ENALAPRIL MALEATE HYDROCHLOROTHIAZIDE TEVA

Main information

  • Trade name:
  • ENALAPRIL MALEATE HYDROCHLOROTHIAZIDE TEVA
  • Dosage:
  • 20/ 12.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENALAPRIL MALEATE HYDROCHLOROTHIAZIDE TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/029/001
  • Authorization date:
  • 01-06-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0749/029/001

CaseNo:2072784

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TevaPharmaB.V.

Computerweg10,3542DRUtrecht,Netherlands

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EnalaprilMaleateHydrochlorothiazideTeva20mg/12.5mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom30/03/2010until31/05/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EnalaprilMaleateHydrochlorothiazideTeva20mg/12.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgofenalaprilmaleateand12.5mgofhydrochlorothiazide(HCT).

Excipients:

Eachtabletcontains140mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

White,round,slightlyarchedtablets,debossed“EL”,“20”andscorelineononesideandplainontheother.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

Thisfixeddosecombinationisindicatedinpatientswhosebloodpressureisnotadequatelycontrolledwith

enalaprilalone.

Thisfixeddosemayalsoreplacethecombinationof20mgenalaprilmaleateand12.5mghydrochlorothiazidein

patientswhohavebeenstabilisedontheindividualactivesubstancesgiveninthesameproportionsasseparate

medications.

Thisfixeddosecombinationisnotsuitableforinitialtherapy

4.2Posologyandmethodofadministration

Enalapril/HCTcanbeadministeredinasingledose/daywithorwithoutfood.

Individualdosetitrationwithbothactivesubstancescanberecommended.

Whenclinicallyappropriate,directchangefromACEinhibitormonotherapytothefixedcombinationmaybe

considered.

Dosageinpatientswithnormalrenalfunction

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Dosageinrenalinsufficiency

-Creatinineclearance ≥30ml/min:Thedoseofenalaprilshouldbetitratedinpatientswithrenalimpairmentwhose

creatinineclearanceis ≥30ml/minbeforeswitchingtothefixedcombination.Loopdiureticsarepreferredtothiazides

inthispopulation.Thedoseofenalaprilmaleateandhydrochlorothiazideshouldbekeptaslowaspossible(seesection

4.4).

Potassiumandcreatinineshouldbemonitoredperiodicallyinthesepatients,e.g.every2monthswhenthetreatment

hasbeenstabilised(seesection4.4).

-Creatinineclearance<30ml/min:seesection4.3.

Specialpopulation

Insalt/volumedepletedpatients,thestartingdoseis5mgenalaprilorlower.Individualdosetitrationwithenalapriland

hydrochlorothiazideisrecommended.

Useintheelderly

Theuseinelderlyhasbeenshownasgoodasinyoungerhypertensivepatients.Incaseofphysiologicalrenal

impairment,titrationwiththemonocomponentenalaprilisrecommendedpriortousingthefixedcombination.

Useinchildrenandadolescents

SafetyandeffectivenessofEnalapril/HCTinchildrenhasnotbeenestablished.

4.3Contraindications

Associatedwithenalapril:

Thismedicinalproductmustnotbeusedinpatientswith:

-hypersensitivitytoenalapril,otherACEinhibitorsortoanyoftheexcipients,

-ahistoryofangiooedema(Quincke’soedema)linkedtoprevioustreatmentwithanACEinhibitorand/orinpatients

withinheritedoridiopathicangioedema.

-duringthesecondandthirdtrimestersofpregnancy(see sections4.4and 4.6).

Associatedwithhydrochlorothiazide:

Thismedicinalproductmustnotbeusedinpatientswith:

-hypersensitivitytohydrochlorothiazideorothersulphonamides

-severerenalimpairment(creatinineclearance<30ml/min)

-Severehepaticimpairment/hepaticencephalopathy

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4.4Specialwarningsandprecautionsforuse

Warnings

ASSOCIATEDWITHTHEEXCIPIENTS

Thismedicinalproductcontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,

theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

ASSOCIATEDWITHENALAPRIL

Symptomatichypotension

Symptomatichypotensionisrarelyseeninuncomplicatedhypertensivepatients.Inhypertensivepatientsreceiving

enalapril,symptomatichypotensionismorelikelytooccurifthepatienthasbeenvolume-depletede.g.bydiuretic

therapy,dietarysaltrestriction,dialysis,diarrhoeaorvomiting(seesection4.5).Inpatientswithheartfailure,withor

withoutassociatedrenalinsufficiency,symptomatichypotensionhasbeenobserved.Thisismostlikelytooccurin

thosepatientswithmoreseveredegreesofheartfailure,asreflectedbytheuseofhighdosesofloopdiuretics,

hyponatremiaorfunctionalrenalimpairment.Inthesepatients,therapyshouldbestartedundermedicalsupervision

andthepatientsshouldbefollowedcloselywheneverthedoseofenalapriland/ordiureticisadjusted.Similar

considerationsmayapplytopatientswithischemicheartorcerebrovasculardiseaseinwhomanexcessivefallinblood

pressurecouldresultinamyocardialinfarctionorcerebrovascularaccident.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionand,ifnecessary,shouldreceivean

intravenousinfusionofnormalsaline.Atransienthypotensiveresponseisnotacontraindicationtofurtherdoses,

whichcanbegivenusuallywithoutdifficultyoncethebloodpressurehasincreasedaftervolumeexpansion.

Insomepatientswithheartfailurewhohavenormalorlowbloodpressure,additionalloweringofsystematicblood

pressuremayoccurwithenalapril.Thiseffectisanticipatedandusuallyisnotareasontodiscontinuetreatment.If

hypotensionbecomessymptomatic,areductionofdoseand/ordiscontinuationofthediureticand/orenalaprilmaybe

necessary.

Aorticormitralvalvestenosis/hypertophiccardiomyopathy

Aswithallvasodilators,ACEinhibitorsshouldbegivenwithcautioninpatientswithleftventricularvalvularand

outflowtractobstructionandavoidedincasesofcardiogenicshockandhaemodynamicallysignificantobstruction.

Renalfunctionimpairment

Incasesofrenalimpairment(creatinineclearance<80ml/min),theinitialenalaprildosageshouldbeadjusted

accordingtothepatient’screatinineclearance(seesection4.2)andthenasafunctionofthepatient’sresponseto

treatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforthesepatients.

Renalfailurehasbeenreportedinassociationwithenalapril,andhasbeenmainlyinpatientswithsevereheartfailure

orunderlyingrenaldisease,includingrenalarterystenosis.Ifrecognisedpromptlyandtreatedappropriately,renal

failurewhenassociatedwiththerapywithenalaprilisusuallyreversible.

Somehypertensivepatients,withnoapparentpre-existingrenaldiseasehavedevelopedincreasesinbloodureaand

creatininewhenenalaprilhasbeengivenconcurrentlywithadiuretic.Dosagereductionofenalapriland/or

discontinuationofthediureticmayberequired.Thissituationshouldraisethepossibilityofunderlyingrenalartery

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Renovascularhypertension

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.Lossofrenalfunctionmayoccur

withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

Kidneytransplantation

Thereisnoexperienceregardingtheadministrationofenalaprilinpatientswitharecentkidneytransplantation.

Treatmentwithenalaprilisthereforenotrecommended

Hepaticfailure

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceorhepatitisand

progressestofulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.

PatientsreceivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinue

theACEinhibitorandreceiveappropriatemedicalfollow-up.

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Enalaprilshouldbe

usedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifenalaprilisusedinsuchpatients,periodicalmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection

Hypersensitivity/angioneuroticoedema

Angioneuroticoedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedinpatientstreated

withangiotensinconvertingenzymeinhibitors,includingenalapril.Thismayoccuratanytimeduringtreatment.In

suchcases,enalaprilshouldbediscontinuedpromptly,andappropriatemonitoringshouldbeinstitutedtoensure

completeresolutionofsymptomspriortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfined

tothefaceandlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulin

relievingsymptoms.Eveninthoseinstanceswhereswellingofonlythetongueisinvolved,withoutrespiratorydistress,

patientsmayrequireprolongedobservationsincetreatmentwithantihistaminesandcorticosteroidsmaynotbe

sufficient.

Angioneuroticoedemaassociatedwithlaryngealoedemamaybefatal.Veryrarely,fatalitieshavebeenreporteddueto

angiooedemaassociatedwithlaryngealoedemaortongueoedema.Patientswithinvolvementofthetongueglottisor

larynxarelikelytoexperienceairwayobstruction,especiallythosewithahistoryofairwaysurgery.

Wherethereisinvolvementofthetongue,glottisorlarynx,likelytocauseairwayobstruction,appropriatetherapy,

whichmayincludesubcutaneousepinephrinesolution1:1000(0.3mlto0.5ml)and/ormeasurestoensureapatent

airway,shouldbeadministeredpromptly.

BlackpatientstakingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedtonon-

blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

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Anaphylactoidreactionsduringhymenopteradesensitization

Rarely,patientsreceivingACEinhibitorsduringdesensitizationwithhymenopteravenomhaveexperiencedlife-

threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-inhibitortherapy

priortoeachdesensitization.

AnaphylactoidreactionsduringLDLapheresis

Rarely,patientsreceivingACEinhibitorsduringlowdensitylipoprotein(LDL)-apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-

inhibitortherapypriortoeachapheresis.

Haemodialysispatients

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

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofantihypertensiveagent.

Diabeticpatients

Indiabeticpatientstreatedwithoralantidiabeticagentsorinsulin,glycemiccontrolshouldbecloselymonitoredduring

thefirstmonthoftreatmentwithanACEinhibitor.(seesection4.5).

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

Surgery/anaesthesia

Inpatientsundergoingmajorsurgeryorduringanesthesiawithagentsthatproducehypotension,enalaprilblocks

angiotensinIIformationsecondarytocompensatoryreninrelease.Ifhypotensionoccursandisconsideredtobedueto

thismechanism,itcanbecorrectedbyvolumeexpansion.

Hyperkalaemia

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingenalapril.

Patientsatriskforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,diabetesmellitus,orthose

usingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes;or

thosepatientstakingotherdrugsassociatedwithincreasesinserumpotassium(e.g.heparin).Ifconcomitantuseofthe

abovementionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumisrecommended.

Ethnicdifferences

Aswithotherangiotensinconvertingenzymeinhibitors,enalaprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Pregnancy

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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Interactions

ThismedicinalproductISGENERALLYNOTRECOMMENDEDincombinationwithpotassium-sparingdiuretics,

potassiumsaltsandestramustine(seesection4.5).

ASSOCIATEDWITHHYDROCHLOROTHIAZIDE

Hepaticimpairment

Thiazideshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticencephalopathyinpatientswithhepatic

disease.Inthiscase,treatmentwiththediureticmustbestoppedimmediately.

Enalapril/HCTisgenerallynotrecommendedincombinationwithsultopride(seesection4.5).

ASSOCIATEDWITHENALAPRILANDHYDROCHLOROTHIAZIDE

Interaction

Thismedicinalproductisgenerallynotrecommendedincombinationwithlithiumduetothepotentialisationoflithium

toxicity(seesection4.5).

PRECAUTIONSFORUSE

ASSOCIATEDWITHHYDROCHLOROTHIAZIDE

Fluid/electrolytebalance

Asforanypatientreceivingdiuretictherapy,periodicdeterminationofserumelectrolytesshouldbeperformedat

appropriateintervals.

Thiazides(includinghydrochlorothiazide)cancausefluidorelectrolyteimbalance(hypokalaemia,hyponatraemia,and

hypochloraemicalkalosis).Warningsignsoffluidorelectrolyteimbalancearedrynessofmouth,thirst,weakness,

lethargy,drowsiness,restlessness,musclepainorcramps,muscularfatigue,hypotension,oliguria,tachycardia,and

gastrointestinaldisturbancessuchasnauseaorvomiting.

Althoughhypokalaemiamaydevelopwiththeuseofthiazidediuretics,concurrenttherapywithenalaprilmayreduce

diuretic-inducedhypokalaemia.Theriskofhypokalaemiaisgreatestinpatientswithcirrhosisoftheliver,inpatients

experiencingbriskdiuresis,inpatientswhoarereceivinginadequateoralintakeofelectrolytesandinpatientsreceiving

concomitanttherapywithcorticosteroidsorACTH(seesection4.5).

Dilutionalhyponatraemiamayoccurinoedematouspatientsinhotweather.Chloridedeficitisgenerallymildand

usuallydoesnotrequiretreatment.

Natraemia

Sodiumlevelsmustbeassessedbeforetheinitiationoftreatment,andatregularintervalsthereafter.Alldiuretic

treatmentcancausehyponatraemia,withpotentiallyseriousconsequences.Sinceadecreaseinnatraemiamayinitially

beasymptomatic,regularmonitoringisessentialandmustbeevenmorefrequentinat-riskpopulationssuchasthe

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Kalaemia

Potassiumdepletionandhypokalaemiaarethemajorrisksassociatedwiththiazideandrelateddiuretics.Hypokalaemia

(<3.5mmol/l)mustbepreventedincertainat-riskpopulations,suchaselderlyand/ormalnourishedpatients,especially

whenreceivingcombinationtherapy,cirrhoticpatientswithoedemaandascites,coronarypatients,patientswithheart

failure.Inthesecases,hypokalaemiaincreasesthecardiotoxicityofdigitalisglycosidesandtheriskofarrhythmia.

InpatientswithalongQTinterval,whethercongenitalorsubstance-induced,hypokalaemiaincreasestheriskofsevere

arrhythmia,inparticularpotentiallyfataltorsadedepointes,especiallyinpatientswithbradycardia.

Potassiumlevelsmustberegularlymonitored,startinginthefirstweekoftreatment.

Calcaemia

Thiazidemaydecreaseurinarycalciumexcretionandmaycauseintermittentandslightelevationofserumcalcium.

Markedhypercalcaemiamaybeevidenceofhiddenhyperparathyroidism.Thiazidesshouldbediscontinuedbefore

carryingouttestsforparathyroidfunction.

Magnesiumplasmalevels

Thiazideshavebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Metabolicandendocrineeffects

Thiazidetherapymayimpairglucoseintolerance.Indiabeticpatientsdosageadjustmentsofinsulinororal

hypoglycaemicagentsmayberequired.Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.

Increasesincholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretictherapy.Thesaltandvolume

depletioncausedbythiazidesreducestheurinaryeliminationofuricacid.Hyperuricaemiamayoccurorfrankgout

maybeprecipitatedincertainpatientsreceivingthiazidetherapy.

Renalimpairment

Thiazidediureticsarefullyefficaciousonlyinpatientswithnormalrenalfunctionormildrenalimpairment(evaluated,

forexample,accordingtocreatinineclearance).Intheelderly,thevalueforcreatinineclearancemustbeadjustedfor

age,weightandsex.

Hypovolaemia,secondarytodiuretic-inducedfluidandsodiumlossatthebeginningoftreatment,leadstoreduced

glomerularfiltration.Thiscancauseanincreaseinbloodureaandcreatinine.

Thistransientfunctionalrenalimpairmentiswithoutconsequenceinpatientswithnormalrenalfunction,butcan

aggravatepre-existingrenalimpairment.

Thiazidesshouldbeusedwithcautioninsevererenaldisease.Inpatientswithrenaldisease,thiazidesmayprecipitate

azotaemia.Cumulativeeffectsofthedrugmaydevelopinpatientswithimpairedrenalfunction.Ifprogressiverenal

impairmentbecomesevident,asindicatedbyarisingnon-proteinnitrogen,carefulreappraisaloftherapyisnecessary,

withconsiderationgiventodiscontinuingdiuretictherapy.

Athletes/anti-dopingtest

Theattentionofathletesisdrawntothefactthatthismedicinalproductcontainsanactivesubstancewhichmayinduce

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Other

Sensitivityreactionsmayoccurinpatientswithorwithoutahistoryofallergyorbronchialasthma.Thepossibilityof

exacerbationoractivationofsystemiclupuserythematosushasbeenreported.

ASSOCIATEDWITHENALAPRILANDHYDROCHLOROTHIAZIDE

Functionalrenalimpairment

Somehypertensivepatientswithnoapparentpre-existingrenaldiseasehavedevelopedsignsoffunctionalrenal

impairment.Ifthisoccurs,treatmentmustbediscontinued.Reinstitutionoftherapyatreduceddosagemaybepossible,

oreitherofthecomponentsmaybeusedappropriatelyalone.

Hypotensionandfluid/electrolyteimbalance

Patientsmustbesystematicallymonitoredforclinicalsignsoffluid/electrolyteimbalance,whichmayoccurduring

intercurrentdiarrhoeaorvomiting.Regularmonitoringofplasmaelectrolytesmustbeundertakeninsuchpatients.

Significanthypotensionmayrequiretheinitiationofintravenousisotonicsaline.

Transienthypotensionisnotacontra-indicationtocontinuedtreatment.Aftervolumerepletionandestablishmentof

satisfactorybloodpressure,treatmentcanbereinstituted,eitheratalowerdosageoreitherofthecomponentsmaybe

usedappropriatelyalone.

Riskofhypokalaemia

ThecombinationofanACEinhibitorandnon-potassium-sparingdiureticdoesnotprecludethedevelopmentof

hypokalaemia,inparticularindiabeticorrenallyimpairedpatients.Plasmapotassiummustberegularlymonitored.

Paediatricuse

Thesafetyandefficacyofthisproducthavenotbeendemonstratedincontrolledstudiesinchildren.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

RELATEDTOENALAPRIL

Someactivesubstancesortherapeuticclassesmayfavourthedevelopmentofhyperkalaemia:potassiumsalts,

potassium-sparingdiuretics,ACEinhibitors,angiotensinIIinhibitors,non-steroidalanti-inflammatoryagents,heparins

(lowmolecularweightorunfractionned),ciclosporinandtacrolimus,trimethoprim.

Theoccurrenceofhyperkalaemiamaydependontheexistenceofassociatedriskfactors.

Thisriskisincreasedincombinationwiththeabove-mentionedmedicinalproducts.

Notrecommendedcombinations

-Potassium-sparingdiureticsaloneorincombination:amiloride,potassiumcanrenoate,spironolactone,triamterene,

potassium(salts)Hyperkalaemia(potentiallylethal),especiallyinconjunctionwithrenalimpairment(additive

hyperkalaemiceffects)

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-Estramustine:

Riskofincreasedadverseeffectssuchasangioneuroticoedema(angioedema).

Combinationsrequiringprecautionsforuse

-Antidiabeticagents(insulin,hypoglycaemicsulphonamides):

TheuseofACEinhibitorsmayincreasethehypoglycaemiceffectindiabeticpatientstreatedwithinsulinor

hypoglycaemiasulphonamides.

Hypoglycaemicepisodesappeartoberare(improvedglucosetolerancewhichcouldleadtoreducedneedforinsulin).

Self-monitoringofglycaemiashouldbereinforced.

-Non-potassium-sparingdiuretics:

Riskofsuddenhypotensionand/oracuterenalimpairmentoninitiationoftreatmentwithanACEinhibitorinpatients

withpre-existingsalt/volumedepletion

Inarterialhypertension,whenpriordiuretictherapyhascausedsalt/volumedepletion,eitherthediureticmustbe

discontinuedbeforeinitiatingtheACEinhibitor,inwhichcaseanon-potassium-sparingdiureticcanbethereafter

reintroducedortheACEinhibitormustbeinitiatedwithalowdosageandprogressivelyincreased.

-Indiuretic-treatedcongestiveheartfailure,theACEinhibitormustbeinitiatedataverylowdosage,possiblyafter

reducingthedosageoftheassociatednon-potassium-sparingdiuretic.

Inallcases,renalfunction(creatininelevels)mustbemonitoredduringthefirstfewweeksofACEinhibitortherapy.

RELATEDTOHYDROCHLOROTHIAZIDE

Notrecommendedassociations

-Sultopride:

Increasedriskofventriculararrhythmia,especiallytorsadedepointes(hypokalaemiafavourstheoccurrenceofthis

adversereaction).

Combinationsrequiringprecautionsforuse

-Substancesthatcausetorsadedepointes(exceptsultopride):

ClassIAantidysrhythmicagents(quinidine,hydroquinidine,disopyramide);classIIIantidysrhythmicagents

(amiodarone,dofetilide,ibutilide,sotalol);someneuroleptics(chlorpromazine,cyamemazine,levomepromazine,

thioridazine,trifluoperazine),benzamides(amisulpride,sulpiride,tiapride),butyrophenones(droperidol,haloperidol),

otherneuroleptics(pimozide);othersubstancessuchasbepridil,cisapride,diphemanil,IVerythromycin,halofantrine,

mizolastine,moxifloxacin,pentamidine,sparfloxacin,IVvincamine,methadone.

Increasedriskofventriculararrhythmia,especiallytorsadedepointes(hypokalaemiafavourstheoccurrenceofthis

adversereaction).

Hypokalaemiamustbecorrectedbeforeadministration,andclinical,electrolyteandelectrocardiographicmonitoring

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-Otherhypokalaemicagents:

amphotericinB(intravenous),glucocorticoids(systemic),tetracosactide,stimulantlaxatives.

Increasedriskofhypokalaemia(additiveeffect).

Potassiumlevelsmustbemonitoredand,ifnecessary,corrected.Takeparticularlyintoaccountwithconcomitant

digitalistherapy.Usenon-stimulantlaxatives.

-Digitalisglycosides:

Hypokalaemiafavouringthetoxiceffectsofdigitalisglycosides.

MonitorpotassiumandpossiblyECG.

-Metformin:

Metformin-inducedlacticacidosismaybetriggeredbypossiblefunctionalrenalimpairmentinducedbydiuretics,

especiallyloopdiuretics.

Metforminmustnotbeusedwhencreatininelevelsexceed15mg/l(135micromol/l)inmenand12mg/l(110

micromol/l)inwomen.

-Iodinatedcontrastmedia:

Increasedriskofacuterenalfailure,inparticularwhenhighdosesofiodinatedcontrastmediaareused,inpatients

dehydratedasaconsequenceofdiureticuse.

Patientsmustbere-hydratedbeforeadministrationoftheiodinatedproduct.

-Carbamazepine:

Riskofsymptomatichyponatraemia.

Clinicalandbiologicalmonitoring.Ifpossible,useanotherclassofdiuretics.

Combinationstobetakenintoaccount

-Calcium(salts):

Riskofhypercalcaemiathroughdecreasedurinarycalciumexcretion.

-Ciclosporin:

Riskofincreasedcreatininelevelswithoutalterationofplasmaciclosporinconcentration,evenintheabsenceof

salt/volumedepletion.

INTERACTIONSCOMMONTOENALAPRILANDHYDROCHLOROTHIAZIDE

Notrecommendedcombinations

Lithium:

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-Alpha-blockingagentsusedasanti-hypertensivedrugs:prazosin,timazosin,urapidal:increasedantihypertensive

effect.Increasedriskoforthostatichypotension(additiveeffect).

Combinationsrequiringprecautionsforuse

-Non-steroidalanti-inflammatoryagents(NSAIDs,systemic),includingselectivecyclooxygenase(COX)2inhibitors,

high-doseacetylsalicylicacid(aspirin)( ≥3g/day):

Acuterenalfailureinat-riskpatients(elderlyand/ordehydrated)throughreducedglomerularfiltration(NSAID-

inducedinhibitionofvasodilatingprostaglandins).

Alsoreducedantihypertensiveeffect.

Hydratethepatient;monitorrenalfunctionatthebeginningoftreatment.

-Baclofen:Increasedantihypertensiveeffect.

Monitorbloodpressureandadaptantihypertensivedosageifnecessary.

Combinationstobetakenintoaccount

-Amifostine:Increasedantihypertensiveeffect.

-Tricyclicantidepressants,neuroleptics:Increasedantihypertensiveeffectandriskoforthostatichypotension(additive

effect).

-Corticosteroids,tetracosactide(systemic)(excepthydrocortisoneusedasasubstituteinAddison’sdisease):

Reducedantihypertensiveeffect(corticosteroid-inducedsalt/volumeretention).

Alpha-blockersagentsusedinurology:alfuzosin,doxazosin,prazosin,tamsulosin,terazosin:increasedhypotensive

effect.Increasedriskofortostatichypotension(additiveeffect).

4.6Pregnancyandlactation

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancyandlactation:

Enalapril/HCTisnotrecommendedduringthefirsttrimesterofpregnancy.Enalapril/HCTiscontraindicatedduringthe

secondandthirdtrimestersofpregnancy.

Enalapril/HCTiscontraindicatedduringlactation.Adecisionshouldthereforebemadewhethertodiscontinuenursing

ortodiscontinueEnalapril/HCTtakingaccounttheimportanceofthistherapyforthemother.

Pregnancy

Linkedtoenalapril

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

ACEinhibitorsiscontra-indicatedduringthe2ndand3rdtrimesterofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

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Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,

alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).ShouldexposuretoACEinhibitorhaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Linkedtohydrochlorothiazide

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide

itsuseduringthesecondandthirdtrimestermaycompromisefoeto-placentalperfusionandmaycausefoetaland

neonataleffectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionorpreeclampsiaduetothe

riskofdecreasedplasmavolumeandplacentalhypoperfusion,withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomenexceptinraresituationswhere

noothertreatmentcouldbeused.

Lactation

Bothenalaprilandhydrochlorothiazideareexcretedinbreastmilk.

Enalapril

Limitedpharmacokineticdatademonstrateverylowconcentrationsinbreastmilk(seesection5.2).Althoughthese

concentrationsseemtobeclinicallyirrelevant,theuseofenalaprilinbreastfeedingisnotrecommendedforpreterm

infantsandforthefirstfewweeksafterdelivery,becauseofthehypotheticalriskofcardiovascularandrenaleffects

andbecausethereisnotenoughclinicalexperience.Inthecaseofanolderinfant,theuseofenalaprilinabreast-

feedingmothermaybeconsideredifthistreatmentisnecessaryforthemotherandthechildisobservedforany

adverseeffect.

Hydrochlorothiazide

Thiazidesduringbreastfeedinghavebeenassociatedwithdecreaseorevensuppressionofmilklactation.

Hypersensitivitytosulphonamide-deriveddrugs,hypokalaemiaandnuclearicterusmightoccur.

Adecisionshouldbemadewhethertodiscontinuenursingortodiscontinuetherapytakingintoaccounttheimportance

ofthistherapyforthemother.

4.7Effectsonabilitytodriveandusemachines

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallyvertigoorfatiguemay

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4.8Undesirableeffects

RELATEDTOENALAPRIL

Undesirableeffectsreportedforenalaprilinclude:Verycommon(>1/10),Common( ≥1/100to<1/10),Uncommon(≥

1/1000to<1/100),Rare( ≥1/10,000to<1/1000),Veryrare(<10,000),Notknown(cannotbeestimatedfromthe

availabledata)

Bloodandlymphaticsystemdisorders:

uncommon:anaemia(includingaplasticandhaemolytic)

rare:neutropenia,decreasesinhaemoglobin,decreasesinhaematocrit,thrombocytopenia,agranulocytosis,

myelosuppression,pancytopenia,lymphadenopathy,autoimmunediseases.

Metabolicandnutritiondisorders:

uncommon:hypoglycemia(seesection4.4,diabeticpatients).

Nervoussystemandpsychiatricdisorders

Common;headache,depression

Uncommon:confusion,somnolence,insomnia,nervousness,paraesthesia,vertigo

Rare:dreamabnormality,sleepdisorders

Eyedisorders:

verycommon:blurredvision.

Cardiacandvasculardisorders:

verycommon:dizziness

common:hypotension(includingorthostatichypotension),syncope,myocardialinfarctionorcerebrovascularaccident,

possiblysecondarytoexcessivehypotensioninriskpatients(seesection4.4),chestpain,rhythmdisorders,angina

pectoris,tachycardia

uncommon:orthostatichypotension,palpitations

rare:Raynaud'ssyndrome.

Respiratory,thoracicandmediastinaldisorders:

verycommon:cough

common:dyspnea

uncommon:rhinorrhea,sorethroatandhoarseness,bronchospasm/asthma

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Gastrointestinaldisorders:

verycommon:nausea

common:diarrhoea,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/angioneuroticoedema,angioneuroticoedemaoftheface,extremities,lips,tongue,

glottisand/orlarynxhasbeenreported(see4.4).

uncommon:diaphoresis,pruritus,urticaria,alopecia

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

erythroderma

Asymptomcomplexhasbeenreportedwhichmayincludesomeorallofthefollowing:fever,serositis,vasculitis,

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

photosensitivityorotherdermatologicmanifestationsmayoccur.

Renalandurinarydisorders:

uncommon:renaldysfunction,renalfailure,proteinuria

rare:oliguria.

Reproductivesystemandbreastdisorders:

uncommon:impotence

rare:gynaecomastia.

Generaldisordersandadministrationsiteconditions:

verycommon:asthenia

common:fatigue

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Investigations:

common:hyperkalaemia,increasesinserumcreatinine

uncommon:increasesinbloodureacontent,hyponatraemia

rare:elevationsofliverenzymes,elevationsofserumbilirubin.

RELATEDTOHYDROCHLOROTHIAZIDE

Infectionsandinfestations:

Sialadenitis

Bloodandlymphaticsystemdisorders:

Leucopenia,neutropenia/agranulocytosis,thrombocytopenia,aplasticanaemia,haemolyticanaemia,bonemarrow

depression

Metabolismandnutritiondisorders:

Anorexia,hyperglycaemia,glycosuria,hyperuricaemia,electrolyteimbalance(includinghyponatraemiaand

hypokalemia),increasesincholesterolandtriglycerides

Psychiatricdisorders:

Restlessness,depression,sleepdisturbances

Nervoussystemdisorders:

Lossofappetite,paraesthesia,light-headedness

Eyedisorders:

Xanthopsia,transientblurredvision

Earandlabyrinthdisorders:

Vertigo

Cardiacdisorders:

Posturalhypotension,cardiacarrhythmias

Vasculardisorders:

Necrotisingangiitis(vasculitis,cutaneousvasculitis)

Respiratory,thoracicandmediastinaldisorders:

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Gastrointestinaldisorders:

Gastricirritation,diarrhoea,constipation,pancreatitis

Hepato-billarydisorders:

Jaundice(intrahepaticcholestaticjaundice)

Skinandsubcutaneoustissuedisorders:

Photosensitivityreactions,rash,cutaneouslupuserythematosus-likereactions,reactivationofcutaneouslupus

erythematosus,urticaria,anaphylacticreactions,toxicepidermalnecrolysis

Musculoskeletal,connectivetissueandbonedisorders:

Musclespasm

Renalandurinarydisorders:

Renaldysfunction,interstitialnephritis

Generaldisordersandadministrationsiteconditions:

Fever,weakness

4.9Overdose

NospecificinformationisavailablewithrespecttothetreatmentofanoverdoseofEnalapril/HCT20mg/12.5mg.

Symptomsofoverdoseareseverehypotension,shock,stupor,bradycadia,electrolytedisturbancesandrenalfailure.

ASSOCIATEDWITHENALAPRIL

Limiteddataareavailableonoverdoseinhumans.

Symptoms

Themostprominentfeaturesofoverdosereportedtodatearemarkedhypotensionbeginningsomesixhoursafter

ingestionofthetablets,concomitantwithblockadeoftherenin-angiotensinsystem,andstupor.

SymptomsassociatedwithoverdoseofACEinhibitorsmayincludecirculatoryshock,electrolytedisturbances,renal

failure,hyperventilation,tachycardia,palpitations,bradycardia,dizziness,anxietyandcough.Serumenalaprilatlevels

100-and200-foldhigherthanusuallyseenaftertherapeuticdoseshavebeenreportedafteringestionof300mgand

440mgofenalaprilrespectively.

ASSOCIATEDWITHHYDROCHLOROTHIAZIDE

Thesignsofacuteintoxicationareprimarilyrelatedtofluid/electrolyteimbalance(hyponatramia,hypokalaemia).

Inadditiontotheexpecteddiuresis,overdoseofthiazidesmayproducevaryingdegreesoflethargy,whichmay

progresstocomawithinafewhours,withminimaldepressionofrespirationandcardiovascularfunction,andwithout

evidenceofserumelectrolytechangesordehydration.Themechanismofthiazide-inducedCNSdepressionis

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GastrointestinalirritationinBUNhasbeenreported,andserumelectrolytechangesmayoccur,especiallyinpatients

withimpairedrenalfunction.

Clinically,nausea,vomiting,hypotension,cramps,dizziness,somnolence,confusionalstates,polyuriaoroliguriatothe

pointofanuria(throughhypovolaemia)mayoccur.

COMBINATION

Treatmentissymptomaticandsupportive.TreatmentwithEnalapril/HCT20mg/12.5mgshouldbediscontinuedand

thepatientshouldbecarefullymonitored.Recommendedmeasuresincludeinductionofvomiting,administrationof

activatedcharcoalandadministrationofalaxativeand/orgastriclavageifthetabletsweretakenrecently.Any

dehydration,disturbancesintheelectrolytebalanceandhypotensionshouldbetreatedinanappropriatemanner.

Enalaprilatcanbeeliminatedfrombloodcirculationviahaemodialysis(seesection4.4).Theextenttowhich

hydrochlorothiazideisremovedisnotestablished.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitorsanddiuretics

ATCcode:C09BA02

Pharmacologicalmechanismofaction

ASSOCIATEDWITHENALAPRIL

Enalaprilmaleateisthemaleatesaltofenalapril,aderivativeoftwoamno-acids,LalanineandL-proline.Angiotensin

convertingenzyme(ACE)isapeptidyldipeptidasewhichcatalysestheconversionofangiotensinItothepressor

substanceangiotensinII.Afterabsorbtion,enalaprilishydrolysedtoenalaprilat,whichinhibitsACE.Inhibitionof

ACEresultsindecreasedplasmaangiotensinII,whichleadstoincreasedplasmarenninactivity(duetoremovalof

negativefeedbackofrenninrelease),anddecreasedaldosteronesecretion.

ACEisidenticaltokininaseII.Thusenalaprilmayalsoblockthedegradationofbradykinin,apotentvasodepressor

peptide.However,therolethatthisplaysinthetherapeuticeffectsofenalaprilremainstobeelucidated.

ASSOCIATEDWITHNHYDROCHLOROTHIAZIDE

Hydrochlorothiazideisathiazidediureticwhichactsbyinhibitingfluid-expellingandbloodpressure-loweringagent

whichincreasethetubularre-absorptionofsodiuminthecorticaldilutingsegment.

Itincreasestheurinaryexcretionofsodiumandchlorideand,toalesserdegree,theexcretionofpotassiumand

magnesium,thusincreasingdiuresisandexertinganantihypertensiveeffect.

Characteristicsoftheantihypertensivetherapy

Whilethemechanismthroughwhichenalparillowersbloodpressureisbelievedtobeprimarilysuppressionofthe

renin-angiotensinaldosteronesystem,enalaprilisantihypertensiveeveninpatientswithlow-reninhypertension.

Administrationofenalapriltopatientswithhypertensionresultsinareductionofbothsupineandstandingblood

pressurewithoutasignificantincreaseinheartrate.

Symptomaticposturalhypotensionisinfrequent.Insomepatientsthedevelopmentofoptimalbloodpressurereduction

mayrequireseveralweeksoftherapy.Abruptwithdrawalofenalaprilhasnotbeenassociatedwithrapidincreasein

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EffectiveinhibitionofACEactivityusuallyoccurs2to4hoursafteroraladministrationofanindividualdoseof

enalapril.Onsetofantihypertensiveactivitywasusuallyseenatonehour,withpeakreductionofbloodpressure

achievedby4to6hoursafteradministration.Thedurationofeffectisdose-related.However,atrecommendeddoses,

antihypertensiveandhaemodynamiceffectshavebeenshowntobemaintainedforatleast24hours.

Inhaemodynamicstudiesinpatientswithessentialhypertension,bloodpressurereductionwasaccompaniedbya

reductioninperipheralarterialresistancewithanincreaseincardiacoutputandlittleornochangeinheartrate.

Followingadministrationofenalapriltherewasanincreaseinrenalbloodflow;glomerularfiltrationratewas

unchanged.Therewasnoevidenceofsodiumorwaterretention.However,inpatientswithlowpre-treatment

glomerularfiltrationrates,therateswereusuallyincreased.

Inshort-termclinicalstudiesindiabeticandnon-diabeticpatientswithrenaldisease,decreasesinalbuminuriaand

urinaryexcretionofIgGandtotalurinaryproteinwereseenaftertheadministrationofenalapril.

Whengiventogetherwiththiazide-typediuretics,thebloodpressure-loweringeffectsofenalaprilareatleastadditive.

Enalaprilmayreduceorpreventthedevelopmentofthiazide-inducedhypokalaemia.

ASSOCIATEDWITHHYDROCHLROTHIAZIDE

Thetimetoonsetofdiureticactivityisapproximately2hours.Diureticactivityreachesapeakafter4hoursandis

maintainedfor6to12hours.

Aboveacertaindose,thiazidediureticsreachaplateauintermsoftherapeuticeffectwhereasadversereactions

continuetomultiply.Whentreatmentisineffective,increasingthedosebeyondrecommendeddosesservesnouseful

purposeandoftengivesrisetoadversereactions.

ASSOCIATEDWITHTHECOMBINATION

Inclinicalstudies,theconcomitantadministrationofenalaprilandhydrochlorothiazidereducedbloodpressuremore

significantlythaneithersubstancealone.

Theadministrationofenalaprilinhibitstherenin-angiotensin-aldosteronesystemandtendstoreducethe

hydrochlorothiazide-inducedpotassium.

CombinationofanACEinhibitorwithathiazidediureticproducesasynergisticeffectandalsolessenstheriskof

hypokalaemiaprovokedbythediureticalone.

5.2Pharmacokineticproperties

Co-administrationofenalaprilandhydrochlorothiazideinvariousdoseshaslittleornoeffectonthebioavailabilityof

thesetwosubstances.

ASSOCIATEDWITHENALAPRIL

Absorption

Oralenalaprilisrapidlyabsorbed,withpeakserumconcentrationsofenalapriloccurringwithin1hour.Basedon

urinaryrecovery,theextentofabsorptionofenalaprilfromoralenalaprilmaleateisapproximately60%.The

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Distribution

Followingabsorption,oralenalaprilisrapidlyandextensivelyhydrolysedtoenalaprilat,apotentangiotensin

convertingenzymeinhibitor.Peakserumconcentrationsofenalaprilatoccur3to4hoursafteranoraldoseofenalapril

maleate.Theeffectivehalf-lifeforaccumulationofenalaprilfollowingconcentrationsofenalaprilatwerereachedafter

fourdaysoftreatment.

Overtherangeofconcentrationswhicharetherapeuticallyrelevant,enalaprilbindingtohumanplasmaproteinsdoes

notexeed60%

Biotransformation

Exceptforconversiontoenalaprilat,thereisnoevidenceforsignificantmetabolismofenalapril.

Elimination

Excretionofenalaprilatisprimarilyrenal.Theprincipalcomponentsinurineareenalaprilat,accountingforabout40%

ofthedose,andintactenalapril(about20%).

Renalimpairment

Theexposureofenalaprilandenalaprilatisincreasedinpatientswithrenalinsufficiency.Inpatientswithmildto

moderaterenalinsufficiency(creataninceclearance40-60ml/min)steadystateAUCofenalaprilatwasapproximately

two-foldhigherthaninpatientswithnormalrenalfunctionafteradministrationof5mgoncedaily.Insevererenal

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

enalaprilatfollowingmultipledosesofenalaprilmaleateisprolongedatthislevelofrenalinsufficiencyandtimeto

steadystateisdelayed.(Seesection4.2,DosageinrenalInsufficiency).

Enalaprilatmayberemovedfromthegeneralcirculationbyhemodialysis.Thedialysisclearanceis62ml/min.

Lactation

Afterasingle20mgoraldoseinfivepostpartumwomen,theaveragepeakenalaprilmilklevelwas1.7µg/L(range

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

peaksoccurredatvarioustimesoverthe24-hourperiod.Usingthepeakmilkleveldata,theestimatedmaximumintake

ofanexclusivelybreastfedinfantwouldbeabout0.16%ofthematernalweightadjusteddosage.Awomanwhohad

beentakingoralenalapril10mgdailyfor11monthshadpeakenalaprilmilklevelsof2µg/L4hoursafteradoseand

peakenalaprilatlevelsof0.75µg/Labout9hoursafterthedose.Thetotalamountofenalaprilandenalaprilatmeasured

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

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

levelswerenotdetermined.

ASSOCIATEDWITHHYDROCHLOROTHIAZIDE

Absorption

Oralabsorptionofhydrochlorothiazideisrelativelyrapid.

Thebioavailabilityofhydrochlorothiazidevariesbetween60and80%.Thetimetopeakplasmaconcentration(Tmax)

variesbetween1.5and5hours,withameanofabout4hours.

Distribution

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Themeanplasmahalf-lifeinfastedindividualshasbeenreportedtobe5to15hours.

Elimination

Hydrochlorothiazideiseliminatedrapidlybythekidneyandexcretedunchanged(>95%)intheurine.Atleast61%of

theoraldoseiseliminatedunchangedwithin24hours.

Inrenalandcardiacimpairment,asintheelderly,therenalclearanceofhydrochlorothiazideisreduced,andthe

eliminationhalf-lifeincreased.Elderlysubjectsalsoshowincreasedpeakplasmaconcentrations.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.

Reproductivetoxicitystudiessuggestthatenalaprilhasnoeffectsonfertilityandreproductiveperformanceinrats,and

isnotteratogenic.Inastudyinwhichfemaleratsweredosedpriortomatingthroughgestation,anincreasedincidence

ofratpupdeathsoccurredduringlactation.

Thecompoundhasbeenshowntocrosstheplacentaandissecretedinmilk.

Angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntobefetotoxic(causinginjuryand/ordeathto

thefetus)whengiveninthesecondorthirdtrimester.

Hydrochlorothiazidecrossestheplacentalbutnottheblood-brainbarrier.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Pregelatinisedstarch(maize)

Sodiumhydrogencarbonate

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

OrientedPolyamide(OPA)/Alu/PVCcoldformablefoil/Aluminiumfoilblisterpackscontaining14,20,28,28(4x7),

30,49,49(49x1),50,56,60,90,98,98(14x7)and100tablets.Hospitalpacksof50and300tablets.

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/29/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1stJune2007.

10DATEOFREVISIONOFTHETEXT

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