ESOMEPRAZOLE ARROW

Main information

  • Trade name:
  • ESOMEPRAZOLE ARROW
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Tablets Gastro-Resistant
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESOMEPRAZOLE ARROW
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1130/035/001
  • Authorization date:
  • 20-01-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EsomeprazoleArrow20mggastro-resistanttablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachgastro-resistanttabletcontains20mgesomeprazole(asmagnesiumdihydrate).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Gastro-resistanttablet

lightpink,oblong,biconvex,film-coatedtablet,with“20”engravedononesideanddimensionsofapproximately

14.9x7.6mm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

EsomeprazoleArrowtabletsareindicatedfor:

GastrooesophagealRefluxDisease(GORD):

-Treatmentoferosiverefluxoesophagitis

-Long-termmanagementofpatientswithhealedoesophagitistopreventrelapse

-Symptomatictreatmentofgastrooesophagealrefluxdisease(GORD)

IncombinationwithappropriateantibacterialtherapeuticregimensfortheeradicationofHelicobacter

pylori:

-HealingofHelicobacterpyloriassociatedduodenalulcer

-PreventionofrelapseofpepticulcersinpatientswithHelicobacterpyloriassociatedulcers

PatientsrequiringcontinuedNSAIDtherapy:

-HealingofgastriculcersassociatedwithNSAIDtherapy

-PreventionofgastricandduodenalulcersassociatedwithNSAIDtherapy,inpatientsatrisk

Prolongedtreatmentafteri.v.inducedpreventionofrebleedingofpepticulcers.

TreatmentofZollingerEllisonSyndrome.

Adolescentsfromtheageof12years

GastrooesophagealRefluxDisease(GORD)

treatmentoferosiverefluxoesophagitis

long-termmanagementofpatientswithhealedoesophagitistopreventrelapse

symptomatictreatmentofgastrooesophagealrefluxdisease(GORD)

IncombinationwithantibioticsintreatmentofduodenalulcercausedbyHelicobacterpylori

4.2Posologyandmethodofadministration

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Forpatientswhohavedifficultyinswallowingthetabletscanalsobedispersedinhalfaglassofnon-carbonatedwater.

Nootherliquidsshouldbeusedastheentericcoatmaybedissolved.Stiruntilthetabletsdisintegrateanddrinkthe

liquidwiththepelletsimmediatelyorwithin30minutes.Rinsetheglasswithhalfaglassofwateranddrink.The

pelletsmustnotbechewedorcrushed.

Forpatientswhocannotswallow,thetabletscanbedispersedinnon-carbonatedwaterandadministeredthrougha

gastrictube.Itisimportantthattheappropriatenessoftheselectedsyringeandtubeiscarefullytested.Forpreparation

andadministrationinstructionsseesection6.6.

Adultsandadolescentsfromtheageof12years:

GastrooesophagealRefluxDisease(GORD):

Treatmentoferosiverefluxoesophagitis

40mgoncedailyfor4weeks.

Anadditional4weekstreatmentisrecommendedforpatientsinwhomoesophagitishasnothealedorwhohave

persistentsymptoms.

Long-termmanagementofpatientswithhealedesophagitistopreventrelapse

20mgoncedaily.

Symptomatictreatmentofgastrooesophagealrefluxdisease(GORD)

20mgoncedailyinpatientswithoutoesophagitis.Ifsymptomcontrolhasnotbeenachievedafter4weeks,the

patientshouldbefurtherinvestigated.Oncesymptomshaveresolved,subsequentsymptomcontrolcanbe

achievedusing20mgoncedaily.Inadults,anondemandregimentaking20mgoncedaily,whenneeded,canbe

used.InNSAIDtreatedpatientsatriskofdevelopinggastricandduodenalulcers,subsequentsymptomcontrol

usinganondemandregimenisnotrecommended.

Adults:

IncombinationwithappropriateantibacterialtherapeuticregimensfortheeradicationofHelicobacter

pylori:

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),

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Theposologyrecommendationis:

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

Weight Posology

-40kg Combinationwithtwoantibiotics:Esomeprazole20mg,amoxicillin750mg

andclarithromycin7.5mg/kgbodyweightarealladministeredtogether

twicedailyforoneweek.

>40kg Combinationwithtwoantibiotics:Esomeprazole20mg,amoxicillin1gand

clarithromycin500mgarealladministeredtogethertwicedailyfor

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EsomeprazoleisaCYP2C19inhibitor.Whenstartingorendingtreatmentwithesomeprazole,thepotentialfor

interactionswithdrugsmetabolisedthroughCYP2C19shouldbeconsidered.Aninteractionisobservedbetween

clopidogrelandomeprazole(seesection4.5).Theclinicalrelevanceofthisinteractionisuncertain.Asaprecaution,

concomitantuseofesomeprazoleandclopidogrelshouldbediscouraged.

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.Concomitant

administrationof40mgesomeprazoleresultedina13%increaseintroughplasmalevelsofphenytoininepileptic

patients.Itisrecommendedtomonitortheplasmaconcentrationsofphenytoinwhentreatmentwithesomeprazoleis

introducedorwithdrawn.Omeprazole(40mgoncedaily)increasedvoriconazole(aCYP2C19substrate)Cmaxand

AUCby15%and41%,respectively.

Concomitantadministrationof40mgesomeprazoletowarfarin-treatedpatientsinaclinicaltrialshowedthat

coagulationtimeswerewithintheacceptedrange.However,post-marketing,afewisolatedcasesofelevatedINR

ofclinicalsignificancehavebeenreportedduringconcomitanttreatment.Monitoringisrecommendedwhen

initiatingandendingconcomitantesomeprazoletreatmentduringtreatmentwithwarfarinorothercoumarine

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Inhealthyvolunteers,concomitantadministrationof40mgesomeprazoleresultedina32%increaseinareaunderthe

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

inpeakplasmalevelsofcisapride.TheslightlyprolongedQTcintervalobservedafteradministrationofcisapride

alone,wasnotfurtherprolongedwhencisapridewasgivenincombinationwithesomeprazole(seealsosection4.4).

Esomeprazolehasbeenshowntohavenoclinicallyrelevanteffectsonthepharmacokineticsofamoxicillin,quinidine.

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)

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Common Uncommon Rare Veryrare

Bloodand

lymphatic

systemdisorders Leukopenia,

thrombocytopenia Agranulocytosis,

pancytopenia

Immunesystem

disorders Hypersensitivity

reactionse.g.

fever,angioedema

andanaphylactic

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

Earand

labyrinth

disorders Vertigo

Respiratory,

thoracicand

mediastinal

disorders Bronchospasm

Gastrointestinal

disorders Abdominalpain,

constipation,

diarrhoea,

flatulence,

nausea/vomiting Drymouth Stomatitis,

gastrointestinal

candidiasis

Hepatobiliary

disorders Increased

liverenzymes Hepatitiswithor

withoutjaundice Hepaticfailure,

encephalopathyin

patientswithpre-

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 Muscularweakness

Renaland

urinarydisorders Interstitial

nephritis

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4.9Overdose

Thereisverylimitedexperiencetodatewithdeliberateoverdose.Thesymptomsdescribedinconnectionwith280mg

weregastrointestinalsymptomsandweakness.Singledosesof80mgesomeprazolewereuneventful.Nospecific

antidoteisknown.Esomeprazoleisextensivelyplasmaproteinboundandisthereforenotreadilydialyzable.Asinany

caseofoverdose,treatmentshouldbesymptomaticandgeneralsupportivemeasuresshouldbeutilised.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:drugsforpepticulcerandgastro-oesophagealrefluxdisease(GORD),protonpump

inhibitors,ATCcode:A02BC05.

EsomeprazoleistheS-isomerofomeprazoleandreducesgastricacidsecretionthroughaspecifictargetedmechanism

ofaction.Itisaspecificinhibitoroftheacidpumpintheparietalcell.BoththeR-andS-isomerofomeprazolehave

similarpharmacodynamicactivity.

Siteandmechanismofaction

Esomeprazoleisaweakbaseandisconcentratedandconvertedtotheactiveforminthehighlyacidicenvironmentof

thesecretorycanaliculioftheparietalcell,whereitinhibitstheenzymeHK-ATPase

–theacidpumpandinhibitsbothbasalandstimulatedacidsecretion.

Effectongastricacidsecretion

Afteroraldosingwithesomeprazole20mgand40mgtheonsetofeffectoccurswithinonehour.Afterrepeated

administrationwith20mgesomeprazoleoncedailyforfivedays,meanpeakacidoutputafterpentagastrin

stimulationisdecreased90%whenmeasured6-7hoursafterdosingondayfive.

Afterfivedaysoforaldosingwith20mgand40mgofesomeprazole,intragastricpHabove4wasmaintainedfora

meantimeof13hoursand17hours,respectivelyover24hoursinsymptomaticGORDpatients.Theproportionof

patientsmaintaininganintragastricpHabove4foratleast8,12and16hoursrespectivelywereforesomeprazole

20mg76%,54%and24%.Correspondingproportionsforesomeprazole40mgwere97%,92%and56%.

UsingAUCasasurrogateparameterforplasmaconcentration,arelationshipbetweeninhibitionofacidsecretion

andexposurehasbeenshown.

Therapeuticeffectsofacidinhibition

Healingofrefluxoesophagitiswithesomeprazole40mgoccursinapproximately78%ofpatientsafterfourweeks,

andin93%aftereightweeks.

Oneweektreatmentwithesomeprazole20mgb.i.d.andappropriateantibiotics,resultsinsuccessfuleradicationof

H.pyloriinapproximately90%ofpatients.

Aftereradicationtreatmentforoneweekthereisnoneedforsubsequentmonotherapywithantisecretorydrugsfor

systemand

breastdisorders

General

disordersand

administration

siteconditions Malaise,increased

sweating

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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

for27daysforacidsuppressionTheoccurrenceofrebleedingwithin3dayswas5.9%intheesomeprazoletreated

groupcomparedto10.3%fortheplacebogroup.At30dayspost-treatment,theoccurrenceofrebleedinginthe

esomeprazoletreatedversustheplacebotreatedgroup7.7%vs13.6%.

Othereffectsrelatedtoacidinhibition

Duringtreatmentwithantisecretorydrugsserumgastrinincreasesinresponsetothedecreasedacidsecretion.

AnincreasednumberofECLcellspossiblyrelatedtotheincreasedserumgastrinlevels,havebeenobservedin

somepatientsduringlongtermtreatmentwithesomeprazole.

Duringlong-termtreatmentwithantisecretorydrugsgastricglandularcystshavebeenreportedtooccurata

somewhatincreasedfrequency.Thesechangesareaphysiologicalconsequenceofpronouncedinhibitionofacid

secretion,arebenignandappeartobereversible.

Decreasedgastricacidityduetoanymeansincludingprotonpumpinhibitors,increasesgastriccountsofbacteria

normallypresentinthegastrointestinaltract.Treatmentwithprotonpumpinhibitorsmayleadtoslightlyincreased

riskofgastrointestinalinfectionssuchasSalmonellaandCampylobacter.

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).Themajorpartofthemetabolism

ofesomeprazoleisdependentonthepolymorphicCYP2C19,responsiblefortheformationofthehydroxy-and

desmethylmetabolitesofesomeprazole.Theremainingpartisdependentonanotherspecificisoform,CYP3A4,

responsiblefortheformationofesomeprazolesulphone,themainmetaboliteinplasma.

TheparametersbelowreflectmainlythepharmacokineticsinindividualswithafunctionalCYP2C19enzyme,

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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.

Themetabolismofesomeprazoleisnotsignificantlychangedinelderlysubjects(71-80yearsofage).

Followingasingledoseof40mgesomeprazolethemeanareundertheplasmaconcentration-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

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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)

Talc(E553b)

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.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

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Putthetabletintoanappropriatesyringeandfillthesyringewithapproximately25mlwaterandapproximately5

mlair.

Forsometubes,dispersionin50mlwaterisneededtopreventthepelletsfromcloggingthetube.

Immediatelyshakethesyringeforapproximately2minutestodispersethetablet.

Holdthesyringewiththetipupandcheckthatthetiphasnotclogged.

Attachthesyringetothetubewhilstmaintainingtheaboveposition.

Shakethesyringeandpositionitwiththetippointingdown.Immediatelyinject5–10mlintothetube.Invert

thesyringeafterinjectionandshake(thesyringemustbeheldwiththetippointinguptoavoidcloggingofthetip).

Turnthesyringewiththetipdownandimmediatelyinjectanother5–10mlintothetube.Repeatthisprocedure

untilthesyringeisempty.

Fillthesyringewith25mlofwaterand5mlofairandrepeatstep5ifnecessarytowashdownanysedimentleft

inthesyringe.Forsometubes,50mlwaterisneeded.

7MARKETINGAUTHORISATIONHOLDER

ArrowGenericsLimited

Unit2,EastmanWay

Stevenage

Hertfordshire

SG14SZ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1130/035/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20thJanuary2012

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