COVERSYL

Main information

  • Trade name:
  • COVERSYL Tablets 8 Milligram
  • Dosage:
  • 8 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COVERSYL Tablets 8 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/022/002
  • Authorization date:
  • 10-11-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/022/002

CaseNo:2034068

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrants

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Coversyl8MilligramTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjectto

thegeneralconditionsasmaybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2007until09/11/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Coversyl8mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains8mgperindopriltert-butylaminesalt,equivalentto6.676mgperindopril

Excipients:Lactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromtheUK:

Green,round,biconvextablet,engravedwithaheartononefaceandalogoontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofhypertension

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCOVERSYListakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(see4.4“Specialwarningsand

specialprecautionsforuse”)andbloodpressureresponse.

Hypertension

COVERSYLmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensive

therapy.

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Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascular

hypertension,saltand/orvolumedepletion,cardiacdecompensationorseverehypertension)may

experienceanexcessivedropinbloodpressurefollowingtheinitialdose.Astartingdoseof2mgis

recommendedinsuchpatientsandtheinitiationoftreatmentshouldtakeplaceundermedical

supervision.

Thedosemaybeincreasedto8mgoncedailyafteronemonthoftreatment.

SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCOVERSYL;thisismore

likelyinpatientswhoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommended

sincethesepatientsmaybevolumeand/orsaltdepleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywith

COVERSYL(seesection4.4“Specialwarningsandspecialprecautionsforuse”).

Inhypertensivepatientsinwhomthediureticcannotbediscontinued,therapywithCOVERSYL

shouldbeinitiatedwitha2mgdose.Renalfunctionandserumpotassiumshouldbemonitored.The

subsequentdosageofCOVERSYLshouldbeadjustedaccordingtobloodpressureresponse.If

required,diuretictherapymayberesumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2mgwhichmaybeprogressively

increasedto4mgafteronemonththento8mgifnecessarydependingonrenalfunction(seetable

below).

Stablecoronaryarterydisease

COVERSYLshouldbeintroducedatadoseof4mgoncedailyfortwoweeks,thenincreasedto8mg

oncedaily,dependingonrenalfunctionandprovidedthatthe4mgdoseiswelltolerated.

Elderlypatientsshouldreceive2mgoncedailyforoneweek,then4mgoncedailythenextweek,

beforeincreasingthedoseupto8mgoncedailydependingonrenalfunction(seeTable1“Dosage

adjustmentinrenalimpairment”).Thedoseshouldbeincreasedonlyifthepreviouslowerdoseiswell

tolerated.

Dosageadjustmentinrenalimpairment

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearanceasoutlinedintable

1below:

Table1:dosageadjustmentinrenalimpairment

Creatinineclearance(ml/min) recommendeddose

CR≥ 60 4mgperday

30<Cl

<60 2mgperday

15<Cl

<30 2mgeveryotherday

Haemodialysedpatients*

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takenafterdialysis.

Dosageadjustmentinhepaticimpairment

Nodosageadjustmentisnecessaryinpatientswithhepaticimpairment(seesections4.4“Special

warningsandspecialprecautionsforuse”and5.2“Pharmacokineticproperties”)

Paediatricuse

Efficacyandsafetyofuseinchildrenhasnotbeenestablished.Therefore,useinchildrenisnotrecommended.

4.3Contraindications

Hypersensitivitytoperindopril,toanyoftheexcipientsortoanyotherACEinhibitor;

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy;

Hereditaryoridiopathicangioedema;

Secondandthirdtrimestersofpregnancy(see4.6“Pregnancyandlactation”).

4.4Specialwarningsandprecautionsforuse

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsoptionshouldnottakethismedicine.

Stablecoronaryarterydisease

Ifanepisodeofunstableanginapectoris(majorornot)occursduringthefirstmonthofperindopril

treatment,acarefulappraisalofthebenefit/riskshouldbeperformedbeforetreatmentcontinuation.

Hypotension

ACEinhibitorsmaycauseafallinbloodpressure.Symptomatichypotensionisseenrarelyin

uncomplicatedhypertensivepatientsandismorelikelytooccurinpatientswhohavebeenvolume-

depletede.g.bydiuretictherapy,dietarysaltrestriction,dialysis,diarrhoeaorvomiting,orwhohave

severerenin-dependenthypertension(seesections4.5“Interactionwithothermedicamentsandother

formsofinteraction”and4.8“Undesirableeffects”).

Inpatientswithsymptomaticheartfailure,withorwithoutassociatedrenalinsufficiency,

symptomatichypotensionhasbeenobserved.Thisismostlikelytooccurinthosepatientswithmore

severedegreesofheartfailure,asreflectedbytheuseofhighdosesofloopdiuretics,hyponatraemia

orfunctionalrenalimpairment.Inpatientsatincreasedriskofsymptomatichypotension,initiationof

therapyanddoseadjustmentshouldbecloselymonitored(see4.2“Posologyandmethodof

administration”and4.8“Undesirableeffects”).

Similarconsiderationsapplytopatientswithischaemicheartorcerebrovasculardiseaseinwhoman

excessivefallinbloodpressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,should

receiveanintravenousinfusionofnormalsaline.Atransienthypotensiveresponseisnota

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pressurehasincreasedaftervolumeexpansion.

Insomepatientswithcongestiveheartfailurewhohavenormalorlowbloodpressure,additional

loweringofsystemicbloodpressuremayoccurwithCOVERSYL.Thiseffectisanticipatedandis

usuallynotareasontodiscontinuetreatment.Ifhypotensionbecomessymptomatic,areductionof

doseordiscontinuationofCOVERSYLmaybenecessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy

AswithotherACEinhibitors,COVERSYLshouldbegivenwithcautiontopatientswithmitralvalve

stenosisandobstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophic

cardiomyopathy.

Renalimpairment

Incasesofrenalimpairment(creatinineclearance<60ml/min)theinitialperindoprildosageshould

beadjustedaccordingtothepatient'screatinineclearance(see4.2“Posologyandmethodof

administration”)andthenasafunctionofthepatient'sresponsetotreatment.Routinemonitoringof

potassiumandcreatininearepartofnormalmedicalpracticeforthesepatients(see4.8“Undesirable

effects”).

Inpatientswithsymptomaticheartfailure,hypotensionfollowingtheinitiationoftherapywithACE

inhibitorsmayleadtosomefurtherimpairmentinrenalfunction.Acuterenalfailure,usually

reversible,hasbeenreportedinthissituation.

Insomepatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,who

havebeentreatedwithACEinhibitors,increasesinbloodureaandserumcreatinine,usually

reversibleupondiscontinuationoftherapy,havebeenseen.Thisisespeciallylikelyinpatientswith

renalinsufficiency.Ifrenovascularhypertensionisalsopresentthereisanincreasedriskofsevere

hypotensionandrenalinsufficiency.Inthesepatients,treatmentshouldbestartedunderclosemedical

supervisionwithlowdosesandcarefuldosetitration.

Sincetreatmentwithdiureticsmaybeacontributoryfactortotheabove,theyshouldbediscontinued

andrenalfunctionshouldbemonitoredduringthefirstweeksofCOVERSYLtherapy.

Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedeveloped

increasesinbloodureaandserumcreatinine,usuallyminorandtransient,especiallywhen

COVERSYLhasbeengivenconcomitantlywithadiuretic.Thisismorelikelytooccurinpatients

withpre-existingrenalimpairment.Dosagereductionand/ordiscontinuationofthediureticand/or

COVERSYLmayberequired.

Haemodialysispatients

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhighfluxmembranes,and

treatedconcomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousing

adifferenttypeofdialysismembraneordifferentclassofantihypertensiveagent.

Kidneytransplantation

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transplantation.

Hypersensitivity/Angioedema

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

reportedrarelyinpatientstreatedwithACEinhibitors,includingCOVERSYL(see4.8Undesirable

effects).Thismayoccuratanytimeduringtherapy.Insuchcases,COVERSYLshouldpromptlybe

discontinuedandappropriatemonitoringshouldbeinitiatedandcontinueduntilcompleteresolution

ofsymptomshasoccurred.Inthoseinstanceswhereswellingwasconfinedtothefaceandlipsthe

conditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthe

tongue,glottisorlarynx,likelytocauseairwayobstruction,emergencytherapyshouldbe

administeredpromptly.Thismayincludetheadministrationofadrenalineand/orthemaintenanceofa

patentairway.Thepatientshouldbeunderclosemedicalsupervisionuntilcompleteandsustained

resolutionofsymptomshasoccurred.

Angiotensinconvertingenzymeinhibitorscauseahigherrateofangioedemainblackpatientsthanin

non-blackpatients.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskof

angioedemawhilereceivinganACEinhibitor(See4.3Contraindications).

Anaphylactoidreactionsduringlow-densitylipoproteins(LDL)apheresis

Rarely,patientsreceivingACEinhibitorsduringlow-densitylipoprotein(LDL)apheresiswith

dextransulphatehaveexperiencedlife-threateninganaphylactoidreactions.Thesereactionswere

avoidedbytemporarilywithholdingACEinhibitortherapypriortoeachapheresis.

Anaphylacticreactionsduringdesensitisation

PatientsreceivingACEinhibitorsduringdesensitisationtreatment(e.g.hymenopteravenom)have

experiencedanaphylactoidreactions.Inthesamepatients,thesereactionshavebeenavoidedwhenthe

ACEinhibitorsweretemporarilywithheld,buttheyreappeareduponinadvertentrechallenge.

Hepaticfailure

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceand

progressestofulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeis

notunderstood.PatientsreceivingACEinhibitorswhodevelopjaundiceormarkedelevationsof

hepaticenzymesshoulddiscontinuetheACEinhibitorandreceiveappropriatemedicalfollow-up(4.8

Undesirableeffects).

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceiving

ACEinhibitors.Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropenia

occursrarely.Perindoprilshouldbeusedwithextremecautioninpatientswithcollagenvascular

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thesecomplicatingfactors,especiallyifthereispre-existingimpairedrenalfunction.Someofthese

patientsdevelopedseriousinfections,whichinafewinstancesdidnotrespondtointensiveantibiotic

therapy.Ifperindoprilisusedinsuchpatients,periodicmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection.

Race

ACEinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblack

peoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-

productive,persistentandresolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcough

shouldbeconsideredaspartofthedifferentialdiagnosisofcough.

Surgery/Anaesthesia

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,

COVERSYLmayblockangiotensinIIformationsecondarytocompensatoryreninrelease.The

treatmentshouldbediscontinuedonedaypriortothesurgery.Ifhypotensionoccursandisconsidered

tobeduetothismechanism,itcanbecorrectedbyvolumeexpansion.

Hyperkalaemia

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,

includingperindopril.Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenal

insufficiency,uncontrolleddiabetesmellitus,orthoseusingconcomitantpotassium-sparingdiuretics,

potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

associatedwithincreasesinserumpotassium(e.g.heparin).Ifconcomitantuseoftheabove-

mentionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumisrecommended.

Diabeticpatients

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbeclosely

monitoredduringthefirstmonthoftreatmentwithanACEinhibitor.(See4.5Interactionwithother

medicinalproductsandotherformsofinteraction,Antidiabetics.)

Lithium

Thecombinationoflithiumandperindoprilisgenerallynotrecommended(see4.5Interactionwith

othermedicinalproductsandotherformsofinteraction).

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes

Thecombinationofperindoprilandpotassiumsparingdiuretics,potassiumsupplementsorpotassium-

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productsandotherformsofinteraction).

Pregnancyandlactation

(Seesection4.3“Contraindications”andsection4.6“Pregnancyandlactation”).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics

Patientsondiuretics,andespeciallythosewhoarevolumeand/orsaltdepleted,mayexperience

excessivereductioninbloodpressureafterinitiationoftherapywithanACEinhibitor.Thepossibility

ofhypotensiveeffectscanbereducedbydiscontinuationofthediuretic,byincreasingvolumeorsalt

intakepriortoinitiatingtherapywithlowandprogressivedosesofperindopril.

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes

Althoughserumpotassiumusuallyremainswithinnormallimits,hyperkalaemiamayoccurinsome

patientstreatedwithperindopril.Potassiumsparingdiuretics(e.g.spironolactone,triamterene,or

amiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificant

increasesinserumpotassium.Thereforethecombinationofperindoprilwiththeabove-mentioned

drugsisnotrecommended(seesection4.4).Ifconcomitantuseisindicatedbecauseofdemonstrated

hypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringofserumpotassium.

Lithium

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduring

concomitantadministrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmay

increasetheriskoflithiumtoxicityandenhancethealreadyincreasedriskoflithiumtoxicitywith

ACEinhibitors.Useofperindoprilwithlithiumisnotrecommended,butifthecombinationproves

necessary,carefulmonitoringofserumlithiumlevelsshouldbeperformed(seesection4.4).

Non-steroidalanti-inflammatorydrugs(NSAIDs)includingaspirin ≥

3g/day

Theadministrationofanon-steroidalanti-inflammatorydrugsmayreducetheantihypertensiveeffect

ofACEinhibitors.Additionally,NSAIDsandACEinhibitorsexertanadditiveeffectontheincrease

inserumpotassiumandmayresultinadeteriorationofrenalfunction.Theseeffectsareusually

reversible.Rarely,acuterenalfailuremayoccur,especiallyinpatientswithcompromisedrenal

functionsuchasthosewhoareelderlyordehydrated.

Antihypertensiveagentsandvasodilators

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindopril.Concomitantuse

withnitroglycerinandothernitrates,orothervasodilators,mayfurtherreducebloodpressure.

Antidiabeticagents

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACEinhibitorsand

antidiabeticmedicines(insulins,oralhypoglycaemicagents)maycauseanincreasedblood-glucose

loweringeffectwithriskofhypoglycaemia.Thisphenomenonappearedtobemorelikelytooccur

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Acetylsalicylicacid,thrombolytics,beta-blockers,nitrates

Perindoprilmaybeusedconcomitantlywithacetylsalicylicacid(whenusedasathrombolytic),

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Tricyclicantidepressants/Antipsychotics/Anesthetics

Concomitantuseofcertainanaestheticmedicinalproducts,tricyclicantidepressantsand

antipsychoticswithACEinhibitorsmayresultinfurtherreductionofbloodpressure(seesection4.4).

Sympathomimetics

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

4.6Pregnancyandlactation

Pregnancy

COVERSYLshouldnotbeusedduringthefirsttrimesterofpregnancy.Whenapregnancyisplanned

orconfirmed,theswitchtoanalternativetreatmentshouldbeinitiatedassoonaspossible.Controlled

studieswithACEinhibitorshavenotbeendoneinhumans,butinalimitednumberofcaseswithfirst

trimesterexposuretheredonotappeartohavebeenanymalformationsconsistentwithhuman

foetotoxicityasdescribedbelow.

Perindopriliscontraindicatedduringthesecondandthirdtrimestersofpregnancy.

ProlongedACEinhibitorexposureduringthesecondandthirdtrimestersisknowntoinducehuman

foetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonatal

toxicity(renalfailure,hypotension,hyperkalaemia).(see5.3“Preclinicalsafetydata”)

Shouldexposuretoperindoprilhaveoccurredfromthesecondtrimesterofpregnancy,ultrasound

checkofrenalfunctionandskullisrecommended.

Lactation

Itisnotknownwhetherperindoprilisexcretedintohumanbreastmilk.ThereforetheuseofCOVERSYLisnot

recommendedinwomenwhoarebreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorweariness

mayoccur.

4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedduringtreatmentwithperindoprilandranked

underthefollowingfrequency:

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

<1/1000);veryrare(<1/10000),includingisolatedreports.

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances

Nervoussystemdisorders:

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Veryrare:confusion

Eyedisorders:

Common:visiondisturbance

Earandlabyrinthdisorders:

Common:tinnitus

Cardio-vasculardisorders:

Common:hypotensionandeffectsrelatedtohypotension

Veryrare:arrhythmia,anginapectoris,myocardialinfarctionandstroke,possiblysecondaryto

excessivehypotensioninhighriskpatients(see4.4Specialwarningsandspecialprecautionsforuse).

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(seesection4.4Specialwarningsandspecial

precautionsforuse)

Skinandsubcutaneoustissuedisorders:

Common:rash,pruritus

Uncommon:angioedemaofface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynx,

urticaria(see4.4Specialwarningsandspecialprecautionsforuse).

Veryrare:erythemamultiforme

Musculoskeletal,connectivetissueandbonedisorders:

Common:musclecramps

Renalandurinarydisorders:

Uncommon:renalinsufficiency

Veryrare:acuterenalfailure

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Uncommon:impotence

Generaldisorders:

Common:asthenia

Uncommon:sweating

Bloodandthelymphaticsystemdisorders:

Decreasesinhaemoglobinandhaematocrit,thrombocytopenia,leucopenia/neutropenia,andcasesof

agranulocytosisorpancytopenia,havebeenreportedveryrarely.

InpatientswithacongenitaldeficiencyofG-6PDH,veryrarecasesofhaemolyticanaemiahavebeen

reported(seesection4.4Specialwarningsandspecialprecautionsforuse).

Investigations:

Increasesinbloodureaandplasmacreatinine,hyperkalaemiareversibleondiscontinuationmay

occur,especiallyinthepresenceofrenalinsufficiency,severeheartfailureandrenovascular

hypertension.Elevationofliverenzymesandserumbilirubinhavebeenreportedrarely.

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.SymptomsassociatedwithoverdosageofACE

inhibitorsmayincludehypotension,circulatoryshock,electrolytedisturbances,renalfailure,

hyperventilation,tachycardia,palpitations,bradycardia,dizziness,anxiety,andcough.

Therecommendedtreatmentofoverdosageisintravenousinfusionofnormalsalinesolution.Ifhypotensionoccurs,the

patientshouldbeplacedintheshockposition.Ifavailable,treatmentwithangiotensinIIinfusionand/orintravenous

catecholaminesmayalsobeconsidered.Perindoprilmayberemovedfromthegeneralcirculationbyhaemodialysis.

(See4.4Specialwarningsandspecialprecautionsforuse,HaemodialysisPatients.)Pacemakertherapyisindicatedfor

therapy-resistantbradycardia.Vitalsigns,serumelectrolytesandcreatinineconcentrationsshouldbemonitored

continuously.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:C09AA04

PerindoprilisaninhibitoroftheenzymethatconvertsangiotensinIintoangiotensinII(Angiotensin

ConvertingEnzymeACE).Theconvertingenzyme,orkinase,isanexopeptidasethatallows

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ofthevasodilatorbradykininintoaninactiveheptapeptide.InhibitionofACEresultsinareductionof

angiotensinIIintheplasma,whichleadstoincreasedplasmareninactivity(byinhibitionofthe

negativefeedbackofreninrelease)andreducedsecretionofaldosterone.SinceACEinactivates

bradykinin,inhibitionofACEalsoresultsinanincreasedactivityofcirculatingandlocalkallikrein-

kininsystems(andthusalsoactivationoftheprostaglandinsystem).Itispossiblethatthismechanism

contributestothebloodpressure-loweringactionofACEinhibitorsandispartiallyresponsiblefor

certainoftheirsideeffects(e.g.cough).

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesshownoinhibition

ofACEactivityinvitro.

Hypertension

Perindoprilisactiveinallgradesofhypertension:mild,moderate,severe;areductioninsystolicand

diastolicbloodpressuresinbothsupineandstandingpositionsisobserved.

Perindoprilreducesperipheralvascularresistance,leadingtobloodpressurereduction.Asa

consequence,peripheralbloodflowincreases,withnoeffectonheartrate.

Renalbloodflowincreasesasarule,whiletheglomerularfiltrationrate(GFR)isusuallyunchanged.

Theantihypertensiveactivityismaximalbetween4and6hoursafterasingledoseandissustainedfor

atleast24hours:trougheffectsareabout87-100%ofpeakeffects.

Thedecreaseinbloodpressureoccursrapidly.Inrespondingpatients,normalisationisachieved

withinamonthandpersistswithouttheoccurrenceoftachyphylaxis.

Discontinuationoftreatmentdoesnotleadtoareboundeffect.

Perindoprilreducesleftventricularhypertrophy.

Inman,perindoprilhasbeenconfirmedtodemonstratevasodilatoryproperties.Itimproveslarge

arteryelasticityanddecreasesthemedia:lumenratioofsmallarteries.

Anadjunctivetherapywithathiazidediureticproducesanadditive-typeofsynergy.Thecombination

ofanACEinhibitorandathiazidealsodecreasestheriskofhypokalaemiainducedbythediuretic

treatment.

Patientswithstablecoronaryarterydisease

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

clinicaltriallasting4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto

perindopril8mg(n=6110)orplacebo(n=6108).

Thetrialpopulationhadevidenceofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheart

failure.Overall,90%ofthepatientshadapreviousmyocardialinfarctionand/orapreviouscoronary

revascularisation.Mostofthepatientsreceivedthestudymedicationontopofconventionaltherapy

includingplateletinhibitors,lipidloweringagentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardial

infarctionand/orcardiacarrestwithsuccessfulresuscitation.Thetreatmentwithperindopril8mg

oncedailyresultedinasignificantabsolutereductionintheprimaryendpointof1.9%(relativerisk

reductionof20%,95%CI[9.4;28.6]–p<0.001).

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

comparisontoplacebo.

5.2Pharmacokineticproperties

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationcomplete

within1hour.Bioavailabilityis65to70%.

About20%ofthetotalquantityofperindoprilabsorbedisconvertedintoperindoprilat,theactive

metabolite.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

plasmahalf-lifeofperindoprilisequalto1hour.Thepeakplasmaconcentrationofperindoprilatis

achievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,COVERSYLshould

beadministeredorallyinasingledailydoseinthemorningbeforeameal.

Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingis

slight(bindingofperindoprilattoangiotensinconvertingenzymeislessthan30%),butis

concentration-dependent.

Perindoprilatiseliminatedintheurineandthehalf-lifeoftheunboundfractionisapproximately3to

5hours.Dissociationofperindoprilatboundtoangiotensinconvertingenzymeleadstoan“effective”

eliminationhalf-lifeof25hours,resultinginsteady-statewithin4days.

Afterrepeatedadministration,noaccumulationofperindoprilisobserved.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure.

Dosageadjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment

(creatinineclearance).

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(seealso

sections4.2“Posologyandmethodofadministration”and4.4“Specialwarningsandspecialprecautionsforuse”).

5.3Preclinicalsafetydata

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversible

damage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicity

orteratogenicity.However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshownto

induceadverseeffectsonlatefoetaldevelopment,resultinginfoetaldeathandcongenitaleffectsin

rodentsandrabbits:renallesionsandanincreaseinperi-andpostnatalmortalityhavebeenobserved.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

Irish Medicines Board

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6.1Listofexcipients

Microcrystallinecellulose

Lactose

Colloidalanhydroussilica

Magnesiumstearate

Aluminiumcoppercomplexesofchlorophyllinslake

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageof

theproductonthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

PVC/aluminiumblisterstripof30tabletspackagedincartonbox.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerials

derivedfromsuchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

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7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/22/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:10 th

November2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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