4.1. Therapeutic indications

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

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.

Posology

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 (1.25ml) once daily for 1 week, if well tolerated increase to

• 2.5 mg (2.5ml) once daily for a further week, if well tolerated increase to

• 3.75 mg (3.75ml) once daily for a further week, if well tolerated increase to

• 5 mg (5ml) once daily for the 4 following weeks, if well tolerated increase to

• 7.5 mg (7.5ml) once daily for the 4 following weeks, if well tolerated increase to

• 10 (10ml) mg once daily for the maintenance therapy. The maximum recommended dose is 10 mg (10ml) 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 patient's condition.

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

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.

Older people

No dosage adjustment is required.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.

Method of administration

Bisoprolol fumarate oral solution is for oral use only.

Bisoprolol fumarate oral solution should be taken in the morning and can be taken with food.

Instructions for use

• Open the bottle: press the cap and turn it anticlockwise (figure 1)

• Separate the adaptor from the syringe (figure 2). Insert the adaptor into the bottle neck (figure 3). Ensure it is well fixed.

• Take the syringe and put it in the adaptor opening (figure 4). Turn the bottle upside down (figure 5).

• Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then push the piston upward in order to remove any possible bubble (figure 5B). Pull the piston down to the graduation mark corresponding to the quantity in milliliters (ml) prescribed by your doctor (figure 5C).

• Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B).

• Close the bottle with the plastic screw cap.

• Empty the contents of the syringe into your mouth.

• After dosing, wash the syringe with water only (figure 7).

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

• 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 section 4.4)

• metabolic acidosis

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

4.4. Special warnings and precautions for use

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

• 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, 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 fumarate 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.

Excipients warnings

Bisoprolol fumarate oral solution contains

Methyl parahydroxybenzoate (E218) and Ethyl parahydroxybenzoate (E214): May cause allergic reactions (possibly delayed).

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium-free'.

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

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 (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.

4.6. Fertility, pregnancy and lactation

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:

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)

Frequency not known (cannot be estimated from available data).

Cardiac disorders:

Very common:

bradycardia.

Common:

worsening of heart failure.

Uncommon:

AV-conduction disturbances.

Investigations:

Rare:

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

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

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.

Skin and subcutaneous tissue disorders:

Rare:

hypersensitivity reactions (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 and cramps.

Vascular disorders:

Common:

feeling of coldness or numbness in the extremities, hypotension.

Uncommon:

orthostatic hypotension.

General disorders:

Common:

asthenia, fatigue.

Hepatobiliary disorders:

Rare:

hepatitis.

Reproductive system and breast disorders:

Rare:

erectile dysfunction.

Psychiatric disorders:

Uncommon:

sleep disorder, depression.

Rare:

nightmare, hallucination.

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:

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

Symptoms

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia, and dizziness have been reported. In general the most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with bisoprolol have been reported in patients suffering from hypertension and/or coronary heart disease showing bradycardia and/or hypotension; all patients recovered. There is a wide interindividual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive. Therefore, it is mandatory to initiate the treatment of these patients with a gradual uptitration according to the scheme given in section 4.2.

Management

If overdose occurs, bisoprolol treatment should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol is hardly dialysable. 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 transvenous cardiac pacemaker insertion.

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