COMPOSITION: Each tablet contains 5 mg or 10 mg bisoprolol fumarate (2:1).
Bisoprolol is (±)-1-[[alpha-(2-isopropoxyethoxy)-p-tolyl]oxy]-3-(isopropylamino)-2-propanol fumarate (2:1).
PHARMACOLOGICAL CLASSIFICATION: A 5.2 Adrenolytics (sympathicolytics).
PHARMACOLOGICAL ACTION: Bisoprolol is a highly beta1-selective beta-adrenoceptor antagonist with low beta2-receptor affinity. It has no intrinsic sympathomimetic activity nor membrane-stabilising properties. It reduces blood pressure, and by blockade of the cardiac beta1-receptors, it reduces cardiac action, and hence myocardial oxygen demand.
The mechanism of action of beta1-adrenergic blocking agents in hypertension is not clear, but it is known that bisoprolol reduces the heart rate and depresses plasma renin levels.
Bisoprolol is rapidly absorbed after oral administration in man and excreted predominantly via the urine as unaltered substance and metabolites. In man 50% of a dose is metabolised in the liver while the other 50% is eliminated unchanged via the kidneys. None of the metabolites found in man has beta1-receptor blocking action.
In man, the plasma elimination half-life is 10-12 hours, resulting in a duration of action of 24 hours. Because of its moderate hepatic metabolism, it is subject only to a very small hepatic first pass metabolism. Therefore, bisoprolol displays a high bioavailability of 90% after an oral dose.
INDICATIONS: Concor* is indicated in the management of mild to moderate hypertension and angina pectoris.
CONTRA-INDICATIONS: Hypersensitivity to bisoprolol.
Particular caution should be exercised with patients suffering from the following: Asthma, bronchitis, chronic respiratory diseases (See Special Precautions), second and third degree heart block, bradycardia less than 50 beats per minute, peripheral vascular disease and Raynaud's phenomenon.
Uncontrolled cardiac failure excluding that due to hypertrophic obstructive cardiomyopathy. Not to be used during pregnancy or lactation.
The normal dose should be reduced in elderly patients, or in patients suffering from renal dysfunction.
Patients with metabolic acidosis and sinus bradycardia.
Safety and efficacy in children have not been established.
WARNINGS: If bisoprolol is to be withdrawn prior to surgery, at least 48 hours should be allowed to elapse between the last dose and anaesthesia. If bisoprolol treatment is to be continued during surgery, care should be taken when using anaesthetic agents such as ether, cyclopropane and trichloroethylene. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg i.v.).
In the perioperative period it is generally unwise to reduce the dosage to which the patient is accustomed, as there may be danger of aggravation of angina pectoris or of hypertension.
A patient's normal tachycardiac response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard.
In patients suffering from ischaemic heart disease, treatment should not be discontinued abruptly.
Caution should be taken in prescribing bisoprolol with Class 1 antidysrhythmic agents such as disopyramide, myocardial depressants, and inhibitors of AV conduction such as calcium antagonists.
Use with caution in combination with verapamil in patients with impaired ventricular function. This combination should not be given to patients with conduction abnormalities. Neither drug should be administered intravenously within 48 hours of discontinuing the other.
The intravenous administration of calcium antagonists and antiarrhythmic agents is not recommended during bisoprolol therapy.
Caution should be exercised when transferring a patient from clonidine. The withdrawal of clonidine may result in the release of large amounts of catecholamines, which may give rise to a hypertensive crisis. If beta-blockers are administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If a beta-blocker and clonidine are given concurrently, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker, as severe rebound hypertension may occur.
Bisoprolol modifies the tachycardia of hypoglycaemia. The dosage of bisoprolol should be adjusted in cases of severe renal function impairment.
Pregnancy: Administration to pregnant mothers shortly before giving birth or during labour result in the newborn infant being born hypotonic, collapsed or hypoglycaemic.
DOSAGE AND DIRECTIONS FOR USE: 5 mg should be taken once a day in the morning, either on an empty stomach or with breakfast. If necessary, the dosage can be increased to 10 mg in the morning. An increase in the dosage to 20 mg daily may sometimes be necessary.
The dose should always be selected individually, particularly according to the heart rate and the therapeutic result. It is not necessary to adjust the dose in patients suffering from mild to moderate disturbance of the liver or renal function. In patients with severe renal impairment (creatinine clearance < 20 mL/min) and in patients with severe liver function disturbance, the daily dose of 10 mg bisoprolol must not be exceeded. In some of these patients, halving the dose may be necessary. The normal dose of beta-blockers should be reduced in elderly patients.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Side-effects: These include lassitude, dizziness, mild headache, perspiration, bradycardia, sleep disorders, restlessness, cold extremities, nausea, vomiting, diarrhoea and skin rash. Constipation, hypotension, paradoxical hypertension, depression, mass gain, paraesthesia, transient hearing loss, heart block, hallucinations, disturbances of vision, blood disorders, fluid retention, muscle cramps, allergic reactions, metabolic disturbances, alopecia, myopathies and stomatitis may occur. Overt psychosis has been reported with other beta-blockers.
Exacerbation of peripheral vascular disease, or the development of Raynaud's phenomenon (due to the unopposed arteriolar alpha-sympathetic activation), hypoglycaemia, skeletal muscle weakness and gastro-intestinal disturbances may occur during treatment with beta-blockers. Severe peripheral vascular disease and even peripheral gangrene may be precipitated. Special precautions: Abrupt discontinuation of therapy may cause exacerbation of angina pectoris in patients suffering from ischaemic heart disease. Discontinuation of therapy should be gradual, and patients should be advised to limit the extent of their physical activity during the period in which the medicine is being discontinued.
Bronchoconstriction may occur in patients suffering from asthma, bronchitis and other chronic pulmonary diseases. Since bisoprolol is a highly selective beta1-adrenoceptor blocking agent, it may be used with caution in patients with chronic obstructive airway disease. However, in some asthmatic patients, an increase in airway resistance may occur. This bronchospasm can usually be reversed by commonly-used bronchodilators. Congestive cardiac failure and marked bradycardia may occur.
Bisoprolol may mask the symptoms of hyperthyroidism.
It should be used with caution in patients with hypoglycaemia. Special note: Digitalisation of patients receiving long-term beta-blocker therapy may be necessary if congestive cardiac failure is likely to develop. This combination can be considered despite the potentiation of negative chronotropic effect of the two medicines. Careful control of dosages and of the individual patient's response (and notably pulse rate) is essential in this situation.
Patients with phaeochromocytoma usually require treatment with an alpha-adrenergic blocker.
Adverse reactions are more common in patients with renal decompensation.
Alterations in the following serum biochemical values have been observed in patients receiving bisoprolol: Liver enzymes, lipoproteins, uric acid. Drug Interactions: It can be dangerous to administer bisoprolol concomitantly with the following medicines:
Hypoglycaemic agents, phenothiazines and various antiarrhythmic agents.
N.B. - Such medicine interactions can have life-threatening consequences. It may enhance the effects of hypoglycaemic agents in patients with diabetes mellitus as well as the effects of myocardial depressants such as lignocaine, procainamide and quinidine.
The effects may be antagonised by beta-adrenoceptor stimulating agents (e.g. isoprenaline). The hypotensive effects may be dangerously reversed by alpha-adrenoceptor stimulants. The vasoconstrictor effects may be dangerously enhanced by alpha-adrenoceptor stimulants. The effects may be enhanced by adrenergic neurone blocking agents such as guanethidine and reserpine.
The anaesthetist should be informed of bisoprolol therapy prior to any operation.
The half-life of bisoprolol can be slightly shortened by the simultaneous administration of rifampicin. An increase in the dose is generally unnecessary. The pharmacokinetics of bisoprolol are not significantly influenced by cimetidine.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Overdosage may produce bradycardia and severe hypotension. Bronchospasm and heart failure may be produced in certain individuals.
Bradycardia associated with severe hypotension should be treated with intravenous atropine (1 - 2 mg). If necessary this should be followed up by a slow intravenous infusion of 25 micrograms isoprenaline. Bronchospasm should be treated with intravenous aminophylline, and heart failure with digitalis and diuretics.
IDENTIFICATION: CONCOR* 5 tablets: Light yellow, heart-shaped biconvex film-coated tablets, scored on both sides.
CONCOR* 10 tablets: Light orange, heart-shaped biconvex film-coated tablets, scored on both sides.