ACERYCAL 5/10 mg/mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
PERINDOPRIL ARGININE AMLODIPINE
Available from:
Imbat Limited
INN (International Name):
PERINDOPRIL ARGININE AMLODIPINE
Dosage:
5/10 mg/mg
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Authorization status:
Authorised
Authorization number:
PPA1151/167/002
Authorization date:
0000-00-00

PACKAGELEAFLET:INFORMATIONFORTHEUSER

ACERYCAL ® 5mg/10mgtablets

perindoprilarginine/amlodipine

Yourmedicineisavailableusingtheabovenamesbutwillbereferred

toasACERYCALthroughoutthisleaflet.

Readall ofthisleafletcarefullybeforeyoustarttaking

thismedicine.

Keepthisleaflet.Youmayneedtoreaditagain.

Ifyouhaveanyfurtherquestions,askyourdoctororpharmacist.

Thismedicinehasbeenprescribedforyou.Donotpassitonto

others.Itmayharmthem,eveniftheirsymptomsarethesameas

yours.

Ifanyofthesideeffectsgetserious,orifyounoticeanyside

effectsnotlistedinthisleaflet,pleasetellyourdoctoror

pharmacist.

Inthisleaflet:

1.WhatACERYCALisandwhatitisusedfor

2.BeforeyoutakeACERYCAL

3.HowtotakeACERYCAL

4.Possiblesideeffects

5.HowtostoreACERYCAL

6.Furtherinformation

1. WHAT ACERYCALIS ANDWHAT IT ISUSED

FOR

ACERYCALisprescribedfortreatmentofhighbloodpressure

(hypertension)and/ortreatmentofstablecoronaryarterydisease(a

conditionwherethebloodsupplytotheheartisreducedorblocked).

Patientsalreadytakingperindoprilandamlodipinefromseparate

tabletsmayinsteadreceiveonetabletofACERYCALwhichcontains

bothingredients.

ACERYCALisacombinationoftwoactiveingredients,perindopriland

amlodipine.PerindoprilisanACE(angiotensinconvertingenzyme)

inhibitor.Amlodipineisacalciumantagonist(whichbelongstoaclass

ofmedicinescalleddihydropyridines).Togethertheyworktowidenand

relaxthebloodvesselssothatbloodpassesthroughthemmoreeasily

andmakesiteasierforyourhearttomaintainagoodbloodflow.

2. BEFOREYOUTAKEACERYCAL

DonottakeACERYCAL

ifyouareallergic(hypersensitive)toperindopriloranyotherACE

inhibitor,ortoamlodipineoranyothercalciumantagonists,orany

oftheotheringredientsofACERYCAL,

ifyouaremorethan3monthspregnant(Itisalsobettertoavoid

ACERYCALinearlypregnancy-seepregnancysection),

ifyouhaveexperiencedsymptomssuchaswheezing,swellingof

thefaceortongue,intenseitchingorsevereskinrasheswith

previousACEinhibitortreatmentorifyouoramemberofyour

familyhavehadthesesymptomsinanyothercircumstances(a

conditioncalledangioedema),

ifyouhavenarrowingoftheaorticheartvalve(aorticstenosis)or

cardiogenicshock(aconditionwhereyourheartisunabletosupply

enoughbloodtothebody),

ifyouhaveseverelowbloodpressure(hypotension),

ifyousufferfromheartfailureafteraheartattack.

TakespecialcarewithACERYCAL

Ifyouhaveanyofthefollowingpleasetalktoyourdoctorbefore

takingACERYCAL:

hypertrophiccardiomyopathy(cardiacmuscledisease)orrenal

arterystenosis(narrowingofthearterywhichsuppliesthekidney

withblood),

heartfailure,

severeincreaseinbloodpressure(hypertensivecrisis),

anyotherheartproblems,

liverproblems,

kidneyproblemsorifyouarereceivingdialysis,

collagenvasculardisease(diseaseoftheconnectivetissue)suchas

systemiclupuserythematosusorscleroderma,

diabetes,

ifyouareonasaltrestricteddietorusesaltsubstituteswhich

containpotassium(awellbalancedpotassiumbloodlevelis

essential),

ifyouareelderlyandyourdoseneedstobeincreased.

Youmusttellyourdoctorifyouthinkyouare(ormightbecome)

pregnant.ACERYCALisnotrecommendedinearlypregnancy,and

causeseriousharmtoyourbabyifusedatthatstage(seepregnancy

section).

WhenyouaretakingACERYCAL,youshouldalsoinformyourdoctoror

themedicalstaffifyou:

aregoingtohaveageneralanaestheticand/ormajorsurgery,

haverecentlysufferedfromdiarrhoeaorvomiting(beingsick),

aretoundergoLDLapheresis(theremovalofcholesterolfromyour

bloodbyamachine),

aregoingtohavedesensitisationtreatmenttoreducetheeffectsof

anallergytobeeorwaspstings.

ACERYCALisnotrecommendedforuseinchildrenandadolescents.

Takingothermedicines

Pleasetellyourdoctororpharmacistifyouaretakingorhaverecently

takenanyothermedicines,includingmedicinesobtainedwithouta

prescription.

YoushouldavoidACERYCALwith:

lithium(usedtotreatmaniaordepression),

Estramustine(usedincancertherapy),

potassium-sparingdiuretics(spironolactone,triamterene),

potassiumsupplementsorpotassium-containingsaltsubstitutes.

TreatmentwithACERYCALcanbeaffectedbyothermedicines.Make

suretotellyourdoctorifyouaretakinganyofthefollowingmedicines

asspecialcaremayberequired:

othermedicinesforhighbloodpressure,includingdiuretics

(medicineswhichincreasetheamountofurineproducedbythe

kidneys),

non-steroidalanti-inflammatorydrugs(e.g.ibuprofen)forpain

relieforhighdoseaspirin,

medicinestotreatdiabetes(suchasinsulin),

medicinestotreatmentaldisorderssuchasdepression,anxiety,

schizophreniaetc(e.g.tricyclicantidepressants,antipsychotics,

imipramine-likeantidepressants,neuroleptics),

immunosuppressants(medicineswhichreducethedefence

mechanismofthebody)usedforthetreatmentofauto-immune

disordersorfollowingtransplantsurgery(e.g.ciclosporin),

allopurinol(forthetreatmentofgout),

procainamide(forthetreatmentofanirregularheartbeat),

vasodilatorsincludingnitrates(productsthatwidentheblood

vessels),

heparin(medicinesusedtothinblood),

ephedrine,noradrenalineoradrenaline(medicinesusedtotreat

lowbloodpressure,shockorasthma),

baclofenordantrolene(infusion)bothusedtotreatmuscle

stiffnessindiseasessuchasmultiplesclerosis;dantroleneisalso

usedtotreatmalignanthyperthermiaduringanaesthesia

(symptomsincludingveryhighfeverandmusclestiffness),

someantibioticssuchasrifampicin,erythromycin,clarithromycin,

antiepilepticagentssuchascarbamazepine,phenobarbital,

phenytoin,fosphenytoin,primidone,

itraconazole,ketoconazole(medicinesusedfortreatmentoffungal

infections),

alpha-blockersusedforthetreatmentofenlargedprostatesuchas

prazosin,alfuzosin,doxazosin,tamsulosin,terazosin,

amifostine(usedtopreventorreducesideeffectscausedbyother

medicinesorradiationtherapythatareusedtotreat

cancer),

corticosteroids(usedtotreatvariousconditionsincludingsevere

asthmaandrheumatoidarthritis),

goldsalts,especiallywithintravenousadministration(usedtotreat

symptomsofrheumatoidarthritis),

ritonavir,indinavir,nelfinavir(socalledproteaseinhibitorsusedto

treatHIV).

TakingACERYCALwithfoodanddrink

ACERYCALshouldbetakenbeforeameal.

Grapefruitjuiceandgrapefruitshouldnotbeconsumedbypeoplewho

aretakingACERYCAL.Thisisbecausegrapefruitandgrapefruitjuice

canleadtoanincreaseinthebloodlevelsoftheactiveingredient

amlodipine,whichcancauseanunpredictableincreaseintheblood

pressureloweringeffectofACERYCAL.

Pregnancyandbreast-feeding

Askyourdoctororpharmacistforadvicebeforetakinganymedicine.

Pregnancy

Youmusttellyourdoctorifyouthinkyouare(ormightbecome)

pregnant.Yourdoctorwillnormallyadviseyoutostoptaking

ACERYCALbeforeyoubecomepregnantorassoonasyouknowyou

arepregnantandwilladviseyoutotakeanothermedicineinsteadof

ACERYCAL.ACERYCALisnotrecommendedinearlypregnancy,and

mustnotbetakenwhenmorethan3monthspregnant,asitmay

causeseriousharmtoyourbabyifusedafterthethirdmonthof

Breast-feeding

Tellyourdoctorifyouarebreast-feedingorabouttostartbreast-

feeding.ACERYCALisnotrecommendedformotherswhoarebreast-

feeding,andyourdoctormaychooseanothertreatmentforyouifyou

wishtobreast-feed,especiallyifyourbabyisnewborn,orwasborn

prematurely.

Drivingandusingmachines

ACERYCALmayaffectyourabilitytodriveorusemachines.Ifthe

tabletsmakeyoufeelsick,dizzy,weakortired,orgiveyoua

headache,donotdriveorusemachinesandcontactyourdoctor

immediately.

Importantinformationaboutsomeoftheingredientsof

ACERYCAL

ACERYCALcontainslactosemonohydrate(atypeofsugar).Ifyouhave

beentoldbyyourdoctorthatyouhaveanintolerancetosomesugars,

contactyourdoctorbeforetakingthismedicinalproduct.

3. HOWTOTAKEACERYCAL

AlwaystakeACERYCALexactlyasyourdoctorhastoldyou.Youshould

checkwithyourdoctororpharmacistifyouarenotsure.

Swallowyourtabletwithaglassofwater,preferablyatthesametime

eachday,inthemorning,beforeameal.Yourdoctorwilldecideonthe

correctdoseforyou.Thiswillnormallybeonetabletperday.

ACERYCALwillusuallybeprescribedforpatientsalreadytaking

perindoprilandamlodipinefromseparatetablets.

IfyoutakemoreACERYCALthanyoushould

Ifyoutaketoomanytablets,contactyournearestaccidentand

emergencydepartmentortellyourdoctorimmediately.Themostlikely

effectincaseofoverdoseislowbloodpressurewhichcanmakeyou

feeldizzyorfaint.Ifthishappens,lyingdownwithyourlegsraisedcan

help.

IfyouforgettotakeACERYCAL

Itisimportanttotakeyourmedicineeverydayasregulartreatment

worksbetter.However,ifyouforgettotakeadoseofACERYCAL,take

thenextdoseattheusualtime.Donottakeadoubledosetomakeup

foraforgottendose.

IfyoustoptakingACERYCAL

AsthetreatmentwithACERYCALisusuallylife-long,youshoulddiscuss

withyourdoctorbeforeyoustoptakingyourtablets.

Ifyouhaveanyfurtherquestionsontheuseofthisproduct,askyour

doctororpharmacist.

4. POSSIBLESIDEEFFECTS

Likeallmedicines,ACERYCALcancausesideeffects,althoughnot

everybodygetsthem.

Ifyouexperienceanyofthefollowing,stoptakingthemedicinal

productatonceandtellyourdoctorimmediately:

suddenwheeziness,chestpain,shortnessofbreath,ordifficultyin

breathing,

swellingofeyelids,faceorlips,

swellingofthetongueandthroat,whichcausesgreatdifficulty

breathing,

severeskinreactionsincludingintenseskinrash,hives,reddening

oftheskinoveryourwholebody,severeitching,blistering,peeling

andswellingoftheskin,inflammationofmucousmembranes

(StevensJohnsonSyndrome)orotherallergicreactions,

severedizzinessorfainting,

heartattack,unusualfastorabnormalheartbeat,

inflamedpancreaswhichmaycausesevereabdominalandback

painaccompaniedwithfeelingveryunwell.

Thefollowingcommonsideeffectshavebeenreported.Ifanyof

thesecauseyouproblemsoriftheylastformorethanoneweek,

youshouldcontactyourdoctor.

Commonsideeffects(occurinlessthan1in10usersbutinmore

than1in100users):headache,dizziness,sleepiness(especiallyat

thebeginningoftreatment),vertigo,numbnessortingling

sensationinyourlimbs,visiondisturbances(includingdouble

vision),tinnitus(sensationofnoisesintheears),palpitations

(awarenessofyourheartbeat),flushing,light-headednessdueto

lowbloodpressure,cough,shortnessofbreath,nausea(feeling

sick),vomiting(beingsick),abdominalpain,tastedisturbances,

dyspepsiaordifficultyofdigestion,diarrhoea,constipation,allergic

reactions(suchasskinrashes,itching),musclecramps,tiredness,

weakness,ankleswelling(oedema).

Othersideeffectsthathavebeenreportedincludethefollowinglist.If

anyofthesegetserious,orifyounoticeanysideeffectsnotlistedin

thisleaflet,pleasetellyourdoctororpharmacist.

Uncommonsideeffects(occurinlessthan1in100usersbutin

morethan1in1,000users):moodswings,anxiety,depression,

sleeplessness,sleepdisturbances,trembling,fainting,lossofpain

sensation,rhinitis(blockeduporrunnynose),alteredbowel

habits,hairloss,redpatchesonskin,skindiscolouration,back

pain,muscleorjointpain,chestpain,disorderinpassingurine,

increasedneedtourinateatnight,increasednumberoftimesof

passingurine,pain,feelingunwell,bronchospasm(tighteningof

thechest,wheezingandshortnessofbreath),drymouth,

angioedema(symptomssuchaswheezing,swellingofthefaceor

tongue),kidneyproblems,impotence,increasedsweating,

discomfortorenlargementofthebreastsinmen,weightincrease

ordecrease.

Raresideeffects(occurinlessthan1in1,000usersbutinmore

than1in10,000users):confusion.

Veryraresideeffects(occurinlessthan1in10,000users):

cardiovasculardisorders(irregularheartbeat,angina,heartattack

andstroke),eosinophilicpneumonia(araretypeofpneumonia),

swellingofeyelids,faceorlips,swellingofthetongueandthroat,

whichcausesgreatdifficultyinbreathing,severeskinreactions

includingintenseskinrash,hives,reddeningoftheskinoveryour

wholebody,severeitching,blistering,peelingandswellingofthe

skin,inflammationofmucousmembranes(StevensJohnson

Syndrome),erythemamultiforme(askinrashwhichoftenstarts

withreditchypatchesonyourface,armsorlegs),sensitivityto

light,disordersoftheblood,inflamedpancreaswhichmaycause

severeabdominalandbackpainaccompaniedwithfeelingvery

unwell,abnormalliverfunction,inflammationoftheliver

(hepatitis),yellowingoftheskin(jaundice),liverenzymeincrease

whichmayhaveaneffectonsomemedicaltests,abdominal

bloating(gastritis),disorderofthenerveswhichcancause

weakness,tinglingornumbness,increasedmuscletension,

vasculitis(inflammationofbloodvessels),swellingofthegums,

excesssugarinblood(hyperglycaemia).

Thefollowingsideeffectshavealsobeenreportedbypatients

takingACERYCAL:hypoglycaemia(verylowbloodsugarlevel),

disorderscombiningrigidity,tremorand/ormovementsdisorders.

Ifanyofthesideeffectsgetserious,orifyounoticeanysideeffects

notlistedinthisleaflet,pleasetellyourdoctororpharmacist.

5. HOWTOSTOREACERYCAL

Keepoutofthesightandreachofchildren.

DonotuseACERYCALaftertheexpirydatewhichisstatedonthe

cartonandbottle.Theexpirydatereferstothelastdayofthat

month.

Keepthebottletightlyclosedinordertoprotectfrommoisture.

Storeintheoriginalpackage.

Ifyourmedicineappearstobediscoloured,damagedorshowsany

othersignsofdeterioration,pleasereturnittoyourpharmacist

whowilladviseyoufurther.

Medicinesshouldnotbedisposedofviawastewaterorhousehold

waste.Askyourpharmacisthowtodisposeofmedicinesnolonger

required.Thesemeasureswillhelptoprotecttheenvironment.

6. FURTHERINFORMATION

WhatACERYCALcontains

Theactivesubstancesareperindoprilarginineandamlodipine.

Eachtabletcontains3.395mgperindoprilequivalentto5mg

perindoprilarginineand13.870mgamlodipinebesilateequivalent

to10mgamlodipine.

Theotheringredientsinthetabletare:lactosemonohydrate,

magnesiumstearate(E470B),cellulosemicrocrystalline(E460),

colloidalanhydroussilica(E551).

WhatACERYCALlookslikeandcontentsofthepack

ACERYCAL5mg/10mgtabletsarewhite,square-shapedtablets

engravedwith5/10ononefaceand ontheotherface.

ACERYCALcomesinpacksof30tabletsinaplasticcontainerequipped

withaflowreducerandastoppercontainingadesiccantgel,inan

outercarton.

Manufacturer

Yourmedicineismanufacturedby:

AnpharmPrzedsiebiorstwoFamaceutyczneS.A.,

ul.Annopol6B,03-236Warsaw,Poland.

ProcuredfromwithintheEUbythePPAholder:

ImbatLtd.,Santry,Dublin9.

Repackagedby:DoncasterPharmaceuticalsGroupLtd.,

KirkSandall,Doncaster,SouthYorkshire,DN31QR,UK.

Distributedby:EurodrugLtd.,Santry,Dublin9.

PPANo:1151/167/2

ThismedicinalproductisauthorisedintheMemberStatesof

theEEAunderthefollowingnames:

BelgiumCOVERAM BulgariaPRESTARIUM-CO

CyprusCOVERAM CzechRepublicPRESTANCE

DenmarkCOVERSICAL EstoniaCOVERAM

FinlandCOVERAM FranceCOVERAM

GreeceCOVERAM HungaryARMIXXAM

IcelandCOVERSICAL IrelandACERYCAL

ItalyCOVERLAM LatviaPRESTERAM

LithuaniaPRESTERAM LuxembourgCOVERAM

MaltaCOVERAM NetherlandsCOVERAMarg

PolandCo-Prestarium PortugalCOVERAM

RomaniaPRESTANCE SlovakiaPRESTANCE

SloveniaPRESTANCE SpainCOVERLAM

UnitedKingdomACERYCAL

Leafletissueandrevisiondate(ref):21.06.13

ACERYCAL ® isaregisteredtrademarkofBIOFARMA.

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Acerycal5mg/10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains3.395mgperindoprilequivalentto5mgperindoprilarginineand13.870mgamlodipinebesilate

equivalentto10mgamlodipine

Excipient:lactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablets

ProductimportedfromPoland:

White,square-shapedtabletengravedwith5/10ononefaceand ontheotherface.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Acerycalisindicatedassubstitutiontherapyfortreatmentofessentialhypertensionand/orstablecoronaryartery

disease,inpatientsalreadycontrolledwithperindoprilandamlodipinegivenconcurrentlyatthesamedoselevel.

4.2Posologyandmethodofadministration

Oralroute.

Onetabletperdayasasingledose,preferablytobetakeninthemorningandbeforeameal.

Thefixeddosecombinationisnotsuitableforinitialtherapy.

Ifachangeofposologyisrequired,thedoseofAcerycalcouldbemodifiedorindividualtitrationwithfree

combinationmaybeconsidered.

Specialpopulations

Patientswithrenalimpairmentandelderly(seesections4.4and5.2)

Eliminationofperindoprilatisdecreasedintheelderlyandinpatientswithrenalfailure.Therefore,theusualmedical

follow-upwillincludefrequentmonitoringofcreatinineandpotassium.

AcerycalcanbeadministeredinpatientswithClcr 60ml/min,andisnotsuitableforpatientswithClcr<60ml/min.In

thesepatients,anindividualdosetitrationwiththemonocomponentsisrecommended.

Amlodipineusedatsimilardosesinelderlyoryoungerpatientsisequallywelltolerated.Normaldosageregimensare

recommendedintheelderly,butincreaseofthedosageshouldtakeplacewithcare.Changesinamlodipineplasma

concentrationsarenotcorrelatedwithdegreeofrenalimpairment.Amlodipineisnotdialysable.

Patientswithhepaticimpairment:seesections4.4and5.2

Dosagerecommendationshavenotbeenestablishedinpatientswithmildtomoderatehepaticimpairment;therefore

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Tofindtheoptimalstartingdoseandmaintenancedoseofpatientswithhepaticimpairment,thepatientsshouldbe

individuallytitratedusingthefreecombinationofamlodipineandperindopril.Thepharmacokineticsofamlodipine

havenotbeenstudiedinseverehepaticimpairment.Amlodipineshouldbeinitiatedatthelowestdoseandtitrated

slowlyinpatientswithseverehepaticimpairment.

Paediatricpopulations

Acerycalshouldnotbeusedinchildrenandadolescentsastheefficacyandtolerabilityofperindoprilandamlodipine,

incombination,havenotbeenestablishedinchildrenandadolescents.

4.3Contraindications

Linkedtoperindopril:

-HypersensitivitytoperindoprilortoanyotherACEinhibitor,

-HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy,

-Hereditaryoridiopathicangioedema,

-Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Linkedtoamlodipine:

-Severehypotension,

-Hypersensitivitytoamlodipineortodihydropyridinesderivatives,

-Shock,includingcardiogenicshock,

-Obstructionoftheoutflow-tractoftheleftventricle(e.g.highgradeaorticstenosis),

-Haemodynamicallyunstableheartfailureafteracutemyocardialinfarction.

LinkedtoAcerycal:

Allcontraindicationsrelatedtoeachmonocomponent,aslistedabove,shouldapplyalsotothefixedcombinationof

Acerycal.

-Hypersensitivitytoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Allwarningsrelatedtoeachmonocomponent,aslistedbelow,shouldapplyalsotothefixedcombinationofAcerycal.

Linkedtoperindopril

Specialwarnings

Hypersensitivity/Angioedema:

Angioedemaoftheface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynxhasbeenreportedrarelyin

patientstreatedwithACEinhibitors,includingperindopril(seesection4.8).Thismayoccuratanytimeduringtherapy.

Insuchcases,Acerycalshouldpromptlybediscontinuedandappropriatemonitoringshouldbeinitiatedandcontinued

untilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhereswellingwasconfinedtothefaceand

lipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

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IntestinalangioedemashouldbeincludedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwith

abdominalpain(seesection4.8).

Anaphylactoidreactionsduringlow-densitylipoproteins(LDL)apheresis:

Rarely,patientsreceivingACEinhibitorsduringlow-densitylipoprotein(LDL)apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE

inhibitortherapypriortoeachapheresis.

Anaphylactoidreactionsduringdesensitisation:

PatientsreceivingACEinhibitorsduringdesensitisationtreatment(e.g.hymenopteravenom)haveexperienced

anaphylactoidreactions.Inthesamepatients,thesereactionshavebeenavoidedwhentheACEinhibitorswere

temporarilywithheld,buttheyreappeareduponinadvertentrechallenge.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfections,whichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever).

Pregnancy:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitorsisconsideredessential,

patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablished

safetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbestopped

immediately,and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and4.6).

Precautionsforuse

Hypotension:

ACEinhibitorsmaycauseafallinbloodpressure.Symptomatichypotensionisseenrarelyinuncomplicated

hypertensivepatientsandismorelikelytooccurinpatientswhohavebeenvolume-depletede.g.bydiuretictherapy,

dietarysaltrestriction,dialysis,diarrhoeaorvomiting,orwhohavesevererenin-dependenthypertension(seesections

4.5and4.8).Inpatientsathighriskofsymptomatichypotension,bloodpressure,renalfunctionandserumpotassium

shouldbemonitoredcloselyduringtreatmentwithAcerycal.

Similarconsiderationsapplytopatientswithischaemicheartorcerebrovasculardiseaseinwhomanexcessivefallin

bloodpressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofsodiumchloride9mg/ml(0.9%)solution.Atransienthypotensiveresponseisnota

contraindicationtofurtherdoses,whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreased

aftervolumeexpansion.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy:

AswithotherACEinhibitors,perindoprilshouldbegivenwithcautiontopatientswithmitralvalvestenosisand

obstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophiccardiomyopathy.

Renalimpairement:

Incasesofrenalimpairment(creatinineclearance<60ml/min)anindividualdosetitrationwiththemonocomponents

isrecommended(seesection4.2).

Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforpatientswithrenalimpairment

(seesection4.8).

Insomepatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,whohavebeentreated

withACEinhibitors,increasesinbloodureaandserumcreatinine,usuallyreversibleupondiscontinuationoftherapy,

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Ifrenovascularhypertensionisalsopresentthereisanincreasedriskofseverehypotensionandrenalinsufficiency.

Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodurea

andserumcreatinine,usuallyminorandtransient,especiallywhenperindoprilhasbeengivenconcomitantlywitha

diuretic.Thisismorelikelytooccurinpatientswithpre-existingrenalimpairment.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Race:

ACEinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethanin

nonblacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblackhypertensivepopulation.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/Anaesthesia:

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,Acerycalmayblock

angiotensinIIformationsecondarytocompensatoryreninrelease.Thetreatmentshouldbediscontinuedonedayprior

tothesurgery.Ifhypotensionoccursandisconsideredtobeduetothismechanism,itcanbecorrectedbyvolume

expansion.

Hyperkaliemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

age(>70years),diabetesmellitus,intercurrentevents,inparticulardehydratation,acutecardiacdecompensation,

metabolicacidosis,andconcomitantuseofpotassium-sparingdiuretics(e.g.spironolactone,eplerenone,triamterene,or

amiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

associatedwithincreasesinserumpotassium(e.g.heparin).Theuseofpotassiumsupplements,potassium-sparing

diuretics,orpotassium-containingsaltsubstitutesparticularlyinpatientswithimpairedrenalfunctionmayleadtoa

significantincreaseinserumpotassium.Hyperkalemiacancauseserious,sometimesfatalarrhythmias.Ifconcomitant

useofperindoprilandanyoftheabovementionedagentsisdeemedappropriate,theyshouldbeusedwithcautionand

withfrequentmonitoringofserumpotassium(seesection4.5).

Diabeticpatients:

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor(seesection4.5).

Linkedtoamlodipine:

Precautionsforuse

Thesafetyandefficacyofamlodipineinhypertensivecrisishasnotbeenestablished.

Useinpatientswithcardiacfailure:

Patientswithheartfailureshouldbetreatedwithcaution.

Inalong-term,placebocontrolledstudyinpatientswithsevereheartfailure(NYHAclassIIIandIV)thereported

incidenceofpulmonaryoedemawashigherintheamlodipinetreatedgroupthanintheplacebogroup(seesection5.1).

Calciumchannelblockers,includingamlodipine,shouldbeusedwithcautioninpatientswithcongestiveheartfailure,

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Useinpatientswithimpairedhepaticfunction:

Thehalf-lifeofamlodipineisprolongedandAUCvaluesarehigherinpatientswithimpairedliverfunction;dosage

recommendationshavenotbeenestablished.Amlodipineshouldthereforebeinitiatedatthelowerendofthedosing

rangeandcautionshouldbeused,bothoninitialtreatmentandwhenincreasingthedose.Slowdosetitrationand

carefulmonitoringmayberequiredinpatientswithseverehepaticimpairment.

Useinelderlypatients:

Intheelderlyincreaseofthedosageshouldtakeplacewithcare(seesections4.2and5.2).

Useinrenalfailure:

Amlodipinemaybeusedinsuchpatientsatnormaldoses.Changesinamlodipineplasmaconcentrationsarenot

correlatedwithdegreeofrenalimpairment.Amlodipineisnotdialysable.

LinkedtoAcerycal

Allwarningsrelatedtoeachmonocomponent,aslistedabove,shouldapplyalsotothefixedcombinationofAcerycal.

Precautionsforuse

Excipients:

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,glucose-galactose

malabsorption,ortheLapplactasedeficiencyshouldnottakethismedicinalproduct.

Interactions

TheconcomitantuseofAcerycalwithlithium,potassium-sparingdiureticsorpotassiumsupplements,ordantroleneis

notrecommended(seesection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Linkedtoperindopril

Concomitantusenotrecommended:

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes:

Althoughserumpotassiumusuallyremainswithinnormallimits,hyperkalaemiamayoccurinsomepatientstreated

withperindopril.Potassiumsparingdiuretics(e.g.spironolactone,triamterene,oramiloride),potassiumsupplements,

orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesinserumpotassium.Thereforethe

combinationofperindoprilwiththeabove-mentioneddrugsisnotrecommended(seesection4.4).Ifconcomitantuseis

indicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringof

serumpotassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicity(severeneurotoxicity)havebeenreportedduring

concurrentuseofACEinhibitors.Thecombinationofperindoprilwithlithiumisnotrecommended.Ifthecombination

provesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended(seesection4.4).

Estramustine:

Riskofincreasedadverseeffectssuchasangioneuroticoedema(angioedema).

Concomitantusewhichrequiresspecialcare:

Non-steroidalanti-inflammatorymedicinalproducts(NSAIDs)includingaspirin 3g/day:

WhenACE-inhibitorsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(i.e.acetylsalicylic

acidatanti-inflammatorydosageregimens,COX-2inhibitorsandnon-selectiveNSAIDs),attenuationofthe

antihypertensiveeffectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

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Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbeadequatelyhydrated

andconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationofconcomitanttherapy,andperiodically

thereafter.

Antidiabeticagents(insulin,hypoglycaemicsulphonamides):

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.Theonsetofhypoglycaemicepisodesisveryrare(there

isprobablyanimprovementinglucosetolerancewitharesultingreductionininsulinrequirements).

Concomitantusetobetakenintoconsideration:

Diuretics:

Patientsondiuretics,andespeciallythosewhoarevolumeand/orsaltdepleted,mayexperienceexcessivereductionin

bloodpressureafterinitiationoftherapywithanACEinhibitor.Thepossibilityofhypotensiveeffectscanbereduced

bydiscontinuationofthediuretic,byincreasingvolumeorsaltintakepriortoinitiatingtherapywithlowand

progressivedosesofperindopril.

Sympathomimetics:

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

Gold:

Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreportedrarelyin

patientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapyincluding

perindopril.

Linkedtoamlodipine

Concomitantusenotrecommended:

Dantrolene(infusion):Inanimals,lethalventricularfibrillationandcardiovascularcollapseareobservedinassociation

withhyperkalemiaafteradministrationofverapamilandintravenousdantrolene.Duetoriskofhyperkalemia,itis

recommendedthattheco-administrationofcalciumchannelblockerssuchasamlodipinebeavoidedinpatients

susceptibletomalignanthyperthermiaandinthemanagementofmalignanthyperthermia.

Concomitantusewhichrequiresspecialcare:

CYP3A4inducers:ThereisnodataavailableregardingtheeffectofCYP3A4inducersonamlodipine.The

concomitantuseofCYP3A4inducers(e.g.,rifampicin,hypericumperforatum)maygivealowerplasmaconcentration

ofamlodipine.AmlodipineshouldbeusedwithcautiontogetherwithCYP3A4inducers.

CYP3A4inhibitors:ConcomitantuseofamlodipinewithstrongormoderateCYP3A4inhibitors(proteaseinhibitors,

azoleantifungals,macrolideslikeerythromycinorclarithromycin,verapamilordiltiazem)maygiverisetosignificant

increaseinamlodipineexposure.TheclinicaltranslationofthesePKvariationsmaybemorepronouncedintheelderly.

Clinicalmonitoringanddoseadjustmentmaythusberequired.

Concomitantusetobetakenintoconsideration:

Thebloodpressureloweringeffectsofamlodipineaddstothebloodpressure-loweringeffectsofothermedicinal

productswithantihypertensiveproperties.

Otherscombinations:

Inclinicalinteractionstudies,amlodipinedidnotaffectthepharmacokineticsofatorvastatin,digoxin,warfarinor

cyclosporin.

Administrationofamlodipinewithgrapefruitorgrapefruitjuiceisnotrecommendedasbioavailabilitymaybe

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LinkedtoAcerycal:

Concomitantusewhichrequiresspecialcare:

Baclofen:Potentiationofantihypertensiveeffect.Monitoringofbloodpressureandrenalfunction,anddoseadaptation

oftheantihypertensiveifnecessary.

Concomitantusetobetakenintoconsideration:

Antihypertensiveagents(suchasbeta-blockers)andvasodilatators:

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindoprilandamlodipine.Concomitant

usewithnitroglycerineandothernitratesorothervasodilatators,mayfurtherreducebloodpressureandtherefore

shouldbeconsideredwithcaution.

Corticosteroids,tetracosactide:reductioninantihypertensiveeffect(saltandwaterretentionduetocorticosteroids).

Alpha-blockers(prazosin,alfuzosin,doxazosin,tamsulosin,terazosin):increasedantihypertensiveeffectand

increasedriskoforthostatichypotension.

Amifostine:maypotentiatetheantihypertensiveeffectofamlodipine.

Tricyclicantidepressants/antipsychotics/anaesthetics:increasedantihypertensiveeffectandincreasedriskof

orthostatichypotension.

4.6Fertility,pregnancyandlactation

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancyandlactation:

Acerycalisnotrecommendedduringthefirsttrimesterofpregnancy.Acerycaliscontraindicatedduringthesecondand

thirdtrimestersofpregnancy.

Acerycalisnotrecommendedduringlactation.Adecisionshouldthereforebemadewhethertodiscontinuenursingor

todiscontinueAcerycaltakingaccounttheimportanceofthistherapyforthemother.

Pregnancy:

Linkedtoperindopril

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Linkedtoamlodipine

Thesafetyofamlodipineinhumanpregnancyhasnotbeenestablished.

Inanimalstudies,reproductivetoxicitywasobservedathighdoses(seesection5.3).Useinpregnancyisonly

recommendedwhenthereisnosaferalternativeandwhenthediseaseitselfcarriesgreaterriskforthemotherand

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection

4.4).TheuseofACEinhibitorsiscontraindicatedduringthesecondandthirdtrimesterof

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Lactation:

Linkedtoperindopril

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Linkedtoamlodipine

Itisnotknownwhetheramlodipineisexcretedinbreastmilk.Adecisiononwhethertocontinue/discontinuebreast-

feedingortocontinue/discontinuetherapywithamlodipineshouldbemadetakingintoaccountthebenefitofbreast-

feedingtothechildandthebenefitofamlodipinetherapytothemother.

Fertility:

Reversiblebiochemicalchangesintheheadofspermatozoahavebeenreportedinsomepatientstreatedbycalcium

channelblockers.Clinicaldataareinsufficientregardingthepotentialeffectofamlodipineonfertility.Inoneratstudy,

adverseeffectswerefoundonmalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectsofAcerycalontheabilitytodriveandusemachineshavebeenperformed.Amlodipinecan

haveminorormoderateinfluenceontheabilitytodriveandusemachines.Ifpatientssufferfromdizziness,headache,

fatigue,wearinessornausea,theabilitytoreactmaybeimpaired.Cautionisrecommendedespeciallyatthestartof

treatment.

4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithperindopriloramlodipinegivenseparately

andrankedundertheMedDRAclassificationbybodysystemandunderthefollowingfrequency:

Verycommon(1/10);common(1/100to<1/10);uncommon(1/1000to<1/100);rare(1/10000to<1/1000);very

rare(<1/10000);notknown(cannotbeestimatedfromtheavailabledata).

MedDRA

SystemOrgan

Class UndesirableEffects Frequency

Amlodipine Perindopril

Bloodandthe

lynphaticSystem

Disorders Leucopenia/neutropenia(seesection4.4) Veryrare Veryrare

Agranulocytosisorpancytopenia(seesection

4.4) - Veryrare

Thrombocytopenia(seesection4.4) Veryrare Veryrare

Haemolyticanaemiainpatientswitha

congenitaldeficiencyofG-6PDH(seesection

4.4) - Veryrare

Decreaseinhaemoglobinandhaematocrit - Veryrare

ImmuneSystem

Disorders Allergicreactions Veryrare Uncommon

Metabolismand

Nutrition

Disorders Hyperglycaemia Veryrare -

Hypoglycaemia(seesections4.4and4.5) - Notknown

Psychiatric

disorders Insomnia Uncommon -

Moodchanges(includinganxiety) Uncommon Uncommon

Depression Uncommon -

Sleepdisturbances - Uncommon

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NervousSystem

disorders Somnolence(especiallyatthebeginningofthe

treatment) Common -

Dizziness(especiallyatthebeginningofthe

treatment) Common Common

Headache(especiallyatthebeginningofthe

treatment) Common Common

Dysgeusia Uncommon Common

Tremor Uncommon -

Hypoesthaesia

Paresthaesia Uncommon

Uncommon -

Common

Syncope Uncommon -

Hypertonia Veryrare -

Peripheralneuropathy Veryrare -

Vertigo - Common

EyeDisorders Visualdisturbances(includingdiplopia) Uncommon Common

Earandlabyrinth

disorders Tinnitus Uncommon Common

CardiacDisorders Palpitations Common -

Anginapectoris - Veryrare

Myocardialinfarction,possiblysecondaryto

excessivehypotensioninhighriskpatients(see

section4.4) Veryrare Veryrare

Arrythmia(includingbradycardia,ventricular

tachycardiaandatrialfibrillation) Veryrare Veryrare

Vascular

Disorders Flushing Common -

Hypotension(andeffectsrelatedto

hypotension) Uncommon Common

Strokepossiblysecondarytoexcessive

hypotensioninhigh-riskpatients(seesection

4.4) - Veryrare

Vasculitis VeryRare Notknown

Respiratory,

Thoracicand

Mediastinal

Disorders Dyspnoea Uncommon Common

Rhinitis Uncommon Veryrare

Cough Veryrare Common

Bronchospasm - Uncommon

Eosinophilicpneumonia - Veryrare

Gastro-intestinal

Disorders Gingivalhyperplasia Veryrare -

Abdominalpain,nausea Common Common

Vomiting Uncommon Common

Dyspepsia Uncommon Common

Alteredbowelhabits Uncommon -

Drymouth Uncommon Uncommon

Diarrhoea,constipation Uncommon Common

Pancreatitis Veryrare Veryrare

Gastritis Veryrare -

Hepato-biliary

Disorders Hepatitis,jaundice

Hepatitiseithercytoliticorcholestatic(see

section4.4) Veryrare

Veryrare

Hepaticenzymesincreased(mostlyconsistent

withcholestasis) Veryrare -

Skinand

Subcutaneous

TissueDisorders Quincke’soedema

Angioedemaofface,extremities,lips,mucous

membranes,tongue,glottisand/orlarynx(see

section4.4) Veryrare

Veryrare -

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Additionalinformationlinkedtoamlodipine

Exceptionalcasesofextrapyramidalsyndromehavebeenreported.

4.9Overdose

ThereisnoinformationonoverdosagewithAcerycalinhumans.

Foramlodipine,experiencewithintentionaloverdoseinhumansislimited.

Symptoms:availabledatasuggestthatgrossoverdosagecouldresultinexcessiveperipheralvasodilatationandpossibly

reflextachycardia.Markedandprobablyprolongedsystemichypotensionuptoandincludingshockwithfataloutcome

havebeenreported.

Treatment:clinicallysignificanthypotensionduetoamlodipineoverdosagecallsforactivecardiovascularsupport

includingfrequentmonitoringofcardiacandrespiratoryfunction,elevationofextremitiesandattentiontocirculating

fluidvolumeandurineoutput.

Avasoconstrictormaybehelpfulinrestoringvasculartoneandbloodpressure,providedthatthereisno

contraindicationtoitsuse.Intravenouscalciumgluconatemaybebeneficialinreversingtheeffectsofcalciumchannel

blockade.

Gastriclavagemaybeworthwhileinsomecases.Inhealthyvolunteerstheuseofcharcoalupto2hoursafter

Erythemamultiform Veryrare Veryrare

Alopecia Uncommon -

Purpura Uncommon -

Skindiscoloration Uncommon -

Hyperhidrosis Uncommon Uncommon

Prurit Uncommon Common

Rash,exanthema Uncommon Common

Urticaria Veryrare Uncommon

Stevens-JohnsonSyndrome Veryrare -

Exfoliativedermatitis Veryrare -

Photosensitivity Veryrare -

Musculoskeletal

AndConnective

TissueDisorders Ankleswelling Common -

Arthralgia,myalgia Uncommon -

Musclecramps Uncommon Common

Backpain Uncommon -

Renaland

UrinaryDisorders Micturitiondisorder,nocturia,increasedurinary

frequency Uncommon -

Renalimpairment - Uncommon

Acuterenalfailure - Veryrare

Reproductive

SystemandBreast

Disorders Impotence Uncommon Uncommon

Gynaecomastia Uncommon -

GeneralDisorders

and

Administration

SiteCondition Oedema Common -

Fatigue Common -

Chestpain Uncommon -

Asthenia Uncommon Common

Pain Uncommon -

Malaise Uncommon -

Investigations Weightincrease,weightdecrease Uncommon -

Serumbilirubinandliverenzymeselevation - Rare

Increasesinbloodureaandserumcreatinine,

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Sinceamlodipineishighlyprotein-bound,dialysisisnotlikelytobeofbenefit.

Forperindopril,limiteddataareavailableforoverdosageinhumans.Symptomsassociatedwiththeoverdosageof

ACEinhibitorsmayincludehypotension,circulatoryshock,electrolytedisturbances,renalfailure,hyperventilation,

tachycardia,palpitations,bradycardia,dizziness,anxiety,andcough.

Therecommendedtreatmentofoverdosageisintravenousinfusionofnormalsalinesolution.Ifhypotensionoccurs,the

patientshouldbeplacedintheshockposition.Ifavailable,treatmentwithangiotensinIIinfusionand/orintravenous

catecholaminesmayalsobeconsidered.Perindoprilcanberemovedfromthesystemiccirculationbyhaemodialysis

(seesection4.4).Pacemakertherapyisindicatedfortreatment-resistantbradycardia.Vitalsigns,serumelectrolytesand

creatinineconcentrationsshouldbemonitoredcontinuously.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitorsandcalciumchannelblockers,ATCcode:C09BB04

Perindopril:

PerindoprilisaninhibitoroftheenzymethatconvertsangiotensinIintoangiotensinII(AngiotensinConverting

EnzymeACE).Theconvertingenzyme,orkinase,isanexopeptidasethatallowsconversionofangiotensinIintothe

vasoconstrictorangiotensinIIaswellascausingthedegradationofthevasodilatorbradykininintoaninactive

heptapeptide.InhibitionofACEresultsinareductionofangiotensinIIintheplasma,whichleadstoincreasedplasma

reninactivity(byinhibitionofthenegativefeedbackofreninrelease)andreducedsecretionofaldosterone.SinceACE

inactivatesbradykinin,inhibitionofACEalsoresultsinanincreasedactivityofcirculatingandlocalkallikrein-kinin

systems(andthusalsoactivationoftheprostaglandinsystem).Itispossiblethatthismechanismcontributestothe

bloodpressure-loweringactionofACEinhibitorsandispartiallyresponsibleforcertainoftheirsideeffects(e.g.

cough).

Perindoprilactsthroughitsactivemetabolite,perindoprilat.TheothermetabolitesshownoinhibitionofACEactivity

invitro.

Hypertension:

Perindoprilisactiveinallgradesofhypertension:mild,moderate,severe;areductioninsystolicanddiastolicblood

pressuresinbothsupineandstandingpositionsisobserved.

Perindoprilreducesperipheralvascularresistance,leadingtobloodpressurereduction.Asaconsequence,peripheral

bloodflowincreases,withnoeffectonheartrate.

Renalbloodflowincreasesasarule,whiletheglomerularfiltrationrate(GFR)isusuallyunchanged.

Theantihypertensiveactivityismaximalbetween4and6hoursafterasingledoseandissustainedforatleast24

hours:trougheffectsareabout87-100%ofpeakeffects.

Thedecreaseinbloodpressureoccursrapidly.Inrespondingpatients,normalisationisachievedwithinamonthand

persistswithouttheoccurrenceoftachyphylaxis.

Discontinuationoftreatmentdoesnotleadtoareboundeffect.

Perindoprilreducesleftventricularhypertrophy.

Inman,perindoprilhasbeenconfirmedtodemonstratevasodilatoryproperties.Itimproveslargearteryelasticityand

decreasesthe

media:lumenratioofsmallarteries.

Patientswithstablecoronaryarterydisease:

TheEUROPAstudywasamulticentre,international,randomised,double-blind,placebo-controlledclinicaltriallasting

4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopril

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Thetrialpopulationhadevidenceofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheartfailure.Overall,

90%ofthepatientshadapreviousmyocardialinfarctionand/orapreviouscoronaryrevascularisation.Mostofthe

patientsreceivedthestudymedicationontopofconventionaltherapyincludingplateletinhibitors,lipidlowering

agentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardialinfarctionand/or

cardiacarrestwithsuccessfulresuscitation.Thetreatmentwith8mgperindopriltert-butylamine(equivalentto10mg

perindoprilarginine)oncedailyresultedinasignificantabsolutereductionintheprimaryendpointof1.9%(relative

riskreductionof20%,95%CI[9.4;28.6]–p<0.001).

Inpatientswithahistoryofmyocardialinfarctionand/orrevascularisation,anabsolutereductionof2.2%

correspondingtoaRRRof22.4%(95%CI[12.0;31.6]–p<0.001)intheprimaryendpointwasobservedby

comparisontoplacebo.

Amlodipine:

Amlodipineisacalciumioninfluxinhibitorofthedihydropyridinegroup(slowchannelblockerorcalciumion

antagonist)andinhibitsthetransmembraneinfluxofcalciumionsintocardiacandvascularsmoothmuscle.

Themechanismoftheantihypertensiveactionofamlodipineisduetoadirectrelaxanteffectonvascularsmooth

muscle.Theprecisemechanismbywhichamlodipinerelievesanginahasnotbeenfullydeterminedbutamlodipine

reducestotalischaemicburdenbythefollowingtwoactions:

Amlodipinedilatesperipheralarteriolesandthus,reducesthetotalperipheralresistance(afterload)againstwhichthe

heartworks.Sincetheheartrateremainsstable,thisunloadingoftheheartreducesmyocardialenergyconsumption

andoxygenrequirements.

Themechanismofactionofamlodipinealsoprobablyinvolvesdilatationofthemaincoronaryarteriesandcoronary

arterioles,bothinnormalandischaemicregions.Thisdilatationincreasesmyocardialoxygendeliveryinpatients

withcoronaryarteryspasm(Prinzmetal'sorvariantangina).

Inpatientswithhypertension,oncedailydosingprovidesclinicallysignificantreductionsofbloodpressureinboththe

supineandstandingpositionsthroughoutthe24hourinterval.Duetotheslowonsetofaction,acutehypotensionisnot

afeatureofamlodipineadministration.

Inpatientswithangina,oncedailyadministrationofamlodipineincreasestotalexercisetime,timetoanginaonset,and

timeto1mmSTsegmentdepression,anddecreasesbothanginaattackfrequencyandglyceryltrinitratetablet

consumption.

Amlodipinehasnotbeenassociatedwithanyadversemetaboliceffectsorchangesinplasmalipidsandissuitablefor

useinpatientswithasthma,diabetes,andgout.

Patientswithcoronaryarterydisease(CAD):

Theeffectivenessofamlodipineinpreventingclinicaleventsinpatientswithcoronaryarterydisease(CAD)hasbeen

evaluatedinanindependent,multi-center,randomized,double-blind,placebo-controlledstudyof1997patients;

ComparisonofAmlodipinevs.EnalapriltoLimitOccurrencesofThrombosis(CAMELOT).Ofthesepatients,663

weretreatedwithamlodipine5-10mg,673patientsweretreatedwithenalapril10-20mg,and655patientsweretreated

withplacebo,inadditiontostandardcareofstatins,beta-blockers,diureticsandaspirin,for2years.Thekeyefficacy

resultsarepresentedinTable1.Theresultsindicatethatamlodipinetreatmentwasassociatedwithfewer

hospitalizationsforanginaandrevascularizationproceduresinpatientswithCAD.

Table1.IncidenceofsignificantclinicaloutcomesforCAMELOT

Cardiovasculareventrates,No.(%) Amlodipinevs.placebo

Outcomes Amlodipine Placebo Enalapril HazardRatio

(95%CI) PValue

PrimaryEndpoint

Adversecardiovascularevents -

110(16.6) -

151(23.1) -

136(20.2) -

0.69(0.54-

0.88) -

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Abbreviations:CHF,congestiveheartfailure;CI,confidenceinterval;MI,myocardialinfarction;TIA,transient

ischemicattack.

Useinpatientswithheartfailure:

HaemodynamicstudiesandexercisebasedcontrolledclinicaltrialsinNYHAClassII-IVheartfailurepatientshave

shownthatamlodipinedidnotleadtoclinicaldeteriorationasmeasuredbyexercisetolerance,leftventricularejection

fractionandclinicalsymptomatology.

Aplacebocontrolledstudy(PRAISE)designedtoevaluatepatientsinNYHAClassIII-IVheartfailurereceiving

digoxin,diureticsandACEinhibitorshasshownthatamlodipinedidnotleadtoanincreaseinriskofmortalityor

combinedmortalityandmorbiditywithheartfailure.

Inafollow-up,longterm,placebocontrolledstudy(PRAISE-2)ofamlodipineinpatientswithNYHAIIIandIVheart

failurewithoutclinicalsymptomsorobjectivefindingssuggestiveorunderlyingischaemicdisease,onstabledosesof

ACEinhibitors,digitalis,anddiuretics,amlodipinehadnoeffectontotalcardiovascularmortality.Inthissame

populationamlodipinewasassociatedwithincreasedreportsofpulmonaryoedema.

Treatmenttopreventheartattacktrial(ALLHAT):

Arandomizeddouble-blindmorbidity-mortalitystudycalledtheAntihypertensiveandLipid-LoweringTreatmentto

PreventHeartAttackTrial(ALLHAT)wasperformedtocomparenewerdrugtherapies:amlodipine2.5-10mg/d

(calciumchannelblocker)orlisinopril10-40mg/d(ACE-inhibitor)asfirst-linetherapiestothatofthethiazide-diuretic,

chlorthalidone12.5-25mg/dinmildtomoderatehypertension.

Atotalof33,357hypertensivepatientsaged55orolderwererandomizedandfollowedforameanof4.9years.The

patientshadatleastoneadditionalCHDriskfactor,including:previousmyocardialinfarctionorstroke>6months

priortoenrollmentordocumentationofotheratheroscleroticCVD(overall51.5%),type2diabetes(36.1%),HDL-C<

35mg/dL(11.6%),leftventricularhypertrophydiagnosedbyelectrocardiogramorechocardiography(20.9%),current

cigarettesmoking(21.9%).

TheprimaryendpointwasacompositeoffatalCHDornon-fatalmyocardialinfarction.Therewasnosignificant

differenceintheprimaryendpointbetweenamlodipine-basedtherapyandchlorthalidone-basedtherapy:RR0.98(95%

CI(0.90-1.07)p=0.65).Amongsecondaryendpoints,theincidenceofheartfailure(componentofacomposite

combinedcardiovascularendpoint)wassignificantlyhigherintheamlodipinegroupascomparedtothechlorthalidone

group(10.2%vs7.7%,RR1.38,(95%CI[1.25-1.52]p<0.001)).However,therewasnosignificantdifferencein

allcausemortalitybetweenamlodipine-basedtherapyandchlorthalidone-basedtherapy,RR0.96(95%CI[0.89-1.02]

IndividualComponents

Coronaryrevascularization

Hospitalizationforangina

NonfatalMI

StrokeorTIA

Cardiovasculardeath

HospitalizationforCHF

Resuscitatedcardiacarrest

New-onsetperipheralvascular

78(11.8)

51(7.7)

14(2.1)

6(0.9)

5(0.8)

3(0.5)

5(0.8) 103(15.7)

84(12.8)

19(2.9)

12(1.8)

2(0.3)

5(0.8)

4(0.6)

2(0.3) 95(14.1)

86(12.8)

11(1.6)

8(1.2)

5(0.7)

4(0.6)

1(0.1)

8(1.2) 0.73(0.54-

0.98)

0.58(0.41-

0.82)

0.73(0.37-

1.46)

0.50(0.19-

1.32)

2.46(0.48-

12.7)

0.59(0.14-

2.47)

.002

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5.2Pharmacokineticproperties

TherateandextentofabsorptionofperindoprilandamlodipinefromAcerycalarenotsignificantlydifferent,

respectively,fromtherateandextentofabsorptionofperindoprilandamlodipinefromindividualtabletformulations.

Perindopril:

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationisachievedwithin1hour.

Theplasmahalf-lifeofperindoprilisequalto1hour.

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindoprilarginineshouldbe

administeredorallyinasingledailydoseinthemorningbeforeameal.

Ithasbeendemonstratedalinearrelationshipbetweenthedoseofperindoprilanditsplasmaexposure.

Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingofperindoprilatto

plasmaproteinsis20%,principallytoangiotensinconvertingenzyme,butisconcentration-dependent.Perindoprilatis

eliminatedintheurineandtheterminalhalf-lifeoftheunboundfractionisapproximately17hours,resultingin

steadystatewithin4days.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure(seesection4.2).

Therefore,theusualmedicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(see

sections4.2and4.4).

Amlodipine:

Afteroraladministrationoftherapeuticdoses,amlodipineiswellabsorbedwithpeakbloodlevelsbetween6-12hours

postdose.Absolutebioavailabilityhasbeenestimatedtobebetween64and80%.Thevolumeofdistributionis

approximately21l/kg.Invitrostudieshaveshownthatapproximately97.5%ofcirculatingamlodipineisboundto

plasmaproteins.

Thebioavailabilityofamlodipineisnotaffectedbyfoodintake.

Theterminalplasmaeliminationhalf-lifeisabout35-50hoursandisconsistentwithoncedailydosing.Amlodipineis

extensivelymetabolisedbythelivertoinactivemetaboliteswith10%oftheparentcompoundand60%ofmetabolites

excretedintheurine.

Useintheelderly:thetimetoreachpeakplasmaconcentrationsofamlodipineissimilarinelderlyandyounger

subjects.AmlodipineclearancetendstobedecreasedwithresultingincreasesinAUCandeliminationhalf-lifein

elderlypatients.IncreasesinAUCandeliminationhalf-lifeinpatientswithcongestiveheartfailurewereasexpected

forthepatientagegroupstudied.

Useinpatientswithimpairedhepaticfunction:Verylimitedclinicaldataareavailableregardingamlodipine

administrationinpatientswithhepaticimpairment.Patientswithhepaticinsufficiencyhavedecreasedclearanceof

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5.3Preclinicalsafetydata

Perindopril:

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversibledamage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefetal

development,resultinginfetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreasein

periandpostnatalmortalityhavebeenobserved.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

Amlodipine:

Reproductivetoxicology

Reproductivestudiesinratsandmicehaveshowndelayeddateofdelivery,prolongeddurationoflabouranddecreased

pupsurvivalatdosagesapproximately50timesgreaterthanthemaximumrecommendeddosageforhumansbasedon

mg/kg.

Impairmentoffertility

Therewasnoeffectonthefertilityofratstreatedwithamlodipine(malesfor64daysandfemales14dayspriorto

mating)atdosesupto10mg/kg/day(8times*themaximumrecommendedhumandoseof10mgonamg/m2basis).

Inanotherratstudyinwhichmaleratsweretreatedwithamlodipinebesilatefor30daysatadosecomparablewiththe

humandosebasedonmg/kg,decreasedplasmafollicle-stimulatinghormoneandtestosteronewerefoundaswellas

decreasesinspermdensityandinthenumberofmaturespermatidsandSertolicells.

Carcinogenesis,mutagenesis

Ratsandmicetreatedwithamlodipineinthedietfortwoyears,atconcentrationscalculatedtoprovidedailydosage

levelsof0.5,1.25,and2.5mg/kg/dayshowednoevidenceofcarcinogenicity.Thehighestdose(formice,similarto,

andforratstwice*themaximumrecommendedclinicaldoseof10mgonamg/m2basis)wasclosetothemaximum

tolerateddoseformicebutnotforrats.

Mutagenicitystudiesrevealednodrugrelatedeffectsateitherthegeneorchromosomelevels.

*Basedonpatientweightof50kg

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Cellulose,microcrystalline(E460)

Silica,colloidalanhydrous(E551)

Magnesiumstearate(E470B)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainer&outerpackageoftheproductonthe

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6.4Specialprecautionsforstorage

Keepthecontainertightlyclosedinordertoprotectfrommoisture.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

30tabletsinaplasticcontainerequippedwithaflowreducerandastoppercontainingadesiccantgel,inanouter

carton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2,NorthRingBusinessPark

Santry

Dublin9

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1151/167/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27 th

January2012

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 09/08/2013 CRN 2131639 page number: 16

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