CARDICOR 1.25 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:
1.25 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:
PA0654/007/001
Authorization date:
2000-03-20

Packageleaflet:Informationforthe user

Cardicor1.25mgfilm-coatedtablets

Cardicor2.5mgfilm-coated tablets

Cardicor3.75mgfilm-coatedtablets

Cardicor5mgfilm-coated tablets

Cardicor7.5mgfilm-coated tablets

Cardicor10mgfilm-coated tablets

Bisoprololfumarate

Read allofthis leafletcarefully before youstarttaking thismedicinebecauseitcontains

importantinformationfor you.

- Keep thisleaflet. You mayneedto readitagain.

- Ifyou have anyfurtherquestions,askyourdoctororyourpharmacist.

- This medicine hasbeen prescribedforyouonly. Do notpass itonto others. Itmay harmthem,

even iftheirsigns ofillnessarethesame as yours.

- Ifyou getanyside effects,talkto yourdoctororpharmacist.Thisincludes anypossibleside

effects notlistedinthis leaflet.Seesection 4.

Whatisin thisleaflet:

1. WhatCardicoris andwhatitis usedfor

2. Whatyou needto knowbefore you takeCardicor

3. Howto takeCardicor

4. Possibleside effects

5. Howto storeCardicor

6. Contents ofthe packand otherinformation

1. WhatCardicoris andwhatitis usedfor

Theactive substanceinCardicoris bisoprolol. Bisoprololbelongs to a groupofmedicines called beta-

blockers.These medicinesworkbyaffectingthebody`s response tosome nerve impulses, especially

in the heart. As aresult, bisoprololslowsdown the heartrate andmakesthe heartmore efficientat

pumpingblood around thebody.

Heartfailureoccurs when the heartmuscle is weakand unable to pump enough bloodto supplythe

body's needs.Cardicoris used totreatstable chronic heartfailure.

Itis usedincombination with othermedicinessuitableforthis condition (such asACE-inhibitors,

diuretics,and heartglycosides).

2. What you needto knowbefore youtakeCardicor

Do not takeCardicor

Do nottakeCardicorifoneofthe followingconditionsappliesto you:

allergy(hypersensitivity)tobisoprololorto anyoftheotheringredients(seesection 6 ‘What

Cardicorcontains’)

severe asthma

severe bloodcirculation problems in yourlimbs (suchasRaynaud’s syndrome), which may

causeyourfingersand toesto tingle orturn pale orblue

untreated phaeochromocytoma, which is araretumourofthe adrenalgland

metabolic acidosis, whichis acondition whenthereistoo much acid inthe blood.

Do nottakeCardicorifyou have oneofthe followingheartproblems:

acute heartfailure

worseningheartfailure requiringinjectionofmedicines into a vein, thatincreasethe forceof

contraction oftheheart

slowheartrate

lowblood pressure

certain heartconditionscausinga veryslowheartrateorirregularheartbeat

cardiogenicshock, which isan acuteserious heartcondition causinglowblood pressure and

circulatoryfailure.

Warnings and precautions

Ifyou have anyofthefollowingconditions tellyourdoctorbefore takingCardicor;he orshemay

wantto take specialcare(forexample give additionaltreatmentorperformmore frequentchecks):

diabetes

strictfasting

certain heartdiseasessuchasdisturbancesinheartrhythm, orseverechestpainatrest

(Prinzmetal’sangina)

kidneyorliverproblems

lesssevereblood circulation problems in yourlimbs

chroniclungdisease orlesssevere asthma

historyofascalyskin rash(psoriasis)

tumourofthe adrenalgland(phaeochromocytoma)

thyroid disorder.

In addition,tellyourdoctorifyou are goingto have:

desensitizationtherapy(forexample forthe preventionofhayfever), becauseCardicormay

make itmore likelythatyou experiencean allergicreaction, orsuch reaction maybe more

severe

anaesthesia (forexample forsurgery), becauseCardicormayinfluence how yourbodyreacts to

this situation.

Ifyou have chronic lungdisease orlesssevere asthma pleaseinformyourdoctorimmediatelyifyou

startto experiencenew difficultiesin breathing, cough, wheezingafterexercise, etc. when using

Cardicor.

Childrenandadolescents

Cardicoris notrecommended foruse inchildrenoradolescents.

OthermedicinesandCardicor

Tellyourdoctororpharmacistifyou are taking,haverecentlytakenormighttakeanyother

medicines.

Do nottake thefollowingmedicineswithCardicorwithoutspecialadvicefromyourdoctor:

certain medicinesusedto treatirregularorabnormalheartbeat(Class Iantiarrhythmicmedicines

such as quinidine, disopyramide, lidocaine, phenytoin;flecainide, propafenone)

certain medicinesusedto treathigh blood pressure,angina pectoris orirregularheartbeat

(calciumantagonists such as verapamiland diltiazem)

certain medicinesusedto treathigh blood pressuresuch asclonidine, methyldopa,moxonodine,

rilmenidine.However,do notstop takingthese medicineswithoutcheckingwithyourdoctor

first.

Checkwith yourdoctorbeforetakingthefollowingmedicineswithCardicor;yourdoctormayneed to

checkyourcondition morefrequently:

certain medicinesusedto treathigh blood pressure orangina pectoris(dihydropyridine-type

calciumantagonistssuchasfelodipineandamlodipine)

certain medicinesusedto treatirregularorabnormalheartbeat(Class IIIantiarrhythmic

medicinessuchasamiodarone)

beta-blockersappliedlocally(such astimololeye drops forglaucoma treatment)

certain medicinesusedto treatforexample Alzheimer’s disease orglaucoma

(parasympathomimeticssuch astacrine orcarbachol)ormedicinesthatare used to treatacute

heartproblems (sympathomimeticssuch as isoprenaline and dobutamine)

antidiabetic medicines includinginsulin

anaesthetic agents (forexample duringsurgery)

digitalis, used to treatheartfailure

non-steroidalanti-inflammatorymedicines(NSAIDs)usedto treatarthritis, painor

inflammation(forexample ibuprofen ordiclofenac)

anymedicine, which can lowerblood pressureasa desiredorundesired effectsuch as

antihypertensives, certainmedicinesfordepression (tricyclicantidepressantssuch as

imipramine oramitriptyline), certain medicines used totreatepilepsyorduringanaesthesia

(barbiturates such as phenobarbital), orcertain medicinestotreatmentalillnesscharacterized by

a loss ofcontactwithreality(phenothiazinessuch as levomepromazine)

mefloquine, used forprevention ortreatmentofmalaria

depressiontreatmentmedicinescalled monoamine oxidaseinhibitors (exceptMAO-B

inhibitors)such as moclobemide.

Pregnancyandbreast-feeding

Pregnancy

Thereisa riskthatuse ofCardicorduringpregnancymayharmthe baby. Ifyou are pregnantor

planningto become pregnant, tellyourdoctor. He orshe willdecide whetheryou can takeCardicor

duringpregnancy.

Breast-feeding

Itis notknown whetherbisoprololpassesintohuman breastmilk. Therefore, breastfeedingis not

recommended duringtherapywithCardicor.

Driving andusingmachines

Yourabilityto drive orusemachinerymaybe affecteddependingon howwellyoutoleratethe

medicine. Pleasebe especiallycautious atthe startoftreatment, whenthe dose is increasedorthe

medication is changed, aswellasin combinationwithalcohol.

3. HowtotakeCardicor

Always takethis medicineexactlyasyourdoctorhastold you. Checkwithyourdoctororpharmacist

ifyou are notsure.

TreatmentwithCardicorrequiresregularmonitoringbyyourdoctor.Thisis particularlynecessaryat

the startoftreatment,duringdoseincrease, andwhenyou stoptreatment.

Take the tabletwithsome waterinthe morning, withorwithoutfood. Donotcrush orchewthetablet.

Thescoredtablets can be divided into twoequaldoses.

TreatmentwithCardicorisusuallylong-term.

Adultsincludingtheelderly

Treatmentwithbisoprololmustbe started atalowdose andincreased gradually.

Yourdoctorwilldecide howto increasethedose, andthis willnormallybe done in thefollowingway:

1.25 mgbisoprololoncedailyforone week

2.5 mgbisoprololonce dailyforone week

3.75 mgbisoprololoncedailyforone week

5 mgbisoprololoncedailyforfourweeks

7.5 mgbisoprololonce dailyforfourweeks

10 mgbisoprololonce dailyformaintenance(on-going)therapy.

Themaximumrecommended dailydoseis 10 mgbisoprolol.

Dependingon howwellyou toleratethemedicine, yourdoctormayalso decide tolengthenthetime

between dose increases.Ifyourcondition gets worseoryou no longertolerate thedrug, itmaybe

necessaryto reducethedose again ortointerrupttreatment.In some patients amaintenancedose

lowerthan 10mgbisoprololmaybe sufficient.

Yourdoctorwilltellyou whatto do.

Ifyou have to stop treatmententirely, yourdoctorwillusuallyadviseyou toreducethe dose

gradually, asotherwiseyourcondition maybecome worse.

IfyoutakemoreCardicorthanyoushould

Ifyou have taken moreCardicortabletsthan you should, tellyourdoctorimmediately. Yourdoctor

willdecide whatmeasuresare necessary.

Symptoms ofan overdosemayincludeslowed heartrate,severe difficultyin breathingfeelingdizzy,

ortrembling(dueto decreased blood sugar).

Ifyouforgetto takeCardicor

Do nottake adoubledoseto make up fora forgotten dose.Take yourusualdosethe nextmorning.

IfyoustoptakingCardicor

NeverstoptakingCardicorunless on yourdoctor’s advice. Otherwise yourcondition could become

much worse.

Ifyou have anyfurtherquestions onthe useofthis product,askyourdoctororpharmacist.

4. Possiblesideeffects

Like allmedicines,this medicinecan causeside effects, although noteverybodygetsthem.

To preventserious reactions, speakto a doctorimmediatelyifaside effectissevere, occurred

suddenlyorgets worserapidly.

Themostserious side effects arerelated to the heartfunction:

slowingofheartrate(mayaffectmorethan1 in10 people)

worseningofheartfailure(mayaffectupto 1in 10people)

sloworirregularheartbeat(mayaffectupto 1in 100people)

Ifyou feeldizzyorweak, orhave breathingdifficultiespleasecontactyourdoctorassoon aspossible.

Furtherside effectsare listed belowaccordingto howfrequentlytheymayoccur:

Common(mayaffectupto1 in10people):

tiredness,feelingweak, dizziness, headache

feelingofcoldness ornumbnessin hands orfeet

lowblood pressure

stomach orintestine problems such as nausea, vomiting, diarrhoea,orconstipation.

Uncommon(mayaffectupto 1in 100people):

sleep disturbances

depression

dizziness whenstandingup

breathingproblems in patients withasthma orchroniclungdisease

muscle weakness, muscle cramps.

Rare(mayaffectupto 1in1,000people):

hearingproblems

allergicrunnynose

reducedtearflow

inflammation oftheliverwhichcan cause yellowingofthe skinorwhites ofthe eyes

certain bloodtestresultsforliverfunction orfatlevelsdifferingfromnormal

allergy-like reactions suchasitching, flush,rash

impairederection

nightmares, hallucinations

fainting

Very rare(mayaffectupto 1 in 10,000 people):

irritationandrednessoftheeye (conjunctivitis)

hairloss

appearanceorworseningofscalyskin rash(psoriasis);psoriasis-like rash.

Ifyougetanysideeffects,talk toyour doctor or pharmacist. This includesanypossible side

effects notlisted in this leaflet.Youcan also report theside effectsdirectly via HPRA

Pharmacovigilance, EarlsfortTerrace, IRL–Dublin2;Tel:+353 16764971;Fax:+353 1 6762517.

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

Byreportingsideeffects you can helpprovide moreinformation onthe safetyofthis medicine.

5. HowtostoreCardicor

Keepthis medicineoutofthesightandreach ofchildren

Do notusethis medicineaftertheexpirydate which isstated on the blisterandthecarton after

EXP.Theexpirydate refers tothelastdateofthatmonth.

Storage conditions forPVC/Alublister

Cardicor1.25mg film-coated tablets:

Cardicor2.5 mgfilm-coated tablets:

Cardicor3.75mg film-coated tablets:

Do notstore above 25°C.

Cardicor5 mgfilm-coatedtablets:

Cardicor7.5 mgfilm-coated tablets:

Cardicor10 mgfilm-coated tablets:

Do notstore above 30°C.

Storage conditions forAlu/Alublister

Cardicor1.25 mg film-coated tablets:

Cardicor2.5 mgfilm-coated tablets:

Cardicor3.75 mg film-coated tablets:

Cardicor5 mg film-coated tablets:

Cardicor7.5 mgfilm-coated tablets:

Cardicor10 mgfilm-coated tablets:

This medicine doesnotrequire anyspecialstorage conditions.

Donotthrowawayanymedicinesvia wastewaterorhousehold waste. Askyourpharmacisthowto

throwawaymedicinesyouno longeruse.These measureswillhelp protecttheenvironment.

6. Contents ofthe pack andotherinformation

WhatCardicorcontains

Cardicor1.25mg film-coated tablets

Theactive substanceisbisoprololfumarate.Eachfilm-coated tabletcontains1.25mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;pregelatinised

maize starch;maize starch;microcrystallinecellulose;calciumhydrogen phosphate

(anhydrous).

Filmcoating:dimethicone;talc;macrogol400;titaniumdioxide (E171);hypromellose.

Cardicor2.5 mgfilm-coated tablets

Theactive substanceisbisoprololfumarate.Eachfilm-coated tabletcontains 2.5mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;maizestarch;

microcrystallinecellulose;calciumhydrogen phosphate (anhydrous).

Filmcoating:dimethicone;macrogol400;titaniumdioxide(E171);hypromellose.

Cardicor3.75mg film-coated tablets

Theactive substanceisbisoprololfumarate.Eachfilm-coated tabletcontains 3.75mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;maizestarch;

microcrystallinecellulose;calciumhydrogen phosphate (anhydrous).

Filmcoating;Iron oxide yellow(E172);dimethicone;macrogol400;titaniumdioxide(E171);

hypromellose.

Cardicor5 mgfilm-coatedtablets

Theactive substanceisbisoprololfumarate.Eachfilm-coated tabletcontains 5mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;maizestarch;

microcrystallinecellulose;calciumhydrogen phosphate (anhydrous).

Filmcoating:Iron oxide yellow(E172);dimethicone;macrogol400;titaniumdioxide(E171);

hypromellose.

Cardicor7.5 mgfilm-coated tablets

Theactive substanceisbisoprololfumarate.Eachfilm-coated tabletcontains 7.5mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;maizestarch;

microcrystallinecellulose;calciumhydrogen phosphate (anhydrous).

Filmcoating:Iron oxide yellow(E172);dimethicone;macrogol400;titaniumdioxide(E171);

hypromellose.

Cardicor10 mgfilm-coated tablets

Theactive substanceisbisoprololfumarate.Eachfilm-coatedtabletcontains 10mg.

Theotheringredients are:

Tabletcore:Silica, colloidalanhydrous;magnesiumstearate;crospovidone;maizestarch;

microcrystallinecellulose;calciumhydrogen phosphate (anhydrous).

Filmcoating:Iron oxidered (E172);Iron oxideyellow(E172);dimethicone;macrogol400;

titaniumdioxide (E171);hypromellose.

WhatCardicorlookslikeandcontentsofthe pack

Cardicor1.25 mgfilm-coated tabletsarewhite and round.

Cardicor2.5 mgfilm-coated tablets are white and heart-shaped with a break-line on bothsides.

Cardicor3.75 mgfilm-coated tabletsareoff-white andheart-shaped with abreak-line onboth sides.

Cardicor5 mgfilm-coatedtabletsare yellowish-whiteand heart-shaped with a break-line on both

sides.

Cardicor7.5 mgfilm-coated tablets are pale yellowand heart-shaped with abreak-line on both sides.

Cardicor10 mgfilm-coated tablets are paleorange–lightorange and heart-shaped witha break-line

on bothsides.

Each packcontains20, 28,30, 50, 56,60, 90,or100 tablets.

Notallpacksizesmaybe marketed.

MarketingAuthorisationHolder

MerckSerono Limited, BedfontCross, StanwellRoad, Feltham, Middlesex,TW14 8NX, United

Kingdom

Manufacturer

MerckKGaA,FrankfurterStrasse250, 64293 Darmstadt, Germany

MerckKGaA &Co., Hösslgasse20, 9800 Spittal/Drau, Austria

TjoapackB.V. Emmen, Columbusstraat4,7825VREmmen, The Netherlands

MerckS.L., PolígonoMerck, MolletdelVallés, 08100Barcelona, Spain

Thismedicinalproductisauthorisedinthe MemberStatesoftheEEAunderthefollowing

names:

Austria: ConcorCOR

Belgium: EmconcorMinor*

Croatia: ConcorCOR

Finland: EmconcorCHF

France: Cardensiel

Germany: ConcorCOR

Ireland Cardicor

Italy: Sequacor

Luxemburg: ConcorCor

Netherlands: EmcorDeco

Portugal: ConcorIC

Spain: EMCONCORCOR

Sweden: EmconcorCHF

UnitedKingdom: Cardicor

Thisleafletwaslastrevisedin09/2015

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Cardicor 1.25 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.25 mg bisoprolol fumarate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White, round 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.

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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.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and

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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

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

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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

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

administration of bisoprolol.

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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:

Common:

feeling of coldness or numbness in the extremities, hypotension.

Uncommon:

orthostatic hypotension.

General disorders:

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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.

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.

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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.

Distribution

The distribution volume is 3.5 l/kg.

The plasma protein binding of bisoprolol is about 30%.

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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

Pregelatinised maize starch

Maize Starch

Microcrystalline cellulose

Calcium hydrogen phosphate, anhydrous

Film coating:

Dimethicone

Talc

Macrogol 400

Titanium dioxide (E171)

Hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

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Do not store above 25°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

PA0654/007/001

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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