ARCOXIA

Main information

  • Trade name:
  • ARCOXIA Film Coated Tablet 120 Milligram
  • Dosage:
  • 120 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARCOXIA Film Coated Tablet 120 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1286/007/004
  • Authorization date:
  • 03-04-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arcoxia120mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains120mgofetoricoxib.

Excipient:

120mg:lactose5.3mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet/tablet.

120mgTablets:Pale-green,apple-shaped,biconvextabletsdebossed‘204’ononesideand‘ARCOXIA120’onthe

otherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthesymptomaticreliefofosteoarthritis(OA),rheumatoidarthritis(RA),ankylosingspondylitis,andthepainand

signsofinflammationassociatedwithacutegoutyarthritis.

Fortheshort-termtreatmentofmoderatepainassociatedwithdentalsurgery.

ThedecisiontoprescribeaselectiveCOX-2inhibitorshouldbebasedonanassessmentoftheindividualpatient's

overallrisks(seesections4.3,4.4).

4.2Posologyandmethodofadministration

Posology

Asthecardiovascularrisksofetoricoxibmayincreasewithdoseanddurationofexposure,theshortestduration

possibleandthelowesteffectivedailydoseshouldbeused.Thepatient'sneedforsymptomaticreliefandresponseto

therapyshouldbere-evaluatedperiodically,especiallyinpatientswithosteoarthritis(seesections4.3,4.4,4.8and5.1).

Osteoarthritis

Therecommendeddoseis30mgoncedaily.Insomepatientswithinsufficientrelieffromsymptoms,anincreaseddose

of60mgoncedailymayincreaseefficacy.Intheabsenceofanincreaseintherapeuticbenefit,othertherapeutic

optionsshouldbeconsidered.

Rheumatoidarthritis

Therecommendeddoseis90mgoncedaily.

Ankylosingspondylitis

Therecommendeddoseis90mgoncedaily.

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Acutegoutyarthritis

Therecommendeddoseis120mgoncedaily.Inclinicaltrialsforacutegoutyarthritis,etoricoxibwasgivenfor8days.

Postoperativedentalsurgerypain

Therecommendeddoseis90mgoncedaily,limitedtoamaximumof3days.Somepatientsmayrequireadditional

postoperativeanalgesia.

Dosesgreaterthanthoserecommendedforeachindicationhaveeithernotdemonstratedadditionalefficacyorhavenot

beenstudied.Therefore:

ThedoseforOAshouldnotexceed60mgdaily.

ThedoseforRAandankylosingspondylitisshouldnotexceed90mgdaily.

Thedoseforacutegoutshouldnotexceed120mgdaily,limitedtoamaximumof8daystreatment.

Thedoseforpostoperativeacutedentalsurgerypainshouldnotexceed90mgdaily,limitedtoamaximumof3days.

Specialpopulations

Elderly

Nodosageadjustmentisnecessaryforelderlypatients.Aswithotherdrugs,cautionshouldbeexercisedinelderly

patients(seesection4.4).

Hepaticinsufficiency

Regardlessofindication,inpatientswithmildhepaticdysfunction(Child-Pughscore5 -6)adoseof60mgoncedaily

shouldnotbeexceeded.Inpatientswithmoderatehepaticdysfunction(Child-Pughscore7 -9),regardlessofindication,

thedoseof60mgeveryotherdayshouldnotbeexceeded;administrationof30mgoncedailycanalsobeconsidered.

Clinicalexperienceislimitedparticularlyinpatientswithmoderatehepaticdysfunctionandcautionisadvised.Thereis

noclinicalexperienceinpatientswithseverehepaticdysfunction(Child-Pughscore10);therefore,itsuseiscontra-

indicatedinthesepatients(seesections4.3,4.4and5.2).

Renalinsufficiency

Nodosageadjustmentisnecessaryforpatientswithcreatinineclearance30ml/min(seesection5.2).Theuseof

etoricoxibinpatientswithcreatinineclearance<30ml/miniscontra-indicated(seesections4.3and4.4).

Paediatricpatients

Etoricoxibiscontra-indicatedinchildrenandadolescentsunder16yearsofage(seesection4.3).

Methodofadministration

ARCOXIAisadministeredorallyandmaybetakenwithorwithoutfood.Theonsetoftheeffectofthemedicinal

productmaybefasterwhenARCOXIAisadministeredwithoutfood.Thisshouldbeconsideredwhenrapid

symptomaticreliefisneeded.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

Activepepticulcerationoractivegastro-intestinal(GI)bleeding.

Patientswhohaveexperiencedbronchospasm,acuterhinitis,nasalpolyps,angioneuroticoedema,urticaria,orallergic-

typereactionsaftertakingacetylsalicylicacidorNSAIDsincludingCOX-2(cyclo-oxygenase-2)inhibitors.

Pregnancyandlactation(seesection4.6and5.3).

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Estimatedrenalcreatinineclearance<30ml/min.

Childrenandadolescentsunder16yearsofage.

Inflammatoryboweldisease.

Congestiveheartfailure(NYHAII-IV).

Patientswithhypertensionwhosebloodpressureispersistentlyelevatedabove140/90mmHgandhasnotbeen

adequatelycontrolled.

Establishedischaemicheartdisease,peripheralarterialdiseaseand/orcerebrovasculardisease.

4.4Specialwarningsandprecautionsforuse

Gastro-intestinaleffects

Uppergastro-intestinalcomplications[perforations,ulcersorbleedings(PUBs)],someofthemresultinginfatal

outcome,haveoccurredinpatientstreatedwithetoricoxib.

CautionisadvisedwithtreatmentofpatientsmostatriskofdevelopingagastrointestinalcomplicationwithNSAIDs;

theelderly,patientsusinganyotherNSAIDoracetylsalicylicacidconcomitantly,orpatientswithapriorhistoryof

gastro-intestinaldisease,suchasulcerationandGIbleeding.

Thereisafurtherincreaseintheriskofgastro-intestinaladverseeffects(gastrointestinalulcerationorothergastro-

intestinalcomplications)whenetoricoxibistakenconcomitantlywithacetylsalicylicacid(evenatlowdoses).A

significantdifferenceinGIsafetybetweenselectiveCOX-2inhibitors+acetylsalicylicacidvs.NSAIDs+

acetylsalicylicacidhasnotbeendemonstratedinlong-termclinicaltrials(seesection5.1).

Cardiovasculareffects

ClinicaltrialssuggestthattheselectiveCOX-2inhibitorclassofdrugsmaybeassociatedwithariskofthrombotic

events(especially myocardialinfarction(MI)andstroke),relativetoplaceboandsomeNSAIDs. Asthe

cardiovascularrisksofetoricoxibmayincreasewithdoseanddurationofexposure,theshortestdurationpossibleand

thelowesteffectivedailydoseshouldbeused.Thepatient’sneedforsymptomaticreliefandresponsetotherapy

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

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

smoking)shouldonlybetreatedwithetoricoxibaftercarefulconsideration(seesection5.1).

COX-2selectiveinhibitorsarenotasubstituteforacetylsalicylicacidforprophylaxisofcardiovascularthrombo-

embolicdiseasesbecauseoftheirlackofantiplateleteffect.Thereforeantiplatelettherapiesshouldnotbediscontinued

(seesectionsabove,4.5and5.1).

Renaleffects

Renalprostaglandinsmayplayacompensatoryroleinthemaintenanceofrenalperfusion.Therefore,underconditions

ofcompromisedrenalperfusion,administrationofetoricoxibmaycauseareductioninprostaglandinformationand,

secondarily,inrenalbloodflow,andtherebyimpairrenalfunction.Patientsatgreatestriskofthisresponsearethose

withpre-existingsignificantlyimpairedrenalfunction,uncompensatedheartfailure,orcirrhosis.Monitoringofrenal

functioninsuchpatientsshouldbeconsidered.

Fluidretention,oedemaandhypertension

Aswithothermedicinalproductsknowntoinhibitprostaglandinsynthesis,fluidretention,oedemaandhypertension

havebeenobservedinpatientstakingetoricoxib.AllNonsteroidalAntiinflammatoryDrugs(NSAIDs)including

etoricoxib,canbeassociatedwithnewonsetorrecurrentcongestiveheartfailure.Forinformationregardingadose

relatedresponseforetoricoxibseesection5.1.Cautionshouldbeexercisedinpatientswithahistoryofcardiacfailure,

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clinicalevidenceofdeteriorationintheconditionofthesepatients,appropriatemeasuresincludingdiscontinuationof

etoricoxibshouldbetaken.

EtoricoxibmaybeassociatedwithmorefrequentandseverehypertensionthansomeotherNSAIDsandselective

COX-2inhibitors,particularlyathighdoses.Therefore hypertensionshouldbecontrolledbeforetreatmentwithetoricoxib

(seesection4.3)and specialattentionshouldbepaidtobloodpressuremonitoringduringtreatmentwith

etoricoxib. Bloodpressureshouldbemonitoredwithintwoweeksafterinitiationoftreatmentandperiodicallythereafter. If

bloodpressurerisessignificantly,alternativetreatmentshouldbeconsidered.

Hepaticeffects

Elevationsofalanineaminotransferase(ALT)and/oraspartateaminotransferase(AST)(approximatelythreeormore

timestheupperlimitofnormal)havebeenreportedinapproximately1%ofpatientsinclinicaltrialstreatedforupto

oneyearwithetoricoxib30,60and90mgdaily.

Anypatientswithsymptomsand/orsignssuggestingliverdysfunction,orinwhomanabnormalliverfunctiontesthas

occurred,shouldbemonitored.Ifsignsofhepaticinsufficiencyoccur,orifpersistentlyabnormalliverfunctiontests

(threetimestheupperlimitofnormal)aredetected,etoricoxibshouldbediscontinued.

General

Ifduringtreatment,patientsdeteriorateinanyoftheorgansystemfunctionsdescribedabove,appropriatemeasures

shouldbetakenanddiscontinuationofetoricoxibtherapyshouldbeconsidered.Medicallyappropriatesupervision

shouldbemaintainedwhenusingetoricoxibintheelderlyandinpatientswithrenal,hepatic,orcardiacdysfunction.

Cautionshouldbeusedwheninitiatingtreatmentwithetoricoxibinpatientswithdehydration.Itisadvisableto

rehydratepatientspriortostartingtherapywithetoricoxib.

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofNSAIDsandsomeselectiveCOX-2

inhibitorsduringpost-marketingsurveillance(seesection4.8).Patientsappeartobeathighestriskforthesereactions

earlyinthecourseoftherapy,withtheonsetofthereactionoccurringinthemajorityofcaseswithinthefirstmonthof

treatment.Serioushypersensitivityreactions(suchasanaphylaxisandangioedema)havebeenreportedinpatients

receivingetoricoxib(seesection4.8).SomeselectiveCOX-2inhibitorshavebeenassociatedwithanincreasedriskof

skinreactionsinpatientswithahistoryofanydrugallergy.Etoricoxibshouldbediscontinuedatthefirstappearance

ofskinrash,mucosallesions,oranyothersignofhypersensitivity.

Etoricoxibmaymaskfeverandothersignsofinflammation.

Cautionshouldbeexercisedwhenco-administeringetoricoxibwithwarfarinorotheroralanticoagulants(seesection

4.5).

Theuseofetoricoxib,aswithanymedicinalproductknowntoinhibitcyclooxygenase/prostaglandinsynthesis,isnot

recommendedinwomenattemptingtoconceive(seesections4.6,5.1and5.3).

ARCOXIAtabletscontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Oralanticoagulants:Insubjectsstabilisedonchronicwarfarintherapy,theadministrationofetoricoxib120mgdaily

wasassociatedwithanapproximate13%increaseinprothrombintimeInternationalNormalisedRatio(INR).

Therefore,patientsreceivingoralanticoagulantsshouldbecloselymonitoredfortheirprothrombintimeINR,

particularlyinthefirstfewdayswhentherapywithetoricoxibisinitiatedorthedoseofetoricoxibischanged(see

section4.4).

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antihypertensivedrugs.Insomepatientswithcompromisedrenalfunction(e.g.dehydratedpatientsorelderlypatients

withcompromisedrenalfunction)theco-administrationofanACEinhibitororAngiotensinIIAntagonistandagents

thatinhibitcyclo-oxygenasemayresultinfurtherdeteriorationofrenalfunction,includingpossibleacuterenalfailure,

whichisusuallyreversible.Theseinteractionsshouldbeconsideredinpatientstakingetoricoxibconcomitantlywith

ACEinhibitorsorangiotensinIIantagonists.Therefore,thecombinationshouldbeadministeredwithcaution,

especiallyintheelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringof

renalfunctionafterinitiationofconcomitanttherapy,andperiodicallythereafter.

AcetylsalicylicAcid:Inastudyinhealthysubjects,atsteadystate,etoricoxib120mgoncedailyhadnoeffectonthe

anti-plateletactivityofacetylsalicylicacid(81mgoncedaily).Etoricoxibcanbeusedconcomitantlywith

acetylsalicylicacidatdosesusedforcardiovascularprophylaxis(low-doseacetylsalicylicacid).However,concomitant

administrationoflow-doseacetylsalicylicacidwithetoricoxibmayresultinanincreasedrateofGIulcerationorother

complicationscomparedtouseofetoricoxibalone.Concomitantadministrationofetoricoxibwithdosesof

acetylsalicylicacidabovethoseforcardiovascularprophylaxisorwithotherNSAIDsisnotrecommended(seesections

5.1and4.4.).

Ciclosporinandtacrolimus:Althoughthisinteractionhasnotbeenstudiedwithetoricoxib,co-administrationof

ciclosporinortacrolimuswithanyNSAIDmayincreasethenephrotoxiceffectofciclosporinortacrolimus.Renal

functionshouldbemonitoredwhenetoricoxibandeitherofthesedrugsisusedincombination.

Pharmacokineticinteractions

Theeffectofetoricoxibonthepharmacokineticsofotherdrugs

Lithium:NSAIDsdecreaselithiumrenalexcretionandthereforeincreaselithiumplasmalevels.Ifnecessary,monitor

bloodlithiumcloselyandadjustthelithiumdosagewhilethecombinationisbeingtakenandwhentheNSAIDis

withdrawn.

Methotrexate:Twostudiesinvestigatedtheeffectsofetoricoxib60,90or120mgadministeredoncedailyforseven

daysinpatientsreceivingonce-weeklymethotrexatedosesof7.5to20mgforrheumatoidarthritis.Etoricoxibat60

and90mghadnoeffectonmethotrexateplasmaconcentrationsorrenalclearance.Inonestudy,etoricoxib120mg

hadnoeffect,butintheotherstudy,etoricoxib120mgincreasedmethotrexateplasmaconcentrationsby28%and

reducedrenalclearanceofmethotrexateby13%.Adequatemonitoringformethotrexate-relatedtoxicityis

recommendedwhenetoricoxibandmethotrexateareadministeredconcomitantly.

Oralcontraceptives:Etoricoxib60mggivenconcomitantlywithanoralcontraceptivecontaining35micrograms

ethinylestradiol(EE)and0.5to1mgnorethindronefor21daysincreasedthesteadystateAUC0-24hrofEEby37%.

Etoricoxib120mggivenwiththesameoralcontraceptiveconcomitantlyorseparatedby12hours,increasedthesteady

stateAUC0-24hrofEEby50to60%.ThisincreaseinEEconcentrationshouldbeconsideredwhenselectinganoral

contraceptiveforusewithetoricoxib.AnincreaseinEEexposurecanincreasetheincidenceofadverseevents

associatedwithoralcontraceptives(e.g.venousthrombo-emboliceventsinwomenatrisk).

HormoneReplacementTherapy(HRT):Administrationofetoricoxib120mgwithhormonereplacementtherapy

consistingofconjugatedestrogens(0.625mgPREMARIN™Wyeth)for28days,increasedthemeansteadystate

AUC0-24hrofunconjugatedestrone(41%),equilin(76%)and17--estradiol(22%).Theeffectoftherecommended

chronicdosesofetoricoxib(30,60and90mg)hasnotbeenstudied.Theeffectsofetoricoxib120mgontheexposure

(AUC0-24hr)totheseestrogeniccomponentsofPREMARINwerelessthanhalfofthoseobservedwhenPREMARIN

wasadministeredaloneandthedosewasincreasedfrom0.625to1.25mg.Theclinicalsignificanceoftheseincreases

isunknown,andhigherdosesof

PREMARINwerenotstudiedincombinationwithetoricoxib.Theseincreasesinestrogenicconcentrationshouldbe

takenintoconsiderationwhenselectingpost-menopausalhormonetherapyforusewithetoricoxibbecausetheincrease

inestrogenexposuremightincreasetheriskofadverseeventsassociatedwithHRT.

Prednisone/prednisolone:Indrug-interactionstudies,etoricoxibdidnothaveclinicallyimportanteffectsonthe

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Digoxin:Etoricoxib120mgadministeredoncedailyfor10daystohealthyvolunteersdidnotalterthesteady-state

plasmaAUC0-24hrorrenaleliminationofdigoxin.TherewasanincreaseindigoxinCmax(approximately33%).

Thisincreaseisnotgenerallyimportantformostpatients.However,patientsathighriskofdigoxintoxicityshouldbe

monitoredforthiswhenetoricoxibanddigoxinareadministeredconcomitantly.

Effectofetoricoxibondrugsmetabolisedbysulfotransferases

Etoricoxibisaninhibitorofhumansulfotransferaseactivity,particularlySULT1E1,andhasbeenshowntoincreasethe

serumconcentrationsofethinylestradiol.Whileknowledgeabouteffectsofmultiplesulfotransferasesispresently

limitedandtheclinicalconsequencesformanydrugsarestillbeingexamined,itmaybeprudenttoexercisecarewhen

administeringetoricoxibconcurrentlywithotherdrugsprimarilymetabolisedbyhumansulfotransferases(e.g.oral

salbutamolandminoxidil).

EffectofetoricoxibondrugsmetabolisedbyCYPisoenzymes

Basedoninvitrostudies,etoricoxibisnotexpectedtoinhibitcytochromesP450(CYP)1A2,2C9,2C19,2D6,2E1or

3A4.Inastudyinhealthysubjects,dailyadministrationofetoricoxib120mgdidnotalterhepaticCYP3A4activityas

assessedbytheerythromycinbreathtest.

Effectsofotherdrugsonthepharmacokineticsofetoricoxib

ThemainpathwayofetoricoxibmetabolismisdependentonCYPenzymes.CYP3A4appearstocontributetothe

metabolismofetoricoxibinvivo.InvitrostudiesindicatethatCYP2D6,CYP2C9,CYP1A2andCYP2C19alsocan

catalysethemainmetabolicpathway,buttheirquantitativeroleshavenotbeenstudiedinvivo.

Ketoconazole:Ketoconazole,apotentinhibitorofCYP3A4,dosedat400mgonceadayfor11daystohealthy

volunteers,didnothaveanyclinicallyimportanteffectonthesingle-dosepharmacokineticsof60mgetoricoxib(43%

increaseinAUC).

Rifampicin:Co-administrationofetoricoxibwithrifampicin,apotentinducerofCYPenzymes,produceda65%

decreaseinetoricoxibplasmaconcentrations.Thisinteractionmayresultinrecurrenceofsymptomswhenetoricoxib

isco-administeredwithrifampicin.Whilethisinformationmaysuggestanincreaseindose,dosesofetoricoxibgreater

thanthoselistedforeachindicationhavenotbeenstudiedincombinationwithrifampicinandarethereforenot

recommended(seesection4.2).

Antacids:Antacidsdonotaffectthepharmacokineticsofetoricoxibtoaclinicallyrelevantextent.

4.6Fertility,pregnancyandlactation

Pregnancy

Theuseofetoricoxib,aswithanydrugsubstanceknowntoinhibitCOX -2,isnotrecommendedinwomenattempting

toconceive.

Noclinicaldataonexposedpregnanciesareavailableforetoricoxib.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).Thepotentialforhumanriskinpregnancyisunknown.Etoricoxib,aswithothermedicinal

productsinhibitingprostaglandinsynthesis,maycauseuterineinertiaandprematureclosureoftheductusarteriosus

duringthelasttrimester.Etoricoxibiscontraindicatedinpregnancy(seesection4.3).Ifawomanbecomespregnant

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Breastfeeding

Itisnotknownwhetheretoricoxibisexcretedinhumanmilk.Etoricoxibisexcretedinthemilkoflactatingrats.

Womenwhouseetoricoxibmustnotbreastfeed(seesections4.3and5.3).

4.7Effectsonabilitytodriveandusemachines

Patientswhoexperiencedizziness,vertigoorsomnolencewhiletakingetoricoxibshouldrefrainfromdrivingor

operatingmachinery.

4.8Undesirableeffects

Inclinicaltrials,etoricoxibwasevaluatedforsafetyin7152individuals,including4614patientswithOA,

RA,chroniclowbackpainorankylosingspondylitis(approximately600patientswithOAorRAwere

treatedforoneyearorlonger).

Inclinicalstudies,theundesirableeffectsprofilewassimilarinpatientswithOAorRAtreatedwith

etoricoxibforoneyearorlonger.

Inaclinicalstudyforacutegoutyarthritis,patientsweretreatedwithetoricoxib120mgoncedailyfor

eightdays.Theadverseexperienceprofileinthisstudywasgenerallysimilartothatreportedinthe

combinedOA,RA,andchroniclowbackpainstudies.

Inacardiovascularsafetyoutcomesprogramofpooleddatafromthreeactivecomparatorcontrolledtrials,

17,412patientswithOAorRAweretreatedwithetoricoxib(60mgor90mg)forameandurationof

approximately18months.Thesafetydataanddetailsfromthisprogramarepresentedinsection5.1.

Thefollowingundesirableeffectswerereportedatanincidencegreaterthanplaceboinclinicaltrialsin

patientswithOA,RA,chroniclowbackpainorankylosingspondylitistreatedwithetoricoxib30mg,

60mgor90mgforupto12weeks,orintheMEDALProgramstudies,orinpost-marketingexperience:

[VeryCommon(1/10)Common(1/100to<1/10)Uncommon(1/1000to<1/100)Rare(1/10,000to

<1/1,000)Veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)]

Infectionsandinfestations:

Uncommon:gastroenteritis,upperrespiratoryinfection,urinarytractinfection.

Bloodandlymphaticsystemdisorders:

Uncommon:anaemia(primarilyassociatedwithgastrointestinalbleeding),leukopenia,thrombocytopenia.

Immunesystemdisorder:

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includingshock.

Metabolismandnutritiondisorders:

Common:oedema/fluidretention

Uncommon:appetiteincreaseordecrease,weightgain.

Psychiatricdisorders:

Uncommon:anxiety,depression,mentalacuitydecreased.

Veryrare:confusion,hallucinations.

Nervoussystemdisorder:

Common:dizziness,headache.

Uncommon:dysgeusia,insomnia,paresthaesia/hypaesthesia,somnolence.

Eyedisorders:

Uncommon:blurredvision,conjunctivitis.

Earandlabyrinthdisorders:

Uncommon:tinnitus,vertigo.

Cardiacdisorders:

Common:palpitations.

Uncommon:atrialfibrillation,congestiveheartfailure,non-specificECGchanges,anginapectoris,

myocardialinfarction.

Notknown:tachycardia.

Vasculardisorders:

Common:hypertension.

Uncommon:flushing,cerebrovascularaccident,transientischaemicattack.

Veryrare:hypertensivecrisis.

Respiratory,thoracicandmediastinaldisorders:

Uncommon:cough,dyspnoea,epistaxis.

Veryrare:bronchospasm.

Gastrointestinaldisorders:

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epigastricdiscomfort,nausea.

Uncommon:abdominaldistention,acidreflux,bowelmovementpatternchange,constipation,drymouth,

gastroduodenalulcer,irritablebowelsyndrome,oesophagitis,oralulcer,vomiting,gastritis.

Veryrare:pepticulcersincludinggastrointestinalperforationandbleeding(mainlyintheelderly).

Notknown:pancreatitis.

Hepatobiliarydisorders:

Common:ALTincreased,ASTincreased.

Veryrare:hepatitis.

Notknown:jaundice,hepaticfailure.

Skinandsubcutaneoustissuedisorders:

Common:ecchymosis.

Uncommon:facialoedema,pruritus,rash.

Rare:erythema.

Veryrare:urticaria,Stevens-Johnsonsyndrome,toxicepidermalnecrolysis.

Musculoskeletal,connectivetissueandbonedisorders:

Uncommon:muscularcramp/spasm,musculoskeletalpain/stiffness.

Renalandurinarydisorders:

Uncommon:proteinuria,serumcreatinineincreased.

Veryrare:renalinsufficiency,includingrenalfailure,usuallyreversibleupondiscontinuationoftreatment

(seesection4.4).

Generaldisordersandadministrationsiteconditions:

Common:asthenia/fatigue,flu-likedisease.

Uncommon:chestpain.

Basedonanalysesoflong-termplaceboandactivecontrolledclinicaltrials,selectiveCOX-2inhibitors

havebeenassociatedwithanincreasedriskofseriousthromboticarterialevents,includingmyocardial

infarctionandstroke.Theabsoluteriskincreaseforsucheventsisunlikelytoexceed1%peryearbased

onexistingdata(uncommon).

Investigations:

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increased.

Rare:bloodsodiumdecreased.

ThefollowingseriousundesirableeffectshavebeenreportedinassociationwiththeuseofNSAIDsand

cannotberuledoutforetoricoxib:nephrotoxicityincludinginterstitialnephritisandnephroticsyndrome;

hepatotoxicityincludinghepaticfailure.

4.9Overdose

Inclinicalstudies,administrationofsingledosesofetoricoxibupto500mgandmultipledosesupto150mg/dayfor

21daysdidnotresultinsignificanttoxicity.Therehavebeenreportsofacuteoverdosagewithetoricoxib,although

adverseexperienceswerenotreportedinthemajorityofcases.Themostfrequentlyobservedadverseexperienceswere

consistentwiththesafetyprofileforetoricoxib(e.g.gastrointestinalevents,cardiorenalevents).

Intheeventofoverdose,itisreasonabletoemploytheusualsupportivemeasures,e.g.,removeunabsorbedmaterial

fromtheGItract,employclinicalmonitoring,andinstitutesupportivetherapy,ifrequired.

Etoricoxibisnotdialysablebyhaemodialysis;itisnotknownwhetheretoricoxibisdialysablebyperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-inflammatoryandantirheumaticproducts,non-steroids,coxibs,ATC

Code:MO1AH05

MechanismofAction

Etoricoxibisanoral,selectivecyclo-oxygenase -2(COX-2)inhibitorwithintheclinicaldoserange.

Acrossclinicalpharmacologystudies,ARCOXIAproduceddose-dependentinhibitionofCOX-2withoutinhibitionof

COX-1atdosesupto150mgdaily.Etoricoxibdidnotinhibitgastricprostaglandinsynthesisandhadnoeffecton

plateletfunction.

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

beenetablished.

Clinicalefficacyandsafety

Efficacy

Inpatientswithosteoarthritis(OA),etoricoxib60mgoncedailyprovidedsignificantimprovementsinpainandpatient

assessmentsofdiseasestatus.Thesebeneficialeffectswereobservedasearlyastheseconddayoftherapyand

maintainedforupto52weeks.Studieswithetoricoxib30mgoncedailydemonstratedefficacysuperiortoplacebo

overa12weektreatmentperiod(usingsimilarassessmentsastheabovestudies).Inadoserangingstudy,etoricoxib60

mgdemonstratedsignificantlygreaterimprovementthan30mgforall3primaryendpointsover6weeksoftreatment.

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Inpatientswithrheumatoidarthritis(RA),etoricoxib90mgoncedailyprovidedsignificantimprovementsinpain,

inflammation,andmobility.Thesebeneficialeffectsweremaintainedoverthe12-weektreatmentperiods.

Inpatientsexperiencingattacksofacutegoutyarthritis,etoricoxib120mgoncedailyoveraneight-daytreatment

period,relievedmoderatetoextremejointpainandinflammationcomparabletoindomethacin50mgthreetimesdaily.

Painreliefwasobservedasearlyasfourhoursafterinitiationoftreatment.

Inpatientswithankylosingspondylitis,etoricoxib90mgoncedailyprovidedsignificantimprovementsinspinepain,

inflammation,stiffnessandfunction.Theclinicalbenefitofetoricoxibwasobservedasearlyastheseconddayof

therapyafterinitiationoftreatmentandwasmaintainedthroughoutthe52-weektreatmentperiod.

Inaclinicalstudyevaluatingpostoperativedentalpain,etoricoxib90mgwasadministeredoncedailyforuptothree

days.Inthesubgroupofpatientswithmoderatepainatbaseline,etoricoxib90mgdemonstratedasimilaranalgesic

effecttothatofibuprofen600mg(16.11vs.16.39;P=0.722),andgreaterthanthatofacetaminophen/codeine

600mg/60mg(11.00;P<0.001)andplacebo(6.84;P<0.001)asmeasuredbytotalpainreliefoverthefirst6hoursfor

(TOPAR6).Theproportionofpatientsreportingrescuemedicationusagewithinthefirst24hoursofdosingwas40.8%

foretoricoxib90mg,25.5%foribuprofen600mgQ6h,and46.7%foracetaminophen/codeine600mg/60mgQ6h

comparedto76.2%forplacebo.

Instudiesspecificallydesignedtomeasuretheonsetofactionofetoricoxib,theonsetofactionoccurredasearlyas24

minutesafterdosing.

Safety

MultinationalEtoricoxibandDiclofenacArthritisLong-term(MEDAL)Program

TheMEDALProgramwasaprospectivelydesignedCardiovascular(CV)SafetyOutcomesProgramofpooleddata

fromthreerandomized,double-blindactivecomparatorcontrolledtrials,theMEDALstudy,EDGEIIandEDGE.

TheMEDALStudy,wasanendpointdrivenCVOutcomesstudyin17,804OAand5,700RApatientstreatedwith

etoricoxib60(OA)or90mg(OAandRA)ordiclofenac150mgdailyforameanperiodof20.3months(maximumof

42.3months,median21.3months).Inthistrial,onlyseriousadverseeventsanddiscontinuationsduetoanyadverse

eventswererecorded.

TheEDGEandEDGEIIstudiescomparedthegastrointestinaltolerabilityofetoricoxibversusdiclofenac.TheEDGE

studyincluded7111OApatientstreatedwithadoseofetoricoxib90mgdaily(1.5timesthedoserecommendedfor

OA)ordiclofenac150mgdailyforameanperiodof9.1months(maximum16.6months,median11.4months).The

EDGEIIstudyincluded4086RApatientstreatedwithetoricoxib90mgdailyordiclofenac150mgdailyforamean

periodof19.2months(maximum33.1months,median24months).

InthepooledMEDALProgram,34,701patientswithOAorRAweretreatedforameandurationof17.9months

(maximum42.3months,median16.3months)withapproximately12,800patientsreceivingtreatmentformorethan24

months.PatientsenrolledintheProgramhadawiderangeofcardiovascularandgastrointestinalriskfactorsat

baseline.Patientswitharecenthistoryofmyocardialinfarction,coronaryarterybypassgraftingorpercutaneous

coronaryinterventionwithin6monthsprecedingenrollmentwereexcluded.Useofgastroprotectiveagentsandlow

doseaspirinwerepermittedinthestudies.

OverallSafety:

Therewasnosignificantdifferencebetweenetoricoxibanddiclofenacintherateofcardiovascularthromboticevents.

Cardiorenaladverseeventswereobservedmorefrequentlywithetoricoxibthanwithdiclofenac,andthiseffectwas

dose-dependent(seespecificresultsbelow).Gastrointestinalandhepaticadverseeventswereobservedsignificantly

morefrequentlywithdiclofenacthanetoricoxib.TheincidenceofadverseexperiencesinEDGEandEDGEIIandof

adverseexperiencesconsideredseriousorresultingindiscontinuationintheMEDALstudywashigherwithetoricoxib

thandiclofenac.

Cardiovascularsafetyresults:

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peripheralvascularevents)wascomparablebetweenetoricoxibanddiclofenac,anddataaresummarizedinthetable

below.Therewerenostatisticallysignificantdifferencesinthromboticeventratesbetweenetoricoxibanddiclofenac

acrossallsubgroupsanalyzedincludingpatientcategoriesacrossarangeofbaselinecardiovascularrisk.When

consideredseparately,therelativerisksforconfirmedthromboticcardiovascularseriousadverseeventswithetoricoxib

60mgor90mgcomparedwithdiclofenac150mgweresimilar.

CVmortality,aswellasoverallmortality,wassimilarbetweentheetoricoxibanddiclofenactreatmentgroups.

CardiorenalEvents:

Approximately50%ofpatientsenrolledintheMEDALstudyhadahistoryofhypertensionatbaseline.Inthestudy,

theincidenceofdiscontinuationsduetohypertension-relatedadverseeventswasstatisticallysignificantlyhigherfor

etoricoxibthanfordiclofenac.Theincidenceofcongestiveheartfailureadverseevents(discontinuationsandserious

events)occurredatsimilarratesonetoricoxib60mgcomparedtodiclofenac150mgbutwashigherforetoricoxib90

mgcomparedtodiclofenac150mg(statisticallysignificantfor90mgetoricoxibvs.150mgdiclofenacinMEDALOA

cohort).Theincidenceofconfirmedcongestiveheartfailureadverseevents(eventsthatwereseriousandresultedin

hospitalisationoravisittoanemergencydepartment)wasnon-significantlyhigherwithetoricoxibthandiclofenac150

mg,andthiseffectwasdose-dependent.Theincidenceofdiscontinuationsduetoedema-relatedadverseeventswas

higherforetoricoxibthandiclofenac150mg,andthiseffectwasdose-dependent(statisticallysignificantforetoricoxib

90mg,butnotforetoricoxib60mg).

ThecardiorenalresultsforEDGEandEDGEIIwereconsistentwiththosedescribedfortheMEDALStudy.

IntheindividualMEDALProgramstudies,foretoricoxib(60mgor90mg),theabsoluteincidenceofdiscontinuation

Table1:RatesofConfirmedThromboticCVEvents(PooledMEDAL

Program)

Etoricoxib

(N=16819)

25836Patient-

Years Diclofenac

(N=16483)

24766Patient-

Years Between

Treatment

Comparison

Rate

(95%CI) Rate

(95%CI) RelativeRisk

(95%CI)

ConfirmedThromboticCardiovascularSeriousAdverseEvents

Per-protocol 1.24(1.11,1.38) 1.30(1.17,1.45) 0.95(0.81,1.11)

Intent-to-treat 1.25(1.14,1.36) 1.19(1.08,1.30) 1.05(0.93,1.19)

ConfirmedCardiacEvents

Per-protocol 0.71(0.61,0.82) 0.78(0.68,0.90) 0.90(0.74,1.10)

Intent-to-treat 0.69(0.61,0.78) 0.70(0.62,0.79) 0.99(0.84,1.17)

ConfirmedCerebrovascularEvents

Per-protocol 0.34(0.28,0.42) 0.32(0.25,0.40) 1.08(0.80,1.46)

Intent-to-treat 0.33(0.28,0.39) 0.29(0.24,0.35) 1.12(0.87,1.44)

ConfirmedPeripheralVascularEvents

Per-protocol 0.20(0.15,0.27) 0.22(0.17,0.29) 0.92(0.63,1.35)

Intent-to-treat 0.24(0.20,0.30) 0.23(0.18,0.28) 1.08(0.81,1.44)

Eventsper100Patient-Years;CI=confidenceinterval

N=totalnumberofpatientsincludedinPer-protocolpopulation

Per-protocol:alleventsonstudytherapyorwithin14daysofdiscontinuation

(excluded:patientswhotook<75%oftheirstudymedicationortooknon-study

NSAIDs>10%ofthetime).

Intent-to-treat:allconfirmedeventsuptotheendofthetrial(includedpatients

potentiallyexposedtonon-studyinterventionsfollowingdiscontinuationofstudy

medication).Totalnumberofpatientsrandomised,n=17412onetoricoxiband

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failure,withhigherratesofdiscontinuationobservedwithetoricoxib90mgthanetoricoxib60mg.

MEDALProgramGastrointestinalTolerabilityResults:

Asignificantlylowerrateofdiscontinuationsoftreatmentforanyclinical(e.g.,dyspepsia,abdominalpain,ulcer)GI

adverseeventwasobservedwithetoricoxibcomparedwithdiclofenacwithineachofthethreecomponentstudiesof

theMEDALProgram.TheratesofdiscontinuationsduetoadverseclinicalGIeventsperhundredpatient-yearsover

theentireperiodofstudywereasfollows:3.23foretoricoxiband4.96fordiclofenacintheMEDALStudy;9.12with

etoricoxiband12.28withdiclofenacintheEDGEstudy;and3.71withetoricoxiband4.81withdiclofenacinthe

EDGEIIstudy.

MEDALProgramGastrointestinalSafetyResults:

OverallupperGIeventsweredefinedasperforations,ulcersandbleeds.ThesubsetofoverallupperGIevents

consideredcomplicatedincludedperforations,obstructions,andcomplicatedbleeding;thesubsetofupperGIevents

considereduncomplicatedincludeduncomplicatedbleedsanduncomplicatedulcers.Asignificantlylowerrateof

overallupperGIeventswasobservedwithetoricoxibcomparedtodiclofenac.Therewasnosignificantdifference

betweenetoricoxibanddiclofenacintherateofcomplicatedevents.ForthesubsetofupperGIhemorrhageevents

(complicatedanduncomplicatedcombined),therewasnosignificantdifferencebetweenetoricoxibanddiclofenac.

TheupperGIbenefitforetoricoxibcomparedwithdiclofenacwasnotstatisticallysignificantinpatientstaking

concomitantlow-doseaspirin(approximately33%ofpatients).

Theratesperhundredpatient-yearsofconfirmedcomplicatedanduncomplicatedupperGIclinicalevents

(perforations,ulcersandbleeds(PUBs))were0.67(95%CI0.57,0.77)withetoricoxiband0.97(95%CI0.85,1.10)

withdiclofenac,yieldingarelativeriskof0.69(95%CI0.57,0.83).

TherateforconfirmedupperGIeventsinelderlypatientswasevaluatedandthelargestreductionwasobservedin

patients 75yearsofage(1.35[95%CI0.94,1.87]vs.2.78[95%CI2.14,3.56]eventsperhundredpatient-yearsfor

etoricoxibanddiclofenac,respectively.

TheratesofconfirmedlowerGIclinicalevents(smallorlargebowelperforation,obstruction,orhemorrhage,(POBs))

werenotsignificantlydifferentbetweenetoricoxibanddiclofenac.

MEDALProgramHepaticSafetyResults:

Etoricoxibwasassociatedwithastatisticallysignificantlylowerrateofdiscontinuationsduetohepatic-relatedadverse

experiencesthandiclofenac.InthepooledMEDALProgram,0.3%ofpatientsonetoricoxiband2.7%ofpatientson

diclofenacdiscontinuedduetohepatic-relatedadverseexperiences.Therateperhundredpatient-yearswas0.22on

etoricoxiband1.84fordiclofenac(p-valuewas<0.001foretoricoxibvs.diclofenac).However,mosthepaticadverse

experiencesintheMEDALProgramwerenon-serious.

AdditionalThromboticCardiovascularSafetyData

InclinicalstudiesexcludingtheMEDALProgramStudies , approximately3100patientsweretreatedwithetoricoxib

60mgdailyfor12weeksorlonger.Therewasnodiscernibledifferenceintherateofconfirmedseriousthrombotic

cardiovasculareventsbetweenpatientsreceivingetoricoxib60mg,placebo,ornon-naproxenNSAIDs.However,the

rateoftheseeventswashigherinpatientsreceivingetoricoxibcomparedwiththosereceivingnaproxen500mgtwice

daily.ThedifferenceinantiplateletactivitybetweensomeCOX -1inhibitingNSAIDsandselectiveCOX-2inhibitors

maybeofclinicalsignificanceinpatientsatriskofthrombo-embolicevents.SelectiveCOX-2inhibitorsreducethe

formationofsystemic(andthereforepossiblyendothelial)prostacyclinwithoutaffectingplateletthromboxane.The

clinicalrelevanceoftheseobservationshasnotbeenestablished.

AdditionalGastrointestinalSafetyData

Intwo12 -weekdouble-blindendoscopystudies,thecumulativeincidenceofgastroduodenalulcerationwas

significantlylowerinpatientstreatedwithetoricoxib120mgoncedailythaninpatientstreatedwitheithernaproxen

500mgtwicedailyoribuprofen800mgthreetimesdaily.Etoricoxibhadahigherincidenceofulcerationascompared

toplacebo.

RenalFunctionStudyintheElderly

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etoricoxib(90mg),celecoxib(200mgbid),naproxen(500mgbid)andplaceboonurinarysodiumexcretion,blood

pressure,andotherrenalfunctionparametersinsubjects60to85yearsofageona200-mEq/daysodiumdiet.

Etoricoxib,celecoxib,andnaproxenhadsimilareffectsonurinarysodiumexcretionoverthe2weeksoftreatment.All

activecomparatorsshowedanincreaserelativetoplacebowithrespecttosystolicbloodpressures;however,etoricoxib

wasassociatedwithastatisticallysignificantincreaseatDay14whencomparedtocelecoxibandnaproxen(mean

changefrombaselineforsystolicbloodpressure:etoricoxib7.7mmHg,celecoxib2.4mmHg,naproxen3.6mmHg).

5.2Pharmacokineticproperties

Absorption

Orallyadministeredetoricoxibiswellabsorbed.Theabsolutebioavailabilityisapproximately100%.Following120

mgonce-dailydosingtosteadystate,thepeakplasmaconcentration(geometricmeanCmax=3.6µg/ml)wasobserved

atapproximately1hour(Tmax)afteradministrationtofastedadults.Thegeometricmeanareaunderthecurve

(AUC0-24hr)was37.8µghr/ml.Thepharmacokineticsofetoricoxibarelinearacrosstheclinicaldoserange.

Dosingwithfood(ahigh-fatmeal)hadnoeffectontheextentofabsorptionofetoricoxibafteradministrationofa120

mgdose.Therateofabsorptionwasaffected,resultingina36%decreaseinCmaxandanincreaseinTmaxby2

hours.Thesedataarenotconsideredclinicallysignificant.Inclinicaltrials,etoricoxibwasadministeredwithout

regardtofoodintake.

Distribution

Etoricoxibisapproximately92%boundtohumanplasmaproteinovertherangeofconcentrationsof0.05to5µg/ml.

Thevolumeofdistributionatsteadystate(Vdss)wasapproximately120linhumans.

Etoricoxibcrossestheplacentainratsandrabbits,andtheblood-brainbarrierinrats.

Metabolism

Etoricoxibisextensivelymetabolisedwith<1%ofadoserecoveredinurineastheparentdrug.Themajorrouteof

metabolismtoformthe6’-hydroxymethylderivativeiscatalysedbyCYPenzymes.CYP3A4appearstocontributeto

themetabolismofetoricoxibinvivo.InvitrostudiesindicatethatCYP2D6,CYP2C9,CYP1A2andCYP2C19alsocan

catalysethemainmetabolicpathway,buttheirquantitativerolesinvivohavenotbeenstudied.

Fivemetaboliteshavebeenidentifiedinman.Theprincipalmetaboliteisthe6’-carboxylicacidderivativeof

etoricoxibformedbyfurtheroxidationofthe6’-hydroxymethylderivative.Theseprincipalmetaboliteseither

demonstratenomeasurableactivityorareonlyweaklyactiveasCOX-2inhibitors.Noneofthesemetabolitesinhibit

COX-1.

Elimination

Followingadministrationofasingle25-mgradiolabeledintravenousdoseofetoricoxibtohealthysubjects,70%of

radioactivitywasrecoveredinurineand20%infaeces,mostlyasmetabolites.Lessthan2%wasrecoveredas

unchangeddrug.

Eliminationofetoricoxiboccursalmostexclusivelythroughmetabolismfollowedbyrenalexcretion.Steadystate

concentrationsofetoricoxibarereachedwithinsevendaysofoncedailyadministrationof120mg,withan

accumulationratioofapproximately2,correspondingtoahalf-lifeofapproximately22hours.Theplasmaclearance

aftera25-mgintravenousdoseisestimatedtobeapproximately50ml/min.

Characteristicsinpatients

Elderly:Pharmacokineticsintheelderly(65yearsofageandolder)aresimilartothoseintheyoung.

Gender:Thepharmacokineticsofetoricoxibaresimilarbetweenmenandwomen.

Hepaticinsufficiency:Patientswithmildhepaticdysfunction(Child-Pughscore5-6)administeredetoricoxib60mg

oncedailyhadanapproximately16%highermeanAUCascomparedtohealthysubjectsgiventhesameregimen.

Patientswithmoderatehepaticdysfunction(Child-Pughscore7-9)administeredetoricoxib60mgeveryotherdayhad

similarmeanAUCtothehealthysubjectsgivenetoricoxib60mgoncedaily;etoricoxib30mgoncedailyhasnotbeen

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(Child-Pughscore10).(Seesections4.2and4.3.)

Renalinsufficiency:Thepharmacokineticsofasingledoseofetoricoxib120mginpatientswithmoderatetosevere

renalinsufficiencyandpatientswithend-stagerenaldiseaseonhaemodialysiswerenotsignificantlydifferentfrom

thoseinhealthysubjects.Haemodialysiscontributednegligiblytoelimination(dialysisclearanceapproximately50

ml/min).(Seesections4.3and4.4.)

Paediatricpatients:Thepharmacokineticsofetoricoxibinpaediatricpatients(<12yearsold)havenotbeenstudied.

Inapharmacokineticstudy(n=16)conductedinadolescents(aged12to17)thepharmacokineticsinadolescents

weighing40to60kggivenetoricoxib60mgoncedailyandadolescents>60kggivenetoricoxib90mgoncedaily

weresimilartothepharmacokineticsinadultsgivenetoricoxib90mgoncedaily.Safetyandeffectivenessof

etoricoxibinpaediatricpatientshavenotbeenestablished(seesection4.2.).

5.3Preclinicalsafetydata

Inpreclinicalstudies,etoricoxibhasbeendemonstratednottobegenotoxic.Etoricoxibwasnotcarcinogenicinmice.

Ratsdevelopedhepatocellularandthyroidfollicularcelladenomasat>2-timesthedailyhumandose[90mg]basedon

systemicexposurewhendoseddailyforapproximatelytwoyears.Hepatocellularandthyroidfollicularcelladenomas

observedinratsareconsideredtobeaconsequenceofrat-specificmechanismrelatedtohepaticCYPenzyme

induction.EtoricoxibhasnotbeenshowntocausehepaticCYP3Aenzymeinductioninhumans.

Intherat,gastro-intestinaltoxicityofetoricoxibincreasedwithdoseandexposuretime.Inthe14-weektoxicitystudy,

etoricoxibcausedgastro-intestinalulcersatexposuresgreaterthanthoseseeninmanatthetherapeuticdose.Inthe53-

and106weektoxicitystudy,gastro-intestinalulcerswerealsoseenatexposurescomparabletothoseseeninmanatthe

therapeuticdose.Indogs,renalandgastro-intestinalabnormalitieswereseenathighexposures.

Etoricoxibwasnotteratogenicinreproductivetoxicitystudiesconductedinratsat15mg/kg/day(thisrepresents

approximately1.5timesthedailyhumandose[90mg]basedonsystemicexposure).Inrabbits,atreatmentrelated

increaseincardiovascularmalformationswasobservedatexposurelevelsbelowtheclinicalexposureatthedaily

humandose(90mg).Howevernotreatment-relatedexternalorskeletalfoetalmalformationswereobserved.Inratsand

rabbits,therewasadosedependentincreaseinpostimplantationlossatexposuresgreaterthanorequalto1.5timesthe

humanexposure(seesections4.3and4.6).

Etoricoxibisexcretedinthemilkoflactatingratsatconcentrationsapproximatelytwo-foldthoseinplasma.Therewas

adecreaseinpupbodyweightfollowingexposureofpupstomilkfromdamsadministeredetoricoxibduringlactation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Calciumhydrogenphosphate(anhydrous)

Croscarmellosesodium

Magnesiumstearate

Microcrystallinecellulose

Tabletcoating:

Carnaubawax

Lactosemonohydrate

Hypromellose

Titaniumdioxide(E171)

Triacetin.

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Yellowferricoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Bottles:Keepthecontainertightlyclosedinordertoprotectfrommoisture.

Blisters:Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Aluminum/aluminiumblistersinpackscontaining2,5,7,10,14,20,28,30,50,84,100tabletsormulti-packs

containing98(2packsof49)tablets.

Aluminum/aluminiumblisters(unitdoses)inpacksof50or100tablets.

White,round,HDPEbottleswithawhite,polypropyleneclosurecontaining30tabletsandtwo1-gramdesiccant

containersor90tabletsandone1-gramdesiccantcontainer.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSharp&DohmeIreland(HumanHealth)Limited

PelhamHouse

SouthCountyBusinessPark

Leopardstown

Dublin18

8MARKETINGAUTHORISATIONNUMBER

PA1286/007/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11October2002

Dateoflastrenewal:13February2007

10DATEOFREVISIONOFTHETEXT

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