CARDICOR 5 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BISOPROLOL HEMIFUMARATE
Available from:
Merck Serono Limited
ATC code:
C07AB07
INN (International Name):
BISOPROLOL HEMIFUMARATE
Dosage:
5 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Beta blocking agents, selective
Authorization status:
Transfer Pending
Authorization number:
PA0654/007/004
Authorization date:
2000-03-20

Placeholder

MC-2314-2016/TW1205731

Do not take Cardicor if you have one of the

following heart problems:

acute heart failure

worsening

heart

failure

requiring

injection of medicines into a vein, that

increase the force of contraction of the

heart

slow heart rate

low blood pressure

certain heart conditions causing a very

slow heart rate or irregular heartbeat

cardiogenic shock, which is an acute

serious heart condition causing low

blood pressure and circulatory failure.

Warnings and precautions

If you have any of the following conditions

tell your doctor before taking Cardicor;

he or she may want to take special care

(for example give additional treatment or

perform more frequent checks):

diabetes

strict fasting

certain

heart

diseases

such

disturbances in heart rhythm, or severe

chest pain at rest (Prinzmetal’s angina)

kidney or liver problems

less severe blood circulation problems

in your limbs

chronic lung disease or less severe asthma

history of a scaly skin rash (psoriasis)

tumour

adrenal

gland

(phaeochromocytoma)

thyroid disorder.

In addition, tell your doctor if you are

going to have:

desensitization therapy (for example for

the prevention of hay fever), because

Cardicor may make it more likely that

you experience an allergic reaction,

or such reaction may be more severe

anaesthesia (for example for surgery),

because Cardicor may influence how

your body reacts to this situation.

If you have chronic lung disease or less

severe asthma please inform your doctor

immediately if you start to experience new

difficulties in breathing, cough, wheezing

after exercise, etc. when using Cardicor.

Children and adolescents

Cardicor is not recommended for use in

children or adolescents

Other medicines and Cardicor

Tell your doctor or pharmacist if you are

taking, have recently taken or might take

any other medicines.

Do not take the following medicines with

Cardicor without special advice from your

doctor:

certain

medicines

used

treat

irregular or abnormal heartbeat (Class

I antiarrhythmic medicines such as

quinidine,

disopyramide,

lidocaine,

phenytoin;

flecainide,

propafenone)

certain medicines used to treat high

blood

pressure,

angina

pectoris

irregular heartbeat (calcium antagonists

such as verapamil and diltiazem)

certain medicines used to treat high

blood

pressure

such

clonidine,

methyldopa, moxonodine, rilmenidine.

However, do not stop taking these

medicines without checking with your

doctor first.

Check with your doctor before taking the

following medicines with Cardicor; your

doctor may need to check your condition

more frequently:

certain medicines used to treat high

blood

pressure

angina

pectoris

(dihydropyridine-type calcium antagonists

such

felodipine

amlodipine)

certain

medicines

used

treat

irregular or abnormal heartbeat (Class

III antiarrhythmic medicines such as

amiodarone)

beta-blockers applied locally (such as

timolol eye drops for glaucoma treatment)

Cardicor 10 mg film-coated tablets

The active substance is bisoprolol fumarate.

Each film-coated tablet contains 10 mg.

The other ingredients are:

Tablet core: Silica, colloidal anhydrous;

magnesium

stearate;

crospovidone;

maize starch; microcrystalline cellulose;

calcium hydrogen phosphate (anhydrous).

Film coating: Iron oxide red (E172);

Iron oxide yellow (E172); dimethicone;

macrogol 400; titanium dioxide (E171);

hypromellose.

What Cardicor looks like and contents

of the pack

Cardicor 1.25 mg film-coated tablets are

white and round.

Cardicor 2.5 mg film-coated tablets are

white and heart-shaped with a break-line

on both sides.

Cardicor 3.75 mg film-coated tablets are

off-white and heart-shaped with a break-

line on both sides.

Cardicor 5 mg film-coated tablets are

yellowish-white and heart-shaped with a

break-line on both sides.

Cardicor 7.5 mg film-coated tablets are

pale yellow and heart-shaped with a

break-line on both sides.

Cardicor 10 mg film-coated tablets are

pale orange – light orange and heart-

shaped with a break-line on both sides.

Each pack contains 20, 28, 30, 50, 56, 60,

90, or 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Merck Serono Ltd

Bedfont Cross, Stanwell Road, Feltham,

Middlesex, TW14 8NX, UK

Manufacturer

Famar Lyon

29, Avenue Charles de Gaulle

F-69230 Saint Genis Laval

This medicinal product is authorised in

the Member States of the EEA under

the following names:

Austria: Concor COR, Belgium: Emconcor

Minor,

Croatia:

Concor

COR,

Finland:

Emconcor CHF, France: Cardensiel, Germany:

Concor COR, Ireland: Cardicor, Italy: Sequacor,

Luxemburg: Concor Cor, Netherlands: Emcor

Deco, Portugal: Concor IC, Spain: EMCONCOR

COR,

Sweden:

Emconcor

CHF,

United

Kingdom: Cardicor

This leaflet was last revised in 10/2016

MC-2314-2016/TW1205731

If you have to stop treatment entirely,

your doctor will usually advise you to

reduce the dose gradually, as otherwise

your condition may become worse.

If you take more Cardicor than you should

If you have taken more Cardicor tablets

than

should,

tell

your

doctor

immediately. Your doctor will decide what

measures are necessary.

Symptoms of an overdose may include

slowed heart rate, severe difficulty in

breathing, feeling dizzy, or trembling (due

to decreased blood sugar).

If you forget to take Cardicor

Do not take a double dose to make up for

a forgotten dose. Take your usual dose the

next morning.

If you stop taking Cardicor

Never stop taking Cardicor unless on your

doctor’s advice. Otherwise your condition

could become much worse.

If you have any further questions on the

use of this product, ask your doctor or

pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side

effects, although not everybody gets them.

To prevent serious reactions, speak to a

doctor immediately if a side effect is severe,

occurred suddenly or gets worse rapidly.

The most serious side effects are related to

the heart function:

slowing of heart rate (may affect more

than 1 in 10 people)

worsening of heart failure (may affect

up to 1 in 10 people)

slow or irregular heartbeat (may affect

up to 1 in 100 people)

If you feel dizzy or weak, or have breathing

difficulties please contact your doctor as

soon as possible.

Further

side

effects

listed

below

according to how frequently they may occur:

Common (may affect up to 1 in 10 people):

tiredness, feeling weak, dizziness, headache

feeling of coldness or numbness in hands

or feet

low blood pressure

stomach or intestine problems such

nausea,

vomiting,

diarrhoea,

constipation.

Uncommon (may affect up to 1 in 100

people):

sleep disturbances

depression

dizziness when standing up

breathing problems in patients with

asthma or chronic lung disease

muscle weakness, muscle cramps.

Rare (may affect up to 1 in 1,000 people):

hearing problems

allergic runny nose

reduced tear flow

inflammation of the liver which can cause

yellowing of the skin or whites of the eyes

certain blood test results for liver function

or fat levels differing from normal

allergy-like reactions such as itching,

flush, rash

impaired erection

nightmares, hallucinations

fainting.

Very rare (may affect up to 1 in 10,000

people):

irritation

redness

(conjunctivitis)

hair loss

appearance or worsening of scaly skin

rash (psoriasis); psoriasis-like rash.

Reporting side effects

If you get any side effects, talk to your doctor

or pharmacist. This includes any possible

side effects not listed in this leaflet. You

can also report side effects directly via

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

By reporting side effects you can help

provide more information on the safety of

this medicine.

5. How to store Cardicor

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 blister and

the carton after EXP. The expiry date

refers to the last date of that month.

Cardicor 1.25, 2.5 mg, 3.75 mg film-coated

tablets:

Do not store above 25°C.

Cardicor 5, 7.5 mg, 10 mg film-coated tablets:

Do not store above 30°C.

Do not throw away any medicines via

wastewater or household waste. Ask your

pharmacist how to throw away of medicines

you no longer use. These measures will help

protect the environment.

6. Contents of the pack and other

information

What Cardicor contains

Cardicor 1.25 mg film-coated tablets

The

active

substance

bisoprolol

fumarate.

Each

film-coated

tablet

contains 1.25 mg.

The other ingredients are:

Tablet core: Silica, colloidal anhydrous;

magnesium

stearate;

crospovidone;

pregelatinised

maize

starch;

maize

starch; microcrystalline cellulose; calcium

hydrogen

phosphate

(anhydrous).

Film

coating:

dimethicone;

talc;

macrogol 400; titanium dioxide (E171);

hypromellose.

Cardicor 2.5 mg film-coated tablets

The

active

substance

bisoprolol

fumarate.

Each

film-coated

tablet

contains 2.5 mg.

The other ingredients are:

Tablet core: Silica, colloidal anhydrous;

magnesium

stearate;

crospovidone;

maize

starch;

microcrystalline

cellulose; calcium hydrogen phosphate

(anhydrous).

Film coating: dimethicone; macrogol 400;

titanium dioxide (E171); hypromellose.

Cardicor 3.75 mg film-coated tablets

The active substance is bisoprolol fumarate.

Each film-coated tablet contains 3.75 mg.

The other ingredients are: Tablet core:

Silica, colloidal anhydrous; magnesium

stearate; crospovidone; maize starch;

microcrystalline

cellulose;

calcium

hydrogen

phosphate

(anhydrous).

Film coating: Iron oxide yellow (E172);

dimethicone; macrogol 400; titanium

dioxide (E171); hypromellose.

Cardicor 5 mg film-coated tablets

The active substance is bisoprolol fumarate.

Each film-coated tablet contains 5 mg.

The other ingredients are:

Tablet core: Silica, colloidal anhydrous;

magnesium

stearate;

crospovidone;

maize starch; microcrystalline cellulose;

calcium hydrogen phosphate (anhydrous).

Film coating: Iron oxide yellow (E172);

dimethicone; macrogol 400; titanium

dioxide (E171); hypromellose.

Cardicor 7.5 mg film-coated tablets

The active substance is bisoprolol fumarate.

Each film-coated tablet contains 7.5 mg.

The other ingredients are:

Tablet core: Silica, colloidal anhydrous;

magnesium

stearate;

crospovidone;

maize starch; microcrystalline cellulose;

calcium hydrogen phosphate (anhydrous).

Film coating: Iron oxide yellow (E172);

dimethicone; macrogol 400; titanium

dioxide (E171); hypromellose.

MC-2314-2016/TW1205731

Package leaflet: Information for the user

Cardicor

®

1.25 mg film-coated tablets

Cardicor

®

2.5 mg film-coated tablets

Cardicor

®

3.75 mg film-coated tablets

Cardicor

®

5 mg film-coated tablets

Cardicor

®

7.5 mg film-coated tablets

Cardicor

®

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 your 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 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:

1. What Cardicor is and what it is used for

2. What you need to know before you take

Cardicor

3. How to take Cardicor

4. Possible side effects

5. How to store Cardicor

6. Contents of the pack and other information

1. What Cardicor is and what it is

used for

The active substance in Cardicor is bisoprolol.

Bisoprolol belongs to a group of medicines

called beta-blockers. These medicines work

by affecting the body`s response to some

nerve impulses, especially in the heart. As

a result, bisoprolol slows down the heart

rate and makes the heart more efficient

pumping

blood

around

body.

Heart failure occurs when the heart muscle

is weak and unable to pump enough blood

to supply the body’s needs. Cardicor is

used to treat stable chronic heart failure.

It is used in combination with other medicines

suitable for this condition (such as ACE-

inhibitors, diuretics, and heart glycosides).

2. What you need to know before

you take Cardicor

Do not take Cardicor

Do not take Cardicor if one of the following

conditions applies to you:

allergy (hypersensitivity) to bisoprolol

or to any of the other ingredients (see

section 6 ‘What Cardicor contains’)

severe asthma

severe blood circulation problems in your

limbs (such as Raynaud’s syndrome),

which may cause your fingers and toes

to tingle or turn pale or blue

untreated phaeochromocytoma, which

is a rare tumour of the adrenal gland

metabolic acidosis, which is a condition

when there is too much acid in the blood.

certain medicines used to treat for

example Alzheimer’s disease or glaucoma

(parasympathomimetics such as tacrine

or carbachol) or medicines that are

used to treat acute heart problems

(sympathomimetics such as isoprenaline

and dobutamine)

antidiabetic medicines including insulin

anaesthetic agents (for example during

surgery)

digitalis, used to treat heart failure

non-steroidal anti-inflammatory medicines

(NSAIDs) used to treat arthritis, pain or

inflammation (for example ibuprofen or

diclofenac)

any medicine, which can lower blood

pressure

desired

undesired

effect such as antihypertensives, certain

medicines

depression

(tricyclic

antidepressants such as imipramine or

amitriptyline), certain medicines used

to treat epilepsy or during anaesthesia

(barbiturates such as phenobarbital), or

certain medicines to treat mental illness

characterized by a loss of contact with reality

(phenothiazines such as levomepromazine)

mefloquine, used for prevention or

treatment of malaria

depression treatment medicines called

monoamine oxidase inhibitors (except

MAO-B inhibitors) such as moclobemide.

Pregnancy and breast-feeding

Pregnancy

There is a risk that use of Cardicor during

pregnancy may harm the baby. If you are

pregnant or planning to become pregnant,

tell your doctor. He or she will decide whether

you can take Cardicor during pregnancy.

Breast-feeding

It is not known whether bisoprolol passes into

human breast milk. Therefore, breastfeeding

is not recommended during therapy with

Cardicor.

Driving and using machines

Your ability to drive or use machinery may be

affected depending on how well you tolerate

the medicine. Please be especially cautious

at the start of treatment, when the dose

is increased or the medication is changed,

as well as in combination with alcohol.

3. How to take Cardicor

Always take this medicine exactly as your

doctor has told you. Check with your

doctor or pharmacist if you are not sure.

Treatment

with

Cardicor

requires

regular monitoring by your doctor. This

is particularly necessary at the start of

treatment, during dose increase and when

you stop treatment.

Take the tablet with some water in the

morning, with or without food. Do not

crush or chew the tablet. The scored tablets

can be divided into two equal doses.

Treatment with Cardicor is usually long-term.

Adults including the elderly:

Treatment with bisoprolol must be started

at a low dose and increased gradually.

Your doctor will decide how to increase

the dose, and this will normally be done in

the following way:

1.25 mg bisoprolol once daily for one week

2.5 mg bisoprolol once daily for one week

3.75 mg bisoprolol once daily for one week

5 mg bisoprolol once daily for four weeks

7.5 mg bisoprolol once daily for four weeks

10

bisoprolol

once

daily

maintenance (on-going) therapy.

The maximum recommended daily dose is

10 mg bisoprolol.

Depending on how well you tolerate the

medicine, your doctor may also decide to

lengthen the time between dose increases. If

your condition gets worse or you no longer

tolerate the drug, it may be necessary to reduce

the dose again or to interrupt treatment. In

some patients a maintenance dose lower

than 10 mg bisoprolol may be sufficient.

Your doctor will tell you what to do.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cardicor 5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg bisoprolol fumarate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Yellowish white, heart-shaped, scored and film-coated tablets.

The scored tablets can be divided into two equal doses.

4 CLINICAL PARTICULARS

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 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

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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.

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 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 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.

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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

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 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.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhytmic

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, Cardicor 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 beta

-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.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations not recommended

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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

-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.

-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both

agents.

Sympathomimetics that activate both

- and

-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with

bisoprolol may unmask the

-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

-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, beta

-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

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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)

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 (itching, flush, rash).

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:

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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:

potency disorders.

Psychiatric disorders:

Uncommon:

sleep disorders, depression.

Rare:

nightmares, hallucinations.

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

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.

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Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta

-sympathomimetic drugs and/or

aminophylline.

Hypoglycaemia: Administer i.v. glucose.

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 stimulating 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.

Clinical efficacy and safety

In total 2647 patients were included in the CIBIS II trial. 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-blockers, 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 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.

Bisoprolol is also used for the treatment of hypertension and angina.

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

Bisoprolol is absorbed and has a biological availability of about 90% after oral administration.

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Distribution

The distribution volume is 3.5 l/kg.

The plasma protein binding of bisoprolol is about 30%.

Biotransformation and Elimination

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. 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.

Linearity

The kinetics of bisoprolol are linear and independent of age.

Special population

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 has not been studied. 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-blockers,

bisoprolol

caused maternal

(decreased food

intake and decreased body weight) and embryo/fetal 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

Tablet core:

Silica, colloidal anhydrous

Magnesium stearate

Crospovidone

Microcrystalline cellulose

Maize starch

Calcium hydrogen phosphate, anhydrous

Film coating:

Iron oxide yellow (E172)

Dimethicone

Macrogol 400

Titanium dioxide (E171)

Hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

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5 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

The container is a blister, which is made of a polyvinylchloride base film and an aluminium cover foil.

The container is a blister, which is made of an aluminium forming foil and an aluminium sealing foil.

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Merck Serono Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA0654/007/004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 March 2000

Date of last renewal: 04 June 2009

10 DATE OF REVISION OF THE TEXT

May 2016

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