- bisoprolol fumarate
POM: Prescription only medicine
This information is intended for use by health professionals
Titration PhaseThe treatment of stable chronic heart failure with bisoprolol requires a titration phase.The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps: - 1.25 mg once daily for 1 week, if well tolerated increase to - 2.5 mg once daily for a further week, if well tolerated increase to - 3.75 mg once daily for a further week, if well tolerated increase to - 5 mg once daily for the 4 following weeks, if well tolerated increase to - 7.5 mg once daily for the 4 following weeks, if well tolerated increase to - 10 mg once daily for the maintenance therapy.The maximum recommended dose is 10 mg once daily.Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating therapy.
Treatment ModificationIf the maximum recommended dose is not well tolerated, gradual dose reduction may be considered.In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation. The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again. If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patient's condition. Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.
Method of administrationBisoprolol Fumarate tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.
Renal or liver impairmentThere is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.
ElderlyNo dosage adjustment is required.
Paediatric PopulationThere is no experience with bisoprolol in children, therefore its use cannot be recommended for children.
WarningsThe treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2).Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transitional worsening of heart condition (see section 4.2).
PrecautionsThe initiation and cessation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. For the dosage and method of administration see section 4.2.There is no therapeutic experience of bisoprolol treatment in heart failure in patients with the following diseases and conditions: • insulin-dependent diabetes mellitus (type I) • severely impaired renal function • severely impaired liver function • restrictive cardiomyopathy • congenital heart disease • haemodynamically significant organic valvular disease • myocardial infarction within 3 months Bisoprolol must be used with caution in:- diabetes mellitus with large fluctuations in blood glucose values. Symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked,- strict fasting,- ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine treatment may not always yield the expected therapeutic effect,- First degree AV block,- Prinzmetal's angina,- peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy.Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits against risks.The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol.In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance of beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia, and decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.In bronchial asthma or other chronic obstructive pulmonary diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Combinations not recommendedClass-I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone):Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypoension and atrio-ventricular block.Centrally-acting antihypertensive drugs (e.g. clonidine methyldopa, moxonidine, rilmenidine):Concomitant use of centrally-acting antihypertensive drugs may further decrease the central sympathetic tonus and may thus lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase the risk of "rebound hypertension".
Combinations to be used with cautionCalcium antagonists of the dihydropyridine type (e.g. felodipine and amlodipine): Concomitant use may increase the risk of hypotension, and an increase in the risk of further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.Topical beta-blockers (e.g. eye-drops for glaucoma treatment) may add to the systemic effects of bisoprolol.Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia.Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on general anaesthesia see section 4.4).Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate. Non-steroidal anti-inflammatory drugs (NSAIDs):NSAIDs may reduce the hypotensive effect of bisoprolol.Beta-sympathomimetics (eg. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. norepinephrine, epinephrine): Combination with bisoprolol may unmask the alpha-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective beta-blockers.Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.
Combinations to be consideredMefloquine: increased risk of bradycardia.Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk of hypertensive crisis.Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of the hepatic drugmetabolising enzymes. Normally no dosage adjustment is necessary.Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.
PregnancyBisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment is considered necessary, monitoring of the uteroplacental blood flow and the foetal growth is recommended. In case of harmful effects on pregnancy or the foetus consideration of alternative treatment is recommended. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
BreastfeedingThere is no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol.
|Uncommon:||depression, sleep disorders|
|Nervous system disorders|
|Rare:||reduced tear flow (to be considered if the patient uses contact lenses)|
|Ear and labyrinth disorders|
|Common:||worsening of pre-existing heart failure|
|Common:||feeling of coldness or numbness in the extremities, hypotension|
|Respiratory, thoracic and mediastinal disorders|
|Uncommon:||bronchospasm in patients with bronchial asthma or a history of obstructive airway disease|
|Common:||gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation|
|Skin and subcutaneous tissue disorders|
|Rare:||hypersensitivity reactions such as itching, flush, rash|
|Very rare:||alopecia. Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.|
|Musculoskeletal and connective tissue disorders|
|Uncommon:||muscle weakness, muscle cramps|
|Reproductive system and breast disorders|
|Rare:||increased triglycerides, increased liver enzymes (ALAT, ASAT)|
Reporting of suspected adverse reactionsReporting 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
SymptomsThe most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.
ManagementIn general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may be considered when clinically warranted.Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagons may be useful.AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing.Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline. Hypoglycaemia:Administer i.v.-glucose.Limited data suggest that bisoprolol is hardly dialysable.