ENAPRIL STADA

Main information

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

Documents

Localization

  • Available in:
  • ENAPRIL STADA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0593/024/002
  • Authorization date:
  • 23-03-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EnaprilStada5mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgofenalaprilmaleate.

Excipients:ContainsLactoseMonohydrate129.8mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Round,white,convex'snap-tab'tablets,onesidescored.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofHypertension.

TreatmentofSymptomaticHeartFailure.

PreventionofSymptomaticHeartFailureinpatientswithAsymptomaticLeftVentricularDysfunction(ejection

fraction ≤35%).

4.2Posologyandmethodofadministration

TheabsorptionofEnaprilStada2.5mg/5mg/10mg/20mgtabletsisnotaffectedbyfood.

Thedoseshouldbeindividualizedaccordingtopatientprofile(see4.4Specialwarningsandspecialprecautionsfor

use)andbloodpressureresponse.

Hypertension

Theinitialdoseis5tomaximally20mg,dependingonthedegreeofhypertensionandtheconditionofthepatient(see

below).EnaprilStada2.5mg/5mg/10mg/20mgtabletsaregivenoncedaily.Inmildhypertension,therecommended

initialdoseis5to10mg.Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystem(e.g.,renovascular

hypertension,saltand/orvolumedepletion,cardiacdecompensation,orseverehypertension)mayexperiencean

excessivebloodpressurefallfollowingtheinitialdose.Astartingdoseof5mgorlowerisrecommendedinsuch

patientsandtheinitiationoftreatmentshouldtakeplaceundermedicalsupervision.

Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskofhypotensionwheninitiating

therapywithenapril.Astartingdoseof5mgorlowerisrecommendedinsuchpatients.Ifpossible,diuretictherapy

shouldbediscontinuedfor2-3dayspriortoinitiationoftherapywithEnaprilStada2.5mg/5mg/10mg/20mgtablets.

Renalfunctionandserumpotassiumshouldbemonitored.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 1

HeartFailure/AsymptomaticLeftVentricularDysfunction

Inthemanagementofsymptomaticheartfailure,EnaprilStada2.5mg/5mg/10mg/20mgtabletsisusedinadditionto

diureticsand,whereappropriate,digitalisorbeta-blockers.TheinitialdoseofEnaprilStada2.5mg/5mg/10mg/20mg

tabletsinpatientswithsymptomaticheartfailureorasymptomaticleftventriculardysfunctionis2.5mg,anditshould

beadministeredunderclosemedicalsupervisiontodeterminetheinitialeffectonthebloodpressure.Intheabsenceof,

oraftereffectivemanagementof,symptomatichypotensionfollowinginitiationoftherapywithEnaprilStada

2.5mg/5mg/10mg/20mgtabletsinheartfailure,thedoseshouldbeincreasedgraduallytotheusualmaintenancedose

of20mg,giveninasingledoseortwodivideddoses,astoleratedbythepatient.Thisdosetitrationisrecommendedto

beperformedovera2to4weekperiod.Themaximumdoseis40mgdailygivenintwodivideddoses.

SuggestedDosageTitrationofEnaprilStada2.5mg/5mg/10mg/20mgtabletsinPatientswithHeart

Failure/AsymptomaticLeftVentricularDysfunction.

*Specialprecautionsshouldbefollowedinpatientswithimpairedrenalfunctionortaking

diuretics(See4.4Specialwarningsandspecialprecautionsforuse).

BloodpressureandrenalfunctionshouldbemonitoredcloselybothbeforeandafterstartingtreatmentwithEnapril

Stada2.5mg/5mg/10mg/20mgtablets(see4.4Specialwarningsandspecialprecautionsforuse)becausehypotension

and(morerarely)consequentrenalfailurehavebeenreported.Inpatientstreatedwithdiuretics,thedoseshouldbe

reducedifpossiblebeforebeginningtreatmentwithEnaprilStada2.5mg/5mg/10mg/20mgtablets.Theappearanceof

hypotensionaftertheinitialdoseofEnaprilStada2.5mg/5mg/10mg/20mgtabletsdoesnotimplythathypotensionwill

recurduringchronictherapywithEnaprilStada2.5mg/5mg/10mg/20mgtabletsanddoesnotprecludecontinueduseof

thedrug.Serumpotassiumandrenalfunctionalsoshouldbemonitored.

DosageinRenalInsufficiency

Generally,theintervalsbetweentheadministrationofEnaprilshouldbeprolongedand/orthedosagereduced.

*See4.4Specialwarningsandspecialprecautionsforuse-HemodialysisPatients.Enaprilatisdialyzable.Dosageon

nondialysisdaysshouldbeadjusteddependingonthebloodpressureresponse.

UseinElderly

Thedoseshouldbeinlinewiththerenalfunctionoftheelderlypatient(see4.4Specialwarningsandspecial

precautionsforuse,RenalFunctionImpairment).

Useinpaediatrics

ThereislimitedclinicaltrialexperienceoftheuseofEnaprilStada2.5mg/5mg/10mg/20mgtabletsinhypertensive

paediatricpatients(see4.4Specialwarningsandspecialprecautionsforuse,5.1Pharmacodynamicpropertiesand5.2

Week Dose

mg/day

Week1 Days1to3:2.5mg/day*inasingledose

Days4to7:5mg/dayintwodivideddoses

Week2 10mg/dayinasingledoseorintwodivideddoses

Weeks3and4 20mg/dayinasingledoseorintwodivideddoses

CreatinineClearance(CrCL) InitialDose

mL/min mg/day

30<CrCL<80ml/min 5-10mg

10<CrCL ≤30ml/min. 2.5mg

CrCL ≤10ml/min.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 2

Forpatientswhocanswallowtablets,thedoseshouldbeindividualizedaccordingtopatientprofileandbloodpressure

response.Therecommendedinitialdoseis2.5mginpatients20to<50kgand5mginpatients ≥50kg.EnaprilStada

2.5mg/5mg/10mg/20mgtabletsisgivenoncedaily.Thedosageshouldbeadjustedaccordingtotheneedsofthepatient

toamaximumof20mgdailyinpatients20to<50kgand40mginpatients ≥50kg.(See4.4Specialwarningsand

specialprecautionsforuse.)

EnaprilStada2.5mg/5mg/10mg/20mgtabletsarenotrecommendedinneonatesandinpaediatricpatientswith

glomerularfiltrationrate<30ml/min/1.73m,asnodataareavailable.

Instructionforuse

PlacetheEnaprilStada5mg/10mg/20mgsnaptabtabletonahardsurfacewiththecentregroovefacingupward.Exert

pressurefromthetopwithyourthumbandthesnaptabwillbreakintotwoequalpieces.

4.3Contraindications

HypersensitivitytoEnalapril,toanyoftheexcipientsoranyotherACEinhibitor

HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy

Hereditaryoridiopathicangioedema

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

SymptomaticHypotension

Symptomatichypotensionisrarelyseeninuncomplicatedhypertensivepatients.Inhypertensivepatientsreceiving

EnaprilStada2.5mg/5mg/10mg/20mgtablets,symptomatichypotensionismorelikelytooccurifthepatienthasbeen

volume-depleted,e.g.,bydiuretictherapy,dietarysaltrestriction,dialysis,diarrheaorvomiting(see4.5Interaction

withothermedicamentsandotherformsofinteractionand4.8UndesirableEffects).Inpatientswithheartfailure,with

orwithoutassociatedrenalinsufficiency,symptomatichypotensionhasbeenobserved.Thisismostlikelytooccurin

thosepatientswithmoreseveredegreesofheartfailure,asreflectedbytheuseofhighdosesofloopdiuretics,

hyponatremiaorfunctionalrenalimpairment.Inthesepatients,therapyshouldbestartedundermedicalsupervision

andthepatientsshouldbefollowedcloselywheneverthedoseofEnaprilStada2.5mg/5mg/10mg/20mgtabletsand/or

diureticisadjusted.Similarconsiderationsmayapplytopatientswithischemicheartorcerebrovasculardiseasein

whomanexcessivefallinbloodpressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofnormalsaline.Atransienthypotensiveresponseisnotacontraindicationtofurtherdoses,

whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreasedaftervolumeexpansion.

Insomepatientswithheartfailurewhohavenormalorlowbloodpressure,additionalloweringofsystemicblood

pressuremayoccurwithEnaprilStada2.5mgtablets.Thiseffectisanticipated,andusuallyisnotareasonto

discontinuetreatment.Ifhypotensionbecomessymptomatic,areductionofdoseand/ordiscontinuationofthediuretic

and/orEnaprilStada2.5mg/5mg/10mg/20mgtabletsmaybenecessary.

AorticorMitralValveStenosis/HypertrophicCardiomyopathy

Aswithallvasodilators,ACEinhibitorsshouldbegivenwithcautioninpatientswithleftventricularvalvularand

outflowtractobstructionandavoidedincasesofcardiogenicshockandhaemodynamicallysignificantobstruction.

RenalFunctionImpairment

Incasesofrenalimpairment(creatinineclearance<80ml/min)theinitialEnalaprildosageshouldbeadjusted

accordingtothepatient’screatinineclearance(see4.2Posologyandmethodofadministration)andthenasafunction

ofthepatient’sresponsetotreatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedical

practiceforthesepatients.

RenalfailurehasbeenreportedinassociationwithEnalaprilandhasbeenmainlyinpatientswithsevereheartfailure

orunderlyingrenaldisease,includingrenalarterystenosis.Ifrecognizedpromptlyandtreatedappropriately,renal

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 3

Somehypertensivepatients,withnoapparentpre-existingrenaldiseasehavedevelopedincreasesinbloodureaand

creatininewhenEnalaprilhasbeengivenconcurrentlywithadiuretic.DosagereductionofEnalapriland/or

discontinuationofthediureticmayberequired.Thissituationshouldraisethepossibilityofunderlyingrenalartery

stenosis(see4.4Specialwarningsandspecialprecautionsforuse,Renovascularhypertension).

Renovascularhypertension

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.Lossofrenalfunctionmayoccur

withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitration,andmonitoringofrenalfunction.

KidneyTransplantation

ThereisnoexperienceregardingtheadministrationofEnaprilStada2.5mg/5mg/10mg/20mgtabletsinpatientswitha

recentkidneytransplantation.TreatmentwithEnaprilStada2.5mg/5mg/10mg/20mgtabletsisthereforenot

recommended.

Hepaticfailure

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceorhepatitisand

progressestofulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.

PatientsreceivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinue

theACEinhibitorandreceiveappropriatemedicalfollow-up.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis,thrombocytopeniaandanemiahavebeenreportedinpatientsreceivingACEinhibitors.In

patientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Enalaprilshouldbe

usedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.IfEnalaprilisusedinsuchpatients,periodicmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection.

Hypersensitivity/AngioneuroticEdema

Angioneuroticedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedinpatientstreated

withangiotensinconvertingenzymeinhibitors,includingEnaprilStada2.5mg/5mg/10mg/20mgtablets.Thismay

occuratanytimeduringtreatment.Insuchcases,EnaprilStada2.5mg/5mg/10mg/20mgtabletsshouldbediscontinued

promptlyandappropriatemonitoringshouldbeinstitutedtoensurecompleteresolutionofsymptomspriorto

dismissingthepatient.Eveninthoseinstanceswhereswellingofonlythetongueisinvolved,withoutrespiratory

distress,patientsmayrequireprolongedobservationsincetreatmentwithantihistaminesandcorticosteroidsmaynot

besufficient.

Veryrarely,fatalitieshavebeenreportedduetoangioedemaassociatedwithlaryngealedemaortongueedema.

Patientswithinvolvementofthetongue,glottisorlarynxarelikelytoexperienceairwayobstruction,especiallythose

withahistoryofairwaysurgery.Wherethereisinvolvementofthetongue,glottisorlarynx,likelytocauseairway

obstruction,appropriatetherapy,whichmayincludesubcutaneousepinephrinesolution1:1000(0.3mlto0.5ml)

and/ormeasurestoensureapatentairway,shouldbeadministeredpromptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor.(Alsosee4.3Contraindications.)

AnaphylactoidReactionsduringHymenopteraDesensitization

Rarely,patientsreceivingACEinhibitorsduringdesensitizationwithhymenopteravenomhaveexperiencedlife-

threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-inhibitortherapy

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 4

AnaphylactoidReactionsduringLDLApheresis

Rarely,patientsreceivingACEinhibitorsduringlowdensitylipoprotein(LDL)-apheresiswithdextransulfatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-

inhibitortherapypriortoeachapheresis.

HemodialysisPatients

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

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofantihypertensiveagent.

Hypoglycemia

DiabeticpatientstreatedwithoralantidiabeticagentsorinsulinstartinganACEinhibitor,shouldbetoldtoclosely

monitorforhypoglycemia,especiallyduringthefirstmonthofcombineduse.(See4.5Interactionwithothermedicinal

productsandotherformsofinteraction,Antidiabetics.)

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnonproductive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/Anesthesia

Inpatientsundergoingmajorsurgeryorduringanesthesiawithagentsthatproducehypotension,Enalaprilblocks

angiotensinIIformationsecondarytocompensatoryreninrelease.Ifhypotensionoccursandisconsideredtobedueto

thismechanism,itcanbecorrectedbyvolumeexpansion.

Hyperkalemia

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingenalapril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

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

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

amiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

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

diuretics,orpotassium-containingsaltsubstitutesparticularlyinpatientswithimpairedrenalfunctionmayleadtoa

significantincreaseinserumpotassium.Hyperkalemiacancauseserious,sometimesfatalarrhythmias.Ifconcomitant

useofenalaprilandanyoftheabove-mentionedagentsisdeemedappropriate,theyshouldbeusedwithcautionand

withfrequentmonitoringofserumpotassium.(See4.5Interactionwithothermedicinalproductsandotherformsof

interaction.)

Lithium

ThecombinationoflithiumandEnalaprilisgenerallynotrecommended(see4.5Interactionwithothermedicinal

productsandotherformsofinteraction).

Lactose

EnaprilStada2.5mgtabletscontainslactose-monohydrate.Patientswithrarehereditaryproblemsofgalactose

intolerance,theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

PaediatricUse

Thereislimitedefficacyandsafetyexperienceinhypertensivechildren>6yearsold,butnoexperienceinother

indications.Limitedpharmacokineticdataareavailableinchildrenabove2monthsofage.(Alsosee4.2Posologyand

methodofadministration,5.1Pharmacodynamicproperties,and5.2Pharmacokineticproperties.)EnaprilStada

2.5mg/5mg/10mg/20mgtabletsisnotrecommendedinchildreninotherindicationsthanhypertension.

EnaprilStada2.5mg/5mg/10mg/20mgtabletsisnotrecommendedinneonatesandinpaediatricpatientswith

glomerularfiltrationrate<30ml/min/1.73m,asnodataareavailable.(See4.2Posologyandmethodof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 5

Pregnancyandlactation

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Useofenalaprilisnotrecommendedduringbreastfeeding(seesections4.6and5.2).

Ethnicdifferences

Aswithotherangiotensinconvertingenzymeinhibitors,Enalaprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potassiumsparingdiureticsorpotassiumsupplements

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiuretics(e.g.spironolactone,eplerenone,

triamtereneoramiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificant

increasesinserumpotassium.Ifconcomitantuseisindicatedbecauseofdemonstratedhypokalemiatheyshouldbe

usedwithcautionandwithfrequentmonitoringofserumpotassium(see4.4Specialwarningsandspecialprecautions

foruse).

Diuretics(thiazideorloopdiuretics)

Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskofhypotensionwheninitiating

therapywithEnalapril(see4.4Specialwarningsandspecialprecautionsforuse).Thehypotensiveeffectscanbe

reducedbydiscontinuationofthediuretic,byincreasingvolumeorsaltintakeorbyinitiatingtherapywithalowdose

ofEnalapril.

Otherantihypertensiveagents

ConcomitantuseoftheseagentsmayincreasethehypotensiveeffectsofEnalapril.Concomitantusewith

nitroglycerineandothernitrates,orothervasodilators,mayfurtherreducebloodpressure.

Lithium

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayfurtherincreaselithium

levelsandenhancetheriskoflithiumtoxicitywithACEinhibitors.UseofEnalaprilwithlithiumisnotrecommended,

butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsshouldbeperformed(see4.4

Specialwarningsandspecialprecautionsforuse).

Tricyclicantidepressants/Antipsychotics/Anesthetics/Narcotics

Concomitantuseofcertainanestheticmedicinalproducts,tricyclicantidepressantsandantipsychoticswithACE

inhibitorsmayresultinfurtherreductionofbloodpressure(see4.4Specialwarningsandspecialprecautionsforuse).

Non-SteroidalAnti-InflammatoryDrugs(NSAIDs)

ChronicadministrationofNSAIDsmayreducetheantihypertensiveeffectofanACEinhibitor.

NSAIDs(includingCOX-2inhibitors)andACEinhibitorsexertanadditiveeffectontheincreaseinserumpotassium,

andmayresultinadeteriorationofrenalfunction.Theseeffectsareusuallyreversible.Rarely,acuterenalfailuremay

occur,especiallyinpatientswithcompromisedrenalfunction(suchastheelderlyorpatientswhoarevolume-depleted,

includingthoseondiuretictherapy).Patientsshouldbeadequatelyhydratedandconsiderationshouldbegivento

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 6

Gold

Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeenreportedrarelyin

patientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACEinhibitortherapyincluding

enalapril.

Sympathomimetics

SympathomimeticsmayreducetheantihypertensiveeffectsofACEinhibitors.

Antidiabetics

EpidemiologicalstudieshavesuggestedthatconcomitantadministrationofACEinhibitorsandantidiabeticmedicines

(insulins,oralhypoglycemicagents)maycauseanincreasedblood-glucose-loweringeffectwithriskofhypoglycemia.

Thisphenomenonappearedtobemorelikelytooccurduringthefirstweeksofcombinedtreatmentandinpatientswith

renalimpairment.

Alcohol

AlcoholenhancesthehypotensiveeffectofACEinhibitors.

Acetylsalicylicacid,thrombolyticsandß-blockers

Enalaprilcanbesafelyadministeredconcomitantlywithacetylsalicylicacid(atcardiologicdoses),thrombolyticsand

ß-blockers.

4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehuman

foetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renal

failure,hypotension,hyperkalaemia).(Seesection5.3.)ShouldexposuretoACEinhibitorhaveoccurredfromthe

secondtrimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothers

havetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

Limitedpharmacokineticdatademonstrateverylowconcentrationsinbreastmilk(seesection5.2).Althoughthese

concentrationsseemtobeclinicallyirrelevant,theuseofEnaprilStadainbreastfeedingisnotrecommendedfor

preterminfantsandforthefirstfewweeksafterdelivery,becauseofthehypotheticalriskofcardiovascularandrenal

effectsandbecausethereisnotenoughclinicalexperience.Inthecaseofanolderinfant,theuseofEnaprilStadaina

breast-feedingmothermaybeconsideredifthistreatmentisnecessaryforthemotherandthechildisobservedforany

adverseeffect.

4.7Effectsonabilitytodriveandusemachines

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorweariness

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 7

4.8Undesirableeffects

UndesirableeffectsreportedforEnalaprilinclude:

[Verycommon(>1/10);common(>1/100,<1/10);uncommon(>1/1,000,<1/100);rare(>1/10,000,<1/1,000);very

rare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)]

Bloodandthelymphaticsystemdisorders:

uncommon:anemia(includingaplasticandhemolytic)

rare:neutropenia,decreasesinhemoglobin,decreasesinhematocrit,thrombocytopenia,agranulocytosis,bonemarrow

depression,pancytopenia,lymphadenopathy,autoimmunediseases

Endocrinedisorders:

notknown:syndromeofinappropriateantidiuretichormonesecretion(SIADH).

Metabolismandnutritiondisorders:

uncommon:hypoglycemia(see4.4Specialwarningsandspecialprecautionsforuse,Diabeticpatients)

Nervoussystemandpsychiatricdisorders:

common:headache,depression

uncommon:confusion,somnolence,insomnia,nervousness,paresthesia,vertigo

rare:dreamabnormality,sleepdisorders

Eyedisorders:

verycommon:blurredvision

Cardiacandvasculardisorders:

verycommon:dizziness

common:hypotension(includingorthostatichypotension),syncope,,chestpain,rhythmdisturbances,anginapectoris,

tachycardia

uncommon:orthostatichypotension,palpitationsmyocardialinfarctionorcerebrovascularaccident*,possibly

secondarytoexcessivehypotensioninhighriskpatients(see4.4Specialwarningsandspecialprecautionsforuse)

rare:Raynaud‘sphenomenon

Respiratory,thoracicandmediastinaldisorders:

verycommon:cough

common:dyspneauncommon:rhinorrhea,sorethroatandhoarseness,bronchospasm/asthma

rare:pulmonaryinfiltrates,rhinitis,allergicalveolitis/eosinophilicpneumonia

Gastrointestinaldisorders:

verycommon:nausea

common:diarrhea,abdominalpain,tastealteration

uncommon:ileus,pancreatitis,vomiting,dyspepsia,constipation,anorexia,gastricirritations,drymouth,pepticulcer

rare:stomatitis/aphthousulcerations,glossitis

veryrare:intestinalangioedema

Hepatobiliarydisorders:

rare:hepaticfailure,hepatitis-eitherhepatocellularorcholestatic,hepatitisincludingnecrosis,cholestasis(including

jaundice)

Skinandsubcutaneoustissuedisorders:

common:rash,hypersensitivity/angioneuroticedema:angioneuroticedemaoftheface,extremities,lips,tongue,glottis

and/orlarynxhasbeenreported(see4.4Specialwarningsandspecialprecautionsforuse)

uncommon:diaphoresis,pruritus,urticaria,alopecia

rare:erythemamultiforme,Stevens-Johnsonsyndrome,exfoliativedermatitis,toxicepidermalnecrolysis,pemphigus,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 8

Asymptomcomplexhasbeenreportedwhichmayincludesomeorallofthefollowing:fever,serositis,vasculitis,

myalgia/myositis,arthralgia/arthritis,apositiveANA,elevatedESR,eosinophilia,andleukocytosis.Rash,

photosensitivityorotherdermatologicmanifestationsmayoccur.

Renalandurinarydisorders:

uncommon:renaldysfunction,renalfailure,proteinuria

rare:oliguria

Reproductivesystemandbreastdisorders:

uncommon:impotence

rare:gynecomastia

Generaldisordersandadministrationsiteconditions:

verycommon:asthenia

common:fatigueuncommon:musclecramps,flushing,tinnitus,malaise,fever

Investigations:

common:hyperkalemia,increasesinserumcreatinine

uncommon:increasesinbloodurea,hyponatremia

rare:elevationsofliverenzymes,elevationsofserumbilirubin

*Incidencerateswerecomparabletothoseintheplaceboandactivecontrolgroupsintheclinicaltrials.

4.9Overdose

Limiteddataareavailableforoverdosageinhumans.Themostprominentfeaturesofoverdosagereportedtodateare

markedhypotension,beginningsomesixhoursafteringestionoftablets,concomitantwithblockadeoftherenin-

angiotensinsystem,andstupor.SymptomsassociatedwithoverdosageofACEinhibitorsmayincludecirculatory

shock,electrolytedisturbances,renalfailure,hyperventilation,tachycardia,palpitations,bradycardia,dizziness,

anxiety,andcough.SerumEnalaprilatlevels100-and200-foldhigherthanusuallyseenaftertherapeuticdoseshave

beenreportedafteringestionof300mgand440mgofEnalapril,respectively.

Therecommendedtreatmentofoverdosageisintravenousinfusionofnormalsalinesolution.Ifhypotensionoccurs,the

patientshouldbeplacedintheshockposition.Ifavailable,treatmentwithangiotensinIIinfusionand/orintravenous

catecholaminesmayalsobeconsidered.Ifingestionisrecent,takemeasuresaimedateliminatingEnalaprilmaleate

(e.g.,emesis,gastriclavage,administrationofabsorbents,andsodiumsulphate).Enalaprilatmayberemovedfromthe

generalcirculationbyhemodialysis.(See4.4Specialwarningsandspecialprecautionsforuse,HemodialysisPatients.)

Pacemakertherapyisindicatedfortherapy-resistantbradycardia.Vitalsigns,serumelectrolytesandcreatinine

concentrationsshouldbemonitoredcontinuously.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Angiotensinconvertingenzymeinhibitors,ATCCode:C09AA02

EnaprilStada2.5mg/5mg/10mg/20mgtablets(Enalaprilmaleate)isthemaleatesaltofEnalapril,aderivativeoftwo

amino-acids,L-alanineandL-proline.Angiotensinconvertingenzyme(ACE)isapeptidyldipeptidasewhichcatalyzes

theconversionofangiotensinItothepressorsubstanceangiotensinII.Afterabsorption,Enalaprilishydrolyzedto

Enalaprilat,whichinhibitsACE.InhibitionofACEresultsindecreasedplasmaangiotensinII,whichleadstoincreased

plasmareninactivity(duetoremovalofnegativefeedbackofreninrelease),anddecreasedaldosteronesecretion.

ACEisidenticaltokininaseII.ThusEnalapriltabletsmayalsoblockthedegradationofbradykinin,apotent

vasodepressorpeptide.However,therolethatthisplaysinthetherapeuticeffectsofEnaprilStada

2.5mg/5mg/10mg/20mgtabletsremainstobeelucidated.

WhilethemechanismthroughwhichEnaprilStada2.5mg/5mg/10mg/20mgtabletslowersbloodpressureisbelievedto

beprimarilysuppressionoftherenin-angiotensin-aldosteronesystem,EnaprilStada2.5mg/5mg/10mg/20mgtabletsis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 9

AdministrationofEnaprilStada2.5mg/5mg/10mg/20mgtabletstopatientswithhypertensionresultsinareductionof

bothsupineandstandingbloodpressurewithoutasignificantincreaseinheartrate.

Symptomaticposturalhypotensionisinfrequent.Insomepatientsthedevelopmentofoptimalbloodpressurereduction

mayrequireseveralweeksoftherapy.AbruptwithdrawalofEnalapriltabletshasnotbeenassociatedwithrapid

increaseinbloodpressure.

EffectiveinhibitionofACEactivityusuallyoccurs2to4hoursafteroraladministrationofanindividualdoseof

Enalapril.Onsetofantihypertensiveactivitywasusuallyseenatonehour,withpeakreductionofbloodpressure

achievedby4to6hoursafteradministration.Thedurationofeffectisdose-related.However,atrecommendeddoses,

antihypertensiveandhemodynamiceffectshavebeenshowntobemaintainedforatleast24hours.

Inhemodynamicstudiesinpatientswithessentialhypertension,bloodpressurereductionwasaccompaniedbya

reductioninperipheralarterialresistancewithanincreaseincardiacoutputandlittleornochangeinheartrate.

FollowingadministrationofEnalapriltabletstherewasanincreaseinrenalbloodflow;glomerularfiltrationratewas

unchanged.Therewasnoevidenceofsodiumorwaterretention.However,inpatientswithlowpretreatment

glomerularfiltrationrates,therateswereusuallyincreased.

Inshorttermclinicalstudiesindiabeticandnondiabeticpatientswithrenaldisease,decreasesinalbuminuriaand

urinaryexcretionofIgGandtotalurinaryproteinwereseenaftertheadministrationofEnalapril.

Whengiventogetherwiththiazide-typediuretics,thebloodpressure-loweringeffectsofEnalapriltabletsareatleast

additive.Enalapriltabletsmayreduceorpreventthedevelopmentofthiazide-inducedhypokalemia.

Inpatientswithheartfailureontherapywithdigitalisanddiuretics,treatmentwithoralorInjectionEnalapriltablets

wereassociatedwithdecreasesinperipheralresistanceandbloodpressure.Cardiacoutputincreased,whileheartrate

(usuallyelevatedinpatientswithheartfailure)decreased.Pulmonarycapillarywedgepressurewasalsoreduced.

Exercisetoleranceandseverityofheartfailure,asmeasuredbyNewYorkHeartAssociationcriteria,improved.These

actionscontinuedduringchronictherapy.

Inpatientswithmildtomoderateheartfailure,Enalaprilretardedprogressivecardiacdilatation/enlargementand

failure,asevidencedbyreducedleftventricularenddiastolicandsystolicvolumesandimprovedejectionfraction.

Amulticenter,randomised,double-blind,placebo-controlledtrial(SOLVDPreventiontrial)examinedapopulation

withasymptomaticleftventriculardysfunction(LVEF<35%).4228patientswererandomizedtoreceiveeitherplacebo

(n=2117)orEnalapril(n=2111).Intheplacebogroup,818patientshadheartfailureordied(38.6%)ascomparedwith

630intheEnalaprilgroup(29.8%)(riskreduction:29%;95%CI;21-36%;p<0.001).518patientsintheplacebo

group(24.5%)and434intheEnalaprilgroup(20.6%)diedorwerehospitalizedforneworworseningheartfailure

(riskreduction20%;95%CI;9-30%;p<0.001).

Amulticenter,randomised,double-blind,placebo-controlledtrial(SOLVDTreatmenttrial)examinedapopulation

withsymptomaticcongestiveheartfailureduetosystolicdysfunction(ejectionfraction<35%).2569patientsreceiving

conventionaltreatmentforheartfailurewererandomlyassignedtoreceiveeitherplacebo(n=1284)orEnalapril

(n=1285).Therewere510deathsintheplacebogroup(39.7%)ascomparedwith452intheEnalaprilgroup(35.2%)

(reductioninrisk,16%;95%CI,526%;p=0.0036).Therewere461cardiovasculardeathsintheplacebogroupas

comparedwith399intheEnalaprilgroup(riskreduction18%,95%CI,6-28%,p<0.002),mainlyduetoadecreaseof

deathsduetoprogressiveheartfailure(251intheplacebogroupvs209intheEnalaprilgroup,riskreduction22%,

95%CI,6-35%).

Fewerpatientsdiedorwerehospitalizedforworseningheartfailure(736intheplacebogroupand613intheEnalapril

group;riskreduction,26%;95%CI,18-34%;p<0.0001).OverallinSOLVDstudy,inpatientswithleftventricular

dysfunction,EnaprilStada2.5mg/5mg/10mg/20mgtabletsreducedtheriskofmyocardialinfarctionby23%(95%CI,

11-34%;p<0.001)andreducedtheriskofhospitalizationforunstableanginapectorisby20%(95%CI,9-29%;

p<0.001).

Thereislimitedexperienceoftheuseinhypertensivepediatricpatients>6years.Inaclinicalstudyinvolving110

hypertensivepediatricpatients6to16yearsofagewithabodyweight ≥20kgandaglomerularfiltrationrate>30

ml/min/1.73m,patientswhoweighed<50kgreceivedeither0.625,2.5or20mgofEnalaprildailyandpatientswho

weighed<50kgreceivedeither1.25,5or40mgofEnalaprildaily.Enalapriladministrationoncedailyloweredtrough

bloodpressureinadose-dependentmanner.Thedose-dependentantihypertensiveefficacyofEnalaprilwasconsistent

acrossallsubgroups(age,Tannerstage,gender,race).However,thelowestdosesstudied,0.625mgand1.25mg,

correspondingtoanaverageof0.02mg/kgoncedaily,didnotappeartoofferconsistentantihypertensiveefficacy.The

maximumdosestudiedwas0.58mg/kg(upto40mg)oncedaily.Theadverseexperienceprofileforpediatricpatients

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 10

5.2Pharmacokineticproperties

Absorption

OralEnalaprilisrapidlyabsorbed,withpeakserumconcentrationsofEnalapriloccurringwithinonehour.Basedon

urinaryrecovery,theextentofabsorptionofEnalaprilfromoralEnalapriltabletisapproximately60%.Theabsorption

oforalEnaprilStada2.5mg/5mg/10mg/20mgtabletsisnotinfluencedbythepresenceoffoodinthegastrointestinal

tract.

Followingabsorption,oralEnalaprilisrapidlyandextensivelyhydrolyzedtoEnalaprilat,apotentangiotensin

convertingenzymeinhibitor.PeakserumconcentrationsofEnalaprilatoccurabout4hoursafteranoraldoseof

Enalapriltablet.Theeffectivehalf-lifeforaccumulationofEnalaprilatfollowingmultipledosesoforalEnalaprilis11

hours.Insubjectswithnormalrenalfunction,steady-stateserumconcentrationsofEnalaprilatwerereachedafter4

daysoftreatment.

Distribution

Overtherangeofconcentrationswhicharetherapeuticallyrelevant,Enalaprilatbindingtohumanplasmaproteinsdoes

notexceed60%.

Biotransformation

ExceptforconversiontoEnalaprilat,thereisnoevidenceforsignificantmetabolismofEnalapril.

Elimination

ExcretionofEnalaprilatisprimarilyrenal.TheprincipalcomponentsinurineareEnalaprilat,accountingforabout40%

ofthedose,andintactEnalapril(about20%).

Renalimpairment

TheexposureofEnalaprilandEnalaprilatisincreasedinpatientswithrenalinsufficiency.Inpatientswithmildto

moderaterenalinsufficiency(creatinineclearance40-60ml/min)steadystateAUCofEnalaprilatwasapproximately

two-foldhigherthaninpatientswithnormalrenalfunctionafteradministrationof5mgoncedaily.Insevererenal

impairment(creatinineclearance ≤30ml/min),AUCwasincreasedapproximately8-fold.Theeffectivehalf-lifeof

EnalaprilatfollowingmultipledosesofEnalaprilmaleateisprolongedatthislevelofrenalinsufficiencyandtimeto

steadystateisdelayed.(See4.2Posologyandmethodofadministration.)Enalaprilatmayberemovedfromthegeneral

circulationbyhemodialysis.

Thedialysisclearanceis62ml/min.

Childrenandadolescents

Amultipledosepharmacokineticstudywasconductedin40hypertensivemaleandfemalepediatricpatientsaged2

monthsto ≤16yearsfollowingdailyoraladministrationof0.07to0.14mg/kgEnalaprilmaleate.Therewerenomajor

differencesinthepharmacokineticsofEnalaprilatinchildrencomparedwithhistoricdatainadults.Thedataindicate

anincreaseinAUC(normalisedtodoseperbodyweight)withincreasedage;however,anincreaseinAUCisnot

observedwhendataarenormalisedbybodysurfacearea.Atsteadystate,themeaneffectivehalf-lifeforaccumulation

ofEnalaprilatwas14hours.

Lactation

Afterasingle20mgoraldoseinfivepostpartumwomen,theaveragepeakenalaprilmilklevelwas1.7µg/L(range

0.54to5.9µg/L)at4to6hoursafterthedose.Theaveragepeakenalaprilatlevelwas1.7µg/L(range1.2to2.3µg/L);

peaksoccurredatvarioustimesoverthe24-hourperiod.Usingthepeakmilkleveldata,theestimatedmaximumintake

ofanexclusivelybreastfedinfantwouldbeabout0.16%ofthematernalweight-adjusteddosage.Awomanwhohad

beentakingoralenalapril10mgdailyfor11monthshadpeakenalaprilmilklevelsof2µg/L4hoursafteradoseand

peakenalaprilatlevelsof0.75µg/Labout9hoursafterthedose.Thetotalamountofenalaprilandenalaprilatmeasured

inmilkduringthe24hourperiodwas1.44µg/Land0.63µg/Lofmilkrespectively.Enalaprilatmilklevelswere

undetectable(<0.2µg/L)4hoursafterasingledoseofenalapril5mginonemotherand10mgintwomothers;enalapril

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 11

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.ReproductivetoxicitystudiessuggestthatEnalaprilhasno

effectsonfertilityandreproductiveperformanceinrats,andisnotteratogenic.Inastudyinwhichfemaleratswere

dosedpriortomatingthroughgestation,anincreasedincidenceofratpupdeathsoccurredduringlactation.The

compoundhasbeenshowntocrosstheplacentaandissecretedinmilk.Angiotensinconvertingenzymeinhibitors,asa

class,havebeenshowntobefetotoxic(causinginjuryand/ordeathtothefetus)whengiveninthesecondorthird

trimester.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumhydrogencarbonate

Lactosemonohydrate

Maizestarch

Hyprolose

Talc

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeis3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Aluminium/OPA-Al-PVCblisterfoil

Originalpackof

10,20,28,30,50,56,60,98,100,150,200,250,300,400,500,1000tablets

*notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

STADAArzneimittelAG

Stadastraße2-18

61118BadVilbel,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 12

8MARKETINGAUTHORISATIONNUMBER

PA593/24/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23 rd

March2001

Dateoflastrenewal:21stMarch2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/07/2011 CRN 2060224 page number: 13