ENTOCORT CR

Main information

  • Trade name:
  • ENTOCORT CR
  • Dosage:
  • 3 Milligram
  • Pharmaceutical form:
  • Capsules Gastro-Resistant
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ENTOCORT CR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/039/002
  • Authorization date:
  • 24-09-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EntocortCR3mgGastro-ResistantProlonged-ReleaseHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontainsbudesonide3mg

Excipients:notmorethan295mgsucrose

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Gastro-resistant,prolongedreleasecapsules,hard.

Hardgelatincapsuleswithanopaque,lightgreybodyandopaque,pinkcapmarkedCIR3mginblackradialprint

4CLINICALPARTICULARS

4.1TherapeuticIndications

EntocortCRCapsulesareindicatedfortheinductionofremissioninpatientswithmildtomoderateCrohn'sdisease

affectingtheileumand/ortheascendingcolon.Thefulleffectisusuallyachievedwithin2-4weeks.

4.2Posologyandmethodofadministration

Adults:

ActiveCrohn'sdisease:Therecommendeddailydoseforinductionofremissionis9mgoncedailyinthemorning,for

uptoeightweeks.Thefulleffectisusuallyachievedwithin2-4weeks.

Whentreatmentistobediscontinued,thedoseshouldnormallybereducedforthelast2to4weeksoftherapy.

Forlong-termuse,toprolongremission,therecommendeddoseis6mg,administeredoncedailyinthemorning.

Toreplaceprednisoloneinsteroiddependentpatients,therecommendeddoseis6mg,administeredoncedailyinthe

morning.WhentreatmentwithEntocortCRcapsulesisinitiatedtheprednisolonedoseshouldbetapered.

Topreventrecurrenceaftersurgeryinpatientswithhighdiseaseactivity,therecommendeddoseis6mg,administered

oncedailyinthemorning.NobenefitofEntocorthasbeenshowninpostsurgicalpatientswithobstructive

fibrostenoticCrohn’sdisease.

Children:

ThereispresentlynoexperiencewithEntocortCRCapsulesinchildren.Entocortisnotrecommendedforusein

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Elderly:

Nospecialdoseadjustmentisrecommended.However,experiencewithEntocortCRCapsulesintheelderlyislimited.

Thecapsulesshouldbeswallowedwholewithwater.Thecapsulesmustnotbechewed.

4.3Contraindications

Knownhypersensitivitytobudesonideortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Sideeffectstypicalofsystemiccorticosteroidsmayoccur.Potentialsystemiceffectsincludeglaucoma.

Usewithcautioninpatientswithbacterial,fungalorviralinfections,hypertension,diabetesmellitus,osteoporosis,peptic

ulcer,glaucomaorcataractsorwithafamilyhistoryofdiabetesorglaucomaorwithanyotherconditionwheretheuseof

glucocorticosteroidsmayhaveunwantedeffects.

Thisproductcontainssucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactose

malabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

Particularcareisrequiredwhenconsideringtheuseofsystemiccorticosteroidsinpatientswithexistingorprevioushistory

ofsevereaffectivedisordersinthemselvesorintheirfirstdegreerelatives.Thesewouldincludedepressiveormanic

depressiveillnessandprevioussteroidpsychosis.

TreatmentwithEntocortCRCapsulesresultsinlowersystemicsteroidlevelsthanconventionaloralglucocorticosteroid

therapy.WhenpatientsaretransferredfromsystemicglucocorticosteroidtreatmentwithhighersystemiceffecttoEntocort

CRCapsules,theymayhaveadrenocorticalsuppression.Therefore,monitoringofadrenocorticalfunctionmaybe

consideredinthesepatientsandtheirdoseofsystemicsteroidshouldbereducedcautiously.

ReplacementofhighsystemiceffectglucocorticosteroidtreatmentwithEntocortCRCapsules,sometimesunmasks

allergies,e.g.rhinitisandeczema,whichwerepreviouslycontrolledbythesystemicdrug.

Chickenpoxandmeaslescanhaveamoreseriouscourseinpatientsonoralglucocorticosteroids.Particularcareshouldbe

takentoavoidexposureinpatientswhohavenotpreviouslyhadthesediseases.Ifexposed,therapywithvaricellazoster

immuneglobulin(VZIG)orpooledintravenousimmunoglobulin(IVIG),asappropriate,maybeindicated.Ifchickenpox

develops,treatmentwithantiviralagentsmaybeconsidered.

Glucocorticosteroidsmaycausesuppressionofthehypothalamus-pituitary-adrenal(HPAaxis)andreducethestress

response.Wherepatientsaresubjecttosurgeryorotherstresssituations,supplementarysystemicglucocorticoidtreatmentis

recommended.

Aswithallglucocorticosteroidsthepossibilityoflocalorsystemicinfectionsshouldbeborneinmindwhenusingthis

product,particularlyinviewofthepossibleabsenceofsystemicresponsethereto.

Reducedliverfunctionmayaffecttheeliminationofglucocorticosteroids,causinglowereliminationrateandhigher

systemicexposure.Beawareofpossiblesystemicsideeffects.Thepharmacokineticsafteroralingestionofbudesonidewas

affectedbycompromisedliverfunctionasevidencedbyincreasedsystemicavailability.Theintravenouspharmacokinetics

ofbudesonidehoweverwassimilarincirrhoticpatientsandinhealthysubjects.

Whentreatmentistobediscontinued,thedoseshouldnormallybereducedforthelast2to4weeksoftherapy.Some

patientsfeelunwellinanon-specificwayduringthewithdrawalphase,e.g.paininmusclesandjoints.Insomeinstances

withdrawalsymptomsmayinvolveorresembleaclinicalrelapseofthediseaseforwhichthepatienthasbeenundergoing

treatment.Ageneralinsufficientglucocorticosteroideffectshouldbesuspectedif,inrarecases,symptomssuchastiredness,

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Inthesecasesatemporaryincreaseinthedose ofsystemicglucocorticosteroidsissometimesnecessary.

ConcomitantuseofketoconazoleorotherpotentCYP3A4inhibitorsshouldbeavoided.Ifthisisnotpossible,theperiod

betweentreatmentsshouldbeaslongaspossibleandareductionofthebudesonidedosecouldalsobeconsidered(seealso

section4.5).

Afterextensiveintakeofgrapefruitjuice(whichinhibitsCYP3A4activitypredominantlyintheintestinalmucosa),the

systemicexposurefororalbudesonideincreasedabouttwotimes.Aswithotherdrugsprimarilymetabolisedthrough

CYP3A4,regularingestionofgrapefruitoritsjuice,shouldbeavoidedinconnectionwithEntocortCRCapsules

administration(otherjuicessuchasorangejuiceorapplejuicedonotinhibitCYP3A4).Seealsosection4.5.

WhenEntocortCRCapsulesareusedchronicallyinexcessivedoses,systemicglucocorticosteroideffectssuchas

hypercorticismandadrenalsuppressionmayappear,andveryrarelyawiderangeofpsychiatric/behaviouraleffectsmay

alsooccur(seesection4.8).

Itisrecommendedthattheheightofchildrenreceivingprolongedtreatmentwithglucocorticosteroidsisregularlymonitored.

Ifgrowthisslowed,therapyshouldbere-evaluated.Thebenefitsoftheglucocorticosteroidtherapyandthepossiblerisksof

growthsuppressionmustbecarefullyweighed.Long-termstudieshavenotbeenperformedinchildrentreatedwithEntocort

CRCapsules.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Althoughnotstudied,concomitantadministrationofcolestyraminemayreduceEntocortuptake,incommonwithother

drugs.

Raisedplasmaconcentrationsofandenhancedeffectsofcorticosteroidshavebeenreportedinwomenalsotreatedwith

oestrogensandcontraceptivesteroids.However,alow-dosecombinationoralcontraceptivethatmorethandoubledthe

plasmaconcentrationoforalprednisolone,hadnosignificanteffectontheplasmaconcentrationoforalbudesonide.

Atrecommendeddoses,omeprazoledoesnotaffectthepharmacokineticsoforalbudesonidewhereascimetidinehasaslight

butclinicallyinsignificanteffect.ThemetabolismofbudesonideisprimarilymediatedbyCYP3A4,asubfamilyof

cytochromeP450.Inhibitionofthisenzymebye.g.ketoconazole,itraconazole,HIVproteaseinhibitorsandgrapefruitjuice

canthereforeincreasethesystemicexposuretobudesonideseveraltimes,seesection4.4.Sincethereisnodatatosupporta

dosagerecommendation,thecombinationshouldbeavoided.Ifthisisnotpossible,theperiodbetweentreatmentsshouldbe

aslongaspossibleandareductionofthebudesonidedosecouldalsobeconsidered.Budesonideisunlikelytoinhibitother

drugsmetabolisedbyCYP3A4sinceithaslowaffinitytotheenzyme.

ConcomitanttreatmentwithCYP3A4inducerssuchascarbamazepinemayreducebudesonideexposure,whichmayrequire

adoseincrease.

4.6Fertility,pregnancyandlactation

Inpregnantanimals,administrationofbudesonide,likeotherglucocorticosteroids,isassociatedwithabnormalitiesinfoetal

development.Therelevanceofthistohumanshasnotbeenestablished.AswithotherdrugstheadministrationofEntocort

CRCapsulesduringpregnancyrequiresthatthebenefitsforthemotherareweighedagainsttheriskforthefoetus.

Lactation

Budesonideisexcretedinbreastmilk.

Maintenancetreatmentwithinhaledbudesonide(200or400microgramstwicedaily)inasthmaticnursingwomenresultsin

negligiblesystemicexposureto

budesonideinbreast-fedinfants.

Inapharmacokineticstudytheestimateddailyinfantdosewas0.3%ofthedailymaternaldoseforbothdoselevels,andthe

averageplasmaconcentrationininfantswasestimatedtobe1/600thoftheconcentrationsobservedinmaternalplasma,

assumingcompleteinfantoralbioavailability.Budesonideconcentrationsininfantplasmasampleswerealllessthanthe

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BasedondatafrominhaledbudesonideandthefactthatbudesonideexhibitslinearPKpropertieswithinthetherapeutic

dosageintervalsafterinhaled,oralandrectaladministrations,attherapeuticdosesofbudesonide,exposuretothesuckling

childisanticipatedtobelow .

Thesedatasupportcontinueduseofbudesonide,oralandrectaladministrations,duringbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

EntocortCRCapsulesdonotaffecttheabilitytodriveandusemachines.

4.8Undesirableeffects

Tableofundesirableeffects

Thefollowingdefinitionsapplytotheincidenceofundesirableeffects: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).

Descriptionofselectedadverseevents

Sideeffectstypicalofsystemiccorticosteroids(e.g.cushingoidfeaturesandgrowthretardation)mayoccur.Theseside

effectsaredependentondose,treatmenttime,concomitantandpreviouscorticosteroidintake,andindividual

sensitivity.

ClinicalstudiesshowedthefrequencyofsteroidassociatedsideeffectsforEntocortCRCapsulestobeapproximately

halfthatofconventionalprednisolonetreatment,atequipotentdoses.Veryrarelyawiderangeof

psychiatric/behaviouraleffectsmayoccur,whensystemicsteroidsareprescribedathighdosesandforprolonged

periods(seesection4.4).

4.9Overdose

Reportsofacutetoxicityordeathfollowingoverdosageofglucocorticosteroidsarerare.Thus,acuteoverdosagewith

EntocortCRCapsules,eveninexcessivedoses,isnotexpectedtoleadtoanacuteclinicalcrisis.Intheeventofacute

overdosage,nospecificantidoteisavailable.Treatmentconsistsofsupportiveandsymptomatictherapy.

Chronicoverdosagemayleadtosystemiccorticosteroideffects,suchasCushingoidfeatures.Ifsuchchangesoccur,the

SOC Frequency Reaction

Cardiacdisorders Common Palpitations

Endocrinedisorders Common Cushingoidfeatures

Veryrare Growthretardation

Eyedisorders Common BlurredVision

Unknown Glaucoma

Gastrointestinaldisorders Common Dyspepsia

Immunesystemdisorders Veryrare Anaphylacticreaction

Metabolismandnutrition

disorders Common Hypokalemia

Musculoskeletalandconnective

tissuedisorders Common Musclecramps

Nervoussystemdisorders Uncommon Tremor

Psychiatricdisorders Common Behavioralchangessuchas

nervousness,insomniaandmood

swings

Reproductivesystemandbreast

disorders Common Menstrualdisorders

Skinandsubcutaneoustissue

disorder Common Skinreactions(urticaria,

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proceduresforthediscontinuationofprolongedoralglucocorticosteroidtherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Budesonideisaglucocorticosteroidwithahighlocalanti-inflammatoryeffect.

ATCCode:A07EA06.

TheexactmechanismofbudesonideinthetreatmentofCrohn’sdiseaseisnotfullyunderstood.Datafromclinical

pharmacologystudiesandcontrolledclinicaltrialsstronglyindicatethatthemodeofactionofEntocortCRCapsulesis

based,atleastpartly,onalocalactioninthegut.Atdosesclinicallyequivalenttoprednisolone,budesonidegives

significantlylessHPAaxissuppressionandhasalowerimpactoninflammatorymarkers.

Atrecommendeddoses,EntocortCRCapsulescausedsignificantlylesseffectthanprednisolone20–40mgdailyon:

morningplasmacortisols;24hourplasmacortisol(AUC0-24h)and24hoururinecortisollevels.

ACTHtestshaveshownEntocortCRCapsulestohavesignificantlylesseffectthanprednisoloneonadrenalfunctions.

InastudyinvestigatingbonemineraldensityduringtreatmentwithEntocortCRCapsulesorprednisoloneforuptotwo

years,treatmentwithEntocortCRCapsulesresultedinsignificantlylessbonelossthanprednisolonetreatmentin

steroidnaïvepatients.

Paediatricpopulation

HPAaxisfunction.Atrecommendeddoses,EntocortCRCapsulescausesignificantlylesseffectthanprednisole20-40

mgdailyonmorningplasmacortisol,on24-hourplasmacortisol(AUC0-24h)andon24-hoururinecortisol.Also

ACTHtestshaveshownthatEntocortCRCapsules,comparedwithprednisolone,havesignificantlylessimpactonthe

adrenalfunction.ChildrenwithCrohn’sdiseasehaveaslightlyhighersystemicexposureandcortisolsuppressionthan

adultswithCrohn’sdisease.

Long-termstudieshavenotbeenperformedinchildrentreatedwithEntocortCRCapsules.Inastudyevaluatingthe

effectofEntocortCRCapsulesoncortisolsuppressionin8children(range9–14years)and6adults,theoral

administrationof9mgEntocortCRCapsulesfor7daysinducedameancortisolsuppression(±SD)of64%(±18%)in

childrenand50%(±27%)inadultswithrespecttobaselinevalues.Noclinicallyrelevantfindingsintermsofsafety

havebeenreported.(Study08-3044)

AstudyperformedinchildrenwithmildtomoderateCrohn’sdisease(CDAI 200)comparedtheactivityofEntocort

CRCapsulesatthedoseof9mgoncedailywiththatofprednisolone,administeredattaperingdoses,startingfrom1

mg/kg.22patientsweretreatedwithEntocortCRCapsulesand26patientsweretreatedwiththereferencedrug

prednisolone.After8weeksoftreatment,70.8%ofpatientstreatedwithprednisolonereachedtheendpoint(CDAI

150),ascomparedto54.5%ofsubjectstreatedwithEntocortCRCapsules,thedifferencewasnotstatistically

significant(p=0.13).Inthecourseofthestudy,adverseeventswereobservedin96%ofpatientstreatedwith

prednisoloneand91%ofpatientstreatedwithEntocortCRCapsules.Thenatureoftheseadverseeventswassimilarin

bothstudyarms,buttheincidenceofglucocorticoid-relatedside-effects(suchasacneandmoonface)waslowerin

patientstreatedwithEntocortCRCapsules.(StudySD-008-3037)

5.2Pharmacokineticproperties

Absorption

Afteroraldosingofplainmicronisedcompound,absorptionisrapidandseemstobecomplete.Alargeproportionof

thedrugisabsorbedfromtheileumandascendingcolon.Systemicavailabilityinhealthysubjectsisapproximately9–

12%forEntocortCRCapsules,similartothesystemicavailabilityofplainmicronisedbudesonide,indicatingcomplete

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Distribution

Budesonidehasahighvolumeofdistribution(about3L/kg).Plasmaproteinbindingaverages85–90%.Inhealthy

volunteersmeanmaximalplasmaconcentrationsof5–10nmol/Lwereseenat3–5hoursfollowingasingleoraldoseof

EntocortCRCapsules9mg.

Biotransformation

Budesonidethenundergoesextensivebiotransformationinthelivertometabolitesoflowglucocorticosteroidactivity.

Theglucocorticosteroidactivityofthemajormetabolites,6-hydroxybudesonideand16-hydroxy-prednisolone,is

lessthan1%ofthatofbudesonide.ThemetabolismofbudesonideisprimarilymediatedbyCYP3A,asubfamilyof

cytochromeP450.

Elimination

Eliminationisrate-limitedbyabsorption.Theaverageterminalhalf-lifeis4hours.Budesonidehasahighsystemic

clearance(about1.2L/min).

Paediatricpopulation

InastudycomparingthepharmacokineticsofEntocortCRCapsulesin8children(range9–14years)and6adults,

EntocortCRCapules9mgfor7daysinducedasystemicexposure(AUC)thatwas17%higherinchildrenthanin

adults,withmaximumconcentrations(C

)50%higherinchildrenthaninadults(meanAUC±SD:children41.3

nmol/L±21.2;adults35.0nmol/L±19.8.MeanC

±SD:children5.99nmo/L±3.45;adults3.97nmo/L±2.11.)

(Study08-3044).

5.3Preclinicalsafetydata

Resultsfromacute,subacuteandchronictoxicitystudiesshowthatthesystemiceffectsofbudesonidearelesssevere

orsimilartothoseobservedafteradministrationofotherglucocorticosteroids,e.g.decreasedbody-weightgainand

atrophyoflymphoidtissuesandadrenalcortex.

Budesonide,evaluatedinsixdifferenttestsystems,didnotshowanymutagenicorclastogeniceffects.

Anincreasedincidenceofbraingliomasinmaleratsinacarcinogenicitystudycouldnotbeverifiedinarepeatstudy,

inwhichtheincidenceofgliomasdidnotdifferbetweenanyofthegroupsonactivetreatment(budesonide,

prednisolone,triamcinoloneacetonide)andthecontrolgroups.

Liverchanges(primaryhepatocellularneoplasms)foundinmaleratsintheoriginalcarcinogenicitystudywerenoted

againintherepeatstudywithbudesonideaswellasthereferenceglucocorticosteroids.Theseeffectsaremost

probablyrelatedtoareceptoreffectandthusrepresentaclasseffect.

Availableclinicalexperienceshowsthattherearenoindicationsthatbudesonideorotherglucocorticosteroidsinduce

braingliomasorprimaryhepatocellularneoplasmsinman.

ThetoxicityofEntocortCRCapsules,withfocusonthegastro-intestinaltract,hasbeenstudiedincynomolgus

monkeysindosesupto5mg/kgafterrepeatedoraladministrationforupto6months.Noeffectswereobservedinthe

gastrointestinaltract,neitheratgrosspathologynorinthehistopathologicalexamination.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Ethylcellulose

Tributylacetylcitrate

Methacrylicacid-ethylacrylatecopolymer(1:1)dispersion30percent

Triethylcitrate

Simeticone(AntifoamM)

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Talc

Sugarspheres(consistingofsucroseandmaizestarch).

Capsuleshell:

Blackironoxide(E172)

Titaniumdioxide(E171)

Gelatin

Sodiumlaurilsulfate

Colloidalanhydroussilica

Liquidparaffin

Redironoxide(E172)

Yellowironoxide(E172)

Shellac

Soyalecithin

Siliconantifoam

Ammoniumhydroxide

Potassiumhydroxide

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackage.Keepthecontainertightlyclosed.

6.5Natureandcontentsofcontainer

White,polyethylenebottlesof100capsules,havingatamper-evident,childproofpolypropylenescrewcap,withan

integraldesiccant.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLimited

600CapabilityGreen

Luton

LU13LU

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24September1996

Dateoflastrenewal:24September2006

10DATEOFREVISIONOFTHETEXT

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