BELLISIN

Main information

  • Trade name:
  • BELLISIN Tablets 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BELLISIN Tablets 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/057/003
  • Authorization date:
  • 11-07-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellisin10mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mglisinoprilaslisinoprildihydrate

Eachtabletcontains50.0mgofexcipientMannitol

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablets

Lightyellowcoloured,capsuleshaped,biconvexuncoatedtabletsdebossedwith‘1’and‘0’oneithersideofthe

scorelineandadeepscorelineontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofhypertension

Cardiacinsufficiency

Treatmentofsymptomaticcardiacinsufficiency

Acutemyocardialinfarct

Short-termtreatment(6weeks)ofhaemodynamicallystablepatientsinthe24hoursfollowingacutemyocardialinfarct.

Renalcomplicationsofdiabetesmellitus

TreatmentofrenaldiseaseinhypertensivepatientswithType2diabetesandincipientnephropathy(seesection5.1).

4.2Posologyandmethodofadministration

Bellisintabletsshouldbeadministeredorallyasasingledailydose.Aswithalldrugstakenonceaday,Bellisintablets

shouldalwaysbeadministeredatapproximatelythesametime.Theconsumptionoffooddoesnotaffectabsorptionof

Bellisintablets.

Dosageshouldbeadjustedonanindividualbasisaccordingtopatientprofileandarterialpressureresponse(seesection

4.4)

Hypertension

Bellisintabletsmaybeusedasmonotherapyorincombinationwithotherclassesofantihypertensivedrugs.

Startingdose

Inpatientswithhypertensiontheusualrecommendedstartingdoseis10mg.Patientswithahighlyactivatedrenin-

angiotensin-aldosteronesystem(specificallypatientswithrenovascularhypertension,saltand/orvolumedepletion,

cardiacdecompensationorseverehypertension)maysufferanexcessivefallinarterialpressureaftertheinitialdose.In

suchpatientsastartingdoseof2.5-5mgisrecommendedandtreatmentshouldbeintroducedundermedical

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Maintenancedose

Theusualeffectivemaintenancedoseis20mg,administeredasasingledailydose.Ingeneral,ifthedesired

therapeuticeffectcannotbeachievedwithinaperiodof2to4weekswithagivendosagelevel,thedosemaybe

increased.Themaximumdoseusedincontrolledlong-termclinicaltrialswas80mg/day.

Patientstreatedwithdiuretics

AfterstartingtreatmentwithBellisintablets,symptomatichypotensionmayoccur;thisismorelikelyinpatientswho

arereceivingsimultaneousdiuretictreatment.Cautionisthereforerecommended,assuchpatientsmayhavevolume

and/orsaltdepletion.Ifpossible,thediureticshouldbewithdrawn2to3daysbeforestartingtreatmentwithBellisin

tablets.Inhypertensivepatientswhocannotstoptakingthediuretictreatment,treatmentwithBellisintabletsshould

beginwithadoseof5mg;renalfunctionandbloodpotassiumconcentrationsshouldbemonitored.Subsequent

Bellisintabletsdosageshouldbeadjustedaccordingtoarterialpressureresponse.Ifnecessary,diuretictreatmentmay

beresumed(seesection4.4andsection4.5).

Dosageadjustmentinrenalimpairment

Dosageinpatientswithrenalimpairmentshouldbebasedoncreatinineclearance,asshowninTable1below.

Table1.Dosageadjustmentinrenalimpairment

UseinHypertensivePaediatricPatientsaged6-16years

Therecommendedinitialdoseis2.5mgoncedailyinpatients20to<50kg,and5mgoncedailyinpatients50kg.

Thedosageshouldbeindividuallyadjustedtoamaximumof20mgdailyinpatientsweighing20to<50kg,and40mg

inpatients50kg.Dosesabove0.61mg/kg(orinexcessof40mg)havenotbeenstudiedinpaediatricpatients(see

section5.1).

Inchildrenwithdecreasedrenalfunction,alowerstartingdoseorincreaseddosingintervalshouldbeconsidered.

HeartFailure

Inpatientswithsymptomaticheartfailure,Bellisintabletsshouldbeusedasadjuvanttreatmenttodiureticsand,where

appropriate,digitalicagentsorbetablockers.Treatmentmaybeginwithastartingdoseof2.5mgonceaday,which

shouldbeadministeredundermedicalsupervisioninordertodeterminetheinitialeffectonarterialpressure.Bellisin

tabletsdosageshouldbeincreased:

byincrementsofnotmorethan10mg;

atintervalsofnotlessthantwoweeks;

tothehighestdosetoleratedbythepatient,uptoamaximumof35mgonceaday.

Dosageadjustmentshouldbebasedontheclinicalresponseofindividualpatients.

Inpatientswithahighriskofsymptomatichypotension,e.g.patientswithsaltdepletionwithorwithout

hyponatraemia,hypovolaemiaorwhohavebeenreceivingintensivediuretictreatment,theseproblemsshouldif

possiblebecorrectedbeforestartingtreatmentwithBellisintablets.Renalfunctionandserumpotassiumconcentration

shouldbemonitored(seesection4.4).

Acutemyocardialinfarct

Patientsshouldreceive,asappropriate,thetreatmentsusuallyrecommended,suchasthrombolyticagents,aspirinand

Creatinineclearance(ml/min) Startingdose(mg/day)

Lessthan10ml/min(including

patientsondialysis) 2.5mg*

10-30ml/min 2.5-5mg

31-80ml/min 5-10mg/day

*Doseand/orfrequencyofadministrationshouldbeadjustedaccordingto

arterialpressureresponse.

Dosagemaybeincreaseduntilarterialpressureiscontrolledoruptoa

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Startingdose(firstthreedaysaftertheinfarct)

TreatmentwithBellisintabletsmaybegininthe24hoursfollowingtheonsetofsymptoms.Treatmentshouldnotbe

introducedifsystolicarterialpressureislessthan100mmHg.ThefirstdoseofBellisintabletsis5mgadministered

orally,followedby5mgafter24hours,10mgafter48hoursand,thereafter,10mgonceaday.Patientswithlow

systolicarterialpressure(120mmHgorless)whentreatmentbeginsorduringthefirstthreedaysaftertheinfarct

shouldreceivealowerdose:2.5mgorally(seesection4.4).

Intheeventofrenalinsufficiency(creatinineclearance<80ml/min)thestartingdoseofBellisintabletsshouldbe

adjustedaccordingtothepatient'screatinineclearance(seeTable1).

Maintenancedose

Themaintenancedoseis10mgonceaday.Ifhypotensionoccurs(systolicarterialpressurelessthanorequalto100

mmHg),adailymaintenancedoseof5mgmaybeadministered,withtemporarydecreasesto2.5mgifnecessary.If

prolongedhypotensionoccurs(systolicarterialpressurelessthan90mmHgformorethanonehour),Bellisintablets

shouldbewithdrawn.

Treatmentshouldcontinueforsixweeks,afterwhichthepatientshouldbereassessed.Patientswhodevelopsymptoms

ofcardiacinsufficiencyshouldcontinuewithBellisintablets(seesection4.2).

Renalcomplicationsofdiabetesmellitus

InhypertensivepatientswithType2diabetesmellitusandincipientnephropathy,thedoseis10mgofBellisintablets

onceaday.Thisdosemaybeincreasedto20mgonceadayifnecessaryinordertoachieveseateddiastolicpressureof

lessthan90mmHg.

Intheeventofrenalimpairment(creatinineclearance<80ml/min),thestartingdoseofBellisintabletsshouldbe

adjustedaccordingtothepatient'screatinineclearance(seeTable1).

Paediatricuse

Thereislimitedefficacyandsafetyexperienceinhypertensivechildren>6yearsold,butnoexperienceinother

indications(seesection5.1).Bellisinisnotrecommendedinchildreninotherindicationsthanhypertension.Bellisinis

notrecommendedinchildrenbelowtheageof6,orinchildrenwithsevererenalimpairment(GFR

<30ml/min/1.73m2)(seesection5.2).

Useintheelderly

Inclinicalstudiestherewerenoage-relatedchangesintheefficacyandsafetyprofileofthedrug.However,when

advancedageisassociatedwithadecreaseinrenalfunction,theguidelinesshowninTable1shouldbeusedto

determinethestartingdoseofBellisintablets.Thedoseshouldbeadjustedsubsequentlyaccordingtoarterialpressure

response.

Useinkidneytransplantpatients

ThereisnoexperienceofadministrationofBellisintabletsinrecentkidneytransplantpatients.TreatmentwithBellisin

tabletsisthereforenotrecommended.

4.3Contraindications

HypersensitivitytoBellisintablets,toanyoftheexcipientsortoanyotherangiotensin-convertingenzyme

(ACE)inhibitor.

HistoryofangioedemaassociatedwithpriortreatmentwithanACEinhibitor.

Hereditaryoridiopathicangioedema

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4.4Specialwarningsandprecautionsforuse

Symptomatichypotension

Symptomatichypotensionhasoccasionallybeenobservedinuncomplicatedhypertensivepatients.Inhypertensive

patientstreatedwithBellisintablets,hypotensionismorelikelyifthepatientissufferingfromvolumedepletiondue,

forexample,todiuretictherapy,alow-saltdiet,dialysis,diarrhoeaorvomiting,orhassevererenin-dependent

hypertension(seesection4.5andsection4.8).Inpatientswithheartfailure,withorwithoutassociatedrenal

insufficiency,symptomatichypotensionhasbeenobserved;thisismorelikelyinthosepatientswithmoresevere

gradesofheartfailure,reflectedintheuseofhighdosesofloopdiuretics,hyponatraemiaorimpairedrenalfunction.In

patientswithahighriskofsymptomatichypotension,theintroductionoftreatmentanddosageadjustmentshouldbe

monitoredunderclosemedicalsupervision.Similarconsiderationsareapplicabletopatientswithischaemic

cardiopathyorcerebrovasculardiseaseinwhomanexcessivedecreaseinarterialpressurecouldcausemyocardial

infarctorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinedecubituspositionand,ifnecessary,shouldreceivean

intravenousperfusionofphysiologicalserum.Atransienthypotensiveresponseisnotacontraindicationtosubsequent

doses,whichcanusuallybeadministeredwithoutdifficulty,asarterialpressureincreasesfollowingvolumeexpansion.

Insomepatientswithheartfailurewithnormalorlowarterialpressure,anadditionaldecreaseinsystemicarterial

pressuremayoccurwithBellisintablets.Thiseffectisexpectedandisnotusuallyareasontowithdrawtreatment.If

thehypotensionbecomessymptomaticitmaybenecessarytoreducethedoseorwithdrawBellisintablets.

Hypotensioninacutemyocardialinfarct

TreatmentwithBellisintabletsshouldnotbestartedinpatientswithacutemyocardialinfarctwhorunaseriousriskof

additionalhaemodynamicdeteriorationfollowingtreatmentwithavasodilator.Thesearepatientswithsystolicarterial

pressureof100mmHgorlessorincardiogenicshock.Duringthefirstthreedaysfollowingtheinfarctthedoseshould

bereducedifsystolicarterialpressureis120mmHgorless.Maintenancedosesshouldbereducedto5mgor

temporarilyto2.5mgifsystolicarterialpressureis100mmHgorless.Ifhypotensionpersists(systolicarterialpressure

lessthan90mmHgformorethanonehour)thentreatmentwithBellisintabletsshouldbewithdrawn.

Aorticandmitralvalvestenosis/hypertrophicmyocardiopathy

AswithotherACEinhibitors,Bellisintabletsshouldbeadministeredwithcautioninpatientswithmitralvalvestenosis

andleftventricleoutflowobstruction,asinaortalstenosisorhypertrophicmyocardiopathy.

Impairedrenalfunction

Intheeventofrenalimpairment(creatinineclearance<80ml/min),thestartingdoseofBellisintabletsshouldbe

adjustedaccordingtothepatient'screatinineclearance(seeTable1insection4.2.),andsubsequentlyaccordingto

responsetotreatment.Systematicmonitoringofbloodpotassiumandcreatinineconcentrationsformspartofnormal

medicalpracticeinsuchpatients.

Inpatientswithheartfailure,hypotensionfollowingtheintroductionoftreatmentwithACEinhibitorsmaycause

additionalimpairmentofrenalfunction.Acuterenalfailure,usuallyreversible,hasbeenreportedinthissituation.

Insomepatientswithbilateralrenalarterystenosisorstenosisofthearteryinasinglekidneywhohavebeentreated

withACEinhibitors,increasesinbloodureaandserumcreatinineconcentrations,usuallyreversibleonwithdrawalof

thetreatment,havebeenobserved.Thisisespeciallylikelyinpatientswithrenalinsufficiency.Ifrenovascular

hypertensionisalsopresentthereisagreaterriskofseverehypotensionandrenalinsufficiency.Insuchpatients

treatmentshouldbeintroducedunderstrictmedicalsupervisionwithlowdosesandcarefuldosageadjustment.As

treatmentwithdiureticsmaybeacontributingfactortowhatisdescribedabove,administrationofdiureticsshouldbe

haltedandrenalfunctionshouldbemonitoredduringthefirstfewweeksoftreatmentwithBellisintablets.

Somehypertensivepatients,withnoapparentpre-existingrenovasculardisease,havedevelopedincreasesinbloodurea

andserumcreatinineconcentrations,usuallyslightandtransient,especiallywhenBellisintabletswasadministered

concomitantlywithadiuretic.Thisismorelikelyinpatientswithpre-existingrenalimpairmentanditmaybe

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Inacutemyocardialinfarct,treatmentwithBellisintabletsshouldnotbestartedinpatientswithsignsofrenal

dysfunction,definedasserumcreatinineconcentrationgreaterthan177micromol/land/orproteinuriaabove500mg/24

hours.IfsuchrenaldysfunctiondevelopsduringtreatmentwithBellisintablets(serumcreatinineconcentrationgreater

than265micromol/lortwicethepre-treatmentvalue)thenthedoctorshouldconsiderwithdrawalofBellisintablets.

Hypersensitivity/Angioedema

Therehavebeenoccasionalreportsofangioedemaoftheface,extremities,lips,tongue,glottisand/orlarynxinpatients

treatedwithangiotensinconvertingenzymeinhibitors,includingBellisintablets.Thismayoccuratanytimeduring

treatment.Insuchcases,treatmentwithBellisintabletsshouldbewithdrawnimmediatelyandappropriatetreatment

andmonitoringestablishedtoensurecompleteresolutionofsymptomsbeforepatientsaredischarged.Evenincasesin

whichonlyswellingofthetongueisobserved,withoutrespiratorydifficulty,patientsmayneedprolongedobservation,

astreatmentwithanti-histaminicagentsandcorticoidsmaynotbesufficient.

Therehavebeenveryrarereportsofdeathsduetoangioedemaassociatedwithoedemaofthelarynxortongue.Patients

whosetongue,glottisorlarynxisaffectedareliabletosufferairwayobstruction,especiallythosewhohavepreviously

undergonesurgeryontheairway.Insuchcasesemergencytreatmentshouldbeadministeredimmediately.Such

treatmentmayconsistofadministrationofadrenalineand/ormaintenanceofapatentairway.Thepatientshouldremain

underclosemedicalsurveillanceuntilcompleteandmaintainedresolutionofsymptoms.

AngiotensinconvertingenzymeinhibitorscauseahigherrateofangioedemainAfro-Americanpatientsthaninother

patients.

PatientswithahistoryofangioedemanotrelatedtoACEinhibitortherapymayincreasetheriskofangioedemawhen

theyaretreatedwiththisgroupofdrugs(seesection4.3.).

Anaphylactoidreactionsinhaemodialysispatients

Therehavebeenreportsofanaphylactoidreactionsinpatientsundergoingdialysiswithhigh-fluxmembranes(e.g.AN

69)treatedsimultaneouslywithanACEinhibitor.Insuchpatientsuseofadifferenttypeofdialysismembraneora

differentclassofanti-hypertensiveagentshouldbeconsidered.

Anaphylactoidreactionsduringlow-densitylipoprotein(LDL)apheresis

Onrareoccasions,patientsreceivingACEinhibitorsduringapheresisoflow-densitylipoproteins(LDL)withdextran

sulphatehavesufferedlife-threateninganaphylactoidreactions.Suchreactionswereavoidedbytemporarily

withholdingtheACEinhibitorbeforeeachapheresis.

Densensitisation

PatientswhoreceiveACEinhibitorsduringdesensitisationtreatment(e.g.forbeeorwaspstings)havesuffered

sustainedanaphylactoidreactions;inthesamepatientsthesereactionswereavoidedwhentheACEinhibitorswere

temporarilywithheld,butreappearedwithinadvertentreadministrationofthepharmaceuticalspecialty.

Hepaticfailure

InveryrarecasesACEinhibitorshavebeenassociatedwithasyndromethatbeginswithcholestaticjaundiceor

hepatitisandprogressestofulminantnecrosisand(sometimes)death;however,themechanismofthissyndromeisnot

known.PatientswhoreceiveBellisintabletsandwhodevelopjaundiceorsignificanthepaticenzymeelevationshould

stoptakingthetreatmentandseekappropriatemedicalattention.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandwithnoothercomplications,neutropeniaoccursoccasionally.Neutropenia

andagranulocytosisarereversiblefollowingwithdrawaloftheACEinhibitor.Bellisintabletsshouldbeusedwithgreat

cautioninpatientswithcollagenvasculardisease,immunosuppressivetreatment,treatmentwithallopurinolor

procainamideoracombinationofthesefactors,especiallyifthereispriorimpairmentofrenalfunction.Somesuch

patientsmaydevelopsevereinfections,whichinrarecasesdonotrespondtointensiveantibiotictreatment.IfBellisin

tabletsareusedinsuchpatients,periodicalmonitoringofleucocytecountsisrecommendedandpatientsshouldbe

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Race

AngiotensinconvertingenzymeinhibitorscauseahigherrateofangiooedemainAfro-Americanpatientsthaninother

patients.

AswithotherACEinhibitors,BellisintabletsmaybelesseffectiveinreducingarterialpressureinAfro-American

patientsthaninotherpatients,possiblybecauseofahigherprevalenceoflowreninstatusinthehypertensiveAfro-

Americanpopulation.

Cough

CoughhasbeenreportedwithuseofACEinhibitors.Typicallythecoughisnotproductive,persistentandceaseswhen

treatmentiswithdrawn.CoughinducedbyACEinhibitorsshouldbeconsideredaspartofthedifferentialdiagnosisof

cough.

Surgery/Anesthesia

Inpatientswhoundergomajorsurgeryorduringanaesthesiawithagentsthatcausehypotension,Bellisintabletsmay

blocktheformationofangiotensinII,secondarytocompensatoryreninrelease.Ifhypotensionoccursanditisthought

tobeduetothismechanism,itmaybecorrectedbyvolumeexpansion.

Hyperkalaemia

ElevationofserumpotassiumconcentrationhasbeenobservedinsomepatientstreatedwithACEinhibitors,including

Bellisintablets.Patientsatriskofdevelopinghyperkalaemiaincludethosewithrenalinsufficiency,diabetesmellitusor

thosesimultaneouslyreceivingpotassium-sparingdiuretics,potassiumsupplementsorsaltsubstitutesthatcontain

potassium,orpatientswhoaretakingotherdrugsthatareassociatedwithanincreaseinserumpotassium(e.g.heparin).

Ifsimultaneoususeoftheagentsreferredtoaboveisconsideredappropriate,regularmonitoringofserumpotassium

concentrationisrecommended(seesection4.5).

Diabeticpatients

Indiabeticpatientstreatedwithoralanti-diabeticagentsorinsulin,glycaemiccontrolshouldbecloselymonitored

duringthefirstmonthoftreatmentwithanACEinhibitor(seesection4.5).

Lithium

IngeneralthecombinationoflithiumandBellisintabletsisnotrecommended(seesection4.5).

Pregnancyandlactation

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Useoflisinoprilisnotrecommendedduringbreast-feeding.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics

WhenadiureticisaddedtothetreatmentofapatientwhoisreceivingBellisintablets,theanti-hypertensiveeffectis

usuallyadditive.

Inpatientsreceivingtreatmentwithdiuretics,andespeciallythoseinwhomdiuretictreatmenthasbegunrecently,an

excessivedecreaseinarterialtensionmayoccurwhenBellisintabletsisadministeredconcomitantly.Thepossibilityof

symptomatichypotensionwithBellisintabletsmaybeminimisedbywithdrawingthediureticbeforeadministering

Bellisintablets(seesection4.4.).

Potassiumsupplements,potassium-sparingdiureticsorsaltsubstitutescontainingpotassium

Althoughinclinicalstudiesserumpotassiumgenerallyremainedwithinnormallimits,hyperkaliaemiaoccurredin

somepatients.Riskfactorsforthedevelopmentofhyperkaliaemiaare:renalinsufficiency,diabetesmellitusand

concomitantuseofpotassium-sparingdiuretics(e.g.spironolactone,triamtereneoramiloride),potassiumsupplements

orsaltsubstitutescontainingpotassium;useofanyofthese,particularlyinpatientswithimpairedrenalfunction,may

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IfBellisintabletsisadministeredwithapotassium-losingdiuretic,thehypokaliaemiacausedbythediureticmaybe

reduced.

Lithium

Therehavebeenreportsofreversibleincreasesinserumlithiumconcentrationsandtoxicityduringsimultaneous

administrationoflithiumandACEinhibitors.Simultaneoususeofthiazidediureticsmayincreasetheriskoflithium

toxicityandpotentiatethealreadyincreasedtoxicityoflithiumwithACEinhibitors.UseofBellisintabletswith

lithiumisnotrecommended,butifthiscombinationisconsiderednecessaryserumlithiumlevelsshouldbemonitored

carefully(seesection4.4.).

Non-steroidalanti-inflammatorydrugs(NSAIs),includingacetylsalicylicacid 3g/day

ChronicadministrationofNSAIsmayreducetheanti-hypertensiveeffectofanACEinhibitor.NSAIsandACE

inhibitorshaveanadditiveeffectontheincreaseinserumpotassiumandmaycauseadeteriorationinrenalfunction.

Sucheffectsareusuallyreversible.Acuterenalinsufficiencymayoccuronrareoccasions,especiallyinpatientswith

compromisedrenalfunction,suchaselderlyordehydratedpatients.

Gold

Nitritoidreactions(symptomsofvasodilatationincludingflushing,nausea,dizzinessandhypotension,whichcanbe

verysevere)followinginjectablegold(forexample,sodiumaurothiomalate)havebeenreportedmorefrequentlyin

patientsreceivingACEinhibitortherapy.

Otheranti-hypertensiveagents

SimultaneoususeofsuchagentsmayincreasethehypotensiveeffectsofBellisintablets.Concomitantusewith

nitroglycerinandothernitratesorothervasodilatoragentsmaylowerarterialpressureyetfurther.

Tricyclicantidepressants/Antipsychoticagents/Anaesthetics

Simultaneoususeofcertainanaestheticdrugs,tricyclicantidepressantsandantipsychoticagentswithACEinhibitors

maycauseanadditionaldecreaseinarterialpressure(seesection4.4.).

Sympathicomimeticagents

Sympathicomimeticagentsmayreducetheanti-hypertensiveeffectsofACEinhibitors.

Anti-diabeticagents

EpidemiologicalstudieshaveindicatedthatsimultaneoususeofACEinhibitorsandanti-diabeticdrugs(insulins,oral

anti-diabeticagents)maycauseanincreaseinhypoglycaemiceffectwithariskofhypoglycaemia.Itappearsthatthis

phenomenonismorelikelytooccurduringthefirstfewweeksofcombinedtreatmentandinpatientswithrenal

impairment.

Acetylsalicylicacid,thrombolyticagents,betablockers,nitrates

Bellisintabletsmaybeusedtogetherwithacetylsalicylicacid(atcardiologicaldoses),thrombolyticagents,beta

blockersand/ornitrates.

4.6Fertility,pregnancyandlactation

Pregnancy

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy

(seesection4.4).TheuseofACEinhibitorsiscontraindicatedduringthesecondand

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EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

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

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

Itisnotknownwhetherlisinoprilisexcretedintohumanbreastmilk.Lisinoprilisexcretedintothemilkoflactating

rats.Theuseoflisinoprilisnotrecommendedinwomenwhoarebreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Whendrivingoroperatingmachinery,itshouldbeborneinmindthatfeelingsofdizzinessortirednessmayoccur

occasionally.

4.8Undesirableeffects

ThefollowingadversereactionshavebeenobservedandreportedduringtreatmentwithBellisintabletsandotherACEinhibitors,

withthefrequenciesindicatedbelow:Veryfrequent(10%),frequent(1%,<10%),infrequent(0.1%,<1%),rare(0.01%,

<0.1%),veryrare(<0.01%)includingreportsofisolatedcases.

Bloodandlymphaticsystemdisorders:

Metabolismandnutritiondisorders:

Nervoussystemandpsychiatricdisorders:

frequencyunknown:depressivesymptoms,syncope.

Cardiacandvasculardisorders:

rare: decreasedhaemoglobin,decreasedhaematocrit

veryrare: bonemarrowdepression,anaemia,thrombocytopenia,leucopenia,

neutropenia, agranulocytosis (see section 4.4.), haemolytic

anaemia,lymphadenopathy,autoimmunedisease.

veryrare: Hypoglycaemia

common: dizziness,headache

uncommon: moodalterations,paraesthesia,vertigo,tastedisturbances,sleep

disorders.

rare: mentalconfusion

common: orthostaticeffects(includinghypotension).

uncommon: myocardial infarction or cerebrovascular accident, possibly

secondarytoexcessivehypotensioninhigh-riskpatients(see

section4.4.),palpitations,tachycardia,Raynaud'sphenomenon.

common: cough.

uncommon: rhinitis.

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Gastrointestinaldisorders:

Skinandsubcutaneoustissuesdisorders:

Asymptomaticcomplexhasbeenreportedthatmayincludeoneormoreofthefollowingsituations:fever,vasculitis,myalgia,

arthralgia/arthritis,positiveantinuclearantibodies(ANA),elevatederythrocytesedimentationrate(ESR),eosinophiliaand

leucocytosis,skinrash,photosensitivityorotherdermatologicalmanifestations.

Renalandurinarydisorders:

Reproductivesystemandbreastdisorders:

Endocrinedisorders:

rare: syndromeofinappropriateantidiuretichormonesecretion(SIADH)

Generaldisordersandadministrationsiteconditions:

Investigations:

Safetydatafromclinicalstudiessuggestthatlisinoprilisgenerallywelltoleratedinhypertensivepaediatricpatients,andthatthe

safetyprofileinthisagegroupiscomparabletothatseeninadults.

4.9Overdose

Therearelimiteddataavailableonoverdosageinhumans.ThesymptomsassociatedwithACEinhibitoroverdosage

maybehypotension,circulatoryshock,electrolyticchanges,renalfailure,hyperventilation,tachycardia,palpitations,

bradycardia,dizziness,anxietyandcough.

Therecommendedtreatmentforoverdoseisintravenousperfusionofphysiologicalserum.Ifhypotensionoccursthe

patientshouldbeplacedintheshockposition.Ifavailable,treatmentwithaperfusionofintravenousangiotensinII

and/orcatecholaminesmayalsobeconsidered.Ifadministrationisrecent,stepsshouldbetakentoeliminateBellisin

tablets(e.g.emesis,gastriclavage,administrationofabsorbentagentsandsodiumsulphate).Bellisintabletsmaybe

removedfromthegeneralcirculationbyhaemodialysis(seesection4.4.).Intheeventofbradycardiaresistantto

treatment,useofapacemakerisindicated.Vitalconstantsandserumelectrolyteandcreatinineconcentrationsshould

common: diarrhoea,vomiting.

uncommon: nausea,abdominalpainandindigestion

rare: drymouth

veryrare: pancreatitis,intestinalangiooedema,hepatitis(hepatocellularor

cholestatic),jaundiceandhepaticfailure(seesection4.4).

uncommon: rash,pruritus

rare: urticaria, alopecia, psoriasis; hypersensitivity/angioneurotic

oedema:angioneuroticoedemaoftheface,extremities,lips,

tongue,glottis,and/orlarynx(seesection4.4).

veryrare: sweating,pemphigus,toxicepidermalnecrolysis,Stevens-Johnson

syndrome,erythemamultiforme,cutaneouspseudolymphoma.

common: renaldysfunction.

rare: uraemia,acuterenalinsufficiency.

veryrare: oliguria/anuria

uncommon: impotence.

rare: Gynaecomastia.

uncommon: fatigue,asthenia.

uncommon: increasedbloodurea,increasedserumcreatinine,increasedhepatic

enzymes,hyperkaliaemia.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:Angiotensinconvertingenzymeinhibitors,ATCcode:C09AA03.

Bellisintabletsisaninhibitorofpeptidyldipeptidasewhichinhibitstheangiotensinconvertingenzyme(ACE)that

catalysestheconversionofangiotensinItothevasoconstrictorpeptideangiotensinII.AngiotensinIIalsostimulates

secretionofaldosteronebythesuprarenalcortex.InhibitionofACEresultsinlowerconcentrationsofangiotensinII,

whichleadstoareductioninvasopressoractivityanddecreasedaldosteronesecretion;thelattermaycauseanincrease

inserumpotassiumconcentration.

Althoughitisthoughtthatthemechanismbywhichlisinoprilreducesarterialpressureisdueprincipallytoinhibition

oftherenin-angiotensin-aldosteronesystem,lisinoprilhasbeenshowntohaveananti-hypertensiveeffectevenin

hypertensivepatientswithlowreninlevels.ACEisidenticaltokininaseII,anenzymethatdegradesbradykinin.Ithas

notyetbeendeterminedwhetherelevatedlevelsofbradykinin,apotentvasodilatorpeptide,playaroleinthe

therapeuticeffectsoflisinopril.

TheeffectofBellisintabletsonmortalityandmorbidityincardiacinsufficiencyhasbeenstudiedbycomparingahigh

dose(32.5mgor35mgonceaday)withalowdose(2.5mgor5mgonceaday).Inonestudyof3164patients,with

medianobservationofsurvivingpatientsof46months,thehighdoseofBellisintabletsresultedina12%decreasein

theriskofthecombinedevaluationparameterofmortalityandhospitalisationforanyreason(p=0.002)andan8%

decreaseintheriskofmortalityduetoallcausesandcardiovascularhospitalisation(p=0.036),comparedwiththelow

dose.Decreasesintheriskofmortalityduetoallcauses(8%,p=0.128)andcardiovascularmortality(10%;p=0.073)

wereobserved.Inaposthocanalysis,thenumberofhospitaladmissionsforcardiacinsufficiencywasreducedby24%

(p=0.002)inpatientstreatedwithBellisintabletsathighdoses,comparedwithlowdoses.Beneficialeffectswere

similarinpatientstreatedwithhighdosesandlowdosesofBellisintablets.

Thestudyresultsshowedthattheoveralladversereactionprofilesforpatientstreatedwithhighorlowdosesof

Bellisintabletsweresimilarbothinnatureandnumber.ForeseeablereactionsresultingfromACEinhibition,suchas

hypotensionorimpairedrenalfunction,weretreatableandrarelypromptedwithdrawalofthetreatment.Coughwas

lessfrequentinpatientstreatedwithhighdosesofBellisintabletsthanwithlowdoses.

IntheGISSI-3clinicaltrial,inwhicha2x2factorialdesignwasusedtocomparetheeffectsofBellisintabletsand

nitroglycerinseparatelyorincombinationforsixweeksversusacontrolin19,394patientstowhomthetreatmentwas

administeredwithin24hoursofanacutemyocardialinfarct,Bellisintabletsproducedastatisticallysignificant

decreaseof11%intheriskofmortalitycomparedwiththecontrol(2p=0.03).Thedecreaseinriskwithnitroglycerin

wasnotsignificant,butthecombinationofBellisintabletsandthatdrugproducedasignificantdecreaseintheriskof

mortalityof17%versusthecontrol(2p=0.02).Inthesubgroupsofelderlypatients(age>70years)andwomen,

predefinedaspatientswithahighriskofmortality,significantbeneficialeffectswereobservedinthecombined

evaluationparameterofmortalityandcardiacfunction.Thecombinedevaluationparameterinallpatients,aswellasin

thehigh-risksubgroups,aftersixmonthsalsoshowedabeneficialeffectinpatientstreatedwithBellisintabletsor

Bellisintabletsplusnitroglycerinforsixweeks,whichindicatesapreventiveeffectofBellisintablets.Asistobe

expectedwithanyvasodilatortreatment,therapywithBellisintabletswasassociatedwithanincreasedincidenceof

hypotensionandrenaldysfunction,butthelatterwerenotassociatedwithaproportionalincreaseinmortality.

Inonemulticentre,randomised,double-blindclinicaltrialwhichcomparedBellisintabletswithacalciumantagonistin

335hypertensivepatientswithType2diabetesmellituswithincipientnephropathycharacterisedbymicroalbuminuria,

administrationofBellisintablets10mgto20mgonceadayfor12monthsreducedsystolicanddiastolicarterial

pressureby13/10mmHgandurinaryexcretionofalbuminby40%.Incomparisonwiththecalciumantagonist,which

producedasimilardecreaseinarterialpressure,thepatientstreatedwithBellisintabletsdisplayedasignificantly

greaterdecreaseinurinaryalbuminexcretion,whichprovidesaproofthatBellisintabletsinhibitoryactiononACE

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Treatmentwithlisinoprildoesnotaffectglycaemiccontrol,asshownbytheabsenceofanysignificanteffectonlevels

ofglycosylatedhaemoglobin(HbA

Inaclinicalstudyinvolving115paediatricpatientswithhypertension,aged6-16years,patientswhoweighedlessthan50kg

receivedeither0.625mg,2.5mgor20mgoflisinoprilonceaday,andpatientswhoweighed50kgormorereceivedeither1.25

mg,5mgor40mgoflisinoprilonceaday.Attheendof2weeks,lisinopriladministeredoncedailyloweredtroughblood

pressureinadose-dependentmannerwithaconsistentantihypertensiveefficacydemonstratedatdosesgreaterthan1.25mg.

Thiseffectwasconfirmedinawithdrawalphase,wherethediastolicpressurerosebyabout9mmHgmoreinpatients

randomizedtoplacebothanitdidinpatientswhowererandomizedtoremainonthemiddleandhighdosesoflisinopril.Thedose-

dependentantihypertensiveeffectoflisinoprilwasconsistentacrossseveraldemographicsubgroups:age,Tannerstage,gender,

andrace.

5.2Pharmacokineticproperties

Lisinoprilisanorallyactivenonsulph-hydrylicACEinhibitor.

Absorption

Afteroraladministrationoflisinopril,peakserumconcentrationsareobtainedinaroundsevenhours,althoughtherewasa

tendencyforpeakserumconcentrationstobedelayedslightlyinpatientswithacutemyocardialinfarct.Accordingtourinary

recovery,meanabsorptionoflisinoprilis25%,withinterpatientvariabilityof6-60%inthedosagerangestudied(5-80mg).In

patientswithcardiacinsufficiency,absolutebioavailabilityisreducedbyapproximately16%.Absorptionoflisinoprilis

unaffectedbythepresenceoffood.

Distribution

Lisinoprildoesnotappeartobindtoserumproteinsotherthanangiotensinconvertingenzyme(ACE).Studiesinratsindicatethat

lisinoprilscarcelycrossestheblood-brainbarrier.

Elimination

Lisinoprildoesnotundergometabolismandisexcretedunchangedintheurine.Aftermultipleadministrationlisinoprildisplays

aneffectivehalf-lifeofaccumulationof12.6hours.Clearanceoflisinoprilinhealthypatientsisapproximately50ml/min.The

decreaseinserumconcentrationsdisplaysaprolongedterminalphasewhichdoesnotcontributetoaccumulationofthedrug.This

terminalphaseprobablyrepresentssaturablebindingtoACEandisnotproportionaltodose.

Hepaticimpairment

Hepaticimpairmentincirrhoticpatientscausedadecreaseinabsorptionoflisinopril(around30%,determinedbyurinary

recovery)andanincreaseinexposure(around50%)comparedwithhealthysubjectsbecauseofadecreaseinclearance.

Renalimpairment

Renalimpairmentdecreaseseliminationoflisinopril,whichisexcretedviathekidneys,althoughthisdecreasebeginstobe

clinicallysignificantonlywhentherateofglomerularfiltrationislowerthan30ml/min.Inslighttomoderaterenalimpairment

(creatinineclearance30-80ml/min.)meanAUCincreasedonlyby13%,whileinsevererenalimpairment(creatinineclearance5-

30ml/min.)thisvalueincreasedbyafactorof4.5.

Lisinoprilmaybeeliminatedbydialysis.Overfourhoursofhaemodialysis,plasmalisinoprilconcentrationsfellbyanaverageof

60%,withclearancebydialysisofbetween40and55ml/min.

Cardiacinsufficiency

Patientswithcardiacinsufficiencyhavegreaterexposuretolisinoprilthanhealthyindividuals(meanincreaseinAUC125%),

althoughbasedonurinaryrecoveryofthisdrug,thereisadecreaseinabsorptionofaround16%comparedwithsaidgroupof

healthyindividuals.

Elderlypatients

Elderlypatientshavehigherbloodconcentrationsandhighervaluesforareaunderthecurveofconcentrationagainsttime

(increaseofaround60%)incomparisonwithyoungindividuals.

Paediatrics

Thepharmacokineticprofileoflisinoprilwasstudiedin29paediatrichypertensivepatients,agedbetween6and16years,witha

GFRabove30ml/min/1.73m2.Afterdosesof0.1to0.2mg/kg,steadystatepeakplasmaconcentrationsoflisinopriloccurred

within6hours,andtheextentofabsorptionbasedonurinaryrecoverywasabout28%.Thesevaluesaresimilartothoseobtained

previouslyinadults.

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5.3Preclinicalsafetydata

Pre-clinicaldatadonotshowanyspecialriskstohumansaccordingtoconventionalstudiesofgeneralpharmacology,

repeat-dosetoxicity,genotoxicityandcarcinogenicpotential.Ithasbeenshownthatangiotensinconvertingenzyme

inhibitors,asaclass,haveadverseeffectsonlatefoetaldevelopmentthatcausefoetaldeathandcongenitaldefects,

especiallyinthecranium.Therehavealsobeenreportsoffoetotoxicity,retardedintrauterinegrowthandpatentductus

arteriosus.ItisthoughtthatthesedevelopmentalabnormalitiesaredueinparttothedirectactionofACEinhibitorson

thefoetalrenin-angiotensinsystemandinparttotheischaemiacausedbymaternalhypotensionandthedecreaseinthe

foetal-placentalbloodflowandinthesupplyofoxygen/nutrientstothefoetus.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol

Calciumhydrogenphosphateanhydrous

Maizestarch

Pregelatinisedstarch(maize)

Magnesiumstearate

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

BlisterstripcomprisingofcleartransparentPVCfilm(coateduniformlywithPVdContheinnerside)withabacking

ofaluminiumfoil(coatedwithheatseallacquer).Thetabletsareavailableinpacksizesof14,28,30,50,56,98and

100tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialinstructionsarenecessary.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLtd

Spafield

CorkRoad

Cashel

Co.Tipperary

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8MARKETINGAUTHORISATIONNUMBER

PA408/57/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11 th

July2003

Dateoflastrenewal:4 th

April2007

10DATEOFREVISIONOFTHETEXT

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