COVERSYL ARGININE

Main information

  • Trade name:
  • COVERSYL ARGININE
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COVERSYL ARGININE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/014/003
  • Authorization date:
  • 09-11-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylArginine5mgfilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainsperindopril3.395mgcorrespondingto5mgperindoprilarginine.

Excipients:lactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromGreece,PolandandHungary:

PolandandGreece

Light-green,rod-shapedfilm-coatedtabletengravedwiththeServierlogoononefaceandplainontherother.

Hungary:

Light-green,rod-shapedfilm-coatedtabletengravedwiththeservierlogoononefaceandplainontheother,scoredon

bothedges.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Treatmentofhypertension.

Heartfailure:

Treatmentofsymptomaticheartfailure.

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCOVERSYLARGININEistakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressureresponse.

Hypertension:

COVERSYLARGININEmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensive

therapy.

Therecommendedstartingdoseis5mggivenoncedailyinthemorning.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascularhypertension,salt

and/orvolumedepletion,cardiacdecompensationorseverehypertension)mayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof2.5mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision.

Thedosemaybeincreasedto10mgoncedailyafteronemonthoftreatment.

SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCOVERSYLARGININE;thisismorelikely

inpatientswhoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatients

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Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithCOVERSYLARGININE

(seesection4.4).

Inhypertensivepatientsinwhomthediureticcannotbediscontinued,therapywithCOVERSYLARGININEshouldbe

initiatedwitha2.5mgdose.Renalfunctionandserumpotassiumshouldbemonitored.Thesubsequentdosageof

COVERSYLARGININEshouldbeadjustedaccordingtobloodpressureresponse.Ifrequired,diuretictherapymaybe

resumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2.5mgwhichmaybeprogressivelyincreasedto5mgafter

onemonththento10mgifnecessarydependingonrenalfunction(seetablebelow).

Symptomaticheartfailure:

ItisrecommendedthatCOVERSYLARGININE,generallyassociatedwithanon-potassium-sparingdiureticand/or

digoxinand/orabeta-blocker,beintroducedunderclosemedicalsupervisionwitharecommendedstartingdoseof2.5

mgtakeninthemorning.Thisdosemaybeincreasedafter2weeksto5mgoncedailyiftolerated.Thedose

adjustmentshouldbebasedontheclinicalresponseoftheindividualpatient.

Insevereheartfailureandinotherpatientsconsideredtobeathighrisk(patientswithimpairedrenalfunctionanda

tendencytohaveelectrolytedisturbances,patientsreceivingsimultaneoustreatmentwithdiureticsand/ortreatment

withvasodilatingagents),treatmentshouldbeinitiatedundercarefulsupervision(seesection4.4).

Patientsathighriskofsymptomatichypotensione.g.patientswithsaltdepletionwithorwithouthyponatraemia,

patientswithhypovolaemiaorpatientswhohavebeenreceivingvigorousdiuretictherapyshouldhavetheseconditions

corrected,ifpossible,priortotherapywithCOVERSYLARGININE.Bloodpressure,renalfunctionandserum

potassiumshouldbemonitoredclosely,bothbeforeandduringtreatmentwithCOVERSYLARGININE(seesection

4.4).

Stablecoronaryarterydisease:

COVERSYLARGININEshouldbeintroducedatadoseof5mgoncedailyfortwoweeks,thenincreasedto10mg

oncedaily,dependingonrenalfunctionandprovidedthatthe5mgdoseiswelltolerated.

Elderlypatientsshouldreceive2.5mgoncedailyforoneweek,then5mgoncedailythenextweek,beforeincreasing

thedoseupto10mgoncedailydependingonrenalfunction(seeTable1“Dosageadjustmentinrenalimpairment”).

Thedoseshouldbeincreasedonlyifthepreviouslowerdoseiswelltolerated.

Dosageadjustmentinrenalimpairment:

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearanceasoutlinedintable1below:

Table1:dosageadjustmentinrenalimpairment

*Dialysisclearanceofperindoprilatis70ml/min.

Forpatientsonhaemodialysis,thedoseshouldbetakenafterdialysis.

Dosageadjustmentinhepaticimpairment:

Nodosageadjustmentisnecessaryinpatientswithhepaticimpairment(seesections4.4and5.2)

Childrenandadolescents(lessthan18yearsofage):

Efficacyandsafetyofuseinchildrenandadolescentshavenotbeenestablished.Therefore,useinchildrenand

Creatinineclearance(ml/min) Recommendeddose

>60 5mgperday

30<Cl

<60 2.5mgperday

15<Cl

<30 2.5mgeveryotherday

Haemodialysedpatients*

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4.3Contraindications

Hypersensitivitytoperindopril,toanyoftheexcipientsortoanyotherACEinhibitor;

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy;

Hereditaryoridiopathicangioedema;

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Stablecoronaryarterydisease:

Ifanepisodeofunstableanginapectoris(majorornot)occursduringthefirstmonthofperindopriltreatment,acareful

appraisalofthebenefit/riskshouldbeperformedbeforetreatmentcontinuation.

Hypotension:

ACEinhibitorsmaycauseafallinbloodpressure.Symptomatichypotensionisseenrarelyinuncomplicated

hypertensivepatientsandismorelikelytooccurinpatientswhohavebeenvolume-depletede.g.bydiuretictherapy,

dietarysaltrestriction,dialysis,diarrhoeaorvomiting,orwhohavesevererenin-dependenthypertension(seesections

4.5and4.8).Inpatientswithsymptomaticheartfailure,withorwithoutassociatedrenalinsufficiency,symptomatic

hypotensionhasbeenobserved.Thisismostlikelytooccurinthosepatientswithmoreseveredegreesofheartfailure,

asreflectedbytheuseofhighdosesofloopdiuretics,hyponatraemiaorfunctionalrenalimpairment.Inpatientsat

increasedriskofsymptomatichypotension,initiationoftherapyanddoseadjustmentshouldbecloselymonitored(see

4.2and4.8).Similarconsiderationsapplytopatientswithischaemicheartorcerebrovasculardiseaseinwhoman

excessivefallinbloodpressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofsodiumchloride9mg/ml(0.9%)solution.Atransienthypotensiveresponseisnota

contraindicationtofurtherdoses,whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreased

aftervolumeexpansion.

Insomepatientswithcongestiveheartfailurewhohavenormalorlowbloodpressure,additionalloweringofsystemic

bloodpressuremayoccurwithCOVERSYLARGININE.Thiseffectisanticipatedandisusuallynotareasonto

discontinuetreatment.Ifhypotensionbecomessymptomatic,areductionofdoseordiscontinuationofCOVERSYL

ARGININEmaybenecessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy:

AswithotherACEinhibitors,COVERSYLARGININEshouldbegivenwithcautiontopatientswithmitralvalve

stenosisandobstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophiccardiomyopathy.

Renalimpairment:

Incasesofrenalimpairment(creatinineclearance<60ml/min)theinitialperindoprildosageshouldbeadjusted

accordingtothepatient'screatinineclearance(seesection4.2)andthenasafunctionofthepatient'sresponseto

treatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforthesepatients(see

section4.8).

Inpatientswithsymptomaticheartfailure,hypotensionfollowingtheinitiationoftherapywithACEinhibitorsmay

leadtosomefurtherimpairmentinrenalfunction.Acuterenalfailure,usuallyreversible,hasbeenreportedinthis

situation.

Insomepatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,whohavebeentreated

withACEinhibitors,increasesinbloodureaandserumcreatinine,usuallyreversibleupondiscontinuationoftherapy,

havebeenseen.Thisisespeciallylikelyinpatientswithrenalinsufficiency.Ifrenovascularhypertensionisalso

presentthereisanincreasedriskofseverehypotensionandrenalinsufficiency.Inthesepatients,treatmentshouldbe

startedunderclosemedicalsupervisionwithlowdosesandcarefuldosetitration.Sincetreatmentwithdiureticsmaybe

acontributoryfactortotheabove,theyshouldbediscontinuedandrenalfunctionshouldbemonitoredduringthefirst

weeksofCOVERSYLARGININEtherapy.

Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodurea

andserumcreatinine,usuallyminorandtransient,especiallywhenCOVERSYLARGININEhasbeengiven

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reductionand/ordiscontinuationofthediureticand/orCOVERSYLARGININEmayberequired.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhighfluxmembranes,andtreatedconcomitantly

withanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeofdialysismembraneor

differentclassofantihypertensiveagent.

Kidneytransplantation:

ThereisnoexperienceregardingtheadministrationofCOVERSYLARGININEinpatientswitharecentkidney

transplantation.

Hypersensitivity/Angioedema:

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

patientstreatedwithACEinhibitors,includingCOVERSYLARGININE(seesection4.8).Thismayoccuratanytime

duringtherapy.Insuchcases,COVERSYLARGININEshouldpromptlybediscontinuedandappropriatemonitoring

shouldbeinitiatedandcontinueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhere

swellingwasconfinedtothefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamines

havebeenusefulinrelievingsymptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangiodemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangiodemaandC-1

esteraselevelswerenormal.TheangiodemawasdiagnosedbyproceduresincludingabdominalCTscan,orultrasound

oratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangiodemashouldbeincludedinthe

differentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

Anaphylactoidreactionsduringlow-densitylipoproteins(LDL)apheresis:

Rarely,patientsreceivingACEinhibitorsduringlow-densitylipoprotein(LDL)apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE

inhibitortherapypriortoeachapheresis.

Anaphylacticreactionsduringdesensitisation:

PatientsreceivingACEinhibitorsduringdesensitisationtreatment(e.g.hymenopteravenom)haveexperienced

anaphylactoidreactions.Inthesamepatients,thesereactionshavebeenavoidedwhentheACEinhibitorswere

temporarilywithheld,buttheyreappeareduponinadvertentrechallenge.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfections,whichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicmonitoringofwhitebloodcellcountsis

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Race:

ACEinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon-

blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblackhypertensivepopulation.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/Anaesthesia:

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,COVERSYL

ARGININEmayblockangiotensinIIformationsecondarytocompensatoryreninrelease.Thetreatmentshouldbe

discontinuedonedaypriortothesurgery.Ifhypotensionoccursandisconsideredtobeduetothismechanism,itcan

becorrectedbyvolumeexpansion.

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

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

metablicacidosisandconcomitantuseofpotassium-sparingdiuretics(e.g.spironolactone,eplerenone,triamterene,or

amiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

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

diuretics,orpotassium-containingsaltsubsititutesparticularlyinpatientswithimpairedrenalfunctionmayleadtoa

significantincreaseinserumpotassium.Hyperkalaemiacancauseserious,sometimesfatalarrhythmias.Ifconcomitant

useoftheabove-mentionedagentsisdeemedappropriate,theyshouldbeusedwithcautionandwithfrequent

monitoringofserumpotassium(seesection4.5).

Diabeticpatients:

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor(seesection4.5).

Lithium:

Thecombinationoflithiumandperindoprilisgenerallynotrecommended(seesection4.5).

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes:

Thecombinationofperindoprilandpotassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsalt

substitutesisgenerallynotrecommended(seesection4.5).

Pregnancy:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Excipients:

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,glucose-galactose

malabsorption,ortheLapplactasedeficiencyshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics:

Patientsondiuretics,andespeciallythosewhoarevolumeand/orsaltdepleted,mayexperienceexcessivereductionin

bloodpressureafterinitiationoftherapywithanACEinhibitor.Thepossibilityofhypotensiveeffectscanbereduced

bydiscontinuationofthediuretic,byincreasingvolumeorsaltintakepriortoinitiatingtherapywithlowand

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Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes:

Althoughserumpotassiumusuallyremainswithinnormallimits,hyperkalaemiamayoccurinsomepatientstreated

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

orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesinserumpotassium.Thereforethe

combinationofperindoprilwiththeabove-mentioneddrugsisnotrecommended(seesection4.4).Ifconcomitantuseis

indicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringof

serumpotassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflithium

toxicityandenhancethealreadyincreasedriskoflithiumtoxicitywithACEinhibitors.Useofperindoprilwithlithium

isnotrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsshouldbe

performed(seesection4.4).

Non-steroidalanti-inflammatorydrugs(NSAIDs)includingaspirin3g/day:

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

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

antihypertensiveeffectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacutefailure,andanincreaseinserumpotassium,especiallyinpatients

withpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.

Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiation

ofconcomitanttherapy,andperiodicallythereafter.

Antihypertensiveagentsandvasodilators:

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindopril.Concomitantusewith

nitroglycerinandothernitrates,orothervasodilators,mayfurtherreducebloodpressure.

Antidiabeticagents:

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACEinhibitorsandantidiabeticmedicines

(insulins,oralhypoglycaemicagents)maycauseanincreasedblood-glucoseloweringeffectwithriskof

hypoglycaemia.Thisphenomenonappearedtobemorelikelytooccurduringthefirstweeksofcombinedtreatment

andinpatientswithrenalimpairment.

Tricyclicantidepressants/Antipsychotics/Anesthetics:

Concomitantuseofcertainanaestheticmedicinalproducts,tricyclicantidepressantsandantipsychoticswithACE

inhibitorsmayresultinfurtherreductionofbloodpressure(seesection4.4).

Sympathomimetics:

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

Acetylsalicylicacid,thrombolytics,beta-blockers,nitrates:

Perindoprilmaybeusedconcomitantlywithacetylsalicylicacid(whenusedasathrombolytic),thrombolytics,beta-

blockersand/ornitrates.

Gold:

Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreportedrarelyin

patientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapyincluding

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4.6Fertility,pregnancyandlactation

Pregnancy:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia).(Seesection5.3.)ShouldexposuretoACEinhibitorhaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation:

BecausenoinformationisavailableregardingtheuseofCoversylArginineduringbreastfeeding,CoversylArginineis

notrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

COVERSYLARGININEhasnodirectinfluenceontheabilitytodriveandusemachinesbutindividualreactions

relatedtolowbloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorincombinationwith

anotherantihypertensivemedication.

Asaresulttheabilitytodriveoroperatemachinerymaybeimpaired.

4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithperindoprilandrankedunderthe

followingfrequency:

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

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

Bloodandthelymphaticsystemdisorders:

Decreasesinhaemoglobinandhaematocrit,thrombocytopenia,leucopenia/neutropenia,andcasesofagranulocytosisor

pancytopenia,havebeenreportedveryrarely.InpatientswithacongenitaldeficiencyofG-6PDH,veryrarecasesof

haemolyticanaemiahavebeenreported(seesection4.4).

Metabolismandnutritiondisorders:

NotKnown:hypoglycaemia(seesections4.4and4.5).

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances.

Nervoussystemdisorders:

Common:headache,dizziness,vertigo,paresthaesia.

Veryrare:confusion.

Eyedisorders:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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Earandlabyrinthdisorders:

Common:tinnitus.

Cardiacdisorders:

Veryrare:arrhythmia,anginapectoris,myocardialinfarction,possiblysecondarytoexcessivehypotensioninhigh-risk

patients(seesection4.4).

Vasculardisorders:

Common:hypotensionandeffectsrelatedtohypotension

Veryrare:strokepossiblysecondarytoexcessivehypotensioninhigh-riskpatients(seesection4.4).

Notknown:vasculitis

Respiratory,thoracicandmediastinaldisorders:

Common:cough,dyspnoea.

Uncommon:bronchospasm.

Veryrare:eosinophilicpneumonia,rhinitis.

Gastro-intestinaldisorders:

Common:nausea,vomiting,abdominalpain,dysgeusia,dyspepsia,diarrhoea,constipation.

Uncommon:drymouth.

Veryrare:pancreatitis.

Hepato-biliarydisorders:

Veryrare:hepatitiseithercytolyticorcholestatic(seesection4.4).

Skinandsubcutaneoustissuedisorders:

Common:rash,pruritus.

Uncommon:angioedemaofface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynx,urticaria(see

section4.4).

Veryrare:erythemamultiforme.

Musculoskeletalandconnectivetissuedisorders:

Common:musclecramps.

Renalandurinarydisorders:

Uncommon:renalinsufficiency.

Veryrare:acuterenalfailure.

Reproductivesystemandbreastdisorders:

Uncommon:impotence.

Generaldisordersandadministrationsiteconditions:

Common:asthenia.

Uncommon:sweating.

Investigations:

Increasesinbloodureaandplasmacreatinine,hyperkalaemiareversibleondiscontinuationmayoccur,especiallyinthe

presenceofrenalinsufficiency,severeheartfailureandrenovascularhypertension.Elevationofliverenzymesand

serumbilirubinhavebeenreportedrarely.

ClinicalTrials:

DuringtherandomisedperiodoftheEUROPAstudy,onlyseriousadverseeventswerecollected.Fewpatients

experiencedseriousadverseevents:16(0.3%)ofthe6122perindoprilpatientsand12(0.2%)ofthe6107placebo

patients.Inperindopril-treatedpatients,hypotensionwasobservedin6patients,angioedemain3patientsandsudden

cardiacarrestin1patient.Morepatientswithdrewforcough,hypotensionorotherintoleranceonperindoprilthanon

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4.9Overdose

Limiteddataareavailableforoverdosageinhumans.SymptomsassociatedwithoverdosageofACEinhibitorsmay

includehypotension,circulatoryshock,electrolytedisturbances,renalfailure,hyperventilation,tachycardia,

palpitations,bradycardia,dizziness,anxiety,andcough.

Therecommendedtreatmentofoverdosageisintravenousinfusionofsodiumchloride9mg/ml(0.9%)solution.If

hypotensionoccurs,thepatientshouldbeplacedintheshockposition.Ifavailable,treatmentwithangiotensinII

infusionand/orintravenouscatecholaminesmayalsobeconsidered.Perindoprilmayberemovedfromthegeneral

circulationbyhaemodialysis(seesection4.4).Pacemakertherapyisindicatedfortherapy-resistantbradycardia.Vital

signs,serumelectrolytesandcreatinineconcentrationsshouldbemonitoredcontinuously.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitors,plain

ATCcode:C09AA04

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.

Anadjunctivetherapywithathiazidediureticproducesanadditive-typeofsynergy.ThecombinationofanACE

inhibitorandathiazidealsodecreasestheriskofhypokalaemiainducedbythediuretictreatment.

Heartfailure:

Perindoprilreducescardiacworkbyadecreaseinpre-loadandafter-load.

Studiesinpatientswithheartfailurehavedemonstrated:

decreasedleftandrightventricularfillingpressures,

reducedtotalperipheralvascularresistance,

increasedcardiacoutputandimprovedcardiacindex.

Incomparativestudies,thefirstadministrationof2.5mgofperindoprilargininetopatientswithmildtomoderateheart

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Patientswithstablecoronaryarterydisease:

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

4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopriltert-

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

ofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheartfailure.Overall,90%ofthepatientshada

previousmyocardialinfarctionand/orapreviouscoronaryrevascularisation.Mostofthepatientsreceivedthestudy

medicationontopofconventionaltherapyincludingplateletinhibitors,lipidloweringagentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardialinfarctionand/or

cardiacarrestwithsuccessfulresuscitation.Thetreatmentwith8mgperindopriltert-butylamine(equivalentto10mg

perindoprilarginine)oncedailyresultedinasignificantabsolutereductionintheprimaryendpointof1.9%(relative

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

Inpatientswithahistoryofmyocardialinfarctionand/orrevasularisation,anabsolutereductionof2.2%corresponding

toaRRRof22.4%(95%CI[12.0;31.6]-p<0.001)intheprimaryendpointwasobservedbycomparisontoplacebo.

5.2Pharmacokineticproperties

Afteroraladministration,theabsoptionofperindoprilisrapidandthepeakconcentrationisachievedwithin1hour.

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.Dosage

adjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment(creatinineclearance).

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(see

sections4.2and4.4).

5.3Preclinicalsafetydata

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversibledamage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefetal

development,resultinginfetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreaseinperi-

andpostnatalmortalityhavebeenobserved.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Magnesiumstearate

Maltodextrin

Hydrophobiccolloidalsilica

Sodiumstarchglycolate(typeA)

Film-coating:

Glycerol

Hypromellose

Copperchlorophyllin

Macrogol

Magnesiumstearate

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecountainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Keepthecontainertightlyclosedinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Whiteplastictabletcontainerwithaflowreducerandgreenorwhiteopaquestoppercontainingadessicantgel.

Packsize:30

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Medicinesnolongerrequiredshouldnotbedisposedofviathewastewaterorthemunicipalsewagesystem.Return

themtoapharmacyoraskyourpharmacisthowtodisposeoftheminaccordancewiththenationalregulations.These

measureswillhelptoprotecttheenvironment.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1151/14/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:9thNovember2007

10DATEOFREVISIONOFTHETEXT

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