol is excreted into breast milk reaching higher concentration than in plasma. A risk in the breastfed child cannot be excluded (beta-blockade). Therefore, breastfeeding should be discontinued during treatment with atenolol.

4.7 Effects on ability to drive and use machines

There are no studies on the effect of this medicine on the ability to drive. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

4.8 Undesirable effects

The following undesirable effects have been observed during treatment with atenolol and other beta blockers with the following frequencies: Very common (≥1/10), Common (≥1/100 to <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10000, < 1/1000) very rare (<1/10000), Not known (cannot be estimated from the available data).

Blood and Lymphatic System Disorders

Rare: Thrombocytopenia.

Endocrine Disorders

Beta-blockers may mask the symptoms of thyrotoxicosis.

Metabolic and Nutrition Disorders

Beta-blockers may mask the symptoms of hypoglycaemia.

Psychiatric Disorders

Uncommon: Sleep disturbances.

Rare: Hallucinations, psychoses, confusion, depression, mood changes and nightmares have been reported. Rarely cases of insomnia have been reported.

Nervous System Disorders

Rare: Dizziness, headaches, paraesthesia.

Eye Disorders

Rare: Dry eyes, impaired vision.

Cardiac Disorders

Common: Bradycardia,

Rare: A slowed AV-conduction or increase of an existing AV-block, postural hypotension which may be associated with syncope, heart failure deterioration

Unknown: cardiac arrest and circulatory collapse.

Vascular Disorders

Common: Cold extremities.

Rare: increase of an existing intermittent claudication, Raynauds phenomenon

Unknown: Cyanotic extremities.

Respiratory Disorders

Rare: Bronchospasm in patients with bronchial asthma or a history of asthmatic complaints.

Gastrointestinal Disorders

Common: Nausea, diarrhoea, gastrointestinal disturbances.

Rare: Dry mouth.

Unknown: Vomiting.

Hepatobiliary Disorders

Uncommon: Elevations of transaminase levels

Rare: cases of hepatic toxicity, including intrahepatic cholestasis have been reported.

Skin and Subcutaneous Tissue Disorders

Rare: Skin rash, purpura, exacerbation of psoriasis, alopecia, psoriasiform skin reactions.

Unknown: Hypersensitivity reactions, including angio-oedema, urticaria.

Musculoskeletal and Connective Tissue Disorders:

Common: Muscle fatigue.

Not known: Lupus like syndrome

Reproductive system and breast disorders:

Rare: Impotence

General Disorders and Administration Site Conditions:

Common: Fatigue.

Investigations:

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 the drug should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions. In all cases cessation of therapy 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 most important effects are on the heart. Bradycardia, hypotension, pulmonary oedema, syncope and cardiogenic shock may develop. First or second degree AV block may occur and rarely arrhythmias.

After ingestion of an overdose or in the case of hypersensitivity, the patient should be kept under close supervision and treated in an intensive care ward.

Activated charcoal and a laxative should be used to prevent absorption of any drug still present in the gastrointestinal tract, plasma or plasma substitutes can be used to treat hypotension or shock. The use of haemodialysis or haemoperfusion may be considered.

Excessive bradycardia can be treated with atropine 1-2mg intravenously and or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10mg intravenously and 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 to 10 micrograms/kg/minute by intravenous infusion 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. Bronchospasm can usually be reversed by bronchodilators.

5. Pharmacological properties
5.1 Pharmacodynamic properties

ATC CODE CO7A B03

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 and as with other beta-blockers, has negative inotropic effects (and is therefore contraindicated in uncontrolled heart failure). Its mode of action in the treatment of hypertension is unclear.

It is probably the action of atenolol in reducing cardiac rate and contractility which makes it effective in eliminating or reducing the symptoms of patients with angina.

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. However the response may be less in black patients.

Atenolol is effective for at least 24 hours after a single oral dose. The drug facilitates compliance by its acceptability to patients and simplicity of dosing. The narrow dose range and early patient response ensure that the effect of the drug in individual patients is quickly demonstrated. Atenolol is compatible with diuretics, other hypotensive agents and antianginals (but see section 4.5). Since it acts preferentially on beta-receptors in the heart, atenolol may, with care, be used successfully in the treatment of patients with respiratory disease, who cannot tolerate non-selective beta-blockers.

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

Early intervention in acute myocardial infarction reduces infarct size and may decrease morbidity and morality. Fewer patients with a threatened infarction progress to frank infarction; the incidence of ventricular arrhythmias is decreased and marked pain relief may result in reduced need of opiate analgesics. Early mortality is decreased. Atenolol is an additional treatment to standard coronary care.

5.2 Pharmacokinetic properties

Absorption: The oral bioavailability is about 50 to 60%. The bioavailability is decreased by 20% when taken with food. Peak plasma concentrations are found 2-4 hours after repeated oral administration. There is a linear relationship between dosage and plasma concentration. The inter-subject variability in AUC and Cmax is about 30-40%.

Distribution: The volume of distribution is 50 to 75 L. Only small amounts are reported to cross the blood-brain barrier and plasma-protein binding is minimal (less than 5%).

(Women - it crosses the placenta and is distributed into breast milk where concentrations higher than those in maternal plasma have been achieved).

Metabolism: Atenolol undergoes little or no hepatic metabolism.

Elimination: Most of an absorbed dose (85-100%) is excreted unchanged via the urine. The clearance is about 6 L/h and the half-life is about 6 to 9 hours. In elderly patients, clearance is decreased and elimination half-life increased. The clearance is correlated to renal function and the elimination is prolonged in patients with renal impairment. Impaired liver function does not influence the pharmacokinetics of atenolol.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Also contains:

Tablet core:

Silica colloidal anhydrous

Magnesium stearate

Maize starch

Crospovidone

Sodium lauryl sulfate

Hydrogenated vegetable oil

Calcium hydrogen phosphate dihydrate (E341)

Cellulose microcrystalline (E460)

Tablet coat:

Propylene glycol

Titanium dioxide (E171)

Hypromellose 5cP (E464)

Purified talc (E553)

6.2 Incompatibilities

None known.

6.3 Shelf life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special precautions for storage

Blister packs

Do not store above 25°C

Store in the original package

Keep container in the outer carton

Polypropylene containers, polyethylene containers and amber glass bottles

Do not store above 25°C

Store in the original container

Keep the container tightly closed

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene containers and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass containers with screw caps.

The product may also be supplied in blister packs and cartons:

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

b) Blister pack: (i) 250 µm white rigid PVC. (ii) Surface printed 20 µm hard temper aluminium foil with 5-6g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.

The product may be contained in blister packs which enhances security of the pack increasing resistance to deliberate contamination, pilfering, etc.

Pack sizes: 28s, 30s, 50s, 100s, 250s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 50,000.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

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

8. Marketing authorisation number(s)

PL 0142/0353

9. Date of first authorisation/renewal of the authorisation

5.7.93

Renewed November 1999

10. Date of revision of the text

14th April 2017

11. Dosimetry

IF APPLICABLE

12. Instructions for preparation of radiopharmaceuticals

IF APPLICABLE