Concor

/ Merck

Chronic Heart Failure:
Patients should be stable (without acute failure) when bisoprolol treatment is initiated.
Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.
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.
If 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.
Doses of 5 mg & 10 mg only- Hypertension and Coronary heart disease (angina pectoris):
Treatment should principally be initiated gradually with low doses, which are then increased slowly. In all cases the dosage should be adjusted individually, in particular according to the pulse rate and therapeutic success.
Hypertension: The recommended dosage is 5 mg once daily. In milder forms of hypertension (diastolic blood pressure up to 105 mmHg) therapy with 2.5 mg once daily may be adequate. If necessary, the dosage may be increased to 10 mg once daily. Any further increase of dosage is justified only in exceptional cases. The maximum recommended dosage is 20 mg once daily.
Coronary heart disease (angina pectoris): The recommended dosage is 5 mg bisoprolol fumarate once daily. If necessary, the dosage may be increased to 10 mg once daily. Any further increase of dosage is justified only in exceptional cases. The maximum recommended dosage is 20 mg once daily. The duration of treatment is not limited. It depends upon the nature and severity of the disease. 
Patients with hepatic or renal impairment: There 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.
For hypertension and coronary heart disease (angina pectoris) indications, no dosage adjustment is normally required in patients with liver or kidney function disorders of mild to moderate severity. In patients with severe kidney function disorders (creatinine clearance < 20 ml/min) and in patients with severely impaired liver function a daily dose of 10 mg bisoprolol fumarate should not be exceeded. There is only limited experience with the use of bisoprolol in dialysis patients. There are no indications of the necessity to alter the dose regimen. 
Older people: No dose adjustment is required.
Paediatric population: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.
For full details see prescribing information.

Treatment of stable chronic, moderate to severe heart failure with impaired systolic ventricular function (ejection fraction < 35 %, determined by echocardiography) in addition to ACE inhibitors and diuretics, and optionally cardiac glycosides.
For doses of 5 mg & 10 mg: hypertension, coronary heart disease (angina pectoris).

– acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy
– cardiogenic shock
– second or third degree AV block
– sick sinus syndrome
– sinoatrial block
– symptomatic bradycardia
– symptomatic hypotension
– severe bronchial asthma
– severe forms of peripheral arterial occlusive disease or severe forms of Raynaud’s syndrome
– untreated phaeochromocytoma (see prescribing information for full details)
– metabolic acidosis
– hypersensitivity to bisoprolol or to any of the excipients.
See prescribing information for full details.

• The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase.
• 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.
• The initiation and cessation of treatment with bisoprolol necessitates regular monitoring.
• 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 hepatic function, restrictive cardiomyopathy, congenital heart disease, haemodynamically significant organic valvular disease, and myocardial infarction within 3 months.
• Bisoprolol must be used with caution in:
  – bronchospasm (bronchial asthma, obstructive airways diseases)
  – diabetes mellitus with large fluctuations in blood glucose values; Symptoms of hypoglycaemia 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 does not always yield the expected therapeutic effect.
  – first degree AV block
  – Prinzmetal’s angina; Cases of coronary vasospasm have been observed. Despite its high beta1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with 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 ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs, 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-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.
• Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not recommended, see prescribing information for full details.
• Although cardioselective (beta1) 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 obstructive airways diseases, unless there are compelling clinical reasons for their use. Where such reasons exist, the drug may be used with caution. In patients with obstructive airways diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully monitored for new symptoms (e.g. dyspnea, exercise intolerance, cough). 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.
• Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (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 thyreotoxicosis may be masked.

Very common: bradycardia.
Common: worsening of heart failure, dizziness, headache, gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation, feeling of coldness or numbness in the extremities, hypotension, asthenia, fatigue.
See prescribing information for full details.

Combinations not recommended:
– Calcium 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.
– Class 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.
– Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive drugs 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-blocker discontinuation, may increase risk of “rebound hypertension”.
Combinations to be used with caution:
– Calcium 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 drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.
– Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.
– Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.
– 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.
– 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-Sympathomimetics 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.
– Antihypertensive agents as well as with other drugs with blood
pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines): Concomitant use may increase the risk of hypotension.
Combinations to be considered:
– Mefloquine: increased risk of bradycardia
– Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for hypertensive crisis.
See prescribing information for full details.

Pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/new-born infant.
In general, beta-blockers reduce placental perfusion which has been associated with intrauterine growth retardation, intra-uterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and the new-born infant. If treatment with a beta-blocker is necessary, beta1-selective beta-blockers are preferable. Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, utero-placental blood flow and foetal growth must be monitored. In the case of harmful effects on pregnancy or the foetus, alternative therapeutic measures should be considered. The new-born infant must be monitored closely. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days of life.
Breast-feeding: It is not known whether bisoprolol is excreted in human breast milk. Therefore, breastfeeding is not recommended during bisoprolol therapy.

Symptoms of intoxication :The most common signs of overdose with a beta-blocker are bradycardia, hypotension, bronchospasm, acute heart failure and hypoglycaemia. To date a few cases of overdose (maximum 2,000 mg) with bisoprolol have been reported in patients with hypertension and/or coronary heart disease. These patients exhibited bradycardia and hypotension. All patients recovered.
The sensitivity to high single doses of bisoprolol varies greatly between individuals. It is to be considered that patients with heart failure are probably very sensitive.
Therapy of intoxication: In general, if overdose occurs, biosoprolol treatment should be stopped and supportive and symptomatic treatment should be initiated. Limited data suggest that bisoprolol is hardly dialysable. Based on the expected pharmacological actions and recommendations for other beta-blockers, the following general measures should be carried out if clinically required. Bradycardia: Intravenous administration of atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under certain circumstances, transvenous pacemaker insertion may become necessary. Hypotension: Intravenous administration of fluids and vasopressors. Intravenous glucagon may also be useful. AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or transvenous cardiac pacemaker insertion. Acute worsening of heart failure: Intravenous administration of diuretics, inotropic agents, as well as vasodilators.
Bronchospasm: Administration of bronchodilators such as isoprenaline, beta2sympathomimetics and/or aminophylline. Hypoglycaemia: Intravenous administration of glucose.

Effects on ability to drive and use machines:
This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.