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Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergicrhinitis

TherClinRiskManag.2008Oct4(5):10091022.

PMCID:PMC2621402

Publishedonline2008Oct.

Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergic
rhinitis
FriedrichHorak
MedicalUniversityVienna,ENTUniv.Clinic,Vienna,Austria
Correspondence:FriedrichHorakHNOUniv.KlinikWien,WaehringerGuertel1820,A1090Vienna,AustriaTel+431404003336Fax+43178976
76Emailfriedrich.horak@vienna.at
Copyright2008DoveMedicalPressLimited.Allrightsreserved
ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract

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Azelastinenasalspray(Allergodil,Lastin,AfluonMedaAB,Stockholm,Sweden)isafastacting,efficacious
andwelltoleratedH1receptorantagonistforthetreatmentofrhinitis.Inadditionitalsohasmastcellstabilizing
andantiinflammatoryproperties,reducingtheconcentrationofleukotrienes,kininsandplateletactivatingfactorin
vitroandinvivo,aswellasinflammatorycellmigrationinrhinitispatients.Wellcontrolledstudiesinpatientswith
seasonalallergicrhinitis(SAR),perennialrhinitis(PR)orvasomotorrhinitis(VMR)confirmthatazelastinenasal
sprayhasarapidonsetofaction,andimprovesnasalsymptomsassociatedwithrhinitissuchasnasalcongestion
andpostnasaldrip.Azelastinenasalsprayiseffectiveatthelowerdoseof1sprayaswellatadoseof2spraysper
nostriltwicedaily,butwithanimprovedtolerabilityprofilecomparedtothe2spraypernostriltwicedailyregimen.
Comparedwithintranasalcorticosteroids,azelastinenasalsprayhasafasteronsetofactionandabettersafety
profile,showingatleastcomparableefficacywithfluticasonepropionate(FlonaseGSK,USA),andasuperior
efficacytomometasonefuroate(NasonexScheringPlough,USA).Incombinationwithfluticasonepropionate,
azelastinenasalsprayexhibitsgreaterefficacythaneitheragentusedalone,andthiscombinationmayprovide
benefitforpatientswithdifficulttotreatseasonalallergicrhinitis.Inaddition,azelastinenasalspraycanbeusedon
anasneededbasiswithoutcompromisingclinicalefficacy.Comparedwithoralantihistamines,azelastinenasal
sprayalsodemonstratessuperiorefficacyandamorerapidonsetofaction,andiseffectiveeveninpatientswhodid
notrespondtopreviousoralantihistaminetherapy.Unlikemostoralantihistamines,azelastinenasalsprayis
effectiveinalleviatingnasalcongestion,aparticularlybothersomesymptomforrhinitissufferers.Azelastinenasal
sprayiswelltoleratedinbothadultsandchildrenwithallergicrhinitis.Bittertastewhichseemstobeassociated
withincorrectdosingtechniqueisthemostcommonsideeffectreportedbypatients,butthisproblemcanbe
minimizedbycorrectdosingtechnique.
Keywords:azelastinenasalspray,rhinitis,intranasalcorticosteroids,oralantihistamines,seasonalallergicrhinitis
Introduction

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Rhinitisisaninflammatorydiseaseoftheupperairways,affectingapproximately58millionpeopleonlyinthe
UnitedStatesalone(Settipane2001)anditsprevalenceisincreasing.Thecostofthediseaseissignificantwith
betweenUS$2andUS$5billionincurredannuallyinbothdirectandindirectcosts(Rayetal1999Reedetal
2004).IntheUS,thenumberoflostworkdaysisestimatedasapproximately3.5millionayear(MahrandSheth
2005).Itcanbeclassifiedasallergic,nonallergicormixedupperrespiratorydisorder(Berstein2007).Itis
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Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergicrhinitis

classifiedasallergicifsymptomsoccurinassociationwithaspecificIgEmediatedresponseasnonallergicif
symptomsareinducedbyirritanttriggers,butwithoutanIgEmediatedresponseandasofmixedetiologyifIgE
mediatedresponsesoccurinconjunctionwithsymptomsinducedbybothallergensandnonallergicirritanttriggers.
Allergicrhinitis(AR)isfurtherclassifiedasseasonalorperennial(Dykewiczetal1998).Seasonalallergicrhinitis
(SAR)symptomsareinducedbyexposuretopollensfromtrees,grass,weedsorseasonalmouldspores,whilst
perennialrhinitis(PR)isassociatedwithenvironmentalallergenswhicharegenerallypresentonayearroundbasis
suchashousedust,animaldanderandinsectdroppings(Dykewiczetal1998).Incontrast,theAllergicRhinitis
anditsImpactonAsthma(ARIA)guidelinesrecommendaclassificationinintermittentallergicrhinitisand
persistentallergicrhinitisaccordingtothefrequencyandpersistenceofsymptoms(Bousquetetal2001).
SymptomsofSARincludenasalcongestion,runnynose,nasalandnasopharyngealitching,earsymptoms,
sneezingandocularsymptomsinmanypatients,includingitchyandwateryeyes(BieloryandAmbrosio2002).
Thesymptomsofsneezing,itchingandrhinorrheaarelesscommonwithPR(EconomidesandKaliner2002).As
manyashalfofallpatientsdiagnosedwithrhinitishavenonallergicdisease(sometimescalledvasomotorrhinitis
[VMR])whereanallergiccomponentcannotbeidentified(Dykewiczetal1998).Symptomsareofteninducedby
irritanttriggerssuchastobaccosmoke,strongodorsandtemperatureandpressurechanges(DevyaniandCorey
2004).ThesymptomsofVMRaresimilartothoseofAR(DevyaniandCorey2004).Tofurthercomplicaterhinitis
classification,asmanyashalfofallpatientswithARarealsosensitivetononallergictriggersaconditionreferred
toasmixedrhinitis(SettipaneandSettipane2002Libermanetal2005).Symptomsofrhinitiscanhaveamajor
impactonpatientsqualityoflife(QoL)byinterferingwithsleepwhichcausesfatigue,andimpairingdaily
activitiesandcognitivefunction(Dykewiczetal1998).Patientsoftencomplainofaninabilitytoconcentrate,and
inthecaseofSARoftenavoidoutdooractivitiesinordertoavoidexposuretosymptominducingallergen(s).The
JointTaskForceonAllergyPracticeandParametersadvisesthatimprovingthenegativeimpactondailylifein
rhinitispatientsdefinessuccessfultreatmentasmuchasprovidingsymptomrelief(Dykewiczetal1998).Indeed,
Juniper(1997)recommendsthatformostpatientswithrhinitis,improvingpatientwellbeingandQoLshouldbe
theprimarygoaloftreatment.
TreatmentguidelinesfromtheJointTaskForceandWHOrecommendthatantihistamines,bothtopical(eg,
azelastine[AllergodilMedaAB,Stockholm,Sweden])andoralsecondgeneration(eg,loratadine[Claritin,
ScheringPlough,USA],desloratadine[ClarinexScheringPlough,USA],fexofenadine[Allegra
SanofiAventis,USA]orcetirizine[ZyrtecPfizer,USA],andlevocetirizine[XyzallUCB,EU])beusedas
firstlinetherapyforAR(Dykewiczetal1998Bousquetetal2001).Intranasalcorticosteroids(eg,fluticasone
propionate[Flonase,GSK,USA],mometasonefuroate[NasonexScheringPlough,USA])mayalsobe
consideredasinitialtherapyforARinpatientswithmoreseveresymptoms,particularlynasalcongestion
[(Dykewiczetal1998LaForce1999).TheAllergicRhinitisanditsImpactonAsthma(ARIA)guidelines
recommendasteppedapproachtotherapybaseduponthefrequencyandseverityofsymptoms(Table1)
(Bousquetetal2001).Interestingly,arecentUSnationwidesurveyincorporatingapproximately2500adultallergy
sufferers,revealedthat66%weredissatisfiedwiththeircurrentallergymedicationduetolackofeffectiveness
(Anon2006).Furthermore,morethantwothirdsofprimarycarephysiciansreportedpatientdissatisfactionwith
therapyasthemainreasonforstoppingorswitchingmedications(Anon2001).Clearly,effectivetherapieswitha
goodsafetyprofileareneededtotreatARsufferers.
Table1
SummaryofARIAallergicrhinitismanagementguidelines

Azelastine

Azelastinenasalsprayisatopicallyadministeredsecondgenerationantihistamineandselectivelyantagonizesthe
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Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergicrhinitis

H1receptor(Zecheletal1981)beingapproximatelytenfoldmorepotentthanchlorpheniramineinthisregard
(Casale1989).Ithasoneofthefastestonsetsofaction(15minwithnasalsprayandupto3minwitheyedrops)
amongthecurrentlyavailablerhinitismedications(Baumgartenetal1994Greiffetal1997).Theeffectof
azelastinelastsatleast12hours,thusallowingforaonceortwicedailydosingregimen(Greiffetal1997).Ithas
provenefficacyintreatingbothallergicandnonallergicrhinitis,andistheonlyprescriptionantihistamine
approvedintheUS,PortugalandtheNetherlandsforthetreatmentofbothSAR(1996)andVMR(1999).InSAR
patientsazelastinetherapy(twosprayspernostriltwicedaily),improvedbothtotalsymptomandmajorsymptom
complexscorestoasignificantlygreaterextentthanplacebo(McTavishandSorkin1989Stormsetal1994

Pharmacologicalandtoxicologicalpropertiesofazelastine,anovel
antiallergicagent.
LaForceetal1996RatnerandSacks2007).Similarly,inPRpatients,azelastinenasalspraysignificantlyimproved
ZechelHJ,BrockN,LenkeD,AchterrathTuckermannU
sleeping,reduceddaytimesomnolenceandnasalcongestioncomparedwithplacebo(Goldenetal2000).Liberman
Arzneimittelforschung.198131(8):118493.
etal(2005)werethefirsttoshowthatazelastinewasalsoeffectiveinthemanagementofVMRandeveninmixed
[PubMed][Reflist]
rhinitis.Azelastinenasalspraysignificantly(p<0.01)reducedthetotalVMRsymptomscore(TVRSS)compared
withplaceboafter21daydoubleblindtreatment,andwasassociatedwithclinicalimprovementineachsymptom
oftheTVRSS(ie,rhinorrhea,sneezing,nasalcongestion,andpostnasaldrip).Inalargeopenlabeltrial4364
patientsreceivedazelastinenasalspray(2sprayspernostriltwicedaily)asmonotherapyfor2weeks.78%ofVMR
patientsreportedsomeorcompletecontrolofpostnasaldripwhichroseto90%ofSARpatientsforthesymptom
ofsneezing.Ofpatientsreportingsleepdifficultiesorimpaireddaytimeactivitiesbecauseofrhinitissymptoms,
85%experiencedimprovementsintheseparameterswithazelastine.Baselinesleepdifficultiesandimpairmentof
daytimeactivitiesweresignificant(p<0.01)predictorsofapositivetreatmenteffectwithazelastinenasalspray.
Femalepatients(p=0.02),patientswithSAR(p<0.01)andpatientswithSARplussensitivitytononallergic
triggers(p=0.03)wereidentifiedasbeingmostlikelytorespondtoazelastinenasalspray(Libermanetal2005)
Duetoitsrapidonsetofaction,azelastinenasalspraycontinuestocontrolrhinitissymptomswhenusedonanas
neededbasis(Ciprandietal1997).Thispropertyofazelastineisdiscussedlater.FirstmarketedintheUKin1991
forthetreatmentofbothSARandPR,itiscurrentlyavailableinmorethan70countriesworldwide.
Modeofaction

However,azelastineismorethanjustanantihistamine.Itexhibitsaveryfastandlongactingeffectbasedona
triplemodeofaction,withantiinflammatoryandmastcellstabilizingpropertiesinadditiontoitsantiallergic
effects(Bernstein2007LeeandCorren2007).Forexample,azelastineinhibitstheactivationofculturedmastcells
andreleaseofinterleukin(IL)6,tryptase,andhistamine(Kempurajetal2002).Italsoreducesmediatorsofmast
celldegranulationsuchasleukotrieneswhichareinvolvedinthelatephaseallergicresponse(Howarth1997),in
thenasallavagefluidofpatientswithrhinitis(Shinetal1992).Itdoesthispossiblybyreducingtheproductionof
leukotriene(LT)B4synthaseandLTC4,inhibitingphospholipaseA2andLTC4(Hamasakietal1996).
Leukotrienesareassociatedwithdilationofvessels,increasedvascularpermeabilityandedemawhichresultsin
nasalcongestion,mucusproductionandrecruitmentofinflammatorycells(Goldenetal2006).SubstancePand
bradykininconcentrationswhichareformedinbiologicalfluidsandtissuesduringinflammation,arealsoreduced
byazelastine(Shinetal1992Nieberetal1993Shinodaetal1997).TheseagentsareassociatedwiththeAR
symptomsofnasalitchingandsneezing,butmayalsocontributetotheonsetofnonallergicVMRsymptoms.
Otherantiinflammatorypropertiesofazelastineincludeinhibitionoftumornecrosisfactoralpha(TNF)release
(Hideetal1997MatsuoandTakayama1998),reductionofgranulocytemacrophagecolonystimulatingfactor
(GMCSF)generation,aswellasareductioninthenumberofarangeofinflammatorycytokinesincluding
interleukin(IL)1,IL6,IL4andIL8(Yonedaetal1997Itoetal1998Becketal2000).Thesecytokines
perpetuatetheinflammatoryresponse(Settipane2001).Finally,inSARpatients,azelastinenasalsprayhasbeen
showntolowerneutrophilandeosinophilcountsanddecreaseintercellularadhesionmolecule1(ICAM1)
expressiononnasalepithelialcellsurfacesinboththeearlyandlatephasesoftheallergicreaction(Ciprandietal
1996).Italsodecreasesfreeradicalproductionbyhumaneosinophilsandneutrophils(Busseetal1989Umeki
1992)andcalciuminfluxinducedbyplateletactivatingfactorinvitro(Nakamuraetal1988Moritaetal1993).
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Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergicrhinitis

Theuseofatopicaltreatmenthasmanyadvantagesoverasystemictreatment.Firstly,withanasalspray,
medicationcanbedelivereddirectlytothesiteofallergicinflammation.Secondly,thehigherconcentrationsof
antihistaminesthatcanbeachievedinthenasalmucosabytopicalasopposedtooraladministrationshouldenhance
theantiallergicandpotentialantiinflammatoryeffectsoftheseagents.Thirdly,adoseof0.28mgintranasallyhas
afasteronsetofactionthanadoseof2.2mgadministratedorally(Horaketal1994).Andfinally,withtopical
administrationtheriskofinteractionwithconcomitantmedicationisminimized(Daviesetal1996)andthe
potentialofsystemiceffectsreduced.
Dosage

Recentresultsfrom2studieshaveshownthatazelastinenasalsprayatadosageof1spraypernostriltwicedailyis
effectiveandhasabettertolerabilityprofilecomparedto2sprayspernostriltwicedailyinpatients(12yearsn=
554)withmoderatetosevereSAR(Lumryetal2007).Thetotalnasalsymptomscore(TNSS)improvedby14.1%
instudy1andby22.1%instudy2withazelastinenasalspray(1spraypernostriltwicedaily)comparedwith4.5%
and12.0%withplaceboinstudy1(p=0.01)and2(p<0.01)respectively.Thiscompareswitha24%29%
improvementinrhinitissymptomsscoreswitha2spraydosageofazelastine(Ratneretal1994Stormsetal1994
LaForceetal1996).Forindividualsymptoms,itchynose,runnynose,sneezing,andnasalcongestionwereall
significantlyimprovedafterthe1sprayazelastineregimencomparedwithplacebo.Onespraypernostriltwice
dailyofazelastinewasalsoassociatedwithsignificantimprovementsintheRhinitisQualityofLifeQuestionnaire
(RQLQ)dailyactivityandnasalsymptomsdomainsandpatientglobalevaluationscomparedwithplacebo.In
addition,theincidenceofabittertasteafterazelastineapplicationmorethanhalvedandtheincidenceof
somnolencedecreasedalmost30timesinthe1spraygroupversusthelabeledincidencewiththe2sprayregimen
(Lumryetal2007).Althoughanearlierstudyshowedanimprovementinrhinitissymptomsversusplacebowith
azelastine1spraypernostriltwicedaily,thisimprovementfailedtoreachstatisticalsignificance.However,aglobal
evaluationnotedasignificantclinicalimprovementversusplacebo(49%)inthe1sprayregimen(75%,p<0.001)
aswellasa2sprayoncedaily(89%,p=0.028)anda2spraytwicedailyregimen(83%,p<0.001)(Weileretal
1994).
Fromtheseresultsonecanconcludethatagreaterdegreeofeffectivenesswouldbeexpectedwithtwospraysper
nostriltwicedaily.Althoughonespraypernostriltwicedailymayprovidesomewhatlessefficacythisis
compensatedforbyanimprovedtolerabilityprofilecomparedwiththe2sprayregimen.Therefore,thechoiceof
dosageofazelastinenasalsprayshouldbebasedontheseverityandpersistenceofsymptomsaswellasthe
patientsacceptanceofthenasalspray(Bernstein2007).Forexample,the2spraydosecouldbeusedasthe
startingdoseforpatientswithseveresymptomsofSAR,andeithermaintainedortaperedtothe1spraydoseas
required.The1spraydosecouldbeusedasastartingdoseinpatientswithmildtomoderatesymptoms,andif
necessarythedoseincreasedto2sprayspernostriltwicedailyifsymptomcontrolprovedtobeinadequate(Lumry
etal2007).
Asneeded

Becauseazelastinestartsworkingwithin15minutesofapplicationinvestigatorswonderedhoweffectiveanas
neededregimenwouldbeincontrollingthesymptomsofrhinitis(Ciprandietal1997).Arandomizedcontrolled
studywascarriedoutin30patientssensitizedtoParietariapollenorgrass.Patientsweretreatedwiththestandard
Europeandoseofazelastine(0.56mg/day),halfthisdose(0.22mg/day),orasneeded.Bothgroupswhoreceived
thestandardandhalfstandarddosesshowedanimprovementintheirrhinitissymptoms,withaconcomitant
reductioninmarkersofinflammation,namelyneutrophilandeosinophilcountsaswellasICAM1expressionin
nasalscrapings.However,patientswhousedazelastinenasalsprayonanasneededbasisalsoshowedan
improvementintheirrhinitissymptoms,butwithoutareductioninthemarkersofinflammation.Theresultsofthis
smallstudysuggestthatalthoughregulartreatmentwithazelastineissuperioratcontrollingsymptoms,asneeded
therapymaybeusefulinthetreatmentofclinicalsymptoms(Ciprandietal1997).Theuseofazelastinenasalspray
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onanasneededbasiswouldbeexpectedtoimprovedrugtolerabilityandhasimportantimplicationsforpatient
compliance.Anotheroptionistouseazelastineasneededinadditiontoanoralantihistaminetreatmentondays
withseveresymptomsofSAR.
Comparisonswithotheragentsusedtotreatrhinitis

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Thecomplexityofrhinitisasadiseaseandthemultiplepathwaysinvolvedinitspathophysiologymeanthatthere
areseveralclassesofdrugsavailabletotreatit.Theseincludeintranasalcorticosteroids,oralantihistamines,
intranasalantihistaminesandmastcellstabilizers(eg,cromolyncompounds).Ausefulmetrictocompareeachof
thesetreatmentmodalitiesisthenumberneededtotreat(NNT),whichestimatesthenumberofpatientswhomust
betreatedwithaparticulardruginordertohaveonepositiveoutcome.Obviously,drugswithlowaNNTare
consideredmoreeffectivethanthosewithahigherNNT.OnereportestimatedtheNNTrangefororal
antihistaminesas935,36forintranasalcorticosteroids,56.3forazelastine,and4.6forimmunotherapy(Portnoy
etal2004).However,inthatstudytheNNTwascalculatedusingonlyasingletrialforeachdrug,andsonotallof
theevidencewasconsidered.Amorerecentmetaanalysissystematicallyreviewedtheefficacyofazelastinenasal
spray,intermsofglobalassessmentofefficacy,versusactivecomparatorsusingNNTsastheoutcomemeasure
(LeeandPickard2007).Theactivecomparatorsincludedbeclomethasone(BeconaseGSK,USA)and
budesonidenasalsprays(RhinocortAstraZeneca,USA),loratadine,terfenadine(SeldaneSanofiAventis,
USA),cetirizine,ebastine(Kestine),andlevocabastine.Fortysixstudieswereinitiallyidentifiedand21separate
publicationswereincludedintheanalysis.In5comparisonsazelastinewasmoreefficaciousthanplacebowitha
summaryNNTof5.0.Nostatisticallysignificantdifferencewasfoundbetweenazelastinenasalsprayandtheother
treatments,includingintranasalcorticosteroids,intermsoftheirefficacyintreatingrhinitis.However,whenthe
analysiswaslimitedtostudiesinwhichanoralallergytreatmentwasthecomparator,thepointestimateofthe
pooledresultsfavoredazelastinenasalspray(Figure1).TheresultswereconsistentacrossbothSARand
nonallergicVMR,andacrosstrialsofdifferentdurations.Theriskdifferencewouldhavebeenevenmore
favourableforazelastineifonlyresultsforazelastineatadoseof1.12mg/daywereincludedintheanalysis,butthe
smallnumberofstudiesavailableforthemetaanalysisprecludedthatstratification(LeeandPickard2007).
Figure1
Numberneededtotreataglobalassessmentofefficacyasanoutcomefor
azelastinenasalspraycomparedwithoralagentsforthetreatmentofallergic
rhinitis.ReprintedwithpermissionfromLeeT,PickardS.2007.Meta
analysisofazelastinenasal...
Comparisonswithintranasalcorticosteroids

Azelastinenasalsprayisanonsteroidaltreatmentandhassomeadvantagesoverintranasalcorticosteroidsinthe
treatmentofSAR,eventhoughitsantiinflammatoryeffectisnotasstrong(Wangetal1997).Ithasafasteronset
ofactioncomparedwithintranasalcorticosteroids(Berkowitzetal1999Horaketal2006),withatleast
comparable(inthecaseofintranasalfluticasonepropionate)orsuperior(inthecaseofintranasalmometasone
furoate)efficacy,andhasabettersafetyprofile(Behnckeetal2006Pateletal2007).Likeintranasal
corticosteroids,azelastineiseffectiveintreatingthesymptomofnasalcongestion.Whereasintranasalcorticosteroid
therapyshouldbeginbeforetheonsetofsymptomsinordertoobtainoptimalbenefitfromtherapyantihistamines
canalsobetakenonanasneededbasis.Butincontrasttointranasalcorticosteroidsazelastinemayinduceabitter
tasteandnasalburningafterapplication.
Azelastineversusmometasonefuroate Azelastinenasalsprayissuperiortothetopicalcorticosteroidmometasone

nasalsprayinreducingnasalsymptoms(Pateletal2007).PatientswithahistoryofSARandsymptomaticwhile
exposedtoragweedpolleninanenvironmentalexposurechamber(EEC)wererandomizedto2sprayspernostril
ofazelastinenasalspray(137g/sprayn=150),mometasonenasalspray(50g/sprayn=150),orplacebo.At
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15minutesafteradministrationofstudydrugs,azelastinenasalspraysignificantlyreducedtheTNSSfrombaseline
by29.5%comparedwith12.3%withplacebo(p<0.001)andthissignificantsuperiorityofazelastineoverplacebo
persistedateachtimepointthroughoutthe8hourallergenexposure(Figure2).At8hourpostallergenchallenge,
azelastinehadreducedtheTNSSby33.9%frombaselineversus18.6%withplacebo.Conversely,mometasone
furoatenasalspraydidnotsignificantlyreducetheTNSSfrombaselinecomparedwithplaceboatanytimepoint(p
0.09),andazelastinenasalspraywassignificantlymoreeffectivethanmometasoneateachtimepointduringthe
8hourstudyperiod(p0.001Figure2)(Pateletal2007).Apreviouslypublishedstudyhasshowna12to72
houronsetofactionformometasone(Berkowitzetal1999)whichwouldexplainwhymometasonedidnot
significantlyimproveSARsymptomscomparedtoplacebowithin8hoursafterallergenexposure.Anonline
surveybytheAmericanCollegeofAllergy,AsthmaandImmunologyshowedthat77%ofallergistsand69%of
primarycarephysiciansthoughtrapidonsetofactionwasanessentialelementoftherapy(PhysicianSurvey2001).
Arapidonsetofactionwithin15minutes,asshownwithazelastinenasalspray,mayenhancecompliancewith
therapy.
Figure2
Onsetofactionofazelastinehydrochloridenasalsprayinrelievingnasal
symptomsofseasonalallergicrhinitis.*p<0.001azelastinevsplacebo*p
0.001azelastinevsmometasonemometasonevsplacebo=notsignificant.
Reprinted...
Azelastineversusfluticasonepropionate Astudyingeriatricpatientswithallergicornonallergicrhinitisshowed

thatazelastinenasalspray(2sprayspernostriltwicedaily1.1mg)wasjustaseffectiveasfluticasonepropionate
nasalspray2sprayspernostrildaily200g)atimprovingpatientsRQLQscores(Figure3)andrhinitis
symptoms(Figure4)(Behnckeetal2006).Azelastinenasalsprayandoralantihistaminesareoftenused
concurrentlywithanintranasalcorticosteroidsprayinpatientswithdifficulttotreatrhinitissymptoms.Several
studieswithoralantihistaminesincombinationwithintranasalcorticosteroidsshowednoincreasedclinicalbenefit
withthesedrugsincombination(Weineretal1998NielsenandDahl2003).However,arecentproofofconcept
studyshowedthatazelastinenasalsprayandfluticasonenasalsprayincombinationprovidedasubstantial
therapeuticbenefitforpatientswithSARcomparedwiththerapywitheitheragentalone(RatnerandSacks2007).
Patientswererandomizedtoreceiveeitherazelastinenasalspray(2sprayspernostriltwicedaily),fluticasonenasal
spray(2sprayspernostriltwicedaily),orbothagentstogether(samedosage).Allthreegroupshadstatistically
significant(p<0.01)improvementfrombaselineinTNSSafter2weekstreatment,buttheimprovementwas
significant(p<0.05)withthecombinationregimen(38%)versuseitheragentalone(azelastine:25%fluticasone:
27%)(RatnerandSacks2007).
Figure3
Effectofazelastinenasalsprayorfluticasonepropionatenasalsprayon
RhinitisQualityofLifeQuestionnaire(RQLQ)scoresingeriatricpatients
witheitherallergicornonallergicrhinitis.Reprintedwithpermissionfrom
BehnckeVB,AlemarGO,Kaufman...
Figure4
Effectofazelastinenasalsprayorfluticasonepropionatenasalsprayon
TotalDailySymptomScore(TDSS)ingeriatricpatientswitheitherallergic
ornonallergicrhinitis.ReprintedwithpermissionfromBehnckeVB,
AlemarGO,KaufmanDA,etal2006...
Comparisonswithoralantihistamines
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Effectivenessoftwicedailyazelastinenasalsprayinpatientswithseasonalallergicrhinitis

Wellcontrolledstudiesinpatientswithrhinitishaveshownthatazelastinenasalspraydemonstratessuperior
efficacyandamorerapidonsetofactioncomparedtooralantihistamines(McNeelyandWiseman1998Correnet
al2005Bergeretal2006Horaketal2006MeltzerandSacks2006SherandSacks2006).Azelastineisapotent
drugandhasbeenshowntobeeffectiveinpatientssufferingfromrhinitiswhohavenotrespondedtopreviousoral
antihistaminetherapy(BergerandWhite2003LaForceetal2004).Additionally,itsignificantlyreducesnasal
congestion(Hermanetal1997),aparticularlybothersomesymptomforrhinitissufferers.Unlikesomeoftheearlier
antihistamines,topicalapplicationofazelastineproducesverylowplasmaconcentrationsofthedrugwhichreduces
thesedativepotential.Indeed,comparedwithcetirizineandloratadine,azelastineactuallyincreasedalertnessin
patientswithseasonalorperennialrhinitis(Spaethetal1996).
Azelastineversusdesloratadine Desloratadineisanewantihistaminetablet.Incontrasttoantihistaminesofearlier

generations,thesedrugsarethoughttonoticeablyreducenasalcongestion(McClellanandJarvis2001Horaketal
2002bHoraketal2003),arenonsedatinganddonotcausecardiacsideeffects.Arecentlypublishedstudywas
thefirsttoassesstheefficacyandonsetofactionofazelastinenasalspray(onespraypernostril)comparedto
desloratadinetablets(5mg)inpatientswithSAR(Horaketal2006).Resultsshowedthatazelastinenasalspray
wassignificantlybetterthandesloratadinetabletsinreducingthesymptomsofSARincludingnasalcongestion
inducedbyallergenchallengeintheViennaChallengeChamber(VCC).Bothazelastinenasalsprayand
desloratadinetabletssignificantly(p<0.001)reducedtheMajorNasalSymptomScore(MNSSdefinedasthesum
ofscoresofsneezing,rhinorrheaandnasalitching)comparedtoplacebo(Figure5)(Horaketal2006),with
azelastinesignificantly(p=0.005)superiortodesloratadineinthisregard(Figure5).Inaddition,theonsetofaction
ofazelastinenasalspraywas15min.comparedwith150min.fordesloratadinetablets.Regardingdesloratadine
tablets,theonsetofactionof150minreportedbyHoraketal(2006)wasnotablylongerthanthatpreviously
described(Horaketal2002a).Thismayhavebeenduetotheencapsulationofdesloratadinetabletsforthepurpose
ofblinding.
Figure5
Majornasalsymptomscoresaveragedovertreatmentandtimefortheper
protocolpopulationafteradministrationofazelastine(1spraypernostril),
desloratadine(5mg),orplaceboinpatientswithSAR.Reprintedwith
permissionfromHorakF,Zieglmayer...
Themean4to6hourchangeinTNSS,whichcomprisedascorefornasalcongestion,wereconsistentwiththose
forMNSS.Thelargestimprovementwithazelastinewasobservedfornasalitchingfollowedbysneezing,
rhinorrheaandnasalcongestion(Figure6)(Horaketal2006).Infact,azelastinenasalspraywassuperiorto
desloratadinetabletsatalleviatingnasalcongestionwhencomparingabsolutescoresattheendofthechallenge.
Thisresultwasunexpectedsincetodate,antihistamineshavebeenfoundtohavelittledecongestantactivity,
whereasreductionofnasalcongestionisoneofthemainclinicaladvantagesofthirdgenerationantihistamines
(HorakandStbner2002Murdochetal2003).Significantdecongestantactivityhaspreviouslybeenreportedfor
azelastinenasalspray,butonlyatthehigherdosageof2sprayspernostril(Thomasetal1992).Therefore,these
resultssuggestthatazelastineatadosageof1spraypernostrilisjustaseffectiveas2sprays.However,oneshould
beremindedthattheimprovementinnasalcongestionfollowingazelastinetherapyisasubjectiveone,andfurther
objectivestudies,measuringnasalflowornasalresistance,arerequiredtoconfirmthesefindings.
Figure6
Majornasalsymptomandmeannasalsymptomscoresafteradministration
ofazelastinenasalspray(1spraypernostril),desloratadine(5mg)or
placeboinpatientswithSAR:absolutechangesoflastvalue(6hoursafter
thestartofchallenge)compared...
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Azelastineversuscetirizine Cetirizinehydrochlorideisanoralsecondgenerationantihistamineindicatedforthe

treatmentofSARandPR.Italsohasdemonstratedinhibitoryeffectsonothermediatorsofinflammationincluding
leukotrienes(CheriaSammarietal1995),prostaglandins(Charlesworthetal1989),ICAM1expression,and
eosinophilchemotaxis(Ciprandietal1995).ThefirstAzelastineCetirizineTrial(ACT1)carriedoutintheautumn
of2004,examinedtheeffectivenessandtolerabilityofazelastine(2sprayspernostril)andcetirizinetablets(10mg
oncedaily)in307patientswithmoderatetosevereSAR(Correnetal2005).Duringthe2weekdoubleblind
treatmentperiod,azelastinenasalspraysignificantly(p=0.02)improvedtheoverallTNSScomparedwith
cetirizine.AllfoursymptomcomponentsoftheTNSSwereimprovedafterazelastinetherapy,withasignificantly
greaterimprovementversuscetirizineforrhinorrhea(p=0.003).DifferencesintheTNSSbetweenazelastinenasal
sprayandcetirizineweresustainedthroughoutthestudyperiodandbecamemoreevidentasthestudyprogressed,
withstatisticallysignificantdifferencesfavoringazelastinenasalsprayonstudydays8through14.Inaddition,
comparedwithcetirizine,azelastinenasalspraysignificantly(p=0.049)improvedpatientsHRQoLasassessedby
theRQLQ(Correnetal2005).
Morerecently,two2week,doubleblind,multicenterstudieswereconductedwhichcomparedtheefficacyand
safetyofazelastinenasalspray(2sprays/nostriltwicedaily)withoralcetirizine(10mgdaily)inthetreatmentof
patientswithmoderatetosevereSAR(SherandSacks2006).Acombinedanalysisofresultsshowedthat
azelastinenasalspraysignificantlyimprovedtheTNSS(p<0.001)andeachofthefourindividualsymptomsofthe
TNSS(p<0.01)comparedwithcetirizine.Patientsintheazelastinespraygroupexperiencedanimprovementin
TNSSof32.5%comparedwith24.6%forthosepatientstakingoralcetirizine.Themostcommonsideeffect
reportedbypatientsintheazelastinegroupwasbittertaste(5.7%).Somnolencewasreportedby1.5%ofpatients
takingcetirizine(SherandSacks2006).
Inadditiontonasalsymptoms,patientswithSARcanexperienceimpairmentinHRQoL.Two2week,double
blind,multicenterstudieswereconductedduringautumn2004andspring2005comparingtheimprovementwith
azelastinenasalspray(2sprayspernostriltwicedaily)versuscetirizine(10mgdaily)onsymptomsandHRQoLin
SARpatients(MeltzerandSacks2006).Resultsfromthesestudiesrevealedthatazelastinenasalsprayimproved
theoverallRQLQscoretoasignificantly(p<0.05)greaterdegreethancetirizinetablets.Whenresultsfromboth
studieswerepooled,thecombinedanalysisconfirmedthesignificantsuperiorityofazelastinespraybothintermsof
theoverallRQLQscore(p<0.001)aswellaseachRQLQdomain(p<0.03)includingthenasalsymptoms
domain(p<0.001).Morepatientsintheazelastinenasalspraygroupexperiencedaclinicallyimportant
improvementfrombaselineinHRQoL(ie,2unitsonthe06ratingscale)comparedwithpatientsinthecetirizine
group(35%vs20%respectively)(MeltzerandSacks2006).
Bergeretal(2006)alsoshowedthatazelastinenasalspray(2sprayspernostril)andoralcetirizine(10mgonce
daily)effectivelytreatednasalsymptomsinpatientswithSAR(n=360).Rapidreliefofrhinitissymptomswas
evidentinbothgroupsatthefirstevaluationafterinitialadministrationandcontinuedduringthe14studydays,
withtheazelastinepatientsshowingthegreatestdegreeofimprovementduringthesecondweekoftreatment.
ImprovementsintheTNSSandindividualsymptomsfavoredazelastineovercetirizine(Figure7),withsignificant
differencesfornasalcongestion(p=0.049)andsneezing(p=0.01).AzelastinenasalsprayimprovedTNSSbya
meanof4.6(23.9%)comparedwith3.9(19.6%)withcetirizine.Thepositiveeffectofazelastinenasalsprayon
congestionwasobserveddespitethefactthatthecetirizinegrouphadtheaddedbenefitofdailyuseofaplacebo
salinespray.AzelastinenasalsprayalsosignificantlyimprovedtheRQLQoverall(p=0.002)andindividual
domain(p0.05)scorescomparedwithcetirizine(Bergeretal2006).Althoughoralcetirizinesignificantly
improvedRQLQscores,patientstreatedwithazelastinenasalsprayreportedadditionalstatisticallysignificant
improvementbeyondthatreportedwithcetirizineforeachindividualRQLQdomainincludingactivities,sleep,
nonnose/noneyesymptoms,practicalproblems,nasalsymptoms,eyesymptoms,andemotions(Figure8).
AlthoughitisoftenassumedthatpatientspreferoralmedicationstospraysinboththeACTIandACTIItrials,
patientsreportedsuperiorimprovementsinQoLvariableswithazelastinenasalspraycomparedwithoralcetirizine
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(Correnetal2005).
Figure7
Meandailyimprovementsfrombaselinetoday14incombinedmorningand
evening12hourreflectivetotalnasalsymptomscores(TNSSs).*p<0.05
versuscetirizine.ReprintedwithpermissionfromBergerW,HampelF,
BernsteinJ,etal2006.Impact...
Figure8
Meanimprovementfrombaselinetoday14inoverallRhinoconjunctivitis
QualityofLifeQuestionnaire(RQLQ)scoreandindividualRQLQdomain
scores(intentiontotreatpopulation).*p0.05vscetirizine**p<0.01vs
cetirizine.Reprinted...
Azelastinenasalsprayandcetirizinewerewelltoleratedinthisstudy(Bergeretal2006).Relativelyhigh
incidencesofsomnolenceandbittertastehavebeenpreviouslyreportedinearlytrialswithazelastinenasalspray
(Meltzeretal1994Stormsetal1994Weileretal1994LaForceetal2004RatnerandSacks2007).However,
subsequenttrialsinpatientswithVMR(BanovandLiberman2001)andpostmarketingstudiesinpatientswho
remainedsymptomaticaftertreatmentwithloratadine(BergerandWhite2003)orfexofenadine(LaForce1999)
reportedsomnolencerateswithazelastinenasalspraythatweresimilartothosewithplacebo.
Nonresponders

Asmanyas20%ofallARpatientsdonotrespondtoblockersatall(BergerandWhite2003).TwooralH1studies
assessedtheefficacyofazelastineinpatientswithmoderatetosevereSARwhohadanunsatisfactoryresponseto
oralsecondgenerationantihistamines(BergerandWhite2003LaForceetal2004).Thefirststudycomprised435
patientswhohadasuboptimalresponsetoloratadineandshowedthatbothazelastinemonotherapyandazelastine
plusloratadinesignificantly(p<0.001)improvedtotalsymptomscomparedwithplacebo(BergerandWhite
2003).Thesecondstudycomprised334patientswhohadfailedtoresponseto1weektreatmentwith
fexofenadine.Similarresultswereobtained,inthatpatientsinboththeazelastineandcombinationgroupsshowed
significant(p<0.01)improvementintheirsymptomscomparedwithplacebo.
Azelastineversusotherintranasalantihistamines
Azelastineversuslevocabastine LevocabastineisapotentandselectivehistamineH 1receptorantagonist.Previous

limiteddataindicatedequivalentefficacyoflevocabastinetothatoforalloratadine,oralcetirizineorazelastine
nasalspray(NobleandMcTavish1995).Morerecently,theefficacyandtolerabilityofazelastinenasalspray(1.12
mg,2spraystwicedaily)wasshowntobestatisticallysuperiortothatoftopicalintranasallevocabastine(0.4mg,2
spraystwicedaily)ina4week,doubleblind,parallelgroupstudyin180patients(Falseretal2001).Results
showedthatazelastinewassignificantly(p<0.001)superioratreducingbothmorningandeveningnasal
symptomscomparedtolevocabastine,andwasjudgedtobesignificantly(p<0.007)moreefficaciousinaglobal
evaluationbytheinvestigator.Globalefficacywasjudgedbyphysiciansaseitherverygoodorgoodfor90%of
azelastinepatientscomparedto74%ofthelevocabastinegroupmoreover,92%ofazelastinepatientsjudgedthe
treatmentaseithergoodorverygoodcomparedwithjust76%oflevocabastinepatients(Falseretal2001).
Safetyandtolerability

Goto:

Theadvantagesofintranasaldeliveryincludelowerriskofsystemicsideeffectsanddruginteractions(Saliband
Howarth2003).Incontrolledstudies,azelastinenasalspraywaswelltoleratedfortreatmentdurationsupto4
weeksinbothadultsandchildren(12years)(Stormsetal1994Meltzeretal1994Ratneretal1994Weileretal
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1994LaForceetal1996).Bittertaste,headache,somnolenceandnasalburningwerethemostfrequentlyreported
adverseevents,butmostoftheseweremildormoderateinnature.Thesestudiesreportedagreaterincidenceof
somnolencecomparedwithplacebo(11.5%vs5.4%,p<0.05).However,theincidenceofsomnolencebetween
azelastineandplacebotreatedpatients(3.2%vs1.0%)didnotdifferinVMRstudies(BanovandLiberman2001).
Postmarketingsurveillancestudiesalsoreportedasimilardegreeofsomnolence(approx2%)inbothazelastine
andplacebogroups(BergerandWhite2003LaForceetal2004Correnetal2005Bergeretal2006).Thelower
incidenceofazelastinerelatedadverseeventsinlatertrialsismostlikelyduetocorrectdosingtechnique,whenthe
drugisadministeredwithouttippingbacktheheadordeeplyinhalingthespray,bothofwhichwouldincrease
systemicabsorptionandcouldresultinbittertasteandsomnolence.Astheincidenceofsomnolencewhilstusing
azelastinenasalsprayhasbeenreportedtobegreaterthanplaceboincertainstudies,USprescribing
recommendationswarnagainstconcurrentuseofalcoholand/orotherCNSsuppressants.However,todateno
studieshavebeendesignedtoassessspecificallytheeffectsofazelastinenasalsprayontheCNSinhumans.
Abbreviations

Goto:

ACT1 firstAzelastineCetirizineTrial
AR allergicrhinitis
ARIA allergicrhinitisanditsimpactonasthma
EEC environmentalexposurechamber
GMCSF granulocytemacrophagecolonystimulatingfactor
HRQoL healthrelatedqualityoflife
ICAM1 intercellularadhesionmolecule1
IL interleukin
LT leukotriene
MNSS majornasalsymptomscore
NNT numberneededtotreat
PR perennialrhinitis
QoL qualityoflife
RQLQ RhinoconjunctivitisQualityofLifeQuestionnaire
SAR seasonalallergicrhinitis
TNF tumornecrosisfactoralpha
TNSS totalnasalsymptomscore
TVRSS TotalVMRSymptomScale
VCC ViennaChallengeChamber
VMR vasomotorrhinitis.
Footnotes

Goto:

Disclosures
Theauthorhasnoconflictsofinteresttoreport.

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Goto:

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