· Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, et al; French Registry...

62 Variability in response to clopidogrel (editorial)AJMcLachlan&TJCampbell

64 Letters

68 Multiresistant organisms at the front line JTurnidge

71 Dental notesMultiresistantorganismsatthefrontline

72 Managing cardiovascular disease in Aboriginal and Torres Strait Islander people JReath&NBrown

76 The safety of plasma-derived products in Australia AGuirguis&EWood

80 Therapeutic Goods Administration. Medicines Safety Update No.3;2010AUSTRandAUSTLnumbers;Sibutramine;Drug-inducedpancreatitisandexenatide(Byetta)

84 Abnormal laboratory results: Tests for cell-mediated immunity SLimaye

88 Medicinal mishap Tamsulosin-inducedintraoperativefloppyirissyndromeduringcataractsurgery

89 New drugsazacitidine,caffeinecitrate,humanC1esteraseinhibitor,miglustat,vildagliptin

Fulltextwithsearchfacilityonlineatwww.australianprescriber.com

VoLUMe 33 NUMber 3 AN INDepeNDeNT reVIew JUNe 2010 C o N T E N T S

62 | VoLUMe 33 | NUMber 3 | JUNe 2010 www.austral ianprescriber.com

Editorial

Variability in response to clopidogrelAndrew J McLachlan, Professor of Pharmacy (Aged Care), Faculty of Pharmacy, University of Sydney, and Centre for Education and Research on Ageing, Concord Hospital; and Terence J Campbell, Professor of Medicine, University of New South Wales, and Head, University Department of Medicine, St Vincent's Hospital, Sydney

Keywords:pharmacokinetics,plateletantagonists,protonpump

inhibitors.

(Aust Prescr 2010;33:62–3)

Theantiplateletdrugclopidogreliseffectivewhenusedin

combinationwithaspirinforthepreventionofcoronaryevents

inpatientswithcoronaryarterystentsandacutecoronary

syndromes.However,thereisgrowingevidencethatdespite

thisdualantiplatelettherapysomepatientsexperiencemore

atherothromboticeventsthanexpected.1Thistherapeuticfailure

hasbeencalled'clopidogrelresistance'.Thepossiblefactors

contributingtovariabilityintheresponsetoclopidogrelinclude

pooradherence,variablebioavailability,druginteractions,and

geneticpolymorphismsindrugmetabolisingenzymesorin

plateletreceptors.

Clopidogrelisaprodruganditsactivemetaboliteirreversibly

bindstoandinhibitstheadenosinediphosphateP2Y12receptor

onplatelets.Approximately85%ofthedoseismetabolised

toaninactivemetabolite(byplasmaesterases)and15%is

activatedbyhepaticcytochromeP450(CYP)isoenzymesina

two-stepmetabolicprocessinvolvingCYP3A4andCYP2C19.2

Theimpactofpolymorphismsinthegenesthatcontrol

clopidogrelabsorption,metabolicactivationand

pharmacologicaleffectwasexaminedintheFrenchRegistry

ofAcuteST-ElevationandNon-ST-ElevationMyocardial

Infarction(FAST-MI).Thisstudyfoundthatpatientswho

weregivenclopidogrelafteramyocardialinfarctionwere

morelikelytohavearecurrentcardiaceventiftheyhadan

allelicvariationoftheCYP2C19genethatledtoreduced

enzymeactivity.3Thisfindingwassupportedbyanother

studywhichincludedhealthyvolunteers,andpatients

receivingclopidogrelforacutecoronarysyndrome(Trialto

AssessImprovementinTherapeuticoutcomesbyoptimizing

PlateletInhibitionwithPrasugrel-ThrombolysisinMyocardial

Infarction,TRIToN-TIMI38).Thetrialfoundthatpeoplewith

CYP2C19variantsencodingforreducedmetabolicactivity

hadlowerconcentrationsofclopidogrel'sactivemetabolite,

reducedplateletinhibitionandahigherrateofmajoradverse

cardiovascularevents.4Takentogetherthesedatasuggest

thattheabilitytogenerateadequateconcentrationsofthe

activemetaboliteiscentraltothevariabilityinresponseto

clopidogrel.

Thepossibleimpactofconcomitantdrugtherapyonclopidogrel

efficacy(viaaneffectonconcentrationsoftheactivemetabolite)

hasalsobeeninvestigated.Tworetrospectivestudies,involving

130005and80006patients,havesuggestedaclinically

significantreductionofefficacy,intermsofrecurrentcoronary

events,inpatientstreatedwithclopidogreliftheywerealso

receivingprotonpumpinhibitors.Theeffectwasmodest

(approximately25%increasedriskinbothstudies)andof

onlyborderlinestatisticalsignificance,suggestingtheneed

forcautionininterpretingtheseresults.Pantoprazoledoes

notappeartoattenuateclopidogrel'sbenefits.Thishasbeen

attributedtoitspredominanteffectonCYP2C9inhibitionand

weakereffectonCYP2C19activity.5

In this issue…Atthetimeofwritingthereisamoratoriumontheuse

ofseasonalinfluenzavaccineinchildrenunderfiveyears

ofage.QuestionsarealsobeingraisedabouttheH1N1

immunisationcampaign.Itishopedthattheseconcerns

donotdetractfromtheoverallbenefitsofimmunisation

againstinfectiousdiseases.

Preventingbacterialinfectionsisimportantasantibiotic

resistanceisincreasing.JohnTurnidgeadviseshowto

tacklethemultiresistantorganismswhichareemerging

incommunitypractice.Preventinginfectioniscriticalin

transfusionsandAndrewGuirguisandEricaWoodtellus

ofthemethodsusedtomaximisethesafetyofplasma-

derivedproducts.

PreventionisthefocusofthearticlebyJennyReathand

NgiareBrownonthemanagementofcardiovascular

diseaseinAboriginalandTorresStraitIslanderpeople.

Screeningfromtheageof18yearsshouldhelptoreduce

thehighratesofcardiovascularmorbidityandmortality.

| VoLUMe 33 | NUMber 3 | JUNe 2010 63www.austral ianprescriber.com

Protonpumpinhibitorsareoftenprescribedtopatients

takingdualantiplatelettherapytotryandreducetheriskof

gastrointestinalbleeding,soitisparticularlyrelevanttoknowif

theydoreducetheefficacyofclopidogrel.Arecentprospective

randomisedcomparisonofclopidogrelwithprasugrel,anew

thienopyridineantiplateletdrug,inwhichone-thirdof14000

patientsweretakingaprotonpumpinhibitoratstudyentry,7

failedtoconfirmanyclinicallysignificantinteractionduringa

400-dayfollow-upperiod.Therewasnodifferenceintheefficacy

ofeitherclopidogrelorprasugrelinpreventingvascularevents,

betweenthosepatientswhoweretakingprotonpumpinhibitors

andthosewhowerenot.Thisappearstohavebeenconfirmed

bytheonlyrandomisedtrialofomeprazoleversusplaceboin

3627patientstakingclopidogrel,theCoGENTstudy,which

waspresentedinSeptember2009(21stannualTranscatheter

CardiovascularTherapeuticsscientificsymposium,California),

butisnotyetpublished.Therewereatotalof136cardiovascular

eventsoverameanfollow-upof133days,andtheKaplan-Meier

curvesforthetwogroupswereabsolutelysuperimposed.While

possiblynotpoweredtodetectverysmalldifferences,this

resultdoesseemtoruleoutanymajorreductionintheefficacy

ofclopidogrelcausedbyomeprazole.Thisisareassuring

findingasithasnotbeenclearwhatcouldbedonetoavoid

thisproblem.TheuseofH2antagonists(suchasranitidine)has

beensuggested,buttherearedoubtsabouttheirequivalent

efficacytoprotonpumpinhibitors(andfewdatatosupportthis

recommendation).

InNovember2009,however,theUSFoodandDrug

Administration(FDA)announcedchangestotheproduct

information,basedonstudiessuggestingreducedefficacyin

termsofplateletfunction.Thenewrecommendationsareto

avoidprescribingomeprazoleoresomeprazoleconcurrently

withclopidogrel.TheFDAstatesthatthereareinsufficient

datatomakearecommendationregardingotherprotonpump

inhibitors,butitalsorecommendsthatpatientsonclopidogrel

avoidcimetidine(butnototherH2antagonists),fluconazole,

ketoconazole,voriconazole,etravirine,fluoxetine,fluvoxamine

andticlopidine.8Understandablythisrecommendationhas

causedconfusioninthecardiologicalcommunity,whobelieve

thatclinicaloutcomesaremoreimportantthanplateletfunction

studies.

Suggestionstoovercomeso-calledclopidogrelresistance

includetheassessmentofadherencetoclopidogreltherapy,

increasingtheclopidogreldose(toincreasetheamountofactive

metabolite),screeningpatientstoidentifyCYP2C19variants,and

avoidingdruginteractionswithprotonpumpinhibitors.Well-

designedtrialstoevaluatetheeffectivenessofthesestrategies

arelacking,butarecentcaseseriessuggestedminimalbenefits

fromincreasingtheclopidogreldosetoashighas300mgdaily.9

RoutinetestingofCYP2C19allelicvariationsisnotcommon

practiceandtheriskofadverseeffectsfromincreasingthe

clopidogreldoserequiresfurtherinvestigation.Assessingpatient

adherencetoclopidogreltherapyandavoidingpossibledrug

interactionscurrentlyappeartobethemostpracticalstrategies.

Lastly,itremainsunclearwhethertheinteractionbetweenproton

pumpinhibitorsandclopidogrelisofclinicalsignificance.

references1. AngiolilloDJ.Variabilityinresponsivenesstooral

antiplatelettherapy.AmJCardiol2009;103(Suppl):27A-34A.

2. KimKA,ParkPW,HongSJ,ParkJY.TheeffectofCYP2C19polymorphismonthepharmacokineticsandpharmacodynamicsofclopidogrel:apossiblemechanismforclopidogrelresistance.ClinPharmacolTher2008;84:236-42.

3. SimonT,VerstuyftC,Mary-KrauseM,QuteinehL,DrouetE,MeneveauN,etal;FrenchRegistryofAcuteST-ElevationandNon-ST-ElevationMyocardialInfarction(FAST-MI)Investigators.Geneticdeterminantsofresponsetoclopidogrelandcardiovascularevents.NEnglJMed2009;360:363-75.

4. MegaJL,CloseSL,WiviottSD,ShenL,HockettRD,BrandtJT,etal.Cytochromep-450polymorphismsandresponsetoclopidogrel.NEnglJMed2009;360:354-62.

5. JuurlinkDN,GomesT,KoDT,SzmitkoPE,AustinPC,TuJV,etal.Apopulation-basedstudyofthedruginteractionbetweenprotonpumpinhibitorsandclopidogrel.CMAJ2009;180:713-8.

6. HoPM,MaddoxTM,WangL,FihnSD,JesseRL,PetersonED,etal.Riskofadverseoutcomesassociatedwithconcomitantuseofclopidogrelandprotonpumpinhibitorsfollowingacutecoronarysyndrome.JAMA2009;301:937-44.

7. o'DonohueML,BraunwaldE,AntmanEM,MurphySA,BatesER,RosenmanY,etal.Pharmacodynamiceffectandclinicalefficacyofclopidogrelandprasugrelwithorwithoutaproton-pumpinhibitor:ananalysisoftworandomisedtrials.Lancet2009;374:989-97.

8. USFoodandDrugAdministration.Informationforhealthcareprofessionals:Updatetothelabelingofclopidogrelbisulfate(marketedasPlavix)toalerthealthcareprofessionalsaboutadruginteractionwithomeprazole(marketedasPrilosecandPrilosecoTC).2009Nov17.www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm[cited2010May7]

9. PenaA,ColletJP,HulotJS,SilvainJ,Barthelemyo,BeyguiF,etal.Canweoverrideclopidogrelresistance?Circulation2009;119:2854-7.

Further readingAcuteCoronarySyndromeGuidelinesWorkingGroup.Guidelinesforthemanagementofacutecoronarysyndromes2006.MedJAust2006;184(8Suppl):S9-29.

Professor McLachlan was a member of a clopidogrel advisory

board sponsored by Sanofi Aventis in 2008.

Professor Campbell: none declared


LettersThe Editorial Executive Committee welcomes letters, which should be less than 250 words. Before a decision to publish is made, letters which refer to a published article may be sent to the author for a response. Any letter may be sent to an expert for comment. Letters are usually published together with their responses or comments in the same issue. The Editorial Executive Committee screens out discourteous, inaccurate or libellous statements and sub-edits letters before publication. The Committee's decision on publication is final.

H1N1 immunisation

Editor,–Havingjustreadtheinterestingeditorial'H1N1immunisation:toomuchtoosoon?'(AustPrescr2010;33:30–1)byPeterCollignon,itwouldbeevidentthatconsiderablewastetookplaceinthedeliveryofthevaccinetothepatient.Notonlyintheuseofmultidosevials,butinthewasteoftheunusedvialswhichnowhavetobediscardedwiththeintroductionofthenew2010trivalentinfluenzavaccine.Iwonderifdetailsofthewastageandrelevantcostsareavailable.

IunderstandthatCSLdevelopedtheswinefluvaccineanddeliveredthevialstotheCommonwealthHealthDepartment.WasCSLpaidbytheGovernmentforthevaccinesordidCSLbeartheloss?

AsDeputyChairoftheReturnUnwantedMedicinesProject,Iwouldalsobeinterestedtoknowhowtheunusedvaccinevialsaretobedestroyed–Ihopeitisinanenvironmentallyresponsiblemanner!

KenBicklePharmacistGreenwich,NSW

Professor Peter Collignon, author of the editorial, comments:

IagreewithKenBicklethatconsiderablewastewasassociatedwiththeH1N1immunisationprogram.Fulldetailsarenotreadilyavailablebecauseof'commercialinconfidence'agreements.FrommediareportsitappearsthatCSLreceivedabout$120millionfromourFederalGovernmentfor21millionvaccinedoses.1AnaddedpotentialcosttotheGovernmentistheindemnityCSLreceivedforanyseriousadverseeventsresultingfromthevaccine.

onlyaquarterofthesedosesweredistributed1andthevaccinewaspresentedinmultidosevials.Multidosevialsresultinmuchhighervaccinewastagecomparedtosingle-usepreloadedsyringes.2Isuspectthat30%ofthedistributedvaccinedoseswereneveradministered.Additionally,mostofthevaccinegivenwastothoseover65years.3Thisagegroupalreadyhadhighlevelsofpre-existingimmunitytoH1N1(swineflu)andthusvaccinationwasnotlikelytohavebeenmuchbenefitforthem.

TheWorldHealthorganizationhasdocumentedthemajorinfectionproblemsassociatedwithunsafeinjectionpractices.4Thisresultsinmillionsofviralandbacterialinfectionseveryyear,especiallyindevelopingcountries.5Multidosevialsandimmunisationpracticesmayonlybeasmallcomponentofthisproblem,butthisriskcanbevirtuallyeliminatedwiththeuseofpreloadedsingle-usesyringesforvaccination(which

weuseforseasonalfluvaccinationshere).Usingsingle-usepreloadedsyringesalsoresultsinconsiderablylesswastageofvaccine.2Thisreducedwastagewillusuallymorethancompensatefortheirsmalladditionalcost(about14cents).2

Multidosevialsmaysometimeshaveaplaceforthedeliveryofinexpensivevaccinesincountrieswithlowresourcesandpoorinfrastructure.2TheyhavenoplaceinacountrysuchasAustralia.

references

1. DaytonL,FranklinM.NicoleRoxoninfluvaccinedilemma.TheAustralian.2010Jan7.www.theaustralian.com.au/news/nation/nicole-roxon-in-flu-vaccine-dilemma/story-e6frg6nf-1225816777813[cited2010May3]

2. DrainPK,NelsonCM,LloydJS.Single-doseversusmulti-dosevaccinevialsforimmunizationprogrammesindevelopingcountries.BullWorldHealthorgan2003;81:726-31.

3. AustralianInstituteofHealthandWelfare.2009Adultvaccinationsurvey.ProvisionaltoplineresultsforH1N1vaccinationuptake.www.aihw.gov.au[cited2010May11]

4. SimonsenL,KaneA,LloydJ,ZaffranM,KaneM.Unsafeinjectionsinthedevelopingworldandtransmissionofbloodbornepathogens:areview.BullWorldHealthorgan1999;77:789-800.

5. KaneA,LloydJ,ZaffranM,SimonsenL,KaneM.TransmissionofhepatitisB,hepatitisCandhumanimmunodeficiencyvirusesthroughunsafeinjectionsinthedevelopingworld:model-basedregionalestimates.BullWorldHealthorgan1999;77:801-7.

Editor,–IwasdisappointedtoreadtheeditorialonH1N1vaccination(AustPrescr2010;33:30–1),especiallywhentheNationalPrescribingServicestatesthatthepublicationisevidence-basedandpeerreviewed.

Inparticular,thearticlestates:'Inthepast,manyinfections,suchas Staphylococcus aureus,hepatitisBandHIV,havebeencausedbyvaccinationprogramsusingmultidosevials.2'Frommylimitedresearch,IamnotawareofanypastdocumentedinfectionsassociatedwithgeneralpracticevaccinationprogramsinAustralia(aswearepredominatelyusingforH1N1vaccination),noranydocumentationofhepatitisBorHIVinfectionsfromanyvaccinationprograms.Referencetwointheeditorialdoesnotbackuphisclaim–itinfactreferstotheauthor'sownarticlewhichhasnocommentontransmissionofdiseasefrommultidosevials.

Inaddition,Iquestionthebalanceoftheauthorwhendiscussinginfluenzavaccination.Hequotedonlyone


studythat'showedthatthedecreaseinall-causemortalityattributabletoseasonalinfluenzavaccinewas4.6%',withoutnotingthelimitationsofthisstudy,norreferringtothewidebodyofinternationalevidencesupportinginfluenzavaccination,includingthosereferencedinthe9theditionoftheAustralianImmunisationHandbook.

Althoughitisfairtocommentthatwewouldbenefitfrommoreeffectiveinfluenzavaccines,andthatpolicymakersmustcarefullyreviewpandemicplanning,includingtheroleofmultidosevials,Idonotbelievethatthedebateisassistedbyclaimsthatarenotcorrectlyreferenced,norhighlightingofsinglestudies.IwouldalsoquestionwhetherthiseditorialisconsistentwiththeNationalPrescribingService'sclaimto'provideaccurate,balanced,evidence-basedinformation'.

GregRowlesGeneralpractitionerRiddellCountryPracticeRiddellsCreek,Vic.

Professor Peter Collignon, author of the editorial, comments:

IagreewithDrRowlesthatweneedmoreeffectiveinfluenzavaccinesandareviewofpandemicplanning.Iacceptthatitisbesttoreferenceprimarysourcesratherthanreviews.Unfortunatelywordandreferencelimitationsininvitededitorialsmakethatdifficulttodoattimes.

ontheissueofefficacy,moststudiesoninfluenzavaccineshavemajorbiases.1Generallyvaccinationratesarelowerinpeoplewhoaremostatriskofdeathandthusthebenefitsfrominfluenzavaccinationarelikelyoverstated.1,2Morbidityandmortalityareoftenlowerinvaccinees,evenbeforethestartofthefluseason,comparedtocontrols.oneofthefewstudiesthathavetriedtountanglethesebiaseswastheoneIquoted.ThisverylargeCalifornianstudyfoundabenefitforvaccination,butitwas10-foldlessthanpreviouslyattributedforinfluenzavaccination.2

Infectioncontrolguidelinesrecommendasbestpracticethatsingle-dosevialsareusedwhereverpossible.Thereisextensivedocumentationonthetransmissionofmanydifferentviralandbacterialinfectionswhenmultidosevialsareused.Thisincludesvaccinationprogramsusingmultidosevials.3–7

InAustraliawehadtheBundabergdisasterin1928.DiphtheriavaccinecontaminatedwithStaphylococcus aureusfrommultidosevialscausedthedeathsof12childrenandresultedinaRoyalCommission.4InGeelonginthelate1960s,twofactoryworkersdiedfromStreptococcus pyogenesfollowingworkplacefluvaccinationsfrommultidosevials.Thecoronersubsequentlyrecommendedagainsttheuseofmultidosevials.5,6Moreextensivereferencesonthisinternationalproblemhavebeendiscussedpreviously.7

Multidosevialsareinvolvedinthetransmissionofinfectiousorganisms.IbelievetheyshouldnotbeusedinmassvaccinationcampaignsinAustralia.

references

1. JeffersonT,DiPietrantonjC,Al-AnsaryLA,FerroniE,ThorningS,ThomasRE.Vaccinesfor

preventinginfluenzaintheelderly.CochraneDatabaseSystRev2010,Issue2:CD004876.

2. FiremanB,LeeJ,LewisN,Bembomo,vanderLaanM,BaxterR.Influenzavaccinationandmortality:differentiatingvaccineeffectsfrombias.AmJEpidemiol2009;170:650-6.

3. SimonsenL,KaneA,LloydJ,ZaffranM,KaneM.Unsafeinjectionsinthedevelopingworldandtransmissionofbloodbornepathogens:areview.BullWorldHealthorgan1999;77:789-800.

4. KellawayCH,MacCallumP,TebbuttAH.ThefatalitiesatBundaberg.ReportoftheRoyalCommission.MedJAust1928;II:2.

5. PlueckhahnVD,BanksJ.Fatalhaemolyticstreptococcalsepticaemiafollowingmassinoculationwithinfluenzavaccine.MedJAust1970;1:405-11.

6. TheGeelongdisaster.MedJAust1970;1:401-2.

7. CollignonP.Whycan'twehavearationaldiscussionaboutthemeritsofpandemicfluvaccination?2009Aug31.http://blogs.crikey.com.au/croakey/2009/08/31/why-cant-we-have-a-rational-discussion-about-the-merits-of-pandemic-flu-vaccination/[cited2010May3]

radiographic contrast media and metformin

Editor,–Iwriteregardingthearticledealingwithradiographic

contrastmedia(AustPrescr2010;33:19–22).

Ihaverecentlyauthoredasystematicreviewrelatingtothe

safetyofiodinatedcontrastinpatientsreceivingmetformin.1

Thereviewfoundnoevidencetosubstantiatebeliefsabout

theneedtoceasemetformininindividualswithstable,

normalrenalfunctionwhoweretohavea'normal'amount

ofintravenousiodinatedcontrastforanexaminationsuch

asaCTscan.Despiteanumberofinternationalguidelines

havingdisparaterecommendationsaboutcessationof

metformin,theRoyalAustralianandNewZealandCollege

ofRadiologists(RANZCR),theRoyalCollegeofRadiologists

(RCR)andtheEuropeanSocietyofUrogenitalRadiology

guidelinesrecommendthatthereisnoneedtostopmetformin

inthesepatients.TheRANZCRrecommendationsarebased

ontheextremelylowriskofprecipitationofcontrast-induced

nephropathyinthisgroup.TheAustralianandRCRguidelines

weremodifiedalongtheselinesinMarchandJune2009,

respectively,soonafterthesystematicreviewwaspresented

attheRadiologicalSocietyofNorthAmericameetingin

December2008.

otherworkbyJeffreyNewhousesupportsourfindings

thattheriskofcontrast-inducednephropathyhasbeen

exaggeratedbyresearchfocusingonpatientswhohave

largevolume,intra-arterialadministrationofiodinatedmedia

andbythelackofagenuinecontrolgroupinmanyofthe

studiesthathavelinkediodinatedmediatohighratesofpost-

proceduralcontrast-inducednephropathy.


Theadvicebytheradiologisttoceasemetformin,whenthis

isnotnecessary,canhavemanyunintendedconsequences

suchasthepatientforgettingtorecommencemetformin.In

addition,patientsmayvisittheirgeneralpractitionerforadvice

aboutwhenitissafetorecommencemetformin,incurring

coststothehealthsystem.

TheadvicegivenintheAustralian Prescriber articleisentirely

appropriateforpatientswho:

n arehavinglargecontrastvolume,intra-arterial

procedures(suchascoronaryangiographyor

interventionalprocedures)or

n areknowntohaveabnormaloracutelydeteriorating

renalfunction.

However,thisimportantdistinctionisnotmadeclearinthe

articleandgeneralpractitionersmayinterpretthisadvice

toapplytotheirownpracticecontext,whichislargelyCT

scanningorotherlowerdoseproceduresassociatedwith

intravenouscontrastmedia.

StacyGoergenAssociateProfessor,DirectorofResearchDepartmentofDiagnosticImagingSouthernHealthClayton,Vic.

reference

1. GoergenSK,RumboldG,ComptonG,HarrisC.Systematicreviewofcurrentguidelines,andtheirevidencebase,onriskoflacticacidosisafteradministrationofcontrastmediumforpatientsreceivingmetformin.Radiology2010;254:261-9.

Professor Ken Thompson and Dr Dinesh Varma, authors of the

article, comment:

WhenwritingthisarticlewewerewellawareoftheRANZCR

guidelinesandtheissuesofhowtohandleapatientwithtype

2diabetestakingmetforminwhorequiresacontrastCT.

TheRANZCRguidelinesagreethatitisdifficulttomeasure

estimatedglomerularfiltrationrate(e-GFR)inallpatientsinan

outpatientsetting,althoughthisisourpractice.

Whileitistruethatthereislittleornohighlevelevidence

torecommendstoppingmetformininpatientswithnormal,

stablerenalfunctionreceivingamoderatedoseofcontrast

media,thegeneralpractitionerwhorequeststhecontrast

examinationhasnocontrolovertheactualamountofcontrast

mediathepatientisgiven.Thismayvaryforawidevarietyof

reasons.Anextremelylowriskisnotthesameasnorisk.

Wewerealsoinfluencedbythedrugmanufacturer's

informationanddecidedtoprovideadvicethatisconsistent

withthepackaginginformation.Inourview,theriskthata

patientwhotakesadrugeverydaywillforgettorecommence

thedrugisunlikely.

Iodine allergy

Editor,–WewouldliketothankProfessorKatelarisand

DrSmithfortheirtimelyarticleonthemisleadinglabel

ofiodineallergy(AustPrescr2009;32:125–8).This,asthe

authorsindicate,isamarkedsourceofanxietyforpatients

whoneedcontrastmediascanning.

Wehavealsonotedsimilaranxietiesinpatientswhoare

potentialcandidatesfortheuseofradioactiveiodine(I-131)

forthetreatmentofhyperthyroidismandthyroidcancer.

Forpatientswhohaveahistoryofseafoodorcontrast

sensitivitywearrangeintravenousaccessasaprecaution.

However,inover3000administrationsoforalhigh-dose

radioactiveiodineforthyroidcancer,wehavenot

encounteredanysignificantallergicphenomena.

Wethereforefeelthatpatientswithseafoodorcontrast

allergycanbereassuredthatthiswillnotoccurwithlow-or

high-doseradioactiveiodine.

RogerAllisonRadiationoncologistandExecutiveDirectorCancerCareServices,RoyalBrisbaneandWomen'sHospital

RobinMortimerAoSeniorEndocrinologist,RoyalBrisbaneandWomen'sHospital,andSeniorDirector,officeofHealthandMedicalResearch

QueenslandHealth

Aliskiren and angioedema

Editor,–Aliskirenisanovelantihypertensivedrugthatisan

orally-activedirectrenininhibitor(AustPrescr2009;32:132−5).

Itsactionsharesacommonbiologicalpathwaywith

angiotensin-convertingenzyme(ACE)inhibitors.However,

ithasbeensuggestedinanarticlebyProfessorDugganthat

somerespiratoryandvascularadverseeventswerelesslikely

thanwiththeolderdrugs(AustPrescr2009;32:135−8).The

proposalwasfairlyreasonablebasedonthedifferentmolecular

targetofthetwodruggroups.However,postmarketing

experiencerevealedcasesofaliskiren-associatedangioedema

anddrugregulatorsimplementedlabellingchangesandsafety

advice.1–3Therefore,physiciansshouldbevigilantforthefirst

signsofangioedemainaliskirenusers.Thebiologicalbasis,

exactfrequencyandriskfactorsofthispotentiallylife-treating

eventarecurrentlynotwellunderstood.Untilevidence

becomesavailable,aliskirenandprobablyothersimilardrugs

shouldnotbeusedinpatientswithpreviousepisodesofACE

inhibitor-inducedangioedemaofanyclinicalpresentation.

DraganMilovanovic,SlobodanJankovic,DejanaRuzicZecevic

andMarkoFolic

DepartmentofClinicalPharmacology,MedicalFacultyand

UniversityHospital

Kragujevac,Serbia


references

1. Aliskiren(Rasilez):riskofangioedemaandrenaldysfunction.DrugSafUpdate2009;2:2.

2. Tekturna(aliskiren)tablets.SafetylabelingchangesapprovedbyFDACenterforDrugEvaluationandResearch(CDER)–November2009.

3. Aliskiren.Newcontraindicationandwarning.WHoPharmaceuticalsNewsletter2009;2:1.

Associate Professor K Duggan, author of the article,

comments:

Thetrueincidenceofadverseeffectsoftenonlybecomes

apparentafterthedrughasbeenmarketedandmyarticle

waspreparedbeforemarketing.De novoangioedemaasan

adverseeffectoftheangiotensinreceptorantagonistsonly

becameapparentpostmarketingandthesameappearsto

beoccurringwithaliskiren.Contraindicationstotheuseof

aliskirenshouldnowincludeangioedemaoccurringasa

consequenceoftheuseofotherrenin-angiotensindrugs.

Thisscenariohighlightstheimportanceofpractitioners

notifyingregulatorybodiesofadverseeffectsnotpreviously

reported.

prescription drug subsidies in Australia and New Zealand

Editor,–Therecenteditorialon'Prescriptiondrugsubsidies

inAustraliaandNewZealand'(AustPrescr2010;33:2–4)

revealsstrikingdifferencesbetweenthetwocountriesin

expenditureonprescriptiondrugs.Thisisattributedinpart

totheNewZealandpolicyofexclusivecontractsforsupplyof

off-patentmedicationsbeingawardedthroughcompetitive

tender.Thecostsavingsareobviousenough,butanadditional

benefitofthissystemistomakethegenericbrandinstantly

recognisablebothforprescribersandconsumers.The

proliferationofgenericbrandsinAustralia,bycontrast,leads

toagreatdealofconfusionforpatients.Thisoftendissuades

doctorsfromprescribinggenericbrands,atgreatcosttothe

healthsystem.

LachlanBrownGeneralpractitioner/Anaesthetist

Batehaven,NSW

Editor,–TheeditorialbySteveMorganandKatherineBoothe

(AustPrescr 2010;33:2–4)makesanumberofconcerning

statements.TheauthorsconsiderthatAustraliaandNew

Zealandappeartobe'convergingintheiruseofcertain

[pharmaceuticalprocurement]policytools'.

Theauthorsdonotidentifythemajorfactorresponsible

forthesuccessofthePharmaceuticalManagementAgency

ofNewZealand(PHARMAC)inreducingpricespaidfor

pharmaceuticals.PHARMACisexemptfromtheentire

portionoftheNewZealandCommerceAct1986thatdeals

withrestrictivetradepractices.TheresultisthatPHARMAC

isinadominantpositionasamonopsonyandisableto

embarkonnegotiatingtacticsnotallowedunderWorld

Tradeorganizationrulesornationallegislationinmost

otherfirstworldcountries.

Theauthorshavemadecomparisonsofgrowthincosts

betweenPHARMACandoECD(organisationforEconomic

Co-operationandDevelopment)data.Theconclusions

drawnareunreliableasthereportingmethodsusedto

collectthesedataarenotcomparableovertime(asstated

bytheoECD).1

Wheretheauthorsreport'conspicuouslylittleevidence'of

healthoutcomesrelatedtopharmaceuticalaccessbeing

differentbetweenthecountries,theyindicatenoattempt

toidentifydifferencesinhealthoutcomes.Itwouldbe

imprudenttoassumethatthelackofepidemiological

evidencetosupportworsehealthoutcomesinNewZealand

linkedtopharmaceuticalaccessvindicatesthereduced

accesstomedicines.

Forthesereasons,itisunlikelythatAustraliacouldorwould

choosetoalignitselfmorecloselywiththeNewZealand

methodsofpharmaceuticalsprocurement.

KevinSheehyResearchedMedicinesIndustryAssociationofNewZealandWellington,NewZealand

reference

1. oECDHealthData2009.Country-specificinformationonhealthexpenditureandfinancedata–NewZealand.www.ecosante.org/oCDEENG/520.html[cited2010May7]

Editor,–Regardingyoureditorialon'Prescriptiondrug

subsidiesinAustraliaandNewZealand'(AustPrescr

2010;33:2–4),thereisapointwhichisnotdiscussed

whichgreatlyreducescostsinNewZealand–thatofbulk

dispensing.NewZealandallowspeoplewithcommon

chronicdiseasestohavethreeorsixmonthssupplyof

medicinesdispensedatonetime,asopposedtothe

monthlydispensingusualinAustralia.Thismeansthata

NewZealanderwithsay,highbloodpressure,willpaytwo

dispensingfeesperyear,whereasanAustralianwilllikely

pay12dispensingfees.

Iunderstandtherationalebehindmonthlydispensing,but

really,doesapersonwhowillbetakingadrugfortherestof

theirlivesneedmonthlyinterventionbyapharmacist,and

doesthishappeninanybutasmallminorityofcases?Ihave

monthlyprescriptionsforbloodpressuremedication,and

invariablyIhandtherepeattoanassistant,whohandsitto

apharmacist,whotypesoutalabelsaying'Takeoneinthe

morning',passesitbacktotheassistant,whoputsitinabag

andsaystome'$33.30please'.

JonathanRoutAconcernedconsumerRedwoodPark,SA


Multiresistant organisms at the front line

John Turnidge, Clinical Director, Microbiology and Infectious Diseases, SA Pathology, Adelaide

Summary

Multiresistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus, multiresistant Streptococcus pneumoniae, vancomycin-resistant enterococci and multiresistant Pseudomonas aeruginosa are being seen with increasing frequency in the community and not just in hospital practice. Treatment options for infections caused by these pathogens are limited, but in most cases a suitable drug can be found. In particular, there are options for the treatment of the community-associated strains of MrSA, such as trimethoprim-sulfamethoxazole, and often macrolides or lincosamides.

Keywords:antibioticresistance,MRSA.

(Aust Prescr 2010;33:68–71)

IntroductionGeneralpractitionersareoftenfacedwithpatientssuffering

frominfectionscausedbybacteriaharbouringsomekindof

antibioticresistance.Manyoftheseresistancesaresocommon

thatwetakethemforgranted–forexample,penicillin

resistanceinStaphylococcus aureusoccursinabout90%of

communitystrains,andamoxycillinresistanceinabout50%

ofEscherichia coli.Usuallythereareoptionsforantibiotic

treatment(seeTable1),andlaboratoriesattempttoprovide

susceptibilitydata.However,forsomeresistantorganismsthe

optionsarelimited,problematicorboth.Thegenerictermfor

thesestrainsismultiresistantorganisms.

Methicillin-resistant Staphylococcus aureus (MrSA)Eventhoughmethicillinitselfisnolongerused,theterm

methicillin-resistantisstillusedtoidentifytheseveryimportant

multiresistantorganisms.Thegeneralpractitionerislikelyto

encountertwotypesofMRSA.Thesearethemultiresistant

MRSAstrainsthatarehospital-associatedwhicharefound

colonisingoroccasionallyinfectingpatientswhohave

previouslybeenhospitalised,andthenon-multiresistant

community-associatedMRSAstrainswhicharefoundinall

thosecommoncircumstanceswhereonewouldexpectto

seesusceptibleS. aureus,namelyboils,furuncles,cellulitis

andwoundinfections.Purulentformsofstaphylococcalskin

infectionrespondbesttodrainage,andforsmalllesions

drainagewithoutantibacterialtreatmentwillbeusually

adequate.1

WhenantibacterialtreatmentisrequiredforMRSAinfection,

thechoiceisdrivenbywhethertheinfectingstrainis

hospital-orcommunity-associated.Choicesforhospital-

associatedMRSAarequitelimited.Seriousinfectionrequires

hospitalisationandintravenousvancomycin,whilelessserious

infectionsrequireanoralcombinationofrifampicinand

fusidicacid.Thisoralcombinationisessentialtoavoidthe

selectionoffurtherresistanceduringtreatment.Unfortunately,

thePharmaceuticalBenefitsScheme(PBS)onlysubsidises

rifampicinforindicationsotherthanstaphylococcalinfection,

whilefusidicacid–whichthePBSstatesmustbeusedin

combination–isavailableforjustsuchanindication.Hence,

adequatetreatmentforhospital-associatedMRSAoften

requiresareturnvisittohospitaltoensuretimelyaccessto

appropriatedrugs.

Thereareusuallymoretreatmentoptionsforcommunity-

associatedMRSAthanforhospital-associatedinfections.

Moststrainsaresusceptibletomacrolides(erythromycin,

roxithromycin,clarithromycinandazithromycin)and

lincosamides(clindamycinandlincomycin),aswell

astrimethoprim/sulfamethoxazoleandtetracyclines.

Susceptibilitytoerythromycinpredictssusceptibilityto

clindamycin,whichisconsideredthedrugofchoice(when

oneisrequired)formildtomoderatecommunity-associated

MRSA.Theotherdrugforwhichthereismostexperience

inlesssevereinfectionistrimethoprim/sulfamethoxazole.

Thisisrecommendedforyoungchildrenasclindamycin

suspensionisnotavailable,orwhenresistanceto

erythromycin(whichmoreoftenthannotpredictsresistance

toclindamycin)issuspectedorproven.Tetracyclinessuch

asdoxycyclinecanbeusedforminorcommunity-associated

MRSA,althoughtheiruseshouldprobablybereserved

forpatientsallergictoatrimethoprim/sulfamethoxazole

component,andonlyinthosemorethaneightyearsof

age.Patientswithseriousinfectionscausedbycommunity-

associatedMRSAshouldbehospitalisedandtreatedwith

vancomycininitially.


Table 1

Treating multi-drug resistant infections in the community

Multiresistant organism resistance pattern Infection Drug of choice for mild to moderate infection

Hospital-associatedMRSA Pattern1PenicillinrMethicillinrErythromycinrTetracyclinerTrimethoprim/sulfamethoxazolerCiprofloxacinrorS

Any Rifampicinplusfusidicacid

Pattern2PenicillinrMethicillinrErythromycinrmostlyTetracyclineSTrimethoprim/sulfamethoxazoleSCiprofloxacinr

Community-associatedMRSA PenicillinrMethicillinrErythromycinSmostlyTetracyclineSTrimethoprim/sulfamethoxazoleSCiprofloxacinS

Any Clindamycin

MultiresistantStreptococcus pneumoniae

PenicillinrAmoxycillinSorrErythromycinrTetracyclinerTrimethoprim/sulfamethoxazoler

otitismedia,sinusitis,acuteexacerbationsofchronicbronchitis,pneumonia

Amoxycillin

Moxifloxacinforadultpatients(≥18years)withpenicillinallergy

Vancomycin-resistantenterococci

Penicillinand/oramoxycillinSorrVancomycinr

Urinarytract Nitrofurantoinornorfloxacin

MultiresistantEscherichia coli AmoxycillinrAmoxycillin/clavulanateS/I /rCefazolin/cephalexinrTrimethoprim/sulfamethoxazolerCefotaximeorceftriaxoneSorr

Urinarytract Amoxycillin-clavulanateifsusceptible.otherwisenorfloxacinifsusceptible.

othersites Amoxycillin-clavulanateifsusceptible.otherwiseciprofloxacinifsusceptible.

othermultiresistantentericbacteria

KlebsiellaspeciesAmoxycillinrAmoxycillin/clavulanateSorrCefazolin/cephalexinrTrimethoprim/sulfamethoxazoleSorrCefotaximeorceftriaxoneSorr

Urinarytract Amoxycillin-clavulanateifsusceptible.otherwisenorfloxacinifsusceptible.

EnterobacterspeciesAmoxycillinrAmoxycillin/clavulanaterCefazolin/cephalexinrTrimethoprim/sulfamethoxazoleSorrCefotaximeorceftriaxoneSorr

othersites Amoxycillin-clavulanateifsusceptible.otherwiseciprofloxacinifsusceptible.

MultiresistantPseudomonas aeruginosa

TicarcillinSorrCeftazidimeSorrMeropenemSorrGentamicinSorrTobramycinSorrNorfloxacinSorrCiprofloxacinSorr

Urinarytract Norfloxacinorciprofloxacinifsusceptible

MRSAmethicillin-resistantStaphylococcus aureusrresistantSsusceptibleIintermediate


ColonisationIngeneral,treatmentshouldnotbeadministeredtopatients

whoaremerelycolonisedwithMRSA,eveninlong-termcare

facilities,wheretheriskoftransmissionishigher.Topical

(nasal)mupirocininparticularhasaverylimitedrolebecause

itseffectisshort-livedandconfinedtothenostrils.Eradication

ofthecolonisedstateisdifficultandtreatmentshouldonlybe

consideredifthepatienthasprovenrecurrentfurunculosisdue

tonasalcarriageofMRSA.Topicaltreatmentshouldonlybe

usedaspartofamoreintensiveregimeninvolvingsystemic

antimicrobialsnotreadilyavailableincommunitypractice.

Multiresistant Streptococcus pneumoniae Beforetheintroductionofaconjugatepneumococcalvaccine

intothechildhoodimmunisationschedule,theproportionof

multiresistantS. pneumoniaestrainsinthecommunitywas

increasing.Theyarelessprevalentnow,inpartduetothe

overalldecreaseinpneumococcalinfectionsasaresultofthe

conjugatevaccine,buttheywillstillbeencountered.2

AsmanymultiresistantS. pneumoniaestrainsareisolated

fromyoungchildren,thecombinationofmultiresistanceand

amorerestrictedrangeoforalsuspensionsmakesoptimising

treatmentdifficult.Resistancetomacrolides,lincosamides,

tetracyclinesandtrimethoprim/sulfamethoxazoleiscommon

inS. pneumoniae,especiallyinstrainswithreduced

susceptibilitytopenicillins.over10%ofAustralianisolates

havethisresistancepattern.Paradoxically,strainswithreduced

susceptibilitytopenicillinsgenerallyremainsusceptibletooral

amoxycillininhigherdoses(upto1geveryeighthours).This

makesamoxycillinthedrugofchoiceformildtomoderate

infections,evenforthegreatmajorityofmultiresistantstrains,

anditiscurrentlyrecommendedinAustralianguidelines.3

Penicillin-allergic patientsProblemsariseinthepenicillin-allergicpatient.oral

cephalosporinsareineffectiveagainststrainsofS. pneumoniae

withevenslightlyreducedsusceptibilitytopenicillin.Inadults,

moxifloxacinisthemostsuitablechoice,althoughthisisnot

readilyavailableonthePBS.Forchildrenwithanallergyto

beta-lactamantibiotics(12yearsoryounger)thereiscurrently

noentirelysatisfactoryoraltreatment.Fortunately,penicillin

allergyinyoungchildrenisuncommon.optionsrangefrom

tryingamacrolideortrimethoprim/sulfamethoxazoleifthey

areonlymildlyunwell,tohospitalisationforparenteraltherapy

inasickerchild.

Vancomycin-resistant enterococci Vancomycin-resistantenterococciareusuallyhospital-

associatedmultiresistantorganisms.Whiletheyareunlikely

tospreadwidelyinthecommunity,anincreasingnumber

ofpatientsarebecomingcolonisedinhospitalandasmall

percentagewillsubsequentlydevelopaninfectionwith

thecolonisingstrainafterbeingdischarged.Mostofthese

infectionswillbeintheurinarytract.

Vancomycin-resistantenterococcistrainsaredifficultto

manageforanumberofreasons,includingtheirhigh

transmissibilityinthehospitalsetting,andmoreimportantly

becauseoftheverylimitedrangeofantimicrobialsavailable

totreatthem.Enterococciarenaturallyresistanttomany

antibacterialdrugsincludingmacrolides,lincosamides,

cephalosporinsandtrimethoprim/sulfamethoxazole.Thereare

twoprominentvancomycin-resistantenterococciphenotypes:

resistanttovancomycinandteicoplanin(so-calledVanA),and

resistanttovancomycinbutsusceptiblein vitrototeicoplanin

(so-calledVanB).Unlikeinothercountries,thepredominant

phenotypeinAustraliaisVanB.

Thechoiceoftreatmentforvancomycin-resistant

enterococciinfectiondependsontheseverityofthe

infectionandwhichspeciesiscausingit.Enterococcus

faecalisstrainsaremostlysusceptibletopenicillinand

amoxycillin,andthesedrugscanbeused(inhigher

dosages)providedthepatientisnotallergictopenicillin.

ontheotherhand,mostEnterococcus faeciumstrainsare

resistanttopenicillinandamoxycillin,anddrugsthatare

onlyavailableinhospitalmaybetheonlyoption.These

importantreservedrugs,suchaslinezolidanddaptomycin,

areeffectiveparenteraldrugs.Fortunately,nitrofurantoin

andnorfloxacinremainoptionsforurinarytractinfections

causedbyeitherVanAorVanB.

ColonisationTherearenoeffectivetreatmentsforthecolonisedstate.

Furthermore,iftheisolateisfromtheurineofapatientwith

anindwellingcatheterwithoutanysystemicsymptoms,

thisrepresentscolonisationratherthantrueinfectionand

treatmentisnotwarranted.

Multiresistant Escherichia coliover5%ofclinicalE. coliisolatesinAustraliaareresistant

tomorethanthreeantibacterialdrugsrecommendedfor

use–resistancetoamoxycillin,cefazolin/cephalexinand

trimethoprim/sulfamethoxazoleisthecommonestprofile.4

Reducedsusceptibilityorresistancetoamoxycillin-clavulanate

isalsofoundinmorethan8%ofallE. coliandinupto13%of

amoxycillin-resistantstrains,sostrainswithmultiresistance

areencounteredingeneralpractice.Fortunately,moststrains

atpresentstillremainsusceptibletothefluoroquinolones

(norfloxacinandciprofloxacin)andtonitrofurantoin.The

recentincreaseincommunitystrainsharbouringextended-

spectrumbeta-lactamasesisconcerning–theseenzymes

makeE. coliresistanttothird-generationcephalosporins


(cefotaximeandceftriaxone).Thesestrainsareoftenresistant

togentamicinand/orfluoroquinolonessowhentreating

multiresistantE. coliinfection,thesusceptibilitytestresults

arerequiredtoensurethatanappropriateeffectivedrugis

chosen.

other multiresistant enteric bacteria Klebsiellaspeciesarefoundinsimilarclinicalsettings

toE. coliincommunitypractice.Theyarenaturally

resistanttoamoxycillin,andhaveahigherpropensityto

acquireresistancesthanE. coli.Almost10%ofstrainsare

multiresistant(morethanthreeacquiredresistances).4

TreatmentoptionsaresimilartoE. coli,againtakingcareful

heedofthesusceptibilitytestresults.

Lesscommonlyencounteredmultiresistantentericbacteria

areEnterobacterspecies,whicharenaturallyresistantto

amoxycillin,amoxycillin-clavulanateandcefazolin/cephalexin.

Furthermore,thesespeciescanbecomeresistanttothird-

generationcephalosporinsduringtreatment.Treatment

choicesarerestrictedtotrimethoprim/sulfamethoxazoleor

fluoroquinolonesifsusceptibleontesting,orcarbapenemsfor

seriousinfection.

Multiresistant Pseudomonas aeruginosaP. aeruginosaisnaturallyresistanttomanyantibacterialdrugs.

Withoutacquiredresistance,thisspeciesisonlysusceptible

toalimitedrangeofbeta-lactams(ticarcillin,piperacillin,

ceftazidime,cefepimeandmeropenem),aminoglycosides

(gentamicin,tobramycinandamikacin)andfluoroquinolones

(norfloxacinandciprofloxacin).Furthermore,P. aeruginosahas

ahighpropensitytomutatetooracquireresistancetoanyof

thesedrugs.Hence,incertainclinicalsettingssuchasintensive

careandinpatientswithcysticfibrosis,multiresistantstrains

ofP. aeruginosaarecommon.

Multiresistantstrainsmaybeencounteredinthecommunity,

mostcommonlyincomplicatedurinarytractinfection.

Treatmentofmildtomoderateurinaryinfectioncausedby

thesestrainswillbedefinedbytheresultsofsusceptibility

tests.Iftheisolateissusceptibletociprofloxacin,thisdrugcan

begivenorallytooutpatients.otherwise,allotherdrugsmust

beadministeredparenterally,andhospitalmanagementis

usuallyrequired.Strainsisolatedfromotitisexternawillusually

respondadequatelytotopicaltreatment.

Conclusion Althoughtherearelimitedtreatmentoptionsforinfections

causedbymultiresistantorganisms,therearestilldrugs

availableinthecommunityinmanycasesandhospitalisation

formorecomplexparenteraltherapycanbeavoided.

Ingeneral,treatmentofcolonisationwithmultiresistant

organismsisnotrequired.

references1. RajendranPM,YoungD,MaurerT,ChambersH,

Perdreau-RemingtonF,RoP,etal.Randomized,double-blind,placebo-controlledtrialofcephalexinfortreatmentofuncomplicatedskinabscessesinapopulationatriskforcommunity-acquiredmethicillin-resistantStaphylococcusaureusinfection.AntimicrobAgentsChemother2007;51:4044-8.

2. RochePW,KrauseV,CookH,BarraletJ,ColemanD,SweenyA,etal;EnhancedInvasivePneumococcalDiseaseSurveillanceWorkingGroup,etal;PneumococcalWorkingPartyoftheCommunicableDiseasesNetworkAustralia.InvasivepneumococcaldiseaseinAustralia,2006.CommunDisIntell2008;32:18-30.

3. TherapeuticGuidelines:Antibiotic.Version13.Melbourne:TherapeuticGuidelinesLimited;2006.

4. AustralianGrouponAntimicrobialResistance.Gram-negativesurvey.2004AntimicrobialSusceptibilityReport.

www.antimicrobial-resistance.com(gotoAMRsurveillance,GNBSusceptibilityReport)[cited2010May11]

In the last two years, Professor Turnidge has sat on anti-

infective advisory boards for Janssen-Cilag and Pfizer.

Dental notes

Prepared by Michael McCullough, Chair, Therapeutics Committee, Australian Dental Association

Theincreasingprevalenceofmultiresistantbacteriain

community-associatedinfectionsismostlikelycaused

byover-prescriptionofantibiotics.Themajorityofdental

infectionscanbesuccessfullytreatedwithanaccurate

diagnosisandtimelydentaltreatmentwithoutantibacterial

medication.Whenantibacterialdrugsareneeded,theprinciple

ofusingadrugwiththenarrowestspectrumhaslongbeen

heldandisclearlyoutlinedinrecentguidelines.1Studieshave

shownthat85%oforalbacteriaaresusceptibletopenicillinV.

Thisisonlymarginallyhigher–91%–withamoxycillin.2

over10%ofAustralianStreptococcus pneumoniaeisolates

havereducedsusceptibilitytopenicillins,yettheseisolates

paradoxicallyremainsusceptibletohigherdosesoforal

amoxycillin.Potentiallylife-threateningS. pneumoniae

infectionsinchildrencanbeeffectivelytreatedwithhigh-

doseamoxycillinandthisisoneoftheclinicalreasonswhy

amoxycillinisnotrecommendedasthefirstdrugofchoicefor

oralinfections.1Dentistsshouldbeawareofchangingdrug-

resistancepatternsanduseantibioticsjudiciously.

references1. TherapeuticGuidelines:oralandDental.Melbourne:

TherapeuticGuidelinesLimited;2007.

2. BaumgartnerJC,XiaT.Antibioticsusceptibilityofbacteriaassociatedwithendodonticabscesses.JEndod2003;29:44-7.


Managing cardiovascular disease in Aboriginal and Torres Strait Islander peopleJenny Reath, Professor, Peter Brennan Chair of General Practice, School of Medicine, University of Western Sydney; and Ngiare Brown, Associate Professor and Director, Bullana – the Poche Centre for Indigenous Health, University of Sydney

Summary

Cardiovascular diseases are responsible for much of the reduced life expectancy of Aboriginal and Torres Strait Islander people. Modification of cardiovascular risk factors is important, especially as calculators may underestimate the absolute risk of a cardiovascular event. Smoking cessation is a key component of primary and secondary prevention. As cardiovascular disease can begin early in life, screening for risk factors from the age of 18 years is recommended. Drug therapy is similar to that for other patients, but may need to be started sooner, particularly as comorbidities are common. risk factors do not account for all of the increased mortality, so psychosocial and other factors need to be considered.

Keywords:hypertension,preventivemedicine.

(Aust Prescr 2010;33:72–5)

Introduction

AboriginalandTorresStraitIslanderAustralianpeoplebornin

2005–2007areexpectedtodieapproximately11yearsearlier

thanotherAustralians.1Manyfactorsareresponsiblefor

thisgapinlifeexpectancyandcomprehensiveapproaches

arerequiredtoaddressthisinequality.Primaryhealthcare

providerscanplayanimportantrole,particularlyin

prevention.

Cardiovasculardiseaseistheleadingcauseofreduced

lifeexpectancy.Between2002and2005cardiovascular

diseaseaccountedfor27%ofallAboriginalandTorresStrait

Islanderdeaths.2Thereareexcessdeathratesineveryage

categoryandacrossalljurisdictionswherereliabledataare

available.Theincidenceofcardiovasculareventsinurban

communitiesislikelytobesimilartothatinruralandremote

communities.3

Thespecificdiseasescontributingtotheseexcessdeathsare

coronaryheartdisease,cerebrovasculardisease,heartfailure

andhypertension.Rheumaticheartdiseasecontributesasmall

proportionoftheoverallmortality,buttherateofrheumatic

heartdiseaseinAboriginalandTorresStraitIslanderpeople

isamongthehighestintheworld.

Whilethemanagementofcardiovasculardiseasehas

similaritiesforallpatients,someapproachesarespecific

toAboriginalandTorresStraitIslanderpeople.Relevant

resourcesandmanagementrecommendationsare

summarisedinTable1andBox1.

Table 1

resources specific for Aboriginal and Torres Strait Islander people

resource Source *

CalculatorforabsoluteriskassessmentwithprovisionforestimationofriskforAboriginalandTorresStraitIslanderpeoplefromage35years

www.heartfoundation.org.au

NationalguidetoapreventivehealthassessmentinAboriginalandTorresStraitIslanderpeoples,NACCHoandRACGP,NACCHo2005

www.racgp.org.au

Guidelinesforthediagnosisandmanagementofacuterheumaticfeverandrheumaticheartdisease

www.heartfoundation.org.au

PreferentialaccesstoPharmaceuticalBenefitsSchemeitemsforAboriginalandTorresStraitIslanderpeople,e.g.nicotinereplacementtherapy

www.pbs.gov.au

Culturalsafetytraining www.culturalsafetytraining.com.au

NACCHoNationalAboriginalCommunityControlledHealthorganisation

RACGPRoyalAustralianCollegeofGeneralPractitioners

*SeefullURLsonlinewiththisarticleatwww.australianprescriber.com


primary preventionModifyingriskfactorswithAboriginalandTorresStraitIslander

patientsisakeypreventivehealthstrategy.Theyaremorelikely

thanotherAustralianstosmokeandtohavehypertension,

obesity,hyperlipidaemia,diabetesandrenaldisease.4

Absoluteriskassessmentisimportantinthepreventionof

cardiovasculardisease.5Modificationshavebeenmadeto

absoluteriskassessmenttoolstofacilitatetheestimationof

riskfromage35yearsinAboriginalandTorresStraitIslander

peoplenotalreadyknowntobeathighriskforcardiovascular

disease.Itislikely,however,thatthesetoolswillstill

underestimatetheriskinthispopulation.5Clinicaljudgement

isthereforerequiredwhenusingabsoluteriskcalculatorsfor

AboriginalandTorresStraitIslanderpeople.

Individualriskassessmentevery1–2yearsisrecommended

forAboriginalandTorresStraitIslanderpeoplefrom18years

ofage.ThisscreeningissupportedbyaccesstotheAboriginal

andTorresStraitIslanderAdultHealthCheckMedicareitems.

Screeningincludeslifestyleassessmentandmeasurementof

bloodpressure,weight,bodymassindex,waistcircumference

andfastinglipidstatus.Giventhehighprevalenceofdiabetesand

renaldiseaseandtheimpactofthesediseasesoncardiovascular

diseaserisk,routinescreeningshouldincludedipsticktestingfor

proteinuriaandfastingbloodglucose,startingfrom15–18years

ofage.6Screeningshouldalsoincludeassessmentofpulseand

follow-upofirregularitiestodiagnoseandtreatatrialfibrillation.

Screeningprovidesanidealopportunitytopromoteahealthy

diet,physicalactivity,smokingcessation,moderationofalcohol

consumptionandweightcontrol.6

Theseriskfactorsdonot,however,explainalloftheincreased

burdenofcardiovasculardiseaseamongAboriginaland

TorresStraitIslanderpeople.Psychosocial,7socio-economic

andin uterofactors8arelikelytocontributesubstantially

totheriskinthesecommunities.Thesynergisticeffectof

multipleriskfactorsalsoimpactsonthedifferentialburdenof

cardiovasculardisease.4

Giventhemultiplemorbiditiescommonintheircommunities,

AboriginalandTorresStraitIslanderpeoplearemorelikely

thanotherAustralianstofallwithinagroupdefinedasathigh

riskofcardiovasculardisease.5Thoseathighriskwillbenefit

fromintensivemanagementincludingdrugtherapy.

Secondary preventionSecondarypreventionstrategiesaimtopreventfurther

deteriorationinthosewhohavebeendiagnosedwith

cardiovasculardisease.4Thereductionofriskofamajor

coronaryeventordeathhasbeenquantified(Box2).4These

benefitsarelikelytoapplytoAboriginalandTorresStrait

Islanderpeople.

Smoking cessationAboriginalandTorresStraitIslanderpeopleareapproximately

twiceaslikelytosmokeasotherAustralians.Addressing

thisriskfactorislikelytohaveasubstantialimpacton

reducingmorbidityandprematuredeathrates.Ingeneral

practice,abriefinterventioncounsellingapproachis

recommended.9Nicotinereplacementtherapyisavailable

onthePharmaceuticalBenefitsScheme(PBS)forAboriginal

andTorresStraitIslanderpatients.Theuseofotherdrugsto

assistinsmokingcessationrequirescarefulconsiderationof

thebenefitsandrisksfortheindividualpatient.Thereisalso

evidenceinAboriginalandTorresStraitIslandercommunities

oftheefficacyofcommunity-basedapproaches.9

Box 1

recommended approaches to cardiovascular disease in Aboriginal and Torres Strait Islander people

Screening and prevention

Individualriskassessmentevery1–2yearsfromage18yearsincluding:9

• measurementofbloodpressure,weight,bodymassindex,waistcircumference,pulseforatrialfibrillation,fastinglipidandbloodglucose,andurinetestingforproteinuria

• calculationofabsolutecardiovascularriskfromage35years5

• promotionofhealthydiet,weightcontrol,physicalactivity,smokingcessationandmoderationofalcoholconsumption

Treatment

Earlyuseofantihypertensives4–considerACEinhibitorsorangiotensinreceptorantagonistsasfirst-linedrugs

Starttreatmentwithcholesterol-loweringdrugswhenLDLcholesterolremains>2.5mmol/Lafterlifestylemodification12

Cholesterol-loweringdrugsmaybeprescribedonthePharmaceuticalBenefitsScheme:

• atanylipidlevelforpatientswithdiabetes

• iftotalcholesterol>6.5mmol/Lortotalcholesterol>5.5mmol/LandHDLcholesterol<1mmol/L

ACEangiotensin-convertingenzyme

HDLhighdensitylipoprotein

LDLlowdensitylipoprotein


Nutrition and physical activityAdoptionoftraditionaldietaryandfoodgatheringpracticeshas

beenshowntoreduceriskfactorsformetabolicsyndrome.10

FormostAboriginalandTorresStraitIslanderpeoplethis

isnotpossible.Thereisalsooftendifficultyinaccessing

affordable,healthyfood.6Community-basedprogramsmay

assistinimprovingbothaccesstoandacceptabilityofhealthy

foods.Reductioninalcoholconsumptionmayreducetherisk

ofcardiovasculardiseasethroughitsimpactondiet,blood

pressureandweight.5Itmayalsoincreaseadherencetoother

riskreductionmeasures.

Regularphysicalactivitypreventsthedevelopmentofrisk

factorsforcardiovasculardisease.Whencombinedwithother

secondarypreventionstrategiesincardiacrehabilitation

programsithasbeenshowntoreducecardiovascularmortality.4

Pharmacological managementRecommendationsforpharmacologicalmanagementforthose

atriskorwithapasthistoryofcardiovasculardiseaseare

similartothosefornon-indigenousAustralians.11Aspirinin

adoseof75–150mg/dayreducestheriskofseriousvascular

eventsinthosewhohavebeendiagnosedwithcardiovascular

disease.Forthosewhoareintolerantorallergictoaspirin,

clopidogrelisanappropriatealternative.11

InrecognitionoftheriskforAboriginalandTorresStrait

Islanderpeople,cholesterol-loweringdrugsareavailable

throughthePBSatlowerthresholdsthanforotherpatients.

'Statin'therapyisrecommendedforAboriginalandTorres

StraitIslanderpatientsiftheirlowdensitylipoprotein

cholesterolremainsabove2.5mmol/Lafterlifestyle

modification.12

Earlytreatmentwithantihypertensivemedicationis

recommendedforAboriginalandTorresStraitIslanderpatients

withhypertension.13Whilethefirstchoiceofdrugdependson

comorbiditiesandcontraindications,inAboriginalandTorres

StraitIslanderpatients,giventhehighprevalenceofdiabetes,

anangiotensinconvertingenzyme(ACE)inhibitororan

angiotensinIIreceptorantagonistisrecommended.4

Polypillformulationsincludingcombinationsofthe

recommendedpharmaceuticaldrugsarecurrentlybeingtrialled

toevaluatetheirusefulnessasanaidtoadherencetothelong-

termuseofmultipledrugs.Theresultsofthesestudiesare

likelytoinformbestpracticeguidelinesinthefuture.

Acute management of symptomatic diseaseHealthprofessionalsworkinginAboriginalandTorresStrait

Islandercommunitiesneedtomaintainahighindexof

suspicionregardingcardiovasculardisease.Itoccursinpeople

ofallagesandinwomenaswellasmen.Patientsmayalso

overlookorminimisesymptoms.

Evenwhererelevanthealthfacilitiesareavailable,Aboriginal

andTorresStraitIslanderpatientsarelesslikelyto

receivecardiovascularproceduresincludingangiography,

percutaneouscoronaryinterventionsandbypasssurgery.4

Theprimaryhealthcareproviderhasakeyroleinrecognising

theneedforproceduralinterventionandadvocatingfor

accesstoappropriateinterventionandtosubsequentcardiac

rehabilitation.

primary healthcare approaches Akeytoeffectiveprimaryhealthcareisidentificationof

AboriginalandTorresStraitIslanderpatientsandawareness

oftheirincreasedprevalenceofcardiovasculardiseaseand

relatedriskfactorsatamuchearlierage.Computerisedalerts

andpractice-basedscreeningcanassistinpreventiveand

follow-upactivities.

Culturalissues,thehistoryofAboriginalandTorresStrait

Islanderpeopleandtheoverwhelmingburdenofdiseasemay

makelifestylechangeandaccesstoappropriatehealthcare

achallengeforsomeAboriginalandTorresStraitIslander

patients.Itisimportanttoavoidjudgementandblame

andtoseektounderstandthebarriersandfacilitatorsfor

eachpatient.Culturalsafetytrainingmayassisthealthcare

providersinunderstandingtheseissues(Table1).Ahealth

professionalwhounderstandsthebarriersforapatientin

accessinghealthcareisabletoworkmoreeffectivelywith

thepatientandotherhealthprofessionalstoimproveaccess,

ratherthanassumingthatareferralwillresultintherequired

healthcare.

The'normality'ofprematuredeathandmultiplemorbidityin

AboriginalandTorresStraitIslandercommunitiescanresult

inanacceptanceofillhealththatattimesbecomesabarrier

tochange.Ifhealthcareprovidersfocusoneachdisease,

thiscansometimescontributetothepatient'ssensethatitis

'alltoomuch'.Itiscriticaltoworkwiththepatientusingan

optimisticandholisticapproachtoidentifyingchangesthey

areabletomake.Thisisbestgroundedinatrustinglong-term

Box 2

relative reduction in risk of major coronary event or death

following secondary prevention activities 4

67%riskreductionforpeopleunder65yearswhohaveneversmoked

40%riskreductionforpeople65yearsandoverwhohaveneversmoked

22%riskreductionwithACEinhibitors

20%riskreductionwithbetablockers

20%riskreductionifcholesterolcontrolled

20%riskreductioninpeoplewhoarephysicallyactive

19%riskreductionwithaspirin

14%riskreductionifbloodpressurecontrolled


relationshipwitharespectfulpractitionerwhoiswillingto

learnfromandadvocatefortheirpatient.

Community-based approachesAccesstocareisakeyconsiderationinthemanagementof

cardiovasculardisease.AboriginalandTorresStraitIslander

peoplearedisadvantagedbyreducedaccesstomedicines,

delayedaccesstoacutecarefacilitiesandlowerratesof

interventiononcetheyareadmittedtothesefacilities.4

Thereisaneedtoaddresscommunityawarenessaswell

assystemicbarrierscontributingtoprematuredeathfrom

cardiovasculardisease.Primaryhealthcareprovidershavea

keyroleinimprovingawarenessandaccesstolocalservices

forAboriginalandTorresStraitIslanderpeople.Community-

basedprogramswithafocusoneducationandempowerment

asameansofimprovingaccesstointegratedhealthservices

havebeenshowntoimprovehealthoutcomes.14

HealthservicescontrolledbyAboriginalcommunitiesalso

provideexpertiseandoftenarangeofrelevantprograms

includingaccesstoAboriginalhealthworkersandotherallied

andspecialisthealthcareproviders.Theseservicesmayalso

offerprogramsaddressingpsychosocialandotherriskfactors

contributingtotheincreasedburdenofcardiovasculardisease.

Indigenous-specificresourcessuchasinformationbrochures

andwaitingroomposterswhichaddresscardiovascular

diseaseandrelatedriskfactorsmaybeavailablefromstate

andterritoryhealthdepartments.

ConclusionEffectivemanagementofcardiovasculardiseaseinAboriginal

andTorresStraitIslandercommunitieshasthepotentialto

makeahugedifferenceinhealthoutcomesbeyondthoseof

theindividualpatient.Themanagementtoolsarethesameas,

oradaptationsof,thoseusedinthegeneralcommunityand

arereadilyaccessibletothepractitionerwithAboriginaland

TorresStraitIslanderpatients.

Acknowledgement: Dr Alex Brown, Head of the Centre for

Indigenous Vascular and Diabetes Research at the Baker IDI,

provided valuable editorial input to this paper.

references1. AustralianBureauofStatistics.Experimentallifetablesfor

AboriginalandTorresStraitIslanderAustralians:2005–2007Canberra:AustralianBureauofStatistics;2009.

2. PenmE.CardiovasculardiseaseanditsassociatedriskfactorsinAboriginalandTorresStraitIslanderpeoples2004–05.Canberra:AustralianInstituteofHealthandWelfare;2008.

3. BradshawPJ,AlfonsoHS,FinnJC,owenJ,ThompsonPL.CoronaryheartdiseaseeventsinAboriginalAustralians:incidenceinanurbanpopulation.MedJAust2009;190:583-6.

4. BrownA,WalshW,RingI.Coronaryheartdisease.In:CouzosS,MurrayR,editors.Aboriginalprimaryhealthcare:anevidence-basedapproach.SouthMelbourne:oxfordUniversityPress;2008.

5. NationalVascularDiseasePreventionAlliance.Guidelinesfortheassessmentofabsolutecardiovasculardiseaserisk.NationalHeartFoundationofAustralia.2009.

6. CouzosS,MurrayR,editors.Aboriginalprimaryhealthcare:anevidence-basedapproach.SouthMelbourne:oxfordUniversityPress;2008.

7. BunkerSJ,ColquhounDM,EslerDE,HickieIB,HuntD,JelinekVM,etal.'Stress'andcoronaryheartdisease:psychosocialriskfactors.NationalHeartFoundationofAustraliapositionstatementupdate.MedJAust2003;178:272-6.

8. SinghGR,HoyWE.Theassociationbetweenbirthweightandcurrentbloodpressure:across-sectionalstudyinanAustralianAboriginalcommunity.MedJAust2003;179:532-5.

9. NationalAboriginalCommunityControlledHealthorganisation.NationalguidetoapreventivehealthassessmentinAboriginalandTorresStraitIslanderpeoples.SouthMelbourne:RoyalAustralianCollegeofGeneralPractitioners;2005.

10. o'DeaK.MarkedimprovementincarbohydrateandlipidmetabolismindiabeticAustralianAboriginesaftertemporaryreversiontotraditionallifestyle.Diabetes1984;33:596-603.

11. HeartFoundation.Reducingriskinheartdisease2007.Guidelinesforpreventingcardiovasculareventsinpeoplewithcoronaryheartdisease.Updated2008.www.heartfoundation.org.au[cited2010May11]

12. NationalHeartFoundationofAustraliaandtheCardiacSocietyofAustraliaandNewZealand.Positionstatementonlipidmanagement,2005.HeartLungCirc2005;14:275-91.

13. HeartFoundation.Guidetomanagementofhypertension2008.Assessingandmanagingraisedbloodpressureinadults.www.heartfoundation.org.au/SiteCollectionDocuments/A_Hypert_Guidelines2008_2009Update_FINAL.pdf[cited2010May11]

14. ZeitzC.Indigenousvascularhealth–bridgingthesurvivalgap:strategiesforcommunity-basedservices.HeartLungCirc2009;18:94-5.

Conflict of interest: none declared

Self-test questionsThe following statements are either true or false

(answers on page 95)

1. Lifestyleinterventionsforcardiovasculardiseaseare

ineffectiveinAboriginalandTorresStraitIslander

people.

2. ScreeningforcardiovascularriskfactorsinAboriginal

andTorresStraitIslanderpeopleshouldbeginfrom

theageof18years.


The safety of plasma-derived products in AustraliaAndrew Guirguis, Transfusion Medicine Registrar, and Erica Wood, Transfusion Medicine Specialist, Australian Red Cross Blood Service, and Alfred Hospital, Melbourne

Summary

plasma-derived products are used in Australia in a wide variety of clinical settings. The majority of these products are manufactured locally from voluntary blood donations. The preparation of plasma products is subject to rigorous safety measures, including screening blood donors, testing plasma for infectious material, and subjecting plasma to dedicated pathogen inactivation steps. The safe use of plasma derivatives requires correct storage and handling.

Keywords:coagulation,intravenousimmunoglobulin,

pathogeninactivation.

(Aust Prescr 2010;33:76–9)

IntroductionPlasmaderivatives,preparedbyfractionatingdonatedhuman

plasma,areusedinawiderangeofmedicalconditions.

Australia'snationalpolicyfortheseessentialproductsisto

striveforself-sufficiency.Arecentreviewofthepolicyfound

that,whileAustraliahasnevercompletelyproducedallofits

ownplasmaderivatives,'Australiashouldbeasself-sufficient

aspossible,andthatself-sufficiencyshouldremainan

importantgoal'.1

plasma products used in AustraliaPlasma-derivedproductscanbedividedintothreebroad

categories:immunoglobulins,coagulationfactorsand

albumin(Table1).Theseareprimarilyusedtoreplacemissing

ordysfunctionalelementsoftheimmuneorcoagulation

systems.InthecaseofRhDimmunoglobulinorintravenous

immunoglobulin,theirprimaryroleistomodulatetheimmune

system'sresponses.Theusesofintravenousimmunoglobulin

continuetoincrease,2particularlyasimmunologicalbasesfor

moreconditionsarerevealed.Futuredemandforintravenous

immunoglobulinmaybealteredbytheadventofnew,more

targetedtherapiesforconditionswithanautoimmunebasis.The

demandforcoagulationfactorsisinfluencedbytheavailability

ofspecificrecombinantproductswhicharenotplasma-derived.

plasma supplyTheAustralianRedCrossBloodService,undermedical

oversightandoperatingwithintheprinciplesofGood

ManufacturingPracticeandalicencefromtheTherapeutic

GoodsAdministration(TGA),collectsplasmafromvolunteer,

non-remunerateddonors.

Thesafetyoftheseblood-derivedproductsremainsofutmost

importance.AlthoughAustralia'sbloodsupplyissaferthan

ithaseverbeenfromaninfectiousdiseasespointofview,

vigilanceisstillrequiredagainstknownpathogens(suchas

prionsassociatedwithvariantCreutzfeldt-Jakobdisease),

currentlyunknownpathogensandotherassociatedrisks.

TheBloodServiceactivelymonitorsfornewandemerging

infectiousthreatstobloodsafety.

Screening blood donorsStringentcriteriamustbemetbeforethedonationofblood

ispermittedinAustralia,andrecruitmentandretentionof

low-risk,volunteerdonorsisakeyelementinmaintaining

thesafetyoftheplasmasupply.Donorswithtemporaryor

indefiniteineligibilityaredeferredasappropriate,tominimise

therisksofpathogensbeingpresentintheplasmasentfor

fractionation.Eachdonorundergoesadetailed,confidential

interviewandhealthscreen.

Collecting, testing and processing plasmaoncedonoreligibilityhasbeenestablished,collectionofwhole

bloodorplasma(byplasmapheresis)occursinaccordance

withstrictsafetyandqualityrequirements.Wholebloodis

separatedintoitscomponents(redcells,plateletsandplasma)

withinspecifiedtimeandtemperatureconditionstomaintain

plasmaintegrity.Barcodingofallsamplesandkitspermits

traceabilityateachstepoftheprocess.

Alldonorsamplesundergopathogenscreeningusingroutine

serologicalandnucleicacidtesting(seebox).Targeted

serologicaltestingmayalsobeperformed,suchasmalaria

testingforadonorwitharelevanttravelhistory.

Nucleicacid-basedamplificationtestsareusedtodirectly

detectviralgenomes,whilemostserologicaltestsrelyupon

detectionofanimmuneresponsetoinfection,suchasan

antibody.Theexquisitesensitivityofnucleicacidtestingcan

reducethewindowperiodfordetection(fromtimeofinfection

totimeofdetection)from66daystoapproximately5daysfor

hepatitisC,andfrom22daysto9daysforHIV.onlydonations

withacceptabletestresultsarereleasedforfurtherprocessing.


Table 1

Fractionated plasma products commonly used in Australia

product Indication or use Comments*

Immunoglobulins

Normalimmunoglobulin

-intravenous ImmunereplacementincongenitalandacquiredimmunedeficienciesImmunomodulationinarangeofhaematological(e.g.immunethrombocytopenicpurpura),neurological(e.g.Guillain-Barrésyndrome),dermatologicalandotherconditions(e.g.Kawasakisyndrome),usuallyonlywhenothertreatmentshavefailedorarecontraindicated

Noalternativetherapyformanypatientswithimmunedeficiency.Therehasbeenincreaseddemandinrecentyearsforimmunomodulation,withawiderangeofconditionsreportedtobenefitfromtreatmentwithIVimmunoglobulin.See'CriteriafortheclinicaluseofintravenousimmunoglobulininAustralia',2www.transfusion.com.au,www.cslbioplasma.com.auandwww.octapharma.com

-intramuscular Forpassiveimmunisationofcontactsofcases–hepatitisA,measles,poliomyelitisandrubella

Lesscommonlyusedfortheseindicationssincevaccinationprogramshavebeenexpanded.Seewww.transfusion.com.auandwww.cslbioplasma.com.au

Hyperimmuneimmunoglobulin

-RhD

PreventionofantenatalandpostnatalRhDsensitisationinRhDnegativewomen.AlsousedtopreventRhDalloimmunisationintheunlikelyeventofanRhDincompatibletransfusion.

Moreinformationonprophylaxisinpregnancyincludingtypesofsensitisingevents,dosesusedatdifferentstagesofpregnancyandpostpartumisavailableatwww.transfusion.com.auForlargedosesorifIMpreparationcannotbeused(e.g.verylargefetomaternalhaemorrhage,orRhDincompatibleredcelltransfusion,orRhDincompatibleplatelettransfusioninapatientwiththrombocytopenia),anIVpreparationisavailable.

-cytomegalovirus Preventionortreatmentofcytomegalovirusinfectioninimmunocompromisedpatients

Seewww.transfusion.com.auandwww.cslbioplasma.com.au

-zoster Preventionofchickenpoxorshinglesinimmunocompromisedpatientsexposedtovaricellazostervirus

-tetanus Preventionoftetanusintetanus-pronewounds(IMformulation)ortreatmentofclinicaltetanus(IVformulation)

-hepatitisB Post-exposureprophylaxisforhepatitisBwherevaccinationhasnotbeengivenorisincomplete,includinginfantsborntohepatitisB-positivemothers

-others(e.g.rabiesimmunoglobulin)

UsedrarelyinAustraliaandonlywithspecialistadvice

Coagulation factors

Prothrombincomplexconcentrate

WarfarinreversalandprophylaxisandtreatmentofbleedinginpatientswithsingleormultiplecongenitaloracquireddeficienciesoffactorIIorXormultipleacquiredprothrombincomplexfactordeficienciesrequiringpartialorcompletereversal

ContainsfactorIX,IIandXandlowlevelsoffactorVII.Useinaccordancewithguidelines.8

FactorVIII,vonWillebrandfactor

ProphylaxisandmanagementofbleedinginpatientswithvonWillebranddisorder

ContainsbothcoagulationfactorVIIIandvonWillebrandfactor.MostpatientswithhaemophiliaAarenowtreatedwithrecombinantfactorVIII.

otherplasma-derivedfactorconcentrates(e.g.factorXI,XIII,antithrombin)

Theseareusedinverylimitedcircumstancesunderthesupervisionofaspecialist

Formoreinformationontheuseofplasma-derivedproductsforbleedingdisorders,seetheAustralianHaemophiliaCentreDirectors'organisationwww.ahcdo.org.au

Albumin

Albumin4% Forhypovolaemiaassociatedwithhypoalbuminaemia,andintherapeuticplasmaexchange

Albuminandsalineforvolumereplacementinthecriticallyillwerefoundtobeequallysafeandeffective.9

Albumin20% Usedinshockandhypoproteinaemicstatessuchasburnsandparacentesisofascites

The20%formulationishyperoncoticandfluidoverloadcandeveloprapidly

*SeefullURLsonlinewiththisarticleatwww.australianprescriber.com

IMintramuscularIVintravenous


Currentrisksoftransfusion-transmittedinfectionsfromfresh

bloodcomponents–redcells,plateletsandplasma–collected

inAustraliaareextremelylow.Theseestimatesareavailable

fromtheAustralianRedCrossBloodService3andareupdated

annually.

oncepathogenscreeningiscomplete,mostplasmais

dispatchedformanufacturing.Asmallpercentageisretained

forclinicaluseasfreshfrozenplasmaandcryoprecipitate.

Transportandstorageoccursatbelow–20oCtoretainplasma

coagulationfactorlevelsandotherfunctionalactivity.

Manufacturing plasma productsThemajorityofplasma-derivedproductsusedinAustralia

aremanufacturedfromAustralian-sourcedplasma.Some

productsareimported,includingsomecoagulationfactors

andimmunoglobulins,eithertosupplementdomesticsupplies

(forexample,intravenousimmunoglobulin)ortoprovide

productswhicharenotpresentlymanufacturedinAustralia,

suchasfibrinogenconcentrates.AreviewofAustralia'splasma

fractionationarrangementsfoundthatmaintenanceofproduct

safety,qualityandavailabilitywouldbebestachievedby

fractionationofAustralianplasmacontinuinglocally.1other

advantagesoflocalproductionwerealsonoted,interms

ofoverallcosts,turnaroundtimes,managementofrisksto

safetyandavailabilityofplasmasuppliesand,importantly,

maintainingtheconfidenceandsupportofAustralianblood

donors.

Plasma-derivedproductsaretypicallypreparedfrom

pooledplasma,withapooloftenconsistingofthousands

ofdonations.Allplasmasamplesareuniquelyidentifiedto

ensureongoingtraceability.Poolingminimisestheinfective

risk,shouldtheplasmapoolbecontaminatedbyapotentially

infecteddonation.Infectiousmaterialpresentinonedonation

mayberenderedbelowtheinfectiousthresholdbydilution

inapoolofthousandsofdonationsormaybeneutralisedby

protectiveantibodypresentfromotherdonationsinthepool.

However,pooledplasmaproductsareusuallydistributed

tomanypatients,soinfectiousmaterialnoteliminated

duringmanufacturingcouldpotentiallycauseharmtomany

recipients.Furtherserologicalandnucleicacidtestingisalso

performedonstartingpoolsamplesandonlypoolswith

acceptabletestingresultsproceedtofurthermanufacturing.

Plasma fractionation

Thefractionationprocessincludesphysicalseparationusing

precipitationandchromatography.Chromatographyseparates

moleculesfromaliquidsolutionbasedonchemicaland

physicalproperties,enablingpartitionandpurificationof

immunoglobulins,clottingfactorsandalbuminfromplasma.

Thefractionationprocessalsocontributestonon-specific

reductionofvirusesandotherpathogens,includingprions

(althoughvariantCreutzfeldt-Jakobdiseasehasnotbeen

identifiedinAustralia).Eachcomponentmanufactured

fromAustralianplasmaundergoestwodedicatedpathogen

reductionsteps.Thesehavebeenvalidatedtoremoveor

inactivatepotentialpathogens4andinclude:

n dryheattreatment(80oCfor72hours)orpasteurisation

(vapourheatat60oCfor10hours)

n useofsolventsanddetergents

n exposuretolowpHconditions

n nanofiltration.

Theseareperformedaccordingtoapprovedmanufacturing

processesforeachproduct.Noconfirmedtransmissionsof

viruseshaveoccurredfromproductsusedinAustraliasince

effectivededicatedpathogeninactivationandremovalsteps

wereintroduced.However,non-envelopedvirusessuchas

parvovirusB19andhepatitisAremainaconcernforsome

products,ascurrentviralinactivationorremovaltechniques

arevariablyeffectiveagainstthese.

Quality control

Thefractionationprocessproceedsunderstrictregulatory

oversightinahighlycontrolledmanufacturingenvironment.

Cleaningandsanitationprotocolspreventcross-contamination

ofbatches.Qualitycontrolandreleasetestingmonitorsinterim

andfinalproductsagainstapprovedplasmaspecifications

agreeduponbythemanufacturerandtheTGA.

AlltherapeuticproductsusedinAustralia,whether

manufacturedlocallyorimported,areregisteredonthe

AustralianRegisterofTherapeuticGoodsandmustmeetthe

stringentregulatoryrequirementsoftheTGA.However,some

variationsbetweenlocalandimportedproductscanoccur,

andthesemayhaveclinicalconsequences.Forexample,the

differencesinintravenousimmunoglobulinproducts,suchas

antibodyprofile,mayreflectthe:

Box

routine pathogen screening tests for blood donor samples in Australia

Nucleic acid tests HIV-1

HepatitisB(thistestwillbeimplementedin2010)

HepatitisC

Serological tests HIV-1/2

HepatitisB

HepatitisC

Syphilis

HumanTcelllymphomavirusI/II


n geographiclocations,infectiousexposuresandimmunity

ofthedonorpopulation

n plasmacollection(wholeblooddonation,orbyapheresis)

n testingperformed

n manufacturingmethods.

Using fractionated plasma productsBloodproductsshouldonlybeprescribedwithawarenessof

theirassociatedharmsandbenefits.Allplasmaproductsused

inAustraliahaveapprovedproductinformationandconsumer

medicineinformationavailablefromthemanufactureror

distributorortheTGA(www.ebs.tga.gov.au).otherresourcesare

availableforcliniciansandpatients,5,6andmedicalspecialists

andtransfusionnursesattheAustralianRedCrossBloodService

canprovideexpertadvice(www.transfusion.com.au/Contact-

Us.aspx).Ultimately,informedprescribingequatestomaximal

safety,efficacyandappropriateuseofplasma-derivedproducts.

Storage and handling Storageandtransportrequirementsaredefinedforallplasma-

derivedproducts.Theyrequirestorageinsecure,monitored

environmentstoensuretheirsafetyandefficacy.Somerequire

refrigeration,whileothersmaybestoredatcontrolledroom

temperatureroutinelyorforshortperiods.

Althoughsafety-relatedrecallsarerare,theabilitytotraceeach

producttoitsfinaldestination(transfusiontoapatient)isa

requirementdocumentedinhealthdepartmentcircularsand

otherregulationsinanumberofstates.7

Adverse reactionsAdherencetothemanufacturer'sguidanceandinstitutional

infusionpolicies,andcarefulmonitoringofthepatientduring

infusion,canminimisethelikelihoodofadverseevents,orallow

forearlyinterventionshouldtheyoccur.

Seriousadversereactionstoplasmaproductsarerare,butminor

reactionsarenotuncommon.Whenseriousreactionsdooccur,

theyshouldbereportedpromptlytothelocaltransfusionservice

(hospitalbloodbankorissuinglaboratory),andthemanufacturer.

Medicaladviceregardingreportingandmanagementofadverse

reactionsisavailablethroughthemanufacturerordistributorand

theAustralianRedCrossBloodService.

recombinant productsCurrently,recombinantproductsareusedprimarilyfor

coagulationfactortherapyinpatientswithbleedingdisorders

andincludefactorVIIa,factorVIII(haemophiliaA)andfactorIX

(haemophiliaB).Theyshouldbeusedinconsultationwith

aspecialistexperiencedinthecareofthesepatients,such

asthroughahaemophiliatreatmentcentre.Complications

oftherapycanstilloccur,suchasdevelopmentofinhibitory

antibodiesinpatientswithhaemophilia.

RecombinantactivatedfactorVII(VIIa)isapprovedinAustralia

onlyforverylimitedindications,suchasforpatientswith

haemophiliawhohaveinhibitoryantibodies.However,there

hasbeenrecentgrowthin'offlabel'useinpatientswithcritical

bleedinginarangeofsettings.Evidencetosupportthisuse

remainslimited.

ConclusionTheprocessfromblooddonationtoadministrationofa

fractionatedbloodproductislengthyandcomplex,with

multiplecheckpointstodeliversafeandeffectiveproducts.

Astreatingclinicians,itisourresponsibilitytoensurethat

theyareadministeredcorrectlyandfortheappropriate

indications.

Acknowledgement: the authors thank Dr Janet Wong,

Transfusion Medicine Specialist, for her helpful comments and

review of the manuscript.

references1. ReviewofAustralia'splasmafractionationarrangements.

CommonwealthofAustralia2006.www.health.gov.au/plasmafractionationreview[cited2010May7]

2. CriteriafortheclinicaluseofintravenousimmunoglobulininAustralia.AustralianHealthMinisters'Conference.2007Dec.www.nba.gov.au/ivig/index.html[cited2010May7]

3. AustralianRedCrossBloodService.Transfusion-transmittedinfectionFAQs.www.transfusion.com.au/Consent-and-Risk/Transfusion-Transmitted-Infection-FAQs.aspx[cited2010May7]

4. optimizingthequality,pathogensafetyandpurityofourplasma-derivedtherapeutics[brochure].CSLBiotherapies.2010.[AvailablefromCSLBiotherapies.]

5. Flippin'Blood:aBloodSafeflipcharttohelpmaketransfusionstraightforward.BloodSafeProgram.2006Aug.www.health.sa.gov.au/bloodsafe/Portals/0/flippn'bloodchartSept06.pdf[cited2010May7]

6. TransfusionMedicineManual.AustralianRedCrossBloodService.www.manual.transfusion.com.au[cited2010May11]

7. Traceabilityoftransfusedbloodandbloodproducts.HospitalCircular32/2008.VictorianGovernmentHealthInformation.2008Nov24.www.health.vic.gov.au/hospitalcirculars/circ08/circ3208.htm[cited2010May7]

8. BakerRI,CoughlinPB,GallusAS,HarperPL,SalemHH,WoodEM.Warfarinreversal:consensusguidelines,onbehalfoftheAustralasianSocietyofThrombosisandHaemostasis.MedJAust2004;181:492-7.

9. FinferS,BellomoR,BoyceN,FrenchJ,MyburghJ,NortonR;SAFEStudyInvestigators.Acomparisonofalbuminandsalineforfluidresuscitationintheintensivecareunit.NEnglJMed2004;350:2247-56.


80 | VoLUMe 33 | NUMber 3 | JUNe 2010 www.austral ianprescriber.com80 | VoLUMe 33 | NUMber 2 | AprIL 2010 www.austral ianprescriber.com

Medicines Safety UpdateMedicines Safety Update No. 3; 2010

n AUSTRandAUSTLnumbers–whyaretheyimportant?

n Sibutramine

n Drug-inducedpancreatitisandexenatide(Byetta)

theimportanceofidentifyinganAUSTLorAUSTRnumberon

theproductlabelhasincreased.TheidentificationoftheAUSTL

orAUSTRnumberanditsconcomitantentryontheARTGcan

reassureconsumersandpractitionersoftheproduct'ssafety.

TheTGAencouragesallhealthcarepractitionersandconsumers

toreportadverseeventsrelatedtoanymedicineormedical

deviceviatheelectronicreportingsystemavailablethrough

theTGAwebsite(www.tga.gov.au)orviathebluecardsystem.

Furtherinformationaboutmedicinelabelscanbeobtainedon

theTGAwebsite.2

references1. McEwenJ.WhatdoesTGAapprovalofmedicinesmean?

AustPrescr2004;27:156-8.

2. Buyingmedicines–What'sonthelabelforme?www.tga.gov.au/docs/html/buymed.htm#mean[cited2010May10]

Dr Jane Cook, Senior Medical Officer, Office of Medicines

Safety Monitoring

Recentmediaarticleshavehighlightedtheimportanceof

identifyingtheAUSTLnumberonthelabelofcomplementary

medicinessuspectedofcausingadversereactions.

TheTherapeuticGoodsAdministration(TGA)canusetheAUSTL

numbertodeterminetheexactidentityofthecomplementary

medicinesuspectedofcausingtheadversereaction.

AllmedicinesenteredontotheAustralianRegisterof

TherapeuticGoods(ARTG)includeauniqueAUSTLorAUSTR

numberonthelabel.Thislabellingisrequiredforthelawful

supplyofatherapeuticgoodinAustralia.1

TheLreferstolistedmedicines(primarilycomplementary

medicines)andtheRtoregisteredmedicines(primarily

prescriptionandover-the-countermedicines)andshouldbe

readilyidentifiableonthelabel(Fig.1).

Ifahealthpractitionersuspectsthatamedicineisresponsible

foranadverseevent,requestingfurtherinformationfrom

thepatient,includingwhereitwaspurchased,isimportant

inassistingtocorrectlyidentifytheproduct.Whereaserious

adverseeventisthoughttohaveoccurred,reportingtheevent

totheTGAisstronglyencouraged.IncludingtheAUSTLor

AUSTRnumber(ortheabsenceofanAustralianRegister

number)ofthesuspectedmedicineinthereportwillallowthe

TGAtoensureappropriateinvestigationandsubsequentaction.

WherethemedicinelabeldoesnotincludeanAUSTLor

AUSTRnumbertheTGAhasnotevaluatedthequality,safetyor

efficacyoftheproductandthereforethesafetyoftheproductis

unknown.ProductswithoutanAustralianRegisternumbermay

havebeensuppliedillegallyifboughtinAustralia,purchased

overtheinternetbytheconsumerorhavebeenimportedfrom

overseasforpersonaluse.

TheincreasinguseoftheinternetbyAustralianconsumersto

accessmedicineshasresultedintheincreaseduseofmedicinal

productsthathavenotbeenevaluatedbytheTGA.Asaresult

Fig. 1

Label of complementary medicine

Product Name

Purpose of Product

Name and Address of Supplier

Batch Number

Australian Register Number

Storage Conditions

Expiry Date

AUST r and AUST L numbers – why are they important?

| VoLUMe 33 | NUMber 3 | JUNe 2010 81www.austral ianprescriber.com | VoLUMe 33 | NUMber 2 | AprIL 2010 81www.austral ianprescriber.com

(whicharelistedinthePI);inadditionchestpainanddyspnoea

werealsoreported.Therehavebeenfourreportseachofangina,

ventricularfibrillationandcardiacarrestinassociationwiththe

useofsibutramine.ofconcernisthenumberofreportswhere

sibutraminehasbeenused'offlabel',i.e.prescribedforexample

topatientswithaBMIlessthanthatspecifiedinapproved

indicationsforuse(BMIgreaterorequalto30kg/m2inobese

patients,andgreaterorequalto27kg/m2wherediabetesmellitus

type2ordyslipidaemiaarepresent).

TGA actionInlightoftheinterimresultsoftheSCoUTstudy,theTGAhas

reinforcedexistingadviceinthesibutraminePIregardingits

useinpatientswithcardiovascularriskfactors(currentorpast

historyofmyocardialinfarctionoranginaetc).Ithasalsoadded

adescriptionoftheSCoUTstudyandaprecautionthattheuse

ofsibutramineshouldbeceasedifithasnotbeeneffectivein

achievingweightlosswithintheexpectedtimeframe(3months

fornon-diabeticsand6monthsfordiabetics).

Astatementregardingtheuseofsibutraminewaspublishedon

theTGA'swebsitesafetyalertspageinJanuary2010.2

recommendationsHealthcarepractitionersareadvisedtoreviewanyinformation

regardingsibutramine,including'Dearhealthcareprofessional'

letterssentbyAbbottAustralasia,theAustraliansponsorof

sibutramine,advisingdoctorsofthechangestothePIand

toensuretheyconsultthemostcurrentPIwhenprescribing.

AcopyofthecurrentPImaybeobtainedfromtheTGAeBS

ProductandConsumerMedicineInformationsite.3Inaddition

prescribersshouldnotetheuseofsibutramineshouldbelimited

tooneyearinanypatientandshouldnotberecommencedifthe

patienthadfailedtoloseweightwithprioruseofthedrug.

TheTGA'sreviewofthesafetyoftheproductremainsongoing,

andhealthpractitionersareencouragedtoreportanyadverse

eventsoccurringinassociationwiththeuseofsibutramineto

theTGA.

references1. JamesWP.TheSCoUTstudy:risk-benefitprofileof

sibutramineinoverweighthigh-riskcardiovascularpatients.EurHeartJSuppl2005;7(SupplL):L44-8.

2. Reductil(sibutramine)productinformation.www.tga.gov.au/alerts/medicines/reductil.htm[cited2010May11]

3. TGAeBusinessServices.www.ebs.tga.gov.au(gotoTGAinformation)[cited2010May11]

Sibutramine

SummaryInterim results of the SCoUT trial of sibutramine have revealed higher rates of heart attack and stroke in subjects who were overweight or obese and at high baseline risk of a cardiovascular event. The TGA is reviewing the safety of the product and while that review is ongoing has reinforced existing advice to healthcare professionals to carefully review the sibutramine product Information (pI), before prescribing the product.

IntroductionSibutramineisanorallyadministeredserotonin

(5-hydroxytryptamine,5HT)andnoradrenalinereuptake

inhibitor,indicatedforweightloss,andmaintenanceofweight

loss,aspartofaweightmanagementprograminobese

adults.Itshouldonlybeprescribedtopatientswhohavenot

adequatelyrespondedtoanappropriateweight-reducing

regimenalone.Sibutramineisnotrecommendedforusein

patientswithahistoryofcardiovasculardiseaseincluding

inadequatelycontrolledhypertension.

The SCoUT trial Latelastyeartheinterimresultsofaclinicaltrialknownas

theSibutramineCardiovascularoUTcomes(SCoUT)trial,

conductedbyAbbottLaboratories,becameavailable.1This

studywasadouble-blind,randomized,placebo-controlled,

parallel-groupstudyintotheeffectsofsibutramine(10mgonce-

daily)onmortalityinoverweightandobesesubjectsathighrisk

ofacardiovascularevent.Allsubjectswereolderthan55years

andhadahistoryofmanifestcardiovasculardisease,ortype2

diabetesmellitus.

Thestudyshowedhigherratesofcardiovasculareventssuch

asheartattackandstrokeinpatientsusingsibutramine,than

inthosereceivingaplacebo.Whiletherateswerestatistically

significantinoverweightandobesepatientsathighriskof

acardiovascularevent,thedifferencewasnotstatistically

significantinoverweightandobesepatientswithtype2

diabetesmellitus.

TGA monitoringAreviewoftheTGA'sadversedrugreactionsdatabase(asat

endMarch2010)showsthat61reportsofsuspectedadverse

reactionshavebeenreceivedbytheTGA.Themajorityofthese

haveoccurredinwomen(47)whoarealsothepredominant

usersofsibutramine.Themostcommonlyreportedadverse

eventsweredizziness,palpitations,tachycardiaandhypertension

82 | VoLUMe 33 | NUMber 3 | JUNe 2010 www.austral ianprescriber.com82 | VoLUMe 33 | NUMber 2 | AprIL 2010 www.austral ianprescriber.com

Reviewsoftheoriginalcaseseriesof30patients(median

age60years)showedthemediantimetoonsetofsymptoms

afterinitiationoftherapywas34days.Abdominalpainwas

apresentingfeaturein75%ofcases.5-7Atpresentation

amylaseandlipaselevelswereusuallysubstantiallyelevated,

withamylaselevelsrangingfrom40to1845U/L(median

384U/L;normalrange30–170U/L)andlipaselevelsfrom

62to16970U/L(median545U/L;normalrange7–60U/L).

Therewasatleastoneconfoundingfactor(e.g.obesity,

hypertriglyceridaemiaoralcoholconsumption)in27(90%)

ofthepatients.In22casesthepancreatitisresolvedon

withdrawalofthedrugandinthreecasesthepancreatitis

recurredonresumptionofthemedicine.Hospitalisationwas

requiredin21casesandseriouscomplicationsincludedacute

renalfailureandparalyticileus.

Despitethesespontaneousadversedrugreactiondata,an

analysisofdatafromaclaims-basedactivedrugsurveillance

systemintheUSAfoundnoevidenceofanincreasedrisk

ofacutepancreatitisamongpatientstreatedwithexenatide

(around28000patients)comparedwiththosetreatedwith

metforminorasulfonylurea.8

Australian adverse reaction reportsTodatetheTGAhasreceivedatotalof22reportsof

suspectedadversedrugreactionsforexenatide.Eight(36%)

ofthesereportsrelatetopancreatitisand/orelevationof

pancreaticenzymes.In4of5casesreportedaspancreatitis,

exenatidewasthesolesuspectedmedicine.Anadditional

fourreportsdescribeepisodesofupperabdominalpainand/

orileus,raisingthepossibilityofunderlyingpancreatitis,so

thatasmanyas12ofthe22reportsmayrelatetoanepisode

ofpancreatitis.

Whileacutepancreatitisislistedasarareadversedrug

reactionintheAustralianPIforexenatide,theTGA

recommendsthatpatientsareinformedofthecharacteristic

symptomsofacutepancreatitis,andifthisdiagnosisis

suspectedexenatideandotherpotentiallysuspectmedicines

shouldbediscontinued.

references1. GreenbergerNJ,ToskesPP.Acuteandchronic

pancreatitis.In:FauciAS,BraunwaldE,KasperD,HauserS,LongoD,JamesonJ,etal,editors.Harrison'sPrinciplesofInternalMedicine.17thed.NewYork:McGraw-Hill;2008.

2. TrivediCD,PitchumoniCS.Drug-inducedpancreatitis:anupdate.JClinGastroenterol2005;39:709-16.

3. ADRAC.Druginducedpancreatitis.AustAdvDrugReactBull2006;25:22.

Dr Margaret Ward, Office of Medicines Safety Monitoring

IntroductionDrug-inducedpancreatitisisestimatedtoaccountfor

betweentwoandfivepercentofacutepresentationsofthe

condition.Medicinescausepancreatitiseitherbyinducing

ahypersensitivityreactionorbythegenerationofatoxic

metabolite.1A2005reviewofdrug-inducedpancreatitisin

theJournal of Clinical Gastroenterologylistsmanydifferent

medicinesthatmaybeimplicatedandsuggeststhatdrug-

inducedpancreatitisshouldalwaysbeconsideredwhen

otheraetiologieshavebeenexcluded.2

Thereviewidentifiedcertain'atrisk'groups,includingthose

whowere:

n theelderly

n onmultiplemedications

n HIVpositive

n diagnosedwithcancer;or

n receivingimmunomodulatoryagents.

Adverse drug reaction reports of drug-induced pancreatitisTheTGA'sadversedrugreactionsdatabaseincluded581

reportsofpancreatitisasofFebruary2009.Eighteenof

thesereportsdocumentedafataloutcome.Manydifferent

medicineshavebeenimplicated,butthemostfrequent

reportsincludeazathioprine(41reports),valproate(35

reports)andsimvastatin(26reports).3Commonlyimplicated

medicineclassesincludeantiviralagents,hypolipidaemic

agentsandatypicalantipsychoticmedications.

exenatide (byetta)Whilemanydifferentmedicineshavebeenassociatedwith

pancreatitis,prescribersshouldbeawarethatinternational

postmarketingreportsofadverseeventsassociatedwith

exenatide(Byetta)haveincludedcasesofpancreatitis.

Exenatideisapeptideamidewithseveralantihyperglycaemic

actionsofglucagon-likepeptide(GLP-1)andisregistered

foruseasadjunctivetherapytoimproveglycaemiccontrol

inpatientswithtype2diabeteswhoaretakingmetformin,

asulfonylurea,oracombinationofthesedrugs,butarenot

achievingadequateglycaemiccontrol.

Tooctober2007theUSFoodandDrugAdministration(FDA)

hadreceived30spontaneousadversedrugreactionreports

ofacutepancreatitisassociatedwiththeuseofexenatide.A

furthersixcasesofhaemorrhagicornecrotisingpancreatitis,

twoofwhichwerefatal,werereportedbytheFDAinAugust

2008.4

Drug-induced pancreatitis and exenatide (byetta)


4. USFoodandDrugAdministration.Informationforhealthcareprofessionals:Exenatide(marketedasByetta)-8/2008update.www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm[cited2010May10]

5. GallwitzB.Benefit-riskassessmentofexenatideinthetherapyoftype2diabetesmellitus.DrugSaf2010;33:87-100.

6. CureP,PileggiA,AlejandroR.Exenatideandrareadverseevents.NEnglJMed2008;358:1969-70.

7. AhmadSR,SwannJ.Exenatideandrareadverseevents.NEnglJMed2008;358:1970-1.

8. DoreDD,SeegerJD,ArnoldChanK.Useofaclaims-basedactivedrugsafetysurveillancesystemtoassesstheriskofacutepancreatitiswithexenatideorsitagliptincomparedtometforminorglyburide.CurrMedResopin2009;25:1019-27.

©CommonwealthofAustralia2010

TheaboveinformationfromtheTherapeuticGoodsAdministrationiscopyright.ApartfromanyuseaspermittedundertheCopyright Act 1968,nopartmaybereproducedbyanyprocesswithoutpriorwrittenpermissionfromtheCommonwealth.RequestsandinquiriesconcerningreproductionandrightsshouldbeaddressedtotheCommonwealthCopyrightAdministration,AttorneyGeneral'sDepartment,NationalCircuit,BartonACT2600orpostedatwww.ag.gov.au/cca

wHAT To reporT? (You do not need to be certain, just suspicious!)

TheTGAencouragesthereportingofallsuspectedadversereactionstomedicines,includingvaccines,over-the-counter

medicines,herbal,traditionaloralternativeremedies.TheTGAparticularlyrequestsreportsof:

n ALLsuspectedreactionstonew medicinesn ALLsuspectedmedicinesinteractionsn Suspectedreactionscausing

•death•admissiontohospitalorprolongationofhospitalisation•increasedinvestigationsortreatment•birthdefects

For blue cards

Reportsofsuspectedadversedrugreactionsarebestmadebyusingaprepaidreportingform('bluecard')whichis

availablefromthewebsite:www.tga.gov.au/adr/bluecard.pdforfromtheofficeofMedicinesSafetyMonitoring,

phone1800044114.

Reportscanalsobesubmitted:

onlineontheTGAwebsitewww.tga.gov.auclickon'Reportaproblem'ontheleft

byfax0262328392

[email protected]

For further informationfromtheofficeofMedicinesSafetyMonitoring:

[email protected]


Abnormallaboratoryresults

Tests for cell-mediated immunity Sandhya Limaye, Immunologist, Concord Hospital, Sydney South West Area Health Service

Summary

patients with cell-mediated immunodeficiency experience recurrent infections with a broad range of pathogens, and an accompanying humoral immunodeficiency is not uncommon. A persistently low lymphocyte differential on a full blood count may provide a clue and should prompt further testing with quantification of lymphocyte subsets. Measurement of total immunoglobulins is a first-line screening investigation in suspected humoral immunodeficiency. Further investigations, which provide an in vitro or in vivo functional assessment, are highly specialised assays which are difficult to perform and interpret. Consultation with a specialist immunologist and the diagnostic laboratory is recommended.

Keywords:hypogammaglobulinaemia,immunodeficiency.

(Aust Prescr 2010;33:84–7)

IntroductionDefenceagainstpotentiallyharmfulpathogensisachievedby

physicalbarrierssuchasskinandmucousmembranes,andthe

coordinatedeffortsoftheinnateandadaptiveimmunesystems.

Innateimmuneresponsesarecarriedoutbymacrophages,

neutrophilsandnaturalkillercells,togetherwithcytokines,

complementandacutephasereactantssuchasC-reactive

protein.AdaptiveimmunityreliesuponBandTlymphocytes

whichexpressantigen-specificsurfacereceptors.Itcanbe

dividedintohumoral(antibody-mediatedanddependentupon

Blymphocytes)andcellular(coordinatedbyTlymphocytes)

immunity.Whilethisdistinctionisoversimplifiedandsomewhat

inaccurateinthatbothtypesofresponsesaredependentupon

helperTlymphocytes,itprovidesausefulmodelforclassifying

andevaluatingsuspectedimmunodeficiency.

ImmunodeficiencyThisoccurswhenfailureofanypartoftheimmunesystem

leadstoanincreasedpredispositiontoinfectionandassociated

sequelaesuchasautoimmunityandmalignancy.Primary

immunodeficiencyresultsfromgeneticmutationsofcomponents

intrinsictotheimmunesystem.Clinicaldiagnosisshouldbe

accompaniedbymolecularidentificationofageneticmutation

whereverpossibletoconfirmthediagnosis,identifygenotype-

phenotypecorrelation,assistwithgeneticcounsellingand

identifysuitablecandidatesforgene-specifictherapy.Secondary

immunodeficiencyresultsfromdefectiveimmunefunctionasa

consequenceofanotherconditionsuchasHIVinfection.Drugs

suchascorticosteroids,azathioprine,methotrexateorcyclosporin

canalsocausesecondaryimmunodeficiency.Subtleimpairment

ofimmunefunctioncanalsoaccompanycertainchronicmedical

conditionsincludingdiabetesandchronicrenalfailure.

Immunodeficiencycanbeclassifiedfunctionallyintohumoral

orcell-mediatedarms,asdysfunctionofeitherpathwayis

characterisedbyspecificclinicalpresentations(Table1).Possible

investigationsforsuspectedimmunodeficiencyarepresented

inTable2.Thesetestsshouldbeperformedwhenthepatientis

clinicallywell,andnotduringanacuteinfectiveillness.

Humoral immunodeficiencyAntibodydeficiency,orhypogammaglobulinaemia,canoccur

asaresultofintrinsicdefectsofhumoralimmunity(primary),

orsecondarytoanotherpathologicalcondition.Itisthemost

commonmanifestationofprimaryimmunodeficiencyand

encompassesabroadrangeofclinicaldiagnoses.Clinical

presentationcanrangefromasymptomatic,torecurrent,

atypicalorlife-threateninginfections.Encapsulatedbacteria,

suchasStreptococcus pneumoniae,Neisseriaespeciesand

Haemophilus influenzae,poseaparticularthreataswellasother

bacterialspeciesincludingStaphylococcus aureus,Pseudomonas

aeruginosa,Campylobacter fetusandMycoplasmaspecies.

Recurrentorunusuallyseveresinopulmonaryinfection,other

infections(gastrointestinal,skin,jointorcentralnervoussystem),

orevidenceofend-organdamagesuchasbronchiectasis,should

alertthedoctortothepossibilityofanunderlyinghumoral

immunodeficiency.

Measuring humoral immunityThesimplestinitialinvestigationforthisconditionistoquantify

immunoglobulin(Ig)concentrations(IgG,IgAandIgM).Normal

levels,however,donotexcludeahumoraldefectandifclinical

suspicionishigh,thenmoreadvancedinvestigationscanbe

undertaken.Thisincludesmeasuringantibodiestospecific


antigensfollowingvaccinationtoassessifthepatientproduces

afunctionalantibodyresponse.Thisisusuallyperformed

inconjunctionwithassessmentbyaclinicalimmunologist.

ImmunoglobulinGsubclassescanalsobequantified–however

theclinicalutilityofthisinvestigationissomewhatcontroversial.

Cell-mediated immunodeficiencyDefectiveTcell-mediatedimmunitypredisposespatientstoa

broaderrangeofinfectionsthanhumoralimmunodeficiency,

includingintracellularpathogens,persistentsuperficial

candidiasisorrecurrentviral,fungalorprotozoalinfections

Table 1

Characteristic clinical presentations of immunodeficiency

Type of immunodeficiency Clinical presentation

Humoral immunodeficiency

Hypogammaglobulinaemia Recurrentsinopulmonaryinfection:- Streptococcus pneumoniae- Haemophilus influenzae- Neisseriaspeciesotherbacterialinfectionssuchasgastrointestinal,centralnervoussystem,jointEvidenceofend-organdamagesuchasbronchiectasis,conductivehearingloss

Cellular immunodeficiency

Tcelldysfunction Infectionswith:-intracellularbacteria(mycobacteria,salmonella)-viruses(EpsteinBarr,cytomegalovirus,varicellazoster,herpessimplex)-fungi(candida,aspergillus,cryptococcus,histoplasma,pneumocystis)-protozoa(toxoplasma,microsporidium,cryptosporidium)

Interleukin-12interferongammaaxisdeficiency Atypicalmycobacterialandsalmonellainfections

ImpairedresponsetoCandidaspecies PersistentmucocutaneouscandidiasisAutoimmuneendocrinopathy

Combined immunodeficiency

CombinedTandBcelldysfunction CombinedfeaturesofTcelldeficiencyandhypogammaglobulinaemia

Severecombinedimmunodeficiencysyndromes Failuretothriveinchildrenopportunisticinfectionoverwhelmingsepsis

Wiskott-Aldrichsyndrome ThrombocytopeniaEczemaInfectionwithencapsulatedbacteria

Ataxiatelangiectasia SinopulmonarydiseaseCerebellarataxiaoculocutaneoustelangiectasia

DiGeorgesyndrome HypocalcaemiaRecurrentinfectionCardiacdiseaseAbnormalfacialfeatures

HyperIgMsyndromes Recurrentpyogenicinfectionopportunisticinfection

Naturalkillercelldysfunction RecurrentherpesvirusinfectionRecurrentpapillomavirusinfection(warts)

Phagocytedefects RecurrentpyogenicinfectionsRecurrentabscesses

Igimmunoglobulin


(Table1).Defectscanagainbeclassifiedaseitherprimary,

orsecondarytoextrinsicfactors.HIVinfectionresultingin

progressivedepletionofCD4Tcellsisaparticularconsideration.

AshelperTcellsarerequiredforBcell-mediatedantibody

production,Tcellimmunodeficiencycanresultinfunctional

Bcelldefects,thuspatientswithcell-mediatedimmunodeficiency

oftenhaveanaccompanyinghypogammaglobulinaemia.Thisis

termedcombinedimmunodeficiency.

Measuring cellular immunityMeasurementofcell-mediatedimmunitycanbeundertaken

bybothin vitroandin vivomethods.Itis,however,more

problematicthanhumoralassessmentasassaysareplaguedby

difficultiesinstandardisation,biologicalvariability,imprecision

andtechnicalcomplexity.Mosttestsarehighlyspecialisedand

referraltoaclinicalimmunologistisrecommended.

Flow cytometry

Thefirststepintheevaluationofcell-mediatedimmunityis

toquantifycirculatingimmunecellsandtheirsubsetsbyflow

cytometricanalysis.Patients'bloodcellsareincubatedwith

fluorochrome-labelledmonoclonalantibodiesdirectedagainst

cellsurfacemoleculesandanalysedbyaflowcytometer,which

measureslightscatterandfluorescenceemissionfromindividual

cells.Differentcellpopulations(Bcells,andCD4/CD8Tcellsand

naturalkillercells)canbedistinguishedbasedontheirscatter

profileandsurfacemoleculeexpression.Absolutecellnumbers

arecalculatedasapercentageofthetotalwhitecellcountand

resultsarecomparedtoage-matchedreferenceranges.Itis

importanttonote,however,thatanalogoustoimmunoglobulin

measurement,quantificationoflymphocytenumbersdoesnot

giveanindicationoftheirfunctionalcapacity.Lymphocytesubset

analysisaidsinthediagnosisandclassificationofpaediatric

severecombinedimmunodeficiencysyndromes,andisalso

recommendedintheevaluationofhypogammaglobulinaemia

incommonvariableimmunodeficiency.Quantifying

CD4Tlymphocytesprovidesprognosticinformationandgives

anindicationofsusceptibilitytoopportunisticinfectionsin

patientswithHIVinfection.

Delayed-type hypersensitivity skin testing

Delayed-typehypersensitivityskintestingprovidesafunctional

in vivoassessmentofcellularimmunity.Theskinresponse

followingintradermalinoculationofantigenisdependenton

antigen-specificmemoryTcellsandresultsinlocalinflammation

after48–72hoursduetotherecruitmentofmononuclearcells

(lymphocytes,monocytes)andneutrophils.Byconvention,a

diameterof5mmindurationisacceptedasapositiveresult.

ThemostwidespreaduseofthistypeoftestistheMantouxtest,

whichassessespreviousexposuretoMycobacterium tuberculosis

orBacillusCalmette-Guérin(BCG)vaccinationbyevaluating

theskinresponsetointradermaltuberculin.otherubiquitous

antigensthatcanbetestedincludetetanus,candidaandcertain

bacterialantigens.Skinresponsesaredependentuponprevious

exposuretotheantigenandthusthistestisoflittleuseininfants

lessthansixmonthsofage.

SkintestingidentifiesfunctionalmemoryTcellstoaparticular

antigen,orthepresenceofcutaneousanergy.Thelatteris

definedasanimpairedcutaneoushypersensitivityresponse

toapanelofcommonantigensandisconsistentwithcellular

immunedysfunction.Causesofcutaneousanergyarelistedin

Table3.

Lymphocyte proliferation assays

Lymphocyteproliferationassaysareindicatedifthereisa

suspicionofadefectivecellularimmuneresponseeither

globallyortoaspecificantigensuchascandida.Thepatient's

peripheralbloodmononuclearcellsareincubatedin vitro

for3–5dayswitheitheramitogen(substancewhichinduces

cellulardivision)orarecallantigen(towhichthepatienthas

beenpreviouslyexposed).Radioactivethymidineisaddedtothe

cultureandsubsequentlyincorporatedintotheDNAofdividing

cells.Radioactivityofthecellcultureismeasuredafter24hours

andisdirectlyproportionaltothedegreeofinducedcellular

proliferation.Peripheralbloodmononuclearcellsfromahealthy

controlareevaluatedinparallelforcomparison.

Theseassaysaretechnicallycomplexandareonlyperformed

byspecialistlaboratories.Astheinvestigationcanbetime-

consuming,itisadvisabletofirstdiscusstheappropriateness

oftestingandchoiceofassaywiththelaboratory.Results

areaffectedbyimmunosuppressivedrugs,severenutritional

deficienciesandintercurrentillness1andthesefactorsmust

beconsideredwheninterpretingresults.Aswithskintesting,

thepatientmusthavebeenpreviouslyexposedtotheantigen,

thusantigenproliferationassaysarenotfeasibleinbabiesless

Table 2

Investigations for suspected immunodeficiency

Suspected immunodeficiency

Screening tests

Advanced investigations

Humoralimmunodeficiency

IgG,IgA,IgM

Fullbloodcountanddifferential*

Lymphocytesubsets*

IgGsubclasses

Specificantibodytitresandresponsetovaccination

Cellularimmunodeficiency

Fullbloodcountanddifferential*

Lymphocytesubsets*

HIVtestingifindicated

IgG,IgA,IgM

Delayed-typehypersensitivityskintests

Lymphocyteproliferationassays

Naturalkillercellcytotoxicity

Igimmunoglobulin

*defertestinguntilresolutionofacuteinfectiveillness


thansixmonthsofage.Responsetomitogens,however,canbe

performedatanyagefrombirthonwards.2

Other assays measuring lymphocyte activation

otherfunctionalin vitromeasuresoflymphocyteactivation

includedeterminingchangesinsurfacemarkerexpression

(CD25,CD69,CD71)followingactivation3ormeasurementof

intracellularcytokinesofTlymphocytes.

Tcellproliferationfollowingstimulationcanbemeasured

bysuccinimidylesterofcarboxyfluoresceindiacetate(CFSE)

dilutiontechniques,4orTcellcytokineproductionquantified

byELISPoTassays.Theseassays,however,arenotinroutine

useandareconfinedtoresearchorspecialisedreference

immunologylaboratories.

Therecentlyintroducedinterferongamma(IFNγ)releaseassays

measureTlymphocyteproductionofIFNγinresponsetoantigen

exposuretherebyprovidinganassessmentofcell-mediated

immunity.Aswithdelayed-typehypersensitivityskintesting,

clinicalapplicationiscurrentlyconfinedtothedomainof

tuberculosislatencyandexposure.

Natural killer cell cytotoxicity assays

Assessingnaturalkillercellsisindicatedinpatientssuffering

recurrentinfectionwithherpesvirus,orpapillomavirus(associated

withcutaneouswarts).Naturalkillercellcytotoxicityisassessed

bya51Cr-releaseassayinwhichpatients'naturalkillercellsare

incubatedwith51Cr-labelledtargetcells.Lysisofthetargetcells

bynaturalkillercellsleadstothereleaseofradioactivitywhich

canbemeasured.Naturalkillercelldysfunctionmayoccurin

patientswithCD16geneticmutations,chronicmucocutaneous

candidiasis,severecombinedimmunodeficiencyandother

cellularimmunodeficiencysyndromes.5Theseconditionsneed

tobeconsideredandexcludedifnaturalkillercelldysfunctionis

confirmed.AswithTandBlymphocytes,functionalnaturalkiller

celldeficitscanoccurevenwhennaturalkillercellcountsare

normal.Naturalkillercellassaysaretechnicallycomplexandare

rarelyperformedindiagnosticimmunologylaboratories.

ConclusionTheevaluationofsuspectedimmunodeficiencyisguidedby

clinicalpresentation.Screeningtestsofhumoralandcellular

immunefunctionareinitiallyperformed,followedbyreferraltoa

specialistformoreadvancedinvestigationsifclinicallyindicated

(Table2).Secondarycausesofimmunodeficiency,includingHIV

infection,needtobeconsideredandexcluded.Wheninterpreting

results,confoundingfactorssuchasimmunosuppressivedrug

therapyandpatientcomorbidities,aswellasanalyticalvariables

suchasassayprecisionandreproducibility,needtobeconsidered.

references1. BonillaFA.Interpretationoflymphocyteproliferationtests.

AnnAllergyAsthmaImmunol2008;101:101-4.

2. HicksMJ,JonesJF,ThiesAC,WeigleKA,MinnichLL.Age-relatedchangesinmitogen-inducedlymphocytefunctionfrombirthtooldage.AmJClinPathol1983;80:159-63.

3. CarusoA,LicenziatiS,CorulliM,CanarisAD,DeFrancescoMA,FiorentiniS,etal.FlowcytometricanalysisofactivationmarkersonstimulatedTcellsandtheircorrelationwithcellproliferation.Cytometry1997;27:71-6.

4. FulcherDA,WongSWJ.Carboxyfluoresceinsuccinimidylester-basedproliferativeassaysforassessmentofTcellfunctioninthediagnosticlaboratory.ImmunolCellBiol1999;77:559-64.

5. BonillaFA,BernsteinIL,KhanDA,BallasZK,ChinenJ,FrankMM,etal.Practiceparameterforthediagnosisandmanagementofprimaryimmunodeficiency.AnnAllergyAsthmaImmunol2005;94:S1-63.


Self-test questionsThe following statements are either true or false

(answers on page 95)

1. Persistentsuperficialcandidiasismaybeasignof

Tcelldysfunction.

2. Normalimmunoglobulinconcentrationsexcludea

humoralimmunodeficiency.

Table 3

Causes of cutaneous anergy*

Cause examples

Drugs Corticosteroids(usuallyhighdose)

Immunosuppressants

Chemotherapy

Immunodeficiency Ataxiatelangiectasia

Severecombinedimmunodeficiencysyndrome

DiGeorgesyndrome

Wiskott-Aldrichsyndrome

Infection HIV

Influenza

Measles

Mumps

Activetuberculosis

otherconditions Malignancy

Chroniclymphocyticleukaemia

Sarcoidosis

Chronicrenalfailure

Chronicliverdisease

Testingerrors Poortechnique

Inadequateantigendose

*impairedskinresponsetoantigen


Tamsulosin-induced intraoperative floppy iris syndrome during cataract surgery

Prepared by Adrian Fung, Senior Registrar, Sydney Eye Hospital; and Peter McCluskey, Director of Save Sight Institute, and Professor of Clinical Ophthalmology, Sydney Eye Hospital, Sydney

CaseA67-year-oldmanwasreferredforcataractsurgery.Hehad

noticeddeterioratingvisioninthelefteye,greaterthantheright,

overthelasteightmonthswithdifficultydrivingduetoglare.He

hadahistoryofessentialhypertensioncontrolledbyperindopril

andhadbeentakingtamsulosinforthreeyearsforbenign

prostatichypertrophywithsomesymptomaticrelief.

onexamination,best-correctedvisualacuitywas6/12inthe

rightand6/24inthelefteye.Bothpupilsdilatedminimallywith

topicaltropicamide1%,butlightresponseswerenormal.Apart

fromnuclearscleroticcataracts,therestoftheanteriorand

posteriorsegmentexaminationincludingintraocularpressures

wasnormal.

Cataractsurgerytothelefteyewasperformedunderlocal

anaesthesia.Despiteroutinepreoperativedilationwithtopical

tropicamide1%,cyclopentolate1%andphenylephrine2.5%,the

patient'spupilremainedmiosedat3mmindiameter.Thisdidnot

improvewithinstillationoftopicalphenylephrine10%.Further

interventiononlyincreasedthepupillarydiameterto3.5mm.

Theiriswasnotedtobeatonicandhadapropensityto

prolapseoutofthemainclearcornealincision.Adiagnosisof

intraoperativefloppyirissyndromewassuspected.Routine

cataractsurgerycouldnotproceedwithsuchasmallpupil

size.Fouririsretractinghookswereneededtostretchthepupil

toover6mmtoenablethecataracttoberemoved(Fig.1).

Postoperatively,thepatient'sbest-correctedvisualacuityinhis

lefteyeimprovedto6/12ondayoneand6/6atfourweeks.

CommentIntraoperativefloppyirissyndromeisacondition

characterisedby:

n poorpreoperativepupildilation

n afloppyiriswithapropensitytobillowandprolapsefrom

surgicalwounds

n progressiveintraoperativemiosis.

Afloppyirismakescataractsurgerymoredifficult,witha

higherincidenceofcomplicationsincludingposteriorcapsular

rupture,vitreouslossandiristrauma.1

Intraoperativefloppyirissyndromehasmostcommonly

beenassociatedwithtamsulosin,aselectivealpha1adrenergic

antagonistusedforreliefoflowerurinarytractsymptoms

associatedwithbenignprostatichypertrophy.Thesyndrome

isninetimesmoreprevalentinmales.2Between40%3and

90%1ofpatientsontamsulosindevelopintraoperativefloppy

irissyndrome.Tamsulosinhasalsobeenassociatedwitha

2.3timesincreasedpostoperativecataractcomplicationrate.3

otherlessselectivealpha1adrenergicantagonistsincluding

terazosinandprazosinhavealsobeenimplicated.Although

itcanoccurwithoutuseofalpha1adrenergicantagonists,no

statisticallysignificantassociationhasbeenfoundbetween

intraoperativefloppyirissyndromeandothermedicationsor

disease.2

Alpha1adrenergicantagonistsrelaxsmoothmuscle,

includingthatofthedilatormuscleoftheiris.3However,

themechanismbywhichtamsulosininducesintraoperative

floppyirissyndromeislikelytobemorecomplexgiventhe

multiplesignallingpathwaysintheiris.2Histologicalstudies

havealsofailedtoshowchangesinthedilatormuscle.1

Disappointingly,preoperativecessationofalpha1adrenergic

antagonistsdoesnotpreventintraoperativefloppyiris

syndrome,evenwhenstoppedyearsbeforesurgery,whereas

theycaninduceintraoperativefloppyirissyndromewithin

weeksoffirstuse.1,3

Themostimportantfactorgoverningcataractsurgery

outcomesinpatientsonanalpha1adrenergicantagonist

isrecognitionofitsabilitytoinduceintraoperativefloppy

irissyndrome.Theastutesurgeoncanthenplanasuitable

managementapproach.Somestudieshaveshown

Fig. 1

Iris retracting hooks used to stretch the pupil during cataract surgery

Fung & McCluskey 5

Fig. 1

Iris retracting hooks used to stretch the pupil during surgery

X:/AP Shared/Fillers/Fung & McCluskey

Medicinal mishap


intraoperativecataractcomplicationrates(posteriorcapsular

rupturewithvitreousloss)withundiagnosedintraoperative

floppyirissyndromeashighas12%,2fallingto0.6%whenthe

surgeonisawarethepatienthasusedtamsulosin.1

ConclusionAscataractsandtheuseofalpha1adrenergicantagonists

increasewithage,itisnotsurprisingthattheincidenceof

intraoperativefloppyirissyndromehasbeenreportedtooccur

inupto3.7%ofcataractsurgeries.2Itisimportantthatpatients

dueforcataractsurgeryaretoldtoremindtheirophthalmologist

iftheyhaveevertakentamsulosin.Theophthalmologistshould

alsoseekthishistory.Preoperativecessationofthedrugis

notcurrentlyrecommended.Withrecognitionofthepotential

problemandcarefulpre-andintraoperativeplanning,the

ophthalmologistcanminimisesurgicalcomplicationsassociated

withintraoperativefloppyirissyndrome.

references1. ChangDF,osherRH,WangL,KochDD.Prospective

multicenterevaluationofcataractsurgeryinpatientstakingtamsulosin(Flomax).ophthalmol2007;114:957-64.

2. NeffKD,SandovalHP,FernandezdeCastroLE,NowackiAS,VromanDT,SolomonKD.Factorsassociatedwithintraoperativefloppyirissyndrome.ophthalmol2009;116:658-63.

3. BellCM,HatchWV,FischerHD,CernatG,PatersonJM,GrunierA,etal.Associationbetweentamsulosinandseriousophthalmicadverseeventsinoldermenfollowingcataractsurgery.JAMA2009;301:1991-6.


Drug information resourcesAsof1July2010theTherapeuticAdviceandInformation

Service(TAIS)nationaldruginformationserviceforhealth

professionalswillnolongerbeoperational.TheNational

PrescribingServiceacknowledgesthededicationand

expertiseofthestaffwhocontributedtothehighqualityof

TAISoveritstenyearsofoperation.

Closertothecessationdate,healthprofessionalswill

beabletoaccessanindexofothersourcesofdrug

informationontheNPSwebsiteatwww.nps.org.au/

health_professionals.Pleasenotethatwhilesomeofthese

linkedresourcesareopenaccess,othersmayrequirea

subscriptionfee.

AzacitidineVidaza(Celgene)

vialscontaining100mgaslyophilisedpowderfor

reconstitution

Approvedindication:myelodysplasia,leukaemia

AustralianMedicinesHandbooksection14

Themyelodysplasticsyndromesaredisordersinwhichthe

pluripotentstemcellsfunctionabnormally.Asanycelllines

canbeaffectedthepatientmayhaveanaemia,neutropenia

orthrombocytopenia.Thesyndromesincludechronic

myelomonocyticleukaemiaandthemyelodysplasiamay

progresstoacutemyeloidleukaemia.

Inmyelodysplasia,tumoursuppressorgenesmaybe

inactivatedbyhypermethylation.Preventinghypermethylation

mayreducetheproliferationofabnormalcells.

Azacitidineisananalogueofcytidine,oneofthenucleosides

whichmakeupnucleicacids.Whenazacitidineisincorporated

intoDNAitinhibitsDNAmethyltransferase,reducing

hypermethylation,andhasadirectcytotoxiceffecton

abnormallyproliferatingcells.

Inthefirsttreatmentcycleazacitidineisgivenbydaily

subcutaneousinjectionforsevendays.Thiscycleisrepeated

everyfourweeksforaslongasthepatientcontinuestobenefit.

Mostofthedoseisexcretedintheurineasazacitidineand

itsmetabolites.Azacitidineiscontraindicatedinpatientswith

malignanthepatictumoursandthosewithrenalfailure.

AfterphaseIItrialsofintravenousandsubcutaneousdoses

producedfavourableresults,aphaseIIItrialwascarriedoutin

191patientswithmyelodysplasia.Thesepatientswererandomly

assignedtoazacitidineorsupportivecare.Theywereassessed

afterfourtreatmentcycles,andthosewhohadresponded

toazacitidinecouldcontinue.Responseswereassessedby

changesinthebloodandbonemarrowandtheneedfor

transfusion.Intheazacitidinegroup,16%ofthepatientshad

apartialresponseand7%hadacompleteresponse.The

mediandurationofalltheimprovementswas15months.

No-oneinthesupportivecaregrouphadacompleteorapartial

Some of the views expressed in the following notes on newly approved products should be regarded as tentative, as there may be limited published data and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. As a result of fuller experience, initial comments may need to be modified. The Committee is prepared to do this. Before new drugs are prescribed, the Committee believes it is important that full information is obtained either from the manufacturer's approved product information, a drug information centre or some other appropriate source.

New drugs


response.Withsupportivecare,themediantimetodeathorthe

developmentofacuteleukaemiawas12months,comparedwith

21monthsinthepatientstreatedwithazacitidine.1

DatafromthistrialandthephaseIItrialswerereanalysed

whenanapplicationwasmadetomarketthedrugin

theUSA.Theassessmentcriteriahadchangedandthe

reanalysisshowedthatfewpatientshadpartialremissions,

but10–17%hadcompleteremissionsand23–36%hadsome

haematologicalimprovement.Underthenewcriteriasome

patientswerefoundtohavehadacutemyeloidleukaemiaat

thestartofthestudies.Thosetreatedwithazacitidinehada

mediansurvivalof19.3monthscomparedwith12.9months

forsupportivecare.2

Anotherstudycomparedazacitidinewithconventionalcare

whichcouldincludechemotherapy.Thisstudyrandomised

358patientswithmyelodysplasticsyndromesincluding

chronicmyelomonocyticleukaemia.Acutemyeloidleukaemia

developedafteramedianof17.8monthswithazacitidine

and11.5monthswithconventionalcare.Thepatientshad

amediansurvivalof24.5monthswithazacitidineand15

monthswithconventionalcare.However,only25patientsin

theconventionalcaregroupreceivedintensivechemotherapy

andtheirsurvivalratewasnotstatisticallydifferentfromthat

oftheazacitidinegroup.Patientsgivenazacitidinehadhigher

haemoglobinconcentrationssotherewasareducedneed

forredbloodcelltransfusions.Theapprovedindicationsfor

azacitidinearebasedonthistrial.Thesearespecifiedforms

ofmyelodysplasticsyndromes,chronicmyelomonocytic

leukaemia,andacutemyeloidleukaemia,whenallogenicstem

celltransplantisnotindicated.3

Althoughazacitidinemayreducetransfusionrequirementsit

isacytotoxicdrugsopatientsstillneedtobemonitoredfor

anaemia,neutropeniaandthrombocytopenia,particularly

atthestartoftreatment.Infectionsarecommonandsome

patientswilldevelopfebrileneutropenia.Inadditiontofull

bloodcountsthepatient'sliverandrenalfunctionshould

beregularlycheckedbecauseoftheriskoftoxicity.As

gastrointestinalproblemsarefrequent,antiemeticdrugs

shouldbegivenbeforeeachtreatment.otherfrequent

adversereactionsincludeinjectionsitereactions,dyspnoea,

anorexia,arthralgia,dizzinessandbruising.Despitethewide

rangeofpotentiallysevereadverseeffects,thereisevidence

thatazacitidineleadstoabetterqualityoflifebyimproving

thepatient'sphysicalfunctioning,fatigueanddyspnoea.1

Mostofthepatientswithmyelodysplasticsyndromes

areelderly.Theyarenotusuallysuitableforstemcell

transplantation,somanagementhasinvolvedsupportive

care.Azacitidineseemstoofferimprovedsurvivaltospecific

groupsofthesepatients.

T T manufacturerprovidedadditionalusefulinformation

references *†

1. SilvermanLR,DemakosEP,PetersonBL,KornblithAB,HollandJC,odchimar-ReissigR,etal.Randomizedcontrolledtrialofazacitidineinpatientswiththemyelodysplasticsyndrome:astudyofthecancerandleukemiagroupB.JClinoncol2002;20:2429-40.

2. SilvermanLR,McKenzieDR,PetersonBL,HollandJF,BackstromJT,BeachCL,etal.Furtheranalysisoftrialswithazacitidineinpatientswithmyelodysplasticsyndrome:studies8421,8921,and9221bythecancerandleukemiagroupB.JClinoncol2006;24:3895-903.

3. FenauxP,MuftiGJ,Hellstrom-LindbergE,SantiniV,FinelliC,GiagounidisA,etal;InternationalVidazaHigh-RiskMDSSurvivalStudyGroup.Efficacyofazacitidinecomparedwiththatofconventionalcareregimensinthetreatmentofhigher-riskmyelodysplasticsyndromes:arandomised,open-label,phaseIIIstudy.Lancetoncol2009;10:223-32.

Caffeine citrateCafnea(Phebra)

2mLvialscontaining40mg/2mLforinjectionand7mLvials

containing25mg/5mLoralsolution

Approvedindication:apnoeaofprematurity

AustralianMedicinesHandbooksection19

Prematurebabiesareatriskofapnoea.Thiscanoccurinthe

absenceofotherproblems,suchasinfection.Primaryapnoea

appearsbetweentwoandsevendaysafterbirthandismost

commoninprematurebabieswithalowbirthweight.Ifthe

apnoeaofprematurityisrecurrentandprolonged,ventilation

maybeneeded.Methylxanthinessuchastheophylline

havebeenusedasrespiratorystimulants.Caffeineisalsoa

methylxanthineandithasbeenusedoverseastotreatthe

apnoeaofprematurity.

Themechanismofactionisuncertain,butcaffeineisthought

toincreasetheresponsetohypercapniaandincreasethe

respiratoryrate.Aloadingdoseisgivenintravenouslyover

30minutes.Thesubsequentdailymaintenancedosescan

begivenintravenouslyorbymouth.Someofthedoseis

convertedtotheophylline,butthisoccursslowlyinpremature

babies.Thehalf-lifeofcaffeineinthesebabiesis80–120

hours.Mostofthedoseisexcretedunchangedintheurine.

Astudycomparedcaffeinecitratewithplaceboin82babies,

bornbetween25and32weeksofgestation,whowerehaving

atleastsixepisodesofapnoeain24hours.over7–10days

69%ofthecaffeinegroup,butonly43%oftheplacebogroup,

achievedatleasta50%reductioninepisodesofapnoea.1

Alargerplacebo-controlledstudyincludedbabieswithbirth

weightsof500–1250g.The2006babieshadanaverage

gestationalageof27weeks.Manywerebeingtreatedfor

apnoea,butsomebabiesweregiventreatmenttoprevent

apnoeaortoassisttheremovalofanendotrachealtube.The


firstdosesweregivenatamedianageof28weeksandwere

stoppedbefore35weeks.Supplementaloxygenwasneeded

by36%ofthebabiesgivencaffeinecitrateand47%ofthose

givenaplacebo.Comparedtotheplacebogroup,babiesgiven

caffeinecitrateweresignificantlylesslikelytorequiresurgical

closureofapatentductusarteriosus.2

Babiesgivencaffeinemayinitiallygainlessweightthanother

prematurebabies.Mostadverseeffectsareprobablyrelated

tothestimulantactionofcaffeine.Theyincludetachycardia,

tachypnoeaandjitteriness.Maternalconsumptionofcaffeine

shouldbeconsideredwhenprescribingcaffeinecitrate.

Prematurebabiesareveryvulnerablepatients.Inlong-term

follow-up,40%ofthebabiesgivencaffeinediedorsurvived

withaneurodevelopmentaldisability.Thiswasastatistically

betteroutcomethanthe46%rateseenintheplacebogroup.

Topreventoneadverseoutcome16babiesneedtobetreated

for37days.Muchofthebenefitofcaffeineisfromearlier

discontinuationofpositiveairwayspressure.3

Theresultsofthelargerstudyaredifficulttointerpretbecause

ofthedifferentindicationsforgivingcaffeine.InAustralia

theuseofcaffeinecitratewillberestrictedtotheshort-term

treatmentoftheapnoeaofprematurityinbabiesbetween28

and33weeksofgestationalage.

T T T manufacturerprovidedclinicalevaluation

references *†

1. ErenbergA,LeffRD,HaackDG,MosdellKW,HicksGM,WynneBA;CaffeineCitrateStudyGroup.Caffeinecitrateforthetreatmentofapneaofprematurity:adouble-blind,placebo-controlledstudy.Pharmacother2000;20:644-52.

2. SchmidtB,RobertsRS,DavisP,DoyleLW,BarringtonKJ,ohlssonA,etal;CaffeineforApneaofPrematurityTrialGroup.Caffeinetherapyforapneaofprematurity.NEnglJMed2006;354:2112-21.

3. SchmidtB,RobertsRS,DavisP,DoyleLW,BarringtonKJ,ohlssonA,etal;CaffeineforApneaofPrematurityTrialGroup.Long-termeffectsofcaffeinetherapyforapneaofprematurity.NEnglJMed2007;357:1893-902.

Human C1 esterase inhibitorBerinert(CSL)

vialscontaining500unitsasfreeze-driedpowderfor

reconstitution

Approvedindication:hereditaryangioedema

AustralianMedicinesHandbookAppendixA

C1esteraseinhibitorisaproteinderivedfromhumanplasma.

Itisindicatedforthetreatmentofacuteattacksofhereditary

angioedema.Thisconditionischaracterisedbyepisodesof

swellingintheskinormucosaandcanoccuranywhereinthe

body(face,larynx,gut,limbs).Itcanbepainful,particularly

withgastrointestinalattacks,andifthelarynxisaffected

asphyxiationanddeathcanoccur.

TypeIandtypeIIhereditaryangioedemaarecausedby

mutationsinthegeneencodingtheC1esteraseinhibitor.

Althoughnotwelldefined,theabsenceordysfunctionofthis

proteinisthoughttoleadtoincreasedvascularpermeability

duetounregulatedbradykininactivation.Replacing

C1esteraseinhibitorintravenouslyduringanacuteattack

reducesongoinginflammatoryprocesses.Treatmentsfor

histamine-inducedangioedema,suchascorticosteroids,

antihistaminesoradrenaline,havenoeffectinpatientswith

hereditaryangioedema.

TheefficacyofC1esteraseinhibitorhasbeeninvestigated

inarandomisedcontrolledtrialin125adultsandchildren

withconfirmedacutemoderatetoseverehereditary

angioedema.overall,79%ofpatientspresentedwitha

gastrointestinalattackand20.2%withafacialattack.Patients

wererandomisedtoreceiveC1esteraseinhibitor10U/kgor

20U/kg(39and43patients)orplacebo(42patients).Within

fourhoursoftreatment,70%ofpatientshadrespondedinthe

C1esteraseinhibitor20U/kggroupcomparedto43%inthe

placebogroup.Themediantimetoonsetofsymptomrelief

wassignificantlyshorterforC1esteraseinhibitor20U/kg

(0.5hours)thanforplacebo(1.5hours).Themedianresponse

timeforthelower-doseC1esteraseinhibitor(10U/kg)was

onlyslightlyshorterthanforplacebo(1.2vs1.5hours).

Mediantimetocompleteresolutionofsymptomswasmuch

shorterforC1esteraseinhibitor20U/kgthanforplacebo

(4.9vs7.8hours)butnotforC1esteraseinhibitor10U/kg

(20hours).1The20U/kgdoseiscurrentlyrecommendedfor

hereditaryangiodema.

Inthetrial,themostfrequentadverseeventswerenausea,

diarrhoea,abdominalpainandmusclespasms.Mostofthe

adverseeventsweremorecommonwithplacebothanwith

C1esteraseinhibitor20U/kg(43.9%vs19.6%)andmayhave

beenrelatedtothepatients'angioedemaattacks.1Taste

disturbancewasreportedwithC1esteraseinhibitor20U/kg

(2/46patients)butnotwithplacebo(0/41patients).Anincrease

inseverityofpainassociatedwithhereditaryangioedema

wasthemostsevereadverseeffectreportedbypatients

whoreceivedtheactivetreatment.AntibodiestoC1esterase

inhibitorandtheireffectonefficacyoradversereactionswere

notmeasuredinthetrial.

Inanobservationalstudyofthreewomen,thecommencement

offrequenttreatmentswithC1esteraseinhibitorwas

associatedwithanincreaseinangioedemaattacks(4-fold,

5-foldand12-fold).Acontrolgroupof24age-matchedmen

andwomendidnotshowthesameincreaseinattacksovera

nine-yearperiod.Itwasnotclearwhatcausedthisincrease,

butinvestigatorsspeculatedthatfrequenttreatmentsmay

haveloweredthethresholdforactivationofanattack.2

ThisC1esteraseinhibitorismadefromhumanplasma

sourcedfromoverseas.Likeallplasmaproducts,ithas


thepotentialtotransmitinfectionscausedbyvirusesand

prions(e.g.variantCreutzfeldt-Jakobdisease).During

therandomisedcontrolledtrial,noneofthepatients

seroconvertedtoproduceantibodiestoHIV,hepatitisor

humanparvovirus19virus.1Theinfectiousdiseaseriskof

C1esteraseinhibitorhasbeenreducedbyscreeningblood

donorsandtheirplasmaforevidenceofviralinfectionssuch

asHIVandhepatitisC.Alsoduringfractionation,plasma

undergoesprocessestoinactivateorremovecertainviruses.

Nevertheless,patientsshouldbewarnedthatthereisstillan

infectiousdiseaseriskwiththisproduct.Vaccinationagainst

virusesthatcouldpotentiallybepresentinplasma,suchas

hepatitisB,shouldbeconsidered.

SeverehypersensitivityreactionscanoccurwithC1esterase

inhibitorandadrenalineshouldbeavailablewheninjections

aregiven.Forpatientswhoareknowntohaveatendencyto

allergies,antihistaminesandcorticosteroidsshouldbegiven

prophylactically.Prescribersshouldbeawarethatthrombosis

hasbeenreportedwithC1esteraseinhibitorwhenusedat

doseshigherthan20U/kgandforunapprovedindications.

C1esteraseinhibitorseemstobeaneffectivetreatmentfor

hereditaryangioedemaandhasbeenusedoverseasformore

than30years.However,therehavebeenreportsinaminority

ofpatientsthatitmayincreasethefrequencyofangioedema

attacks.

manufacturerdeclinedtosupplydata

references *A 1. CraigTJ,LevyRJ,WassermanRL,BewtraAK,HurewitzD,

obtulowiczK,etal.EfficacyofhumanC1esteraseinhibitorconcentratecomparedwithplaceboinacutehereditaryangioedemaattacks.JAllergyClinImmunol2009;124:801-8.

2. BorkK,HardtJ.Hereditaryangioedema:IncreasednumberofattacksafterfrequenttreatmentswithC1inhibitorconcentrate.AmJMed2009;122:780-3.

MiglustatZavesca(Actelion)

100mgcapsules

Approvedindication:typeIGaucherdiseaseandNiemann-

PickdiseasetypeC

AustralianMedicinesHandbookAppendixA

Miglustatisindicatedforpeoplewithmildtomoderate

typeIGaucherdisease,andforprogressiveneurological

manifestationsinadultsandchildrenwithNiemann-Pick

typeCdisease.Thesearebothrareinheriteddisorderswhich

resultinthebuild-upofglycosphingolipidsinthebody.

MiglustatisasyntheticanalogueofD-glucoseandisa

competitiveinhibitorofglucosylceramidesynthase,an

enzymeinvolvedinthesynthesisofmostglycosphingolipids.

Treatmentwithmiglustataimstoreducetheproductionof

glycosphingolipids.

TypeIGaucherdiseaseiscausedbyadeficiencyinbeta-

glucocerebrosidase–anenzymewhichbreaksdownthe

glycosphingolipidglucocerebroside.Thislipidbuildsup

inmacrophagesfoundprimarilyintheliver,spleenand

bonemarrow.Clinicalfeaturesofthisdiseaseinclude

hepatomegaly,splenomegaly,anaemia,thrombocytopenia

andbonelesions.

Regularintravenousinfusionofrecombinantglucocerebroside

(seeAustPrescr1999;22:95–8)isthemainstayoftreatment

andbenefitsmostpatientswithtypeIGaucherdisease.

Miglustatisanoraloptionforpeoplewhocannothave

enzymetherapy.

Thesafetyandefficacyofmiglustathasbeenassessedin

severalopen-labelstudies.1−4Inthemaintrialof28patients,

treatmentwithoralmiglustat100mgthreetimesaday

reducedmeanliversizeby12%(CI‡7.8−16.4)andmean

spleensizeby19%(CI14.3−23.7)after12months.(Seven

patientshadhadaprevioussplenectomy.)Nineofthe22

patientswhocompletedtreatmenthadanaemia(<115g/L)

atbaseline.After12months,haemoglobinhadincreasedby

morethan5g/Linfiveofthesepeople.ofthe21patientswho

couldbeassessedforplateletcount,fourhadanincreaseof

atleast15x109/Lplatelets.Glycolipidbiosynthesis–assessed

bymeasuringsurfaceexpressionofGm1onleucocytes−

wasfoundtohavedecreasedbyanaverageof38.5%over

12monthsinasampleoffivepatients.Plasmachitotriosidase

activity−ameasureofstoredlipids−hadalsodecreasedby

theendofthetrial.1Thebenefitsofmiglustatweremaintained

foruptothreeyearsinanextensionofthetrial.2Similar

effectsontheliverandspleenwereobservedintheother

open-labeltrials.2−4

Themostfrequentadverseeventduringthetrialwas

diarrhoea(79%ofpatients).Sixpatientsdroppedout–two

ofthesewerebecauseofgastrointestinalproblems.Two

patientswerewithdrawnbecauseofparaesthesiaewhich

wereconfirmedtobeperipheralneuropathy.1othercommon

adverseeventsreportedintheopen-labeltrialsincluded

weightloss,tremor,flatulenceandabdominalpain.2−4

Dosereductionordiscontinuationmayberequiredfor

tremor.PeripheralneuropathymayberelatedtovitaminB12

deficiency,whichiscommonintypeIGaucherdisease,so

regularmonitoringofvitaminB12aswellasneurological

evaluationisrecommended.

Niemann-PicktypeCdiseaseisanincurableprogressive

diseasethatleadstoprematuredeath.Impairedtransport

oflipidswithincellscausessomefattyacidsincluding

glycosphingolipidstoaccumulateintissuesandorgans,

Tx

‡confidenceinterval


particularlythebrain.Thiscanleadtosupranucleargaze

palsy,ataxia,problemswithspeechandswallowing,dystonia,

seizures,dementia,psychiatricproblemsandgelastic

cataplexy§.

Untilnow,treatmentforthisdiseasehasmainlybeen

supportive.Asmiglustatcancrosstheblood–brainbarrier,its

efficacyhasbeenassessedinNiemann-PicktypeCdisease.

Inarandomisedcontrolled12-monthtrial,oralmiglustat

200mggiventhreetimesadaywascomparedtostandard

care(drugtreatmentandphysical,speechandoccupational

therapy)ina2:1ratioin28patientsaged12yearsorolder.

Inaddition,12childrenagedunder12yearsenrolledinthe

trialwereallgivenmiglustat(dosewasadjustedaccordingto

bodysurfacearea).Mostoftheparticipantshadsevereclinical

manifestationsatbaselineandwereallowedtocontinue

theirmedicationswhichincludedanalgesics,antibiotics,

antidiarrhoeadrugs,sedativesandhypnotics,antiepileptics

anddrugstotreatdystonia.5

Themainmeasureofefficacyinthetrialwasthespeedof

horizontaleyemovementsbetweenfixedpoints.Afterayear

oftreatment,improvementswereobservedinpatientsgiven

miglustat,butthiswasnotsignificantlydifferenttoresultsseen

inpatientsgivenstandardcarealone.Improvementsinthe

abilitytoswallowandinintellectualperformance(mini-mental

statusexamination)werealsoseeninolderpatients(>12years

old)givenmiglustatcomparedtothosewhoreceivedstandard

care.5open-labelextensionsofthisstudy(uptothreeyears)

reportedthatpatients'neurologicalsymptomsdidnotprogress

whiletakingmiglustat.6,7

Aretrospectiveobservationalstudyanalysedphysician

questionnairesaboutambulation,manipulation,language

andswallowinginpatientswhohadbeentakingmiglustatfor

anaverageof1.5years.overall,74.5%(49/65)ofpatientshad

reduceddiseaseprogressionorstabilisationofneurological

symptoms.8

AdverseeventsinNiemann-Pickdiseaseweresimilartothose

seenintypeIGaucherdisease,withdiarrhoeabeingthe

mostcommon(85%ofpatients).Weightloss(63%),tremor

(46%)andflatulence(44%)werealsofrequentlyreported.

Severeadverseeventsincludedsevereconfusionalstateand

salivaryhypersecretion,severedehydrationandrespiratory

syncyticalvirusinfection.Thesewerethoughttobeunrelated

tomiglustat.Threepeoplewerewithdrawnfromthetrial

becauseofanadverseevent–onebecauseofinsomniaand

confusionalstate,oneduetodiarrhoearelatedtoCrohn's

diseaseandonefromlethargy,impairedmemoryand

depression(inachild).5

Asweightlosswascommonlyreportedwithmiglustat,growth

rateshouldbemonitoredinchildrenandadolescentstaking

miglustat.Reductionsinplateletcountshaveoccurredwith

miglustatinNiemann-Pickdiseasesobloodcountsshould

bemonitored.Dizzinesswasacommonadverseeffectand

patientsshouldnotdriveiftheyexperiencethis.Thebenefit

ofmiglustatinNiemann-Pickdiseaseshouldbereviewedat

six-monthintervals.

Toreducegastrointestinaleffectssuchasdiarrhoea,miglustat

shouldnotbetakenwithfood.Aftera100mgdose,maximum

plasmaconcentrationsarereachedafterapproximately

twohours.Itshalf-lifeisabout6−7hourssosteady-state

concentrationsarepredictedtobereachedafter1.5−2days.

Miglustatisexcretedmainlybythekidneyssodose

adjustmentmaybenecessarywithmilderrenalimpairment.It

isnotrecommendedinsevererenalimpairment.

MiglustatshowedmodestefficacyinmildtomoderatetypeI

GaucherdiseaseandNiemann-Pickdisease,althoughnumbers

ofpatientsinthetrialsweresmall.Ithasbeenapprovedasan

orphandruginAustraliaandisonlyavailablethroughtheLife

SavingDrugsProgram.

manufacturerprovidedonlytheproductinformation

references *†A 1. CoxT,LachmannR,HollakC,AertsJ,vanWeelyS,

HrebicekM,etal.NoveloraltreatmentofGaucher'sdiseasewithN-butyldeoxynojirimycin(oGT918)todecreasesubstratebiosynthesis.Lancet2000;355:1481-5.

2. ElsteinD,HollakC,AertsJM,vanWeelyS,MaasM,CoxTM,etal.Sustainedtherapeuticeffectsoforalmiglustat(Zavesca,N-butyldeoxynojirimycin,oGT918)intypeIGaucherdisease.JInheritMetabDis2004;27:757-66.

3. HeitnerR,ElsteinD,AertsJ,WeelyS,ZimranA.Low-doseN-butyldeoxynojirimycin(oGT918)fortypeIGaucherdisease.BloodCellsMolDis2002;28:127-33.

4. PastoresGM,BarnettNL,KolodnyEH.Anopen-label,noncomparativestudyofmiglustatintypeIGaucherdisease:efficacyandtolerabilityover24monthsoftreatment.ClinTher2005;27:1215-27.

5. PattersonMC,VecchioD,PradyH,AbelL,WraithJE.MiglustatfortreatmentofNiemann-PickCdisease:arandomisedcontrolledstudy.LancetNeurol2007;6:765-72.

6. WraithJE,VecchioD,JacklinE,AbelL,Chadha-BorehamH,LuzyC,etal.MiglustatinadultandjuvenilepatientswithNiemann-PickdiseasetypeC:long-termdatafromaclinicaltrial.MolGenetMetab2010;99:351-7.

7. PattersonMC,VecchioD,JacklinE,AbelL,Chadha-BorehamH,LuzyC,etal.Long-termmiglustattherapyinchildrenwithNiemann-PickdiseasetypeC.JChildNeurol2009;000:1-6.

8. PinedaM,WraithJE,MengelE,SedelF,HwuWL,RohrbachM,etal.MiglustatinpatientswithNiemann-PickdiseasetypeC(NP-C):amulticenterobservationalretrospectivecohortstudy.MolGenetMetab2009;98:243-9.

T

§suddenweaknessorcollapseassociatedwithstrongemotion,particularlylaughter


VildagliptinGalvus(Novartis)

50mgtablets

Approvedindication:type2diabetes

AustralianMedicinesHandbooksection10.1.3

Patientswithtype2diabetesoftenneedmorethanonedrugto

controltheirbloodglucose.Whenfirst-linetreatmentfails,the

incretinmimeticsandenhancersareaclassofdrugswhichcan

beaddedtotreatment(seeAustPrescr2008;31:102–8).Within

thisclassaretheinhibitorsofdipeptidylpeptidase4(DPP4)

suchassitagliptin.Thesedrugsblockincretinmetabolismand

thisleadstoreductionsinbloodglucoseconcentrations.

VildagliptinisaDPP4inhibitorwhichistakentwicedaily

withmetforminorathiazolidinedioneandoncedailywitha

sulfonylurea.A50mgdosewillinhibitmostDPP4activityfor

atleast12hours.Mostofthedoseisconvertedtoinactive

metabolites.Thismetabolismdoesnotinvolvethecytochrome

P450systemsothepotentialformetabolicdruginteractionsis

reduced.Theeliminationhalf-lifeisthreehourswithmostof

themetabolitesbeingexcretedintheurine.Vildagliptinisnot

recommendedforpatientswithhepaticormoderateorsevere

renalimpairment.

Asystematicreviewwhichincluded14trialsofvildagliptin

involving6121patientsconcludedthattreatmentreduces

glycatedhaemoglobin(HbA1c)by0.6%.1Severalstudies

haveinvestigatedifthismakesasignificantdifferencewhen

vildagliptinisaddedtootherdrugs.

Vildagliptin50mgdailywasaddedtothetreatmentof56people

whosediabeteswasnotcompletelycontrolledbymetformin.

After12weekstheirmeanHbA1chadreducedby0.6%froma

baselineof7.7%.Therewasnochangeincontrolin51other

patientswhoweregivenaplacebototakewiththeirmetformin.

Someofthepatientscontinuedinanextensionofthetrial

with32ofthevildagliptingroupand26oftheplacebogroup

completingoneyearoftreatment.Therewasnosignificant

changeinthevildagliptingroup,butHbA1cincreasedinthe

placebogroupsothattherewasadifferenceof1.1%between

thegroupsafterayear.AnHbA1cbelow7%wasachievedby

41.7%ofthosewhoaddedvildagliptin,butonly10.7%ofthose

whoaddedaplacebo.2

Anothertrialstudiedvildagliptin100mg,aswellas50mg,asan

additiontotreatmentwithmetformin.After24weekstheHbA1c

concentrationhadfallenby0.9%inthe185peoplerandomised

toadd50mgtwicedaily,by0.5%inthe177randomisedtoadd

50mgoncedaily,andincreasedby0.2%inthe182randomised

toaddaplacebo.Theproportionofpatientsachievingan

HbA1cunder7%dependedontheirbaselineconcentrations.If

thebaselineHbA1cwasgreaterthan8.5%,itwasonlyreduced

below7%in16.3%ofpatientsgivenvildagliptin100mg,7.5%of

thosegiven50mgand2.1%ofthosegivenplacebo.3

Whentype2diabetesisnotcontrolledbymetforminalonea

sulfonylureacanbeadded.Thisapproachhasbeencompared

withaddingvildagliptininastudyof2789patients.There

were1396whowererandomisedtoaddvildagliptin50mg

twicedailyand1393whowererandomisedtoaddglimepiride.

After52weeksthemeanreductioninHbA1cwas0.44%with

vildagliptinand0.53%withglimepiride.Fromameanbaseline

of7.3%,atargetHbA1cofunder7%wasreachedby54%of

thevildagliptingroupand56%oftheglimepiridegroup.4

Vildagliptinhasalsobeenaddedtothetreatmentofpatients

withdiabeteswhichwasinadequatelycontrolledbya

sulfonylurea.TheirmeanHbA1cwas8.5%.While170patients

wererandomisedtoaddvildagliptin50mgoncedailyand169

toaddvildagliptin50mgtwicedaily,another176patientswere

givenaplacebo.Allthepatientsalsotookglimepiride.After

24weeksthemeanHbA1cdeclined0.58%withvildagliptin50

mgand0.63%withvildagliptin100mgwhileitincreasedby

0.07%intheplacebogroup.only12%ofthepatientsinthe

placebogroupachievedanHbA1cbelow7%comparedto21%

ofthevildagliptin50mggroupand25%ofthe100mggroup.

Astherewasnosignificantadvantagewiththehigherdose,the

recommendeddailydoseofvildagliptin,incombinationwitha

sulfonylurea,is50mg.5

Althoughmonotherapywithathiazolidinedioneisnottheusual

first-linetherapy,atrial,in463peoplewithtype2diabetes,

hasstudiedtheeffectofaddingvildagliptintotreatmentwith

pioglitazone.After24weeks,addingvildagliptin50mgonce

dailyreducedthemeanHbA1cby0.8%,twicedailyreducedit

by1%,whileplaceboreduceditby0.3%.TheHbA1cfellbelow

7%in29%ofthosegiven50mg,36%ofthosegiven100mg

and15%ofthosegivenaplacebo.6

Intrialsofmonotherapytheincidenceofadverseeventshasbeen

similarforvildagliptinandplacebo.However,thefrequencyof

infections(1.4%vs0.3%)andneurologicalsymptoms(0.9%vs

0.6%)wasgreaterwithvildagliptinthanwithplacebo.Tremor,

dizzinessandheadachearecommonwhenvildagliptinisgiven

withmetforminorasulfonylurea.Peripheraloedemaismore

frequentwithvildagliptin,thanwithplacebo,whenaddedto

treatmentwithathiazolidinedione.6Addingvildagliptintoother

oralhypoglycaemicdrugscanincreasetheriskofhypoglycaemia.

Thefrequencywithglimepirideis1.2%and1%withmetformin.

Hypoglycaemiaismorelikelytooccurifglimepiride,ratherthan

vildagliptin,iscombinedwithmetformin.4Therehavebeen

rarecasesofangioedemaandhepatitisduringtreatmentwith

vildagliptin.Liverfunctionshouldbecheckedbeforeandduring

treatment.Thepatient'srenalfunctionshouldalsobechecked

beforetreatmentwithvildagliptin.

Inanimalstudiesvildagliptinhascausedproblemswithskin

ulcerationandcardiacconduction,whilethesignificancein

humansisunknown.Animalstudiesalsoshowincreased

mammarytumoursathighdoses.


CorrectionsNebivolol (AustPrescr2010;33:52–9)

IntheSENIoRStrial,thereductionof4.2%inthecompositeendpointofall-causemortalityorhospitalisation,isthe

absoluteriskreduction,nottherelativeriskreduction.

Ustekinumab T-score(AustPrescr2010;33:52–9)


Janssen-Cilagdidrespondtotherequestfordata,buttheirresponsewasnotreceivedintheAustralian Prescriberoffice.Thecompanydeclinedtoprovidetheclinicalevaluation.

TheT-score()isexplainedin'Newdrugs:transparency',AustPrescr2009;32:80–1.

* Atthetimethecommentwasprepared,informationaboutthisdrugwasavailableonthewebsiteoftheFoodandDrugAdministrationintheUSA(www.fda.gov).

† Atthetimethecommentwasprepared,ascientificdiscussionaboutthisdrugwasavailableonthewebsiteoftheEuropeanMedicinesAgency(www.emea.eu).

A Atthetimethecommentwasprepared,informationaboutthisdrugwasavailableonthewebsiteoftheTherapeuticGoodsAdministration(www.tga.gov.au/pmeds/auspar.htm)

T

www.australianprescriber.comAustralian Prescriberisavailableontheinternetinfulltext,

freeofcharge.Readerscanreceiveanew issue email alert

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editorial officeForgeneralcorrespondencesuchasLetterstotheEditor,contacttheEditor.

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1. False

2. True

3. True

4. False

Answers to self-test questions

Sulfonylureascancausepatientstogainweightandtherewas

asignificantdifferencebetweentheweightofpatientswho

addedglimepiridecomparedtothosewhoaddedvildagliptinto

treatmentwithmetformin.However,overayeartheweightofthe

patientstakingvildagliptinonlyfellanaverageof0.23kg.4This

wassimilartothe0.2kgreductionseeninbothgroupsinthe52-

weekplacebo-controlledtrialofmetforminandvildagliptin.2

ArolefortheDPP4inhibitorsasadd-ontreatmentsisyettobe

established,particularlyinpatientswhoarealreadyusingmore

thanonedrug.Theirlong-termsafetyisalsounknown.The

systematicreviewconcludedthatDPP4inhibitorscurrentlyhave

noadvantageoverotherdrugswhichlowerbloodglucose.1


references †A

1. RichterB,Bandeira-EchtlerE,BergerhoffK,LerchC.Dipeptidylpeptidase-4(DPP-4)inhibitorsfortype2diabetesmellitus(review).TheCochraneDatabaseofSystematicReviews2009,Issue3.

2. AhrenB,GomisR,StandlE,MillsD,SchweizerA.Twelve-and52-weekefficacyofthedipeptidylpeptidaseIVinhibitorLAF237inmetformin-treatedpatientswithtype2diabetes.DiabetesCare2004;27:2874-80.

3. BosiE,CamisascaRP,ColloberC,RochotteE,GarberAJ.Effectsofvildagliptinonglucosecontrolover24weeksinpatientswithtype2diabetesinadequatelycontrolledwithmetformin.DiabetesCare2007;30:890-5.

4. FerranniniE,FonsecaV,ZinmanB,MatthewsD,AhrenB,ByiersS,etal.Fifty-two-weekefficacyandsafetyofvildagliptinvs.glimepirideinpatientswithtype2diabetesmellitusinadequatelycontrolledonmetforminmonotherapy.DiabetesobesMetab2009;11:157-66.

5. GarberAJ,FoleyJE,BanerjiMA,EbelingP,GudbjörnsdottirS,CamisascaRP,etal.Effectsofvildagliptinonglucosecontrolinpatientswithtype2diabetesinadequatelycontrolledwithasulphonylurea.DiabetesobesMetab2008;10:1047-56.

6. GarberAJ,SchweizerA,BaronMA,RochotteE,DejagerS.Vildagliptinincombinationwithpioglitazoneimprovesglycaemiccontrolinpatientswithtype2diabetesfailingthiazolidinedionemonotherapy:arandomized,placebo-controlledstudy.DiabetesobesMetab2007;9:166-74.

Tx

Tx

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