EPOPROSTENOL DREHM

Main information

  • Trade name:
  • EPOPROSTENOL DREHM
  • Dosage:
  • 1.5 Milligram
  • Pharmaceutical form:
  • Pdr+Solv for soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPOPROSTENOL DREHM
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1533/001/002
  • Authorization date:
  • 17-06-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EpoprostenolDrehm1.5mgPowderandSolventforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1vialcontains1.593mgEpoprostenolSodium,correspondingto1.5mgEpoprostenol.

Eachvialofsolventcontains50mlofasterileglycinebuffersolutioncontainingapproximately55mgsodium.

When1vialwith1.5mgepoprostenolisreconstitutedwith50mlsterilediluent,theresultantconcentrationis30,000

nanogramsperml.

Excipients:contains0.05mmolsodium(1.15mg)pervial.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderandsolventforsolutionforinfusion

Whitelyophilisedpowdercakeincolourlessglass-vials,andaclear,colourlesssolutionin50mlglassvials.

When1.5mgepoprostenolpowderisreconstitutedwith50mloftheGlycineBufferDiluent,thefinalinjectionhasa

pHofapproximately10.5andasodiumioncontentofapproximately56mg.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Haemodialysis

EpoprostenolDrehmisindicatedforuseinrenaldialysiswhenuseofheparincarriesahighriskofcausingor

exacerbatingbleedingorwhenheparinisotherwisecontraindicated.

Primaryandsecondarypulmonaryhypertension

EpoprostenolDrehmisalsoindicatedfortheintravenouslong-termtreatmentofprimarypulmonaryhypertension

(PPH)inNewYorkHeartAssociation(NYHA)functionalClassIIIandClassIVpatientswhodonotrespond

adequatelytoconventionaltherapy,andsecondarypulmonaryhypertension(SPH)inthesclerodermaspectrumof

diseases(SSD)duetointrinsicprecapillarypulmonaryvasculardiseaseinpatientswithNYHAfunctionalclassIIIand

Therearelimiteddataonlong-termuse.

4.2Posologyandmethodofadministration

EpoprostenolDrehmmustbereconstitutedonlywithspecificsterilediluentforEpoprostenol.Forinformation

regardingreconstitution,dilutionandcalculationofdose,pleaseseesection6.6.

AfterreconstitutionEpoprostenolDrehmisacolourlesssolution,practicallyfreeofparticles.

EpoprostenolDrehmissuitableforcontinuousinfusiononly,eitherintravascularorintothebloodsupplyingthe

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EpoprostenolDrehmisnottobeusedforbolusadministration.

RenalDialysis:

Adults:

Thefollowinggeneralscheduleofinfusionhasbeenfoundeffectiveinadults:

Priortodialysis:4nanograms/kg/minintravenouslyfor15minutes.

Duringdialysis:4nanograms/kg/minintothearterialinletofthedialyser.

Theinfusionshouldbestoppedattheendofdialysis.

Therecommendeddoseforrenaldialysisshouldbeexceededonlywithappropriatepatientmonitoring.

Childrenandtheelderly:

ThereisnospecificinformationavailableontheuseofEpoprostenolforrenaldialysisinchildrenorinelderlypatients.

PrimaryandSecondaryPulmonaryHypertension:

Adults:

Thefollowingscheduleshavebeenfoundeffective:

Short-term(acute)doseranging:

Ashort-termdose-rangingprocedureadministeredviaeitheraperipheralorcentralvenouslineisrequiredtodetermine

thelong-terminfusionrate.

Theinfusionrateisinitiatedat2nanograms/kg/minandincreasedbyincrementsof2nanograms/kg/minevery15

minutesorlongeruntilmaximumhaemodynamicbenefitordose-limitingpharmacologicaleffectsareelicited.

Iftheinitialinfusionrateof2nanograms/kg/minisnotwelltolerated,alowerdosagehastobedetermined.

Duringacutedoseranginginclinicaltrials,themeanmaximumtolerateddosewas8.6±0.3nanograms/kg/min.

Long-termcontinuousinfusion:

Long-termcontinuousinfusionofEpoprostenolDrehmshouldbeadministeredthroughacentralvenouscatheter.

Temporaryperipheralintravenousinfusionsmaybeuseduntilcentralaccessisestablished.Long-terminfusionsshould

beinitiatedat4nanograms/kg/minlessthanthemaximumtoleratedinfusionratedeterminedduringshort-termdose-

ranging.Ifthemaximumtoleratedinfusionrateislessthan5nanograms/kg/min;thelong-terminfusionshouldbe

startedatone-halfthemaximumtoleratedinfusionrate.

Dosageadjustments:

Changesinthelong-terminfusionrateshouldbebasedonpersistence,recurrenceorworseningofthepatient's

symptomsofPPHortheoccurrenceofadverseeventsduetoexcessivedosesofEpoprostenolDrehm.

Ingeneral,theneedforincreasesindosefromtheinitiallong-termdoseshouldbeexpectedovertime.Increasesin

doseshouldbeconsideredifsymptomspersist,orrecurafterimproving.

Theinfusionrateshouldbeincreasedby1to2nanograms/kg/minincrementsatintervalssufficienttoallow

assessmentofclinicalresponse;theseintervalsshouldbeofatleast15minutes.

Followingestablishmentofanewinfusionrate,thepatientshouldbeobserved,anderectandsupinebloodpressure

andheartratemonitoredforseveralhourstoensurethatthenewdoseistolerated.

Duringlong-terminfusion,theoccurrenceofdose-relatedpharmacologicaleventssimilartothoseobservedduringthe

dose-rangingperiodmaynecessitateadecreaseininfusionrate,buttheadverseeventmayoccasionallyresolvewithout

dosageadjustment.

Dosagedecreasesshouldbemadegraduallyin2nanograms/kg/mindecrementsevery15minutesorlongeruntilthe

dose-limitingeffectsresolve.AbruptwithdrawalofEpoprostenolDrehmorsuddenlargereductionsininfusionrates

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Exceptinlife-threateningsituations(e.g.unconsciousness,collapse,etc)infusionratesofEpoprostenolDrehmshould

beadjustedonlyunderthedirectionofaphysician.

OralanticoagulationwascontinuedinthePPHclinicaltrialpopulationinadditiontocontinuousintravenous

Epoprostenoladministrationandwaswelltolerated.Concurrentoralanticoagulationisrecommended.

Children:

ThereislimitedinformationontheuseofEpoprostenolforPPH/SPHinchildren.

Elderly:

ThereislimitedinformationontheuseofEpoprostenolinpatientsover65.Ingeneral,doseselectionforanelderly

patientshouldbemadecarefully,reflectingthegreaterfrequencyofdecreasedhepatic,renalorcardiacfunctionandof

concomitantdiseaseorotherdrugtherapy.

4.3Contraindications

EpoprostenolDrehmiscontraindicatedinpatientswithknownhypersensitivitytothedrug.

EpoprostenolDrehmiscontraindicatedinpatientswithcongestiveheartfailurearisingfromsevereleftventricular

dysfunction.

EpoprostenolDrehmshouldnotbeusedchronicallyinpatientswhodeveloppulmonaryoedemaduringdose-ranging.

4.4Specialwarningsandprecautionsforuse

BecauseofthehighpHofthefinalinfusionsolutions,careshouldbetakentoavoidextravasationduringtheir

administrationandconsequentriskoftissuedamage.

Epoprostenolisapotentpulmonaryandsystemicvasodilator.Thecardiovasculareffectsduringinfusiondisappear

within30minutesoftheendofadministration.

BloodpressureandheartrateshouldbemonitoredduringadministrationofEpoprostenol.

Epoprostenolmayeitherdecreaseorincreaseheartrate.Thechangeisthoughttodependontheconcentrationof

epoprostenoladministered.HypotensionmayoccurduringinfusionsofEpoprostenol.

TheeffectsofEpoprostenolonheartratemaybemaskedbyconcomitantuseofdrugswhichaffectcardiovascular

reflexes.

IfexcessivehypotensionoccursduringadministrationofEpoprostenol,thedoseshouldbereducedortheinfusion

discontinued.Hypotensionmaybeprofoundwithoverdoseandmayresultinlossofconsciousness(seesection4.9).

Short-termdose-rangingwithEpoprostenolmustbeperformedinahospitalsettingwithadequatepersonneland

equipmentforhaemodynamicmonitoringandemergencycare.

ElevatedserumglucoselevelshavebeenreportedduringinfusionofEpoprostenol.

RenalDialysis:

Epoprostenolisnotaconventionalanticoagulant.Epoprostenolhasbeensuccessfullyusedinsteadofheparininrenal

dialysis,butinasmallproportionofdialysesclottinghasdevelopedinthedialysiscircuit,requiringterminationof

dialysis.

DuringrenaldialysiswithEpoprostenolthereisaneedforcarefulhaematologicalmonitoringanditshouldbeensured

thatcardiacoutputisadequatelymaintainedsothatdeliveryofoxygentoperipheraltissuesisnotdiminished.

HaemorrhagiccomplicationshavenotbeenencounteredwithEpoprostenolbutthepossibilityshouldbeconsidered

whenthedrugisadministeredtopatientswithspontaneousordrug-inducedhaemorrhagicdiatheses.When

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ThehypotensiveeffectofEpoprostenolmaybeenhancedbytheuseofacetatebufferinthedialysisbathduringrenal

dialysis.

PrimaryandSecondaryPulmonaryHypertension:

ThehazardsofEpoprostenoltreatmentareconsideredtooutweightherisksofthediseaseinpatientswithfunctional

capacityofNewYorkHeartAssociation(NYHA)ClassIandClassII.Epoprostenoltherapyshouldthereforenotbe

initiatedinthesepatients.

Epoprostenolshouldbeusedonlybycliniciansexperiencedinthediagnosisandtreatmentofthisdisorder.

Somepatientswithprimarypulmonaryhypertensionhavedevelopedpulmonaryoedemaduringdose-ranging,

whichmaybeassociatedwithpulmonaryveno-occlusivedisease.

Epoprostenolisinfusedcontinuouslythroughapermanentindwellingcentralvenouscatheterviaasmall,portable

infusionpump.Thus,therapywithEpoprostenolrequirescommitmentbythepatienttosteriledrugreconstitution,drug

administration,careofthepermanentcentralvenouscatheter,andaccesstointenseandongoingpatienteducation.

Steriletechniquemustbeadheredtoinpreparingthedrugandinthecareofthecatheter.

EvenbriefinterruptionsinthedeliveryofEpoprostenolmayresultinrapidsymptomaticdeterioration.Thedecisionto

receiveEpoprostenolforPPHandSPHshouldbebasedupontheunderstandingthatthereisahighlikelihoodthat

therapywithEpoprostenolwillbeneededforprolongedperiods,possiblyyears,andthepatient'sabilitytoacceptand

careforapermanentintravenouscatheterandinfusionpumpshouldbecarefullyconsidered.

TheenclosedGlycineBufferDiluentcontainsnopreservative;consequentlyavialshouldbeusedonceonlyandthen

discarded.

Thismedicinalproductcontainsapproximately2.43mmol(or56mg)sodiumafterreconstitutionwith50mlofthe

GlycineBufferDiluent.

Tobetakenintoconsiderationbypatientsonacontrolledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

WhenEpoprostenolDrehmisadministeredtopatientsreceivingconcomitantanticoagulantsstandardanticoagulant

monitoringisadvisableastheremaybepotentiationofeffect.

WhenNSAIDSorotherdrugsaffectingplateletsaggregationareusedconcomitantly,thereisthepotentialfor

EpoprostenolDrehmtoincreasetheriskofbleeding.

ThevasodilatoreffectofEpoprostenolDrehmmayaugmentorbeaugmentedbyconcomitantuseofothervasodilators.

TheeffectsofEpoprostenolDrehmonheart-ratemaybemaskedbyconcomitantuseofdrugswhichaffect

cardiovascularreflexes.

EpoprostenolDrehmmayreducethethrombolyticefficacyoftissueplasminogenactivator(t-PA)byincreasinghepatic

clearanceoft-PA.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoorlimitedamountofdatafromtheuseofepoprostenolsodiuminpregnantwomen.Animalstudiesdonot

indicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonic/fetaldevelopment,parturitionor

postnataldevelopment(seesection5.3).Asaprecautionarymeasure,itispreferabletoavoidtheuseofEpoprostenol

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Lactation

Itisnotknownwhetherepoprostenolisexcretedinbreastmilk.Arisktothenewborns/infantscannotbeexcluded.

Breast-feedingshouldbediscontinuedduringtreatmentwithEpoprostenol.

Fertility

Epoprostenolhadnoeffectonmaleorfemalefertilityinanimals(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

4.8Undesirableeffects

Adversereactionsarelistedbelowbysystemorganclassandfrequency.Thefollowingterminologieshavebeenused

inordertoclassifytheoccurrenceofundesirableeffects

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),notknown(cannotbeestimatedfromtheavailabledata)

TheinterpretationofadverseeventsduringlongtermadministrationofEpoprostenoliscomplicatedbytheclinical

featuresoftheunderlyingdiseasebeingtreated.

Infectionsandinfestations

Verycommon:Sepsis,septicaemia*

Bloodandlymphaticsystemdisorders

Common:Decreasedplateletcount

Psychiatricdisorders

Common:Anxiety,nervousness

VeryRare:Agitation

Nervoussystemdisorders

VeryCommon:Headache

Cardiacdisorders

Common:TachycardiahasbeenreportedasaresponsetoEpoprostenolatdosesof5nanograms/kg/minandbelow.]

Bradycardia,sometimesaccompaniedbyorthostatichypotension,hasoccurredinhealthyvolunteersatdosesof

Epoprostenol,greaterthan5nanograms/kg/min.Bradycardiaassociatedwithaconsiderablefallinsystolicand

diastolicbloodpressurehasfollowedi.v.administrationofadoseofEpoprostenolequivalentto30nanograms/kg/min

inhealthyconsciousvolunteers.

VascularDisorders

VeryCommon:Facialflushing(seenevenintheanaesthetisedpatient)

VeryRare:Pallor

GastrointestinalDisorders

VeryCommon:Nausea,vomiting

Common:Abdominalcolic,sometimesreportedasabdominaldiscomfort

Uncommon:Drymouth

Skinandsubcutaneoustissuedisorders

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Musculoskeletalandconnectivetissuedisorders

VeryCommon:Jawpain

Generaldisordersandadministrationsiteconditions

Rare:Localinfection*,chestpain

VeryRare:Reddeningovertheinfusionsite*,occlusionofthelongi.v.catheter*,painattheinjectionsite*,lassitude,

chesttightness

*Associatedwiththedeliverysystemforepoprostenol.

4.9Overdose

Themainfeatureofoverdoseislikelytobehypotension.

Ingeneral,eventsseenafteroverdoseofepoprostenolrepresentexaggeratedpharmacologicaleffectsofthedrug.If

overdoseoccursreducethedoseordiscontinuetheinfusionandinitiateappropriatesupportivemeasuresasnecessary;

forexample,plasmavolumeexpansionand/oradjustmenttopumpflow.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AntithromboticAgents;Plateletaggregationinhibitorsexcl.heparin,ATCcode:

B01AC09

EpoprostenolDrehmisepoprostenolsodium,themonosodiumsaltofepoprostenol,anaturallyoccurringprostaglandin

producedbytheintimaofbloodvessels.Epoprostenolisthemostpotentinhibitorofplateletaggregationknown.Itis

alsoapotentvasodilator.

Infusionsof4ng/kg/minfor30minuteshavebeenshowntohavenosignificanteffectonheartrateorbloodpressure,

althoughfacialflushingmayoccurattheselevels.

RenalDialysis:

Manyoftheactionsofepoprostenolareexertedviathestimulationofadenylatecyclase,whichleadstoincreased

intracellularlevelsofcyclicadenosine3'5'monophosphate(cAMP).Asequentialstimulationofadenylatecyclase,

followedbyactivationofphosphodiesterase,hasbeendescribedinhumanplatelets.ElevatedcAMPlevelsregulate

intracellularcalciumconcentrationsbystimulatingcalciumremoval,andthisplateletaggregationisultimately

inhibitedbythereductionofcytoplasmiccalcium,uponwhichplateletshapechange,aggregationandtherelease

reactiondepend.

Theeffectofepoprostenolonplateletaggregationisdose-relatedwhenbetween2and16ng/kg/minisadministered

intravenously,andsignificantinhibitionofaggregationinducedbyadenosinediphosphateisobservedatdoses

4ng/kg/minandabove.

Effectsonplateletshavebeenfoundtodisappearwithin2hoursofdiscontinuingtheinfusion,andhaemodynamic

changesduetoepoprostenoltoreturntobaselinewithin10minutesofterminationof60-minuteinfusionsat1-16

ng/kg/min.

Higherdosesofepoprostenolsodium(20nanograms/kg/min)dispersecirculatingplateletaggregatesandincreaseby

uptotwofoldthecutaneousbleedingtime.

Epoprostenolpotentatestheanticoagulantactivityofheparinbyapproximately50%,possiblyreducingthereleaseof

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PrimaryandSecondaryPulmonaryHypertension:

IntravenousEpoprostenolDrehminfusionsofupto15minuteshavebeenfoundtoproducedose-relatedincreasesin

cardiacindex(CI)andstrokevolume(SV),anddose-relateddecreasesinpulmonaryvascularresistance(PVR),total

pulmonaryresistance(TPR),andmeansystemicarterialpressure(SAPm).TheeffectsofEpoprostenolDrehmonmean

pulmonaryarterypressure(PAPm)inpatientswithPPHwerevariableandminor.

Chronichaemodynamiceffectsaregenerallysimilartoacuteeffects.Duringchronicinfusioncardiacindex(CI),stroke

volume(SV)andarterialoxygensaturationareincreasedandmeansystemicarterialpressure(SAPm),rightatrial

pressure,totalpulmonaryresistance(TPR)andsystemicvascularresistancearedecreased.

5.2Pharmacokineticproperties

Intravenouslyadministeredepoprostenolsodiumisrapidlydistributedfrombloodtotissue.Atnormalphysiological

pHandtemperature,itbreaksdownspontaneouslyto6-oxo-prostaglandinF

a,althoughthereissomeenzymatic

degradationtootherproducts.Thehalf-lifeforthisprocessinmanisexpectedtobenomorethan6minutes,andmay

beasshortas2-3minutes,asestimatedfrominvitroratesofdegradationofepoprostenolinhumanwholeblood.

Pharmacokineticstudiesinanimalshaveshownthewholebodydistributiontobe1015ml/kg,andthewholebody

clearancetobe4.27ml/kg/sec.Followingintravenousinjectionofradiolabelledepoprostenol,thehighest

concentrationsarefoundintheliver,kidneysandsmallintestine.Steady-stateplasmaconcentrationsarereached

within15minutesandareproportionaltoinfusionrates.Extensiveclearancebytheliverhasbeendemonstrated,with

approximately80%beingremovedinasinglepass.Urinaryexcretionofthemetabolitesofepoprostenolaccountsfor

between40%and90%oftheadministereddose,withbiliaryexcretionaccountingfortheremainder.Urinaryexcretion

isgreaterthan95%completewithin25hoursofdosing.Tissuelevelsdeclinerapidlywithnoevidenceof

accumulation.

Followingtheadministrationofradiolabelledepoprostenoltohumans,theurinaryandfaecalrecoveriesofradioactivity

were82%and4%respectively.Atleast16compoundswerefound,10ofwhichwerestructurallyidentified.Unlike

manyotherprostaglandins,epoprostenolisnotmetabolisedduringpassagethroughthepulmonarycirculation.

Duetothechemicalinstability,highpotencyandshorthalf-lifeofepoprostenol,nopreciseandaccurateassayhasbeen

identifiedasappropriateforquantifyingepoprostenolinbiologicalfluids.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,toxicitytoreproduction.

Fertility:Astudyinwhichmaleandfemaleratsweredosedsubcutaneouslyfor74or63daysrespectively,with0,10,

30or100mg/kg/day,showednoeffectsonfertility.

TherewasnoevidenceofmutagenicityintheAmestest,micronucleusassayorDNAelution.

Carcinogenicity:Oncologystudieshavenotbeenperformed.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Powderforsolutionforinfusion:

Mannitol

Glycine

SodiumChloride

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Solvent:

Glycine

SodiumChloride

SodiumHydroxide(forpHadjustment)

Waterforinjection

6.2Incompatibilities

EpoprostenolDrehmmustbereconstitutedusingonlythesterilebufferprovided.Thismedicinalproductmustnotbe

mixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Powderforsolutionforinfusion:2years

Solvent:2years

Protectinfusionbagsfromlightduringinfusion.

RenalDialysis:

WhenreconstitutedwiththeGlycineBufferDiluentanddilutedwithphysiologicalsalineasinstructed(see6.6,

InstructionsforUse/Handling,RenalDialysis),freshlypreparedEpoprostenolsolutionsshouldbeusedwithina

maximumtimeframeof12hoursat25°C.

PrimaryandSecondaryPulmonaryHypertension:

WhenreconstitutedanddilutedwiththeGlycineBufferDiluentasinstructed(see6.6,InstructionsforUse/Handling,

PrimaryPulmonaryHypertension),freshlypreparedEpoprostenolsolutionsshouldbeinfusedimmediately.Ifnotused

immediately,in-usestoragetimesaretheresponsibilityoftheuserandshouldnotbelongerthan24hoursat2-8°C.

Wherethesolutionisheldinanambulatoryinfusionpumpsystem,acoldpouchmustbeusedtomaintainthe

temperatureofthesolutionat2-8°Cforthefulladministrationperiod.EpoprostenolDrehmsolutionmaythenbeused

overa24hourperiodprovidedthatthecoldpouchischangedasnecessarythroughouttheday.

Whereanambulatorycoldpouchsystemcannotbeusedthemaximumadministrationtimeat25°Cis12hoursfor

freshlypreparedsolutions.

6.4Specialprecautionsforstorage

Powderforsolutionforinfusion:

Keepthevialintheoutercartoninordertoprotectfromlight.

Keepthevialtightlyclosedinordertoprotectfrommoisture.

Storebelow25°C

Solvent:

Keepthevialintheoutercartoninordertoprotectfromlight.

Storebelow25°C

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

Eachpackunitcontains

-onevialEpoprostenolDrehm1.5mg,awhitefreeze-driedpowdercakepackedina15mlclearglassvialTypeIwith

greylyostopperandaluminiumcapswithredflip-offinserts.

-Two50mlsterileGlycinebuffersolution,pH10.5inaclearglassvial

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6.6Specialprecautionsfordisposal

Reconstitutionanddilution:

Particularcareshouldbetakeninthepreparationoftheinfusionandincalculatingtherateofinfusion.Theprocedure

givenbelowshouldbecloselyfollowed.

ReconstitutionanddilutionofEpoprostenolDREHM1.5mgmustbecarriedoutusingsteriletechniques,immediately

priortoclinicaluse.

Reconstitutiontimeshouldbebelow30seconds.

AfterreconstitutionEpoprostenolDREHMisacolourlesssolution,practicallyfreeofparticles.

Renaldialysis

Reconstitution:

1.UseonlytheGlycineBufferDiluentprovidedforreconstitution.

2.Withdrawapproximately10mloftheGlycineBufferDiluentintoasterilesyringe,injectthecontentsofthe

syringeintothevialcontaining1.5mgfreeze-driedepoprostenolandshakegentlyuntilthepowderhas

dissolved.

3.Drawuptheresultingepoprostenolsolutionintothesyringe,re-injectitintotheremainingvolumeofthe

GlycineBufferDiluentsolutionandmixthoroughly.

Thissolutionisnowreferredtoastheconcentratedsolutionandcontains30,000nanogramspermlepoprostenol.Only

thisconcentratedsolutionissuitableforfurtherdilutionpriortouse.

When1.5mgepoprostenolpowderisreconstitutedwith50mloftheGlycineBufferDiluent,thefinalinjectionhasa

pHofapproximately10.5andasodiumioncontentofapproximately56mg.

Dilution:

Foradministrationusingapumpcapableofdeliveringsmallvolumeconstantinfusions,suitablealiquotsof

concentratedsolutionmaybedilutedwithsterilephysiologicalsaline.

Itmaybedilutedwithphysiologicalsaline(0.9%),providedaratioof6volumesofsalineto1volumeofconcentrated

solutionisnotexceeded;e.g.50mlofconcentratedsolutionfurtherdilutedwithamaximumof300mlsaline.

OthercommonintravenousfluidsareunsatisfactoryforthedilutionoftheconcentratedsolutionastherequiredpHis

notattained.EpoprostenolsolutionsarelessstableatlowpH.

Priortousingtheconcentratedsolution,orthedilutedform,afiltrationstepisneeded.Tofilter,drawthereconstituted

productintoalargesyringeandthenattachthesterilefilterprovidedtothesyringe.

Dispensetheconcentratedsolutiondirectlyintothechoseninfusionsolutionusingfirmbutnotexcessivepressure;the

typicaltimetakenforfiltrationof50mlofconcentratedsolutionis70seconds.Mixwell.

Thefilterunitmustbeusedonceonlyandthendiscarded.

Whenreconstitutedanddilutedasdirectedabove,epoprostenolinfusionsolutionshaveapHofapproximately10and

willretain90%oftheirinitialpotencyforapproximately12hoursat25°C.

CALCULATIONOFINFUSIONRATE:

Theinfusionratemaybecalculatedbythefollowingformula:

Infusionrate= dosage(ng/kg/min)xbodyweight(kg)

(ml/min) concentrationofsolution(ng/ml)

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Infusionrateformulae-examples

WhenusedinrenaldialysisEpoprostenolDREHM1.5mgmaybeadministeredastheconcentratedsolution(a)orin

dilutedform(b).

a.Usingconcentratedsolutioni.e.30,000ng/mlepoprostenol.

*Verylowflowratesrequired.Dilutedsolutionsinphysiologicalsalineshouldbeconsidered.

b.Usingconcentratedsolution,diluted:

10mlconcentratedsolution+50mlphysiologicalsaline(0.9%).Togiveafinaltotalvolumeof60ml.

Resultantconcentration=5,000nanograms/mlepoprostenol.

PrimaryandSecondaryPulmonaryHypertension

Thefollowingpackisavailableforuseinthetreatmentofprimarypulmonaryhypertension:

Onevialcontainingsterilefreeze-driedepoprostenolsodiumequivalentto1.5mgepoprostenolsuppliedwithtwo50

mlvialofsterileGlycineBufferDiluentsolution.

Initiallyapackcontainingdiluentbuffermustbeused.Duringchronicepoprostenoltherapythefinalconcentrationof

solutionmaybeincreasedbytheadditionofasecondvialoffreezedriedepoprostenol.

Onlyvialsofthesameamountasthatincludedintheinitialstarterpackmaybeusedtoincreasethefinalconcentration

Concentrationofsolution=30,000ng/mlepoprostenol

Dosage

(ng/kg/min) Bodyweight(kilograms)

30 40 50 60 70 80 90 100

1 n/a*n/a* n/a* n/a*n/a* n/a*0.180.20

2 n/a*n/a* 0.200.240.280.320.360.40

3 0.180.240.300.360.420.480.540.60

4 0.240.320.400.480.560.640.720.80

5 0.300.400.500.600.700.800.901.00

Flowratesinml/hr

Concentrationofsolution=5,000ng/mlepoprostenol

Dosage

(ng/kg/min) Bodyweight(kilograms)

30 40 50 60 70 80 90 100

1 0.4 0.5 0.6 0.7 0.9 1.0 1.1 1.2

2 0.7 1.0 1.2 1.4 1.7 1.9 2.2 2.4

3 1.1 1.5 1.8 2.2 2.5 2.9 3.2 3.6

4 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

5 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0

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Date Printed 28/06/2011 CRN 2091199 page number: 10

Reconstitution:

Thisshouldbecarriedoutaccordingtotheinstructionsgivenforrenaldialysis.Whereapackcontaining1.5mg

epoprostenolisreconstitutedwith50mlsterilediluenttheresultantconcentrationis30,000nanogramsperml.

Dilution:

EpoprostenolDREHM1.5mgmaybeusedeitherasconcentratedsolutionorinadilutedformforthetreatmentof

PPH/SPH.OnlytheGlycineBufferDiluentprovidedmaybeusedforthefurtherdilutionofreconstitutedEpoprostenol

DREHM1.5mg.PhysiologicalsalinemustnotbeusedwhenEpoprostenolDREHM1.5mgistobeusedforthe

treatmentofprimaryorsecondarypulmonaryhypertension.

Concentrationscommonlyusedinthetreatmentofprimarypulmonaryorsecondaryhypertensionareasfollows:

30,000ng/ml-1.5mgepoprostenolreconstitutedtoatotalvolumeof50mlintheGlycineBufferDiluent

15,000ng/ml–1.5mgepoprostenolreconstitutedanddilutedtoatotalvolumeof100mlintheGlycineBuffer

Diluent.

Themaximumrecommendedconcentrationforadministrationinprimarypulmonaryorsecondaryhypertensionis

60,000ng/ml.

EpoprostenolDREHM1.5mgmustnotbeadministeredwithotherparenteralsolutionsormedicationswhenusedfor

primarypulmonaryhypertension.

Todilutetheconcentratedsolution,drawitupintoalargersyringeandthenattachthesterilefilterprovidedtothe

syringe.

Dispensetheconcentratedsolutiondirectlyintothepumpcassetteusingfirmbutnotexcessivepressure;thetypical

timetakenforfiltrationof50mlofconcentratedsolutionis70seconds.

RemovethefilterfromthesyringeanddrawuptheadditionalvolumeoftheGlycineBufferDiluentrequiredto

achievethedesireddilution.

RefitthefiltertothesyringeanddispensetheadditionalbufferthroughthisintotheconcentratedEpoprostenol

DREHM1.5mgsolutioninthecassette.

Mixwell.

Thefilterunitmustbeusedforthedilutionofonepackonlyandthendiscarded.

TheambulatorypumpusedtoadministerEpoprostenolDREHM1.5mgshould(1)besmallandlightweight,(2)be

abletoadjustinfusionratesinng/kg/minincrements,(3)haveocclusion,endofinfusion,andlowbatteryalarms,(4)be

accurateto±6%oftheprogrammedrate(5)bepositivepressuredriven(continuousorpulsatile)withintervals

betweenpulsesnotexceeding3minutesatinfusionratesusedtodeliverEpoprostenolDREHM1.5mg,and(6)include

acoldpouchsystemThereservoirshouldbemadeofpolyvinylchloride,polypropylene,orglass.

Protectinfusionbagsfromlightduringinfusion.

CALCULATIONOFINFUSIONRATE:

Theinfusionratemaybecalculatedfromtheformulagivenaboveforrenaldialysis.

Irish Medicines Board

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Date Printed 28/06/2011 CRN 2091199 page number: 11

Infusionratesforaconcentrationof15,000nanograms/ml:

7MARKETINGAUTHORISATIONHOLDER

DrehmPharmaGmbH

HietzingerHauptstrasse37/2

1130Vienna

Austria

8MARKETINGAUTHORISATIONNUMBER

PA1533/1/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17thJune2011

10DATEOFREVISIONOFTHETEXT

Concentrationofsolution=15,000ng/mlepoprostenol

Dosage

(ng/kg/min) Bodyweight(kilograms)

30 40 50 60 70 80 90 100

4 1.0 1.1 1.3 1.4 1.6

6 1.0 1.2 1.4 1.7 1.9 2.2 2.4

8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2

10 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0

12 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8

14 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6

16 1.9 2.6 3.2 3.8 4.5 5.1 5.8 6.4

Irish Medicines Board

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Date Printed 28/06/2011 CRN 2091199 page number: 12