Cardicor 2.5 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BISOPROLOL FUMARATE
Available from:
IMED Healthcare Ltd.
ATC code:
C07AB; C07AB07
INN (International Name):
BISOPROLOL FUMARATE
Dosage:
2.5 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:
Authorised
Authorization number:
PPA1463/085/002
Authorization date:
2013-10-25

Package leaflet: Information for the user

Cardicor® 2.5 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 at pumping blood around the 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.

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 as 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 of the 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 to 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 or

irregular heartbeat (calcium antagonists such as verapamil and

diltiazem)

certain medicines used to treat high blood pressure such as 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 or angina pectoris

(dihydropyridine-type calcium antagonists such as felodipine and

amlodipine)

certain medicines used to treat irregular or abnormal heartbeat (Class

III antiarrhythmic medicines such as amiodarone)

beta-blockers applied locally (such as timolol eye drops for glaucoma

treatment)

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-infl ammatory medicines (NSAIDs) used to treat

arthritis, pain or infl ammation (for example ibuprofen or diclofenac)

any medicine, which can lower blood pressure as a desired or

undesired effect such as antihypertensives, certain medicines for

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)

mefl oquine, 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 mg bisoprolol once daily for maintenance (ongoing) 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.

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 you 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 are 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 as nausea, vomiting, diarrhoea, or

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 1000 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 and redness of the eye (conjunctivitis)

hair loss

appearance or worsening of scaly skin rash (psoriasis); psoriasis-like

rash.

If you get any side effects, talk to your doctor or pharmacist. This include

any possible side effects not listed in this leaflet. You can also report the

side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL-

Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:

www.hpra.ie; email: 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.

Do not store above 25°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 is 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 is 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.

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.

Each pack contains 28 tablets.

Parallel Product Authorisation Holder

IMED Healthcare Ltd, Unit 625 Kilshane Avenue, Northwest Business

Park, Ballycoolin, Dublin 15, Ireland

Manufacturer

Merck SL, Poligono Merck, 08100 Mollet del Valles, Barcelona, Spain

Repackaged by

IMED Healthcare Ltd, Unit 625 Kilshane Avenue, Northwest Business

Park, Ballycoolin, Dublin 15, Ireland

This medicinal product is authorised in the Member States of the

EEA under the following names:

Austria: Concor COR,

Belgium: Emconcor Minor,

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 March 2018

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cardicor 2.5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg bisoprolol fumarate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

Product imported from the UK

White, heart-shaped, scored film-coated tablets.

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 during

the titration phase. Symptoms may already occur within the first day after initiating the therapy.

Treatment modification

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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.

Renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired

hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Elderly

No dosage adjustment is 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 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 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)

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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.

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 interactions

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

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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, 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

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

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4.8 Undesirable effects

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Uncommon (≥ 1/1,000, < 1/100)

Rare (≥ 1/10,000, < 1/1,000)

Very rare (< 1/10,000)

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:

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:

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Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

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 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.

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, 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 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

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.

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

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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.

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

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Magnesium stearate

Crospovidone

Microcrystalline cellulose

Maize starch

Calcium hydrogen phosphate, anhydrous

Film coating:

Dimethicone

Macrogol 400

Titanium dioxide (E171)

Hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The shelf-life expiry date of this product is the date shown on the container and outer carton of the product on the market in

the country of origin.

6.4 Special precautions for storage

Do not store above 25°C.

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6.5 Nature and contents of container

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

Pack sizes: 28 tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

IMED Healthcare Ltd.

Unit 625 Kilshane Avenue

Northwest Business Park

Ballycoolin

Dublin 15

Ireland

7 PARALLEL PRODUCT AUTHORISATION HOLDER

IMED Healthcare Ltd.

Unit 625 Kilshane Avenue

Northwest Business Park

Ballycoolin

Dublin 15

Ireland

8 MARKETING AUTHORISATION NUMBER

PPA1463/085/002

8 PARALLEL PRODUCT AUTHORISATION NUMBER

PPA1463/085/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25

October 2013

10 DATE OF REVISION OF THE TEXT

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