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:
  • PPA1659/002/001
  • Authorization date:
  • 22-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylArginine5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainsperindopril3.395mgcorrespondingtoperindoprilarginine5mg

Excipients:lactosemonohydrate

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromUK:

Light-green,rod-shapedfilm-coatedtabletengravedwith ononefaceandscoredonbothedges.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Treatmentofhypertension.

Heartfailure:

Treatmentofsymptomaticheartfailure.

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCOVERSYListakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressureresponse.

Hypertension:

COVERSYLmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensivetherapy.

Therecommendedstartingdoseis5mggivenoncedailyinthemorning.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascularhypertension,salt

and/orvolumedepletion,cardiacdecompensationorseverehypertension)mayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof2.5mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision.

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SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCOVERSYL;thisismorelikelyinpatients

whoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatientsmaybe

volumeand/orsaltdepleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithCOVERSYL(seesection

4.4).

Inhypertensivepatientsinwhomthediureticcannotbediscontinued,therapywithCOVERSYLshouldbeinitiated

witha2.5mgdose.Renalfunctionandserumpotassiumshouldbemonitored.ThesubsequentdosageofCOVERSYL

shouldbeadjustedaccordingtobloodpressureresponse.Ifrequired,diuretictherapymayberesumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2.5mgwhichmaybeprogressivelyincreasedto5mgafter

onemonththento10mgifnecessarydependingonrenalfunction(seetablebelow).

Symptomaticheartfailure:

ItisrecommendedthatCOVERSYL,generallyassociatedwithanon-potassium-sparingdiureticand/ordigoxinand/or

abeta-blocker,beintroducedunderclosemedicalsupervisionwitharecommendedstartingdoseof2.5mgtakeninthe

morning.Thisdosemaybeincreasedafter2weeksto5mgoncedailyiftolerated.Thedoseadjustmentshouldbe

basedontheclinicalresponseoftheindividualpatient.

Insevereheartfailureandinotherpatientsconsideredtobeathighrisk(patientswithimpairedrenalfunctionanda

tendencytohaveelectrolytedisturbances,patientsreceivingsimultaneoustreatmentwithdiureticsand/ortreatment

withvasodilatingagents),treatmentshouldbeinitiatedundercarefulsupervision(seesection4.4).

Patientsathighriskofsymptomatichypotensione.g.patientswithsaltdepletionwithorwithouthyponatraemia,

patientswithhypovolaemiaorpatientswhohavebeenreceivingvigorousdiuretictherapyshouldhavetheseconditions

corrected,ifpossible,priortotherapywithCOVERSYL.Bloodpressure,renalfunctionandserumpotassiumshould

bemonitoredclosely,bothbeforeandduringtreatmentwithCOVERSYL(seesection4.4).

Stablecoronaryarterydisease:

COVERSYLshouldbeintroducedatadoseof5mgoncedailyfortwoweeks,thenincreasedto10mgoncedaily,

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)occursduringthefirstmonthofperindropriltreatment,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

sections4.2and4.8).Similarconsiderationsapplytopatientswithischaemicheartorcerebrovasculardiseaseinwhom

anexcessivefallinbloodpressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofsodiumchloride9mg/ml(0.9%)solution.Atransienthypotensiveresponseisnota

contraindicationtofurtherdoses,whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreased

aftervolumeexpansion.

Insomepatientswithcongestiveheartfailurewhohavenormalorlowbloodpressure,additionalloweringofsystemic

bloodpressuremayoccurwithCOVERSYL.Thiseffectisanticipatedandisusuallynotareasontodiscontinue

treatment.Ifhypotensionbecomessymptomatic,areductionofdoseordiscontinuationofCOVERSYLmaybe

necessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy:

AswithotherACEinhibitors,COVERSYLshouldbegivenwithcautiontopatientswithmitralvalvestenosisand

obstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophiccardiomyopathy.

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

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Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodurea

andserumcreatinine,usuallyminorandtransient,especiallywhenCOVERSYLhasbeengivenconcomitantlywitha

diuretic.Thisismorelikelytooccurinpatientswithpre-existingrenalimpairment.Dosagereductionand/or

discontinuationofthediureticand/orCOVERSYLmayberequired.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhighfluxmembranes,andtreatedconcomitantly

withanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeofdialysismembraneor

differentclassofantihypertensiveagent.

Kidneytransplantation:

ThereisnoexperienceregardingtheadministrationofCOVERSYLinpatientswitharecentkidneytransplantation.

Hypersensitivity/Angioedema:

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

patientstreatedwithACEinhibitors,includingCOVERSYL(seesection4.8).Thismayoccuratanytimeduring

therapy.Insuchcases,COVERSYLshouldpromptlybediscontinuedandappropriatemonitoringshouldbeinitiated

andcontinueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhereswellingwasconfinedto

thefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulin

relievingsymptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

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.

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Perindoprilshouldbeusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressant

therapy,treatmentwithallopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthere

ispre-existingimpairedrenalfunction.Someofthesepatientsdevelopedseriousinfections,whichinafewinstances

didnotrespondtointensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicmonitoringofwhite

bloodcellcountsisadvisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever).

Race:

ACEinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon-

blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblackhypertensivepopulation.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/Anaesthesia:

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,COVERSYLmay

blockangiotensinIIformationsecondarytocompensatoryreninrelease.Thetreatmentshouldbediscontinuedoneday

priortothesurgery.Ifhypotensionoccursandisconsideredtobeduetothismechanism,itcanbecorrectedbyvolume

expansion.

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

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,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Excipients:

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,glucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics:

Patientsondiuretics,andespeciallythosewhoarevolumeand/orsaltdepleted,mayexperienceexcessivereductionin

bloodpressureafterinitiationoftherapywithanACEinhibitor.Thepossibilityofhypotensiveeffectscanbereduced

bydiscontinuationofthediuretic,byincreasingvolumeorsaltintakepriortoinitiatingtherapywithlowand

progressivedosesofperindopril.

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-inflammatorymedicinalproducts(NSAIDs)includingaspirin 3g/day:

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

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

antihypertensiveeffectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

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,

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Gold:

Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreportedrarelyin

patientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapyincluding

perindopril.

4.6Fertility,pregnancyandlactation

Pregnancy:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

ACEinhibitorsiscontra-indicatedduringthe2ndand3rdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).ShouldexposuretoACEinhibitorhaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seealsosections4.3and4.4).

Lactation:

BecausenoinformationisavailableregardingtheuseofCOVERSYLduringbreastfeeding,COVERSYLisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

COVERSYLhasnodirectinfluenceontheabilitytodriveandusemachinesbutindividualreactionsrelatedtolow

bloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorincombinationwithanother

antihypertensivemedication.

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).

Bloodandlymphaticsystemdisorders:

Decreasesinhaemoglobinandhaematocrit,thrombocytopenia,leucopenia/neutropenia,andcasesofagranulocytosisor

pancytopenia,havebeenreportedveryrarely.InpatientswithacongenitaldeficiencyofG-6PDH,veryrarecasesof

haemolyticanaemiahavebeenreported(seesection4.4).

Metabolismandnutritiondisorders:

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

Psychiatricdisorders:

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Nervoussystemdisorders:

Common:headache,dizziness,vertigo,paresthaesia.

Veryrare:confusion.

Eyedisorders:

Common:visiondisturbance.

Earandlabyrinthdisorders:

Common:tinnitus.

Cardiacdisorders:

Veryrare:arrhythmia,anginapectorisandmyocardialinfarctionpossiblysecondarytoexcessivehypotensioninhigh-

riskpatients(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

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Clinicaltrials:

DuringtherandomisedperiodoftheEUROPAstudy,onlyseriousadverseeventswerecollected.Fewpatients

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

patients.Inperindopril-treatedpatients,hypotensionwasobservedin6patients,angioedemain3patientsandsudden

cardiacarrestin1patient.Morepatientswithdrewforcough,hypotensionorotherintoleranceonperindoprilthanon

placebo,6.0%(n=366)versus2.1%(n=129)respectively.

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.

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Perindoprilreducesleftventricularhypertrophy.

Inman,perindoprilhasbeenconfirmedtodemonstratevasodilatoryproperties.Itimproveslargearteryelasticityand

decreasesthemedia:lumenratioofsmallarteries.

Anadjunctivetherapywithathiazidediureticproducesanadditive-typeofsynergy.ThecombinationofanACE

inhibitorandathiazidealsodecreasestheriskofhypokalaemiainducedbythediuretictreatment.

Heartfailure:

Perindoprilreducescardiacworkbyadecreaseinpre-loadandafter-load.

Studiesinpatientswithheartfailurehavedemonstrated:

decreasedleftandrightventricularfillingpressures,

reducedtotalperipheralvascularresistance,

increasedcardiacoutputandimprovedcardiacindex.

Incomparativestudies,thefirstadministrationof2.5mgofperindoprilargininetopatientswithmildtomoderateheart

failurewasnotassociatedwithanysignificantreductionofbloodpressureascomparedtoplacebo.

Patientswithstablecoronaryarterydisease:

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

4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopriltert-

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

Thetrialpopulationhadevidenceofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheartfailure.Overall,

90%ofthepatientshadapreviousmyocardialinfarctionand/orapreviouscoronaryrevascularisation.Mostofthe

patientsreceivedthestudymedicationontopofconventionaltherapyincludingplateletinhibitors,lipidlowering

agentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardialinfarctionand/or

cardiacarrestwithsuccessfulresuscitation.Thetreatmentwith8mgperindopriltert-butylamine(equivalentto10mg

perindoprilarginine)oncedailyresultedinasignificantabsolutereductionintheprimaryendpointof1.9%(relative

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

Inpatientswithahistoryofmyocardialinfarctionand/orrevascularisation,anabsolutereductionof2.2%

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

comparisontoplacebo.

5.2Pharmacokineticproperties

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationisachievedwithin1hour.

Theplasmahalf-lifeofperindoprilisequalto1hour.

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindoprilarginineshouldbe

administeredorallyinasingledailydoseinthemorningbeforeameal.

Ithasbeendemonstratedalinearrelationshipbetweenthedoseofperindoprilanditsplasmaexposure.

Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingofperindoprilatto

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Perindoprilatiseliminatedintheurineandtheterminalhalf-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.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Magnesiumstearate

Maltodextrin

Hydrophobiccolloidalsilica

Sodiumstarchglycolate(typeA)

Film-coating:

Glycerol

Hypromellose

Copperchlorophyllin

Macrogol6000

Magnesiumstearate

Titaniumdioxide

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

30tabletsinawhitepolypropylenetabletcontainerequippedwithapolyethyleneflowreducerandawhiteopaque

stoppercontainingadesiccantgel.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Medicinesnolongerrequiredshouldnotbedisposedofviathewastewaterorthemunicipalsewagesystem.Return

themtoapharmacyoraskyourpharmacisthowtodisposeoftheminaccordancewiththenationalregulations.These

measureswillhelptoprotecttheenvironment.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton,Oldham

LancashireOL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22ndofOctober2010

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