DIFENE

Main information

  • Trade name:
  • DIFENE Capsules Modified Release 75 Milligram
  • Dosage:
  • 75 Milligram
  • Pharmaceutical form:
  • Capsules Modified Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIFENE Capsules Modified Release 75 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/185/001
  • Authorization date:
  • 13-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Difene75mgDualReleaseCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains75mgdiclofenacsodiuminamodifiedreleaseformulation(25mggastro-resistantpelletsand

50mgprolongedreleasepellets).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Modifiedreleasecapsule,hard.

ProductimportedfromtheUK:

Size2,hardgelatincapsuleswithlightblueopaquecapsandcolourlesstransparentbodies,printedwith"D75M"in

white,containingwhitetocream-colouredsphericalpellets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asanon-steroidalanti-inflammatoryanalgesicinthesymptomaticmanagementofrheumatoidarthritis,osteoarthritis

andankylosingspondylitis,acutemusculo-skeletaldisorderssuchasperiarthritis,tendinitis,tenosynovitis,bursitis,

sprains,strainsanddislocations,reliefofpaininfractures,lowbackpain,acutegout,psoriaticarthropathy.Inthe

managementofpainandinflammationassociatedwithorthopaedic,dentalandminorsurgery.

Inthemanagementofdysmenorrhoeaandassociatedmenorrhagia.

4.2Posologyandmethodofadministration

Undesirableeffectsmaybeminimisedbyusingthelowesteffectivedosefortheshortestdurationnecessarytocontrol

symptoms(seesection4.4).

Fororaluseonly.Thecapsulesshouldbeswallowedwholewithliquid.

Adults:Oneortwocapsules(75-150mg)individeddoses,daily.Thedailydoseshouldnotexceed150mg.

Elderly:NSAIDsshouldbeusedwithparticularcautioninelderlypatientswhoaremorepronetoadverseevents.The

lowestdosecompatiblewithadequatesafeclinicalcontrolshouldbeemployed.Seealsosection4.4.

Children:Notrecommended.

Treatmentshouldbereviewedatregularintervalsanddiscontinuedifnobenefitisseenorintoleranceoccurs.

4.3Contraindications

Historyofgastrointestinalbleedingorperforation,relatedtopreviousNSAIDstherapy.Active,orhistoryofrecurrent

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Severeheartfailure.

Patientswithahistoryofhypersensitivityreactions(e.g.bronchospasm,rhinitis,urticaria)inresponsetodiclofenac,

aspirin,nonsteroidalanti-inflammatorydrugsoranycomponentsofthepreparation.

4.4Specialwarningsandprecautionsforuse

TheuseofDifenemayimpairfemalefertilityandisnotrecommendedinwomenattemptingtoconceive.Inwomen

whohavedifficultiesconceivingorwhoareundergoinginvestigationofinfertility,withdrawalofDifeneshouldbe

considered.

TheuseofDifenewithconcomitantNSAIDsincludingcyclooxygenase-2selectiveinhibitorsshouldbeavoided.

Gastrointestinalbleeding,ulcerationandbleeding:GIbleeding,ulcerationorperforation,whichcanbefatal,hasbeen

reportedwithallNSAIDsatanytimeduringtreatment,withorwithoutwarningsymptomsoraprevioushistoryof

seriousGIevents.

TheriskofGIbleeding,ulcerationorperforationishigherwithincreasingNSAIDdoses,inpatientswithahistoryof

ulcer,particularlyifcomplicatedwithhaemorrhageorperforation(seesection4.3),andintheelderly.Thesepatients

shouldcommencetreatmentonthelowesedoseavailable.Combinationtherapywithprotectiveagents(e.g.

misoprostolorprotonpumpinhibitors)shouldbeconsideredforthesepatients,andalsoforpatientsrequiring

concomitantlowdoseaspirin,orotherdrugslikelytoincreasegastrointestinalrisk(seebelowand4.5)

PatientswithahistoryofGItoxicity,particularlywhenelderly,shouldreportanyunusualabdominalsymptoms

(especiallyGIbleeding)particularlyintheinitialstagesoftreatment.

Cautionshouldbeadvisedinpatientsreceivingconcomitantmedicationswhichcouldincreasetheriskofulcerationor

bleeding,suchasoralcorticosteroids,anticoagulantssuchaswarfarin,selectiveserotonin-reuptakeinhibitorsoranti-

plateletagentssuchasaspirin(seesection4.5).

WhenGIbleedingorulcerationoccursinpatientsreceivingDifenethetreatmentshouldbewithdrawn.

NSAIDsshouldbegivenwithcaretopatientawithahistoryofgastrointestinaldisease(ulcerativecolitis,Chron’s

disease)astheirconditionmaybeexacerbated(seesection4.8–undesirableeffects).

Cautionisrequiredinpatientswithahistoryofhypertensionand/orheartfailureasfluidretentionandoedemahave

beenreportedinassociationwithNSAIDtherapy

Seriousskinreactions,someofthemfatal,includingexfoliativedermatitis,Stevens-Johnsonsyndrome,andtoxic

epidermalnecrolysis,havebeenreportedrarelyinassociationwiththeuseofNSAIDs(see4.8).Patientsappeartobe

athighestriskofthesereactionsearlyinthecourseoftherapy,theonsetofthereactionoccurringinthemajorityof

caseswithinthefirstmonthoftreatment.Difeneshouldbediscontinuedatthefirstappearanceofskinrash,mucoal

lesions,oranyothersignohhypersensitivity.

Undesirableeffectsmaybeminimisedbyusingtheminimumeffectivedosefortheshortestdurationnecessaryto

controlthesymptoms(seesection4.2,andGIandcardiovascularrisksbelow)

Cardiovascularandcerebrovasculareffects

Appropriatemonitoringandadvicearerequiredforpatientswithahistoryofhypertensionand/ormildtomoderate

congestiveheartfailureasfluidretentionandoedemahavebeenreportedinassociationwithNSAIDtherapy.

Clinicaltrialandepidemiologicaldatasuggestthattheuseofdiclofenac,particularlyathighdose(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexample

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Patientswithuncontrolledhypertension,congestiveheartfailure,establishedischaemicheartdisease,peripheral

aerterialdisease,and/orcerebrovasculardiseaseshouldnotbetreatedwithdiclofenscaftercarefulconsideration.

Similarconsiderationshouldbemadebeforeinitiatinglonger-termtreatmentofpatientswithriskfactorsfor

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

Undesirableeffectsmaybereducedbyusingtheminimumeffectivedosefortheshortestpossibleduration.Patients

treatedwithNSAIDslongtermshouldundergoregularmedicalsupervisiontomonitorforadverseevents.

Inpatientswithrenal,cardiacorhepaticimpairment,cautionisrequiredsincetheuseofNSAIDsmayresultin

deteriorationofrenalfunction.Assessmentofrenalfunctionshouldoccurpriortotheinitiationoftherapyandregularly

thereafter.

ElderlypatientsareparticularlysusceptibletotheadverseeffectsofNSAIDs.ProlongeduseofNSAIDsintheelderly

isnotrecommended.Whereprolongedtherapyisrequired,patientsshouldbereviewedregularly.

Diclofenacshouldbeusedwithcautioninpatientswithahistoryofpepticulcerationorinflammatoryboweldisease.

AsNSAIDscaninterferewithplateletfunction,theyshouldbeusedwithcautioninpatientswithintracranial

haemorrhageandbleedingdiathesis.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Corticosteroids:increasedriskofgastrointestinalulcerationorbleeding(seesection4.4)

Anticoagulants:NSAIDsmayenhancetheeffectsofanti-coagulants,suchaswarfarin(seesection4.4)

Anti-plateletagentsandselectiveserotoninreuptakeinhibitors(SSRIs):increasedriskofgastrointestinalbleeding(see

section4.4)

Careshouldbetakeninpatientstreatedwithanyofthefollowingdrugsasinteractionshavebeenreported:

Anti-hypertensives:reducedanti-hypertensiveeffect.

Diuretics:reduceddiureticeffect.DiureticscanincreasetheriskofnephrotoxicityofNSAIDs.

Cardiacglycosides:NSAIDsmayexacerbatecardiacfailure,reduceGFRandincreaseplasmacardiacglycosidelevels.

Lithium:decreasedeliminationoflithium.

Methoterexate:decreasedeliminationofmethotrexate.

Cyclosporin:increasedriskofnephrotoxicitywithNSAIDs.

Aminoglycosides:reductioninrenalfunctioninsusceptibleindividuals,decreasedeliminationofaminoglycosideand

increasedplasmaconcentrations.

Probenecid:reductioninmetabolismandeliminationofNSAIDandmetabolites.

Oralhypoglycemicagents:inhibitionofmetabolismofsulfonylureadrugs,prolongedhalf-lifeandincreasedriskof

hypoglycaemia.

4.6Fertility,pregnancyandlactation

Althoughanimalstudieshavenotdemonstratedteratogeniceffects,Difeneshouldnotbeusedinpregnancyorlactation

unlessconsideredessentialbythephysicianandifsothelowesteffectivedoseshouldbeused.Useofprostaglandin

synthetaseinhibitorsinthethirdtrimestermayresultinprematureclosureoftheductusarteriosus.Tracesofdrugare

detectableinbreastmilkbutarenotclinicallysignificant.

4.7Effectsonabilitytodriveandusemachines

Isolatedcasesofdisorientationandblurredvisionhavebeenreportedwithdiclofenacsodium.Ifaffectedrefrainfrom

drivingoroperatingmachinery.

4.8Undesirableeffects

Gastro-intestinal:

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sometimesfatal,particularlyintheelderly,mayoccur(seesection4.4).Nausea,vomiting,diarrhoea,flatulence,

constipation,dyspepsia,abdominalpain,melaaena,haematemesis,ulcerativestomatitis,exacerbationofcolitisand

hron’sdisease(seesection4.4–Specialwarningsandprecautionsforuse)havebeenreportedfollowing

administration.Lessfrequently,gastritishasbeenobserved.

Ifseriousside-effectsoccur,Difeneshouldbewithdrawn.

CentralNervousSystem:

Occasional:headache,dizzinessorvertigo.

Rare:drowsiness,tiredness.

Isolatedcases:disturbancesofsensation(paraesthesiae,memorydisturbance,disorientation,disturbanceofvision,

blurredvision,diplopia),impairedhearing,tinnitus,insomnia,irritability,convulsions,depression,anxiety,nightmares,

tremor,psychoticreactions.Tastealterationdisorders.

Skin:

Occasional:rashesorskineruptions.Rare:urticaria

Isolatedcases:bullouseruptions,eczema,erythemamultiforme,Stevens-Johnsonsyndrome,lyell'ssyndrome,(acute

toxicepidermolysis),erythroderma(exfoliativedermatitis),lossofhair,photosensitivityreactions,purpuraincluding

allergicpurpura.

Kidney:

Isolatedcases:acuterenalinsufficiency,urinaryabnormalities(e.g.haematuria,proteinuria),interstitialnephritis,

nephroticsyndrome,papillarynecrosis.

Liver:

Occasional:elevationofserumaminotransferaseenzymes(SGOT,SGPT).

Rare:liverfunctiondisordersincludinghepatitis(inisolatedcasesfulminant)withorwithoutjaundice.

Blood:

Isolatedcases:thrombocytopenia,leucopenia,agranulocytosis,haemolyticanaemia,aplasticanaemia.

Otherorgansystems:

Rare:oedema,hypersensitivityreactions(e.g.bronchospasm,anaphylactic/anaphylactoidsystemicreactionsincluding

hypotension).

Isolatedcases:impotence(associationwithDiclofenacsodiumintakeisdoubtful),palpitation,chestpain,

hypertension.

Oedema,hypertensionandcardiacfailure,havebeenreportedinassociationwithNSAIDtreatment.

Clinicaltrialandepidemiologicaldatasuggeststhatuseofdiclofenac,particularlyathighdoses(150mgdaily)andin

longtermtreatmentmaybeassociatedwithasmallincreasedriskofarterialthromboticevents(forexample

myocardialinfarctionorstroke)(seesection4.4).

4.9Overdose

Managementofacutepoisoningwithdiclofenacandothernon-steroidalanti-inflammatorydrugsconsistsofsupportive

andsymptomaticmeasures.Therapeuticmeasuresthatcanbetakeninclude;supportiveandsymptomatictreatmentfor

thecomplicationsofoverdosagesuchashypotension,renalfailure,convulsions,gastro-intestinalirritationand

respiratorydepression;Forceddiuresisordialysisareprobablyofnohelpineliminatingdiclofenacandothernon-

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Additionalmeasuresincludegastriclavageandtreatmentwithactivatedcharcoal.Difene75mgand100mgDual

Releasearecontrolledreleasesystemswhichwillcontinuetoreleasediclofenacforsomehours.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

MO1AB05Anti-inflammatoryandanti-rheumaticproducts,non-steroids,aceticacidderivativesandrelated

substancesdiclofenac.

Diclofenacsodiumisaphenylaceticacidderivativeandanon-steroidalanti-inflammatoryagentwithanalgesic,anti-

inflammatoryandanti-pyreticproperties.

Diclofenacisaninhibitorofcyclo-oxygenaseandthereforereducesprostaglandinsynthesis.Reductionin

prostaglandinlevelsreducestheinflammatoryresponsebythebody.

5.2Pharmacokineticproperties

Theentericcoatedpelletcomponentofthepreparationensuresquickavailability,followingrapidgastricpassage,of

theactivecomponentinthebloodstreamandthesustainedreleasepelletcausesadelayedreleaseoftheactive

component.

Attherapeuticconcentrations,diclofenacisextensivelybound(morethan99%)toplasmaproteins.Itissubjecttofirst

passmetabolismandextensivelymetabolisedintheliver(50-60%).Diclofenacisexcretedmostlythroughtheurine

withasmallamountexcretedinthebile,italsoentersthesynovialfluidandisexcretedinbreastmilk.Diclofenachasa

shorthalf-lifeofabout1-4hours.

5.3Preclinicalsafetydata

Animalstudieshavebeencarriedoutinanumberofspeciestodeterminethetoxicityofdiclofenacsodium.Acute

toxicitystudieshavebeencarriedoutintheratandwhenadministeredorallyanLD50of53mg/kgproduced

behaviouraleffectsandrespiratorystimulation.Acuteoraltoxicitystudiesintherabbitshowednotoxiceffectatadose

of157mg/kg.

Reproductivetoxicityhasbeenstudiedinboththeratandtherabbit,adoseof1mg/kg/dayfor21daysinratshasbeen

showntoproducedevelopmentalabnormalitiesofthecardiovascularsystem.Intherabbitadoseof10mg/kghasbeen

showntoreducefertility.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose(E460)

Povidonek25

MethacrylicacidcopolymertypeC

Talc

AmmoniomethacrylatecopolymertypesAandB

Colloidalanhydroussilica

Propyleneglycol

Sodiumhydroxide

Dibutylphthalate.

Gelatin(bovine)

Purifiedwater

Titaniumdioxide(E171)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

PVC/PVDC/aluminiumblister.Packsize:56capsules

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/185/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:13thOctober2006

10DATEOFREVISIONOFTHETEXT

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