ARTHROTEC

Main information

  • Trade name:
  • ARTHROTEC Modified-release Tablets 75 Milligram
  • Dosage:
  • 75 Milligram
  • Pharmaceutical form:
  • Modified-release Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARTHROTEC Modified-release Tablets 75 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/074/001
  • Authorization date:
  • 18-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arthrotec75modified-releasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletconsistsofagastro-resistantcorecontaining75mgdiclofenacsodiumsurroundedbyanoutermantle

containing200microgramsmisoprostol.

Excipients:Containslactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Modified-releasetablet.

ProductimportedfromItaly:

White,round,biconvextabletsmarked'SEARLE'over'1421'ononeside,andfourtimes'A'aroundthecircumference

with'75'inthecentreonthereverseside

White,roundbiconvextabletswithnomarkings.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Arthrotec75isindicatedforpatientswhorequirethenon-steroidalanti-inflammatorydrugdiclofenactogetherwith

misoprostol.

ThediclofenaccomponentofArthrotec75isindicatedforthesymptomatictreatmentofosteoarthritisandrheumatoid

arthritis.ThemisoprostolcomponentofArthrotec75isindicatedforpatientswithaspecialneedfortheprophylaxisof

NSAID-inducedgastricandduodenalulceration.

4.2Posologyandmethodofadministration

Adults

Onetablettobetakenwithfood,twotimesdaily.Tabletsshouldbeswallowedwhole,notchewed.

Elderly/Renal,CardiacandHepaticImpairment

Noadjustmentofdosageisnecessaryintheelderlyorinpatientswithhepaticimpairmentormildtomoderaterenal

impairmentaspharmacokineticsarenotalteredtoanyclinicallyrelevantextent.Nevertheless,elderlypatientsand

patientswithrenal,cardiacorhepaticimpairmentshouldbecloselymonitored(seesection4.4andsection4.8).

Children(under18years)

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4.3Contraindications

Arthrotec75iscontraindicatedin:

Patientswithactivepepticulcer/haemorrhageorperforationorwhohaveactiveGIbleedingorotheractive

bleedingse.g.cerebrovascularbleedings.

Pregnantwomenandinwomenplanningapregnancy.

Patientswithaknownhypersensitivitytodiclofenac,aspirin,otherNSAIDs,misoprostol,otherprostaglandins,

oranyotheringredientoftheproduct.

Patientsinwhom,attacksofasthma,urticariaoracuterhinitisareprecipitatedbyaspirinorothernon-steroidal

anti-inflammatoryagents.

Treatmentofperi-operativepaininthesettingofcoronaryarterybypassgraft(CABG)surgery.

Patientswithsevererenalandhepaticfailure.

Patientswithsevereheartfailure.

4.4Specialwarningsandprecautionsforuse

Warnings

Theuseofdiclofenac/misoprostolwithconcomitantNSAIDsincludingCOX-2inhibitorsshouldbeavoided.

Useinpre-menopausalwomen(seealsosection4.3)

Arthrotec75shouldnotbeusedinpre-menopausalwomenunlesstheyuseeffectivecontraceptionandhavebeen

advisedoftherisksoftakingtheproductifpregnant(seesection4.6).

Thelabelwillstate:‘Notforuseinpre-menopausalwomenunlessusingeffectivecontraception’.

Precautions

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.2,andGIandcardiovascularrisksbelow).

Renal/Cardiac/Hepatic

Inpatientswithrenal,cardiacorhepaticimpairmentandintheelderly,cautionisrequiredsincetheuseofNSAIDs

mayresultindeteriorationofrenalfunction.InthefollowingconditionsArthrotec75shouldbeusedonlyin

exceptionalcircumstancesandwithcloseclinicalmonitoring:advancedcardiacfailure,advancedkidneyfailure,

advancedliverdisease,severedehydration.

Diclofenacmetabolitesareeliminatedprimarilybythekidneys(seesection5.2).Theextenttowhichthemetabolites

mayaccumulateinpatientswithrenalfailurehasnotbeenstudied.AswithotherNSAIDs,metabolitesofwhichare

excretedbythekidney,patientswithsignificantlyimpairedrenalfunctionshouldbemorecloselymonitored.

Inrarecases,NSAIDs,includingdiclofenac/misoprostol,maycauseinterstitialnephritis,glomerulitis,papillary

necrosisandthenephroticsyndrome.

NSAIDsinhibitthesynthesisofrenalprostaglandinwhichplaysasupportiveroleinthemaintenanceofrenalperfusion

inpatientswhoserenalbloodflowandbloodvolumearedecreased.Inthesepatients,administrationofanNSAIDmay

precipitateovertrenaldecompensation,whichistypicallyfollowedbyrecoverytopretreatmentstateupon

discontinuationofNSAIDtherapy.Patientsatgreatestriskofsuchareactionarethosewithcongestiveheartfailure,

livercirrhosis,nephroticsyndromeandovertrenaldisease.Suchpatientsshouldbecarefullymonitoredwhilereceiving

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Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

AswithallNSAIDS,diclofenac/misoprostolcanleadtotheonsetofnewhypertensionorworseningofpre-existing

hypertension,eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.NSAIDs,including

diclofenac/misoprostol,shouldbeusedwithcautioninpatientswithhypertension.Bloodpressureshouldbemonitored

closelyduringtheinitiationoftherapywithdiclofenac/misoprostolandthroughoutthecourseoftherapy.

Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheral

arterialdisease,and/orcerebrovasculardiseaseshouldonlybetreatedwithdiclofenacaftercarefulconsideration.

Similarconsiderationshouldbemadebeforeinitiatinglonger-termtreatmentofpatientswithriskfactorsfor

cardiovascularevents(e.g.hypertension,hyperlipidaemia,diabetesmellitus,smoking).

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdose(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofseriousarterialthromboticevents(forexample

myocardialinfarctionorstroke).

Physiciansandpatientsshouldremainalertforthedevelopmentofsuchevents,evenintheabsenceofprevious

cardiovascularsymptoms.Patientsshouldbeinformedaboutthesignsand/orsymptomsofseriouscardiovascular

toxicityandthestepstotakeiftheyoccur(seesection4.3).

Bloodsystem/Gastrointestinal

NSAIDs,includingdiclofenac/misoprostol,cancauseseriousgastrointestinal(GI)adverseeventsincluding

inflammation,bleeding,ulceration,andperforationofthestomach,smallintestine,orlargeintestine,whichcanbe

fatal.WhenGIbleedingorulcerationoccursinpatientsreceivingdiclofenac/misoprostol,thetreatmentshouldbe

withdrawn.Theseeventscanoccuratanytimeduringtreatment,withorwithoutwarningsymptomsorinpatientswith

aprevioushistoryofseriousGIevents.

PatientsmostatriskofdevelopingthesetypesofGIcomplicationswithNSAIDsarethosetreatedathigherdoses,the

elderly,patientswithcardiovasculardisease,patientsusingconcomitantaspirin,orpatientswithapriorhistoryof,or

active,gastrointestinaldisease,suchasulceration,GIbleedingorinflammatoryconditions.

Therefore,diclofenac/misoprostolshouldbeusedwithcautioninthesepatientsandcommenceontreatmentatthe

lowestdoseavailable(seesection4.3).

PatientswithahistoryofGItoxicity,particularlywhenelderly,shouldreportanyunusualabdominalsymptoms

(especiallyGIbleeding)particularlyintheinitialstagesoftreatment.Cautionshouldbeadvisedinpatientsreceiving

concomitantmedicineswhichcouldincreasetheriskofulcerationorbleeding,suchasoralcorticosteroids,

anticoagulantssuchaswarfarin,selectiveserotonin-reuptakeinhibitorsoranti-plateletagentssuchasaspirin(see

section4.5).

Arthrotec75incommonwithotherNSAIDs,maydecreaseplateletaggregationandprolongbleedingtime.Extra

supervisionisrecommendedinhaematopoieticdisordersorinconditionswithdefectivecoagulationorinpatientswith

ahistoryofcerebrovascularbleeding.

CautionisrequiredinpatientssufferingfromulcerativecolitisorCrohn'sDiseaseastheseconditionsmaybe

exacerbated(seesection4.8).

Careshouldbetakeninelderlypatientsandinpatientstreatedwithcorticosteroids,otherNSAIDs,oranti-coagulants

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SkinReactions

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedveryrarelyinassociationwiththeuseofNSAIDs,including

diclofenac/misoprostol(seesection4.8).Patientsappeartobeathighestriskfortheseeventsearlyinthecourseof

therapy,theonsetoftheeventoccurringinthemajorityofcaseswithinthefirstmonthoftreatment.

Diclofenac/misoprostolshouldbediscontinuedatthefirstappearanceofskinrash,mucosallesions,oranyothersign

ofhypersensitivity

Hypersensitivity

NSAID’smayprecipitatebronchospasminpatientssufferingfrom,orwithahistoryofbronchialasthmaorallergic

disease.

Long-termtreatment

Allpatientswhoarereceivinglong-termtreatmentwithNSAIDsshouldbemonitoredasaprecautionarymeasure(e.g.

renal,hepaticfunctionandbloodcounts).Duringlong-term,highdosetreatmentwithanalgesic/anti-inflammatory

drugs,headachescanoccurwhichmustnotbetreatedwithhigherdosesofthemedicinalproduct.

Arthrotecmaymaskfeverandthusanunderlyinginfection.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NSAIDsmayattenuatethenatriureticefficacyofdiureticsduetoinhibitionofintrarenalsynthesisofprostaglandins.

Concomitanttreatmentwithpotassium-sparingdiureticsmaybeassociatedwithincreasedserumpotassiumlevels;

henceserumpotassiumshouldbemonitored.

Becauseoftheireffectonrenalprostaglandins,cyclo-oxygenaseinhibitorssuchasdiclofenaccanincreasethe

nephrotoxicityofciclosporin.ThereisapossibleincreasedriskofnephrotoxicitywhenNSAIDsaregivenwith

tacrolimus.

Steadystateplasmalithiumanddigoxinlevelsmaybeincreasedandketoconazolelevelsmaybedecreased.

Pharmacodynamicstudieswithdiclofenachaveshownnopotentiationoforalhypoglycaemicandanticoagulantdrugs.

HoweverasinteractionshavebeenreportedwithotherNSAIDs,cautionandadequatemonitoringare,nevertheless

advised(seestatementonplateletaggregationinPrecautions).

BecauseofdecreasedplateletaggregationcautionisadvisedwhenusingArthrotec75withanti-coagulants.NSAIDs

mayenhancetheeffectsofanti-coagulants,suchaswarfarin,aniplateletagents,suchasaspirin,andserotoninre-uptake

inhibitors(SSRIs)therebyincreasingtheriskofgastrointestinalbleeding(seesection4.4).

Casesofhypoandhyperglycaemiahavebeenreportedwhendiclofenacwasassociatedwithantidiabeticagents.

CautionisadvisedwhenmethotrexateisadministeredconcurrentlywithNSAIDsbecauseofpossibleenhancementof

itstoxicitybytheNSAIDasaresultofincreaseinmethotrexateplasmalevels.

ConcomitantusewithotherNSAIDsorwithcorticosteroidsmayincreasethefrequencyofgastrointestinalulceration

orbleedingandofsideeffectsgenerally.

Anti-hypertensivesincludingdiuretics,angiotensin-convertingenzyme(ACE)inhibitorsandangiotensinIIantagonists

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Inpatientswithimpairedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenalfunction),

theco-administrationofanACEinhibitororanAIIAwithacyclo-oxygenaseinhibitorcanincreasethedeteriorationof

therenalfunction,includingthepossibilityofacuterenalfailure,whichisusuallyreversible.Theoccurrenceofthese

interactionsshouldbeconsideredinpatientstakingdiclofenac/misoprostolwithanACEinhibitororanAIIA.

Antacidsmaydelaytheabsorptionofdiclofenac.Magnesium-containingantacidshavebeenshowntoexacerbate

misoprostol-associateddiarrhoea.

AnimaldataindicatethatNSAIDscanincreasetheriskofconvulsionsassociatedwithquinoloneantibiotics.Patients

takingNSAIDsandquinolonesmayhaveanincreasedriskofdevelopingconvulsions.

NSAIDsshouldnotbeusedfor8-12daysaftermifepristoneadministrationasNSAIDscanreducetheeffectof

mifepristone

4.6Fertility,pregnancyandlactation

Pregnancy

Arthrotec75iscontraindicatedinpregnantwomenandinwomenplanningapregnancybecausemisoprostolinduces

uterinecontractionsandisassociatedwithabortion,prematurebirth,andfetaldeath.Useofmisoprostolhasbeen

associatedwithbirthdefects.Alsodiclofenacmaycauseprematureclosureoftheductusarteriosus.

Womenofchildbearingpotentialshouldnotbestartedondiclofenac/misoprostoluntilpregnancyisexcluded,and

shouldbefullycounseledontheimportanceofadequatecontraceptionwhileundergoingtreatment.Ifpregnancyis

suspected,useoftheproductshouldbediscontinued.

Lactation:

Misoprostolisrapidlymetabolisedinthemothertomisoprostolacid,whichisbiologicallyactiveandisexcretedin

breastmilk.Diclofenacisexcretedinbreastmilkinverysmallquantities.Ingeneral,thepotentialeffectsontheinfant

fromanyexposuretomisoprostolanditsmetabolitesviabreastfeedingareunknown.However,diarrhoeaisa

recognisedsideeffectofmisoprostolandcouldoccurininfantsofnursingmothers.Arthrotec75shouldthereforenot

beadministeredtonursingmothers.

4.7Effectsonabilitytodriveandusemachines

PatientswhoexperiencedizzinessorothercentralnervoussystemdisturbanceswhiletakingNSAIDsshouldrefrain

fromdrivingoroperatingmachinery.

4.8Undesirableeffects

InthetablebelowtheincidenceofadversedrugreactionsreportedincontrolledclinicalstudieswhereArthrotecwas

administeredtomorethan2000patientsarelisted.Additionally,adversedrugreactionsreportedduringpost-marketing

surviellancearewhosefrequencycannotbeestimatedfromtheavailalbedata,suchasspontaneousreports,havebeen

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OrganSystem Very

Common

(1/10) Common

(1/100

and<1/10) Uncommon

(1/1,000

and<1/100) Rare

(1/10,000,

and<1/1,000) Frequency:Unknown

(Post-marketing

experience)

Infectionsand

infestations Asepticmeningitis 1

Bloodand

lymphaticsystem

disorders Thrombo-

cytopenia Aplasticanaemia,

agranulocytosis,haemolytic

anaemia,leucopenia

Immunesystem

disorders Anaphylactic

reaction Hypersensitivity

Metabolismand

nutritiondisorders Anorexia

Psychiatric

disorders Insomnia Psychoticreaction,

disorientation,depression,

anxiety,nightmares,mood

change,irritability

Nervoussystem

disorders Headache,

dizziness Convulsions,memory

disturbance,drowsiness,

tremor,tastedisturbance,

paraesthesia

Eyesdisorders Visualdisturbances,blurred

vision

Earandlabyrinth

disorders Tinnitus

Cardiacdisorders Cardiacfailure,palpitations

Vasculardisorders Shock,hypertension,

hypotension,vasculitis

Respiratory,

thoracicand

mediastinal

disorders Asthma,pneumonitis,

dyspnoea

Gastrointestinal

disorders Abdominal

pain,

diarrhoea 2

nausea,

dyspepsia Gastritis,

vomiting,

flatulence,

eructation,

constipation,

pepticulcer Stomatitis

GIperforation 3

gastrointestinalbleeding 3

melaena,haematemesis,

colitis,Crohn'sdisease,

oesophagealdisorder,mouth

ulceration,glossitis,tongue

odema,drymouth

Hepato-biliary

disorders Alanine

amino-

transferase

increased Hepatitis,

jaundice Hepatitisfulminant,

aspartateaminotransferase

increased,bloodbilirubin

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Symptomsofasepticmeningitis(stiffneck,headache,nausea,vomiting,feverorimpairedconsciousness)have

beenreportedduringtreatmentwithNSAIDs.Patientssufferingfromautoimmunedisease(e.g.lupus

erythematosus,mixedconnectivetissuedisorders)seemtobemoresusceptible.

DiarrhoeaisusuallymildtomoderateandtransientandcanbeminimisedbytakingArthrotec75withfoodandby

avoidingtheuseofpredominantlymagnesium-containingantacids.

Skinand

subcutaneous

tissuedisorders Erythema

multiforme,

rash,pruritus Purpura,

urticaria Angioedema

Toxicepidermalnecrolysis 4

Stevens-Johnson

syndrome 4

,dermatitis

exfoliative 4

,dermatitis

bullous,HenochSchonlein

purpura,mucocutaneous

rash,rashvesicular,

photosensitivityreaction,

alopecia,urticaria

Renalandurinary

disorders Renalfailure,acuterenal

failure,renalpapillary

necrosis,nephritis

interstitial,nephrotic

syndrome,proteinuria,

haematuria

Pregnancy,

puerperiumand

perinatal

conditions Intra-uterinedeath,uterine

rupture,

incompleteabortion,

prematurebaby,

anaphylactoidsyndromeof

pregnancy,retainedplacenta

ormembranes,uterine

contractionsabnormal

Reproductive

systemandbreast

disorders Menorrhagia,

metrorrhagia,

vaginal

haemorrhage,

postmenopausal

haemorrhage Uterinehaemorrhage

Congenital,

familialand

geneticdisorders Birthdefects

Generaldisorders

andadministration

siteconditions Oedema 5

,chestpain,face

oedema,fatigue,pyrexia,

chills,inflammation

Investigations Blood

alkaline

phosphatase

increased Decreasedhaemoglobin

Injury,poisoning

andprocedural

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Seriousskinreactions,someofthemfatal,havebeenreportedveryrarely(seesection4.4).

Especiallyinpatientswithhypertensionorimpairedrenalfunction(seesection4.4).

Giventhelackofpreciseand/orreliabledenominatorandnumeratorfigures,thespontaneousadverseeventreporting

systemthroughwhichpostmarketingsafetydataarecollecteddoesnotallowforamedicallymeaningfulfrequencyof

occurrenceofanyundesirableeffects.

Withregardtotherelativefrequencyofreportingofadversereactionsduringpostmarketingsurveillance,the

undesirableeffectsatthegastrointestinallevelwerethosereceivedmostfrequentlybytheMAH(approximately45%

ofallcasereportsinthecompanysafetydatabase)followedbycutaneous/hypersensitivity-typereactions,whichisin

agreementwiththeknownsideeffectsprofileoftheNSAIDsdrugclass.

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdoses(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexample

myocardialinfarctionorstroke)(seesection4.4).

4.9Overdose

ThetoxicdoseofArthrotec75hasnotbeendeterminedandthereisnoexperienceofoverdosage.Intensificationofthe

pharmacologicaleffectsmayoccurwithoverdosage.

ManagementofacutepoisoningwithNSAIDsessentiallyconsistsofsupportiveandsymptomaticmeasures.Itis

reasonabletotakemeasurestoreduceabsorptionofanyrecentlyconsumeddrugbyforcedemesis,gastriclavageor

activatedcharcoal.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup(ATCcode):M01BX

Arthrotec75isanon-steroidal,anti-inflammatorydrug,whichiseffectiveintreatingthesignsandsymptomsof

arthriticconditions.

Thisactivityisduetothepresenceofdiclofenac,whichhasbeenshowntohaveanti-inflammatoryandanalgesic

properties.

Arthrotec75alsocontainsthegastroduodenalmucosalprotectivecomponentmisoprostol,whichisasynthetic

prostaglandinE1analoguethatenhancesseveralofthefactorsthatmaintaingastroduodenalmucosalintegrity.

Arthrotec75administeredbdprovides200microgramslessmisoprostolthanArthrotectds,whilstprovidingthesame

dailydose(150mg)ofdiclofenacandmayofferabettertherapeuticratioforcertainpatients.

5.2Pharmacokineticproperties

Thepharmacokineticprofilesfollowingoraladministrationofasingledoseormultipledosesofdiclofenacsodiumand

misoprostoladministeredasArthrotec75aresimilartotheprofileswhenthetwodrugsareadministeredasseparate

tablets.Therearenopharmacokineticinteractionsbetweenthetwocomponents,apartfromaslightdecreasein

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Diclofenacsodiumiscompletelyabsorbedfromthegastrointestinal(GI)tractafterfastingoraladministration.Only50

%oftheabsorbeddoseissystemicallyavailableduetofirstpassmetabolism.Peakplasmalevelsareachievedin2

hours(range1-4hours)whengivenasasingledoseunderfastingconditions.UnderfedconditionsdiclofenacTmaxis

increasedto4hours.Thearea-under-theplasma-concentrationcurve(AUC)isdoseproportionalwithintherangeof25

mgto150mg.ThesteadystateabsorptionofdiclofenacisreducedfollowingtheadministrationofArthrotec75tablets

withfood,CmaxandAUCarereducedbyapproximately40%and20%,respectively.

Theterminalhalf-lifeisapproximately2hours.Clearanceandvolumeofdistributionareabout350ml/minand550

ml/kg,respectively.Morethan99%ofdiclofenacsodiumisreversiblyboundtohumanplasmaalbumin,andthishas

beenshownnottobeagedependent.

Diclofenacsodiumiseliminatedthroughmetabolismandsubsequenturinaryandbiliaryexcretionoftheglucuronide

andthesulfateconjugatesofthemetabolites.Approximately65%ofthedoseisexcretedintheurineand35%inthe

bile.Lessthan1%oftheparentdrugisexcretedunchanged.

Misoprostolisrapidlyandextensivelyabsorbed,anditundergoesrapidmetabolismtoitsactivemetabolite,

misoprostolacid,whichiseliminatedwithaneliminationt

ofabout30minutes.Noaccumulationofmisoprostolacid

wasfoundinmultiple-dosestudies,andplasmasteadystatewasachievedwithin2days.Theserumproteinbindingof

misoprostolacidislessthan90%.Approximately70%oftheadministereddoseisexcretedintheurine,mainlyas

biologicallyinactivemetabolites.

SingleandmultipledosestudieshavebeenconductedcomparingthepharmacokineticsofArthrotec75withthe

diclofenac75mgandmisoprostol200microgramscomponentsadministeredseparately.Bioequivalencebetweenthe

twomethodsofprovidingdiclofenacweredemonstrableforAUCandabsorptionrate(Cmax/AUC).Inthesteadystate

comparisonsunderfastedconditionsbioequivalencewasdemonstrableintermsofAUC.

FoodreducedtherateandextentofabsorptionofdiclofenacforbothArthrotec75andco-administereddiclofenac.

DespitethevirtuallyidenticalmeanAUCsinthefed,steadystate,statisticalbioequivalencewasnotestablished.This

howeverisduetothebroadco-efficientsofvariationinthesestudiesduetothewideinter-individualvariabilityintime

toabsorptionandtheextensivefirst-passmetabolismthatoccurswithdiclofenac.

BioequivalenceintermsofAUC(0-24h)wasdemonstrablewhencomparingsteadystatepharmacokineticsof

Arthrotec75givenbdwithdiclofenac50mg/misoprostol200microgramsgiventds,bothregimensprovidingatotal

dailydoseof150mgdiclofenac.

Withrespecttoadministrationofmisoprostol,bioequivalencewasdemonstratedafterasingledoseofArthrotec75or

misoprostoladministeredalone.UndersteadystateconditionsfooddecreasesthemisoprostolCmaxafterArthrotec75

administrationandslightlydelaysabsorption,buttheAUCisequivalent.

5.3Preclinicalsafetydata

Inco-administrationstudiesinanimals,theadditionofmisoprostoldidnotenhancethetoxiceffectsofdiclofenac.The

combinationwasalsoshownnottobeteratogenicormutagenic.Theindividualcomponentsshownoevidenceof

carcinogenicpotential.

Misoprostolinmultiplesoftherecommendedtherapeuticdoseinanimalshasproducedgastricmucosalhyperplasia.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Arthrotec75tabletscontain:

LactoseMonohydrate

MicrocrystallineCellulose

MaizeStarch

PovidoneK-30

MagnesiumStearate

MethylacrylicAcid

SodiumHydroxide

Talc

Triethylcitrate

Hypromellose

Crospovidone

HydrogenatedCastorOil

ColloidalSiliconDioxide

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Cardboardcartoncontainingthreeblisters(10tabletsperblister).

Packsize:30tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd.

Unit625,KilshaneAvenue

NorthwestBusinessPark

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/074/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18 th

February2011

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