CELEBREX 100 MG CAPSULES.

Main information

  • Trade name:
  • CELEBREX 100 MG CAPSULES.
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CELEBREX 100 MG CAPSULES.
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/057/001
  • Authorization date:
  • 29-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1328/057/001

CaseNo:2033989

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Celebrex100mgcapsules.

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/08/2007until28/09/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 23/09/2007 CRN 2033989 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Celebrex100mgcapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains100mgcelecoxib

Excipient:Lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

ProductimportedfromFrance:

Opaque,whitewithtwobluebandsmarked7767and100 .

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomaticreliefinthetreatmentofosteoarthritisorrheumatoidarthritis.

ThedecisiontoprescribeaselectiveCOX-2inhibitorshouldbebasedonanassessmentoftheindividualpatient's

overallrisks(seesections4.3,4.4).

4.2Posologyandmethodofadministration

Asthecardiovascularrisksofcelecoxibmayincreasewithdoseanddurationofexposure,theshortestdurationpossible

andthelowesteffectivedailydoseshouldbeused.Thepatient'sneedforsymptomaticreliefandresponsetotherapy

shouldbere-evaluatedperiodically,especiallyinpatientswithosteoarthritis(4.3,4.4,4.8and5.1).

Osteoarthritis:Theusualrecommendeddailydoseis200mgtakenoncedailyorintwodivideddoses.Insome

patients,withinsufficientrelieffromsymptoms,anincreaseddoseof200mgtwicedailymayincreaseefficacy.Inthe

absenceofanincreaseintherapeuticbenefitaftertwoweeks,othertherapeuticoptionsshouldbeconsidered.

Rheumatoidarthritis:Theinitialrecommendeddailydoseis200mgtakenintwodivideddoses.Thedosemay,if

needed,laterbeincreasedto200mgtwicedaily.Intheabsenceofanincreaseintherapeuticbenefitaftertwoweeks,

othertherapeuticoptionsshouldbeconsidered.

Themaximumrecommendeddailydoseis400mgforbothindications.

Celebrexmaybetakenwithorwithoutfood.

Elderly:>65years),Asinyoungeradults,200mgperdayshouldbeusedinitially.Thedosemay,ifneeded,laterbe

increasedto200mgtwicedaily.Particularcautionshouldbeexercisedinelderlywithabodyweightlessthan50kg

(See4.4and5.2).

Hepaticimpairment:Treatmentshouldbeinitiatedathalftherecommendeddoseinpatientswithestablishedmoderate

liverimpairmentwithaserumalbuminof25-35g/l.Experienceinsuchpatientsislimitedtocirrhoticpatients(See4.3,

4.4and5.2).

Renalimpairment:Experiencewithcelecoxibinpatientswithmildormoderaterenalimpairmentislimited;therefore

suchpatientsshouldbetreatedwithcaution.(See4.3,4.4and5.2).

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4.3Contraindications

Historyofhypersensitivitytotheactivesubstanceortoanyoftheexcipients(see6.1).

Knownhypersensitivitytosulphonamides

Activepepticulcerationorgastrointestinal(GI)bleeding.

Patientswhohaveexperiencedasthma,acuterhinitis,nasalpolyps,angioneuroticoedema,urticariaorotherallergic-

typereactionsaftertakingacetylsalicylicacidorNSAIDsincludingCOX-2(cyclooxygenase-2)inhibitors.

Inpregnancyandinwomenofchildbearingpotentialunlessusinganeffectivemethodofcontraception(See4.5).

Celecoxibhasbeenshowntocausemalformationsinthetwoanimalspeciesstudied(See4.6and5.3).Thepotential

forhumanriskinpregnancyisunknown,butcannotbeexcluded.

Breastfeeding(See4.6and5.3).

Severehepaticdysfunction(serumalbumin<25g/lorChild-Pughscore>10).

Patientswithestimatedcreatinineclearance<30ml/min.

Inflammatoryboweldisease.

Congestiveheartfailure(NYHAII-IV).

Establishedischaemicheartdisease,peripheralarterialdiseaseand/orcerebrovasculardisease.

4.4Specialwarningsandprecautionsforuse

TheuseofCelebrexmayimpairfemalefertilityandisnotrecommendedinwomenattemptingtoconceive.Inwomen

whohavedifficultiesconceivingorwhoareundergoinginvestigationofinfertility,withdrawalofCelebrexshouldbe

considered.

Uppergastrointestinalcomplications[perforations,ulcersorbleedings(PUBs)],someofthemresultinginfatal

outcome,haveoccurredinpatientstreatedwithcelecoxib.Cautionisadvisedwithtreatmentofpatientsmostatriskof

developingagastrointestinalcomplicationwithNSAIDs;theelderly,patientsusinganyotherNSAIDoracetylsalicylic

acidconcomitantlyorpatientswithapriorhistoryofgastrointestinaldisease,suchasulcerationandGIbleeding.

Thereisfurtherincreaseintheriskofgastrointestinaladverseeffectsforcelecoxib(gastrointestinalulcerationorother

gastrointestinalcomplications),whencelecoxibistakenconcomitantlywithacetylsalicylicacid(evenatlowdoses).A

significantdifferenceinGIsafetybetweenselectiveCOX-2inhibitors+acetylsalicylicacidvs.NSAIDs+

acetylsalicylicacidhasnotbeendemonstratedinlong-termclinicaltrials(see5.1).

Increasednumberofseriouscardiovascularevents,mainlymyocardialinfarction,hasbeenfoundinalong-term

placebo-controlledstudyinsubjectswithsporadicadenomatouspolypstreatedwithcelecoxibatdosesof200mgBID

and400mgBIDcomparedtoplacebo(see5.1).

Asthecardiovascularrisksofcelecoxibmayincreasewithdoseanddurationofexposure,theshortestdurationpossible

andthelowesteffectivedailydoseshouldbeused.Thepatient'sneedforsymptomaticreliefandresponsetotherapy

shouldbere-evaluatedperiodically,especiallyinpatientswithosteoarthritis(4.2,4.3,4.8and5.1).

Patientswithsignificantriskfactorsforcardiovascularevents(e.g.hypertension,hyperlipidaemia,diabetesmellitus,

smoking)shouldonlybetreatedwithcelecoxibaftercarefulconsideration(see5.1).

COX-2selectiveinhibitorsarenotasubstituteforacetylsalicylicacidforprophylaxisofcardiovascularthrombo-

embolicdiseasesbecauseoftheirlackofantiplateleteffects.Therefore,antiplatelettherapiesshouldnotbe

discontinued(seesection5.1).

Aswithotherdrugsknowntoinhibitprostaglandinsynthesisfluidretentionandoedemahavebeenobservedinpatients

takingcelecoxib.Therefore,celecoxibshouldbeusedwithcautioninpatientswithhistoryofcardiacfailure,left

ventriculardysfunctionorhypertension,andinpatientswithpre-existingoedemafromanyotherreason,since

prostaglandininhibitionmayresultindeteriorationofrenalfunctionandfluidretention.Cautionisalsorequiredin

patientstakingdiuretictreatmentorotherwiseatriskofhypovolaemia.

Compromisedrenalorhepaticfunctionandespeciallycardiacdysfunctionaremorelikelyintheelderlyandtherefore

medicallyappropriatesupervisionshouldbemaintained.Clinicaltrialswithcelecoxibhaveshownrenaleffectssimilar

tothoseobservedwithcomparatorNSAIDs.

Ifduringtreatment,patientsdeteriorateinanyoftheorgansystemfunctionsdescribedabove,appropriatemeasures

shouldbetakenanddiscontinuationofcelecoxibtherapyshouldbeconsidered.

CelecoxibinhibitsCYP2D6.Althoughitisnotastronginhibitorofthisenzyme,adosereductionmaybenecessaryfor

individuallydose-titrateddrugsthataremetabolisedbyCYP2D6(See4.5).

PatientsknowntobeCYP2C9poormetabolisersshouldbetreatedwithcaution(see5.2.).

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

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tobeathighestriskforthesereactionsearlyinthecourseoftherapy:theonsetofthereactionoccurringinthemajority

ofcaseswithinthefirstmonthoftreatment.Serioushypersensitivityreactions(anaphylaxisandangioedema)havebeen

reportedinpatientsreceivingcelecoxib(see4.8).

Patientswithahistoryofsulphonamideallergyoranydrugallergymaybeatgreaterriskofseriousskinreactionsor

hypersensitivityreactions(see4.3).Celecoxibshouldbediscontinuedatthefirstappearanceofskinrash,mucosal

lesionsoranyothersignofhypersensitivity.

Celecoxibmaymaskfeverandothersignsofinflammation.

Inpatientsonconcurrenttherapywithwarfarin,seriousbleedingeventshaveoccurred.Cautionshouldbeexercised

whencombiningcelecoxibwithwarfarinandotheroralanticoagulants(See4.5).

Celebrex100mgand200mgcapsulescontainlactose(149.7mgand49.8mg,respectively).Patientswithrare

hereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorptionshould

nottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Anticoagulantactivityshouldbemonitoredparticularlyinthefirstfewdaysafterinitiatingorchangingthedoseof

celecoxibinpatientsreceivingwarfarinorotheranticoagulantssincethesepatientshaveanincreasedriskofbleeding

complications.Therefore,patientsreceivingoralanticoagulantsshouldbecloselymonitoredfortheirprothrombintime

INR,particularlyinthefirstfewdayswhentherapywithcelecoxibisinitiatedorthedoseofcelecoxibischanged(see

4.4).Bleedingeventsinassociationwithincreasesinprothrombintimehavebeenreported,predominantlyinthe

elderly,inpatientsreceivingcelecoxibconcurrentlywithwarfarin,someofthemfatal.

NSAIDsmayreducetheeffectofdiureticsandantihypertensivemedicinalproducts.AsforNSAIDs,theriskofacute

renalinsufficiency,whichisusuallyreversible,maybeincreasedinsomepatientswithcompromisedrenalfunction

(e.g.dehydratedpatientsorelderlypatients)whenACEinhibitorsorangiotensinIIreceptorantagonistsarecombined

withNSAIDs,includingcelecoxib.Therefore,thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringofrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

CoadministrationofNSAIDsandcyclosporinortacrolimushavebeensuggestedtoincreasethenephrotoxiceffectof

cyclosporinandtacrolimus.Renalfunctionshouldbemonitoredwhencelecoxibandanyofthesedrugsarecombined.

Celecoxibcanbeusedwithlow-doseacetylsalicylicacidbutisnotasubstituteforacetylsalicylicacidfor

cardiovascularprophylaxis.Inthesubmittedstudies,aswithotherNSAIDs,anincreasedriskofgastrointestinal

ulcerationorothergastrointestinalcomplicationscomparedtouseofcelecoxibalonewasshownforconcomitant

administrationoflow-doseacetylsalicylicacid(see5.1).

Pharmacokineticinteractions

Effectsofcelecoxibonotherdrugs

CelecoxibisaninhibitorofCYP2D6.Duringcelecoxibtreatment,theplasmaconcentrationsoftheCYP2D6substrate

dextromethorphanwereincreasedby136%.Theplasmaconcentrationsofdrugsthataresubstratesofthisenzymemay

beincreasedwhencelecoxibisusedconcomitantly.ExamplesofdrugswhicharemetabolisedbyCYP2D6are

antidepressants(tricyclicsandSSRIs),neuroleptics,anti-arrhythmicdrugs,etc.Thedoseofindividuallydose-titrated

CYP2D6substratesmayneedtobereducedwhentreatmentwithcelecoxibisinitiatedorincreasediftreatmentwith

celecoxibisterminated.

InvitrostudieshaveshownsomepotentialforcelecoxibtoinhibitCYP2C19catalysedmetabolism.Theclinical

significanceofthisinvitrofindingisunknown.ExamplesofdrugswhicharemetabolisedbyCYP2C19arediazepam,

citalopramandimipramine.

Inaninteractionstudy,celecoxibhadnoclinicallyrelevanteffectsonthepharmacokineticsoforalcontraceptives(1mg

norethisterone/35microgethinylestradiol).

Celecoxibdoesnotaffectthepharmacokineticsoftolbutamide(CYP2C9substrate),orglibenclamidetoaclinically

relevantextent.

Inpatientswithrheumatoidarthritiscelecoxibhadnostatisticallysignificanteffectonthepharmacokinetics(plasmaor

renalclearance)ofmethotrexate(inrheumatologicdoses).However,adequatemonitoringformethotrexate-related

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Inhealthysubjects,co-administrationofcelecoxib200mgtwicedailywith450mgtwicedailyoflithiumresultedina

meanincreaseinCmaxof16%andinAUCof18%oflithium.Therefore,patientsonlithiumtreatmentshouldbe

closelymonitoredwhencelecoxibisintroducedorwithdrawn.

Effectsofotherdrugsoncelecoxib

SincecelecoxibispredominantlymetabolisedbyCYP2C9itshouldbeusedathalftherecommendeddoseinpatients

receivingfluconazole.Concomitantuseof200mgsingledoseofcelecoxiband200mgoncedailyoffluconazole,a

potentCYP2C9inhibitor,resultedinameanincreaseincelecoxibCmaxof60%andinAUCof130%.Concomitant

useofinducersofCYP2C9suchasrifampicin,carbamazepineandbarbituratesmayreduceplasmaconcentrationsof

celecoxib.

Ketoconazoleorantacidshavenotbeenobservedtoaffectthepharmacokineticsofcelecoxib.

4.6Pregnancyandlactation

Noclinicaldataonexposedpregnanciesareavailableforcelecoxib.Studiesinanimals(ratsandrabbits)haveshown

reproductivetoxicity,includingmalformations(see4.3and5.3).Thepotentialforhumanriskinpregnancyis

unknown,butcannotbeexcluded.Celecoxib,aswithotherdrugsinhibitingprostaglandinsynthesis,maycauseuterine

inertiaandprematureclosureoftheductusarteriosusduringthelasttrimester.Celecoxibiscontraindicatedin

pregnancyandinwomenwhocanbecomepregnant(see4.3and4.4).Ifawomanbecomespregnantduringtreatment,

celecoxibshouldbediscontinued.

Therearenostudiesontheexcretionofcelecoxibinhumanmilk.Celecoxibisexcretedinthemilkoflactatingratsat

concentrationssimilartothoseinplasma.Womenwhotakecelecoxibshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Patientswhoexperiencedizziness,vertigoorsomnolencewhiletakingcelecoxibshouldrefrainfromdrivingor

operatingmachinery.

4.8Undesirableeffects

Approximately7400patientsweretreatedwithcelecoxibincontrolledtrialsandofthoseapproximately2300have

receiveditfor1yearorlonger.Thefollowingeventshavebeenreportedinpatientsreceivingcelecoxibin12placebo

and/oractivecontrolledtrials.Side-effectslistedhavearateequalorgreaterthanplacebo,andthediscontinuationrate

duetosideeffectswas7.1%inpatientsreceivingcelecoxiband6.1%inpatientsreceivingplacebo.

Additionalreactionsreportedfrompost-marketingexperiencein>70milliontreatedpatientsincludeheadache,nausea

andarthralgia,andthereactionsincludedasveryrare,initalicsinthelistbelow.

[VeryCommon>1/10),Common( ≥1/100,<1/10),Uncommon(≥1/1000,<1/100,)Rare(≥1/10,000,<1/1000),Very

rare(<1/10,000includingisolatedcases)]

Infectionsandinfestations

Common:sinusitis,upperrespiratorytractinfection

Uncommon:urinarytractinfection

Bloodandthelymphaticsystemdisorders

Uncommon:anaemia

Rare:leucopenia,thrombocytopenia

Veryrare:pancytopenia

Immunesystemdisorders:

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Metabolismandnutritiondisorders

Uncommon:hyperkalaemia

Psychiatricdisorders

Common:insomnia

Uncommon:anxiety,depression,tiredness.

Veryrare:confusion,hallucinations.

Nervoussystemdisorders

Common:dizziness

Uncommon:blurredvision,hypertonia,paraesthesia

Rare:ataxia,tastealteration

Veryrare:aggravatedepilepsy,meningitisaseptic,ageusia,anosmia

Earandlabyrinthdisorders

Uncommon:tinnitus

Veryrare:decreasedhearing

Cardiacdisorders

Uncommon:myocardialinfarction*,heartfailure,palpitations

Vasculardisorders

Uncommon:hypertension,hypertensionaggravated

Rare:ischaemicstroke*

Veryrare:vasculitis.

Respiratory,thoracicandmediastinaldisorders

Common:pharyngitis,rhinitis

Uncommon:cough,dyspnoea

Veryrare:bronchospasm.

Gastrointestinaldisorders

Common:abdominalpain,diarrhoea,dyspepsia,flatulence

Uncommon:constipation,eructation,gastritis,stomatitis,vomiting,aggravationofgastrointestinalinflammation

Rare:duodenal,gastricandoesophageal,intestinalandcoloniculceration,dysphagia,intestinalperforation,

oesophagitis,melaena.

Veryrare:gastrointestinalhaemorrhage,acutepancreatitis,colitis/colitisaggravated.

Hepato-biliarydisorders

Uncommon:abnormalhepaticfunction

Veryrare:hepatitis,jaundice,hepaticfailure.

Skinandsubcutaneoustissuedisorders

Common:rash

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Rare:alopecia,photosensitivity

Veryrare:angioedema,exfoliativedermatitis,erythemamultiforme,Stevens-Johnsonsyndrome,epidermalnecrolysis

Musculoskeletalandconnectivetissuedisorders

Uncommon:legcramps

Veryrare:myositis

Renalandurinarydisorders:

Veryrare:acuterenalfailure,interstitialnephritis

Reproductivesystemandbreastdisorders:

Veryrare:menstrualdisorderNOS

Generaldisordersandadministrationsiteconditions

Common:peripheraloedema/fluidretention

Investigations

Uncommon:increasedSGOTandSGPT,increasedcreatinine,BUNincreased

*Inapooledanalysisof20placebo-controlledstudieswithdurationgreaterthan2weeksupto1yearinpatientswith

OAandRA,theexcessrateofmyocardialinfarctioninpatientstreatedwithcelecoxib200or400mgdailyover

placebowas0.7eventsper1000patients(Rare)andtherewasnoexcessofstrokes.

Inpreliminarydatafromtwostudiesinpatientswithcolorectalpolypstreatedwithcelecoxib400mgdaily(seeSection

5.1)theexcessrateoverplaceboofmyocardialinfarctionover3yearswas7eventsper1000patients(Uncommon).In

thesamestudies,theexcessrateforclearlyidentifiedischaemicstrokeforthe400mgdailydose(notincludingevents

thatwerehaemorrhagicorofunknownaetiology)was0.5eventper1000over3years(Rare).Forallstrokes,therewas

noincreasedeventratewithcelecoxibcomparedwithplacebo.

4.9Overdose

Thereisnoclinicalexperienceofoverdose.Singledosesupto1200mgandmultipledosesupto1200mgtwicedaily

havebeenadministeredtohealthysubjectsforninedayswithoutclinicallysignificantadverseeffects.Intheeventof

suspectedoverdose,appropriatesupportivemedicalcareshouldbeprovidede.g.byeliminatingthegastriccontents,

clinicalsupervisionand,ifnecessary,theinstitutionofsymptomatictreatment.Dialysisisunlikelytobeanefficient

methodofdrugremovalduetohighproteinbinding.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ATCcode:M01AH01.

Celecoxibisanoral,selective,cyclooxygenase-2(COX-2)inhibitorwithintheclinicaldoserange(200-400mgdaily).

NostatisticallysignificantinhibitionofCOX-1(assessedasexvivoinhibitionofthromboxaneB

[TxB

]formation)

wasobservedinthisdoserangeinhealthyvolunteers.

Cyclooxygenaseisresponsibleforgenerationofprostaglandins.Twoisoforms,COX-1andCOX-2,havebeen

identified.COX-2istheisoformoftheenzymethathasbeenshowntobeinducedbypro-inflammatorystimuliandhas

beenpostulatedtobeprimarilyresponsibleforthesynthesisofprostanoidmediatorsofpain,inflammation,andfever.

COX-2isalsoinvolvedinovulation,implantationandclosureoftheductusarteriosus,regulationofrenalfunction,and

centralnervoussystemfunctions(feverinduction,painperceptionandcognitivefunction).Itmayalsoplayarolein

ulcerhealing.COX-2hasbeenidentifiedintissuearoundgastriculcersinmanbutitsrelevancetoulcerhealinghasnot

beenestablished.

ThedifferenceinantiplateletactivitybetweensomeCOX-1inhibitingNSAIDsandCOX-2selectiveinhibitorsmay

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COX-2selectiveinhibitorsreducetheformationofsystemic(andthereforepossiblyendothelial)prostacyclinwithout

affectingplateletthromboxane.

Celecoxibisadiaryl-substitutedpyrazole,chemicallysimilartoothernon-arylaminesulfonamides(e.g.thiazides,

furosemide)butdiffersfromarylaminesulfonamides(e.g.sulfamethoxizoleandothersulfonamideantibiotics).

AdosedependenteffectonTxB

formationhasbeenobservedafterhighdosesofcelecoxib.However,inhealthy

subjects,insmallmultipledosestudieswith600mgBID(threetimesthehighestrecommendeddose)celecoxibhadno

effectonplateletaggregationandbleedingtimecomparedtoplacebo.

Severalclinicalstudieshavebeenperformedconfirmingefficacyandsafetyinosteoarthritisandrheumatoidarthritis.

CelecoxibwasevaluatedforthetreatmentoftheinflammationandpainofOAofthekneeandhipinapproximately

4200patientsinplaceboandactivecontrolledtrialsofupto12weeksduration.Itwasalsoevaluatedfortreatmentof

theinflammationandpainofRAinapproximately2100patientsinplaceboandactivecontrolledtrialsofupto24

weeksduration.Celecoxibatdailydosesof200mg-400mgprovidedpainreliefwithin24hoursofdosing.Five

randomiseddouble-blindcontrolledstudieshavebeenconductedincludingscheduleduppergastrointestinalendoscopy

inapproximately4500patientsfreefrominitialulceration(celecoxibdosesfrom50mg-400mgBID).Intwelveweek

endoscopystudiescelecoxib(100-800mgperday)wasassociatedwithasignificantlylowerriskofgastroduodenal

ulcerscomparedwithnaproxen(1000mgperday)andibuprofen(2400mgperday).Thedatawereinconsistentin

comparisonwithdiclofenac(150mgperday).Intwoofthe12-weekstudiesthepercentageofpatientswithendoscopic

gastroduodenalulcerationwerenotsignificantlydifferentbetweenplaceboandcelecoxib200mgBIDand400mg

BID.

Inaprospectivelong-termsafetyoutcomestudy(6to15monthduration,CLASSstudy),5,800OAand2,200RA

patientsreceivedcelecoxib400mgBID(4-foldand2-foldtherecommendedOAandRAdoses,respectively),

ibuprofen800mgTIDordiclofenac75mgBID(bothattherapeuticdoses).Twenty-twopercentofenrolledpatients

tookconcomitantlow-doseacetylsalicylicacid( ≤325mg/day),primarilyforcardiovascularprophylaxis.Forthe

primaryendpointcomplicatedulcers(definedasgastrointestinalbleeding,perforationorobstruction)celecoxibwasnot

significantlydifferentthaneitheribuprofenordiclofenacindividually.AlsoforthecombinedNSAIDgrouptherewas

nostaticallysignificantdifferenceforcomplicatedulcers(relativerisk0,77,95%CI0.41-1.46,basedonentirestudy

duration).Forthecombinedendpoint,complicatedandsymptomaticulcers,theincidencewassignificantlylowerin

thecelecoxibgroupcomparedtotheNSAIDgroup,relativerisk0.66,95%CI0.45-0.97butnotbetweencelecoxiband

diclofenac.Thosepatientsoncelecoxibandconcomitantlow-doseacetylsalicylicacidexperienced4foldhigherrates

ofcomplicatedulcersascomparedtothoseoncelecoxibalone.Theincidenceofclinicallysignificantdecreasesin

haemoglobin>2g/dL),confirmedbyrepeattesting,wassignificantlylowerinpatientsoncelecoxibcomparedtothe

NSAIDgroup,relativerisk0.29,95%CI0.17-0.48.Thesignificantlylowerincidenceofthiseventwithcelecoxibwas

maintainedwithorwithoutacetylsalicylicaciduse.

OngoingClinicalTrials:Preliminarysafetyinformationfromthreelong-termstudiesinvolvingpatientswithSporadic

AdenomatousPolypsorwhowerepredisposedtodevelopingAlzheimer'sdiseasetreatedwithcelecoxibisavailable.In

oneofthethreestudies,theAPC(PreventionofSporadicColorectalAdenomaswithCelecoxib),therewasadose-

relatedincreaseincardiovascularevents(mainlymyocardialinfarction,MI)atcelecoxibdosesof200mgBIDand400

mgBIDcomparedtoplacebo.Theincreasedriskbecameapparentafterapproximately1yearoftreatment.Therelative

risk(RR)forthecompositeendpoint(cardiovasculardeathMIorstroke)was3.4(95%CI1.4–8.5)forthehigher

doseand2.5(95%CI1.0–6.4)forthelowerdoseofcelecoxibcomparedtoplacebo.Theabsoluteriskforthe

compositeendpointwas3.0%forthehigherdoseofcelecoxib,2.2%forthelowerdoseofcelecoxib,and0.9%for

placebo.Preliminarydatafromtheothertwolong-termstudiesdidnotshowasignificantlyincreasedcardiovascular

riskwithcelecoxib200mgBIDand400mgQDcomparedtoplacebo.Thisinformationwillbeupdatedasfinaldata

becomeavailable.

5.2Pharmacokineticproperties

Celecoxibiswellabsorbedreachingpeakplasmaconcentrationsafterapproximately2-3hours.Dosingwithfood(high

fatmeal)delaysabsorptionbyabout1hour.

Celecoxibismainlyeliminatedbymetabolism.Lessthan1%ofthedoseisexcretedunchangedinurine.Theinter-

subjectvariabilityintheexposureofcelecoxibisabout10-fold.Celecoxibexhibitsdose-andtime-independent

pharmacokineticsinthetherapeuticdoserange.Plasmaproteinbindingisabout97%attherapeuticplasma

concentrationsandthedrugisnotpreferentiallyboundtoerythrocytes.Eliminationhalf-lifeis8-12hours.Steadystate

plasmaconcentrationsarereachedwithin5daysoftreatment.Pharmacologicalactivityresidesintheparentdrug.The

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Celecoxibismetabolisedintheliverbyhydroxylation,oxidationandsomeglucuronidation.

ThephaseImetabolismismainlycatalysedbyCYP2C9.Thereisageneticpolymorphismofthisenzyme.Lessthan

1%ofthepopulationarepoormetabolisersandhaveanenzymewithdecreasedactivity.Plasmaconcentrationsof

celecoxibareprobablymarkedlyincreasedinsuchpatients.PatientsknowntobeCYP2C9poormetabolisersshouldbe

treatedwithcaution.

NoclinicallysignificantdifferenceswerefoundinPKparametersofcelecoxibbetweenelderlyAfrican-Americansand

Caucasians.

Theplasmaconcentrationofcelecoxibisapproximately100%increasedinelderlywomen>65years).

Comparedtosubjectswithnormalhepaticfunction,patientswithmildhepaticimpairmenthadameanincreasein

Cmaxof53%andinAUCof26%ofcelecoxib.Thecorrespondingvaluesinpatientswithmoderatehepatic

impairmentwere41%and146%respectively.Themetaboliccapacityinpatientswithmildtomoderateimpairmentwas

bestcorrelatedtotheiralbuminvalues.Treatmentshouldbeinitiatedathalftherecommendeddoseinpatientswith

moderateliverimpairment(withserumalbumin25-35g/L).Patientswithseverehepaticimpairment(serumalbumin

<25g/l)havenotbeenstudiedandcelecoxibiscontraindicatedinthispatientgroup.

Thereislittleexperienceofcelecoxibinrenalimpairment.Thepharmacokineticsofcelecoxibhasnotbeenstudiedin

patientswithrenalimpairmentbutisunlikelytobemarkedlychangedinthesepatients.Thuscautionisadvisedwhen

treatingpatientswithrenalimpairment.Severerenalimpairmentiscontraindicated.

5.3Preclinicalsafetydata

Conventionalembryo-fetaltoxicitystudiesresultedindosedependentoccurrencesofdiaphragmaticherniainrat

fetusesandofcardiovascularmalformationsinrabbitfetusesatsystemicexposurestofreedrugapproximately5X(rat)

and3X(rabbit)higherthanthoseachievedatthemaximumrecommendeddailyhumandose(400mg).Diaphragmatic

herniawasalsoseeninaperi-postnataltoxicitystudyinrats,whichincludedexposureduringtheorganogenetic

period.Inthelatterstudy,atthelowestsystemicexposurewherethisanomalyoccurredinasingleanimal,the

estimatedmarginrelativetothemaximumrecommendeddailyhumandosewas3X.

Inanimals,exposuretocelecoxibduringearlyembryonicdevelopmentresultedinpre-implantationandpost-

implantationlosses.Theseeffectsareexpectedfollowinginhibitionofprostaglandinsynthesis.

Celecoxibwasexcretedinratmilk.Inaperi-postnatalstudyinrats,puptoxicitywasobserved.

Basedonconventionalstudies,genotoxicityorcarcinogenicity,nospecialhazardforhumanswasobserved,beyond

thoseaddressedinothersectionsoftheSmPC.Inatwo-yeartoxicitystudyanincreaseinnonadrenalthrombosiswas

observedinmaleratathighdoses.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulescontain:

Lactosemonohydrate

Sodiumlaurylsulphate

PovidoneK30

Croscarmellosesodium

Magnesiumstearate.

Capsuleshellscontain:

Gelatin

Titaniumdioxide(E171)

Inkcontainsindigotine(E132)

6.2Incompatibilities

Irish Medicines Board

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Date Printed 23/09/2007 CRN 2033989 page number: 9

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin .

6.4Specialprecautionsforstorage

Donotstoreabove30 0

6.5Natureandcontentsofcontainer

ClearPVCblistersoraluminiumcold-formedblisters.Packof30capsules.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/57/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:29thSeptember2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 23/09/2007 CRN 2033989 page number: 10