ACERYCAL 5/5 mg/mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
PERINDOPRIL ARGININE AMLODIPINE BESILATE
Available from:
Clear Pharmacy
INN (International Name):
PERINDOPRIL ARGININE AMLODIPINE BESILATE
Dosage:
5/5 mg/mg
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Authorization status:
Authorised
Authorization number:
PPA1596/033/001
Authorization date:
0000-00-00

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ACERYCAL5mg/5mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains3.395mgperindoprilequivalentto5mgperindoprilarginineand6.935mgamlodipinebesilate

equivalentto5mgamlodipine.

Excipient:lactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromHungary

White,rod-shapedtabletengravedwith5/5ononefaceand[Servierlogo]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.Inthesepatients,anindividualdosetitrationwiththemono-componentsisrecommended.

Amlodipineusedatsimilardosesinelderlyoryoungerpatientsisequallywelltolerated.Normaldosageregimensare

recommendedintheelderly,butincreaseofthedosageshouldtakeplacewithcare.Changesinamlodipineplasma

concentrationsarenotcorrelatedwithdegreeofrenalimpairment.Amlodipineisnotdialysable.

Patientswithhepaticimpairment:seesections4.4and5.2

Dosagerecommendationshavenotbeenestablishedinpatientswithmildtomoderatehepaticimpairment;therefore

doseselectionshouldbecautiousandshouldstartatthelowerendofthedosingrange(seesections4.4and5.2).To

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individuallytitratedusingthefreecombinationofamlodipineandperindopril.Thepharmacokineticsofamlodipine

havenotbeenstudiedinseverehepaticimpairment.Amlodipineshouldbeinitiatedatthelowestdoseandtitrated

slowlyinpatientswithseverehepaticimpairment.

Paediatricpopulations

ACERYCALshouldnotbeusedinchildrenandadolescentsastheefficacyandtolerabilityofperindopriland

amlodipine,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,shouldapplyalsotothefixedcombinationof

ACERYCAL.

Linkedtoperindopril

Specialwarnings

Hypersensitivity/Angioedema:

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

patientstreatedwithACEinhibitors,includingperindopril(seesection4.8).Thismayoccuratanytimeduringtherapy.

Insuchcases,ACERYCALshouldpromptlybediscontinuedandappropriatemonitoringshouldbeinitiatedand

continueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhereswellingwasconfinedtothe

faceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

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esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain(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.

Renalimpairment:

Incasesofrenalimpairment(creatinineclearance<60ml/min)anindividualdosetitrationwiththemonocomponents

isrecommended(seesection4.2).

Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforpatientswithrenalimpairment

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Insomepatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,whohavebeentreated

withACEinhibitors,increasesinbloodureaandserumcreatinine,usuallyreversibleupondiscontinuationoftherapy,

havebeenseen.Thisisespeciallylikelyinpatientswithrenalinsufficiency.Ifrenovascularhypertensionisalso

presentthereisanincreasedriskofseverehypotensionandrenalinsufficiency.Somehypertensivepatientswithno

apparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodureaandserumcreatinine,usuallyminor

andtransient,especiallywhenperindoprilhasbeengivenconcomitantlywithadiuretic.Thisismorelikelytooccurin

patientswithpre-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,ACERYCALmay

blockangiotensinIIformationsecondarytocompensatoryreninrelease.Thetreatmentshouldbediscontinuedoneday

priortothesurgery.Ifhypotensionoccursandisconsideredtobeduetothismechanism,itcanbecorrectedbyvolume

expansion.

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

age(>70years),diabetesmellitus,intercurrentevents,inparticulardehydration,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

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Diabeticpatients:

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor(seesection4.5).

Linkedtoamlodipine:

Precautionsforuse

Thesafetyandefficacyofamlodipineinhypertensivecrisishasnotbeenestablished.

Useinpatientswithcardiacfailure:

Patientswithheartfailureshouldbetreatedwithcaution.

Inalong-term,placebocontrolledstudyinpatientswithsevereheartfailure(NYHAclassIIIandIV)thereported

incidenceofpulmonaryoedemawashigherintheamlodipinetreatedgroupthanintheplacebogroup(seesection5.1).

Calciumchannelblockers,includingamlodipine,shouldbeusedwithcautioninpatientswithcongestiveheartfailure,

astheymayincreasetheriskoffuturecardiovasculareventsandmortality.

Useinpatientswithimpairedhepaticfunction:

Thehalf-lifeofamlodipineisprolongedandAUCvaluesarehigherinpatientswithimpairedliverfunction;dosage

recommendationshavenotbeenestablished.Amlodipineshouldthereforebeinitiatedatthelowerendofthedosing

rangeandcautionshouldbeused,bothoninitialtreatmentandwhenincreasingthedose.Slowdosetitrationand

carefulmonitoringmayberequiredinpatientswithseverehepaticimpairment.

Useinelderlypatients:

Intheelderlyincreaseofthedosageshouldtakeplacewithcare(seesections4.2and5.2).

Useinrenalfailure:

Amlodipinemaybeusedinsuchpatientsatnormaldoses.Changesinamlodipineplasmaconcentrationsarenot

correlatedwithdegreeofrenalimpairment.Amlodipineisnotdialysable.

LinkedtoACERYCAL

Allwarningsrelatedtoeachmono-component,aslistedabove,shouldapplyalsotothefixedcombinationof

ACERYCAL.

Precautionsforuse

Excipients:

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,glucose-galactose

malabsorption,ortheLapplactasedeficiencyshouldnottakethismedicinalproduct.

Interactions

TheconcomitantuseofACERYCALwithlithium,potassium-sparingdiureticsorpotassiumsupplements,or

dantroleneisnotrecommended(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

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serumpotassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicity(severeneurotoxicity)havebeenreportedduring

concurrentuseofACEinhibitors.Thecombinationofperindoprilwithlithiumisnotrecommended.Ifthecombination

provesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended(seesection4.4).

Estramustine:

Riskofincreasedadverseeffectssuchasangioneuroticoedema(angioedema).

Concomitantusewhichrequiresspecialcare:

Non-steroidalanti-inflammatorymedicinalproducts(NSAIDs)includingaspirin3g/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(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.

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azoleantifungals,macrolideslikeerythromycinorclarithromycin,verapamilordiltiazem)maygiverisetosignificant

increaseinamlodipineexposure.TheclinicaltranslationofthesePKvariationsmaybemorepronouncedintheelderly.

Clinicalmonitoringanddoseadjustmentmaythusberequired.

Concomitantusetobetakenintoconsideration:

Thebloodpressureloweringeffectsofamlodipineaddstothebloodpressure-loweringeffectsofothermedicinal

productswithantihypertensiveproperties.

Otherscombinations:

Inclinicalinteractionstudies,amlodipinedidnotaffectthepharmacokineticsofatorvastatin,digoxin,warfarinor

cyclosporin.

Administrationofamlodipinewithgrapefruitorgrapefruitjuiceisnotrecommendedasbioavailabilitymaybe

increasedinsomepatientsresultinginincreasedbloodpressureloweringeffects.

LinkedtoACERYCAL:

Concomitantusewhichrequiresspecialcare:

Baclofen:Potentiationofantihypertensiveeffect.Monitoringofbloodpressureandrenalfunction,anddoseadaptation

oftheantihypertensiveifnecessary.

Concomitantusetobetakenintoconsideration:

Antihypertensiveagents(suchasbeta-blockers)andvasodilators:

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindoprilandamlodipine.Concomitant

usewithnitroglycerineandothernitratesorothervasodilators,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.ACERYCALiscontraindicatedduringthe

secondandthirdtrimestersofpregnancy.

ACERYCALisnotrecommendedduringlactation.Adecisionshouldthereforebemadewhethertodiscontinue

nursingortodiscontinueACERYCALtakingaccounttheimportanceofthistherapyforthemother.

Pregnancy:

Linkedtoperindopril

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).The

useofACEinhibitorsiscontraindicatedduringthesecondandthirdtrimesterofpregnancy(seesections4.3

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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

foetus.

Lactation:

Linkedtoperindopril

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Linkedtoamlodipine

Itisnotknownwhetheramlodipineisexcretedinbreastmilk.Adecisiononwhethertocontinue/discontinue

breastfeedingortocontinue/discontinuetherapywithamlodipineshouldbemadetakingintoaccountthebenefitof

breastfeedingtothechildandthebenefitofamlodipinetherapytothemother.

Fertility:

Reversiblebiochemicalchangesintheheadofspermatozoahavebeenreportedinsomepatientstreatedbycalcium

channelblockers.Clinicaldataareinsufficientregardingthepotentialeffectofamlodipineonfertility.Inoneratstudy,

adverseeffectswerefoundonmalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectsofACERYCALontheabilitytodriveandusemachineshavebeenperformed.Amlodipine

canhaveminorormoderateinfluenceontheabilitytodriveandusemachines.Ifpatientssufferfromdizziness,

headache,fatigue,wearinessornausea,theabilitytoreactmaybeimpaired.Cautionisrecommendedespeciallyatthe

startoftreatment.

4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithperindopriloramlodipinegivenseparately

andrankedundertheMedDRAclassificationbybodysystemandunderthefollowingfrequency:

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

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

MedDRASystem

OrganClass UndesirableEffects Frequency

Amlodipine Perindopril

Bloodandthe

lymphaticSystem

Disorders Leukopenia/neutropenia(seesection4.4) Veryrare Veryrare

Agranulocytosisorpancytopenia(seesection4.4) - Veryrare

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Haemolyticanaemiainpatientswithacongenital

deficiencyofG-6PDH(seesection4.4) - Veryrare

Decreaseinhaemoglobineandhaematocrit - Veryrare

ImmuneSystem

Disorders Allergicreactions Veryrare Uncommon

Metabolismand

NutritionDisorders Hyperglycaemia Veryrare -

Hypoglycaemia(seesections4.4and4.5) - Notknown

Psychiatric

disorders Insomnia Uncommon -

Moodchanges(includinganxiety) Uncommon Uncommon

Depression Uncommon -

Sleepdisturbances - Uncommon

Confusion Rare Veryrare

NervousSystem

disorders Somnolence(especiallyatthebeginningoftreatment) Common -

Dizziness(especiallyatthebeginningoftreatment) Common Common

Headache(especiallyatthebeginningoftreatment) Common Common

Dysgeusia Uncommon Common

Tremor Uncommon -

Hypoesthaesia Uncommon -

Paresthaesia 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,possiblysecondarytoexcessive

hypotensioninhighriskpatients(seesection4.4) Veryrare Veryrare

Arrhythmia(includingbradycardia,ventricular

tachycardiaandatrialfibrillation) Veryrare Veryrare

VascularDisorders Flushing Common -

Hypotension(andeffectsrelatedtohypotension) Uncommon Common

Strokepossiblysecondarytoexcessivehypotensionin

high-riskpatients(seesection4.4) - 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 Veryrare -

Hepatitiseithercytoliticorcholestatic(seesection4.4) - Veryrare

Hepaticenzymesincreased(mostlyconsistentwithcholestasis) 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

administrationofamlodipine10mghasbeenshowntoreducetheabsorptionrateofamlodipine.

SkinandSubcutaneous

TissueDisorders Angioedemaofface,extremities,lips,mucousmembranes,tongue,

glottisand/orlarynx(seesection4.4) Veryrare Uncommon

Erythemamultiform Veryrare Veryrare

Alopecia Uncommon -

Purpura Uncommon -

Skindiscoloration Uncommon -

Hyperhidrosis Uncommon Uncommon

Pruritis Uncommon Common

Rash,exanthema Uncommon Common

Urticaria Veryrare Uncommon

Stevens-JohnsonSyndrome Veryrare -

Exfoliativedermatitis Veryrare -

Photosensitivity Veryrare -

MusculoskeletalAnd

ConnectiveTissue

Disorders Ankleswelling Common -

Arthralgia,myalgia Uncommon -

Musclecramps Uncommon Common

Backpain Uncommon -

Renaland

UrinaryDisorders Micturitiondisorder,nocturia,increasedurinaryfrequency Uncommon -

Renalimpairment - Uncommon

Acuterenalfailure - Veryrare

ReproductiveSystem

andBreastDisorders Impotence Uncommon Uncommon

Gynaecomastia Uncommon -

GeneralDisordersand

AdministrationSite

Condition Oedema Common -

Fatigue Common -

Chestpain Uncommon -

Asthenia Uncommon Common

Pain Uncommon -

Malaise Uncommon -

Investigations Weightincrease,weightdecrease Uncommon -

Serumbilirubinandliverenzymeselevation - Rare

Increasesinbloodureaandserumcreatinine,hyperkalaemia(see

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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

decreasesthemedia:lumenratioofsmallarteries.

Patientswithstablecoronaryarterydisease:

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

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Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopril

tertbutylamine(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)against

whichtheheartworks.Sincetheheartrateremainsstable,thisunloadingoftheheartreducesmyocardial

energyconsumptionandoxygenrequirements.

Themechanismofactionofamlodipinealsoprobablyinvolvesdilatationofthemaincoronaryarteriesand

coronaryarterioles,bothinnormalandischaemicregions.Thisdilatationincreasesmyocardialoxygendelivery

inpatientswithcoronaryarteryspasm(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

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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

priortoenrolmentordocumentationofotheratheroscleroticCVD(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

PrimaryEndpoint

Adverse

cardiovascular

events 110(16.6) 151(23.1) 136(20.2) 0.69(0.54-

0.88) .003

IndividualComponents

Coronary

revascularization 78(11.8) 103(15.7) 95(14.1) 0.73(0.54-

0.98) .03

Hospitalizationfor

angina 51(7.7) 84(12.8) 86(12.8) 0.58(0.41-

0.82) .002

NonfatalMI 14(2.1) 19(2.9) 11(1.6) 0.73(0.37-

1.46) .37

StrokeorTIA 6(0.9) 12(1.8) 8(1.2) 0.50(0.19-

1.32) .15

Cardiovasculardeath 5(0.8) 2(0.3) 5(0.8) 2.46(0.48-

12.7) .27

Hospitalizationfor

3(0.5) 5(0.8) 4(0.6) 0.59(0.14-

2.47) .46

Resuscitatedcardiac

arrest 0 4(0.6) 1(0.1) NA .04

New-onset

peripheral

vasculardisease 5(0.8) 2(0.3) 8(1.2) 2.6(0.50-

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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,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.

Nomutagenicityhasbeenobservedinvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefetal

development,resultinginfetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreaseinperi-

andpostnatalmortalityhavebeenobserved.

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-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackagingoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

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Date Printed 21/12/2012 CRN 2116796 page number: 15

6.5Natureandcontentsofcontainer

Onecontainerof30tabletsequippedwithaflowreducerandastoppercontainingadesiccantgelinacardboardcarton.

6.6Specialprecautionsfordisposalandotherhandling

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Date Printed 21/12/2012 CRN 2116796 page number: 16

7PARALLELPRODUCTAUTHORISATIONHOLDER

ClearPharmacy

157-173RodenStreet

Belfast

BT125QA

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1596/33/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:4thofMarch2011

10DATEOFREVISIONOFTHETEXT

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Date Printed 21/12/2012 CRN 2116796 page number: 17

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