BISOPROLOL Film-coated tablet Ref.[6547] Active ingredients: Bisoprolol

Special warnings

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).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

5 mg, 7.5 mg and 10 mg tablets only: Contains sunset yellow (E110) that may cause allergic reactions.

Precautions

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 with bisoprolol necessitates regular monitoring. For the posology and method of administration please (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 hepatic function
• restrictive cardiomyopathy
• congenital heart disease
• haemodynamically significant organic valvular disease
• myocardial infarction within 3 months

Applies to all indications

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 (e.g. tachycardia, palpitations, 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 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.

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 anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of 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.

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, for details please refer to section 4.5.

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, bisoprolol 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. dyspnoea, exercise intolerance, cough). 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.

Combinations not recommended

Applies only to chronic heart failure:

• Class-I antiarrhythmic drugs (e.g. disopyramide, quinidine, lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications:

• 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 beta-blocker treatment may lead to profound hypotension and atrioventricular 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 a reduction of heart rate and cardiac output, and to vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

Applies only to hypertension or angina pectoris:

• Class-I antiarrhythmic drugs (e.g. disopyramide, quinidine, lidocaine, phenytoin; flecainide, propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Applies to all indications:

• Calcium antagonists of the dihydropyridine type (e.g. nifedipine, amlodipine, felodipine): 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 (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.
• Beta-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.
• Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. noradrenaline, adrenaline): 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.
• Sympathomimetic agents: Combination with bisoprolol may reduce the effect of both agents. Higher doses of epinephrine may be necessary for treatment of allergic reactions.
• 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 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.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-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 fetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary, β₁-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 fetal growth is recommended. In case of harmful effects on pregnancy or the fetus 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.

Breast-feeding

There are 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.

In a study of coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patient’s response to treatment, the ability to drive a vehicle or to use machines may be impaired. This should be considered particularly at the start of treatment and upon change of medication or in conjunction with alcohol.

The following definitions apply to the frequency terminology used hereafter: Very common (≥1/10), Common (≥1/100, <1/10), Uncommon (≥1/1,000, <1/100), Rare (≥1/10,000, <1/1,000), Very rare (<1/10,000).

Psychiatric disorders

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucination.

Nervous system disorders

Common: dizziness*, headache*.

Rare: syncope.

Eye disorders

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders

Rare: hearing disorders.

Cardiac disorders

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing 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).

Vascular disorders

Common: feeling of coldness or numbness in the extremities, hypotension especially in patients with heart failure.

Uncommon: orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.

Rare: allergic rhinitis.

Gastrointestinal disorders

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

Hepatobiliary disorders

Rare: hepatitis.

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions such as pruritus, flush, rash and angioedema.

Very rare: alopecia, beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.

Musculoskeletal and connective tissue disorders

Uncommon: muscular weakness, muscle cramps.

Reproductive system and breast disorders

Rare: erectile dysfunction

General disorders

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with hypertension or angina pectoris).

Investigations

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Paediatric population

No data are available.

applies only to hypertension or angina pectoris:

* These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1 to 2 weeks.

Reporting of suspected adverse reactions

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.

Not applicable.