BI PRETERAX

Main information

  • Trade name:
  • BI PRETERAX
  • Dosage:
  • 4mg/ 1.25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BI PRETERAX
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0568/008/002
  • Authorization date:
  • 14-08-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BiPreterax4mg/1.25mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains3.338mgperindoprilcorrespondingto4mgperindopriltert-butylanineand1.25mgindapamide.

Excipient:61.55mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet.

White,rod-shapedtablet

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension, BiPreterax 4mg/1.25mgTabletsisindicatedinpatientswhosebloodpressureis

notadequatelycontrolledonperindoprilalone.

4.2Posologyandmethodofadministration

Oralroute

OneBiPreterax4mg/1.25mgtabletperdayasasingledose,preferablytobetakeninthemorning,andbeforeameal.

Whenpossibleindividualdosetitrationwiththecomponentsisrecommended.BiPreterax4mg/1.25mgtabletshould

beusedwhenbloodpressureisnotadequatelycontrolledonPreterax2mg/0.625mgTablets(whereavailable).When

clinicallyappropriate,directchangefrommonotherapytoBiPreterax4mg/1.25mgTabletstabletmaybeconsidered.

Elderly(seesection4.4)

Treatmentshouldbeinitiatedafterconsideringbloodpressureresponseandrenalfunction.

Patientswithrenalimpairment(seesection4.4)

Insevererenalimpairment(creatinineclearancebelow30ml/min),treatmentiscontraindicated.

Inpatientswithmoderaterenalimpairment(creatinineclearance30-60ml/min),itisrecommendedtostarttreatment

withtheadequatedosageofthefreecombination.

Inpatientswithcreatinineclearancegreaterthanorequalto60ml/min,nodosemodificationisrequired.Usual

medicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Patientswithhepaticimpairment(seesections4.3,4.4and5.2)

Inseverehepaticimpairment,treatmentiscontraindicated.

Inpatientswithmoderatehepaticimpairment,nodosemodificationisrequired.

Childrenandadolescents

BiPreterax4mg/1.25mgTabletsshouldnotbeusedinchildrenandadolescentsastheefficacyandtolerabilityof

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4.3Contraindications

Linkedtoperindopril:

-HypersensitivitytoperindopriloranyotherACEinhibitor

-Historyofangioedema(Quincke’soedema)associatedwithpreviousACEinhibitortherapy

-Hereditary/idiopathicangioedema

-Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Linkedtoindapamide:

-Hypersensitivitytoindapamideortoanyothersulphonamides

-Severerenalimpairment(creatinineclearancebelow30ml/min)

-Hepaticencephalopathy

-Severehepaticimpairment

-Hypokalaemia

-Asageneralrule,thismedicineisinadvisableincombinationwithnonantiarrhythmicagentscausingtorsadesde

pointes(seesection4.5)

-Lactation(seesection4.6).

LinkedtoBiPreterax4mg/1.25mgTablets:

-Hypersensitivitytoanyoftheexcipients

Duetothelackofsufficienttherapeuticexperience,BiPreterax4mg/1.25mgTabletsshouldnotbeusedin:

-Dialysispatients

-Patientswithuntreateddecompensatedheartfailure.

4.4Specialwarningsandprecautionsforuse

Specialwarnings

Commontoperindoprilandindapamide:

Lithium:

Thecombinationoflithiumandthecombinationofperindoprilandindapamideisusuallynotrecommended(see

section4.5).

Linkedtoperindopril:

Neutropenia/agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicalmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever).

Hypersensitivity/angioedema:

Angioedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarelyinpatientstreatedwith

angiotensinconvertingenzymeinhibitors,includingperindopril.Thismayoccuratanytimeduringtreatment.Insuch

casesperindoprilshouldbediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensurecomplete

resolutionofsymptomspriortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfinedtotheface

andlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

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1:1000(0.3mlto0.5ml)and/ormeasurestoensureapatentairway,shouldbeadministeredpromptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

Anaphylactoidreactionsduringdesensitisation:

Therehavebeenisolatedreportsofpatientsexperiencingsustained,life-threateninganaphylactoidreactionswhile

receivingACEinhibitorsduringdesensitisationtreatmentwithhymenoptera(bees,wasps)venom.ACEinhibitors

shouldbeusedwithcautioninallergicpatientstreatedwithdesensitisation,andavoidedinthoseundergoingvenom

immunotherapy.HoweverthesereactionscouldbepreventedbytemporarywithdrawalofACEinhibitorforatleast24

hoursbeforetreatmentinpatientswhorequirebothACEinhibitorsanddesensitisation.

AnaphylactoidreactionsduringLDLapheresis:

Rarely,patientsreceivingACEinhibitorsduringlowdensitylipoprotein(LDL)-apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-

inhibitortherapypriortoeachapheresis.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhigh-fluxmembranes(e.g.,AN69®)andtreated

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofantihypertensiveagent.

Potassium-sparingdiuretics,potassiumsalts:

Thecombinationofperindoprilandpotassium-sparingdiuretics,potassiumsaltsisusuallynotrecommended(see

section4.5).

Pregnancy:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Linkedtoindapamide:

Whenliverfunctionisimpaired,thiazidediureticsandthiazide-relateddiureticsmaycausehepaticencephalopathy.

Administrationofthediureticshouldbestoppedimmediatelyifthisoccurs.

Photosensitivity:

Casesofphotosensitivityreactionshavebeenreportedwiththiazidesandrelatedthiazidesdiuretics(seesection4.8).If

photosensitivityreactionoccursduringtreatment,itisrecommendedtostopthetreatment.Ifare-administrationofthe

diureticisdeemednecessary,itisrecommendedtoprotectexposedareastothesunortoartificialUVA.

Precautionsforuse

Commontoperindoprilandindapamide:

Renalimpairment:

Incasesofsevererenalimpairment(creatinineclearance<30ml/min),treatmentiscontraindicated.

Incertainhypertensivepatientswithoutpre-existingapparentrenallesionsandforwhomrenalbloodtestsshow

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constituentonly.

Inthesepatientsusualmedicalfollow-upwillincludefrequentmonitoringofpotassiumandcreatinine,aftertwoweeks

oftreatmentandtheneverytwomonthsduringtherapeuticstabilityperiod.Renalfailurehasbeenreportedmainlyin

patientswithsevereheartfailureorunderlyingrenalfailureincludingrenalarterystenosis.

Thedrugisusuallynotrecommendedincaseofbilateralrenalarterystenosisorasinglefunctioningkidney.

Hypotensionandwaterandelectrolytedepletion:

Thereisariskofsuddenhypotensioninthepresenceofpre-existingsodiumdepletion(inparticularinindividualswith

renalarterystenosis).Thereforesystematictestingshouldbecarriedoutforclinicalsignsofwaterandelectrolyte

depletion,whichmayoccurwithanintercurrentepisodeofdiarrhoeaorvomiting.Regularmonitoringofplasma

electrolytesshouldbecarriedoutinsuchpatients.

Markedhypotensionmayrequiretheimplementationofanintravenousinfusionofisotonicsaline.

Transienthypotensionisnotacontraindicationtocontinuationoftreatment.Afterre-establishmentofasatisfactory

bloodvolumeandbloodpressure,treatmentcanbestartedagaineitheratareduceddoseorwithonlyoneofthe

constituents.

Potassiumlevels:

Thecombinationofperindoprilandindapamidedoesnotpreventtheonsetofhypokalaemiaparticularlyindiabetic

patientsorinpatientswithrenalfailure.Aswithanyantihypertensiveagentcontainingadiuretic,regularmonitoringof

plasmapotassiumlevelsshouldbecarriedout.

Excipients:

BiPreterax4mg/1.25mgshouldnotbeadministeredtopatientswithrarehereditaryproblemsofgalactoseintolerance,

theLapplactasedeficiencyorglucose-galactosemalabsorption.

Linkedtoperindopril:

Cough:

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

eventofthissymptom.Iftheprescriptionofanangiotensinconvertingenzymeinhibitorisstillpreferred,continuation

oftreatmentmaybeconsidered.

Childrenandadolescents:

Theefficacyandtolerabilityofperindoprilinchildrenandadolescents,aloneorincombination,havenotbeen

established.

Riskofarterialhypotensionand/orrenalinsufficiency(incasesofcardiacinsufficiency,waterandelectrolyte

depletion,etc.):

Markedstimulationoftherenin-angiotensin-aldosteronesystemhasbeenobservedparticularlyduringmarkedwater

andelectrolytedepletions(strictsodium-freedietorprolongeddiuretictreatment),inpatientswhosebloodpressure

wasinitiallylow,incasesofrenalarterystenosis,congestiveheartfailureorcirrhosiswithoedemaandascites.

Theblockingofthissystemwithanangiotensinconvertingenzymeinhibitormaythereforecause,particularlyatthe

timeofthefirstadministrationandduringthefirsttwoweeksoftreatment,asuddendropinbloodpressureand/oran

increaseinplasmalevelsofcreatinine,showingafunctionalrenalinsufficiency.Occasionallythiscanbeacutein

onset,althoughrare,andwithavariabletimetoonset.

Insuchcases,thetreatmentshouldthenbeinitiatedatalowerdoseandincreasedprogressively.

Elderly:

Renalfunctionandpotassiumlevelsshouldbetestedbeforethestartoftreatment.Theinitialdoseissubsequently

adjustedaccordingtobloodpressureresponse,especiallyincasesofwaterandelectrolytedepletion,inordertoavoid

suddenonsetofhypotension.

Patientswithknownatherosclerosis:

Theriskofhypotensionexistsinallpatientsbutparticularcareshouldbetakeninpatientswithischaemicheartdisease

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Renovascularhypertension:

Thetreatmentforrenovascularhypertensionisrevascularisation.Nonetheless,angiotensinconvertingenzyme

inhibitorscanbebeneficialinpatientspresentingwithrenovascularhypertensionwhoareawaitingcorrectivesurgery

orwhensuchasurgeryisnotpossible.

IfBiPreterax4mg/1.25mgisprescribedtopatientswithknownorsuspectedrenalarterystenosis,treatmentshouldbe

startedinahospitalsettingatalowdoseandrenalfunctionandpotassiumlevelsshouldbemonitored,sincesome

patientshavedevelopedafunctionalrenalinsufficiencywhichwasreversedwhentreatmentwasstopped.

Otherpopulationsatrisk:

Inpatientswithseverecardiacinsufficiency(gradeIV)orinpatientswithinsulindependentdiabetesmellitus

(spontaneoustendencytoincreasedlevelsofpotassium),treatmentshouldbestartedundermedicalsupervisionwitha

reducedinitialdose.Treatmentwithbeta-blockersinhypertensivepatientswithcoronaryinsufficiencyshouldnotbe

stopped:theACEinhibitorshouldbeaddedtothebeta-blocker.

Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,perindoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Surgery/anaesthesia:

Angiotensinconvertingenzymeinhibitorscancausehypotensionincasesofanaesthesia,especiallywhenthe

anaestheticadministeredisanagentwithhypotensivepotential.

Itisthereforerecommendedthattreatmentwithlong-actingangiotensinconvertingenzymeinhibitorssuchas

perindoprilshouldbediscontinuedwherepossibleonedaybeforesurgery.

Aorticormitralvalvestenosis/hypertrophiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientwithanobstructionintheoutflowtractoftheleftventricle.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

age(>70years),diabetesmellitus,intercurrentevents,inparticulardehydration,acutecardiacdecompensation,

metabolicacidosisandconcomitantuseofpotassium-sparingdiuretics(e.g.,spironolactone,eplerenone,triamterene,or

amiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

associatedwithincreasesinserumpotassium(e.g.heparin).Theuseofpotassiumsupplements,potassium-sparing

diuretics,orpotassium-containingsaltsubstitutesparticularlyinpatientswithimpairedrenalfunctionmayleadtoa

significantincreaseinserumpotassium.Hyperkalemiacancauseserious,sometimesfatalarrhythmias.Ifconcomitant

useoftheabove-mentionedagentsisdeemedappropriate,theyshouldbeusedwithcautionandwithfrequent

monitoringofserumpotassium(seesection4.5).

Linkedtoindapamide:

Waterandelectrolytebalance:

Sodiumlevels:

Theseshouldbetestedbeforetreatmentisstarted,thenatregularintervals.Alldiuretictreatmentcancauseareduction

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regulartestingisthereforeessential.Testingshouldbemorefrequentinelderlyandcirrhoticpatients(seesections4.8

and4.9).

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:

=(140-age)xbodyweight/0.814xplasmacreatininelevel

with:ageexpressedinyears

bodyweightinkg

plasmacreatininelevelinmicromol/l

Thisformulaissuitableforanelderlymaleandshouldbeadaptedforwomenbymultiplyingtheresultby0.85.

Hypovolaemia,resultingfromthelossofwaterandsodiumcausedbythediureticatthestartoftreatment,causesa

reductioninglomerularfiltration.Itmayresultinanincreaseinbloodureaandcreatininelevels.Thistransitory

functionalrenalinsufficiencyisofnoadverseconsequenceinpatientswithnormalrenalfunctionbutmayhowever

worsenapre-existingrenalimpairment.

Athletes:

Athletesshouldnotethatthisproductcontainsanactivesubstancewhichmaycauseapositivereactionindopingtests.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Commontoperindoprilandindapamide:

Concomitantusenotrecommended:

Lithium:reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayfurtherincreaselithium

levelsandenhancetheriskoflithiumtoxicitywithACEinhibitors.Useofperindoprilcombinedwithindapamidewith

lithiumisnotrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevels

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Concomitantusewhichrequiresspecialcare:

Baclofen:Potentiationofantihypertensiveeffect.Monitoringofbloodpressureandrenalfunction,anddose

adaptationoftheantihypertensiveifnecessary.

Non-steroidalanti-inflammatorymedicinalproducts(includedacetylsalicylicacidathighdoses):whenACE-

inhibitorsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(i.e.acetylsalicylicacidat

anti-inflammatorydosageregimens,COX-2inhibitorsandnon-selectiveNSAIDs),attenuationofthe

antihypertensiveeffectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyin

theelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunction

afterinitiationofconcomitanttherapy,andperiodicallythereafter.

Concomitantusewhichrequiressomecare:

- Imipramine-likeantidepressants(tricyclics),neuroleptics:Increasedantihypertensiveeffectandincreasedriskof

orthostatichypotension(additiveeffect).

-Corticosteroids,tetracosactide:Reductioninantihypertensiveeffect(saltandwaterretentionduetocorticosteroids).

-otherantihypertensiveagents:useofotherantihypertensivemedicinalproductswithperindopril/indapamidecould

resultinadditionalbloodpressureloweringeffect.

Linkedtoperindopril:

Concomitantusenotrecommended:

- Potassium-sparingdiuretics(spironolactone,triamterene,aloneorincombination),potassium(salts):ACE

inhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiureticse.g.spironolactone,triamterene,or

amiloride,potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium(potentiallylethal).Ifconcomitantuseisindicatedbecauseofdocumentedhypokalemiathey

shouldbeusedwithcautionandwithfrequentmonitoringofserumpotassiumandbyECG.

Concomitantusewhichrequiresspecialcare:

-Antidiabeticagents(insulin,hypoglycaemicsulphonamides):Reportedwithcaptoprilandenalapril.

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.Theonsetofhypoglycaemicepisodesisveryrare

(improvementinglucosetolerancewitharesultingreductionininsulinrequirements).

Concomitantusewhichrequiressomecare:

Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroidsorprocainamide:Concomitant

administrationwithACEinhibitorsmayleadtoanincreasedriskforleucopenia.

-Anaestheticdrugs:ACEinhibitorsmayenhancethehypotensiveeffectsofcertainanaestheticdrugs.

-Diuretics(thiazideorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandin

ariskofhypotensionwheninitiatingtherapywithperindopril.

-Gold:Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreported

rarelyinpatientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapy

includingperindopril.

Linkedtoindapamide:

Concomitantusewhichrequiresspecialcare:

Torsadesdepointesinducingdrugs:Duetotheriskofhypokalemia,indapamideshouldbeadministeredwith

cautionwhenassociatedwithmedicinalproductsthatinducedtorsadesdepointessuchasclassIAantiarrhythmic

agents(quinidine,hydroquinidine,disopyramide);classIIIantiarrhythmicagents(amiodarone,dofetilide,ibutilide,

bretylium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine,

trifluoperazine),benzamides(amisulpride,sulpiride,sultopride,tiapride),butyrophenones(droperidol,haloperidol),

otherneuroleptics(pimozide);othersubstancessuchasbepridil,cisapride,diphemanil,IVerythromycin,

halofantrine,mizolastine,moxifloxacin,pentamidine,sparfloxacin,IVvincamine,methadone,astemizole,

terfenadine.Preventionoflowpotassiumlevelsandcorrectionifnecessary:monitoringoftheQTinterval.

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tetracosactide,stimulantlaxatives:Increasedriskoflowpotassiumlevels(additiveeffect).Monitoringofpotassium

levels,andcorrectionifnecessary;particularconsiderationrequiredincasesoftreatmentwithcardiacglycosides.

Nonstimulantlaxativesshouldbeused.

-Cardiacglycosides:Lowpotassiumlevelsfavourthetoxiceffectsofcardiacglycosides.PotassiumlevelsandECG

shouldbemonitoredandtreatmentreconsideredifnecessary.

Concomitantusewhichrequiressomecare:

-Metformin:Lacticacidosisduetometformincausedbypossiblefunctionalrenalinsufficiencylinkedtodiuretics

andinparticulartoloopdiuretics.Donotusemetforminwhenplasmacreatininelevelsexceed15mg/l

(135micromol/l)inmenand12mg/l(110micromol/l)inwomen.

Iodinatedcontrastmedia:Incasesofdehydrationcausedbydiuretics,thereisanincreasedriskofacuterenal

insufficiency,particularlywhenhighdosesofiodinatedcontrastmediaareused.Rehydrationshouldbecarriedout

beforetheiodinatedcompoundisadministered.

-Calcium(salts):Riskofincreasedlevelsofcalciumduetoreducedeliminationofcalciumintheurine.

-Ciclosporin:Riskofincreasedcreatininelevelswithnochangeincirculatinglevelsofciclosporin,evenwhenthere

isnosaltandwaterdepletion.

4.6Fertility,pregnancyandlactation

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancyandlactation,

BiPreterax4mg/1.25mgisnotrecommendedduringthefirsttrimesterofpregnancy.BiPreterax4mg/1.25mg

Tabletsiscontraindicatedduringthesecondandthirdtrimestersofpregnancy.

BiPreterax4mg/1.25mgiscontraindicatedduringlactation.Adecisionshouldthereforebemadewhetherto

discontinuenursingortodiscontinueBiPreterax4mg/1.25mgTabletstakingaccounttheimportanceofthistherapy

forthemother.

Pregnancy:

Linkedtoperindopril:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Linkedtoindapamide:

Prolongedexposuretothiazideduringthethirdtrimesterofpregnancycanreducematernalplasmavolumeaswellas

uteroplacentalbloodflow,whichmaycauseafeto-placentalischemiaandgrowthretardation.Moreover,rarecasesof

hypoglycemiaandthrombocytopeniainneonateshavebeenreportedfollowingexposurenearterm.

Lactation:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy

(seesection4.4).TheuseofACEinhibitorsiscontra-indicatedduringthesecondand

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Linkedtoperindopril:

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Linkedtoindapamide:

Indapamideisexcretedinhumanmilk.Indapamideiscloselyrelatedtothiazidediureticswhichhavebeenassociated,

duringbreast-feeding,withdecreaseorevensuppressionofmilklactation.Hypersensitivitytosulfonamide-derived

drugs,hypokalaemiaandnuclearicterusmightoccur.

4.7Effectsonabilitytodriveandusemachines

Linkedtoperindopril,indapamideandBiPreterax4mg/1.25mgTablets:

NeitherthetwoactivesubstancesnorBiPreterax4mg/1.25mgTabletsaffectalertnessbutindividualreactionsrelated

tolowbloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorincombinationwithanother

antihypertensivemedication.

Asaresulttheabilitytodriveoroperatemachinerymaybeimpaired.

4.8Undesirableeffects

Theadministrationofperindoprilinhibitstherenin-angiotensin-aldosteroneaxisandtendstoreducethepotassiumloss

causedbyindapamide.FourpercentofthepatientsontreatmentwithBiPreterax4mg/1.25mgTabletsexperience

hypokalaemia(potassiumlevel<3.4mmol/l).

Thefollowingundesirableeffectscouldbeobservedduringtreatmentandrankedunderthefollowingfrequency:

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

(<1/10000),notknown(cannotbeestimatedfromtheavailabledata).

Bloodandthelymphaticsystemdisorders:

Veryrare:

-Thrombocytopenia,leucopenia/neutropenia,agranulocytosis,aplasticanaemia,haemolyticanaemia.

Anaemia(seesection4.4)hasbeenreportedwithangiotensinconvertingenzymeinhibitorsinspecific

circumstances(patientswhohavehadkidneytransplants,patientsundergoinghaemodialysis).

Psychiatricdisorders:

Uncommon:moodorsleepdisturbances.

Nervoussystemdisorders:

Common:Paresthesia,headache,asthenia,feelingsofdizziness,vertigo.

Veryrare:Confusion.

Eyedisorders:

Common:Visiondisturbance.

Earandlabyrinthdisorders:

Common:Tinnitus.

Vasculardisorders:

Common:Hypotensionwhetherorthostaticornot(seesection4.4).

Cardiacdisorders:

Veryrare:Arrhythmiaincludingbradycardia,ventriculartachycardia,atrialfibrillation,anginapectorisandmyocardial

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Respiratory,thoracicandmediastinaldisorders:

Common:

-Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredin

thepresenceofthissymptom.Dyspnoea.

Uncommon:Bronchospasm.

Veryrare:Eosinophilicpneumonia,rhinitis.

Gastrointestinaldisorders:

Common:Constipation,drymouth,nausea,epigastricpain,anorexia,vomiting,abdominalpain,tastedisturbance,

dyspepsia,diarrhoea.

Veryrare:Pancreatitis.

Hepato-biliarydisorders:

Veryrare:Hepatitiseithercytolyticorcholestatic(seesection4.4).

Notknown:Incaseofhepaticinsufficiency,thereisapossibilityofonsetofhepaticencephalopathy(seesections4.3

and4.4).

Skinandsubcutaneoustissuedisorders:

Common:Rash,pruritus,maculopapulareruptions.

Uncommon:

-Angioedemaofface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynx,urticaria(seesection4.4).

-Hypersensitivityreactions,mainlydermatological,insubjectswithapredispositiontoallergicandasthmatic

reactions.

-Purpura.

Possibleaggravationofpre-existingacutedisseminatedlupuserythematosus.

Veryrare:erythemamultiforme,toxicepidermicnecrolysis,StevenJohnsonsyndrome.

Casesofphotosensitivityreactionshavebeenreported(seesection4.4).

Musculoskeletal,connectivetissueandbonedisorders:

Common:Cramps.

Renalandurinarydisorders:

Uncommon:Renalinsufficiency.

Veryrare:Acuterenalfailure.

Reproductivesystemandbreastdisorders:

Uncommon:Impotence.

Generaldisordersandadministrationsiteconditions:

Common:Asthenia.

Uncommon:Sweating.

Investigations:

-Potassiumdepletionwithparticularlyseriousreductioninlevelsofpotassiuminsomeatriskpopulations(see

section4.4).

-Reducedsodiumlevelswithhypovolaemiacausingdehydrationandorthostatichypotension.

-Increaseinuricacidlevelsandinbloodglucoselevelsduringtreatment.

-Slightincreaseinureaandinplasmacreatininelevels,reversiblewhentreatmentisstopped.Thisincreaseismore

frequentincasesofrenalarterystenosis,arterialhypertensiontreatedwithdiuretics,renalinsufficiency.

-Increasedlevelsofpotassium,usuallytransitory.

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4.9Overdose

Themostlikelyadversereactionincasesofoverdoseishypotension,sometimesassociatedwithnausea,vomiting,

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

waterdisturbances(lowsodiumlevels,lowpotassiumlevels)mayoccur.

Thefirstmeasurestobetakenconsistofrapidlyeliminatingtheproduct(s)ingestedbygastriclavageand/or

administrationofactivatedcharcoal,thenrestoringfluidandelectrolytebalanceinaspecialisedcentreuntiltheyreturn

tonormal.

Ifmarkedhypotensionoccurs,thiscanbetreatedbyplacingthepatientinasupinepositionwiththeheadlowered.If

necessaryanintravenousinfusionofisotonicsalinemaybegiven,oranyothermethodofvolaemicexpansionmaybe

used.

Perindoprilat,theactiveformofperindopril,canbedialysed(seesection5.2).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:perindoprilanddiuretics,ATCcode:C09BA04

BiPreterax4mg/1.25mgTabletsisacombinationofperindopriltert-butylaminesalt,anangiotensinconverting

enzymeinhibitor,andindapamide,achlorosulphamoyldiuretic.Itspharmacologicalpropertiesarederivedfromthose

ofeachofthecomponentstakenseparately,inadditiontothoseduetotheadditivesynergicactionofthetwoproducts

whencombined.

Pharmacologicalmechanismofaction

LinkedtoBiPreterax4mg/1.25mgTablets:

BiPreterax4mg/1.25mgTabletsproducesanadditivesynergyoftheantihypertensiveeffectsofthetwocomponents.

Linkedtoperindopril:

Perindoprilisaninhibitoroftheangiotensinconvertingenzyme(ACEinhibitor)whichconvertsangiotensinIto

angiotensinII,avasoconstrictingsubstance;inadditiontheenzymestimulatesthesecretionofaldosteronebythe

adrenalcortexandstimulatesthedegradationofbradykinin,avasodilatorysubstance,intoinactiveheptapeptides.

Thisresultsin:

-areductioninaldosteronesecretion,

-anincreaseinplasmareninactivity,sincealdosteronenolongerexercisesnegative feedback,

-areductionintotalperipheralresistancewithapreferentialactiononthevascularbedinmuscleandthekidney,with

noaccompanyingsaltandwaterretentionorreflextachycardia,withchronictreatment.

Theantihypertensiveactionofperindoprilalsooccursinpatientswithlowornormalreninconcentrations.

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesareinactive.

Perindoprilreducestheworkoftheheart:

-byavasodilatoryeffectonveins,probablycausedbychangesinthemetabolismofprostaglandins:reductioninpre-

load,

-byreductionofthetotalperipheralresistance:reductioninafterload.

Studiescarriedoutonpatientswithcardiacinsufficiencyhaveshown:

-areductioninleftandrightventricularfillingpressures,

-areductionintotalperipheralvascularresistance,

-anincreaseincardiacoutputandanimprovementinthecardiacindex,

-anincreaseinregionalbloodflowinmuscle.

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Linkedtoindapamide:

Indapamideisasulphonamidederivativewithanindolering,pharmacologicallyrelatedtothethiazidegroupof

diuretics.Indapamideinhibitsthereabsorptionofsodiuminthecorticaldilutionsegment.Itincreasestheurinary

excretionofsodiumandchloridesand,toalesserextent,theexcretionofpotassiumandmagnesium,therebyincreasing

urineoutputandhavinganantihypertensiveaction.

Characteristicsofantihypertensiveaction

LinkedtoBiPreterax4mg/1.25mgTablets:

Inhypertensivepatientsregardlessofage,BiPreterax4mg/1.25mgTabletsexertsadose-dependentantihypertensive

effectondiastolicandsystolicarterialpressurewhilstsupineorstanding.Thisantihypertensiveeffectlastsfor24

hours.Thereductioninbloodpressureisobtainedinlessthanonemonthwithouttachyphylaxis;stoppingtreatment

hasnoreboundeffect.Duringclinicaltrials,theconcomitantadministrationofperindoprilandindapamideproduced

antihypertensiveeffectsofasynergicnatureinrelationtoeachoftheproductsadministeredalone.

PICXEL,amulticenter,randomised,doubleblindactivecontrolledstudyhasassessedonechocardiographytheeffect

ofperindopril/indapamidecombinationonLVHversusenalaprilmonotherapy.

InPICXEL,hypertensivepatientswithLVH(definedasleftventricularmassindex(LVMI)>120g/m 2

inmaleand

>100g/m 2

infemale)wererandomisedeithertoperindopril2mg/indapamide0.625mgortoenalapril10mgoncea

dayforaone-yeartreatment.Thedosewasadaptedaccordingtobloodpressurecontrol,uptoperindopril8mgand

indapamide2.5mgorenalapril40mgonceaday.Only34%ofthesubjectsremainedtreatedwithperindopril

2mg/indapamide0.625mg(versus20%withEnalapril10mg).

Attheendoftreatment,LVMIhaddecreasedsignificantlymoreintheperindopril/indapamidegroup(-10.1g/m²)than

intheenalaprilgroup(-1.1g/m²)intheallrandomisedpatientspopulation.ThebetweengroupdifferenceinLVMI

changewas-8.3(95%CI(-11.5,-5.0),p<0.0001).

AbettereffectonLVMIwasreachedwithhigherperindopril/indapamidedosesthanthoselicensedforPreterax

2mg/0.625mgTabletsandBiPreterax4mg/1.25mgTablets.

Regardingbloodpressure,theestimatedmeanbetween-groupdifferencesintherandomisedpopulationwere-5.8

mmHg(95%CI(-7.9,-3.7),p<0.0001)forsystolicbloodpressureand-2.3mmHg(95%CI(-3.6,-0.9),p=0.0004)

fordiastolicbloodpressurerespectively,infavouroftheperindopril/indapamidegroup.

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

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increased.

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

-hasnoeffectonlipidmetabolism:triglycerides,LDL-cholesterolandHDL-cholesterol,

-hasnoeffectoncarbohydratemetabolism,evenindiabetichypertensivepatients.

5.2Pharmacokineticproperties

LinkedtoBiPreterax4mg/1.25mgTablets:

Theco-administrationofperindoprilandindapamidedoesnotchangetheirpharmacokineticpropertiesbycomparison

toseparateadministration.

Linkedtoperindopril:

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationisachievedwithin1hour.

Theplasmahalf-lifeofperindoprilisequalto1hour.

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindopriltert-butylaminesalt

shouldbeadministeredorallyinasingledailydoseinthemorningbeforeameal.

Ithasbeendemonstratedalinearrelationshipbetweenthedoseofperindoprilanditsplasmaexposure.

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).

Linkedtoindapamide:

Indapamideisrapidlyandcompletelyabsorbedfromthedigestivetract.

Thepeakplasmalevelisreachedinhumansapproximatelyonehourafteroraladministrationoftheproduct.Plasma

proteinbindingis79%.

Theeliminationhalf-lifeisbetween14and24hours(average18hours).Repeatedadministrationdoesnotproduce

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

metabolites.

Thepharmacokineticsareunchangedinpatientswithrenalinsufficiency.

5.3Preclinicalsafetydata

BiPreterax4mg/1.25mgTabletshasslightlyincreasedtoxicitythanthatofitscomponents.Renalmanifestationsdo

notseemtobepotentiatedintherat.However,thecombinationproducesgastro-intestinaltoxicityinthedogandthe

toxiceffectsonthemotherseemtobeincreasedintherat(comparedtoperindopril).

Nonetheless,theseadverseeffectsareshownatdoselevelscorrespondingtoaverymarkedsafetymarginby

comparisontothetherapeuticdosesused.

Preclinicalstudiesperformedseparatelywithperindoprilandindapamidedidnotshowgenotoxic,carcinogenicor

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Magnesiumstearate(E470B)

Colloidalhydrophobicsilica

Microcrystallinecellulose

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

14,20,28,30,50,56,60,90,100and500tabletsinblister(PVC/aluminium).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

LesLaboratoiresServier

22,rueGarnier

92200Neuilly-sur-Seine

France

8MARKETINGAUTHORISATIONNUMBER

PA568/8/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14 th

August1998

Dateoflastrenewal:25 th

November2007

10DATEOFREVISIONOFTHETEXT

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