FAMCICLOVIR

Main information

  • Trade name:
  • FAMCICLOVIR Film Coated Tablet 500 Milligram
  • Dosage:
  • 500 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FAMCICLOVIR Film Coated Tablet 500 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1585/005/003
  • Authorization date:
  • 14-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Famciclovir500mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains500mgfamciclovir.

Eachtabletcontains44mglactose.

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Famciclovir500mgtabletsarewhitetooff-whitecoloured,capsuleshaped,biconvexfilm-coatedtablets

plainonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Varicellazostervirus(VZV)infections–herpeszoster

Famciclovirisindicatedfor

-thetreatmentofherpeszosterandophthalmiczosterinimmunocompetentadults(see

section4.4)

-thetreatmentofherpeszosterinimmunocompromisedadults(seesection4.4)

Herpessimplexvirus(HSV)infections–genitalherpes

Famciclovirisindicatedfor

-thetreatmentoffirstandrecurrentepisodesofgenitalherpesinimmunocompetentadults

-thetreatmentofrecurrentepisodesofgenitalherpesinimmunocompromisedadults

-thesuppressionofrecurrentgenitalherpesinimmunocompetentandimmunocompromisedadults

ClinicalstudieshavenotbeenconductedinHSV-infectedpatientsimmunocompromisedforothercauses

thanHIV-infection(seesection5.1).

4.2Posologyandmethodofadministration

Herpeszosterinimmunocompetentadults

500mgthreetimesdailyforsevendays.

Treatmentshouldbeinitiatedassoonaspossibleafteradiagnosisofherpeszoster.

Herpeszosterinimmunocompromisedadults

500mgthreetimesdailyfortendays.

Treatmentshouldbeinitiatedassoonaspossibleafteradiagnosisofherpeszoster.

Genitalherpesinimmunocompetentadults

Firstepisodeofgenitalherpes:250mgthreetimesdailyforfivedays.Initiationoftreatmentisrecommendedassoon

aspossibleafteradiagnosisoffirstepisodeofgenitalherpes.

Episodictreatmentofrecurrentgenitalherpes:125mgtwicedailyforfivedays.Initiationoftreatmentisrecommended

assoonaspossibleafteronsetofprodromalsymptoms(e.g.tingling,itching,burning,pain)orlesions.

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Episodictreatmentofrecurrentgenitalherpes:500mgtwicedailyforsevendays.Initiationoftreatmentis

recommendedassoonaspossibleafteronsetofprodromalsymptoms(e.g.tingling,itching,burning,pain)orlesions.

Suppressionofrecurrentgenitalherpesinimmunocompetentadults

250mgtwicedaily.Suppressivetherapyshouldbediscontinuedafteramaximumof12monthsofcontinuousantiviral

therapytoreassessrecurrencefrequencyandseverity.Theminimumperiodofreassessmentshouldincludetwo

recurrences.Patientswhocontinuetohavesignificantdiseasemayrestartsuppressivetherapy.

Suppressionofrecurrentgenitalherpesinimmunocompromisedadults500mgtwicedaily.

Patientswithrenalimpairment

Becausereducedclearanceofpenciclovirisrelatedtoreducedrenalfunction,asmeasuredbycreatinineclearance,

specialattentionshouldbegiventodosesinpatientswithimpairedrenalfunction.Doserecommendationsforadult

patientswithrenalimpairmentareprovidedinTable1.

Table1 Doserecommendationsforadultpatientswithrenalimpairment

Indicationofnominaldose

regimen Creatinineclearance

[ml/min] Adjusteddoseregimen

Herpeszosterin

immunocompetentadults

500mgthreetimesdailyfor7days 60 500mgthreetimesdailyfor7

days

40to59 500mgtwicedailyfor7days

20to39 500mgoncedailyfor7days

<20 250mgoncedailyfor7days

Haemodialysispatients 250mgfollowingeachdialysis

during7days

Herpeszosterin

immunocompromisedadults

500mgthreetimesdailyfor

10days 60 500mgthreetimesdailyfor10

days

40to59 500mgtwicedailyfor10days

20to39 500mgoncedailyfor10days

<20 250mgoncedailyfor10days

Haemodialysispatients 250mgfollowingeachdialysis

during10days

Genitalherpesin

immunocompetentadults–first

episodicofgenitalherpes

125mgtwicetimesdailyfor

5days 40 250mgthreetimesdailyfor5

days

20to39 250mgtwicedailyfor5days

<20 250mgoncedailyfor5days

Haemodialysispatients 250mgfollowingeachdialysis

during5days

Genitalherpesin

immunocompetentadults–

episodictreatmentorrecurrent

genitalherpes

125mgtwicetimesdailyfor

5days 20 125mgthreetimesdailyfor5

days

<20 125mgoncedailyfor5days

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Patientswithrenalimpairmentonhaemodialysis

Since4hhaemodialysisresultedinupto75%reductioninplasmapenciclovirconcentrations,famciclovirshouldbe

administeredimmediatelyfollowingdialysis.Therecommendeddoseregimensforhaemodialysispatientsareincluded

inTable1.

Patientswithhepaticimpairment

Nodoseadjustmentisrequiredinpatientswithmildormoderatehepaticimpairment.Nodataareavailableforpatients

withseverehepaticimpairment(seesections4.4and5.2).

Elderlypatients(65years)

Dosemodificationisnotrequiredunlessrenalfunctionisimpaired.

Childrenandadolescents

Famciclovirisnotrecommendedforuseinchildrenandadolescentsbelow18yearsofageduetolackofdataonsafety

andefficacy.

Methodofadministration

Famciclovircanbetakenwithoutregardtomeals(seesection5.2).

4.3Contraindications

during5days

Genitalherpesin

immunocompromisedadults–

episodictreatmentorrecurrent

genitalherpes

500mgtwicetimesdailyfor

7days 40 500mgthreetimesdailyfor7

days

20to39 500mgtwicedailyfor7days

<20 250mgoncedailyfor7days

Haemodialysispatients 250mgfollowingeachdialysis

during7days

Suppressionofrecurrentgenital

herpesinimmunocompetentadult

250mgtwicedaily 40 250mgtwicedaily

20to39 125mgtwicedaily

<20 125mgoncedaily

Haemodialysispatients 125mgfollowingeachdialysis

Suppressionofrecurrentgenital

herpesinimmunocompromised

adults

500mgtwicedaily 40 500mgtwicedaily

20to39 500mgtwicedaily

<20 250mgoncedaily

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4.4Specialwarningsandprecautionsforuse

Useinpatientswithrenalimpairment

Inpatientswithimpairedrenalfunctiondoseadjustmentisnecessary(seesections4.2and4.9).

Useinpatientswithhepaticimpairment

Famciclovirhasnotbeenstudiedinpatientswithseverehepaticimpairment.Conversionoffamciclovirtoitsactive

metabolitepenciclovirmaybeimpairedinthesepatientsresultinginlowerpenciclovirplasmaconcentrations,andthus

adecreaseofefficacyoffamciclovirmayoccur.

Useforzostertreatment

Clinicalresponseshouldbecloselymonitored,particularlyinimmunocompromisedpatients.

Considerationshouldbegiventointravenousantiviraltherapywhenresponsetooraltherapyisconsideredinsufficient.

Patientswithcomplicatedherpeszoster,i.e.thosewithvisceralinvolvement,disseminatedzoster,motorneuropathies,

encephalitisandcerebrovascularcomplicationsshouldbetreatedwithintravenousantiviraltherapy.

Moreover,immunocompromisedpatientswithophthalmiczosterorthosewithahighriskfordiseasedisseminationand

visceralorganinvolvementshouldbetreatedwithintravenousantiviraltherapy.

Transmissionofgenitalherpes

Patientsshouldbeadvisedtoavoidintercoursewhensymptomsarepresenteveniftreatmentwithanantiviralhasbeen

initiated.Duringsuppressivetreatmentwithantiviralagents,thefrequencyofviralsheddingissignificantlyreduced.

However,transmissionisstillpossible.Therefore,inadditiontotherapywithfamciclovir,itisrecommendedthat

patientsusesafersexpractices.

Other

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucosegalactose

malabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectsofothermedicinalproductsonfamciclovir

Noclinicallysignificantinteractionshavebeenidentified.

Concurrentuseofprobenecidmayresultinincreasedplasmaconcentrationsofpenciclovir,theactivemetaboliteof

famciclovir,bycompetingforelimination.

Therefore,patientsreceivingfamcicloviratadoseof500mgthreetimesdailyco-administeredwithprobenecid,should

bemonitoredfortoxicity.Ifpatientsexperienceseveredizziness,somnolence,confusionorothercentralnervous

systemdisturbances,adosereductionoffamciclovirto250mgthreetimesdailymaybeconsidered.

Famciclovirneedsaldehydeoxidasetobeconvertedintopenciclovir,itsactivemetabolite.Raloxifenhasbeenshown

tobeapotentinhibitorofthisenzymeinvitro.Co-administrationofraloxifenecouldaffecttheformationof

penciclovirandthustheefficacyoffamciclovir.Whenraloxifeniscoadministeredwithfamciclovirtheclinical

efficacyoftheantiviraltherapyshouldbemonitored.

4.6Fertility,pregnancyandlactation

Pregnancy

Thereisalimitedamountofdata(lessthan300pregnancyoutcomes)fromtheuseoffamciclovirinpregnantwomen.

Basedontheselimitedamountsofinformation,thecumulativeanalysisofbothprospectiveandretrospective

pregnancycasesdidnotprovideevidenceindicatingthattheproductcausesanyspecificfoetaldefectorcongenital

anomaly.Animalstudieshavenotshownanyembryotoxicorteratogeniceffectswithfamciclovirorpenciclovir(the

activemetaboliteoffamciclovir).Famciclovirshouldonlybeusedduringpregnancywhenthepotentialbenefitsof

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Lactation

Itisunknownwhetherfamciclovirisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

penciclovirinbreastmilk.Ifthewoman’sconditionmandatestreatmentwithfamciclovir,discontinuationofbreast-

feedingmaybeconsidered.

Fertility

Clinicaldatadonotindicateanimpactoffamciclovironmalefertilityfollowinglong-termtreatmentatanoraldoseof

250mgtwicedaily(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,patientswho

experiencedizziness,somnolence,confusionorothercentralnervoussystemdisturbanceswhiletakingFamciclovir

shouldrefrainfromdrivingoroperatingmachinery.

4.8Undesirableeffects

Headacheandnauseahavebeenreportedinclinicalstudies.Theseweregenerallymildormoderateinnatureand

occurredatasimilarincidenceinpatientsreceivingplacebotreatment.Allotheradversereactionswereaddedduring

postmarketing.

Atotalof1,587patientshavereceivedfamcicloviratrecommendeddosesinplacebo-(n=657)andactive-(n=930)

controlledstudies.Theseclinicalstudieswereretrospectivelyreviewedtoobtainafrequencycategoryforalladverse

reactionsmentionedbelow.Foradversereactionswhichhaveneverbeenobservedinthesestudies,theupperlimitof

the95%confidenceintervalisnotexpectedtobehigherthan3/X(basedonthe“ruleofthree”),withXrepresenting

thetotalsamplesize(n=1,587).

Adversereactions(Table2)arerankedunderheadingsoffrequency,usingthefollowingconvention:

verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to<1/100);rare(1/10,000to<1/1,000);

veryrare(<1/10,000).

Table2AdverseReactions

Bloodandlymphaticsystemdisorders

Rare: Thrombocytopenia

Psychiatricdisorders

Uncommon: Confusion

Rare: Hallucinations

Nervoussystemdisorders

Verycommon: Headache

Common: Dizziness,somnolence

Gastrointestinaldisorders

Common: Nausea,vomiting

Rare: Vomiting

Hepatobiliarydisorders

Common: Abnormalliverfunctiontests

Rare: Cholestaticjaundice

Skinandsubcutaneoustissuedisorders

Common: Rash,pruritus

Uncommon: Urticaria,seriousskinreactions*(e.g.erythemamultiforme,Stevens-

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*Neverreportedinclinicaltrials;categoryisbasedonthe"ruleofthree"

Overall,adversereactionsreportedfromclinicalstudieswithimmunocompromisedpatientsweresimilartothose

reportedintheimmunocompetentpopulation.Nausea,vomitingandabnormalliverfunctiontestswerereportedmore

frequently,especiallyathigherdoses.

4.9Overdose

Overdoseexperiencewithfamciclovirislimited.Intheeventofanoverdosesupportiveandsymptomatictherapy

shouldbegivenasappropriate.Acuterenalfailurehasbeenreportedrarelyinpatientswithunderlyingrenaldisease

wherethefamciclovirdosehasnotbeenappropriatelyreducedforthelevelofrenalfunction.Penciclovirisdialysable;

plasmaconcentrationsarereducedbyapproximately75%following4hhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Nucleosidesandnucleotidesexcludingreversetranscriptaseinhibitors,ATCcode:

JO5AB09

Mechanismofaction

Famcicloviristheoralprodrugofpenciclovir.Famciclovirisrapidlyconvertedinvivointopenciclovir,whichhasin

vitroactivityagainstherpessimplexviruses(HSVtypes1and2),varicellazostervirus,Epstein-Barrvirusand

cytomegalovirus.

Theantiviraleffectoforallyadministeredfamciclovirhasbeendemonstratedinseveralanimalmodels:thiseffectis

duetoinvivoconversiontopenciclovir.Invirus-infectedcellstheviralthymidinekinase(TK)phosphorylates

penciclovirtoamonophosphateformthat,inturn,isconvertedtopenciclovirtriphosphatebycellularkinases.This

triphosphatepersistsininfectedcellsinexcessof12hoursandinhibitsviralDNAchainelongationbycompetitive

inhibitionwithdeoxyguanosinetriphosphateforincorporationintothegrowingviralDNA,thushaltingvirus

replicationofviralDNA.Inuninfectedcellstreatedwithpenciclovir,concentrationsofpenciclovir-triphosphateare

onlybarelydetectable.Hencetheprobabilityoftoxicitytomammalianhostcellsislowanduninfectedcellsare

unlikelytobeaffectedbytherapeuticconcentrationsofpenciclovir.

Resistance

Likeaciclovir,themostcommonformofresistanceencounteredamongHSVstrainsisadeficiencyintheproduction

ofthethymidinekinase(TK)enzyme.SuchTKdeficientstrainswouldgenerallybeexpectedtobecross-resistantto

bothpenciclovirandaciclovir.

Resultsfrom11worldwideclinicalstudiesinvolvingpenciclovir(topicalorintravenousformulations)orfamciclovirin

immunocompetentorimmunocompromisedpatients,includingstudiesofupto12monthstreatmentwithfamciclovir,

haveshownasmalloverallfrequencyofpenciclovirresistantisolates:0.2%(2/913)inimmunocompetentpatientsand

2.1%(6/288)inimmunocompromisedpatients.Theresistantisolatesweremostlyfoundatthestartoftreatmentorina

placebogroup,withresistanceoccurringonoraftertreatmentwithfamciclovirorpenciclovironlyintwo

immunocompromisedpatients.

Clinicalefficacy

Inplacebo-controlledandactive-controlledstudiesbothinimmunocompetentandimmunocompromisedpatientswith

uncomplicatedherpeszoster,amciclovirwaseffectiveintheresolutionoflesions.Inanactive-controlledclinicalstudy,

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Efficacyoffamciclovirinimmunocompetentpatientswithfirstepisodeofgenitalherpeswasshowninthreeactive-

controlledstudies.Twoplacebo-controlledstudiesinimmunocompetentpatientsandoneactivecontrolledstudyin

HIV-infectedpatientswithrecurrentgenitalherpesshowedthatfamciclovirwaseffective.

Twoplacebo-controlled12-monthstudiesinimmunocompetentpatientswithrecurrentgenitalherpesshowedthat

famciclovir-treatedpatientshadasignificantreductionofrecurrencesascomparedtoplacebo-treatedpatients.Placebo-

controlledanduncontrolledstudiesofupto16weeksdurationshowedthatfamciclovirwaseffectiveinthesuppression

ofrecurrentgenitalherpesinHIV-infectedpatients;theplacebo-controlledstudyshowedthatfamciclovirsignificantly

decreasedtheproportionofdaysofbothsymptomaticandasymptomaticHSVshedding.

5.2Pharmacokineticproperties

Generalcharacteristics

Absorption

Famcicloviristheoralprodrugoftheantivirallyactivecompoundpenciclovir.Followingoraladministration,

famciclovirisrapidlyandextensivelyabsorbedandconvertedtopenciclovir.Bioavailabilityofpenciclovirafteroral

administrationoffamciclovirwas77%.Meanpeakplasmaconcentrationofpenciclovir,followinga125mg,250mg,

500mgand750mgoraldoseoffamciclovir,was0.8microgram/ml,1.6micrograms/ml,3.3micrograms/mland5.1

micrograms/ml,respectively,andoccurredatamediantimeof45minutespost-dose.

Plasmaconcentration-timecurvesofpencicloviraresimilarfollowingsingleandrepeat(t.i.d.andb.i.d.)dosing,

indicatingthatthereisnoaccumulationofpenciclovironrepeateddosingwithfamciclovir.

Theextentofsystemicavailability(AUC)ofpenciclovirfromoralfamciclovirisunaffectedbyfood.

Distribution

Penciclovirandits6-deoxyprecursorarepoorly(<20%)boundtoplasmaproteins.

Metabolismandelimination

Famcicloviriseliminatedprincipallyaspenciclovirandits6-deoxyprecursor,whichareexcretedinurine.No

unchangedfamciclovirhasbeendetectedinurine.Tubularsecretioncontributestotherenaleliminationofpenciclovir.

Theterminalplasmahalf-lifeofpenciclovirafterbothsingleandrepeatdosingwithfamciclovirwasapproximately2

hours.

EvidencefrompreclinicalstudieshasshownnopotentialforinductionofcytochromeP450enzymesandinhibitionof

CYP3A4.|

Characteristicsinspecialpopulations

Patientswithherpeszosterinfection

Uncomplicatedherpeszosterinfectiondoesnotsignificantlyalterthepharmacokineticsofpenciclovirmeasuredafter

theoraladministrationoffamciclovir.Theterminalplasmahalf-lifeofpenciclovirinpatientswithherpeszosterwas

2.8hand2.7h,respectively,aftersingleandrepeateddosingoffamciclovir.

Subjectswithrenalimpairment

Theapparentplasmaclearance,renalclearance,andplasmaeliminationrateconstantofpenciclovirdecreasedlinearly

withreductionsinrenalfunction,bothaftersingleandrepeateddosing.Doseadjustmentisnecessaryinpatientswith

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Subjectswithhepaticimpairment

Mildandmoderatehepaticimpairmenthadnoeffectontheextentofsystemicavailabilityofpenciclovirfollowingoral

administrationoffamciclovir.Nodoseadjustmentisrecommendedforpatientswithmildandmoderatehepatic

impairment(seesections4.2and4.4).Thepharmacokineticsofpenciclovirhavenotbeenevaluatedinpatientswith

severehepaticimpairment.Conversionoffamciclovirtotheactivemetabolitepenciclovirmaybeimpairedinthese

patientsresultinginlowerpenciclovirplasmaconcentrations,andthuspossiblyadecreaseofefficacyoffamciclovir.

Elderlypatients(65years)

Basedoncross-studycomparisons,themeanpenciclovirAUCwasabout30%higherandpenciclovirrenalclearance

about20%lowerafteroraladministrationoffamciclovirinelderlyvolunteers(65-79years)comparedtoyounger

volunteers.Partlythisdifferencemaybeduetodifferencesinrenalfunctionbetweenthetwoagegroups.Nodose

adjustmentbasedonageisrecommendedunlessrenalfunctionisimpaired(seesection4.2).

Gender

Smalldifferencesinrenalclearanceofpenciclovirbetweenfemalesandmaleshavebeenreportedandwereattributed

togenderdifferencesinrenalfunction.Nodoseadjustmentbasedongenderisrecommended.

5.3Preclinicalsafetydata

Generaltoxicity

Studiesonsafetypharmacologyandrepeateddosetoxicityrevealnospecialhazardforhumans.

Genotoxicity

Famciclovirwasnotfoundtobegenotoxicinacomprehensivebatteryofinvivoandinvitrotestsdesignedtodetect

genemutation,chromosomaldamageandrepairabledamagetoDNA.Penciclovir,incommonwithothersubstancesof

thisclass,hasbeenshowntocausechromosomaldamage,butdidnotinducegenemutationinbacterialormammalian

cellsystems,norwasthereevidenceofincreasedDNArepairinvitro.

Carcinogenicity

Athighdosesinfemalerats,therewasanincreasedincidenceofmammaryadenocarcinoma,atumourcommonly

observedinthestrainofratsusedinthecarcinogenicitystudy.Therewasnoeffectontheincidenceofneoplasiain

maleratsorinmiceofeithersex.

Reproductivetoxicity

Impairedfertility(includinghistopathologicalchangesinthetestis,alteredspermmorphology,reducedsperm

concentrationandmotility,andreducedfertility)wasobservedinmaleratsgiven500mg/kg/day.Furthermore,

degenerativechangesofthetesticularepitheliumwerenotedinthegeneraltoxicitystudies.Thisfindingwasreversible

andhasalsobeenobservedwithothersubstancesofthisclass.Animalstudiesdidnotindicateanynegativeeffecton

femalefertility.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Croscarmellosesodium

Crospovidone

Magnesiumstearate

Tabletcoat:

OpadryWhite:

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Titaniumdioxide(E171)

Macrogol

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Storeintheoriginalpackaging.

6.5Natureandcontentsofcontainer

Famciclovir500mgtabletsarepackedinblisterstripofPVC/PVdCfilmandAluminiumfoil.

Packsizesof14,30and56tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

Fannin(UK)Ltd

42-46BoothDrive

ParkFarmSouth

Wellingborough

NorthamptonshireNN86GT

8MARKETINGAUTHORISATIONNUMBER

PA1585/5/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thSeptember2011

10DATEOFREVISIONOFTHETEXT

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