FAMCICLOVIR

Main information

  • Trade name:
  • FAMCICLOVIR Film Coated Tablet 125 Milligram
  • Dosage:
  • 125 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FAMCICLOVIR Film Coated Tablet 125 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/025/001
  • Authorization date:
  • 15-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FamciclovirTeva125mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains125mgoffamciclovir

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Whitetooff-white,round,film-coatedtablets,engraved8117ononesideand93ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Varicellazostervirus(VZV)infections–herpeszoster

Famciclovirisindicatedfor

thetreatmentofherpeszosterandophthalmiczosterinimmunocompetentadults(seesection4.4)

thetreatmentofherpeszosterinimmunocompromisedadults(seesection4.4).

Herpessimplexvirus(HSV)infections–genitalherpes

Famciclovirisindicatedfor

thetreatmentoffirstandrecurrentepisodesofgenitalherpesinimmunocompetentadults

thetreatmentofrecurrentepisodesofgenitalherpesinimmunocompromisedadults

thesuppressionofrecurrentgenitalherpesinimmunocompetentandimmunocompromisedadults.

ClinicalstudieshavenotbeenconductedinHSV -infectedpatientsimmunocompromisedforothercausesthanHIV

infection(seesection5.1).

4.2Posologyandmethodofadministration

Herpeszosterinimmunocompetentadults

500mgthreetimesdailyforsevendays.

Treatmentshouldbeinitiatedassoonaspossibleafteradiagnosisofherpeszoster.

Herpeszosterinimmunocompromisedadults

500mgthreetimesdailyfortendays.

Treatmentshouldbeinitiatedassoonaspossibleafteradiagnosisofherpeszoster.

Genitalherpesinimmunocompetentadults

Firstepisodeofgenitalherpes:250mgthreetimesdailyforfivedays.Initiationoftreatmentisrecommendedassoon

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Episodictreatmentofrecurrentgenitalherpes:125mgtwicedailyforfivedays.Initiationoftreatmentis

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

Recurrentgenitalherpesinimmunocompromisedadults

Episodictreatmentofrecurrentgenitalherpes:500mgtwicedailyforsevendays.Initiationoftreatmentis

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

Suppressionofrecurrentgenitalherpesinimmunocompetentadults

250mgtwicedaily.Suppressivetherapyshouldbediscontinuedafteramaximumof12monthsofcontinuousantiviral

therapytoreassessrecurrencefrequencyandseverity.Theminimumperiodofreassessmentshouldincludetwo

recurrences.Patientswhocontinuetohavesignificantdiseasemayrestartsuppressivetherapy.

Suppressionofrecurrentgenitalherpesinimmunocompromisedadults

500mgtwicedaily.

Patientswithrenalimpairment

Becausereducedclearanceofpenciclovirisrelatedtoreducedrenalfunction,asmeasuredbycreatinineclearance,

specialattentionshouldbegiventodosesinpatientswithimpairedrenalfunction.Doserecommendationsforadult

patientswithrenalimpairmentareprovidedinTable1.

Table1Doserecommendationsforadultpatientswithrenalimpairment

Indicationandnominaldoseregimen Creatinineclearance

[ml/min] Adjusteddoseregimen

Herpeszosterinimmunocompetentadults

500mgthreetimesdailyfor7days 60 500mgthreetimesdailyfor7

days

40to59 500mgtwicedailyfor7days

20to39 500mgoncedailyfor7days

<20 250mgoncedailyfor7days

Haemodialysispatients 250mgfollowingeachdialysis

for7days

Herpeszosterinimmunocompromisedadults

500mgthreetimesdailyfor10days 60 500mgthreetimesdailyfor10

days

40to59 500mgtwicedailyfor10days

20to39 500mgoncedailyfor10days

<20 250mgoncedailyfor10days

Haemodialysispatients 250mgfollowingeachdialysis

for10days

Genitalherpesinimmunocompetentadults–firstepisodeofgenital

herpes

250mgthreetimesdailyfor5days 40 250mgthreetimesdailyfor

5days

20to39 250mgtwicedailyfor5days

<20 250mgoncedailyfor5days

Haemodialysispatients 250mgfollowingeachdialysis

for5days

Genitalherpesinimmunocompetentadults–episodictreatmentof

recurrentgenitalherpes

125mgtwicedailyfor5days 20 125mgtwicedailyfor5days

<20 125mgoncedailyfor5days

Haemodialysispatients 125mgfollowingeachdialysis

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Patientswithrenalimpairmentonhaemodialysis

Since4 -hhaemodialysisresultedinupto75%reductioninplasmapenciclovirconcentrations,famciclovirshouldbe

administeredimmediatelyfollowingdialysis.Therecommendeddoseregimensforhaemodialysispatientsareincluded

inTable1.

Patientswithhepaticimpairment

Nodoseadjustmentisrequiredinpatientswithmildormoderatehepaticimpairment.Nodataareavailableforpatients

withseverehepaticimpairment(seesections4.4and5.2).

Elderlypatients(65years)

Dosemodificationisnotrequiredunlessrenalfunctionisimpaired.

Childrenandadolescents

Famciclovirisnotrecommendedforuseinchildrenandadolescentsbelow18yearsofageduetolackofdataonsafety

andefficacy.

Methodofadministration

Famciclovircanbetakenwithoutregardtomeals(seesection5.2).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Genitalherpesinimmunocompromisedpatients–episodictreatment

ofrecurrentgenitalherpes

500mgtwicedailyfor7days 40 500mgtwicedailyfor7days

20to39 500mgoncedailyfor7days

<20 250mgoncedailyfor7days

Haemodialysispatients 250mgfollowingeachdialysis

for7days

Suppressionofrecurrentgenitalherpesinimmunocompetentadults

250mgtwicedaily 40 250mgtwicedaily

20to39 125mgtwicedaily

<20 125mgoncedaily

Haemodialysispatients 125mgfollowingeachdialysis

Suppressionofrecurrentgenitalherpesinimmunocompromised

adults

500mgtwicedaily 40 500mgtwicedaily

20to39 500mgoncedaily

<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.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectsofothermedicinalproductsonfamciclovir

Noclinicallysignificantinteractionshavebeenidentified.

Concurrentuseofprobenecidmayresultinincreasedplasmaconcentrationsofpenciclovir,theactivemetaboliteof

famciclovir,bycompetingforelimination.Thereforepatientsreceivingfamcicloviratadoseof500mgthreetimes

dailyco -administeredwithprobenecid,shouldbemonitoredfortoxicity.Ifpatientsexperienceseveredizziness,

somnolence,confusionorothercentralnervoussystemdisturbances,adosereductionoffamciclovirto250mgthree

timesdailymaybeconsidered.

Famciclovirneedsaldehydeoxidasetobeconvertedintopenciclovir,itsactivemetabolite.Raloxifenehasbeenshown

tobeapotentinhibitorofthisenzymeinvitro.Co -administrationofraloxifenecouldaffecttheformationof

penciclovirandthustheefficacyoffamciclovir.Whenraloxifeneisco -administeredwithfamciclovirtheclinical

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4.6Fertility,pregnancyandlactation

Pregnancy

Thereisalimitedamountofdata(lessthan300pregnancyoutcomes)fromtheuseoffamciclovirinpregnantwomen.

Basedontheselimitedamountsofinformation,thecumulativeanalysisofbothprospectiveandretrospective

pregnancycasesdidnotprovideevidenceindicatingthattheproductcausesanyspecificfetaldefectorcongenital

anomaly.

Animalstudieshavenotshownanyembryotoxicorteratogeniceffectswithfamciclovirorpenciclovir(theactive

metaboliteoffamciclovir).Famciclovirshouldonlybeusedduringpregnancywhenthepotentialbenefitsoftreatment

outweighthepotentialrisks.

Lactation

Itisunknownwhetherfamciclovirisexcretedinhumanbreastmilk.Animalstudieshaveshownexcretionof

penciclovirinbreastmilk.Ifthewoman’sconditionmandatestreatmentwithfamciclovir,discontinuationof

breast -feedingmaybeconsidered.

Fertility

Clinicaldatadonotindicateanimpactoffamciclovironmalefertilityfollowinglong -termtreatmentatanoraldoseof

250mgtwicedaily(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,patientswho

experiencedizziness,somnolence,confusionorothercentralnervoussystemdisturbanceswhiletakingfamciclovir

shouldrefrainfromdrivingoroperatingmachinery.

4.8Undesirableeffects

Headacheandnauseahavebeenreportedinclinicalstudies.Theseweregenerallymildormoderateinnatureand

occurredatasimilarincidenceinpatientsreceivingplacebotreatment.Allotheradversereactionswereaddedduring

post -marketing.

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

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*Neverreportedinclinicaltrials;categoryisbasedonthe“ruleofthree”

Overall,adversereactionsreportedfromclinicalstudieswithimmunocompromisedpatientsweresimilartothose

reportedintheimmunocompetentpopulation.Nausea,vomitingandabnormalliverfunctiontestswerereportedmore

frequently,especiallyathigherdoses.

4.9Overdose

Overdoseexperiencewithfamciclovirislimited.Intheeventofanoverdosesupportiveandsymptomatictherapy

shouldbegivenasappropriate.Acuterenalfailurehasbeenreportedrarelyinpatientswithunderlyingrenaldisease

wherethefamciclovirdosehasnotbeenappropriatelyreducedforthelevelofrenalfunction.Penciclovirisdialysable;

plasmaconcentrationsarereducedbyapproximately75%following4 -hhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Nucleosidesandnucleotidesexcludingreversetranscriptaseinhibitors

ATCcode:J05AB09

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,concentrationsofpenciclovirtriphosphateare

onlybarelydetectable.Hencetheprobabilityoftoxicitytomammalianhostcellsislowanduninfectedcellsare

Nervoussystemdisorders

Verycommon: headache

Common: dizziness,somnolence

Gastrointestinaldisorders

Common: nausea,vomiting

Hepato-biliarydisorders

Common: abnormalliverfunctiontests

Rare: cholestaticjaundice

Skinandsubcutaneoustissuedisorders

Common: rash,pruritus

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

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Resistance

Likeaciclovir,themostcommonformofresistanceencounteredamongHSVstrainsisadeficiencyintheproduction

ofthethymidinekinase(TK)enzyme.SuchTKdeficientstrainswouldgenerallybeexpectedtobecross -resistantto

bothpenciclovirandaciclovir.

Resultsfrom11worldwideclinicalstudiesinvolvingpenciclovir(topicalorintravenousformulations)orfamciclovirin

immunocompetentorimmunocompromisedpatients,includingstudiesofupto12months'treatmentwithfamciclovir,

haveshownasmalloverallfrequencyofpenciclovirresistantisolates:0.2%(2/913)inimmunocompetentpatientsand

2.1%(6/288)inimmunocompromisedpatients.Theresistantisolatesweremostlyfoundatthestartoftreatmentorina

placebogroup,withresistanceoccurringonoraftertreatmentwithfamciclovirorpenciclovironlyintwo

immunocompromisedpatients.

Clinicalefficacy

Inplacebo -controlledandactive-controlledstudiesbothinimmunocompetentandimmunocompromisedpatientswith

uncomplicatedherpeszoster,famciclovirwaseffectiveintheresolutionoflesions.Inanactive -controlledclinical

study,famciclovirwasshowntobeeffectiveinthetreatmentofophthalmiczosterinimmunocompetentpatients.

Efficacyoffamciclovirinimmunocompetentpatientswithfirstepisodeofgenitalherpeswasshowninthree

active -controlledstudies.Twoplacebo-controlledstudiesinimmunocompetentpatientsandoneactive-controlled

studyinHIV -infectedpatientswithrecurrentgenitalherpesshowedthatfamciclovirwaseffective.

Twoplacebo -controlled12-monthstudiesinimmunocompetentpatientswithrecurrentgenitalherpesshowedthat

famciclovir -treatedpatientshadasignificantreductionofrecurrencesascomparedtoplacebo-treatedpatients.

Placebo -controlledanduncontrolledstudiesofupto16weeks'durationshowedthatfamciclovirwaseffectiveinthe

suppressionofrecurrentgenitalherpesinHIV -infectedpatients;theplacebo-controlledstudyshowedthatfamciclovir

significantlydecreasedtheproportionofdaysofbothsymptomaticandasymptomaticHSVshedding.

5.2Pharmacokineticproperties

Generalcharacteristics

Absorption

Famcicloviristheoralprodrugoftheantivirallyactivecompoundpenciclovir.Followingoraladministration,

famciclovirisrapidlyandextensivelyabsorbedandconvertedtopenciclovir.Bioavailabilityofpenciclovirafteroral

administrationoffamciclovirwas77%.Meanpeakplasmaconcentrationofpenciclovir,followinga125mg,250mg,

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

5.1micrograms/ml,respectively,andoccurredatamediantimeof45minutespost-dose.

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

indicatingthatthereisnoaccumulationofpenciclovironrepeateddosingwithfamciclovir.

Theextentofsystemicavailability(AUC)ofpenciclovirfromoralfamciclovirisunaffectedbyfood.

Distribution

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Metabolismandelimination

Famcicloviriseliminatedprincipallyaspenciclovirandits6 -deoxyprecursor,whichareexcretedinurine.No

unchangedfamciclovirhasbeendetectedinurine.Tubularsecretioncontributestotherenaleliminationofpenciclovir.

Theterminalplasmahalf -lifeofpenciclovirafterbothsingleandrepeatdosingwithfamciclovirwasapproximately

2hours.

EvidencefrompreclinicalstudieshasshownnopotentialforinductionofcytochromeP450enzymesandinhibitionof

CYP3A4.

Characteristicsinspecialpopulations

Patientswithherpeszosterinfection

Uncomplicatedherpeszosterinfectiondoesnotsignificantlyalterthepharmacokineticsofpenciclovirmeasuredafter

theoraladministrationoffamciclovir.Theterminalplasmahalf -lifeofpenciclovirinpatientswithherpeszosterwas

2.8hand2.7h,respectively,aftersingleandrepeateddosingoffamciclovir.

Subjectswithrenalimpairment

Theapparentplasmaclearance,renalclearance,andplasmaeliminationrateconstantofpenciclovirdecreasedlinearly

withreductionsinrenalfunction,bothaftersingleandrepeateddosing.Doseadjustmentisnecessaryinpatientswith

renalimpairment(seesection4.2).

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

Studiesonsafetypharmacologyandrepeated -dosetoxicityrevealnospecialhazardforhumans.

Genotoxicity

Famciclovirwasnotfoundtobegenotoxicinacomprehensivebatteryofinvivoandinvitrotestsdesignedtodetect

genemutation,chromosomaldamageandrepairabledamagetoDNA.Penciclovir,incommonwithothersubstancesof

thisclass,hasbeenshowntocausechromosomaldamage,butdidnotinducegenemutationinbacterialormammalian

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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

Core:

MicrocrystallinecelluloseE460

ColloidalanhydroussilicaE551

Sodiumstarchglycolate(TypeA)

Low-substitutedhydroxypropylcellulose

Croscarmellosesodium

Sodiumstearylfumarate

Film-coat:

Titaniumdioxide(E171)

Polydextrose(E1200)

Hypromellose(E464)

Triacetin(E1518)

Macrogol8000

6.2Incompatibilities

Notapplicable

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Keepblisterintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

WhiteopaquePVC/PE/Aclar–Aluminiumblisterspacks

1,10,21&30film-coatedtablets.Hospitalpacksof50(50x1)film-coatedtablets.

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6.6Specialprecautionsfordisposal

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/25/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15 th

February2008

Dateoflastrenewal:11thSeptember2010

10DATEOFREVISIONOFTHETEXT

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