ESOMEPRAZOLE TEVA PHARMA BV

Main information

  • Trade name:
  • ESOMEPRAZOLE TEVA PHARMA BV
  • Dosage:
  • 40 Milligram
  • Pharmaceutical form:
  • Tablets Gastro-Resistant
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESOMEPRAZOLE TEVA PHARMA BV
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/134/002
  • Authorization date:
  • 21-12-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EsomeprazoleTevaPharmaB.V.40mgGastro-resistantTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachgastro-resistanttabletcontains40mgesomeprazole(asmagnesiumdihydrate).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Gastro-resistanttablet

Apink,oblong,biconvex,filmcoatedtablet,with“40”engravedononesideanddimensionsofapproximately17.2x

8.7mm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

EsomeprazoleTevaPharmaB.V.tabletsareindicatedfor:

Gastro-oesophagealRefluxDisease(GORD):

-Treatmentoferosiverefluxoesophagitis

-Long-termmanagementofpatientswithhealedoesophagitistopreventrelapse

-Symptomatictreatmentofgastro-oesophagealrefluxdisease(GORD)

IncombinationwithappropriateantibacterialtherapeuticregimensfortheeradicationofHelicobacterpylori:

-HealingofHelicobacterpyloriassociatedduodenalulcer

-PreventionofrelapseofpepticulcersinpatientswithHelicobacterpyloriassociatedulcers

PatientsrequiringcontinuedNSAIDtherapy:

-HealingofgastriculcersassociatedwithNSAIDtherapy

-PreventionofgastricandduodenalulcersassociatedwithNSAIDtherapy,inpatientsatrisk

Prolongedtreatmentafteri.v.inducedpreventionofrebleedingofpepticulcers.

TreatmentofZollingerEllisonSyndrome.

Adolescentsfromtheageof12years

Gastro-oesophagealRefluxDisease(GORD)

-treatmentoferosiverefluxoesophagitis

-long-termmanagementofpatientswithhealedoesophagitistopreventrelapse

-symptomatictreatmentofgastro-oesophagealrefluxdisease(GORD)

IncombinationwithantibioticsintreatmentofduodenalulcercausedbyHelicobacterpylori.

4.2Posologyandmethodofadministration

Thetabletsshouldbeswallowedwholewithliquid.Thetabletsshouldnotbechewedorcrushed.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 1

Nootherliquidsshouldbeusedastheentericcoatmaybedissolved.Stiruntilthetabletsdisintegrateanddrinkthe

liquidwiththepelletsimmediatelyorwithin30minutes.Rinsetheglasswithhalfaglassofwateranddrink.The

pelletsmustnotbechewedorcrushed.

Forpatientswhocannotswallow,thetabletscanbedispersedinnon-carbonatedwaterandadministeredthrougha

gastrictube.Itisimportantthattheappropriatenessoftheselectedsyringeandtubeiscarefullytested.Forpreparation

andadministrationinstructionsseesection6.6.

Adultsandadolescentsfromtheageof12years:

Gastro-oesophagealRefluxDisease(GORD):

-Treatmentoferosiverefluxoesophagitis

40mgoncedailyfor4weeks.

Anadditional4weekstreatmentisrecommendedforpatientsinwhomoesophagitishasnothealedorwhohave

persistentsymptoms.

-Long-termmanagementofpatientswithhealedoesophagitistopreventrelapse

20mgoncedaily.

-Symptomatictreatmentofgastro-oesophagealrefluxdisease(GORD)

20mgoncedailyinpatientswithoutoesophagitis.Ifsymptomcontrolhasnotbeenachievedafter4weeks,thepatient

shouldbefurtherinvestigated.Oncesymptomshaveresolved,subsequentsymptomcontrolcanbeachievedusing20

mgoncedaily.Inadults,anondemandregimentaking20mgoncedaily,whenneeded,canbeused.InNSAIDtreated

patientsatriskofdevelopinggastricandduodenalulcers,subsequentsymptomcontrolusinganondemandregimenis

notrecommended.

Adults:

IncombinationwithappropriateantibacterialtherapeuticregimensfortheeradicationofHelicobacterpylori:

-HealingofHelicobacterpyloriassociatedduodenalulcer

-PreventionofrelapseofpepticulcersinpatientswithHelicobacterpyloriassociatedulcers

20mgEsomeprazolewith1gamoxicillinand500mgclarithromycin,alltwicedailyfor7days.

PatientsrequiringcontinuedNSAIDtherapy

-HealingofgastriculcersassociatedwithNSAIDtherapy:

Theusualdoseis20mgoncedaily.Thetreatmentdurationis4-8weeks.

-PreventionofgastricandduodenalulcersassociatedwithNSAIDtherapyinpatientsatrisk:

20mgoncedaily.

Prolongedtreatmentafteri.v.inducedpreventionofrebleedingofpepticulcers.

40mgoncedailyfor4weeksafteri.v.inducedpreventionofrebleedingofpepticulcers.

TreatmentofZollingerEllisonSyndrome

Therecommendedinitialdosageis40mgEsomeprazoletwicedaily.Thedosageshouldthenbeindividuallyadjusted

andtreatmentcontinuedaslongasclinicallyindicated.Basedontheclinicaldataavailable,themajorityofpatientscan

becontrolledondosesbetween80to160mgesomeprazoledaily.Withdosesabove80mgdaily,thedoseshouldbe

dividedandgiventwicedaily.

Adolescentsfromtheageof12years

TreatmentofduodenalulcercausedbyHelicobacterpylori

Whenselectingappropriatecombinationtherapy,considerationshouldbegiventoofficialnational,regionalandlocal

guidanceregardingbacterialresistance,durationoftreatment(mostcommonly7daysbutsometimesupto14days),

andappropriateuseofantibacterialagents.Thetreatmentshouldbesupervisedbyaspecialist.

Theposologyrecommendationis:

Weight Posology

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 2

Childrenbelowtheageof12years

Thismedicinalproductshouldnotbeusedinchildrenyoungerthan12yearssincenodataisavailable.

Impairedrenalfunction

Doseadjustmentisnotrequiredinpatientswithimpairedrenalfunction.Duetolimitedexperienceinpatientswith

severerenalinsufficiency,suchpatientsshouldbetreatedwithcaution(seesection5.2).

Impairedhepaticfunction

Doseadjustmentisnotrequiredinpatientswithmildtomoderateliverimpairment.Forpatientswithsevereliver

impairment,amaximumdoseof20mgEsomeprazoleshouldnotbeexceeded(seesection5.2).

Elderly

Doseadjustmentisnotrequiredintheelderly.

4.3Contraindications

Hypersensitivitytotheactivesubstance,substitutedbenzimidazolesortoanyoftheexcipients.

Esomeprazoleshouldnotbeadministeredwithnelfinavir(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Inthepresenceofanyalarmsymptom(e.g.significantunintentionalweightloss,recurrentvomiting,dysphagia,

haematemesisormelaena)andwhengastriculcerissuspectedorpresent,malignancyshouldbeexcluded,astreatment

withthismedicinalproductmayalleviatesymptomsanddelaydiagnosis.

Patientsonlong-termtreatment(particularlythosetreatedformorethanayear)shouldbekeptunderregular

surveillance.

Patientsonon-demandtreatmentshouldbeinstructedtocontacttheirphysicianiftheirsymptomschangeincharacter.

Whenprescribingesomeprazoleforondemandtherapy,theimplicationsforinteractionswithotherpharmaceuticals,

duetofluctuatingplasmaconcentrationsofesomeprazoleshouldbeconsidered.Seesection4.5.

WhenprescribingesomeprazoleforeradicationofHelicobacterpyloripossibledruginteractionsforallcomponentsin

thetripletherapyshouldbeconsidered.ClarithromycinisapotentinhibitorofCYP3A4andhencecontraindications

andinteractionsforclarithromycinshouldbeconsideredwhenthetripletherapyisusedinpatientsconcurrentlytaking

otherdrugsmetabolisedviaCYP3A4suchascisapride.

Treatmentwithprotonpumpinhibitorsmayleadtoslightlyincreasedriskofgastrointestinalinfectionssuchas

SalmonellaandCampylobacter(seesection5.1).

Co-administrationofesomeprazolewithatazanavirisnotrecommended(seesection4.5).Ifthecombinationof

atazanavirwithaprotonpumpinhibitorisjudgedunavoidable,closeclinicalmonitoringisrecommendedin

combinationwithanincreaseinthedoseofatazanavirto400mgwith100mgofritonavir;esomeprazole20mgshould

notbeexceeded.

EsomeprazoleisaCYP2C19inhibitor.Whenstartingorendingtreatmentwithesomeprazole,thepotentialfor

interactionswithdrugsmetabolisedthroughCYP2C19shouldbeconsidered.Aninteractionisobservedbetween

clopidogrelandomeprazole(seesection4.5).Theclinicalrelevanceofthisinteractionisuncertain.Asaprecaution,

750mgandclarithromycin7.5mg/kgbodyweightareall

administeredtogethertwicedailyforoneweek.

>40kg Combinationwithtwoantibiotics:Esomeprazole20mg,amoxicillin

1gandclarithromycin500mgarealladministeredtogethertwice

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 3

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Effectsofesomeprazoleonthepharmacokineticsofotherdrugs

MedicinalproductswithpHdependentabsorption

Thedecreasedintragastricacidityduringtreatmentwithesomeprazole,mightincreaseordecreasetheabsorptionof

drugsifthemechanismofabsorptionisinfluencedbygastricacidity.Incommonwiththeuseofotherinhibitorsof

acidsecretionorantacids,theabsorptionofketoconazoleanditraconazolecandecreaseduringtreatmentwith

esomeprazole.

Omeprazolehasbeenreportedtointeractwithsomeproteaseinhibitors.Theclinicalimportanceandthemechanisms

behindthesereportedinteractionsarenotalwaysknown.IncreasedgastricpHduringomeprazoletreatmentmay

changetheabsorptionoftheproteaseinhibitors.OtherpossibleinteractionmechanismsareviainhibitionofCYP

2C19.Foratazanavirandnelfinavir,decreasedserumlevelshavebeenreportedwhengiventogetherwithomeprazole

andconcomitantadministrationisnotrecommended.Co-administrationofomeprazole(40mgoncedaily)with

atazanavir300mg/ritonavir100mgtohealthyvolunteersresultedinasubstantialreductioninatazanavirexposure

(approximately75%decreaseinAUC,CmaxandCmin).Increasingtheatazanavirdoseto400mgdidnotcompensate

fortheimpactofomeprazoleonatazanavirexposure.Theco-administrationofomeprazole(20mgqd)withatazanavir

400mg/ritonavir100mgtohealthyvolunteersresultedinadecreaseofapproximately30%intheatazanavirexposure

ascomparedwiththeexposureobservedwithatazanavir300mg/ritonavir100mgqdwithoutomeprazole20mgqd.

Co-administrationofomeprazole(40mgqd)reducedmeannelfinavirAUC,CmaxandCminby36–39%andmean

AUC,CmaxandCminforthepharmacologicallyactivemetaboliteM8wasreducedby75-92%.Forsaquinavir(with

concomitantritonavir),increasedserumlevels(80-100%)havebeenreportedduringconcomitantomeprazoletreatment

(40mgqd).Treatmentwithomeprazole20mgqdhadnoeffectontheexposureofdarunavir(withconcomitant

ritonavir)andamprenavir(withconcomitantritonavir).Treatmentwithesomeprazole20mgqdhadnoeffectonthe

exposureofamprenavir(withandwithoutconcomitantritonavir).Treatmentwithomeprazole40mgqdhadnoeffect

ontheexposureoflopinavir(withconcomitantritonavir).Duetothesimilarpharmacodynamiceffectsand

pharmacokineticpropertiesofomeprazoleandesomeprazole,concomitantadministrationwithesomeprazoleand

atazanavirisnotrecommendedandconcomitantadministrationwithesomeprazoleandnelfinaviriscontraindicated.

DrugsmetabolisedbyCYP2C19

EsomeprazoleinhibitsCYP2C19,themajoresomeprazolemetabolisingenzyme.Thus,whenesomeprazoleis

combinedwithdrugsmetabolisedbyCYP2C19,suchasdiazepam,citalopram,imipramine,clomipramine,phenytoin

etc.,theplasmaconcentrationsofthesedrugsmaybeincreasedandadosereductioncouldbeneeded.Thisshouldbe

consideredespeciallywhenprescribingesomeprazoleforondemandtherapy.Concomitantadministrationof30mg

esomeprazoleresultedina45%decreaseinclearanceoftheCYP2C19substratediazepam.Concomitantadministration

of40mgesomeprazoleresultedina13%increaseintroughplasmalevelsofphenytoininepilepticpatients.Itis

recommendedtomonitortheplasmaconcentrationsofphenytoinwhentreatmentwithesomeprazoleisintroducedor

withdrawn.Omeprazole(40mgoncedaily)increasedvoriconazole(aCYP2C19substrate)CmaxandAUCby15%

and41%,respectively.

Concomitantadministrationof40mgesomeprazoletowarfarin-treatedpatientsinaclinicaltrialshowedthat

coagulationtimeswerewithintheacceptedrange.However,post-marketing,afewisolatedcasesofelevatedINRof

clinicalsignificancehavebeenreportedduringconcomitanttreatment.Monitoringisrecommendedwheninitiatingand

endingconcomitantesomeprazoletreatmentduringtreatmentwithwarfarinorothercoumarinederivatives.

Inhealthyvolunteers,concomitantadministrationof40mgesomeprazoleresultedina32%increaseinareaunderthe

plasmaconcentration-timecurve(AUC)anda31%prolongationofeliminationhalf-life(t½)butnosignificant

increaseinpeakplasmalevelsofcisapride.TheslightlyprolongedQTcintervalobservedafteradministrationof

cisapridealone,wasnotfurtherprolongedwhencisapridewasgivenincombinationwithesomeprazole(seealso

section4.4).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 4

Studiesevaluatingconcomitantadministrationofesomeprazoleandeithernaproxenorrofecoxibdidnotidentifyany

clinicallyrelevantpharmacokineticinteractionsduringshort-termstudies.

Inacrossoverclinicalstudy,clopidogrel(300mgloadingdosefollowedby75mg/day)aloneandwithomeprazole(80

mgatthesametimeasclopidogrel)wereadministeredfor5days.Theexposuretotheactivemetaboliteofclopidogrel

wasdecreasedby46%(Day1)and42%(Day5)whenclopidogrelandomeprazolewereadministeredtogether.Mean

inhibitionofplateletaggregation(IPA)wasdiminishedby47%(24hours)and30%(Day5)whenclopidogreland

omeprazolewereadministeredtogether.Inanotherstudyitwasshownthatadministeringclopidogrelandomeprazole

atdifferenttimesdidnotpreventtheirinteractionthatislikelytobedrivenbytheinhibitoryeffectofomeprazoleon

CYP2C19.InconsistentdataontheclinicalimplicationsofthisPK/PDinteractionintermsofmajorcardiovascular

eventshavebeenreportedfromobservationalandclinicalstudies.

Effectsofotherdrugsonthepharmacokineticsofesomeprazole

EsomeprazoleismetabolisedbyCYP2C19andCYP3A4.ConcomitantadministrationofesomeprazoleandaCYP3A4

inhibitor,clarithromycin(500mgb.i.d.),resultedinadoublingoftheexposure(AUC)toesomeprazole.Concomitant

administrationofesomeprazoleandacombinedinhibitorofCYP2C19andCYP3A4mayresultinmorethandoubling

oftheesomeprazoleexposure.TheCYP2C19andCYP3A4inhibitorvoriconazoleincreasedomeprazoleAUCby

280%.Adoseadjustmentofesomeprazoleisnotregularlyrequiredineitherofthesesituations.However,dose

adjustmentshouldbeconsideredinpatientswithseverehepaticimpairmentandiflong-termtreatmentisindicated.

4.6Fertility,pregnancyandlactation

Foresomeprazole,clinicaldataonexposedpregnanciesareinsufficient.Withtheracemicmixture,omeprazole,dataon

alargernumberofexposedpregnanciesfromepidemiologicalstudiesindicatenomalformativenorfoetotoxiceffect.

Animalstudieswithesomeprazoledonotindicatedirectorindirectharmfuleffectswithrespecttoembryonal/fetal

development.Animalstudieswiththeracemicmixturedonotindicatedirectorindirectharmfuleffectswithrespectto

pregnancy,parturitionorpostnataldevelopment.Cautionshouldbeexercisedwhenprescribingtopregnantwomen.

Itisnotknownwhetheresomeprazoleisexcretedinhumanbreastmilk.Nostudiesinlactatingwomenhavebeen

performed.Thereforethismedicinalproductshouldnotbeusedduringbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Noeffectshavebeenobserved.

4.8Undesirableeffects

Thefollowingadversedrugreactionshavebeenidentifiedorsuspectedintheclinicaltrialsprogrammefor

esomeprazoleandpost-marketing.Nonewasfoundtobedose-related.

Thereactionsareclassifiedaccordingtofrequency:

-Verycommon(1/10)

-Common(1/100to<1/10)

-Uncommon(1/1,000to<1/100)

-Rare(1/10,000to<1/1,000)

-Veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Common Uncommon Rare Veryrare

Bloodand

lymphaticsystem

disorders Leukopenia,

thrombocytopenia Agranulocytosis,

pancytopenia

Immunesystem

disorders Hypersensitivity

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 5

4.9Overdose

Thereisverylimitedexperiencetodatewithdeliberateoverdose.Thesymptomsdescribedinconnectionwith280mg

weregastrointestinalsymptomsandweakness.Singledosesof80mgesomeprazolewereuneventful.Nospecific

antidoteisknown.Esomeprazoleisextensivelyplasmaproteinboundandisthereforenotreadilydialyzable.Asinany

fever,

angioedemaand

anaphylactic

reaction/shock

Metabolismand

nutrition

disorders Peripheral

oedema Hyponatraemia Hypomagnesaemia

Psychiatric

disorders Insomnia Agitation,

confusion,

depression Aggression,

hallucinations

Nervoussystem

disorders Headache Dizziness,

paraesthesia,

somnolence Tastedisturbance

Eyedisorders Blurredvision

Earandlabyrinth

disorders Vertigo

Respiratory,

thoracicand

mediastinal

disorders Bronchospasm

Gastrointestinal

disorders Abdominalpain,

constipation,

diarrhoea,

flatulence,

nausea/vomiting Drymouth Stomatitis,

gastrointestinal

candidiasis

Hepatobiliary

disorders Increasedliver

enzymes Hepatitiswithor

withoutjaundice Hepaticfailure,

encephalopathy

inpatientswith

pre-existingliver

disease

Skinand

subcutaneous

tissuedisorders Dermatitis,

pruritus,rash,

urticaria Alopecia,

photosensitivity Erythema

multiforme,

Stevens-Johnson

syndrome,toxic

epidermal

necrolysis(TEN)

Musculoskeletal

andconnective

tissuedisorders Arthralgia,

myalgia Muscular

weakness

Renaland

urinarydisorders Interstitial

nephritis

Reproductive

systemandbreast

disorders Gynaecomastia

Generaldisorders

administration

siteconditions Malaise,

increased

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 6

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:drugsforpepticulcerandgastro-oesophagealrefluxdisease(GORD),protonpump

inhibitors,ATCcode:A02BC05.

EsomeprazoleistheS-isomerofomeprazoleandreducesgastricacidsecretionthroughaspecifictargetedmechanism

ofaction.Itisaspecificinhibitoroftheacidpumpintheparietalcell.BoththeR-andS-isomerofomeprazolehave

similarpharmacodynamicactivity.

Siteandmechanismofaction

Esomeprazoleisaweakbaseandisconcentratedandconvertedtotheactiveforminthehighlyacidicenvironmentof

thesecretorycanaliculioftheparietalcell,whereitinhibitstheenzymeH +

-ATPase–theacidpumpandinhibits

bothbasalandstimulatedacidsecretion.

Effectongastricacidsecretion

Afteroraldosingwithesomeprazole20mgand40mgtheonsetofeffectoccurswithinonehour.Afterrepeated

administrationwith20mgesomeprazoleoncedailyforfivedays,meanpeakacidoutputafterpentagastrinstimulation

isdecreased90%whenmeasured6-7hoursafterdosingondayfive.

Afterfivedaysoforaldosingwith20mgand40mgofesomeprazole,intragastricpHabove4wasmaintainedfora

meantimeof13hoursand17hours,respectivelyover24hoursinsymptomaticGORDpatients.Theproportionof

patientsmaintaininganintragastricpHabove4foratleast8,12and16hoursrespectivelywereforesomeprazole20

mg76%,54%and24%.Correspondingproportionsforesomeprazole40mgwere97%,92%and56%.

UsingAUCasasurrogateparameterforplasmaconcentration,arelationshipbetweeninhibitionofacidsecretionand

exposurehasbeenshown.

Therapeuticeffectsofacidinhibition

Healingofrefluxoesophagitiswithesomeprazole40mgoccursinapproximately78%ofpatientsafterfourweeks,and

in93%aftereightweeks.

Oneweektreatmentwithesomeprazole20mgb.i.d.andappropriateantibiotics,resultsinsuccessfuleradicationofH.

pyloriinapproximately90%ofpatients.

Aftereradicationtreatmentforoneweekthereisnoneedforsubsequentmonotherapywithantisecretorydrugsfor

effectiveulcerhealingandsymptomresolutioninuncomplicatedduodenalulcers.

Inarandomized,doubleblind,placebo-controlledclinicalstudy,patientswithendoscopicallyconfirmedpepticulcer

bleedingcharacterisedasForrestIa,Ib,IIaorIIb(9%,43%,38%and10%respectively)wererandomizedtoreceive

esomeprazolesolutionforinfusion(n=375)orplacebo(n=389).Followingendoscopichemostasis,patientsreceived

either80mgesomeprazoleasanintravenousinfusionover30minutesfollowedbyacontinuousinfusionof8mgper

hourorplacebofor72hours.Aftertheinitial72hourperiod,allpatientsreceivedopen-label40mgoralesomeprazole

for27daysforacidsuppression.Theoccurrenceofrebleedingwithin3dayswas5.9%intheesomeprazoletreated

groupcomparedto10.3%fortheplacebogroup.At30dayspost-treatment,theoccurrenceofrebleedinginthe

esomeprazoletreatedversustheplacebotreatedgroupwas7.7%vs13.6%.

Othereffectsrelatedtoacidinhibition

Duringtreatmentwithantisecretorydrugsserumgastrinincreasesinresponsetothedecreasedacidsecretion.

AnincreasednumberofECLcellspossiblyrelatedtotheincreasedserumgastrinlevels,havebeenobservedinsome

patientsduringlongtermtreatmentwithesomeprazole.

Duringlong-termtreatmentwithantisecretorydrugsgastricglandularcystshavebeenreportedtooccuratasomewhat

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 7

benignandappeartobereversible.

Decreasedgastricacidityduetoanymeansincludingprotonpumpinhibitors,increasesgastriccountsofbacteria

normallypresentinthegastrointestinaltract.Treatmentwithprotonpumpinhibitorsmayleadtoslightlyincreasedrisk

ofgastrointestinalinfectionssuchasSalmonellaandCampylobacter.

Intwostudieswithranitidineasanactivecomparator,esomeprazoleshowedbettereffectinhealingofgastriculcersin

patientsusingNSAIDs,includingCOX-2selectiveNSAIDs.

Intwostudieswithplaceboascomparator,esomeprazoleshowedbettereffectinthepreventionofgastricandduodenal

ulcersinpatientsusingNSAIDs(aged>60and/orwithpreviousulcer),includingCOX-2selectiveNSAIDs.

5.2Pharmacokineticproperties

Absorptionanddistribution

Esomeprazoleisacidlabileandisadministeredorallyasenteric-coatedgranules.InvivoconversiontotheR-isomeris

negligible.Absorptionofesomeprazoleisrapid,withpeakplasmalevelsoccurringapproximately1-2hoursafterdose.

Theabsolutebioavailabilityis64%afterasingledoseof40mgandincreasesto89%afterrepeatedonce-daily

administration.For20mgesomeprazolethecorrespondingvaluesare50%and68%respectively.Theapparentvolume

ofdistributionatsteadystateinhealthysubjectsisapproximately0.22L/kgbodyweight.Esomeprazoleis97%plasma

proteinbound.

Foodintakebothdelaysanddecreasestheabsorptionofesomeprazolealthoughthishasnosignificantinfluenceonthe

effectofesomeprazoleonintragastricacidity.

Metabolismandexcretion

EsomeprazoleiscompletelymetabolisedbythecytochromeP450system(CYP).Themajorpartofthemetabolismof

esomeprazoleisdependentonthepolymorphicCYP2C19,responsiblefortheformationofthehydroxy-anddesmethyl

metabolitesofesomeprazole.Theremainingpartisdependentonanotherspecificisoform,CYP3A4,responsiblefor

theformationofesomeprazolesulphone,themainmetaboliteinplasma.

TheparametersbelowreflectmainlythepharmacokineticsinindividualswithafunctionalCYP2C19enzyme,

extensivemetabolisers.

Totalplasmaclearanceisabout17L/hafterasingledoseandabout9L/hafterrepeatedadministration.Theplasma

eliminationhalf-lifeisabout1.3hoursafterrepeatedonce-dailydosing.Thepharmacokineticsofesomeprazolehas

beenstudiedindosesupto40mgb.i.d.Theareaundertheplasmaconcentration-timecurveincreaseswithrepeated

administrationofesomeprazole.Thisincreaseisdose-dependentandresultsinamorethandoseproportionalincrease

inAUCafterrepeatedadministration.Thistime-anddose-dependencyisduetoadecreaseoffirstpassmetabolism

andsystemicclearanceprobablycausedbyaninhibitionoftheCYP2C19enzymebyesomeprazoleand/oritssulphone

metabolite.Esomeprazoleiscompletelyeliminatedfromplasmabetweendoseswithnotendencyforaccumulation

duringonce-dailyadministration.

Themajormetabolitesofesomeprazolehavenoeffectongastricacidsecretion.Almost80%ofanoraldoseof

esomeprazoleisexcretedasmetabolitesintheurine,theremainderinthefaeces.Lessthan1%oftheparentdrugis

foundinurine.

Specialpatientpopulations

Approximately2.9±1.5%ofthepopulationlackafunctionalCYP2C19enzymeandarecalledpoormetabolisers.In

theseindividualsthemetabolismofesomeprazoleisprobablymainlycatalysedbyCYP3A4.Afterrepeatedonce-daily

administrationof40mgesomeprazole,themeanareaundertheplasmaconcentration-timecurvewasapproximately

100%higherinpoormetabolisersthaninsubjectshavingafunctionalCYP2C19enzyme(extensivemetabolisers).

Meanpeakplasmaconcentrationswereincreasedbyabout60%.Thesefindingshavenoimplicationsfortheposology

ofesomeprazole.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 8

Followingasingledoseof40mgesomeprazolethemeanareaundertheplasmaconcentration-timecurveis

approximately30%higherinfemalesthaninmales.Nogenderdifferenceisseenafterrepeatedonce-daily

administration.Thesefindingshavenoimplicationsfortheposologyofesomeprazole.

Impairedorganfunction

Themetabolismofesomeprazoleinpatientswithmildtomoderateliverdysfunctionmaybeimpaired.Themetabolic

rateisdecreasedinpatientswithsevereliverdysfunctionresultinginadoublingoftheareaundertheplasma

concentration-timecurveofesomeprazole.Therefore,amaximumof20mgshouldnotbeexceededinpatientswith

severedysfunction.

Esomeprazoleoritsmajormetabolitesdonotshowanytendencytoaccumulatewithonce-dailydosing.

Nostudieshavebeenperformedinpatientswithdecreasedrenalfunction.Sincethekidneyisresponsibleforthe

excretionofthemetabolitesofesomeprazolebutnotfortheeliminationoftheparentcompound,themetabolismof

esomeprazoleisnotexpectedtobechangedinpatientswithimpairedrenalfunction.

Paediatric

Adolescents12-18years:

Followingrepeateddoseadministrationof20mgand40mgesomeprazole,thetotalexposure(AUC)andthetimeto

reachmaximumplasmadrugconcentration(tmax)in12to18year-oldswassimilartothatinadultsforboth

esomeprazoledoses.

5.3Preclinicalsafetydata

Preclinicalbridgingstudiesrevealnoparticularhazardforhumansbasedonconventionalstudiesofrepeateddose

toxicity,genotoxicity,andtoxicitytoreproduction.Carcinogenicitystudiesintheratwiththeracemicmixturehave

showngastricECL-cellhyperplasiaandcarcinoids.Thesegastriceffectsintherataretheresultofsustained,

pronouncedhypergastrinaemiasecondarytoreducedproductionofgastricacidandareobservedafterlong-term

treatmentintheratwithinhibitorsofgastricacidsecretion.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

annitol

Cellulose,Microcrystalline

SodiumLaurilsulfate

Hydroxypropylcellulose

Talc

MethacrylicAcid-EthylAcrylatecopolymer1:1,dispersion30%

PropyleneGlycol

TriethylCitrate

Polysorbate80

Glycerolmonostearate40-55

SilicaColloidalAnhydrous

Hypromellose

MagnesiumStearate

CalciumHydrogenPhosphateDihydrate

Crospovidone

abletcoating:

Hypromellose15cP(E464)

TitaniumDioxide(E171)

Polydextrose(E1200)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 9

Maltodextrin

Triglycerides,MediumChain

IronOxideYellow(E172)

IronOxideRed(E172)

6.2Incompatibilities

Notapplicable

6.3Shelflife

15months

6.4Specialprecautionsforstorage

Donotstoreabove25ºC

6.5Natureandcontentsofcontainer

Blisterpack(OPA/Aluminium/PVC/Aluminium):7,14,15,28,30,50,56,60,90,98and100gastro-resistanttablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Administrationthroughgastrictube

1.Putthetabletintoanappropriatesyringeandfillthesyringewithapproximately25mlwaterandapproximately5ml

air.Forsometubes,dispersionin50mlwaterisneededtopreventthepelletsfromcloggingthetube.

2.Immediatelyshakethesyringeforapproximately2minutestodispersethetablet.

3.Holdthesyringewiththetipupandcheckthatthetiphasnotclogged.

4.Attachthesyringetothetubewhilstmaintainingtheaboveposition.

5.Shakethesyringeandpositionitwiththetippointingdown.Immediatelyinject5–10mlintothetube.Invertthe

syringeafterinjectionandshake(thesyringemustbeheldwiththetippointinguptoavoidcloggingofthetip).

6.Turnthesyringewiththetipdownandimmediatelyinjectanother5–10mlintothetube.Repeatthisprocedure

untilthesyringeisempty.

7.Fillthesyringewith25mlofwaterand5mlofairandrepeatstep5ifnecessarytowashdownanysedimentleftin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 10

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10,

P.O.Box43028,

3540AAUtrecht,

Netherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/134/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stDecember2011

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 22/12/2011 CRN 2082082 page number: 11