Atenolol Tablets Summary of Product Characteristics 1. NAME OF THE MEDICINAL PRODUCT Atenolol Accord 25 mg tablets Atenolol Accord 50 mg tablets Atenolol Accord 100 mg tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Atenolol Accord 25 mg tablets Each tablet contains 25 mg of atenolol Atenolol Accord 50 mg tablets Each tablet contains 50 mg of atenolol Atenolol Accord 100 mg tablets Each tablet contains 100 mg of atenolol For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablets Atenolol Accord 25 mg tablets White, round, flat, bevelled tablets with the inscription 'AA' on one side and a scoreline on the other. The tablet can be divided into equal doses. Atenolol Accord 50 mg tablets White, round, flat, bevelled tablets with the inscription 'AB' on one side and a scoreline on the other The tablet can be divided into equal doses. Atenolol Accord 100 mg tablets White, round, flat, bevelled tablets with the inscription 'AC' on one side and a scoreline on the other The tablet can be divided into equal doses. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hypertension Module 1 Page: 1 of 11 Atenolol Tablets Chronic stable angina pectoris Secondary prevention after acute myocardial infarction: early intervention within 12 hours. 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. 4.2 Posology and method of administration Posology and method of administration The dosage should be determined on an individual basis, especially based on the clinical effect. It is recommended to start with the lowest possible dosage so that heart failure, bradycardia and bronchial symptoms are noticed timely. Hypertension: A starting dose of 50 mg is recommended. The usual maintenance dosage in hypertension is one tablet (50-100 mg) 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. The 25 mg dose is only indicated in patients with severe renal insufficiency or for elderly patients as initiation therapy if necessary. Angina pectoris: 50-100 mg daily depending, on the clinical effect. Increasing the dose above 100 mg daily does not generally lead to an increased antianginous effect. If desired the dosage of 100 mg daily can be divided in two dosages. Arrhythmias: The regular oral maintenance dose is 50 to 100 mg atenolol daily. Secondary prevention after myocardial infarction: Oral maintenance therapy until hospital discharge is 50 - 100 mg daily in 1-2 dosages in patients that are hemodynamically stabilised. Children: There is no experience with use of atenolol in children. It is therefore not recommended to use atenolol in children. Elderly patients: In elderly therapy should be started with a lower dosage. Dosage should be titrated according to clinical effect. Renal impairment: Module 1 Page: 2 of 11 Atenolol Tablets Glomerular filtration rate (ml/min/1.73 m2 body surface > 35 15-35 < 15 Recommended atenolol dose (mg/day) No dose modification 25-50 (or 50-100 / 2 days) 25 – 50 / 2 days In haemodialysis a 50 mg tablet is administered after each dialysis. The administration should be done in hospital since sudden decrease of the arterial pressure may occur. Hepatic impairment: No dose modifications necessary. Atenolol should be swallowed with a sufficient amount of fluid (e.g. one glass of water) before food intake. It is not recommended that atenolol treatment is stopped abruptly since this might lead to a worsening of hypertension, heart failure or ischaemic heart disease which could lead to myocardial infarction. The dosage of atenolol should always be reduced gradually. 4.3 Contraindications Contra-indications Cardiogenic shock Uncontrolled heart failure Sick sinus syndrome (including sino-atrial block) Second and third degree heart block Untreated phaeochromocytoma Metabolic acidosis Bradycardia (< 50 bpm before treatment initiation) Hypotension Hypersensitivity to the active substance atenolol or any of the excipients listed in section 6.1. Severe peripheral circulatory disturbances Floctafenine Severe asthma and severe chronic obstructive pulmonary disorders, such as airway obstructions The intravenous application of calcium channel blockers (verapamil / diltiazem type) is contraindicated in patients who use atenolol (except in intensive care unit) 4.4 Special warnings and precautions for use Ischaemic heart diseases Especially in patients with ischaemic heart disease, treatment should not be discontinued suddenly. The dosage should gradually be 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 on myocardial infarction and sudden death. Atenolol should not be used in patients with untreated congestive heart failure. This condition should first be stabilised. Module 1 Page: 3 of 11 Atenolol Tablets Surgery: When it has been decided to interrupt a beta-blockade in preparation for surgery, 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. Peripheral circulatory disorders: In patients with peripheral circulatory disorders (Raynauds’s disease or syndrome, intermittent claudication), atenolol should be used with great caution as aggravation of these disorders may occur. Severe peripheral circulatory disorders are a contra-indication (see contraindications) Heart rate: Atenolol 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. Airways: 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. Heart block: Due to its negative effect on conduction time, atenolol should only be given with caution to patients with first degree heart block. Renal impairment: In patients with renal impairment dosage should be adjusted to reduced glomerular filtration rate (see section 4.2. Posology) Elderly: The elderly should be treated with caution (see section 4.2. Posology). Prinzmetal’s angina: Atenolol may increase the number and the 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. Psoriasis: Patients with anamnestically known psoriasis should take atenolol only after careful consideration. Allergens: Atenolol may increase both the sensitivity toward allergens and the seriousness of anaphylactic reactions. Atenolol may reduce the efficacy of epinephrine. Module 1 Page: 4 of 11 Atenolol Tablets Hypersensitivity: Atenolol may cause a hypersensitivity reaction including angioedema and urticaria. Diabetics The symptoms of hypoglycaemia may be masked by atenolol, in particular tachycardia. Insulin sensitivity may be reduced in patients treated with atenolol. Thyrotoxicosis: Beta-blockade may mask cardiovascular signs of thyrotoxicosis. Treated pheochromocytoma: Patients with pheochromocytoma (adrenal gland tumour; a pre-treatment with alphareceptor inhibitors is necessary) 4.5 Interactions with other medicinal products and other forms of interaction Combinations contra-indicated: Floctafenine: Beta-adrenergic blocking agents may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by floctafenine. Calcium antagonists: verapamil and to a lesser extent diltiazem: negative influence on the contractility and AV-conduction. Not recommended association: Digitalis glycosides: association with atenolol may increase the AV-conduction time. Monoamineoxidase inhibitors (except MAO-B inhibitors) Clonidine: Betablockers increase the risk of rebound hypertension. Sultopride: Atenolol should not be concomitantly administered with sultopride since there is an increased risk of ventricular arrhythmias, e.g. torsades de pointes. Precautions for use: Class I anti-arrhythmic drugs (e.g. disopyramide, quinidine) and amiodaron: 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 effect (especially non-selective betablockers) Beta-adrenergic blockade may prevent the appearance of signs of hypoglycaemia (tachycardia). Anaesthetic drugs: attenuation of the reflex tachycardia and increase the risk of hypotension. Continuation of beta-blockades reduce the risk of arrhythmia during induction and intubation. The anaesthesiologist should be informed when the patient is receiving a Module 1 Page: 5 of 11 Atenolol Tablets 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. 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. Amiodaron:Combination with atenolol may result in additive depressant effects on conduction and negative inotropic effects, especially in patients with underlying sinus node dysfunction or atrioventricular node dysfunction. Take into account: Calcium antagonists: dihydropyridine derivates such as nifedipine: the risk of hypotension may be increased. In patients with latent cardiac insufficiency, treatment with atenolol may lead to cardiac failure. Prostaglandin synthetase inhibiting drugs: (like NSAID’s) may decrease the hypotensive effects of atenolol. Sympathicomimetic agents: (f.e. adrenaline) 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. 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 Antihypertensives, diuretics, vasodilatators, tricyclic antidepressants, barbiturate and phenothiacine could increase the antihypertensive effect of atenolol. Peripheral muscle relaxants (e.g. Suxamethonium halogenide, Tubocurarine): concomitant use of atenolol could increase and extent the relaxative effect of muscle relaxants. 4.6 Fertility, pregnancy and breastfeeding Pregnancy and lactation Pregnancy Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Therefore the neonate should be monitored carefully. Module 1 Page: 6 of 11 Atenolol Tablets Atenolol crosses the placenta. If atenolol is used regularly during pregnancy a medical practitioner should be consulted. Atenolol was used with good results, under careful surveillance, for hypertension of pregnancy. There were no indications for foetal abnormalities, it should be mentioned that atenolol was used only after the 20th week of pregnancy. Furthermore there are no indications for adverse effects during childbirth or during the lactation period. Nevertheless a harmful effect on the foetus may not be excluded. Breastfeeding The concentration in mothers milk is three times higher than in blood. During lactation only low levels of atenolol are found in the child. Nevertheless the occurrence of beta blocking properties in the child can not be excluded in the long term. If possible, it is advised, to keep a six hour time interval between atenolol intake and breastfeeding. During this interval the child may be bottle-fed. When used during pregnancy and lactation the advantages and disadvantages should be carefully weighed. 4.7 Effects on ability to drive and use machines This medicinal product has minor influence on the ability to drive and use machines. The individual response to react with the ability to drive or operate the machinery can be affected due to occasional dizziness or fatigue. 4.8 Undesirable effects The following terminologies have been used in order to classify the occurrence of undesirable effects Very common: Common: Uncommon: Rare: Very rare: ta) ≥1/10 ≥1/100 and <1/10 ≥1/1000 and <1/100 ≥1/10 000 and <1/1000 <1/10 000, not known (cannot be estimated from the available da- Blood and lymphatic system disorders Rare: Thrombocytopenia, leukopenia Endocrine disorders Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia. Psychiatric disorders Uncommon: Sleep disturbances Rare: Hallucinations, psychoses, confusion, depression, nightmares, anxiety Nervous system disorders Rare: Headaches, dizziness, paraesthesia of the extremities, Module 1 Page: 7 of 11 Atenolol Tablets Eye disorders Rare: Impaired vision, visual disturbances, dry eyes Cardiac disorders Common: Bradycardia, Rare: Slow AV-conduction or increase of an existing AV-block, aggravation of heart failure Vascular disorders Common: Cold and cyanotic extremities Rare: Hypotension (sometimes associated with syncope), Raynaud phenomenon, increase of an existing intermittent claudication. Respiratory, thoracic and mediastinal disorders Rare: Bronchospasm in patients with bronchial asthma or a history of asthmatic complaints. Gastrointestinal disorders Common: Gastro-intestinal problems, nausea, vomiting, diarrhoeaand constipation. Rare: Dry mouth. Skin and subcutaneous tissue disorders Rare: Rash, alopecia, psoriasis like skin reactions, aggravation of psoriasis, purpura Frequency not known: Hypersensitivity reactions, including angioedema and urticaria. General disorders and administration site conditions Common: Fatigue, sweating Investigations Very rare: An increase in Anti Nuclear Antibodies has been seen; its clinical relevance is not clear. Hepato-biliary disorders: Uncommon: Elevations of transaminase levels. Rare: Hepatic toxicity including intrahepatic cholestasis. Reproductive system and breast disorders Rare: Impotence 4.9 Overdose Overdose Symptoms of overdosage are: Bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. After ingestion of an overdose or in case of hypersensitivity, the patient should be kept under close supervision and be treated in an intensive-care ward. Absorption of atenolol Module 1 Page: 8 of 11 Atenolol Tablets still present in the gastro-intestinal tract can be prevented by gastric lavage, administration of activated charcoal and a laxative. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine or methylatropine. Hypotension and shock should be treated with plasma/plasma substitutes and, if necessary, catecholamines. The beta-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 micrograms/minute, or dobutamine, starting with a dose of 2,5 microgram/minute, until required effect has been obtained. In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of 8-10 mg glucagon may be considered. If required the injection should be repeated within one hour, to be followed - if required - by an i.v. infusion of glucagon at an administration rate of 1-3 mg/hour. Administration of calcium ions, or the use of a cardiac pacemaker may also be considered. As for the hydrophylic character, the low plasma protein binding and the small distribution volume of atenolol hemodialysis or hemoperfusion may be considered. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacodynamic properties ATC code: C07AB03 Atenolol is a selective beta-1-adrenergic blocking agent, without intrinsic sympathomimetic of membrane stabilising characteristics. Clinical effects are reached fast and will maintain at least 24 hours after the intake of atenolol. Therefore both Atenolol 50 and Atenolol 100 can be taken once daily, which simplifies the therapy. Atenolol is a very hydrophylic compound which passes the blood-brain barrier only in very limited amounts. This causes a relatively low incidence of CNS-side effects. Atenolol mainly acts on the beta receptors of the heart and can therefore, contrary to non-selective beta adrenergic blocking agents, be administered, under carefull surveillance and check-up of the lung function, to patients with chronic obstructive pulmonal diseases, who can not bear a non-selective beta adrenergic blocking agent. The beta-1-selectivity is reduced with increased dose. Beta-adrenergic blocking agents have a negative inotropic and chronotropic effect and inhibit the effect of catecholamines resulting in reduced heart rate and blood pressure. 5.2 Pharmacokinetic properties 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%. The volume of distribution is 50 to 75 L. The protein binding is less then 5%. Metabolism of atenolol is minimal. 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, clear- Module 1 Page: 9 of 11 Atenolol Tablets ance 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 Preclinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity. Reproduction studies show that atenolol has no teratogenic potential; however a study in rats showed that dosages of 200 mg/kg/day on the 6th and 15th day of the pregnancy did result in a decrease in number of fetuses per dam and an increased incidence of embryo resorptions. 6. PHARMACEUTICAL PROPERTIES 6.1 List of excipients Heavy magnesium carbonate Maize starch Sodium lauryl sulphate Gelatine Magnesium stearate (E572) Cellulose, microcrystalline Talc 6.2 Incompatibilities Not applicable 6.3 Shelf-life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Atenolol Accord 25 mg tablets are packed in PVC/PVDC/aluminium blisters. Pack sizes: 14, 20, 28, 30, or 90 tablets. Atenolol Accord 50 mg tablets are packed in PVC/PVDC/aluminium blisters. Pack sizes: 14, 20, 28, 30, 50, 90 or 100 tablets. Atenolol Accord 100 mg tablets are packed in PVC/PVDC/aluminium blisters. Pack sizes: 14, 20, 28, 30, 50 or 90 tablets. Module 1 Page: 10 of 11 Atenolol Tablets Atenolol Accord 25 mg tablets are available in an HDPE tablet container with a PP screw cap. Pack sizes: 100, 500, 1000, or 5000 tablets. Atenolol Accord 50 mg and 100 mg tablets are available in an HDPE tablet container with a PP screw cap. Pack sizes: 500 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handlings No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Accord Healthcare Limited Sage House, 319 Pinner Road, North Harrow, Middlesex HA1 4HF, United Kingdom 8. MARKETING AUTHORISATION NUMBER To be completed nationally. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION To be completed nationally. 10. DATE OF REVISION OF THE TEXT To be completed nationally. Module 1 Page: 11 of 11
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