4.1. Therapeutic indications

Treatment of Hypertension

Treatment of stable chronic angina

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1).

4.2. Posology and method of administration

Bisoprolol tablet should be taken in morning and can be taken with food in morning. They should be swallowed in liquid and should not be chewed.

Posology

Treatment for hypertension and chronic stable angina pectoris

Adults:

The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10mg once daily, with a maximum recommended dose of 20mg per day.

Patients with renal impairment:

In patients with severe renal impairment (creatinine clearance <20ml/minute), the dose should not exceed 10mg once daily. This dosage may eventually be divided into halves.

Patients with severe liver impairment

No dosage adjustment is required, however careful monitoring is advised.

Discontinuation of treatment

The treatment should not be stopped suddenly (see section 4.4). The dose should be diminished slowly by weekly halving of the dose.

Treatment of Chronic heart failure

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocker, 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.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The 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 the therapy.

Treatment modification

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.

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 patients condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

Special population

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.

Elderly

No dosage adjustment is normally required.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

Method of administration

For oral use

4.3. Contraindications

Bisoprolol is contraindicated in chronic heart failure patients with:

• acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

• cardiogenic shock

• second or third degree AV block (without a pacemaker)

• sick sinus syndrome

• sinoatrial block

• symptomatic bradycardia

• symptomatic hypotension

• severe bronchial asthma or severe chronic obstructive pulmonary disease

• last stages of peripheral arterial occlusive disease and Raynaud's syndrome

• untreated phaeochromocytoma (see section 4.4)

• metabolic acidosis

• hypersensitivity to the active substance or to any of the excipients listed in section 6.1

4.4. Special warnings and precautions for use

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 ischemic heart disease the cessation of therapy with bisoprolol must not be done abruptly, unless clearly indicated, because this may lead to a transition worsening of heart condition (see section 4.2).

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 of treatment with bisoprolol necessitates regular monitoring. For posology and method of administration please (see 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 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)

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to 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. Beta-blockers could further increase the risk of severe hypoglycaemia when used concurrently with sulfonylureas. Diabetic patients should be advised to carefully monitor blood glucose levels (see Section 4.5).

• strict fasting

• Ongoing desensitization therapy

• As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always yield the expected therapeutic effect.

• first degree AV block

• Prinzmetal's angina

• peripheral arterial occlusive disease (intensification of complaints might happen especially during start of 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 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 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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

Combinations not recommended

Applies only to chronic heart failure:

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.

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 β-blocker treatment may lead to profound hypotension and atrioventricular block.

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

Applies only to hypertension or angina pectoris:

Class I antiarrhythmics (eg quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): The effect of atrioventricular conduction time can be enhanced and negative inotropic effect increased.

Applies to all indications

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. . The concomitant use of beta-blockers with sulfonylureas could increase the risk of severe hypoglycaemia (see Section 4.4).

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 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.

Rifampicin: Slight reduction of the half-life of bisoprolol due to the induction of hepatic drugmetabolising enzymes. Normally no dosage adjustment is necessary.

Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

4.6. Fertility, pregnancy and lactation

Fertility

No relevant data available.

Pregnancy

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/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 fetus and newborn infant. If treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Breast-feeding

It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7. Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8. Undesirable effects

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

not known (cannot be estimated from the available data)

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

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 patient with heart failure.

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 itching, flush, rash and angioedema).

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

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps.

Reproductive system and breast disorders:

Rare: potency disorders.

General disorders and administration site conditions:

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).

Applies only to hypertension or angina pectoris:

*These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1 - 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The 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 (maximum: 2000 mg) 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.

In 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 should 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 glucagon 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.