1 Name of Medicine
Atenolol.
2 Qualitative and Quantitative Composition
Atenolol-WGR tablets: contain 50 mg of the active ingredient atenolol.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Atenolol-WGR tablets are white, film coated, biconvex and round with a breakline on one face and plain on the other face.
4.1 Therapeutic Indications
All grades of hypertension, including hypertension of renal origin.
Frequent disabling angina without evidence of cardiac failure. Cardiac arrhythmias (maintenance treatment of supraventricular and ventricular arrhythmias including those associated with acute myocardial infarction).
Myocardial infarction: late intervention (β-blocker class effect greater than 12 hours after onset of chest pain).
4.2 Dose and Method of Administration
Oral.
Adults.
Hypertension.
Therapy should be initiated with Atenolol-WGR 50 mg daily. This may be increased each week in daily doses of 50 mg up to a maximum of 200 mg. Where patients are controlled on daily doses of 50 to 100 mg this may be given once daily. Doses above 100 mg daily should be given on a divided basis. Where necessary, a further reduction in blood pressure may be achieved by combining Atenolol-WGR with other antihypertensive agents.
Patients can be transferred to Atenolol-WGR from other antihypertensive treatments with the exception of clonidine (see Section 4.4 Special Warnings and Precautions for Use).
Angina pectoris.
Therapy should be initiated with Atenolol-WGR 50 mg daily. This may be increased, if required, to 100 mg daily given as a single or divided dose. It is unlikely that additional benefit will be gained by increasing dose.
Cardiac dysrhythmias.
Having controlled the dysrhythmias with other intravenous agents a suitable oral maintenance dosage is 50 to 100 mg daily.
Acute myocardial infarction - late intervention (> 12 hours from onset of chest pain).
Atenolol has been shown to reduce infarct size, reduce the incidence of ventricular dysrhythmias, reduce the need for opiate analgesics and reduce mortality in the first 7 post-infarction days, most of the benefit being in the first 48 hours. Data from other β-blocker trials suggest that there is a significant reduction in mortality and a reduced incidence of nonfatal reinfarction if the β-blocker is continued for 1 to 3 years.
Hence, maintenance oral therapy of Atenolol-WGR 50 mg daily is recommended for 1 to 3 years following myocardial infarction, beginning after early intervention with other agents, or immediately in those patients who present more than 12 hours after suffering an acute myocardial infarction.
Impaired renal function.
Since Atenolol-WGR is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of Atenolol-WGR occurs at a creatinine clearance greater than 35 mL/minute/1.73 m2 (normal range is 100 to 150 mL/minute/1.73 m2). For patients with a creatinine clearance of 15 to 35 mL/min/1.73 m2 (equivalent to serum creatinine of 300 to 600 micromol/L) the oral dose should be 50 mg daily to 100 mg on alternate days. For patients with a creatinine clearance less than 15 mL/minute/1.73 m2 (equivalent to serum creatinine of greater than 600 micromol/L) the oral dose should be 50 mg on alternate days or 100 mg every fourth day.
Patients on haemodialysis should be given 50 mg orally after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.
Elderly.
Dosage requirements may be reduced especially in patients with impaired renal function.
Children.
There is no experience with the use of atenolol in children.4.3 Contraindications
Bronchospasm: The β-adrenergic blockade of the smooth muscle of bronchi and bronchioles may result in an increased airways resistance. These drugs also reduce the effectiveness of asthma treatment. This may be dangerous in susceptible patients. Therefore, β-blockers are contraindicated in any patient with a history of airways obstruction or tendency to bronchospasm. Use of cardioselective β-blockers can also result in severe bronchospasm. If such therapy must be used, great caution should be exercised. Alternative therapy should be considered.
Congestive heart failure.
Allergic disorders (including allergic rhinitis) which may suggest a predisposition to bronchospasm.
Right ventricular failure secondary to pulmonary hypertension.
Significant right ventricular hypertrophy.
Sick sinus syndrome.
Sinus bradycardia (less than 45 to 50 beats/minute).
Second and third degree atrioventricular block.
Shock (including cardiogenic and hypovolaemia shock).
Anaesthesia with agents that produce myocardial depression (e.g. ether, chloroform, cyclopropane).
Hypersensitivity to atenolol.
Hypotension.
Metabolic acidosis.
Severe peripheral arterial circulatory disturbances.
Untreated phaeochromocytoma.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
4.4 Special Warnings and Precautions for Use
Cardiac failure.
β-Blockade depresses myocardial contractility and may precipitate cardiac failure in some patients with a history of cardiac failure, chronic myocardial insufficiency or unsuspected cardiomyopathy as may occur in chronic alcoholism. In patients without a history of cardiac failure, continuing depression of the myocardium may lead to cardiac failure. If signs of cardiac failure present, the patients should be fully digitalised and/or given an ACE inhibitor or vasodilators with or without a diuretic and carefully monitored. If cardiac failure persists, the β-blocker should be withdrawn (see Abrupt withdrawal of therapy).
Note.
Although congestive heart failure has been considered to be a contraindication to the use of β-blockers, there is growing literature on the experimental use of β-adrenergic blocking drugs in heart failure. As further trials are needed to identify which patients are most likely to respond to which drugs, β-blockers should not normally be prescribed for heart failure outside of specialist centres.
Abrupt withdrawal of therapy.
Care should be taken if β-blockers have to be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias have occurred following abrupt discontinuation of β-blockade in patients with ischaemic heart disease. Therefore, it is recommended that the dosage be reduced gradually over a period of about 8 to 14 days during which time the patient's progress should be reassessed. The drug may be temporarily reinstituted if the angina worsens. If the drug must be withdrawn abruptly, close observation is required. In the peri-operative period, β-blockers should not be withdrawn, unless indicated.
Allergic reactions.
While taking β-adrenoreceptor blocking drugs, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.
First degree heart block.
Due to its negative effect on conduction time, caution must be exercised if atenolol is given to patients with first degree heart block.
Peripheral circulation.
β-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease.
Prinzmetal angina.
There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a β-blocker. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.
Euthyroid hyperthyroxinaemia.
The effects of β-blockers on thyroid hormone metabolism may result in elevations of serum free thyroxine (T4) levels. In the absence of any signs or symptoms of hyperthyroidism, additional investigation is necessary before a diagnosis of thyrotoxicosis can be made.
Use in acute myocardial infarction.
In addition to the contraindications listed (see Section 4.3 Contraindications), patients with the following conditions are not suitable for treatment with atenolol:
(a) Systolic blood pressure less than 120 mmHg (systolic blood pressure less than 120 mmHg in combination with a heart rate greater than 90 beats/min has a particularly poor prognosis).
(b) First degree A-V block. There is an increased incidence of cardiogenic shock (and need for inotropes), complete heart block and cardiovascular death in these patients, following atenolol.
Patients with atrial fibrillation following myocardial infarction, who were treated with atenolol, also had increased cardiovascular mortality compared with those not treated with atenolol. It is suggested that such patients be digitalised before atenolol therapy is commenced.
Bradycardia.
If a treated patient develops symptoms which may be attributable to a slow heart rate, the dose may be reduced.
Anaesthesia and the peri-operative period.
β-Blockade may have beneficial effects in decreasing the incidence of arrhythmias and myocardial ischaemia during anaesthesia and the postoperative period. It is currently recommended that maintenance β-blockade be continued peri-operatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other drugs, resulting in severe bradyarrhythmias and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal induced bradycardia. Incidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during anaesthesia have been reported. Modern inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of β-blockade.
Diabetes.
β-Blockers affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
In patients with insulin or non-insulin dependent diabetes (NIDD), especially labile diabetes, or with a history of spontaneous hypoglycaemia, β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment.
Other metabolic effects.
β-adrenoreceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some drugs affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect appears to be less for drugs with intrinsic sympathomimetic activity.
Phaeochromocytoma.
In patients with this condition, an alpha-blocking drug (e.g. phentolamine/phenoxybenzamine) should be administered before the β-blocker to avoid exacerbation of hypertension.
Eye and skin reactions.
Various skin rashes and conjunctival xerosis have been reported with β-blockers. Cross reactions may occur between β-blockers, therefore, substitutions within the group may not necessarily preclude occurrence of symptoms.
During the long-term treatment with the β-blocking drug, practolol, a specific rash bearing a superficial resemblance to psoriasis was occasionally described. In a number of patients affected, this rash was accompanied by adverse effects on the eye (xerophthalmia and/or keratoconjunctivitis) of varying severity. This condition is called the oculomucocutaneous syndrome or practolol syndrome. In a few patients, these eye changes occurred independently of a skin rash. On rare occasions, serious otitis media, sclerosing peritonitis, pericarditis and pleurisy have been reported. Although the practolol syndrome has not been observed in patients taking other β-blockers, the possibility of such side effects occurring should be borne in mind.
More recently an association between Peyronie's disease (a fibrosing induration of the penis) and various β-blockers has been suggested but is not proven.
Allergic conditions.
These may be exaggerated by β-blockade (e.g. allergic rhinitis during the pollen season and allergic reactions to bee and wasp stings). β-blockers should be avoided if there is a risk of bronchospasm.
Hyperthyroidism.
Since β-blockers may mask the clinical signs of developing or continuing hyperthyroidism, resulting in symptomatic improvement without any change in thyroid hormone status, special care should be exercised in those patients who are hyperthyroid and are also receiving β-blockers.
Significant cardiomegaly.
Use in renal impairment.
In patients with severe renal disease, haemodynamic changes following β-blockade may impair renal function further. β-Blockers which are excreted mainly by the kidney may require dose adjustment in patients with renal failure.
Use in the elderly.
See Section 4.2 Dose and Method of Administration.
Paediatric use.
No data available.
Effects on laboratory tests.
No data available. See Section 4.8 Adverse Effects (Undesirable Effects), Biochemical abnormalities.4.5 Interactions with Other Medicines and Other Forms of Interactions
Concomitant therapy with calcium antagonists.
The concomitant use of β-blockers and calcium antagonists with myocardial depressant and sinus node activity, e.g. verapamil, and to a lesser extent diltiazem, may cause hypotension, bradycardia and asystole, particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. Extreme caution is required if these drugs have to be used together.
The dihydropyridine calcium antagonists (e.g. nifedipine) have a weaker myocardial depressant effect and can be administered cautiously with β-blockers. If excessive hypotension develops, the calcium antagonist should be stopped or the dosage reduced.
Antiarrhythmic drugs.
Class 1 anti-arrhythmic drugs (e.g. disopyramide) and the Class III agent, amiodarone may have potentiating effect on atrial conduction time and induce negative inotropic effect, this is seen less frequently with quinidine; Class IB agents, tocainide, mexiletine and lignocaine; Class IC agents, flecainide and propafenone (not available in Australia); and the Class IV antiarrhythmic agents.
Use of catecholamine depleting agents.
Concomitant use of drugs such as reserpine and guanethidine requires careful monitoring since the added effect of β-blockade may produce an excessive reduction of the resting sympathetic nervous tone.
Clonidine.
Concurrent use of β-blockers and clonidine should be avoided because of the risk of adverse interaction and severe withdrawal symptoms. If administered concomitantly, the clonidine should not be discontinued until several days after the withdrawal of the β-blocker.
Insulin and oral hypoglycaemics.
(See Section 4.4 Special Warnings and Precautions for Use, Diabetes).
Anaesthetics.
Anaesthetics such as methoxyflurane are contraindicated with Atenolol-WGR (see Section 4.4 Special Warnings and Precautions for Use, Anaesthesia and the peri-operative period).
Digitalis/digitalis glycosides.
Digitalis/digitalis glycosides and β-blockers are commonly used together, although there have been reports of excessive bradycardia when β-blockers are used to treat digitalis intoxication.
Sympathomimetic agents.
Concomitant use of sympathomimetic agents, e.g. adrenaline, may counteract the effects of β-blockers.
Prostaglandin synthetase inhibitors.
Concomitant use of prostaglandin synthetase inhibiting drugs, e.g. ibuprofen and indomethacin may decrease the hypotensive effects of β-blockers.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No data available.
(Category C)
β-adrenergic blocking agents may cause bradycardia in the foetus and newborn infant. During the final part of pregnancy and parturition, these drugs should, therefore, be given only after weighing the needs of the mother against the risk to the foetus.
Atenolol crosses the placental barrier in pregnant women, and under steady state conditions, maternal and foetal blood levels of atenolol are approximately equal.
No studies have been performed on the use of atenolol in the first trimester and the possibility of foetal injury cannot be excluded. Atenolol has been used under close supervision for the treatment of hypertension in the third trimester. Administration of atenolol for longer periods to pregnant women in the management of mild to moderate hypertension has been associated with intra-uterine growth retardation.
The use of Atenolol-WGR in women who are or may become pregnant, requires that the anticipated benefit be weighed against the possible risks, particularly in the first and second trimesters. In general, β-blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion and early labour.
Atenolol has been shown to produce a dose related increase in embryo/foetal resorptions in rats at doses equal to or greater than 50 mg/kg. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg.
There is significant accumulation of atenolol in breast milk. Caution should be exercised when Atenolol-WGR is administered to nursing women and the infant should be regularly assessed for signs of β-blockade.4.7 Effects on Ability to Drive and Use Machines
Use is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.
4.8 Adverse Effects (Undesirable Effects)
Adverse reactions reported in clinical trials of atenolol are mainly attributable to pharmacological actions. The adverse reactions listed below have been observed in patients in clinical trials who have received dosages of about 100 mg/day. It is not possible to give percentage incidences for each reaction, but if all mild and transient reactions are included as well as more serious ones, up to 10% of patients may experience some form of adverse reaction.
More common reactions.
Gastrointestinal.
Gastrointestinal disturbances including indigestion, constipation. Dry mouth.
Nervous system.
Fatigue, dizziness.
Respiratory.
Wheezing. Bronchospasm. (See Section 4.3 Contraindications).
Less common reactions.
Biochemical abnormalities.
Increases in SGOT, blood urea and serum creatinine have been reported.
Cardiovascular.
Bradycardia, left ventricular insufficiency, postural hypotension which may be associated with syncope, intermittent claudication may occur if already present, Raynaud's phenomenon, cold extremities, deterioration in heart failure, heart block.
Dermatological.
Rash, alopecia, psoriasiform skin reactions, exacerbation of psoriasis.
Gastrointestinal.
Diarrhoea. Elevations of transaminase levels have been seen infrequently. Rare cases of hepatic toxicity including intrahepatic cholestasis have been reported.
Genitourinary.
Impotence.
Musculoskeletal.
Ataxia.
Nervous system.
Vivid dreams, nightmares, paraesthesiae, tinnitus, vertigo, malaise, headache, insomnia, mood changes, confusion.
Ocular.
Dry eyes and visual disturbances.
Psychiatric.
Hallucinations, depression and psychoses.
Respiratory.
Asthma, dyspnoea, nasal congestion.
Haematological.
Thrombocytopenia, purpura. An increase in ANA (Antinuclear Antibodies) has been observed, however, the clinical relevance of this is not clear.
Serious or life-threatening reactions.
Myocardial insufficiency may require treatment with digitalis and diuretics. Bradycardia may respond to atropine. Bronchospasm may be reversed with a β2-stimulant. Hypotension, if severe, may require use of a vasopressor.
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.4.9 Overdose
Symptoms.
Overdosage has not been reported with atenolol but in overdosage with other β-blocking agents, severe bradycardia and hypotension are commonly found. Acute heart failure and bronchospasm may also occur.
Treatment.
Severe bradycardia.
Atropine 1 to 2 mg intravenously may be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline (25 microgram initially) or orciprenaline (0.5 mg given by slow intravenous injection) may be given. In refractory cases, the use of a cardiac pacemaker may be considered.
Hypotension.
Severe hypotension should respond to a sympathomimetic amine such as noradrenaline. In refractory cases, the use of glucagon hydrochloride should be considered.
Bronchospasm.
Therapy with a β2-stimulant such as salbutamol or terbutaline or therapy with aminophylline may be considered.
Acute cardiac failure.
Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases, the use of intravenous isoprenaline, followed if necessary by glucagon hydrochloride or intravenous aminophylline, should be considered.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Atenolol is a β-adrenoceptor blocking drug which acts preferentially on β-receptors in the heart. Selectivity decreases with increasing dose. It has little intrinsic sympathomimetic activity and no membrane stabilising activity. Atenolol is a racemic mixture and its activity resides in the S(-) enantiomer. It reduces raised blood pressure by an unknown mechanism and also inhibits exercise induced tachycardia and decreases plasma renin concentration. It causes slight airways obstruction but less than that seen with nonselective β-blockers. The inhibition of exercise induced tachycardia is correlated with blood levels but there is no correlation between plasma concentrations and antihypertensive effect. Atenolol is effective and well-tolerated in most ethnic populations although the response may be less in Afro-Caribbean black patients.
The possible mechanism of the antianginal activity of atenolol appears to be due to a reduction in left ventricular work and oxygen utilisation resulting (mainly) from the decrease in heart rate.
The antiarrhythmic effect of atenolol is apparently due to its antisympathetic effect. There is no evidence that membrane stabilising activity or intrinsic sympathomimetic activity are necessary for antiarrhythmic efficacy. By its antisympathetic effect, atenolol depresses sinus node function, atrioventricular node function and prolongs atrial refractory periods. It has no direct effect on electrophysiological properties of the His-Purkinje system.
Because of their negative ionotropic effects, beta-adrenoreceptor blocking agents should be avoided in uncontrolled heart failure.
Clinical trials.
No data available.
5.2 Pharmacokinetic Properties
Absorption.
Although the absorption of atenolol is variable and incomplete (40 to 60%), the virtual lack of hepatic metabolism results in relatively consistent systemic bioavailability compared to other β-blockers. Blood levels in humans peak two to four hours after a single 100 mg oral dose and are of the order of 0.4 to 0.9 microgram/mL. Blood levels are consistent and the levels after chronic oral administration are in good agreement with those predicted from single dose results.
Distribution and metabolism.
The drug is distributed throughout the body tissues and less than 10% of the dose is metabolised, the minor urinary metabolite identified being an hydroxylated derivative.
Excretion.
The main route of elimination is renal excretion. The plasma half-life, measured by blood level decay or urinary build up, is approximately 7 to 9 hours. In patients with impaired renal function there is a progressive prolongation of the half-life. In patients with normal renal function, the therapeutic effect (i.e. control of raised blood pressure) lasts for at least 24 hours following a 50 mg oral dose.
5.3 Preclinical Safety Data
Genotoxicity.
No data available.
Carcinogenicity.
No data available.6 Pharmaceutical Particulars
6.1 List of Excipients
The tablets also contain pregelatinised maize starch, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycollate, colloidal anhydrous silica, magnesium stearate, hypromellose and opadry white Y-1-7000B (containing hypromellose, titanium dioxide, macrogol 400 and indigo carmine aluminium lake CI 73015).
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C. Protect from light and moisture.
6.5 Nature and Contents of Container
They are available in bottles^ (HDPE) and blister packs (PVC/PVdC/Al) of 30 tablets.
^ The bottle packaging is for dispensing only and not to be supplied to a patient.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Atenolol is a β-adrenoceptor blocking agent structurally related to propranolol and differing from propranolol by substitution on the aromatic ring.
Chemical structure.
Atenolol is 2-[4-(2-hydroxy-3-isopropyl-aminopropoxy) phenyl] acetamide. The molecular formula and weight of atenolol are C14H22N2O3 and 266.3 respectively. The molecular structure is as below:
CAS number.
2912268-7.7 Medicine Schedule (Poisons Standard)
Prescription Only Medicine - S4.
Summary Table of Changes
