CARACE

Main information

  • Trade name:
  • CARACE Tablets 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARACE Tablets 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0002/072/003
  • Authorization date:
  • 23-02-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0002/072/003

CaseNo:2040468

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Bristol-MyersSquibbPharmaceuticalsLtd

Swords,Co.Dublin,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CaraceTablets20mg.

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom23/02/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CaraceTablets20mg.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgoflisinopril(asdihydrate).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablets.

Orange,half-scored,ovaltablets,marked‘CARACE’and‘20’.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Allgradesofessentialhypertensionandrenovascularhypertension.“Carace”maybeusedaloneorwithother

antihypertensiveagents.

HeartFailure

Inheartfailure,“Carace”isindicatedasadjunctivetherapywithnon-potassium-sparingdiureticsand,where

appropriate,digitalis.

SevereHeartFailure

Treatmentwith“Carace”shouldalwaysbeinitiatedinhospitalunderclosemedicalsupervision.

MildtoModerateHeartFailure

Treatmentwith“Carace”shouldalwaysbeinitiatedunderclosemedicalsupervision.

AcuteMyocardialInfarction

“Carace”isindicatedforthetreatmentofhaemodynamicallystablepatientswithin24hoursofacutemyocardial

infarction,topreventthesubsequentdevelopmentofleftventriculardysfunctionorheartfailureandtoimprove

survival.Patientsshouldreceive,asappropriate,thestandardrecommendedtreatmentssuchasthrombolytics,

aspirinandbeta-blocker.

4.2Posologyandmethodofadministration

Theabsorptionof“Carace”isnotaffectedbyfood.“Carace”shouldbeadministeredinasingledose.Aswith

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Hypertension

Theneedfordosagetitrationshouldbedeterminedbymeasurementofthebloodpressurejustbeforethenext

dose.

Essentialhypertension

Inpatientswithessentialhypertensiontheusualrecommendedstartingdoseis10mg.Theusualeffective

maintenancedosageis20mgadministeredinasingledailydose.Dosageshouldbeadjustedaccordingtoblood

pressureresponse.Insomepatients,achievementofoptimalbloodpressurereductionmayrequiretwotofour

weeksoftherapy.Themaximumdoseusedinlong-term,controlledclinicaltrialswas80mg/day.

RenovascularHypertension

Somepatientswithessentialhypertension,especiallythosewithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney,maydevelopanexaggeratedresponsetothefirstdoseof“Carace”.Therefore,a

lowerdoseof2.5or5mgisrecommended.Thereafter,thedosagemaybeadjustedaccordingtotheblood

pressureresponse.

Diuretic-treatedpatients

Symptomatichypotensioncanoccurfollowinginitiationoftherapywith“Carace”;thisismorelikelywhen

“Carace”isaddedtopreviousdiuretictherapy.Cautionisrecommended,therefore,sincethesepatientsmaybe

volumeorsaltdepleted.

Ifpossible,thediureticshouldbediscontinued,orthedosereduced,twotothreedaysbeforebeginningtherapy

with“Carace”(seesection4.4.,Specialwarningsandprecautionsforuse)andmayberesumedlaterif

required.Insuchdiuretic-treatedpatients,therapywith“Carace”shouldbeinitiatedwitha5mgdose.The

subsequentdosageof“Carace”shouldbeadjustedaccordingtobloodpressureresponse.

“Carace”reducesthedevelopmentofthiazide-inducedhypokalaemiaandhyperuricaemia.

Useintheelderly

Agealonedoesnotappeartoaffecttheefficacyorsafetyprofileof“Carace”.Thus,elderlypatientsshouldstart

treatmentwith“Carace”asdirectedabove,exceptwherethereisrenalimpairment.

Congestiveheartfailure

“Carace”canbeusedasadjunctivetherapywithnon-potassium-sparingdiureticsand/ordigitalis.“Carace”

shouldbeintroducedforthetreatmentofheartfailurefollowingstabilisationofthepatientondiuretictherapy.

Therapywith“Carace”shouldbeinitiatedunderclosemedicalsupervision(inhospitalforsevereheartfailure)

witharecommendedstartingdoseof2.5mgoncedaily.Thedoseof“Carace”shouldbegraduallyincreased,

dependingupontolerabilitytotherecommendedmaintenancedose(5-20mg)givenasasingledose.

Thedosetitrationof“Carace”maybeperformedoveratwotofour-weekperiodormorerapidlyifindicatedby

thepresenceofresidualsignsandsymptomsofheartfailure.Bloodpressureandrenalfunctionshouldbe

monitoredcloselybothbeforeandduringtreatmentwith“Carace”becauseseverehypotensionandmorerarely

consequentrenalfailurehavebeenreportedwithangiotensin-convertingenzyme(ACE)inhibitors.Serum

potassiumshouldalsobemonitored.

Inordertodecreasethepossibilityofsymptomatichypotension,patientspreviouslyonhigh-dosediuretics

shouldhavethediureticdosereducedbeforeintroducing“Carace”.Theappearanceofhypotensionafterthe

initialdoseof“Carace”doesnotprecludesubsequentcarefuldosetitrationwiththedrug,followingeffective

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a)InitialDose

Treatmentshouldbeinitiatedwithastartingdoseof2.5mg.Ifpossible,thedoseofdiureticshouldbereduced

beforebeginningtreatment.

b)MaintenanceDosage

Thedosageshouldbegraduallyincreased,dependingonthepatient’sresponsetotheusualmaintenancedose

(5-20mg).Thisdoseadjustmentmaybeperformedoveratwo-to-fourweekperiod,ormorerapidlyif

clinicallyindicated.

Impairedrenalfunction

“Carace”isexcretedbythekidney,andshouldbeusedwithcautioninpatientswithrenalinsufficiency.The

recommendedstartingdoseis2.5mgandshouldbeadjustedaccordingtotheresponse.

“Carace”isdialysable.Dialysispatientsmaybegiventheusualdoseof“Carace”ondialysisdays.Onthedays

whenpatientsarenotondialysisthedosageshouldbetailoredtothebloodpressureresponse.

AcuteMyocardialInfarction

Treatmentwith“Carace”maybestartedwithin24hoursoftheonsetofsymptoms.Thefirstdoseof“Carace”

is5mggivenorally,followedby5mgafter24hours,10mgafter48hoursandthen10mgoncedaily

thereafter.Patientswithalowsystolicbloodpressure(120mmHgorless)whentreatmentisstartedorduring

thefirst3daysaftertheinfarctshouldbegivenalowerdose-2.5mgorally(seesection4.4.,Specialwarnings

andprecautionsforuse).Ifhypotensionoccurs(systolicbloodpressurelessthanorequalto100mmHg)a

dailymaintenancedoseof5mgmaybegivenwithtemporaryreductionto2.5mgifneeded.Ifprolonged

hypotensionoccurs(systolicbloodpressurelessthan90mmHgformorethan1hour)“Carace”shouldbe

withdrawn.

Dosingforpatientswithacutemyocardialinfarctionshouldcontinuefor6weeks.Forpatientswhodevelop

symptomsofheartfailureseeDosageandAdministration,CongestiveHeartFailure.

“Carace”iscompatiblewithintravenousortransdermalglyceryltrinitrate.

PaediatricUse

“Carace”hasnotbeenstudiedforuseinchildren.

4.3Contraindications

“Carace”iscontraindicatedinpatientswhoarehypersensitivetoanycomponentofthisproduct.

"Carace"iscontraindicatedinpatientswithahistoryofangioneuroticoedemarelatingtoprevious

treatmentwithangiotensin-convertingenzymeinhibitorandinpatientswithhereditaryoridiopathic

angioedema.

Useinpatientswithcorpulmonaleoroutflowtractobstruction.

Useinpatientswithaorticstenosis.

Theuseof“Carace”inpregnancyandinwomenbreastfeedinginfantsiscontraindicated(seesection

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4.4Specialwarningsandprecautionsforuse

General

Treatmentofseverecongestiveheartfailurewithlisinoprilshouldbeintroducedunderhospitalconditionsin

specialistunitswithadequatefacilitiesformonitoringofclinicalandlaboratoryresponse.

Where“Carace”isusedasasingleagentinhypertension,Afro-Caribbeanpatientsmayshowareduced

therapeuticresponse.

Assessmentofrenalfunction

Evaluationofthepatientshouldincludeassessmentofrenalfunctionpriortoinitiationoftherapy,andduring

treatment.

Impairedrenalfunction

“Carace”shouldbeusedwithcautioninpatientswithrenalinsufficiency,astheymayrequirereducedorless

frequentdoses(seesection4.2.,Posologyandmethodofadministration).Closemonitoringofrenalfunction

duringtherapyshouldbeperformedasdeemedappropriateinthosewithrenalinsufficiency.Inthemajority,

renalfunctionwillnotalter,ormayimprove.

RenalfailurehasbeenreportedinassociationwithACEinhibitorsandhasbeenmainlyinpatientswithsevere

congestiveheartfailureorunderlyingrenaldisease,includingrenalarterystenosis.Ifrecognisedpromptlyand

treatedappropriately,renalfailureisusuallyreversible.

Somehypertensivepatients,withnoapparentpre-existingrenaldisease,havedevelopedincreasesinbloodurea

andcreatininewhen“Carace”hasbeengivenconcurrentlywithadiuretic.Dosagereductionof“Carace”and/or

discontinuationofthediureticmayberequired.Thissituationshouldraisethepossibilityofunderlyingrenal

arterystenosis(see‘Renovascularhypertension’).

Symptomatichypotensionwasseenrarelyinuncomplicatedhypertensivepatients.Itismorelikelytooccurin

patientswhohavebeenvolume-depletedbydiuretictherapy,dietarysaltrestriction,dialysis,diarrhoea,or

vomiting.Inthesepatients,bydiscontinuingdiuretictherapyorsignificantlyreducingthediureticdosefortwo

tothreedayspriortoinitiating“Carace”,thepossibilityofthisoccurrenceisreduced.Byinitiatingtherapywith

asmalldose(5mg“Carace”)thedurationofanyhypotensiveeffectmaybelessened.

Similarcautionandclosesupervisionmayapplyalsotopatientswithischaemicheartorcerebrovasculardisease

inwhomseverehypotensioncouldresultinamyocardialinfarctorcerebrovascularaccident.(Seesection4.8,

UndesirableEffects).

Inhypertensivepatients,thepharmacologicalactionof“Carace”maypreventthenormalbodyresponseto

hypotensioninpatientspresentingwithsymptomsofhypovolaemicshock.Suchdepressionofbloodpressure

shouldbecorrectedbyvolumeexpansion.

SeverehypotensionhasbeenreportedwithACEinhibitors,mainlyinpatientswithsevereheartfailure.Many

ofthesepatientswereonahighdoseofloopdiuretics,andsomehadhyponatraemiaorfunctionalrenal

impairment.Ifhypotensiondevelops,thepatientshouldbeplacedinasupineposition.Volumerepletionwith

oralfluidsorintravenousnormalsalinemayberequired.Intravenousatropinemaybenecessaryifthereis

associatedbradycardia.Treatmentwith“Carace”mayberestartedwithcarefuldosetitrationfollowing

restorationofeffectivebloodvolumeandpressure.

Insomepatientswithcongestiveheartfailurewhohavenormalorlowbloodpressure,additionalloweringof

systemicbloodpressuremayoccurwith“Carace”.Suchpatientsshouldbekeptunderclosemedical

supervision.Ifsuchhypotensionbecomessymptomatic,areductionofdoseordiscontinuationof“Carace”

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Theappearanceofhypotensionaftertheinitialdoseof‘Carace’doesnotprecludesubsequentcarefuldose

titrationwiththedrugaftereffectivemanagementofhypotension.

HypotensioninAcuteMyocardialInfarction

Treatmentwithlisinoprilmustnotbeinitiatedinacutemyocardialinfarctionpatientswhoareatriskoffurther

serioushaemodynamicdeteriorationaftertreatmentwithavasodilator.Thesearepatientswithsystolicblood

pressureof100mmHgorlowerorcardiogenicshock.Duringthefirst3daysfollowingtheinfarction,thedose

shouldbereducedifthesystolicbloodpressureis120mmHgorlower.Maintenancedosesshouldbereduced

to5mgortemporarilyto2.5mgifsystolicbloodpressureis100mgHgorlower.Ifhypotensionpersists

(systolicbloodpressurelessthan90mmHgformorethan1hour)then“Carace”shouldbewithdrawn.

RenovascularHypertension

“Carace”canbeusedwhensurgeryisnotindicated,orpriortosurgery.Insomepatientswithbilateralrenal

arterystenosisorstenosisofthearterytoasolitarykidney,increasesofbloodureaandcreatinine,usually

reversibleupondiscontinuationoftherapy,havebeenseen.Thisisespeciallylikelyinpatientstreatedwith

diureticsand/orthosewithrenalinsufficiency.Itmaynotbepossibletoachieveamaximalresponseinblood

pressureandmaintainadequaterenalperfusion.

Inacutemyocardialinfarction,treatmentwithlisinoprilshouldnotbeinitiatedinpatientswithevidenceofrenal

dysfunctiondefinedasserumcreatinineconcentrationexceeding177micromol/1and/orproteinuriaexceeding

500mg/24h.

Ifrenaldysfunctiondevelopsduringtreatmentwith“Carace”(serumcreatinineconcentrationexceeding265

micromol/1oradoublingfromthepre-treatmentvalue)thenthephysicianshouldconsiderwithdrawalof

“Carace”.

Hypersensitivity/Angioneuroticoedema:(Seesection4.3,Contraindications)Angioneuroticoedemahasbeen

reportedwithangiotensin-convertingenzymeinhibitors,including“Carace”.Thismayoccuratanytime

duringtreatment.Insuchcases,“Carace”shouldbediscontinuedpromptlyandappropriatemonitoringshould

beinstitutedtoensurecompleteresolutionofsymptomspriortodismissingthepatient. Whereswellingis

confinedtotheface,lipsandmouth,theconditionwillusuallyresolvewithoutfurthertreatment,although

antihistaminesmaybeusefulinrelievingsymptoms.Thesepatientsshouldbefollowedcarefullyuntilthe

swellinghasresolved.However,wherethereisinvolvementofthetongue,glottisorlarynxlikelytocause

airwaysobstruction,appropriatetherapy(whichmayincludesubcutaneousepinephrine(adrenaline)(0.5ml

1:1,000)and/ormeasurestoensureapatentairway)shouldbeadministeredpromptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacompared

tonon-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskof

angioedemawhilereceivinganACEinhibitor.(Seesection4.3,Contraindications).

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Anaphylactoidreactionshymenopteradesensitisation:Rarely,patientsreceivingACEinhibitorsduring

desensitisationwithhymenopteravenom(e.g.BeeorWaspvenom)haveexperiencedlife-threatening

anaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithdrawingACEinhibitortherapyprior

toeachdesensitisation.

Haemodialysispatients:Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhigh-flux

membranes(e.g.AN69)andtreatedconcomitantlywithanACEinhibitor.Inthesepatientsconsideration

shouldbegiventousingadifferenttypeofdialysismembraneoradifferentclassofantihypertensiveagent.

AnaphylactoidreactionsduringLDLapheresis:Rarely,patientsreceivingACEinhibitorsduringlow-density

lipoprotein(LDL)apheresiswithdextransulphatehaveexperiencedlife-threateninganaphylactoidreactions.

ThesereactionswereavoidedbytemporarilywithholdingACEinhibitortherapypriortoeachapheresis.

Cough:CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-

productive,persistent,andresolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbe

consideredaspartofthedifferentialdiagnosisofcough.

Surgery/AnaesthesiaInpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproduce

hypotension“Carace”blocksangiotensin,IIformulationsecondarytocompensatoryreninrelease.Thismay

leadtohypotensionwhichcanbecorrectedbyvolumeexpansion.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Otherantihypertensiveagentse.g.-adrenoceptorblockers,calciumantagonists,methyldopaanddiureticsmay

supplementthehypotensiveeffectsoflisinopril.

Plasmapotassiumusuallyremainswithinnormallimits,althoughafewcasesofhyperkalaemiahaveoccurred.

If“Carace”isgivenwithadiuretic,thelikelihoodofdiuretic-inducedhypokalaemiamaybelessened.“Carace”

mayelevateplasmapotassiumlevelsinpatientswithrenalfailure.Potassiumsupplements,potassium-sparing

diureticsandpotassium-containingsaltssubstitutesarenotrecommended.

Indomethacinmayreducetheantihypertensiveefficacyoflisinopril.

Insomepatientswithcompromisedrenalfunctionwhoarebeingtreatedwithnon-steroidalanti-inflammatory

drugs,theco-administrationofACEinhibitorsmayresultinafurtherdeteriorationofrenalfunction.These

effectsareusuallyreversible.

“Carace”hasbeenusedwithnitrateswithoutsignificantclinicalinteraction.

Aslisinoprilmayreducetheeliminationoflithium,serumlevelsoflithiumshouldbemonitorediflithiumsalts

areadministered.

“Carace”reducesthedevelopmentofthiazide-inducedhypokalaemiaandhyperuricaemia.

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACE-inhibitorsandantidiabetic

medicines(insulins,oralhypoglycaemicagents)maycauseanincreasedblood-glucoseloweringeffectwithrisk

ofhypoglycaemia;however,long-termcontrolledclinicaltrialswithlisinoprilhavenotconfirmedthese

findings.

Alcoholmayenhancethehypotensiveeffectofanyantihypertensive.

Narcoticdrugs/antipsychotics:PosturalhypotensionmayoccurwithACE-inhibitors.

Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroids,orprocainamide:Concomitant

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Antacids:inducedecreasedbioavailabilityofACEinhibitors.

Sympathomimetics:mayreducetheantihypertensiveeffectsofACEinhibitors;patientsshouldbecarefully

monitoredtoconfirmthatthedesiredeffectisbeingobtained.

Ciclosporins:increasetheriskofhyperkalaemiawithACEinhibitors.

4.6Pregnancyandlactation

Pregnancy

“Carace”hasbeenshowntobefoetotoxicinrabbitsduringmiddleandlatepregnancy.

EffectsofexposureofthefoetustoACEinhibitorsduringthefirsttrimesterofhumanpregnancyareunknown.

Foetalexposureduringthesecondandthirdtrimestersofpregnancyhasbeenassociatedwithfoetaland

neonatalmorbidityandmortality.

ACEinhibitorsinhumanpregnancyhavebeenassociatedwitholigohydramnios.Hypotensionandrenalfailure

haveoccurredinthenew-born.

Becauseofthesefindings“Carace”iscontraindicatedinpregnancy.

Whenpregnancyisdetected,treatmentwith“Carace”shouldbediscontinuedassoonaspossible.

Lactation

Itisnotknownwhetherlisinoprilisexcretedinhumanmilk;however,otherACEinhibitorsdoappearinhuman

milk.“Carace”iscontraindicatedinwomenbreast-feedinginfants.

4.7Effectsonabilitytodriveandusemachines

Nodataareknownabouttheeffectontheabilitytodriveandtooperatemachinery.

4.8Undesirableeffects

Hypotensionhasoccurredinassociationwiththerapywith“Carace”.Thisappearstooccurincertainspecific

sub-groups(seesection4.4.,Specialwarningsandprecautionsforuse).

Hypersensitivity/angioneuroticoedema:

Angioneuroticoedemaofface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarely(see

section4.3.and4.4.).IntestinalangioedemahasalsobeenreportedveryrarelyinpatientstreatedwithACE

inhibitorsandshouldbeincludedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwith

abdominalpain.

Otheradversereactions

Dizziness,headache,diarrhoea,fatigue,cough,andnauseaarethemostfrequent.Otherlessfrequentside

effectsinclude:orthostaticeffects(includinghypotension),rashandasthenia.

Raresideeffectsinclude:

Cardiovascular:myocardialinfarctionorcerebrovascularaccidentpossiblysecondarytoexcessivehypotension

inhighriskpatients(seesection4.4.,Specialwarningsandprecautionsforuse),palpitation,tachycardia,angina

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Gastrointestinal:pancreatitis,abdominalpain,drymouth,hepatitis(hepatocellularorcholestatic),jaundice,

constipation,dyspepsia,vomiting.

Nervoussystem/psychiatric: moodalterations,mentalconfusion,paraesthesia,depression,insomnia,

somnolence,vertigo.

Respiratory:bronchospasm,bronchitis,dyspnoea,nasalcongestion,rhinitis,sinusitis.

Skin:urticaria,pruritus,diaphoresis,alopecia,erythemamultiforme,pemphigus,Stevens-Johnsonsyndrome,

toxicepidermalnecrolysis.

Urogenital:uraemia,oliguria/anuria,renaldysfunction,acuterenalfailure,impotence.

Other:syncope,blurredvision,tastedisturbances.

Therehavebeenreportsofhaemolyticanaemiainpatientstakinglisinopril,althoughnocausalrelationshiphas

beenestablished.

Asymptomcomplexhasbeenreportedwhichmayincludefever,vasculitis,myalgia,arthralgia/arthritis,a

positiveANA,elevatederythrocytesedimentationrate,eosinophiliaandleucocytosis.Rash,photosensitivity,

orotherdermatologicalmanifestationsmayoccur.

LaboratoryTestFindings

Increaseinbloodureaandcreatinine,reversibleondiscontinuationof“Carace”,aremostlikelyinthepresence

ofbilateralrenalarterystenosis,especiallyinpatientswithrenalinsufficiency(seesection4.4.,Special

warningsandprecautionsforuse).However,increaseinbloodureaandcreatininemayoccurwithoutevidence

ofpre-existingrenalimpairment,especiallyinpatientstakingdiuretics.Inthisevent,undiagnosedrenalartery

stenosisshouldbesuspected.Dosagereductionof“Carace”and/ordiscontinuationofthediureticshouldbe

considered.Rarecasesofneutropeniahavebeenreported,althoughnocausalrelationshiphasbeenshown.

Increaseinliverenzymeandserumbilirubinhaveoccurredwhichareusuallyreversibleondiscontinuationof

“Carace”.

Bonemarrowdepression,manifestasanaemiaand/orthrombocytopeniaand/orleucopenia,hasbeenreported.

Decreasesinhaemoglobinandhaematocrithavebeenreportedinafewpatients,butwererarelyofclinical

importanceunlessanothercauseofanaemiawaspresent.

Hyperkalaemiaandhyponatraemiahaveoccurredoccasionally(seealso‘Plasmapotassium’).

4.9Overdose

Themostlikelymanifestationofoverdosagewouldbehypotension,whichcanbetreated,ifnecessary,by

intravenousinfusionofnormalsalinesolution,ifavailable,angiotensinIImaybebeneficial.“Carace”canbe

removedbyhaemodialysis.(seesection4.4.,Specialwarningsandprecautionsforuse-Haemodialysis

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

“Carace”hasbeenshowntoinhibitangiotensin-convertingenzyme(ACE)inhumansubjectsandanimals.ACE

isapeptidyldipeptidasethatcatalysestheconversionofangiotensinItothevasoconstrictorsubstance,

angiotensinII.AngiotensinIIalsostimulatesaldosteronesecretionbytheadrenalcortex.InhibitionofACE

resultsindecreasedplasmaangiotensinIIwhichleadstodecreasedaldosteronesecretion.ACEisidenticalto

kininase,theenzymethatdegradesbradykinin.Whetherincreasedlevelsofbradykinin,apotentvasodepressor

peptide,playaroleinthetherapeuticeffectsof“Carace”remainstobeelucidated.Whilethemechanism

throughwhich“Carace”lowersbloodpressureisbelievedtobeprimarilysuppressionoftherenin-angiotensin-

aldosteronesystem,“Carace”hasbeenshowntobeantihypertensiveeveninpatientswithlow-renin

hypertension.

5.2Pharmacokineticproperties

Inmostpatientstheonsetofactionwasseen1-2hoursfollowingoraladministration,withthemaximumeffect

usuallyoccurringbysixhours.Decliningserumconcentrationsexhibitedaprolongedterminalphasewhich

didnotcontributetodrugaccumulation.“Carace”didnotappeartobeboundtoplasmaproteinsotherthan

ACE.Uponmultipledosing,“Carace”exhibitedaneffectivehalf-lifeofaccumulationof12hours.“Carace”

doesnotundergometabolismandisexcretedunchangedentirelyintheurine.Basedonurinaryrecoveryin

clinicalstudies,theextentofabsorptionof“Carace”wasapproximately25%.Absorptionof“Carace”wasnot

influencedbythepresenceoffoodinthegastrointestinaltract.

Singledailydosesof“Carace”5mgweregivenforsevenconsecutivedaystoyoungandelderlyhealthy

volunteersandtoelderlypatientswithcongestiveheartfailure.Maximumserumconcentrationsof“Carace”on

Day7werehigherintheelderlyvolunteersthanintheyoung,andstillhigherintheelderlypatientswith

congestiveheartfailure.

Thedispositionof“Carace”inpatientswithrenalinsufficiencywassimilartothatinpatientswithnormalrenal

functionuntiltheglomerularfiltrationratereached30ml/minorless,peakandtroughlevelsof“Carace”then

increased,andtimetopeakconcentrationwasincreasedandtosteadystatesometimesprolonged.

5.3Preclinicalsafetydata

Norelevantinformation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Calciumhydrogenphosphate

Magnesiumstearate

Pregelatinisedmaizestarch

Mannitol

Maizestarch

Redironoxide(E172)

Yellowironoxide(E172)

6.2Incompatibilities

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6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisterpacksof28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

Bristol-MyersSquibbPharmaceuticalsLimited

Swords

CountyDublin

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0002/072/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 10May1989

Dateoflastrenewal: 23February2008

10DATEOFREVISIONOFTHETEXT

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