Attachment 1: Product information for AusPAR mepolizumab (rch) Nucala GlaxoSmithKline Australia Pty Ltd PM-2014-03872-1-5Final 8 March 2017. This Product Information was approved at the time this AusPAR was published.

NUCALA®PRODUCTINFORMATION

NAME OFTHE MEDICINE

Theactiveingredientof NUCALA ismepolizumab.Structureofmepolizumab:

CASnumber:196078-29-2

DESCRIPTION

Mepolizumabisahumanisedmonoclonalantibody(IgG1,kappa)directedagainsthumaninterleukin-5(IL-5).MepolizumabisexpressedasasolubleglycoproteinsecretedfromarecombinantChinesehamster ovarycell line.

The totalestimatedmolecular weight formepolizumabis149kDa.NUCALA isasterilelyophilised powderforinjection inasingle-usevial.

Eachvialcontainsmepolizumab100mg(100mg/mLafterreconstitution).NUCALAalsocontainstheexcipientssucrose,disodiumhydrogenphosphateheptahydrateandpolysorbate80.

PHARMACOLOGY

Pharmacodynamics

Mechanismofaction

Mepolizumabisahumanisedmonoclonalantibody(IgG1,kappa),whichtargetshumanIL-5withhighaffinityandspecificity.IL-5isthemajorcytokineresponsibleforthegrowthanddifferentiation,recruitment,activationandsurvivalofeosinophils.

MepolizumabinhibitsthebioactivityofIL-5withnanomolar potencybyblockingthebindingofIL-5tothealphachainoftheIL-5receptorcomplexexpressedontheeosinophilcellsurface,therebyinhibitingIL-5signallingandreducingtheproductionandsurvivalofeosinophils.

Pharmacodynamiceffects

Inclinicaltrials,reductioninbloodeosinophilswasobservedconsistentlyfollowingtreatmentwithmepolizumab.Themagnitudeanddurationofthisreductionwasdose-dependent.Followingadoseof100mgadministeredsubcutaneouslyevery4weeksfor32weeks,bloodeosinophilswerereducedtoageometricmeancountof40cells/µL.Thiscorrespondstoageometricmeanreductionof84%comparedtoplacebo.Thismagnitudeofreductionwasobservedwithin4weeksoftreatmentandwasmaintainedthroughoutthetreatmentperiod.

Immunogenicity

Consistentwiththepotentiallyimmunogenicpropertiesofproteinandpeptidetherapeutics,patientsmaydevelopantibodiestomepolizumabfollowingtreatment.Overall,15/260(6%) ofsubjectstreatedwith100mgdosesubcutaneouslydevelopedanti-mepolizumabantibodiesafterhavingreceivedatleastonedoseofmepolizumab.

Neutralisingantibodiesweredetectedinonesubjectreceivingmepolizumab.Anti-mepolizumabantibodiesdidnotdiscerniblyimpactthepharmacokineticorpharmacodynamiceffectsofmepolizumabtreatmentinthemajorityofpatientsandtherewas noevidence ofacorrelationbetweenantibodytitresandchangeineosinophillevel.

Pharmacokinetics

Followingsubcutaneousdosinginsubjectswithmoderate/severeasthma,mepolizumabexhibitedapproximatelydose-proportionalpharmacokineticsoveradoserangeof12.5mgto250mg.

Absorption

Followingsubcutaneousadministrationtohealthysubjectsorpatientswithasthma,mepolizumabwasabsorbedslowlywithamediantimetoreachmaximumplasmaconcentration(Tmax) rangingfrom4 to8days.

Followingasinglesubcutaneousadministrationintheabdomen,thighorarmofhealthysubjects,mepolizumababsolutebioavailabilitywas64%,71%and75%,respectively.Inpatientswithasthma,theabsolutebioavailabilityofmepolizumabadministeredsubcutaneouslyinthearmrangedfrom74-80%.Followingrepeatsubcutaneousadministrationevery4weeks,thereisapproximatelyatwo-foldaccumulationatsteadystate.

Distribution

Followingasingleintravenousadministrationofmepolizumabtopatientswithasthma,themeanvolume ofdistributionis55to85mL/kg.

Attachment 1: Product information for AusPAR mepolizumab (rch) Nucala GlaxoSmithKline Australia Pty Ltd PM-2014-03872-1-5Final 8 March 2017. This Product Information was approved at the time this AusPAR was published.

Metabolism

MepolizumabisahumanisedIgG1monoclonalantibodydegradedbyproteolyticenzymeswhicharewidelydistributedinthebodyandnotrestrictedtohepatictissue.

Elimination

Followingasingleintravenousadministrationtopatientswithasthma,themeansystemicclearance(CL)rangedfrom1.9to3.3mL/day/kg,withameanterminalhalf-lifeofapproximately20days.Followingsubcutaneousadministrationofmepolizumabthemeanterminalhalf-life(t1/2)rangedfrom 16to22days.Inthepopulationpharmacokineticanalysisestimatedmepolizumabsystemicclearancewas3.1mL/day/kg.

SpecialPatient Populations

Thepopulationpharmacokineticsofmepolizumabwereanalysedtoevaluatetheeffectsofdemographiccharacteristics.Analysesoftheselimiteddatasuggestthatnodoseadjustmentsarenecessaryforraceorgender.

Elderly(65yearsor older)

Noformalstudieshavebeenconductedinelderlypatients.However,inthepopulationpharmacokineticanalysis,therewasnoindicationofaneffectofage(12-82yearsofage)onthepharmacokineticsofmepolizumab.

Renalimpairment

Noformalstudieshavebeenconductedtoinvestigatethe effect ofrenalimpairmenton thepharmacokineticsofmepolizumab.Basedonpopulationpharmacokineticanalyses,nodoseadjustmentisrequiredinpatientswithcreatinineclearancevaluesbetween50-80mL/min.Therearelimiteddataavailableinpatientswithcreatinineclearancevalues

<50mL/min.

Hepaticimpairment

Noformalstudieshavebeenconductedtoinvestigatetheeffectofhepaticimpairmentonthepharmacokineticsofmepolizumab.Sincemepolizumabisdegradedbywidelydistributedproteolyticenzymes,notrestrictedtohepatictissue,changesinhepaticfunctionareunlikelyto haveanyeffectontheelimination ofmepolizumab.

CLINICALTRIALS

TheefficacyofNUCALAinthetreatmentofatargetedgroupofsubjectswithsevereeosinophilicasthmawasevaluatedin3randomised,double-blind,parallel-groupclinicalstudiesofbetween24-52weeksduration,inpatientsaged12yearsandolder.Thesestudiesweredesignedtoevaluatetheefficacyofmepolizumabadministeredonceevery4weeksbysubcutaneousor intravenousinjectioninsevereeosinophilicasthmapatientsnotcontrolledontheirstandardofcare[e.g.,inhaledcorticosteroids(ICS),oralcorticosteroids(OCS),combinationICSandlong-actingbeta2-adrenergicagonists(LABA),leukotrienemodifiers,short-actingbeta2-adrenergicagonists(SABA)].

PlaceboControlledStudies

Dose-RangingEfficacy (MEA112997)

InstudyMEA112997,arandomised,double-blind,placebo-controlled,parallel-group,multi-centrestudyof52weeksdurationin616patients,resultsdemonstratedthatmepolizumab(75 mg,250mgor750mg)significantlyreduced asthma exacerbationswhenadministeredintravenouslycomparedtoplacebo.Therewasnostatisticallysignificantdifferenceineffectseenbetweenthe3studieddoses.Bloodeosinophilcountsgreaterthanorequalto150 cells/µlatscreening;orbloodeosinophils≥300cells/µlinthepast12monthspredictedsubjectswhowouldbenefitmostfrommepolizumabtherapy.Resultsfromthisstudywereusedtodeterminedoseselectionforthestudiesusingsubcutaneousmepolizumabadministration.Mepolizumabisnotindicatedforintravenoususe,andshouldonlybeadministeredbythesubcutaneousroute.

ExacerbationReduction (MEA115588)

StudyMEA115588wasarandomised,double-blind,placebo-controlled,parallel-group,multi-centrestudywhichevaluatedtheefficacyandsafetyofmepolizumabasadd-ontherapyin576patientswithsevereeosinophilicasthma.Thisstudyevaluatedthefrequencyofclinicallysignificantexacerbationsofasthma,definedas:worseningofasthmarequiringuseoforal/systemiccorticosteroidsand/orhospitalisationand/oremergencydepartmentvisits.

Patientswereaged12yearsofageorolder,withahistoryoftwoormoreasthmaexacerbationsinthepast12monthsandnotcontrolledontheircurrentasthmatherapies[i.e.,high-doseinhaledcorticosteroids(ICS)incombinationwithatleastanothercontrollersuchaslong-actingbeta2-adrenergicagonists(LABA)orleukotrienemodifiers].Patientswereallowedtobeonoralcorticosteroidtherapyandcontinuedtoreceivetheirexistingasthmamedicationduringthestudy.Severeeosinophilicasthmawasdefinedasperipheralbloodeosinophilsgreaterthanorequalto150cells/μlwithin6weeksofrandomisation(firstdose)orbloodeosinophilsgreaterthanorequalto300cells/μlwithinthepast12months ofrandomisation.

Patientsreceivedeithermepolizumab100mgadministeredsubcutaneously(SC),mepolizumab75 mgadministeredintravenously(IV),orplacebotreatmentonceevery4weeksover32-weeks.

Theprimaryendpoint,reductioninthefrequencyofclinicallysignificantexacerbationsofasthmawasstatisticallysignificant(p<0.001).Table1providestheresultsoftheprimaryendpointandsecondaryendpointsofMEA115588.

Table1:ResultsofprimaryandsecondaryendpointsatWeek32intheIntenttoTreatpopulation(MEA115588)

Mepolizumab(100mgSC)
N=194 / Placebo
N=191
Primary endpoint
FrequencyofClinicallySignificant Exacerbations
Exacerbationrateperyear / 0.83 / 1.74
PercentreductionRateratio(95% CI) / 53%
0.47(0.35,0.64) / -
p-value / <0.001 / -
Secondary endpoints
Attachment 1: Product information for AusPAR mepolizumab (rch) Nucala GlaxoSmithKline Australia Pty Ltd PM-2014-03872-1-5Final 8 March 2017. This Product Information was approved at the time this AusPAR was published.
FrequencyofExacerbationsrequiringhospitalisations/emergencyroom visits
Exacerbationrateperyear / 0.08 / 0.20
PercentreductionRateratio(95% CI) / 61%
0.39(0.18,0.83) / -
p-value / 0.015 / -
FrequencyofExacerbationsrequiringhospitalisation
Exacerbations rateperyear / 0.03 / 0.10
PercentreductionRateratio(95% CI) / 69%
0.31(0.11,0.91) / -
-
p-value / 0.034 / -
Pre-bronchodilatorFEV1(mL) at Week32
MeanChangefromBaseline(SE) / 183(31.1) / 86(31.4)
Difference(mepolizumabvs.placebo) / 98 / -
95% CI / 11,184 / -
p-value / 0.028 / -
St.George’sRespiratoryQuestionnaire(SGRQ)atweek32
MeanChangeFrom Baseline(SE) / -16.0(1.13) / -9.0(1.16)
Difference(mepolizumabvs.placebo) / -7.0 / -
95% CI / -10.2,-3.8 / -
p-value / <0.001 / -

Oral CorticosteroidReduction(MEA115575)

StudyMEA115575evaluatedtheeffectofmepolizumab100 mgSConreducingtheuseofmaintenanceoralcorticosteroids(OCS)whilemaintainingasthmacontrolinsubjectswithsevereeosinophilicasthmawhoweredependentonsystemiccorticosteroids.Patientshadaperipheralbloodeosinophilcountof300cells/Linthe12monthspriorscreeningoraperipheralbloodeosinophilcountof150cells/Latbaseline.Patientswereadministeredmepolizumaborplacebotreatmentonceevery4weeksoverthetreatmentperiod.TheOCSdosewasreducedevery4weeksduringtheOCSreductionphase(Weeks4-20),aslongasasthmacontrolwasmaintained.Duringthestudypatientscontinuedtheirbaselineasthmatherapy[i.e.,high-doseinhaledcorticosteroids(ICS)incombinationwithatleastanothercontrollersuchaslong-actingbeta2-adrenergicagonists(LABA)orleukotrienemodifiers].

Thisstudyenrolledatotalof135patients:meanageof50years,55%werefemale,48%hadbeenreceivingoralsteroidtherapyforatleast5years,andhadabaselinemeanprednisoneequivalentdoseofapproximately13mgper day.

TheprimaryendpointwasthereductionindailyOCSdose(weeks20-24)whilstmaintainingasthmacontrolcomparedwith patientstreatedwith placebo(seeTable2).

Attachment 1: Product information for AusPAR mepolizumab (rch) Nucala GlaxoSmithKline Australia Pty Ltd PM-2014-03872-1-5Final 8 March 2017. This Product Information was approved at the time this AusPAR was published.

Table2:Resultsof theprimaryandsecondary endpointsintheIntent toTreatpopulation(MEA115575)

Number (%) of Subjects
Mepolizumab(100mgSC)
N=69 / Placebo
N=66
PrimaryEndpoint:
PercentReductioninOCS from Baselineat Weeks20-24(%)
n / 16(23%) / 7(11%)
90% -100%
75% -<90% / 12(17%) / 5(8%)
50% -<75% / 9(13%) / 10(15%)
>0% -<50% / 7(10%) / 7(11%)
NodecreaseinOCS/lackofasthmacontrol/ / 25(36%) / 37(56%)
withdrawal fromtreatment
Oddsratio(95% CI) / 2.39(1.25,4.56) / -
p-value / 0.008 / -
SecondaryEndpoints:
ReductioninthedailyOCSdose
Atleast50% reductionindailyOCSdosefrom / 37(54%) / 22(33%)
baseline,n(%)
Oddsratio(95% CI) / 2.26(1.10,4.65) / -
p-value / 0.027 / -
Reductionto≤5mg/dayindailyOCSdose,n(%) / 37(54%) / 21(32%)
Oddsratio(95% CI) / 2.45(1.12,5.37) / -
p-value / 0.025 / -
Reductionto0mg/dayindailyOCSdose,n(%) / 10(14%) / 5(8%)
Oddsratio(95% CI) / 1.67(0.49,5.75) / -
p-value / 0.414 / -
Median PercentageReductioninDailyOCS Dose
Median% reductionfrombaseline(95% CI) / 50.0(20.0,75.0) / 0.0(-20.0,33.3)
Mediandifference(95%CI) / -30.0(-66.7,0.0)
p-value / 0.007

OCS:prednisone/prednisolone

Additionally,health-relatedqualityoflifewasmeasuredusingSGRQ.AtWeek24,therewasastatisticallysignificantimprovementinthemeanSGRQscoreformepolizumabcomparedwithplacebo:-5.8(95%CI:-10.6,-1.0;P=0.019).AtWeek24,theproportionofsubjectswithaclinicallymeaningfuldecreaseinSGRQscore(definedasadecreaseofatleast4unitsfrombaseline)wasgreaterformepolizumab(58%,40/69)comparedwithplacebo(41%,27/66).

OpenLabelExtensionStudy(MEA115661)

Followingcompletionofthedouble-blindMEA115575andMEA115588studies,allpatientswereofferedtheopportunitytoparticipateinMEA115661,a52weekopen-labelextension(OLE)study,duringwhichtimeall patientsreceivedopenlabelmepolizumab(100mg SC). Intotal,651patients(126subjectswhohadpreviouslyparticipatedinstudyMEA115575and525subjectswhohadpreviouslyparticipatedinStudyMEA115588),received100mgofmepolizumabsubcutaneouslyevery4weeks.Duringopen-labeltreatmentofallsubjects withmepolizumabinMEA115661,theratesofexacerbationsperyear remainedlowin thesubjectswhowerepreviouslytreatedwithmepolizumaband wereconsistentwithresultsdemonstratedduringthe32-weekdouble-blindperiodofstudyMEA115588.Inaddition,theimpactofmepolizumabonsteroidreductionwasmaintainedfollowingMEA115575 with averagedailysteroiddoseremainingconsistentwiththelevelachievedwith mepolizumabtreatmentatweeks20-24duringMEA115575.

INDICATIONS

NUCALAisindicatedasanadd-ontreatmentforsevererefractory eosinophilicasthmainpatientsaged12yearsandover (see CLINICAL TRIALS).

CONTRAINDICATIONS

Hypersensitivitytomepolizumaborto anyoftheexcipients (seeDESCRIPTION).

PRECAUTIONS

NUCALAshouldnotbeusedtotreatacuteasthmaexacerbations.

Asthma-relatedadverseeventsorexacerbationsmayoccurduringtreatmentwithNUCALA.Patientsshouldbeinstructedtoseekmedicaladviceiftheirasthmaremainsuncontrolledor worsensafterinitiation oftreatmentwith NUCALA.

AbruptdiscontinuationofcorticosteroidsafterinitiationofNUCALAtherapyisnotrecommended.Reductionsincorticosteroiddoses,ifrequired,shouldbegradualandperformedunder thesupervision ofaphysician.

HypersensitivityandAdministrationReactions

Acuteanddelayedsystemicreactions,includinghypersensitivityreactions(e.g.urticaria,angioedema,rash,bronchospasm,hypotension),have occurredfollowingadministrationofNUCALA.Thesereactionsgenerallyoccurwithinhoursofadministration,butinsomeinstanceshadadelayedonset(i.e.,days). These reactions may occur for the first time after a long duration of treatment (see ADVERSE EFFECTS). In the event of a hypersensitivity reaction, NUCALA should be discontinued.

ParasiticInfections

Eosinophilsmaybeinvolvedintheimmunologicalresponsetosomehelminthinfections.Patientswithpre-existinghelminthinfectionswereexcludedfromparticipationin theclinicalprogramme.Patientswithpre-existinghelminthinfectionsshouldbetreatedfortheirinfectionpriortoNUCALAtherapy.IfpatientsbecomeinfectedwhilstreceivingtreatmentwithNUCALAanddonotrespondtoanti-helminthtreatment,temporarydiscontinuation ofNUCALAshouldbeconsidered.

Opportunistic Infections: Herpes Zoster

In controlled clinical trials, 2 serious adverse reactions of herpes zoster occurred in patients treated with NUCALA versus none in the placebo group.

EffectsonFertility:

Therearenofertilitydatain humans.Animalstudiesshowednoadverseeffectsofanti-IL5treatmentonfertility.

NoimpairmentoffertilitywasobservedinafertilityandgeneralreproductiontoxicitystudyinmaleandfemalemiceperformedwithahomologousantibodythatinhibitsIL-5inmice.Thisstudydidnotincludealitteringor functionalF1assessment.

UseinPregnancy(CategoryB1):

TheeffectofNUCALAonhumanpregnancyisunknown.Notreatmentrelatedeffectsonembryofetalorpostnataldevelopmenthavebeenshowninanimalstudies.

Incynomolgusmonkeys,mepolizumabhadnoeffectonpregnancyoronembryonic/fetalandpostnataldevelopment(includingimmunefunction)oftheoffspringwhengivendosesupto100mg/kgIVpermonththroughoutgestation(yielding31timestheAUCinhumansattheclinicaldose).Examinationsforinternalorskeletalmalformationswerenotperformed.Dataincynomolgusmonkeys demonstratethatmepolizumabcrosses theplacenta.Concentrationsofmepolizumabwereapproximately2.4timeshigherininfantsthaninmothersforseveralmonthspostpartumanddidnotaffecttheimmunesystemoftheinfants.

Inaddition,inafertility,earlyembryonic,andembryo-fetaldevelopmentstudy,pregnantCD-1micereceivedahomologousantibody,whichinhibitstheactivityofmurineIL-5,atanIVdoseof50mg/kgonceperweekthroughoutgestation.Thehomologousantibodydidnotproduceobviousteratogenicityorotherwiseaffectembryo-fetaldevelopmentinmice.Embryo-fetaldevelopmentofIL-5–deficientmicehasbeenreportedtobegenerallyunaffectedrelativetowild-typemice.

NUCALAshouldbeusedduringpregnancyonlyiftheexpectedbenefittothemotherjustifiesthepotentialrisktothefetus.

UseinLactation:

TherearenodataregardingtheexcretionofNUCALAinhumanmilk.However,mepolizumabwasexcretedintothemilkofcynomolgusmonkeyspostpartumfollowingdosingduringpregnancyatconcentrationsthatwerelessthan0.5%ofthosedetectedinplasma.

Adecisionshouldbemadewhether todiscontinuebreast-feedingor discontinueNUCALA,takingintoaccounttheimportanceofbreast-feedingtotheinfantandtheimportanceofthedrugtothemother.

PaediatricUse:

The safetyandefficacyofNUCALAin childrenundertheageof12yearshasnotyetbeenestablished.

UseintheElderly:

Noformalstudieshavebeenconductedinelderly patients(seePharmacokinetics–SpecialPatientPopulations).

Genotoxicity:

Asmepolizumabisamonoclonalantibody,nogenotoxicitystudieshavebeenconducted.Beingalargeproteinmolecule,mepolizumabisnotexpectedtointeractdirectlywithDNAorotherchromosomalmaterial.

Carcinogenicity:

As mepolizumab is a monoclonal antibody, no carcinogenicity studies have beenconducted.

AbilitytoDriveand UseMachines:

TherehavebeennostudiestoinvestigatetheeffectofNUCALAondrivingperformanceortheabilitytooperatemachinery.

AdetrimentaleffectonsuchactivitieswouldnotbeanticipatedfromthepharmacologyoradversereactionprofileofNUCALA.

INTERACTIONSWITHOTHERMEDICINES

NoformalinteractionstudieshavebeenperformedwithNUCALA.

ADVERSEEFFECTS

The following adverse reactions are described in greater detail in other sections:

  • Hypersensitivity reactions (see PRECAUTIONS)
  • Opportunistic infections: herpes zoster (see PRECAUTIONS)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 1,327 subjects with asthma were evaluated in 3 randomized, placebo-controlled, multicenter trials of 24 to 52 weeks’ duration (MEA112997, MEA115588 and MEA115575). Of these, 1,192 had a history of 2 or more exacerbations in the year prior to enrollment despite regular use of high-dose inhaled corticosteroids plus an additional controller(s) (MEA112997 and MEA115588), and 135 subjects required daily oral corticosteroids in addition to regular use of high-dose inhaled corticosteroids plus an additional controller(s) to maintain asthma control (MEA115575). All subjects had markers of eosinophilic airway inflammation (see CLINICAL STUDIES). Of the subjects enrolled, 59% were female, 85% were white, and subjects ranged in age from 12 to 82 years. Mepolizumab was administered subcutaneously or intravenously once every 4 weeks; 263 subjects received NUCALA (mepolizumab 100 mg subcutaneous [SC]) for at least 24 weeks. Serious adverse events that occurred in more than 1 subject and in a greater percentage of subjects treated with NUCALA (n= 263) than placebo (n= 257) included 1 event, herpes zoster (2 subjects vs. 0 subjects, respectively). Approximately 2% of subjects receiving NUCALA withdrew from clinical trials due to adverse events compared with 3% of subjects receiving placebo.

The incidence of adverse reactions in the first 24 weeks of treatment in the 2 confirmatory efficacy and safety trials (MEA115588 and MEA115575) with NUCALA is shown in Table 3.

Table 3. Adverse Reactions with NUCALA with Greater than or Equal to 3% Incidence and More Common than Placebo in Subjects with Asthma (MEA115588 and MEA115575)

Adverse Reaction / NUCALA
(Mepolizumab 100 mg Subcutaneous)
(n = 263)
% / Placebo
(n = 257)
%
Headache / 19 / 18
Injection site reaction / 8 / 3
Back pain / 5 / 4
Fatigue / 5 / 4
Influenza / 3 / 2
Urinary tract infection / 3 / 2
Abdominal pain upper / 3 / 2
Pruritus / 3 / 2
Eczema / 3 / <1
Muscle spasms / 3 / <1

52-Week Trial

Adverse reactions from MEA112997 with 52 weeks of treatment with mepolizumab 75 mg intravenous (IV) (n = 153) or placebo (n = 155) and with greater than or equal to 3% incidence and more common than placebo and not shown in Table 3 were: abdominal pain, allergic rhinitis, asthenia, bronchitis, cystitis, dizziness, dyspnea, ear infection, gastroenteritis, lower respiratory tract infection, musculoskeletal pain, nasal congestion, nasopharyngitis, nausea, pharyngitis, pyrexia, rash, toothache, viral infection, viral respiratory tract infection, and vomiting. In addition, 3 cases of herpes zoster occurred in subjects treated with mepolizumab 75 mg IV, compared with 2 subjects in the placebo group.

Systemic Reactions, including Hypersensitivity Reactions

In MEA112997, MEA115588 and MEA115575 described above, the percentage of subjects who experienced systemic (allergic and non-allergic) reactions was 7% in the placebo group and 10% in the group receiving NUCALA. Systemic allergic/hypersensitivity reactions were reported by 2% of subjects in the placebo group and 1% of subjects in the group receiving NUCALA. The most commonly reported manifestations of systemic allergic/hypersensitivity reactions reported in the group receiving NUCALA included rash, pruritus, headache, and myalgia. Systemic non-allergic reactions were reported by 2% of subjects in the group receiving NUCALA and 3% of subjects in the placebo group. The most commonly reported manifestations of systemic nonallergic reactions reported in the group receiving NUCALA included rash, flushing, and myalgia. A majority of the systemic reactions in subjects receiving NUCALA (5/7) were experienced on the day of dosing.

Injection Site Reactions

Injection site reactions (e.g., pain, erythema, swelling, itching, burning sensation) occurred at a rate of 8% in subjects treated with NUCALA compared with 3% in subjects treated with placebo.

Long-Term Safety

Nine hundred ninety-eight (998) subjects have received NUCALA in ongoing open-label extension studies, during which additional cases of herpes zoster have been reported. The overall adverse event profile was similar to the asthma trials described above.

Immunogenicity

Overall, 15/260 (6%) of subjects treated with NUCALA developed antimepolizumab antibodies. The reported frequency may underestimate the actual frequency due to lower assay sensitivity in the presence of high drug concentration. Neutralizing antibodies were detected in 1 subject receiving mepolizumab. Anti-mepolizumab antibodies slightly increased (approximately 20%) the clearance of mepolizumab. There was no evidence of a correlation between antimepolizumab antibody titers and change in eosinophil level. The clinical relevance of the presence of anti-mepolizumab antibodies is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to mepolizumab in specific assays. The observed incidence of antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.

DOSAGEANDADMINISTRATION

NUCALA should be prescribed by a specialist experienced in the diagnosis and treatment of severe asthma.

NUCALAshouldbereconstituted and administeredbyahealthcareprofessional. In line with clinical practice, monitoring of patients after administration of biological agents is recommended (see PRECAUTIONS).

Followingreconstitution,NUCALAshouldonlybeadministeredas a subcutaneousinjection (e.g.upper arm,thigh,orabdomen)(seeUseandHandling).

Adultsandadolescents(12 yearsorolder)

Therecommendeddoseis100mgofNUCALAadministeredbysubcutaneousinjectiononceevery4weeks.

The safety and efficacy of NUCALA have not been established in adolescents weighing less than 45 kg.

Children (below12years)

ThesafetyandefficacyofNUCALAhavenotbeenestablishedinchildrenlessthan12yearsofage.

Elderly(65yearsorolder)

Nodosageadjustmentisrecommendedinpatients65yearsorolder(seePharmacokinetics–SpecialPatientPopulations).

Renalimpairment

Dose adjustments in patients with renal impairment are unlikelyto be required (seePharmacokinetics–SpecialPatientPopulations).

Hepatic Impairment

Doseadjustmentsinpatientswithhepaticimpairmentareunlikelytoberequired(seePharmacokinetics–SpecialPatientPopulations).

UseandHandling:

NUCALAisprovidedasalyophilisedpowderinasingle-usevialfor subcutaneousinjectiononlyandshouldbereconstitutedbyahealthcareprofessionalusingstandardaseptictechniques asfollows:

ReconstitutionInstructions

1.ReconstitutetheNUCALApowderinthevialwith1.2mLofsterileWaterforInjectionspreferablyusinga2to3mLsyringeanda21Gneedle.Thereconstitutedsolutionwillcontainaconcentrationof100mg/mLmepolizumab.

2.Thestreamofsterile WaterforInjectionsshouldbedirectedverticallyontothecentreofthelyophilisedcake.Allow thevialtositatroomtemperatureduringreconstitution,gentlyswirlingthe vial for 10secondswithcircular motion,followedby restingthe vialfor5seconds,until thepowderisdissolved.

Note:Donotshakethereconstitutedsolutionduringtheprocedureasthismayleadtoproductfoamingorprecipitation.Reconstitutionistypicallycompletewithin5minutesafter thesterilewaterhasbeenadded,butitmaytake additionaltime.

Ifamechanicalreconstitutiondevice(swirler)isusedtoreconstituteNUCALA,reconstitutioncanbeaccomplishedbyswirlingat450rpmfornolongerthan10minutes.Alternatively,swirlingat1000rpmfornolongerthan5minutesisacceptable.

3.Followingreconstitution,NUCALAshouldbevisuallyinspectedforparticulatematterandclaritypriortouse.Thesolutionshouldbecleartoopalescent,andcolourlesstopaleyelloworpalebrown,freeofvisibleparticles.Smallairbubbles,however,areexpectedandacceptable.Ifparticulatematterremainsinthesolutionor if thesolutionappearscloudyormilky,thesolutionshouldnotbeused.

Reconstitutedsolution

NUCALA isforsingle use inonepatientonlyandcontainsnoantimicrobialagent.Toreducemicrobiologicalhazard,useassoonaspracticableafterreconstitution.Discardanyunusedsolution.

Ifstorageisnecessary,storebelow30°C fornotmorethan6 hours.

Administration

1.Forsubcutaneousadministrationa1mLpolypropylenesyringefittedwithadisposableneedle21Gto27G x0.5inch (13mm)shouldpreferablybeused.

2.Justpriortoadministration,remove1mLofreconstitutedNUCALA.DonotshakethereconstitutedNUCALAsolutionduringtheprocedureasthiscouldleadtoproductfoamingorprecipitation.

3.Administerthe1mLinjection(equivalentto100mgmepolizumab)subcutaneouslyintotheupperarm,thigh,orabdomen.

OVERDOSAGE

Thereisnoclinicalexperiencewith overdoseofNUCALA.

Singledosesofupto1500mgwereadministeredintravenouslyin aclinicaltrialtopatientswith eosinophilicdisease withoutevidence ofdose-relatedtoxicities.

ThereisnospecifictreatmentforanoverdosewithNUCALA.Ifoverdoseoccurs,thepatientshouldbetreatedsupportively withappropriatemonitoringasnecessary.

Forinformationonthemanagementofoverdose,contactthePoisonInformationCentreon131126(Australia).

PRESENTATIONANDSTORAGECONDITIONS

Storage

Unopenedvial

Storeat2oC - 8oC(Refrigerate. Donotfreeze).

Protectfromlight.Storeintheoriginalcartonuntiluse.Reconstitutedsolution

AfterreconstitutionwithWaterforInjectionstheproductisstableforupto6hourswhenstoredbelow30°C.

Donotfreeze.

Duringadministration,protectionfromlightisnotnecessary.NatureandContentsofContainer

NUCALA(mepolizumab)100mgpowder forinjection.

NUCALAispresentedasasterilelyophilisedpowderina10mLtypeIglassvialwithbromobutylrubber(non-latex)stopperandagrayaluminiumoversealwithaplasticflip-cap.Eachvialcontains144mgofmepolizumab(100mg/mLafterreconstitutionwith1.2mL ofWFI).

NUCALA issuppliedinapackcontainingonesingleusevial withoutapreservative.

NAMEANDADDRESSOFTHESPONSOR

GlaxoSmithKlineAustraliaPtyLtdLevel4,436JohnstonStreet

Abbotsford,Victoria,3067

POISONSCHEDULEOFTHEMEDICINE

Schedule4–PrescriptionOnlyMedicine

Attachment 1: Product information for AusPAR mepolizumab (rch) Nucala GlaxoSmithKline Australia Pty Ltd PM-2014-03872-1-5Final 8 March 2017. This Product Information was approved at the time this AusPAR was published.

DATEOFFIRSTINCLUSIONINTHEAUSTRALIANREGISTEROFTHERAPEUTICGOODS(THEARTG):

2 February 2016

NUCALA isaregisteredtrademarkoftheGSK groupofcompanies.Version 1.0