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:
  • PPA1151/014/002
  • Authorization date:
  • 05-01-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1151/014/002

CaseNo:2069197

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ImbatLimited

UnitL2,NorthRingBusinessPark,Santry,Dublin9

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Coversyl,8Milligram

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/08/2009until04/01/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Coversyl8mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains8mgofPerindopriltert-butylaminesalt,equivalentto6.676mgofPerindopril.

Excipients:Lactose

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromtheUK:

Green,round,biconvextablet,engravedwithheartshapeononefaceand2triangleshapesontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofhypertension

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCOVERSYListakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(see4.4“Specialwarningsandspecialprecautions

foruse”)andbloodpressureresponse.

Hypertension

COVERSYLmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensivetherapy.

Therecommendedstartingdoseis4mggivenoncedailyinthemorning.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascularhypertension,salt

and/orvolumedepletion,cardiacdecompensationorseverehypertension)mayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof2mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision.

Thedosemaybeincreasedto8mgoncedailyafteronemonthoftreatment.

SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCOVERSYL;thisismorelikelyinpatients

whoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatientsmaybe

volumeand/orsaltdepleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithCOVERSYL(seesection4.4

“Specialwarningsandspecialprecautionsforuse”).

Inhypertensivepatientsinwhomthediureticcannotbediscontinued,therapywithCOVERSYLshouldbeinitiated

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ThesubsequentdosageofCOVERSYLshouldbeadjustedaccordingtobloodpressureresponse.Ifrequired,diuretic

therapymayberesumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2mgwhichmaybeprogressivelyincreasedto4mgafter

onemonththento8mgifnecessarydependingonrenalfunction(seetablebelow).

Stablecoronaryarterydisease

COVERSYLshouldbeintroducedatadoseof4mgoncedailyfortwoweeks,thenincreasedto8mgoncedaily,

dependingonrenalfunctionandprovidedthatthe4mgdoseiswelltolerated.

Elderlypatientsshouldreceive2mgoncedailyforoneweek,then4mgoncedailythenextweek,beforeincreasing

thedoseupto8mgoncedailydependingonrenalfunction(seeTable1"Dosageadjustmentinrenalimpairment").

Thedoseshouldbeincreasedonlyifthepreviouslowerdoseiswelltolerated.

Dosageadjustmentinrenalimpairment

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearanceasoutlinedintable1below:

Table1:dosageadjustmentinrenalimpairment

creatinineclearance(ml/min) recommendeddose

4mgperday

30<Cl <60 2mgperday

15<Cl <30 2mgeveryotherday

Haemodialysedpatients*

<15 2mgonthedayofdialysis

*Dialysisclearanceofperindoprilatis70ml/min.Forpatientsonhaemodialysis,thedoseshouldbetakenafter

dialysis.

Dosageadjustmentinhepaticimpairment

Nodosageadjustmentisnecessaryinpatientswithhepaticimpairment(seesections4.4“Specialwarningsandspecial

precautionsforuse”and5.2“Pharmacokineticproperties”)

Paediatricuse

Efficacyandsafetyofuseinchildrenhasnotbeenestablished.Therefore,useinchildrenisnotrecommended.

4.3Contraindications

Hypersensitivitytoperindopril,toanyoftheexcipientsortoanyotherACEinhibitor;

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy;

Hereditaryoridiopathicangioedema;

Secondandthirdtrimestersofpregnancy(see4.6“Pregnancyandlactation”).

4.4Specialwarningsandprecautionsforuse

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsoptionshouldnottakethismedicine.

Stablecoronaryarterydisease

Ifanepisodeofunstableanginapectoris(majorornot)occursduringthefirstmonthofperindropiltreatment,acareful

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Hypotension

ACEinhibitorsmaycauseafallinbloodpressure.Symptomatichypotensionisseenrarelyinuncomplicated

hypertensivepatientsandismorelikelytooccurinpatientswhohavebeenvolumedepletede.g.bydiuretictherapy,

dietarysaltrestriction,dialysis,diarrhoeaorvomiting,orwhohavesevererenin-dependenthypertension(seesections

4.5“Interactionwithothermedicamentsandotherformsofinteraction”and4.8“Undesirableeffects”).Inpatientswith

symptomaticheartfailure,withorwithoutassociatedrenalinsufficiency,symptomatichypotensionhasbeenobserved.

Thisismostlikelytooccurinthosepatientswithmoreseveredegreesofheartfailure,asreflectedbytheuseofhigh

dosesofloopdiuretics,hyponatraemiaorfunctionalrenalimpairment.Inpatientsatincreasedriskofsymptomatic

hypotension,initiationoftherapyanddoseadjustmentshouldbecloselymonitored(see4.2“Posologyandmethodof

administration”and4.8“Undesirableeffects”).Similarconsiderationsapplytopatientswithischaemicheartor

cerebrovasculardiseaseinwhomanexcessivefallinbloodpressurecouldresultinamyocardialinfarctionor

cerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofnormalsaline.Atransienthypotensiveresponseisnotacontraindicationtofurtherdoses,

whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreasedaftervolumeexpansion.

Insomepatientswithcongestiveheartfailurewhohavenormalorlowbloodpressure,additionalloweringofsystemic

bloodpressuremayoccurwithCOVERSYL.Thiseffectisanticipatedandisusuallynotareasontodiscontinue

treatment.Ifhypotensionbecomessymptomatic,areductionofdoseordiscontinuationofCOVERSYLmaybe

necessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy

AswithotherACEinhibitors,COVERSYLshouldbegivenwithcautiontopatientswithmitralvalvestenosisand

obstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophiccardiomyopathy.

Renalimpairment

Incasesofrenalimpairment(creatinineclearance<60ml/min)theinitialperindoprildosageshouldbeadjusted

accordingtothepatient'screatinineclearance(see4.2“Posologyandmethodofadministration”)andthenasafunction

ofthepatient'sresponsetotreatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedical

practiceforthesepatients(see4.8“Undesirableeffects”).

Inpatientswithsymptomaticheartfailure,hypotensionfollowingtheinitiationoftherapywithACEinhibitorsmay

leadtosomefurtherimpairmentinrenalfunction.Acuterenalfailure,usuallyreversible,hasbeenreportedinthis

situation.

Insomepatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,whohavebeentreated

withACEinhibitors,increasesinbloodureaandserumcreatinine,usuallyreversibleupondiscontinuationoftherapy,

havebeenseen.Thisisespeciallylikelyinpatientswithrenalinsufficiency.Ifrenovascularhypertensionisalso

presentthereisanincreasedriskofseverehypotensionandrenalinsufficiency.Inthesepatients,treatmentshouldbe

startedunderclosemedicalsupervisionwithlowdosesandcarefuldosetitration.Sincetreatmentwithdiureticsmaybe

acontributoryfactortotheabove,theyshouldbediscontinuedandrenalfunctionshouldbemonitoredduringthefirst

weeksofCOVERSYLtherapy.

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(see4.8Undesirableeffects).Thismayoccuratanytime

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Insuchcases,COVERSYLshouldpromptlybediscontinuedandappropriatemonitoringshouldbeinitiatedand

continueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhereswellingwasconfinedtothe

faceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.

Angiotensinconvertingenzymeinhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-black

patients.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(See4.3Contraindications).

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(4.8Undesirableeffects).

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfections,whichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection.

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

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Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,uncontrolleddiabetes

mellitus,orthoseusingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsalt

substitutes;orthosepatientstakingotherdrugsassociatedwithincreasesinserumpotassium(e.g.heparin).If

concomitantuseoftheabove-mentionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumis

recommended.

Diabeticpatients

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor.(See4.5Interactionwithothermedicinalproductsandother

formsofinteraction,Antidiabetics.)

Lithium

Thecombinationoflithiumandperindoprilisgenerallynotrecommended(see4.5Interactionwithothermedicinal

productsandotherformsofinteraction).

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes

Thecombinationofperindoprilandpotassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsalt

substitutesisgenerallynotrecommended(see4.5Interactionwithothermedicinalproductsandotherformsof

interaction).

PregnancyandLactation

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

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-inflammatorydrugs(NSAIDs)includingaspirin3g/day

Theadministrationofnon-steroidalanti-inflammatorydrugsmayreducetheantihypertensiveeffectofACEinhibitors.

Additionally,NSAIDsandACEinhibitorsexertanadditiveeffectontheincreaseinserumpotassiumandmayresultin

adeteriorationofrenalfunction.Theseeffectsareusuallyreversible.Rarely,acuterenalfailuremayoccur,especially

inpatientswithcompromisedrenalfunctionsuchasthosewhoareelderlyordehydrated.

Antihypertensiveagentsandvasodilators

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindopril.Concomitantusewith

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Antidiabeticagents

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACEinhibitorsandantidiabeticmedicines

(insulins,oralhypoglycaemicagents)maycauseanincreasedblood-glucoseloweringeffectwithriskof

hypoglycaemia.Thisphenomenonappearedtobemorelikelytooccurduringthefirstweeksofcombinedtreatment

andinpatientswithrenalimpairment.

Acetylsalicylicacid,thrombolytics,beta-blockers,nitrates

Perindoprilmaybeusedconcomitantlywithacetylsalicylicacid(whenusedasathrombolytic),thrombolytics,beta-

blockersand/ornitrates.

Tricyclicantidepressants/Antipsychotics/Anesthetics

Concomitantuseofcertainanaestheticmedicinalproducts,tricyclicantidepressantsandantipsychoticswithACE

inhibitorsmayresultinfurtherreductionofbloodpressure(seesection4.4).

Sympathomimetics

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

4.6Pregnancyandlactation

Pregnancy

COVERSYLshouldnotbeusedduringthefirsttrimesterofpregnancy.Whenapregnancyisplannedorconfirmed,

theswitchtoanalternativetreatmentshouldbeinitiatedassoonaspossible.ControlledstudieswithACEinhibitors

havenotbeendoneinhumans,butinalimitednumberofcaseswithfirsttrimesterexposuretheredonotappearto

havebeenanymalformationsconsistentwithhumanfoetotoxicityasdescribedbelow.

Perindopriliscontraindicatedduringthesecondandthirdtrimestersofpregnancy.

ProlongedACEinhibitorexposureduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

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

Shouldexposuretoperindoprilhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

Lactation

Itisnotknownwhetherperindoprilisexcretedintohumanbreastmilk.ThereforetheuseofCOVERSYLisnot

recommendedinwomenwhoarebreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorweariness

mayoccur.

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),includingisolatedreports.

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances

Nervoussystemdisorders:

Common:headache,dizziness,vertigo,paresthaesia

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Eyedisorders:

Common:visiondisturbance

Earandlabyrinthdisorders:

Common:tinnitus

Cardio-vasculardisorders:

Common:hypotensionandeffectsrelatedtohypotension

Veryrare:arrhythmia,anginapectoris,myocardialinfarctionandstroke,possiblysecondarytoexcessivehypotension

inhighriskpatients(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(seesection4.4Specialwarningsandspecialprecautionsforuse)

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

Reproductivesystemandbreastdisorders:

Uncommon:impotence

Generaldisorders:

Common:asthenia

Uncommon:sweating

Bloodandthelymphaticsystemdisorders:

Decreasesinhaemoglobinandhaematocrit,thrombocytopenia,leucopenia/neutropenia,andcasesofagranulocytosisor

pancytopenia,havebeenreportedveryrarely.InpatientswithacongenitaldeficiencyofG-6PDH,veryrarecasesof

haemolyticanaemiahavebeenreported(seesection4.4Specialwarningsandspecialprecautionsforuse).

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.

Therecommendedtreatmentofoverdosageisintravenousinfusionofnormalsalinesolution.Ifhypotensionoccurs,the

patientshouldbeplacedintheshockposition.Ifavailable,treatmentwithangiotensinIIinfusionand/orintravenous

catecholaminesmayalsobeconsidered.Perindoprilmayberemovedfromthegeneralcirculationbyhaemodialysis.

(See4.4Specialwarningsandspecialprecautionsforuse,HaemodialysisPatients.)Pacemakertherapyisindicatedfor

therapy-resistantbradycardia.Vitalsigns,serumelectrolytesandcreatinineconcentrationsshouldbemonitored

continuously.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

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.

Patientswithstablecoronaryarterydisease

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

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Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedtoperindopril8mg

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

Thetrialpopulationhadevidenceofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheartfailure.Overall,

90%ofthepatientshadapreviousnyocardialinfarctionand/orapreviouscoronaryrevascularisation.Mostofthe

patientsreceivedthestudymedicationontopofconventionaltherapyinlcudingplateletinhibitors,lipidlowering

agentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardialinfarctionand/or

cardiacarrestwithsuccessfulresuscitation.Thetreatmentwithperindopril8mgoncedailyresultedinasignificant

absolutereductionintheprimaryendpointof1.9%(relativeriskreductionof20%,95%CI[9.4;28.6]-p<0.001).

Inpatientswithahistoryofmyocardialinfarctionand/orrevascularisation,anabsolutereductionof2.2%

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

toplacebo.

5.2Pharmacokineticproperties

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationcompletewithin1hour.

Bioavailabilityis

65to70%.

About20%ofthetotalquantityofperindoprilabsorbedisconvertedintoperindoprilat,theactivemetabolite.In

additiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.Theplasmahalf-lifeofperindoprilis

equalto1hour.Thepeakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,COVERSYLshouldbeadministered

orallyinasingledailydoseinthemorningbeforeameal.

Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingisslight(bindingof

perindoprilattoangiotensinconvertingenzymeislessthan30%),butisconcentration-dependent.

Perindoprilatiseliminatedintheurineandthehalf-lifeoftheunboundfractionisapproximately3to5hours.

Dissociationofperindoprilatboundtoangiotensinconvertingenzymeleadstoan“effective”eliminationhalf-lifeof25

hours,resultinginsteady-statewithin4days.

Afterrepeatedadministration,noaccumulationofperindoprilisobserved.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure.Dosage

adjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment(creatinineclearance).

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(seealso

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

5.3Preclinicalsafetydata

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversibledamage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefoetal

development,resultinginfoetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreasein

peri-andpostnatalmortalityhavebeenobserved.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Lactose

Hydrophobiccolloidalanhydroussilica

Irish Medicines Board

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Aluminiumcoppercomplexesofchlorophyllinslake(E141ii)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Aluminiumblisterinacardboardcartoncontaining30tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

Dublin9

8ParallelProductAuthorisationNumber

PPA1151/14/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:5thJanuary2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 04/09/2009 CRN 2069197 page number: 11