CARACE 10 PLUS

Main information

  • Trade name:
  • CARACE 10 PLUS
  • Dosage:
  • 10/12.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARACE 10 PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0002/073/001
  • Authorization date:
  • 03-01-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Carace10PlusTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mglisinoprilasdihydrateand12.5mghydrochlorothiazide.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Tablets.

Blue,hexagonal,biconvextabletwiththeproductcode‘145’ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Managementofhypertensionwhereafurtherreductioninbloodpressureisrequiredfollowingtheuseof20mg

lisinopril.Managementofhypertensioninpatientswhohavebeenstabilisedontheindividualcomponents.

4.2Posologyandmethodofadministration

Adults

Essentialhypertension

Theusualdosageisonetablet,takenoncedaily.Ifnecessary,thedosagemaybeincreasedbyasmallincrementof

eitherconstituent.

Dosagerenalinsufficiency

Thiazidesmaynotbeappropriatediureticsforuseinpatientswithrenalimpairmentandareineffectiveatcreatinine

clearancevaluesof30ml/minorbelow(i.e.moderateorsevererenalinsufficiency).

Carace10Plusisnottobeusedasinitialtherapyinanypatientwithrenalinsufficiency.Inpatientsforwhomtherapy

withCarace10Plusisintended,thestateofrenalfunctionwillhavebeenestablishedbeforeintroductionoflisinopril.

Shouldtherebepre-existingrenaldysfunction,patientsshouldbekeptunderregularsurveillanceforeffectsonblood

ureaandserumcreatinine.

Inpatientswithcreatinineclearanceof>30and<80ml/min,Carace10Plusmaybeused,butonlyaftertitrationofthe

individualcomponents.

PriorDiureticTherapy

SymptomatichypotensionmayoccurfollowingtheinitialdoseofCarace10Plus:thisismorelikelyinpatientswho

arevolumeand/orsaltdepletedasaresultofpriordiuretictherapy.Ifpossible,thediuretictherapyshouldbe

discontinuedfor2-3dayspriortoinitiationoftherapywithCarace10Plus.Ifthisisnotpossible,treatmentshouldbe

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Useintheelderly

Lisinoprilwasequallyeffectiveinelderly(65yearsorolder)andnon-elderlyhypertensivepatients.

Inelderlyhypertensivepatients,monotherapywithlisinoprilwasaseffectiveinreducingdiastolicbloodpressureas

monotherapywitheitherhydrochlorothiazideoratenolol.Inclinicalstudies,agedidnotaffectthetolerabilityof

lisinopril.

Inclinicalstudiestheefficacyandtolerabilityoflisinoprilandhydrochlorothiazide,administeredconcomitantly,were

similarinbothelderlyandyoungerhypertensivepatients.

PaediatricUse

Safetyandeffectivenessinchildrenhavenotbeenestablished.

4.3Contraindications

Useinpatientswithanuria,oraorticstenosisorhyperkalaemia.

Useinpatientswhoarehypersensitivetoanycomponentoftheproduct.

Useinpatientswithahistoryofangioneuroticoedemarelatingtoprevioustreatmentwithanangiotensin-converting

enzymeinhibitorandinpatientswithhereditaryoridiopathicangioedema.

Useinpatientswhoarehypersensitivetoothersulphonamide-deriveddrugs.

Useinacutehypertension.

Useincongestiveheartfailureduetoalackofclinicaldatawiththefixedcombination.Thisfacthasnobearingonthe

useinheartfailureoftheindividualcomponentswhichareeffectivetreatmenteitheraloneorincombinationwhen

titratedappropriately.

Useinpregnancyandinwomenbreastfeedinginfantsiscontraindicated(seeSection4.6PregnancyandLactation).

4.4Specialwarningsandprecautionsforuse

HypotensionandElectrolyte/FluidImbalance

Aswithallanti-hypertensivetherapy,symptomatichypotensionmayoccurinsomepatients.Thiswasrarelyseenin

uncomplicatedhypertensivepatientsbutismorelikelyinthepresenceoffluidorelectrolyteimbalance,e.g.volume

depletionhyponatraemia,hypochloraemicalkalosis,hypomagnesaemiaorhypokalaemiawhichmayoccurfromprior

diuretictherapy,dietarysaltrestriction,dialysis,orduringintercurrentdiarrhoeaorvomiting.Diuretictherapyshould

bediscontinuedfor2-3dayspriortoinitiationoftherapywithCarace10Plus.Periodicdeterminationofserum

electrolytesshouldbeperformedatappropriateintervalsinsuchpatients.

Particularconsiderationshouldbegivenwhentherapyisadministeredtopatientswithischaemicheartor

cerebrovasculardiseasebecauseanexcessivefallinbloodpressurecouldresultinamyocardialinfarctionor

cerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofnormalsaline.Atransienthypotensiveresponseisnotacontraindicationtofurtherdoses.

Followingrestorationofeffectivebloodvolumeandpressure,reinstitutionoftherapyatreduceddosagemaybe

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Aorticstenosis/HypertrophicCardiomyopathy

Aswithallvasodilators,ACEinhibitorsshouldbegivenwithcautiontopatientswithobstructionintheoutflowtract

oftheleftventricle.

RenalFunctionImpairment

Thiazidesmaynotbeappropriatediureticsforuseinpatientswithrenalimpairmentandareineffectiveatcreatinine

clearancevaluesof30ml/minorbelow(i.e.moderateorsevererenalinsufficiency).Carace10Plusshouldnotbe

administeredtopatientswithrenalinsufficiency(creatinineclearance<80ml/min)untiltitrationoftheindividual

componentshasshowntheneedforthedosespresentinthecombinationtablet.

Somehypertensivepatientswithnoapparentpre-existingrenaldiseasehavedevelopedusuallyminorandtransient

increasesinbloodureaandserumcreatininewhenlisinoprilhasbeengivenconcomitantlywithadiuretic.Ifthis

occursduringtherapywithCarace10Plus,thecombinationshouldbediscontinued.Reinstitutionoftherapyatreduced

dosagemaybepossible,oreitherofthecomponentsmaybeusedappropriatelyalone.

Insomepatients,withbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney,increasesinbloodurea

andserumcreatinine,usuallyreversibleupondiscontinuationoftherapy,havebeenseenwithangiotensinconverting

enzyme(ACE)inhibitors.

Patientswhoarebeingtreatedwiththispreparationrequireregularsupervisionwithmonitoringoffluidandelectrolyte

statetoavoidinadequatepotassiumsupplementationorexcessivelossoffluidandtodetectanydevelopmentofrenal

dysfunctionwhichmightrequirediscontinuationofCarace10Plus.

Thepreparationshouldbeusedwithparticularcareinelderlypatientsorinpatientswithdisordersrenderingtheir

electrolytebalanceprecarious.

HepaticDisease

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.

Surgery/Anaesthesia

Inpatientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension,lisinoprilmayblock

angiotensinIIformationsecondarytocompensatoryreninrelease.Ifhypotensionoccursandisconsideredtobedueto

thismechanism,itcanbecorrectedbyvolumeexpansion.

Metabolicandendocrineeffects

Thiazidetherapymayimpairglucosetolerance.Dosageadjustmentofanti-diabeticagents,includinginsulin,maybe

required.

Thiazidesmaydecreaseurinarycalciumexcretionandmaycauseintermittentandslightelevationofserumcalcium.

Markedhypercalcaemiamaybeevidenceofhiddenhyperparathyroidism.Thiazidesshouldbediscontinuedbefore

carryingouttestsforparathyroidfunction.

Increasesincholesterolandtriglyceridelevelsmaybeassociatedwiththiazidediuretictherapy.

Thiazidetherapymayprecipitatehyperuricaemiaand/orgoutincertainpatients.However,lisinoprilmayincrease

urinaryuricacidandthusmayattenuatethehyperuricaemiceffectofhydrochorothiazide.

Hypersensitivity/angioneuroticoedema

Angioneuroticoedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarelyinpatients

withangiotensin-convertingenzymeinhibitors,includinglisinopril.Thismayoccuratanytimeduringtreatment.In

suchcases,Carace10Plusshouldbediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensure

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Inthoseinstanceswhereswellinghasbeenconfinedtothefaceandlipstheconditiongenerallyresolvedwithout

treatment,althoughantihistamineshavebeenusefulinrelievingsymptoms.

Angioneuroticoedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,

glottisorlarynx,likelytocauseairwayobstruction,appropriatetherapy(whichmayincludesubcutaneousepinephrime

adrenalinesolution1:1,000(0.3mlto0.5ml)and/ormeasurestoensureapatentairway)shouldbeadministered

promptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACE-inhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor.(Seealso4.3'Contraindications').

Inpatientsreceivingthiazides,sensitivityreactionsmayoccurwithorwithoutahistoryofallergytobronchialasthma.

Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazides.

AnaphylactoidReactionsduringHymenopteraDesensitisation

Rarely,patientsreceivingACEinhibitorsduringdesensitisationwithhymenopteravenom(e.g.BeeorWaspvenom)

haveexperiencedlife-threateninganaphylactoidreactions.Thesereactionswereavoidedbytemporarilywithholding

ACEinhibitortherapypriortoeachdesensitisation.

HaemodialysisPatients

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhigh-fluxmembranes(e.g.AN69)andtreated

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofanti-hypertensiveagent.Carace10Plusisnotrecommendedinpatientson

haemodialysisforrenalfailure.

AnaphylactoidreactionsduringLDLapherisis

Rarely,patientsreceivingACEinhibitorsduringlow-densitylipoprotein(LDL)apherisiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE

inhibitortherapypriortoeachapherisis.

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistent

andresolvesafterdiscontinuationoftherapy.ACEinhibitorinducedcoughshouldbeconsideredaspartofthe

differentialdiagnosisofcough.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Serumpotassium

Thepotassium-losingeffectofthiazidediureticsisusuallyattenuatedbythepotassiumconservingeffectoflisinopril.

Theuseofpotassiumsupplements,potassium-sparingagentsorpotassium-containingsaltsubstitutes,particularlyin

patientswithimpairedrenalfunction,mayleadtoasignificantincreaseinserumpotassium.Ifconcomitantuseof

Carace10Plusandanyoftheseagentsisdeemedappropriate,theyshouldbeusedwithcautionandwithfrequent

monitoringofserumpotassium.

Anti-diabeticdrugs(oralagentsandinsulin)

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACE-inhibitorsandanti-diabeticmedicines

(insulin,oralhypoglycaemiaagents)maycauseanincreasedblood-glucoseloweringeffectwithriskof

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Lithium

DiureticagentsandACEinhibitorsreducetherenalclearanceoflithiumandaddahighriskoflithiumtoxicity:

concomitantuseisnotrecommended.Refertotheprescribinginformationforlithiumpreparationsbeforeuseofsuch

preparations.

Narcoticdrugs/anti-psychotics

PosturalhypotensionmayoccurwithACEinhibitors.

Alcohol

Alcoholmayenhancethehypotensiveeffectofanyhypotensive.

Otheragents

IndomethacinmaydiminishtheantihypertensiveeffectofconcomitantlyadministeredCarace10Plus.Insome

patientswithcompromisedrenalfunctionthatarebeingtreatedwithnon-steroidalanti-inflammatorydrugstheco-

administrationofACEinhibitorsmayresultinafurtherdeteriorationofrenalfunction.Theseeffectsareusually

reversible.

Otheranti-hypertensiveagents

Additiveeffectsmayoccur.Theconcomitantadministrationofthispreparationwithcardiacglycosidesofhypotensive

agentsmaynecessitateadjustmentofthedosageofthosedrugs.

Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroids,orprocainamide

ConcomitantadministrationwithACEinhibitorsmayleadtoanincreasedriskofleucopenia.

Antacids

InducedecreasedbioavailabilityofACEinhibitors.

Sympathomimetics

MayreducetheantihypertensiveeffectsofACEinhibitors:patientsshouldbecarefullymonitoredtoconfirmthatthe

desiredeffectisbeingobtained.

Ciclosporin

IncreasetheriskofhyperkalaemiawithACEinhibitors.

Non-depolarisingmusclerelaxants

Thiazidesmayincreasetheresponsivenesstotubocurarine.

Whenadministeredconcurrently,thefollowingdrugsmayinteractwiththiazidediuretics.

Alcohol,barbituratesornarcotics

Potentiationoforthostatichypotensionmayoccur.

Anti-diabeticdrugs(oralagentsandinsulin)

Dosageadjustmentoftheanti-diabeticdrugmayberequired.

Colestyramineandcolestipolresins

Absorptionofhydrochlorothiazideisimpairedinthepresenceofanionicexchangeresins.Singledosesofeither

cholestyramineorcolestipolresinsbindtothehydrochlorothiazideandreduceitsabsorptionfromthegastrointestinal

tractbyupto85and43percentrespectively.

Corticosteroids,ACTH

Intensifiedelectrolytedepletion,particularlyhypokalaemia.

Pressoramines(e.g.adrenaline)

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Non-steroidalanti-inflammatorydrugs

Insomepatients,theadministrationofanon-steroidalanti-inflammatoryagentcanreducethediuretic,natriureticand

antihypertensiveeffectsofdiuretics.

4.6Pregnancyandlactation

Useinpregnancy.ACEinhibitorshavebeenshowntobefetotoxicinrabbitsduringthemiddleandlatepregnancy.

EffectsofexposureofthefoetustoACEinhibitorsduringthefirsttrimesterofhumanpregnancyareunknown.Foetal

exposureduringthesecondandthirdtrimestersofpregnancyhasbeenassociatedwithfoetalandneonatalmorbidity

andmortality.ACEinhibitorsinhumandpregnancyhavebeenassociatedwitholigohydramnios.Hypotensionand

renalfailurehaveoccurredinthenewborn.

Theroutineuseofdiureticsinotherwisehealthypregnantwomenisnotrecommendedandexposesmotherandfoetus

tounnecessaryhazardincludingfoetalorneonataljaundice,thrombocytopeniaandpossiblyotheradversereactions

whichhaveoccurredintheadult.

Useinlactatingwomenwhoarebreast-feedinginfants.Itisnotknownwhetherlisinoprilisexcretedinhumanmilk.

Thiazidesdoappearinhumanmilk.Therefore,ifuseofCarace10Plusisdeemedessential,breastfeedingmuststop.

4.7Effectsonabilitytodriveandusemachines

UsuallyCarace10Plusdoesnotinterferewiththeabilitytodriveandtooperatemachinery.Patientsshouldbe

instructedtofirstdeterminehowtheyrespondtoCarace10Plusbeforeperforminghazardoustasks.

4.8Undesirableeffects

Side-effects

Carace10Plusisusuallywelltolerated.Inclinicalstudies,sideeffectshaveusuallybeenmildandtransient,andin

mostinstanceshavenotrequiredinterruptionoftherapy.Thesideeffectsthathavebeenobservedhavebeenlimitedto

thosereportedpreviouslywithlisinoprilorhydrochlorothiazide.

Themostcommonclinicalsideeffectwasdizziness,whichgenerallyrespondedtodosagereductionandseldom

requireddiscontinuationoftherapy.

Other,lessfrequent,sideeffectswereheadache,drycough,fatigue,andhypotensionincludingorthostatichypotension.

Stilllesscommonwerediarrhoea,nausea,vomiting,drymouth,rash,goutpalpitations,chestdiscomfort,muscle

crampsandweakness,parasthesiae,astheniaandimpotence.

Hypersensitivity/AndioneuroticOedema

Angioneuroticoedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarely(see4.4

‘SpecialWarningsandSpecialPrecautionsforUse’).Intestinalangioedemahasalsobeenreportedveryrarelyin

patientstreatedwithACEinhibitorsandshouldbeincludedinthedifferentialdiagnosisofpatientsonACEinhibitors

presentingwithabdominalpain.

Asymptomcomplexhasbeenreportedwhichmayincludesomeorallofthefollowing:fever,vasculitis,myalgia,

arthralgia/arthritis,apositiveANA,elevatedESR,eosinophiliaandleucocytosis.Rash,photosensitivityorother

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Laboratorytestfindings

Laboratorysideeffectshaverarelybeenofclinicalimportance.Occasionalhyperglycaemia,hyperuricaemiaand

hyperkalaemiaorhypokalaemiahavebeennoted.Usuallyminorandtransientincreasesinbloodureanitrogenand

serumcreatininehavebeenseeninpatientswithoutevidenceofpre-existingrenalimpairment.Ifsuchincreases

persist,theyareusuallyreversibleupondiscontinuationofCarace10Plus.Smalldecreasesinhaemoglobinand

haematocrithavebeenreportedfrequentlyinhypertensivepatientstreatedwithCarace10Plusbutwererarelyof

clinicalimportanceunlessanothercauseofanaemiaco-existed.Rarecasesofneutropeniahavebeenreported,

althoughnocausalrelationshiphasbeenestablished.Rarely,elevationofliverenzymesand/orserumbilirubinhave

occurred,butacasualrelationshiptoCarace10Plushasnotbeenestablished.

Othersideeffectsreportedwiththeindividualcomponentsalone,andwhichmaybepotentialsideeffectswithCarace

10Plus,are:

Lisinopril

Myocardialinfarctionorcerebrovascularaccidentpossiblysecondarytoexcessivehypotensioninhigh-riskpatients

(see‘precautions’),tachycardia,abdominalpain,moodalterations,mentalconfusion,broncho-spasm,urticaria,

pruritus,diaphoresis,alopecia,uraemia,oliguria/anuria,renaldysfunction,acuterenalfailure,hepatitis–either

hepatocellularorcholestaticjaundice,bonemarrowdepressionmanifestasanaemiaand/orthrombocytopeniaand/or

leucopenia,hyponatraemia.Rarecasesofneutropeniahavebeenreported,althoughnocausalrelationshiphasbeen

established.Therehavebeenreportsofhaemolyticanaemiainpatientstakinglisinopril,althoughnocausal

relationshiphasbeenestablished.

Hydrochlorothiazide

Anorexia,gastricirritation,constipation,jaundice(intrahepaticcholestaticjaundice),pancreatitis,sialo-adenitis,

vertigo,xanthopsia,leucopenia,agranulocytosis,thrombocytopenia,aplasticanaemia,haemolyticanaemia,purpura,

photosensitivity,urticaria,necrotisingangiitis(vasculitis,cutaneousvasculitis),fever,respiratorydistressincluding

pneumonitisandpulmonaryoedema,anaphylacticreactions,toxicepidermalnecrolysis,hyperglycaemia,glycosuria,

hyperuricaemia,electrolyteimbalanceincludinghyponatraemia,musclespasm,restlessness,transientblurredvision,

renalfailure,renaldysfunctionandinterstitalnephritis.

4.9Overdose

NospecificinformationisavailableonthetreatmentofoverdosagewithCarace10Plus.Treatmentissymptomatic

andsupportive.TherapywithCarace10Plusshouldbediscontinuedandthepatientobservedclosely.Suggested

measuresincludeinductionofemesisand/orgastriclavage,ifingestionisrecent,andcorrectionofdehydration,

electrolyteimbalanceandhypotensionbyestablishedprocedures.

Lisinopril

Themostlikelyfeaturesofoverdosagewouldbehypotension,forwhichtheusualtreatmentwouldbeintravenous

infusionofnormalsaline,ifavailableangiotensinIImaybebeneficial.

Lisinoprilmayberemovedfromthegeneralcirculationbyhaemodialysis.(See4.4Precautions,Haemodialysis

Patients).

Hydrochlorothiazode

Themostcommonsignsandsymptomsobservedarethosecausedbyelectrolytedepletion(hypokalaemia,

hypochloraemia,hyponatraemia)anddehydrationresultingfromexcessivediuresis.Ifdigitalishasalsobeen

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Carace10Plusisafixedcombinationofangiotensin-convertingenzymeinhibitor(lisinopril)andadiuretic

(hydrochlorothiazide).Carace10Plusishighlyeffectiveinthetreatmentofhypertension.Hydrochlorothiazide

stimulatestherenin-angiotensin-aldosteronesystemandproducedanadditiveanti-hypertensiveeffectwithlisinopril

whichissustainedforatleast24hours.

Hydrochlorothiazideisadiureticandanti-hypertensiveagentwhichincreasesplasmareninactivity.

5.2Pharmacokineticproperties

Inclinicalstudies,peakserumconcentrationsoflisinopriloccurredwithinabout6to8hoursfollowingoral

administration.Decliningserumconcentrationsexhibitedaprolongedterminalphasewhichdidnotcontributetodrug

accumulation.ThisterminalphaseprobablyrepresentssaturablebindingtoACEandwasnotproportionaltodose.

Lisinoprildidnotappeartobeboundtoplasmaproteins.

Lisinoprildoesnotundergosignificantmetabolismandisexcretedunchangedpredominantlyintheurine.Basedon

urinaryrecoveryinclinicalstudies,theextentofabsorptionoflisinoprilwasapproximately25%.Lisinoprilabsorption

wasnotinfluencedbythepresenceoffoodinthegastrointestinaltract.

Onmultipledosing,lisinoprilexhibitedaneffectiveaccumulationhalf-lifeof1hour.

Hydrochlorothiazideisnotmetabolisedandisexcretedthroughthekidney.PlasmaeliminationT½isbetween5.5-15

hours.

5.3Preclinicalsafetydata

Lisinoprilandhydrochlorothiazidearewellestablishedinmedicaluse.Preclinicaldataisbroadlyconsistentwith

clinicalexperience.Forreproductiontoxicity,seesection4.6‘PregnancyandLactation’.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol

CalciumHydrogenPhosphateDihydrate

IndigoCarmine(E132)

MaizeStarch

PregelatinisedStarch

MagnesiumStearate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

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6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Keeptheblisterintheoutercarton.

6.5Natureandcontentsofcontainer

PVC/ALblisterpackof28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

Bristol-MyersSquibbPharmaceuticalsLtd

Swords

CoDublin

8MARKETINGAUTHORISATIONNUMBER

PA0002/073/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3 rd

January1995

Dateoflastrenewal:3 rd

January2005

10DATEOFREVISIONOFTHETEXT

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