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:
  • PPA1562/035/002
  • Authorization date:
  • 15-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arthrotec75modified-releasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletconsistsofagastro-resistantcorecontaining75mgdiclofenacsodiumsurroundedbyanoutermantle

containing200micrograms(0.2mg)misoprostol.

Excipient(s):

Eachtabletcontains19.5mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Modified-releasetablet.

ProductimportedfromtheUK

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

with'75'inthecentreonthereverseside.

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)

ThesafetyandefficacyofArthrotec75inchildrenhasnotbeenestablished.

4.3Contraindications

Arthrotec75iscontraindicatedin:

Patientswithactivepepticulcer/haemorrhageorperforationorwhohaveactiveGIbleedingorotheractive

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Pregnantwomenandinwomenplanningapregnancy.

Patientswithaknownhypersensitivitytodiclofenac,aspirin,otherNSAIDs,misoprostol,otherprostaglandins,

oranyotheringredientoftheproduct.

Patientsinwhom,attacksofasthma,urticariaoracuterhinitisareprecipitatedbyaspirin orothernon-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

NSAIDtherapy.

Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

AswithallNSAIDS,diclofenac/misoprostolcanleadtotheonsetofnewhypertensionorworseningofpre-existing

hypertension,eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.NSAIDs,including

diclofenac/misoprostol,shouldbeusedwithcautioninpatientswithhypertension.Bloodpressureshouldbemonitored

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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/misoprostolshouldbeusedwithcautioninthesepatientsandcommenceontreatmentatthelowestdose

available(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

(seesection4.5).

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

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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

(AIIA):NSAIDscanreducetheefficacyofdiureticsandotherantihypertensivedrugs.

Inpatientswithimpairedrenalfunction(e.g.dehydratedpatientsorelderlypatientswithcompromisedrenalfunction),

theco-administrationofanACEinhibitororanAIIAwithacyclo-oxygenaseinhibitorcanincreasethedeteriorationof

therenalfunction,includingthepossibilityofacuterenalfailure,whichisusuallyreversible.Theoccurrenceofthese

interactionsshouldbeconsideredinpatientstakingdiclofenac/misoprostolwithanACEinhibitororanAIIA.

Antacidsmaydelaytheabsorptionofdiclofenac.Magnesium-containingantacidshavebeenshowntoexacerbate

misoprostol-associateddiarrhoea.

AnimaldataindicatethatNSAIDscanincreasetheriskofconvulsionsassociatedwithquinoloneantibiotics.Patients

takingNSAIDsandquinolonesmayhaveanincreasedriskofdevelopingconvulsions.

NSAIDsshouldnotbeusedfor8-12daysaftermifepristoneadministrationasNSAIDscanreducetheeffectof

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4.6Pregnancyandlactation

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-

marketingsurviellancearewhosefrequencycannotbeestimatedfromtheavailabledata,suchasspontaneousreports,

havebeenlistedatfrequency‘unknown’.Themostcommonlyobservedadverseeventsaregastrointestinalinnature.

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 Aseptic

meningitis 1

Bloodand

lymphatic

system

disorders Thrombo-

cytopenia Aplasticanaemia,

agranulocytosis,

haemolytic

anaemia,

leucopenia

Immunesystem

disorders Anaphylactic

reaction Hypersensitivity

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Insomnia Psychotic

reaction,

disorientation,

depression,

anxiety,

nightmares,

moodchange,

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Nervoussystem

disorders Headache,

dizziness Convulsions,

memory

disturbance,

drowsiness,

tremor,taste

disturbance,

paraesthesia

Eyesdisorders Visual

disturbances,

blurredvision

Earand

labyrinth

disorders Tinnitus

Cardiac

disorders Cardiacfailure,

palpitations

Vascular

disorders 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

gastrointestinal

bleeding 3

melaena,

haematemesis,

colitis,Crohn's

disease,

oesophageal

disorder,mouth

ulceration,

glossitis,tongue

odema,dry

mouth

Hepato-biliary

disorders Alanine

amino-

transferase

increased Hepatitis,

jaundice Hepatitis

fulminant,

aspartate

aminotransferase

increased,blood

bilirubin

increased

Skinand

subcutaneous

tissuedisorders Erythema

multiforme,

rash,pruritus Purpura,

urticaria Angioedema Toxicepidermal

necrolysis 4

Stevens-Johnson

syndrome 4

dermatitis

exfoliative 4

dermatitis

bullous,Henoch

Schonlein

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mucocutaneous

rash,rash

vesicular,

photosensitivity

reaction,

alopecia,urticaria

Renaland

urinary

disorders Renalfailure,

acuterenal

failure,renal

papillary

necrosis,

nephritis

interstitial,

nephrotic

syndrome,

proteinuria,

haematuria

Pregnancy,

puerperiumand

perinatal

conditions Intra-uterine

death,uterine

rupture,

incomplete

abortion,

prematurebaby,

anaphylactoid

syndromeof

pregnancy,

retainedplacenta

ormembranes,

uterine

contractions

abnormal

Reproductive

systemand

breastdisorders Menorrhagia,

metrorrhagia,

vaginal

haemorrhage,

postmenopausal

haemorrhage Uterine

haemorrhage

Congenital,

familialand

genetic

disorders Birthdefects

General

disordersand

administration

siteconditions Oedema 5

,chest

pain,face

oedema,fatigue,

pyrexia,chills,

inflammation

Investigations Blood

alkaline

phosphatase

increased Decreased

haemoglobin

Injury,

poisoningand

procedural

complications Uterine

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

reportedduringtreatmentwithNSAIDs.Patientssufferingfromautoimmunedisease(e.g.lupuserythematosus,mixed

connectivetissuedisorders)seemtobemoresusceptible.

DiarrhoeaisusuallymildtomoderateandtransientandcanbeminimisedbytakingArthrotec50withfoodandby

avoidingtheuseofpredominantlymagnesium-containingantacids.

GIperforationorbleedingcansometimesbefatal,particularlyintheelderly(seesection4.4).

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

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5.2Pharmacokineticproperties

Thepharmacokineticprofilesfollowingoraladministrationofasingledoseormultipledosesofdiclofenacsodiumand

misoprostoladministeredasArthrotec75aresimilartotheprofileswhenthetwodrugsareadministeredasseparate

tablets.Therearenopharmacokineticinteractionsbetweenthetwocomponents,apartfromaslightdecreasein

diclofenacsodiumCmaxwhenadministeredconcomitantlywithmisoprostol.

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.Approximately

65%ofthedoseisexcretedintheurineand35%inthebile.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

Lactosemonohydrate

Microcrystallinecellulose

Maizestarch

Povidonek-30

Magnesiumstearate

Methylacrylicacid

Sodiumhydroxide

Talc

Triethylcitrate

Hypromellose

Crospovidone

Colloidalsilicondioxide

Hydrogenatedcastoroil

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownontheblisterandouterpackageoftheproductonthemarket

inthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Arthrotec75ispresentedincoldformedaluminiumblistersinpacksizesof60tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLtd

Unit18OxleasowRoad

EastMoonsMoat

Redditch

Worcestershire,B980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15thofOctober2010

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