ACERYCAL

Main information

  • Trade name:
  • ACERYCAL Tablets 5/ 10 Milligram
  • Dosage:
  • 5/ 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACERYCAL Tablets 5/10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/167/002
  • Authorization date:
  • 27-01-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

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.

Patientswithrenalimpairmentandelderly(seesections4.4and5.2)

Eliminationofperindoprilatisdecreasedintheelderlyandinpatientswithrenalfailure.Therefore,theusualmedical

follow-upwillincludefrequentmonitoringofcreatinineandpotassium.

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

Inthesepatients,anindividualdosetitrationwiththemonocomponentsisrecommended.

Changesinamlodipineplasmaconcentrationsarenotcorrelatedwithdegreeofrenalimpairment.

Patientswithhepaticimpairment:seesections4.4and5.2

Adosageregimenforpatientswithhepaticimpairmenthasnotbeenestablished.Therefore,Acerycalshouldbe

administeredwithcaution.

Childrenandadolescents

Acerycalshouldnotbeusedinchildrenandadolescentsastheefficacyandtolerabilityofperindoprilandamlodipine,

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4.3Contraindications

Linkedtoperindopril:

HypersensitivitytoperindoprilortoanyotherACEinhibitor,

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy,

Hereditaryoridiopathicangioedema,

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Linkedtoamlodipine:

Severehypotension,

Hypersensitivitytoamlodipineortoanyotherdihydropyridines,

Shock,includingcardiogenicshock,

Obstructionoftheoutflow-tractoftheleftventricle(e.g.highgradeaorticstenosis),

Unstableanginapectoris(excludingPrinzmetal'sangina),

Heartfailureafteracutemyocardialinfarction(duringthefirst28days).

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

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

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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,

havebeenseen.Thisisespeciallylikelyinpatientswithrenalinsufficiency.Ifrenovascularhypertensionisalso

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Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodurea

andserumcreatinine,usuallyminorandtransient,especiallywhenperindoprilhasbeengivenconcomitantlywitha

diuretic.Thisismorelikelytooccurinpatientswithpre-existingrenalimpairment.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.

PatientsreceivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinue

theACEinhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Race:

ACEinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon-

blacks,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

Patientswithimpairedhepaticfunction:

Aswithallcalciumantagonists,amlodipine'shalf-lifeisprolongedinpatientswithimpairedliverfunction.Thedrug

shouldthereforebeadministeredwithcautioninthesepatientsandwithaclosemonitoringofthehepaticenzymes.

Patientswithheartfailure:

Patientswithcardiacfailureshouldbetreatedwithcaution.

Inalong-term,placebocontrolledstudy(PRAISE-2)ofamlodipineinpatientswithNYHAIIIandIVheartfailureof

nonischaemicaetiology,amlodipinewasassociatedwithincreasedreportsofpulmonaryoedemadespitenosignificant

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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

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

Antidiabeticagents(insulin,hypoglycaemicsulphonamides):

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.

Theonsetofhypoglycaemicepisodesisveryrare(thereisprobablyanimprovementinglucosetolerancewitha

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Concomitantusewhichrequiresspecialcare:

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,lethalventricularfibrillationsareobservedafteradministrationofverapamiland

dantroleneI.V.Byextrapolation,thecombinationofamlodipineanddantroleneshouldbeavoided.

Concomitantusewhichrequiresspecialcare:

CYP3A4inducers(rifampicine,Hypericumperforatum,anticonvulsantagentsi.ecarbamazepine,phenobarbital,

phenytoine,fosphenytoine,primidone):co-administrationmayleadtoreducedplasmaconcentrationofamlodipinedue

toanincreaseofthehepaticmetabolismofamlodipinebytheseinducers.Cautionshouldbeexercisedincombination

ofamlodipinewithCYP3A4inducersandposologyofamlodipinecouldbeadaptedifneeded.

CYP3A4inhibitors(itraconazole,ketoconazole):co-administrationmayincreasetheplasmaconcentrationof

amlodipineandconsequentlyitsadverseeffects.Cautionshouldbeexercisedwhencombiningamlodipinewith

itraconazoleorketoconazoleandposologyofamlodipineshouldbeadjustedifneeded.

Concomitantusetobetakenintoconsideration:

Beta-blockersusedinheartfailure(bisoprolol,carvedilol,metoprolol):

Riskofhypotension,heartweaknessinpatientswithcardiacheartfailure,beitlatentoruncontrolled(additionof

negativeinotropeeffect).Furthermore,thebeta-blockermayminimizethesympathicreflexincaseofexcessive

heamodynamicrepercussion.

Otherscombinations:

Inmonotherapy,amlodipinehasbeensafelyadministeredwiththiazidediuretics,betablockers,ACEinhibitors,long-

actingnitrates,sublingualnitroglycerin,digoxin,warfarin,atorvastatin,sildenafil,anti-acidmedicines(aluminium

hydroxidegel,magnesiumhydroxide,simeticone),cimetidine,non-steroidalanti-inflammatorymedicines,antibiotics

andoralhypoglycaemicmedicines.

Indeed,specificstudiesconductedwithsomedrugshaveshownnoinfluenceonamlodipine:

-co-administrationofamlodipinewithcimetidinedidnotalterthepharmacokineticsofamlodipine.

-whensildenafilandamlodipinewereusedincombination,eachoneindependentlyexerteditsownbloodpressure

loweringeffect.

-grapefruitjuice:co-administrationof240mlofgrapefruitjuicewithasingleoraldoseof10mgamlodipinein20

healthyvolunteershadnosignificanteffectonthepharmacokineticsofamlodipine.

Moreover,specificstudiesconductedwithsomedrugshaveshownthatamlodipinehasnoinfluenceontheir

pharmacokineticsparameters:

atorvastatin:co-administrationofmultipledosesof10mgamlodipinewith80mgofatorvastatinresultedinno

significantchangeinthesteady-statepharmacokineticsparametersofatorvastatin.

digoxin:co-administrationofamlodipinewithdigoxindidnotchangeserumdigoxinlevelsordigoxinrenal

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warfarin:inhealthymalevolunteers,theco-administrationofamlodipinedidnotsignificantlyaltertheeffectof

warfarinonprothrombinresponsetime.Co-administrationofamlodipinewithwarfarindidnotchangethewarfarin

prothrombinresponsetime.

ciclosporin:Pharmacokineticstudieswithciclosporinhavedemonstratedthatamlodipinedoesnotsignificantly

alterthepharmacokineticsofciclosporin.

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.

Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,

alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Linkedtoamlodipine

Dataonalimitednumberofexposedpregnanciesdonotindicatethatamlodipineandothercalciumreceptor

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy

(seesection4.4).TheuseofACEinhibitorsiscontraindicatedduringthesecondand

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Animalstudieshavenotshownteratogeniceffect(seesection5.3).

Lactation:

Linkedtoperindopril

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Linkedtoamlodipine

Itisnotknownwhetheramlodipineisexcretedinbreastmilk.Similarcalciumchannelblockersofthedihydropyridine

typeareexcretedinbreastmilk.

Therefore,asaprecaution,lactationisnotrecommendedduringthetreatmentwithamlodipine.

Fertility:

Reversiblebiochemicalchangesintheheadofspermatozoawhichcanimpairfecundationhavebeenreportedinsome

patientstreatedbycalciumchannelblockers.

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectsofAcerycalontheabilitytodriveandusemachineshavebeenperformed.Whendriving

vehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccur.

4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithperindopriloramlodipinegiven

separatelyandrankedundertheMedDRAclassificationbybodysystemandunderthefollowingfrequency:

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

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

MedDRA

SystemOrganClass UndesirableEffects Frequency

Amlodipine Perindopril

Bloodandthe

lynphaticSystem

Disorders Leucopenia/neutropenia(see

section4.4) Veryrare Veryrare

Agranulocytosisor

pancytopenia(seesection4.4) - Veryrare

Thrombocytopenia(seesection

4.4) Veryrare Veryrare

Haemolyticanaemiainpatients

withacongenitaldeficiencyof

G-6PDH(seesection4.4) - Veryrare

Decreaseinhaemoglobineand

haematocrit - Veryrare

ImmuneSystemDisorders Allergicreaction:Urticaria Veryrare Uncommon

MetabolismandNutrition

Disorders Hyperglycaemia Veryrare -

Weightgain Uncommon -

Weightdecrease Uncommon -

Hypoglycaemia(seesections

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Psychiatricdisorders Insomnia Uncommon -

Moodchanges Uncommon Uncommon

Sleepdisturbances - Uncommon

NervousSystemdisorders Somnolence Common -

Dizziness Common Common

Headache Common Common

Tremor Uncommon -

Hypoesthaesia Uncommon -

Paresthaesia Uncommon Common

Hypertonia Veryrare -

Peripheralneuropathy Veryrare -

Vertigo - Common

Confusion - Veryrare

EyeDisorders Visualdisturbances Uncommon Common

Earandlabyrinth

disorders Tinnitus Uncommon Common

CardiacDisorders Palpitations Common -

Syncope Uncommon -

Anginapain Rare -

Anginapectoris - Veryrare

Myocardialinfarction,possibly

secondarytoexcessive

hypotensioninhighrisk

patients(seesection4.4) Veryrare Veryrare

Arrythmia(including

bradycardia,ventricular

tachycardiaandatrial

fibrillation) Veryrare Veryrare

VascularDisorders Flushing Common -

Hypotension(andeffects

relatedtohypotension) Uncommon Common

Strokepossiblysecondaryto

excessivehypotensioninhigh-

riskpatients(seesection4.4) - Veryrare

Vasculitis Veryrare Notknown

Respiratory,Thoracicand

MediastinalDisorders Dyspnoea Uncommon Common

Rhinitis Uncommon Veryrare

Cough Veryrare Common

Bronchospasm - Uncommon

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Gastro-intestinal

Disorders Gingivalhyperplasia Veryrare -

Abdominalpain,nausea Common Common

Vomiting Uncommon Common

Dyspepsia Uncommon Common

Alteredbowelhabits Uncommon -

Drymouth Uncommon Uncommon

Dysgeusia - Common

Tasteperversion Uncommon -

Diarrheoa,constipation - Common

Pancreatitis Veryrare Veryrare

Gastritis Veryrare -

Hepato-biliary

Disorders Hepatitis,cholestaticjaundice Veryrare -

Hepatitisetheircytoliticor

cholestatic(seesection4.4) - Veryrare

SkinandSubcutaneous

TissueDisorders Quincke’soedema Veryrare -

Angioedemaofface,

extremities,lips,mucous

membranes,tongue,glottis

and/orlarynx(seesection4.4) - Uncommon

Erythemamultiform Veryrare Veryrare

Alopecia Uncommon -

Purpura Uncommon -

Skindiscoloration Uncommon -

Increasedsweating Uncommon -

Sweating - Uncommon

Prurit Uncommon Common

Rash Uncommon Common

Stevens-JohnsonSyndrome Veryrare -

MusculoskeletalAnd

ConnectiveTissue

Disorders Arthralgia,myalgia Uncommon -

Musclecramps Uncommon Common

Backpain Uncommon -

RenalandUrinary

Disorders Micturitiondisorder,nocturia,

increasedurinaryfrequency Uncommon -

Renalimpairment - Uncommon

Acuterenalfailure - Veryrare

ReproductiveSystemand

BreastDisorders Impotence Uncommon Uncommon

Gynaecomastia Uncommon -

GeneralDisordersand

AdministrationSite

Condition Oedema,peripheraloedema Common -

Fatigue Common -

Chestpain Uncommon -

Asthenia Uncommon Common

Pain Uncommon -

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Additionalinformationlinkedtoamlodipine

Exceptionalcasesofextrapyramidalsyndromehavebeenreportedwithcalciumchannelblockers.

4.9Overdose

ThereisnoinformationonoverdosagewithAcerycalinhumans.

Foramlodipine,experiencewithintentionaloverdoseinhumansislimited.Largeoverdosagecouldresultinexcessive

peripheralvasodilatationwithsubsequentmarkedandprobablyprolongedsystemichypotension.Anyhypotensiondue

toamlodipineoverdosagecallsforamonitoringincardiologicintensivecareunit.Avasoconstrictormaybehelpfulin

restoringvasculartoneandbloodpressure,providedthatthereisnocontraindicationtoitsuse.Intravenouscalcium

gluconatemaybebeneficialinreversingtheeffectsofcalciumchannelblockade.

Amlodipineisnotdialyzable.

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:perindopilandamlodipine,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

Investigations Hepaticenzymeselevations:

ALT,AST(mostlyconsistent

withcholestasis) Veryrare -

Serumbilirubinandliver

enzymeselevation - Rare

Increasesinbloodureaand

serumcreatinine,

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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

decreasesthemedia:lumenratioofsmallarteries.

Patientswithstablecoronaryarterydisease:

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

4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopriltert-

butylamine(equivalentto10mgperindoprilarginine)(n=6110)orplacebo(n=6108).

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

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Inpatientswithangina,oncedailyadministrationofamlodipineincreasestotalexercisetime,timetoanginaonset,and

timeto1mmSTsegmentdepression,anddecreasesbothanginaattackfrequencyandglyceryltrinitratetablet

consumption.

Amlodipinehasnotbeenassociatedwithanyadversemetaboliceffectsorchangesinplasmalipidsandissuitablefor

useinpatientswithasthma,diabetes,andgout.

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,therewasnosignificantdifferenceinall-

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

p=0.20).

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,resultinginsteady-

statewithin4days.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure(seesection4.2).

Therefore,theusualmedicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(see

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Amlodipine:

Afteroraladministrationoftherapeuticdoses,amlodipineiswellabsorbedwithpeakbloodlevelsbetween6-12hours

postdose.Absolutebioavailabilityhasbeenestimatedtobebetween64and80%.Thevolumeofdistributionis

approximately21l/kg.Itsbioavailabilityisnotinfluencedbyfood.Invitrostudieshaveshownthatapproximately

97.5%ofcirculatingamlodipineisboundtoplasmaproteins.

Theterminalplasmaeliminationhalf-lifeisabout35-50hoursandisconsistentwithoncedailydosing.Amlodipineis

extensivelymetabolisedbythelivertoinactivemetabolites.About60%oftheadministereddoseisexcretedinthe

urine,10%asunchangedamlodipine.

Useintheelderly:thetimetoreachpeakplasmaconcentrationsofamlodipineissimilarinelderlyandyounger

subjects.AmlodipineclearancetendstobedecreasedwithresultingincreasesinAUCandeliminationhalf-lifein

elderlypatients.Therecommendeddosageregimenfortheelderlyisthesame,althoughincreasingthedoseshould

takeplacewithcaution.

Useinpatientswithrenalfailure:seesection4.2.

Useinpatientswithimpairedhepaticfunction:Aswithallcalciumantagonists,amlodipine'shalf-lifeisprolongedin

patientswithimpairedliverfunction.

5.3Preclinicalsafetydata

Perindopril:

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversibledamage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefetal

development,resultinginfetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreaseinperi-

andpostnatalmortalityhavebeenobserved.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

Amlodipine:

Toxicologicalstudiesinanimalrevealnospecialhazardsforhumansregardingsafetypharmacology,genotoxicity,

carcinogenicity,fertilityandstudieswithrepeateddosing.Reproductivetoxicologystudiesinratsshowedaprolonged

durationofpregnancyandanincreaseinperiandpostnatalmortality.

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

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