CICLOSPORIN DUMEX

Main information

  • Trade name:
  • CICLOSPORIN DUMEX
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CICLOSPORIN DUMEX
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/028/003
  • Authorization date:
  • 11-01-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1380/028/003

CaseNo:2057297

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ActavisGroupPTCehf

Reykjavikurvegi76-78,220Hafnarfjordur,Iceland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CiclosporinDumex,100Milligram

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom05/11/2008until.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 06/11/2008 CRN 2057297 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiclosporinDumex100mgCapsule.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains100mgCiclosporin.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,soft.

CiclosporinDumex100mgCapsulesaregreysoftgelatincapsuleswithimprinting“DX100mg”.

4CLINICALPARTICULARS

4.1TherapeuticIndications

OrganTransplantation

Preventionofgraftrejectionfollowingkidney,liver,heart,combinedheart-lung,

lungorpancreastransplants.

Treatmentoftransplantrejectioninpatientspreviouslyreceivingotherimmunosuppressiveagents.

BoneMarrowTransplantation

Preventionofgraftrejectionfollowingbonemarrowtransplantationandprophylaxisofgraft-versus-hostdisease

(GVHD).

Treatmentofestablishedgraft-versus-hostdisease(GVHD).

Psoriasis

CiclosporinDumex100mgCapsulesareindicatedinpatientswithseverepsoriasisinwhomconventionaltherapyis

ineffectiveorinappropriate.

AtopicDermatitis

CiclosporinDumex100mgCapsulesareindicatedforshorttermtreatment(8weeks)ofpatientswithsevereatopic

dermatitisinwhomconventionaltherapyisineffectiveorinappropriate.

NephroticSyndrome

CiclosporinDumex100mgCapsulesareindicatedinthetreatmentofadultsandchildrenwithsteroid-dependentand

steroid-resistantnephroticsyndromeowingtoglomerulardiseasessuchasminimalchangenephropathy,focal

segmentalglomerulosclerosisormembranousglomerulonephritis.

CiclosporinDumex100mgCapsulescanbeusedtoinduceremissionsandformaintenancetreatment.Itcanalsobe

usedforthemaintenanceofsteroid-inducedremission,allowingwithdrawalofsteroids.

RheumatoidArthritis

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whomclassicalslow-actinganti-rheumaticagentsareinappropriateorineffective.

4.2Posologyandmethodofadministration

RouteofAdministration

Oral.Ciclosporinshouldnotbetakenwithgrapefruitjuice.

RecommendedDosageSchedule

Forallindications,ciclosporinbloodlevelsmustbemonitoredonaroutinebasis.Thesemeasurementsshouldbeused

asguidancetodeterminethedoseofCiclosporinDumex100mgCapsulesrequiredtoobtainthedesiredbloodlevelsof

ciclosporin(Seesection4.4).

OrganTransplantation

Initially,adoseof10to15mg/kgbodyweightintwodivideddoses,shouldbegivenfourtotwelvehoursbefore

transplantation.Asageneralrule,treatmentshouldcontinueatadoseof10to15mg/kg/dayintwodivideddosesfor

onetotwoweekspost-operatively.Dosageshouldthenbegraduallyreduceduntilamaintenancedoseof2to

6mg/kg/dayisreached.Thistotaldailydoseshouldbegivenintwodivideddoses.Dosageshouldbeadjustedby

monitoringciclosporinbloodlevelsandkidneyfunction.WhenCiclosporinDumex100mgCapsulesaregivenwith

otherimmunosuppressants(e.g.withcorticosteroidsoraspartofatripleorquadrupledrugtherapy)lowerdoses(e.g.3

to6mg/kg/dayintwodivideddosesorallyinitially)maybeused.

BoneMarrowTransplantation/PreventionandTreatmentofGraft-Versus-HostDisease(GVHD)

MaintenancetreatmentwithCiclosporinDumex100mgCapsulesshouldcontinueusingtheoralformsatadosageof

12.5mg/kg/dayforatleastthreeandpreferablysixmonthsbeforetailingofftozero.

Insomecases,itmaynotbepossibletowithdrawCiclosporinDumex100mgCapsulesuntilayearafterbonemarrow

transplantation.HigheroraldosesortheuseofI.V.therapymaybenecessaryinthepresenceofgastrointestinal

disturbanceswhichmightdecreaseabsorption.

Iforaltreatmentisusedtoinitiatetherapy,therecommendeddoseis12.5to15mg/kg/daystartingonthedaybefore

transplantation.

IfGVHDdevelopsafterCiclosporinDumex100mgCapsulesarewithdrawn,itshouldrespondtore-institutionof

therapy.Lowdosesshouldbeusedformild,chronicGVHD.

Psoriasis

Referalsoto"AdditionalPrecautionsinPsoriasis"section.

Toinduceremission,therecommendedinitialdoseis2.5mg/kg/daygivenorallyintwodivideddoses.Ifthereisno

improvementafteronemonth,thedailydosemaybegraduallyincreased,butshouldnotexceed5mg/kg/dayorally.

Treatmentshouldbediscontinuedifsufficientresponseisnotachievedwithinsixweekson5mg/kg/dayorally,orif

theeffectivedoseisnotcompatiblewiththesafetyguidelinesgivenbelow(seePrecautions).Initialdosesof5

mg/kg/dayorallyarejustifiedinpatientswhoseconditionrequiresrapidimprovement.

Formaintenancetreatment,dosagemustbeindividuallytitratedtothelowesteffective

level,andshouldnotexceed5mg/kg/dayorally.

AtopicDermatitis

Referalsoto"AdditionalPrecautionsinAtopicDermatitis"section.

Therecommendeddoserangeis2.5–5mg/kg/dayorallyintwodivideddosesforamaximumofeightweeks.Ifa

startingdoseof2.5mgkg/daydoesnotachieveagoodinitialresponsewithintwoweeksthedosemayberapidly

increasedtoamaximumof5mg/kg/day.Inveryseverecases,rapidandadequatecontrolofdiseaseismorelikelywith

astartingdoseof5mg/kg/day.

NephroticSyndrome

Referto"AdditionalPrecautionsinNephroticSyndrome"section.

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mg/kg/daygivenorallyintwodivideddosesforchildren,if,withtheexceptionofproteinuria,renalfunctionis

normal.Inpatientswithimpairedrenalfunction,theinitialdoseshouldnotexceed2.5mg/kg/dayorally.

ThecombinationofCiclosporinDumex100mgCapsuleswithlowdosesoforalcorticosteroidsisrecommendedifthe

effectofCiclosporinDumex100mgCapsulesaloneisnotsatisfactory,especiallyinsteroid-resistantpatients.

Intheabsenceofefficacyafter3months'treatment,CiclosporinDumex100mgCapsulestherapyshouldbe

discontinued.

Thedosesneedtobeadjustedindividuallyaccordingtoefficacy(proteinuria)andsafety(primarilyserumcreatinine),

butshouldnotexceed5mg/kg/dayorallyinadultsor6mg/kg/dayorallyinchildren.

Formaintenancetreatment,thedoseshouldbeslowlyreducedtothelowesteffectivelevel.

RheumatoidArthritis

Referalsoto"AdditionalPrecautionsinRheumatoidArthritis"section.

Forthefirst6weeksoftreatment,therecommendeddoseis3mg/kg/daygivenorallyintwodivideddoses.Ifthe

effectisinsufficient,thedailydosemaythenbeincreasedgraduallyastolerabilitypermits,butshouldnotexceed5

mg/kg/dayorally.Toachievefulleffectiveness,upto12weeksofCiclosporinDumex100mgCapsulestherapymay

berequired.

Formaintenancetreatmentthedosehastobetitratedindividuallyaccordingtotolerability.

CiclosporinDumex100mgCapsulescanbegivenincombinationwithlow-dosecorticosteroidsand/ornon-steroidal

anti-inflammatorydrugs.

Administration

ThetotaldailydosageofCiclosporinDumex100mgCapsulesshouldalwaysbegivenintwodivideddoses.

Ciclosporinshouldnotbetakenwithgrapefruitjuice(seeinteractions).

UseintheElderly

Experienceintheelderlyislimitedbutnoparticularproblemshavebeenreportedfollowingtheuseofthedrugatthe

recommendeddose.However,factorssometimesassociatedwithageing,inparticularimpairedrenalfunction,make

carefulsupervisionessentialandmaynecessitatedosageadjustment.

UseinChildren

ExperiencewithCiclosporinDumex100mgCapsulesinyoungchildrenisstilllimited.Transplantrecipientsfrom

threemonthsofagehavereceivedthedrugattherecommendeddosagewithnoparticularproblems,although,at

dosagesabovetheupperendoftherecommendedrange,childrenseemtobemoresusceptibletofluidretention,

convulsionsandhypertension.Thisrespondstodosagereduction.

4.3Contraindications

Knownhypersensitivitytociclosporinortoanyoftheexcipients.

CiclosporinDumex100mgCapsulesarecontraindicatedinpsoriaticandatopicdermatitispatientswithabnormalrenal

function,uncontrolledhypertension,uncontrolledinfectionsoranykindofmalignancyotherthanoftheskin(see

Precautions).

CiclosporinDumex100mgCapsulesarecontraindicatedinrheumatoidarthritispatientswithabnormalrenalfunction,

uncontrolledhypertension,uncontrolledinfectionsoranykindofmalignancy.

HerbalpreparationscontainingHypericumperforatum(St.John’sWort)arecontra-indicatedduringtreatmentwith

CiclosporinDumex100mgCapsules,asconcomitantusemayleadtodecreasedplasmaconcentrationsandreduced

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4.4Specialwarningsandprecautionsforuse

Precautions

CiclosporinDumex100mgCapsulescanimpairrenalfunction.Closemonitoringofserumcreatinineandureais

requiredanddosageadjustmentmaybenecessary.Increasesinserumcreatinineandureaoccurringduringthefirst

fewweeksofCiclosporinDumex100mgCapsulestherapyaregenerallydose-dependentandreversibleandusually

respondtodosagereduction.Duringlong-termtreatment,somepatientsmaydevelopstructuralchangesinthekidney

(eg.interstitialfibrosis)which,inrenaltransplantrecipients,mustbedistinguishedfromchronicrejection.

CiclosporinDumex100mgCapsulesmayalsoaffectliverfunctionanddosageadjustment,basedontheresultsof

bilirubinandliverenzymemonitoring,maybenecessary.

RegularmonitoringofbloodpressureisrequiredduringCiclosporinDumex100mgCapsulestherapy.Ifhypertension

develops,appropriateantihypertensivetreatmentmustbeinstituted.

Since,onrareoccasions,CiclosporinDumex100mgCapsuleshavebeenreportedtoinduceareversibleslightincrease

inbloodlipids,itisadvisabletoperformlipiddeterminationsbeforetreatmentandafterthefirstmonthoftherapy.In

theeventofincreasedlipidsbeingfound,restrictionofdietaryfatand,ifappropriate,adosereduction,shouldbe

considered.

SinceCiclosporinDumex100mgCapsulesoccasionallycauseshyperkalaemiaormayaggravatepre-existing

hyperkalaemia,monitoringofserumpotassiumisrecommended,especiallyinpatientswithmarkedrenaldysfunction.

PatientsreceivingCiclosporinDumex100mgCapsulesshouldavoidahighdietarypotassiumintake.Referalsoto

DrugInteractions.

Ciclosporinenhancestheclearanceofmagnesium.Thiscanleadtosymptomatichypomagnesaemia,especiallyinthe

peri-transplantperiod.Controlofserummagnesiumlevelsisthereforerecommendedintheperi-transplantperiod,

particularlyinthepresenceofneurologicalsymptom/signs.Ifconsiderednecessary,magnesiumsupplementation

shouldbegiven.

Ciclosporinpredisposespatientstoinfectionwithavarietyofpathogensincludingbacteria,parasites,virusesandother

opportunisticpathogens.Thisappearstoberelatedtothedegreeanddurationofimmunosuppressionratherthantothe

specificuseofciclosporin.Asthiscanleadtoafataloutcome,effectivepre-emptiveandtherapeuticstrategiesshould

beemployedparticularlyinpatientsonmultiplelong-termimmunosuppressivetherapy.

Cautionisrequiredintreatingpatientswithhyperuricaemia.

CiclosporinDumex100mgCapsulesshouldpreferablynotbeadministeredwithotherimmunosuppressiveagents

exceptcorticosteroids.However,sometransplantcentresuseCiclosporinDumex100mgCapsulestogetherwith

azathioprineandcorticosteroidsorotherimmunosuppressiveagents(allinlowdoses)withtheaimofreducingtherisk

ofCiclosporinDumex100mgCapsules-inducedrenaldysfunctionorrenalstructuralchanges.WhenCiclosporin

Dumex100mgCapsulesareusedwithotherimmunosuppressiveagents,thereisariskofover-immunosuppression,

whichcanleadtoincreasedsusceptibilitytoinfectionandtopossibledevelopmentoflymphoma.

InCiclosporinDumex100mgCapsules-treatedrenaltransplantrecipients,amachineperfusiontimeofmorethan24

hoursandareanastomosistimeofmorethan45minutescanhaveasignificanteffectongraftfunction.Bothfactors

appeartoincreasetheincidenceofacutetubularnecrosis.

Occurrenceofnon-cardiogenicpulmonaryoedema(indicatedbywheezing)asaresultofcapillaryleaksyndromeis

possible.

CiclosporinmayincreasetheriskofBenignIntracranialHypertension.Patientspresentingwithsignsofraised

intracranialpressureshouldbeinvestigatedandifBenignIntracranialHypertensionisdiagnosed,ciclosporinshouldbe

withdrawnduetothepossibleriskofpermanentvisualloss.

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onlybecarriedoutwhendetailedinformationonthemethodusedisavailable.Methodsbywhichunalteredciclosporin

ismeasured(HPLC,monoclonalradioimmunoassay)areavailable,aswellasnon-specificmethodsthatalsomeasure

severalmetabolites.Theresultsfromdifferentmethodsarethereforenotinterchangeable.Whenusingplasma,levels

willpartiallydependonthetemperatureusedduringseparationoftheplasmafromwholeblood.Plasmalevelsvary,

rangingfrom20%to50%ofwholeblood.Ciclosporinlevelsinblood,plasmaorurineareonlyoneofmanyfactors

determiningtheclinicalstateofthepatient.Measurementsarethereforeonlytoberegardedasaguidelineon

treatment,incombinationwithotherlaboratoryvaluesandclinicalparameters.Inkidneytransplantpatientsexhibiting

deteriorationofkidneyfunctionparametersinconjunctionwithexcessivelyhighbloodlevelsofciclosporin,which

doesnotrespondtodosereduction,furtherdiagnosticsarerequired.Renalbiopsycouldbeconsidered.

AdditionalPrecautionsinPsoriasisandAtopicDermatitis

Onlytheoralformsofciclosporinarerecommendedforthetreatmentofpatientswithpsoriasisoratopicdermatitis.

Carefuldermatologicalandphysicalexaminations,includingmeasurementsofbloodpressureandrenalfunctiononat

leasttwooccasionspriortostartingtherapyshouldbeperformedtoestablishanaccuratebaselinestatus.

Developmentofmalignancies(particularlyoftheskin)havebeenreportedinpsoriaticpatientstreatedwithciclosporin

aswellasduringtreatmentwithconventionaltherapy.Asearchforallformsofpre-existingtumours,includingthose

oftheskinandcervix,shouldbecarriedout.Skinlesionswhicharenottypicalforpsoriasisshouldbebiopsiedbefore

startingCiclosporinDumex100mgCapsulestreatmenttoexcludeskincancers,mycosisfungoidesorotherpre-

malignantdisorders.Patientswithmalignantorpre-malignantalterationsoftheskinshouldbetreatedwithCiclosporin

Dumex100mgCapsulesonlyafterappropriatetreatmentofsuchlesionsandonlyifnootheroptionforsuccessful

therapyexists.

Becauseofthepossibilityofrenaldysfunctionorrenalstructuralchanges,serumcreatinineshouldbemeasuredattwo-

weeklyintervalsduringthefirstthreemonthsoftherapy.Thereafter,ifcreatinineremainsstable,measurementsshould

berepeatedattwo-monthintervalsinpatientsreceivingdosesof2.5mg/kg/dayandatmonthlyintervalsinpatients

whorequirehigherdoses.Ifserumcreatinineincreasestomorethan30%abovebaseline,evenifthevaluesarestill

withinthenormalrange,CiclosporinDumex100mgCapsulesdosagemustbereducedby25to50%.Ifdosage

reductionisnotsuccessfulwithinonemonth,treatmentshouldbediscontinued.

Inatopicdermatitispatients,serumcreatinineshouldbemeasuredattwoweeklyintervalsthroughoutthetreatment

period.

IfhypertensiondevelopswhichcannotbecontrolledbyCiclosporinDumex100mgCapsulesdosagereductionor

appropriateantihypertensivetherapy,discontinuationofthedrugisrecommended.

Inviewofthepotentialriskofskinmalignancy,patientsonCiclosporinDumex100mgCapsulesshouldbewarnedto

avoidexcessunprotectedsunexposureandshouldnotreceiveconcomitanttherapeuticultravioletBirradiationor

PUVAphotochemotherapy.Aftercompletionofciclosporintreatment,a2to3daytreatment-freeperiodshouldbe

observedbeforecommencingPUVAorBtherapy.

AdditionalprecautionsinAtopicDermatitis

ActiveherpessimplexinfectionsshouldbeallowedtoclearbeforeinitiatingtreatmentwithCiclosporinDumex100mg

Capsulesbutarenotnecessarilyareasonfordrugwithdrawaliftheyoccurduringtreatmentunlessinfectionissevere.

SkininfectionswithstaphylococcusaureusarenotanabsolutecontraindicationforCiclosporinDumex100mg

Capsulestherapybutshouldbecontrolledwithappropriateantibacterialagents.Orallyerythromycin,knowntohave

thepotentialtoincreasethebloodconcentrationofCiclosporinDumex100mgCapsules(seeInteractions)shouldbe

avoidedor,ifthereisnoalternative,itsconcomitantusemustbeaccompaniedbyclosemonitoringofthebloodlevels

ofCiclosporinDumex100mgCapsules.

Asexperiencewithciclosporininchildrenwithatopicdermatitisisstilllimited,itsuseinchildrenunder16yearsof

agecannotberecommended.

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Onlytheoralformsofciclosporinarerecommendedforthetreatmentofpatientswithnephroticsyndrome.

Developmentofmalignancies(includingHodgkin'slymphoma)hasoccasionallybeenreportedinnephroticsyndrome

patientstreatedwithciclosporin,aswellasduringtreatmentwithotherimmunosuppressiveagents.

Sinceciclosporincanimpairrenalfunction,itisnecessarytoassessrenalfunctionfrequentlyandiftheserum

creatinineremainsincreasedbymorethan30%abovebaselineatmorethanonemeasurement,toreducethedoseby

25-50%.Patientswithabnormalbaselinerenalfunctionareathigherrisk,theyshouldinitiallybetreatedwith

2.5mg/kg/dayorallyandmustbecontrolledverycarefully.

Insomepatientsitmaybedifficulttodetectciclosporininducedrenaldysfunctionbecauseofchangesinrenalfunction

relatedtotheunderlyingrenaldisease.IfCiclosporinDumex100mgCapsulesareindicatedformorethanoneyearin

thelongtermmanagement,theserialrenalbiopsiesshouldbeperformedat1to2-yearlyintervalstoassessthe

progressionoftherenaldiseaseandtheextentofanyCiclosporinDumex100mgCapsules-associatedchangesinthe

renalmorphologythatmayco-exist.

AdditionalPrecautionsinRheumatoidArthritis

Onlytheoralformsofciclosporinarerecommendedforthetreatmentofpatientswithrheumatoidarthritis.

SinceCiclosporinDumex100mgCapsulescanimpairrenalfunction,areliablebaselinelevelofserumcreatinine

shouldbeestablishedbyatleasttwomeasurementspriortotreatment,andserumcreatinineshouldbemonitoredat2-

weeklyintervalsduringthefirst3monthsoftherapy.Thereafter,measurementscanbemadeevery4weeks,butmore

frequentchecksarenecessarywhentheCiclosporinDumex100mgCapsulesdoseisincreasedorconcomitant

treatmentwithanon-steroidalanti-inflammatorydrugisinitiatedoritsdosageincreased.

Iftheserumcreatinineremainsincreasedbymorethan30%abovebaselineatmorethanonemeasurement,thedosage

ofCiclosporinDumex100mgCapsulesshouldbereduced.Iftheserumcreatinineincreasesbymorethan50%,a

dosagereductionof50%ismandatory.Theserecommendationsapplyevenifthepatient’svaluesstillliewithinthe

laboratorynormalrange.Ifdosagereductionisnotsuccessfulinreducinglevelswithinonemonth,CiclosporinDumex

100mgCapsulestreatmentshouldbediscontinued.

DiscontinuationofthedrugmayalsobecomenecessaryifhypertensiondevelopingduringCiclosporinDumex100mg

Capsulestherapycannotbecontrolledbyappropriateantihypertensivetherapy.

Aswithotherlong-termimmunosuppressivetreatments,anincreasedriskoflymphoproliferativedisordersmustbe

considered.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

CareshouldbetakenwhenusingCiclosporinDumex100mgCapsulesincombinationwithsystemicantibioticsor

othercompoundsknowntohavenephrotoxiceffects,eg.

Aminoglycosides,amphoteracinB,ciprofloxacin,melphalanandtrimethorpim.

Variousagentsareknowntoeitherincreaseordecreasetheplasmaorwholebloodconcentrationsofciclosporinby

competitiveinhibitionorinductionofhepaticenzymesinvolvedinthemetabolismandexcretionofCiclosporin

Dumex100mgCapsules,inparticularcytochromeP450.

Agentsknowntoincreasetheplasmaorwholebloodconcentrationincludeketoconazole,fluconazole,itraconazole,

erythromycin,clarithromycin,oralcontraceptives,diltiazem,nicardipine,verapamil,metoclopromide,danazol,

methylprednisolone(highdose),allopurinol,amiodarone,bileacidandderivatives.

Agentsknowntodecreaseplasmaorwholebloodciclosporinconcentrationsincludephenytoin,nafcillin,

sulphadimidine(intravenousadministration),octreotide,probucol,orlistat,Hypericumperforatum,troglitazone,

ticlopidine,terbinafine,carbamazepine,barbituratesandrifampicin.

Intransplantpatients,frequentmeasurementsofciclosporinlevelsand,ifnecessary,CiclosporinDumex100mg

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drug.Innon-transplantpatients,thevalueofciclosporinbloodlevelmonitoringisquestionable,asinthesepatientsthe

relationshipbetweenbloodlevelsandclinicaleffectislesswellestablished.Ifdrugsknowntoincreaseciclosporin

levelsaregivenconcomitantly,frequentassessmentofrenalfunctionandcarefulmonitoringforCiclosporinDumex

100mgCapsules-relatedside-effectsmaybemoreappropriatethanbloodlevelmeasurement.

Intravenous(butnotoral)administrationofsulphadimidineandtrimethprimhasalsoresultedinamarkedreductionof

plasmaorwholebloodlevels.ConcomitantadministrationofsuchdrugswithCiclosporinDumex100mgCapsules

shouldthereforebeavoided.Wherecombinedadministrationisunavoidable,carefulmonitoringofciclosporinblood

levelsandadjustmentofCiclosporinDumex100mgCapsulesdosageareessential.

Inaddition,ithasbeennotedthatciclosporinreducestheclearanceofprednisoloneand

conversely,high-dosetherapywithmethylprednisolonecanincreasethebloodconcentrationofciclosporin.

Asnon-steroidalanti-inflammatorydrugsalonecanhaveanadverseeffectonrenalfunction,additionofthesedrugsto

CiclosporinDumex100mgCapsulestherapyoranincreaseintheirdosageshouldinitiallybeaccompaniedby

particularlyclosemonitoringofrenalfunction.

CiclosporinDumex100mgCapsulesmayenhancethepotentialoftheHMG-CoAreductaseinhibitorlovastatinto

inducerhabdomyolysis.Thepotentialforinteractionwithotherdrugsinthisclassshouldbeconsidered.

Musculartoxicity,includingmusclepainsandweakness,hasalsobeenreportedinpatientsreceivingcolchicine

concurrentlywithciclosporin.

Theconcurrentadministrationofnifedipineandciclosporinhasresultedinanincreasedrateofgingivalhyperplasia

whencomparedwiththatforciclosporinalone.

Wherethereisariskofhyperkalaemia,potassium-sparingdiureticsshouldbeavoidedandcareshouldbetakenwhen

prescribingpotassiumsupplementsorpotassium-containingmedications.

Duringtreatmentwithciclosporin,vaccinationmaybelesseffective,andtheuseofliveattenuatedvaccinesshouldbe

avoided.

Ciclosporinshouldnotbetakenwithgrapefruitjuicebecauseitsmetabolismmaybeinhibited.

4.6Pregnancyandlactation

Pregnancy

Limitedexperiencewithciclosporininpregnantwomendoesnotindicateanincreasedriskofcongenital

malformations.Animalstudieshaveshownreproductivetoxicityinratsandrabbits(seesection5.3).Ciclosporin

crossestheplacenta.Intransplantationpatientstreatedwithimmunosuppressants,thereisanincreasedriskof

prematurebirthsandlowbirthweight.

Ciclosporinshouldnotbeusedduringpregnancyunlessclearlyindicated.

Lactation

Ciclosporinpassesintothebreastmilk.Becauseofpossibleadverseeffectsontheinfant’simmunesystem,mothers

receivingtreatmentwithciclosporinshouldnotbreastfeedtheirinfants.

4.7Effectsonabilitytodriveandusemachines

NotApplicable

4.8Undesirableeffects

Manysideeffectsassociatedwithciclosporintherapyaredose-dependantandresponsivetodosereduction.Inthe

variousindicationstheoverallspectrumofsideeffectsisessentiallythesame:therearehowever,differencesin

incidenceandseverity.Asaconsequenceofthehigherinitialdosesandlongermaintenancetherapyrequiredafter

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otherindications.

Frequencyestimate:verycommon>10%,common>1%to<10%.

Uncommon>0.1%to<1%,rare>0.01%to<0.1%,veryrare<0.01%.

Bloodandthelymphaticsystemdisorders:

Uncommon:anaemia,thrombocytopenia

Rare:micro-angiopathichaemolyticanaemia,haemolyticuraemicsyndrome

Endocrinedisorders:

Rare:menstrualdisturbances,gynaecomastia

Metabolismandnutritiondisorders:

Verycommon:hyperlipidaemia

Common:Hyperuricaemia,hyperkalaemia,hypomagnesaemia

Rare:hyperglycaemia

Nervoussystemdisorders:

Verycommon:tremor,headache

Common:paraesthesia

Uncommon:signsofencephalopathyordemyelination,especiallyinlivertransplantpatients,suchasconvulsions,

confusion,disorientation,decreasedresponsiveness,agitation,insomnia,visualdisturbances,corticalblindness,coma,

paresis,cerebellarataxia,perceptiondeafness.

Rare:MotorPolyneuropathy

Veryrare:opticdiscoedemaincludingpapilloedemawithpossiblevisualimpairmentsecondarytoBenignIntracranial

hypertension.

Cardiovasculardisorders:

Verycommon:hypertension

Gastrointestinaldisorders:

Common:anorexia,nausea,vomiting,abdominalpain,diarrhoea,gingivalhyperplasia

Hepato-biliarydisorders:

Common:hepaticdysfunction

Rare:pancreatitis

Skinandsubcutaneoustissuedisorders:

Common:hypertrichosis

Uncommon:allergicrashes

Musculoskeletal,connectivetissueandbonedisorders:

Common:musclecramps,myalgia

Rare:muscleweakness,myopathy

Renalandurinarydisorders:

Verycommon:renaldysfunction(see4.4Specialwarningsandprecautionsforuse).

Generaldisordersandadministrationsiteconditions:

Common:fatigue

Uncommon:oedema,weightincrease

Theincreasedriskofdevelopingmalignanciesandlymphoproliferativedisordersappearstoberelatedtothedegree

anddurationofimmunosuppressionratherthantotheuseofspecificagents(refertoSection4.4Specialwarningsand

precautionsforuse).

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Rare:Acuterespiratorystress,dyspnoeaand‘wheezing’duetocapillaryleaksyndrome.

4.9Overdose

Symptoms:

Littleexperienceisavailablewithoverdosage.Hypertensionandconvulsionshavebeenreportedinsomepatients

receivingciclosporintherapyatdosesabovetherecommendedrangeandinotherswithhightroughbloodlevelsof

ciclosporin.Thismightthereforebeexpectedasafeatureofoverdosage.Signsofnephrotoxicitymightoccurwhich

wouldbeexpectedtoresolvefollowingdrugwithdrawal.

Treatmentmeasures:

Symptomatictreatmentandgeneralsupportivemeasuresshouldbefollowedinallcasesofoverdosage.Forcedemesis

couldbeofvaluewithinthefirstfewhoursafterintake.Ciclosporinisnotdialysabletoanygreatextent,norisitwell

clearedbycharcoalhaemoperfusion.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Selectiveimmunosuppressiveagents(ATCcodeL04AA01).

CiclosporinAisacyclicundecapeptidewithimmunosuppressantproperties. StudiessuggestthatciclosporinA

inhibitsthedevelopmentofcell-mediatedreactions,includingallograftimmunity,delayedcutaneoushypersensitivity,

experimentalallergicencephalomyelitis,Freund'sadjuvantarthritis,graft-versus-hostdiseaseandalsoT-celldependent

antibodyproduction.Italsoinhibitslymphokineproductionandrelease,includinginterleukin2orT-cellgrowthfactor

(TCGF).CiclosporinappearstoblocktherestinglymphocytesintheG0orG1phaseofthecellcycle.

Allavailableevidencesuggeststhatciclosporinactsspecificallyandreversiblyonlymphocytes.Unlikecytostatic

agentsitdoesnotdepresshaemopoieisisandhasnoeffectonthefunctionofphagocyticcells.

5.2Pharmacokineticproperties

Absolutebioavailabilityis25-50%atsteadyandpeakbloodconcentrationsareachievedwithin1-6hours.

Ciclosporinisdistributedlargelyoutsidethebloodvolume.Withinblood,33-47%ispresentinplasma,4-9%in

lymphocytes,5-12%and41-58%inerythrocytes.Inplasma,approximately90%isboundinproteins,mainly

lipoproteins.

Ciclosporinisextensivelybiotransformedtoapproximately15metabolites,therebeingnosinglemajormetabolic

pathway.Eliminationisprimarilybiliary,withonly6%oftheoraldoseexcretedintheurine;only0.1%isexcretedin

theurineasunchangeddrug.Theterminaleliminationhalf-lifefrombloodisapproximately19hours,irrespectiveof

thedoseorrouteofadministration.

5.3Preclinicalsafetydata

Incarcinogenicitystudiesinmice,theincidenceofmalignantlymphomaincreased.Ciclosporinwasnotfoundtobe

genotoxic.

Inrats,decreaseswereobservedintesticularweight,spermcount,serumtestosteronelevelsandhaploidcellpopulation

inthetestis,resultingindecreasedfertility.

Inratsandrabbits,orallyadministeredciclosporinwasnotfoundtobeteratogenic,butwasfoundtobefoetotoxicat

dosesalsocausingmaternaltoxicity.Offspringofsubcutaneouslytreatedratsshowedadecreasednumberofnephrons,

renalhypertrophy,systemichypertensionandprogressivekidneyinsufficiency.Afterintravenousadministration,an

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Disturbancesoftheimmunesystemwereobservedinoffspringofratstreatedduringpregnancyorlactation.

Thehumanrelevanceofthesefindingsisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Polysorbate20

Sorbitanoleate

Lecithin

Triglyceride

Polyoxyl40hydrogenatedcastoroil

Ethyllactate

Ingredientsofthecapsuleshell:

Gelatin

Glycerol

Ferricoxideblack(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

Donotrefrigerateand/orfreeze.

Leaveyourcapsulesinthefoil.Onlyremovethemwhenitistimetotakeyourmedicine.Whenapackagedblisteris

opened,acharacteristicsmellisnoticeable.Thisisnormalanddoesnotmeanthatthereisanythingwrongwiththe

capsule.

6.5Natureandcontentsofcontainer

Thecapsulesareavailableinblisterpacksofdouble-sidedaluminiumconsistingofanaluminiumbottomfoilandan

aluminiumcoveringfoil,whicharecontainedwithinaprintedcardboardcarton.CiclosporinDumex100mgCapsules

areavailablein30,50or60capsulesineachcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

IS-220Hafnarfjordur

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8MARKETINGAUTHORISATIONNUMBER

PA1380/028/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28 th

January2005

10DATEOFREVISIONOFTHETEXT

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