COVERSYL ARGININE

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/014/004
  • Authorization date:
  • 09-11-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylArginine10mgfilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainsperindopril6.790mgcorrespondingto10mgperindoprilarginine.

Excipients:lactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromPolandandHungary

Green,round,biconvex,film-coatedtabletengravedwithaheartonononefaceandtheServierlogoontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Treatmentofhypertension.

Stablecoronaryarterydisease:

Reductionofriskofcardiaceventsinpatientswithahistoryofmyocardialinfarctionand/orrevascularisation.

4.2Posologyandmethodofadministration

ItisrecommendedthatCoversylArginine10mg,film-coatedtabletistakenoncedailyinthemorningbeforeameal.

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressureresponse.

Hypertension:

CoversylArginine10mgmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensive

therapy.

Therecommendedstartingdoseis5mggivenoncedailyinthemorning.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(inparticular,renovascularhypertension,salt

and/orvolumedepletion,cardiacdecompensationorseverehypertension)mayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof2.5mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision.

Thedosemaybeincreasedto10mgoncedailyafteronemonthoftreatment.

SymptomatichypotensionmayoccurfollowinginitiationoftherapywithCoversylArginine10mg;thisismorelikely

inpatientswhoarebeingtreatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatients

maybevolumeand/orsaltdepleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithCoversylArginine10mg(see

section4.4).

Inhypertensivepatientsinwhomthediureticcannotbediscontinued,therapywithCoversylArginineshouldbe

initiatedwitha2.5mgdose.Renalfunctionandserumpotassiumshouldbemonitored.Thesubsequentdosageof

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resumed.

Inelderlypatientstreatmentshouldbeinitiatedatadoseof2.5mgwhichmaybeprogressivelyincreasedto5mgafter

onemonththento10mgifnecessarydependingonrenalfunction(seetablebelow).

Stablecoronaryarterydisease:

COVERSYLARGININEshouldbeintroducedatadoseof5mgoncedailyfortwoweeks,thenincreasedto10mg

oncedaily,dependingonrenalfunctionandprovidedthatthe5mgdoseiswelltolerated.

Elderlypatientsshouldreceive2.5mgoncedailyforoneweek,then5mgoncedailythenextweek,beforeincreasing

thedoseupto10mgoncedailydependingonrenalfunction(seeTable1“Dosageadjustmentinrenalimpairment”).

Thedoseshouldbeincreasedonlyifthepreviouslowerdoseiswelltolerated.

Dosageadjustmentinrenalimpairment:

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearanceasoutlinedintable1below:

Table1:dosageadjustmentinrenalimpairment

*Dialysisclearanceofperindoprilatis70ml/min.

Forpatientsonhaemodialysis,thedoseshouldbetakenafterdialysis.

Dosageadjustmentinhepaticimpairment:

Nodosageadjustmentisnecessaryinpatientswithhepaticimpairment(seesections4.4and5.2)

Paediatricuse:

Efficacyandsafetyofuseinchildrenandadolescentshavenotbeenestablished.Therefore,useinchildrenand

adolescentsisnotrecommended.

4.3Contraindications

Hypersensitivitytoperindopril,toanyoftheexcipientsortoanyotherACEinhibitor;

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy;

Hereditaryoridiopathicangioedema;

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Stablecoronaryarterydisease:

Ifanepisodeofunstableanginapectoris(majorornot)occursduringthefirstmonthofperindopriltreatment,acareful

Creatinineclearance(ml/min) Recommendeddose

>60 5mgperday

30<Cl

<60 2.5mgperday

15<Cl

<30 2.5mgeveryotherday

Haemodialysedpatients*

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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

bloodpressuremayoccurwithCoversylArginine10mg.Thiseffectisanticipatedandisusuallynotareasonto

discontinuetreatment.Ifhypotensionbecomessymptomatic,areductionofdoseordiscontinuationofCoversyl

Arginine10mgmaybenecessary.

Aorticandmitralvalvestenosis/hypertrophiccardiomyopathy:

AswithotherACEinhibitors,CoversylArginine10mgshouldbegivenwithcautiontopatientswithmitralvalve

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

weeksofCoversylArginine10mgtherapy.

Somehypertensivepatientswithnoapparentpre-existingrenalvasculardiseasehavedevelopedincreasesinbloodurea

andserumcreatinine,usuallyminorandtransient,especiallywhenCoversylArginine10mghasbeengiven

concomitantlywithadiuretic.Thisismorelikelytooccurinpatientswithpre-existingrenalimpairment.Dosage

reductionand/ordiscontinuationofthediureticand/orCoversylArginine10mgmayberequired.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhighfluxmembranes,andtreatedconcomitantly

withanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeofdialysismembraneor

differentclassofantihypertensiveagent.

Kidneytransplantation:

ThereisnoexperienceregardingtheadministrationofCoversylArginine10mginpatientswitharecentkidney

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Hypersensitivity/Angioedema:

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

patientstreatedwithACEinhibitors,includingCoversylArginine10mg(seesection4.8).Thismayoccuratanytime

duringtherapy.Insuchcases,CoversylArginine10mgshouldpromptlybediscontinuedandappropriatemonitoring

shouldbeinitiatedandcontinueduntilcompleteresolutionofsymptomshasoccurred.Inthoseinstanceswhere

swellingwasconfinedtothefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamines

havebeenusefulinrelievingsymptoms.

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.

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

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Surgery/Anaesthesia:

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,CoversylArginine10

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).

Pregnancy:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Excipients:

Duetothepresenceoflactose,patientswithrarehereditaryproblemsofgalactoseintolerance,glucose-galactose

malabsorption,ortheLapplactasedeficiencyshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics:

Patientsondiuretics,andespeciallythosewhoarevolumeand/orsaltdepleted,mayexperienceexcessivereductionin

bloodpressureafterinitiationoftherapywithanACEinhibitor.Thepossibilityofhypotensiveeffectscanbereduced

bydiscontinuationofthediuretic,byincreasingvolumeorsaltintakepriortoinitiatingtherapywithlowand

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,especiallyinpatientswithcompromisedrenalfunctionsuchasthosewhoare

elderlyordehydrated.

Antihypertensiveagentsandvasodilators:

Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofperindopril.Concomitantusewith

nitroglycerinandothernitrates,orothervasodilators,mayfurtherreducebloodpressure.

Antidiabeticagents:

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACEinhibitorsandantidiabeticmedicines

(insulins,oralhypoglycaemicagents)maycauseanincreasedblood-glucoseloweringeffectwithriskof

hypoglycaemia.Thisphenomenonappearedtobemorelikelytooccurduringthefirstweeksofcombinedtreatment

andinpatientswithrenalimpairment.

Tricyclicantidepressants/Antipsychotics/Anesthetics:

Concomitantuseofcertainanaestheticmedicinalproducts,tricyclicantidepressantsandantipsychoticswithACE

inhibitorsmayresultinfurtherreductionofbloodpressure(seesection4.4).

Sympathomimetics:

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

Acetylsalicylicacid,thrombolytics,beta-blockers,nitrates:

Perindoprilmaybeusedconcomitantlywithacetylsalicylicacid(whenusedasathrombolytic),thrombolytics,beta-

blockersand/ornitrates.

Gold:

Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreportedrarelyin

patientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapyincluding

perindopril.

4.6Fertility,pregnancyandlactation

Pregnancy:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

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

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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Lactation:

BecausenoinformationisavailableregardingtheuseofCoversylArginineduringbreastfeeding,CoversylArginineis

notrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

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).

Metabolismandnutritiondisorders:

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

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.

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Hepato-biliarydisorders:

Veryrare:hepatitiseithercytolyticorcholestatic(seesection4.4).

Skinandsubcutaneoustissuedisorders:

Common:rash,pruritus.

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

section4.4).

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

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Theconvertingenzyme,orkinase,isanexopeptidasethatallowsconversionofangiotensinIintothevasoconstrictor

angiotensinIIaswellascausingthedegradationofthevasodilatorbradykininintoaninactiveheptapeptide.Inhibition

ofACEresultsinareductionofangiotensinIIintheplasma,whichleadstoincreasedplasmareninactivity(by

inhibitionofthenegativefeedbackofreninrelease)andreducedsecretionofaldosterone.SinceACEinactivates

bradykinin,inhibitionofACEalsoresultsinanincreasedactivityofcirculatingandlocalkallikrein-kininsystems(and

thusalsoactivationoftheprostaglandinsystem).Itispossiblethatthismechanismcontributestothebloodpressure-

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

4years.

Twelvethousandtwohundredandeighteen(12218)patientsagedover18wererandomisedto8mgperindopriltert-

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

ofcoronaryarterydiseasewithnoevidenceofclinicalsignsofheartfailure.Overall,90%ofthepatientshada

previousmyocardialinfarctionand/orapreviouscoronaryrevascularisation.Mostofthepatientsreceivedthestudy

medicationontopofconventionaltherapyincludingplateletinhibitors,lipidloweringagentsandbeta-blockers.

Themainefficacycriterionwasthecompositeofcardiovascularmortality,nonfatalmyocardialinfarctionand/or

cardiacarrestwithsuccessfulresuscitation.Thetreatmentwith8mgperindopriltert-butylamine(equivalentto10mg

perindoprilarginine)oncedailyresultedinasignificantabsolutereductionintheprimaryendpointof1.9%(relative

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

Inpatientswithahistoryofmyocardialinfarctionand/orrevasularisation,anabsolutereductionof2.2%corresponding

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

5.2Pharmacokineticproperties

Afteroraladministration,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

Macrogol

Magnesiumstearate

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecountainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Whiteplastictabletcontainerwithaflowreducerandgreenorwhiteopaquestoppercontainingadessicantgel.

Packsize:30

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Medicinesnolongerrequiredshouldnotbedisposedofviathewastewaterorthemunicipalsewagesystem.Return

themtoapharmacyoraskyourpharmacisthowtodisposeoftheminaccordancewiththenationalregulations.These

measureswillhelptoprotecttheenvironment.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

Dublin9

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1151/14/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:9thNovember2007

10DATEOFREVISIONOFTHETEXT

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