CELEBREX

Main information

  • Trade name:
  • CELEBREX Capsules Hard 200 Milligram
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CELEBREX Capsules Hard 200 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/038/001
  • Authorization date:
  • 12-03-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PPA1500/038/001

CaseNo:2083758

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ProfindWholesaleLtd.

Unit625,KilshaneAvenue,NorthwestBusinessPark,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Celebrex200mgcapsules,hard

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/07/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Celebrex200mgcapsules,hard.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains200mgcelecoxib

Excipients:containslactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsule,hard.

ProductimportedfromItaly:

Opaque,whitecapsulewithtwogoldbandsmarked7767and200

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomaticreliefinthetreatmentofosteoarthritis,rheumatoidarthritisandankylosingspondylitis.

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.

AnkylosingSpondylitis:Therecommendeddailydoseis200mgtakenoncedailyorintwodivideddoses.Inafew

patients,withinsufficientrelieffromsymptoms,anincreaseddoseof400mgoncedailyorintwodivideddosesmay

increaseefficacy.Intheabsenceofanincreaseintherapeuticbenefitaftertwoweeks,othertherapeuticoptionsshould

beconsidered.

Themaximumrecommendeddailydoseis400mgforallindications.

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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).

Children:Celecoxibisnotindicatedforuseinchildren.

CYP2C9PoorMetabolizers:Patientswhoareknown,orsuspectedtobeCYP2C9poormetabolizersbasedon

genotypingorprevioushistory/experiencewithotherCYP2C9substratesshouldbeadministeredcelecoxibwithcaution

astheriskofdose-dependentadverseeffectsisincreased.Considerreducingthedosetohalfthelowestrecommended

dose.(See5.2)

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-Pughscore10).

Patientswithestimatedcreatinineclearance<30ml/min.

Inflammatoryboweldisease.

Congestiveheartfailure(NYHAII-IV).

Establishedischaemicheartdisease,peripheralarterialdiseaseand/orcerebrovasculardisease.

4.4Specialwarningsandprecautionsforuse

Uppergastrointestinalcomplications[perforations,ulcersorbleedings(PUBs)],someofthemresultinginfatal

outcome,haveoccurredinpatientstreatedwithcelecoxib.Cautionisadvisedwithtreatmentofpatientsmostatriskof

developingagastrointestinalcomplicationwithNSAIDs;theelderly,patientsusinganyotherNSAIDoracetylsalicylic

acidconcomitantlyorpatientswithapriorhistoryofgastrointestinaldisease,suchasulcerationandGIbleeding.

Thereisfurtherincreaseintheriskofgastrointestinaladverseeffectsforcelecoxib(gastrointestinalulcerationorother

gastrointestinalcomplications),whencelecoxibistakenconcomitantlywithacetylsalicylicacid(evenatlowdoses).

AsignificantdifferenceinGIsafetybetweenselectiveCOX-2inhibitors+acetylsalicylicacidvs.NSAIDs+

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Theconcomitantuseofcelecoxibandanon-aspirinNSAIDshouldbeavoided.

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.

AswithallNSAIDS,celecoxibcanleadtotheonsetofnewhypertensionorworseningofpre-existinghypertension,

eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.Therefore,bloodpressureshouldbe

monitoredcloselyduringtheinitiationoftherapywithcelecoxibandthroughoutthecourseoftherapy.

Compromisedrenalorhepaticfunctionandespeciallycardiacdysfunctionaremorelikelyintheelderlyandtherefore

medicallyappropriatesupervisionshouldbemaintained.

NSAIDs,includingcelecoxib,maycauserenaltoxicity.Clinicaltrialswithcelecoxibhaveshownrenaleffectssimilar

tothoseobservedwithcomparatorNSAIDs.

Patientsatgreatestriskforrenaltoxicityarethosewithimpairedrenalfunction,heartfailure,liverdysfunction,andthe

elderly.Suchpatientsshouldbecarefullymonitoredwhilereceivingtreatmentwithcelecoxib.

Somecasesofseverehepaticreactions,includingfulminanthepatitis(somewithfataloutcome),livernecrosisand,

hepaticfailure(somewithfataloutcomeorrequiringlivertransplant),havebeenreportedwithcelecoxib.Amongthe

casesthatreportedtimetoonset,mostofthesevereadversehepaticeventsdevelopedwithinonemonthafterinitiation

ofcelecoxibtreatment(see4.8).

Ifduringtreatment,patientsdeteriorateinanyoftheorgansystemfunctionsdescribedabove,appropriatemeasures

shouldbetakenanddiscontinuationofcelecoxibtherapyshouldbeconsidered.

CelecoxibinhibitsCYP2D6.Althoughitisnotastronginhibitorofthisenzyme,adosereductionmaybenecessaryfor

individuallydose-titrateddrugsthataremetabolisedbyCYP2D6(See4.5).

PatientsknowntobeCYP2C9poormetabolisersshouldbetreatedwithcaution(see5.2.).

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofcelecoxib(see4.8).Patientsappear

tobeathighestriskforthesereactionsearlyinthecourseoftherapy:theonsetofthereactionoccurringinthemajority

ofcaseswithinthefirstmonthoftreatment.Serioushypersensitivityreactions(anaphylaxisandangioedema)havebeen

reportedinpatientsreceivingcelecoxib(see4.8).Patientswithahistoryofsulphonamideallergyoranydrugallergy

maybeatgreaterriskofseriousskinreactionsorhypersensitivityreactions(see4.3).Celecoxibshouldbediscontinued

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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.

Ina28-dayclinicalstudyinpatientswithlisinopril-controlledStageIandIIhypertension,administrationofcelecoxib

200mgBIDresultedinnoclinicallysignificantincreases,whencomparedtoplacebotreatment,inmeandailysystolic

ordiastolicbloodpressureasdeterminedusing24-hourambulatorybloodpressuremonitoring.Amongpatientstreated

withcelecoxib200mgBID,48%wereconsideredunresponsivetolisinoprilatthefinalclinicvisit(definedaseither

cuffdiastolicbloodpressure>90mmHgorcuffdiastolicbloodpressureincreased>10%comparedtobaseline),

comparedto27%ofpatientstreatedwithplacebo;thisdifferencewasstatisticallysignificant.

CoadministrationofNSAIDsandciclosporinortacrolimushavebeensuggestedtoincreasethenephrotoxiceffectof

ciclosporinandtacrolimus.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,

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Inaninteractionstudy,celecoxibhadnoclinicallyrelevanteffectsonthepharmacokineticsoforalcontraceptives(1

mgnorethistherone/35microgethinylestradiol).

Celecoxibdoesnotaffectthepharmacokineticsoftolbutamide(CYP2C9substrate),orglibenclamidetoaclinically

relevantextent.

Inpatientswithrheumatoidarthritiscelecoxibhadnostatisticallysignificanteffectonthepharmacokinetics(plasmaor

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

toxicityshouldbeconsideredwhencombiningthesetwodrugs.

Inhealthysubjects,co-administrationofcelecoxib200mgtwicedailywith450mgtwicedailyoflithiumresultedina

meanincreaseinCmaxof16%andinAUCof18%oflithium.Therefore,patientsonlithiumtreatmentshouldbe

closelymonitoredwhencelecoxibisintroducedorwithdrawn.

Effectsofotherdrugsoncelecoxib

InindividualswhoareCYP2C9poormetabolisersanddemonstrateincreasedsystemicexposuretocelecoxib,

concomitanttreatmentwithCYP2C9inhibitorscouldresultinfurtherincreasesincelecoxibexposure.Such

combinationsshouldbeavoidedinknownCYP2C9poormetabolisers(seesections4.2and5.2).

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.

Celecoxibisexcretedinthemilkoflactatingratsatconcentrationssimilartothoseinplasma.Administrationof

celecoxibtoalimitednumberoflactatingwomenhasshownaverylowtransferofcelecoxibintobreastmilk.Women

whotakecelecoxibshouldnotbreastfeed.

4.7Effectsonabilitytodriveandusemachines

Patientswhoexperiencedizziness,vertigoorsomnolencewhiletakingcelecoxibshouldrefrainfromdrivingor

operatingmachinery.

4.8Undesirableeffects

AdversereactonsarelistedbysystemorganclassandrankedbyfrequencyinTable1,reflectingdatafromthe

followingsourses:

Adversereactionsreportedinosteoarthritispatientsandrheumatoidarthritispatientsatincidenceratesgreaterthan

0.01%andgreaterthanthosereportedforplaceboduring12placebo-and/oractive-controlledclinicaltrialsof

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Inadditionalstudiesusingnon-selectiveNSAIDcomparators,approximately7400arthritispatientshavebeen

treatedwithcelecoxibatdailydosesupto800mg,includingapproximately2300patientstreatedfor1yearor

longer.Theadversereactionsobservedwithcelecoxibintheseadditionalstudieswereconsistentwiththosefor

osteoarthritisandrheumatoidarthritispatientslistedinTable1.

Adversereactionsreportedatincidenceratesgreaterthanplaceboforsubjectstreatedwithcelecoxib400mgdaily

inlong-termpolyppreventiontrialsofdurationupto3years(theAPCandPreSAPtrials;seeSection5.1,

Pharmacodynamicproperties:CardiovascularSafety–Long-TermStudiesInvolvingPatientsWithSporadic

AdenomatousPolyps).

Adversedrugreactionsfrompost-marketingsurveillanceasspontaneouslyreportedduringaperiodinwhichan

estimated>70millionpatientsweretreatedwithcelecoxib(variousdoses,durations,andindications).Becausenot

alladversedrugreactionsarereportedtotheMAHandincludedinthesafetydatabase,thefrequenciesofthese

reactionscannotbereliablydetermined.

Table1.AdverseDrugReactionsinCelecoxibClinicalTrialsandSurveillanceExperience(MedDRAPreferred

Terms) 1,2

AdverseDrugReactionFrequency

Very

Common

≥1/10) Common

≥1/100to<1/10) Uncommon

≥1/1000to<1/100) Rare

≥1/10,000to

<1/1000) FrequencyNot

Known

(Post-marketing

experience) 3

Infectionsandinfestations

Sinusitis,upper

respiratorytract

infection,urinary

tractinfection

Bloodandlymphaticsystemdisorders

Anemia Leucopenia,

thrombocytopenia Pancytopenia

Immunesystemdisorders

Allergyaggravated Seriousallergic

reactions,

anaphylacticshock,

anaphylaxis

Psychiatricdisorders

Insomnia Anxiety,depression,

tiredness Confusion Hallucinations

Metabolismandnutritiondisorders

Hyperkaelemia

Nervoussystemdisorders

Dizziness,

hypertonia Paraesthesia,

somnolence,cerebral

infarction 1 Ataxia,taste

alteration Headache,aggravated

epilepsy,meningitis

aseptic,ageusia,

anosmia,fatal

intracranial

haemorrhage

Eyedisorders

Blurredvision Conjunctivitis,ocular

haemorrhage,retinal

arteryorvein

occlusion

Earandlabyrinthdisorders

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Cardiacdisorders

Myocardial

infarction 1 Heartfailure,

palpitations,

tachycardia Arrhythmia

Vasculardisorders

Hyper-

tension 1 Hypertension

aggravated Flushing,vasculitis

Respiratory,thoracic,andmediastinaldisorders

Pharyngitis,rhinitis,

cough,dyspnoea 1 Bronchospasm

Gastrointestinaldisorders

Abdominalpain,

diarrhoea,dyspepsia,

flatulence,

vomiting 1

dysphagia 1 Constipation,

eructation,gastritis,

stomatitis,

aggravationof

gastrointestinal

inflammation Duodenal,gastric,

oesophageal,

intestinal,andcolonic

ulceration;intestinal

perforation;

oesophagitis,

melaena;pancreatitis Nausea,

gastrointestinal

haemorrhage,

colitis/colitis

aggravated

Hepatobiliarydisorders

Abnormalhepatic

function,increased

SGOTandSGPT Elevationofhepatic

enzymes Hepaticfailure

(sometimesfatalor

requiringliver

transplant),fulminant

hepatitis(somewith

fataloutcome),liver

necrosis,hepatitis

jaundice

Skinandsubcutaneoustissuedisorders

Rash,pruritus Urticaria Alopecia,

photosensitivity Ecchymosis,

bullouseruption,

exfoliativedermatitis,

erythemamultiforme,

Stevens-Johnson

syndrome,toxic

epidermalnecrolysis,

angioedema,acute

generalized

exanthematous

pustulosis

Musculoskeletalandconnectivetissuedisorders

Legcramps Arthralgia,myositis

Renalandurinarydisorders

Increasedcreatinine,

BUNincreased Acuterenalfailure,

interstitialnephritis,

hyponatraemia

Reproductivesystemandbreastdisorders

Menstrualdisorder

Generaldisordersandadministrativesiteconditions

Flu-likesymptoms,

peripheraloedema/

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Infinaldata(adjudicated)fromtheAPCandPreSAPtrialsinpatientstreatedwithcelecoxib400mgdailyforupto

3years(pooleddatafrombothtrials;seeSection5.1forresultsfromindividualtrials),theexcessrateoverplacebofor

myocardialinfarctionwas7.6eventsper1000patients(uncommon)andtherewasnoexcessrateforstroke(typesnot

differentiated)overplacebo.

4.9Overdose

Thereisnoclinicalexperienceofoverdose.Singledosesupto1200mgandmultipledosesupto1200mgtwicedaily

havebeenadministeredtohealthysubjectsforninedayswithoutclinicallysignificantadverseeffects.Intheeventof

suspectedoverdose,appropriatesupportivemedicalcareshouldbeprovidede.g.byeliminatingthegastriccontents,

clinicalsupervisionand,ifnecessary,theinstitutionofsymptomatictreatment.Dialysisisunlikelytobeanefficient

methodofdrugremovalduetohighproteinbinding.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Non-steroidalantiinflammatoryandantirheumaticdrugs,NSAIDs,Coxibs.

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

Adversedrugreactionsthatoccurredinpolyppreventiontrials,representingsubjectstreatedwith

celecoxib400mgdailyin2clinicaltrialsofdurationupto3years(theAPCandPreSAPtrials).The

adversedrugreactionslistedaboveforthepolyppreventiontrialsareonlythosethathavebeen

previouslyrecognizedinthepost-marketingsurveillanceexperience,orhaveoccurredmorefrequently

thaninthearthritistrials.

Furthermore,thefollowingpreviouslyunknownadversereactionsoccurredinpolyppreventiontrials,

representingsubjectstreatedwithcelecoxib400mgdailyin2clinicaltrialsofdurationupto3years(the

APCandPreSAPtrials):

Common:anginapectoris,irritablebowelsyndrome,nephrolithiasis,bloodcreatinineincreased,benign

prostatichyperplasia,weightincreased.Uncommon:helicobacterinfection,herpeszoster,erysipelas,

bronchopneumonia,labyrinthitis,gingivalinfection,lipoma,vitreousfloaters,conjunctivalhaemorrhage,

deepveinthrombosis,dysphonia,haemorrhoidalhaemorrhage,frequentbowelmovements,mouth

ulceration,allergicdermatitis,ganglion,nocturia,vaginalhaemorrhage,breasttenderness,lowerlimb

fracture,bloodsodiumincreased.

Adversedrugreactionsspontaneouslyreportedtothesafetysurveillancedatabaseoveraperiodinwhich

anestimated>70millionpatientsweretreatedwithcelecoxib(variousdoses,durations,and

indications).Asaresult,thefrequenciesoftheseadversedrugreactionscannotbereliablydetermined.

Adversedrugreactionslistedforthepost-marketingpopulationareonlythosethatarenotalreadylisted

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COX-2isalsoinvolvedinovulation,implantationandclosureoftheductusarteriosus,regulationofrenalfunction,and

centralnervoussystemfunctions(feverinduction,painperceptionandcognitivefunction).Itmayalsoplayarolein

ulcerhealing.COX-2hasbeenidentifiedintissuearoundgastriculcersinmanbutitsrelevancetoulcerhealinghasnot

beenestablished.

ThedifferenceinantiplateletactivitybetweensomeCOX-1inhibitingNSAIDsandCOX-2selectiveinhibitorsmaybe

ofclinicalsignificanceinpatientsatriskofthrombo-embolicreactions.COX-2selectiveinhibitorsreducethe

formationofsystemic(andthereforepossiblyendothelial)prostacyclinwithoutaffectingplateletthromboxane.

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

furosemide)butdiffersfromarylaminesulfonamides(e.g.sulfamethoxizoleandothersulfonamideantibiotics).

AdosedependenteffectonTxB

formationhasbeenobservedafterhighdosesofcelecoxib.However,inhealthy

subjects,insmallmultipledosestudieswith600mgBID(threetimesthehighestrecommendeddose)celecoxibhadno

effectonplateletaggregationandbleedingtimecomparedtoplacebo.

Severalclinicalstudieshavebeenperformedconfirmingefficacyandsafetyinosteoarthritis,rheumatoidarthritisand

ankylosingspondylitis.CelecoxibwasevaluatedforthetreatmentoftheinflammationandpainofOAofthekneeand

hipinapproximately4200patientsinplaceboandactivecontrolledtrialsofupto12weeksduration.

ItwasalsoevaluatedfortreatmentoftheinflammationandpainofRAinapproximately2100patientsinplaceboand

activecontrolledtrialsofupto24weeksduration.Celecoxibatdailydosesof200mg–400mgprovidedpainrelief

within24hoursofdosing.Celecoxibwasevaluatedforthesymptomatictreatmentofankylosingspondylitisin896

patientsinplaceboandactivecontrolledtrialsofupto12weeksduration.Celecoxibatdosesof100mgBID,200mg

QD,200mgBIDand400mgQDinthesestudiesdemonstratedsignificantimprovementinpain,globaldisease

activityandfunctioninankylosingspondylitis.

Fiverandomiseddouble-blindcontrolledstudieshavebeenconductedincludingscheduleduppergastrointestinal

endoscopyinapproximately4500patientsfreefrominitialulceration(celecoxibdosesfrom50mg-400mgBID).In

twelveweekendoscopystudiescelecoxib(100-800mgperday)wasassociatedwithasignificantlylowerriskof

gastroduodenalulcerscomparedwithnaproxen(1000mgperday)andibuprofen(2400mgperday).Thedatawere

inconsistentincomparisonwithdiclofenac(150mgperday).Intwoofthe12-weekstudiesthepercentageofpatients

withendoscopicgastroduodenalulcerationwerenotsignificantlydifferentbetweenplaceboandcelecoxib200mgBID

and400mgBID.

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.

CardiovascularSafety–Long-TermStudiesInvolvingSubjectsWithSporadicAdenomatousPolyps

Twostudiesinvolvingsubjectswithsporadicadenomatouspolypswereconductedwithcelecoxibi.e.,theAPCtrial

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IntheAPCtrial,therewasadose-relatedincreaseinthecompositeendpointofcardiovasculardeath,myocardial

infarction,orstroke(adjudicated)withcelecoxibcomparedtoplaceboover3yearsoftreatment.ThePreSAPtrialdid

notdemonstrateastatisticallysignificantincreasedriskforthesamecompositeendpoint.

IntheAPCtrial,therelativeriskscomparedtoplaceboforacompositeendpoint(adjudicated)ofcardiovasculardeath,

myocardialinfarction,orstrokewere3.4(95%CI1.4-8.5)withcelecoxib400mgtwicedailyand2.8(95%CI

1.1-7.2)withcelecoxib200mgtwicedaily.Cumulativeratesforthiscompositeendpointover3yearswere3.0%

(20/671subjects)and2.5%(17/685subjects),respectively,comparedto0.9%(6/679subjects)forplacebo.The

increasesforbothcelecoxibdosegroupsversusplaceboweremainlyduetoanincreasedincidenceofmyocardial

infarction.

InthePreSAPtrial,therelativeriskcomparedtoplaceboforthissamecompositeendpoint(adjudicated)was1.2(95%

CI0.6-2.4)withcelecoxib400mgoncedailycomparedtoplacebo.Cumulativeratesforthiscompositeendpoint

over3yearswere2.3%(21/933subjects)and1.9%(12/628subjects),respectively.Theincidenceofmyocardial

infarction(adjudicated)was1.0%with(9/933subjects)withcelecoxib400mgoncedailyand0.6%(4/628subjects)

withplacebo.

Datafromathirdlong-termstudy,ADAPT(TheAlzheimer'sDiseaseAnti-inflammatoryPreventionTrial),didnot

showasignificantlyincreasedcardiovascularriskwithcelecoxib200mgBIDcomparedtoplacebo.

Therelativeriskcomparedtoplaceboforasimilarcompositeendpoint(CVdeath,MI,stroke)was1.14(95%CI

0.61-2.12)withcelecoxib200mgtwicedaily.Theincidenceofmyocardialinfarctionwas1.1%(8/717patients)with

celecoxib200mgtwicedailyand1.2%(13/1070patients)withplacebo.

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

mainmetabolitesfoundinthecirculationhavenodetectableCOX-1orCOX-2activity.

CelecoxibmetabolismisprimarilymediatedviacytochromeP4502C9.Threemetabolites,inactiveasCOX-1orCOX-

2inhibitors,havebeenidentifiedinhumanplasmai.e.,aprimaryalcohol,thecorrespondingcarboxylicacidandits

glucuronideconjugate.

CytochromeP4502C9activityisreducedinindividualswithgeneticpolymorphismsthatleadtoreducedenzyme

activity,suchasthosehomozygousfortheCYP2C9*3polymorphism.

Inapharmacokineticstudyofcelecoxib200mgadministeredoncedailyinhealthyvolunteers,genotypedaseither

CYP2C9*1/*1,CYP2C9*1/*3,orCYP2C9*3/*3,themedianCmaxandAUC0-24ofcelecoxibonday7were

approximately4-foldand7-fold,respectively,insubjectsgenotypedasCYP2C9*3/*3comparedtoothergenotypes.In

threeseparatesingledosestudies,involvingatotalof5subjectsgenotypedasCYP2C9*3/*3,single-doseAUC0-24

increasedbyapproximately3-foldcomparedtonormalmetabolizers.Itisestimatedthatthefrequencyofthe

homozygous*3/*3genotypeis0.3-1.0%amongdifferentethnicgroups.

Patientswhoareknown,orsuspectedtobeCYP2C9poormetabolizersbasedonprevioushistory/experiencewith

otherCYP2C9substratesshouldbeadministeredcelecoxibwithcaution(seeSection4.2).

NoclinicallysignificantdifferenceswerefoundinPKparametersofcelecoxibbetweenelderlyAfrican-Americansand

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Theplasmaconcentrationofcelecoxibisapproximately100%increasedinelderlywomen(>65years).

Comparedtosubjectswithnormalhepaticfunction,patientswithmildhepaticimpairmenthadameanincreasein

Cmaxof53%andinAUCof26%ofcelecoxib.Thecorrespondingvaluesinpatientswithmoderatehepatic

impairmentwere41%and146%respectively.Themetaboliccapacityinpatientswithmildtomoderateimpairment

wasbestcorrelatedtotheiralbuminvalues.Treatmentshouldbeinitiatedathalftherecommendeddoseinpatients

withmoderateliverimpairment(withserumalbumin25-35g/L).Patientswithseverehepaticimpairment(serum

albumin<25g/l)havenotbeenstudiedandcelecoxibiscontraindicatedinthispatientgroup.

Thereislittleexperienceofcelecoxibinrenalimpairment.Thepharmacokineticsofcelecoxibhasnotbeenstudiedin

patientswithrenalimpairmentbutisunlikelytobemarkedlychangedinthesepatients.Thuscautionisadvisedwhen

treatingpatientswithrenalimpairment.Severerenalimpairmentiscontraindicated.

5.3Preclinicalsafetydata

Conventionalembryo-fetaltoxicitystudiesresultedindosedependentoccurrencesofdiaphragmaticherniainrat

fetusesandofcardiovascularmalformationsinrabbitfetusesatsystemicexposurestofreedrugapproximately5X(rat)

and3X(rabbit)higherthanthoseachievedatthemaximumrecommendeddailyhumandose(400mg).

Diaphragmaticherniawasalsoseeninaperi-postnataltoxicitystudyinrats,whichincludedexposureduringthe

organogeneticperiod.Inthelatterstudy,atthelowestsystemicexposurewherethisanomalyoccurredinasingle

animal,theestimatedmarginrelativetothemaximumrecommendeddailyhumandosewas3X.

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)

Inkcontains:

ironoxideyellow(E172)

6.2Incompatibilities

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6.3ShelfLife

Theshelflifeexpirydateoftheproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin

6.4Specialprecautionsforstorage

Donotstoreabove30 ˚C

6.5Natureandcontentsofcontainer

Anover-labelledcardboardcartoncontainingthreeblisters(10capsulesperblister)

Packsize30capsules.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/038/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12thMarch2010

10DATEOFREVISIONOFTHETEXT

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