BYZESTRA

Main information

  • Trade name:
  • BYZESTRA Tablets 5 Milligram
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYZESTRA Tablets 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0966/007/002
  • Authorization date:
  • 22-04-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ByZestra5mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgoflisinopril(asdihydrate)

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablets.

White,ovaltablets,marked‘LSN5’ononefaceandwithascorelineontheother.

Thescorelineistofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Arterialhypertension

Itmaybeusedaloneorconcomitantlywithotherclassesofantihypertensiveagents,e.g.thiazidediuretics.

Treatmentofheartfailureasadditivetherapytonon-potassium-sparingdiureticsandwhereappropriate,

digitalis.

Treatmentofacutemyocardialinfarction,inhaemodynamicallystablepatients(systolicbloodpressure>100

mmHg)withoutsignificantrenaldysfunction(serumcreatinine<177micromol/l[2.0mg/dl]andproteinuria

<500mg/24hours.)LisinoprilshouldbegiveninadditiontousualstandardtherapyinMI(thrombolytics,

acetylsalicylicacidandßblockingagents),especiallytogetherwithnitrates.

RenalComplicationsofDiabetesMellitus

Treatmentofrenaldiseaseinhypertensivepatientswithtype2daibetesmellitusandincipientnephropathy.

4.2Posologyandmethodofadministration

Precautionarynote:

Excessivefirstdosehypotensionmayoccurinhighriskpatients(inpatientswithsaltand/orfluiddeficiency,e.g.after

dialysis,vomiting,inconcomitantdiuretictherapy,inpatientswithheartfailure,severeorrenalhypertension).

Initiationoftherapyrequires,ifpossible,correctioninsaltand/orbodyfluidsdeficiencies,discontinuationor

reductionofanexistingdiuretictherapyfortwotothreedaysbeforestartingACEinhibitionandstartingtherapywith

thelowestsingledoseof2.5mglisinoprilinthemorning.

Patientsathighriskforsevereacutehypotensionshouldbemonitoredmedicallypreferablyinhospital,foraslongas

itsmaximaleffectisexpected(generallyforatleast8hours)afteradministrationofthefirstdoseandwheneverthe

doseofACEinhibitorsand/ordiureticisincreased.Thisalsoappliestopatientswithanginapectorisor

cerebrovasculardiseaseinwhomexcessivehypotensioncouldresultinamyocardialinfarctionorcerebrovascular

accident.

Inpatientswithmalignanthypertensionorseverecardiacinsufficiencyinitiationoftherapyanddoseadjustment

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Unlessprescribedotherwise,thefollowingdosageregimenisrecommended:

Arterialhypertension

Treatmentshouldbeinitiatedwith5-10mginthemorning.

Thedoseshouldbetitratedtogivetheoptimumcontrolofbloodpressure.Thetimeintervalbetweendoseincreases

shouldnotbelessthan3weeks.

Theusualmaintenancedoseis20mglisinopriloncedaily,butdosesupto80mgoncedailymaybeused.

Alowerinitialdose(2.5mglisinoprilinthemorning)willbenecessaryatrenalimpairment,atheartfailure,inpatients

whodonottoleratediscontinuationifdiuretictreatment,inpatientswhoarevolumeand/orsaltdepleted(e.g.after

vomiting,diarrhoeaordiuretictherapy),inpatientswithsevereorrenovascularhypertensionandinelderlypatients.

Heartfailure

Lisinoprilcanbegiveninadditiontoexistingtherapywithdiureticsanddigitalis.

Theinitialdoseis2.5mglisinoprilinthemorning.Themaintenancedoseshouldbetitratedinincrementsof2.5mg

lisinoprilatintervalsoftwotofourweeks.

Doseincreasesmustbegradualandreflectindividualpatientresponsetotherapy.

Theusualmaintenancedoseis5-20mgoncedaily.Themaximumdoseof35mglisinoprilperdayshouldnotbe

exceeded.

Acutemyocardialinfarctioninhaemodynamicallystablepatients

LisinoprilshouldbegivenasasupplementtotheusualstandardtherapyinMI.Treatmentwithlisinoprilmaybe

initiatedwithin24hoursofsymptomonsetprovidedthatthepatientsarehaemodynamicallystable.Theinitialdoseis

5mglisinoprilandthen5mgafter24hours,10mgafter48hoursandthereafter10mgoncedaily.Patientswithalow

systolicbloodpressure(120mmHgorless)atthestartoftreatmentorduringthefirst3daysfollowingtheinfarction

shouldbegivenalowerdose-2.5mgorally(seesection4.4,Specialwarningsandprecautionsforuse).

Incaseofhypotensionoccurs(systolicbloodpressurelowerthan100mmHg),adailymaintenancedoseof5mg

shouldnotbeexceeded,withreductionto2.5mgifnecessary.Ifhypotensionpersists(systolicbloodpressureless

than90mmHgformorethan1hour)despiteofadosereductionto2.5mglisinoprilperday,lisinoprilshouldbe

discontinued.

Thetreatmentshouldbecontinuedfor6weeks.Theminimalmaintenancedoseis5mglisinoprilperday.Patientswith

symptomsofcardiacinsufficiencyshouldcontinuetreatmentwithlisinopril(seesection4.2)

Lisinopriliscompatiblewithintravenousortransdermaladministrationofglyceryltrinitrate.

Dosageinmoderaterenalimpairment

Ifthecreatinineclearanceis30-70ml/minrespectively,andinelderlypatients(over65years):

Theinitialdoseis2.5mglisinoprilinthemorning,themaintenancedoseisusually5-10mglisinoprilperday

accordingtobloodpressurecontrol.Themaximumdoseof20mglisinoprilperdayshouldnotbeexceeded.

Itisrecommendeddiscontinuingadministrationofdiuretics2or3daysbeforeinitiationoftherapywithlisinopril.The

possibilityofhypotensiveeffectswithlisinoprilcanbeminimisedbyeitherdiscontinuingthediureticorincreasingthe

saltintakepriortoinitiationoftreatmentwithlisinopril.

Children

Efficacyandsafetyofuseinchildrenhasnotbeenestablished.Thereforeuseinchildrenisnotrecommended.

Renalcomplicationsofdiabetesmellitus

Inhypertensivepatientswithtype2diabetesmellitus,thedoseis10mglisinopriloncedailywhichshouldbeincreased

to20mgoncedaily,ifnecessary,toachieveasittingbloodpressurebelow90mmHg.

Lisinoprilcanbetakenindependentlyfrommeals,butshouldbetakenwithasufficientamountofliquid.

Lisinoprilshouldbeadministeredoncedaily.

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yourthumbandthesnaptabwillbreakintotwoequalpieces.

4.3Contraindications

HypersensitivitytotheactivesubstanceortoanyoftheexcipientsorotherACEinhibitors.

HistoryofangioneuroticoedemarelatedtopreviousACE-inhibitortreatmentandhereditary/idiopathic

angioneuroticoedema(seesection4.4)

Severerenalimpairment(creatinineclearance<30ml/min)

Haemodynamicallyrelevantaorticormitralvalvestenosisothypertrophiccardiomyopathy

Inhaemodynamicallyunstablepatientsafteracutemyocardialinfarction

Systolicbloodpressure ≤100mmHgbeforeinitiationofthetreatmentwithlisinopril

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Concurrentuseoflisinoprilandpoly(acrylonitrile,sodium-2-methylallyl-sulphonate)highfluxmembranes

foremergencydialysisbearstheriskofanaphylacticreactions(hypersensitivityreactionstothepointif

shock).Thiscombinationmustthereforebeavoidedeitherbyusingotherdrugs(butnotACEinhibitor)for

thetreatmentofhypertensionand/orheartfailure,orbyusingothermembranefordialysis(seesection4.4).

Cardiogenicshock

4.4Specialwarningsandprecautionsforuse

Patientsonmultipleorhighdosediuretics(>80mgoffrusemide)withhypovolaemia,hypontraemia(serumsodium

<130mmol/l)pre-existinghypotension,unstablecardiacfailure,renalimpairment,high-dosevasodilatortherapyand

patientsage70yearsoroverarerecommendedtohavelisinopriltherapyinitiatedinhospital.

Pregnancy

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Hypotension

Lisinoprilmaycauseaprofoundfallinbloodpressureespeciallyafterthefirstdose.

Symptomatichypotensionisrareinuncomplicatedhypertensivepatients.Itismorelikelytooccurinpatientswho

havebeenelectrolyte-orvole-depletedbydiuretic,dietarysaltrestriction,dialysis,diarrhoeaorvomiting.Ithasbeen

reportedmainlyinpatientswithsevereheartfailurewithorwithoutassociatedrenalinsufficiency.Thisismorelikely

inpatientsonhighdosesofloopdiuretics,orthosewithhyponatreamiaorfunctionalrenalimpairment.Inthese

patientstreatmentshouldbestartedunderclosemedicinalsupervisionpreferablyinhospital,withlowdosesand

carefuldosetitrationwithsimultaneouscontrolofrenalfunctionaswellasserumpotassiumlevels.Ifpossible,

diuretictreatmentshouldbediscontinuedtemporarily.Suchconsiderationsapplyalsotopatientswithanginapectoris

orcerebrovasculardiseaseinwhomexcessivehypotensioncouldresultinamyocardialinfarctionorcerebrovascular

accident.

Ifhypotensiondevelopsthepatientshouldbeplacedinsupinepositionandvolumerepletionwithoralorintravenous

fluidsmayberequired.Atropinemaybenecessaryfortreatmentofassociatedbradycardia.

Theappearanceofhypotensionafterinitialdosedoesnotprecludesubsequentcarefuldosetitrationwithmedicinal

productaftereffectivetreatment.Ifnon-acutehypotensioninpatientswithheartfailurebecomessymptomatic,a

reductionofdoseand/ordiscontinuationofthediureticand/orlisinoprilmaybecomenecessary.

Ifpossible,diuretictherapyshouldbediscontinuedfor2-3dayspriortoinitiationoflisinopril.

Hypotensioninacutemyocardialinfarction

Treatmentwithlisinoprilmustnotbeinitiatedinacutemyocardialinfarctionpatientsifthereisariskofadditional

serioushaemodynamicexacerbationfollowingtreatmentwithavasodilator.Thesearepatientswithasystolicblood

pressureof100mmHgorlowerorwithcardiogenicshock.Themaintenancedoseshouldbereducedto5mgor

temporarilyto2.5mg,incasethesystolicbloodpressureis100mmHgorlower.

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hypotension(systolicbloodpressure<90mmHgformorethan1hour),lisinoprilshouldbediscontinued.

Inpatientswithsevereheartfailurefollowinganacutemyocardialinfarctionlisinoprilshouldonlybeadministeredif

thepatientishaemodynamicallystable.

Renovascularhypertension/Renalarterystenosis

Thereisanincreasedriskforseverehypotensionandrenalinsufficiencywhenpatientswithrenovascularhypertension

andpre-existingbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidneyaretreatedwithlisinopril.

Treatmentwithdiureticsmaybeacontributoryfactor.Lossofrenalfunctionmayoccurwithonlymildchangesin

serumcreatinineeveninpatientswithunilateralrenalarterystenosis.Inthesepatientstreatmentshouldbestartedin

hospitalunderclosemedicalsupervisionwithlowdosesandcarefuldosetitration.Diuretictreatmentshouldbe

discontinuedandrenalfunctionmonitoredduringthefirstweeksoftherapy.

Impairedrenalfunction

Inpatientswithsevererenalfailure(creatinineclearance<30ml/min)theuseoflisinopriliscontra-indicated(see

section4.3).

Lisinoprilshouldbeusedwithcautioninpatientswithrenalinsufficiencywhomayrequirereducedorlessfrequent

doses(seesection4.2).

Changesinrenalfunctionmaybeanticipatedinsusceptibleindividualsduetotheinhibitionoftherenin-angiotensin-

aldosteronesystem.Closemonitoringoftherenalfunctionduringtherapyshouldbeperformedasdeemedappropriate

inthosewithrenalinsufficiency.Renalfailurehasbeenreportedinassociationwithlisinoprilmainlyinpatientswith

severeheartfailureorunderlyingrenaldiseaseincludingrenalarterystenosis.Ifrecognisedpromptlyandtreated

appropriately,renalfailurewhenassociatedwithlisinopriltreatmentisusuallyreversible.

Spmehypertensivepatientswithnoapparentpre-existingrenaldiseasehavedevelopedincreasesinbloodureaand

creatininewhenlisinoprilhasbeengivenconcurrentlywithadiuretic.Thissituationshouldleadtoreductionof

dose/discontinuationoflisinopril/diureticsandraisethepossibilityofunderlyingrenalarterystenosis.

Inacutemyocardialinfarctiontreatmentwithlisinoprilshouldnotbeinitiatedinpatientswithsignsofrenal

impairment,definedasaserumcreatinineconcentration ≥177micromol/l(2.0mg/dl)and/orproteinuriaabove500

mg/day.Ifrenalimpairmentdevelopsduringtreatmentwithlisinopril(serumcreatinineclearance<30ml/min,ora

doublingofpre-treatmentcreatininevalue),lisinoprilmustbediscontinued.

Thereislimitedexperienceoflisinoprilinrenaltransplantrecipients.Treatmentwithlisinoprilisthereforegenerally

notrecommendedforthecategoryofpatients.

Haemodialysis

Inpatientsinpermanenthaemodialysistheuseoflisinopriliscontra-indicated(seesection4.3).

Concomitantapplicationoflisinoprilandpoly(acrylonitrile,sodium-2-methylallyl-sulphonate)high-fluxmembranes

duringdialysisorhaemofiltrationcarriesariskofanaphylacticreactions(hypersensitivityreactionsuptoanaphylactic

shock).Firstindicationsofthisanaphylaxisareswellingoftheface,redness,hypotensionanddyspneawithinfew

minutesofcommencinghaemodialysis.Itisrecommendedtouseanalternativemembraneindialysisoranalternative

antihypertensivedruginthetreatmentofhypertensiononheartfailure(seesection4.3).

Hyperkalemia

Hyperkalemiamayoccurduringtreatmentwithlisinopril,especiallyinthepresenceofrenalinsufficiencyand/orheart

failure.Potassiumsupplementsorpotassiumsparingdiureticsaregenerallynotrecommended,sincetheymayleadto

significantincreasesinserumpotassium.Ifconcomitantuseoftheabovementionedagentsisdeemedappropriate,

theyshouldbeusedwithfrequentmonitoringofserumpotassium.

Primaryhyperaldesteronism

Patientswithprimaryhyperaldesteronismgenerallydonotrespondtoantihypertensiveswithamodeofactionbased

oninhibitionoftherenin-angiotensin-system.Theuseoflisinoprilis,therefore,notrecommended.

Proteinuria

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occur.Inpatientswithclinicallyrelevantproteinuria(morethan1g/day)lisinoprilshouldbegivenafterverycritical

assessmentoftheriskversusbenefitandwithregularmonitoringofclinicalandlaboratoryparameters.

Elderly

SomeelderlypatientsmaybemoreresponsivetoanACEinhibitorthanyoungerpatients.Inpatientsolderthan65

yearsadministrationoflowinitialdoses(2.5mglisinopril)andmonitoringofbloodpressure,evaluationofrenal

functionand/orrepresentativelaboratoryparametersintheinitialphaseoftherapyisrecommended.

LDL-lipidapheresis/Desensitisationtherapy

DuringLDL(low-densitylipoprotein)apheresiswithdextransulphate,life-threateninganaphylacticreactionsmay

occurwhenACE-inhibitorisadministered.

Life-threateninganaphylacticreactions(e.g.bloodpressuredecrease,breathlessness,vomiting,allergicskinreactions)

mayalsooccurduringdesensitisationtherapyforinsectvenom(e.g.bee,waspstings)andconcurrentuseoflisinopril.

IfLDLapheresisordesensitisationtherapyforinsectvenomisnecessary,lisinoprilshouldbetemporarilyreplacedby

differentdrugs(otherACEinhibitorsexcluded)forhypertensionorheartfailure.

Angioneuroticoedema(seesection4.3)

Angioneuroticoedemaoftheface,extremities,lipsmucousmembranes,tongue,glottisand/orlarynxrarelyhavebeen

reportedinpatientstreatedwithACE-inhibitorsincludinglisinoprilwhichespeciallyoccursduringthefirstweeksof

treatment.However,inrarecasesangioedemamaydevelopafterlong-termtreatmentwithanACE-inhibitor.Insuch

cases,lisinopriltherapyshouldbediscontinuedpromptlyandanappropriatemonitoringofthepatienthastobe

instituted.

Incaseswhereswellinghasbeenconfinedtothefaceandlips,theconditiongenerallyresolveswithouttreatment

althoughantihistamineshavebeenusefulinrelievingsymptoms.Patientswithaknownhistoryofangioedema

unrelatedtoACE-inhibitortherapymayhaveanincreasedriskfordevelopingangioedemaaftertakinganACE-

inhibitor.Angioedemainvolvingthetongue,glottisand/orlarynxcanbefatal.Emergencytherapyshouldbeinitiated,

including,butnotnecessarilylimitedtoimmediatesubcutaneousinjectionof0.3-0.5mgepinephrineorslow

intravenousadministrationof0.1mgepinephrine(dilutioninstructionstobeobserved)withECGandbloodpressure

monitoring.Patientshavetobehospitalised.Suitablemonitoringshouldbeinitiatedoveraminimumof12to24hours

inordertoensurecompleteresolutionofthesymptomsbeforethepatientisdischargedfromhospital.

ACE-inhibitorscauseahigherrateofangioedemainblackpatientsthaninnon-blackpatients.

Aorticstenosis/Hypertrophiccardiomyopathy

ACE-inhibitorsshouldbeusedwithcautioninpatientswithleftventricularoutflowtractobstructions.Ifthe

obstructionishaemodynamicallyrelevant,lisinopriliscontra-indicated.

Neutropenia/Agranulocytosis

Theriskofneutropeniaappearstobedose-and-typerelatedandisdependentonpatient’sclinicalstatus.

NeutropeniaandagranulocytosisrarelyhavebeenobservedinhypertensivepatientstreatedwithACE-inhibitors.Itis

rarelyseeninpatientswithuncomplicatedhypertensionbutwheremorecommoninpatientswithrenalimpairment

especiallyifassociatedwithcollagenvasculardisease(e.g.systemiclupuserythematosusorscleroderma)or

concurrenttreatmentwithimmunosuppressiveagents.Regularwhitecellcountsshouldbeobtainedinthosepatients.

NeutropeniaandagranulocytosisarereversibleafterwithdrawaloftheACE-inhibitor.

Cough

CoughhasbeenreportedwiththeuseofACE-inhibitors.Itischaracteristicallynon-productive,persistentandresolves

afterdiscontinuationoftherapy.

Surgery/Anaesthesia

LisinoprilblocksangiotensinIIformationsecondarytocompensatoryreninreleaseinpatientsundergoingmajor

surgeryoranaesthesiawithagentsthatproducehypotension.Resultanthypotensioncanbecorrectedbyvolume

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Diuretics

Whenadiureticisadministeredconcomitantlywithlisinopriltreatment,theantihypertensiveeffectisgenerally

additive.

Patientsalreadyintreatmentwithdiureticsandespeciallythosepatients,whomthediuretichasbeeninstituted

recently,mayoccasionallyexperienceafallinbloodpressurewhenlisinoprilisaddedtothetherapy.Theriskof

symptomatichypotensionduringtreatmentwithlisinoprilcanbereducedbydiscontinuingthediureticpriortostarting

ByZestra.(seesection4.4andsection4.2).

Potassium-sparingdiureticsorpotassiumsupplements

Additivepotassium-enhancingtheeffectscanoccurwithpotassium-sparingdiuretics,particularlyinpatientswith

renalimpairment.

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiureticse.g.spironolactone,triamterene,

oramiloride,potassiumsupplementsorpotassiumcontainingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium.Ifconcomitantuseisindicatedbecauseofdocumentedhypokalemiatheyshouldbeusedwith

cautionandwithfrequentmonitoringofserumpotassium.

Sodiumchloride

Reducesthebloodpressureloweringandheartfailuresymptomimprovingeffectoflisinopril.

Antihypertensiveagents

Increasethebloodpressureloweringandheartfailuresymptomimprovingeffectoflisinopril.

Analgesicandanti-inflammatoryagents

(e.gacetylsalicylicacid,indomethacin):mayreducethebloodpressureloweringeffectoflisinopril.

Lithium

Aswiththerapyinvolvingotherdrugsthatpromotesodiumexcretion,lithiumclearancemaybelowered.Serum

lithiumlevelsshouldthereforebemonitoredcarefullyiflithiumsaltsaretobeadministered.Theposologyshouldbe

adaptedwhennecessary.

Alcohol

ACEinhibitorsincreasetheeffectofalcohol.AlcoholenhancesthehypotensiveeffectsofACEinhibitors.

Anaesthetics/narcotics/hypnotics

Greaterbloodpressurefall(sotheanaesthetisthastobeinformedoflisinopriltherapy).

Sympathomimetics

MayreducetheantihypertensiveeffectsofACEinhibitors.

Anincreasedriskofleucopeniahasbeennotedwiththeconcomitantadministrationofallopurinol,cytostaticor

immunosuppressiveagents,systemiccorticosteroidsorprocaiamide.

Oralantidiabetics(e.gsulphonylureadrugs/biguanides),insulin

ACEinhibitorsmayenhancethehypoglycaemiceffectsofantidiabeticmedication,particularlyduringthefirstweeks

ofcombinedtreatment.

Antacids

MayreducethebioavailabilityofACEinhibitors.

Non-steroidalanti-inflammatorydrugs

Theadministrationofanon–steroidalanti-inflammatoryagentmayreducetheantihypertensiveeffectoflisinopril.

Lisinoprilexertsanadditiveeffectontheincreaseofserumpotassium,whereasrenalfunctionmaydecrease.These

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4.6Pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia).(Seesection5.3)ShouldexposuretoACEinhibitorshaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofByZestraduringbreastfeeding,ByZestraisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionaldizzinessorweariness

mayoccur.

4.8Undesirableeffects

ThefollowingundesirableeffectshavebeenobservedinassociationwithlisinopriltherapyorwithotherACE

inhibitors:

Cardiovascularsystem:

Occasionally,severehypotensionmayoccurafterinitiationoftherapyorwithincreaseofthedosageoflisinopril

and/ordiuretics.Thisoccursespeciallyincertainriskgroups,e.g.inpatientssufferingfromsaltorfluiddeficiency

afterdiuretictherapy,heartfailureandsevereorrenalhypertension.Symptomslikedizziness,feelingofweakness,

impairedvision,rarelyaccompaniedbylossofconsciousness(syncope),canoccur.

Individualcasesoftachycardia,palpitations,arrhythmia,chestpain,anginapectoris,myocardialinfarction,transient

ischemicattacksandstrokehavebeenreportedforACEinhibitorsinassociationwithpronouncedbloodpressurefall.

Iflisinoprilisadministeredinacutemyocardialinfarctionpatients,occasionally-especiallywithinthefirst24hours-

secondorthirddegreeAVblockand/orseverehypotensionand/orrenalimpairment,inrarecasescardiogenicshock

mayoccur.

Kidneys

Renalinsufficiencymayoccurorbeintensified.Acuterenalfailurehasbeenreportedinsinglecases.

Proteinuria,partlywithsimultaneousdeteriorationofrenalfunction,hasbeenobserved.

Respiratorysystem

Occasionally,drycough,sorethroat,hoarsenessandbronchitis,rarelydyspnoea,sinusitis,rhinitis,

bronchospasm/asthma,pulmonalinfiltration,stomatitis,glossitisanddrymouthmayoccur.Inindividualcases

angioneuroticoedemainvolvingtheupperairwayshascausedfoetalairwayobstruction(seesection4.4).

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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Gastrointestinaltract/liver

Occasionallynausea,abdominalpainandindigestion,rarelyvomiting,diarrhoea,constipationandlossofappetitecan

occur.

ACEinhibitorshaverarelybeenassociatedwithasyndromeofcholestaticjaundice,fulminanthepaticnecrosisand

death.Themechanismofthissyndromeisnotunderstood.PatientsreceivingACEinhibitorswhodevelopjaundicethe

ACEinhibitorshouldbestoppedandthepatientshouldbemonitoredmedically.InpatientsreceivingACEinhibitors

individualcasesofhepaticdysfunction,hepatitis,liverinsufficiency,pancreatitisandileushavebeendescribedIn

relationtotherapywithACEinhibitors.

Skin,vessels

Occasionallyallergicskinreactionslikerashcanoccur,rarelypsoriasis,urticariaaswellasangioneuroticoedemaof

theface,lipsand/orlimbs.

Inisolatedcasessevereskinreactionslikepemphigus,erythemamultiforme,exfoliativedermatitis,Stevens-Johnson

syndromeandtoxicepidermalnecrolysishavebeendescribed.Skinreactionscanbeaccompaniedbyfever,myalgia,

arthralgia,vasculitis,eosinophilia,leucocytosisand/orincreasedANA-tires.

Incaseofsuspectedseriousskinreactiontheattendingphysicianhastobeconsultedimmediatelyandtherapywith

lisinoprilneedstobeterminated.

Individualcasesofpsoriasis-likeskinchanges,photosensitivity,flush,diaphoresis,alopecia,onycholysisand

exacerbationofRaynaud’sdiseasehavebeenobservedwithACEinhibitortherapy.

Nervoussystem

Occasionallyheadacheandtiredness,rarelysomnolence,depressions,sleepdisorders,impotence,peripheral

neuropathywithparathesia,disordersofbalance,musclecramps,nervousness,confusion,tinnitus,blurredvision,taste

disturbancesandtemporarylossoftaste.

Laboratoryparameters(blood,urine)

Occasionallyhaemoglobin,haematocrit,whitecellcountorplateletsmaybedecreased.Therehavebeenrarereports

ofanaemia,thrombocytopenia,neutropeniaoreosinophilia,andisolatedreportsofagranulocytosisorpancytopenia,

especiallyinpatientswithimpairedrenalfunction,collagendiseaseorconcurrenttreatmentwithallopurinol,

procainamideorcertainimmunosuppressivedrugs.

InpatientswithacongenitaldeficiencyconcerningG-6-PDHindividualcasesofhaemolyticanaemiahavebeen

reported.

Increasesinserumcreatinine,ureaandpotassiumrespectivelydecreaseinserumsodiumconcentrationmayrarely

occur,especiallyinthepresenceofrenalinsufficiency,severeheartfailureandrenovascularhypertension.Inpatients

withdiabetesmellitushyperkalemiahavebeenobserved.

Proteinuriamaybeincreasedinspecialcases(seesection4.4)

Elevationofliverenzymesandserumbilirubinhasbeenreportedinisolatedcases.

Specialremarks

Theabovementionedlaboratoryparametersshouldbeperformedbeforeandregularlyduringtreatmentwithlisinopril.

Especiallyintheinitialphaseoftreatmentandinhigh-riskpatients(patientswithrenalinsufficiency,incollagen

disease)aswellasconcurrenttreatmentwithimmunosuppressiveorcytostaticagents,allopurinolandprocainamide,

serumelectrolyteandserumcreatinineconcentrationsaswellasfullbloodcountshouldbemonitored.

Patientsexperiencingsuchsymptomsasfever,lymphnodeswellingand/orsorethroatinthecourseoflisinopril

therapyshouldhaveawhitecellcountwithoutdelay.

4.9Overdose

Nocaseofoverdosehasbeenreported.

Themostlikelyoverdosagephenomenonwouldbeseverehypotension,shock,bradycardia,electrolytedisturbances

andrenalfailure,thenormaltreatmentbeinganinfusionwithastandardsalinesolution.

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Afteringestionofanoverdose,thepatientshouldbekeptunderclosesupervision,preferablyinanintensivecareunit.

Serumelectrolytesandcreatinineshouldbemonitoredfrequently.Precautionsshouldbetakenagainstabsorptionsuch

asgastriclavage,administrationofabsorbentsorsodiumsulphateshouldbeinstitutedwithin30minutesofintake.

Measurestohasteneliminationmayalsobetaken.Ifhypotensionoccurs,thepatientshouldbeplacedinshock

positionandintravenouslysaltandvolumesupplementationshouldbegivenrapidly.TreatmentwithangiotensionII

shouldbeconsidered.Bradycardiashouldbetreatedbyadministeringatropine.

Theuseofpacemakermaybeconsidered.ACEinhibitorsmayberemovedfromthecirculationbyhaemodialysis.The

useofhigh-fluxpolyacrylonitrilemembranesshouldbeavoided.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitors,

ATCcode:C09AA03

Lisinoprilisanangiotensinconvertingenzymeinhibitor.Angiotensinconvertingenzyme(ACE)isapeptidyl

dipeptidasewhichcatalysestheconversionofangiotensinItothepressorsubstanceangiotensinII.InhibitionofACE

resultsindecreasedplasmaangiotensinII,whichleadstoincreasedplasmareninactivity(duetoremovalofnegative

feedbackofreninrelease),anddecreasesaldosteronesecretion.

ACEisidenticalwithkininaseII.Thuslisinoprilmayalsoblockthedegradationofbradykinin,apotentvasodepressor

peptide.However,therolethatthisplaysinthetherapeuticeffectsoflisinoprilremainstobeelucidated.

Whilethemechanismthroughwhichlisinoprillowersbloodpressureisbelievedtobeprimarilysuppressionofthe

renin-angitensin-aldosteronesystem,lisinoprilisantihypertensiveeveninpatientswithlow-reninhypertension.

5.2Pharmacokineticproperties

Thebioavailabilityoflisinoprilisabout29%withaninter-patientvariationof6-60%.Maximumplasma

concentrationsarereachedwithinapproximately7hoursafteroraladministration.Fooddoesnotaffecttherateor

extentofabsorption.

Lisinoprilisnotmetabolisedandtheabsorbedfractionisexcretedcompletelyunchangedintheurine.Following

multipledosing,lisinoprildisplayedaneffectivehalf-lifeof12.6hours.Mostofthedrugiseliminatedduringthe

earlierphase,whichdoesnotcontributetodrugaccumulation.Theterminalphaseprobablyrepresentsasaturable

bindingtoACEandisnotproportionaltothedose.Lisinoprildoesnotappeartobindtootherplasmaproteinsthan

ACE.

Acutemyocardialinfarctionpatientstendtohaveaslightlylongertimetopeakconcentrations.Impairedrenal

functionreducestheexcretionoflisinoprilthroughthekidneys.ElderlypatientshavehigherAUCvaluesthanyounger

patients.Dosageadjustmentisrecommendedinpatientswithcreatineclearance<70ml/minandinelderly(seesection

4.2).Lisinoprilcanberemovedbydialysis.

5.3Preclinicalsafetydata

Lisinoprildihydrateissafewithregardtogenotoxicity.2-yearscarcinogenicitystudiesinratsandmicefailedtoshow

anyevidenceofcarcinogeniceffects

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

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Magnesiumstearate

Pregelatinisedstarch

Mannitol

Maizestarch

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

PVC/aluminiumfoilblistersincartonseachcontaining28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ErghaHealthcareLtd.,

Damastown,

Mulhuddart,

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA966/7/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateoffirstAuthorisation:22April2005

Dateoflastrenewal:22April2010

10DATEOFREVISIONOFTHETEXT

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