2 Pharmaceutical marketing and the internet MSweet

5 Letters

6 Prescription pricing demystified MTatchell

9 Treating dementia AMCrouch

13 Medicinal mishap Monitormorphine

14 Treatments for severe psoriasis JRSullivan&VAPreda

18 Patient support organisation PsoriasisAustralia

18 Dental notes Psoriasis

19 Drug treatment of pituitary tumours EMLim

22 New drugs desvenlafaxinesuccinate,

methylnaltrexone,rivaroxaban,

triptorelinembonate,valsartan,

valsartan/hydrochlorothiazide,

amlodipine/valsartan

Fulltextwithsearchfacilityonlineatwww.australianprescriber.com

VoLuMe 32 NuMber 1 AN iNDePeNDeNT reView FebruAry 2009 C o n T E n T S

2 | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

in this issue…

Pharmaceutical marketing and the internetMelissa Sweet, Health Journalist, with honorary appointments at School of Public Health, University of Sydney, and School of Medicine, Notre Dame University (Sydney campus)

Summary

Pharmaceutical companies are capitalising on the advent of the internet and the development of new media forms to promote their products. electronic detailing, interactive websites, email prompts and viral marketing campaigns using social networking sites such as youTube, MySpace and Facebook are among the tools being used. Such campaigns are targeting both health professionals and the general public. The internet is helping to globalise and to change the nature of pharmaceutical marketing, and thus raises some new challenges for regulators.

Keywords:advertising,drugindustry,drugpromotion.

(Aust Prescr 2009;32:2–4)

introductionTheinternetandrelatedtechnologieshaverevolutionisedmany

aspectsofsociety.Forthepharmaceuticalindustry,asforother

sectors,thishasbroughtnewmarketingopportunities.The

internetcangreatlyexpandacompany'sreach.Forexample,

apopularvideoonYouTubemaypotentiallybeseenby

thousandsofpeople.Perhapsmoreimportantly,internet-based

technologiesareenablingnewstylesofcommunication

betweentheindustryanditstargets,includingmoreinteractive

andcustomer-responsivecampaigns.Consultancieshavebeen

establishedandbookswritten1tohelpthepharmaceutical

industrydevelopinternet-basedmarketing.

electronic detailing Inthecontextofdrugpromotion,detailinghastraditionally

involvedface-to-facecontactbetweenavisitingsales

representativeandahealthprofessional.However,drug

companies,especiallyinnorthAmericaandEurope,are

increasinglyturningtoelectronicdetailingore-detailing

forhelpinmarketingtheirproducts.E-detailingincludes

diversestrategies,suchasvideoconferencing,theprovision

ofelectroniceducationmodules,andtheuseofemailand

relatedtechnologiesaspromptsandtopromotetwo-way

communications.Ithasbeenusedfordisease-awareness

campaigns,andfor'customerrelationshipmanagement'.

Presentationstoapharmaceuticalmarketingconferencein

Europesuggestthate-detailingisnotpopularwithalldoctors.2

However,itischeaperthantraditionalsalesrepresentatives

andcanresultinasignificantreturnoninvestmentthrough

increasedsales.Somecompaniesareprovidingfinancial

incentivesfordoctorstoparticipateine-detailing,such

ashonoraria,productsamples,practicetools,andpatient

educationresources.3InPoland,forexample,Sanofi-Aventis

lentphysiciansinternet-connectedhand-helddeviceswhich

wereloadedwithclinicalsupportinformation,drugindexes,

abstractsofclinicalstudies,informationfromkeyopinion

leaders,andadvertisingandeducationalmaterials.Inexchange,

thedoctorsparticipatedinaclinicaltrialofaSanofi-Aventis

drugandenteredanonymouspatientdataintothedevice.The

companyaimedtobuildrelationshipswiththedoctors,touse

thedeviceasanadvertisingmedium,andtogatherfeedback.

Thecompanyalsoreportedthatthesedoctorsthenprescribed

moreofitsdiabetesproducts.3

Animportantaspectofe-detailingisthatitenables'predictive

marketing'.Thismeansthatcompaniescanbemoreeffective

andtimelyinelicitingfeedbackfromprescribersinordertotailor

marketingstrategiestotheirindividualpreferencesandneeds.4

Corporate blogs and websitesTheglobalreachoftheinternetmeansthatAustraliansnow

haveeasyaccesstooverseasblogsandwebsitespromoting

prescriptionmedicinesandotherproducts,andevensellingthem.

Safetyconcernshavebeenraisedaboutthepurchaseof

prescription,non-prescriptionandcomplementarymedicines

overtheinternet.5,6

Companiesarealsousingblogsandwebsitestodevelop

customerrelationships.AsGlaxoSmithKlinesaysonitscorporate

Eachnewyearbringsanincreaseinprescriptioncharges.

However,co-paymentsarenottheonlycomponentin

prescriptionpricing.MichaelTatchellexplainswhatelse

influencesthepricespatientspay.

WhileJohnSullivanandVeronicaPredatellusaboutnew

treatmentsforpsoriasis,AlisaCrouch'sreviewshowsthere

havebeenfewrecentadvancesinthedrugtreatmentof

dementia.Therehavebeenmanyadvancesinelectronic

communication,butMelissaSweetwarnsusthatsome

druginformationontheinternetisactuallymarketing

material.

| VoLuMe 32 | NuMber 1 | FebruAry 2009 3www.austral ianprescriber.com

blogintheUSAforaweightlossproduct(http://alliconnect.com),

'it'saplaceforyoutohaveaconversationwithusaboutweight

lossissues'.Such'conversations'mayenablecompaniesto

gatherpatientstoriesandfeedbackforuseinpositioningtheir

products.Thediscussionsarenotonlyminedforinformation

(http://pharmamkting.blogspot.com),butalsoensurethe

repetitionofmarketingmessages.Sometimescompaniesuse

multiplewebsitestopromotetheirproductsandissuestodifferent

marketsegments.Forexample,GlaxoSmithKlinealsopromotes

weightlossissuesatwww.questioneverything.com

Websitesarealsousedforpatientsupportprogramsand

educationalthoughitisnotalwaysclearfromthewebsite

namewhoisbehindit.IntheUSA,Pfizerrunssuchaprogram

(www.get-quit.com)forvareniclineusers,providingregular

emailsandotherpromptssuchasapersonalisedwebpage

tosupporttheirproductuse.InAustralia,thecompany's

advertisingandmarketingcampaignisbackedbyaconsumer

website(www.outsmartcigarettes.com.au)thatincludesprompts

forquestionstoaskdoctors.Meanwhile,aWyethConsumer

HealthCarewebsite(www.caltrate.com.au)soundsthealarm

onosteoporosisandencouragespeopletoseeadoctorif

theyansweryestoanyquestionsona'oneminuterisktest',

includingthequestion'haveeitherofyourparentsbrokenahip

afteraminorbumporfall?'.

Companywebsitescanlinktoothersitesthatmaynotmeet

regulatoryrequirements.GlaxoSmithKline'sAustralianwebsite

raisingconsumerawarenessofgenitalherpesandtreatment

issues(www.thefacts.com.au)linkstotheAustralianHerpes

ManagementForumbutadvisesthatexternallinkssuchasthis

'maynotcomplywiththeAustralianregulatoryenvironment'.

TheForum,whoseboardcomprisesprominentphysicians,aims

'toimprovetheawareness,understanding,managementand

controlofherpesvirusinfectionsinAustralia',andissponsored

primarilybypharmaceuticalanddiagnosticcompanies.

Pharmaceuticalcompaniesarenotaloneinusingtheinternetto

marketproductsandtoconductawareness-raisingcampaigns

thatmayaffectpatients'interactionswithdoctors.The

complementarymedicinescompanyBlackmores,forexample,

hasasophisticatedwebsite(www.blackmores.com.au),while

nescaféhaslaunchedawebsite(www.nescafe.com.au/hcp

password:Coffee)supportedbyadvertisinginthemedicalpress

whichpromotescoffeeasanagentthatmayhelplowertherisk

ofdevelopingtype2diabetes.

Viral marketing and social networking sites

SocialnetworkingsitessuchasYouTubeandFacebookhave

beensuccessfullyexploitedbymanyconsumerproduct

companiesforviralmarketingcampaigns.Thesecampaignsare

sonamedbecausethetransmissionofamarketingmessage

throughthenetworksisseenasanalogoustothespreadofa

viralinfectioninapopulation.

Itcanbeextremelydifficulttoidentifywhoisresponsiblefor

contentspreadthroughsuchnetworks,anditisnotclearhow

widelythepharmaceuticalindustryisusingthem.Arecent

searchfor'Champix'onYouTube(accessed12november

2008)identified46videos,manyofwhichappearedtobeof

ordinaryviewersdescribingtheirexperienceswithvarenicline.

Itwasunclearwhetheranyofthesevideoswerecommercially

generated.However,thefirstoneidentifiedbythesearch

(http://au.youtube.com/watch?v=Vx7baviT1DQ)linkedtoa

websitewhosenamesuggestsitisanindividual'spersonal

site(www.kims-website.info),althoughitappearsinfacttobe

acommercialsite.ontheotherhand,suchnetworksarealso

beingusedforpublichealthpurposes,includingpromoting

messagesaboutthequalityuseofmedicines.YouTubealso

includes,forexample,aUSFoodandDrugAdministration

(FDA)videodiscussingpotentialadverseeffectsofvarenicline.7

Evenwhenlistingsareclearlycommercials,aswithabizarre

videoonYouTubepromotinganewmedicineforinsomnia,

ramelteon,itisnotnecessarilyclearwhoisresponsibleforposting

them.ThevideofeaturesaninsomniacchattingwithAbraham

Lincolnandatalkingbeaveroverachessboard.Thesecharacters

understanding the lingoblog

Acontractionof'weblog',anonlinejournal.

Consumer opinion leaders

ordinarypeoplewhoinfluencewhatotherconsumersbelieve

andbuy.oftenemployedinweb-basedmarketing.

e-detailing

Informationtechnology-supportedpromotionalactivities

whichprovidecustomers,whetherhealthprofessionalsor

patients,withinformation.

Podcasts

Repositoriesofaudioandvideomaterialsthatcanbe

broadcastovertheinternet,anddownloadedtoportable

mediaplayers.

web 2.0

Asecondgenerationofinternet-basedservices,suchas

socialnetworkingsitesandwikis,thatemphasiseonline

collaborationandsharingamongusers.

wikis

Websitesthatcanbeeditedbyanyonewhohasaccessto

them.ThebestknownexampleisWikipedia.

youTube

Asocialnetworkingsitethatletspeoplewatchandshare

videosovertheinternet.othernetworkingsitesinclude

MySpaceandFacebook.

� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

alsoappearinadirect-to-consumertelevisionadvertising

campaignintheUSA.ThevideowassubmittedtoYouTubein

2006by'lewisusauk',whosaid:'newRozeremAdCampaign.

PossiblythebestprescriptiondrugadsincetheFDArelaxed

therulesondrugadvertising'.Accordingtoapharmaceutical

marketingblogbyJohnMack(http://pharmamkting.blogspot.com),

lewisusaukisa'sockpuppet…afalseidentitythroughwhicha

memberofaninternetcommunityspeakswhilepretendingnotto,

likeapuppeteermanipulatingahandpuppet'.

Apartfromdisseminatingcompany-generatedcontent,social

networkingsitesalsoofferopportunitiesforcompaniesto

insertthemselvesanonymouslyintoconversationsbetween

siteusersthroughpostingsandcommentsonblogs.John

Macksayssomeofthepostingsabouttheramelteonvideoon

YouTubesmackofthispractice,and'areattemptingtohijack

theconversationbysubmittingcommercialmessages(thatis

advertisements)disguisedasgenuinecommentsfrom

ordinarycitizens'.

Meanwhile,inthenetherlands,anindustry-drivencampaign

conductedviaHyves(aDutchequivalentofFacebook)gathered

morethan80000signaturesinonlythreeweeksforapetition

aimedatinfluencingdecisionsaboutfundingforhuman

papillomavirusvaccines.AccordingtoDrRuudCoolenvan

Brakel,DirectoroftheDutchInstitutefortheProperUseof

Medicine,itwas'averyeffectivewaytocreatepublicawareness

andcommitmenttoacommercialcausedisguisedasapublic

healthissue'.

Pharmaceuticalcompaniesarealsoseekingtocapitalise

onmedicalsocialnetworkingsites.Pfizer,forexample,is

reportedlycollaboratingwithSermoInc,awebventurebased

inCambridgeUSA,wheretensofthousandsofdoctorsdiscuss

diagnosticandtreatmentissuesinanonymouspostings.The

collaborationallowsPfizer'sdoctorstoaskquestionsand

respondtoposts.Memberscanalsorankpostings,whichwill

giveinsightslikelytohelpthecompany'sdevelopmentof

marketingmessages.Sermoissaidtobeintalkswithother

companiesaswell.Thesiteearnsmoneybylettingclientssuch

ashedgefundsmonitordoctors'anonymousconversations

andthusgaininsightinto,say,thepopularityofcertain

treatments.Sermorewardsphysicianswhoseinputishighly

rankedbyothermembersandplanstooffertopaydoctorsfor

participatinginitsclients'surveys.8,9

regulation

TheMedicinesAustraliaCodeofConductattemptstoregulate

thepromotionofprescriptionmedicinesontheinternet.

However,itisdifficulttopolicetheanonymousmarketingof

drugsonblogsandforums,ortoregulateconsumers'access

toinformationfromcountrieswherepharmaceuticalmarketing

maybelessregulatedthaninAustralia.

Conclusion

Theongoingdevelopmentofinternet-relatedtechnologiesis

likelytoprovidepharmaceuticalmanufacturerswithfurther

opportunitiestoinfluenceconsumerexpectationsofhealthcare

andprescribingpractices.Itisalsoprovidingnewopportunities

forthoseconcernedwiththequalityuseofmedicinesand

evidence-basededucation.10Muchcanbegainedfrom

constructiveengagementwiththeworldwideweb,and

21stcenturydoctorsalsoneedtounderstanditsuseasa

marketingtool.

references1. DogramatzisD.Pharmaceuticalmarketing:apractical

guide.Englewood(Co):InterpharmPress;2002.2. HeutschiR,LegnerC,SchiesserA,BarakV,ÖsterleH.

Potentialbenefitsandchallengesofe-detailinginEurope.JMedMarket2003;3:263-73.

3. BatesAK.ConferenceInsights:onlinemarketingandeDetailing:in-depthreportfromaneyeforpharmaconference.JMedMarket2006;6:298-300.[Moredetailedversionavailableatwww.keywordpharma.com]

4. LererL.E-businessinthepharmaceuticalindustry.JMedMarket2002;3:69-73.

5. BessellTL,AndersonJn,SilagyCA,SansomLn,HillerJE.Surfing,self-medicatingandsafety:buyingnon-prescriptionandcomplementarymedicinesviatheinternet.QualSafHealthCare2003;12:88-92.

6. ArmstrongK,SchwartzJS,AschDA.Directsaleofsildenafil(Viagra)toconsumersovertheInternet.nEnglJMed1999;341:1389-92.

7. FoodandDrugAdministration.Patientsafetynews:newsafetywarningsaboutChantix[video].www.youtube.com/watch?v=ep3U0SVfpW4[cited2008nov18]

8. Pfizerbecomeslatesttopartnerwithfast-growingonlinedoctors'forumSermo.TheAge(Melbourne).2007oct15.http://healthyskepticism.org/library/2007.phpGotoHSL12469[cited2008nov18]

9. JohnsonA.Pfizer-doctorswebpactmaygetlooks.TheWallStreetJournal.2007oct15.http://healthyskepticism.org/library/2007.phpGotoHSL12470[cited2008nov18]

10. BoulosMn,MarambaI,WheelerS.Wikis,blogsandpodcasts:anewgenerationofWeb-basedtoolsforvirtualcollaborativeclinicalpracticeandeducation.BMCMedEduc2006;6:41.www.biomedcentral.com/1472-6920/6/41[cited2008nov18]

Conflict of interest: none relevant to this article

note:Websitesandlinkscanchangequickly.Thosecitedinthis

articlewereaccessibleatthetimethearticlewasacceptedfor

publication.

| VoLuMe 32 | NuMber 1 | FebruAry 2009 �www.austral ianprescriber.com

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

Severe hyponatraemia due to mirtazapine

Editor,–DrCheahandMsLadhamshighlightedan

importantinteractionbetweenmedicationsprescribedfor

a79-year-oldwoman(AustPrescr2008;31:97).Adiagnosis

ofinappropriateantidiuretichormonesecretion(SIADH)

canonlybemadewhencommoncauses,suchastheuse

ofdiuretics,areexcluded.1Therefore,itisprobablethat

frusemidecontributedtothepresentation.Aserumsodium

concentrationpriortotheinitiationofmirtazapinewould

havebeenhelpful.

TheriskfactorsfordevelopingSIADH(previouslypresented

asrelatingtomirtazapineonly)areapplicabletomost

psychotropicmedications,includingduloxetine,venlafaxine,

fluoxetine,paroxetine,citalopram,escitalopram,tricyclic

antidepressants,neurolepticsandcarbamazepine.2,3,4

Thus,torechallengethepatientwithmirtazapinewould

benecessaryandacceptable,bothtodisprovethenull

hypothesisandbecausetheoccurrenceoftheadverseevent

cannotbepredictedwhenusinganotherdrug.2,3

Therelevantquestionishowtotreatdepressioninthe

elderly,whohaveagreaterprobabilityofdevelopingSIADH.

Areviewsuggeststhathyponatraemiainducedbyselective

serotoninreuptakeinhibitors,inparticular,maybeatransient

effecttowhichthepatientdevelopstolerance.2

AlexanderDFranke

Intern

SlavHKostov

ConsultantPsychiatrist

RoyalPerthHospital

references

1. BartterFC,SchwartzWB.Thesyndromeofinappropriatesecretionofantidiuretichormone.AmJMed1967;42:790-806.

2. KirbyD,AmesD.Hyponatraemiaandselectiveserotoninre-uptakeinhibitorsinelderlypatients.IntJGeriatrPsychiatry2001;16:484-93.

3. MadhusoodananS,BogunovicoJ,MoiseD,BrennerR,MarkowitzS,SoteloJ.Hyponatraemiaassociatedwithpsychotropicmedications.Areviewoftheliteratureandspontaneousreports.AdverseDrugReactToxicolRev2002;21:17-29.

4. EllisonDH,BerlT.Thesyndromeofinappropriateantidiuresis.nEnglJMed2007;356:2064-72.

Dr Cheah and Ms Ladhams, authors of the Medicinal

mishap, comment:

WeagreethatthediagnosisofSIADHrequiresexclusionof

othercauses,includingdiuretictherapy.Thepatienthadbeen

treatedwithfrusemideforyearspriortopresentationwitha

normalserumsodium.Frusemidewasceasedonadmission

andrecommencedatday10withoutasubsequentfallin

sodium.Wealsonotedthatconcomitantuseofotherdrugs

whichcausehyponatraemiaisariskfactorformirtazapine-

inducedhyponatraemia.Infactmostpatientswhodevelop

severehyponatraemiahavemorethanonecontributing

cause.1

Whilemanyantidepressantdrugsareassociatedwith

hyponatraemia,2wearguethatrechallengewithmirtazapine

inthissettingisneithersafenorappropriategiventhe

profoundandrapidfallinserumsodiumprecipitating

hospitaladmission.ourpurposewastohighlight

mirtazapine-inducedhyponatraemiawhichisonlyrarely

describedintheliteratureandnotlistedineithertheproduct

informationorMIMS.

references

1. ClaytonJA,LeJeuneIR,HallIP.Severehyponatraemiainmedicalin-patients:aetiology,assessmentandoutcome.QJM2006;99:505-11.

2. MadhusoodananS,BogunovicoJ,MoiseD,BrennerR,MarkowitzS,SoteloJ.Hyponatraemiaassociatedwithpsychotropicmedications.Areviewoftheliteratureandspontaneousreports.AdverseDrugReactToxicolRev2002;21:17-29.

Australian Medicines Handbook 2009 The2009editionoftheAustralianMedicinesHandbookisnow

available.Itincludesnewmonographsonmedicinesmarketed

during2008andupdatedcontent,reflectingchangedevidence

andpractice.

Advicefromnewpracticeguidelineshasbeenincorporated

inareassuchashypertensionandrheumatoidarthritis,and

safetyinformationhasbeenupdated.

The984-pagepaperbackeditionofthehandbook,andother

formats,canbeorderedonlineatwww.amh.net.auorby

phoning(08)83036977.

� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

Prescription pricing demystifiedMichael Tatchell, Director, Health Economics, The Pharmacy Guild of Australia, Canberra

Summary

Patient status, premiums, special contributions and safety nets all affect the cost of prescription medicines. Depending on their status, patients pay different co-payments for subsidised prescription drugs. extra costs may be added by the manufacturer and the dispensing pharmacist.

Keywords:bioequivalence,costofdrugs,Pharmaceutical

BenefitsScheme.

(Aust Prescr 2009;32:6–8)

introductionManypatientsareunsureaboutthepriceoftheir

PharmaceuticalBenefitsScheme(PBS)orRepatriation

PharmaceuticalBenefitsScheme(RPBS)prescriptionsandoften

asktheirdoctor'Howmuchwillmyprescriptioncost?'.Thefinal

pricepaidbythepatientfortheseprescriptionmedicinescan

bebrokendownintovariouscomponentsanddependsonthe

following(seeFig.1):

n theirstatusasapatient(general,concessionalorrepatriation)

n whetherabrandpricepremium,therapeuticgrouppremium

oraspecialpatientcontributionapplies

n thepatient'ssafetynetstatus.

Thepricingof'private'prescriptionsthatfalloutsidethePBS

andRPBSisnotinfluencedbyanyAustraliangovernment

subsidyorpricingrestrictions.

Patient co-paymentsForthe2009calendaryear,theco-paymentspayablebypatients

areasfollows:

Generalpatients upto$32.90

Concessionalandrepatriationpatients $5.30

Theseamountsareindexedon1Januaryeachyearin

accordancewiththeConsumerPriceIndexintheprevious

12months.TheNational Health Act 1953precludespharmacists

fromdiscountingthepatientco-paymentthatapplieson

government-subsidisedPBSmedicines.

Premiums and special contributionsIncertaininstancesthepharmaceuticalmanufacturermay

choosetoapplyanadditionalchargefortheirproductwhichthe

patientisobligedtopay.Thesecanbeabrandpricepremium,

atherapeuticgrouppremiumoraspecialpatientcontribution.

Whiletheseextrachargesarepaidtothepharmacistatthetime

ofdispensing,theyarepassedontothemanufacturer.

Brand price premiumsSince1990,manufacturershavebeenabletosettheirown

pricesonPBSmedicinesinparticularcircumstances.Thepolicy

operateswhenthereareanumberoftherapeuticallyequivalent

brandsavailable.Thegovernmentsubsidiseseachofthe

availablebrandstothelevelofthecheapestbrand.Thismeans

thatpatientshavetopayextraforthemoreexpensivebrands–

thosewithabrandpricepremium.

Fig. 1

Doctor, how much will my prescription cost?

Concessional,repatriationpatients

Generalpatients

Aftersafetynet

($318threshold)

Beforesafetynet

Aftersafetynet($1264.90threshold)

Beforesafetynet

$5.30* nocharge*

Upto$32.90*† $5.30*

* Plusanypremium(brandpricepremiumortherapeuticgrouppremium)orspecialcontributionthatmayapply† Actualcostdependsonmanufacturerpriceandallowablepharmacistfeesandcharges

Theseamountsapplyduringthe2009calendaryear

| VoLuMe 32 | NuMber 1 | FebruAry 2009 �www.austral ianprescriber.com

Unlesstheprescribingdoctorhasspecificallyindicated

otherwiseontheprescription,apharmacistcandispense

anotherbioequivalentbrandatthepatient'srequest.Inthisway,

patientscanavoidpayingthebrandpricepremium.However,

whenthebrandpricepremiumapplies,itcannotbediscounted

bythepharmacistandthepatientmustpayitinfull.

InAugust2008,334oftheapproximately3000brandslistedon

thePBSattractedabrandpricepremium.Theaveragebrand

pricepremiumwas$2.69andrangedfrom$0.08to$75.30.

Themajorityofbrandpricepremiumswereintherangeof

$1.00–$4.00.

Therapeutic group premiumsSince1998,atherapeuticgrouppremiumpolicyhasappliedto

specificallydefinedgroupsofdrugswhichhavesimilarsafety

andhealthoutcomes.Withinthesegroups,thedrugscanonly

beinterchangedbytheprescriber.Thegovernmentsubsidises

alldrugswithinagrouptothelevelofthelowestpriceddrug.

Thedifferenceinpricebetweenthelowestpriceddrugandthe

highestpriceddrugswithinthegroupiscalledatherapeutic

grouppremium.Thisispaidbythepatientandgoestothe

manufacturer,nottothepharmacyorthegovernment.

Theprincipleisthatthereisalwaysatleastonedrugwithineach

therapeuticgroupofdrugsthatdoesnothavethetherapeutic

grouppremium.Inaddition,whenapatientisonlyabletotake

adrugwithatherapeuticgrouppremiumformedicalreasons,

theprescribingdoctorcanrequestanexemptionfromthe

therapeuticgrouppremiumfromMedicareAustralia.Where

thereisnoexemption,thepatienthastopaythetherapeutic

grouppremiuminfull.

InAugust2008,therewerefourgroupsofdrugsaffectedby

thetherapeuticgrouppremiumpolicy.Thesewereangiotensin

convertingenzyme(ACE)inhibitors,calciumchannelblockers,

protonpumpinhibitors,andtheH2receptorantagonists.of

themanyitemswithinthesetherapeuticgroups,onlyeight

attractedtherapeuticgrouppremiumsrangingfrom$1.52to

$4.02.Thepricesofitemsinthesegroupsarereviewedbythe

PharmaceuticalBenefitsPricingAuthorityeachyear,asareall

drugslistedonthePBS.

Special patient contributions

Forcertainexpensivemedicineswherethegovernmentand

themanufacturercannotnegotiateamutuallyacceptable

price,thegovernmentmakesapartcontributiontowardsthe

manufacturer'sprice.Intheseinstancesthepatientpaystheir

normalco-paymentplusaspecialpatientcontribution.Thisis

thedifferencebetweenthegovernment'spartcontributionand

theactualcostofthesuppliedmedicine.

Thespecialpatientcontributioncannotcounttowardsthesafety

net,nordoesitapplytoRPBSprescriptions,soveteransonly

paytheirnormalco-paymentcontributionandtheDepartment

ofVeterans'Affairspaystherest.

InAugust2008,therewere11itemsonthePBSattractinga

specialpatientcontribution,whichrangedfrom61centsto

$437.01(bleomycinsulfate).

other charges for the patientAsignificantnumberofPBSitemsarepricedbelowthe

maximumco-paymentforgeneralpatientsof$32.90.Asno

governmentsubsidyappliestotheseitems,thepatientpaysthe

fullcostforthesemedicines.

Theamountthepatientpaysfortheseitemswilldependnot

onlyonthemanufacturer'spricefortheitem,butalsoonthe

feesandchargesthepharmacistisentitledtoapply.Theonline

versionofthePBSSchedule(accessibleatwww.pbs.gov.au)

includesa'pricetoconsumer'columnwhichliststheprice

theconsumercanexpecttopay,includingtheallowablefees

andcharges.Thereisalsoacolumnshowingthe'maximum

recordablevalueforsafetynet'–thisisthemaximumamount

thatcanberecordedonthepatient's'prescriptionrecordform'

tocounttowardsthesafetynetforthatpatient.Itdoesnot

necessarilyequatetotheamountthepatientpayswhichcould

wellbehigherduetotheadditionalfeesandchargesthatdonot

countforsafetynetpurposes.

Theallowableextrafeesandchargesthepharmacistcanapply

toitemspricedunderthemaximumco-paymentof$32.90

includethefollowing:

Additionalfeeforsafetynetrecording $1.03

Allowableadditionalpatientcharge upto$3.79

Theadditionalfee($1.03)canbechargedfortheextrawork

involvedinrecordingtheprescriptiondetailsontheprescription

recordform.Itmaytaketheformofapartchargetotakethe

costupto$32.90.Itisnotcompulsoryforthepharmacistto

chargethepatient,butifthefeeischargeditshouldbeaddedto

thePBSdispensedpricerecordedonthepatient'sprescription

recordform.onlyonefeeispayablepermedicine,evenif

therearemultiplequantitiesdispensed.Itdoesnotapplyto

prescriptionsdispensedforconcessionalandrepatriation

patients.

Theallowableadditionalpatientcharge(upto$3.79)applies

wherethePBSdispensedpriceisbelowthegeneralpatient

contributionof$32.90.ItisaddedtothePBSdispensedprice

inlieuofchargingprivateprescriptionrates.Thechargeis

agreedbetweenthePharmacyGuildandthegovernmentand

hasbeeninplacesince1991(whenitstoodat$2).Thischarge

isoptionalanditcanbediscountedbythepharmacist.Itmay

onlybeaddedtogeneralpatients'prescriptionsandcannotbe

enteredontheprescriptionrecordformaspartofthecostofthe

medicine.

Somepharmaciesdiscountbelowthebasepriceofthe

medicine.Suchpricingpracticeisusuallyassociatedwith

pharmaciesofferingalow-overhead,low-servicemodelofcare

whichmaynotbegeographicallyconvenientforsomepatients.

� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

Themaximumamountthatmaybechargedtoageneral

patientis$32.90sothischargecannotbeappliedifthetotal

cost(includingtheadditionalfeeandthisallowableextra

charge)takestheamountover$32.90.However,thisallowable

additionalpatientchargemaytaketheformofapartchargeto

takethecostupto$32.90.

ThePBSreformsthattookeffecton1August2008loweredthe

pricespatientspayformanyitemspricedbelowthemaximum

patientco-payment–thepricesofmorethan1000medicines

havefallenbybetween20centsand$4.65.Thereisa$1.50

governmentincentivepaymenttopharmacistsfordispensing

substitutable,premiumfreeprescriptions.Thisonlyappliesto

subsidiseditemsandisnot paidbythepatient.

Patient safety nets

Sincethelate1980s,aPBSsafetynethasbeeninplaceto

protectpatientsandtheirfamilies(particularlythosewho

maybeusinglargequantitiesofmedicines)fromthehigh

cumulativecostofprescriptionmedicines.

Twosafetynetsapply–oneforpensioner,concessionaland

repatriationpatients,andtheotherforgeneralpatients.The

thresholdsforeachsafetynetareadjustedeachyearinlinewith

theConsumerPriceIndex.Forthe2009calendaryear

therespectivesafetynetthresholdsareasfollows:

General $1264.90

Concessionalandrepatriation $318(equivalentto

60prescriptionsat$5.30)

Thethresholdsdonottakeintoaccountbrandpricepremium,

therapeuticgrouppremiumorspecialpatientcontribution

charges,ortheallowableadditionalpatientcharge.

Afterreachingthethresholdof$1264.90,generalpatientsare

issuedwithasafetynetconcessioncardthatentitlesthemto

paytheconcessionalco-payment($5.30perprescription)forthe

restofthatcalendaryear.Thesepatientsarestillrequiredtopay

anyrelevantbrandpricepremium,therapeuticgrouppremium

orspecialpatientcontributioncharges.

Afterconcessionalpatientshavereachedthethresholdof

$318,theyareissuedwithasafetynetentitlementcardthat

allowsthemtoreceivetheirprescriptionsfreeofchargeforthe

remainderofthatcalendaryear.However,thesepatientsarestill

requiredtopayanyrelevantbrandpricepremium,therapeutic

grouppremiumorspecialpatientcontributioncharges.

Patientscankeeparecordoftheiraccumulatingexpenditureon

PBS/RPBSmedicinesonaprescriptionrecordform.Thisform

isavailablefromcommunitypharmaciesandcaneitherbekept

bythepatientorthepharmacist.Ifkeptbythepatient,theform

needstobehandedtothepharmacistoneveryoccasionaPBS

prescriptionisdispensed.Manypatients(particularlythosewho

useonlyonepharmacy)leaveittothepharmacisttokeeptheir

accumulatingprescriptionusageonthedispensarycomputer.

ConclusionTherearemanyvariablesthatneedtobeconsideredbefore

adefinitiveanswercanbegiventopatientsabouttheir

prescriptioncosts,includingthepatient'sentitlementstatus

(concessional,repatriation,general,safetynet),whethera

premiumorspecialcontributionappliesandwhether(for

generalpatients)theamountfallsbelowthemaximumpatient

co-payment.Insimpleterms,Fig.1providesausefulsummary

ofthelikelycost,takingintoaccountthesevariables.

Conflict of interest: none declared

TheEditorialExecutive

Committeecelebrates

Australian Prescriber's

250thmeetingin

october2008

Fromlefttoright:DrFGMackinnon–DeputyEditor;MsMRyan–EditorialAssistant;DrSTwaddell–ClinicalPharmacologyRegistrar,2008;DrJRandall–Chair,nationalPrescribingServiceBoard;ProfTUsherwood–GeneralPractitioner;DrJSDowden–Editor-in-Chief;ProfJWGTiller–PsychiatristandChair,EditorialExecutiveCommittee;DrLWeekes–PharmacistandChiefExecutiveofficer,nationalPrescribingService;DrSKanagarajah–Geriatrician;DrAKnight–GeneralPhysician;(absent:DrPKubler–ClinicalPharmacologist)

Australian Prescriber's 2�0th meeting

| VoLuMe 32 | NuMber 1 | FebruAry 2009 9www.austral ianprescriber.com

Treating dementiaAlisa M Crouch, Advanced Trainee in Geriatric Medicine, Princess Alexandra Hospital, Brisbane

Summary

with increasing numbers of elderly patients, general practitioners are uniquely placed to investigate and treat dementia. Screening tests can be used, but a thorough history and physical examination are usually needed to make the diagnosis. other conditions such as delirium and depression should be excluded. both pharmacological and non-pharmacological treatments are important, depending on the particular problems facing the patient and their carer. The treatment of concurrent chronic disease may need to be modified as dementia progresses.

Keywords:Alzheimer'sdisease,cholinesteraseinhibitors,

memory.

(Aust Prescr 2009;32:9–12)

introductionTheprevalenceofdementiaapproximatelydoubleswithevery

fiveyearsofagebeyondtheageof65.By2050,theestimated

numberofnewdiagnosesinAustraliawillreach175000

annuallycomparedwith45700in2001.1

Generalpractitionersareoftenthefirstpointofcontactforpatients

orfamilieswhohaveconcernsaboutmemoryandcognitive

function.Theyarealsoinauniquepositiontosuspectthediagnosis

ofdementiawhenapatientpresentswithotherproblems.

Thevariationinpresentationcanmakediagnosisofcognitive

impairmentorearlydementiadifficult.However,earlydiagnosis

mayenableplanningforthefuture,decreaseanxietywith

appropriateeducationandallowconsiderationoftreatment.

AmultinationalsurveyofcarersforpeoplewithAlzheimer's

diseaseshowedadelayof12monthsfromfirstsymptoms

todiagnosis,includingadelayoffourmonthsinmakingan

appointment.IntheAustraliancomponentofthissurvey,30%

ofpatientswerediagnosedbytheirgeneralpractitioners.In93%

oftheAustraliancases,generalpractitionerswerethefirstpoint

ofcontact.2

DiagnosisThediagnosisofdementiaismadeonclinicalassessment

usingformalcriteria.3Theseincludeahistoryofthegradual

onsetofimpairmentsintwoormorecognitivedomains,which

causedifficultyineverydayfunction.Theseimpairmentsshould

notbeattributabletoanothercause,suchasadrugeffector

depression.Cognitivedomainswhicharecommonlyimpaired

includememory,languageanddecision-makingability.

Adetailedhistorywithacollateralhistoryfromfamilyand

friendsisessentialinmakingthediagnosis,determininga

patternofprogressionandassessinganyimpactondailyliving.

Asthisisatime-consumingprocess,ascreeningtestisoften

usedtodeterminewhetherthisisnecessary.

ThemostcommonlyusedscreeningtestistheFolstein

Mini-MentalStateExamination(MMSE).Itsvalidityhasbeen

demonstratedinmanypopulations,howeverinpatientsof

non-EnglishspeakingbackgroundtheRowlandUniversal

DementiaAssessmentScale(RUDAS)maybemoreappropriate.

TheMini-cogandGeneralPractitionerAssessmentofCognition

testsalsohavereasonablesensitivityandspecificityandmay

takelesstimetoadminister.4

Differential diagnosesItisworthdeliberatelyexcludingotherconditionsthatmay

appeartocausecognitiveimpairmentsuchasdelirium,

depressionandtheadverseeffectsofsomedrugssuchas

antipsychotics.Theclinicalfeaturesoftheseconditionsare

usuallydifferentfromthoseofdementiawhenconsidered

closely(seeTable1).Bloodteststohelpexcludeillnesses

mimickingdementiawouldincludemeasurementoffullblood

count,biochemistry,thyroidstimulatinghormone,vitaminB12and

Table 1

Alternative causes of cognitive impairment

Condition Clinical features

Delirium DisorderofattentionFluctuationofsymptomsoverhoursRecentonset(usuallydaystoafewweeks)

Depression LowmoodispredominantfeatureMayhavebiologicalfeaturesofmooddisturbanceMaybemotivatedtoimproveperformanceontestingforashorttimeoftencoexistswithdementiaMayhavehistoryofdepression

Drugeffects Commonoffendersare:• anticholinergics• sedativesandhypnotics• antipsychotics• analgesicsUsuallycausefeaturesofdelirium,butthedurationofsymptomsmaybeverylong

10 | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

folate.ACTscanofthebrainisusefulinexcludingconditionsthat

maybeamenabletotreatment,suchassubduralhaemorrhage

andnormalpressurehydrocephalus.Althoughtheremaybe

reversibleelementsformanywithabnormaltests,reversible

causesofdementiaareextremelyrare(lessthan1.5%).5

Identify the type of dementiaThereisno'cure'formostdementias.However,ifthediagnosis

includesinformationaboutthesubtypeofdementia(seeTable2)

itallowsapatientandtheirfamilyto:

• accessinformationthatmayhelpthemdealwithfunctional

difficulties

• benefitfromspecifictreatments(forexamplecholinergic

therapies)

• avoiddrugsknowntoaggravateproblems(forexample,

anticholinergics,andantipsychoticsindementiawithLewy

bodies)

• makeplansforthefuture.

Thereisagoodcorrelationbetweentheclinicaldiagnosisof

Alzheimer'sdiseaseandtheneuropathologyatautopsy.This

associationislesscertainwithothersubtypesofdementia,but

evenaputativediagnosismayallowapatientandcarertomake

senseofthepatient'ssymptoms.Anexampleistheseverefluent

aphasiaseeninayoungerpatientwithfrontotemporaldementia.

Assessment and planningAssesshowthepatientandtheircarerarecopingandwhatformal

andinformalsupportsandhelpareavailable.Thisassessment

canbetimeconsumingandahomevisit(perhapsbyassociated

nursingoralliedhealthstaff)maybeanefficientwayofgetting

thisinformation.Reimbursementforgainingcollateralinformation

maybeincludedinacomprehensivehealthassessmentwhich

maybereimbursedunderMedicare*.Ifthereareareasofneed

identified,anAgedCareAssessmentTeam(ACAT)evaluationmay

enableaccesstoarangeofservices.

Peoplewithdementiamaybeirritableandaggressive.Theycan

experiencedelusionsandhallucinations.Lookforchallenging

behavioursastheyarecommonandburdensome.Theywarrant

aspecificassessmentandmanagementapproach.6

* MedicareBenefitsSchedule–Items700and702

www9.health.gov.au/mbsSearchfor700and702

[cited2009Jan13]

Table 2

Subtypes and features of dementia

Dementia subtype important features

Alzheimer'sdementia Clinicaldiagnosisrequiresmemoryimpairmentandimpairmentoflanguage,executivefunction,motorfunction(dyspraxia)oragnosia

Vasculardementia Stepwiseprogression,associatedwithphysicalsignsofstrokeorhistoryoftransientischaemicattack

Mixeddementia MostcommonlymixedAlzheimer'sdiseaseandvasculardementia

DementiawithLewybodies Progressivedementiawithatleasttwoofthethreefeaturesoffluctuatingcognition,visualhallucinations,andParkinsonismFallscommonSeverelyintolerantoftheadverseeffectsofantipsychoticdrugsSomeevidenceforbenefitfromcholinesteraseinhibitors

Parkinson'sdiseasewithdementia Abilitytofunctioncanalsoberelatedtoadequacyofdopareplacementandisoftenworsein'off'periodsMaybepartofaspectrumofdiseasewithdementiawithLewybodies

Frontotemporaldementia Youngerpatients(lessthan65yearsofage)Familyhistoryoffrontotemporaldementiaoftenfound'Dysexecutivesyndrome'withchangeinbehaviourandpersonalitycommonDelusionscommonAlsoincludesprogressivefluentandnonfluentaphasiatypesMemoryrelativelysparedMini-MentalStateExaminationunreliableDeteriorateswithuseofantipsychotics

Post-traumatic HistoryofinjurywithconsistentimagingnotprogressiveAppearstoincreasetheriskoflaterdevelopingAlzheimer'stypedementia

Toxicencephalopathy(e.g.alcohol) Historyoftoxinexposure

| VoLuMe 32 | NuMber 1 | FebruAry 2009 11www.austral ianprescriber.com

Askaboutthemakingofwills,enduringpowersofattorney

andadvancehealthdirectives.Ifthesearrangementsarenotin

placeandthepatientiscompetenttomakethesedecisionsthey

shouldbeencouragedtodoso.Ifcapacitytoperformthese

actionshasbeenlost,thecarermayhavetoapplyforthese

powersthroughguardianshiplegislation.

Givethepatientinformationaboutmanagingtheirdiseaseand

considerreferringthemtoalocalpatientsupportorganisation.

Educationofthecarercanbeinvaluable.

Askifthepatientisstilldriving.Theabilitytodrivesafelyis

affectedbymanyfactorsincludingvisuospatialattention,

switchingofattentionbetweentasks,andjudgement.Theseare

difficulttoassessinaroutinemedicalassessment.Aspecialist

off-roadandon-roadassessmentmayberequired.Theremay

bestate-fundedaccesstotheseassessments,butthewaiting

listscanbeverylongandlegalrequirementsvaryfromstate

tostate.

Incontinence,increasednocturnalactivity,impairedmobility7

andaggressivebehaviourincreasetheburdenoncarers.These

problemsarealsopredictorsofnursinghomeplacementwithin

oneyear,independentofthelevelofcognitiveimpairment.

referralSendingthepatienttoamemoryclinicorspecialist(geriatrician,

psychiatristorneurologist)mayberequiredtoaccesssome

treatmentsortoconfirmthediagnosis.offerreferralifthe

diagnosisisindoubt,ifthepatientisyoung,thepresentationis

unusualorifrequestedbythepatientorthefamily.

Non-drug therapyMonitorthepatient'sgeneralhealthandotherchronic

conditions,especiallyvascularriskfactors,tooptimisehealth

andindependence.Shouldtherebeunexpectedchangesin

cognitionorbehaviour,reconsiderthepossibilityofincident

deliriumordepression.otherproblemsthatcancause

aggravatedbehavioursordistressinpatientswithdementia

includepain,constipation,reducedvisionandhearingloss.

Psychosocialinterventionsforcarers,suchasteachingthem

specificproblem-solvingskills,aremoreeffectiveifthepatient

isalsoinvolved.otherfactorsthatappeartobeimportant

includestructuredindividualcounselling,involvementofthe

extendedfamilyandconsistentprofessionallong-termsupport.

Theseinterventionscanhelptoreducethepsychologicalburden

andcanreducetheneedforinstitutionalcareofthepatient.

However,thereislittleimpactonthecarer'soverallburden.8

Interventionsthatdonotimproveoutcomesincludesingle

interviewsandinterventionsnotassociatedwithlong-term

contactsuchasshorteducationalprogramsandsupport

groupsalone.

Thereissomeevidenceforthecost-effectivenessofcommunity-

basedoccupationaltherapyaimedatimprovingthepatient's

dailyfunction.9Cochranereviewshavefoundnosupportive

evidencefortheuseofaromatherapy,musictherapy,

transcutaneouselectricalnervestimulation(TEnS)orbright

lighttherapy.

Inpractice,maintainingcognitive,physicalandsocialactivity

appearstohelpinimprovingqualityoflifeforthepatientand

reducingtheburdenofcare.Thisburdenisalsoimprovedby

educationaboutsymptomprogression,burdenmanagement

andenablingappropriateaccesstoservicesincludingrespite

care.Localpatientsupportorganisationscanbeuseful

resourcesforthis.Itisalsoimportantthatcarersmaintaina

relationshipwiththeirowngeneralpractitionersothattheirown

needsareaddressed.

Drug therapyDementiaisaprogressivedisease.Drugtreatmentatbestonly

slowsthedeclineincognitivefunction.

Cholinesterase inhibitorsThedrugsavailableinAustraliaaredonepezil,galantamine

andrivastigmine(alsonowavailableinatopicalformulation).

Patientsmustmeetspecificcriteriatobeeligibleforsubsidised

treatmentunderthePharmaceuticalBenefitsScheme(PBS).

Thereisastatisticalbenefitofcholinesteraseinhibitorsinmild

tomoderateAlzheimer'sdisease,howevertheclinicalbenefit

remainsuncertainandallthestudiesareshortterm.10There

isnoevidencethatonedrughasabenefitoveranother.Many

specialistsswitchtoanothercholinesteraseinhibitorifthere

isnoefficacyortoleranceofthefirst.Ifrequired,atrialof

memantinemaythenbeappropriate.

Astudyofpatientstakingoneofseveralcholinesterase

inhibitors(donepezil,tacrineandrivastigmine)showed

improvementincognitionandfunctionatoneyearanddelay

innursinghomeplacement.11However,somerandomised

controlledtrialshaveshownthedrugsdonotdelayplacement.

Thereisalsosomeevidencefortheefficacyofcholinesterase

inhibitorsinvasculardementiaanddementiawithLewy

bodies.12,13Thedrugshavenotbeenapprovedforthese

indications.

Commonadverseeffectsincludenausea,vomitingand

diarrhoea.Thesearelesstroublesomewithdosetitration.other

adverseeffectsincludebronchoconstriction(particularlyin

patientswithasthma),bradycardia,crampsandvividdreams.

MemantineMemantineisanon-competitiveantagonistofthen-methyl

D-aspartate(nMDA)receptor.ItisavailableonthePBSand

maybeanalternativeforthosepatientsunabletotolerate

cholinesteraseinhibitors.

Placebo-controlledtrialshaveshownbenefitinpatientswith

moderatetosevereAlzheimer'sdisease.Memantinehas

12 | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

beenusedincombinationwithcholinesteraseinhibitorsin

clinicaltrials.Aswiththecholinesteraseinhibitorstudies,the

outcomesmeasureddonottranslateeasilyintoclinicalpractice.

Memantinerequiresdosetitrationoveramonthtominimisethe

adverseeffectsofagitation,hallucinationandheadache.Itmay

alsoincreasetheriskofseizureactivity.Memantineisexcreted

intheurineandisprobablynotsuitableforuseinthosewith

renalimpairment.

Other drugs for dementia

Hundredsofdifferentdrugsarecurrentlyinvariousstagesof

clinicaltestingincludingvaccinesandmonoclonalantibodies

againstamyloidprotein.Thereisnoconsistentevidenceof

efficacyorsafetyfordrugssuchasvitaminE,selegiline,

vitaminB12orginkgobiloba.

Disease progression

Whilethepatient'sfunctionalstateisstillintact,treatmentof

chronicconditionscanimprovesymptomsandlifeexpectancy.

Asdementiaprogressesthebenefitsarereducedandtheneed

forinvestigationsortherapyshouldbediscussedwiththecarer.

Apreviouslycompletedadvancehealthdirectivecanbevery

valuabletoguidetherapy.

Timingofcessationofdrugtherapyfordementiais

controversial,butshouldbeconsideredifthepatientis

completelydependentintheircareneeds.Cessationshould

bediscussedwiththepatient'sfamily,particularlyastheymay

noticesomedeteriorationinthepatient'sfunctionalabilities.

Conclusion

Mostcasesofdementiaarediagnosedonclinicalassessment.

Excludingtreatablecausesofcognitiveimpairmentisvital.

Managementofthepatientandtheircareneedsshouldbe

individualised.Considertheneedsofthecarersaswellasthe

patientthemselves.Earlyeducationandplanningforfuture

eventscanassistboththepatientandtheirsupportnetwork.

Thanks to Dr Shanthi Kanagarajah, consultant geriatrician,

for guidance and editorial assistance. Thanks also to Dr Olivia

Williams, general practitioner, and Dr Georga Cooke, trainee in

general practice, for feedback on earlier versions of this article.

references1. AccessEconomicsPtyLtd.Dementiaestimatesand

projections:AustralianStatesandTerritories.2005.www.alzheimers.org.au/content.cfm?infopageid=1926[cited2009Jan13]

2. WilkinsonD,StaveC,KeohaneD,Vincenzinoo.TheroleofgeneralpractitionersinthediagnosisandtreatmentofAlzheimer'sdisease:amultinationalsurvey.JIntMedRes2004;32:149-59.

3. Diagnosticandstatisticalmanualofmentaldisorders(DSMIV-TR).4thed.Textrevision.Washington(DC):AmericanPsychiatricAssociation;2000.

4. BrodatyH,LowLF,GibsonL,BurnsK.Whatisthebestdementiascreeninginstrumentforgeneralpractitionerstouse?AmJGeriatrPsychiatry2006;14:391-400.

5. LarsonEB,KukullWA,KatzmanRL.Cognitiveimpairment:dementiaandAlzheimer'sdisease.AnnuRevPublicHealth1992;13:431-49.

6. ByrneGJ.Pharmacologicaltreatmentofbehaviouralproblemsindementia.AustPrescr2005;28:67-70.

7. HopeT,KeeneJ,GedlingK,FairburnCG,JacobyR.Predictorsofinstitutionalizationforpeoplewithdementialivingathomewithacarer.IntJGeriatrPsychiatry1998;13:682-90.

8. BrodatyH,GreenA,KoscheraA.Meta-analysisofpsychosocialinterventionsforcaregiversofpeoplewithdementia.JAmGeriatrSoc2003;51:657-64.

9. GraffMJ,Vernooij-DassenMJ,ThijssenM,DekkerJ,HoefnagelsWH,RikkertMG.Communitybasedoccupationaltherapyforpatientswithdementiaandtheircaregivers:randomisedcontrolledtrial.BMJ2006;333:1196.doi:10.1136.

10. QaseemA,SnowV,CrossJT,ForcieaMA,HopkinsR,ShekelleP,etal;AmericanCollegeofPhysicians/AmericanAcademyofFamilyPhysiciansPanelonDementia.Currentpharmacologictreatmentofdementia:aclinicalpracticeguidelinefromtheAmericanCollegeofPhysiciansandtheAmericanAcademyofFamilyPhysicians.AnnInternMed2008;148:370-8.

11. LopezoL,BeckerJT,WisniewskiS,SaxtonJ,KauferDI,DeKoskyST.CholinesteraseinhibitortreatmentaltersthenaturalhistoryofAlzheimer'sdisease.JneurolneurosurgPsychiatry2002;72:310-4.

12. MaloufR,BirksJ.Donepezilforvascularcognitiveimpairment.CochraneDatabaseofSystematicReviews2004,Issue1.Art.no.:CD004395.DoI:10.1002/14651858.CD004395.pub2.

13. WildR,PettitTA,BurnsA.CholinesteraseinhibitorsfordementiawithLewybodies.CochraneDatabaseofSystematicReviews2003,Issue3.Art.no.:CD003672.DoI:10.1002/14651858.CD003672.

Further readingnSWDepartmentofHealth.Careofpatientswithdementiaingeneralpractice:Guidelines.northSydney:nSWDepartmentofHealth;2003.www.racgp.org.au/guidelines/dementia[cited2009Jan13]

AdministrationguidefortheRowlandUniversalDementiaAssessmentScale(RUDAS).www.immigration.govt.nz/nR/rdonlyres/8EA84EB6-390C-49FB-9FC4-BF3484B0FD97/0/RUDASAdministrationguide.pdf[cited2009Jan13]

Alzheimer'sAustralia:seewww.alzheimers.org.au

Conflict of interest: none declared

| VoLuMe 32 | NuMber 1 | FebruAry 2009 13www.austral ianprescriber.com

Medicinal mishap

Monitor morphinePrepared by John S Dowden, Editor-in-Chief, Australian Prescriber

CaseA29-year-oldwomanpresentedtohergeneralpractitioner,

havingbecomeunwellovernightwithasorethroat.Shewas

shivering,hadmuscleachesandaheadache.Herpastmedical

historyincludedtonsillitisandmigraine.

Thegeneralpractitionerfoundexudateorpusonthewoman's

tonsilsandhercervicallymphnodeswereenlarged.Bacterial

tonsillitiswasdiagnosedandthedoctortookathroatswab.

Hegavethepatientintramuscularprocainepenicillinand

aprescriptionforphenoxymethylpenicillin.Ibuprofenwas

recommendedforsymptomatictreatment.

nextmorning,thepatientwasstillunwellandcontacted

hergeneralpractitionerseveraltimes.Hemadeahousecall

around6.30pm,bywhichtimethepatientwascomplainingof

headache,nauseaandvomiting.onexaminationhertonsils

werestillswollen,buta'thicktonsillarmembrane'madethe

doctorthinkthediagnosiscouldbeglandularfever.Hethought

thismayhavebroughtonamigraine.

Thegeneralpractitionerdecidedtogiveintramuscularmorphine

andmetoclopramide.Afterestimatingthepatient'sweighthe

gaveadoseof30mgmorphinefromhisdoctor'sbagsupplies.

Bymidnightthepatient'sheadachehadreturnedandshewas

vomiting,soherhusbandcalledthedoctoragain.Thegeneral

practitioner,whohadbeenworkingsince5am,hadonlygot

homeashorttimebeforethecall.Hedecidednottoseethe

patientagain,buttoadmithertothelocalhospital.

Thiswasasmallcountryhospitalwhichonlyhadtwonurseson

dutyatnight.Thedoctorspoketooneofthenursesandgave

anorderforintramuscularmorphineandprochlorperazine.At

aquartertooneinthemorning,30mgmorphinewasgiven.

Thenursesdecidedtomakeobservationsofthepatient'spulse,

bloodpressure,temperatureandrespirationeveryfourhours.

onenursethenwenttoattendtoamotherandnewbornbaby,

whiletheotherwentintoanotherroomforacoupleofhours.

Eachnurseassumedtheotherwoulddotheregularroundofall

patientsat2am.

At3.15amthenursewhohadattendedthenewmother

checkedthepatient.Thewomanwaslyingpronewithherfacein

thepillow.Shewasnotbreathing.Resuscitationstartedandthe

doctorwascalled.Hearrivedquicklyandintubatedthepatient,

butshecouldnotberevived.

Apost-mortemexaminationfoundenlargedtonsilswith

narrowingoftheupperairway.Thediagnosisofglandularfever

wasconfirmed.Thebloodconcentrationofmorphinewasfound

tobe0.16mg/L.Deathwasattributedtorespiratorydepression

causedbymorphineintoxicationonabackgroundofupper

airwaysnarrowingwhichwasaconsequenceofinfectious

mononucleosis.

Comment

Morphineisanappropriatedrugforsevereacutepain,butit

isnotusuallyrecommendedformigraine.Thedosetouseis

determinedbythepatient'sage,nottheirweight.Fora

29-year-oldwoman,therecommendedintramusculardoseis

7.5–12.5mgwhichcanberepeatedaftertwohours,depending

ontheresponse.Thedoseisadjustedaccordingtothe

response,sopatientsneedtobeobservedmorefrequently

thanfour-hourly.

Thereisanoverlapbetweenthetherapeuticandtoxic

concentrationsofmorphine.Although0.16mg/Liswithinthe

therapeuticrange,thisconcentrationwastoohighforsomeone

whohadnotbeentakingmorphineregularly.

Therapeuticdosesofmorphinecauserespiratorydepression.

Theeffectincreaseswiththedoseandrespiratoryarrestis

afrequentcauseofdeathinoverdose.Metoclopramideand

prochlorperazinewouldhaveaddedtothesedativeeffectsof

the60mgmorphinethepatientreceivedoverfivehours.

Inmanyhospitalsitismandatoryfornursingstafftomonitora

patient'spainscoreandsedationscoreaftergivinganopioid.

Ifthepatientisbeingobserved,respiratorydepressionshould

bedetected.Itcanbemanagedbygivingnaloxone,anopioid

antagonist.Thereisarapidresponsetoaninjectionofnaloxone,

althoughitseffectmaywearofffasterthantheeffectofmorphine.

Conclusion

Patientswhohavenotpreviouslybeentakingopioidsshould

startwithalowdoseofmorphine.Ifthesubcutaneousor

intramuscularrouteisused,thefirstdoseshouldbedetermined

bythepatient'sage.

Hospitalsshouldhaveprotocolsforobservingpatientswho

havebeengivenopioidanalgesics.Thisistoassessthe

responseandtomonitorforadverseeffects,particularly

respiratorydepression.

Further readingAustralianandnewZealandCollegeofAnaesthetistsandFacultyofPainMedicine.Acutepainmanagement:scientificevidence.2nded.2005.www.anzca.edu.au/resources/books-and-publications/acutepain.pdf[cited2009Jan13]

MacintyrePE,SchugSA.Acutepainmanagement:apracticalguide.3rded.Edinburgh:ElsevierSaunders;2007.

Prepared with the assistance of the general practitioner and

clinical pharmacologist involved in the case.

1� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

Treatments for severe psoriasisJohn R Sullivan, Dermatologist and Clinical Pharmacologist, Southderm Kogarah, Skin and Cancer Foundation Australia, St Vincent’s Hospital, and University of New South Wales, and Veronica A Preda, Dermatology Research Officer, Skin and Cancer Foundation Australia, St Vincent’s Hospital and University of New South Wales, Sydney

Summary

Methotrexate, cyclosporin, acitretin and narrow-band ultraviolet b phototherapy help most patients with severe psoriasis. However, toxicity tends to limit the dose and duration of therapy, so other treatments are being developed. biological therapies of proven benefit in severe psoriasis include etanercept, adalimumab and infliximab, which target tumour necrosis factor. Lymphocytes are the target of other therapies including efalizumab and alefacept. biological therapies have a range of safety concerns which differ from, but overlap with, those of other systemic treatments for psoriasis. in Australia, the Pharmaceutical benefits Scheme subsidises a therapeutic trial of approved biological therapies in severe psoriasis if traditional therapies are insufficiently effective or are contraindicated by intercurrent disease or adverse effects. ongoing therapy is only subsidised for patients whose psoriasis significantly improves. Care must be taken when withdrawing efalizumab or cyclosporin in case of rebound disease.

Keywords:adalimumab,efalizumab,etanercept,infliximab,

ustekinumab.

(Aust Prescr 2009;32:14–18)

introductionPsoriasisisachronicdisordercharacterisedbyerythematous

plaques,patchesandpapuleswhichmaybepruriticand

classicallyhavesilverscale.Morphologicallytherearevarying

forms,with80–90%beingoftheplaquevariety.otherless

commonpsoriasisformsincludeinversepsoriasis(involving

theskinfolds),erythrodermic(fromchronicplaquepsoriasisor

acute),pustularandguttate(with'dewdrop'lesions).1

Thepeakonsetofpsoriasisoccursduringtheteenageandearly

adultyearswhichmeansthatmostpatientswillbeaffectedfor

themajorityoftheirlives.Thisnecessitatescarefulconsideration

astotheshort-,medium-andlong-termrisksofpsoriasis,its

comorbiditiesanditstreatments.Theconsequencesofsevere

psoriasisaremorethanjustskindeep.Itmaybeassociatedwith

conditionssuchasarthritis,liverdisease,cardiovasculardisease

andthemetabolicsyndrome.Severepsoriasisinvolveslarge

areasoftheskin'ssurface.Duetothechronicandveryvisual

natureofthisdisease,therecanbeprofoundpsychosocial

consequences.2

Theautoimmunelesionsofpsoriasisarehyperproliferative,

hyperaemic,abnormallythickandshedincreasedamounts

ofhighlyvisiblescales.Psoriasisplaquesarepackedwith

enormousnumbersofactivatedTcellswhichdrivethe

inflammatoryprocess,causedysmaturationofepidermal

cellsandimpairskinfunction.Thisresults,forexample,in

theincreasedlossofwaterthroughtheepidermisandmakes

psoriaticskinmoresusceptibletophysicalandchemical

irritation,contributingtoitchingandirritation.Theplaquesare

alsopronetodeveloppainfulfissuresandcracks.

Psoriasisinvolvingsensitiveskinareassuchasgenitals,groin

andfaceortheglabrousskinofthehandsandfeetisoften

symptomatic.Involvementoftheseareasisparticularlylikely

toadverselyimpactonactivitiesofdailyliving,personal

interactions,especiallythoseinvolvingskincontact,andthe

abilitytowork.

The aims and frustrations of therapyPatientswantasafe,convenienttherapythatwillrapidlyclear

theirdiseaseandkeepitinremission.Surveysofpatient

supportgroupshavefoundmostpatientswerenotsatisfied

withthecontrolobtainedwithstandardtherapies.Around

athirdfeltthattheirmedicaltreatmentwasinsufficiently

aggressive.Toaddtotheirfrustration,patientsoftentriala

therapyforseveralmonthsbeforetheirtreatmentisaltered

becauseofaninadequateresponse.Followingaswitch,the

meantimetotreatmentfailureisanother3–6months.3

Untreatedseverepsoriasistendstofollowafluctuatingbut

persistentcourse.Incontrast,thecourseofdiseaseinmildto

moderatepsoriasisisgenerallyoneofrelapseandremission.

Phototherapy and standard systemic drugs in severe psoriasisourstandardtherapiescancontrolpsoriasisinthemajority

ofpatientswithseverepsoriasis(Table1),howeverpotential

therapy-relatedtoxicitieslimitthedoseanddurationof

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therapy.Thishasledtointermittent,sequential,rotationand

combinationtherapieswhichaimtomaintainreasonable

diseasecontrolwhilereducingtheriskoftreatment-specific

cumulativetoxicities.otherthanacitretin(anoralretinoid)

allsystemictreatments,includingbiologicaltherapies,are

immunosuppressiveandarecontraindicatedinpatientswith

cancerorinfections.onlyaroundathirdofpatientswithchronic

plaquepsoriasisachieveandmaintaingooddiseasecontrol

whenacitretinisusedasmonotherapyalthoughitsefficacyin

pustularanderythrodermicpsoriasisishigher.

narrow-bandphototherapyisgenerallyadministeredthree

timesaweek.Moderatepsoriasiscanusuallybeclearedwith

aroundsixweeksofphototherapyandwillnormallyresult

inaround3–6monthsofimproveddiseasecontrol.onsetof

significantchangeusuallyoccurswithin20–25treatments(at

approximatelythreeweeksintotherapy).Phototherapycanbe

combinedwithtopicaltherapy.Concurrentacitretincanspeed

upandincreasetheresponsetophototherapy.onceadequate

clearancehasbeenachieved,phototherapyisnormallystopped.

Phototherapycancauseerythema,pruritusandnausea.High

cumulativedosesincreasetheriskofskincancer.4

Cyclosporinusuallyworksquicklytoclearpsoriasis(6–12weeks)

andisgenerallyveryeffectiveinmaintainingdiseaseremission.

Dependingonthedoserequiredformaintainingcontrol,

hypertension,nephrotoxicity,malignancyandmetabolic

concernsusuallylimitthetotaldurationofcyclosporintherapyto

12–24months.

Methotrexateisgenerallysloweratclearingpsoriasisthan

cyclosporinpartlybecauseofcautiousinitialdosing.Itoften

takesthreeormoremonthstoinduceremission,butiftolerated

andthereisnohaematologicalorhepatictoxicitymethotrexate

canoftenbecontinuedformanyyearstomaintaingooddisease

control.Thedoseistitratedtothelowestdosethatbalances

safetyconcernsanddiseasecontrol.Monthlyormorefrequent

monitoringisneededforthefirstsixmonthswhenstarting

orincreasingthedoseofmethotrexate.Secondmonthly

monitoringoffullbloodcount,liverfunctiontests,ureaand

electrolytesneedstobecontinuedlong-termtohelpavoid

preventabletoxicities.Takingfolatesupplementsdaily(5mg

folicacid)mayhelppreventanumberofpotentialtoxicitiessuch

asgastrointestinaladverseeffectsandbonemarrowtoxicityand

isthestandardofcareinAustralia.5

biological therapiesBiologicaltherapiesforseverepsoriasiseithertargetTcellsor

blockpro-inflammatorycytokines.Efalizumabisarecombinant

humanisedmonoclonalantibodyagainstcellswiththeCD11a

marker.BindinginterfereswithTcellactivationinlymphnodes

andTcelltraffickingtoskinandinterfereswiththeiractivation

andreactivationintheskin.AlefaceptbindstotheCD2receptor

Table 1

Treatments for severe psoriasis

Administration Dosing induction therapy Maintenance therapy

Standard

Acitretin oral 10–50mgdaily Lowinitialdosefollowedbydoseescalationoftenused

Maybedaily,alternatedaysorless,usedlong-term,oftenyears

Cyclosporin oral 2–5mg/kgdailyintwodoses

3.5–5mg/kgdaily 2–4mg/kgdaily,6–24months

Methotrexate oralorintramuscular

5–25mgweekly Closeclinicalandbloodmonitoringneeded

Long-term,oftenyears

Phototherapy Incabinet 3timesaweek Dosingtailoreddependingonskintypeandresponse

6–12weekcourse,intermittenttherapy

biologicalAdalimumab Subcutaneous Fortnightly 80mgfollowedby

40mgoneweeklater40mgfortnightly

Alefacept Intravenous Weekly 7.5mgfor12weeks Ifthecourseisrepeatedtheremustbeagapofatleast12weeksbetweencoursesIntramuscular Weekly 15mgfor12weeks

Efalizumab Subcutaneous 1mg/kgweekly 0.7mg/kgfirstdose Long-term,potentiallyyears

Etanercept Subcutaneous Weeklyortwice-weekly

50–100mgweeklyforupto12weeks*

50mgweeklyeithercontinuouslyor12weekson/12weeksoff,potentiallyyears

Infliximab Intravenous 5mg/kg Weeks0,2,6,12 6–8weeklymaintenance,potentiallyyears

* AustralianMedicinesHandbookandproductinformationgive50mgtwiceweeklyasanoptionforinitialtreatment

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onlymphocytes.ItreducesthenumberofTlymphocytes

andinterfereswiththeiractivation.Etanercept,infliximaband

adalimumabbindwithtumournecrosisfactor(TnF),akey

pro-inflammatorycytokineinpsoriasis.Ustekinumabisahuman

monoclonalantibodyagainstinterleukin-12andinterleukin-23.

ItisthoughttorebalancetheTcellresponseawayfromthe

psoriaticdiathesis.

Biologicaltherapiesappeartoworkinseverepsoriasis

irrespectiveoftheresponsetostandardtherapies.However,

theremusthavebeenaninadequateresponseorsignificant

intolerancetoatleastthreetreatmentsbeforepatientscanuse

abiologicaltherapysubsidisedbythePharmaceuticalBenefits

Scheme(PBS).Therearenomarkers,otherthanatrialof

therapy,tohelpusidentifyresponderstobiologicaltherapies.

Mostpatientsstarttoimprovebyfourweeksandachieve

goodreductionsindiseaseseverityby12weeks.Infliximab

isassociatedwiththebestresponseratesas80%ofpatients

achievea75%improvementintheirpsoriasisareaandseverity

indexwhichequatescloselytodiseaseclearance.Thegreatest

improvementsinqualityoflifearewithinfliximabfollowedby

etanercept.6

Todatetheliteratureoncombinationtherapyinvolving

biologicalsisextremelylimited.Thisareaneedstobefurther

exploredtoimprovepatientoutcomesandimportantdrug

safetyissuessuchasskincancer.

Safety

Theefficacyandsafetyofthebiologicaltherapiesrequireslong-

termdisease-specificdata.Theeffectsassociatedwithpsoriasis

andthetoxicitiesofprevioustherapiesarelikelytoinfluencethe

frequencyandseverityoftheharmassociatedwithlong-term

treatment,particularlywhenusinganimmunosuppressivedrug.

Thesafetydatafromacohortofpatientstreatedwith

efalizumabcontinuouslyforlongerthan2.5yearsisareassuring

beginningandsuggeststhatefficacyiswellmaintained.7

However,thiscohortdifferssignificantlyintheirdiseaseseverity

andprevioustreatmentsfromthosecurrentlyqualifyingfor

therapysubsidisedbythePBS.Seriousadverseeventswith

efalizumabincludeinfectionsandseverearthritis.

Long-termefficacyandsafetydataaremorelimitedforthe

therapieswhichactonTnF.WhenTnFinhibitorsareusedto

treatrheumatoidarthritisthepatients'alreadyelevatedrisk

oflymphomamayincrease.Thereisalsoariskofserious

infectionsincludingtuberculosisreactivation.Thesetherapies

canalsoworsencongestivecardiacfailure.newneurological

symptomssuchasvisualdisturbanceandparaesthesiawarrant

stoppingtreatmentifademyelinatingcauseissuspected.There

arerarereportsofdemyelinatingdisease,suchasopticneuritis,

andexacerbationsofmultiplesclerosisoccurringinpatients

takingTnFinhibitors.

risk of disease reboundAreboundinpsoriasiscanoccurafterstoppingadrugor

therapy.Inareboundepisodethediseasebecomesunstable

andrapidlymoreseverethanbeforetherapy.Itmayalso

affectpreviouslyuninvolvedbodyregionsorchangeitsform,

forexamplebecomingerythrodermicorpustular.Theriskof

reboundvarieswiththetreatment.

Ceasingefalizumabappearstohaveasignificantriskofcausing

severeandunstablediseasethatcanresultinprolonged

hospitalisation.Efalizumabshouldonlybestoppedunderthe

guidanceofadermatologistfamiliarwithitsuse.Tominimise

risksofadiseasereboundwhenswitchingtherapy,these

patientsneedtobecloselymonitored.Combinationtherapy

maybeneededduringthetransitionperiod.Pharmacogenetics

showpromiseforhelpingtopredictandpreventthisadverse

effectinsubpopulationsofpatients.

renal and cardiovascular problems Patientswithseverepsoriasishaveseveralfactorsthatplace

thematincreasedriskofclinicallysignificantrenaland

cardiovasculardisease.Theyaremorelikelytosmoke,with

thenumberofcigarettessmokedperdaycorrelatingwith

diseaseseverity.Theyarealsomorelikelytohavehypertension,

hyperuricaemia,nephrocalcinosisandhyperlipidaemia.

Althoughmostoftheevidenceisfromtransplantationmedicine,

calciumantagonistsarenephroprotectivewhenusedforsmall

increasesinbloodpressureoccurringduringthefirst1–2

monthsofcyclosporintherapy.Anincreaseinbloodpressure

afterthistimewarnsofcyclosporinnephrotoxicity,especially

ifassociatedwithanelevatedcreatinineoranincreaseinthe

patient'screatinineofmorethan30%abovebaseline.Ifthisfails

tosettlewithdosereduction,cyclosporinshouldbestopped

beforesignificantpermanentrenaldamagecanoccur.

The liver and obesityPatientswithseverepsoriasishaveanincreasedriskofliver

diseaseincludingnon-alcoholicsteatohepatitisandcirrhosisdue

toassociatedcomorbidities.Methotrexateandacitretintherapy

cancontributetotheseliverproblems.

Lifestyleinterventionscanreducetheriskofmedically

significantliver-associatedcomorbidities.Healthprofessionals

shouldregularlycounselallpatients,butparticularlythosewith

severepsoriasis,abouttheimportanceofmaintainingahealthy

weight,regularlyexercising,havingadietwithalowglycaemic

indexandlowfatplusmoderationoftheiroftenexcessive

alcoholconsumption.Patientswithpsoriasisshouldbeoffered

vaccinationforhepatitisAandB.

MalignancyPatientswithseverepsoriasisareatincreasedriskofskin

cancerandthisincreasesfurtherifphototherapyisfollowed

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orcombinedwithcyclosporinormethotrexate.Education

abouttheimportanceofsunprotection,sunavoidance,skin

monitoringandlifelongregular(atleastannual)fullskin

examinationsiswarranted.

Itisunclearifimmunosuppressivetherapiesfurtherincrease

theriskofskincancer.Theyarelikelytoincreasetherisk

ofoncogenicvirus-relatedmalignanciesincludinghuman

papillomavirus-relatedcervical,vulvalandpenilecancer,

warrantingregularcheck-ups.Patientswithpsoriasisshould

beregularlycounselledregardinglifestylemodificationand

interventionstoreducetheimpactofassociatedcomorbidities

andexposuresknowntoincreasemalignancyincluding

smoking,obesityanddiet.

Goodlong-termcontroloftheinflammationduetosevere

psoriasiscouldtheoreticallyreducethebackgroundriskof

malignancysuchaslymphoma.However,thisislikelyto

becounterbalancedbytheimmunosuppressiveactionsof

therapiesforseverepsoriasis.Allappropriaterecommendations

forcancerscreeningshouldbefollowed.

Periodontal diseaseGooddentalhygieneandregulardentalreviewareimportant

foreveryoneonimmunosuppressivetherapy.Cyclosporin

carriesthegreatestrisksforcausingaswellasworsening

periodontaldisease,includingacuteandchronicgingivitisand

gingivalhypertrophy.

infections and vaccinationPatientswithseverepsoriasisshouldkeeptheirimmunisations

uptodate.Ingeneral,vaccinationsarerecommendedbefore

commencingbiologicaltherapy.Thestandardofcarethat

isappropriatetofollowmaybesimilartothatoforgan

transplantationwherepneumococcal,hepatitisAandB,

influenzaandtetanus-diphtheriavaccinesarerecommended

beforestartingimmunosuppressivetherapy.1Livevaccines

shouldnotbegivenwithoutspecialistadviceifthepatient

istakingimmunosuppressivetherapy.Allpatientsshouldbe

screenedfortuberculosisbeforeimmunosuppressivetherapy

especiallywhenstartingaTnFinhibitor.8

Whenapatientwithpsoriasispresentswithsepsiswhileon

systemictherapy,alwaysconsideratypicalinfections.Careful

considerationisalsorequiredregardingongoingtherapy

fortheirpsoriasis.Incontrasttoefalizumab,aTnFinhibitor

canbestopped,giventheabsenceoftheriskofrebound

oncessation.Thoughtneedstobegiventothepossible

ongoingimmunosuppressiveeffectofthebiologicaltherapies;

etanercepthasashorthalf-lifeofdays,butthehalf-lifeof

adalimumabandinfliximabisconsiderablylonger,uptoweeks

induration.

Whentakingamedicationhistoryforapatientpresentingwith

potentialsepsis,remembertoaskaboutinjectabledrugs,

includingthebiologicaltherapies.

Pregnancy and lactation

Effectivepregnancypreventionadviceandprecautions

needtoberegularlyprovidedandcheckedwhenwomen

ofchildbearingagearetakingsystemicpsoriasistherapies.

Shouldpregnancyoccur,allsystemicpsoriasisdrugsshould

bestoppedimmediatelyandspecialistadvicesought.Therisk

ofdiseasereboundwithefalizumabhastobebalancedagainst

theuncertainrisktothefetus.Acitretinandmethotrexatehave

significantprovenadverseeffectsonthefetus.Thelonghalf-life

ofacitretinmeansthataplannedpregnancymustbepostponed

forseveralyearsafterstoppingtreatment.Cyclosporinhasbeen

usedinpregnancywhenseverepsoriasishasnotrespondedto

othertherapies.Thesafetyofbiologicaltherapiesinpregnancy

andbreastfeedingisunknown.

Psoriatic arthritis

Approximately10%ofpatientswithpsoriasisalsohavepsoriatic

arthropathy.Drugswhichimprovetheskinmayhavelesseffect

onthearthritis.

Thetreatmentofpsoriaticarthritisissimilartothatofotherjoint

diseasesandmayinvolvedisease-modifyingdrugs.Ifthereis

noresponsetodrugssuchassulfasalazineandmethotrexate,

biologicaltherapiesmaybeconsidered.Adalimumab,

etanercept,infliximabandustekinumabcanbeusedtotreat

severeactivepsoriaticarthritis.

Conclusion

Biologicaltherapiesforpsoriasisareprovingvaluablefor

achievingandmaintainingdiseasecontrolinpatientswith

severepsoriasis.Theycomplementratherthanreplaceour

standardtherapies.Theyalsoprovidealternativesinresistant

diseaseandgreatertherapeuticchoiceshouldallowbetter

tailoringoftreatmenttothepatient'sneeds.Treatmentchoice

shouldtakeintoconsiderationtheorderinwhichdrugsare

prescribed,aperson'sstageinlife,associatedcomorbiditiesand

variationindiseaseseverity.Thebestuseofbiologicaltherapies

willbeguidedbytheongoingcollectionofdataontheirlong-

termsafety.

references1. MenterA,GottliebA,FeldmanSR,VanVoorheesAS,

LeonardiCL,GordonKB,etal.Guidelinesofcareforthemanagementofpsoriasisandpsoriaticarthritis:Section1.overviewofpsoriasisandguidelinesofcareforthetreatmentofpsoriasiswithbiologics.JAmAcadDermatol2008;58:826-50.

2. KruegerG,KooJ,LebwohlM,MenterA,SternRS,RolstadT.Theimpactofpsoriasisonqualityoflife:resultsofa1998nationalPsoriasisFoundationpatient-membershipsurvey.ArchDermatol2001;137:280-4.

3. FeldmanSR,EvansC,RussellMW.Systemictreatmentformoderatetoseverepsoriasis:estimatesoffailureratesanddirectmedicalcostsinanorth-easternUSmanagedcareplan.JDermatologTreat2005;16:37-42.

1� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

4. SternRS.PsoralenandultravioletAlighttherapyforpsoriasis.nEnglJMed2007;357:682-90.

5. ortizZ,SheaB,SuarezAlmazorM,MoherD,WellsG,TugwellP.Folicacidandfolinicacidforreducingsideeffectsinpatientsreceivingmethotrexateforrheumatoidarthritis.CochraneDatabaseofSystematicReviews1999,Issue3.Art.no.:CD000951.DoI:10.1002/14651858.CD000951.

6. KatugampolaRP,LewisVJ,FinlayAY.TheDermatologyLifeQualityIndex:assessingtheefficacyofbiologicaltherapiesforpsoriasis.BrJDermatol2007;156:945-50.

7. GottliebAB,HamiltonT,CaroI,KwonP,ComptonPG,LeonardiCL;Efalizumabstudygroup.Long-termcontinuousefalizumabtherapyinpatientswithmoderatetoseverechronicplaquepsoriasis:updatedresultsfromanongoingtrial.JAmAcadDermatol2006;54Suppl1:S154-63.

8. LuTY-T,HillC.Managingpatientstakingtumournecrosisfactorinhibitors.AustPrescr2006;29:67-70.

Self-test questionsThe following statements are either true or false

(answers on page 27)

1. Patientswithseverepsoriasismayexperienceaflare-upof

thediseasewhentreatmentwithefalizumabisceased.

2. Womentakingacitretinshouldnotplantobecome

pregnantuntilatleasttwoyearsafterstoppingtreatment.

Further readingSwaminathanS,RimintonS.Monoclonalantibodytherapyfornon-malignantdisease.AustPrescr2006;29:130-3.

Conflict of interest: Dr Sullivan has served on advisory committees

for Schering and Wyeth, and has received (unconditional)

educational grants from Merck Serono. Dr Preda: none declared.

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

Treatments for severe psoriasisDentistshavebecomeincreasinglyawareoftheeffects

thatsystemicmedicationscanhaveontheoralcavity.

Cyclosporinhaslongbeenknowntobeassociatedwith

gingivalenlargement,andthedegreeofenlargement

appearstobeassociatedwithboththedailydoseand

lengthoftimethedrugistaken.Thiswasfirstobservedin

patientswithrenaltransplantsandthesepatientsremain

thegroupmostcommonlyaffectedbycyclosporin-induced

gingivalhyperplasia.1However,cyclosporinandother

immunomodulatorydrugsarecommonlyusedforpatientswith

severepsoriasis.Cyclosporin-inducedgingivalenlargement

resolvesfollowingcessationofthedrugand,insomepatients,

itwillalsoresolvefollowingareductionindrugdosage.2

Arecentstudyhasshownthatisotretinoin(aretinoidusedfor

severeacne)hassignificantoraladverseeffectswithadecrease

insalivaryflowandaconcomitantincreaseinthenumberof

decayed,missingorfilledteeth.3Itispossiblethatacitretin(a

retinoidusedforseverepsoriasis)couldhaveasimilareffect.

Acitretinisknowntocausedrymouthandgingivitis.Patients

takingmethotrexatealsohaveadecreaseinsalivaryfunction,

althoughthishasnotbeenstudiedinpatientswithsevere

psoriasis.Peopletakingmedicationforseverepsoriasisrequire

veryhighlevelsoforalhygieneandregularprofessional

cleaningtopreventorminimisedeteriorationoftheir

periodontalstructures.Itwouldbeadvisableforthesemeasures

tostartatthesametimetheybegintheirtreatmentforpsoriasis.

references1. SeymourRA.Effectsofmedicationsontheperiodontal

tissuesinhealthanddisease.Periodontol20002006;40:120-9.

2. DalyCG.ResolutionofcyclosporinA(CsA)-inducedgingivalenlargementfollowingreductioninCsAdosage.JClinPeriodontol1992;19:143-5.

3. Lupi-PegurierL,Muller-BollaM,FontasE,ortonneJP.Reducedsalivaryflowinducedbysystemicisotretinoinmayleadtodentaldecay.Aprospectiveclinicalstudy.Dermatology2007;214:221-6.

Patient support organisationPsoriasis Australia PsoriasisAustraliaprovidesinformationaboutpsoriasis,and

supporttopeoplewithpsoriasis,toenableinformeddecisions

ontreatmentchoicesandlifestyle.Itprovidespamphletsand

othermaterialforhealthprofessionalsandthepublic.Although

basedinVictoriaitisanationalorganisation.

Website: http://home.vicnet.net.au/~psorias/

Email: info@psoriasisaustralia.org.au

Phone: (03)98138080Thursdays10am–1pm

Address: 334HighStreetASHBURTonVIC3147

| VoLuMe 32 | NuMber 1 | FebruAry 2009 19www.austral ianprescriber.com

Drug treatment of pituitary tumoursEe Mun Lim, Clinical Endocrinologist, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, and Head, Department of Clinical Biochemistry, PathWest Queen Elizabeth II Medical Centre, Perth

Summary

The primary therapeutic aims in the management of pituitary tumours are to correct the excess hormone secretion and to reduce tumour size to prevent damage to normal pituitary tissue and adjacent structures such as the optic chiasma. Treatment of pituitary tumours has been improved by advances in transphenoidal surgery and radiotherapy and by the development of effective drug therapy for prolactinoma and acromegaly. Dopamine agonists are first-line treatment in prolactinomas, and somatostatin analogues are often used in the management of acromegaly.

Keywords:acromegaly,dopamineagonists,prolactinoma,

somatostatinanalogues.

(Aust Prescr 2009;32:19–21)

introductionPituitarytumoursarealmostalwaysbenignadenomas

classifiedbysizeandcelloforigin.Lesionssmallerthan1cm

areclassifiedasmicroadenomas,andlargerlesionsare

macroadenomas.Prolactin,adrenocorticotrophichormone,

thyroid-stimulatinghormone,luteinisinghormone,follicle

stimulatinghormoneandgrowthhormoneareallsecretedby

cellsintheanteriorpituitaryandthetumourmayarisefrom

anyofthesecelltypes.Patientswithpituitarytumoursmay

thereforepresentwith:

• hormonalhypersecretion(forexampleprolactinoma,

Cushing'sdisease,acromegaly)

• symptomsofmasseffectduetotumourcompressionof

adjacentstructures(forexamplevisualfielddefects)

• hormonedeficienciescausedbythetumourdamagingother

celltypesinthepituitary.

Tumoursmayalsobeanincidentalfindingonradiological

imaging.

investigationsThediagnosisofpituitarytumoursrestsonbiochemical

assessmentandmagneticresonanceimaging(MRI).Specific

testscanbeorganisedtoassesssecretoryabnormalitiesor

hormonaldeficiencies.

ManagementThemanagementoptionsforpituitarytumoursinclude

neurosurgery,medicaltherapyorirradiation,dependingon

theclinicalpresentationandtypeofpituitarytumours.Drug

treatmentscanbeusedasfirst-linetherapyforprolactinomas

andacromegaly.

ProlactinomaStress,renalfailureanddrugscancausemildtomoderate

hyperprolactinaemia,butagreatlyincreasedconcentration

isusuallycausedbyapituitaryadenoma.Prolactinomasare

themostcommonhormone-secretingpituitaryadenomas,

accountingforapproximately60%offunctioningtumours.over

90%ofprolactinomasaresmall,benignintrasellartumoursthat

rarelyincreaseinsize.1

Dopamine agonistsDopamineagonistsareusuallythefirsttherapyforpatientswith

eitherprolactin-secretingmicroadenomasormacroadenomas.

Theaimoftreatmentistonormaliseprolactinconcentrations,

restoregonadalfunctionandshrinkthetumour.notall

patientswithprolactin-secretingmicroadenomasrequire

treatmentwithdopamineagonists.Premenopausalwomen

withnormalmenstrualcyclesorpostmenopausalwomenwith

tolerablegalactorrhoeacanbemonitoredwith6–12monthly

measurementsofserumprolactin.Womentreatedwith

dopamineagonistswhodonotdesirepregnancybutrequire

contraceptionmaytakeanoralcontraceptiveprovidedthat

thereistightcontrolandmonitoringofserumprolactinbecause

oestrogenmaystimulatelactotrophgrowth.

Patientswithprolactin-secretingmacroadenomas,including

thosewithassociatedvisualfielddefects,canbesafelytreated

withdopamineagonists.Tumourshrinkageoftenoccurswithin

1–2weeksofcommencingtherapy,andmaycontinueformany

monthstoyears.

ThedopamineagonistscurrentlyavailableinAustraliaare

bromocriptine,cabergolineandquinagolide.Ifthepatient

cannottoleratethefirstdopamineagonistprescribed,orserum

prolactindoesnotnormalise,itisreasonabletoswitchto

anotherdopamineagonist.Transphenoidalsurgeryisreserved

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forpatientswhoareeitherresistantorintoleranttomedical

therapy.

Cabergoline

Cabergolineisanergotderivativewithaveryprolonged

durationofaction.Itispreferredtobromocriptineasitis

morepotentandeffectiveinachievingnormoprolactinaemia.

Cabergolineisgivenonceortwiceweeklyandtheusual

maintenancedoseis0.5–2mgweekly.Itisbettertoleratedthan

bromocriptineandmaybeeffectiveinpatientsresistantto

bromocriptine.

Thereisanincreasedriskofcardiacvalveregurgitationwith

theuseofcabergolineinpatientswithParkinson'sdisease.2The

dosesusedtotreatprolactinomasaremuchsmaller,butitmay

bereasonabletoofferechocardiogramstopatientswhohave

beenonprolongedtreatmentwithcabergoline.

Bromocriptine

Bromocriptineisanergotalkaloidandsuppressesprolactin

secretionbydirectlybindingtoD2dopaminereceptorswithin

theanteriorpituitary.Therapyshouldbestartedat0.625to1.25mg

atnighttominimisetheadverseeffectsofnausea,vomiting,

dizzinessandposturalhypotensionwiththeinitialdose.The

dosecanbegraduallyincreasedtoamaintenancedoseof

2.5mgtwiceorthreetimesdaily.Bromocriptinenormalises

prolactinandreducestumourmassin80–90%ofpatientswith

microadenomasandin70%ofpatientswithmacroadenomas.1

Quinagolide

Quinagolideisanon-ergot,well-tolerated,oraldopamine

agonist.Ifpatientscannottoleratebromocriptineorcabergoline,

itisbesttoswitchthemovertoquinagolideasitmaybebetter

toleratedgivenitsspecificityfortheD2dopaminereceptor.

Quinagolideisgivenoncedailyandastarterpackisusedto

graduallyincreasethedoseoversevendaystoamaintenance

doseof75microgramdaily.Thedosecanbeincreasedfurther

to150–300microgramdailyifrequired.

Monitoring patients with prolactinomaSerumprolactinshouldbecheckedonemonthafterstartinga

dopamineagonistandthen3–6monthlyasclinicallyindicated.

oncehyperprolactinaemiaisnormalised,serumprolactincan

bemonitoredannually.Whenprolactinhasbeennormalfor

morethantwoyearsandthereductionintumoursizeismore

than50%,thedoseofdopamineagonistscanbegradually

decreasedtothelowestmaintenancedose.1However,cessation

oftreatmentmayleadtotumourregrowthandrecurrenceof

hyperprolactinaemia.Follow-upofthesepatientsisimportant

withregular(3–6monthly)monitoringofserumprolactin.

Patientswithmicroadenomaswhoseserumprolactin

concentrationshavebeensuppressedformorethan1–2years

bydopamineagonisttherapymaybeabletostoptheir

medication.Itisalsoreasonabletowithdrawtreatmentinthose

patientswithmacroadenomasandnoevidenceofresidual

tumouronMRI,butthedopamineagonistsshouldbegradually

taperedbeforecessation.Serumprolactinshouldbemonitored

everythreemonthsduringthefirstyearofdrugwithdrawal.3

Therapyshouldbecontinuedinpatientswithanytumourmass

onMRI.

Pregnancyoncepregnancyisconfirmed,bromocriptineorcabergolineare

oftenwithdrawninpatientswithmicroadenomas,butdopamine

agonistsmaybecontinuedinpatientswithmacroadenomas.

Patientsareaskedtoreportheadachesandvisualdisturbances

duringpregnancyasprolactinomas,especiallymacroadenomas,

maygrowduringpregnancyundercontinuedoestrogen

stimulation.

Bromocriptinehasanextensivesafetyrecordinpregnancyand

emergingexperiencesuggestscabergolinemayalsobesafein

earlypregnancy.Insufficientsafetydataonquinagolidepreclude

itsuseduringpregnancy.

AcromegalyGrowthhormonesecretingadenomasaccountfor20%

offunctionalpituitarytumours.Theaimsoftreatmentin

acromegalyareto:

• removethetumourandresolvesymptomsduetotumour

mass

• normalisegrowthhormoneandinsulin-likegrowthfactor

(IGF-1)secretion

• preventprogressivedisfigurement,boneexpansionand

osteoarthritis

• improvecardiovascularandmetabolicabnormalities.

Transphenoidalsurgeryisthemainstayoftreatment,with

surgicalcureachievedinmorethan80%ofpatientswith

microadenomas.4However,only50%ofpatientswith

macrodenomascanbecuredsurgicallyandthisrateis

significantlyreducedinpatientswithinvasivemacroadenomas.

CureisdefinedbiochemicallyasnormalisationofIGF-1within

theage-relatedreferenceintervalorarandomgrowthhormone

concentrationlessthan2.5microgram/L(5mU/L)oradequate

suppressionofgrowthhormonesecretionduringanoral

glucosetolerancetest.

Medicaltreatmentwithsomatostatinanalogueshasassumed

aprominentroleinthemanagementofacromegalyandis

successfulinthecontrolofhormoneexcessinabout60%

ofpatients.4Ithasoftenbeenusedasadjuvanttherapyafter

unsuccessfulsurgery,butmorerecentlysomatostatinanalogues

havebeenproposedasfirst-linetherapy.Studieshaveshown

thatbiochemicalcontrolofacromegalyandtumourshrinkage

canbeachievedwhensomatostatinanaloguesareusedasfirst-

linetherapy,especiallywhensurgicalcureisnotpossiblefor

invasivemacroadenomas.5Somatostatinanaloguesmayalso

beusedinpreoperativetreatmentofpatientswithsignificant

| VoLuMe 32 | NuMber 1 | FebruAry 2009 21www.austral ianprescriber.com

obstructivesleepapnoeaorcardiovasculardisease,toattempt

torapidlylowergrowthhormoneconcentrationsandpossibly

reduceperioperativecomplications.

Theavailabilityoflong-actingdepotpreparationsof

somatostatinanalogueshasimprovedtheeaseof

administrationandpatients'compliance.octreotideand

lanreotidearecurrentlyavailableinAustralia.Patientsresistant

tomedicaltherapyareoftenreferredforradiotherapy.

Octreotide octreotideisaneight-aminoacidsyntheticsomatostatin

analogue.Theshort-actingformisavailableassubcutaneous

injections,givenas100–200microgramthreetimesdaily.The

modified-release,long-actingformulationofoctreotideisgiven

asamonthlyintramuscularinjection.Gastrointestinaladverse

effects,duetodrug-inducedsuppressionofgastrointestinal

motilityandsecretion,occurinone-thirdofpatients.These

effectsincludenausea,abdominaldiscomfort,fatmalabsorption,

diarrhoeaandflatulence,butareoftenshort-lived.Themost

significantadverseeffectinvolvestheformationofgallstones

andinsymptomaticpatientscholecystectomymayberequired.

Mildglucoseintolerancemaydevelopduetotransient

suppressionofinsulinsecretion.

Lanreotide Lanreotideisacyclicoctapeptideanalogueofsomatostatin.

Lanreotideacetateisgivenasfortnightlyintramuscular

injections.Theavailabilityoflanreotideasagelinapre-filled

syringe(60,90,120mg)hasfurtherimprovedtheeaseof

administration.Thisisgivenasadeepsubcutaneousinjection

everyfourweeks.Extendeddosingwith120mgevery6–8weeks

maybeaseffectiveforpatientsestablishedon60–90mgevery

4weeks.Theadverseeffectprofileissimilartothatofoctreotide.

Dopamine agonists Dopamineagonistsmaysuppressgrowthhormonesecretionin

patientswithacromegalyandsomegrowthhormone-secreting

adenomasmayco-secreteprolactin.Thesedrugsareoftenused

inconjunctionwithsomatostatinanaloguesforanadditive

suppressiveeffectwhenbiochemicalcureisnotachievedwith

somatostatinanaloguesalone.Dopamineagonistsaloneare

rarelyeffectiveinthetreatmentofacromegaly.

PegvisomantPegvisomantisapegylatedrecombinantanalogueofhuman

growthhormonewhichactsasagrowthhormonereceptor

antagonist.ItnormalisesIGF-1inover90%ofpatientswith

acromegaly.Pegvisomantisgivenassubcutaneousinjections.

Thisdrugcanbeusedinpatientswithactiveacromegalynot

curedbysurgeryandresistanttosomatostatinanalogues.

Pegvisomant,asagrowthhormoneantagonist,doesnotact

onthetumourandisunlikelytoinfluencetumourgrowth

andsecretion.Itiswelltoleratedandlong-termsafetydata

aregraduallyaccumulating,butitmaycauseelevated

transaminasesonliverfunctiontests.Thistreatmentisnot

readilyavailableinAustralia.

Future directionsThedevelopmentofnewtherapiesandtheavailabilityof

long-actingdepotformulationshaveprovidedimproved

therapeuticoptionsinthemanagementofgrowthhormone-

andprolactin-secretingpituitarytumours.Furtherdrug

developmentforthemanagementofpituitarytumoursshould

enablemorepatientswithhormone-secretingadenomastobe

successfullytreatedmedically.

references1. CasanuevaFF,MolitchME,SchlechteJA,AbsR,BonertV,

BronsteinMD,etal.GuidelinesofthePituitarySocietyforthediagnosisandmanagementofprolactinomas.ClinEndocrinol2006;65:265-73.

2. SchadeR,AndersohnF,SuissaS,HaverkampW,GarbeE.Dopamineagonistsandtheriskofcardiac-valveregurgitation.nEnglJMed2007;356:29-38.

3. SchlechteJA.Long-termmanagementofprolactinomas.JClinEndocrinolMetab2007;92:2861-5.

4. MelmedS.Medicalprogress:Acromegaly.nEnglJMed2006;355:2558-73.

5. ColaoA,PivonelloR,AuriemmaRS,BrigantiF,GaldieroM,TortoraF,etal.Predictorsoftumorshrinkageafterprimarytherapywithsomatostatinanalogsinacromegaly:aprospectivestudyin99patients.JClinEndocrinolMetab2006;91:2112-8.

Conflict of interest: none declared

Self-test questionsThe following statements are either true or false

(answers on page 27)

3. Dopamineagonistsarefirst-linetherapyforprolactin-

secretingmicroadenomas.

4. Gallstonesareanadverseeffectofoctreotide.

22 | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

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

Desvenlafaxine succinatePristiq(Wyeth)

50mgand100mgextendedreleasetablets

Approvedindication:depression

AustralianMedicinesHandbooksection18.1.4

Venlafaxineisaserotoninreuptakeinhibitorwhich,athigher

doses,alsoinhibitsreuptakeofnoradrenaline.Itismetabolised

inthelivertodesvenlafaxinewhichalsohasantidepressant

actions.Thedecisiontomarkettheactivemetabolitemight

berelatedtotheexpiryofthepatentonthecontrolledrelease

formulationofvenlafaxine.

Desvenlafaxineiswellabsorbedandonlyneedstobetaken

onceaday.Althoughitismainlymetabolisedbyconjugation,

desvenlafaxineispartlymetabolisedbycytochromeP4503A4.

Inhibitorsofthisenzyme,suchasketoconazole,mayincrease

plasmaconcentrationsofdesvenlafaxine.Thehalf-lifeof

desvenlafaxineis11hours,butthismaybeincreasedbyhepatic

impairment.Asalmosthalfthedoseisexcretedunchangedin

theurine,lessfrequentdosingisrecommendedforpeoplewith

renalimpairment.

Desvenlafaxinewascomparedtoplaceboin234patientswith

majordepressivedisorder.ThemeanscoreontheHamilton

RatingScaleforDepressionwas23.7.The120patients

randomisedtousedesvenlafaxinetook100mgfortwo

weeksthenincreasedto200mg.Aftereightweeksthemean

depressionscorehadfallento14.1withdesvenlafaxineand15.1

withplacebo.Thisdifferencewasnotsignificant.1

Alargerrandomisedtrialevaluatedtheefficacyofdaily

desvenlafaxinein114patientswhotook100mg,116whotook

200mg,113whotook400mgandin118whotookaplacebo.

AtthestartofthestudythemeanscoreontheHamiltonRating

ScaleforDepressionwasapproximately23.Aftereightweeks

themeanreductioninthescorewas10.6with100mg,9.6

with200mg,10.7with400mgand7.7withplacebo.onlythe

reductionsinthe100mgand400mggroupsweresignificantly

betterthantheplaceboresponse.2

Anothereight-weekstudycompareddesvenlafaxine200mg

and400mgtoplacebo.ThescoresontheHamiltonRatingScale

werereducedby12.6with200mg,12.1with400mgandby9.3

withplacebo.3

Intheclinicaltrialsthemostcommonadverseeffectsof

desvenlafaxinewerenausea,drymouth,somnolence,anorexia,

constipationandnervousness.1,2otheradverseeffects

includevomiting,dizziness,blurredvision,sexualdysfunction,

hypertension,increasedcholesterolandtriglyceridesand

alteredliverfunction.Approximately12%ofpatientswhotook

desvenlafaxinewithdrewfromtrialsbecauseofadverseevents.

Ideally,thedoseshouldbetaperedoffasstoppingthedrug

abruptlycancausediscontinuationreactions.

Venlafaxineismetabolisedtodesvenlafaxinebycytochrome

P4502D6.Givingthemetaboliteasadrugbypassesthisstep

sotherecouldbelesspotentialfordruginteractions,but

thereislittleevidencethatdesvenlafaxinehasanyadvantage

overvenlafaxine.Theprecautionsforprescribingthetwo

drugsaresimilar.overseas,themanufacturerappliedtohave

desvenlafaxineapprovedforthetreatmentofmenopausalhot

flushes,buttheUSFoodandDrugAdministrationhasaskedfor

moredataandinEuropetheapplicationhasbeenwithdrawn.

Therecommendeddoseindepressionis50mgdaily,but

untilrecentlytherewaslittlepublishedinformationaboutthis

dose.Twotrialshavecompareddesvenlafaxine50mgand

100mgtoplacebo.Aftereightweeks,bothdoseshadreduced

thescoresontheHamiltonRatingScale,butonlythe50mg

dosewassignificantlybetterthanplaceboinbothtrials.4,5It

appearsthathigherdosesmayhavemoreadverseeffects,but

noadditionalbenefit.Forpatientswhoarebeingsatisfactorily

managedwithvenlafaxinethereseemslittlereasontochangeto

desvenlafaxine.

manufacturerprovidedadditionalusefulinformation

references *1. LiebowitzMR,YeungPP,EntsuahR.Arandomized,

double-blind,placebo-controlledtrialofdesvenlafaxinesuccinateinadultoutpatientswithmajordepressivedisorder.JClinPsychiatry2007;68:1663-72.

2. DeMartinisnA,YeungPP,EntsuahR,ManleyAL.Adouble-blind,placebo-controlledstudyoftheefficacyandsafetyofdesvenlafaxinesuccinateinthetreatmentofmajordepressivedisorder.JClinPsychiatry2007;68:677-88.

3. Septien-VelezL,PitroskyB,PadmanabhanSK,GermainJM,TourianKA.Arandomized,double-blind,placebo-controlledtrialofdesvenlafaxinesuccinateinthetreatmentofmajordepressivedisorder.IntClinPsychopharmacol2007;22:338-47.

4. LiebowitzMR,ManleyAL,PadmanabhanSK,GangulyR,TummalaR,TourianKA.Efficacy,safety,andtolerabilityofdesvenlafaxine50mg/dayand100mg/dayinoutpatientswithmajordepressivedisorder.CurrMedResopin2008;24:1877-90.

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5. BoyerP,MontgomeryS,LepolaU,GermainJM,BrisardC,GangulyR,etal.Efficacy,safety,andtolerabilityoffixed-dosedesvenlafaxine50and100mg/dayformajordepressivedisorderinaplacebo-controlledtrial.IntClinPsychopharmacol2008;23:243-53.

Methylnaltrexone bromideRelistor(Wyeth)

vialscontaining12mg/0.6mLsolution

Approvedindication:opioid-inducedconstipation

AustralianMedicinesHandbooksection12.4.4

Constipationisoneofthecommonadverseeffectsofopioid

analgesics.Thisconstipationiscausedbyseveralmechanisms

suchasalteredsmoothmuscletoneinthegut.

Methylnaltrexoneisrelatedtotheopioidantagonistnaltrexone.

Whereasnaltrexoneisparticularlyusedtoblocktheeffectsof

opioidsonthecentralnervoussystem,methylnaltrexoneis

moreselectiveforperipheralopioidreceptors.Thisisbecause

addingamethylgroupreduceslipidsolubilitywhichlimitsthe

molecule'sabilitytocrosstheblood-brainbarrier.Blocking

opioidreceptorsinthegutshouldrelieveconstipationwithout

counteractingtheanalgesiceffectsofopioids.

Whilenaltrexoneistakenbymouth,methylnaltrexonehastobe

givenbysubcutaneousinjection.Ithasahalf-lifeofapproximately

eighthoursandmostofthedoseisexcretedunchanged,mainly

intheurine.Thedoseisadjustedaccordingtothepatient'sweight

andisusuallygivenonalternatedaysasneeded.

Adose-rangingstudywascarriedoutin33patientsreceiving

opioidsforpalliativecare.Forpatientsreceivingaminimum

doseofatleast5mgthemediantimeuntilabowelmovement

was1.26hours.Almosthalfofthesepatientsrespondedwithin

fourhours.Higherdosesdidnotimprovetheresponse.1

Adouble-blindplacebo-controlledtrialwascarriedoutin133

terminallyillpatientstakingopioidsandlaxatives.Theywere

giveninjectionseveryotherdayfortwoweeks.Abowelmotion

occurredwithinfourhoursofthefirstinjectionin48%ofthe

methylnaltrexonegroupandin15%oftheplacebogroup.The

mediantimebetweentheinjectionandabowelmovement

was6.3hourswithmethylnaltrexone,butmorethan48hours

withplacebo.Aftertwoweekstheresponseratewas38%with

methylnaltrexoneand8%withplacebo.Painscoreswerelargely

unchangedduringthestudy.2

Patientsgivenmethylnaltrexonearemorelikelythanthose

givenplacebotocomplainofnausea,dizziness,flatulence,

abdominalpainandincreasedtemperature.2Diarrhoeacan

occurandifitispersistent,treatmentshouldbediscontinued.

Thedrugshouldnotbeusedifthepatientissuspectedof

havinganobstructionofthebowel.

Thelonger-termefficacyofmethylnaltrexoneisuncertain

becausethepatientsinthetrialshadalimitedlifeexpectancy.

Atpresentmethylnaltrexoneisreservedforpalliativecare

patientswithopioid-inducedconstipationwhoseresponseto

laxativeshasbeeninsufficient.

manufacturerprovidedclinicalevaluation

references *†

1. PortenoyRK,ThomasJ,MoehlBoatwrightML,TranD,GalassoFL,Stamblern,etal.Subcutaneousmethylnaltrexoneforthetreatmentofopioid-inducedconstipationinpatientswithadvancedillness:adouble-blind,randomized,parallelgroup,dose-rangingstudy.JPainSymptomManage2008;35:458-68.

2. ThomasJ,KarverS,CooneyGA,ChamberlainBH,WattCK,SlatkinnE,etal.Methylnaltrexoneforopioid-inducedconstipationinadvancedillness.nEnglJMed2008;358:2332-43.

rivaroxabanXarelto(BayerSchering)

10mgfilm-coatedtablets

Approvedindication:preventionofpostoperativevenous

thrombosis

AustralianMedicinesHandbooksection7.1.3

Thesearchforalternativestoheparinandwarfarinhaslooked

atdifferentsectionsofthecoagulationcascade.oneapproach

istoinhibitactivatedfactorX(Xa)whichisresponsibleforthe

conversionofprothrombintothrombin.Fondaparinuxisan

indirectinhibitoroffactorXa,buthastobegivenbyinjection.

Rivaroxabanoffersanoralalternativeandhasamoredirect

action.

Rivaroxabaniswellabsorbedfromthegutandmaximum

inhibitionoffactorXaoccursthreehoursafteradose.Theeffect

lasts8–12hours,butfactorXaactivitydoesnotreturntonormal

within24hourssoonce-dailydosingispossible. Rivaroxabanis

eliminatedintheurineandbymetabolism.Itiscontraindicated

inpatientswithsignificantrenalorhepaticdisease.Asthe

hepaticmetabolisminvolvescytochromeP4503A4thereisa

potentialforinteractionswithdrugssuchasrifampicinandthe

azoleantifungals.Therearealsotheoreticalinteractionswith

inhibitorsoftheP-glycoproteintransporter,suchasverapamil

anddiltiazem.

Anticoagulationafterorthopaedicsurgeryonthelowerlimb

canreducetheincidenceofdeepveinthrombosis.Adose-

rangingstudyofrivaroxabanwasthereforecarriedoutin873

patientshavingtotalhipreplacements.Thesepatientswere

randomisedtooneoffivedosesofrivaroxabanoradaily

injectionofenoxaparin.After5–9daysoftreatmentthepatients

hadvenography.Deepveinthrombosiswaslessfrequent

inthepatientstakingrivaroxaban.Therewasnosignificant

relationshipbetweendoseandefficacy,buttheriskofmajor

bleedingincreasedwithdose.1Adoseof10mgrivaroxaban

wasthenselectedforthePhaseIIItrialscalledtheRECoRD

studies.

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RECoRD1randomised2275patientstodailyinjectionsof40mg

enoxaparinand2266totakerivaroxabanaftertotalhip

replacement.Efficacywasassessedbyvenographyafter35days

ofprophylaxis.Theprimaryoutcomemeasurewasacomposite

ofdeath,pulmonaryembolismanddeepveinthrombosis.This

outcomeoccurredin3.7%oftheenoxaparingroupand1.1%of

therivaroxabangroup.Therewerefourdeathsineachgroup

sothedifferencebetweenthegroupswasaccountedforby

asignificantlylowerincidenceofdeepveinthrombosiswith

rivaroxaban.2

RECoRD2alsostudiedpatientshavingatotalhipreplacement

andhadthesameprimaryefficacyoutcomeasRECoRD1.A

totalof2509patientswererandomisedtodailyinjectionsof

40mgenoxaparinfor10–14daysorrivaroxabanfor31–39days.

Theenoxaparingrouptookplacebotabletsandtherivaroxaban

grouphadinjectionsofplacebo.After32–40daysthepatients

hadvenography.Theprimaryoutcomeoccurredin9.3%ofthe

enoxaparingroupand2%oftherivaroxabangroup.Therewere

significantlyfewerthromboseswithrivaroxaban.3

RECoRD3hadasimilarprimaryefficacyoutcometotheother

trials,butenrolledpatientshavingtotalkneereplacements.A

groupof1277wasrandomisedtoreceive40mgenoxaparin

dailywhileagroupof1254tookrivaroxabanfor10–14days.

Venographyaftertreatmentfounddeepveinthrombosisin

18.2%oftheenoxaparingroupand9.6%oftherivaroxaban

group.Theprimaryoutcomeoccurredin18.9%ofthe

enoxaparingroupand9.6%oftherivaroxabangroup.4

RECoRD4alsostudiedpatientswhohadkneereplacement

surgery,butcomparedrivaroxabanwithanAmericanregimen

ofenoxaparin(30mgtwicedaily).The3148patientswere

treatedfor10–14daysandhadvenographyafter40days.The

primaryoutcomeoccurredin10.1%oftheenoxaparingroup

and6.9%oftherivaroxabangroup.

Althoughrivaroxabanpreventsmorethrombosesthan

enoxaparin,thefrequencyofbleedingisslightlyhigher.In

RECoRD1majorbleedingoccurredin0.3%oftherivaroxaban

groupand0.1%oftheenoxaparingroup.2InRECoRD3the

correspondingfigureswere0.6%and0.5%.4Lessserious,

butclinicallyrelevant,bleedingisalsomorefrequentwith

rivaroxaban.Theincidenceofotheradverseeffectsissimilarfor

rivaroxabanandenoxaparin.Specialprecautionsareneeded

ifthepatienthashadspinalorepiduralanaesthesia.Although

rivaroxabancanincreasetheconcentrationsofliverenzymes

ithasnotyetshownthetoxicitywhichwasassociatedwith

ximelagatran,anotheroralanticoagulant.Moresafetydatawill

emergefromlonger-termstudyofthedruginconditionssuch

asatrialfibrillation.Whenusedforshort-termpreventionof

thrombosis,routinemonitoringoftheanticoagulanteffectisnot

required.

Ifoverdoseoccurs thereisnospecificantidotetorivaroxaban.

Thecurrentlyavailabledatasuggestthatrivaroxabanwillbeas

effectiveaslowmolecularweightheparinforprophylaxisafter

surgerytothelowerlimb.Patientswillprobablypreferadaily

tablettoadailyinjection.

manufacturerprovidedsomeinformation

references 1. ErikssonBI,BorrisLC,DahloE,HaasS,HuismanMV,

KakkarAK,etal;oDIXa-HIPStudyInvestigators.Aonce-daily,oral,directfactorXainhibitor,rivaroxaban(BAY59-7939),forthromboprophylaxisaftertotalhipreplacement.Circulation2006;114:2374-81.

2. ErikssonBI,BorrisLC,FriedmanRJ,HaasS,HuismanMV,KakkarAK,etal;RECoRD1StudyGroup.Rivaroxabanversusenoxaparinforthromboprophylaxisafterhiparthroplasty.nEnglJMed2008;358:2765-75.

3. KakkarAK,BrennerB,DahloE,ErikssonBI,MouretP,MuntzJ,etal;RECoRD2Investigators.Extendeddurationrivaroxabanversusshort-termenoxaparinforthepreventionofvenousthromboembolismaftertotalhiparthroplasty:adouble-blind,randomisedcontrolledtrial.Lancet2008;372:31-9.

4. LassenMR,AgenoW,BorrisLC,LiebermanJR,Rosenchern,BandelTJ,etal;RECoRD3Investigators.Rivaroxabanversusenoxaparinforthromboprophylaxisaftertotalkneearthroplasty.nEnglJMed2008;358:2776-86.

Triptorelin embonate

Diphereline(Ipsen)

6mLvialscontaining3.75mgor11.25mgaspowderfor

reconstitution

Approvedindication:prostatecancer

AustralianMedicinesHandbooksection14.3.3

Locallyadvancedormetastaticprostatecancercanbemanaged

byandrogenablation.Thiscanbeachievedbyorchidectomyor

hormonaltreatment.Severalagonistsofluteinisinghormone

releasinghormone,suchasgoserelinandleuprorelin,are

approvedforthisindication.Likeotheragonists,triptorelin

initiallycausesasurgeinluteinisinghormoneconcentrations,

butcontinuedusereducespituitarysecretion.Thisleadsto

reducedandrogenproductionwithtestosteroneconcentrations

fallingtolevelssimilartothoseseenafterorchidectomy.

Patientscanbegivenamonthlyintramuscularinjection

(3.75mg)oraninjectionofthelong-actingformulation(11.25mg)

everythreemonths.Asthemoleculeisasyntheticpeptideit

isprobablydegradedlikeaprotein.Clearanceisreducedby

hepaticorrenalimpairment.

ASouthAfricantrialrandomised172menwithadvanced

prostatecancertohavemonthlyinjectionsand174toreceive

thelong-actingformulation.After29days93%ofthepatients

onthemonthlyregimenand98%ofthoseonthethree-monthly

regimenhadreachedthetargettestosteroneconcentration.Both

regimensmaintainedtheseconcentrationsinmostpatients

duringthe36weeksofthestudy.

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AnotherSouthAfricantrialrandomised140mentoreceive

monthlytriptorelinand144toreceivemonthlyleuprorelin.

After29daystheproportionofmenwithtargettestosterone

concentrationswassignificantlyhigherwithleuprorelin(99%

vs91%).By57daystherewasnosignificantdifference.1

Thehormonalsurgeatthestartoftreatmentmayexacerbate

symptoms,suchasbonepainandbladderoutflowobstruction.

Astreatmentcontinuespatientsmaycomplainofdecreased

libido,impotence,breastpainandhotflushes.otheradverse

eventsincludeskeletalpain,hypertension,oedema,weightgain

andpainattheinjectionsite.

Althoughtriptorelinhasbeenavailableoverseasforafew

yearsthereislittlepublishedinformationaboutitsimpacton

survival.Althoughsurvivalwasnottheprimaryendpointofthe

comparativestudy,thenine-monthsurvivalratewas97%with

monthlytriptorelinand91%withleuprorelin.1

manufacturerdeclinedtosupplydata

reference *1. HeynsCF,SimoninMP,GrosgurinP,SchallR,PorchetHC.

Comparativeefficacyoftriptorelinpamoateandleuprolideacetateinmenwithadvancedprostatecancer.BJUInt2003;92:226-31.

Valsartan

Diovan(novartis)

80mgand160mgfilm-coatedtablets

Approvedindications:hypertension,heartfailure

AustralianMedicinesHandbooksection6.3.5

Valsartan/hydrochlorothiazide

Co-Diovan(novartis)

80mg/12.5mg,160mg/12.5mg,160mg/25mgfilm-coatedtablets

Approvedindication:hypertension

AustralianMedicinesHandbooksection6.3.5

Amlodipine/valsartan

Exforge(novartis)

5mg/80mg,5mg/160mgand10mg/160mgfilm-coatedtablets

Approvedindication:hypertension

AustralianMedicinesHandbooksection6.3.5

Valsartan

ValsartanisanangiotensinIIantagonistwhichwaslaunched

overseasmorethan10yearsago,butwasnotmarketedin

Australia.Likeothermembersoftheclass,suchascandesartan

andlosartan,valsartanlowersbloodpressurebyactingatthe

angiotensintypeIreceptor.

Theantihypertensiveeffectofvalsartanreachesamaximum

afterfourweeks.Althoughraisingthedosecanincreasethe

antihypertensiveeffect,doublingthedosefrom160mgto

320mgmayonlyreducebloodpressurebyanextra1–2mmHg,

whileincreasingadverseeffectssuchasdizziness.1

Patientstakethetabletsonceadayforhypertensionandtwice

adayforheartfailure.Mostofthedoseisexcretedunchanged

inbile,butitisrecommendedthatthemaximumdoseshould

belimitedinpatientswithsevererenalimpairmentaswell

asinthosewithmildtomoderatehepaticimpairment.Itis

contraindicatedinpregnancy.

Alargetrialhascomparedvalsartanwithamlodipineinmore

than15000hypertensivepatients.Afterameanfollow-upof

4.2yearsthereductioninmeanbloodpressurewasgreater

inpatientstakingamlodipinethaninthosetakingvalsartan.

Systolicpressurefellby17mmHgwithamlodipineandby

15mmHgwithvalsartan,whilethediastolicpressuresfellby

10mmHgand8mmHg.Althoughthecompositeendpointof

cardiovascularmorbidityandmortalitywasnotsignificantly

different,thereweremoremyocardialinfarctionsinthepatients

takingvalsartan.Theincidenceofinfarctionper1000patient

yearswas11.4withvalsartanand9.6withamlodipine.2

Valsartanhasbeenstudiedinpatientswithacutemyocardial

infarction.Theywereenrollediftheyhadsignsofheartfailureor

leftventricularsystolicdysfunction.Morethan14000patients

wererandomisedtoreceivevalsartan,captoprilorbothdrugs.

Afteramedianfollow-upof24.7months,19–20%ofthepatients

ineachgrouphaddied.Valsartanwasnotinferiortocaptopril,

buttheircombinationhadnoadvantageandresultedinmore

patientsstoppingtreatmentbecauseofadverseeffects.3

Valsartanhasalsobeenusedtotreatchronicheartfailure.

Inacontrolledtrialvalsartan,oraplacebo,wasaddedto

thetreatmentof5010patientswithheartfailure(newYork

HeartAssociationclassII,IIIorIV).Afterameanfollow-upof

23months,19–20%ofthepatientsineachgrouphaddied,

howeveracombinedendpointofmortalityandmorbidity

showedanadvantageforvalsartan.Thiswasmainlybecause

fewerpatients,thanintheplacebogroup,wereadmittedto

hospitalbecauseofworseningheartfailure(13.8%vs18.2%).

Valsartanshouldnotbeusedinpatientswhoarealreadytaking

anACEinhibitorandabetablocker.Inthetrial,addingvalsartan

tothiscombinationsignificantlyincreasedmortality.4

Valsartan with hydrochlorothiazideInthecomparisonwithamlodipine,moreofthepatientstaking

valsartanneededtotakeadditionaldrugs,suchas

hydrochlorothiazide,tocontroltheirbloodpressure.2These

patientscannowbeconsideredformanagementwitha

combinationtabletcontainingvalsartanandhydrochlorothiazide.

Thereisaninteractionbetweenthedrugs.Hydrochlorothiazide

reducestheconcentrationsofvalsartanandvalsartanreduces

theavailabilityofhydrochlorothiazide.Thesechangesdonot

negatetheantihypertensiveeffect.

T

2� | VoLuMe 32 | NuMber 1 | FebruAry 2009 www.austral ianprescriber.com

Thecombinationofvalsartanandhydrochlorothiazidewas

comparedwithvalsartaninaplacebo-controlledtrialinvolving

871patientswithessentialhypertension.Thesepatientswere

randomisedtooneofninegroupsusingdifferentdosesof

thecombination,ormonotherapy.Aftereightweeksallthe

activetreatmentshadreducedthemeansittingbloodpressure

significantlymorethanplacebo.Anycombinationofvalsartan

andhydrochlorothiazidereducedbloodpressuremorethan

eitherdrugalone.Forexample,valsartan80mgwith12.5mg

ofhydrochlorothiazidewillreducethediastolicpressureby

3.2mmHgmorethan80mgvalsartanandby4.7mmHgmore

than12.5mghydrochlorothiazide.5

Anothertrialcomparedtwocombinationsofvalsartanand

hydrochlorothiazidewithvalsartanalonein774patientswith

systolichypertension.Aftereightweeksthemeansittingsystolic

bloodpressurehadbeenreducedby20.7mmHgwithvalsartan

160mg.Incombinationwithhydrochlorothiazide12.5mgthe

reductionwas27.9mmHgandwithhydrochlorothiazide25mg

itwas28.3mmHg.6

Thecombinationofvalsartanandhydrochlorothiazidehasalso

beencomparedwithamlodipine.Inadditiontohypertension,

the1088patientsinthisstudyallhadatleastoneother

cardiovascularriskfactor.After24weeksamlodipine10mghad

reducedthemeansystolicsittingbloodpressureby27.6mmHg.

Valsartanreducedthepressureby27.1mmHgwhencombined

withhydrochlorothiazide12.5mgandby29.7mmHgwith

hydrochlorothiazide25mg.7

Themainadverseeffectsofthecombinationsaredizziness,

headacheandfatigue.5Approximately4%ofpatientswillhavea

greaterthan20%decreaseinserumpotassium.

Amlodipine with valsartanValsartanhasalsobeencombinedwithacalciumchannel

blockertotreathypertension.Thecombinationofamlodipine

andvalsartanistakenoncedaily.Thebioavailabilityofthe

tabletisequivalenttothatofitscomponentswhentheyare

givenseparately.Thereisnosignificantinteractionbetween

thedrugs,sotheirpharmacokineticparametersareexpectedto

bethesamewhentheyaregiveninacombinedformulation.

Twoplacebo-controlledstudiesinvolvingmorethan3000

patientshavecomparedtheantihypertensiveeffectsof

amlodipineandvalsartanalonewithdifferentstrengthsof

thecombination.overeightweeks,mostofthecombined

formulationsproducedsignificantlylargerreductionsinblood

pressurethaneitherdrugaloneorplacebo.8

Anotherstudycomparedthecombinedtablets(amlodipine

5mgor10mgwithvalsartan160mg)withacombination

oflisinoprilandhydrochlorothiazidein130patientswhohad

diastolicbloodpressuresof110–119mmHg.Aftersixweeks

bothcombinationshadcontrolledthediastolicbloodpressure

in77–80%ofpatients.Themeanreductionindiastolicpressure

withamlodipineandvalsartanwas29mmHgandwithlisinopril

andhydrochlorothiazideitwas28mmHg.9

Combinationproductsexposepatientstotheadverseeffects

ofbothcomponents,butinsomecasesonedrugmay

amelioratetheeffectsoftheother.Peripheraloedemaoccursin

approximately5%ofthosetakingamlodipineandvalsartan.

Thisissignificantlylessthanwithamlodipinealone(9%),but

morethanwithvalsartanalone(2%).8Lessfrequentreactions

areheadacheanddizziness.

Mostpatientswillneedmorethanonedrugtocontroltheir

bloodpressure,butthetreatmentofhypertensionshouldnot

beginwithacombinationproduct.Ideally,thedosesofthe

individualdrugsshouldbetitratedtoanoptimumdose.Ifthese

dosescorrespondtothoseofacombinationproduct,thepatient

canbeswitchedtothecombination.Theproblemwithfixeddose

combinationsisthattheabilitytotitratethedoseislimited.10

manufacturerprovidedonlytheproductinformation

references *†

1. oparilS,DykeS,HarrisF,KiefJ,JamesD,HesterA,etal.Theefficacyandsafetyofvalsartancomparedwithplacebointhetreatmentofpatientswithessentialhypertension.ClinTher1996;18:797-810.

2. JuliusS,KjeldsenSE,WeberM,BrunnerHR,EkmanS,HanssonL,etal.outcomesinhypertensivepatientsathighcardiovascularrisktreatedwithregimensbasedonvalsartanoramlodipine:theVALUErandomisedtrial.Lancet2004;363:2022-31.

3. PfefferMA,McMurrayJJV,VelazquezEJ,RouleauJ-L,KoberL,MaggioniAP,etal.Valsartan,captopril,orbothinmyocardialinfarctioncomplicatedbyheartfailure,leftventriculardysfunction,orboth.nEnglJMed2003;349:1893-906.

4. CohnJn,TognoniG;ValsartanHeartFailureTrialInvestigators.Arandomizedtrialoftheangiotensin-receptorblockervalsartaninchronicheartfailure.nEnglJMed2001;345:1667-75.

5. BenzJR,BlackHR,GraffA,ReedA,FitzsimmonsS,ShiY.Valsartanandhydrochlorothiazideinpatientswithessentialhypertension.Amultipledose,double-blind,placebocontrolledtrialcomparingcombinationtherapywithmonotherapy.JHumHypertens1998;12:861-6.

6. LacourciereY,PoirierL,HebertD,AssoulineL,StoltP,RehelB,etal.Antihypertensiveefficacyandtolerabilityoftwofixed-dosecombinationsofvalsartanandhydrochlorothiazidecomparedwithvalsartanmonotherapyinpatientswithstage2or3systolichypertension:an8-week,randomized,double-blind,parallel-grouptrial.ClinTher2005;27:1013-21.

7. RuilopeLM,MalaccoE,KhderY,KandraA,BonnerG,HeintzD.Efficacyandtolerabilityofcombinationtherapywithvalsartanplushydrochlorothiazidecomparedwithamlodipinemonotherapyinhypertensivepatientswithothercardiovascularriskfactors:theVASTstudy.ClinTher2005;27:578-87.

8. PhilippT,SmithTR,GlazerR,WernsingM,YenJ,JinJ,etal.Twomulticenter,8-week,randomized,double-blind,placebo-controlled,parallel-groupstudiesevaluatingthe

T

| VoLuMe 32 | NuMber 1 | FebruAry 2009 2�www.austral ianprescriber.com

Answers to self-test questions

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efficacyandtolerabilityofamlodipineandvalsartanincombinationandasmonotherapyinadultpatientswithmildtomoderateessentialhypertension.ClinTher2007;29:563-80.

9. PoldermansD,GlazerR,KaragiannisS,WernsingM,KaczorJ,ChiangYT,etal.Tolerabilityandbloodpressure-loweringefficacyofthecombinationofamlodipineplusvalsartancomparedwithlisinoprilplushydrochlorothiazideinadultpatientswithstage2hypertension.ClinTher2007;29:279-89.

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

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

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

PrintPostApprovedPP349181/00151•ISSn0312-8008©nationalPrescribingService2009

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