ACOXXEL 30 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ETORICOXIB
Available from:
Merck Sharp & Dohme Ireland (Human Health) Limited
INN (International Name):
ETORICOXIB
Dosage:
30 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Authorization status:
Withdrawn
Authorization number:
PA1286/042/001
Authorization date:
2014-08-15

Package leaflet: Information for the user

ACOXXEL 30 mgfilm-coated tablets

ACOXXEL 60 mgfilm-coated tablets

ACOXXEL 90 mgfilm-coated tablets

ACOXXEL 120 mgfilm-coated tablets

Etoricoxib

Read all of this leaflet carefully before you starttaking this medicine because it contains important

information for you.

Keep this leaflet. You mayneed to readit again.

If youhave anyfurtherquestions, ask your doctor orpharmacist.

This medicine has been prescribed for you only. Donot pass it on toothers. It mayharmthem, even

if their signsof illness arethe sameas yours.

If youget any side effects, talk toyour doctor orpharmacist. This includes anypossible side effects

not listed inthis leaflet.

What is in this leaflet

1. What ACOXXELis and what it is usedfor

2. Whatyouneed to know before you takeACOXXEL

3. How to take ACOXXEL

4. Possible side effects

5. How to store ACOXXEL

6. Contents of the pack and other information

1. What ACOXXEL is andwhat it is used for

ACOXXELis one of a group of medicines called selective COX-2inhibitors. These belong toa

familyof medicines callednon-steroidalanti-inflammatorydrugs (NSAIDs).

ACOXXEL helps to reduce the pain andswelling(inflammation) in the joints and muscles of

people with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and gout.

ACOXXEL isalso used for the short termtreatment of moderate pain after dental surgery.

What is osteoarthritis?

Osteoarthritis is a disease of the joints. It resultsfromthe gradual breakdown of cartilage that cushions

the ends of the bones. Thiscauses swelling (inflammation), pain, tenderness, stiffness and disability.

What is rheumatoid arthritis?

Rheumatoid arthritis is a long terminflammatorydisease of the joints. It causespain, stiffness, swelling,

and increasing loss of movement in the joints it affects. It mayalsocause inflammation in other areas of

the body.

What is gout?

Gout is a disease of sudden, recurring attacks of verypainful inflammation and redness in the joints. It is

caused bydeposits of mineral crystals in the joint.

What is ankylosing spondylitis?

Ankylosing spondylitis isan inflammatorydisease of the spine and large joints.

2. What you need to know before you takeACOXXEL

Do not takeACOXXEL:

ifyou are allergic (hypersensitive) to etoricoxibor any of theother ingredients of ACOXXEL (see

Further information, section 6)

ifyou are allergic to non-steroidal anti-inflammatorydrugs (NSAIDs), includingaspirin andCOX-2

inhibitors (see Possible Side Effects, section 4)

ifyouhave a current stomach ulcer orbleeding inyour stomach or intestines

ifyouhave serious liver disease

if you haveseriouskidneydisease

ifyou are orcould be pregnant or are breast-feeding (see ‘Pregnancy and breast feeding’)

ifyou are under 16years of age

ifyouhave inflammatorybowel disease, such as Crohn’s Disease,Ulcerative Colitis, or Colitis

ifyourdoctorhas diagnosed heart problems includingheart failure (moderate or severe types),

angina (chest pain) or ifyou have had aheartattack,bypass surgery, peripheralarterial disease

(poor circulation inlegs orfeet due to narrow orblocked arteries), orany kindofstroke (including

mini-stroke, transient ischaemic attack or TIA).Etoricoxib mayslightlyincrease your riskof heart

attack and stroke and this iswhyitshould notbe usedin those whohave alreadyhad heart

problems or stroke

ifyouhave high bloodpressure that has not been controlled bytreatment (checkwithyourdoctor or

nurse ifyou are not sure whether yourbloodpressure is adequately controlled)

If you think anyof these are relevant to you,donot take the tablets untilyouhaveconsultedyour doctor.

Warnings and precautions

Talk toyourdoctor orpharmacist before taking ACOXXEL if:

You have a history of stomach bleedingor ulcers.

You are dehydrated, for example bya prolonged boutof vomiting or diarrhoea.

You have swelling due tofluid retention.

You have a history of heartfailure,or any other formof heart disease.

You have a history of highblood pressure. ACOXXELcan increase bloodpressure in somepeople,

especiallyinhighdoses, andyour doctor will wantto check your bloodpressure fromtime to time.

You have any historyof liver or kidneydisease.

You are being treated for an infection. ACOXXELcan mask or hide a fever, which is a signof

infection.

You are a woman tryingtobecome pregnant.

You are elderly (i.e., over 65years of age).

You have diabetes, high cholesterol, or are a smoker.These can increase your risk of heart disease.

If you are notsure if any ofthe above applytoyou,talk to your doctor before taking ACOXXELto see

if this medicine is suitable foryou.

ACOXXELworks equally well in older andyoungeradult patients. If you are elderly (i.e., over 65years

of age),yourdoctor will want to appropriatelykeepacheck onyou. No dosage adjustment is necessary

for elderly patients.

Children and adolescents

Do not give this medicineto children and adolescents under 16years of age.

Other medicinesandACOXXEL

Please tell your doctoror pharmacist if you are taking, have recently taken or might take anyother

medicines, including medicines obtained without aprescription.

In particular if you are taking anyof thefollowing medicines, yourdoctor maywant to monitor you to

check that your medicinesare working properly,once you start taking ACOXXEL:

medicines that thinyourblood (anticoagulants), suchas warfarin

rifampicin (an antibiotic)

methotrexate(a drug used for suppressing the immune system, and often used inrheumatoid

arthritis)

medicines used to help control highblood pressure and heart failure called ACE inhibitors and

angiotensin receptor blockers, examplesinclude enalapril and ramipril, and losartan and valsartan

lithium(amedicine used to treat sometypes of depression)

diuretics (water tablets)

ciclosporin ortacrolimus (drugs used forsuppressing the immune system)

digoxin (a medicine for heart failure and irregular heart rhythm)

minoxidil (adrug used totreat high blood pressure)

salbutamol tablets or oral solution (a medicine for asthma)

birth controlpills

hormone replacement therapy

aspirin, the risk of stomach ulcers is greater if you takeACOXXELwith aspirin.

-ACOXXELcan be taken with low-dose aspirin. Ifyouare currently takinglow-dose aspirin

to prevent heart attacks orstroke,you shouldnot stoptaking aspirin untilyou talk toyour doctor

-do not take high dose aspirin or other anti-inflammatorymedicineswhile takingACOXXEL

Pregnancy and breast-feeding

ACOXXELtabletsmust not be taken duringpregnancy.Ifyouare pregnant or thinkyou could be

pregnant,or ifyou are planning tobecome pregnant, do not take the tablets. If you becomepregnant, stop

taking the tablets and consultyour doctor. Consultyour doctor ifyou are unsure or need more advice.

It is not known if ACOXXELis excreted in humanmilk. Ifyou are breast-feeding, orplanning to breast-

feed, consult your doctor before takingACOXXEL. If you are using ACOXXEL,you must not breast-

feed.

ACOXXELwith food and drink

The onset of the effect of ACOXXELmay be faster when taken without food.

Driving andusing machines

Dizzinessand sleepiness have been reported in somepatients taking ACOXXEL.

Do not drive if you experience dizzinessor sleepiness.

Do not use any tools ormachines if youexperience dizziness or sleepiness.

ACOXXEL containslactose

If youhave been told byyour doctor that you are unable to tolerate somesugars, contact your doctor

before takingthis medicinal product.

3. How to take ACOXXEL

Alwaystakethis medicineexactlyasyourdoctor has toldyou. Youshould checkwithyourdoctor or

pharmacist ifyou are not sure.

ACOXXELTablets should notbe taken bychildrenor adolescents under 16years of age.

Take ACOXXELTabletsbymouth once a day. ACOXXELcan be taken with or withoutfood.

Do not takemore than the recommended dose foryourcondition.Your doctorwill want to discuss your

treatment fromtime to time. It is important thatyouuse the lowestdose that controlsyourpain andyou

shouldnot take ACOXXELfor longer than necessary. This is because the risk of heart attacks and strokes

might increase after prolonged treatment, especiallywith high doses.

Osteoarthritis

The recommended dose is30 mgonce aday, increaseto a maximumof 60mgonce a dayifneeded.

Rheumatoid arthritis

The recommended dose is90 mgonce a day.

Ankylosing spondylitis

The recommended dose is90 mgonce a day.

Acute pain conditions

Etoricoxib shouldbe usedonlyfor the acute painful period.

Gout

The recommended dose is120 mgonce a daywhichshouldonly beused for theacute painful

period, limited to a maximumof 8 daystreatment.

Postoperative dental surgery pain

The recommended dose is90 mgonce daily,limited to a maximum of 3 daystreatment.

People with liver problems

If youhave mild liver disease, you shouldnot take more than 60 mga day.

If youhavemoderateliver disease, you should nottakemore than 30 mga day.

If you takemore ACOXXELthan you should

You should never takemore tablets thanthe doctor recommends. If youdo take too many

ACOXXELtablets, you should seek medical attention immediately.

If you forgetto take ACOXXEL

It is important to take ACOXXELas your doctor has prescribed. If you miss a dose, just resume your

usual schedule the followingday. Donot take a double dose to makeup for the forgotten tablet.

If youhave anyfurtherquestions on theuse ofthis product, askyour doctoror pharmacist.

4. Possible sideeffects

Like all medicines, ACOXXELcan cause side effects, althoughnot everybodygets them.

If you develop any of these signs you should stop ACOXXELand talk toyour doctor immediately:

shortness of breath, chest pains, or ankle swelling appear or if theyget worse

yellowing ofthe skin and eyes (jaundice) – these are signs of liverproblems

severe or continual stomachpain oryour stools become black

an allergic reaction- which can include skin problemssuch as ulcersor blistering, or swelling of the

face, lips, tongue, or throat which maycause difficulty in breathing

The frequency of possible side effects listed below is defined usingthe followingconvention:

Verycommon(affectsmore than 1 user in 10)

Common (affects 1 to 10 users in 100)

Uncommon (affects 1 to 10 users in 1,000)

Rare (affects1 to 10users in 10,000)

Veryrare (affects less than 1 user in 10,000).

The following side effectscan occur during treatment with ACOXXEL:

Very Common

stomach pain

Common:

drysocket (inflammation and pain aftera tooth extraction)

swelling of the legs and/or feetdue to fluid retention (oedema)

dizziness, headache

palpitations (fast or irregular heartbeat), irregular heart rhythm(arrythmia),

increased blood pressure

wheezing or shortness of breath (bronchospasms)

constipation,wind (excessive gas), gastritis (inflammation of the lining of the stomach), heartburn,

diarrhoea, indigestion (dyspepsia)/stomach discomfort, nausea, being sick (vomiting), inflammation of

the oesophagus, mouth ulcers

changes in blood tests related toyour liver

bruising

weakness and fatigue, flu-like illness

Uncommon:

gastroenteritis (inflammation of the gastrointestinal tract that involves both the stomach and small

intestine/stomach flu), upper respiratory infection,urinarytract infection

decreased number of red blood cells, decreased number of white blood cells, platelets decreased

hypersensitivity (an allergic reaction includinghiveswhich maybe serious enough torequire

immediate medicalattention

appetite increases or decreases, weight gain

anxiety, depression, decreases inmentalsharpness; seeing, feeling or hearing things that are not there

(hallucinations)

taste alteration, inability to sleep, numbness or tingling, sleepiness

blurred vision, eye irritation and redness

ringing in the ears, vertigo (sensation of spinning while remaining still)

abnormal heart rhythm(atrial fibrillation), fast heartrate, heart failure, feeling oftightness, pressure or

heaviness in the chest (anginapectoris), heart attack

flushing, stroke, mini-stroke (transient ischaemic attack), severe increase in blood pressure.

inflammation of the bloodvessels

cough,breathlessness, nose bleed

stomach or bowel bloating, changes inyour bowel habits , drymouth, stomach ulcer, inflammation of

the stomach lining that can become serious and maylead to bleeding, irritable bowel syndrome,

inflammation of the pancreas

swelling of the face, skin rash or itchyskin, redness of the skin

muscle cramp/spasm,muscle pain/stiffness

high levels of potassiuminyourblood, changes in blood orurine tests relating toyourkidney,serious

kidneyproblems

chest pain

Rare:

angioedema (an allergic reaction with swelling of theface, lips, tongue and/or throat whichmaycause

difficultyinbreathing or swallowing, which maybe serious enough to require immediatemedical

attention)/anaphylactic/anaphylactoid reactions including shock (a serious allergic reaction that

requires immediatemedical attention)

confusion, restlessness

liver problems (hepatitis)

low blood levels of sodium

liver failure, y ellowingof the skin and/or eyes (jaundice)

severe skin reactions

If youget any side effects,talk toyour doctor or pharmacist. This includes anypossible side effects not

listed in this leaflet.

5. How to storeACOXXEL

Keep thismedicine out of the sight and reach of children.

Do not use ACOXXELafter the expirydate which is stated on thepack. The expirydate refers to the last

dayof the month.

Bottles: Keepthe container tightly closed in order toprotect frommoisture.

Blisters: Store in the original package in order to protect frommoisture.

Do not throw awayanymedicines via wastewater orhouseholdwaste. Ask yourpharmacist how to throw

awaymedicines you nolonger use. Thesemeasureswill help toprotect the environment.

6. Contents of the pack andother information

What ACOXXELcontains

The active substance is etoricoxib. Eachfilmcoated tablet contains 30, 60, 90or120 mgof

etoricoxib.

The other ingredients are:

Core: calciumhydrogenphosphate (anhydrous),croscarmellose sodium,magnesiumstearate,

microcrystalline cellulose.

Tablet coating: carnauba wax, lactosemonohydrate,hypromellose, titaniumdioxide (E171),

triacetin. The 30-, 60- and120-mgtablets also containyellow ferric oxide (E172,colouring agent)

and indigo carmine lake (E132, colouring agent).

What ACOXXELlookslike and contents of the pack

ACOXXELTablets are available in four strengths:

30 mgblue-green, apple-shaped, biconvex filmcoatedtabletsmarked ‘ACX 30’onone sideand ‘101’on

the other.

60 mgdark green, apple-shaped, biconvex filmcoatedtabletsmarked ‘200’ onone side andplain onthe

other.

90 mgwhite, apple-shaped, biconvex filmcoated tabletsmarked ‘202’ onone side and plainon the other.

120 mgpale-green, apple-shaped, biconvex filmcoatedtabletsmarked ‘204’ onone side andplain onthe

other.

Pack sizes:

30 mg:

Pack sizes of 2, 7,14,20,28 tablets or multi-packs containing98 (2packs of 49) tablets in blisters.

60, 90, 120 mg:

Pack sizes of 2, 5,7, 10, 14, 20,28,30,50, 84, 100 tablets ormulti-packs containing 98 (2packs of 49)

tablets in blisters; or 30 and 90 tablets in bottles with desiccant containers. The desiccant (one or

two containers) in the bottle, used to keepthe tablets dry,should notbe swallowed.

Not all pack sizesmaybemarketed.

Marketing Authorization Holder and Manufacturer

The Marketing Authorisation Holderinthe UKandMalta is Merck Sharp & Dohme Ltd, HertfordRoad,

Hoddesdon, Herts,EN11 9BU,UK.

The Marketing Authorisation Holderin Ireland is Merck Sharp & Dohme Ireland (Human

Health) Ltd, Red Oak North, South County Business Park, Leopardstown, Dublin18, Ireland.

Manufacturer: Merck Sharp & DohmeBV, Waarderweg39,2031 BN Haarlem, The Netherlands.

ThismedicinalproductisauthorizedintheMember States ofthe EEAunderthe followingnames:

Hungary AUXIB 30mg,60mg, 90mg, 120mgfilmtabletta

Ireland ACOXXEL 30 mg, 60 mg, 90 mg, 120 mgfilm-coatedtablets

Norway TUROX

Slovenia TUROX30 mg,60 mg, 90mg, 120mg filmsko obložene tablete

United Kingdom ETORICOXIB 30mg, 60mg, 90 mg, 120 mgfilm-coatedtablets

This leaflet was last revised in March 2013.

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Acoxxel30mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains30mgofetoricoxib.

Excipientswithknowneffect:

30mg:lactose1.3mg

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet(tablet).

30mgTablets:Blue-green,apple-shapedbiconvextabletsmarked‘ACX30’ononesideand‘101’ontheotherside.

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,

thedoseof30mgoncedailyshouldnotbeexceeded.

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

ACOXXELisadministeredorallyandmaybetakenwithorwithoutfood.Theonsetoftheeffectofthemedicinal

productmaybefasterwhenACOXXELisadministeredwithoutfood.Thisshouldbeconsideredwhenrapid

symptomaticreliefisneeded.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1.

Activepepticulcerationoractivegastro-intestinal(GI)bleeding.

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

typereactionsaftertakingacetylsalicylicacidorNSAIDsincludingCOX-2(cyclooxygenase-2)inhibitors.

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Severehepaticdysfunction(serumalbumin<25g/lorChild-Pughscore10).

Estimatedrenalcreatinineclearance<30ml/min.

Childrenandadolescentsunder16yearsofage.

Inflammatoryboweldisease.

Congestiveheartfailure(NYHAII-IV).

Patientswithhypertensionwhosebloodpressureispersistentlyelevatedabove140/90mmHgandhasnotbeen

adequatelycontrolled.

Establishedischaemicheartdisease,peripheralarterialdisease,and/orcerebrovasculardisease.

4.4Specialwarningsandprecautionsforuse

Gastrointestinaleffects

Uppergastrointestinalcomplications[perforations,ulcersorbleedings(PUBs)],someofthemresultinginfatal

outcome,haveoccurredinpatientstreatedwithetoricoxib.

CautionisadvisedwithtreatmentofpatientsmostatriskofdevelopingagastrointestinalcomplicationwithNSAIDs;

theelderly,patientsusinganyotherNSAIDoracetylsalicylicacidconcomitantlyorpatientswithapriorhistoryof

gastrointestinaldisease,suchasulcerationandGIbleeding.

Thereisafurtherincreaseintheriskofgastrointestinaladverseeffects(gastrointestinalulcerationorother

gastrointestinalcomplications)whenetoricoxibistakenconcomitantlywithacetylsalicylicacid(evenatlowdoses).A

significantdifferenceinGIsafetybetweenselectiveCOX-2inhibitors+acetylsalicylicacidvs.NSAIDs+

acetylsalicylicacidhasnotbeendemonstratedinlong-termclinicaltrials(seesection5.1).

Cardiovasculareffects

ClinicaltrialssuggestthattheselectiveCOX-2inhibitorclassofdrugsmaybeassociatedwithariskofthrombotic

events(especiallymyocardialinfarction(MI)andstroke),relativetoplaceboandsomeNSAIDs.Asthecardiovascular

risksofetoricoxibmayincreasewithdoseanddurationofexposure,theshortestdurationpossibleandthelowest

effectivedailydoseshouldbeused.Thepatient'sneedforsymptomaticreliefandresponsetotherapyshouldbere-

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

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Fluidretention,oedemaandhypertension

Aswithothermedicinalproductsknowntoinhibitprostaglandinsynthesis,fluidretention,oedemaandhypertension

havebeenobservedinpatientstakingetoricoxib.AllNon-steroidalAnti-inflammatoryDrugs(NSAIDs),including

etoricoxib,canbeassociatedwithnewonsetorrecurrentcongestiveheartfailure.Forinformationregardingadose

relatedresponseforetoricoxibseesection5.1.Cautionshouldbeexercisedinpatientswithahistoryofcardiacfailure,

leftventriculardysfunction,orhypertensionandinpatientswithpre-existingoedemafromanyotherreason.Ifthereis

clinicalevidenceofdeteriorationintheconditionofthesepatients,appropriatemeasuresincludingdiscontinuationof

etoricoxibshouldbetaken.

EtoricoxibmaybeassociatedwithmorefrequentandseverehypertensionthansomeotherNSAIDsandselective

COX-2inhibitors,particularlyathighdoses.Therefore,hypertensionshouldbecontrolledbeforetreatmentwith

etoricoxib(seesection4.3)andspecialattentionshouldbepaidtobloodpressuremonitoringduringtreatmentwith

etoricoxib.Bloodpressureshouldbemonitoredwithintwoweeksafterinitiationoftreatmentandperiodically

thereafter.Ifbloodpressurerisessignificantly,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

earlyinthecourseoftherapywiththeonsetofthereactionoccurringinthemajorityofcaseswithinthefirstmonthof

treatment.Serioushypersensitivityreactions(suchasanaphylaxisandangioedema)havebeenreportedinpatients

receivingetoricoxib(seesection4.8).SomeselectiveCOX-2inhibitorshavebeenassociatedwithanincreasedriskof

skinreactionsinpatientswithahistoryofanydrugallergy.Etoricoxibshouldbediscontinuedatthefirstappearanceof

skinrash,mucosallesions,oranyothersignofhypersensitivity.

Etoricoxibmaymaskfeverandothersignsofinflammation.

Cautionshouldbeexercisedwhenco-administeringetoricoxibwithwarfarinorotheroralanticoagulants(seesection

4.5).

Theuseofetoricoxib,aswithanymedicinalproductknowntoinhibitcyclooxygenase/prostaglandinsynthesis,isnot

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

ACOXXELtabletscontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Oralanticoagulants:Insubjectsstabilisedonchronicwarfarintherapy,theadministrationofetoricoxib120mgdaily

wasassociatedwithanapproximate13%increaseinprothrombintimeInternationalNormalisedRatio(INR).

Therefore,patientsreceivingoralanticoagulantsshouldbecloselymonitoredfortheirprothrombintimeINR,

particularlyinthefirstfewdayswhentherapywithetoricoxibisinitiatedorthedoseofetoricoxibischanged(see

section4.4).

Diuretics,ACEinhibitorsandAngiotensinIIAntagonists:NSAIDsmayreducetheeffectofdiureticsandother

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.).

Cyclosporinandtacrolimus:Althoughthisinteractionhasnotbeenstudiedwithetoricoxib,co-administrationof

cyclosporinortacrolimuswithanyNSAIDmayincreasethenephrotoxiceffectofcyclosporinortacrolimus.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

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HormoneReplacementTherapy(HRT):Administrationofetoricoxib120mgwithhormonereplacementtherapy

consistingofconjugatedestrogens(0.625mgPREMARIN™)for28days,increasedthemeansteadystateAUC0-24hr

ofunconjugatedestrone(41%),equilin(76%)and17--estradiol(22%).Theeffectoftherecommendedchronicdoses

ofetoricoxib(30,60and90mg)hasnotbeenstudied.Theeffectsofetoricoxib120mgontheexposure(AUC0-24hr)

totheseestrogeniccomponentsofPREMARINwerelessthanhalfofthoseobservedwhenPREMARINwas

administeredaloneandthedosewasincreasedfrom0.625to1.25mg.Theclinicalsignificanceoftheseincreasesis

unknown,andhigherdosesof

PREMARINwerenotstudiedincombinationwithetoricoxib.Theseincreasesinestrogenicconcentrationshouldbe

takenintoconsiderationwhenselectingpost-menopausalhormonetherapyforusewithetoricoxibbecausetheincrease

inoestrogenexposuremightincreasetheriskofadverseeventsassociatedwithHRT.

Prednisone/prednisolone:Indrug-interactionstudies,etoricoxibdidnothaveclinicallyimportanteffectsonthe

pharmacokineticsofprednisone/prednisolone.

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).

VoriconazoleandMiconazole:Co-administrationofeitheroralvoriconazoleortopicalmiconazoleoralgel,strong

CYP3A4inhibitors,withetoricoxibcausedaslightincreaseinexposuretoetoricoxib,butisnotconsideredtobe

clinicallymeaningfulbasedonpublisheddata.

Rifampicin:Co-administrationofetoricoxibwithrifampicin,apotentinducerofCYPenzymes,produceda65%

decreaseinetoricoxibplasmaconcentrations.Thisinteractionmayresultinrecurrenceofsymptomswhenetoricoxib

isco-administeredwithrifampicin.Whilethisinformationmaysuggestanincreaseindose,dosesofetoricoxibgreater

thanthoselistedforeachindicationhavenotbeenstudiedincombinationwithrifampicinandarethereforenot

recommended(seesection4.2).

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4.6Fertility,pregnancyandlactation

Pregnancy

Noclinicaldataonexposedpregnanciesareavailableforetoricoxib.Studiesinanimalshaveshownreproductive

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

productsinhibitingprostaglandinsynthesis,maycauseuterineinertiaandprematureclosureoftheductusarteriosus

duringthelasttrimester.Etoricoxibiscontraindicatedinpregnancy(seesection4.3).Ifawomanbecomespregnant

duringtreatment,etoricoxibmustbediscontinued.

Breastfeeding

Itisnotknownwhetheretoricoxibisexcretedinhumanmilk.Etoricoxibisexcretedinthemilkoflactatingrats.

Womenwhouseetoricoxibmustnotbreastfeed(seesections4.3and5.3).

Fertility

Theuseofetoricoxib,aswithanydrugsubstanceknowntoinhibitCOX -2,isnotrecommendedinwomenattempting

toconceive.

4.7Effectsonabilitytodriveandusemachines

Patientswhoexperiencedizziness,vertigoorsomnolencewhiletakingetoricoxibshouldrefrainfromdrivingor

operatingmachinery.

4.8Undesirableeffects

Summaryofthesafetyprofile

Inclinicaltrials,etoricoxibwasevaluatedforsafetyin7152individuals,including4614patientswithOA,RA,chronic

lowbackpainorankylosingspondylitis(approximately600patientswithOAorRAweretreatedforoneyearor

longer).

Inclinicalstudies,theundesirableeffectsprofilewassimilarinpatientswithOAorRAtreatedwithetoricoxibforone

yearorlonger.

Inaclinicalstudyforacutegoutyarthritis,patientsweretreatedwithetoricoxib120mgoncedailyforeightdays.The

adverseexperienceprofileinthisstudywasgenerallysimilartothatreportedinthecombinedOA,RA,andchronic

lowbackpainstudies.

Inacardiovascularsafetyoutcomesprogramofpooleddatafromthreeactivecomparatorcontrolledtrials,17,

412patientswithOAorRAweretreatedwithetoricoxib(60mgor90mg)forameandurationofapproximately

18months.Thesafetydataanddetailsfromthisprogramarepresentedinsection5.1.

Inclinicalstudiesforacutepostoperativedentalpainfollowingsurgeryincluding614patientstreatedwithetoricoxib

(90mgor120mg),theadverseexperienceprofileinthesestudieswasgenerallysimilartothatreportedinthe

combinedOA,RA,andchroniclowbackpainstudies.

Tabulatedlistofadversereactions

Thefollowingundesirableeffectswerereportedatanincidencegreaterthanplaceboinclinicaltrialsinpatientswith

OA,RA,chroniclowbackpainorankylosingspondylitistreatedwithetoricoxib30mg,60mgor90mguptothe

recommendeddoseforupto12weeks:intheMEDALProgramstudiesforupto3½years:inshorttermacutepain

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Table1:

SystemOrganClass AdverseExperienceTerm Frequency

Category*

Infectionsand

infestations alveolarosteitis Common

gastroenteritis,upperrespiratory

infection,urinarytractinfection Uncommon

Bloodandlymphatic

systemdisorders anaemia(primarilyassociatedwith

gastrointestinalbleeding),leukopenia,

thrombocytopenia Uncommon

Immunesystemdisorders hypersensitivity ‡ ß Uncommon

angioedema/anaphylactic/anaphylactoid

reactionsincludingshock ‡ Rare

Metabolismandnutrition

disorders oedema/fluidretention Common

appetiteincreaseordecrease,weight

gain Uncommon

Psychiatricdisorders anxiety,depression,mentalacuity

decreased,hallucinations ‡ Uncommon

confusion ‡

, restlessness ‡ Rare

Nervoussystemdisorders dizziness,headache Common

dysgeusia,insomnia,

paresthaesia/hypaesthesia,somnolence Uncommon

Eyedisorders blurredvision,conjunctivitis Uncommon

Earandlabyrinth

disorders tinnitus,vertigo Uncommon

Cardiacdisorders

palpitations,arrhythmia ‡ Common

atrialfibrillation,tachycardia ‡ ,

congestiveheartfailure,non-specific

ECGchanges,anginapectoris ‡ ,

myocardialinfarction § Uncommon

Vasculardisorders hypertension Common

flushing,cerebrovascularaccident § ,

transientischaemicattack,hypertensive

crisis ‡

, vasculitis ‡ Uncommon

Respiratory,thoracicand

mediastinaldisorders bronchospasm ‡ Common

cough,dyspnoea,epistaxis Uncommon

Gastrointestinaldisorders abdominalpain Verycommon

Constipation,flatulence,gastritis,

heartburn/acidreflux , diarrhea,

dyspepsia/epigastricdiscomfort,nausea,

vomiting,oesophagitis,oralulcer Common

abdominaldistention,bowelmovement

patternchange,drymouth,

gastroduodenalulcer,pepticulcers

includinggastrointestinalperforation

andbleeding,irritablebowelsyndrome,

pancreatitis ‡ Uncommon

Hepatobiliarydisorders ALTincreased,ASTincreased Common

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ThefollowingseriousundesirableeffectshavebeenreportedinassociationwiththeuseofNSAIDsandcannotbe

ruledoutforetoricoxib:nephrotoxicityincludinginterstitialnephritisandnephroticsyndrome.

4.9Overdose

Inclinicalstudies,administrationofsingledosesofetoricoxibupto500mgandmultipledosesupto150mg/dayfor

21daysdidnotresultinsignificanttoxicity.Therehavebeenreportsofacuteoverdosagewithetoricoxib,although

adverseexperienceswerenotreportedinthemajorityofcases.Themostfrequentlyobservedadverseexperienceswere

hepaticfailure ‡ ,jaundice ‡ Rare †

Skinandsubcutaneous

tissuedisorders ecchymosis Common

facialoedema,pruritus,rash,erythema ‡ ,

urticaria ‡ Uncommon

Stevens-Johnsonsyndrome ‡ ,toxic

epidermalnecrolysis ‡ ,fixeddrug

eruption ‡ Rare †

Musculoskeletaland

connectivetissue

disorders muscularcramp/spasm,musculoskeletal

pain/stiffness Uncommon

Renalandurinary

disorders proteinuria,serumcreatinineincreased,

renalfailure/renalinsufficiency ‡ (see

section4.4) Uncommon

Generaldisordersand

administrationsite

conditions asthenia/fatigue,flu-likedisease Common

chestpain Uncommon

Investigations bloodureanitrogenincreased,creatine

phosphokinaseincreased,

hyperkalaemia,uricacidincreased Uncommon

bloodsodiumdecreased Rare

*FrequencyCategory:DefinedforeachAdverseExperienceTermbytheincidencereportedinthe

clinicaltrialsdatabase:VeryCommon(1/10),Common(1/100to<1/10),Uncommon(1/1000to

<1/100),Rare(1/10,000to<1/1000),VeryRare(<1/10,000).

Thisadversereactionwasidentifiedthroughpost-marketingsurveillance.Itsreportedfrequencyhas

beenestimatedbaseduponthehighestfrequencyobservedacrossclinicaltrialdatapooledbyindication

andapproveddose.

Thefrequencycategoryof“Rare”wasdefinedpertheSummaryofProductCharacteristics(SmPC)

guidance(rev.2,Sept2009)onthebasisofanestimatedupperboundofthe95%confidenceintervalfor

0eventsgiventhenumberofsubjectstreatedwithACOXXELintheanalysisofthePhaseIIIdata

pooledbydoseandindication(n=15,470).

Hypersensitivityincludestheterms"allergy","drugallergy","drughypersensitivity",

"hypersensitivity","hypersensitivityNOS","hypersensitivityreaction"and"nonspecificallergy".

Basedonanalysesoflong-termplaceboandactivecontrolledclinicaltrials,selectiveCOX-2inhibitors

havebeenassociatedwithanincreasedriskofseriousthromboticarterialevents,includingmyocardial

infarctionandstroke.Theabsoluteriskincreaseforsucheventsisunlikelytoexceed1%peryearbased

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Intheeventofoverdose,itisreasonabletoemploytheusualsupportivemeasures,e.g.,removeunabsorbedmaterial

fromtheGItract,employclinicalmonitoring,andinstitutesupportivetherapy,ifrequired.

Etoricoxibisnotdialysablebyhaemodialysis;itisnotknownwhetheretoricoxibisdialysablebyperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-inflammatoryandantirheumaticproducts,non-steroids,coxibs,ATCCode:M01

AH05

MechanismofAction

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

Acrossclinicalpharmacologystudies,ACOXXELproduceddose-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

beenestablished.

Clinicalefficacyandsafety

Efficacy

Inpatientswithosteoarthritis(OA),etoricoxib60mgoncedailyprovidedsignificantimprovementsinpainandpatient

assessmentsofdiseasestatus.Thesebeneficialeffectswereobservedasearlyastheseconddayoftherapyand

maintainedforupto52weeks.Studieswithetoricoxib30mgoncedailydemonstratedefficacysuperiortoplacebo

overa12weektreatmentperiod(usingsimilarassessmentsastheabovestudies).Inadoserangingstudy,etoricoxib

60mgdemonstratedsignificantlygreaterimprovementthan30mgforall3primaryendpointsover6weeksof

treatment.The30mgdosehasnotbeenstudiedinosteoarthritisofhands.

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),and

greaterthanthatofparacetamol/codeine600mg/60mg(11.00;P<0.001)andplacebo(6.84;P<0.001)asmeasuredby

totalpainreliefoverthefirst6hours(TOPAR6).Theproportionofpatientsreportingrescuemedicationusagewithin

thefirst24hoursofdosingwas40.8%foretoricoxib90mg,25.5%foribuprofen600mgQ6h,and46.7%for

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(perceptiblepainrelief)of90mgetoricoxibwas28minutesafterdosing.

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)withapproximately12,800patientsreceivingtreatmentformorethan

24months.PatientsenrolledintheProgramhadawiderangeofcardiovascularandgastrointestinalriskfactorsat

baseline.Patientswitharecenthistoryofmyocardialinfarction,coronaryarterybypassgraftingorpercutaneous

coronaryinterventionwithin6monthsprecedingenrollmentwereexcluded.Useofgastroprotectiveagentsandlow

doseaspirinwerepermittedinthestudies.

OverallSafety:

Therewasnosignificantdifferencebetweenetoricoxibanddiclofenacintherateofcardiovascularthromboticevents.

Cardiorenaladverseeventswereobservedmorefrequentlywithetoricoxibthanwithdiclofenac,andthiseffectwas

dose-dependent(seespecificresultsbelow).Gastrointestinalandhepaticadverseeventswereobservedsignificantly

morefrequentlywithdiclofenacthanetoricoxib.TheincidenceofadverseexperiencesinEDGEandEDGEIIandof

adverseexperiencesconsideredseriousorresultingindiscontinuationintheMEDALstudywashigherwithetoricoxib

thandiclofenac.

Cardiovascularsafetyresults:

Therateofconfirmedthromboticcardiovascularseriousadverseevents(consistingofcardiac,cerebrovascular,and

peripheralvascularevents)wascomparablebetweenetoricoxibanddiclofenac,anddataaresummarizedinthetable

below.Therewerenostatisticallysignificantdifferencesinthromboticeventratesbetweenetoricoxibanddiclofenac

acrossallsubgroupsanalyzedincludingpatientcategoriesacrossarangeofbaselinecardiovascularrisk.When

consideredseparately,therelativerisksforconfirmedthromboticcardiovascularseriousadverseeventswithetoricoxib

60mgor90mgcomparedwithdiclofenac150mgweresimilar.

Table2: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

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CVmortality,aswellasoverallmortality,wassimilarbetweentheetoricoxibanddiclofenactreatmentgroups.

CardiorenalEvents:

Approximately50%ofpatientsenrolledintheMEDALstudyhadahistoryofhypertensionatbaseline.Inthestudy,

theincidenceofdiscontinuationsduetohypertension-relatedadverseeventswasstatisticallysignificantlyhigherfor

etoricoxibthanfordiclofenac.Theincidenceofcongestiveheartfailureadverseevents(discontinuationsandserious

events)occurredatsimilarratesonetoricoxib60mgcomparedtodiclofenac150mgbutwashigherforetoricoxib

90mgcomparedtodiclofenac150mg(statisticallysignificantfor90mgetoricoxibvs.150mgdiclofenacinMEDAL

OAcohort).Theincidenceofconfirmedcongestiveheartfailureadverseevents(eventsthatwereseriousandresulted

inhospitalisationoravisittoanemergencydepartment)wasnon-significantlyhigherwithetoricoxibthandiclofenac

150mg,andthiseffectwasdose-dependent.Theincidenceofdiscontinuationsduetoedema-relatedadverseevents

washigherforetoricoxibthandiclofenac150mg,andthiseffectwasdose-dependent(statisticallysignificantfor

etoricoxib90mg,butnotforetoricoxib60mg).

ThecardiorenalresultsforEDGEandEDGEIIwereconsistentwiththosedescribedfortheMEDALStudy.

IntheindividualMEDALProgramstudies,foretoricoxib(60mgor90mg),theabsoluteincidenceofdiscontinuation

inanytreatmentgroupwasupto2.6%forhypertension,upto1.9%foredema,andupto1.1%forcongestiveheart

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

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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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

Arandomized,double-blind,placebo-controlled,parallel-groupstudyevaluatedtheeffectsof15daysoftreatmentof

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%.Following

120mgonce-dailydosingtosteadystate,thepeakplasmaconcentration(geometricmeanC

=3.6µg/ml)was

observedatapproximately1hour(T

)afteradministrationtofastedadults.Thegeometricmeanareaunderthecurve

(AUC

0-24hr )was37.8µghr/ml.Thepharmacokineticsofetoricoxibarelinearacrosstheclinicaldoserange.

Dosingwithfood(ahigh-fatmeal)hadnoeffectontheextentofabsorptionofetoricoxibafteradministrationofa120-

mgdose.Therateofabsorptionwasaffected,resultingina36%decreaseinC

andanincreaseinT

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Thesedataarenotconsideredclinicallysignificant.Inclinicaltrials,etoricoxibwasadministeredwithoutregardto

foodintake.

Distribution

Etoricoxibisapproximately92%boundtohumanplasmaproteinovertherangeofconcentrationsof0.05to5µg/ml.

Thevolumeofdistributionatsteadystate(V

)wasapproximately120linhumans.

Etoricoxibcrossestheplacentainratsandrabbits,andtheblood-brainbarrierinrats.

Metabolism

Etoricoxibisextensivelymetabolisedwith<1%ofadoserecoveredinurineastheparentdrug.Themajorrouteof

metabolismtoformthe6’-hydroxymethylderivativeiscatalyzedbyCYPenzymes.CYP3A4appearstocontributeto

themetabolismofetoricoxibinvivo.InvitrostudiesindicatethatCYP2D6,CYP2C9,CYP1A2andCYP2C19alsocan

catalysethemainmetabolicpathway,buttheirquantitativerolesinvivohavenotbeenstudied.

Fivemetaboliteshavebeenidentifiedinman.Theprincipalmetaboliteisthe6’ -carboxylicacidderivativeof

etoricoxibformedbyfurtheroxidationofthe6’ -hydroxymethylderivative.Theseprincipalmetaboliteseither

demonstratenomeasurableactivityorareonlyweaklyactiveasCOX -2inhibitors.Noneofthesemetabolitesinhibit

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

studiedinthispopulation.Therearenoclinicalorpharmacokineticdatainpatientswithseverehepaticdysfunction

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

Renalinsufficiency:Thepharmacokineticsofasingledoseofetoricoxib120mginpatientswithmoderatetosevere

renalinsufficiencyandpatientswithend-stagerenaldiseaseonhemodialysiswerenotsignificantlydifferentfrom

thoseinhealthysubjects.Hemodialysiscontributednegligiblytoelimination(dialysisclearanceapproximately

50ml/min).(Seesections4.3and4.4.)

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Inapharmacokineticstudy(n=16)conductedinadolescents(aged12to17)thepharmacokineticsinadolescents

weighing40to60kggivenetoricoxib60mgoncedailyandadolescents>60kggivenetoricoxib90mgoncedaily

weresimilartothepharmacokineticsinadultsgivenetoricoxib90mgoncedaily.Safetyandeffectivenessofetoricoxib

inpaediatricpatientshavenotbeenestablished(seesection4.2).

5.3Preclinicalsafetydata

Inpreclinicalstudies,etoricoxibhasbeendemonstratednottobegenotoxic.Etoricoxibwasnotcarcinogenicinmice.

Ratsdevelopedhepatocellularandthyroidfollicularcelladenomasat>2-timesthedailyhumandose[90mg]basedon

systemicexposurewhendoseddailyforapproximatelytwoyears.Hepatocellularandthyroidfollicularcelladenomas

observedinratsareconsideredtobeaconsequenceofrat-specificmechanismrelatedtohepaticCYPenzyme

induction.EtoricoxibhasnotbeenshowntocausehepaticCYP3Aenzymeinductioninhumans.

Intherat,gastrointestinaltoxicityofetoricoxibincreasedwithdoseandexposuretime.Inthe14-weektoxicitystudy

etoricoxibcausedgastrointestinalulcersatexposuresgreaterthanthoseseeninmanatthetherapeuticdose.Inthe53-

and106-weektoxicitystudy,gastrointestinalulcerswerealsoseenatexposurescomparabletothoseseeninmanatthe

therapeuticdose.Indogs,renalandgastrointestinalabnormalitieswereseenathighexposures.

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

Indigocarminelake(E132)

Yellowferricoxide(E172).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Blisters:Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Aluminum/aluminiumblistersinpackscontaining2,7,14,20,28,49tabletsormulti-packscontaining98(2packsof

49)tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSharp&DohmeIreland(HumanHealth)Limited

RedOakNorth

SouthCountyBusinessPark

Leopardstown

Dublin18

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1286/42/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:16September2011

Dateoflastrenewal:13thFebruary2012

10DATEOFREVISIONOFTHETEXT

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Date Printed 26/06/2013 CRN 2125148 page number: 16

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