ACIC LYOPHILISATE

Main information

  • Trade name:
  • ACIC LYOPHILISATE
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Unknown
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACIC LYOPHILISATE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/017/003
  • Authorization date:
  • 02-05-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ACIC250mgPowderforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains250mgaciclovirasthefreeze-driedsodiumsalt.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion

4CLINICALPARTICULARS

4.1TherapeuticIndications

ACICisindicatedfor:

4.2Posologyandmethodofadministration

RouteofAdministration: Intravenous.

RecommendedDosageSchedule:

TherequireddoseofACICshouldbeadministeredbyslowintravenousinfusionoveraone-hourperiod.

AcourseoftreatmentwithACICusuallylasts5days,butthismaybeadjustedaccordingtothepatient’sconditionand

responsetotherapy.Treatmentforherpessimplexencephalitisusuallylasts10days.

Non-Immuno-compromisedPatients Immuno-compromisedPatients

Severeinitialgenitalherpes Herpessimplexinfection

RecurrentvaricellaZostervirusinfection Primaryandrecurrentvaricellazoster

infection

Prophylaxisofherpessimplexinfection

Herpessimplexencephalitis Herpexsimplexencephalitis

Indication ImmuneStatus Dosage

Herpessimplexinfections NormalorImmuno-compromised 5mg/kgevery8hours

Recurrentvaricellazoster

infections Normal 5mg/kgevery8hours

Primaryandrecurrentvaricella

zosterinfections Immuno-compromised 10mg/kgevery8hours

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PatientswithrenalimpairmentshouldbeadministeredACICwithcaution.Thefollowingmodificationsindosageare

recommended:

Dosageinchildren:ThedosageofACICinneonatesiscalculatedonthebasisofbodyweight.Althoughitsusein

neonatal,herpesisstillexperimental,dosesof10mg/kghavebeenemployed.

ThedoseofACICforchildrenagedbetween3monthsand12yearsiscalculatedonthebasisofbodysurfacearea.

Childrenwithherpessimplex(exceptherpessimplexencephalitis)orvaricellazosterinfectionsshouldbegivenACIC

indosesof250mgpersquaremetreofbodysurfaceareaevery8hours.

Inimmunocompromisedchildrenwithvaricellazosterinfectionsorchildrenwithherpessimplexencephalitis,ACIC

shouldbegivenindosesof500mgpersquaremetrebodysurfaceareaevery8hoursifrenalfunctionisnotimpaired.

Childrenwithimpairedrenalfunctionrequireanappropriatelymodifieddose,accordingtothedegreeofimpairment.

Dosageintheelderly:Intheelderly,totalaciclovirbodyclearancedeclinesinparallelwithcreatinineclearance.

Specialattentionshouldbegiventodosagereductioninelderlypatientswithimpairedcreatinineclearance.

Administration:TherequireddoseofACICforinfusionshouldbeadministeredbyslowintravenousinfusionovera

one-hourperiod.AfterreconstitutionACICforInfusionmaybeadministeredbyacontrolled-rateinfusionpump.

Alternately,thereconstitutedsolutionmaybefurtherdilutedtogiveanaciclovirconcentrationofnotgreaterthan

5mg/ml(0.5%w/v)foradministrationbyinfusion.

4.3Contraindications

Contra-indications:ACICiscontra-indicatedinpatientsknowntobepreviouslyhypersensitivetoaciclovir.

Precautions:Theresultsofawiderangeofmutagenicitytestsinvitroandinvivoindicatethataciclovirdoesnotposea

geneticrisktoman.Aciclovirwasnotfoundtobecarcinogenicinlong-termstudiesintheratandmouse.

Aciclovirshouldbeadministeredwithcautiontopatientswithhepaticorrenalimpairmentandintheelderly.

ThedosageofACICforInfusionmustbeadjustedinpatientswithimpairedrenalfunctioninordertoavoid

accumulationofaciclovirinthebody.InpatientsreceivingACICathigherdoses(e.g.forherpesencephalitis),specific

careregardingrenalfunctionshouldbetaken,particularlywhenpatientsaredehydratedorhaveanyrenalimpairment.

Adequatehydrationofthepatientshouldbemaintained,toavoidrapidincreasesinbloodureaandcreatinineassociated

withI.V.aciclovirandinadequatehydration.

Aciclovirshouldbeadministeredbyslowinfusionoveronehourandnotasabolusintravenousinjection.

CreatineClearance Dosage

25-50ml/min Thedoserecommendedabove(5or10mg/kg)shouldbegivenevery12

hours.

10-25ml/min Thedoserecommendedabove(5or10mg/kg)shouldbegivenevery24

hours.

0(anuric)-10ml/min Inpatientsreceivingcontinuousambulatoryperitonealdialysis(CAPD)the

doserecommendedabove(5or10mg/kg)shouldbehalvedand

administeredevery24hours.Inpatientsreceivinghaemodialysisthedose

recommendedabove(5or10mg/kg)shouldbehalvedandadministered

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4.4Specialwarningsandprecautionsforuse

Nospecialprecautionsnecessary.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Druginteractions:Probenecidincreasestheaciclovirmeanhalf-lifeandareaundertheplasmaconcentrationcurve.

Otherdrugsaffectingrenalphysiologycouldpotentiallyinfluencethepharmacokineticsofaciclovir.However,clinical

experiencehasnotidentifiedotherdruginteractionswithaciclovir.

4.6Pregnancyandlactation

Experienceinhumansislimited,sotheuseofACICshouldbeconsideredonlywhenthepotentialbenefitsoutweigh

thepossibilityofunknownrisks.

Systemicadministrationofaciclovirininternationallyacceptedstandardtestsdidnotproduceembryotoxicor

teratogeniceffectsinrabbits,ratsormice.

Inanon-standardtestinrats,foetalabnormalitieswereobservedbutonlyfollowingsuchhighsubcutaneousdosesthat

maternaltoxicitywasproduced.Theclinicalrelevanceofthesefindingsisuncertain.

Followingoraladministrationof200mgfivetimesaday,aciclovirhasbeendetectedinhumanbreastmilkat

concentrationsrangingfrom0.6to4.1timesthecorrespondingplasmalevels.Theselevelswouldpotentiallyexpose

nursinginfantstoaciclovirdosesofupto0.3mg/kgbodyweight/day.CautionisthereforeadvisedifACICistobe

administeredtoanursingwoman.

4.7Effectsonabilitytodriveandusemachines

Nospecificstudieshavebeenconducted,butthereisnoevidencetosuggestthataciclovirwilladverselyaffectability

todriveandoperatemachines.

4.8Undesirableeffects

RapidincreasesinbloodureaandcreatininelevelsmayoccasionallyoccurinpatientsgivenACIC.Thisisbelievedto

berelatedtopeakplasmalevelsandthestateofhydrationofthepatient.Toavoidthiseffectthedrugshouldnotbe

givenasanintravenousbolusinjectionbutbyslowinfusionoveraone-hourperiod.Adequatehydrationofthepatient

shouldbemaintained.

RenalimpairmentdevelopingduringtreatmentwithACICusuallyrespondsrapidlytohydrationofthepatientand/or

dosagereductionorwithdrawalofthedrug.Progressiontoacuterenalfailure,however,canoccurinexceptionalcases.

Severelocalinflammatoryreactions,leadingtobreakdownoftheskin,hasoccurredwhenACIChasbeeninadvertently

infusedintoextravasculartissues.

Reversibleneurologicalreactions,usuallyconsistingoftremorsometimesassociatedwithconfusionand

electroencephalographicchangeshavebeenassociatedwithACICtherapy.

NauseaandvomitinghavebeenreportedinpatientsreceivingtherapywithACIC.

OthereventsreportedinpatientsreceivingACICincludeincreasesinliver-relatedenzymes,increasesinlevelsof

bilirubin,andrashes.

Largelyreversibleadverseeffectsonspermatogenesisinassociationwithoveralltoxicityinratsanddogshavebeen

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ACICTabletshavebeenshowntohavenodefinitiveeffectuponspermcount,morphologyormotilityinman.

TherehasbeennoexperienceoftheeffectofACIConhumanfemalefertility.Two-generationstudiesinmicedidnot

revealanyeffectofaciclovironfertility.

4.9Overdose

Singleintravenousdosesofupto80mg/kghavebeeninadvertentlyadministeredwithoutadverseeffects.Acicloviris

dialysablebyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

AciclovirisasyntheticpurinenucleosideanaloguewithinvitroandinvivoinhibitoryactivityagainsthumanHerpes

viruses,includingHerpessimplexvirus(HSV)typesIandIIandVaricellazostervirus(VZV),EpsteinBarrvirus

(EBV)andcytomegalovirus(CMV).Incellculture,aciclovirhasthegreatestantiviralactivityagainstHSV-1,followed

(indecreasingorderofpotency)byHSV-2,VZV,EBVandCMV.TheinhibitoryactivityofaciclovirforHSVI,HSV

II,VZV,EBVandCMVishighlyselective.Theenzymethymidinekinase(TK)ofnormal,non-infectedcellsdoesnot

useaciclovireffectivelyasasubstrate,hencetoxicitytomammalianhostcellsislow;however,TKencodedbyHSV,

VZVandEBVconvertsaciclovirtoaciclovirmonophosphate,anucleosideanaloguewhichisfurtherconvertedtothe

diphosphateandfinallytothetriphosphatebycellularenzymes.AciclovirtriphosphateinterfereswiththeviralDNA

polymeraseandinhibitsviralDNAreplicationwithresultantchainterminationfollowingitsincorporationintotheviral

DNA.

Properties:Aciclovir,convertedtotheactivecompoundbyviralthymidinekinase,inhibitstheherpesvirusDNA

polymerase.Absorptionfromtheoralrouteisvariable.Thedrugispoorlyproteinboundandisexcretedmainly

throughthekidneywithaT½of3-4hours.

Prolongedorrepeatedcoursesofaciclovirinseverelyimmunocompromisedindividualsmayresultintheselectionof

virusstrainswithreducedsensitivity,whichmaynotrespondtocontinuedaciclovirtreatment.Mostoftheclinical

isolateswithreducedsensitivityhavebeenrelativelydeficientinviralTK,however,strainswithalteredviralTKor

DNApolymerasehavealsobeenreported.InvitroexposureofHSVisolatestoaciclovircanalsoleadtotheemergence

oflesssensitivestrains.Therelationshipbetweentheinvitro-determinedsensitivityofHSVisolatesandclinical

responsetoaciclovirtherapyisnotclear.

5.2Pharmacokineticproperties

Inadultstheterminalplasmahalflifeofaciclovirafteradministrationofintravenousaciclovirisabout2.9hours.Most

ofthedrugisexcretedunchangedbythekidney.Renalclearanceofaciclovirissubstantiallygreaterthancreatinine

clearance,indicatingthattubularsecretion,inadditiontoglomerularfiltration,contributestotherenaleliminationof

thedrug.9-Carboxymethoxymethylguanineistheonlysignificantmetaboliteofaciclovir,andaccountsfor

approximately10-15%oftheadministereddoserecoveredfromtheurine.Whenaciclovirisgivenonehourafter1

gramofprobenecidtheterminalhalflifeandareaundertheplasmaconcentration-timecurveisextendedby18%and

40%respectively.

Inadults,meanC ss

maxlevelsfollowingaonehourinfusionof2.5mg/kg,5mg/kgand10mg/kgwere22.7mMol

(5.1micrograms/ml),43.6microMol(9.8micrograms/ml)and92microMol(20.7micrograms/ml),respectively.The

correspondingC ss

minlevels7hourslaterwere2.2microMol(0.5micrograms/ml)3.1microMol(0.7micrograms/ml)

and10.2microMol(2.3micrograms/ml),respectively.Inchildrenover1yearofagesimilarmeanC ss

maxandC ss

levelswereobservedwhenadoseof250mg/m2wassubstitutedfor5mg/kgandadoseof500mg/m2was

substitutedfor10mg/kg.

Inneonatesandyounginfants(0-3monthsofage)treatedwithdosesof10mg/kgadministeredbyinfusionoveraone-

hourperiodevery8hourstheC ss

maxwasfoundtobe61.2microMol(13.8micrograms/ml)andtheC ss

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microMol(2.3micrograms/ml).Theterminalplasmahalflifeinthesepatientswas3.8hours.Intheelderlytotalbody

clearancefallswithincreasingageassociatedwithdecreasesincreatinineclearancealthoughthereislittlechangein

theterminalplasmahalflife.

Inpatientswithchronicrenalfailurethemeanterminalhalflifewasfoundtobe19.5hours.Themeanaciclovirhalf

lifeduringhaemodialysiswas5.7hours.Plasmaaciclovirlevelsdroppedapproximately60%duringdialysis.

Cerebrospinalfluidlevelsareapproximately50%ofcorrespondingplasmalevels.Plasmaproteinbindingisrelatively

low(9to33%)anddruginteractionsinvolvingbindingsitedisplacementarenotanticipated.

5.3Preclinicalsafetydata

Theresultsofawiderangeofmutagenicitytestsin-vitroandin-vivoindicatethataciclovirisunlikelytoposeagenetic

risktoman.Aciclovirwasnotcarcinogenicinlongtermstudiesintheratandthemouse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

SodiumHydroxide

6.2Incompatibilities

Noneknown.

6.3ShelfLife

2years.

Chemicalandphysicalin-usestabilityforthereconstitutedsolutionandthedilutedsolutionhasbeendemonstratedfor

24hoursat2to8°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessreconstitutionanddilution(etc)hastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

ACICispackedin25mlcolourlesstypeIPh.Eur.glassvialswithredcolouredrubberstopper,composedof

chlorobutylastomer,B-50-1-05-B,type1Ph.Eur.,andaluminiumflip-offsealwithPP-disc.Itisavailableinpacksof

10vials.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Sincenoantimicrobialpreservativeisincluded,reconstitutionanddilutionmustbecarriedoutunderfullaseptic

conditionsimmediatelybeforeuseandanyunusedsolutionshouldbediscarded.Shouldvisibleturbidityor

crystallisationappearinthesolution,beforeorduringtheinfusion,themixtureshouldbediscarded.

Reconstitution:Eachvial(containingtheequivalentof250mgaciclovir)shouldbereconstitutedbytheadditionof10

mlofeitherDextrose(5%w/v)orSodiumChlorideinjection(0.9%w/v).Thisprovidesasolutioncontaining25mg

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Addtherequiredvolumeofreconstitutedsolutiontothechoseninfusionsolution,asrecommendedbelow,andshake

welltoensureadequatemixingoccurs.Forchildrenandneonates,whereitisadvisabletokeepthevolumeofinfusion

fluidtoaminimumitisrecommendedthatdilutionisonthebasisof4mlreconstitutedsolution(100mgaciclovir)

addedto20mlofinfusionfluid.

Foradults,itisrecommendedthatinfusionbagscontaining100mlofinfusionfluidareused,evenwhenthiswould

giveanaciclovirconcentrationsubstantiallybelow0.5%w/v.Thusone100mlinfusionbagmaybeusedforanydose

between250mgand500mgaciclovir(10and20mlofreconstitutedsolution),butasecondbagmustbeusedfordoes

between500and1000mg.ACICwhendilutedinaccordancewiththeaboveschedulestogiveaconcentrationnot

greaterthan0.5%w/vofaciclovir,isknowntobecompatiblewiththefollowinginfusionfluidsandstableforupto24

hoursat2to8°C).

SodiumChloride(0.9%w/v).

Dextrose(5%w/v).

7MARKETINGAUTHORISATIONHOLDER

ROWEXLTD

Newtown

Bantry

CoCork

8MARKETINGAUTHORISATIONNUMBER

PA711/17/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:02May2003

10DATEOFREVISIONOFTHETEXT

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