COPEGUS 200 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • COPEGUS 200 MG FILM-COATED TABLETS
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COPEGUS 200 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/194/001
  • Authorization date:
  • 06-07-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Copegus200mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains200milligramsofribavirin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheUKandFrance:

Lightpink,oval-shapedfilm-coatedtablets(markedwith'RIB200'ononesideand'ROCHE'ontheoppositeside).

4CLINICALPARTICULARS

4.1TherapeuticIndications

CopegusisindicatedforthetreatmentofchronichepatitisCandmustonlybeusedaspartofacombinationregimen

withpeginterferonalfa-2aorwithinterferonalfa-2a.Copegusmonotherapymustnotbeused.

ThecombinationofCopeguswithpeginterferonalfa-2aorinterferonalfa-2aisindicatedinadultpatientswithelevated

transaminasesandwhoarepositiveforserumHCV-RNA,includingpatientswithcompensatedcirrhosis(Seesection

4.4).Thecombinationwithpeginterferonalfa-2aisalsoindicatedinpatientsco-infectedwithclinicallystableHIV,

includingpatientswithcompensatedcirrhosis(Seesection4.3).Thecombinationregimensareindicatedinpreviously

untreatedpatientsaswellasinpatientswhohavepreviouslyrespondedtointerferonalphatherapyandsubsequently

relapsedaftertreatmentwasstopped.

PleaserefertotheSummaryofProductCharacteristics(SPC)ofpeginterferonalfa-2aorinterferonalfa-2afor

prescribinginformationparticulartoeitheroftheseproducts.

4.2Posologyandmethodofadministration

Treatmentshouldbeinitiated,andmonitored,byaphysicianexperiencedinthemanagementofchronichepatitisC.

MethodofAdministration

Copegustabletsareadministeredorallyintwodivideddoseswithfood(morningandevening).Thetabletsshouldnot

bebrokenorcrushed.Sinceribavirinisconsideredapotentialteratogen,cautionshouldbeobservedinhandlingbroken

tablets.

Posology

Copegusisusedincombinationwithpeginterferonalfa-2aorinterferonalfa-2a.Theexactdoseanddurationof

treatmentdependontheinterferonproductused.

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treatmentwhenCopegusistobeusedincombinationwitheitheroftheseproducts.

Posologyincombinationwithpeginterferonalfa-2a:

Dosetobeadministered

TherecommendeddoseofCopegusincombinationwithpeginterferonalfa-2asolutionforinjectiondependsonviral

genotypeandthepatient'sbodyweight(seeTable1).

Durationoftreatment

Thedurationofcombinationtherapywithpeginterferonalfa-2adependsonviralgenotype.PatientsinfectedwithHCV

genotype1regardlessofviralloadshouldreceive48weeksoftherapy.PatientsinfectedwithHCVgenotype2/3

regardlessofviralloadshouldreceive24weeksoftherapy(seeTable1).

Ingeneral,patientsinfectedwithgenotype4areconsideredhardtotreatandlimitedstudydata(N=66)arecompatible

withaposologyasforgenotype1.Whendecidingonthedurationoftherapy,thepresenceofadditionalfactorsshould

alsobeconsidered.Forpatientsinfectedwithgenotype5or6,thisposologyshouldalsobeconsidered.

HIV-HCVCo-infection

TherecommendeddosageforCopegusincombinationwith180microgramsonceweeklyofpeginterferonalfa-2ais

800milligrams,dailyfor48weeks,regardlessofgenotype.Thesafetyandefficacyofcombinationtherapywith

ribavirindosesgreaterthan800milligramsdailyoradurationoftherapylessthan48weekshasnotbeenstudied.

Predictabilityofresponseandnon-response

Earlyvirologicalresponsebyweek12,definedasa2logviralloaddecreaseorundetectablelevelsofHCVRNAhas

beenshowntobepredictiveforsustainedresponse(seeTable2).

AsimilarnegativepredictivevaluehasbeenobservedinHIV-HCVco-infectedpatientstreatedwithpeginterferonalfa-

2amonotherapyorincombinationwithribavirin(100%(130/130)or98%(83/85),respectively).Positivepredictive

valuesof45%(50/110)and70%(59/84)wereobservedforgenotype1andgenotype2/3HIV-HCVco-infected

patientsreceivingcombinationtherapy.

Posologyincombinationwithinterferonalfa-2a:

Dosetobeadministered

TherecommendeddoseofCopegusincombinationwithinterferonalfa-2asolutionforinjectiondependsonthe

Table1.CopegusDosingRecommendationsinCombinationwithPeginterferonalfa-2aforHVC

patients

Genotype DailyCopegusDose Durationof

treatment Numberof200mgtablets

Genotype1 <75kg=1,000mg 48weeks 5(2morning,3evening)

75kg=1,200mg 48weeks 6(3morning,3evening)

Genotype2/3 800mg 24weeks 4(2morning,2evening)

Table2.PredictiveValueofWeek12VirologicalResponseattheRecommendedDosingRegimenwhile

receivingCopegusandpeginterferonCombinationTherapy

Genotype Negative Positive

response

byweek12 No

sustained

response Predictive

Value Response

byweek12 Sustained

response Predictive

Value

Genotype1(N=569) 102 97 95%(97/102) 467 271 58%(271/467)

Genotype2and3

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Durationoftreatment:

Patientsshouldbetreatedwithcombinationtherapywithinterferonalfa-2aforatleastsixmonths.PatientswithHCV

genotype1infectionsshouldreceive48weeksofcombinationtherapy.InpatientsinfectedwithHCVofother

genotypes,thedecisiontoextendtherapyto48weeksshouldbebasedonotherprognosticfactors(suchashighviral

loadatbaseline,malegender,age>40yearsandevidenceofbridgingfibrosis).

Dosagemodificationforadversereactions

PleaserefertotheSPCofpeginterferonalfa-2aorinterferonalfa-2aforfurtherinformationondoseadjustmentand

discontinuationoftreatmentforeitheroftheseproducts.

IfsevereadversereactionsorlaboratoryabnormalitiesdevelopduringtherapywithCopegusandpeginterferonalfa-2a

orinterferonalfa-2a,modifythedosagesofeachproduct,untiltheadversereactionsabate.Guidelinesweredeveloped

inclinicaltrialsfordosemodification(seeDosageModificationGuidelinesforManagementofTreatment-

EmergentAnaemia,Table4).

Ifintolerancepersistsafterdoseadjustment,discontinuationofCopegusorbothCopegusandpeginterferonalfa-2aor

interferonalfa-2amaybeneeded.

*PatientswhosedoseofCopegusisreducedto600mgdailyreceiveone200mgtabletinthemorningandtwo200mg

tabletsintheevening.

**Iftheabnormalityisreversed,Copegusmayberestartedat600mgdaily,andfurtherincreasedto800mgdailyat

thediscretionofthetreatingphysician.However,areturntohigherdosesisnotrecommended.

Specialpopulations

Useinrenalimpairment:Therecommendeddoseregimens(adjustedbythebodyweightcutoffof75kg)ofribavirin

giverisetosubstantialincreasesinplasmaconcentrationsofribavirininpatientswithrenalimpairment.Thereare

insufficientdataonthesafetyandefficacyofribavirininpatientswithserumcreatinine>2mg/dlorcreatinine

clearance<50ml/min,whetherornotonhaemodialysis,tosupportrecommendationsfordoseadjustments.Therefore,

ribavirinshouldbeusedinsuchpatientsonlywhenthisisconsideredtobeessential.Therapyshouldbeinitiated(or

continuedifrenalimpairmentdevelopswhileontherapy)withextremecautionandintensivemonitoringof

haemoglobinconcentrations,withcorrectiveactionasmaybenecessary,shouldbeemployedthroughoutthetreatment

period.(see4.4Specialwarningsandspecialprecautionsforuseandsee5.2Pharmacokineticproperties).

Useinhepaticimpairment:Nopharmacokineticinteractionappearsbetweenribavirinandhepaticfunction(see5.2

Pharmacokineticproperties).Therefore,nodoseadjustmentofCopegusisrequiredinpatientswithhepatic

impairment.Theuseofpeginterferonalfa-2aandinterferonalfa-2aiscontraindicatedinpatientswithdecompensated

cirrhosisandotherformsofseverehepaticimpairment.

Table3.CopegusDosingRecommendationsinCombinationwithInterferonalfa-2a

Patientweight(kg) DailyCopegusdose Durationoftreatment Numberof200mgtablets

<75 1,000mg 24or48weeks 5(2morning,3evening)

1,200mg 24or48weeks 6(3morning,3evening)

Table4.DosageModificationGuidelinesforManagementofTreatment-EmergentAnaemia

LaboratoryValues ReduceonlyCopegusdoseto600mg/day*if: DiscontinueCopegusif:**

HaemoglobininPatients

withNoCardiacDisease <10g/dl <8.5g/dl

Haemoglobin:Patientswith

HistoryofStableCardiac

Disease >2g/dldecreaseinhaemoglobinduringany4week

periodduringtreatment(permanentdosereduction) <12g/dldespite4weeksat

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pharmacokineticsofribavirin.However,asinyoungerpatients,renalfunctionmustbedeterminedpriorto

administrationofCopegus.

Useinpatientsundertheageof18years:Safetyandeffectivenessofribavirinincombinationwithpeginterferonalfa-

2aandinterferonalfa-2ainthesepatientshavenotbeenfullyevaluated.TreatmentwithCopegusisnotrecommended

foruseinchildrenandadolescentsundertheageof18.

4.3Contraindications

Seepeginterferonalfa-2aorinterferonalfa-2aprescribinginformationforcontraindicationsrelatedtoeitherofthese

products.

-hypersensitivitytoribavirinortoanyoftheexcipients.

-pregnantwomen(see4.4Specialwarningsandspecialprecautionsforuse).Copegusmustnotbeinitiateduntila

reportofanegativepregnancytesthasbeenobtainedimmediatelypriortoinitiationoftherapy.

-womenwhoarebreast-feeding(see4.6Pregnancyandlactation).

-ahistoryofseverepre-existingcardiacdisease,includingunstableoruncontrolledcardiacdisease,intheprevioussix

months.

-severehepaticdysfunctionordecompensatedcirrhosisoftheliver.

-haemoglobinopathies(e.g.thalassaemia,sickle-cellanaemia).

-Initiationofpeginterferonalfa-2aiscontraindicatedinHIV-HCVpatientswithcirrhosisandaChild-Pughscoreless

thanorequalto6(PleaserefertotheSPCofpeginterferonalfa-2aforChild-Pughassessment).

4.4Specialwarningsandprecautionsforuse

PleaserefertotheSPCofpeginterferonalfa-2aorinterferonalfa-2aforfutherinformationonspecialwarningsand

precautionsforuserelatedtoeitheroftheseproducts.

AllpatientsinthechronichepatitisCstudieshadaliverbiopsybeforeinclusion,butincertaincases(ie,patientswith

genotype2or3),treatmentmaybepossiblewithouthistologicalconfirmation.Currenttreatmentguidelinesshouldbe

consultedastowhetheraliverbiopsyisneededpriortocommencingtreatment.

InpatientswithnormalALT,progressionoffibrosisoccursonaverageataslowerratethaninpatientswithelevated

ALT.Thisshouldbeconsideredinconjunctionwithotherfactors,suchasHCVgenotype,age,extrahepatic

manifestations,riskoftransmission,etc.,whichinfluencethedecisiontotreatornot.

Basedonresultsofclinicaltrials,theuseofribavirinasmonotherapyisnoteffectiveandCopegusmustnotbeused

alone.

Teratogenicrisk:See4.6Pregnancyandlactation.

Priortoinitiationoftreatmentwithribavirinthephysicianmustcomprehensivelyinformthepatientoftheteratogenic

riskofribavirin,thenecessityofeffectiveandcontinuouscontraception,thepossibilitythatcontraceptivemethodsmay

failandthepossibleconsequencesofpregnancyshoulditoccurduringtreatmentwithribavirin.

Carcinogenicity:Ribavirinismutagenicinsomeinvivoandinvitrogenotoxicityassays.

Apotentialcarcinogeniceffectofribavirincannotbeexcluded(see5.3Preclinicalsafetydata).

HaemolysisandCardiovascularsystem:Adecreaseinhaemoglobinlevelsto<10g/dlwasobservedinupto15%of

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19%ofpatientsincombinationwithinterferonalfa-2a.WhenCopegus800milligramwascombinedwith

peginterferonalfa-2afor24weeks,3%ofpatientshadadecreaseinhaemoglobinlevelsto<10g/dl.Theriskof

developinganaemiaishigherinthefemalepopulation.Althoughribavirinhasnodirectcardiovasculareffects,anaemia

associatedwithCopegusmayresultindeteriorationofcardiacfunction,orexacerbationofthesymptomsofcoronary

disease,orboth.Thus,Copegusmustbeadministeredwithcautiontopatientswithpre-existingcardiacdisease.

Cardiacstatusmustbeassessedbeforestartoftherapyandmonitoredclinicallyduringtherapy;ifanydeterioration

occurs,stoptherapy(see4.2Posologyandmethodofadministration).Patientswithahistoryofcongestiveheart

failure,myocardialinfarction,and/orpreviousorcurrentarrhythmicdisordersmustbecloselymonitored.Itis

recommendedthatthosepatientswhohavepre-existingcardiacabnormalitieshaveelectrocardiogramstakenpriorto

andduringthecourseoftreatment.Cardiacarrhythmias(primarilysupraventricular)usuallyrespondtoconventional

therapybutmayrequirediscontinuationoftherapy.

Acutehypersensitivity:Ifanacutehypersensitivityreaction(e.g.urticaria,angioedema,bronchoconstriction,

anaphylaxis)develops,Copegusmustbediscontinuedimmediatelyandappropriatemedicaltherapyinstituted.

Transientrashesdonotnecessitateinterruptionoftreatment.

Liverfunction:Inpatientswhodevelopevidenceofhepaticdecompensationduringtreatment,Copegusincombination

withpeginterferonalfa-2aorinterferonalfa-2ashouldbediscontinued.WhentheincreaseinALTlevelsisprogressive

andclinicallysignificant,despitedosereduction,orisaccompaniedbyincreaseddirectbilirubin,therapyshouldbe

discontinued.

PsychiatricandCentralNervousSystem(CNS):

Patientswithexistenceofhistoryofseverepsychiatricconditions:

Iftreatmentwithribavirinandpeginterferonalfa-2aorinterferonalfa-2aisjudgednecessaryinpatientswithexistence

orhistoryofseverepsychiatricconditions,thisshouldbeonlyinitiatedafterhavingensuredappropriateindividualised

diagnosticandtherapeuticmanagementofthepsychiatriccondition.

SevereCNSeffects,particularlydepression,suicidalideationandsuicidehavebeenobservedinsomepatientsduring

Copeguscombinationtherapywithpeginterferonalfa-2aorinterferonalfa-2a.OtherCNSeffectsincludingaggressive

behaviour,confusionandalterationsofmentalstatushavebeenobservedwithinterferonalfa-2a.Ifpatientsdevelop

psychiatricorCNSproblems,includingclinicaldepression,itisrecommendedthatpatientsbecarefullymonitoredby

theprescribingphysician.Ifsuchsymptomsappear,thepotentialseriousnessoftheseundesirableeffectsmustbeborne

inmindbytheprescribingphysician.Ifsymptomspersistorworsen,discontinuebothCopegusandpeginterferonalfa-

2aorinterferonalfa-2a.

Renalimpairment:Thepharmacokineticsofribavirinarealteredinpatientswithrenaldysfunctionduetoreductionof

apparentclearanceinthesepatients(see5.2Pharmacokineticproperties).Therefore,itisrecommendedthatrenal

functionbeevaluatedinallpatientspriortoinitiationofCopegus,preferablybyestimatingthepatient'screatinine

clearance.Substantialincreasesinribavirinplasmaconcentrationsareseenattherecommendeddosingregimenin

patientswithserumcreatinine>2mg/dlorwithcreatinineclearance<50ml/minute.Thereareinsufficientdataonthe

safetyandefficacyofCopegusinsuchpatientstosupportrecommendationsfordoseadjustments.Copegustherapy

shouldnotbeinitiated(orcontinuedifrenalimpairmentoccurswhileontreatment)insuchpatients,whetherornoton

haemodialysis,unlessitisconsideredtobeessential.Extremecautionisrequired.Haemoglobinconcentrationsshould

bemonitoredintensivelyduringtreatmentandcorrectiveactiontakenasnecessary(see4.2.Posologyandmethodof

administrationandsee5.2Pharmacokineticproperties).

HIV/HCVCo-infection:PleaserefertotherespectiveSummaryofProductCharacteristicsoftheantiretroviral

medicinalproductsthataretobetakenconcurrentlywithHCVtherapyforawarenessandmanagementoftoxicities

specificforeachproductandthepotentialforoverlappingtoxicitieswithpeginterferonalfa-2awithorwithout

ribavirin.InstudyNR15961,patientsconcurrentlytreatedwithstavudineandinterferontherapywithorwithout

ribavirin,theincidenceofpancreatitisand/orlacticacidosiswas3%(12/398).

ChronichepatitisCpatientsco-infectedwithHIVandreceivingHighlyActiveAnti-RetroviralTherapy(HAART)may

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Co-infectedpatientswithadvancedcirrhosisreceivingHAARTmayalsobeatincreasedriskofhepatic

decompensationandpossiblydeathiftreatedwithCopegusincombinationwithinterferons.Baselinevariablesinco-

infectedcirrhoticpatientsthatmaybeassociatedwithhepaticdecompensationinclude:increasedserumbilirubin,

decreasedhaemoglobin,increasedalkalinephosphataseordecreasedplateletcount,andtreatmentwithdidanosine

(ddI).Cautionshouldthereforebeexercisedwhenaddingpeginterferonalfa-2aandCopegustoHAARTtherapy.(see

4.5Interactionwithothermedicinalproductsandotherformsofinteraction).

Co-infectedpatientsshouldbecloselymonitored,assessingtheirChild-Pughscoreduringtreatment,andshouldbe

immediatelydiscontinuediftheyprogresstoaChild-Pughscoreof7orgreater.

Laboratorytests:Standardhaematologictestsandbloodchemistries(completebloodcount[CBC]anddifferential,

plateletcount,electrolytes,serumcreatinine,liverfunctiontests,uricacid)mustbeconductedinallpatientspriorto

initiatingtherapy.AcceptablebaselinevaluesthatmaybeconsideredasaguidelinepriortoinitiationofCopegusin

combinationwithpeginterferonalfa-2aorinterferonalfa-2a:

Haemoglobin ≥12g/dl(females);13g/dl(males)

Platelets ≥90,000/mm3

NeutrophilCount ≥1,500/mm3

Inpatientsco-infectedwithHIV-HCV,limitedefficacyandsafetydata(N=51)areavailableinsubjectswithCD4

countslessthan200cells/µL.CautionisthereforewarrantedinthetreatmentofpatientswithlowCD4counts.

Laboratoryevaluationsaretobeconductedatweeks2and4oftherapy,andperiodicallythereafterasclinically

appropriate.

Forwomenofchildbearingpotential:Femalepatientsmusthavearoutinepregnancytestperformedmonthlyduring

treatmentandfor6monthsthereafter.Femalepartnersofmalepatientsmusthavearoutinepregnancytestperformed

monthlyduringtreatmentandfor6monthsthereafter.

UricacidmayincreasewithCopegusduetohaemolysisandthereforethepotentialfordevelopmentofgoutmustbe

carefullymonitoredinpredisposedpatients.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshavebeenconductedwithribavirinincombinationwithpeginterferonalfa-2a,interferonalfa-2band

antacids.Ribavirinconcentrationsaresimilarwhengivenaloneorconcomitantlywithinterferonalfa-2bor

peginterferonalfa-2a.

Anypotentialforinteractionsmaypersistforupto2months(5halflivesforribavirin)aftercessationofCopegus

therapyduetothelonghalf-life.

ResultsofinvitrostudiesusingbothhumanandratlivermicrosomepreparationsindicatednocytochromeP450

enzymemediatedmetabolismofribavirin.RibavirindoesnotinhibitcytochromeP450enzymes.Thereisnoevidence

fromtoxicitystudiesthatribavirininducesliverenzymes.Therefore,thereisaminimalpotentialforP450enzyme-

basedinteractions.

Antacid:Thebioavailabilityofribavirin600milligramswasdecreasedbyco-administrationwithanantacidcontaining

magnesium,aluminiumandmethicone;AUCtfdecreased14%.Itispossiblethatthedecreasedbioavailabilityinthis

studywasduetodelayedtransitofribavirinormodifiedpH.Thisinteractionisnotconsideredtobeclinicallyrelevant.

Nucleosideanalogs:Ribavirinwasshowninvitrotoinhibitphosphorylationofzidovudineandstavudine.Theclinical

significanceofthesefindingsisunknown.However,theseinvitrofindingsraisethepossibilitythatconcurrentuseof

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recommendedthatplasmaHIVRNAlevelsbecloselymonitoredinpatientstreatedwithCopegusconcurrentlywith

eitherofthesetwoagents.IfHIVRNAlevelsincrease,theuseofCopegusconcomitantlywithreversetranscriptase

inhibitorsmustbereviewed.

Didanosine(ddI):Ribavirinpotentiatedtheantiretroviraleffectofdidanosine(ddI)invitroandinanimalsby

increasingtheformationoftheactivetriphosphateanabolite(ddATP).Thisobservationalsoraisedthepossibilitythat

concomitantadministrationofribavirinandddImightincreasetheriskofadversereactionsrelatedtoddI(suchas

peripheralneuropathy,pancreatitis,andhepaticsteatosiswithlacticacidosis).Whiletheclinicalsignificanceofthese

findingsisunknown,onestudyofconcomitantribavirinandddIinpatientswithHIVdiseasedidnotresultinfurther

reductionsinviraemiaoranincreaseinadversereactions.PlasmapharmacokineticsofddIwerenotsignificantly

affectedbyconcomitantribavirininthisstudy,althoughintracellularddATPwasnotmeasured.

HIV-HCVco-infectedpatients

Noapparentevidenceofdruginteractionwasobservedin47HIV-HCVco-infectedpatientswhocompleteda12week

pharmacokineticsubstudytoexaminetheeffectofribavirinontheintracellularphosphorylationofsomenucleoside

reversetranscriptaseinhibitors(lamivudineandzidovudineorstavudine).However,duetohighvariability,the

confidenceintervalswerequitewidePlasmaexposureofribavirindidnotappeartobeaffectedbyconcomitant

administrationofnucleosidereversetranscriptaseinhibitors(NRTIs).

Co-administrationofribavirinanddidanosineisnotrecommended.Exposuretodidanosineoritsactivemetabolite

(dideoxyadenosine5'-triphosphate)isincreasedinvitrowhendidanosineisco-administeredwithribavirin.Reportsof

fatalhepaticfailureaswellsasperipheralneuropathy,pancreatitis,andsymptomatichyperlactataemia/lacticacidosis

havebeenreportedwithuseofribavirin.

4.6Fertility,pregnancyandlactation

Preclinicaldata:Significantteratogenicand/orembryocidalpotentialhavebeendemonstratedforribavirininallanimal

speciesinwhichadequatestudieshavebeenconducted,occurringatdoseswellbelowtherecommendedhumandose.

Malformationsoftheskull,palate,eye,jaw,limbs,skeletonandgastrointestinaltractwerenoted.Theincidenceand

severityofteratogeniceffectsincreasedwithescalationoftheribavirindose.Survivaloffoetusesandoffspringwas

reduced.

Femalepatients:Copegusmustnotbeusedbywomenwhoarepregnant(see4.3Contraindicationsandsee4.4

Specialwarningsandspecialprecautionsforuse).Extremecaremustbetakentoavoidpregnancyinfemale

patients.Copegustherapymustnotbeinitiateduntilareportofanegativepregnancytesthasbeenobtained

immediatelypriortoinitiationoftherapy.Anybirthcontrolmethodcanfail.Therefore,itiscriticallyimportantthat

womenofchildbearingpotentialandtheirpartnersmustuse2formsofeffectivecontraceptionsimultaneously,during

treatmentandfor6monthsaftertreatmenthasbeenconcluded;routinemonthlypregnancytestsmustbeperformed

duringthistime.Ifpregnancydoesoccurduringtreatmentorwithin6monthsfromstoppingtreatmentthepatientmust

beadvisedofthesignificantteratogenicriskofribavirintothefoetus.

Malepatientsandtheirfemalepartners:Extremecaremustbetakentoavoidpregnancyinpartnersofmalepatients

takingCopegus.Ribavirinaccumulatesintracellularlyandisclearedfromthebodyveryslowly.Inanimalstudies,

ribavirinproducedchangesinspermatdosesbelowtheclinicaldose.Itisunknownwhethertheribavirinthatis

containedinspermwillexertitsknownteratogeniceffectsuponfertilisationoftheova.Malepatientsandtheirfemale

partnersofchildbearingagemust,therefore,becounselledtouse2formsofeffectivecontraceptionsimultaneously

duringtreatmentwithCopegusandfor6monthsaftertreatmenthasbeenconcluded.Womenmusthaveanegative

pregnancytestbeforetherapyisstarted.

Menwhosepartnersarepregnantmustbeinstructedtouseacondomtominimisedeliveryofribavirintothepartner.

Lactation:Itisnotknownwhetherribavirinisexcretedinhumanmilk.Becauseofthepotentialforadversereactionsin

nursinginfants,nursingmustbediscontinuedpriortoinitiationoftreatment.

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Copegushasnoornegligibleinfluence;however,peginterferonalfa-2aorinterferonalfa-2ausedincombinationmay

haveaneffect.Thus,patientswhodevelopfatigue,somnolence,orconfusionduringtreatmentmustbecautionedto

avoiddrivingoroperatingmachinery.

4.8Undesirableeffects

Seepeginterferonalfa-2aorinterferonalfa-2aprescribinginformationforadditionalundesirableeffectsforeitherof

theseproducts.

ThemostfrequentlyreportedadversereactionswithCopegusincombinationwithpeginterferonalfa-2a180

microgramsweremostlymildtomoderateinseverityandweremanageablewithouttheneedformodificationofdoses

ordiscontinuationoftherapy.

HIV-HCVco-infectedpatients

InHIV-HCVco-infectedpatients,theclinicaladverseeventprofilesreportedforpeginterferonalfa-2a,aloneorin

combinationwithribavirin,weresimilartothoseobservedinHCVmono-infectedpatients.Peginterferonalfa-2a

treatmentwasassociatedwithdecreasesinabsoluteCD4+cellcountswithinthefirst4weekswithoutareductionin

CD4+cellpercentage.ThedecreaseinCD4+cellcountswasreversibleupondosereductionorcessationoftherapy.

Theuseofpeginterferonalfa-2ahadnoobservablenegativeimpactonthecontrolofHIVviraemiaduringtherapyor

follow-up.Limitedsafetydata(N=31)areavailableinco-infectedpatientswithCD4+cellcounts<200/µl.(see

peginterferonalfa-2aSPC).

Table5summarisesthesafetyoverviewofdifferenttreatmentregimensofCopegusincombinationwithpeginterferon

alfa-2aforHCVandHIV-HCVpatients.

Table6showsthemostcommonundesirableeffectsreportedin10%ofpatientswhohavereceivedCopegusand

peginterferonalfa-2aorinterferonalfa-2atherapy.

Table5.SafetyOverviewofCopegusTreatmentRegimensinCombinationwithPeginteferonalfa-2a

forHCVandHIV-HCVpatients

HCVmono-

infection

Copegus800mg

24weeks

&

PEG-IFNalfa-2a180

HCVmono-

infection

Copegus1000/1200

48weeks

&

PEG-IFNalfa-2a

HIV-HCVco-

Infection

Copegus800mg

48weeks

&

PEG-INFalfa-2a

180mcg

Seriousadverseevents 3% 11% 17%

Anaemia

(haemoglobin<10g/dl) 3% 15% 14%

Ribavirindosemodification 19% 39% 37%

Prematurewithdrawalsdueto

adverseevents 4% 10% 12%

Prematurewithdrawalsdueto

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asforthosereportedforCopegusincombinationwithpeginterferonalfa-2a.Table6:AdverseReactions(10%

IncidenceinAnyTreatmentGroup)forHCVandHIV-HCVpatients

Table6:AdverseReactions( ≥ 10%IncidenceinAnyTreatmentGroup)forHCVandHIV-HCVpatients

Copegus

800mg

&

Peginterferon

alfa-2a

180micrograms

(NV15942)

24weeks

Copegus

1,000or1,200mg

&

Peginterferon

alfa-2a

180micrograms

(NV15801+

NV15942)

48weeks

HIV-HCV

Copegus

800mg

&

Peginterferon

Alfa-2a

180micrograms

(NR15961)

48weeks

N=288

BodySystem % % %

Metabolism&Nutritiondisorders

Anorexia 20% 27% 23%

WeightDecrease 2% 7% 16%

PsychiatricDisorders

Insomnia 30% 32% 19%

Irritability 28% 24% 15%

Depression 17% 21% 22%

ConcentrationImpairment 8% 10% 2%

Nervoussystemdisorders

Headache 48% 47% 35%

Dizziness 13% 15% 7%

Respiratory,thoracicandmediastinal

disorders

Dyspnoea 11% 13% 7%

Cough 8% 13% 3%

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Undesirableeffectsreportedin<10%patientsonCopegusincombinationwithpeginterferonalfa-2aorCopegusin

Nausea 29% 28% 24%

Diarrhoea 15% 14% 16%

AbdominalPain 9% 10% 7%

Skinandsubcutaneoustissuedisorders

Alopecia 25% 24% 10%

Pruritus 25% 21% 5%

Dermatitis 15% 16% 1%

Dryskin 13% 12% 4%

Musculoskeletal,connectivetissueand

bonedisorders

Myalgia 42% 38% 32%

Arthralgia 20% 22% 16%

Generaldisordersandadministrationsite

conditions

Fatigue 45% 49% 40%

Pyrexia 37% 39% 41%

Rigors 30% 25% 16%

Asthenia 18% 15% 26%

Pain 9% 10% 6%

InjectionSiteReaction 28% 21%

Table7.UndesirableEffects(<10%Incidence)ReportedforHCVandHIV-HCVpatients

Bodysystem Common Common UncommontoRareserious

adverseevents

<10%-5% <5%-1% <1%-<0.1%

Infectionsand

infestations herpessimplex,URI

infection,bronchitis,oral

candidiasis Skininfection,lower

respiratorytractinfection,otitis

externa,endocarditis

Neoplasmsbenignand

malignant Hepaticneoplasm

Bloodandlymphatic

systemdisorders Anaemia,

lymphadenopathy,

thrombocytopenia

Immunesystem

disorders ITP,thyroiditis,psoriasis,

rheumatoidarthritis,SLE,

sarcoidosis,anaphylaxis

Endocrinedisorders Hypothyroidism,

hyperthyroidism Diabetes

Psychiatricdisorders moodalteration,emotional

disorders,anxiety Nervousness,libido

decreased,aggression Suicideideation,suicide,

anger

Nervoussystem

disorders memoryimpairment tastedisturbance,

weakness,paraesthesia,

hypoaesthesia,tremor,

migraine,somnolence,

hyperaesthesia,nightmares,

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Veryrarely,alphainterferonsincludingpeginterferonalfa-2a,usedincombinationwithCopegus,maybeassociated

withpancytopeniaincludingaplasticanaemia.

ForHIV-HCVpatientsreceivingCopegusandpeginterferonalfa-2acombinationtherapy,otherundesirableeffects

havebeenreportedin1%to2%ofpatients:hyperlactacidaemia/lacticacidosis,influenza,pneumonia,affectlability,

apathy,tinnitus,pharyngolaryngealpain,cheilitis,acquiredlipodystrophyandchromaturia.

Laboratoryvalues:InclinicaltrialsofCopegusincombinationwithpeginterferonalfa-2aorinterferonalfa-2a,the

majorityofcasesofabnormallaboratoryvaluesweremanagedwithdosemodifications(see4.2Posologyandmethod

ofadministration,DosageModificationGuidelines).Withpeginterferonalfa-2aandCopeguscombination

treatment,upto2%ofpatientsexperiencedincreasedALTlevelsthatledtodosemodificationordiscontinuationof

treatment.

Haemolysisisthedefiningtoxicityofribavirintherapy.Adecreaseinhaemoglobinlevelsto<10g/dlwasobservedin

Eyedisorders visionblurred,eye

inflammation,

xerophthalmia,eyepain Cornealulcer,retinopathy,

retinalvasculardisorder,

retinalhaemorrhage,

papilloedema,optic

neuropathy,visionloss

Earandlabyrinth

disorders vertigo,earache

Cardiacdisorders Palpitations,oedema

peripheral,tachycardia Arrhythmia,supraventricular

tachycardia,atrialfibrillation,

CHF,angina,myocardial

infarction,pericarditis

Vasculardisorders Flushing Cerebralhaemorrhage,

hypertension

Respiratory,thoracicand

mediastinaldisorders sorethroat,dyspnoea

exertional,epistaxis,

nasopharyngitis,sinus

congestion,rhinitis,nasal

congestion Bronchoconstriction,interstitial

pneumonitiswithfatal

outcome,pulmonaryembolism

Gastrointestinal

disorders vomiting,drymouth,

dyspepsia mouthulceration,flatulence,

gingivalbleeding,stomatitis,

dysphagia,glossitis Pepticulcer,gastrointestinal

bleeding,reversiblepancreatic

reaction(ie,amylase/lipase

increasewithorwithout

abdominalpain)

Hepato-biliarydisorders Hepaticfailure,hepatic

dysfunction,fattyliver,

cholangitis

Skinandsubcutaneous

tissuedisorders rash,sweatingincreased Eczema,nightsweats,

psoriasis,photosensitivity

reaction,urticaria,skin

disorder Angioedema

Musculoskeletal,

connectivetissueand

bonedisorders Backpain Musclecramps,neckpain,

musculoskeletalpain,bone

pain,arthritis,muscle

weakness Myositis

Reproductivesystem

andbreastdisorders Impotence

Generaldisordersand

administrationsite

conditions Malaise,lethargy,chest

pain,hotflushes,thirst,

influenzalikeillness

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2aandupto19%ofpatientsincombinationwithinterferonalfa-2a.WhenCopegus800milligramwascombinedwith

peginterferonalfa-2afor24weeks,3%ofpatientshadadecreaseinhaemoglobinlevelsto<10g/dl.Itisnotexpected

thatpatientswillneedtodiscontinuetherapybecauseofdecreaseinhaemoglobinlevelsalone.Inmostcasesthe

decreaseinhaemoglobinoccurredearlyinthetreatmentperiodandstabilisedconcurrentlywithacompensatory

increaseinreticulocytes.

Mostcasesofanaemia,leukopeniaandthrombocytopeniaweremild(WHOgrade1).WHOgrade2laboratorychanges

wasreportedforhaemoglobin(4%ofpatients),leucocytes(24%ofpatients)andthrombocytes(2%ofpatients).

Moderate(absoluteneutrophilcount(ANC):0.749-0.5x109/L)andsevere(ANC:<0.5x109/L)neutropeniawas

observedin24%(216/887)and5%(41/887)ofpatientsreceiving48weeksofCopegus1000/1200milligramsin

combinationwithpeginterferonalfa-2a.

Anincreaseinuricacidandindirectbilirubinvaluesassociatedwithhaemolysiswereobservedinsomepatientstreated

withCopegususedincombinationwithpeginterferonalfa-2aorinterferonalfa-2aandvaluesreturnedtobaseline

levelswithin4weeksaftertheendoftherapy.Inrarecases(2/755)thiswasassociatedwithclinicalmanifestation

(acutegout).

LaboratoryvaluesforHIV-HCVco-infectedpatients

Althoughhaematologicaltoxicitiesofneutropenia,thrombocytopeniaandanaemiaoccurredmorefrequentlyinHIV-

HCVpatients,themajoritycouldbemanagedbydosemodificationandtheuseofgrowthfactorsandinfrequently

requiredprematurediscontinuationoftreatment.DecreaseinANClevelsbelow500cells/mm3wasobservedin13%

and11%ofpatientsreceivingpeginterferonalfa-2amonotherapyandcombinationtherapy,respectively.Decreasein

plateletsbelow50,000/mm3wasobservedin10%and8%ofpatientsreceivingpeginterferonalfa-2amonotherapyand

combinationtherapyrespectively.Anaemia(haemoglobin<10g/dL)wasreportedin7%and14%ofpatientstreated

withpeginterferonalfa-2amonotherapyorincombinationtherapy,respectively.

4.9Overdose

NocasesofoverdoseofCopegushavebeenreportedinclinicaltrials.Hypocalcaemiaandhypomagnesaemiahave

beenobservedinpersonsadministereddosagesgreaterthanfourtimesthemaximalrecommendeddosages.Inmanyof

theseinstancesribavirinwasadministeredintravenously.Ribavirinisnoteffectivelyremovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Directactingantivirals,nucleosidesandnucleotides(excl.reversetranscriptaseinhibitors),

ATCcode:J05AB04.

MechanismofAction:RibavirinisasyntheticnucleosideanalogthatshowsinvitroactivityagainstsomeRNAand

DNAviruses.Themechanismbywhichribavirinincombinationwithpeginterferonalfa-2aorinterferonalfa-2aexerts

itseffectsagainstHCVisunknown.

HCVRNAlevelsdeclineinabiphasicmannerinrespondingpatientswithhepatitisCwhohavereceivedtreatment

with180microgramspeginterferonalfa-2a.Thefirstphaseofdeclineoccurs24to36hoursafterthefirstdoseof

peginterferonalfa-2aandisfollowedbythesecondphaseofdeclinewhichcontinuesoverthenext4to16weeksin

patientswhoachieveasustainedresponse.

Copegushadnosignificanteffectontheinitialviralkineticsoverthefirst4to6weeksinpatientstreatedwiththe

combinationofCopegusandpegylatedinterferonalfa-2aorinterferonalfa.

OralformulationsofribavirinmonotherapyhavebeeninvestigatedastherapyforchronichepatitisCinseveralclinical

trials.Resultsoftheseinvestigationsshowedthatribavirinmonotherapyhadnoeffectoneliminatinghepatitisvirus

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ClinicalTrialResults

Copegusincombinationwithpeginterferonalfa-2a

Predictabilityofresponse

Pleaserefertosection4.2Posologyandmethodofadministration,inTable2.

Studyresults

EfficacyandsafetyofthecombinationofCopegusandpeginterferonalfa-2awereestablishedintwopivotalstudies

(NV15801+NV15942),includingatotalof2405patients.Thestudypopulationcomprisedinterferon-naïvepatients

withCHCconfirmedbydetectablelevelsofserumHCVRNA,elevatedlevelsofALT,andaliverbiopsyconsistent

withchronichepatitisCinfection.OnlyHIV-HCVco-infectedpatientswereincludedinthestudyNR15961(seeTable

10).ThesepatientshadstableHIVdiseaseandmeanCD4T-cellcountwasabout500cells/µl.

StudyNV15801(1121patientstreated)comparedtheefficacyof48weeksoftreatmentwithpeginterferonalfa-2a(180

mcgonceweekly)andCopegus(1000/1200mgdaily)witheitherpeginterferonalfa-2amonotherapyorcombination

therapywithinterferon-alfa-2bandribavirin.Thecombinationofpeginterferonalfa-2aandCopeguswassignificantly

moreefficaciousthaneitherthecombinationofinterferonalfa-2bandribavirinorpeginterferonalfa-2amonotherapy.

StudyNV15942(1284patientstreated)comparedtheefficacyoftwodurationsoftreatment(24weekswith48weeks)

andtwodosagesofCopegus(800mgwith1000/1200mg).

ForHCVmonoinfectedpatientsandHIV-HCVco-infectedpatients,fortreatmentregimens,durationoftherapyand

studyoutcomeseetables8,9and10,respectively.VirologicalresponsewasdefinedasundetectableHCVRNAas

measuredbytheCOBASAMPLICOR™HCVTest,version2.0(limitofdetection100copies/mlequivalentto50

InternationalUnits/ml)andsustainedresponseasonenegativesampleapproximately6monthsaftertheendoftherapy.

ThevirologicalresponsesofpatientstreatedwithCopegusandpeginterferonalfa-2acombinationtherapyinrelationto

genotypeandviralloadaresummarisedintable9

forHCVmonoinfectedpatientsand10forHIV-HCVco-infectedpatientsrespectively.TheresultsofstudyNV15942

Table8VirologicalResponseintheoverallpopulation(includingnon-cirrhoticandcirrhoticpatients)

StudyNV15942 StudyNV15801

Copegus

1,000/1,200mg

&

Peginterferonalfa-2a

180micrograms

(N=436)

Copegus

1,000/1,200mg

&

Peginterferonalfa-2a

180micrograms

(N=453)

Ribavirin

1,000/1,200mg

&

Interferonalfa-2b

3MIU

(N=444)

48weeks

ResponseatEndof

Treatment 68% 69% 52%

OverallSustained

Response 63% 54%* 45%*

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Thedifferencebetweentreatmentregimenswasingeneralnotinfluencedbyviralloadorpresence/absenceof

cirrhosis;thereforetreatmentrecommendationsforgenotype1,2or3areindependentofthesebaselinecharacteristics.

*Copegus1000/1200mg+peginterferonalfa-2a180mcg,48wvs.Copegus800mg+peginterferonalfa-2a180mcg,

48w:OddsRatio(95%CI)=1.52(1.07to2.17)P-value(stratifiedCochran-Mantel-Haenszeltest)=0.020

†Copegus1000/1200mg+peginterferonalfa-2a180mcg,48wvs.Copegus1000/1200mg+peginterferonalfa-2a

180mcg,24w:OddsRatio(95%CI)=2.12(1.30to3.46)P-value(stratifiedCochran-Mantel-Haenszeltest)=0.002

HCVpatientswithnormalALT:

InstudyNR16071,HCVpatientswithnormalALTvalueswererandomisedtoreceivepeginterferonalfa-2a180

micrograms/weekwithaCopegusdoseof800milligrams/dayforeither24or48weeksfollowedbya24week

treatmentfreefollow-upperiodoranuntreatedcontrolgroupfor72weeks.TheSVRsreportedinthetreatmentarmsor

thisstudyweresimilartothecorrespondingtreatmentarmsfromstudyNV15942.

Table9.SustainedVirologicalResponsebasedonGenotypeandViralLoadafterCopegusCombination

Therapywithpeginterferonalfa-2a

StudyNV15942 StudyNV15801

Copegus

800mg

&

PEG-IFN

alfa-2a

180mcg

Copegus

1000/1200mg

&

PEG-IFN

alfa-2a

180mcg

Copegus

800mg

&

PEG-IFN

alfa-2a

180mcg

Copegus

1000/1200mg

&

PEG-IFN

alfa-2a

180mcg

Copegus

1000/1200mg

&

PEG-IFN

alfa-2a

180mcg

Ribavirin

1000/1200mg

&

Interferon

alfa-2b

3MIU

48weeks

Genotype1 29%

(29/101) 42%(49/118)†41%(102/250)

52%(142/271)*†45%(134/298) 36%(103/285)

Lowviralload41%(21/51)52%(37/71) 55%(33/60) 65%(55/85) 53%(61/115) 44%(41/94)

Highviral

load 16%(8/50) 26%(12/47) 36%(69/190)47%(87/186) 40%(73/182) 33%(62/189)

Genotype2/384%(81/96)81%(117/144)79%(78/99) 80%(123/153) 71%(100/140) 61%(88/145)

Lowviralload85%(29/34)83%(39/47) 88%(29/33) 77%(37/48) 76%(28/37) 65%(34/52)

Highviral

load 84%(52/62)80%(78/97) 74%(49/66) 82%(86/105) 70%(72/103) 58%(54/93)

Genotype4 0%(0/5) 67%(8/12) 63%(5/8) 82%(9/11) 77%(10/13) 45%(5/11)

Table10SustainedVirologicalResponsebasedonGenotypeandViralLoad

afterCopegusCombinationTherapywithpeginterferonalfa-2ainHIV-HCVco-

infectedpatients

StudyNR15961

Interferonalfa-2a

3MIU

&

Copegus800mg Peginterferonalfa-

180mcg

& Peginterferonalfa-2a

180mcg

&

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*peginterferonalfa-2a180mcgCopegus800mgvs.Interferonalfa-2a3MIUribavirin800mg:OddsRatio(95%CI)=

5.40(3.42to8.54),.P-value(stratifiedCochran-Mantel-Haenszeltest)=<0.0001

*peginterferonalfa-2a180mcgCopegus800mgvs.peginterferonalfa-2a180µg:OddsRatio(95%CI)=2.89(1.93to

4.32),.P-value(stratifiedCochran-Mantel-Haenszeltest)=<0.0001

*Interferonalfa-2a3MIUCopegus800mgvs.peginterferonalfa-2a180mcg:OddsRatio(95%CI)=0.53(0.33to

0.85),P-value(stratifiedCochran-Mantel-Haenszeltest)=<0.0084.

Ribavirinincombinationwithinterferonalfa-2a

Thetherapeuticefficacyofinterferonalfa-2aaloneandincombinationwithoralribavirinwascomparedinclinical

trialsinnaïve(previouslyuntreated)andrelapsedpatientswhohadvirologically,biochemicallyandhistologically

documentedchronichepatitisC.Sixmonthsafterendoftreatmentsustainedbiochemicalandvirologicalresponseas

wellashistologicalimprovementwereassessed.

Astatisticallysignificant10-foldincrease(from4%to43%;p<0.01)insustainedvirologicalandbiochemical

responsewasobservedinrelapsedpatients(M23136;N=99).Thefavourableprofileofthecombinationtherapywas

alsoreflectedintheresponseratesrelativetoHCVgenotypeorbaselineviralload.Inthecombinationandinterferon

monotherapyarms,respectively,thesustainedresponseratesinpatientswithHCVgenotype-1were28%versus0%

andwithgenotypenon-1were58%versus8%.Inadditionthehistologicalimprovementfavouredthecombination

therapy.Supportivefavourableresults(monotherapyvscombination;6%vs48%,p<0.04)fromasmallpublished

studyinnaïvepatients(N=40)werereportedusinginterferonalfa-2a(3MIU3timesperweek)withribavirin.

5.2Pharmacokineticproperties

RibavirinisabsorbedrapidlyfollowingoraladministrationofasingledoseofCopegus(medianTmax=1-2hours).

Themeanterminalphasehalf-lifeofribavirinfollowingsingledosesofCopegusrangefrom140to160hours.

Ribavirindatafromtheliteraturedemonstratesabsorptionisextensivewithapproximately10%ofaradiolabeleddose

excretedinthefaeces.However,absolutebioavailabilityisapproximately45%-65%,whichappearstobeduetofirst

passmetabolism.ThereisalinearrelationshipbetweendoseandAUCtffollowingsingledosesof200-1,200

milligramsribavirin.Meanapparentoralclearanceofribavirinfollowingsingle600milligramdosesofCopegusranges

from22to29litres/hour.Volumeofdistributionisapproximately4,5001itresfollowingadministrationofCopegus.

Ribavirindoesnotbindtoplasmaproteins.

Ribavirinhasbeenshowntoproducehighinter-andintra-subjectpharmacokineticvariabilityfollowingsingleoral

dosesofCopegus(intra-subjectvariabilityof25%forbothAUCandCmax),whichmaybeduetoextensivefirstpass

metabolismandtransferwithinandbeyondthebloodcompartment.

Ribavirintransportinnon-plasmacompartmentshasbeenmostextensivelystudiedinredcells,andhasbeenidentified

tobeprimarilyviaanes-typeequilibrativenucleosidetransporter.Thistypeoftransporterispresentonvirtuallyallcell

typesandmayaccountforthehighvolumeofdistributionofribavirin.Theratioofwholeblood:plasmaribavirin

concentrationsisapproximately60:1;theexcessofribavirininwholebloodexistsasribavirinnucleotidessequestered

48weeks Placebo

48weeks 48weeks

Allpatients 12%(33/285)* 20%(58/286)* 40%(116/289)*

Genotype1 7%(12/171) 14%(24/175) 29%(51/176)

Lowviralload 19%(8/42) 38%(17/45) 61%(28/46)

Highviralload 3%(4/129) 5%(7/130) 18%(23/130)

Genotype2-3 20%(18/89) 36%(32/90) 62%(59/95)

Lowviralload 27%(8/30) 38%(9/24) 61%(17/28)

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Ribavirinhastwopathwaysofmetabolism:1)areversiblephosphorylationpathway,2)adegradativepathway

involvingderibosylationandamidehydrolysistoyieldatriazolecarboxyacidmetabolite.Ribavirinandbothitstriazole

carboxamideandtriazolecarboxylicacidmetabolitesareexcretedrenally.

Uponmultipledosing,ribavirinaccumulatesextensivelyinplasmawithasix-foldratioofmultiple-dosetosingle-dose

AUC12hrbasedonliteraturedata.Followingoraldosingwith600milligramsBID,steady-statewasreachedby

approximately4weeks,withmeansteadystateplasmaconcentrationsofapproximately2,200ng/ml.Upon

discontinuationofdosingthehalf-lifewasapproximately300hours,whichprobablyreflectssloweliminationfrom

non-plasmacompartments.

Foodeffect:Thebioavailabilityofasingleoral600mgdoseCopeguswasincreasedbycoadministrationofahighfat

meal.TheribavirinexposureparametersofAUC(0-192h)andCmaxincreasedby42%and66%,respectively,when

Copeguswastakenwithahighfatbreakfastcomparedtobeingtakeninthefastedstate.Theclinicalrelevanceof

resultsfromthissingledosestudyisunknown.Ribavirinexposureaftermultipledosingwhentakenwithfoodwas

comparableinpatientsreceivingpeginterferonalfa-2aandCopegusandinterferonalfa-2bandribavirin.Inorderto

achieveoptimalribavirinplasmaconcentrations,itisrecommendedtotakeribavirinwithfood.

Renalfunction:Single-doseribavirinpharmacokineticswerealtered(increasedAUCtfandCmax)inpatientswithrenal

dysfunctioncomparedwithcontrolsubjectswhosecreatinineclearancewasgreaterthan90ml/minute.Theclearance

ofribavirinissubstantiallyreducedinpatientswithserumcreatinine>2mg/dlorcreatinineclearance<50ml/min.

Thereareinsufficientdataonthesafetyandefficacyofribavirininsuchpatientstosupportrecommendationsfordose

adjustments.Plasmaconcentrationsofribavirinareessentiallyunchangedbyhaemodialysis.

Hepaticfunction:Single-dosepharmacokineticsofribavirininpatientswithmild,moderateorseverehepatic

dysfunction(Child-PughClassificationA,BorC)aresimilartothoseofnormalcontrols.

Useinelderlypatientsovertheageof65:Specificpharmacokineticevaluationsforelderlysubjectshavenotbeen

performed.However,inapublishedpopulationpharmacokineticstudy,agewasnotakeyfactorinthekineticsof

ribavirin;renalfunctionisthedeterminingfactor.

Patientsundertheageof18years:Thepharmacokineticpropertiesofribavirinhavenotbeenfullyevaluatedinpatients

undertheageof18years.Copegusincombinationwithpeginterferonalfa-2orinterferonalfa-2aisindicatedforthe

treatmentofchronichepatitisConlyinpatients18yearsofageorolder.

PopulationPharmacokinetics:Apopulationpharmacokineticanalysiswasperformedusingplasmaconcentration

valuesfromfiveclinicaltrials.Whilebodyweightandracewerestatisticallysignificantcovariatesintheclearance

modelonlytheeffectofbodyweightwasclinicallysignificant.Clearanceincreasedasafunctionofbodyweightand

waspredictedtovaryfrom17.7to24.8L/hoveraweightrangeof44to155kg.Creatinineclearance(aslowas34

ml/min)didnotaffectribavirinclearance.

5.3Preclinicalsafetydata

Ribavirinisembryotoxicand/orteratogenicatdoseswellbelowtherecommendedhumandoseinallanimalspeciesin

whichadequatestudieshavebeenconducted.Malformationsoftheskull,palate,eye,jaw,limbs,skeletonand

gastrointestinaltractwerenoted.Theincidenceandseverityofteratogeniceffectsincreasedwithescalationofthedose.

Survivaloffoetusesandoffspringisreduced.

Erythrocytesareaprimarytargetoftoxicityforribavirininanimalstudies,includingstudiesindogsandmonkeys.

Anaemiaoccursshortlyafterinitiationofdosing,butisrapidlyreversibleuponcessationoftreatment.Hypoplastic

anaemiawasobservedonlyinratsatthehighdoseof160milligrams/kg/dayinthesubchronicstudy.

Reducedleucocyteand/orlymphocytecountswereconsistentlynotedintherepeat-doserodentanddogtoxicitystudies

withribavirinandtransientlyinmonkeysadministeredribavirininthesubchronicstudy.Repeat-doserattoxicity

studiesshowedthymiclymphoiddepletionand/ordepletionofthymus-dependentareasofthespleen(periarteriolar

lymphoidsheaths,whitepulp)andmesentericlymphnode.Followingrepeat-dosingofdogswithribavirin,increased

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intestineanderosionoftheileum.

Inrepeatdosestudiesinmicetoinvestigateribavirin-inducedtesticularandspermeffects,abnormalitiesinsperm

occurredatdosesinanimalswellbelowtherapeuticdoses.Uponcessationoftreatment,essentiallytotalrecoveryfrom

ribavirin-inducedtesticulartoxicityoccurredwithinoneortwospermatogeniccycles.

Genotoxicitystudieshavedemonstratedthatribavirindoesexertsomegenotoxicactivity.Ribavirinwasactiveinanin

vitroTransformationAssay.Genotoxicactivitywasobservedininvivomousemicronucleusassays.Adominantlethal

assayinratswasnegative,indicatingthatifmutationsoccurredinratstheywerenottransmittedthroughmalegametes.

Ribavirinisapossiblehumancarcinogen.

Administrationofribavirinandpeginterferonalfa-2aincombinationdidnotproduceanyunexpectedtoxicityin

monkeys.Themajortreatment-relatedchangewasreversiblemildtomoderateanaemia,theseverityofwhichwas

greaterthanthatproducedbyeitheractivesubstancealone.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Pregelatinisedstarch

Sodiumstarchglycolate

Microcrystallinecellulose

Maizestarch

Magnesiumstearate

Film-coating:

Hypromellose

Talc

Titaniumdioxide(E171)

Yellowironoxide(E172)

Redironoxide(E172)

Ethylcelluloseaqueousdispersion

Triacetin

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage

6.5Natureandcontentsofcontainer

Copegusissuppliedinbottleswithachild-resistantcapcontaining42or168tablets.

Notallpacksizesmaybemarketed.

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suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/194/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:6thJuly2007

10DATEOFREVISIONOFTHETEXT

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