ATENOLOL TABLETS BP 100 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Atenolol Tablets BP 100 mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Atenolol 100 mg per tablet

For excipients, see 6.1

3 PHARMACEUTICAL FORM

Tablet.

Atenolol Tablets BP 100 mg are presented as orange film coated, biconvex tablets engraved with company logo on one face and A432 on the other face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

a. Management of hypertension.

b. Management of angina pectoris.

c. Management of cardiac arrhythmias.

d. Myocardial infarction – early intervention in the acute phase.

4.2 Posology and method of administration

ADULTS

Hypertension

Usual Dose: 100 mg daily as a single dose.

Some patients may respond to 50 mg as a single daily dose.

The therapeutic effect is fully established after administration for one to two weeks.

Further reduction in blood pressure, if desired, can be achieved by combining atenolol with other antihypertensive agents.

Angina

100 mg once daily or 50 mg twice daily

Additional benefit is unlikely to be gained by increasing the dose.

Arrhythmias

Having controlled the arrhythmia with intravenous “atenolol” maintenance oral dose:50 – 100 mg daily as a single dose.

Myocardial infarction

Patients presenting within 12 hours of the onset of chest pains and suitable for betaadrenoceptor blockade therapy.

Injection

Atenolol 5–10 mg administered by slow intravenous injection (1 mg/minute).

Oral dose

If no adverse effects occur following the intravenous dose, then 15 minutes later 50 mg is administered orally followed by a further 50 mg, 12 hours after the intravenous dose. Then 12 hours later 100 mg is orally given, once daily.

If bradycardia and/or hypotension requiring treatment, or any other side-effects occur, atenolol therapy should be discontinued.

Elderly Patients

Dosage requirements may be reduced especially in those with impaired renal function.

Children

Not recommended for use in children as there is no paediatric experience with atenolol.

Renal failure

Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs at a GFR greater than 35 ml/min/1.73m2 (normal range is 100 – 150 ml/min/1.73m2).

For patients with a creatinine clearance of 15–35 ml/min/1.73m2, (equivalent to serum creatinine of 300–600 micromol/litre) the oral dose should be 50 mg daily or 100 mg once every two days; and the intravenous dose should be 10 mg once every two days.

For patients with a creatinine clearance of < 15 ml/min/1.73m2 (equivalent to serum creatinine of > 600 micromol/litre), the oral dose should be 50 mg on alternate days or 100 mg once every four days; and the intravenous dose should be 10 mg once every four days.

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.

Route of administration

Oral.

4.3 Contraindications

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

Hypersensitivity to atenolol or any of the excipients Hypotension

Severe peripheral circulatory disturbances

Untreated phaeochromocytoma

Metabolic acidosis

Uncontrolled cardiac failure

Cardiogenic shock

Heart block – 2nd or 3rd degree atrioventricular (AV) block

Prinzmetal’s angina

Sinus bradycardia (heart rate less than 45 beats per minute)

Sick sinus syndrome (including sino-atrial block)

Although cardioselective beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers these should be avoided in patients with asthma or a history of reversible obstructive airways disease or bronchospasm (see 4.4 Special Warnings and Precautions for Use), unless there are compelling clinical reasons for their use.

4.4 Special warnings and precautions for use

Respiratory Disorders: Beta-blockers including those considered to be cardioselective but not totally cardiospecific should not be given to patients with a history of asthma, bronchospasm or reversible obstructive airways disease. However, in patients where there is no alternative to the use of a betablocker, then a cardioselective one can be given with extreme caution and under specialist supervision.

Occasionally, some increase in airways resistance may occur in asthmatic patients and this may usually be reversed by commonly used dosage of bronchodilators such as salbutamol, terbutaline or isoprenaline.

Patient information leaflets and labels will carry the following warnings: Patient Information Leaflet: Do not take this medicine if you have wheezing or asthma. Talk to your doctor or pharmacist first.

Labels: Do not take this medicine if you have wheezing or asthma.

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 whose cardiac reserve is poor. Myocardial contractility must be maintained and signs of failure controlled with digitalis and diuretics.

Bradycardia: Beta-blockers may induce bradycardia. If the pulse rate decreases to less than 50–55 beats per minute when the patient is at rest, the dose should be reduced.

Elderly: These patients should be treated with caution, starting with a lower dose. The elderly may be less sensitive to some of the effects of beta-blockers. Reduced metabolic and excretion capabilities in many elderly patients may lead to increased myocardial depression necessitating reduced dosage, however tolerance is usually good in the elderly.

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

Ischaemic Heart disease: Atenolol therapy should not be discontinued abruptly, especially in patients with ischaemic heart disease, and replacement therapy should be considered to prevent exacerbation of angina, myocardial infarction, rebound hypertension, ventricular arrhythmias and sudden cardiac death (see 4.8 Undesirable effects). Treatment should not be discontinued abruptly in patients on long-term therapy, but should be discontinued over 1–2 weeks.

Anaesthesia: If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia. If beta-blockers are not discontinued before anaesthesia, the anaesthetist should be made aware of the beta-blocker therapy. A drug such as atropine may be given to counter increases in vagal tone. Anaesthetics causing myocardial depression such as ether, cyclopropane, trichloroethane, halothane and enflurane should be avoided (see 4.5 interactions)

Diabetics: Care should be taken in diabetic patients subject to frequent episodes of hypoglycaemia and their blood glucose monitored regularly as atenolol may mask the symptoms of hypoglycaemia (see 4.5 interactions), in particular, tachycardia. Diabetic patients should be warned that this ‚warning sign‘ may not occur. The risk of hyperglycaemia is increased with concomitant use of a beta-blocker and a thiazide.

Myasthenia gravis: Atenolol should also be administered with care if given to patients with myasthenia gravis. Beta-blockers may unmask myasthenia gravis or potentiate a myosthenic condition.

Liver or Kidney Insufficiency: Caution should also be exercised in patients with hepatic and renal function impairment. Liver function is reported to deteriorate in portal hypertension. Hepatic and renal functions should be monitored in order to adjust dosage requirement, especially in the elderly, and a reduced dose of atenolol be given at the start of treatment. Since atenolol is excreted via the kidneys, dosage should be reduced in patients with a creatinine clearance of below 35 ml/min/1.73 m2.

Psoriasis: patients with psoriasis should take beta-blockers only after careful consideration, as psoriasis may be aggravated.

Peripheral Circulatory Disease: In patients with peripheral circulatory disorders (Raynaud’s disease or syndrome, intermittent claudication), betablockers should be used with great caution as aggravation of these disorders may occur.

Allergies: Beta-blockers should be used with caution in patients with a history of hypersensitivity as they may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Beta-blockers may also reduce a response to adrenaline (epinephrine) that is administered in cases of allergic emergency.

Thyrotoxicosis: Atenolol as with other beta-blockers may mask the signs of thyrotoxicosis.

Phaeochromocytoma: As with other beta-blockers, in patients with a phaeochromocytoma, an alpha-blocker should be given concomitantly.

4.5 Interaction with other medicinal products and other forms of interaction

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

Aldesleukin: enhanced hypotensive effect.

Alprostadil: enhanced hypotensive effect.

Ampicillin: reduces atenolol serum levels.

Antacids: reduced absorption of atenolol may occur if antacids containing calcium or aluminium and magnesium are administered concomitantly.

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.

Anaesthetics: concurrent use of atenolol with anaesthetics, such as hydrocarbon inhalation, especially halothane, may increase the risk of reflex tachycardia, myocardial depression and hypotension because beta blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli. Concomitant use is therefore best avoided. The anaesthesiologist should be informed when the patient is receiving a betablocking agent such as atenolol and choice of anaesthetic should be an agent with as little negative inotropic activity as possible, (refer to Section 4.4 for details of warnings and precautions for use, which includes information relating to preparation for surgery.)

Antidiabetics: Dosage of hypoglycaemic agents requirements may need to be increased (see 4.4 Special Warnings and Precautions for Use). Beta-blockers may intensify the blood sugar lowering effect of antidiabetics. Concurrent use of atenolol with insulin and oral antidiabetic drugs may increase the risk of hypoglycaemia (tachycardia). Beta-blockers may mask certain symptoms of developing hypoglycaemia. (Refer to Section 4.4). Hypoglycaemia is more likely in Type I than in Type II diabetics and may be associated with delayed recovery. The risk of hyperglycaemia is increased with concomitant use of a beta-blocker and a thiazide.

NSAIDs: concurrent administration of NSAID agents such as indometacin and ibuprofen with atenolol may reduce the antihypertensive effect possibly due to inhibition of renal prostaglandin synthesis and sodium and fluid retention caused by non-steroidal anti-inflammatory agents.

Oestrogen: concurrent use of oestrogen with atenolol may decrease the antihypertensive effect because oestrogen induced fluid retention may lead to increased blood pressure.

Theophylline: Atenolol antagonises bronchodilator effect of theophylline -avoid concomitant use.

Antidepressants and antipsychotics: concomitant administration of atenolol with phenothiazines may result in an increased plasma concentration of each medication. Phenothiazines and tropisetron may increase the risk of ventricular arrhythmias. Enhanced hypotensive effect with monoamine oxidase inhibitors (MAOIs).

Muscle relaxants: increases or decreases in the extent of neuromuscular blockade have been seen in patients treated with beta-blockers. Some neuromuscular blockers, such as atracurium, may enhance the hypotension and bradycardia associated with anaesthesia in patients taking beta-blockers.

Antimalarials: risk of bradycardia with mefloquine.

Anxiolytics and hypnotics: enhanced hypotensive effect with benzodiazepines.

Calcium-channel blocking agents: Cardiodepressant calcium channel blocking agents such as diltiazem, nifedipine and verapamil may induce negative inotropic effects such as severe hypotension, bradycardia, asystole and heart failure – avoid concomitant use. The risk of hypotension may be increased with concomitant use of other dihydropyridines. In patients with latent cardiac insufficiency, treatment with beta-blocker agents may lead to cardiac failure.

Clonidine: Caution should be exercised when transferring patients from clonidine to beta-adrenoceptor blocking drugs. There is an increased risk of rebound hypertension on withdrawal of clonidine. If beta-adrenoceptor blocking drugs and clonidine are given concurrently, clonidine should not be discontinued until several days after the withdrawal of the beta-adrenoceptor blocking drug.

Contrast media: Concomitant use of contrast media with atenolol may increase the risk of hypotension and/or anaphylactic reaction.

Dopaminergics: There is a potential for enhanced hypotension when atenolol and methyldopa are administered concomitantly.

Anti-arrhythmics and other drugs affecting cardiac conduction: concurrent use of atenolol with class 1 anti-arrhythmic agents such as disopyramide, quinidine or amiodarone increases myocardial depression and may have a potentiating effect on atrial-conduction time and induce negative inotropic effect on the heart, with increased risk of bradycardia, hypotension, ventricular fibrillation, heart block or asystole – avoid concomitant use.

Diuretics: Concomitant use of diuretics with beta-blockers may increase the risk of hypotension.

Cardiac glycosides: Risk of marked bradycardia and AV block with digoxin.

Antihypertensive agents as well as other drugs with blood pressure lowering potential: concomitant administration with antihypertensive agents as well as other drugs with blood pressure lowering potential e.g. tricyclic antidepressants, barbiturates and phenothiazines may increase the blood pressure lowering effect. Enhanced hypotension with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II antagonists. Potential for severe hypotension and heart failure with concomitant administration of betablockers and nisoldipine. Potential for enhanced hypotension with concomitant use of diazoxide and beta-blockers. There is a potential for an enhanced hypotensive effect when hydralazine and atenolol are administered concomitantly.

Sympathomimetics: Risk of severe hypertension and bradycardia with such agents as adrenaline (epinephrine), noradrenaline (norepinephrine) and ephedrine. Beta-blockers may also reduce the response to adrenaline in the management of anaphylaxis (see 4.4 special warnings and precautions for use).

Ergot alkaloids: Increased vasoncostriction – avoid concomitant use.

Moxisylyte: Increased risk of severe postural hypotension.

Nitrates: Potential for an enhanced hypotensive effect when levodopa and beta-blockers are used concomitantly.

Parasympathomi­metics: Increased risk of bradycardia and/or hypotension with neostigmine.

4.6 Fertility, pregnancy and lactation

Atenolol crosses the placental barrier and appears in cord blood.

No studies have been performed on the use of atenolol in the first trimester and the possibility of foetal injury cannot be excluded.

However, Atenolol has been used effectively under close supervision for the treatment of pregnancy-associated hypertension in the third trimester.

Administration of atenolol to pregnant women in the management of mild to moderate hypertension has been associated with intra-uterine growth retardation, which is greatest when started in early pregnancy, such as in the second trimester and is related to the duration of treatment. The risk of adverse effects to the foetus or neonate is greater in severely hypotensive pregnancies (including low birth weight).

Beta-blockers reduce placental perfusion which may result in intra uterine foetal deaths, immature and premature deliveries. Administration of atenolol to pregnant women shortly before or during delivery may result in neonatal bradycardia, hypoglycaemia or hypotension.

Atenolol is excreted in breast milk. Breast feeding can be undertaken but infants should be monitored for bradycardia, respiratory depression, hypotension and hypoglycaemia.

4.7 Effects on ability to drive and use machines

Occasionally dizziness or fatigue may occur. If affected, patients should not drive or operate machinery.

4.8 Undesirable effects

Atenolol is well tolerated. In clinical studies, the undesired events reported are usually attributable to the pharmacological actions of atenolol.

The following undesired events, listed by body system, have been reported during treatment with atenolol and other beta blockers with the following frequencies: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000) including isolated reports, unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Rare: Thrombocytopenia

Unknown: Purpura (thrombocytopenic or nonthrombocyto­penic), eosinophilia and leucopenia including agranulocytosis.

Immune system disorders:

Unknown: Allergic reactions including anaphylaxis.

Metabolism and nutrition disorders:

Unknown: Hyperglycaemia or hypoglycaemia. Non-diabetic patients susceptible to hypoglycaemia include those undergoing regular dialysis, vigorous exercise or prolonged fasting and patients who are long term nutritionally compromised or have liver disease. Atenolol may increase serum triglyceride levels and reduce high-density lipoprotein (HDL) cholesterol levels.

Psychiatric disorders:

Uncommon: Sleep disturbances

Rare: Mood changes, abnormal dreams, nightmares, confusion, psychoses and hallucinations.

Unknown: Mental depression, anxiety, nervousness.

Nervous system disorders:

Rare: Dizziness, headache, paraesthesia.

Unknown: Peripheral neuritis, lethargy. Atenolol may impair performance in psychomotor tests. There is a potential for memory impairment and/or amnesia to occur.

Eye disorders:

Rare: Dry eyes, visual disturbances including blurred vision.

Unknown: Sore eyes, conjunctivitis.

Ear and labyrinth disorders:

Unknown: Vertigo.

Cardiac disorders:

Common: Bradycardia

Rare: Heart failure deterioration, heart block.

Unknown: Heart failure (cardiac arrest).

Vascular disorders:

Common: Cold extremities.

Rare: Postural hypotension which may be associated with syncope, intermittent claudication may be increased if already present, in susceptible patients Raynaud's phe­nomenon.

Unknown: Peripheral vasoconstriction, peripheral gangrene, hypotension.

Respiratory, thoracic and mediastinal disorders:

Common: Dyspnoea

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

Unknown: Pneumonitis, pulmonary fibrosis and pleurisy.

Gastrointestinal disorders:

Common: Gastrointestinal disturbances: nausea, vomiting, diarrhoea, constipation.

Rare: Dry mouth

Unknown: Abdominal cramps, sclerosing peritonitis and retroperitoneal fibrosis.

Hepato-biliary disorders:

Uncommon: Elevations of transaminase levels

Rare: Hepatic toxicity including intrahepatic cholestasis

Unknown: Elevated bilirubin levels.

Skin and subcutaneous tissue disorders:

Rare: Alopecia, psoriasiform skin reactions, exacerbation of psoriasis, skin rashes, skin necrosis.

Unknown: Hypersensitivity reactions, including angioedema and urticaria, sweating, pruritis

Musculoskeletal and connective tissue disorder:

Unknown: Lupus-like syndrome. Myopathies including muscle cramps, arthralgia.

Reproductive system and breast disorders:

Rare: Impotence

Unknown: Peyronie’s disease

General disorders and administration site conditions:

Common: Fatigue, drowsiness

Investigations:

Common: Irregular heart beat

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. Sudden cessation of therapy with a beta-blocker may exacerbate angina, myocardial infarction, ventricular arrhythmias and sudden cardiac death (see 4.4 special warnings and precautions for use).

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

Symptoms: Many cases of beta-blocker overdosage are uneventful, but some patients develop severe and occasionally fatal cardiovascular depression. The most important effects are on the heart. Signs of overdosage are dizziness, bradycardia, severe hypotension, hypoglycaemia, acute cardiac insufficiency, syncope, cardiogenic shock and heart failure. First or second degree AV block may occur and rarely arrhythmias. Convulsions, coma, bronchospasm, respiratory depression, and bronchoconstriction can also occur, although infrequently.

Treatment: If ingestion is within one hour administer activated charcoal to prevent absorption of any drug still present in the gastrointesti­nal tract.

Acute massive overdosage requires hospital management and expert advice should be obtained. Maintenance of a clear airway and adequate ventilation is mandatory. Excessive bradycardia and hypotension may be countered by atropine intravenously. Cardiogenic shock unresponsive to atropine may be treated with an intravenous injection of glucagon. A further dose of glucagon (or an intravenous infusion) may be required if the response is not maintained. If glucagon is unavailable, intravenous isoprenaline or dobutamine are alternatives.

Administration of calcium ions may be considered. A cardiac pacemaker may be used if second or third degree heart block or bradycardia occur. In patients intoxicated with hydrophilic beta-blocking agents, which include atenolol, haemodialysis may be considered. Bronchospasm can usually be reversed by bronchodilators. Hypoglycaemia may be treated with intravenous glucose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group : Beta blocking agents, plain, selective – atenolol

ATC Code             : C07A B03

Atenolol is a beta-adrenoceptor blocking drug which is beta 1– selective (i.e. acts preferentially on beta 1-adrenergic receptors in the heart). It is without intrinsic sympathomimetic and membrane stabilising activities. Human studies indicate that it crosses the blood brain barrier only to a negligible extent.

As with other beta-adrenoceptor blocking drugs, it’s 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.

Early intervention with atenolol in acute myocardial infarction reduces infarct size and decreases morbidity and mortality. 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

Atenolol is not completely absorbed from the gastrointestinal tract, its oral bioavailability being of the order 50–60%. It is approximately 5% bound to plasma proteins. The plasma half-life of atenolol is about 6 hours. However, the duration of therapeutic effect is much longer than this, allowing once daily dosing. Atenolol is excreted largely unchanged in the urine and its dosage should be adjusted in renal failure.

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

Calcium hydrogen phosphate

Povidone

Pregelatinised Maize starch

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Film coating materials:

Orange colour dispersion containing:

– Hypromellose

– Sunset yellow aluminium lake (E110)

– Quinoline yellow aluminium lake (E104)

– Titanium dioxide (E171)

Hypromellose

Hydroxypropyl­cellulose

Macrogol 400

6.2 Incompatibilities

None.

6.3 Shelf life

Blister packs: 36 months as packaged for sale

Tablet containers: 36 months as packaged for sale. After first opening: 3 months.

6.4 Special precautions for storage

Blister packs: Do not store above 25°C. Store in the original package in order to protect the tablets from moisture.

Tablet containers: Do not store above 25°C. Keep the container tightly closed in order to protect the tablets from moisture.

6.5 Nature and contents of container

Blister packs of PVC/PVDC film/aluminium foil (10 or 14 tablets/strip). The blister strips are subsequently packed in printed boxboard cartons in a pack size of 28, 30, 56 and 84 tablets.

Polypropylene tablet containers with LDPE/HDPE caps in a pack size of 1000 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special instructions for use/handling.

Crescent Pharma Limited

Units 3 & 4, Quidhampton Business Units

Polhampton Lane Overton

Hants RG25 3ED United Kingdom