· patient and not just the surrogate marker. Glycated haemoglobin (HbA1c) is a surrogate marker in diabetes. Kris Park warns us that intensive treatment to reduce HbA1c may not

30 How low to go with glucose control (Editorial)

KEJPark

31 Letters

32 Prescribing in liver disease ASloss&PKubler

36 Managing pertussis in adults JMarchant&AChang

39 Clinical use of botulinum toxin AScheinberg

42 Book review TherapeuticGuidelines:

Psychotropic

43 Abnormal laboratory results. Pitfalls in interpreting laboratory results PPhillips

47 Surrogate outcome markers in research and clinical practiceSTwaddell

51 New drugsdabigatranetexilate,daptomycin,

etravirine,nitisinone

Fulltextwithsearchfacilityonlineatwww.australianprescriber.com

VoLuMe 32 NuMBer 2 AN iNdePeNdeNt reView APriL 2009 C o n T E n T S

30 | VoLuMe 32 | NuMBer 2 | APriL 2009 www.austral ianprescriber.com

in this issue…

EditorialHow low to go with glucose controlKris EJ Park, Head of Diabetes and Endocrinology, Sydney West Area Health Service, Western Cluster, Nepean Hospital, Penrith, New South Wales

Keywords:cardiovascularrisk,hypoglycaemia.

(Aust Prescr 2009;32:30–1)

TheDiabetesControlandComplicationsTrial1intype1diabetes

andtheUKProspectiveDiabetesStudy(UKPDS)2intype2

diabetesshowedthatastrategyaimedatintensifiedcontrolof

bloodglucosereducedtheriskofmicrovascularcomplications

ofdiabetes.Theseresultsadvancedthemanagementof

hyperglycaemiaandledtothecurrentrecommendationthatall

patientswithdiabetesaimforaglycatedhaemoglobin(HbA1c)

targetbelow7%.

Therehasbeenageneralacceptancethattightglycaemic

controlwillreducecardiovasculardisease,butthereisalack

ofdefinitiveevidencethatoutcomeswillimprove.Thestudies

involvedrelativelyyoungpatientswhowerethereforeatlower

cardiovascularrisk.Inparticular,theUKPDSrecruitedpeople

withtype2diabetesatthetimeofdiagnosisandthestudymay

havebeentooshortforacardiovascularbenefittoemerge.The

failuretoshowabenefitmayalsorelatetothefactthattheinitial

reductionsinHbA1cwerenotsustained.

Post-studyfollow-up(observational)oftheUKPDScohort3over

10yearsdid,however,showcontinuedreductioninnotonly

microvascular(24%,p=0.001)butalsocardiovascularoutcomes

(15%inmyocardialinfarction,p=0.01)andindeathfromany

cause(13%,p=0.007).Thisbenefit–aso-called'legacyeffect'–

persisteddespiteearlyloss(withinayear)ofwithin-study

differencesinglycaemiccontrolbetweentheintensiveand

standardgroups.

In2008,twomajorcardiovascular-outcometrialsreportedtheir

results.4,5Thesetrialsinvolvedpeoplewithlong-standingtype2

diabeteswithhighvascularrisk.

TheActiontoControlCardiovascularRiskinDiabetes

(ACCoRD)4studyrandomised10251peoplewithpoorly

controlledtype2diabetes(meanage62years,meanduration

10years,medianHbA1c8.1%).Therewasanintensiveglucose

loweringarmaimingfornormoglycaemia(HbA1clessthan6%)

andanarmwithastandardglucosetarget(HbA1cof7–7.9%).

Theprimaryoutcomeswerecardiovasculareventsincluding

cardiovasculardeath,strokeornon-fatalmyocardialinfarct.

Bothgroupsusedalmostalloftheavailabledrugtherapiesin

differentcombinationsanddoses.

TheActioninDiabetesandVascularDisease(ADVAnCE)5study

involved11140patientswithsimilarageanddiabetesduration

(meanage66years,meanduration8years).However,these

patientshadsignificantlybetterglycaemiccontrolatbaseline

(medianHbA1cof7.2%)comparedtotheACCoRDgroups.

Theywererandomisedtoeitheranintensiveglucoselowering

arm(aimingforHbA1cunder6.5%)ortoastandardglucose

loweringarm.Multipledrugtherapieswereused,buttheoral

hypoglycaemicdrugtakenbyeveryoneintheintensivearm

wasmodified-releasegliclazide.Theprimaryoutcomesforthe

ADVAnCEstudyalsodifferedinthattheyincludednotonly

cardiovascularevents,butalsomajormicrovascularevents.

TheintensiveglucoseloweringarmsinbothACCoRDand

ADVAnCEachievedamedianHbA1cof6.4%.Thiswas,

respectively,1.1%and0.6%lowerthantheHbA1cinthe

standardtreatmentarms.DuringtheADVAnCEstudy,intensive

glucoseloweringyieldeda21%(p=0.006)relativereductionin

microvascularevents(innephropathy),butnosignificanteffect

onmajorcardiovascularevents.Unexpectedly,theACCoRD

Manydrugsaremetabolisedbytheliver,sotheirclearance

willbeaffectedbyliverdisease.AndrewSlossandPaulKubler

telluswhatshouldbeconsideredwhenprescribingfora

patientwithreducedliverfunction.

Anincreasedconcentrationofasinglehepaticenzymedoes

notmeanthatthepatienthasliverdisease.PatPhillips

explainshowhealthypeoplemayhaveabnormaltest

results,andsuggestshowerrorscanbereduced.

Laboratorymeasurementsaresometimesusedasan

indicationofthepatient’sprognosis.ScottTwaddellcautions

usthatsuchsurrogatemarkersmaynotalwaysbedirectly

linkedtoclinicaloutcomes.Itisimportanttomanagethe

patientandnotjustthesurrogatemarker.

Glycatedhaemoglobin(HbA1c)isasurrogatemarkerin

diabetes.KrisParkwarnsusthatintensivetreatmentto

reduceHbA1cmaynotimprovecardiovascularoutcomesin

patientswithdiabetes.

Theoutcomesofaninjectionofbotulinumtoxinareusually

quicktoappear.Althoughthereisgreatinterestinthe

cosmeticuseofthisdrug,AdamScheinbergdescribessome

ofitsclinicalapplications.

| VoLuMe 32 | NuMBer 2 | APriL 2009 31www.austral ianprescriber.com

studyshoweda22%(p=0.04)relativeincreaseintotal

mortalityintheintensiveglucoseloweringarm.Although

non-fatalmyocardialinfarctionsreduced,thereweremore

deathsfromcardiovascularcauses.Asaresultofsafety

concerns,theintensivetreatmentarmoftheACCoRDstudywas

stopped18monthsearly,atthreeandahalfyearsintothestudy.

neitherstudyhasshownthatintensiveglucoselowering

(HbA1clessthan6.5%)reducesmacrovasculareventswhen

comparedtostandardglucoselowering(HbA1cof7–7.5%)

inolderindividualswithalonghistoryofdiabetes.Rapid

andintensiveglucoseloweringcouldbeharmfulinthis

high-riskgroup.Todate,thereisnoclearexplanationforthe

highermortalityinACCoRD.nospecificdrugs(including

thiazolidinediones)havebeenimplicated,howeverdrug

therapywasnotrandomisedinthetrials.InACCoRD,severe

hypoglycaemiarequiringmedicalassistancewasthree

timesmorecommonintheintensivegroup(10.5%and3.5%

respectively).Itisplausiblethatseverehypoglycaemiamay

possiblyhavetriggeredfatalcardiaceventssuchasventricular

arrhythmiasparticularlyinthosewithcompromisedcardiac

functionandestablishedautonomicneuropathy.Anadverse

cardiovascularoutcomewasnotseenintheADVAnCEgroup

whohadgenerallybetterglycaemiccontrolatthestartofthe

studyandwhohadamoregradualloweringofglucoseduring

thestudy.Severehypoglycaemiawaslessfrequentthanin

ACCoRD.

Giventheratherunexpectedandconflictingfindingsin

thesestudies,howaggressiveshouldwebeinmanaging

hyperglycaemiainpeoplewithtype2diabetes?Thefindings

fromACCoRDandADVAnCEareimportantandshouldnot

bedismissed,howevertheydonotchangethetreatment

goalformostpatientswithtype2diabetes.TheHbA1ctarget

shouldremainatorlessthan7%becausethereisclearand

consistentevidenceofconsiderablebenefitinmicrovascular

outcomes.1,2,3,5Inyoungerpatientswitharecentdiagnosis

oftype2diabetesandnohistoryofcardiovasculardisease,a

lowerHbA1ctarget,evenbelow6.5%,shouldbeconsideredifit

canbereachedwithrelativeeasewithouttheneedformultiple

drugsandwithalowriskofseverehypoglycaemia.The'legacy

effect'seenintheUKPDSpost-trialperiodcertainlysupportsthis

strategy.However,inpatientswithalongdurationofdiabetes

andestablishedvasculardisease,tightglycaemiccontrolmay

notimprovethecardiovascularoutcomes.Rapidcorrectionof

hyperglycaemiaandexcessivelytightglycaemiccontrolappears

harmfulandshouldbeavoided.Inthesehigh-riskindividuals,

anHbA1ctargetof7–7.5%wouldbeappropriate.Thetargetcan

beadjustedforeachpatientwithregularassessmentforsevere

hypoglycaemicepisodesandhypoglycaemiaunawareness.

Finally,optimaltherapyforpeoplewithdiabetesincludes

addressingnotonlyglycaemiccontrol,butalsoothercoexisting

vascularriskfactorssuchashypertension,lipidabnormalities

andplateletdysfunction.

references1. TheDiabetesControlandComplicationsTrialResearch

Group.Theeffectofintensivetreatmentofdiabetesonthedevelopmentandprogressionoflong-termcomplicationsininsulin-dependentdiabetesmellitus.nEnglJMed1993;329:977-86.

2. UKProspectiveDiabetesStudy(UKPDS)Group.Intensiveblood-glucosecontrolwithsulphonylureasorinsulincomparedwithconventionaltreatmentandriskofcomplicationsinpatientswithtype2diabetes(UKPDS33).Lancet1998;352:837-53.

3. HolmanRR,PaulSK,BethelMA,MatthewsDR,neilHA.10-yearfollow-upofintensiveglucosecontrolintype2diabetes.nEnglJMed2008;359:1577-89.

4. TheActiontoControlCardiovascularRiskinDiabetesStudyGroup.Effectsofintensiveglucoseloweringintype2diabetes.nEnglJMed2008;358:2545-59.

5. TheADVAnCECollaborativeGroup.Intensivebloodglucosecontrolandvascularoutcomesinpatientswithtype2diabetes.nEnglJMed2008;358:2560-72.

Dr Park was a principal investigator for the ADVANCE Study.

LettersLetters,whichmaynotnecessarilybepublishedinfull,shouldberestrictedtonotmorethan250words.Whenrelevant,commentontheletterissoughtfromtheauthor.Duetoproductionschedules,itisnormallynotpossibletopublishlettersreceivedinresponsetomaterialappearinginaparticularissueearlierthanthesecondorthirdsubsequentissue.

Sulfur allergy

Regardingmypreviouscorrespondence(AustPrescr

2008;31:88–9),IsupposeonehastoaccepttheAmericanism

'sulfur',butthisappliestochemical'sulphur'asusedin

dandruffpreparations.Whensulphonamidepreparationsfirst

cameonthemarkettheywereconvenientlyreferredtoas

'sulfa'drugsandthereforeallergytothesedrugsis'sulfa'

allergyandnot'sulfurallergy'asyourarticlestated.

JohnWalker

Ear,noseandThroatSpecialist

Edgecliff,nSW


Prescribing in liver diseaseAndrew Sloss, Advanced Trainee in Internal Medicine, and Paul Kubler, Clinical Pharmacologist, Royal Brisbane Hospital, Brisbane

Summary

As the liver is responsible for the metabolism of many compounds, knowledge of a patient's hepatic function is required for the safe prescribing of many drugs. Assessing liver function by way of a patient history, examination and blood tests such as serum albumin and bilirubin, as well as prothrombin time, is recommended before prescribing some medications. Liver enzyme concentrations may be useful indicators of hepatocellular damage or enzyme induction. For drugs dependent on hepatic elimination, careful choice of compounds and their dose is prudent if liver function is significantly compromised. drug interactions must also be considered if a common metabolic pathway exists.

Keywords:drugprescribing,hepaticmetabolism.

(Aust Prescr 2009;32:32–5)

introductionThemetabolismofmanydrugsdependsonadequatehepatic

function.Drugswithanarrowtherapeuticrange(thatis,with

littledifferencebetweentoxicandtherapeuticdoses)runtherisk

ofaccumulatingandcausingtoxicityinpatientswithhepatic

disease.

Theliverreceivesadualbloodsupplywithabout20%of

bloodcomingfromthehepaticarteryand80%fromtheportal

circulation.Thebloodflowtotheliverisaround20–25%ofthe

totalcardiacoutput.Toxins,infectiousagents,medicationsand

seruminflammatorymediatorsmayresultinadiverserange

ofdiseaseprocessesleadingtolossofnormalhistological

architecture,reducedcellmassandlossofbloodflow.

Consequently,functionallivercapacitymaybelost.

Assessinghepaticfunctionisnecessarysothatappropriate

adjustmentofdrugdosecanbemade.However,thisisnot

alwaysstraightforwardasthereisnosingletestthatreliably

measuresliverfunction.

drug metabolism in the liver

Theliveristheprincipalorganofmetabolisminthebody

althoughothersitesareinvolvedsuchasthegutwall,kidney,

skinandlungs.Drugmetabolism,bymeansofenzyme

reactionsintheliver,isthebody'smainmethodofdeactivating

drugs.Drugmoleculesareconvertedintomorepolar

compounds,whichaidstheirelimination.Generally,metabolism

resultsinthelossofpharmacologicalactivitybecausetransport

tothesiteofactionislimitedduetoreducedlipidsolubility,or

becausethemoleculeisnolongerabletoattachtoitsreceptor

site.However,insomecircumstancesdrugsaremetabolised

tomoreactiveforms,forexampletheconversionofcodeineto

morphine,primidonetophenobarbitoneandamitriptylineto

nortriptyline.

ConcentrationsofenzymesinvolvedinbothphaseIandII

reactionsvarysignificantlybetweenindividualswithnormal

hepaticfunctionandevenmoresobetweenthehealthy

populationandthosewithhepaticimpairment.

Phase I reactions

Mostdrugsarelipophilicandthereforereadilycrossthecell

membraneoftheenterocyte.Intheprocessoflivermetabolism

thesesubstancesareconvertedintomorehydrophilic

compounds.Hydrolysis,oxidationandreductionarethe

threetypesofphaseIreactionsthatdothisintheliver.These

mainlyinvolveasubsetofmono-oxygenaseenzymescalled

thecytochromeP450system.Themostcommonreactionis

hydrolysiswhichinvolvestheadditionofamolecularoxygen

atomtoformahydroxylgroup,withtheotheroxygenatom

beingconvertedtowater(forexample,theconversionof

aspirintosalicylicacid).othertypesofphaseIreactionsinclude

oxidationviasolubleenzymessuchasalcoholdehydrogenase,

andreduction(forexamplenitrazepam).

Phase II reactions

Thesereactionsinvolveconjugationwhichistheattachmentof

moleculesnaturallypresentinthebodytoasuitablelinkinthe

drugmolecule.MostcompoundswillhaveundergoneaphaseI

reaction(forexample,additionofahydroxylgroup)before

theconjugationstepcanoccur.Themainconjugationreaction

involvesglucuronidation(forexamplewithmorphine),butother

conjugationmechanismsincludeacetylation(sulfonamides)or

theadditionofglycine(nicotinicacid)andsulfate(morphine).

naturalsubstancessuchasbilirubinandthyroxinemaybe

metabolisedbythesamepathways.Theresultingconjugate

moleculeisusuallypharmacologicallyinactiveandsubstantially

lesslipophilicthanitsprecursorsoitismorereadilyexcretedin

thebileorurine.


Insomecircumstancestheparentcompoundisaprodrugso

themetaboliteisactive(forexample,codeineisconverted

tomorphine).Acommoncauseofcapacitylimitedhepatic

metabolismistheamountoftheconjugateavailable.

Paracetamoloverdoseisanexampleofthissituation.With

normalprescribeddosesofparacetamol,thetoxicmetabolite

(n-acetyl-p-benzoquinoneimineornAPQI)isefficiently

detoxifiedbyconjugationwithglutathioneasaphaseIIreaction.

However,whenalargeamountofnAPQIisgenerated,the

totalquantityofavailableglutathionemaybeconsumedand

thedetoxifyingprocessbecomesoverwhelmed.Phenytoin

andwarfarinareotherdrugswherecapacitylimitedhepatic

metabolismcanoccur.

ExcretionFollowingmetabolism,compoundsaretheneitherexcreted

directlyintothebile,orre-enterthesystemiccirculationandare

excretedaspolarmetabolitesorconjugatesbythekidney.

Ifexcretedinthebile(mainlyglucuronidateddrugs),the

compoundentersthebiliaryductsystemandissecretedinto

theuppersmallintestine.Thenthroughouttheileum,these

conjugatedbilesalts(someofwhichhavedrugsattachedto

them)arereabsorbedandtransportedbacktotheliverviathe

portalcirculation.Thisisknownasenterohepaticcirculation.

Eachbilesaltisreusedapproximately20timesandoften

repeatedlyinthesamedigestivephase.Theimplicationsof

thisprocessarethatcompoundsmayreachhighhepatic

concentrationsresultinginsignificanthepatotoxicity.Some

drugsthatundergoenterohepaticcyclingtoasignificantextent

includecolchicine,phenytoin,leflunomideandtetracycline

antibiotics.

Systemic drug availability Afterdrugsareabsorbedfromthegut,aproportionofthe

dosemaybeeliminatedbytheliverbeforereachingthe

systemiccirculation.Thispre-systemicorfirstpasselimination

isdeterminedbythehepaticclearanceorextractionforthe

compound.Hepaticclearancedependsonthreefactors:

n extentofdrugbindingtobloodcomponentssuchasalbumin

n bloodflowtoactivemetaboliccells,whichisdependenton

thearchitectureintheliver

n functionalhepatocytes.

Thehepaticextractionratioofadrugwillindicateifits

eliminationisdependentonbloodflowandhepatocyte

function(highlyextracted)orhepatocytefunctionalone(poorly

extracted).Someexamplesofhighandlowextractiondrugsare

listedinTable1.

Hepatic conditions Chronicliverdiseaseismorepredictablyassociatedwith

impairedmetabolismofdrugsthanacuteliverdysfunction.

However,incasesofsevereacuteliverfailure,thecapacityto

metabolisethedrugmaybesignificantlyimpaired.

Inthechronicstate,cirrhosisofanyaetiology,viralhepatitisand

hepatomacandecreasedrugmetabolism.Inmoderatetosevere

liverdysfunction,ratesofdrugmetabolismmaybereducedby

asmuchas50%.Themechanismisthoughttobeduetospatial

separationofbloodfromthehepatocytebyfibrosisalongthe

hepaticsinusoids.

Theuseofcertaindrugsinpatientswithcirrhosisoccasionally

increasestheriskofhepaticdecompensation.Anexampleof

thisistheincreasedriskofhepaticencephalopathyinsome

patientswhoreceivepegylatedinterferonalfa-2aincombination

withribavirinforthetreatmentofchronicactivehepatitisrelated

tothehepatitisCvirus.Inaddition,co-infectionwithhepatitis

BorCvirus,evenintheabsenceofcirrhosis,increasestherisk

ofhepatotoxicityfromantiretroviraltherapyinpatientswith

coexistentHIVinfection.

Inthepresenceofchronicliverdisease,thereispotential

forchangingthesystemicavailabilityofhighextraction

drugs,therebyaffectingplasmaconcentrations.Apotential

consequenceofliverdiseaseisthedevelopmentof

portosystemicshuntsthatmaycarryadrugabsorbedfrom

thegutthroughthemesentericveinsdirectlyintothesystemic

circulation.Assuch,oraltreatmentwithhighhepaticclearance

drugssuchasmorphineorpropranololcanleadtohighplasma

concentrationsandanincreasedriskofadverseeffects.

Liverdamagecanalsoaffectdrugswithlowhepaticclearance.

Forinstance,theeffectofwarfarin,whichhasalowextraction

ratio,isincreasedduetothereducedproductionofvitaminK-

dependentclottingfactors.

Thepharmacokineticinteractionbetweenalcoholanddrugs

ismorecomplex.Anacuteingestionofalcoholmayinhibita

drug'smetabolismbycompetingwiththedrugforthesameset

ofmetabolisingenzymes.Conversely,hepaticenzymeinduction

mayoccurwithchronicexcessivealcoholingestionviaCYP2E1

resultinginincreasedclearanceofcertaindrugs(forexample

phenytoin,benzodiazepines).Aftertheseenzymeshavebeen

induced,theyremainsointheabsenceofalcoholforseveral

Table 1

Some examples of drugs with high and low hepatic

extraction

High extraction ratio Low extraction ratio

Antidepressants

Chlorpromazine/haloperidol

Calciumchannelblockers

Morphine

Glyceryltrinitrates

Levodopa

Propranolol

non-steroidalanti-inflammatorydrugs

Diazepam

Carbamazepine

Phenytoin

Warfarin


weeksaftercessationofdrinking.Inaddition,someenzymes

inducedbychronicalcoholconsumptiontransformsomedrugs

(forexampleparacetamol)intotoxiccompoundsthatcan

damagetheliver.

Inthepresenceofcholestaticjaundice,drugsandtheiractive

metabolitesthataredependentonbiliaryexcretionforclearance

willhaveimpairedelimination.Furtherimpairmentwilloccur

ifthecompoundisexcretedasaglucuronideandissubjectto

enterohepaticcirculation.

evaluating hepatic functionAclearpatienthistorywithrespecttoalcohol,illicitdruguse

andtoxicindustrialexposuremustberecorded.Themedication

listincludingsupplementssuchasiron,vitaminAandherbal

remediesisvital.Afamilyhistoryofdiseasessuchasalpha-1

antitrypsindeficiency,ironstoragediseases,porphyriasand

diabetesmellitusmayalertthephysiciantothepotentialfor

liverimpairment.

Itisalsoimportanttolookforsignsofacuteorchronicliver

diseasesuchasthepresenceofjaundice,spidernaevi,palmar

erythema,ascites,abdominaldistention,hepatomegaly,

splenomegalyandcaputmedusa.Ifthereisclinicalevidenceof

liverdisease,furtherinvestigationisrequired.Thisincludesliver

functiontestsandanultrasoundoftheabdomen.Aportalvein

Dopplerstudyisalsorecommendedtoassessforthepresence

ofportalhypertension.Aslowingorreversalofportalvein

bloodflowindicatesportalhypertensionwhichmayberelated

toeitherlivercirrhosisorportalveinthrombosis.

Inrenaldisease,serumcreatinineconcentrationandthe

glomerularfiltrationrateprovideareasonableguideto

drugdosagerequirements.Incontrast,thereisnosingle

testthatmeasuresliverfunctionsoareliablepredictionof

pharmacokineticsisnotpossible.Someevaluationofhepatic

functionispossiblebyassessingserumalbuminandbilirubin,

andprothrombintime.However,theseparametersarenot

directlyrelatedtodrugclearance.Althoughnotdirectly

correlatedwithliverdysfunction,elevatedliverenzymesmay

raisethesuspicionofhepaticimpairmentrequiringfurther

investigation.

TheChild-Turcottescorewasdesignedtoestimatethe

operativeriskofanalcoholicpatientwithcirrhosis.The

parametersusedincludeserumconcentrationsofbilirubin

andalbumin,prothrombintime,nutritionalstatusandascites.

Theseparametersweremodifiedtosubstitutedegreeof

encephalopathyfornutritionalstatusandthenbecameknown

astheChild-Pughclassification(seeTable2).1Thegrades

A,BandCmayalsobeausefulindicatorofanindividual's

abilitytoeffectivelymetaboliseadrug.Analternativemethod

forassessingliverdysfunctionistheModelforEnd-Stage

LiverDisease(MELD)score(www.unos.org/resources/

MeldPeldCalculator.asp).2Thismaybeamoreaccuratemethod

butislessaccessibletomostcliniciansbecauseitinvolves

calculatingthescore.

evaluating the drug in question

Ifadrugisdependentonhepaticelimination,thereareseveral

factorstoconsiderwhenprescribingforpatientswithliver

disease(seebox).Determiningthehepaticcontributionto

eliminationisparamountandthefollowinggeneralrulesshould

beconsidered.

Drugswithanarrowtherapeuticrangethatareextensively

metabolisedbytheliver(thatis,greaterthan20%oftheirtotal

elimination)shouldeitherbeavoidedaltogether(e.g.pethidine)

orusedwithextremecaution(e.g.morphine,theophylline)in

patientswithsignificantliverdisease.

Drugswithawidetherapeuticrangewhichalsoundergo

extensivehepaticmetabolismshouldbeusedwithcaution.In

particular,thedosingintervalshouldbeincreasedorthetotal

dosereduced(e.g.carvedilol).

Table 2

Child-Pugh classification 1

Parameter Points assigned = 1 Points assigned = 2 Points assigned = 3

Ascites Absent Slight Moderate

Bilirubin,micromol/L <11 11–45 >45

Albumin,g/L >35 28–35 <28

Prothrombintime–secondsovercontrolorInR

<4

<1.7

4–6

1.7–2.3

>6

>2.3

Encephalopathy none Grade1–2 Grade3–4

Totalscoreof5–6isgradeAorwellcompensateddisease(1and2yearsurvivalsare100%and85%)

Totalscoreof7–9isgradeBordiseasewithsignificantfunctionalcompromise(1and2yearsurvivalsare80%and60%)

Totalscoreof10–15isgradeCordecompensatedliverdisease(1and2yearsurvivalsare45%and35%)

Dependingonhepaticclearanceandthetherapeuticindexofthedrug,doseadjustmentsordrugavoidancemayberequiredingradesBorCchronicliverdisease.


Ifhepaticeliminationislimited(thatis,accountingforless

than20%oftotalelimination),thenthetherapeuticrangeof

thecompoundshouldbereviewed.Ifthedrughasawide

therapeuticindex,thenthelikelihoodofanadverseeffect

relatedtohepaticimpairmentislow.However,ifthedrughas

anarrowtherapeuticindex,thencautionshouldbeexercised

assignificanthepaticimpairmentmayhaveaclinicallyrelevant

effectonthepharmacokinetics(e.g.lamotrigine).

Ifgreaterthan90%ofthecompoundisexcretedunchangedin

theurine,thenhepaticimpairmentisunlikelytoplayasignificant

roleintheaccumulationofthedrugandthereforetoxicity.

ConclusionPrescribinginhepaticimpairmentislesswelldefinedwhen

comparedtoguidelinesforprescribinginrenalfailure.Hepatic

dysfunctionislessovertandmaynotbeapparentuntilmuch

ofthefunctioningliverislost.Knowledgeofthemetabolism

ofdrugseliminatedbytheliverisusefulalongwithclose

monitoringofthepatientforunwantedadverseeffectsrelated

topossibletoxicity.Whenintroducinglong-termtreatmentwith

adrugwithhighhepaticclearanceoranarrowtherapeutic

index,assessliverfunction(clinicallyandwithbaselineliver

functiontests).However,oncethedrugiscommencedroutine

monitoringiscostlyanditsroleunclearinmostcasesof

prescribinginpatientswithhepaticdysfunction.

references1. PughRn,Murray-LyonIM,DawsonJL,PietroniMC,

WilliamsR.Transectionoftheoesophagusforbleedingoesophagealvarices.BrJSurg1973;60:646-9.

2. MalinchocM,KamathPS,GordonFD,PeineCJ,RankJ,terBorgPC.Amodeltopredictpoorsurvivalinpatientsundergoingtransjugularintrahepaticportosystemicshunts.Hepatology2000;31:864-71.

Further reading

Feldman:Sleisenger&Fordtran'sGastrointestinalandliverdisease.8thed.Philadelphia(PA):Saunders;2006.

LeeWM.Drug-inducedhepatotoxicity.nEnglJMed2003;349:474-85.

RangHP,DaleMM,RitterJM,FlowerR.Pharmacology.6thed.Edinburgh:ChurchillLivingstone;2007.

SchenkerS,MartinRR,HoyumpaAM.Antecedentliverdiseaseanddrugtoxicity.JHepatol1999;31:1098-105.

WilkinsonGR.Drugmetabolismandvariabilityamongpatientsindrugresponse.nEnglJMed2005;352:2211-21.

BeggEJ.Instantclinicalpharmacology.2nded.Malden(MA):BlackwellPublishing;2008.

Conflict of interest: none declared

Self-test questionsThe following statements are either true or false

(answers on page 55)

1. Liverfunctiontestsareunreliableforcalculatingdrug

dosinginliverdisease.

2. Aswarfarinhasalowextractionratio,liverdamagedoes

notincreaseitseffects.

Factors to consider when prescribing drugs dependent on

hepatic elimination

n Ascertainhowmuchthedrugdependsonhepatic

metabolismforitseliminationfromthebody.

n Determinethedegreeofhepaticimpairmentusingthe

Child-Pughclassification(Table2),hepaticenzymelevels

andpossiblyanultrasoundoftheliverwithportalvein

Dopplerstudy.

n Ifthereisdoubtaboutthedegreeofhepaticimpairmentor

thedrughasanarrowtherapeuticindex(thatis,theupper

doserangeforefficacyisclosetothelowerconcentration

rangeoftoxicity),thenlowertherecommendedstarting

dosebyapproximately50%,andtitratetoeffectunder

carefulsupervision–'startlowandgoslow'.

n Determinepossibleinteractionsbetweenthenewdrug

andanydrugsthepatientisalreadytaking.

NPS rAdAr April 2009ThelatesteditionofNPS RADARreviews:

n desvenlafaxineformajordepressivedisorder

n pramipexoleforrestlesslegssyndrome

n valsartanandcombinationsofvalsartanwith

hydrochlorothiazideoramlodipineforhypertension

n zoledronicacidonce-yearlyinfusionforosteoporosis.

In BriefitemscovernewandrevisedPharmaceuticalBenefits

Schemelistingsforclopidogrelforacutecoronarysyndrome,

ziprasidoneforacutemaniainbipolardisorder,sublingual

desmopressinforprimarynocturnalenuresis,andrisedronate

forcorticosteroid-inducedosteoporosis.

nPSRADARisavailableatwww.npsradar.org.au


Managing pertussis in adultsJulie Marchant, Respiratory Fellow, University of Queensland, Department of Paediatrics, and Queensland Children’s Respiratory Centre, Royal Children’s Hospital, Brisbane; and Anne Chang, Senior Respiratory Consultant, Queensland Children’s Respiratory Centre, Royal Children’s Hospital, Brisbane, and Menzies School of Health Research, Charles Darwin University, Darwin

Summary

Pertussis or whooping cough is typically characterised by paroxysms of coughing with a whooping sound during inhalation. it is thought to be under-diagnosed generally. whooping cough is caused by Bordetella pertussis and is highly contagious. Although childhood immunisation has been effective in preventing the disease, outbreaks in Australia have been associated with waning immunity in older children and adolescents. the peak incidence of infection now occurs in people aged 15 or older. when given early in the illness, antibiotics can decrease the infectious period, but have no effect on the duration or severity of disease. Symptomatic treatment of cough has shown no clear benefit. Antibiotic prophylaxis of contacts is recommended for certain high-risk groups, but there is limited evidence of its effectiveness. Although infants remain the most at risk for severe, life-threatening disease, it is adolescent and adult booster immunisation which remains critical for prevention programs.

Keywords:antibiotics,vaccination,whoopingcough.

(Aust Prescr 2009;32:36–8)

introductionPertussis,alsoknownaswhoopingcough,isahighly

contagiousdiseasecausedbythebacteriumBordetella

pertussis.Itisgenerallythoughttobeunder-diagnosedand

remainstheleastwellcontrolledofallthevaccinepreventable

diseasestargetedbytheAustraliannationalImmunisation

Program.1Epidemicsoccurevery3–4years.Thisisdespite

immunisationcontinuingtoincrease,withmorethan90%of

one-year-oldsbeingfullyvaccinated.

Theliteraturesuggeststhatepidemicsresultfromwaning

immunityinlaterchildhoodandadolescence.Thepeak

incidenceofwhoopingcoughinAustraliaoccursinadolescents

andadultswithmorethan70%ofpertussisnotifications

occurringinpeopleolderthan15yearsin2004–05.Data

suggestthat10–35%ofsubacutecoughingillnessesinadults

areduetopertussisinfection.2Deathinindividualsolderthan

10yearsofageisrareandnon-immunisedinfantsremain

themostlikelygrouptohaveseverelife-threateningdisease

requiringhospitalisation.1

Clinical presentationTheclassicpresentationofpertussisisoneofspasmsof

coughingwithacharacteristicinspiratorywhoop.However,this

islesscommoninolderchildrenandadults.Thefirst1–2weeks

ofillnesswithB. pertussisresemblesotherupperrespiratory

tractinfections,withrunnynoseandmildcough.Thisis

followedbytheparoxysmalcoughingphaseinthesecondand

thirdweeks.

diagnosisAsclassicsymptomsofwhoopingcoughdonotusuallyexist

inadults,exposuretootherswithprolongedcoughisused

bysomeasanindicatorofpertussisinfection.Althoughless

frequentinadults,post-tussivevomitingmayalsoindicate

pertussis.ItisthereforeimportanttorememberB. pertussis

whenreviewingalladolescentsandadultswithachroniccough.

Anumberofinvestigationscanbeperformedtosupportthe

diagnosisofpertussis.Theseinclude:

n bacterialculture,polymerasechainreaction(PCR)or

immunofluorescenceassaysofnasopharyngealswabor

aspiratesamples

n serologicaltestingtodetectrisesinimmunoglobulin(Ig)Aor

IgGtitrestoB. pertussisantigens

n lymphocytecount(raisedcountsareanon-specificindicator

ofinfection).

Forpatientspresentingearly(withinthefirstthreeweeks)and

beforethestartofantibiotictherapy,PCR,immunofluorescence

andculturemaybeuseful.Forpatientswhopresentlater,

serologicaltesting−whichisreliantonanimmuneresponse−

isoftenmorehelpful.3Pertussis-specificIgAisonlyproduced

afternaturalinfection,whereasIgGriseswithvaccination

andnaturalinfection.WhileapositiveIgAtestconfirmsthe

diagnosisofpertussis,anegativeresultdoesnotexcludethe


possibilityofinfection.(Itisimportanttorememberthatasmall

proportionofthepopulationhasanIgAdeficiency.)Paired

samplesshowingrisingtitresofspecificIgAorIgGareamore

reliableindicationthatthepatienthaspertussis.

PCR-basedtestingisthemostsensitiveandspecificofall

investigations,particularlyearlyintheillness.Itissensitive

forlongerthancultureandislesslikelytobeaffectedby

antibiotictreatment(0%detectionviacultureaftersevendays

antibiotics).3Althoughdirectimmunofluorescenceishighly

specific,ithaslimitedsensitivity.Itsmainadvantageisspeed.

Antibiotic treatment Antibioticsarerecommendedintheinitialcatarrhalphaseof

infectionwhentheyareeffectiveineliminatingB. pertussis

fromthenasopharynxandreducingtheinfectiousperiod.

However,afterthreeweeksofcoughing,antibioticshaveno

measurableeffectonreducingtheinfectiousperiodandarenot

recommended.Patientsshouldavoidcontactwithsusceptible

individualsuntilatleastfivedaysofantibioticshavebeentaken.

Table1liststheprovenantimicrobialtherapiesin

nasopharyngealeradicationofB. pertussis.Erythromycin

hasbeencommonlyregardedasthetreatmentofchoicefor

pertussisinfections.A14-dayerythromycincourseisoften

recommended,althoughstudieshaveshownsimilarefficacy

withaseven-dayregimen.4

Thenewermacrolides,suchasclarithromycinandazithromycin,

havereplacederythromycinasthestandardtreatment.

(However,thereisnotenoughclinicalevidencetorecommend

roxithromycinforpertussisinfection.)Thenewermacrolides

havefewergastrointestinaladverseeffectsandreachhigher

concentrationsinrespiratorysecretions.Thisimprovedsafety

profileisofparticularimportanceinatherapeuticregimen

aimedateradicationoforganismsratherthanimprovement

ofsymptoms.Studieshaveshownthatpatientsaremore

compliantwhentakingthenewermacrolidescomparedwith

erythromycin.Trimethoprimwithsulfamethoxazolecanbeused

asanalternativetomacrolidesifnecessary,butisnotthefirst

choiceoftherapy.

Symptomatic treatmentACochranereviewfoundthatsomesymptomatictreatmentsfor

thecoughassociatedwithpertussishadnoclearbenefits.5The

treatmentsreviewedincludedantihistamines,dexamethasone,

salbutamolandpertussisimmunoglobulin.Itispossiblethat

immunoglobulinofferssomeimprovementinmeannumberof

whoops,butfurtherwell-designedgoodqualitytrialsneedtobe

developedtodeterminethis.

Managing household contactsB. pertussisishighlycontagiousandasignificantproportionof

contactsbecomeinfected(70–100%ofhouseholdmembers).

Theincubationperiodistypically7–10days(rangeof4–21

days).Althoughthereisinsufficientevidencethatantibiotic

prophylaxisofclosecontactsreducesthenumberofnewcases

orimprovesclinicalsymptoms4,itisrecommendedprimarily

becauseofthehighrisksofmorbidityandmortalityinnon-

immunisedinfants(seebox).

Itissuggestedthatprophylaxisbegivenassoonaspossible,

butwithinthreeweeksofsymptomonsetintheinfected

contact.Thedoseanddurationofantibioticsforprophylaxisare

thesameasfortreatment(seeTable1).

Asthreeormoreinjectionsarerequiredtoconferprotection,

infantvaccinationisnothelpfulincontrollingapertussis

outbreak.1However,unvaccinatedcontactsagedeightyearsor

oldercanbeofferedadiphtheria,tetanusandacellularpertussis

vaccineandyoungercontactscanbegivenacatch-upcourse.

Table 1

effective antibiotic treatment for pertussis

drug Adult dose daily frequency duration

clarithromycin* 500mg(7.5mg/kgupto500mg)

twice 7days

erythromycin 250mg(10mg/kgupto250mg)

fourtimes 7days

azithromycin*† 10mg/kg(upto500mg) once 3days

azithromycin* day1:500mgfirstday(10mg/kgupto500mg)

days2–5:250mg(5mg/kgupto250mg)

once 5days

trimethoprimwithsulfamethoxazole

160+800mg(4+20mg/kgupto160+800mg)

twice 7days

* bestregimensformicrobiologicalclearancewithfeweradverseeffects4

† thisregimenisdocumentedinaCochranesystematicreview4althoughnotinAustralianantibioticguidelines6


important role of immunisation in adultsImmunisationremainsthemainstayofpreventionof

B. pertussisinfection.ThecurrentAustralianimmunisation

schedule1recommendsthatachildformulationofadiphtheria,

tetanusandacellularpertussisvaccineisgivenattwo,four

andsixmonthsofagewithaboosteratfouryears.Another

boosterisrecommendedat12–17yearsofageusingthe

adolescent/adultformulationwhichhasalowerconcentration

ofpertussisantigensthanchildhoodvaccinations.Itisvitalto

rememberthatadultandadolescentvaccinationisaneffective

meansofcontrollingB. pertussisandwillhavepositivehealth

ramificationswithinthecommunity.1Therearenodataonthe

durationofimmunityfollowingvaccinationinteenagers,but

thisisunlikelytoberequiredatintervalslessthan10years.

Asingleboosterdoseisrecommendedforadultsplanninga

pregnancyorforparentsofanewinfant,preferablybefore

hospitaldischarge.otherhouseholdmemberssuchas

grandparentsorcarersshouldalsobevaccinated.Likewise,

adultsworkinginhealthcareorchildcareshouldbegivena

boostervaccination.Pertussisboostervaccinationcanalsobe

consideredalongwitharoutinediphtheriaandtetanusbooster

atage50.

ConclusionWhenB. pertussisisdiagnosedearlyintheillness,antibiotics

candecreasetheinfectiousperiod,buthavenoeffecton

thedurationorseverityofdisease.Antibioticprophylaxis

withmacrolides,suchasclarithromycinandazithromycin,is

recommendedforcertainhigh-riskcontacts.Symptomatic

treatmentofcoughhasnotbeenproventobesignificantly

helpfulindecreasingB. pertussiscough.Adolescentandadult

boosterimmunisationremainscriticalforpreventingdisease

outbreaks.

references1. nationalHealthandMedicalResearchCouncil.Pertussis.

In:TheAustralianImmunisationHandbook.9thed.Canberra:DepartmentofHealthandAgeing;2008.p.227-39.

2. KapaskelisAM,VouloumanouEK,RafailidisPI,HatzopoulouP,nikitaD,FalagasME.HighprevalenceofantibodytitersagainstBordetella pertussisinanadultpopulationwithprolongedcough.RespirMed2008;102:1586-91.

3. WolfJ,DaleyAJ.Microbiologicalaspectsofbacteriallowerrespiratorytractillnessinchildren:atypicalpathogens.PaediatrRespirRev2007;8:212-9.

4. AltunaijiS,KukuruzovicR,Curtisn,MassieJ.Antibioticsforwhoopingcough(pertussis).CochraneDatabaseofSystematicReviews2007,Issue3.Art.no.:CD004404.DoI:10.1002/14651858.CD004404.pub3.

5. PillayV,SwinglerG.Symptomatictreatmentofthecoughinwhoopingcough.CochraneDatabaseofSystematicReviews2003;CD003257.[withdrawn,asauthorscouldnotupdatethereview]

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

Dr Marchant is supported by the Royal Children's Hospital

Foundation, Brisbane, and the TSANZ/Allen and Hanbury's

Paediatric Respiratory Medicine Career Development Fellowship.

Dr Chang is supported by the Royal Children's Hospital

Foundation, Brisbane, and a Practitioner Fellowship from the

National Health and Medical Research Council.



3. PCRtestingisthemostsensitivemethodtodetect

Bordetella pertussisinnasopharyngealsamples.

4. Macrolidesarerecommendedforpertussisinfectionifthe

patienthashadachroniccoughformorethanfourweeks.

Antibiotic prophylaxis for 'high-risk' contacts of pertussis

cases1

n Womenintheirlastmonthofpregnancy,irrespectiveof

vaccinationstatus

n Membersofahouseholdwhichincludesachildlessthan

2yearswhoisnotfullyvaccinated*

n Childrenandadultswhoattendachildcarefacilitywhere

childrenunder2yearsarenotfullyvaccinated

n Healthcareworkersandbabies(ifexposedfor>1hour)in

amaternitywardornewbornnursery

* Fullyvaccinated=threeeffectivedosesofpertussis

vaccinegivenatleastfourweeksapart1

Your questions to the PBAC Australian Prescriber readersareinvitedtowriteinwith

theirquestionsaboutdecisionsofthePharmaceutical

BenefitsAdvisoryCommittee.Thesegment'Yourquestions

tothePBAC'publishesselectedquestionsfromreaders,and

answersfromtheCommitteeitself.Questionsmayaddress

issuessuchasregulatorydecisions,pharmaceuticalbenefits

listings,withdrawalofadrugfromthemarketandAuthority

prescriptions.Lettersandresponsesmaybeeditedbefore

publication.


Clinical use of botulinum toxin Adam Scheinberg, Statewide Medical Director, Victorian Paediatric Rehabilitation Service, Royal Children's Hospital, Melbourne

Summary

Botulinum neurotoxin type A inhibits the release of acetylcholine from cholinergic motor and autonomic nerves. intramuscular injection leads to muscle relaxation, and intradermal injection reduces sweat gland secretion. the recommended dose depends on which preparation of botulinum toxin type A is used and its dilution, the size of the muscle or gland being injected, and the method used to localise the injection site. repeat doses are usually required as the effect of the toxin wears off after 3–4 months. therapy including stretching, splinting and strengthening may prolong the effect of muscle relaxation. realistic goal setting before treatment is vital.

Keywords:musclespasticity,neurotoxins.

(Aust Prescr 2009;32:39–42)

introductionBotulinumneurotoxinwasfirstidentifiedin1897andisa

productofClostridium botulinum,ananaerobicbacterium

whichcausesbotulismfoodpoisoning.Duringthe1940s,

botulinumtoxintypeAwaspurifiedandisolatedina

crystallineform.In1989theUSFoodandDrugAdministration

(FDA)approvedbotulinumtoxintypeAforthetreatmentof

strabismus,blepharospasmandhemifacialspasm.Ithassince

beenapprovedforcervicaldystonia,hyperhidrosisandcosmetic

use.Therearenowover30conditionsinwhichbotulinumtoxin

typeAhasbeenreportedtobeofbenefit.

Mechanism of actionBotulinumneurotoxintypeAblocksneuromuscularconduction

byinhibitingthereleaseofacetylcholinefrommotoror

autonomicnerveterminals.Injectedintramuscularly,itproduces

alocalisedchemicaldenervationofthemuscle,resulting

inlocalisedmuscleweaknessorparalysis.Wheninjected

intradermally,thetoxinproduceschemicaldenervationofsweat

glandsandreduceslocalsweating.Thedenervationisreversible.

nerveendingsrecoveroverthreeormoremonthsduringwhich

muscletoneincreasesandglandularsecretionrecommences.

Botulinum toxin products TherearetwodifferentpreparationsofthetypeAtoxin

commerciallyavailableinAustralia;theseareapurified

neurotoxincomplex(Botox)andahaemagglutinincomplex

(Dysport).Theyaredispensedinvialsasavacuumdriedpowder

whichisreconstitutedwithsterilenormalsaline.onceopened,

vialsshouldbestoredintherefrigeratorandusedwithin24

hours.Thepotenciesofbothpreparationsareexpressedas

unitsofactivity,whichrelatetothemedianlethaldoseinmice.

Thebiologicalactivityforeachpreparationisunique,soone

unitoftheneurotoxincomplexisnotequaltooneunitofthe

haemagglutinincomplex.Asthepotencyandsafetyofthese

productsdiffer,dosefindingonacasebycasebasismaybe

necessaryifbothproductsareusedinthesamepatient.

AnotherbotulinumtoxintypeAproduct(Xeomin)isformulated

withoutcomplexingproteinsandhasbeenapprovedforusein

severalEuropeancountriesbutnotinAustralia.Ithasrecently

beenshowntobeofbenefitforfocaldystoniaandspasticity.

BotulinumtoxintypeB(Myobloc)israrelyusedinAustralia.

Ithasbeenreportedtobebeneficialinadultswithcervical

dystoniawhohavedevelopedresistancetobotulinumtoxin

typeA.1

Clinical indicationsConsideringwhethertostartapatientonbotulinumtoxin

dependsonbalancingtherisksoftreatmentagainstthe

potentialimprovementsinactiveandpassivefunction,levelof

pain,secondaryeffectsofunwantedmuscleoveractivityand

qualityoflife.InAustralia,specialistmedicalpractitionerssuch

asophthalmologists,neurologists,surgeons,rehabilitation

specialistsandpaediatriciansmayaccessthegovernment's

Section100scheme.Thisprovidesreimbursementforthecost

ofbotulinumtoxintypeAforthefollowingconditions:

n blepharospasm

n spasmodictorticollis

n dynamicequinusfootdeformityassociatedwithcerebral

palsyinchildrentwoyearsorover

n spasticityfollowingstroke.

Botoxisalsoapprovedforthetreatmentofstrabismusin

childrenandadults,focalspasticityofthelimbs,primary

hyperhidrosisoftheaxillae,andspasmodicdysphonia.Botox

andDysportarebothapprovedforthetreatmentofglabellar

foreheadlines.

BlepharospasmInblepharospasmandhemifacialspasm,botulinumtoxintypeA

isadministeredbysubcutaneousinjectionmediallyandlaterally

intothejunctionbetweenthepreseptalandorbitalpartsofthe


upperandlowerorbicularisocculimusclesoftheeyes.Risks

includecornealexposureduetoreducedblinkingandacute

angleclosureglaucomaduetotheanticholinergiceffect.2

Cervical dystonia (spasmodic torticollis) 3

Patientswithcervicaldystoniahaveabnormaltwistingor

sustainedposturesofthehead,neckandshoulders.Botulinum

toxintypeAisinjectedintotheneckmusclestoreducepainand

headrotation.Dependingontheheadposition,acombination

ofthesternocleidomastoid,splenius,paravertebral,scaleneand

trapeziusmusclesmaybeinjected.Morethan50%ofpatients

willhavesignificantimprovementsinsymptoms.Dysphagiais

themostcommonlyreportedadverseevent,whichinsevere

casesmayleadtoaspirationpneumonia.

Focal hand dystonia (writer's cramp) 4

Focalhanddystoniaisatask-specificdystoniathatmayaffect

peoplewhoperformrepetitivemovementsforsustained

periods.Thegoaloftreatmentistoreducethedystonicposture

andimprovefunction.Theeffectmaynotbeasgoodwhen

thegoalisimprovementofcomplexfinemotortasks,such

asoccurswithmusicians.Electromyographyorelectrical

stimulationisusedtoguideinjections,andcorrectmuscle

selectionisvitalforagoodoutcome.

Hyperhidrosis 5

Hyperhidrosisisaconditionofexcessivesweatingoftheaxillae,

palmsandsolesofthefeet.Causesofsecondaryhyperhidrosis

suchashyperthyroidismshouldbeexcludedbeforestarting

treatment.BotulinumtoxintypeAisinjectedintradermallyand

adverseeventsarerare.

Spasmodic dysphonia (focal laryngeal dystonia) 6

Vocalcordspasm,typicallyadductormusclespasm,may

interferewithcommunication,andrespondstobotulinumtoxin

typeAinjections.Spasmoftheabductormusclealsooccursbut

maybelessresponsivetobotulinumtoxintypeAtreatment.

Laryngoscopyandelectromyographyareneededfordiagnostic

evaluationandinjection.Injectionoflaryngealmusclesshould

beavoidedinpatientsrequiringageneralanaestheticfor

electivesurgery.

Focal spasticitySpasticityisonecomponentoftheuppermotorneurone

syndromeandisdefinedasavelocitydependentincreasein

muscletone.BotulinumtoxintypeAisoftenusedformanaging

hypertonicityinconjunctionwithothertreatmentssuchas

splinting,stretchingandstrengtheningantagonistmuscles.

ChildrenIdeally,childrenreceivingtreatmentshouldhaveaccess

toamultidisciplinaryclinicwhereotherinterventionsfor

spasticitycanbeconsidered.Thelargestgroupofchildren

receivingbotulinumtoxintypeAforspasticityarethosewith

cerebralpalsy.Treatmenthasbeenshowntobeeffectivein

reducingequinusgaitpatterninthesechildren(injections

tocalf,hamstringandhipflexormuscles),improvingupper

limbfunction(injectionstoshoulder,elbow,wristandfinger

flexormuscles),reducingpain(injectionstohipadductors)

andreducingtheneedfororthopaedicsurgery.7,8.9,10Children

withdystoniamayalsoimprovewithbotulinumtoxintypeA

treatment,althoughmuscleselectionanddosingisclinically

challenging.

Childrenwithspasticityandminimalcontracture,whohave

functionalorcaregoals,maybenefitfromtreatmentasearly

as12–18months.Ingeneral,botulinumtoxintypeAisless

effective,particularlyinthelowerlimbs,beyondthefirstdecade.

AdultsSpasticityinadultsisseenmostcommonlyafteracquired

braininjury,stroke,multiplesclerosisandspinalcordinjury.

Settinggoalsbeforetreatment,alongwiththepatternof

affectedmusclegroupsandthetoneabnormality,determines

muscleselection.EarlytreatmentwithbotulinumtoxintypeA

afterstrokehasbeenshowntoreducedisabilityandcarer

burden.11,12

Cosmetic use

BotulinumtoxintypeAisusedfortreatingglabellarlines

(corrugatororprocerusmuscles),crow'sfeet(lateralfibresof

orbicularisoculimuscle),andforeheadlines(frontalismuscle).

Other uses

BotulinumtoxintypeAhasalsobeenshowntobeofclinical

benefitforpatientswithParkinson'sdiseasebyreducingjaw

tremorandexcesssalivation.13Ithasbeenusedtorelieve

sensoryandmotorsymptomsassociatedwithtics,Tourette's

syndromeandrestlesslegssyndrome,andforpatientswith

migraine,droolingorneurogenicbladder.

AdministrationBeforeinjectionthetoxinisdiluted,usuallywith0.5−5mLof

salinepervial.Theextentofdilutionaffectsthespreadofthe

toxinonceinjectedandwillvarydependingonanumberof

factorsincluding:

n theconditionbeingtreated

n thesizeofthemusclebeinginjected

n theriskofspreadbeyondthemuscle

n theeffectofpreviousinjectioncourses

n themethodsusedtodeterminetheinjectionsite.

Thereareseveralwaystolocalisethemuscleorglandtobe

injected.Palpationandanatomicallandmarksarenolonger

consideredbestpracticefortreatmentoffocalspasticity.


Electricalstimulation,electromyography,ultrasoundora

combinationofallthree,aregenerallyusedforlocalisationof

themuscleandneuromuscularreceptors.

Duringtheprocedure,whichmayinvolvemultipleinjections,the

patientneedstoremainrelativelystill.Childrenshouldreceive

analgesiaandsedation.InAustralia,severalcentresperform

injectionswhenthechildisundergeneralanaesthesia,while

othersuseconscioussedation(eitherinhalednitrousoxideor

intranasalfentanyl).Topicalanaestheticgelmaybesufficientfor

adolescentandadultpatients.

Researchhassuggestedthatspecificuptakeofbotulinumtoxin

typeAintothenerveterminal,withlesssystemicspread,may

beimprovedbyactivatingthemusclessoonaftertheinjections.

Thiscanbeachievedbypassivelymovingtheinjectedlimb,

usingelectricalstimulation,orbyhavingthepatientexercise

thelimb.

SafetyAdverseeventstendtooccur1–2weeksafterinjectionand

areusuallytransient.Localisedpain,tendernessorbruising

maybeassociatedwiththeinjection.Rareeventsinclude

skinrash,pruritusandallergicreaction.Childrensometimes

experiencetransientincontinence,localweaknessorinrare

casesmoregeneralisedweakness.Localweaknessrepresents

theexpectedpharmacologicalactionofbotulinumtoxintypeA,

butmaybeinexcesstowhatisdesiredclinically.overdosemay

presentwithsymptomsofbotulism,includingptosis,diplopia,

deteriorationinswallowingandspeech,generalisedweakness

andrespiratoryfailure.

Therehavebeenreportsofdeathsinchildrenandadults

followingtreatmentwithbotulinumtoxintypeA.Someofthe

patientshadmajorriskfactorsincludingsignificantswallowing

problems,seizuresandcardiovasculardisease.Cautionis

recommendedinchildrenandadultswhoaresignificantly

debilitatedorhaveriskfactorssuchasseveredysphagia.

BotulinumtoxintypeAiscontraindicatedinpatientswith

knownhypersensitivityandinpatientswithmyastheniagravis,

Eaton-Lambertsyndromeorwhoarepregnant(pregnancy

categoryB3).Itisalsocontraindicatedifthereisinfectionatthe

proposedsiteofinjection.BotulinumtoxintypeAmayinteract

withmedicationsthataffectneuromusculartransmission

includingaminoglycosidesorcurare-likecompounds.The

potentialforinteractionwiththesedrugsmaybeupto

3–6monthsafteradministrationofbotulinumtoxin.Toxin

preparationscontainalbumin,whichcarriesatheoreticalrisk

fortransmissionofviralorpriondiseases.

Lack of response

Explanationsmayincludeinadequatedose,inappropriate

muscleselectionorinjectionsite,underlyingmusclechanges

(suchascontracture),orneutralisingantibodiestothetoxin.As

botulinumtoxintypeAisderivedfromforeignproteins,there

ispotentialforthebodytomountanimmuneresponsewhich

mayreducethetherapeuticbenefitoftreatment.Toavoidthis,

botulinumtoxintypeAinjectionsshouldbegivenatleastthree

monthsapart.

Conclusion

Botulinumtoxinisusedforanincreasinglywiderangeof

clinicalproblems,principallyrelatedtomuscleorsweatgland

overactivity.Theeffectistemporary,lasting3–6months.

Adjunctivetherapiessuchasstretchingorstrengtheningof

antagonistmusclesmayallowformoresustainedfunctional

improvementsafterthebiologicaleffectofthebotulinum

toxinhasceased.Adverseeffectsareuncommonandusually

temporary,althoughmoreseriouseffectsincludinggeneralised

weaknessanddysphagiahavebeenreported.

references1. CostaJ,Espirito-SantoC,BorgesA,FerreiraJJ,CoelhoM,

MooreP,etal.BotulinumtoxintypeBforcervicaldystonia.CochraneDatabaseofSystematicReviews2004,Issue4.Art.no.:CD004315.DoI:10.1002/14651858.CD004315.pub2.

2. KenneyC,JankovicJ.Botulinumtoxininthetreatmentofblepharospasmandhemifacialspasm.JneuralTransm2008;115:585-91.

3. ComellaCL,ThompsonPD.Treatmentofcervicaldystoniawithbotulinumtoxins.EurJneurol2006;13Suppl1:16-20.

4. KarpBI.Botulinumtoxintreatmentofoccupationalandfocalhanddystonia.MovDisord2004;19Suppl8:S116-9.

5. BhidayasiriR,TruongDD.Evidenceforeffectivenessofbotulinumtoxinforhyperhidrosis.JneuralTransm2008;115:641-5.

6. WattsC,nyeC,WhurrR.Botulinumtoxinfortreatingspasmodicdysphonia(laryngealdystonia):asystematicCochranereview.ClinRehabil2006;20:112-22.

7. MallV,HeinenF,SiebelA,BertramC,HafkemeyerU,WisselJ,etal.TreatmentofadductorspasticitywithBTX-AinchildrenwithCP:arandomized,double-blind,placebo-controlledstudy.DevMedChildneurol2006;48:10-3.

8. WasiakJ,HoareB,WallenM.BotulinumtoxinAasanadjuncttotreatmentinthemanagementoftheupperlimbinchildrenwithspasticcerebralpalsy.CochraneDatabaseofSystematicReviews2004,Issue4.Art.no.:CD003469.DoI:10.1002/14651858.CD003469.pub3.

9. MolenaersG,DesloovereK,FabryG,DeCockP.TheeffectsofquantitativegaitassessmentandbotulinumtoxinAonmusculoskeletalsurgeryinchildrenwithcerebralpalsy.JBoneJointSurgAm2006;88:161-70.

10. o'FlahertyS,WaughMC.Pharmacologicmanagementofthespasticanddystonicupperlimbinchildrenwithcerebralpalsy.HandClin2003;19:585-9.

11. vanKuijkAA,GeurtsAC,BevaartBJ,vanLimbeekJ.Treatmentofupperextremityspasticityinstrokepatientsbyfocalneuronalorneuromuscularblockade:asystematicreviewoftheliterature.JRehabilMed2002;34:51-61.


12. GordonMF,BrashearA,ElovicE,KassiciehD,MarciniakC,LiuJ,etal;BoToXPoststrokeSpasticityStudyGroup.RepeateddosingofbotulinumtoxintypeAforupperlimbspasticityfollowingstroke.neurology2004;63:1971-3.

13. SheffieldJK,JankovicJ.Botulinumtoxininthetreatmentoftremors,dystonias,sialorrheaandothersymptomsassociatedwithParkinson'sdisease.ExpertRevneurother2007;7:637-47.

Further readingAdversereactionswithbotulinumtoxinA(Botox,Dysport).AustAdvDrugReactBull2009;28:2.www.tga.gov.au/adr/aadrb/aadr0902.htm[cited2009Mar13]

Worldwideeducationandawarenessformovementdisorders.www.wemove.org[cited2009Mar13]

AmericanAcademyforcerebralpalsyanddevelopmentalmedicine.www.aacpdm.org[cited2009Mar13]

HeinenF,MolenaersG,FiarhurstC,CarrLJ,DesloovereK,ChaleatValayerE,etal.Europeanconsensustable2006onbotulinumtoxinforchildrenwithcerebralpalsy.EurJPaediatrneurol2006;10:215-25.

ComellaCL,PullmanSL.Botulinumtoxinsinneurologicaldisease.Musclenerve2004;29:628-44.

Both Allergan and Ipsen have supported research conducted in

Dr Scheinberg's department and in which he was a researcher.



5. ThetwobotulinumtoxintypeAformulationsavailablein

Australiaarebioequivalent.

6. Droopingeyelidsmayindicateanoverdoseofbotulinum

toxin.

Book review

interactionslistedintheoldtablewerenotclinicallysignificant,

althoughit'sworthheedingthewarningonpage1thatnotall

interactionsarelistedandthatoneshouldrefertotheAustralian

MedicinesHandbookorhttp://medicine.iupui.edu/flockhartfor

moreinformation.

Themostusefultablesintheneweditionarethe'switching'

table(forcheckingantidepressant-freeintervalswhenchanging

antidepressants,pages112−3)andthetablethatdifferentiates

featuresofselectiveserotoninreuptakeinhibitor(SSRI)

discontinuationsyndrome,adverseeffectsofSSRIs,symptoms

ofdepression,andserotonintoxicity(pages4−5).Distinguishing

betweentheseconditionscanbequitetrickyingeneralpractice,

wherepatientsoftenstoptheirmedicationswithouttellingtheir

doctor.

AdrawbackofthePsychotropicGuidelinesisthatitgives

diagnosticadviceinsomesections,butthesecommentscannot

replaceafullmentalhealthassessmentinallpatientsbefore

prescribing.Similarly,whilethereisadviceaboutmedication

adherenceanddurationoftherapy,thereislimitedadviceon

frequencyoffollow-up,andnoreferencetomonitoringtools.

Thesearenotmajoromissionsforaguidethatispredominantly

aboutprescribingmedications,butprescribersshouldnotrely

ontheTherapeuticGuidelinesforassessmentandmanagement

(asopposedtosimplyprescribing)advice.

therapeutic Guidelines: Psychotropic. Version 6.

Melbourne:TherapeuticGuidelinesLimited;2008.325pages.Price$39,students$30,pluspostage.AlsoavailableinelectronicformataseTGcomplete.

Caroline Johnson, General Practitioner, Department of General Practice, University of MelbourneManygeneralpractitionershaveafullsetofTherapeutic

Guidelinesontheirshelforcomputer.Withaveritablerainbow

ofusefulguides(therearenow14intheseries),thechallenge

forageneralististoensurethepearlsofwisdomtheycontain

areusedregularlyandefficiently.Sowhenaneweditionofa

guidelinearrives,myapproachistoscanthroughthecontents

andthetablesintheappendix,beforecheckingoutthechapters

onconditionsIencounterfrequentlyinmypractice.

onreviewingthelatesteditionofPsychotropicGuidelines,it

tookmeawhiletodeterminewhichsectionshadundergone

the'majorrevision'promisedontheTherapeuticGuidelines

website.Therehasbeenareorganisationofchapters,withthe

useful'Gettingtoknowyourpsychotropicdrugs'stillprominent

intheguide.Thelargetableinpreviouseditionslistingpotential

druginteractionshasbeenomitted,soonehastolookup

individualmedicationsforthisinformation.Presumablymany


Abnormallaboratoryresults

Pitfalls in interpreting laboratory results Pat Phillips, Senior Director, Endocrinology Unit, The Queen Elizabeth Hospital, Adelaide

Summary

the results of laboratory tests are affected by the collection and handling of the specimen, the particular laboratory and the method of analysis. they are also affected by variability within the individual and within the laboratory. interpretation at one point in time should consider the position of the measurement within the laboratory reference range appropriate for the sample and the person being tested. interpreting results over time should consider the likely variability of the measurement and the level of certainty required to identify a true change or absence of change. the more variable the measurement and the higher the required level of certainty, the larger the change between measurements needs to be before it can be considered clinically significant.

Keywords:diagnostictests.

(Aust Prescr 2009;32:43–6)

introductionHealthprofessionalsmayfindithardtogetclinicallyuseful

informationfromthebarrageoffigures,ranges,starsand

commentsinlaboratoryresults.Someknowledgeaboutthe

accuracyoflaboratoryresultscanhelptosortoutimportant

clinicalsignalsfromthebackground'noise'.Thelaboratorydoes

notknowallthepatient'sdetails.Cliniciansshouldconsidertest

resultsinthecontextoftheclinicalpresentationandnotrely

completelyonthelaboratory'sinterpretation.

reference rangesQuotedreferencerangesdependonthemethodusedin

thelaboratory,andthepopulationfromwhichthereference

rangewasderived.Theresultsfromonemethodmaybe

systematicallydifferentfromthoseofanotherandthereforethe

referencerangeswillbedifferent.

Somelaboratoriesgivetherangequotedbythemanufacturer

ofthetestorderivedfromaneasilyaccessiblepopulationsuch

asblooddonors.othersgiverangesintermsofage,sexor

biologicalphase.Forexample,therangesquotedforfemale

sexhormonesarerelatedtopre-andpost-menopausalstatus

andthephaseofmenstrualcycle.Someimportantbiological

influences,suchasseasonaleffectson25-hydroxyvitaminD,

areoftennotincludedinthereferenceranges.Perhapsthisis

becauseuserswouldfindithardertointerpretresultsifthe

referencerangeswerechangingallthetimeandbecauseofthe

logisticsandlaboratoryworkloadneededtoderivesuchspecific

referenceranges.

Theidealreferencerangewouldrelatetotheindividualbeing

testedwhilehealthy,atthesameage,biologicalphaseandin

thesameseason.Clearlythisisnotpossible,butsometimes

onegetsinsightsfromlookingbackthroughpreviousresults

(ideallyreportedbythesamelaboratoryusingthesame

method).

Bytradition,laboratoriesquoteareferencerangeincluding95%

ofthereferencepopulation.Ifresultsarenormallydistributed,

thisincludesresultswithinapproximatelytwostandard

deviationsaboveandtwostandarddeviationsbelowthemean

value.Thereferencerangethereforecoversfourstandard

deviations.Someresultsvarysomuchwithinthepopulation

thatthelaboratorymayquoteareferencerangethatincludesa

smallerproportionofthepopulation.Forexample,thereference

rangecommonlyquotedforseruminsulinmayonlyinclude

resultswithinonestandarddeviationaboveandonestandard

deviationbelowthemeanvalue.Thisincludes68%ofthe

referencepopulation.Inthiscase,16%ofnormalpeoplewill

have'abnormal'highinsulinand16%willhave'abnormal'low

insulinaccordingtothequotedreferencerange.Seruminsulin

isthereforenotausefultestforassessing'insulinresistance'.

Resultshavetobeinterpretedintermsoftheparticular

laboratoryreferencerange.Whenmonitoringresultsovertime,

cliniciansalsoneedtobeawarethatdifferentlaboratorieswill

havedifferentreferenceranges.

Asreferencerangesarepopulation-based,apatientmighthave

aresultnearthetoporbottomofthenormalrange.Clinically

significantchangescouldthenoccur,withouttheresultsmoving

outofthepopulationreferencerange.Forexample,ifanelderly

patient'splasmacreatinineconcentrationisusuallynearthe

bottomofthereferencerangebutthenrisestotheupperendof

thatrange,thepatientmayhavehadasignificantdeterioration

inrenalfunction.Similarconsiderationsapplytoahaemoglobin

concentrationfallingfromahighnormaltoalownormalvalue.


Specimen collection and handlingLaboratoryresultscanbeaffectedbytheproceduresfor

specimencollectionandhandling(Table1).1Ifaresultisa

surprise,checkthepatient'snameanddateofbirthonthe

resultreport.Youcanalsocontactthelaboratoryandaskifthe

specimenlookednormalandconsiderrepeatingthetest.

why normal people often have abnormal resultsAmultiplebiochemicalanalysiscanbeperformedbyone

machineandproduce20results.Assumingtheseresultswere

allindependentofeachother(whichtheyarenot)andthat

resultsfromthereferencepopulationarenormallydistributed

(whichtheymaynotbe),only36%ofnormalpeoplewillhave

all20resultsinthereferencerange.Therewillbe64%withat

leastoneabnormalresult(Box1).However,themoreabnormal

theresultandthemorerelatedtestsareabnormal,themore

likelytheabnormalityisclinicallysignificant.

Ifyouconsiderthe99%referencerange(approx.±2.6standard

deviations)andthe99.9%referencerange(approx.±3.3

standarddeviations),82%and98%ofpeoplewillhaveall20

testswithinthereferencerange(0.9920and0.99920respectively).

Thesefactscanbeusefulwheninterpretinganisolated

abnormalresult.

Forexample,thereferencerangeofalkalinephosphataseis

30–110U/L.Thiscoverstwostandarddeviationsbelowthemean

andtwoabovethemean.onestandarddeviationistherefore

20U/L[(110–30)÷4].Aresultof150U/Listwostandarddeviations

abovetheupperlimitofthereferencerangeandthereforefour

standarddeviationsabovethemean.Thisisveryunlikelyto

occurinanormalindividual.However,theresultmaybenormal

ifthequotedreferencerangeisinappropriate.Forexample,in

pregnancyandgrowingchildrenalkalinephosphataseisproduced

bytheplacentaandbone.Thesearegoodexamplesofwhyitis

importanttoconsiderwhetherthepopulationreferencerangeis

appropriatefortheindividualbeingtested.

Whendecidingifaresultisabnormal,lookatrelatedtests.

Alkalinephosphataseisoneofthe'liverfunctiontests'

(othersarebilirubin,gammaglutamyltransferase,alanine

aminotransferase,aspartateaminotransferaseandlactate

dehydrogenase).Abnormalitiesintheothertestswouldsuggest

thattheabnormalalkalinephosphatasecouldbetheresultof

liverdisease.Anelevatedalkalinephosphataseinisolationmay

indicateanotherproblem,suchasbonedisease.

Laboratory accuracyWeoftenknowthewithin-laboratory,within-methodvariability

asthisisusuallyquotedbythelaboratory.Modernlaboratories

provideremarkablyconsistentresultsformanyanalytes–

typicalcoefficientsofvariation(seeBox2)are1–6%forthe

componentsofmultiplebiochemicalanalysis,electrolytes,

calciumandphosphorus,andrenalandliverfunctiontests.

Box 1

Normal results in normal people

Ifthereferencerangecovers95%ofresultsforanormal

population,thechanceofahealthyindividualhavinga

certainnumberofnormaltestsis:

n Twooutoftwotests 90%(0.95x0.95=0.90)

n All20of20tests 36%(0.9520)

Table 1

Abnormal laboratory results caused by incorrect collection and handling †

Step Mechanism result Measurement affectedSample Incorrectsample Incorrectresults Forexample,randomspoturinecalcium:creatinineratio

insteadoffirstvoidedVenepuncture Prolongedvenostasis

Difficultvenepuncture

Plasmafiltrationandconcentration

Haemolysis

Proteinconcentrations–globulins,albuminsandlipoproteinsandmeasurementsaffectedbythem(e.g.calcium)

Redcellleakagewithhighpotassium,phosphateandlactatedehydrogenase

Specimentube Incorrectcollectiontube

Incorrectresults

Assayaddedanalyte

Assayinterference

Lithiumheparinanticoagulant–lithiumassay

IfpotassiumEDTAusedforchemistry–potassiumassay

IfpotassiumEDTAusedforchemistry–assaysforcalciumandenzymes(calciumbindingandenzymeinhibition)

Specimenhandling

Delayintransport Redcelluseofglucoseandleakageofcontents

Bloodglucose(iffluoridetubenotused).Potassium,phosphate,lactatedehydrogenase

Laboratory Specimenmislabelling

Machinemalfunction

Transcriptionerror

Incorrectresults Virtuallyeverything

† Derivedfromreference1


nationalqualitycontrolprogramsmonitortheaccuracyand

imprecisionofdifferentmethodsusedindifferentlaboratories.

oneresulthasbeenthatthedifferencesbetweenlaboratories

forindividualmethodsarenowusuallyasmallcomponentof

theoverallvariabilityofmeasurements.

why values vary within one individualInadditiontothevariationscausedbyspecimencollectionand

handlingandthedifferenceswithinandbetweenlaboratories

andtheirmethods,thereisintra-individualvariation.Assuming

specimencollectionandprocessingerrorsdonotoccur,the

largestsourceofvariabilityiswithintheindividual.Valuesvary

byage,sexandwithinthemenstrual,diurnalandseasonal

cycles.Intra-individualbiologicalvariabilityfordifferentanalytes

canrangefromverylargetomoderate,forexample,8%for

totalcholesterol2versus40%formicroalbuminuria3assessedby

thealbumin:creatinineratio.Inaddition,thelongertheinterval

betweentests,thegreaterthetotalintra-individualvariabilityof

themeasure.

Itismuchmoredifficultforlaboratoriestoprovideinformation

onthetotalintra-individualvariabilitythanforthewithin-

laboratory,within-methodvariabilitywhichisautomatically

generatedbytheirqualitycontrolprograms.However,itisthe

totalvariabilitywithinanindividualwhichisimportantwhen

interpretingresults.

Are changes in results caused by intra-individual variability or the effects of treatment?onetrapisthephenomenonof'regressiontothemean'.4

Resultswithinanapparentlyhomogeneousgroupofpatients

arelikelytoliewithinthe95%referencerangeforthat

measurement.Ifthesamepatientsareretestedatadifferent

time,thepatternoftheoverallresultswilllookmuchthe

same.Inanormaldistribution,valuesarebunchedaround

thegroupmeanandprogressively'thinout'furtherfromthe

mean.However,individualresultsarelikelytohavechanged,

particularlythoseattheextremes.

Theinitialresultsattheextremesaretheresultofextreme

randomvariabilityinonedirectionortheother.Thesame

amountanddirectionofvariabilityisunlikelytooccuronthe

secondmeasurementinthesameindividual.Subsequent

measurementswillthereforemoveclosertothemiddle(or

'regresstothemean').Resultsfromotherindividualswho

initiallywereclosertothemeanmaynowlieclosertothe

extremesofthedistribution.

Thisphenomenoncanbeexploitedintentionallyor

unintentionallyintrialsthatselectandtreatindividualswith

highvaluesofameasurementtodemonstratethatatreatment

iseffective.'Regressiontothemean'isonereasonwhy

randomisedplacebo-controlledprospectivetrialsarethegold

standardforassessingtreatments.

Alargedifferencebetweentwomeasurementsismorelikelyto

beasignalofatruechangethantheresultofthebackground

noiseofmeasurementvariability.Similarly,thesmallerthetotal

intra-individualvariability,themorelikelyaspecificabsolute

changeisasignal.Thelesslikelytheobservedchangeiscaused

byvariability,thesureronecanbethatthechangeisreal.

Thesethreeelementsarebroughttogetherintheconceptofthe

leastsignificantchange.Tobe80%confidenttheobservedchange

isreal,thechangeshouldexceedapproximatelytwicetheintra-

individualcoefficientofvariation(CVi)(Box3).Forexample:

n Atotalcholesterolwhichdecreasesfrom7.0to5.6mmol/L,

afterstartingastatin,isa20%fallfromtheinitialvalue.The

CVifortotalcholesterolis8%sotheleastsignificantchange

Box 2

Coefficient of variation

Thecoefficientofvariation(CV)iscalculatedas:

CV=standarddeviationofthemeasuredvaluex100

meanvalue

Variabilityisdifferentatdifferentabsolutevaluesofthemeasurementandisusuallyquotedataspecificclinicallyrelevantvalue.Forexample:

CVforplasmasodium 0.8%at139mmol/L

CVforplasmabilirubin 6.1%at10micromol/L

Thecoefficientofvariationisonewayofexpressingthevariabilityofbiologicalmeasurements.Laboratoriessometimesalsorefertotheimprecisionofameasurement.

Box 3

Least significant change

1. Theoverallvariabilityofthedifferencebetweentwo

measurementsisgreaterthanthevariabilityofthe

individualmeasurements:√2CVi*

2. Themoreconfidentonewishestobethatthechangeinameasurementisasignalratherthannoise,thegreaterthe

changeneedstoberelativetothis:√2CVixz

Thezvalueisusedtorefertonormallydistributedvaluesanddescribesthedistanceofaparticularvaluefromthemeaninnumbersofstandarddeviations(SD).Thegreaterthedistancefromthemean(thezvalue)thelesslikelyaresulthasoccurredbychance.

zvariesfrom1.28for80%confidenceto2.6for99%confidence.

3. Generally80%confidenceisused(z=1.28):

Leastsignificantchange=√2CVix1.28=1.8CViThisapproximatesto2CVi

CVi Intra-individualcoefficientofvariation* Forexplanationofthevariabilityofthedifference

betweentwomeasurements,seeextendedBox3inthisarticleonlineatwww.australianprescriber.com/magazine/32/2/43/6.


ofbiologicalvariabilitywithintheindividualandwithinthe

endmeasurementvariabilitywithinthelaboratory.Asarough

rule,theleastsignificantchangeistwicetheintra-individual

coefficientofvariation(2CVi).

Ifanimportantclinicaldecisiondependsonwhetherachange

occurswithaparticulartreatment,considermakingtwo(or

more)measurementsbeforeandafterstartingtreatment.This

reducesthevariabilityandthepossibilityofmisinterpreting

theregressiontothemeanofaninitialhighorlowvalue.

Monitoringtrendswithtimeinvolvesmoremeasurements

andgivesamorereliableindicationofchangethanasingle

comparisonattwopoints.

Remember,themoretestsyoudothemorelikelyyouaretoget

atleastone'falsepositive'outsidethelaboratoryreferencerange.

Aimtolimitthenumberofteststothosethatarerelevanttothe

clinicalsituationratherthanrequestingascreeningbattery.

Whenassessingtheeffectsoftreatment,considerhowlong

thetreatmentwilltakebeforethetherapeuticeffectreaches

asteadystate(e.g.4–6half-livesofadrug)andhowlongthe

biologicalresponsewilltakebeforethemeasurementyou

makereachesasteadystate.Tryingtoassesstherapeuticeffects

beforetreatmentandresponsehavereachedasteadystatecan

seriouslyunderestimatethetherapeuticeffect.

references1. PhillipsP,BengC.Electrolytes–'funwithfluids'.Check

(ContinuousHomeEvaluationofClinicalKnowledge)programofselfassessment.no.323.SouthMelbourne:RoyalAustralianCollegeofGeneralPractitioners;1999.

2. CooperGR,MyersGL,SmithSJ,SchlantRC.Bloodlipidmeasurements.Variationsandpracticalutility.JAMA1992;267:1652-60.

3. PhillipouG,PhillipsPJ.Variabilityofurinaryalbuminexcretioninpatientswithmicroalbuminuria.DiabetesCare1994;17:425-7.

4. IrwigL,GlasziouP,WilsonA,MacaskillP.Estimatinganindividual'struecholesterollevelandresponsetointervention.JAMA1991;266:1678-85.

5. PhillipovG,PhillipsPJ.ComponentsoftotalmeasurementerrorforhaemoglobinA(1c)determination.ClinChem2001;47:1851-3.

Conflict of interest: none relevant to this article



7. Alaboratoryresultwhichistwostandarddeviationsfrom

thepopulationmeanisalwaysabnormal.

8. Iftreatmentreducesapatient'stotalcholesterolby5%the

changeissignificant.

isapproximately16%(2CVi).Youcanbe80%surethatthe

20%changeisrealratherthanapparent.

n Adecreaseinmicroalbuminuriafromanalbumin:creatinine

ratioof5.0to2.0mg/mmol,afterstartinganACEinhibitor,is

a60%fall.ThetotalCViofthealbumin:creatinineratiois40%

sotheleastsignificantchangeisapproximately80%(2CVi).It

islikelythatthis60%changeisapparentratherthanreal.

the effects of treatment on measurements may be delayedLaboratoryresultsmaytakealongtimetochangeafterstarting

treatment.Thismayreflectpharmacokinetics,biologyora

combinationofthetwo.

Thehalf-lifeofthyroxineinthebodyisapproximatelyseven

days.Testingafteroneweekwillonlyshowhalftheexpected

totaleffect.(Thismaysometimesstillbeusefulinformation.)By

sixweeks(sixhalf-livesinthiscase)98.4%oftheeffectwillhave

occurred[1–(½)6].

Whenstartingathiazolidinedione(glitazone)thefulleffect

onbloodglucoserequiresasteadystateoftheglitazone

(pharmacokinetic)butalsorequirestheshiftinfatmetabolism

whichinturncausesthereductioninglucose(biologic).Finally,

theglycatedhaemoglobin(HbA1c)reflectstheaverageblood

glucoseoverthepreceding4–6weeksbecauseoftheslow

turnoveroftheredcells(biologicandpharmacokinetic).5The

combinationofthesefactorsmeansthattestingafteroneweek

oftreatmentmayshowlittlechangeintheHbA1cwhichmay

take2–3monthstoshowthefulleffectoftreatment.

Anotherglycatedprotein(albumin,whichbecomes

fructosamine)hasamuchfasterturnover.Itthereforereflects

theaverageglucoseoverashorterperiod(2–3weeks).

onecanreducethevariabilityofthemeasurementchangeby

reducingthevariabilityofthebaselineandfinalmeasurements

(forexample,themeanoftwomeasurementsforeach).Ifboth

initialandfinalmeasurementswererepeatedthevariabilityof

thechangewouldbereducedtoCVi(not√2CVi).

Usingthemicroalbuminuriaexample,withtwomeasurements

beforeandaftertheintervention,theleastsignificantchange

wouldbe51%(1.28x40%).Youcouldthenbe80%surethatthe

60%observedchangewasrealandnotapparent.

recommendationsWheninterpretinglaboratoryresultsitisimportanttoknowthat

thesamplewascollectedandhandledcorrectly.Theappropriate

referencerangeforthetestshouldbeused.Different

laboratoriesmayreportdifferentresultsonthesamespecimen.

Whencomparingresultsovertime,usethesamelaboratory

andmethodfortesting.Considerthevariabilityofresults

withintheindividualandtheleastsignificantchange.Thisisthe

amountofdifferencebetweenmeasurementsthatislikelyto

bearealbiological'signal'insteadofresultingfromthenoise


Surrogate outcome markers in research and clinical practiceScott Twaddell, Clinical Pharmacologist and Clinical Toxicologist, and Advanced Trainee in Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, NSW

Summary

A surrogate measure or marker aims to predict

a clinical outcome or prognosis. Surrogates are

often used in drug or therapeutic intervention

trials as they reduce the size, duration and cost

of the study. Surrogates are commonly used as

trial end points and often become the standard

by which new drugs gain regulatory approval for

marketing. the surrogate marker should be able to

reliably predict an effect of the drug or intervention

on the long-term clinical outcome. Surrogate

markers should be validated in longer term trials to

confirm their association with the clinical outcome.

they should not be adopted as true markers of

disease in the absence of evidence of their validity.

Clinicians should manage the whole patient and

not just their surrogate markers.

Keywords:clinicaltrials,drugregulation.

(Aust Prescr 2009;32:47–50)

introductionAsurrogateendpoint,ormarker,isalaboratory

measurementorphysicalsignthatisusedintherapeutictrials

asasubstituteforaclinicallymeaningfulendpointthatisa

directmeasureofhowapatientfeels,functions,orsurvives

andthatisexpectedtopredicttheeffectofthetherapy.

USFoodandDrugAdministration1

Theessentialfeatureofthisdefinitionisthestrongassociation

betweenthemarkerandtheclinicalendpointoroutcome.The

effectofatreatmentonasurrogatemarkermustreflectitseffect

ontheclinicaloutcome.2Forexample,adrugwhichreduces

intraocularpressurewillreducelossofvisioninpatientswith

glaucoma.

Thecostandtimeconstraintsoflargeclinicaltrialsmakesurrogate

markersanattractivepropositioninresearch.Manynewdrugs

gainapprovalbyshowingpositiveeffectsonsurrogatemeasures

thathavebeenpreviouslyacceptedasmarkersofaparticular

disease,forexample,theconcentrationoflowdensitylipoprotein

(LDL)cholesterolasamarkerofcardiovasculardisease.While

somesurrogatesachieveacceptanceinclinicalpracticeas

markersofdisease,basedontheresultsofphaseIIItrials3,others

areadoptedeventhoughtheyhavelittlecorrelationwiththe

progressionofdisease(Table1).

Table 1

Surrogate markers often used in clinical practice

Generally accepted as valid

Surrogate marker Predicts

HbA1c Diabeticmicrovascularcomplications

FEV1 Mortalityinchronicobstructivepulmonarydisease

Bloodpressure Primaryandsecondarycardiovascularevents

Viralload SurvivalinHIVinfection

Cholesterolconcentration Primaryandsecondarycardiovascularevents

Intraocularpressure Visuallossinglaucoma

HbA1c glycatedhaemoglobin

FEV1 forcedexpiratoryvolumeinonesecond

doubt still exists about validity

Surrogate marker Predicts

HbA1c Diabeticmacrovascularcomplications

Bonemineraldensity Fracturerisk

Prostatespecificantigen Prognosisofprostatecancer

Suppressionofarrhythmia Long-termsurvival

Carotidintima-mediathickness Coronaryarterydisease

Albuminuria Cardiovascularevents


reliable surrogates in clinical practice

Reducingapatient'sbloodpressureisawellacceptedrisk

reductionstrategyfortheprimaryandsecondaryprevention

ofcardiovascularevents.Therelationshipbetweenblood

pressure(thesurrogatemarker)andtheriskofcardiovascular

eventsiscontinuousandindependent.Drugsthatreduce

bloodpressuresignificantlymorethanotherdrugsconsistently

showbetterresultsinclinicaloutcometrials.Therelationshipis

consideredsostrongthatwepresumeadrugwillreducefuture

cardiovasculareventsifiteffectivelycontrolsbloodpressure.

oneofthemostreliableofallsurrogatemeasuresisthe

intraocularpressureinglaucoma.Thereisastrongcorrelation

betweenincreasingintraocularpressureandtheclinicalend

pointofvisualloss.Anydrugwhichlowersintraocularpressure

willreducetheriskofvisualloss.4

Forcedexpiratoryvolumeinonesecond(FEV1)asapercentage

ofthepredictedvolumeisusedforprognosisinchronic

obstructivepulmonarydisease(CoPD).Interventionsthat

slowtherateofdeteriorationofFEV1areconsideredthemost

clinicallyusefultreatmentsforpatientswithCoPD.Thereisgood

long-termevidencetosupporttheutilityofthismeasure.5,6

Surrogate markers in clinical trials

InphaseIItrials3,surrogatemarkersprovideinterimmeasures

ofinterventionsandtherebypredictwhetherlongerterm,

moreextensiveandcostlyphaseIIItrialsareworthwhile.

Thereisgreatinterestinmarkersthatallowresearchersto

makepredictionsofdrugeffectsordiseaseprogressionby

extrapolatingshort-termresultstolong-termclinicalendpoints.

Studiesfrequentlymakeuseofthesemarkersratherthan

clinicaloutcomes.Surrogatemarkerscanbeusedtomonitor

diseasecontrol,forexampleglycatedhaemoglobin(HbA1c)asa

markerofdiabetescontrol.Theycanalsobeusedtodetermine

diseaseprognosis,forexampleincreasedviralloadand

decreasedCD4cellcountasapredictorofprogressiontoAIDSin

patientsinfectedwithHIV.othermarkersareusedtodetermine

theriskofdevelopingaseparateoutcome,forexample,blood

pressureandtheriskofadversecardiovascularevents.

Whilesurrogatemarkersareusefulforreducingtheduration

ofstudies,thetranslationofresultsfromtrialsinvolvingone

drugtotrialsofanotherdrugislikelytobeinvalidunless

themarkerhasbeenshowntobevalidinmultipledifferent

trials.7However,surrogatemarkersarefrequentlyusedindrug

comparisonstudies.Improvementsinsurrogatemarkersmay

beacceptedbydrugregulatoryauthoritiesasevidencethatone

drugismoreefficaciousthananother.

Validating surrogate markers

Theonlywaytoproperlyvalidatepotentialsurrogatemarkers

isthroughstringentexaminationinphaseIIIclinicaltrials.

Theprimaryendpointthenneedstobearelevantclinical

event.Finalevidenceofastrongassociationisshownthrough

consistentperformanceofthemarkerinmeta-analysesof

multiplephaseIIItrials.

Therearecriteriawhichdefinethevalidityofsurrogate

markers.8Althoughthesearecontroversial7,theyprovidea

usefulframeworkonwhichtobaseamodelforsurrogate

markers.Theidealsituationisoneinwhichthesurrogatelies

directlyinthecausalpathwaytotheclinicalendpointandthe

drugorinterventionhasapredictableanddirecteffectonboth

thesurrogateandtheclinicalendpoint.

Perhapsmoreusefulisanexplanationofhowsurrogatesfail

topredictclinicalendpoints.Therearefourpossibilities(see

Fig.1).2

1. Thesurrogatemaynotbeinthecausalpathwayofthe

disease,thereforeanyeffectofthedrugorinterventionon

thesurrogatehasnoeffectontheclinicalendpoint.For

example,themechanismsleadingtothedevelopmentof

macrovascularcomplicationsintype2diabetesmaynot

involveHbA1c.

2. Theremaybeseveralcausalpathways,ofwhichthe

surrogateisone,andthedrugorinterventionmayaffectonly

thesurrogatewithoutaffectingthetrueclinicalendpoint.

Forexample,improvementinbonemineraldensitywith

bisphosphonatesmaynotbeareliablepredictoroffracture

riskbecausereducedbonemineraldensityisnottheonly

reasonfortheincreaseinrisk.

3. Thesurrogatemaybeinvolvedinthecausalpathwayofthe

diseasebutbeunaffectedbythedrugorintervention.In

patientswithHIV,theincidenceofopportunisticinfections

maynotbereducedbyaspecificantiretroviraldrugeven

thoughthedrugimprovesprognosis.

4. Thedrugorinterventionhaseffectsindependentofthe

diseaseandmayormaynotaffectthesurrogateorclinical

endpoint.Forexample,prostatectomymayinfluencesurvival

inprostatecancerviaapathwayforwhichprostatespecific

antigenisamarker,butalsoviamechanismsindependentof

thateffect.Thismakesthemeasurementofprostatespecific

antigenunreliableasasoleprognosticmarker.

Anexampleofasurrogatemarkerwhichmaynotbecausally

relatedtoclinicaloutcomeisthethicknessofthewallsofthe

carotidartery.Aprovenreductionofintima-mediathickness

seenonultrasoundhasbeensuggestedasasurrogatemarker

forthesuccessofdrugsinreducingoverallcardiovascularrisk.

However,concernshavebeenraisedabouttherelianceon

changesinoneareaofthecarotidandtheinferencethatthis

reflectschangesinothervascularareas.Measuringchangesin

themediamaybeapoorsubstituteforadiseaseprocessthat

occursprimarilyintheintima.Thechangesinintima-media

thicknessinducedby'statins'cannotnecessarilybeextrapolated

toeffectsproducedbyotherdrugs.


Fig. 1

examples of failure of surrogate end points to reliably predict true clinical outcomes 2

pathwaysinvolvingsurrogatemarkers

causaldiseasepathways

otherpotentialmechanismsofaction

1. Glycatedhaemoglobin(HbA1c)maynotbeinthecausal

pathwayofmacrovasculardisease.

2. Bisphosphonatesaffectonlythebonemineraldensitybut

theremaybeothercausalpathways.

3. Antiretroviraldrugsaltersurvivalbyeffectsindependentof

thenumberofopportunisticinfections.

4. Prostatectomyforprostatecancerhasmechanismsof

actionincludingbutalsoinadditiontothepathway

affectingprostatespecificantigen.

1. type 2 diabetes

2. osteoporosis

3. HiV

4. Prostate cancer

Macrovascularcomplications

Fracturerisk

Survival

Survival

HbA1c

Bisphosphonates

Bonemineraldensity

Antiretroviral drugs

opportunisticinfections

Prostatectomy

Prostatespecificantigen

Surrogates and safetySurrogatemarkersmayhaveimplicationsforsafety

becausetheymaybeunaffectedbytheadverseeffectsofan

intervention.TheILLUMInATEtrialincardiovasculardisease

wasstoppedbecausetherewashighermortalitywiththestudy

drug(torcetrapib)eventhoughitwaseffectiveatreducingLDL

cholesterol.9

Theuseofasurrogatemarkerinashort-termstudyusing

relativelysmallnumbersofpatientsmaynotrevealrareadverse

effects,whereasalonger,largerphaseIIItrialwouldbemore

likelytodetecttheseevents.Thisriskmaybefurtherincreasedif

thesesurrogatesmovefromresearchtoclinicalpractice.Unless

thereisastrongcorrelationbetweenthesurrogateandthe

clinicaloutcome,cliniciansshouldfocusontreatingthedisease,

notjustthesurrogatemarker.

the risk of translating surrogate markers to clinical practiceEvenifaninterventionhasaneffectonasurrogatemarker

andthatmarkerisclearlyinthecausalpathwayoftheclinical

endpoint,theeffectmaynotpersistlongenoughforthedrug

toalterthelong-termclinicaloutcome.Thedrugmayseemto

beefficaciousbecauseofitsshort-termeffectonthesurrogate

marker,buthavenoeffectontheclinicaloutcome.

ThereisevidencethatLDLandtotalserumcholesterolarevalid

markersor'riskfactors'forcardiovascularoutcomes,basedon

anumberofwellvalidatedlong-termstudies.However,there

isdoubtaboutwhetherareductioninLDLortotalcholesterol

overashortperiodoftimewillpredictthelong-termeffectand

thereforeoutcome.Anexampleofthiswouldbewhenanew

drugisshowntobemoreeffectivethananotheratloweringLDL

cholesterolover16weeksandtheresultisextrapolatedtoimply

agreaterreductioninthelong-termriskofcardiovascularevents.

ArecentexampleistheEnHAnCEtrial.10Althoughthe

combinationofezetimibeandsimvastatinloweredLDL

cholesteroloveratwo-yearperiod,therewasanincrease

inthecarotidintima-mediathickness.Thetrialreliedonthe

combinationofonewellaccepted(LDLcholesterol)andone

controversial(intima-mediathickness)surrogatemarkertoshow

thedrug'seffect.oneofthemanyquestionsraisedbythisstudy

iswhetherareductioninintima-mediathicknesswilltranslate

intoareductionincardiovascularevents.Thisquestionwill

remainuntiltheresultsoflargerphaseIIItrialsareavailable.

Questionsremainastotheutilityofbonemineraldensity

inpredictingfracturerisk.Themajorproblemseemsto

beestablishingathresholdlevelforacceptableriskin

aconditionwhichhasmultiplecontributingriskfactors

suchasage,sex,smokinghistoryandalcoholintake.The

introductionofbisphosphonatesandhowmuchbenefitcan

begained,basedsolelyonchangesinbonemineraldensity,

isdifficulttodetermineforanindividual.11,12Therestrictionof

bisphosphonateuse,atleastinAustralia,tothosewhohave

sustainedafracturemayseemoverlycautiousbutmightbethe

mostreasonablewaytoattributeindividualriskbecauseofthe

poorindividualcorrelationbetweenbonemineraldensityand

riskoffracture.

ConclusionSurrogatemarkersarebornofphaseIItrialsandarenot

necessarilyidealforuseinclinicaldecisionmaking.Phase

IIItrialsshouldbethetruetestinggroundforthevalidityof


surrogatemarkers.Therearesomevalidsurrogatemarkersof

diseaseprogressionwhichcanbereliablyusedtomonitorchronic

conditions,andastreatmentgoals.However,theclinicalutilityof

manysurrogatesisopentoquestionandtheirvalidityislargely

untested.Practitionersneedtokeepinmindthatsomewidely

usedsurrogatemarkersofdiseasehavenotbeenadequately

validatedforuseinclinicalsituations.Adiseasemaybeassociated

withasurrogatemarker,butthisdoesnotmeanthattreatingthe

markerwillimprovetheoutcomeofthatdisease.

references1. DepartmentofHealthandHumanServices.FoodandDrug

Administration.newdrug,antibiotic,andbiologicaldrugproductregulations:acceleratedapproval.FederalRegisterVol57no73.1992.p.13234-42.

2. FlemingTR,DeMetsDL.Surrogateendpointsinclinicaltrials:arewebeingmisled?AnnInternMed1996;125:605-13.

3. BarnesD.Howprescriptiondrugsaredeveloped.AustPrescr2006;29:159-61.

4. VogelR,CrickRP,newsonRB,ShipleyM,BlackmoreH,BulpittCJ.Associationbetweenintraocularpressureandlossofvisualfieldinchronicsimpleglaucoma.BrJophthalmol1990;74:3-6.

5. TraverGA,ClineMG,BurrowsB.Predictorsofmortalityinchronicobstructivepulmonarydisease.AmRevRespirDis1979;119:895-902.

6. DolanS,VarkeyB.Prognosticfactorsinchronicobstructivepulmonarydisease.CurropinPulmMed2005;11:149-52.

7. BergerVW.DoesthePrenticecriterionvalidatesurrogateendpoints?StatMed2004;23:1571-8.

8. PrenticeRL.Surrogateendpointsinclinicaltrials:definitionandoperationalcriteria.StatMed1989;8:431-40.

9. KrumholzHM,LeeTH.Redefiningquality–implicationsofrecentclinicaltrials.nEngJMed2008;358:2537-9.

10. KasteleinJJ,AkdimF,StroesES,ZwindermanAH,BotsML,StalenhoefAF,etal.Simvastatinwithorwithoutezetimibeinfamilialhypercholesterolemia.nEngJMed2008;358:1431-43.

11. KanisJA,BorgstromF,DeLaetC,JohanssonH,Johnello,JonssonB,etal.Assessmentoffracturerisk.osteoporosInt2005;16:581-9.

12. MarshallD,Johnello,WedelH.Meta-analysisofhowwellmeasuresofbonemineraldensitypredictoccurrenceofosteoporoticfractures.BMJ1996;312:1254-9.

Further readingRolanP.Thecontributionofclinicalpharmacologysurrogatesandmodelstodrugdevelopment–acriticalappraisal.BrJClinPharmacol1997;44:219-25.

TempleR.Aresurrogatemarkersadequatetoassesscardiovasculardiseasedrugs?JAMA1999;282:790-5.

Conflict of interest: none declared

treatments for severe psoriasis: updateInMarch2009itwasannouncedthatefalizumabwouldbe

withdrawnfromtheAustralianmarket.Thisfollowsareviewof

thedruginEuropewhichfoundthebenefitsnolongeroutweigh

theriskofharm.Therearereportsofprogressivemultifocal

leucoencephalopathyarisinginpatientswhohavebeentreated

withefalizumabformorethanthreeyears.1Thedrughasalso

beenunderreviewintheUSA.2

references1. EuropeanMedicinesAgency.Questionsandanswersonthe

recommendationtosuspendthemarketingauthorisationforRaptiva.2009Feb19.www.emea.europa.eu/humandocs/PDFs/EPAR/raptiva/RaptivaQ&A_1552509en.pdf[cited2009Mar13]

2. USFoodandDrugAdministrationCenterforDrugEvaluationandResearch.FDAPublicHealthAdvisory.UpdatedsafetyinformationaboutRaptiva(efalizumab).2009Feb19.www.fda.gov/cder/drug/advisory/efalizumab.htm[cited2009Mar13]

Comment from Dr JR Sullivan and Dr V Preda, the authors of

an article about treating severe psoriasis recently published in

Australian Prescriber (Aust Prescr 2009;32:14–18):

Forraresideeffectsittakesanumberofyearsofpost-marketing

surveillanceforasignaltoappear.Thiscantakelongerfor

therapieswithonlyasingletherapeuticindicationsuchas

efalizumab.Thisdrughasonlybeenusedin46000patients

worldwide.

Thetumournecrosisfactor-alfaantagonists,infliximaband

etanercept,forpsoriasishavebeenusedforanumberofclinical

indicationsoveramuchlongerperiod.Wehave15yearsof

patientsafetydataandover1.4millionpatientyearsand

630000patientswithetanercept,and15yearsofpatientsafety

dataand4.3millionpatientyearsand340000patientswith

infliximab.Forthesetwodrugsmuchmoreisknownabouttheir

longer-termsafetyprofiles.

Theuseofbiologicalsforthetreatmentofseverepsoriasisneeds

tobeconsideredinlightofthesafetyprofileofeachdrugand

alsointhecontextoftheindividualpatient.Biologicalsarenot

onlyusedinseverepsoriasisbutalsoforanumberofother

disorders.Thuswithregardtosafetydatawecanbenefitfrom

theexperiencewiththesemedicationsusedinotherspecialties

suchasrheumatologyandgastroenterology.Fromrheumatology

weknowtoscreenfortuberculosisbeforestartingtherapyto

helppreventpotentiallyseriousinfections.Althoughadverse

effectsareoftengroupedtogetherasaclasseffect,itisimportant

toconsidereachbiologicaldrugindividuallyastheyhavetheir

ownuniquepharmacologicalprofiles.


New drugsSomeoftheviewsexpressedinthefollowingnotesonnewlyapprovedproductsshouldberegardedastentative,astheremaybelimitedpublisheddataandlittleexperienceinAustraliaoftheirsafetyorefficacy.However,theEditorialExecutiveCommitteebelievesthatcommentsmadeingoodfaithatanearlystagemaystillbeofvalue.Asaresultoffullerexperience,initialcommentsmayneedtobemodified.TheCommitteeispreparedtodothis.Beforenewdrugsareprescribed,theCommitteebelievesitisimportantthatfullinformationisobtainedeitherfromthemanufacturer'sapprovedproductinformation,adruginformationcentreorsomeotherappropriatesource.

dabigatran etexilate

Pradaxa(BoehringerIngelheim)

75mgand110mgcapsules

Approvedindication:preventionofpostoperativevenous

thrombosis

AustralianMedicinesHandbooksection7.1

Patientswhohavehadmajorsurgeryontheirlegsareatriskof

venousthrombosis.Thisriskcanbereducedbyanticoagulation

withaheparinoranalternativesuchasfondaparinux.A

disadvantageofthesedrugsisthattheyhavetobegivenby

injection,sopatientsmaynotcontinuethemafterleaving

hospital.Anoralanticoagulant,withoutthedisadvantagesof

warfarin,mightimprovetheeffectivenessofprophylaxis.

Dabigatranisadirectinhibitorofthrombinwhichcanbe

takenorallyasaprodrug(dabigatranetexilate).Byinhibiting

thrombin,itblockstheconversionoffibrinogentofibrinand

thusreducesclotformation.Itisgiven1–4hoursaftersurgery.

Inhealthypeopledabigatranetexilateisrapidlyabsorbed

andconvertedtodabigatran.Absorptionisslowerinitially

inpostoperativepatients,butsubsequentlypeakplasma

concentrationsofdabigatranarereachedtwohoursafteradose.

Thehalf-life,12–14hours,isalsoslightlylongeraftersurgery.

Treatmentbeginswithhalftheongoingdose.Mostofthedose

isexcretedasdabigatranintheurine.Peoplewithreducedrenal

function,suchassomeelderlypatients,mayrequirealower

dose.Ifthecreatinineclearanceisunder30mL/min,dabigatran

iscontraindicated.

Adouble-blindtrialhascompareddabigatranetexilate

(220mgand150mgdaily)withadailydoseofsubcutaneous

enoxaparin40mgin3494peoplehavingtotalhipreplacements.

Treatmentcontinuedfor28–35daysuntilthepatientshad

venography.However,manypatientsdidnothavevenography

soefficacycouldonlybeassessedin2651patients.Deathor

venousthromboembolismoccurredin8.6%ofthepatients

takingdabigatran150mg,6%ofthosetaking220mgandin

6.7%ofthepatientsinjectedwithenoxaparin.1

Thesamedrugsanddoseswereusedinastudyof2076

patientshavingtotalkneereplacements.Treatmentcontinued

for6–10days.Assomepatientsdidnothavevenography,

efficacywasassessedin1541patients.Deathorvenous

thromboembolismoccurredin40.5%ofthepatientstaking

dabigatran150mg,36.4%ofthosetaking220mgand37.7%of

theenoxaparingroup.2

Bleedingisamajorconcernwhenanticoagulantsareused

followingsurgery,andthereisnoantidotefordabigatran.

Afterhipreplacement,significantbleedingoccurredin1.3%of

thedabigatran150mggroupand2.0%ofthe220mggroup.

Thiswasfatalforonepatientineachgroup.Intheenoxaparin

group1.6%ofpatientshadsignificantbleeding,buttherewere

nofatalities.1Afterkneereplacementtheincidenceofmajor

bleedingwas1.5%inthedabigatran220mggroupand1.3%

inthe150mgandenoxaparingroups.2Toreducetheriskofa

haematomaforming,dabigatranshouldnotbegivenforatleast

twohoursfollowingtheremovalofaspinalorepiduralcatheter.

Commonadverseeffectsincludenausea,vomiting,feverand

constipation,buttheyoccurirrespectiveofthetreatmentused.

Routinemonitoringisnotrequired,butliverfunctionshouldbe

checkedbeforetreatmentasliverdiseaseisacontraindication

todabigatran.DrugswhichactontheP-glycoproteintransporter

mayaltertheplasmaconcentrationofdabigatran.Thesedrugs

includeamiodarone,verapamil,clarithromycinandStJohn's

wort.Quinidineiscontraindicated.Anticoagulantsand

antiplateletdrugssuchasclopidogrelarenotrecommended

whilethepatientistakingdabigatran.Dosesofaspirinabove

75mgdailyincreasetheriskofbleeding.non-steroidal

anti-inflammatorydrugs(nSAIDs)canbeusedforshort-term

analgesia,buttheremaybeanincreasedriskofbleeding

particularlyifthenSAIDhasalonghalf-life.

Themainstudiesofdabigatranhaveshownthatithassimilar

efficacytoenoxaparin,howeveranAmericanstudyfound

inferiorefficacy.IntheUSAprophylaxiscanbegivenas

enoxaparin30mgtwicedaily.Thestudyof1896patientshaving

kneereplacementfoundvenousthromboembolismin31–34%

ofthepatientstakingdabigatranbutinonly25%ofthosegiven

enoxaparin.3

Thedevelopmentofthefirstdirectthrombininhibitor,

ximelagatran,washaltedbecauseofconcernsaboutadverse

effectsontheliver.Hepatotoxicityhasnotyetemergedas

asignificantproblemwiththerelativelyshort-termuseof

dabigatran.Ifitssafetyandefficacyareconfirmedinmore

widespreaduse,oraldabigatranmaybeacost-effective

alternativetosubcutaneouslowmolecularweightheparins.

manufacturerdeclinedtosupplydatat


references *

1. ErikssonBI,DahloE,Rosenchern,KurthAA,vanDijkCn,FrostickSP,etal;RE-noVATEStudyGroup.Dabigatranetexilateversusenoxaparinforpreventionofvenousthromboembolismaftertotalhipreplacement:arandomised,double-blind,non-inferioritytrial.Lancet2007;370:949-56.

2. ErikssonBI,DahloE,Rosenchern,KurthAA,vanDijkCn,FrostickSP,etal.oraldabigatranetexilatevs.subcutaneousenoxaparinforthepreventionofvenousthromboembolismaftertotalkneereplacement:theRE-MoDELrandomizedtrial.JThrombHaemost2007;5:2178-85.

3. GinsbergJS,DavidsonBL,CompPC,FrancisCW,FriedmanRJ,HuoMH,etal;RE-MoBILIZEWritingCommittee.oralthrombininhibitordabigatranetexilatevsnorthAmericanenoxaparinregimenforpreventionofvenousthromboembolismafterkneearthroplastysurgery.JArthroplasty2009;24:1-9.

daptomycinCubicin(novartis)

lyophilisedpowderforinjection

Approvedindications:skininfections,Staphylococcus aureus

bacteraemia


Daptomycinisacycliclipopeptidederivedfromanatural

productofStreptomyces roseosporus.Itsbactericidaleffects

stemfromitsabilitytorapidlydepolarisethemembrane

potentialofGram-positivebacteria.Thiscausesinhibitionof

DnA,RnAandproteinsynthesis,andresultsincelldeath.

Itisindicatedforadultswithcomplicatedskinandskin

structureinfectionswhorequireinitialparenteraltherapyand

whoareintolerantofalternativeantibiotics(includingthose

withpenicillinallergy).Itshouldonlybeusedforinfections

suspectedtobecausedbysusceptibleGram-positivebacteria.

Steady-stateconcentrationsofdaptomycinarereachedafter

thethirddailyintravenousinfusion.Itisprimarilyexcretedby

thekidneys(mainlyasunchangeddrug)sodoseadjustment

isrequiredforpatientswithsevererenalinsufficiency.Renal

functionandcreatinekinaseshouldbefrequentlymonitoredin

thesepatients.Inpatientsrequiringhaemodialysis,daptomycin

shouldbeadministeredaftertheprocedure.

Theefficacyofdaptomycin(4mg/kgintravenouslyonce

dailyfor7−14days)hasbeencomparedtoapenicillin

(cloxacillin,nafcillin,oxacillinorflucloxacillin)orvancomycin

intworandomisedtrialswithsimilardesignstotalling1092

participants.Thesepatientswerehospitalisedmainlywith

complicatedskininfectionsincludingwoundinfections,major

abscesses,infecteddiabeticulcersorotherulcers.Patients

withmixedinfectionsinvolvingGram-negativeoranaerobic

organismsweregivenconcomitantaztreonamormetronidazole

asappropriate.Amongtheclinicallyevaluablepatients,

treatmentsuccessratesfordaptomycinwerecomparableto

thecomparator(83%vs84%).However,inbothgroupssuccess

ratesformethicillin-resistantStaphylococcus aureusinfections

werelowerthanformethicillin-sensitiveS. aureus (75%vs86%

fordaptomycinand69%vs87%forcomparator).Successrates

werealsolowerinpatientsaged65yearsorolder.1

Inanotheranalysisofthetrialslookingonlyatpatientswith

diabeticulcers(mainlyofthefoot),66%(31/47)ofclinically

evaluablepatientsbenefitedfromdaptomycintreatment

comparedwith70%(39/56)ofpatientstreatedwithapenicillin

orvancomycin.Methicillin-resistantS. aureuswasisolatedfrom

tenpatients;onereceiveddaptomycinandtherestreceiveda

comparator.Afteracourseoftreatment,infectionwascleared

inthreeofthecomparator-treatedpatientsbutnotinthe

daptomycin-treatedpatient.2

Adverseeventsweresimilarbetweengroupswith

gastrointestinaldisordersbeingthemostcommon.Fifteen

ofthe534patients(2.8%)receivingdaptomycindeveloped

elevatedcreatinekinaselevelscomparedtotenofthe558(1.8%)

receivingthecomparator.1

InAustralia,daptomycinhasalsobeenapprovedforadultswith

bacteraemiacausedbyS. aureus,includingthosewithright-

sidednativevalveinfectiveendocarditiscausedbymethicillin-

susceptibleormethicillin-resistantisolates.Thisapproval

wasbasedonanopenlabelrandomisedtrialofpatientswith

bacteraemiawithorwithoutleft-orright-sidedendocarditis.

Daptomycin(6mg/kgintravenouslyoncedaily)wascompared

tostandardtreatmentconsistingofgentamicinplusapenicillin

(nafcillin,oxacillinorflucloxacillin)orvancomycin.(Patientsin

thedaptomycingroupwhohadleft-sidedendocarditiswerealso

givengentamicinforthefirstfourdays.)Themediandurationof

therapywas14daysfordaptomycinand15daysforstandard

treatment.

Successfuloutcomeswerereportedin53of120(44%)patients

receivingdaptomycinand48of115(42%)patientsreceiving

thecomparator.Inpatientsinfectedwithmethicillin-resistant

isolates,successratesweresimilarfordaptomycinbutlower

withstandardtreatment(44%vs32%).Treatmentfailurewas

moreoftenassociatedwithpersistentorrelapsingS. aureus

infectioninthedaptomycingroup(15.8%ofpatients),whereas

inthecomparatorgroupfailurewasmorefrequentlyassociated

withtreatment-limitingadverseevents.Therapyfailedin

allninepatientswhohadleft-sidedendocarditiscausedby

methicillin-resistantS. aureus,regardlessofwhichtreatment

theyreceived.3

Creatinekinaseelevationsweretwiceascommonwith

daptomycinthanwithstandardtreatment(25%vs12.5%).

Adverseeventsrelatedtotheperipheralnervoussystem

werealsomorecommonwithdaptomycinthanwithstandard

treatment(9.2%vs1.7%),whereasrenalimpairmentwasmore

commonwithstandardtreatmentthanwithdaptomycin

(18.1%vs6.7%).3


etravirineIntelence(Janssen-Cilag)

100mgtablets

Approvedindication:HIV


Etravirineisanon-nucleosidereversetranscriptaseinhibitor

(nnRTI).ItbindstoreversetranscriptaseandblockstheRnA-

andDnA-dependentactivitiesofDnApolymerase.Etravirine

isindicatedfortreatment-experiencedadultswithHIVwho

haveevidenceofviralreplicationanddrugresistancetoother

antiretroviraldrugsincludingnnRTIs.

Theapprovalofetravirineisbasedontwoidenticallydesigned

randomisedplacebo-controlledtrials(DUET-1andDUET-2)in

patientswithadvanceddisease.Thesepatientswereresistant

tocurrentlyavailablennRTIsandhadatleastthreeprimary

mutationstoproteaseinhibitors.Allpatientsreceiveddarunavir

(aproteaseinhibitor)boostedwithritonavir,aswellasatleast

twootherantiviraldrugs.Atthebeginningofthestudiesthe

averageviralloadinenrolledpatientswas70000copies/mL

blood.Themainmeasureofeffectivenessforetravirinewas

thenumberofpatientswithlessthan50viralcopies/mL.After

24weeksoftreatment,59%(353/599)ofpatientswhoadded

etravirine(200mgtwicedaily)hadlessthan50viralcopies/mL

comparedto41%(248/604)ofpatientswhoaddedplacebo.

ThemeanincreaseinCD4cellswas84cells/microlitreinthe

etravirinegroupsand65cells/microlitreintheplacebogroups.

Usingotheractiveantiretroviraldrugswithetravirineincreases

thelikelihoodoftreatmentresponse.1,2

Thetrialsareongoingandpreliminaryresultspresentedat

aconferencereportedthatresponseratestoetravirinewere

maintainedafter48weeksoftreatment(www.retroconference.

org/2008/PDFs/790.pdfandwww.retroconference.org/2008/

PDFs/791.pdf).Thetotaldurationofthetrialsisexpectedtobe

96weeks.

ResistancetonnRTIscandevelopeasily.Asinglemutation

inthereversetranscriptasegeneoftheviruscanleadto

reductionsinsusceptibility,oftentoallcurrentlyavailable

inhibitorsintheclass.Thisbroadcross-resistancelimitsthe

sequentialuseofothernnRTIsaftertreatmentfailure.Inthe

DUETtrials,decreasedsusceptibilitytoetravirineemerged

andwasassociatedwithanumberofdifferentviralmutations.

Cross-resistancewithetravirineandothernnRTIswasalso

observed.Themajorityofviralstrainscontainingtwoorthree

mutationsconferringnnRTIresistancealsohaddecreased

susceptibilitytoetravirine.

Themostcommonadverseeventswithetravirinearerash

(17%),diarrhoea(15%)andnausea(14%).Rashwasthemost

commonadverseeventforwhichpatientsdiscontinued

treatmentintheDUETtrials(2%foretravirine,0%forplacebo).

Severeandpotentiallylife-threateningskinreactions,including

Patientsshouldbemonitoredforthedevelopmentofmuscle

painorweakness.Creatinekinaseshouldbemonitored

weeklyandmorefrequentlyinpatientswhohaveahigher

riskofdevelopingmyopathy,suchasthosewithsevererenal

insufficiencyortakingotherdrugsthatareassociatedwith

myopathy(HMG-CoAreductaseinhibitors,fibrates,cyclosporin).

ConsidertemporarilystoppingHMG-CoAreductaseinhibitors

whilepatientsarereceivingdaptomycin.

Inpatientstakingconcomitantwarfarin,anticoagulantactivity

shouldbemonitoredduringthefirstweekofdaptomycin

therapy.Cautionisurgedwhenco-administeringdaptomycin

withtobramycin.

Daptomycin-resistantbacteriahaveemergedinpatientsenrolled

intheclinicaltrials.Toreducethedevelopmentofdaptomycin

resistance,thisantibioticshouldonlybeusedtotreatorprevent

infectionsthatareprovenorstronglysuspectedtobecausedby

susceptiblebacteria.Daptomycindoesnotseemtobeeffective

forinfectionscausedbyenterococci,includingEnterococcus

faecalisandE. faecium.Susceptibilityofbacterialisolates

shouldbemonitoredduringthecourseoftreatment.

Daptomycinprovidesanotheroptionforhospitalisedadults

withseriousinfectionscausedbyGram-positivepathogens.

However,itsefficacymaybelowerinolderadults.Itcanalsobe

usedformixedinfectionsinvolvingGram-negativeoranaerobic

bacteriaifco-administeredwithappropriateantibiotics.

Thisantibioticisnoteffectiveforleft-sidedendocarditis,orfor

pneumoniabecauseitbindstosurfactantandisinactivated.The

efficacyofdaptomycininpatientswithprostheticheartvalves

hasnotbeendemonstrated.

manufacturerprovidedonlytheproductinformation

references *†

1. ArbeitRD,MakiD,TallyFP,CampanaroE,EisensteinBI;Daptomycin98-01and99-01Investigators.Thesafetyandefficacyofdaptomycinforthetreatmentofcomplicatedskinandskin-structureinfections.ClinInfectDis2004;38:1673-81.

2. LipskyBA,SoutenburghU.Daptomycinfortreatinginfecteddiabeticfootulcers:evidencefromarandomized,controlledtrialcomparingdaptomycinwithvancomycinorsemi-syntheticpenicillinsforcomplicatedskinandskin-structureinfections.JAntimicrobChemother2005;55:240-5.

3. FowlerVG,BoucherHW,CoreyGR,AbrutynE,KarchmerAW,RuppME,etal.DaptomycinversusstandardtherapyforbacteraemiaandendocarditiscausedbyStaphylococcusaureus.nEnglJMed2006;355:653-5.

t


Stevens-Johnsonsyndrome,hypersensitivityreactions

anderythemamultiforme,haveoccurredinpatientstaking

etravirine.Treatmentshouldbestoppedifthisoccurs.other

commonadverseeffectsofetravirineincludeabdominalpain,

tirednessandhighbloodpressure.neuropsychiatricevents

occurredin25%ofpatientstakingetravirine.Similarnumbersof

eventswereseenintheplacebogroup.

PatientswhoalsohadhepatitisBand/orhepatitisCwere

includedintheDUETtrials,providingtheywereclinicallystable.

Theincidenceofhepaticevents(suchashepatobiliarydisorders)

tendedtobehigherinpatientstakingetravirinecomparedto

thosetakingplacebo(11%vs6%).

Thisdrugshouldbetakenafteramealtoincreaseits

bioavailability.Followingoraladministration,themaximum

plasmaconcentrationofetravirineisreachedbyfourhours.

Althoughetravirineisprimarilymetabolisedbytheliver,no

doseadjustmentisneededforpatientswithmildtomoderate

liverimpairment.Etravirinehasnotbeenstudiedinpatients

withsevereliverdisease.

AsetravirineinducesCYP3A4andinhibitsCYP2C9and

CYP2C19,co-administrationofdrugsthataremetabolisedby

theseenzymesmayaffectthetherapeuticoradverseeffectsof

etravirine.Manydrugsmayinteractwithetravirine,including

combinationsofotherantivirals.Etravirineshouldnotbe

co-administeredwithothernnRTIsandtherearespecific

recommendationsaboutgivingetravirinewithprotease

inhibitors.otherdrugswhichpotentiallyinteractwithetravirine

includeantiarrhythmics,anticoagulants,anticonvulsants,

antifungals,antibiotics,benzodiazepines,corticosteroids,statins,

immunosuppressants,phosphodiesterasetype5inhibitorsand

StJohn'swort.Itisthereforeimportanttoobtainafullrecordof

thepatient'smedicationsbeforeprescribingetravirine.

Etravirinerepresentsanotheroptionforpatientsinfectedwith

multi-resistantHIVstrains,althoughdecreasedsusceptibility

tothisdrughasbeenobserved.Long-termdataareneededto

assesshowdurabletheobservedresponsesare.Thepatient's

treatmenthistoryandantiviralresistancetestingshouldguide

theuseofthisdrug.

manufacturerdeclinedtosupplydata

references1. MadrugaJV,CahnP,GrinsztejnB,HaubrichR,LalezariJ,

MillsA,etal.EfficacyandsafetyofTMC125(etravirine)intreatment-experiencedHIV-1-infectedpatientsinDUET-1:24-weekresultsfromarandomised,double-blind,placebo-controlledtrial.Lancet2007;370:29-38.

2. LazzarinA,CampbellT,ClotetB,JohnsonM,KatlamaC,MollA,etal.EfficacyandsafetyofTMC125(etravirine)intreatment-experiencedHIV-1-infectedpatientsinDUET-2:24-weekresultsfromarandomised,double-blind,placebo-controlledtrial.Lancet2007;370:39-48.

t

Nitisinoneorfadin(orphan)

2mg,5mgand10mgcapsules

Approvedindication:hereditarytyrosinaemiatype1

Tyrosineisoneoftheaminoacidsinvolvedinthesynthesisof

moleculessuchasdopamineandnoradrenaline.Themetabolic

pathwayfortyrosineincludestheenzymefumarylacetoacetase.

Inhereditarytyrosinaemiathereisadeficiencyofthisenzyme

leadingtoaccumulationofitssubstrates.Thiscausesliver

failure,renaltubulardysfunctionandneurologicalcrises.Inthe

acuteformofthediseasedeathusuallyoccursbeforethechild

isoneyearold.Childrenwithchronicformsofthediseaseare

atriskoflivercancer.Theyneedtohaveadietwitharestricted

tyrosineintake.

nitisinoneblocksanearlierstepinthemetabolismoftyrosine.

Bycompetitivelyinhibitingtheenzymehydroxyphenylpyruvate

dioxygenaseitisthoughttoreducetheproductionofthetoxic

substratesoffumarylacetoacetase.

Ashereditarytyrosinaemiatype1isararedisease,oneofthe

earlystudiesofnitisinoneonlyincludedfivechildren.During

7–9monthsoftreatmentplasmaandurinarymarkersofthe

toxicmetabolitesdeclinedandliverfunctionimproved.1

Theapprovalofnitisinonewasbasedonaninternational,

uncontrolledstudyof207children.Theyweretreatedfor

amediandurationof22months.Thebiochemicalmarkers

improvedandtherewassomeevidenceofimprovedsurvival.

Thefour-yearsurvivalwas93%,butonly35patientswere

includedinthatanalysis.(Deathorlivertransplantationresulted

inthewithdrawalof37patients.)Comparedtothetreatmentof

historicalcontrolswithdietalone,theprobabilityofsurviving

forfouryearsincreasedfrom29–60%to88–94%.Theoccurrence

oflivercancerwasreduced,particularlyinchildrenwho

begantreatmentbeforetheirfirstbirthday.Startingtreatment

beforesixmonthsofageappearstoreducetheneedforliver

transplantation.

Asnitisinoneblocksthemetabolismoftyrosine,theplasma

tyrosineconcentrationwillincrease.Thepatientthereforestill

needstofollowadietdeficientintyrosine.Highconcentrations

oftyrosinecanhavetoxiceffectsontheeyes,skinandnervous

system.

nitisinonewasoriginallydevelopedasaherbicide,but

developmentstoppedwhenanimalstudiesfoundithadocular

adverseeffects.ophthalmologicalassessmentisneededbefore

treatmentandifocularsymptomsdevelop.

Patientsneedregularbloodcountsbecauseleucopeniaand

thrombocytopeniacanoccur.Theseabnormalitiesmaybe

transientbutmayrequireareduceddoseofnitisinone.

Thepharmacokineticsofnitisinonehavenotbeenstudiedin

detail.Therearealsonodruginteractionstudies.


tTheT-score()isexplainedin'newdrugs:transparency',AustPrescr2007;30:26–7.

Answers to self-test questions

1. True

2. False

3. True

4. False

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Althoughitmaybealifelongtreatment,muchremains

unknownaboutnitisinone.Whileitimprovessurvival,itmay

notamelioratethecomplicationsofthedisease.2Atpresent,

thebenefitsofnitisinonewithalowtyrosinedietdoappearto

outweightheharmsintreatinghereditarytyrosinaemiatype1.

manufacturerprovidedadditionalusefulinformation

references *†

1. LindstedtS,HolmeE,LockEA,Hjalmarsono,StrandvikB.TreatmentofhereditarytyrosinaemiatypeIbyinhibitionof4-hydroxyphenylpyruvatedioxygenase.Lancet1992;340:813-17.

2. Masurel-PauletA,Poggi-BachJ,RollandMo,Bernardo,Guffonn,DobbelaereD,etal.nTBCtreatmentintyrosinaemiatypeI:long-termoutcomeinFrenchpatients.JInheritMetabDis2008;31:81-7.

t t

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

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

t t manufacturerprovidedadditionalusefulinformation

manufacturerprovidedonlytheproductinformationt

t manufacturerdeclinedtoprovidedata

manufacturerdidnotrespondtorequestfordata

t t t manufacturerprovidedclinicalevaluation

X

T-scoresareasfollows:

5. False

6. True

7. False

8. False

PrintPostApprovedPP349181/00151•ISSn0312-8008©nationalPrescribingService2009

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