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:
  • PPA1500/011/001
  • Authorization date:
  • 14-08-2009
  • 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

ProductimportedfromtheUKandHungary:

Light-green,rod-shapedfilm-coatedtabletengravedwiththeServierlogoononefaceandscoredonbothedges.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Treatmentofhypertension.

Heartfailure:

Treatmentofsymptomaticheartfailure.

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCoversylArginine5mgfilm-coatedtabletistakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressureresponse.

Hypertension:

CoversylArginine5mgmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensivetherapy.

Therecommendedstartingdoseis5mggivenoncedailyinthemorning.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascularhypertension,salt

and/orvolumedepletion,cardiacdecompensationorseverehypertension)mayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof2.5mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision.

Thedosemaybeincreasedto10mgoncedailyafteronemonthoftreatment.

SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCoversylArginine5mg;thisismorelikelyin

patientswhoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatientsmay

bevolumeand/orsaltdepleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithCoversylArginine5mg(see

section4.4).

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initiatedwitha2.5mgdose.Renalfunctionandserumpotassiumshouldbemonitored.Thesubsequentdosageof

CoversylArginineshouldbeadjustedaccordingtobloodpressureresponse.Ifrequired,diuretictherapymaybe

resumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2.5mgwhichmaybeprogressivelyincreasedto5mgafter

onemonththento10mgifnecessarydependingonrenalfunction(seetablebelow).

Symptomaticheartfailure:

ItisrecommendedthatCoversylArginine,generallyassociatedwithanon-potassium-sparingdiureticand/ordigoxin

and/orabeta-blocker,beintroducedunderclosemedicalsupervisionwitharecommendedstartingdoseof2.5mg

takeninthemorning.Thisdosemaybeincreasedafter2weeksto5mgoncedailyiftolerated.Thedoseadjustment

shouldbebasedontheclinicalresponseoftheindividualpatient.

Insevereheartfailureandinotherpatientsconsideredtobeathighrisk(patientswithimpairedrenalfunctionanda

tendencytohaveelectrolytedisturbances,patientsreceivingsimultaneoustreatmentwithdiureticsand/ortreatment

withvasodilatingagents),treatmentshouldbeinitiatedundercarefulsupervision(seesection4.4).

Patientsathighriskofsymptomatichypotensione.g.patientswithsaltdepletionwithorwithouthyponatraemia,

patientswithhypovolaemiaorpatientswhohavebeenreceivingvigorousdiuretictherapyshouldhavetheseconditions

corrected,ifpossible,priortotherapywithCoversylArginine.Bloodpressure,renalfunctionandserumpotassium

shouldbemonitoredclosely,bothbeforeandduringtreatmentwithCoversylArginine5mg(seesection4.4).

Stablecoronaryarterydisease:

CoversylArginineshouldbeintroducedatadoseof5mgoncedailyfortwoweeks,thenincreasedto10mgoncedaily,

dependingonrenalfunctionandprovidedthatthe5mgdoseiswelltolerated.

Elderlypatientsshouldreceive2.5mgoncedailyforoneweek,then5mgoncedailythenextweek,beforeincreasing

thedoseupto10mgoncedailydependingonrenalfunction(seeTable1“Dosageadjustmentinrenalimpairment”).

Thedoseshouldbeincreasedonlyifthepreviouslowerdoseiswelltolerated.

Dosageadjustmentinrenalimpairment:

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearanceasoutlinedintable1below:

Table1:dosageadjustmentinrenalimpairment

*Dialysisclearanceofperindoprilatis70ml/min.

Forpatientsonhaemodialysis,thedoseshouldbetakenafterdialysis.

Dosageadjustmentinhepaticimpairment:

Nodosageadjustmentisnecessaryinpatientswithhepaticimpairment(seesections4.4and5.2)

Paediatricuse:

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(seesection4.6).

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

bloodpressuremayoccurwithCoversylArginine5mg.Thiseffectisanticipatedandisusuallynotareasonto

discontinuetreatment.Ifhypotensionbecomessymptomatic,areductionofdoseordiscontinuationofCoversyl

Arginine5mgmaybenecessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy:

AswithotherACEinhibitors,CoversylArginine5mgshouldbegivenwithcautiontopatientswithmitralvalve

stenosisandobstructionintheoutflowoftheleftventriclesuchasaorticstenosisorhypertrophiccardiomyopathy.

Impairmentofrenalfunction:

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,especiallywhenCoversylArginine5mghasbeengiven

concomitantlywithadiuretic.Thisismorelikelytooccurinpatientswithpre-existingrenalimpairment.Dosage

reductionand/ordiscontinuationofthediureticand/orCoversylArginine5mgmayberequired.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhighfluxmembranes,andtreatedconcomitantly

withanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeofdialysismembraneor

differentclassofantihypertensiveagent.

Kidneytransplantation:

ThereisnoexperienceregardingtheadministrationofCoversylArginine5mginpatientswitharecentkidney

transplantation.

Hypersensitivity/Angioedema:

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

patientstreatedwithACEinhibitors,includingCoversylArginine5mg(seesection4.8).Thismayoccuratanytime

duringtherapy.Insuchcases,CoversylArginine5mgshouldpromptlybediscontinuedandappropriatemonitoring

shouldbeinitiatedandcontinueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhere

swellingwasconfinedtothefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamines

havebeenusefulinrelievingsymptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,emergencytherapyshouldbeadministeredpromptly.Thismayincludethe

administrationofadrenalineand/orthemaintenanceofapatentairway.Thepatientshouldbeunderclosemedical

supervisionuntilcompleteandsustainedresolutionofsymptomshasoccurred.Patientswithahistoryofangioedema

unrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhilereceivinganACEinhibitor(see

section4.3).

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

advisedandpatientsshouldbeinstructedtoreportanysignofinfection.

Race:

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AswithotherACEinhibitors,perindoprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon-

blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblackhypertensivepopulation.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/Anaesthesia:

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,CoversylArginine5

mgmayblockangiotensinIIformationsecondarytocompensatoryreninrelease.Thetreatmentshouldbediscontinued

onedaypriortothesurgery.Ifhypotensionoccursandisconsideredtobeduetothismechanism,itcanbecorrectedby

volumeexpansion.

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,uncontrolleddiabetes

mellitus,orthoseusingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsalt

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

concomitantuseoftheabove-mentionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumis

recommended.

Diabeticpatients:

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor(seesection4.5).

Lithium:

Thecombinationoflithiumandperindoprilisgenerallynotrecommended(seesection4.5).

Potassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes

Thecombinationofperindoprilandpotassiumsparingdiuretics,potassiumsupplementsorpotassium-containingsalt

substitutesisgenerallynotrecommended(seesection4.5).Duetothepresenceoflactose,patientswithrarehereditary

problemsofgalactoseintolerance,glucose-galactosemalabsorption,ortheLapplactasedeficiencyshouldnottakethis

medicinalproduct.

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,or

potassium-containingsaltsubstitutesmayleadtosignificantincreasesinserumpotassium.Thereforethecombination

ofperindoprilwiththeabove-mentioneddrugsisnotrecommended(seesection4.4).Ifconcomitantuseisindicated

becauseofdemonstratedhypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringofserum

potassium.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflithium

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Useofperindoprilwithlithiumisnotrecommended,butifthecombinationprovesnecessary,carefulmonitoringof

serumlithiumlevelsshouldbeperformed(seesection4.4).

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

Theadministrationofanon-steroidalanti-inflammatorydrugmayreducetheantihypertensiveeffectofACEinhibitors.

Additionally,NSAIDsandACEinhibitorsexertanadditiveeffectontheincreaseinserumpotassiumandmayresultin

adeteriorationofrenalfunction.Theseeffectsareusuallyreversible.Rarely,acuterenalfailuremayoccur,especially

inpatientswithcompromisedrenalfunctionsuchasthosewhoareelderlyordehydrated.

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.

4.6Fertility,pregnancyandlactation

Pregnancy:

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:

BecausenoinformationisavailableregardingtheuseofCoversylArginineduringbreastfeeding,CoversylArginineis

notrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

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.

Bloodandthelymphaticsystemdisorders:

Decreasesinhaemoglobinandhaematocrit,thrombocytopenia,leucopenia/neutropenia,andcasesofagranulocytosisor

pancytopenia,havebeenreportedveryrarely.InpatientswithacongenitaldeficiencyofG-6PDH,veryrarecasesof

haemolyticanaemiahavebeenreported(seesection4.4).

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances.

Nervoussystemdisorders:

Common:headache,dizziness,vertigo,paresthaesia.

Veryrare:confusion.

Eyedisorders:

Common:visiondisturbance.

Earandlabyrinthdisorders:

Common:tinnitus.

Vasculardisorders:

Common:hypotensionandeffectsrelatedtohypotension

Veryrare:strokepossiblysecondarytoexcessivehypotensioninhigh-riskpatients(seesection4.4).

Cardiacdisorders:

Veryrare:arrhythmia,anginapectoris,myocardialinfarctionandstroke,possiblysecondarytoexcessivehypotension

inhigh-riskpatients(seesection4.4).

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

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Veryrare:erythemamultiforme.

Musculoskeletal,connectivetissueandbonedisorders:

Common:musclecramps.

Renalandurinarydisorders:

Uncommon:renalinsufficiency.

Veryrare:acuterenalfailure.

Reproductivesystemandbreastdisorders:

Uncommon:impotence.

Generaldisorders:

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

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.

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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

failurewasnotassociatedwithanysignificantreductionofbloodpressureascomparedtoplacebo.

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

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindoprilarginineshouldbe

administeredorallyinasingledailydoseinthemorningbeforeameal.

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Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingofperindoprilatto

plasmaproteinsis20%,principallytoangiotensinconvertingenzyme,butisconcentration-dependent.

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(E470B)

Maltodextrin

Hydrophobiccolloidalsilica

Sodiumstarchglycolate(typeA)

Film-coating:

Glycerol(E422a)

Hypromellose(E464)

Copperchlorophyllin(E141ii)

Macrogol

Magnesiumstearate(E470B)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandoutercartonoftheproductonthe

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6.4Specialprecautionsforstorage

Keepthecontainertightlyclosedinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Anover-labelledcardboardcartoncontainingawhitepolypropylenetabletcontainerequippedwithapolyethyleneflow

reducerandagreenorwhiteopaquestoppercontainingadessicantgel.

Packsize:30tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Medicinesnolongerrequiredshouldnotbedisposedofviathewastewaterorthemunicipalsewagesystem.Return

themtoapharmacyoraskyourpharmacisthowtodisposeoftheminaccordancewiththenationalregulations.These

measureswillhelptoprotecttheenvironment.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/11/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14thAugust2009

10DATEOFREVISIONOFTHETEXT

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