COVERSYL PLUS

Main information

  • Trade name:
  • COVERSYL PLUS
  • Dosage:
  • 4/ 1.25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/067/003
  • Authorization date:
  • 03-08-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA0465/067/003

CaseNo:2054664

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PCOManufacturingLimited

Unit10,AshbourneBusinessPark,Rath,Ashbourne,Co.Meath,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CoversylPlus4mg/1.25mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/10/2008until02/08/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylPlus4mg/1.25mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains:

Perindopriltert-butylamine 4.00mg,equivalentto3.338mgperindopril

Indapamide 1.25mg

Excipients:LactoseMonohydrate

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromtheNetherlands:

White,rod-shapedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension,COVERSYLPLUS4mg/1.25mgTabletsareindicatedinpatientswhoseblood

pressureisnotadequatelycontrolledonperindoprilalone

4.2Posologyandmethodofadministration

Oralroute

OneCOVERSYLPLUS4mg/1.25mgtabletperdayasasingledose,preferablytobetakeninthemorning,andbefore

ameal.

Whenpossibleindividualdosetitrationwiththecomponentscanberecommended.Whenclinicallyappropriate,direct

changefrommonotherapytoCOVERSYLPLUS4mg/1.25mgTabletsmaybeconsidered.

Patientswithrenalinsufficiency(seeSpecialwarningsandspecialprecautionsforuse).

Insevererenalinsufficiency(creatinineclearancebelow30ml/min),treatmentiscontra-indicated.

Inpatientswithcreatinineclearancegreaterthanorequalto30ml/minandlessthan60ml/min,itisrecommendedto

starttreatmentwiththeadequatedosageofthefreecombination.Itisnotnecessarytochangethedosewhencreatinine

clearanceisgreaterthan60ml/min.Usualmedicalfollow-upwillincludefrequentmonitoringofcreatinineand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 2

Children

COVERSYLPLUS4mg/1.25mgTabletsshouldnotbeusedinchildrenastheefficacyandtolerabilityofperindoprilin

children,aloneorincombination,havenotbeenestablished.

4.3Contraindications

LINKEDTOPERINDOPRIL:

HypersensitivitytoperindopriloranyotherACEinhibitor

Historyofangioneuroticoedema(Quincke'soedema)associatedwithpreviousACEinhibitortherapy

Hereditary/idiopathicangioneuroticoedema

Pregnancy

Lactation

Thedrugisusuallynotrecommendedincaseof:-Combinationswithpotassium-sparingdiuretics,potassiumsalts,

lithium(seeInteractionswithothermedicaments)

-Bilateralrenalarterystenosisorsinglefunctioningkidney.

-Raisedplasmalevelsofpotassium.

LINKEDTOINDAPAMIDE:

Hypersensitivitytosulphonamides

Severerenalfailure(creatinineclearancebelow30ml/min)

Hepaticencephalopathy

Severeimpairmentofliverfunction

Hypokalaemia

Asageneralrule,thismedicineisinadvisableincombinationwithnon-antiarrhythmicagentscausingtorsadesde

pointes(seeInteractionswithothermedicaments).

LINKEDTOCOVERSYLPLUS4MG/1.25MGTABLETS:

Hypersensitivitytoanyoftheexcipients

Duetothelackofsufficienttherapeuticexperience,COVERSYLPLUS4mg/1.25mgTabletsshouldnotbeusedin:

dialysispatients

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 3

4.4Specialwarningsandprecautionsforuse

Specialwarnings

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsoptionshouldnottakethismedicine.

LINKEDTOPERINDOPRIL:

RISKOFNEUTROPENIA/AGRANULOCYTOSISINIMMUNO-SUPPRESSEDPATIENTS:

Theriskofneutropeniaappearstobedoseandtyperelatedandisdependentonpatient'sclinicalstatus.Itisrarelyseen

inuncomplicatedpatientsbutmayoccurinpatientswithsomedegreeofrenalimpairmentespeciallywhenitis

associatedwithcollagenvasculardiseasee.g.systemiclupuserythematosus,sclerodermaandtherapywith

immunosuppressiveagents.ItisreversibleafterdiscontinuationoftheACEinhibitor.

Strictcompliancewiththepredetermineddoseseemstobethebestwaytopreventtheonsetoftheseevents.However,

ifanangiotensinconvertingenzymeinhibitoristobeadministeredtothistypeofpatient,therisk/benefitratioshould

beevaluatedcarefully.

ANGIONEUROTICOEDEMA(QUINCKE'SOEDEMA):

Angioneuroticoedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarelyinpatients

receivingtreatmentwithangiotensinconvertingenzymeinhibitors,includingperindopril.Insuchcases,treatmentwith

perindoprilshouldbestoppedimmediatelyandthepatientshouldbemonitoreduntiltheoedemahasdisappeared.

Whentheoedemaonlyaffectsthefaceandthelips,theeffectgenerallyrecedeswithouttreatment,eventhough

antihistaminesmaybeusedtorelievesymptoms.

Angioneuroticoedemacombinedwithlaryngealoedemamaybefatal.Involvementoftongue,glottisorlarynxmay

leadtoanobstructionoftheairways.

Asubcutaneousinjectionofadrenalineat1:1000(0.3mlto0.5ml)shouldbeadministeredquicklyandother

appropriatemeasurestaken.

Theprescriptionofanangiotensinconvertingenzymeinhibitorshouldnotsubsequentlybeconsideredinthesepatients

(seeContra-indications).

PatientswithaprevioushistoryofQuincke'soedemawhichwasnotlinkedtotakinganangiotensinconvertingenzyme

inhibitorhaveanincreasedriskofQuincke'soedemawithanangiotensinconvertingenzymeinhibitor.

ANAPHYLACTICREACTIONSDURINGDESENSITISATION:

Therehavebeenisolatedreportsofpatientsexperiencingsustained,life-threateninganaphylactoidreactionswhile

receivingACE-inhibitorsduringdesensitisationtreatmentwithhymenoptera(bees,wasps)venom.ACE-inhibitors

shouldbeusedwithcautioninallergicpatientstreatedwithdesensitisation,andavoidedinthoseundergoingvenom

immunotherapy.HoweverthesereactionscouldbepreventedbytemporarywithdrawalofACE-inhibitorforatleast24

hoursbeforetreatmentinpatientswhorequirebothACE-inhibitorsanddesensitisation.

ANAPHYLACTICREACTIONSDURINGMEMBRANEEXPOSURE:

Therehavebeenreportsofpatientsexperiencingsustained,life-threateninganaphylactoidreactionswhilereceiving

ACE-inhibitorsduringdialysiswithhigh-fluxmembranesorlow-densitylipoproteinapheresiswithdextransulphate

adsorption.ACE-inhibitorsshouldbeavoidedinpatientsundergoingdialysiswithhigh-fluxmembranesorLDL

apheresiswithdextransulphateadsorption.Howeverthesereactionscouldbepreventedbytemporarywithdrawalof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 4

LINKEDTOINDAPAMIDE:

Whenliverfunctionisimpaired,thiazidediureticsandthiazide-relateddiureticsmaycausehepaticencephalopathy.

Administrationofthediureticshouldbestoppedimmediatelyifthisoccurs.

Specialprecautionsforuse

LINKEDTOCOVERSYLPLUS4MG/1.25MGTABLETS:

RENALINSUFFICIENCY:

Incasesofsevererenalinsufficiency(creatinineclearance<30ml/min),treatmentiscontra-indicated.

Incertainhypertensivepatientswithoutpre-existingapparentrenallesionandforwhomrenalbloodtestsshow

functionalrenalinsufficiency,treatmentshouldbestoppedandpossiblyrestartedeitheratalowdoseorwithone

constituentonly.

Inthesepatientsusualmedicalfollow-upwillincludefrequentmonitoringofpotassiumandcreatinine,aftertwoweeks

oftreatmentandtheneverytwomonthsduringtherapeuticstabilityperiod.Renalfailurehasbeenreportedmainlyin

patientswithsevereheartfailureorunderlyingrenalfailureincludingrenalarterystenosis.

HYPOTENSIONANDWATERANDELECTROLYTEDEPLETION:

Thereisariskofsuddenhypotensioninthepresenceofpre-existingsodiumdepletion(inparticularinindividualswith

renalarterystenosis).Thereforesystematictestingshouldbecarriedoutforclinicalsignsofwaterandelectrolyte

depletion,whichmayoccurwithanintercurrentepisodeofdiarrhoeaorvomiting.Regularmonitoringofplasma

electrolytesshouldbecarriedoutinsuchpatients.

Markedhypotensionmayrequiretheimplementationofanintravenousinfusionofisotonicsaline.

Transienthypotensionisnotacontra-indicationtocontinuationoftreatment.Afterre-establishmentofasatisfactory

bloodvolumeandbloodpressure,treatmentcanbestartedagaineitheratareduceddoseorwithonlyoneofthe

constituents.

POTASSIUMLEVELS:

Thecombinationofperindoprilandindapamidedoesnotpreventtheonsetofhypokalaemiaparticularlyindiabetic

patientsorinpatientswithrenalfailure.Aswithanyantihypertensiveagentcontainingadiuretic,regularmonitoringof

plasmapotassiumlevelsshouldbecarriedout.

LINKEDTOPERINDOPRIL:

COUGH:

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

eventofthissymptom.Iftheprescriptionofanangiotensinconvertingenzymeinhibitorisstillpreferred,continuation

oftreatmentmaybeconsidered.

CHILDREN:

Theefficacyandtolerabilityofperindoprilinchildren,aloneorincombination,havenotbeenestablished.

RISKOFARTERIALHYPOTENSIONAND/ORRENALINSUFFICIENCY(INCASESOFCARDIAC

INSUFFICIENCY,WATERANDELECTROLYTEDEPLETION,ETC):

Markedstimulationoftherenin-angiotensin-aldosteronesystemhasbeenobservedparticularlyduringmarkedwater

andelectrolytedepletions(strictsodium-freedietorprolongeddiuretictreatment),inpatientswhosebloodpressure

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 5

Theblockingofthissystemwithanangiotensinconvertingenzymeinhibitormaythereforecause,particularlyatthe

timeofthefirstadministrationandduringthefirsttwoweeksoftreatment,asuddendropinbloodpressureand/oran

increaseinplasmalevelsofcreatinine,showingafunctionalrenalinsufficiency.Occasionallythiscanbeacutein

onset,althoughrare,andwithavariabletimetoonset.

Insuchcases,thetreatmentshouldthenbeinitiatedatalowerdoseandincreasedprogressively.

ELDERLY:

Renalfunctionandpotassiumlevelsshouldbetestedbeforethestartoftreatment.Theinitialdoseissubsequently

adjustedaccordingtobloodpressureresponse,especiallyincasesofwaterandelectrolytedepletion,inordertoavoid

suddenonsetofhypotension.

PATIENTSWITHKNOWNATHEROSCLEROSIS:

Theriskofhypotensionexistsinallpatientsbutparticularcareshouldbetakeninpatientswithischaemicheartdisease

orcerebralcirculatoryinsufficiency,withtreatmentbeingstartedatalowdose.

RENOVASCULARHYPERTENSION:

Thetreatmentforrenovascularhypertensionisrevascularisation.Nonetheless,angiotensinconvertingenzyme

inhibitorscanbebeneficialinpatientspresentingwithrenovascularhypertensionwhoareawaitingcorrectivesurgery

orwhensuchasurgeryisnotpossible.

Treatmentshouldbestartedinahospitalsettingatalowdoseandrenalfunctionandpotassiumlevelsshouldbe

monitored,sincesomepatientshavedevelopedafunctionalrenalinsufficiencywhichwasreversedwhentreatmentwas

stopped.

OTHERPOPULATIONSATRISK:

Inpatientswithseverecardiacinsufficiency(gradeIV)orinpatientswithinsulindependentdiabetesmellitus

(spontaneoustendencytoincreasedlevelsofpotassium),treatmentshouldbestartedundermedicalsupervisionwitha

reducedinitialdose.Treatmentwithbeta-blockersinhypertensivepatientswithcoronaryinsufficiencyshouldnotbe

stopped:theACEinhibitorshouldbeaddedtothebeta-blocker.

ANAEMIA:

Anaemiahasbeenobservedinpatientswhohavehadakidneytransplantorhavebeenundergoingdialysis.The

reductioninhaemoglobinlevelsismoreapparentasinitialvalueswerehigh.Thiseffectdoesnotseemtobedose-

dependentbutmaybelinkedtothemechanismofactionofangiotensinconvertingenzymeinhibitors.

Thisreductioninhaemoglobinisslight,occurswithin1to6months,andthenremainsstable.Itisreversiblewhen

treatmentisstopped.Treatmentcanbecontinuedwithregularhaematologicaltesting.

SURGERY:

Angiotensinconvertingenzymeinhibitorscancausehypotensionincasesofanaesthesia,especiallywhenthe

anaestheticadministeredisanagentwithhypotensivepotential.Itisthereforerecommendedthattreatmentwithlong-

actingangiotensinconvertingenzymeinhibitorssuchasperindoprilshouldbediscontinuedwherepossibletwodays

beforesurgery.

AORTICSTENOSIS/HYPERTROPHICCARDIOMYOPATHY:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 6

LINKEDTOINDAPAMIDE:

WATERANDELECTROLYTEBALANCE:

Sodiumlevels:

Theseshouldbetestedbeforetreatmentisstarted,thenatregularintervals.Alldiuretictreatmentcancauseareduction

insodiumlevels,whichmayhaveseriousconsequences.Reductioninsodiumlevelscanbeinitiallyasymptomaticand

regulartestingisthereforeessential.Testingshouldbemorefrequentinelderlyandcirrhoticpatients(seeUndesirable

effectsandOverdose).

Potassiumlevels:

Potassiumdepletionwithhypokalaemiaisamajorriskwiththiazidediureticsandthiazide-relateddiuretics.Theriskof

onsetofloweredpotassiumlevels(<3.4mmol/l)shouldbepreventedinsomehighriskpopulationssuchaselderly

and/ormalnourishedsubjects,whetherornottheyaretakingmultiplemedications,cirrhoticpatientswithoedemaand

ascites,coronarypatientsandpatientswithheartfailure.

Insuchcaseshypokalaemiaincreasesthecardiactoxicityofcardiacglycosidesandtheriskofrhythmdisorders.

SubjectspresentingwithalongQTintervalarealsoatrisk,whethertheoriginiscongenitaloriatrogenic.

Hypokalaemia,aswithbradycardia,actsasafactorwhichfavourstheonsetofsevererhythmdisorders,inparticular

torsadesdepointes,whichmaybefatal.

Inallcasesmorefrequenttestingofpotassiumlevelsisnecessary.Thefirstmeasurementofplasmapotassiumlevels

shouldbecarriedoutduringthefirstweekfollowingthestartoftreatment.

Iflowpotassiumlevelsaredetected,correctionisrequired.

Calciumlevels:

Thiazidediureticsandthiazide-relateddiureticsmayreduceurinaryexcretionofcalciumandcauseamildandtransient

increaseinplasmacalciumlevels.Markedlyraisedlevelsofcalciummayberelatedtoundiagnosed

hyperparathyroidism.Insuchcasesthetreatmentshouldbestoppedbeforeinvestigatingtheparathyroidfunction.

BLOODGLUCOSE:

Monitoringofbloodglucoseisimportantindiabeticpatients,particularlywhenpotassiumlevelsarelow.

URICACID:

Tendencytogoutattacksmaybeincreasedinhyperuricaemicpatients.

RENALFUNCTIONANDDIURETICS:

Thiazidediureticsandthiazide-relateddiureticsareonlyfullyeffectivewhenrenalfunctionisnormaloronlyslightly

impaired(creatininelevelslowerthanapproximately25mg/l,i.e.220µmol/lforanadult).

Intheelderlythevalueofplasmacreatininelevelsshouldbeadjustedtotakeaccountoftheage,weightandsexofthe

patient,accordingtotheCockroftformula:clcr=(140-age)xbodyweight/0.814xplasmacreatininelevelwith:

ageexpressedinyears

bodyweightinkg

Plasmacreatininelevelinmicromol/l

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 7

Hypovolaemia,resultingfromthelossofwaterandsodiumcausedbythediureticatthestartoftreatment,causesa

reductioninglomerularfiltration.Itmayresultinanincreaseinbloodureaandcreatininelevels.Thistransitory

functionalrenalinsufficiencyisofnoadverseconsequenceinpatientswithnormalrenalfunctionbutmayhowever

worsenapre-existingrenalinsufficiency.

ATHLETES:

Athletesshouldnotethatthisproductcontainsanactivesubstancewhichmaycauseapositivereactionindopingtests.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

LINKEDTOCOVERSYLplus4mg/1.25mgtablets:

CombinationswhichareNOTRECOMMENDED:

Lithium

Anincreaseinlithiumlevelsmayproducesignsofoverdose,asoccurswithasodiumfreediet(reductioninrenal

excretionoflithium).Ifthecombinationofanangiotensinconvertingenzymeinhibitorandadiureticisunavoidable,

strictmonitoringoflithiumlevelsandadjustmentofthedosearenecessary.

Combinationswhichrequirespecialcare:

Antidiabeticagents(insulin,hypoglycaemicsulphonamides)

Reportedwithcaptoprilandenalapril

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.Theonsetofhypoglycaemicepisodesisveryrare

(improvementinglucosetolerancewitharesultingreductionininsulinrequirements).

Baclofen

Potentiationofantihypertensiveeffect

Monitoringofbloodpressureandrenalfunction,anddoseadaptationoftheantihypertensiveifnecessary.

N.S.A.I.D(systemicroute),high-dosesalicylates

Acuterenalinsufficiencyindehydratedpatients(reductioninglomerularfiltration).Thepatientshouldbewell

hydrated;renalfunctionshouldbemonitoredatthestartoftreatment.

Combinationswhichrequiresomecare:

Imipramine-likeantidepressants(tricyclics),neuroleptics

Increasedantihypertensiveeffectandincreasedriskoforthostatichypotension(additiveeffect).

Corticosteroids,tetracosactide

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 8

LINKEDTOPERINDOPRIL:

CombinationswhichareNOTRECOMMENDED:

Potassium-sparingdiuretics(spironolactone,triamterene,aloneorincombination.),potassium(salts)

Increasedlevelsofpotassium(potentiallylethal),particularlyincasesofrenalinsufficiency(additionofpotassium-

sparingeffects).Potassium-raisingagentsshouldnotbecombinedwithangiotensinconvertingenzymeinhibitors,

exceptwhenpotassiumlevelsarelow.

Anaestheticdrugs

ACEinhibitorsmayenhancethehypotensiveeffectsofcertainanaestheticdrugs.

Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroidsorprocainamide

ConcomitantadministrationwithACEinhibitorsmayleadtoanincreasedriskforleucopenia.

Antihypertensiveagents

IncreaseofthehypotensiveeffectofACEinhibitors.

LINKEDTOINDAPAMIDE:

CombinationswhichareNOTRECOMMENDED:

NonantiarrhythmicdrugswhichprolongtheQTintervalorcausetorsadesdepointes(astemizole,bepridil,

erythromycinIV,halofantrine,pentamidine,sultopride,terfenadine,vincamine)

Torsadesdepointes(lowpotassiumlevelsisarisk,asarebradycardiaandpre-existinglongQTinterval).Substances

whichdonothavetheunwantedeffectofcausingtorsadesdepointesshouldbeusedincasesoflowpotassiumlevels.

Combinationswhichrequirespecialcare:

N.S.A.I.D(systemicroute),high-dosesalicylates

Possiblereductionintheantihypertensiveeffectofindapamide.

Acuterenalinsufficiencyindehydratedpatients(reductioninglomerularfiltration).

Hydratethepatient;monitorrenalfunctionatthestartoftreatment.

Potassium-loweringdrugs:amphotericinB(IVroute),glucocorticoidsandmineralocorticoids(systemicroute),

tetracosactide,stimulantlaxatives

Increasedriskoflowpotassiumlevels(additiveeffect).

Monitoringofpotassiumlevels,andcorrectionifnecessary;particularconsiderationrequiredincasesoftreatmentwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 9

Cardiacglycosides

Lowpotassiumlevelsfavourthetoxiceffectsofcardiacglycosides.

PotassiumlevelsandECGshouldbemonitoredandtreatmentreconsideredifnecessary.

Combinationswhichrequiresomecare:

Potassium-sparingdiuretics(amiloride,spironolactone,triamterene)

Therationalcombination,whichisusefulforsomepatients,doesnotexcludetheonsetoflowpotassiumlevelsor,

particularlyinpatientswithrenalinsufficiencyordiabetes,raisedpotassiumlevels.PotassiumlevelsandECGshould

bemonitoredandtreatmentreconsideredifnecessary.

Antiarrhythmicdrugswhichproducetorsadesdepointes:Class1Aantiarrhythmicagents(quinidine,hydroquinidine,

disopyramide),amiodarone,bretylium,sotalol

Torsadesdepointes(lowpotassiumlevelsisariskfactor,asarebradycardiaandapre-existinglongQTinterval).

Preventionoflowpotassiumlevelsandcorrectionifnecessary:monitoringoftheQTinterval.Antiarrythmicsshould

notbeadministeredincasesoftorsadesdepointes(managementbypacemaker).

Metformin

Lacticacidosisduetometformincausedbypossiblefunctionalrenalinsufficiencylinkedtodiureticsandinparticular

toloopdiuretics.

Donotusemetforminwhenplasmacreatininelevelsexceed15mg/l(135micromol/l)inmenand12mg/l(110

micromol/l)inwomen.

Iodinatedcontrastmedia

Incasesofdehydrationcausedbydiuretics,thereisanincreasedriskofacuterenalinsufficiency,particularlywhen

highdosesofiodinatedcontrastmediaareused.

Rehydrationshouldbecarriedoutbeforetheiodinatedcompoundisadministered.

Imipramine-likeantidepressants(tricyclics),neuroleptics

Increasedantihypertensiveeffectandincreasedriskoforthostatichypotension(additiveeffect).

Calcium(salts)

Riskofincreasedlevelsofcalciumduetoreducedeliminationofcalciumintheurine.

Cyclosporin

Riskofincreasedcreatininelevelswithnochangeincirculatinglevelsofcyclosporin,evenwhenthereisnosaltand

waterdepletion.

Corticosteroids,tetracosactide(systemicroute)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 10

4.6Pregnancyandlactation

AsthiscombinationincludesanACEinhibitor,COVERSYL®PLUS4mg/1.25mgTabletsarecontra-indicatedduring

pregnancyandlactation.

LINKEDTOPERINDOPRIL:

Pregnancy:

Appropriateandwellcontrolledstudieshavenotbeendoneinhumans.ACEinhibitorscrosstheplacentaandcancause

foetalandneonatalmorbidityandmortalitywhenadministeredtopregnantwomen.

FoetalexposuretoACEinhibitorsduringthesecondandthirdtrimestershasbeenassociatedwithneonatal

hypotension,renalfailure,faceorskulldeformitiesand/ordeath.Maternaloligohydramnioshasalsobeenreported

reflectingdecreasingrenalfunctioninthefoetus.Limbcontractures,craniofacialdeformities,hypoplasticlung

developmentandintrauterinegrowthretardationhavebeenreportedinassociationwitholigohydramnios.Infants

exposedinuterotoACEinhibitorsshouldbecloselyobservedforhypotension,oliguriaandhyperkalaemia.Oliguria

shouldbetreatedwithsupportofbloodpressureandrenalperfusion.

Intrauterinegrowthretardation,prematurity,patentductusarteriosusandfoetaldeathhavealsobeenreportedbutitis

notclearwhethertheyarerelatedtotheACEinhibitionortheunderlyingmaternaldisease.

Itisnotknownwhetherexposurelimitedtothefirsttrimestercanadverselyaffectfoetaloutcome.Womenwho

becomepregnantwhilereceivinganACEinhibitorshouldbeinformedofthepotentialhazardtothefoetus.

Lactation:

ACEinhibitorsmaybeexcretedinbreastmilkandtheireffectonthenursinginfanthasnotbeendetermined.Itis

recommendedthatlactatingmothersshouldnotbreastfeedwhiletakingACEinhibitors.

LINKEDTOINDAPAMIDE:

Pregnancy:

Asageneralrule,theadministrationofdiureticsshouldbeavoidedinpregnantwomenandshouldneverbegivenas

treatmentforphysiologicaloedema(andthereforedonotrequiretreatment)ofpregnancy.Diureticsmayleadtofoeto-

placentalischaemia,withariskofimpairedfoetalgrowth.

Nonethelessdiureticsremainanessentialpartofthetreatmentofoedemafromcardiac,hepaticandrenaloriginarising

inpregnantwomen.

Lactation:

Indapamideisexcretedinsmallquantitiesinbreastmilk.Nonetheless,itshouldnotbeusedinbreast-feedingperiod

dueto:

thedecreaseandevensuppressionofthemilksecretion,

itsundesirableeffectsinparticularbiological(potassiumlevels),

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 11

4.7Effectsonabilitytodriveandusemachines

LINKEDTOPERINDOPRIL,INDAPAMIDEANDCOVERSYLPLUS4MG/1.25MGTABLETS:

NeitherthetwoactivesubstancesnorCOVERSYL®PLUS4mg/1.25mgTabletsaffectalertnessbutindividual

reactionsrelatedtolowbloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorin

combinationwithanotherantihypertensivemedication.Asaresulttheabilitytodriveoroperatemachinerymaybe

impaired.

4.8Undesirableeffects

Theadministrationofperindoprilinhibitstherenin-angiotensin-aldosteroneaxisandtendstoreducethepotassiumloss

causedbyindapamide.FourpercentofthepatientsontreatmentwithCOVERSYL®PLUS4mg/1.25mgTablets

experiencehypokalaemia(potassiumlevel<3.4mmol/l).

GASTRO-INTESTINALTRACT

Common(>1/100,<1/10):constipation,drymouth,nausea,epigastricpain,anorexia,abdominalpains,taste

disturbance

Veryrare(<1/10,000):pancreatitis

Incaseofhepaticinsufficiency,thereisapossibilityofonsetofhepaticencephalopathy(seeContra-indicationsand

Specialwarnings)

RESPIRATORYSYSTEM

Common(>1/100,<1/10):Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.It

ischaracterisedbyitspersistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiology

shouldbeconsideredinthepresenceofthissymptom.

CARDIO-VASCULARSYSTEM

Uncommon(>1/1,000,<1/100):Hypotensionwhetherorthostaticornot(seeSpecialprecautionsforuse).

SKINAPPENDAGES

Uncommon(>1/1,000,<1/100):-Hypersensitivityreactions,mainlydermatological,insubjectswithapredisposition

toallergicandasthmaticreactions

-Maculopapulareruptions,purpura,possibleaggravationofpre-existingacutedisseminatedlupuserythematosus

-Skinrash

Veryrare(<1/10,000):Angioneuroticoedema(Quincke'soedema)(seeSpecialwarnings)

NERVOUSSYSTEM

Uncommon(>1/1,000,<1/100):Headache,asthenia,feelingsofdizziness,mooddisturbancesand/orsleep

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 12

MUSCULARSYSTEM

Uncommon(>1/1,000,<1/100):Cramps,paresthesia.

HAEMICSYSTEM

Veryrare(<1/10,000):-Thrombocytopenia,leucopenia,agranulocytosis,aplasticanaemia,haemolyticanaemia.

-Anaemia(seeSpecialprecautionsforuse)hasbeenreportedwithangiotensinconvertingenzymeinhibitorsinspecific

circumstances(patientswhohavehadkidneytransplants,patientsundergoinghaemodialysis).

LABORATORYPARAMETERS

Potassiumdepletionwithparticularlyseriousreductioninlevelsofpotassiuminsomeatriskpopulations(seeSpecial

precautionsforuse).

Reducedsodiumlevelswithhypovolaemiacausingdehydrationandorthostatichypotension.

Increaseinuricacidlevelsandinbloodglucoselevelsduringtreatment

Slightincreaseinureaandinplasmacreatininelevels,reversiblewhentreatmentisstopped.Thisincreaseismore

frequentincasesofrenalarterystenosis,arterialhypertensiontreatedwithdiuretics,renalinsufficiency.

Increasedlevelsofpotassium,usuallytransitory.

Rare(>1/10,000,<1/1,000):raisedplasmacalciumlevels.

4.9Overdose

Themostlikelyadverseeventincasesofoverdoseishypotension,sometimesassociatedwithnausea,vomiting,

cramps,dizziness,sleepiness,mentalconfusion,oliguriawhichmayprogresstoanuria(duetohypovolaemia).Saltand

waterdisturbances(lowsodiumlevels,lowpotassiumlevels)mayoccur.

Thefirstmeasurestobetakenconsistofrapidlyeliminatingtheproduct(s)ingestedbygastriclavageand/or

administrationofactivatedcharcoal,thenrestoringfluidandelectrolytebalanceinaspecialisedcentreuntiltheyreturn

tonormal.

Ifmarkedhypotensionoccurs,thiscanbetreatedbyplacingthepatientinasupinepositionwiththeheadlowered.If

necessaryanIVinfusionofisotonicsalinemaybegiven,oranyothermethodofvolaemicexpansionmaybeused.

Perindoprilat,theactiveformofperindopril,canbedialysed(seePharmacokineticproperties).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:perindoprilanddiuretics

ATCcode:C09BA04

COVERSYL®PLUS4mg/1.25mgTabletsareacombinationofperindopriltert-butylaminesalt,anangiotensin

convertingenzymeinhibitor,andindapamide,achlorosulphamoyldiuretic.Itspharmacologicalpropertiesarederived

fromthoseofeachofthecomponentstakenseparately,inadditiontothoseduetotheadditivesynergicactionofthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 13

PHARMACOLOGICALMECHANISMOFACTION

LINKEDTOCOVERSYLPLUS4MG/1.25MGTABLETS:

COVERSYLPLUS4mg/1.25mgTabletsproduceanadditivesynergyoftheanti-hypertensiveeffectsofthetwo

components.

LINKEDTOPERINDOPRIL:

Perindoprilisaninhibitoroftheangiotensinconvertingenzyme(ACEinhibitor)whichconvertsangiotensinIto

angiotensinII,avasoconstrictingsubstance;inadditiontheenzymestimulatesthesecretionofaldosteronebythe

adrenalcortexandstimulatesthedegradationofbradykinin,avasodilatorysubstance,intoinactiveheptapeptides.

Thisresultsin:

areductioninaldosteronesecretion,

anincreaseinplasmareninactivity,sincealdosteronenolongerexercisesnegativefeedback,

areductionintotalperipheralresistancewithapreferentialactiononthevascularbedinmuscleandthekidney,with

noaccompanyingsaltandwaterretentionorreflextachycardia,withchronictreatment.

Theantihypertensiveactionofperindoprilalsooccursinpatientswithlowornormalreninconcentrations.

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesareinactive.Perindoprilreducesthe

workoftheheart:

byavasodilatoryeffectonveins,probablycausedbychangesinthemetabolismofprostaglandins:reductioninpre-

load,

byreductionofthetotalperipheralresistance:reductioninafterload.

Studiescarriedoutonpatientswithcardiacinsufficiencyhaveshown:

areductioninleftandrightventricularfillingpressures,

areductionintotalperipheralvascularresistance,

anincreaseincardiacoutputandanimprovementinthecardiacindex,

anincreaseinregionalbloodflowinmuscle.

Exercisetestresultsalsoshowedimprovement.

LINKEDTOINDAPAMIDE:

Indapamideisasulphonamidederivativewithanindolering,pharmacologicallyrelatedtothethiazidegroupof

diuretics.Indapamideinhibitsthereabsorptionofsodiuminthecorticaldilutionsegment.Itincreasestheurinary

excretionofsodiumandchloridesand,toalesserextent,theexcretionofpotassiumandmagnesium,therebyincreasing

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 14

CHARACTERISTICSOFANTIHYPERTENSIVEACTION

LINKEDTOCOVERSYLplus4mg/1.25mgtablets:

Inhypertensivepatientsregardlessofage,Coversyl®Plus4mg/1.25mgTabletsexertadose-dependent

antihypertensiveeffectondiastolicandsystolicarterialpressurewhilstsupineorstanding.Thisantihypertensiveeffect

lastsfor24hours.Thereductioninbloodpressureisobtainedinlessthanonemonthwithouttachyphylaxis;stopping

treatmenthasnoreboundeffect.Duringclinicaltrials,theconcomitantadministrationofperindoprilandindapamide

producedantihypertensiveeffectsofasynergicnatureinrelationtoeachoftheproductsadministeredalone.

LINKEDTOPERINDOPRIL:

Perindoprilisactiveinallgradesofhypertension:mildtomoderateorsevere.Areductioninsystolicanddiastolic

arterialpressureisobservedinthelyingandstandingposition.

Theantihypertensiveactivityafterasingledoseismaximalatbetween4and6hoursandismaintainedover24hours.

Thereisahighdegreeofresidualblockingofangiotensinconvertingenzymeat24hours,approximately80%.

Inpatientswhorespond,normalisedbloodpressureisreachedafteronemonthandismaintainedwithout

tachyphylaxis.

Withdrawaloftreatmenthasnoreboundeffectonhypertension.

Perindoprilhasvasodilatorypropertiesandrestoreselasticityofthemainarterialtrunks,correctshistomorphometric

changesinresistancearteriesandproducesareductioninleftventricularhypertrophy.

Ifnecessary,theadditionofathiazidediureticleadstoanadditivesynergy.

Thecombinationofanangiotensinconvertingenzymeinhibitorwithathiazidediureticdecreasesthehypokalaemia

riskassociatedwiththediureticalone.

LINKEDtoindapamide:

Indapamide,asmonotherapy,hasanantihypertensiveeffectwhichlastsfor24hours.Thiseffectoccursatdosesat

whichthediureticpropertiesareminimal.

Itsantihypertensiveactionisproportionaltoanimprovementinarterialcomplianceandareductionintotaland

arteriolarperipheralvascularresistance.

Indapamidereducesleftventricularhypertrophy.

Whenadoseofthiazidediureticandthiazide-relateddiureticsisexceeded,theantihypertensiveeffectreachesa

plateau,whereastheadverseeffectscontinuetoincrease.Ifthetreatmentisineffective,thedoseshouldnotbe

increased.

Furthermore,ithasbeenshownthatintheshort-term,mid-termandlong-terminhypertensivepatients,indapamide:

hasnoeffectonlipidmetabolism:triglycerides,LDL-cholesterolandHDL-cholesterol,

hasnoeffectoncarbohydratemetabolism,evenindiabetichypertensivepatients.

5.2Pharmacokineticproperties

LINKEDTOCOVERSYLPLUS4MG/1.25MGTABLETS:

Theco-administrationofperindoprilandindapamidedoesnotchangetheirpharmacokineticpropertiesbycomparison

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 15

LINKEDTOPERINDOPRIL:

Perindoprilisrapidlyabsorbedbytheoralroute.Thequantityabsorbedis65to70%ofthedoseadministered.Itis

hydrolysedintoperindoprilatwhichisaspecificangiotensinconvertingenzymeinhibitor.Thequantityofperindoprilat

formedisalteredbyfoodintake.Thepeakplasmaconcentrationofperindoprilatisreachedafter3to4hours.Plasma

proteinbindingislessthan30%butisconcentration-dependent.

Afterrepeatedadministrationofperindoprilasasingledailydose,steadystateisreachedafteranaverageof4days.

Theeffectiveeliminationhalflifeofperindoprilatisapproximately24hours.

Plasmaconcentrationsofperindoprilataresignificantlyhigherinpatientswithcreatinineclearancebelow60ml/min,

whethertheyarepatientswithrenalinsufficiencyorelderly.Eliminationisalsosloweddowninpatientswithcardiac

insufficiency.

Theclearanceofperindoprilbydialysisis70ml/min.

Incirrhoticpatients,thekineticsofperindoprilisaltered:hepaticclearanceoftheparentsubstanceisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedanddoseadjustmentisthereforenotnecessary.

Angiotensinconvertingenzymeinhibitorscrosstheplacenta.

LINKEDTOINDAPAMIDE:

Indapamideisrapidlyandcompletelyabsorbedfromthedigestivetract.

Thepeakplasmalevelisreachedinhumansapproximatelyonehourafteroraladministrationoftheproduct.Plasma

proteinbindingis79%.

Theeliminationhalf-lifeisbetween14and24hours(average18hours).Repeatedadministrationdoesnotproduce

accumulation.Eliminationismainlyintheurine(70%ofthedose)andfaeces(22%)intheformofinactive

metabolites.

Thepharmacokineticsareunchangedinpatientswithrenalinsufficiency.

5.3Preclinicalsafetydata

COVERSYLPLUS4mg/1.25mgTabletshaveslightlyincreasedtoxicitythanthatofitscomponents.Renal

manifestationsdonotseemtobepotentiatedintherat.However,thecombinationproducesgastro-intestinaltoxicityin

thedogandthetoxiceffectsonthemotherseemtobeincreasedintherat(comparedtoperindopril).

Nonetheless,theseadverseeffectsareshownatdoselevelscorrespondingtoaverymarkedsafetymarginby

comparisontothetherapeuticdosesused.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Colloidalhydrophobicsilica

Lactosemonohydrate

Magnesiumstearate

Microcrystallinecellulose

6.2Incompatibilities

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 16

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecountainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpacksof30tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

PCOManufacturingLtd

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8ParallelProductAuthorisationNumber

PPA465/67/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3rdAugust2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/10/2008 CRN 2054664 page number: 17