CELEBREX 100MG HARD CAPSULES

Main information

  • Trade name:
  • CELEBREX 100MG HARD CAPSULES
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/118/001A
  • Authorization date:
  • 19-03-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Celebrex100mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains100mgcelecoxib.

Excipients:ContainsLactose

Forafulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

ProductimportedfromBelgium,GreeceandFrance

HardCapsule.

Opaque,whitecapsulewithtwobluebandsmarked‘7767’and‘100’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomaticreliefinthetreatmentofosteoarthritis,rheumatoidarthritisandankylosingspondylitis.

ThedecisiontoprescribeaselectiveCOX-2inhibitorshouldbebasedonanassessmentoftheindividualpatients

overallrisk(seesection4.3,4.4).

4.2Posologyandmethodofadministration

Asthecardiovascularriskofcelecoxibmayincreasewithdoseanddurationofexposure,theshorestdurationpossible

andthelowesteffectivedailydoseshouldbeused.Thepatientsneedforsymptomaticreliefandresponsetotherapy

shouldbere-evaluatedperiodically,especiallyinpatientswithosteoarthitis(seesection4.3,4.4,4.8and5.1).

Osteoarthritis:

Theusualrecommendeddailydoseis200mgtakenoncedailyorintwodivideddoses.Insomepeople,with

insufficientrelieffromsymptoms,anincreaseddoseof200mgtwicedailymayincreaseefficacy.intheabsenceofan

increaseintherapeuticbenefitaftertwoweeks,othertherapeuticoptionsshouldbeconsidered.

Rheumatoidarthritis:

Therecommendeddailydoseis200takenintwodivideddoses.Thedosemay,ifneeded,laterbeincreasedto200mg

twicedaily.Intheabsenceofanincreaseintherapeuticbenefitaftertwoweeks,othertherapeuticoptionsshouldbe

considered.

Ankylosingspondylitis:

Therecommendeddailydoseis200mgtakenoncedailyorintwodivideddoses.Inafewpatients,withinsufficient

relieffromsymptoms,anincreaseddoseof400mgoncedailyorintwodivideddosesmayincreaseefficacy.Inthe

absenceofanincreaseintherapeuticbenefitaftertwoweeks,othertherapeuticoptionsshouldbeconsidered.

Themaximumrecommendeddailydoseis400mgforbothindications.

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Elderly:

(>65years),asinyoungeradults,200mgperdayshouldbeusedinitially.Thedosemay,ifneeded,laterbeincreasedto

200mgtwicedaily.Particularcautionshouldbeexercisedinelderlywithabodyweightlessthan50kg(see4.4and

5.2).

Hepaticimpairment:

Treatmentshouldbeinitiatedathalftherecommendeddoseinpatientswithestablishedmoderateliverimpairment

withaserumalbuminof25-35g/l.Experienceinsuchpatientsislimitedtocirrhoticpatients(Seesection4.4,

“Specialwarningsandspecialprecautionsforuse”andsection5.2“Pharmacokineticproperties”).

Renalimpairment:

Experiencewithcelecoxibinpatientswithmildormoderaterenalimpairmentislimited,thereforesuchpatientsshould

betreatedwithcaution.(SeeSection4.3“Contra-indications”,section4.4“Specialwarningsandspecialprecautions

foruse”andsection5.2“Pharmacokineticproperties”).

Children:Celecoxibisnotindicatedforuseinchildren.

CYP2C9PoorMetabolizers:Patientswhoareknown,orsuspectedtobeCYP2C9poormetabolizersbasedon

genotypingorprevioushistory/experiencewithotherCYP2C9substratesshouldbeadministeredcelecoxibwith

cautionastheriskofdose-dependentadverseeffectsisincreased.Considerreducingthedosetohalfthelowest

recommendeddose.(See5.2)

4.3Contraindications

Historyofhypersensitivitytotheactivesubstanceortoanyoftheexcipients(see6.1).

Knownhypersensitivitytosulphonamide.

Activepepticulcerationorgastrointestinal(GI)bleeding.

Patientswhohaveexperiencedasthma,acuterhinitis,nasalpolyps,angioneuroticoedema,urticariaorotherallergic-

typereactionsaftertakingacetylsalicylicacidorNSAIDsincludingCOX-2(cyclooxgenase-2)inhibitors.

Inpregnancyandinwomenofchildbearingpotentialunlessusinganeffectivemethodofcontraception(See“Special

warningsandspecialprecautionsforuse”).Celecoxibhasbeenshowntocausemalformationsinthetwoanimal

speciesstudied(See“Pregnancyandlactation”and“Preclinicalsafetydata”).Thepotentialforhumanriskin

pregnancyisunknown,butcannotbeexcluded.

Breast-feeding(See“Pregnancyandlactation”andsection5.3and“Preclinicalsafetydata”).

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

Patientswithestimatedcreatinineclearance<30ml/min.

Inflammatoryboweldisease.

Congestiveheartfailure(NYHAII-IV).

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4.4Specialwarningsandprecautionsforuse

Uppergastrointestinalcomplications[perforations,ulcersorbleeds(PUBs)],someofthemresultinginfataloutcome,

haveoccurredinpatientstreatedwithcelecoxib.cautionisadvisedwithtreatmentofpatientsmostatriskof

developingagastrointestinalcomplicationwithNSAIDs;theelderly,patientsusinganyotherNSAIDsor

acetylsalicylicacidconcomitantlyorpatientswithahistoryofgastrointestinaldisease,suchasulcerationandGI

bleeding.

Thereisfurtherincreasedintheriskofgastrointestinaladverseeffectsforcelecoxib,(gastrointestinalulcerationor

othergastrointestinalcomplications),whencelecoxibistakenconcomitantlywithacetylsalicylicacid(evenatlow

doses).AsignificantdifferenceinGIsafetybetweenselectiveCOX-2inhibitors+acetylsalicylicacid .NSAIDs+

acetylsalicylicacidhasnotbeendemonstratedinlong-termclinicaltrials(see5.1).

Theconcomitantuseofcelecoxibandanon-aspirinNSAIDshouldbeavoided.

Increasednumberofseriouscardiovascularevents,mainlymyocardialinfarction,hasbeenfoundinalong-term

placebo-controlledstudyinsubjectswithsporadicadenomatouspolypstreatedwithcelecoxibatdosesof200mgBID

and400mgBIDcomparedtoplacebo(see5.1).

Asthecardiovascularriskofcelecoxibmayincreasewithdoseanddurationofexposure,theshortestdurationpossible

andthelowesteffectivedailydoseshouldbeused.Thepatientsneedforsymptomaticreliefandresponsetotherapy

shouldbere-evaluatedperiodically,especiallyinpatientswithosteoarthritis(seesections4.2,4.3,4.8and5.1).

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

smoking)shouldonlybetreatedwithcelecoxibaftercarefulconsideration(see5.1).

COX-2selectiveinhibitorsarenotasubstituteforacetylsalicylicacidforprophylaxisofcardiovascularthrombo-

embolicdiseasesbecauseoftheirlackofantiplateleteffects.Thereforeantiplatelettherapiesshouldnotbediscontinued

(seesection5.1).

Aswithotherdrugsknowntoinhibitprostaglandinsynthesisfluidretentionandoedemahavebeenobservedinpatients

takingcelecoxib.Therefore,celecoxibshouldbeusedwithcautioninpatientswithhistoryofcardiacfailure,left

ventriculardysfunctionorhypertension,andinpatientswithpre-existingoedemafromanyotherreason,since

prostaglandininhibitionmayresultindeteriorationofrenalfunctionandfluidretention.Cautionisalsorequiredin

patientstakingdiuretictreatmentorotherwiseatriskofhypovolaemia.

AswithallNSAIDS,celecoxibcanleadtotheonsetofnewhypertensionorworseningofpre-existinghypertension,

eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.Thereforebloodpressureshouldbe

monitoredcloselyduringtheinitiationoftherapywithcelecoxibandthroughoutthecourseoftherapy

Compromisedrenalorhepaticfunctionandespeciallycardiacdysfunctionaremorelikelyintheelderlyandtherefore

medicallyappropriatesupervisionshouldbemaintained.

NSAIDs,includingcelecoxib,maycauserenaltoxicity.Clinicaltrialswithcelecoxibhaveshownrenaleffectssimilar

tothoseobservedwithcomparatorNSAIDs.Patientsatgreatestriskforrenaltoxicityarethosewithimpairedrenal

function,heartfailure,liverdysfunction,andtheelderly.Suchpatientsshouldbecarefullymonitoredwhilereceiving

treatmentwithcelecoxib.

Somecasesofseverehepaticreactions,includingfulminanthepatitis(somewithfataloutcome),livernecrosisand

hepaticfailure(somewithfataloutcomeorrequiringlivertransplant),havebeenreportedwithcelecoxib.Amongthe

casesthatreportedtimetoonset,mostofthesevereadversehepaticeventsdevelopedwithinonemonthafterinitiation

ofcelecoxibtreatment(see4.8).

Ifduringtreatment,patientsdeteriorateinanyoftheorgansystemfunctionsdescribedabove,appropriatemeasures

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CelecoxibinhibitsCYP2D6.Althoughitisnotastronginhibitorofthisenzyme,adosereductionmaybenecessaryfor

individuallydose-titrateddrugsthataremetabolisedbyCYP2D6(See“Interactionswithothermedicamentsandother

formsofinteraction”).

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

atthefirstappearanceofskinrash,mucosallesions,oranyothersignofhypersensitivity.

Celecoxibmaymaskfeverandothersignsofinflammation.

Inpatientsonconcurrenttherapywithwarfarin,seriousbleedingeventshaveoccurred.

Cautionshouldbeexercisedwhencombiningcelecoxibwithwarfarinandotheroralanticoagulations(Seesection4.5

“Interactionswithothermedicamentsandotherformsofinteraction”).

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

hereditaryproblemsofgalactoseintolerance,theLapplactosedeficiencyorglucose-galactosemalabsorptionshould

nottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Anticoagulantactivityshouldbemonitoredparticularlyinthefirstfewdaysafterinitiatingorchangingthedoseof

celecoxibinpatientstakingwarfarinorotheranticoagulantssincethesepatientshaveanincreasedriskofbleeding

complications.Therefore,patientsreceivingoralanticoagulantsshouldbecloselymonitoredfortheirpromthrombin

timeINR,particularlyinthefirstfewdayswhentherapywithcelecoxibisinitiatedorthedoseofcelecoxibischanged.

(see4.4).Bleedingeventsinassociationwithincreasesinprothrombintimehavebeenreported,predominantlyinthe

elderly,inpatientsreceivingcelecoxibconcurrentlywithwarfarin,someofthemfatal.

NSAIDsmayreducetheeffectofdiureticsandantihypertensivemedicinalproducts.AsforNSAIDs,theriskofacute

renalsufficiency,whichisusuallyreversible,maybeincreasedinsomepatientswithcompromisedrenalfunction(e.g.

dehydratedpatientsorelderlypatients)whenACEinhibitorsorangiotensinIIreceptoratagonistsarecombinedwith

NSAIDs,includingcelecoxib.Therefore,thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsideredshouldbegiventomonitoringofrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

Ina28-dayclinicalstudyinpatientswithlisinopril-controlledStageIandIIhypertension,administrationofcelecoxib

200mgBIDresultedinnoclinicallysignificantincreases,whencomparedtoplacebotreatment,inmeandailysystolic

ordiastolicbloodpressureasdeterminedusing24-hourambulatorybloodpressuremonitoring.Amongpatientstreated

withcelecoxib200mgBID,48%wereconsideredunresponsivetolisinoprilatthefinalclinicvisit(definedaseither

cuffdiastolicbloodpressure>90mmHgorcuffdiastolicbloodpressureincreased>10%comparedtobaseline),

comparedto27%ofpatientstreatedwithplacebo;thisdifferencewasstatisticallysignificant.

CoadministrationofNSAIDsandcyclosporinortacrolimushavebeensuggestedtoincreasethenephrotoxiceffectof

cyclosporinandtacrolimus.Renalfunctionshouldbemonitoredwhencelecoxibandanyofthesedrugsarecombined.

Celecoxibcanbeusedwithlowdoseacetylsalicylicacidbutisnotasubstituteforacetylsalicylicacidfor

cardiovascularprophylaxis.inthesubmittedstudies,aswithotherNSAIDs,anincreasedriskofgastrointestinal

ulcerationorothergaastrointestinalcomplicationscomparedtouseofcelecoxibalonewasshownforconcomitant

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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,celecoxibhadnoclinicalrelevanteffectsonthepharmacokineticsoforalcontraception(1mg

norethisterone/35mcgethinylestradiol).

Celecoxibdoesnotaffectthepharmacokineticsoftolbutamide(CYP2C9substrate),orglibenclamidetoaclinically

relevantextent.

Inpatientswithrheumatoidarthritiscelecoxibhadnostatisticallysignificanteffectonthepharmacokinetics(plasmaor

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

toxicityshouldbeconsideredwhencombiningthesetwodrugs.

Inhealthysubjects,co-administrationofcelecoxib200mgtwicedailywith450mgtwicedailyoflithiumresultedina

meanincreaseinC

of16%andinAUCof18%oflithium.Therefore,patientsonlithiumtreatmentshouldbe

closelymonitoredwhencelecoxibisintroducedorwithdrawn.

Effectsofotherdrugsoncelecoxib

InindividualswhoareCYP2C9poormetabolisersanddemonstrateincreasedsystemicexposuretocelecoxib,

concomitanttreatmentwithCYP2C9inhibitorscouldresultinfurtherincreasesincelecoxibexposure.Such

combinationsshouldbeavoidedinknownCYP2C9poormetabolisers(seesections4.2and5.2).

SincecelecoxibispredominantlymetabolisedbyCYP2C9itshouldbeusedathalftherecommendeddoseinpatients

receivingfluconazole.Concomitantuseof200mgsingledoseofcelecoxiband200mgoncedailyoffluconazole,a

potentCYP2C9inhibitor,resultedinameanincreaseincelecoxibC

of60%andinAUCof130%.Concomitantuse

ofinducersofCYP2C9suchasrifampicin,carbamazepineandbarbituratesmayreduceplasmaconcentrationsof

celecoxib.

Ketoconazoleorantacidshavenotbeenobservedtoaffectthepharmacokineticsofcelecoxib.

4.6Fertility,pregnancyandlactation

Noclinicaldataonexposedpregnanciesareavailableforcelecoxib.Studiesinanimals(ratsandrabbits)haveshown

reproductivetoxicity,includingmalformations(see“Contraindications”and“Pre-clinicalsafetydata”).Thepotential

forhumanriskinpregnancyisunknown,butcannotbeexcluded.Celecoxib,aswithotherdrugsinhibiting

prostaglandinsynthesis,maycauseuterineinertiaandprematureclosureoftheductusarteriosusduringthelast

trimester.Celecoxibiscontra-indicatedinpregnancyandinwomenwhocanbecomepregnant(see“Contra-

indications”and“Specialwarningsandspecialprecautionsforuse”).Ifawomanbecomespregnantduringtreatment,

celecoxibshouldbediscontinued.

Celecoxibisexcretedinthemilkoflactatingratsatconcentrationssimilartothoseinplasma.Administrationof

celecoxibtoalimitednumberoflactatingwomenhasshownaverylowtransferofcelecoxibintobreastmilk.Women

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4.7Effectsonabilitytodriveandusemachines

Patientswhoexperiencedizziness,vertigoorsomnolencewhiletakingcelecoxibshouldrefrainfromdrivingor

operatingmachinery.

4.8Undesirableeffects

AdversereactionsarelistedbysystemorganclassandrankedbyfrequencyinTable1,reflectingdatafromthe

followingsources:

Adversereactionsreportedinosteoarthritispatientsandrheumatoidarthritispatientsatincidenceratesgreaterthan

0.01%andgreaterthanthosereportedforplaceboduring12placebo-and/oractive-controlledclinicaltrialsof

durationupto12weeksatcelecoxibdailydosesfrom100mgupto800mg.Inadditionalstudiesusingnon-

selectiveNSAIDcomparators,approximately7400arthritispatientshavebeentreatedwithcelecoxibatdailydoses

upto800mg,includingapproximately2300patientstreatedfor1yearorlonger.Theadversereactionsobserved

withcelecoxibintheseadditionalstudieswereconsistentwiththoseforosteoarthritisandrheumatoidarthritis

patientslistedinTable1.

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

VeryCommon

(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

Allergy

aggravated Seriousallergic

reactions,

anaphylacticshock,

anaphylaxis

Psychiatricdisorders

Insomnia Anxiety,

depression,

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Metabolismandnutritiondisorders

Hyperkaelemia

Nervoussystemdisorders

Dizziness,

hypertonia Paraesthesia,

somnolence,

cerebral

infarction 1 Ataxia,taste

alteration Headache,

aggravatedepilepsy,

meningitisaseptic,

ageusia,anosmia,

fatalintracranial

haemorrhage

Eyedisorders

Blurredvision Conjunctivitis,ocular

haemorrhage,retinal

arteryorvein

occlusion

Earandlabyrinthdisorders

Tinnitus,

hypoacusis 1

Cardiacdisorders

Myocardial

infarction 1 Heartfailure,

palpitations,

tachycardia Arrhythmia

Vasculardisorders

Hypertension 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,and

coloniculceration,

intestinal

perforation,

oesophagitis,

melaena,

Nausea,

gastrointestinal

haemorrhage,

colitis/colitis

aggravated

Hepatobiliarydisorders

Abnormalhepatic

function,

increasedSGOT

andSGPT, Elevationof

hepaticenzymes Hepatitis,jaundice,

hepaticfailure

Skinandsubcutaneoustissuedisorders

Rash,pruritus Urticaria Alopecia,

photosensitivity Ecchymosis,bullous

eruption,exfoliative

dermatitis,erythema

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Infinaldata(adjudicated)fromtheAPCandPreSAPtrialsinpatientstreatedwithcelecoxib400mgdailyforupto3

years(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

Johnsonsyndrome,

toxicepidermal

necrolysis,

angioedema

Musculoskeletalandconnectivetissuedisorders

Legcramps Arthralgia,myositis

Renalandurinarydisorders

Increased

creatinine,BUN

increased Acuterenalfailure,

interstitialnephritis,

hyponatraemia

Reproductivesystemandbreastdisorders

Menstrualdisorder

Generaldisordersandadministrativesiteconditions

Flu-like

symptoms,

peripheral

oedema/fluid

retention

Adversedrugreactionsthatoccurredinpolyppreventiontrialsrepresentingsubjectstreatedwith

celecoxib400mgdailyin2clinicaltrialsofdurationupto3years(theAPCandPreSAPtrials).

Theadversedrugreactionslistedforthepolyppreventiontrialsareonlythosethatoccurredmore

frequentlythaninthearthritistrials.

Furthermore,thefollowingpreviouslyunknownadversereactionsoccurredinpolypprevention

trials,representingsubjectstreatedwithcelecoxib400mgdailyin2clinicaltrialsofdurationup

to3years(theAPCandPreSAPtrials):Common:anginapectoris,irritablebowelsyndrome,

nephrolithiasis,bloodcreatinineincreased,benignprostatichyperplasia,weightincreased.

Uncommon:helicobacterinfection,herpeszoster,erysipelas,bronchopneumonia,labyrinthitis,

gingivalinfection,lipoma,vitreousfloaters,conjunctivalhaemorrhage,deepveinthrombosis,

dysphonia,haemorrhoidalhaemorrhage,frequentbowelmovements,mouthulceration,allergic

dermatitis,ganglion,nocturia,vaginalhaemorrhage,breasttenderness,lowerlimbfracture,blood

sodiumincreased.

Adversedrugreactionsfrompost-marketingsurveillancerepresenteventsspontaneously

reportedtothesafetysurveillancedatabaseoveraperiodinwhichanestimated>70million

patientsweretreatedwithcelecoxib(variousdoses,durations,andindications).Asaresult,the

frequenciesoftheseadversedrugreactionscannotbereliablydetermined.Adversedrugreactions

listedforthepost-marketingpopulationareonlythosethatarenotalreadylistedforthearthritis

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Non-steroidalanti-inflammatoryandantirheumaticdrugs,NSAIDs,Coxibs.

ATCcode:M01AH01.

Celecoxibisanoralactiveselectiveinhibitorofcyclooxygenase-2(COX-2)withinthetherapeuticdoserange(200-400

mgdaily).NostatisticallysignificantinhibitionofCOX-1(assessedasexvivoinhibitionofthromboxaneB

[TxB

formation)wasobservedinthisdoserangeinhealthyvolunteers.

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

identified.COX-2istheisoformoftheenzymethathasbeenshowntobeinducedbypro-inflammatorystimuliandhas

beenpostulatedtobeprimarilyresponsibleforthesynthesisofprostanoidmediatorsofpain,inflammation,andfever.

COX-2isprobablyalsoinvolvedinovulation,implantationandclosureoftheductusarteriosus,regulationofrenal

function,andcentralnervoussystemfunctions(feverinduction,painperceptionandcognitivefunction).Itmayalso

playaroleinulcerhealing.COX-2hasbeenidentifiedintissuearoundgastriculcersinmanbutitsrelevancetoulcer

healinghasnotbeenestablished.

ThedifferenceinantiplateletactivitybetweensomeCOX-1inhibitingNSAIDsandCOX-2selectiveinhibitorsmaybe

ofclinicalsignificanceinpatientsatriskofthromboembolicreactions.COX-2selectiveinhibitorsreducetheformation

ofsystemic(andthereforepossiblyendothelial)prostacyclinwithoutaffectingplateletthromboxane.

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

furosemide)butdiffersfromarylaminesulfonamides(e.g.sulfamethoxazoleandothersulfonamideantibiotics)

AdosedependanteffectonTxB2formationhasbeenobservedafterhighdosesofcelecoxib.However,inhealthy

subjects,insmallmultipledosestudieswith600mgBID(threetimesthehighestrecommendeddose)celecoxibhadno

effectonplateletaggregationandbleedingtimecomparedtoplacebo.

Severalclinicalstudieshavebeenperformedconfirmingefficacyandsafetyinosteoarthritisandrheumatoidarthritis.

CelecoxibwasevaluatedforthetreatmentoftheinflammationandpainofOAofthekneeandhipinapproximately

4200patientsinplaceboandactivecontrolledtrialsofupto12weeksduration.Itwasalsoevaluatedfortreatmentof

theinflammationandpainofRAinapproximately2100patientsinplaceboandactivecontrolledtrialsofupto24

weeksduration.Celecoxibatdailydosesof200mg-400mgprovidedpainreliefwithin24hoursofdosing.

Celecoxibwasevaluatedforthesymptomatictreatmentofankylosingspondylitisin896patientsinplaceboandactive

controlledtrialsofupto12weeksduration.Celecoxibatdosesof100mgBID,200mgQD,200mgBIDand400mgQD

inthesestudiesdemonstratedsignificantimprovementinpain,globaldiseaseactivityandfunctioninankylosing

spondylitis.

Fiverandomiseddouble-blindcontrolledstudieshavebeenconductedincludingscheduleduppergastrointestinal

endoscopyinapproximately4500patientsfreefrominitialulceration(celecoxibdosesfrom50mg-400mgBID).In

Twelve-weekendoscopystudiescelecoxib(100-800mgperday)wasassociatedwithasignificantlowerriskof

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

inconsistentincomparisonwithdiclofenac(150mgperday).Intwoofthe12-weekstudiesthepercentageofpatients

withendoscopicgastroduodenalulcerationwerenotsignificantlydifferentbetweenplaceboandcelecoxib200mgBID

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

patientsreceivedcelecoxib400mgBID(4-foldand2-foldtherecommendedOAandRAdoses,respectively),

ibuprofen800mgTICofdiclofenac75mgBID(bothattherapeuticdoses).Twenty-twopercentofenrolledpatients

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

primaryendpointcomplicatedulcers(definedasgastrointestinalbleedingperforationorobstruction)celecoxibwasnot

significantlydifferentthaneitheribuprofenordiclofenacindividually.AlsoforthecombinedNSAIDsgrouptherewas

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

duration).Forthecombinedendpoint,complicatedandsymptomaticulcers,theincidencewassignificantlylowerinthe

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

diclofenac.Thosepatientsoncelecoxibandconcomitantlow-doseacetylsalicylicacidexperienced4foldshigherrates

ofcomplicatedulcersascomparedtothoseoncelecoxibalone.Theincidenceofclinicalsignificantdecreasesin

haemoglobin(>2g/dL)confirmedbyrepeattestingwassignificantlylowerinpatientsoncelecoxibcomparedtothe

NSAIDsgroup,relativerisk0.29,95%CI0.17-0.48.The

significantlowerincidenceofthiseventwithcelecoxibwasmaintainedwithorwithoutacetylsalicylicaciduse.

CardiovascularSafety–Long-TermStudiesInvolvingSubjectsWithSporadicAdenomatousPolyps

Twostudiesinvolvingsubjectswithsporadicadenomatouspolypswereconductedwithcelecoxibi.e.,theAPCtrial

(AdenomaPreventionwithCelecoxib)andthePreSAPtrial(PreventionofSpontaneousAdenomatousPolyps).In

theAPCtrial,therewasadose-relatedincreaseinthecompositeendpointofcardiovasculardeath,myocardial

infarction,orstroke(adjudicated)withcelecoxibcomparedtoplaceboover3yearsoftreatment.ThePreSAPtrialdid

notdemonstrateastatisticallysignificantincreasedriskforthesamecompositeendpoint.

IntheAPCtrial,therelativeriskscomparedtoplaceboforacompositeendpoint(adjudicated)ofcardiovasculardeath,

myocardialinfarction,orstrokewere3.4(95%CI1.4-8.5)withcelecoxib400mgtwicedailyand2.8(95%CI1.1-

7.2)withcelecoxib200mgtwicedaily.Cumulativeratesforthiscompositeendpointover3yearswere3.0%(20/671

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

bothcelecoxibdosegroupsversusplaceboweremainlyduetoinincreasedincidenceofmyocardialinfarction.

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

CI0.6-2.4)withcelecoxib400mgoncedailycomparedtoplacebo.Cumulativeratesforthiscompositeendpointover

3yearswere2.3%(21/933subjects)and1.9%(12/628subjects),respectively.Theincidenceofmyocardialinfarction

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

Datafromathirdlong-termstudyADAPT(TheAlzheimer'sDiseaseAnti-inflammatoryPreventionTrial)didnotshow

asignificantlyincreasedcardiovascularriskwithcelecoxib200mgBIDcomparedtoplacebo.Therelativerisk

comparedtoplaceboforasimilarcompositeendpoint(CVdeath,MI,stroke)was1.14(95%CI0.61-2.12)with

celecoxib200mgtwicedaily.Theincidenceofmyocardialinfarctionwas1.1%(8/717patients)withcelecoxib200mg

twicedailyand1.2%(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.Themainmetabolitesfoundinthecirculationhavenodetectable

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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).

NoclinicalsignificantdifferenceswerefoundinPKparametersofcelecoxibbetweenelderlyAfrican-Americanand

Caucasians.

Theplasmaconcentrationofcelecoxibisapproximately100%increasedinelderlywomen>65years).

Comparedtosubjectswithnormalhepaticfunction,patientswithmildhepaticimpairmenthadameanincreaseinC

of53%andinAUCof26%ofcelecoxib.Thecorrespondingvaluesinpatientswithmoderatehepaticimpairment

were41%and146%respectively.Themetaboliccapacityinpatientswithmildtomoderateimpairmentwasbest

correlatedtotheiralbuminvalues.Treatmentshouldbeinitiatedathalftherecommendeddoseinpatientswith

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

25g/L)havenotbeenstudiedandcelecoxibiscontra-indicatedinthispatientgroup.

Thereislittleexperienceofcelecoxibinrenalimpairment.Thepharmacokineticsofcelecoxibhasnotbeenstudiedin

patientswithrenalimpairmentbutisunlikelytobemarkedlychangedinthesepatients.Thuscautionisadvisedwhen

treatingpatientswithrenalimpairment.Severerenalimpairmentisacontraindicated.

5.3Preclinicalsafetydata

Conventionalembryo-foetaltoxicitystudiesresultedindosedependentoccurrencesofdiaphragmaticherniainrat

foetusesandofcardiovascularmalformationsinrabbitfoetusesatsystemicexposurestofreedrugapproximately5X

(rat)and3X(rabbit)higherthanthoseachievedatthemaximumrecommendeddailyhumandose(400mg).

Diaphragmaticherniawasalsoseeninaperi-postnataltoxicitystudyinrats,whichincludedexposureduringthe

organogeneticperiod.Inthelatterstudy,atthelowestsystemicexposurewherethisanomalyoccurredinasingle

animal,theestimatedmarginrelativetothemaximumrecommendeddailyhumandosewas3X.

Inanimals,exposuretocelecoxibduringearlyembryonicdevelopmentresultedinpre-implantationandpost-

implantationlosses.Theseeffectsareexpectedfollowinginhibitionofprostaglandinsynthesis.

Celecoxibwasexcretedinratmilk.Inaperi-postnatalstudyinrats,puptoxicitywasobserved.

Basedonconventionalstudiesofrepeateddosetoxicity,genotoxicityorcarcinogenicity,nospecialhazardforhumans

wasobserved,beyondthoseaddressedinothersectionsoftheSPC.Inatwo-yeartoxicitystudyanincreasein

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontains

Lactosemonohydrate

Sodiumlaurilsulfate

PovidoneK30

Croscarmellosesodium

Magnesiumstearate

Capsuleshellscontain

Gelatin

Titaniumdioxide(E171)

Inkcontains

Indigotine(E132)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpacksof20,30or60capsulesinacardboardcarton.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/118/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19 th

March2004

Dateoflastrenewal:19 th

March2009

10DATEOFREVISIONOFTHETEXT

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