COVERSYL ARGININE PLUS 5MG/1.25MG FILM-COATED TABLETS

Main information

  • Trade name:
  • COVERSYL ARGININE PLUS 5MG/1.25MG FILM-COATED TABLETS
  • Dosage:
  • 5/1.25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COVERSYL ARGININE PLUS 5MG/1.25MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/012/001
  • Authorization date:
  • 31-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylArgininePlus5mg/1.25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains3.395mgperindoprilcorrespondingto5mgperindoprilarginineand1.25mg

indapamide.

Excipients:lactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromtheUKandHungary:

White,rod-shapedfilm-coatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension,CoversylArgininePlus5mg/1.25mgfilm-coatedtabletisindicatedinpatients

whosebloodpressureisnotadequatelycontrolledonperindoprilalone.

4.2Posologyandmethodofadministration

Oralroute

OneCoversylArgininePlus5mg/1.25mgfilm-coatedtabletperdayasasingledose,preferablytobetakeninthe

morning,andbeforeameal.

Whenpossibleindividualdosetitrationwiththecomponentsisrecommended.CoversylArgininePlus5mg/1.25mg

film-coatedtabletshouldbeusedwhenbloodpressureisnotadequatelycontrolledonCoversylArgininePlus

2.5mg/0.625mgfilm-coatedtablet(whereavailable).Whenclinicallyappropriate,directchangefrommonotherapyto

CoversylArgininePlus5mg/1.25mgfilm-coatedtabletmaybeconsidered.

Elderly(seesection4.4)

Treatmentshouldbeinitiatedafterconsideringbloodpressureresponseandrenalfunction.

Patientswithrenalimpairment(seesection4.4)

Insevererenalimpairment(creatinineclearancebelow30ml/min),treatmentiscontraindicated.

Inpatientswithmoderaterenalimpairment(creatinineclearance30-60ml/min),itisrecommendedtostarttreatment

withtheadequatedosageofthefreecombination.

Inpatientswithcreatinineclearancegreaterthanorequalto60ml/min,nodosemodificationisrequired.Usual

medicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Patientswithhepaticimpairment(seesections4.3,4.4and5.2)

Inseverehepaticimpairment,treatmentiscontraindicated.

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Childrenandadolescents

CoversylArgininePlus5mg/1.25mgshouldnotbeusedinchildrenandadolescentsastheefficacyandtolerabilityof

perindoprilinchildrenandadolescents,aloneorincombination,havenotbeenestablished.

4.3Contraindications

Linkedtoperindopril:

HypersensitivitytoperindopriloranyotherACEinhibitor

Historyofangioedema(Quincke'soedema)associatedwithpreviousACEinhibitortherapy

Hereditary/idiopathicangioedema

Secondandthirdtrimestersofpregnancy(seesection4.6)

Linkedtoindapamide:

Hypersensitivitytoindapamideortoanyothersulphonamides

Severerenalimpairment(creatinineclearancebelow30ml/min)

Hepaticencephalopathy

Severehepaticimpairment

Hypokalaemia

Asageneralrule,thismedicineisinadvisableincombinationwithnonantiarrhythmicagentscausingtorsadesde

pointes(seesection4.5)

Lactation(seesection4.6).

LinkedtoCoversylArgininePlus5mg/1.25mg:

Hypersensitivitytoanyoftheexcipients

Duetothelackofsufficienttherapeuticexperience,CoversylArginine5mg/1.25mgshouldnotbeusedin:

Dialysispatients

Patientswithuntreateddecompensateheartfailure.

4.4Specialwarningsandprecautionsforuse

Specialwarnings

Commontoperindoprilandindapamide:

Lithium:

Thecombinationoflithiumandthecombinationofperindoprilandindapamideisusuallynotrecommended(see

section4.5).

Linkedtoperindopril:

Neutropenia/agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicalmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever).

Hypersensitivity/angioedema:

Angioedemaoftheface,extremities,lips , tongue,glottisand/orlarynxhasbeenreportedrarelyinpatientstreatedwith

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Insuchcasesperindoprilshouldbediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensure

completeresolutionofsymptomspriortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfined

tothefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulin

relievingsymptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,appropriatetherapy,whichmayincludesubcutaneousepinephrinesolution

1:1000(0.3mlto0.5ml)and/ormeasurestoensureapatentairway,shouldbeadministeredpromptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

Anaphylactoidreactionsduringdesensitisation:

Therehavebeenisolatedreportsofpatientsexperiencingsustained,life-threateninganaphylactoidreactionswhile

receivingACEinhibitorsduringdesensitisationtreatmentwithhymenoptera(bees,wasps)venom.ACEinhibitors

shouldbeusedwithcautioninallergicpatientstreatedwithdesensitisation,andavoidedinthoseundergoingvenom

immunotherapy.HoweverthesereactionscouldbepreventedbytemporarywithdrawalofACEinhibitorforatleast24

hoursbeforetreatmentinpatientswhorequirebothACEinhibitorsanddesensitisation.

AnaphylactoidreactionsduringLDLapheresis:

Rarely,patientsreceivingACEinhibitorsduringlowdensitylipoprotein(LDL)-apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-

inhibitortherapypriortoeachapheresis.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhigh-fluxmembranes(e.g.,AN69®)andtreated

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofantihypertensiveagent.

Potassium-sparingdiuretics,potassiumsalts:

Thecombinationofperindoprilandpotassium-sparingdiuretics,potassiumsaltsisusuallynotrecommended(see

section4.5).

Pregnancyandlactation:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Useofperindoprilisnotrecommendedduringbreastfeeding.

Linkedtoindapamide:

Whenliverfunctionisimpaired,thiazidediureticsandthiazide-relateddiureticsmaycausehepaticencephalopathy.

Administrationofthediureticshouldbestoppedimmediatelyifthisoccurs.

Photosensitivity:

Casesofphotosensitivityreactionshavebeenreportedwiththiazidesandrelatedthiazidesdiuretics(seesection4.8).If

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Ifare-administrationofthediureticisdeemednecessary,itisrecommendedtoprotectexposedareastothesunorto

artificialUVA.

Precautionsforuse

Commontoperindoprilandindapamide:

Renalimpairment:

Incasesofsevererenalimpairment(creatinineclearance<30ml/min),treatmentiscontraindicated.

Incertainhypertensivepatientswithoutpre-existingapparentrenallesionsandforwhomrenalbloodtestsshow

functionalrenalinsufficiency,treatmentshouldbestoppedandpossiblyrestartedeitheratalowdoseorwithone

constituentonly.

Inthesepatientsusualmedicalfollow-upwillincludefrequentmonitoringofpotassiumandcreatinine,aftertwoweeks

oftreatmentandtheneverytwomonthsduringtherapeuticstabilityperiod.Renalfailurehasbeenreportedmainlyin

patientswithsevereheartfailureorunderlyingrenalfailureincludingrenalarterystenosis.

Thedrugisusuallynotrecommendedincaseofbilateralrenalarterystenosisorasinglefunctioningkidney.

Hypotensionandwaterandelectrolytedepletion:

Thereisariskofsuddenhypotensioninthepresenceofpre-existingsodiumdepletion(inparticularinindividualswith

renalarterystenosis).Thereforesystematictestingshouldbecarriedoutforclinicalsignsofwaterandelectrolyte

depletion,whichmayoccurwithanintercurrentepisodeofdiarrhoeaorvomiting.Regularmonitoringofplasma

electrolytesshouldbecarriedoutinsuchpatients.

Markedhypotensionmayrequiretheimplementationofanintravenousinfusionofisotonicsaline.

Transienthypotensionisnotacontraindicationtocontinuationoftreatment.Afterre-establishmentofasatisfactory

bloodvolumeandbloodpressure,treatmentcanbestartedagaineitheratareduceddoseorwithonlyoneofthe

constituents.

Potassiumlevels:

Thecombinationofperindoprilandindapamidedoesnotpreventtheonsetofhypokalaemiaparticularlyindiabetic

patientsorinpatientswithrenalfailure.Aswithanyantihypertensiveagentcontainingadiuretic,regularmonitoringof

plasmapotassiumlevelsshouldbecarriedout.

Excipients:

CoversylArgininePlus

5mg/1.25mgshouldnotbeadministeredtopatientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorption.

Linkedtoperindopril:

Cough:

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

eventofthissymptom.Iftheprescriptionofanangiotensinconvertingenzymeinhibitorisstillpreferred,continuation

oftreatmentmaybeconsidered.

Childrenandadolescents:

Theefficacyandtolerabilityofperindoprilinchildrenandadolescents,aloneorincombination,havenotbeen

established.

Riskofarterialhypotensionand/orrenalinsufficiency(incasesofcardiacinsufficiency,waterandelectrolyte

depletion,etc...):

Markedstimulationoftherenin-angiotensin-aldosteronesystemhasbeenobservedparticularlyduringmarkedwater

andelectrolytedepletions(strictsodium-freedietorprolongeddiuretictreatment),inpatientswhosebloodpressure

wasinitiallylow,incasesofrenalarterystenosis,congestiveheartfailureorcirrhosiswithoedemaandascites.

Theblockingofthissystemwithanangiotensinconvertingenzymeinhibitormaythereforecause,particularlyatthe

timeofthefirstadministrationandduringthefirsttwoweeksoftreatment,asuddendropinbloodpressureand/oran

increaseinplasmalevelsofcreatinine,showingafunctionalrenalinsufficiency.Occasionallythiscanbeacutein

onset,althoughrare,andwithavariabletimetoonset.

Insuchcases,thetreatmentshouldthenbeinitiatedatalowerdoseandincreasedprogressively.

Elderly:

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Theinitialdoseissubsequentlyadjustedaccordingtobloodpressureresponse,especiallyincasesofwaterand

electrolytedepletion,inordertoavoidsuddenonsetofhypotension.

Patientswithknownatherosclerosis:

Theriskofhypotensionexistsinallpatientsbutparticularcareshouldbetakeninpatientswithischaemicheartdisease

orcerebralcirculatoryinsufficiency,withtreatmentbeingstartedatalowdose.

Renovascularhypertension:

Thetreatmentforrenovascularhypertensionisrevascularisation.Nonetheless,angiotensinconvertingenzyme

inhibitorscanbebeneficialinpatientspresentingwithrenovascularhypertensionwhoareawaitingcorrectivesurgery

orwhensuchasurgeryisnotpossible.

IfCoversylArgininePlus5mg/1.25mgisprescribedtopatientswithknownorsuspectedrenalarterystenosis,

treatmentshouldbestartedinahospitalsettingatalowdoseandrenalfunctionandpotassiumlevelsshouldbe

monitored,sincesomepatientshavedevelopedafunctionalrenalinsufficiencywhichwasreversedwhentreatmentwas

stopped.

Otherpopulationsatrisk:

Inpatientswithseverecardiacinsufficiency(gradeIV)orinpatientswithinsulindependentdiabetesmellitus

(spontaneoustendencytoincreasedlevelsofpotassium),treatmentshouldbestartedundermedicalsupervisionwitha

reducedinitialdose.Treatmentwithbeta-blockersinhypertensivepatientswithcoronaryinsufficiencyshouldnotbe

stopped:theACEinhibitorshouldbeaddedtothebeta-blocker.

Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,perindoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Surgery/anaesthesia:

Angiotensinconvertingenzymeinhibitorscancausehypotensionincasesofanaesthesia,especiallywhenthe

anaestheticadministeredisanagentwithhypotensivepotential.

Itisthereforerecommendedthattreatmentwithlong-actingangiotensinconvertingenzymeinhibitorssuchas

perindoprilshouldbediscontinuedwherepossibleonedaybeforesurgery.

Aorticormitralvalvestenosis/hypertrophiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientwithanobstructionintheoutflowtractoftheleftventricle.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

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

metabolicacidosisandconcomitantuseofpotassium-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

useoftheabove-mentionedagentsisdeemedappropriate,theyshouldbeusedwithcautionandwithfrequent

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Linkedtoindapamide:

Waterandelectrolytebalance:

Sodiumlevels:

Theseshouldbetestedbeforetreatmentisstarted,thenatregularintervals.Alldiuretictreatmentcancauseareduction

insodiumlevels,whichmayhaveseriousconsequences.Reductioninsodiumlevelscanbeinitiallyasymptomaticand

regulartestingisthereforeessential.Testingshouldbemorefrequentinelderlyandcirrhoticpatients(seesections4.8

and4.9).

Potassiumlevels:

Potassiumdepletionwithhypokalaemiaisamajorriskwiththiazidediureticsandthiazide-relateddiuretics.Theriskof

onsetofloweredpotassiumlevels(<3.4mmol/l)shouldbepreventedinsomehighriskpopulationssuchaselderly

and/ormalnourishedsubjects,whetherornottheyaretakingmultiplemedications,cirrhoticpatientswithoedemaand

ascites,coronarypatientsandpatientswithheartfailure.

Insuchcaseshypokalaemiaincreasesthecardiactoxicityofcardiacglycosidesandtheriskofrhythmdisorders.

SubjectspresentingwithalongQTintervalarealsoatrisk,whethertheoriginiscongenitaloriatrogenic.

Hypokalaemia,aswithbradycardia,actsasafactorwhichfavourstheonsetofsevererhythmdisorders,inparticular

torsadesdepointes,whichmaybefatal.

Inallcasesmorefrequenttestingofpotassiumlevelsisnecessary.Thefirstmeasurementofplasmapotassiumlevels

shouldbecarriedoutduringthefirstweekfollowingthestartoftreatment.

Iflowpotassiumlevelsaredetected,correctionisrequired.

Calciumlevels:

Thiazidediureticsandthiazide-relateddiureticsmayreduceurinaryexcretionofcalciumandcauseamildandtransient

increaseinplasmacalciumlevels.Markedlyraisedlevelsofcalciummayberelatedtoundiagnosed

hyperparathyroidism.Insuchcasesthetreatmentshouldbestoppedbeforeinvestigatingtheparathyroidfunction.

Bloodglucose:

Monitoringofbloodglucoseisimportantindiabeticpatients,particularlywhenpotassiumlevelsarelow.

Uricacid:

Tendencytogoutattacksmaybeincreasedinhyperuricaemicpatients.

Renalfunctionanddiuretics:

Thiazidediureticsandthiazide-relateddiureticsareonlyfullyeffectivewhenrenalfunctionisnormaloronlyslightly

impaired(creatininelevelslowerthanapproximately25mg/l,i.e.220µmol/lforanadult).

Intheelderlythevalueofplasmacreatininelevelsshouldbeadjustedtotakeaccountoftheage,weightandsexofthe

patient,accordingtotheCockroftformula:

=(140-age)xbodyweight/0.814xplasmacreatininelevel

with:ageexpressedinyears

bodyweightinkg

plasmacreatininelevelinmicromol/l

Thisformulaissuitableforanelderlymaleandshouldbeadaptedforwomenbymultiplyingtheresultby0.85.

Hypovolaemia,resultingfromthelossofwaterandsodiumcausedbythediureticatthestartoftreatment,causesa

reductioninglomerularfiltration.Itmayresultinanincreaseinbloodureaandcreatininelevels.Thistransitory

functionalrenalinsufficiencyisofnoadverseconsequenceinpatientswithnormalrenalfunctionbutmayhowever

worsenapre-existingrenalimpairment.

Athletes:

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Commontoperindoprilandindapamide:

Concomitantusenotrecommended:

Lithium:reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayfurtherincreaselithium

levelsandenhancetheriskoflithiumtoxicitywithACEinhibitors.Useofperindoprilcombinedwithindapamidewith

lithiumisnotrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevels

shouldbeperformed(seesection4.4).

-Concomitantusewhichrequiresspecialcare:

-Baclofen:Potentiationofantihypertensiveeffect.Monitoringofbloodpressureandrenalfunction,anddoseadaptation

oftheantihypertensiveifnecessary.

-Non-steroidalanti-inflammatorymedicinalproducts(includedacetylsalicylicacidathighdoses):whenACE-

inhibitorsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(i.e.acetylsalicylicacidatanti-

inflammatorydosageregimens,COX-2inhibitorsandnon-selectiveNSAIDs),attenuationoftheantihypertensive

effectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

-Concomitantusewhichrequiressomecare:

-Imipramine-likeantidepressants(tricyclics),neuroleptics:Increasedantihypertensiveeffectandincreasedriskof

orthostatichypotension(additiveeffect).

-Corticosteroids,tetracosactide:Reductioninantihypertensiveeffect(saltandwaterretentionduetocorticosteroids).

-otherantihypertensiveagents:useofotherantihypertensivemedicinalproductswithperindopril/indapamidecould

resultinadditionalbloodpressureloweringeffect.

Concomitantusenotrecommended:

-Potassium-sparingdiuretics(spironolactone,triamterene,aloneorincombination),potassium(salts):ACEinhibitors

attenuatediureticinducedpotassiumloss.Potassiumsparingdiureticse.g.spironolactone,triamterene,oramiloride,

potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesinserumpotassium

(potentiallylethal).Ifconcomitantuseisindicatedbecauseofdocumentedhypokalemiatheyshouldbeusedwith

cautionandwithfrequentmonitoringofserumpotassiumandbyECG.

Concomitantusewhichrequiresspecialcare:

-Antidiabeticagents(insulin,hypoglycaemicsulphonamides):Reportedwithcaptoprilandenalapril.

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.Theonsetofhypoglycaemicepisodesisveryrare

(improvementinglucosetolerancewitharesultingreductionininsulinrequirements).

Concomitantusewhichrequiressomecare:

-Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroidsorprocainamide:Concomitant

administrationwithACEinhibitorsmayleadtoanincreasedriskforleucopenia.

-Anaestheticdrugs:ACEinhibitorsmayenhancethehypotensiveeffectsofcertainanaestheticdrugs.

-Diuretics(thiazideorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandina

riskofhypotensionwheninitiatingtherapywithperindopril.

-Gold:Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreported

rarelyinpatientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapy

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Linkedtoindapamide:

Concomitantusewhichrequiresspecialcare:

-Torsadesdepointesinducingdrugs:Duetotheriskofhypokalemia,indapamideshouldbeadministeredwithcaution

whenassociatedwithmedicinalproductsthatinducedtorsadesdepointessuchasclassIAantiarrhythmicagents

(quinidine,hydroquinidine,disopyramide);classIIIantiarrhythmicagents(amiodarone,dofetilide,ibutilide,bretylium,

sotalol);someneuroleptics(chlorpromazine,cyamemazine,levomepromazine,thioridazine,trifluoperazine),

benzamides(amisulpride,sulpiride,sultopride,tiapride),butyrophenones(droperidol,haloperidol),otherneuroleptics

(pimozide);othersubstancessuchasbepridil,cisapride,diphemanil,IVerythromycin,halofantrine,mizolastine,

moxifloxacin,pentamidine,sparfloxacin,IVvincamine,methadone,astemizole,terfenadine.Preventionoflow

potassiumlevelsandcorrectionifnecessary:monitoringoftheQTinterval.

-Potassium-loweringdrugs:amphotericinB(IVroute),glucocorticoidsandmineralocorticoids(systemicroute),

tetracosactide,stimulantlaxatives:Increasedriskoflowpotassiumlevels(additiveeffect).Monitoringofpotassium

levels,andcorrectionifnecessary;particularconsiderationrequiredincasesoftreatmentwithcardiacglycosides.Non

stimulantlaxativesshouldbeused.

-Cardiacglycosides:Lowpotassiumlevelsfavourthetoxiceffectsofcardiacglycosides.PotassiumlevelsandECG

shouldbemonitoredandtreatmentreconsideredifnecessary.

-Concomitantusewhichrequiressomecare:

-Metformin:Lacticacidosisduetometformincausedbypossiblefunctionalrenalinsufficiencylinkedtodiureticsand

inparticulartoloopdiuretics.Donotusemetforminwhenplasmacreatininelevelsexceed15mg/l(135micromol/l)in

menand12mg/l(110micromol/l)inwomen.

-Iodinatedcontrastmedia:Incasesofdehydrationcausedbydiuretics,thereisanincreasedriskofacuterenal

insufficiency,particularlywhenhighdosesofiodinatedcontrastmediaareused.Rehydrationshouldbecarriedout

beforetheiodinatedcompoundisadministered.

-Calcium(salts):Riskofincreasedlevelsofcalciumduetoreducedeliminationofcalciumintheurine.

-Ciclosporin:Riskofincreasedcreatininelevelswithnochangeincirculatinglevelsofciclosporin,evenwhenthereis

nosaltandwaterdepletion.

4.6Fertility,pregnancyandlactation

Pregnancy:

Linkedtoperindopril:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuse

ofACEinhibitorsiscontra-indicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and

4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Linkedtoindapamide:

Prolongedexposuretothiazideduringthethirdtrimesterofpregnancycanreducematernalplasmavolumeaswellas

uteroplacentalbloodflow,whichmaycauseafeto-placentalischemiaandgrowthretardation.Moreover,rarecasesof

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Lactation:

CoversylArgininePlus5mg/1.25mg

iscontraindicatedduringlactation.

Useofperindoprilisnotrecommendedduringbreastfeeding.

Indapamideisexcretedinhumanmilk.Indapamideiscloselyrelatedtothiazidediureticswhichhavebeenassociated,

duringbreast-feeding,withdecreaseorevensuppressionofmilklactation.Hypersensitivitytosulfonamide-derived

drugs,hypokalaemiaandnuclearicterusmightoccur.

As,withbothdrugs,seriousadversereactionsmightoccurinnursinginfants,adecisionshouldbemadewhetherto

discontinuenursingortodiscontinuetherapytakingaccounttheimportanceofthistherapyforthemother.

4.7Effectsonabilitytodriveandusemachines

Linkedtoperindopril,indapamideandCoversylArgininePLus5mg/1.25mg:

NeitherthetwoactivesubstancesnorCoversylArgininePlus5mg/1.25mgaffectalertnessbutindividualreactions

relatedtolowbloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorincombinationwith

anotherantihypertensivemedication.

Asaresulttheabilitytodriveoroperatemachinerymaybeimpaired.

4.8Undesirableeffects

Theadministrationofperindoprilinhibitstherenin-angiotensin-aldosteroneaxisandtendstoreducethepotassiumloss

causedbyindapamide.FourpercentofthepatientsontreatmentwithCoversylArgininePlus5mg/1.25mgexperience

hypokalaemia(potassiumlevel<3.4mmol/l).

Thefollowingundesirableeffectscouldbeobservedduringtreatmentandrankedunderthefollowingfrequency:

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

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

Bloodandthelymphaticsystemdisorders:

Veryrare:

-Thrombocytopenia,leucopenia/neutropenia,agranulocytosis,aplasticanaemia,haemolyticanaemia.

-Anaemia(seesection4.4)hasbeenreportedwithangiotensinconvertingenzymeinhibitorsinspecificcircumstances

(patientswhohavehadkidneytransplants,patientsundergoinghaemodialysis).

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances.

Nervoussystemdisorders:

Common:Paresthesia,headache,asthenia,feelingsofdizziness,vertigo.

Veryrare:Confusion.

Eyedisorders:

Common:Visiondisturbance.

Earandlabyrinthdisorders:

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Vasculardisorders:

Common:Hypotensionwhetherorthostaticornot(seesection4.4).

Cardiacdisorders:

Veryrare:Arrhythmiaincludingbradycardia,ventriculartachycardia,atrialfibrillation,anginapectorisandmyocardial

infarctionpossiblysecondarytoexcessivehypotensioninhigh-riskpatients(seesection4.4).

Respiratory,thoracicandmediastinaldisorders:

Common:

-Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

presenceofthissymptom.Dyspnoea.

Uncommon:Bronchospasm.

Veryrare:Eosinophilicpneumonia,rhinitis.

Gastrointestinaldisorders:

Common:Constipation,drymouth,nausea,epigastricpain,anorexia,vomiting,abdominalpain,tastedisturbance,

dyspepsia,diarrhoea.

Veryrare:Pancreatitis.

Hepato-biliarydisorders:

Veryrare:Hepatitiseithercytolyticorcholestatic(seesection4.4).

Notknown:Incaseofhepaticinsufficiency,thereisapossibilityofonsetofhepaticencephalopathy(seesections4.3

and4.4).

Skinandsubcutaneoustissuedisorders:

Common:Rash,pruritus,maculopapulareruptions.

Uncommon:

Angioedemaofface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynx,urticaria(seesection4.4).

-Hypersensitivityreactions,mainlydermatological,insubjectswithapredispositiontoallergicandasthmatic

reactions.

-Purpura.

Possibleaggravationofpre-existingacutedisseminatedlupuserythematosus.

Veryrare:erythemamultiforme,toxicepidermicnecrolysis,StevenJohnsonsyndrome.

Casesofphotosensitivityreactionshavebeenreported(seesection4.4).

Musculoskeletal,connectivetissueandbonedisorders:

Common:Cramps.

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Uncommon:Renalinsufficiency.

Veryrare:Acuterenalfailure.

Reproductivesystemandbreastdisorders:

Uncommon:Impotence.

Generaldisordersandadministrationsiteconditions:

Common:Asthenia.

Uncommon:Sweating.

Investigations:

-Potassiumdepletionwithparticularlyseriousreductioninlevelsofpotassiuminsomeatriskpopulations(seesection

4.4).

-Reducedsodiumlevelswithhypovolaemiacausingdehydrationandorthostatichypotension.

-Increaseinuricacidlevelsandinbloodglucoselevelsduringtreatment.

-Slightincreaseinureaandinplasmacreatininelevels,reversiblewhentreatmentisstopped.Thisincreaseismore

frequentincasesofrenalarterystenosis,arterialhypertensiontreatedwithdiuretics,renalinsufficiency.

-Increasedlevelsofpotassium,usuallytransitory.

Rare:Raisedplasmacalciumlevels.

4.9Overdose

Themostlikelyadversereactionincasesofoverdoseishypotension,sometimesassociatedwithnausea,vomiting,

cramps,dizziness,sleepiness,mentalconfusion,oliguriawhichmayprogresstoanuria(duetohypovolaemia).Saltand

waterdisturbances(lowsodiumlevels,lowpotassiumlevels)mayoccur.

Thefirstmeasurestobetakenconsistofrapidlyeliminatingtheproduct(s)ingestedbygastriclavageand/or

administrationofactivatedcharcoal,thenrestoringfluidandelectrolytebalanceinaspecialisedcentreuntiltheyreturn

tonormal.

Ifmarkedhypotensionoccurs,thiscanbetreatedbyplacingthepatientinasupinepositionwiththeheadlowered.If

necessaryanintravenousinfusionofisotonicsalinemaybegiven,oranyothermethodofvolaemicexpansionmaybe

used.

Perindoprilat,theactiveformofperindopril,canbedialysed(seesection5.2).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:perindoprilanddiuretics,ATCcode:C09BA04

CoversylArgininePlus5mg/1.25mgisacombinationofperindoprilargininesalt,anangiotensinconvertingenzyme

inhibitor,andindapamide,achlorosulphamoyldiuretic.Itspharmacologicalpropertiesarederivedfromthoseofeach

ofthecomponentstakenseparately,inadditiontothoseduetotheadditivesynergicactionofthetwoproductswhen

combined.

Pharmacologicalmechanismofaction

LinkedtoCoversylArgininePlus5mg/1.25mg:

CoversylArgininePlus5mg/1.25mgproducesanadditivesynergyoftheantihypertensiveeffectsofthetwo

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Linkedtoperindopril:

Perindoprilisaninhibitoroftheangiotensinconvertingenzyme(ACEinhibitor)whichconvertsangiotensinIto

angiotensinII,avasoconstrictingsubstance;inadditiontheenzymestimulatesthesecretionofaldosteronebythe

adrenalcortexandstimulatesthedegradationofbradykinin,avasodilatorysubstance,intoinactiveheptapeptides.

Thisresultsin:

-areductioninaldosteronesecretion,

-anincreaseinplasmareninactivity,sincealdosteronenolongerexercisesnegativefeedback,

-areductionintotalperipheralresistancewithapreferentialactiononthevascularbedinmuscleandthekidney,with

noaccompanyingsaltandwaterretentionorreflextachycardia,withchronictreatment.

Theantihypertensiveactionofperindoprilalsooccursinpatientswithlowornormalreninconcentrations.

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesareinactive.

Perindoprilreducestheworkoftheheart:

-byavasodilatoryeffectonveins,probablycausedbychangesinthemetabolismofprostaglandins:reductioninpre-

load

-byreductionofthetotalperipheralresistance:reductioninafterload.

Studiescarriedoutonpatientswithcardiacinsufficiencyhaveshown:

-areductioninleftandrightventricularfillingpressures,

-areductionintotalperipheralvascularresistance,

-anincreaseincardiacoutputandanimprovementinthecardiacindex,

-anincreaseinregionalbloodflowinmuscle.

Exercisetestresultsalsoshowedimprovement.

Linkedtoindapamide:

Indapamideisasulphonamidederivativewithanindolering,pharmacologicallyrelatedtothethiazidegroupof

diuretics.Indapamideinhibitsthereabsorptionofsodiuminthecorticaldilutionsegment.

Itincreasestheurinaryexcretionofsodiumandchloridesand,toalesserextent,theexcretionofpotassiumand

magnesium,therebyincreasingurineoutputandhavinganantihypertensiveaction.

Characteristicsofantihypertensiveaction

LinkedtoCoversylArgininePlus5mg/1.25mg:

Inhypertensivepatientsregardlessofage,CoversylArgininePlus5mg/1.25mgexertsadose-dependent

antihypertensiveeffectondiastolicandsystolicarterialpressurewhilstsupineorstanding.Thisantihypertensiveeffect

lastsfor24hours.

Thereductioninbloodpressureisobtainedinlessthanonemonthwithouttachyphylaxis;stoppingtreatmenthasno

reboundeffect.Duringclinicaltrials,theconcomitantadministrationofperindoprilandindapamideproduced

antihypertensiveeffectsofasynergicnatureinrelationtoeachoftheproductsadministeredalone.

PICXEL,amulticenter,randomised,doubleblindactivecontrolledstudyhasassessedonechocardiographytheeffect

ofperindopril/indapamidecombinationonLVHversusenalaprilmonotherapy.

InPICXEL,hypertensivepatientswithLVH(definedasleftventricularmassindex(LVMI)>120g/m 2

inmaleand>

100g/m 2

infemale)wererandomisedeithertoperindopriltert-butylamine2mg(equivalentto2.5mgperindopril

arginine)/indapamide0.625mgortoenalapril10mgonceadayforaone-yeartreatment.Thedosewasadapted

accordingtobloodpressurecontrol,uptoperindopriltert-butylamine8mg(equivalentto10mgperindoprilarginine)

andindapamide2.5mgorenalapril40mgonceaday.Only34%ofthesubjectsremainedtreatedwithperindopriltert-

butylamine2mg(equivalentto2.5mgperindoprilarginine)/indapamide0.625mg(versus20%withEnalapril10mg).

Attheendoftreatment,LVMIhaddecreasedsignificantlymoreintheperindopril/indapamidegroup(-10.1g/m²)than

intheenalaprilgroup(-1.1g/m²)intheallrandomisedpatientspopulation.ThebetweengroupdifferenceinLVMI

changewas-8.3(95%CI(-11.5,-5.0),p<0.0001).

AbettereffectonLVMIwasreachedwithhigherperindopril/indapamidedosesthanthoselicensedforPRETERAX

ARGININE2.5mg/0.625mgandCoversylArgininePlus5mg/1.25mg.

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mmHg(95%CI(-7.9,-3.7),p<0.0001)forsystolicbloodpressureand-2.3mmHg(95%CI(-3.6,-0.9),p=0.0004)

fordiastolicbloodpressurerespectively,infavouroftheperindopril/indapamidegroup.

Linkedtoperindopril:

Perindoprilisactiveinallgradesofhypertension:mildtomoderateorsevere.Areductioninsystolicanddiastolic

arterialpressureisobservedinthelyingandstandingposition.

Theantihypertensiveactivityafterasingledoseismaximalatbetween4and6hoursandismaintainedover24hours.

Thereisahighdegreeofresidualblockingofangiotensinconvertingenzymeat24hours,approximately80%.

Inpatientswhorespond,normalisedbloodpressureisreachedafteronemonthandismaintainedwithout

tachyphylaxis.

Withdrawaloftreatmenthasnoreboundeffectonhypertension.

Perindoprilhasvasodilatorypropertiesandrestoreselasticityofthemainarterialtrunks,correctshistomorphometric

changesinresistancearteriesandproducesareductioninleftventricularhypertrophy.

Ifnecessary,theadditionofathiazidediureticleadstoanadditivesynergy.

Thecombinationofanangiotensinconvertingenzymeinhibitorwithathiazidediureticdecreasesthehypokalaemia

riskassociatedwiththediureticalone.

Linkedtoindapamide:

Indapamide,asmonotherapy,hasanantihypertensiveeffectwhichlastsfor24hours.Thiseffectoccursatdosesat

whichthediureticpropertiesareminimal.

Itsantihypertensiveactionisproportionaltoanimprovementinarterialcomplianceandareductionintotaland

arteriolarperipheralvascularresistance.

Indapamidereducesleftventricularhypertrophy.

Whenadoseofthiazidediureticandthiazide-relateddiureticsisexceeded,theantihypertensiveeffectreachesa

plateau,whereastheadverseeffectscontinuetoincrease.Ifthetreatmentisineffective,thedoseshouldnotbe

increased.

Furthermore,ithasbeenshownthatintheshort-term,mid-termandlong-terminhypertensivepatients,indapamide:

-hasnoeffectonlipidmetabolism:triglycerides,LDL-cholesterolandHDL-cholesterol,

-hasnoeffectoncarbohydratemetabolism,evenindiabetichypertensivepatients.

5.2Pharmacokineticproperties

LinkedtoCoversylArgininePlus5mg/1.25mg:

Theco-administrationofperindoprilandindapamidedoesnotchangetheirpharmacokineticpropertiesbycomparison

toseparateadministration.

Linkedtoperindopril:

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.

Perindoprilatiseliminatedintheurineandtheterminalhalf-lifeoftheunboundfractionisapproximately17hours,

resultinginsteady-statewithin4days.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure.Dosage

adjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment(creatinineclearance).

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(see

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Linkedtoindapamide:

Indapamideisrapidlyandcompletelyabsorbedfromthedigestivetract.

Thepeakplasmalevelisreachedinhumansapproximatelyonehourafteroraladministrationoftheproduct.Plasma

proteinbindingis79%.

Theeliminationhalf-lifeisbetween14and24hours(average18hours).Repeatedadministrationdoesnotproduce

accumulation.Eliminationismainlyintheurine(70%ofthedose)andfaeces(22%)intheformofinactive

metabolites.

Thepharmacokineticsareunchangedinpatientswithrenalinsufficiency.

5.3Preclinicalsafetydata

CoversylArgininePlus5mg/1.25mghasslightlyincreasedtoxicitythanthatofitscomponents.Renalmanifestations

donotseemtobepotentiatedintherat.However,thecombinationproducesgastro-intestinaltoxicityinthedogandthe

toxiceffectsonthemotherseemtobeincreasedintherat(comparedtoperindopril).

Nonetheless,theseadverseeffectsareshownatdoselevelscorrespondingtoaverymarkedsafetymarginby

comparisontothetherapeuticdosesused.

Preclinicalstudiesperformedseparatelywithperindoprilandindapamidedidnotshowgenotoxic,carcinogenicor

teratogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Magnesiumstearate(E470b)

Maltodextrin

Silicacolloidalanhydrous(E551)

Sodiumstarchglycolate(typeA)

Film-coating:

Glycerol(E422)

Hypromellose(E464)

Macrogol6000

Magnesiumstearate(E470b)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownonthecontainerandoutercartonoftheproductasmarketed

inthecountryoforigin.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

30tabletsinapolypropylenewhitecontainerequippedwithalowdensitypolyethyleneflowreducerandalowdensity

polyethyleneblueopaquestoppercontainingadessicantgel,containedinanoverlabelledcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/12/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31stJuly2009

10DATEOFREVISIONOFTHETEXT

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