ARTHROTEC

Main information

  • Trade name:
  • ARTHROTEC Modified-release Tablets 50/0.2 Milligram
  • Dosage:
  • 50/0.2 Milligram
  • Pharmaceutical form:
  • Modified-release Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARTHROTEC Modified-release Tablets 50/0.2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/163/001
  • Authorization date:
  • 17-02-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arthrotec50modified-releasetablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletconsistsofagastro-resistantcorecontaining50milligramsdiclofenacsodiumsurroundedbyanouter

mantlecontaining200microgramsmisoprostol.

Excipient(s):

Eachtabletcontains13.0mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Modified-releaseTablets

ProductimportedfromtheUK:

White,round,biconvextabletsmarked'1141’and‘Searle'ononesidewithfour‘A’sonthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Arthrotec50isindicatedforpatientswhorequirethenon-steroidalanti-inflammatorydrugdiclofenactogetherwith

misoprostol.

ThediclofenaccomponentofArthrotec50isindicatedforthesymptomatictreatmentofosteoarthritisandrheumatoid

arthritis.ThemisoprostolcomponentofArthrotec50isindicatedforpatientswithaspecialneedfortheprophylaxisof

NSAID-inducedgastricandduodenalulceration.

4.2Posologyandmethodofadministration

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.4).

Adults

Onetablettobetakenwithfood,twoorthreetimesdaily.Tabletsshouldbeswallowedwhole,notchewed.

Elderly/Renal,CardiacandHepaticImpairment

Noadjustmentofdosageisnecessaryintheelderlyorinpatientswithhepaticimpairmentormildtomoderaterenal

impairmentaspharmacokineticsarenotalteredtoanyclinicallyrelevantextent.Nevertheless,elderlypatientsand

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

Children(under18years)

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4.3Contraindications

Arthrotec50iscontraindicatedin:

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)

Arthrotec50shouldnotbeusedinpre-menopausalwomenunlesstheyuseeffectivecontraceptionandhavebeenadvised

oftherisksoftakingtheproductifpregnant(seesection4.6).Thelabelwillstate:‘Notforuseinpre-menopausalwomen

unlessusingeffectivecontraception’.

Precautions

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.2,andGIandcardiovascularrisksbelow).

Renal/Cardiac/Hepatic

Inpatientswithrenal,cardiacorhepaticimpairmentandintheelderly,cautionisrequiredsincetheuseofNSAIDsmay

resultindeteriorationofrenalfunction.InthefollowingconditionsArthrotec50shouldbeusedonlyinexceptional

circumstancesandwithcloseclinicalmonitoring:advancedcardiacfailure,advancedkidneyfailure,advancedliver

disease,severedehydration.

Diclofenacmetabolitesareeliminatedprimarilybythekidneys(seesection5.2).Theextenttowhichthemetabolites

mayaccumulateinpatientswithrenalfailurehasnotbeenstudied.AswithotherNSAIDs,metabolitesofwhichare

excretedbythekidney,patientswithsignificantlyimpairedrenalfunctionshouldbemorecloselymonitored

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

necrosisandthenephroticsyndrome.NSAIDsinhibitthesynthesisofrenalprostaglandinwhichplaysasupportiverole

inthemaintenanceofrenalperfusioninpatientswhoserenalbloodflowandbloodvolumearedecreased.Inthese

patients,administrationofanNSAIDmayprecipitateovertrenaldecompensation,whichistypicallyfollowedby

recoverytopretreatmentstateupondiscontinuationofNSAIDtherapy.Patientsatgreatestriskofsuchareactionare

thosewithcongestiveheartfailure,livercirrhosis,nephroticsyndromeandovertrenaldisease.Suchpatientsshouldbe

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Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

AswithallNSAIDS,diclofenac/misoprostolcanleadtotheonsetofnewhypertensionorworseningofpre-existing

hypertension,eitherofwhichmaycontributetotheincreasedincidenceofcardiovascularevents.NSAIDs,including

diclofenac/misoprostol,shouldbeusedwithcautioninpatientswithhypertension.Bloodpressureshouldbemonitored

closelyduringtheinitiationoftherapywithdiclofenac/misoprostolandthroughoutthecourseoftherapy.

Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheralarterial

disease,and/orcerebrovasculardiseaseshouldonlybetreatedwithdiclofenacaftercarefulconsideration.Similar

considerationshouldbemadebeforeinitiatinglonger-termtreatmentofpatientswithriskfactorsforcardiovascularevents

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

Clinicaltrialandepidemiologicaldatasuggestthatuseofdiclofenac,particularlyathighdose(150mgdaily)andinlong

termtreatmentmaybeassociatedwithasmallincreasedriskofseriousarterialthromboticevents(forexamplemyocardial

infarctionorstroke).

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,withorwithoutwarningsymptomsorinpatientswitha

previoushistoryofseriousGIevents.

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).

Arthrotec50incommonwithotherNSAIDs,maydecreaseplateletaggregationandprolongbleedingtime.Extra

supervisionisrecommendedinhaematopoieticdisordersorinconditionswithdefectivecoagulationorinpatientswitha

historyofcerebrovascularbleeding.

CautionisrequiredinpatientssufferingfromulcerativecolitisorCrohn'sDiseaseastheseconditionsmaybeexacerbated

(seesection4.8).

Careshouldbetakeninelderlypatientsandinpatientstreatedwithcorticosteroids,otherNSAIDs,oranti-coagulants(see

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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

NSAIDsmayprecipitatebronchospasminpatientssufferingfrom,orwithahistoryofbronchialasthmaorallergic

disease.

Long-termtreatment

Allpatientswhoarereceivinglong-termtreatmentwithNSAIDsshouldbemonitoredasaprecautionarymeasure(e.g.

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

headachescanoccurwhichmustnotbetreatedwithhigherdosesofthemedicinalproduct.

Arthrotecmaymaskfeverandthusanunderlyinginfection.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NSAIDsmayattenuatethenatriureticefficacyofdiureticsduetoinhibitionofintrarenalsynthesisofprostaglandins.

Concomitanttreatmentwithpotassium-sparingdiureticsmaybeassociatedwithincreasedserumpotassiumlevels;hence

serumpotassiumshouldbemonitored.

Becauseoftheireffectonrenalprostaglandins,cyclo-oxygenaseinhibitorssuchasdiclofenaccanincreasethe

nephrotoxicityofciclosporin.ThereisapossibleincreasedriskofnephrotoxicitywhenNSAIDsaregivenwith

tacrolimus.

Steadystateplasmalithiumanddigoxinlevelsmaybeincreasedandketoconazolelevelsmaybedecreased.

Pharmacodynamicstudieswithdiclofenachaveshownnopotentiationoforalhypoglycaemicandanticoagulantdrugs.

HoweverasinteractionshavebeenreportedwithotherNSAIDs,cautionandadequatemonitoringare,neverthelessadvised

(seestatementonplateletaggregationinPrecautions).

BecauseofdecreasedplateletaggregationcautionisadvisedwhenusingArthrotec50withanti-coagulants.NSAIDsmay

enhancetheeffectsofanti-coagulants,suchaswarfarin,antiplateletagents,suchasaspirin,andserotoninre-uptake

inhibitors(SSRIs)therebyincreasingtheriskofgastrointestinalbleeding(seesection4.4).

Casesofhypoandhyperglycaemiahavebeenreportedwhendiclofenacwasassociatedwithantidiabeticagents.

CautionisadvisedwhenmethotrexateisadministeredconcurrentlywithNSAIDsbecauseofpossibleenhancementofits

toxicitybytheNSAIDasaresultofincreaseinmethotrexateplasmalevels.

ConcomitantusewithotherNSAIDsorwithcorticosteroidsmayincreasethefrequencyofgastrointestinalulcerationor

bleedingandofsideeffectsgenerally.

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

Arthrotec50iscontraindicatedinpregnantwomenandinwomenplanningapregnancybecausemisoprostolinduces

uterinecontractionsandisassociatedwithabortion,prematurebirth,andfetaldeath.Useofmisoprostolhasbeen

associatedwithbirthdefects.Alsodiclofenacmaycauseprematureclosureoftheductusarteriosus.

Womenofchildbearingpotentialshouldnotbestartedondiclofenac/misoprostoluntilpregnancyisexcluded,and

shouldbefullycounseledontheimportanceofadequatecontraceptionwhileundergoingtreatment.Ifpregnancyis

suspected,useoftheproductshouldbediscontinued.

Lactation

Misoprostolisrapidlymetabolisedinthemothertomisoprostolacid,whichisbiologicallyactiveandisexcretedin

breastmilk.Diclofenacisexcretedinbreastmilkinverysmallquantities.Ingeneral,thepotentialeffectsontheinfant

fromanyexposuretomisoprostolanditsmetabolitesviabreastfeedingareunknown.However,diarrhoeaisa

recognisedsideeffectofmisoprostolandcouldoccurininfantsofnursingmothers.Arthrotec50shouldthereforenot

beadministeredtonursingmothers.

4.7Effectsonabilitytodriveandusemachines

PatientswhoexperiencedizzinessorothercentralnervoussystemdisturbanceswhiletakingNSAIDsshouldrefrain

fromdrivingoroperatingmachinery.

4.8Undesirableeffects

InthetablebelowtheincidenceofadversedrugreactionsreportedincontrolledclinicalstudieswhereArthrotecwas

administeredtomorethan2000patientsarelisted.Additionally,adversedrugreactionsreportedduringpost-marketing

surveillancearewhosefrequencycannotbeestimatedfromtheavailabledata,suchasspontaneousreports,havebeen

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OrganSystem

Infectionsand

infestations Aseptic

meningitis 1

Bloodand

lymphatic

system

disorders Thrombocytopenia Aplastic

anaemia,

agranulocytosis,

haemolytic

anaemia,

leucopenia

Immunesystem

disorders Anaphylactic

reaction Hypersensitivity

Metabolismand

nutrition

disorders Anorexia

Psychiatric

disorders Insomnia Psychotic

reaction,

disorientation,

depression,

anxiety,

nightmares,

moodchange,

irritability

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, Stomatitis GIperforation 3

gastrointestinal

bleeding 3

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pepticulcer haematemesis,

colitis,Crohn's

disease,

oesophageal

disorder,mouth

ulceration,

glossitis,tongue

odema,dry

mouth

Hepato-biliary

disorders Alanineamino-

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

purpura,

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

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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

retained

placentaor

membranes,

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 Bloodalkaline

phosphatase

increased Decreased

haemoglobin

Injury,

poisoningand

procedural

complications Uterine

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4.9Overdose

ThetoxicdoseofArthrotec50hasnotbeendeterminedandthereisnoexperienceofoverdosage.Intensificationofthe

pharmacologicaleffectsmayoccurwithoverdosage.ManagementofacutepoisoningwithNSAIDsessentially

consistsofsupportiveandsymptomaticmeasures.

Itisreasonabletotakemeasurestoreduceabsorptionofanyrecentlyconsumeddrugbyforcedemesis,gastriclavage

oractivatedcharcoal.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Arthrotec50isanon-steroidal,anti-inflammatorydrug,whichiseffectiveintreatingthesignsandsymptomsof

arthriticconditions.

Thisactivityisduetothepresenceofdiclofenac,whichhasbeenshowntohaveanti-inflammatoryandanalgesic

properties.

Arthrotec50alsocontainsthegastroduodenalmucosalprotectivecomponentmisoprostol,whichisasynthetic

prostaglandinE1analoguethatenhancesseveralofthefactorsthatmaintaingastroduodenalmucosalintegrity.

5.2Pharmacokineticproperties

ThepharmacokineticprofilesofdiclofenacandmisoprostoladministeredasArthrotec50aresimilartotheprofiles

whenthetwodrugsareadministeredasseparatetabletsandtherearenopharmacokineticinteractionsbetweenthetwo

components.

5.3Preclinicalsafetydata

Inco-administrationstudiesinanimals,theadditionofmisoprostoldidnotenhancethetoxiceffectsofdiclofenac.The

combinationwasalsoshownnottobeteratogenicormutagenic.Theindividualcomponentsshownoevidenceof

carcinogenicpotential.

Misoprostolinmultiplesoftherecommendedtherapeuticdoseinanimalshasproducedgastricmucosalhyperplasia.

ThischaracteristicresponsetoE-seriesprostaglandinsrevertstonormalondiscontinuationofthecompound.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Microcrystallinecellulose

Maizestarch

Povidone

Celluloseacetatephthalate

Diethylphthalate

Hypromellose

Crospovidone

Magnesiumstearate

Hydrogenatedcastoroil

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Aluminiumblistersinpacksizesof60tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare,

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/163/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17 th

February2012

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