Bisop 10 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BISOPROLOL FUMARATE
Available from:
Rowex Ltd
ATC code:
C07AB; C07AB07
INN (International Name):
BISOPROLOL FUMARATE
Dosage:
10 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Beta blocking agents, selective; bisoprolol
Authorization status:
Marketed
Authorization number:
PA0711/159/006
Authorization date:
2008-12-08

Package leaflet: Information for the patient

Bisop 5 mg film-coated tablets

Bisop 10 mg film-coated tablets

bisoprolol fumarate

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Bisop is and what it is used for

What you need to know before you take Bisop

How to take Bisop

Possible side effects

How to store Bisop

Contents of the pack and other information

1.

What Bisop is and what it is used for

Bisop belongs to the group of medicinal products that are indicated as beta blockers. They protect the

heart from too much activity.

Bisop is used to treat:

high blood pressure

angina pectoris (heart pain)

heart failure causing breathlessness on exertion or fluid retention. In this instance, Bisop may be

given as an additional treatment to other medications for heart failure.

2.

What you need to know before you take Bisop

Do not take Bisop

if you are allergic to bisoprolol fumarate or any of the other ingredients of this medicine (listed in

section 6)

if you have a cardiogenic shock, a serious heart condition causing a rapid, weak pulse; low blood

pressure; cold, clammy skin; weakness and fainting

if you have ever suffered from severe wheezing or severe asthma, as they can affect your

breathing

if you have a slow heart rate (less than 60 beats per minute). Ask your doctor if you are not sure.

if you have very low blood pressure

if you have severe blood circulation problems (which may cause your fingers and toes to tingle or

turn pale or blue)

if you have certain serious heart rhythm problems

if you have heart failure which has just occurred or is not stabilised and is requiring hospital

treatment

if you have a condition in which there is an accumulation of excessive acid in the body known as

metabolic acidosis. Your doctor will be able to advise you.

if you suffer from a tumour of the adrenal glands known as phaeochromocytoma which is

untreated.

Tell your doctor if you are not sure about any of the above.

Warnings and precautions

Talk to your doctor before taking Bisop

if you suffer from wheezing or difficulty breathing (asthma). Bronchodilating therapy should be

given concomitantly. A higher dose of beta

-stimulants may be needed.

if you have diabetes. The tablets can hide the symptoms of low blood sugar (such as accelerated

heartbeat rate, palpitations or sweating).

if you are fasting from solid food

if you are treated for hypersensitivity (allergic) reactions. Bisop may increase the hypersensitivity

to the substances you are allergic to and increase the severity of the hypersensitivity reactions.

Treatment with adrenalin then may not have the desired result. A higher dose of adrenalin

(epinephrine) may be needed.

with 1st degree heart block (conduction disorder in the heart)

if you suffer from Prinzmetal’s angina which is a type of chest pain caused by spasm of the

coronary arteries that supply the heart muscle

if you have any problems with the circulation to the extremities of the body such as hands and feet

in case of surgery involving an anaesthetic: If you consult a doctor, attend hospital or the dentist

for surgery involving anaesthetics, let them know what medicines you are taking.

in combination with calcium antagonists, such as verapamil and diltiazem. Concomitant use is not

recommended, see also section “Other medicines and Bisop”.

if you suffer (or have suffered) from psoriasis (a recurrent skin disorder involving scaling and dry

skin rash)

if you suffer from phaeochromocytoma (tumour of the adrenal marrow). Your doctor will need to

treat this before prescribing Bisop for you.

if you have a thyroid problem. The tablets can hide symptoms of an overactive thyroid.

There is so far no therapeutic experience of Bisop treatment of heart failure in patients with the

following diseases and conditions:

diabetes mellitus treated with insulin (type I)

severe kidney disease

severe liver disease

certain heart diseases

heart attack within 3 months.

Treatment of heart failure with Bisop requires regular medical monitoring. This is absolutely

necessary, particularly at the beginning of treatment, and upon stopping treatment.

Treatment with Bisop must not be discontinued abruptly unless for compelling reasons.

For patients with hypertension and angina pectoris and accompanying heart failure treatment should

not be stopped abruptly. The dosage should be diminished slowly by a weekly halving of the dose.

Consult your physician if one of the above warnings is applicable to you, or has been in the past.

Other medicines and Bisop

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines. This includes medicines obtained without a prescription. Certain medicines cannot be used

at the same time, while other drugs require specific changes (in the dose, for example).

Always tell your doctor if you are using or receiving any of the following medicines in addition to

Bisop:

medicines for controlling the blood pressure or medicines for heart problems (such as amiodarone,

amlodipine, clonidine, digitalis glycosides, diltiazem, disopyramide, felodipine, flecainide,

lidocaine, methyldopa, moxonidine, phenytoin, propafenone, quinidine, rilmenidine, verapamil)

sedatives and therapies for psychosis (a mental illness) e.g. barbiturates (also used for epilepsy),

phenothiazines (also used for vomiting and nausea)

medicines for depression e.g. tricyclic antidepressants, MAO-A inhibitors

medicines used for anaesthesia during an operation (see also section “Warnings and precautions”)

certain pain killers (for instance acetyl salicylic acid, diclofenac, indomethacin, ibuprofen,

naproxen)

medicines for asthma, blocked nose, or certain eye disorders such as glaucoma (increased pressure

in the eye) or dilation (widening) of the pupil

certain medicines to treat shock (e.g. adrenaline, dobutamine, noradrenaline)

mefloquine, a medicine for malaria

the antibiotic rifampicin

ergotamine derivatives for migraine.

All these drugs as well as Bisop may influence the blood pressure and/or heart function.

insulin or other products for diabetes. The blood glucose reducing effect may be enhanced.

Symptoms of low blood glucose level can be masked.

Bisop with alcohol

The dizziness and light-headedness that may be caused by Bisop can be made worse if you drink

alcohol. If this happens to you, you should avoid drinking alcohol.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask

your doctor for advice before taking this medicine. Bisop may be harmful to the pregnancy and/or the

unborn child. There is an increased possibility of premature birth, miscarriage, low blood sugar level

and reduced heart rate of the child. The growth of the baby may also be affected. Therefore, bisoprolol

should not be taken during pregnancy.

It is not known if bisoprolol is excreted in the breast milk and therefore it is not recommended while

breast-feeding.

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed.

These tablets may make you feel tired, drowsy or dizzy. If you suffer from these side effects, do not

operate vehicles and/or machines. Be aware of the possibility of these effects, particularly at the

beginning of the treatment, with changes in medication and with use in combination with alcohol.

Bisop contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicine.

This medicine contains less than 1 mmol (23 mg) sodium per film-coated tablet, that is to say

essentially sodium free.

3.

How to take Bisop

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Your doctor will tell you how many tablets to take. You should take this medicine in the morning,

before, with or after breakfast. Swallow the tablet(s) with some water and do not chew or crush them.

Elevated blood pressure/ angina pectoris

Adults

The dose is determined individually.

The recommended starting dose is 5 mg once daily.

The usual dose for adults is once daily 10 mg. Your doctor may decide to increase or decrease the

dose.

The maximum dose is once daily 20 mg.

Severe kidney or severe liver function disorders

If you suffer from a

severe kidney or severe liver function disorder

the maximum dose is 10 mg per

day.

Elderly

Normally no dosage adjustment is required. Your doctor will start therapy with the lowest possible

dose.

Heart failure (reduced pumping strength of the heart)

Before you start using Bisop, you are already using an ACE-inhibitor, diuretic or heart glycoside

(heart/ blood pressure product).

The dose will be increased gradually until the dose that is suitable for you has been found:

1.25 mg once daily for 1 week. If this is well tolerated, the dose may be increased to:

2.5 mg once daily during the next week. If this is well tolerated, the dose may be increased to:

3.75 mg once daily during the next week. If this is well tolerated, the dose may be increased to:

5 mg once daily during the next 4 weeks. If this is well tolerated, the dose may be increased to:

7.5 mg once daily during the next 4 weeks. If this is well tolerated, the dose may be increased to:

10 mg once daily as a maintenance dose.

Maximum dose is once daily 10 mg.

The doctor will determine the optimum dose for you amongst others based on possible side effects.

After the very first dose of 1.25 mg the doctor will check your blood pressure, heart rate, heart

function disorders.

Liver or kidney function disorders

The doctor will be extra careful with the increasing of the dose.

Elderly

Normally an adjustment of the dose is not needed.

If you notice that the effect of Bisop is too strong or not strong enough, please consult your doctor or

pharmacist.

Place the tablet on a hard, flat surface with the scored side at the top.

Press with the thumb on the middle of the tablet and the tablet will break into two

halves, press with the thumb in the middle of each half and you will have four parts.

Duration of the treatment

Bisop will usually be used long-term.

Use in children and adolescents

There is no experience with Bisop in children and adolescents, therefore its use is not recommended in

children.

If you take more Bisop than you should

If you have accidentally taken more than the prescribed dose, tell your

doctor/pharmacist

immediately.

Take any remaining tablets or this leaflet with you so the medical staff know exactly

what you have taken. Symptoms of overdose may include dizziness, light-headedness, fatigue,

breathlessness and/or wheezing.

Also, there may be reduced heart rate, reduced blood pressure,

insufficient action of the heart and a low blood glucose level (which may involve feelings of hunger,

sweating and palpitations).

If you forget to take Bisop

Do not take a double dose to

make up for a forgotten dose.

Take the normal dose as soon as you

remember and then carry on with the usual dose the next day.

If you stop taking Bisop

Treatment with Bisop must not be stopped abruptly. If you suddenly stop taking this medicine your

condition may get worse. Instead, it must be reduced gradually over a few weeks as advised by your

doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects that could occur are:

Very common, effects more than 1 per 10 users:

slow heartbeat. In the treatment of hypertension or angina pectoris this side effect occurs

uncommonly.

Common, effects 1 to 10 per 100 users:

exhaustion. In the treatment of hypertension or angina pectoris this side effect occurs

uncommonly.

dizziness, tiredness and headache (especially at the beginning of therapy in patients with

hypertension and angina pectoris; symptoms are generally mild and often disappear within 1–2

weeks)

feeling of coldness or numbness in the extremities (fingers or toes, ears and nose); more frequent

occurrence of a cramp-like pain in the legs when walking

worsening of pre-existing heart failure. In the treatment of hypertension or angina pectoris this

side effect occurs uncommonly.

very low blood pressure (hypotension), particularly in patients with heart failure

feeling sick (nausea), being sick (vomiting)

diarrhoea

constipation.

Uncommon, effects 1 to 10 per 1,000 users:

exhaustion. In the treatment of heart failure this side effect occurs commonly

fall in blood pressure on standing up which may cause dizziness, light-headedness or fainting

sleep disturbances

depression

slow heartbeat. In the treatment of heart failure this side effect occurs very commonly.

irregular heartbeat

worsening of pre-existing heart failure. In the treatment of heart failure this side effect occurs

commonly

patients with asthma or a history of breathing problems may experience difficulty in breathing

muscular weakness and muscle cramps.

Rare, effects 1 to 10 per 10,000 users:

nightmares

hallucinations (imagining things)

syncope

hearing impairment

inflammation of the lining of the nose, causing a runny nose with irritation

allergic reactions (such as itching, flushed appearance, rash)

dry eyes from reduced tear flow (which can be very troublesome if you use contact lenses)

inflammation of the liver (hepatitis), causing abdominal pain, loss of appetite and sometimes

jaundice with yellowing of the whites of the eyes and skin, and dark urine

reduced sexual performance (potency disorder)

increased levels of blood lipids (triglycerides) and liver enzymes.

Very rare, effects less than 1 per 10,000 users:

chest pain

aggravation of the skin condition psoriasis or cause a similar dry, scaly rash and hair loss

itchiness or redness of the eye (conjunctivitis).

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance;

website: www.hpra.ie. By reporting side effects you can help provide more information on the safety

of this medicine.

5.

How to store Bisop

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after “EXP”. The

expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or houshold waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Bisop contains

- The active substance is bisoprolol fumarate. Each film-coated tablet conatins 5 mg of bisoprolol

fumarate.

Each film-coated tablet conatins 10 mg of bisoprolol fumarate.

- The other ingredients are anhydrous calcium hydrogen phosphate, microcrystalline cellulose,

pregelatinised maize starch, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate,

lactose monohydrate, hypromellose, macrogol 4000, titanium dioxide (E171), yellow iron oxide

(E172).

- The other ingredients are: The other ingredients are anhydrous calcium hydrogen phosphate,

microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, colloidal anhydrous

silica, magnesium stearate, lactose monohydrate, hypromellose, macrogol 4000, titanium dioxide

(E171), yellow iron oxide (E172), red iron oxide (E172).

What Bisop looks like and contents of the pack

5 mg film-coated tablets:

Yellow coloured, round, scored film-coated tablets with a one-sided embossment “BIS 5”.

The tablet can be divided into four equal doses.

10 mg film-coated tablets:

Apricot coloured, round, scored film-coated tablet with a one-sided embossment “BIS 10”.

The tablet can be divided into four equal doses.

The film-coated tablets are packed in OPA/Alu/PVC/Alu blisters and inserted in a carton.

Pack sizes:

7, 10, 14, 20, 28, 30, 50, 56, 60, 100, 10x30 film-coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

Salutas Pharma GmbH

Otto-von-Guericke-Allee 1, 39179 Barleben

Germany

Rowa Pharmaceuticals Ltd

Newtown, Bantry, Co. Cork

Ireland

Lek Pharmaceuticals d.d

Verovskova 57, 1526 Ljubljana

Slovenia

Lek S.A

Ul. Domaniewska 50 C, 02-672 Warszawa

Poland

Lek S.A.

Ul. Podlipie 16 C, 95 010 Strykow

Poland

This medicinal product is authorised in the Member States of the EEA under the following

names

Ireland:

Bisop 5 mg film-coated tablets

Bisop 10 mg film-coated tablets

Italy:

BISOPROLOLO ALMUS

BISOPROLOLO ALMUS

The Netherlands:

BISOPROLOLFUMARAAT 1 A PHARMA 5 MG, FILMOMHULDE

TABLETTEN

BISOPROLOLFUMARAAT 1 A PHARMA 10 MG, FILMOMHULDE

TABLETTEN

This leaflet was last revised in 05/2020.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bisop 10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg of bisoprolol fumarate.

Excipients with known effect

Each film-coated tablet contains 2.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Apricot coloured, round, scored film-coated tablet with a one-sided embossment "BIS 10".

The tablet can be divided into four equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypertension

Angina pectoris

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

Posology

Hypertension/Angina pectoris

Adults

The 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.

Elderly

It is recommended to start with the lowest possible dose.

Renal or liver impairment

In 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.

Experience with the use of bisoprolol in renal dialysis patients is limited. However, there is no evidence that the dosage regime

needs to be altered.

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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 failure

Standard 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 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.

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 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.

Duration of treatment

Treatment 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 impairment

There 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.

All indications

Elderly

No dosage adjustment is required.

Paediatric population

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

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Method of administration

For oral administration.

Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and

should not be chewed.

4.3 Contraindications

Bisoprolol is contraindicated in:

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

· cardiogenic shock

· AV block of second or third degree

· sick sinus syndrome

· sinoatrial block

· symptomatic bradycardia

· symptomatic hypotension

· severe bronchial asthma or severe chronic obstructive pulmonary disease

· severe forms of peripheral arterial occlusive disease or severe forms of 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 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).

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 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).

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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 beta

-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.

Bisop contains lactose and sodium

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

should not take this medicinal product.

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

4.5 Interaction with other medicinal products and other forms of interactions

Combinations not recommended

Chronic heart failure only

Class 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 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 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

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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 only

Class 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 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 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 considered

Mefloquine: increased risk of bradycardia

Monoamine 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Bisoprolol 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

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newborn infant. If treatment with beta-adrenoceptor blocking agents is necessary, beta

-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.

Breastfeeding

There are no data on the excretionof bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore,

breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. In a study with coronary heart disease

patients bisoprolol did not impair driving performance. Depending on the individual patient’s response the ability to drive a

vehicle or to use machines may be impaired. This needs to be considered particularly at start of treatment, upon change of

medication, or 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 rare: chest pain

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

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Hepatobiliary disorders

Rare: hepatitis

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions such as itching, flush, rash

Very rare: beta-blocking agents may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia

Musculoskeletal and connective tissue disorders

Uncommon: muscular weakness, muscle cramps

Reproductive system and breast disorders

Rare: potency disorders

General disorders

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

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

Investigations

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

* 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 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

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 overdose of a beta-blocking agent 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 inter-individual 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.

In general, 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-blocking agents, the following general measures should be considered when clinically

warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenalineor 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, beta

-sympathomimetic medicinal products and/or

aminophylline.

Hypoglycaemia: Administer i.v. glucose.

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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective. ATC Code: C07AB07

Mechanism of action

Bisoprolol is a highly beta

-selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane

stabilising activity. It only shows low affinity to the beta

-receptor of the smooth muscles of bronchi and vessels as well as to

the beta

-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the

airway resistance and beta

-mediated metabolic effects. Its beta

-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.

5.2 Pharmacokinetic properties

Absorption and distribution

Bisoprolol 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.

Biotransformation and elimination

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.

Bisoprolol 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-linearity

The kinetics of bisoprolol are linear and independent of age.

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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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose

toxicity, genotoxicity or carcinogenicity. Like other beta-blocking agents, bisoprolol caused maternal (decreased food intake

and decreased body weight) and embryo/foetal toxicity (increased incidence of resorptions, reduced birth weight of the

offspring, retarded physical development) at high doses, but was not teratogenic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

calcium hydrogen phosphate, anhydrous

cellulose, microcrystalline

maize starch, pregelatinised

croscarmellose sodium

silica, colloidal anhydrous

magnesium stearate

lactose monohydrate

hypromellose

macrogol 4000

titanium dioxide (E171)

iron oxide, yellow (E172)

iron oxide, red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

60 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The film-coated tablets are packed in OPA/Alu/PVC/Alu blisters and inserted in a carton.

Pack sizes:

7, 10, 14, 20, 28, 30, 50, 56, 60, 100, 10x30 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The film-coated tablet can be divided by placing it on a solid surface with the score pointing upward. The film-coated tablet is

divided by exerting a slight pressure with the thumb.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

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7 MARKETING AUTHORISATION HOLDER

Rowex Ltd

Newtown

Bantry

Co. Cork

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0711/159/006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 8

December 2008

Date of last renewal: 30

May 2011

10 DATE OF REVISION OF THE TEXT

November 2019

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