CICLOSPORIN GENFARMA

Main information

  • Trade name:
  • CICLOSPORIN GENFARMA
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Capsules, Soft
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/030/002
  • Authorization date:
  • 11-01-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiclosporinGenfarma50mgSoftCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains50mgciclosporin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,soft

CiclosporinGenfarma50mgCapsulesaregreysoftgelatincapsuleswithimprinting“DX50mg”.

4CLINICALPARTICULARS

4.1TherapeuticIndications

OrganTransplantation

Preventionofgraftrejectionfollowingkidney,liver,heart,combinedheart-lung,lungorpancreastransplants.

Treatmentoftransplantrejectioninpatientspreviouslyreceivingotherimmunosuppressiveagents.

BoneMarrowTransplantation

Preventionofgraftrejectionfollowingbonemarrowtransplantationandprophylaxisofgraft-versus-hostdisease

(GVHD).

Treatmentofestablishedgraft-versus-hostdisease(GVHD).

Psoriasis

CiclosporinGenfarmaareindicatedinpatientswithseverepsoriasisinwhomconventionaltherapyisineffectiveor

inappropriate.

AtopicDermatitis

CiclosporinGenfarmaareindicatedforshorttermtreatment(8weeks)ofpatientswithsevereatopicdermatitisin

whomconventionaltherapyisineffectiveorinappropriate.

NephroticSyndrome

CiclosporinGenfarmaareindicatedinthetreatmentofadultsandchildrenwithsteroid-dependentandsteroid-resistant

nephroticsyndromeowingtoglomerulardiseasessuchasminimalchangenephropathy,focalsegmental

glomerulosclerosisormembranousglomerulonephritis.

CiclosporinGenfarmacanbeusedtoinduceremissionsandformaintenancetreatment.

RheumatoidArthritis

CiclosporinGenfarmaareindicatedforthetreatmentofsevere,activerheumatoidarthritisinpatientsinwhomclassical

slow-actinganti-rheumaticagentsareinappropriateorineffective.

4.2Posologyandmethodofadministration

RouteofAdministration

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RecommendedDosageSchedule

Duetodifferencesinbioavailabilitybetweendifferentoralformulationsofciclosporinitisimportantthathealth

professionalsandpatientsbeawarethatsubstitutionofCiclosporinGenfarmaCapsulesforotherformulationsmaylead

toalterationsinciclosporinbloodlevels.

Thereforepatientsshouldnotbetransferredtoorfromotheroralformulationsofciclosporinwithoutappropriateclose

monitoringofciclosporinbloodconcentrations,serumcreatininelevelsandbloodpressure.

OrganTransplantation

Initially,adoseof10to15mg/kgbodyweightintwodivideddosesshouldbegivenwithintwelvehoursbefore

transplantation.Asageneralrule,treatmentshouldcontinueatadoseof10to15mg/kg/dayintwodivideddosesfor

onetotwoweekspost-operatively.Dosageshouldthenbegraduallyreduceduntilamaintenancedoseof2to

6mg/kg/dayisreached.Thistotaldailydoseshouldbegivenintwodivideddoses.Dosageshouldbeadjustedby

monitoringciclosporinbloodlevelsandkidneyfunction.WhenCiclosporinGenfarmaaregivenwithother

immunosuppressants(e.g.withcorticosteroidsoraspartofatripleorquadrupledrugtherapy)lowerdoses(e.g.3to6

mg/kg/dayintwodivideddosesorallyinitially)maybeused.

BoneMarrowTransplantation/PreventionandTreatmentofGraft-Versus-HostDisease(GVHD)

MaintenancetreatmentwithCiclosporinGenfarmashouldcontinueusingtheoralformsatadosageof12.5mg/kg/day

intwodivideddosesforatleastthreeandpreferablysixmonthsbeforetailingofftozero.

Insomecases,itmaynotbepossibletowithdrawCiclosporinGenfarmauntilayearafterbonemarrow

transplantation.HigheroraldosesortheuseofI.V.ciclosporintherapymaybenecessaryinthepresenceof

gastrointestinaldisturbanceswhichmightdecreaseabsorption.

Iforaltreatmentisusedtoinitiatetherapy,therecommendeddoseis12.5to15mg/kg/dayintwodivideddoses

startingonthedaybeforetransplantation.

IfGVHDdevelopsafterCiclosporinGenfarmaarewithdrawn,itshouldrespondtore-institutionoftherapy.Low

dosesshouldbeusedformild,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,dosagemustbeindividuallytitratedtothelowesteffectivelevel,andshouldnotexceed5

mg/kg/dayorallyintwodivideddoses.

Someclinicaldataareavailablewhichprovideevidencethatoncesatisfactoryresponseisachieved,ciclosporinmaybe

discontinuedandsubsequentrelapsemanagedwithreintroductionofciclosporinatthepreviouseffectivedose.Insome

patientscontinuousmaintenancetherapymaybenecessary.

AtopicDermatitis

Referalsoto"AdditionalPrecautionsinAtopicDermatitis"section.

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

startingdoseof2.5mgkg/daydoesnotachieveagoodinitialresponsewithintwoweeksthedosemayberapidly

increasedtoamaximumof5mg/kg/day.Inveryseverecases,rapidandadequatecontrolofdiseaseismorelikelywith

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NephroticSyndrome

Referto"AdditionalPrecautionsinNephroticSyndrome"section.

Toinduceremission,therecommendeddoseis5mg/kg/daygivenorallyintwodivideddosesforadults,and6

mg/kg/daygivenorallyintwodivideddosesforchildren,if,withtheexceptionofproteinuria,renalfunctionis

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

Infocalsegmentalglomerulosclerosis,thecombinationofciclosporinandcorticosteroidsmaybeofbenefit.

Intheabsenceofefficacyafter3monthstreatmentforminimalchangeandfocalsegmentalglomerulosclerosisor6

monthstreatmentformembranousglomerulonephritis,ciclosporintherapyshouldbediscontinued.

Thedosesneedtobeadjustedindividuallyaccordingtoefficacy(proteinuria)andsafety(primarilyserumcreatinine),

butshouldnotexceed5mg/kg/dayorallyinadultsor6mg/kg/dayorallyinchildren.

Formaintenancetreatment,thedoseshouldbeslowlyreducedtothelowesteffectivelevel.

Long-termdataofciclosporininthetreatmentofnephroticsyndromearelimited.However,inclinicaltrialspatients

havereceivedtreatmentfor1to2years.Long-termtreatmentmaybeconsiderediftherehasbeenasignificant

reductioninproteinuriawithpreservationofcreatinineclearanceandprovidedadequateprecautionsaretaken.

RheumatoidArthritis

Referalsoto"AdditionalPrecautionsinRheumatoidArthritis"section.

ItisrecommendedthatinitiationofCiclosporinGenfarmatherapyshouldtakeplaceoveraperiodof12weeks.

Forthefirst6weeksoftreatment,therecommendeddoseis2.5mg/kg/daygivenorallyintwodivideddoses.Ifthe

effectisinsufficient,thedailydosemaythenbeincreasedgraduallyastolerabilitypermits,butshouldnotexceed4

mg/kg/dayorally.

If,after3monthsoftreatmentatthemaximumpermittedortolerabledosetheresponseis

consideredinadequate,treatmentshouldbediscontinued.

Formaintenancetreatmentthedosehastobetitratedindividuallyaccordingtotolerability.

CiclosporinGenfarmacanbegivenincombinationwithlow-dosecorticosteroidsand/ornon-steroidalanti-

inflammatorydrugs.PharmacodynamicinteractionscanoccurbetweenciclosporinandNSAIDsandthereforethis

combinationshouldbeusedwithcare(seesection4.5,Interactionwithothermedicinalproductsandotherformsof

interaction).

Long-termdataontheuseofciclosporininthetreatmentofrheumatoidarthritisarestilllimited.Therefore,itis

recommendedthatpatientsarere-evaluatedafter6monthsofmaintenancetreatmentandtherapyonlycontinuedifthe

benefitsoftreatmentoutweightherisks.

Administration

ThetotaldailydosageofCiclosporinGenfarmashouldalwaysbegivenintwodivideddoses.

Ciclosporinshouldnotbetakenwithgrapefruitorgrapefruitjuicefor1hourpriortodoseadministration(seesection

4.5,Interactionwithothermedicinalproductsandotherformsofinteraction).

UseintheElderly

Experienceintheelderlyislimitedbutnoparticularproblemshavebeenreportedfollowingtheuseofthedrugatthe

recommendeddose.However,factorssometimesassociatedwithageing,inparticularimpairedrenalfunction,make

carefulsupervisionessentialandmaynecessitatedosageadjustment.

UseinChildren

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receivedciclosporinattherecommendeddosagewithnoparticularproblems,although,atdosagesabovetheupperend

oftherecommendedrange,childrenseemtobemoresusceptibletofluidretention,convulsionsandhypertension.This

respondstodosagereduction.

4.3Contraindications

Knownhypersensitivitytociclosporinortoanyoftheexcipients.

CiclosporinGenfarmaarealsocontraindicatedinpsoriaticpatientswithabnormalrenalfunction,uncontrolled

hypertension,uncontrolledinfectionsoranykindofmalignancyotherthanoftheskin(seePrecautions).

CiclosporinGenfarmaarecontraindicatedinrheumatoidarthritispatientswithabnormalrenalfunction,uncontrolled

hypertension,uncontrolledinfectionsoranykindofmalignancy.

CiclosporinGenfarmashouldnotbeusedtotreatrheumatoidarthritisinpatientsundertheageof18years.

CiclosporinGenfarmaarecontra-indicatedinnephroticsyndromepatientswithuncontrolledhypertension,

uncontrolledinfections,oranykindofmalignancy.

Concomitantuseoftacrolimusisspecificallycontraindicated.

4.4Specialwarningsandprecautionsforuse

Precautions

CiclosporinGenfarmacanimpairrenalfunction.Closemonitoringofserumcreatinineandureaisrequiredanddosage

adjustmentmaybenecessary.Increasesinserumcreatinineandureaoccurringduringthefirstfewweeksof

CiclosporinGenfarmatherapyaregenerallydose-dependentandreversibleandusuallyrespondtodosagereduction.

Duringlong-termtreatment,somepatientsmaydevelopstructuralchangesinthekidney(eg.interstitialfibrosis)which,

inrenaltransplantrecipients,mustbedistinguishedfromchronicrejection.

CiclosporinGenfarmamayalsoaffectliverfunctionanddosageadjustment,basedontheresultsofbilirubinandliver

enzymemonitoring,maybenecessary.

RegularmonitoringofbloodpressureisrequiredduringCiclosporinGenfarmatherapy.Ifhypertensiondevelops,

appropriateantihypertensivetreatmentmustbeinstituted.

Since,onrareoccasions,ciclosporinhasbeenreportedtoinduceareversibleslightincreaseinbloodlipids,itis

advisabletoperformlipiddeterminationsbeforetreatmentandafterthefirstmonthoftherapy.Intheeventof

increasedlipidsbeingfound,restrictionofdietaryfatand,ifappropriate,adosereduction,shouldbeconsidered.

Sinceciclosporinoccasionallycauseshyperkalaemiaormayaggravatepre-existinghyperkalaemia,monitoringof

serumpotassiumisrecommended,especiallyinpatientswithmarkedrenaldysfunction.PatientsreceivingCiclosporin

Genfarmashouldavoidahighdietarypotassiumintake.Cautionisalsorequiredwhenciclosporinisco-administered

withpotassiumsparingdiuretics,angiotensinconvertingenzymeinhibitors,angiotensinIIreceptorantagonistsand

potassiumcontainingdrugs.ReferalsotoDrugInteractions.

Ciclosporinenhancestheclearanceofmagnesium.Thiscanleadtosymptomatichypomagnesaemia,especiallyinthe

peri-transplantperiod.Controlofserummagnesiumlevelsisthereforerecommendedintheperi-transplantperiod,

particularlyinthepresenceofneurologicalsymptom/signs.Ifconsiderednecessary,magnesiumsupplementation

shouldbegiven.

Ciclosporinincreasestheriskofmalignanciesincludinglymphomas,skinandothertumours.Theincreasedrisk

appearstoberelatedtothedegreeanddurationofimmunosuppressionratherthantothespecificuseofciclosporin.

Henceatreatmentregimencontainingimmunosuppressantsshouldbeusedwithcautionasthiscouldleadto

lymphoproliferativedisordersandsolidorgantumours,somewithreportedfatalities.

Ciclosporinpredisposespatientstoinfectionwithavarietyofpathogensincludingbacteria,parasites,virusesandother

opportunisticpathogens.Thisappearstoberelatedtothedegreeanddurationofimmunosuppressionratherthantothe

specificuseofciclosporin.Asthiscanleadtoafataloutcome,effectivepre-emptiveandtherapeuticstrategiesshould

beemployedparticularlyinpatientsonmultiplelong-termimmunosuppressivetherapy.

Therearedifferencesinbioavailabilitybetweendifferentoralformulationsofciclosporin.

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intracranialpressureshouldbeinvestigatedandifBenignIntracranialHypertensionisdiagnosed,ciclosporinshouldbe

withdrawnduetothepossibleriskofpermanentvisualloss.

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Ciclosporinshouldpreferablynotbeadministeredwithotherimmunosuppressiveagentsexceptcorticosteroids.

However,sometransplantcentresuseciclosporintogetherwithazathioprineandcorticosteroidsorother

immunosuppressiveagents(allinlowdoses)withtheaimofreducingtheriskofciclosporin-inducedrenaldysfunction

orrenalstructuralchanges.Whenciclosporinisusedwithotherimmunosuppressiveagents,thereisariskofover-

immunosuppression,whichcanleadtoincreasedsusceptibilitytoinfectionandtopossibledevelopmentoflymphoma.

Inciclosporin-treatedrenaltransplantrecipients,amachineperfusiontimeofmorethan24hoursandareanastomosis

timeofmorethan45minutescanhaveasignificanteffectongraftfunction.Bothfactorsappeartoincreasethe

incidenceofacutetubularnecrosis.

AdditionalPrecautionsinPsoriasisandAtopicDermatitis

Onlytheoralformsofciclosporinarerecommendedforthetreatmentofpatientswithpsoriasisoratopicdermatitis.

Treatmentanditsmonitoringshouldbecarriedoutunderthesupervisionofadermatologistexperiencedinthe

managementofsevereskindiseases.

Carefuldermatologicalandphysicalexaminations,includingmeasurementsofbloodpressureandrenalfunctiononat

leasttwooccasionspriortostartingtherapyshouldbeperformedtoestablishanaccuratebaselinestatus.

Developmentofmalignancies(particularlyoftheskin)havebeenreportedinpsoriaticpatientstreatedwithciclosporin

aswellasduringtreatmentwithconventionaltherapy.Asearchforallformsofpre-existingtumours,includingthose

oftheskinandcervix,shouldbecarriedout.Skinlesionswhicharenottypicalforpsoriasisshouldbebiopsiedbefore

startingCiclosporinGenfarmatreatmenttoexcludeskincancers,mycosisfungoidesorotherpre-malignantdisorders.

Patientswithmalignantorpre-malignantalterationsoftheskinshouldbetreatedwithCiclosporinGenfarmaonlyafter

appropriatetreatmentofsuchlesionsandonlyifnootheroptionforsuccessfultherapyexists.

Becauseofthepossibilityofrenaldysfunctionorrenalstructuralchanges,serumcreatinineshouldbemeasuredattwo-

weeklyintervalsduringthefirstthreemonthsoftherapy.Thereafter,ifcreatinineremainsstable,measurementsshould

berepeatedatmonthlyintervalsinpatientswhorequirehigherdoses.Ifserumcreatinineincreasestomorethan30%

abovebaseline,evenifthevaluesarestillwithinthenormalrange,CiclosporinGenfarmadosagemustbereducedby

25to50%.Ifdosagereductionisnotsuccessfulwithinonemonth,treatmentshouldbediscontinued.

Inatopicdermatitispatients,serumcreatinineshouldbemeasuredattwoweeklyintervalsthroughoutthetreatment

period.

IfhypertensiondevelopswhichcannotbecontrolledbyCiclosporinGenfarmadosagereductionorappropriate

antihypertensivetherapy,discontinuationofthedrugisrecommended.

Inviewofthepotentialriskofskinmalignancy,patientsonCiclosporinGenfarmashouldbewarnedtoavoidexcess

unprotectedsunexposureandshouldnotreceiveconcomitanttherapeuticultravioletBirradiationorPUVA

photochemotherapy.

AdditionalprecautionsinAtopicDermatitis

ActiveherpessimplexinfectionsshouldbeallowedtoclearbeforeinitiatingtreatmentwithCiclosporinGenfarmabut

arenotnecessarilyareasonfordrugwithdrawaliftheyoccurduringtreatmentunlessinfectionissevere.

SkininfectionswithstaphylococcusaureusarenotanabsolutecontraindicationforCiclosporinGenfarmatherapybut

shouldbecontrolledwithappropriateantibacterialagents.Orallyerythromycin,knowntohavethepotentialto

increasethebloodconcentrationofciclosporin(seeInteractions)shouldbeavoidedor,ifthereisnoalternative,its

concomitantusemustbeaccompaniedbyclosemonitoringofthebloodlevelsofciclosporin.

Asexperiencewithciclosporininchildrenwithatopicdermatitisisstilllimited,itsuseinchildrenunder16yearsof

agecannotberecommended.

AdditionalPrecautionsinNephroticSyndrome

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Developmentofmalignancies(includingHodgkin'slymphoma)hasoccasionallybeenreportedinnephroticsyndrome

patientstreatedwithciclosporin,aswellasduringtreatmentwithotherimmunosuppressiveagents.

Sinceciclosporincanimpairrenalfunction,itisnecessarytoassessrenalfunctionfrequentlyandiftheserum

creatinineremainsincreasedbymorethan30%abovebaselineatmorethanonemeasurement,toreducethedoseby

25-50%.Patientswithabnormalbaselinerenalfunctionareathigherrisk,theyshouldinitiallybetreatedwith

2.5mg/kg/dayorallyandmustbecontrolledverycarefully.

Insomepatientsitmaybedifficulttodetectciclosporininducedrenaldysfunctionbecauseofchangesinrenalfunction

relatedtotheunderlyingrenaldisease.IfCiclosporinGenfarmaisindicatedformorethanoneyearinthelongterm

management,theserialrenalbiopsiesshouldbeperformedatyearlyintervalstoassesstheprogressionoftherenal

diseaseandtheextentofanyciclosporin-associatedchangesintherenalmorphologythatmayco-exist.

AdditionalPrecautionsinRheumatoidArthritis

Onlytheoralformsofciclosporinarerecommendedforthetreatmentofpatientswithrheumatoidarthritis.

Sinceciclosporincanimpairrenalfunction,areliablebaselinelevelofserumcreatinineshouldbeestablishedbyat

leasttwomeasurementspriortotreatment,andserumcreatinineshouldbemonitoredat2-weeklyintervalsduringthe

first3monthsoftherapy.Thereafter,measurementscanbemadeevery4weeks,butmorefrequentchecksare

necessarywhentheCiclosporinGenfarmadoseisincreasedorconcomitanttreatmentwithanon-steroidalanti-

inflammatorydrugisinitiatedoritsdosageincreased.Becausethepharmacodynamicinteractionbetweenciclosporin

andNSAIDsmayadverselyaffectrenalfunction,cautionshouldbeexercisedifNSAIDtherapyistobecontinued.

Iftheserumcreatinineremainsincreasedbymorethan30%abovebaselineatmorethanonemeasurement,thedosage

ofCiclosporinGenfarmashouldbereduced.Iftheserumcreatinineincreasesbymorethan50%,adosagereductionof

50%ismandatory.Theserecommendationsapplyevenifthepatient’svaluesstillliewithinthelaboratorynormal

range.Ifdosagereductionisnotsuccessfulinreducinglevelswithinonemonth,CiclosporinGenfarmatreatment

shouldbediscontinued.

DiscontinuationofthedrugmayalsobecomenecessaryifhypertensiondevelopingduringCiclosporinGenfarma

therapycannotbecontrolledbyappropriateantihypertensivetherapy.

Ashepatotoxicityisapotentialsideeffectofnon-steroidalanti-inflammatorydrugs,regularmonitoringofhepatic

functionisadvisedwhenCiclosporinGenfarmaareco-administeredwiththesedrugsinrheumatoidarthritispatients.

Aswithotherlong-termimmunosuppressivetreatments,anincreasedriskoflymphoproliferativedisordersmustbe

considered.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Foodinteractions

Theconcomitantintakeofgrapefruitjuicehasbeenreportedtoincreasethebioavailabilityofciclosporin.

Druginteractions

Ofthemanydrugsreportedtointeractwithciclosporin,thoseforwhichtheinteractionsareadequatelysubstantiated

andconsideredtohaveclinicalimplicationsarelistedbelow.

Variousagentsareknowntoeitherincreaseordecreaseplasmaorwholebloodciclosporinlevelsusuallybyinhibition

orinductionofenzymesinvolvedinthemetabolismofciclosporin,inparticularcytochromeP450.

Drugsthatdecreaseciclosporinlevels:

Barbiturates,carbamazepine,phenytoin;rifampicin;octreotide;orlistat;hypericum;perforatum(St.John'sWort);

ticlopidineandintravenoussulphadimidine.

Drugsthatincreaseciclosporinlevels:

Macrolideantibiotics(mainlyerythromycinandclarithromycin);ketoconazole,fluconazole,itraconazole;diltiazem,

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amiodarone;ursodeoxycholicacid;proteaseinhibitors.

Otherrelevantdruginteractions

Careshouldbetakenwhenusingciclosporintogetherwithotherdrugsthatexhibitnephrotoxicsynergy:

aminoglycosides(includinggentamicin,tobramycin),amphotericinB,ciprofloxacin,vancomycin,trimethoprim(+

sulfamethoxazole);non-steroidalanti-inflammatorydrugs(includingdiclofenac,naproxen,sulindac);melphalan.

Duringtreatmentwithciclosporin,vaccinationmaybelesseffective;theuseoflive-attenuatedvaccinesshouldbe

avoided.

Theconcurrentadministrationofnifedipinewithciclosporinmayresultinanincreasedrateofgingivalhyperplasia

comparedwiththatobservedwhenciclosporinisgivenalone.

Theconcomitantuseofdiclofenacandciclosporinhasbeenfoundtoresultinasignificantincreaseinthe

bioavailabilityofdiclofenac,withthepossibleconsequenceofreversiblerenalfunctionimpairment.Theincreaseinthe

bioavailabilityofdiclofenacismostprobablycausedbyareductionofitsfirst-passeffect.Ifnon-steroidalanti-

inflammatorydrugswithalowfirst-passeffect(e.g.acetylsalicylicacid)aregiventogetherwithciclosporin,no

increaseintheirbioavailabilityistobeexpected.

Ciclosporinmayalsoreducetheclearanceofdigoxintherebycausingdigoxintoxicity.

Ciclosporinhasalsobeenreportedtoreducetheclearanceofprednisolone.

AdministrationofciclosporinmayenhancethepotentialofHMG-CoAreductaseinhibitorsandcolchicinetoinduce

musculartoxicityegmusclepainandweakness,myositisandoccasionallyrhabdomyolysis.

Recommendations

Iftheconcomitantuseofdrugknowntointeractwithciclosporincannotbeavoided,thefollowingbasic

recommendationsshouldbeobserved.

Duringtheconcomitantuseofadrugthatmayexhibitnephrotoxicsynergy,closemonitoringofrenalfunction(in

particularserumcreatinine)shouldbeperformed.Ifasignificantimpairmentofrenalfunctionoccurs,thedosageofthe

co-administereddrugshouldbereducedoralternativetreatmentconsidered.

Drugsknowntoreduceorincreasethebioavailabilityofciclosporin:intransplantpatientsfrequentmeasurementof

ciclosporinlevelsand,ifnecessary,ciclosporindosageadjustmentarerequired,particularlyduringtheintroductionor

withdrawaloftheco-administereddrug.Innon-transplantpatientsthevalueofciclosporinbloodlevelmonitoringis

questionable,asinthesepatientstherelationshipbetweenbloodlevelandclinicaleffectislesswellestablished.If

drugsknowntoincreaseciclosporinlevelsaregivenconcomitantly,frequentassessmentofrenalfunctionandcareful

monitoringforciclosporinrelatedside-effectsmaybemoreappropriatethanbloodlevelmeasurement.

Theconcomitantuseofnifedipineshouldbeavoidedinpatientsinwhomgingivalhyperplasiadevelopsasasideeffect

ofciclosporin.

Non-steroidalanti-inflammatorydrugsknowntoundergostrongfirst-passmetabolism(e.g.diclofenac)shouldbegiven

atdoseslowerthanthosethatwouldbeusedinpatientsnotreceivingciclosporin,astheconcomitantuseofdiclofenac

andciclosporinhasbeenfoundtoresultinasignificantincreaseinthebioavailabilityofdiclofenac,mostprobably

causedbyareductionofitsfirst-passeffect.Whendiclofenacisgivenconcomitantlywithciclosporinthedoseof

diclofenacshouldbereducedbyapproximatelyhalf(seesection4.2Posology&Administration).

Ifnon-steroidalanti-inflammatorydrugswithalowfirst-passeffect(e.g.acetylsalicylicacid)aregiventogetherwith

ciclosporin,noincreaseintheirbioavailabilityistobeexpected.

Ifdigoxin,colchicineorHMG-CoAreductaseinhibitorsareusedconcurrentlywithciclosporin,closeclinical

observationisrequiredinordertoenableearlydetectionoftoxicmanifestationsofthedrug,followedbyreductionof

itsdosageoritswithdrawal.

4.6Fertility,pregnancyandlactation

Ciclosporinisnotteratogenicinanimals.Limiteddataavailablefromorgantransplantrecipientsusingearlier

formulationsofciclosporinindicatethat,comparedwithotherimmunosuppressiveagents,ciclosporintreatment

imposesnoincreasedriskofadverseeffectsonthecourseandoutcomeofpregnancy.Howevertherearenoadequate

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established,itshouldonlybeusedinpregnancyifthebenefitoutweighsanypotentialrisks.

Ciclosporinpassesintothebreastmilkandmothersreceivingtreatmentwithciclosporinshouldthereforenotbreast

feedtheirinfants.

4.7Effectsonabilitytodriveandusemachines

Nodataexistsontheeffectsofciclosporinontheabilitytodriveandusemachines.

4.8Undesirableeffects

Manysideeffectsassociatedwithciclosporintherapyaredose-dependentandresponsivetodosereduction.Inthe

variousindicationstheoverallspectrumofsideeffectsisessentiallythesame;thereare,however,differencesin

incidenceandseverity.Asaconsequenceofthehigherinitialdosesandlongermaintenancetherapyrequiredafter

transplantation,sideeffectsaremorefrequentandusuallymoresevereintransplantpatientsthaninpatientstreatedfor

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.

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(see4.4'Specialwarningsandspecialprecautionsforuse')

Generaldisordersandadministrationsiteconditions:

Common:fatigue

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Theincreasedriskofdevelopingmalignanciesandlymphoproliferativedisordersappearstoberelatedtothedegree

anddurationofimmunosuppressionratherthantotheuseofspecificagents(refertoSection4.4'Specialwarningsand

specialprecautions').

4.9Overdose

Littleexperienceisavailablewithoverdosage.Symptomatictreatmentandgeneralsupportivemeasuresshouldbe

followedinallcasesofoverdosage.Forcedemesiscouldbeofvaluewithinthefirstfewhoursafterintake.Signsof

nephrotoxicitymightoccurwhichwouldbeexpectedtoresolvefollowingdrugwithdrawal. Ciclosporinisnot

dialysabletoanygreatextentnorisitwellclearedbycharcoalhaemoperfusion.Hypertensionandconvulsionshave

beenreportedinsomepatientsreceivingciclosporintherapyatdosesabovetherecommendedrangeandinotherswith

hightroughbloodlevelsofciclosporin.Thismightthereforebeexpectedasafeatureofoverdosage.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Selectiveimmunosuppressiveagents(ATCcodeL04AD01).

CiclosporinAisacyclicundecapeptidewithimmunosuppressantproperties. StudiessuggestthatciclosporinA

inhibitsthedevelopmentofcell-mediatedreactions,includingallograftimmunity,delayedcutaneoushypersensitivity,

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

antibodyproduction.Italsoinhibitslymphokineproductionandrelease,includinginterleukin2orT-cellgrowthfactor

(TCGF).CiclosporinappearstoblocktherestinglymphocytesintheG0orG1phaseofthecellcycle.

Allavailableevidencesuggeststhatciclosporinactsspecificallyandreversiblyonlymphocytes.Unlikecytostatic

agentsitdoesnotdepresshaemopoieisisandhasnoeffectonthefunctionofphagocyticcells.

5.2Pharmacokineticproperties

Themaximalbloodconcentration(Cmax)isachievedwithin1-2hours(Tmax).Theabsolutebioavailabilityis~30%.

Theinter-andintra-individualpharmacokineticvariabilityis10-20%forAUCandCmaxinhealthyvolunteers.

Bioequivalencestudiesunderbothfastingandfedconditionswereperformedtocomparethepharmacokinetic

parametersofCiclosporinandtheoriginatorproduct,asfollows:

1.Arandomised,two-waycross-overstudyin24healthymalevolunteersunderfastingconditions.Theresultsofthe

studyarepresentedinTable1below:

Table1Pharmacokineticparameters-fastingconditions

Allpharmacokineticparameterspresentedaremean(SD)values

Geometricmeansoftheindividualratiosand90%parametricCI

MedianDifferenceand90%nonparametricCI

2.Arandomised,two-waycross-overstudyin39healthymalevolunteersunderfedconditions.Thevolunteerswere

fedwithastandardhigh-fathigh-caloriebreakfastbeforeadministrationofciclosporin.Theresultsofthestudyare

Ciclosporin

2x100mg

(Test) Originatorproduct

2x100mg

(Reference) Test/Reference

90%CI

(n=24)

AUCinf(ng*h*ml -1) 4930(1283) 4866(1107)

1.01(0.93–1.09) 1

Cmax(ng/ml) 1184(215) 1203(231)

0.99(0.90–1.09) 1

Tmax(h) 1.65(0.48) 1.63(0.52)

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Table2Pharmacokineticparameters-fedconditions

Allpharmacokineticparameterspresentedaremean(SD)values

Geometricmeansoftheindividualratiosand90%parametricCI

MedianDifferenceand90%nonparametricCI

Aself-referencestudywasalsoconducted,asfollows:

3.Arandomised,two-waycross-over,foodeffectstudyinwhich16healthymalevolunteersreceivedastandardhigh-

fathigh-caloriebreakfastbeforeadministrationofciclosporin.

TheresultsofthestudyarepresentedinTable3below:

Table3Pharmacokineticparameters-fastingversusfedconditions

Allpharmacokineticparameterspresentedaremean(SD)values

Geometricmeansoftheindividualratiosand90%parametricCI

MedianDifferenceand90%nonparametricCI

TheresultsshowthatfoodintakedecreasesAUCandCmaxby7%and15%,respectively,comparedtothevalues

obtainedunderfastingconditions.

ThereductioninAUCandCmaxarenotsignificantandCiclosporincanbeadministeredwithorwithoutfood.

Ciclosporinisdistributedlargelyoutsidethebloodvolume.Withinblood,

33-47%ispresentinplasma,4-9%inlymphocytes,5-12%ingranulocytesand41-58%inerythrocytes.Inplasma,

approximately90%isboundinproteins,mainlylipoproteins.

Ciclosporinisextensivelybiotransformedtoapproximately15metabolites,therebeingnosinglemajormetabolic

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

theurineasunchangeddrug.

Thereisahighvariabilityinthedatareportedontheterminalhalf-lifeofciclosporindependingontheassayapplied

andthetargetpopulation.Theterminalhalf-liferangedfrom6.3hoursinhealthyvolunteersto20.4hoursinpatients

withsevereliverdisease.

Ciclosporin

2x100mg

(Test) Originatorproduct

2x100mg

(Reference) Test/Reference

90%CI

(n=39)

AUCinf(ng*h*ml -1

4323(883) 4098(934) 1.06(1.03–1.10) 1

Cmax(ng/ml) 1076(294) 958(311)

1.13(1.05–1.22) 1

Tmax(h) 1.68(0.65) 1.75(0.71)

0.00(-0.25;0.13) 2

Ciclosporin

2x100mg

Fedconditions

(TestFed) Ciclosporin

2x100mg

Fasting

conditions

(TestFasting) TestFed/Test

Fasting

90%CI

(n=16)

AUCinf(ng*h*ml -1

4992(1237) 5359(1073)

0.93(0.86;1.01) 1

Cmax(ng/ml) 1109(191) 1308(299)

0.85(0.76;0.96) 1

Tmax(h) 1.81(0.63) 1.31(0.31)

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Ciclosporingavenoevidenceofmutagenicorteratogeniceffectsinappropriatetestsystems.Onlyatdoselevelstoxic

todamswereadverseeffectsseeninreproductionstudiesinrats.Attoxicdoses(ratsat30mg/kgandrabbitsat

100mg/kgadayorally),ciclosporinwasembryo-andfoetotoxicasindicatedbyincreasedprenatalandpost-natal

mortalityandreducedfetalweighttogetherwithrelatedskeletalretardation.Inthewell-tolerateddoserange(ratsupto

17mg/kgandrabbitsupto30mg/kgadayorally),ciclosporinprovedtobewithoutanyembryolethalorteratogenic

effects.

Carcinogenicitystudieswerecarriedoutinmaleandfemaleratsandmice.Inthe78-weekmousestudy,atdosesof1,

4,and16mg/kgaday,evidenceofastatisticallysignificanttrendwasfoundforlymphocyticlymphomasinfemales,

andtheincidenceofhepatocellularcarcinomasinmid-dosemalessignificantlyexceededthecontrolvalue.Inthe24-

monthratstudyconductedat0.5,2and8mg/kgaday,pancreaticisletcelladenomassignificantlyexceededthecontrol

rateatthelowdoselevel.Thehepatocellularcarcinomasandpancreaticisletcelladenomaswerenotdose-related.

Noimpairmentinfertilitywasdemonstratedinstudiesinmaleandfemalerats.

Ciclosporinhasnotbeenfoundmutagenic/genotoxicintheAmestest,theV79-HGPRTtest,themicronucleustestin

miceandChinesehamsters,thechromosome-aberrationtestsinChinesehamsterbonemarrow,themousedominant

lethalassay,andtheDNArepairtestinspermfromtreatedmice.Astudyanalysingsisterchromatidexchange(SCE)

inductionbyciclosporinusinghumanlymphocytesinvitrogaveindicationofapositiveeffect(i.e.inductionofSCE)

athighconcentrationsinthissystem.

Anincreasedincidenceofmalignancyisarecognisedcomplicationofimmunosuppressioninrecipientsoforgan

transplants.Themostcommonformsofneoplasmsarenon-Hodgkin'slymphomaandcarcinomasoftheskin.Therisk

ofmalignanciesduringciclosporintreatmentishigherthaninthenormal,healthypopulation,butsimilartothatin

patientsreceivingotherimmunosuppressivetherapies.Ithasbeenreportedthatreductionordiscontinuanceof

immunosuppressionmaycauselesionstoregress.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Polysorbate20

Sorbitanoleate

Lecithin

Triglyceride

Macrogolglycerolhydroxystearate

Ethyllactate

Ingredientsofthecapsuleshell

Gelatin

Glycerol

Ferricoxideblack(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

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GenfarmaCapsulesshouldbeleftintheblisterpackuntilrequiredforuse.Whenablisterisopened,acharacteristic

smellisnoticeable.

6.5Natureandcontentsofcontainer

Thecapsulesareavailableinblisterpacksofdouble-sidedaluminiumconsistingofanaluminiumbottomfoilandan

aluminiumcoveringfoil,whicharecontainedwithinaprintedcardboardcarton.CiclosporinGenfarma50mg

Capsulesareavailablein30,50or60capsulesineachcarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialinstructions.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/030/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11January2008

Dateoflastrenewal:27January2010

10DATEOFREVISIONOFTHETEXT

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