- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsThe dosage should be individually adjusted, in particular according to the pulse rate and therapeutic success. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg once daily.
ElderlyIt is recommended to start with the lowest possible dose.
Renal or liver impairmentIn patients with liver or kidney function disorders of mild to moderate severity, no dosage adjustment is normally required. In patients with severe renal impairment (creatinine clearance < 20 ml/min) and in patients with severe liver function disorders it is recommended that a daily dose of 10 mg is not exceeded.
Discontinuation of treatment:Treatment must not be stopped abruptly (see section 4.4). The dosage should be diminished slowly by a weekly halving of the dose.
Stable chronic heart failureStandard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking agent, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is initiated.It is recommended that the treating physician should be experienced in the management of chronic heart failure.
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.Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.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 the 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.
Duration of treatmentTreatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.The treatment with bisoprolol must not be stopped abruptly since this might lead to a transitory worsening of condition. Especially in patients with ischaemic heart disease, treatment must not be discontinued suddenly. Gradual reduction of the daily dose is recommended.
Renal or liver impairmentThere is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver 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.
Method of administrationFor oral administrationBisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.
Applies only to chronic heart failure:The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2).
Applies to all indications: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).
Applies only to hypertension or angina pectoris:Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.
Applies only to chronic heart failure:The initiation and cessation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. For the posology and method of administration please refer to section 4.2.There is no therapeutic experience of bisoprolol treatment of 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
Applies to all indications:There is a risk of myocardial infarction and sudden death if the treatment is suddenly discontinued in patients with coronary heart disease (see section 4.2).Bisoprolol must be used with caution in:• bronchospasm (bronchial asthma, obstructive airways diseases). In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.• 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.• AV block of first degree• Prinzmetal's angina• peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy.• General anaesthesia. In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance of beta-blockade should be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other medicinal products, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocking agent therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.Patients with psoriasis or with a history of psoriasis should only be given beta-blocking agents (e.g. bisoprolol) after carefully balancing the benefits against the risks.In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.Under treatment with bisoprolol the symptoms of a thyrotoxicosis may be masked.
LactoseThis medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Chronic heart failure onlyClass I antiarrhythmic medicinal products (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
All indicationsCalcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to profound hypotension and atrioventricular block. Centrally-acting antihypertensive medicinal products such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive medicinal products may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocking agent discontinuation, may increase the risk of rebound hypertension.
Combinations to be used with caution
Hypertension/Angina pectoris onlyClass I antiarrhythmic medicinal products (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.
All indicationsCalcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.Class-III antiarrhythmic medicinal product (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.Topical beta-blocking agents (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.Parasympathomimetic medicinal products: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.Insulin and oral antidiabetic medicinal products: Increase of blood sugar lowering effect. Blockade of beta-adrenoceptors 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 also section 4.4.).Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.β-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the α-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 β-blockers. Concomitant use with antihypertensive agents as well as with other medicinal products with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.
Combinations to be consideredMefloquine: increased risk of bradycardiaMonoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blocking agents, but also risk for hypertensive crisis.Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of hepatic drug-metabolising 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 blocking agents 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 blocking agents is necessary, beta1-selective adrenoceptor blocking agents are preferable.Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol 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 breat milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol.
Very rare: chest painVery common: bradycardia (in patients with chronic heart failure)Common: worsening of pre-exsisting heart failure (in patients with chronic heart failure) Uncommon: AV-conduction disturbances Worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris)
InvestigationsRare: increased triglycerides, increased liver enzymes (ALAT, ASAT)
Nervous system disordersCommon: dizziness, headacheRare: syncope
Eye disordersRare: reduced tear flow (to be considered if the patient uses lenses)Very rare: conjunctivitis
Ear and labyrinth disordersRare: hearing disorders
Respiratory, thoracic and mediastinal disordersUncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways diseaseRare: allergic rhinitis
Gastrointestinal disordersCommon: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation
Skin and subcutaneous tissue disordersRare: hypersensitivity reactions such as itching, flush, rashVery rare: beta-blocking agents may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia
Musculoskeletal and connective tissue disordersUncommon: muscular weakness, muscle cramps
Vascular disordersCommon: feeling of coldness or numbness in the extremities, hypotension (especially in patients with heart failure)Uncommon: orthostatic hypotension
General disordersCommon: fatigue*, asthenia (patients with chronic heart failure)Uncommon: asthenia (patients with hypertension or angina pectoris)
Hepatobiliary disordersRare: hepatitis
Reproductive system and breast disordersRare: potency disorders
Psychiatric disordersUncommon: sleep disorders, depressionRare: nightmares, hallucinations* These symptoms especially occur at the beginning of the therapy in patients with hypertension or angina pectoris. They are generally mild and usually disappear within 12 weeks.
Mechanism of actionBisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.Bisoprolol is used for the treatment of hypertension, angina pectoris and heart failure. As with other beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that bisoprolol reduces plasma renin activity markedly.Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.The indication heart failure was investigated in the CIBIS II trial. In total 2647 patients were included, 83% (N = 2202) were in NYHA class III and 17% (N = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction <35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.The CIBIS III trial investigated 1010 patients aged ≥65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had not been treated previously with ACE inhibitors, beta-blocking agents, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril.There was a trend toward a higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.
Absorption and distributionBisoprolol is absorbed and has a biological availability of about 90% after oral administration. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. Total clearance is approximately 15 l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.
Biotransformation and eliminationBisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or renal function have not been studied.
Linearity/non-linearityThe kinetics of bisoprolol are linear and independent of age.In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64+21 ng/ml at a daily dose of 10 mg and the half-life is 17+5 hours.
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