KALBITOR

Israel - English - Ministry of Health

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Active ingredient:
ECALLANTIDE 10 MG / 1 ML
Available from:
NEOPHARM SCIENTIFIC LTD
Pharmaceutical form:
SOLUTION FOR INJECTION
Administration route:
S.C
Manufactured by:
DYAX CORP., USA
Therapeutic indications:
Kalbitor is a plasma kallikrein inhibitor indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 16 years of age and older.
Authorization number:
146223325200
Authorization date:
2011-06-01

FULLPRESCRIBINGINFORMATION

WARNING:ANAPHYLAXIS

Anaphylaxishasbeenreportedafteradministrationof

KALBITOR.Becauseofthe riskofanaphylaxis,KALBITOR

shouldonlybe administeredbyahealthcareprofessionalwith

appropriatemedicalsupporttomanageanaphylaxisand

hereditaryangioedema.Healthcareprofessionalsshouldbe

awareofthe similarityofsymptomsbetweenhypersensitivity

reactionsandhereditaryangioedemaandpatientsshouldbe

monitoredclosely.DonotadministerKALBITORtopatientswith

knownclinicalhypersensitivitytoKALBITOR.[see

Contraindications(4),Warnings andPrecautions(5.1),and

AdverseReactions(6)]

1 INDICATIONSANDUSAGE

KALBITOR ® (ecallantide)isindicatedfortreatmentofacuteattacksof

hereditaryangioedema(HAE)inpatients16yearsofageandolder.

2 DOSAGEANDADMINISTRATION

2.1RecommendedDosing

TherecommendeddoseofKALBITORis30mg(3mL),administered

subcutaneouslyinthree10mg(1mL)injections.Iftheattack

persists,anadditionaldoseof30mgmaybeadministeredwithina24

hourperiod.

2.2AdministrationInstructions

KALBITORshouldonlybeadministeredbyahealthcareprofessional

withappropriatemedicalsupporttomanageanaphylaxisand

hereditaryangioedema.

KALBITORshouldberefrigeratedandprotectedfromthelight.

KALBITORisaclear,colorlessliquid;visuallyinspecteachvialfor

particulatematteranddiscolorationpriortoadministration.Ifthereis

particulatematterordiscoloration,thevialshouldnotbeused.

Usingaseptictechnique,withdraw1mL(10mg)ofKALBITORfrom

thevialusingalargeboreneedle.Changetheneedleonthesyringe

toaneedlesuitableforsubcutaneousinjection.Therecommended

needlesizeis27gauge.InjectKALBITORintotheskinofthe

abdomen,thigh,orupperarm.Repeattheprocedureforeachofthe3

vialscomprisingtheKALBITORdose.Theinjectionsiteforeachof

theinjectionsmaybeinthesameorindifferentanatomiclocations

(abdomen,thigh,upperarm).Thereisnoneedforsiterotation.

Injectionsitesshouldbeseparatedbyatleast2inches(5cm)and

awayfromtheanatomicalsiteofattack.

Thesameinstructionsapplytoanadditionaldoseadministeredwithin

24hours.Differentinjectionsitesorthesameanatomicallocation(as

usedforthefirstadministration)maybeused.

3 DOSAGEFORMSANDSTRENGTHS

KALBITORisaclear,colorlessliquidfreeofpreservatives.Eachvial

ofKALBITORcontainsecallantideataconcentrationof10mg/mL.

4 CONTRAINDICATIONS

DonotadministerKALBITORtoapatientwhohasknownclinical

hypersensitivitytoKALBITOR.[seeWarningsandPrecautions(5.1)].

5 WARNINGSANDPRECAUTIONS

5.1 HypersensitivityReactions,IncludingAnaphylaxis

Potentiallyserioushypersensitivityreactions,includinganaphylaxis,

haveoccurredinpatientstreatedwithKALBITOR.In255HAE

patientstreatedwithintravenousorsubcutaneousKALBITORin

subgroupof187patientstreatedwithsubcutaneousKALBITOR,5

patients(2.7%)experiencedanaphylaxis.Symptomsassociatedwith

thesereactionshaveincludedchestdiscomfort,flushing,pharyngeal

edema,pruritus,rhinorrhea,sneezing,nasalcongestion,throat

irritation,urticaria,wheezing,andhypotension.Thesereactions

occurredwithinthefirsthourafterdosing.

Otheradversereactionsindicativeofhypersensitivityreactions

includedthefollowing:pruritus(5.1%),rash(3.1%),andurticaria

(2.0%).

Patientsshouldbeobservedforanappropriateperiodoftimeafter

administrationofKALBITOR,takingintoaccountthetimetoonsetof

anaphylaxisseeninclinicaltrials.Giventhesimilarityin

hypersensitivitysymptomsandacuteHAEsymptoms,patientsshould

bemonitoredcloselyintheeventofahypersensitivityreaction.

KALBITORshouldnotbeadministeredtoanypatientswithknown

clinicalhypersensitivitytoKALBITOR[seeContraindications(4)].

6 ADVERSEREACTIONS

Hypersensitivityreactions,includinganaphylaxis,haveoccurredin

patientstreatedwithKALBITOR[seeContraindications(4)and

WarningsandPrecautions(5.1)].

6.1 ClinicalTrialsExperience

Becauseclinicaltrialsareconductedundervaryingconditions,

adversereactionratesobservedintheclinicaltrialsofadrugcannot

bedirectlycomparedtoratesintheclinicaltrialsofanotherdrugand

maynotreflecttheratesobservedinpractice.

ThesafetydatadescribedbelowreflectexposuretoKALBITORin255

patientswithHAEtreatedwitheitherintravenousorsubcutaneous

KALBITOR.Ofthe255patients,66%ofpatientswerefemaleand

86%wereCaucasian.PatientstreatedwithKALBITORwerebetween

theagesof10and78years.

Overall,themostcommonadversereactionsin255patientswithHAE

wereheadache(16.1%),nausea(12.9%),fatigue(11.8%),diarrhea

(10.6%),upperrespiratorytractinfection(8.2%),injectionsite

reactions(7.4%),nasopharyngitis(5.9%),vomiting(5.5%),pruritus

(5.1%),upperabdominalpain(5.1%),andpyrexia(4.7%).

Anaphylaxiswasreportedin3.9%ofpatientswithHAE.Injectionsite

reactionswerecharacterizedbylocalpruritus,erythema,pain,

irritation,urticaria,and/orbruising.

Theincidenceofadversereactionsbelowisbasedupon2placebo-

controlled,clinicaltrials(EDEMA3 ® andEDEMA4 ® )inatotalof143

uniquepatientswithHAE.PatientsweretreatedwithKALBITOR30

mgsubcutaneousorplacebo.Patientswerepermittedtoparticipate

sequentiallyinbothplacebo-controlledtrials;safetydatacollected

duringexposuretoKALBITORwasattributedtotreatmentwith

KALBITOR,andsafetydatacollectedduringexposuretoplacebowas

attributedtotreatmentwithplacebo.Table1showsadversereactions

occurringin

3%ofKALBITOR-treatedpatientsthatalsooccurredata

higherratethanintheplacebo-treatedpatientsinthetwocontrolled

trials(EDEMA3andEDEMA4)ofthe30mgsubcutaneousdose.

SomepatientsinEDEMA3andEDEMA4receivedasecond,open-

label30mgsubcutaneousdoseofKALBITORwithin24hours

followingtheinitialdose.Adversereactionsreportedbythese

patientswhoreceivedtheadditional30mgsubcutaneousdoseof

KALBITORwereconsistentwiththosereportedinthepatients

receivingasingledose.

6.2 Immunogenicity

IntheKALBITORHAEprogram,patientsdevelopedantibodiesto

KALBITOR.Ratesofseroconversionincreasedwithexposureto

KALBITORovertime.Overall,7.4%ofpatientsseroconvertedtoanti-

ecallantideantibodies.Neutralizingantibodiestoecallantidewere

determinedinvitrotobepresentin4.7%ofpatients.

Anti-ecallantideandanti-P.pastorisIgEantibodieswerealso

detected.Patientswhoseroconvertmaybeatahigherriskofa

hypersensitivityreaction.Thelong-termeffectsofantibodiesto

KALBITORarenotknown.

Thetestresultsfortheecallantideprogramweredeterminedusing

oneoftwoassayformats:ELISAandbridging

electrochemiluminescence(ECL).Aswithalltherapeuticproteins,

thereisapotentialforimmunogenicitywiththeuseofKALBITOR.

Theincidenceofantibodyformationishighlydependentonthe

sensitivityandspecificityoftheassay.Additionally,theobserved

incidenceofantibody(includingneutralizingantibody)positivityinan

assaymaybeinfluencedbyseveralfactors,includingassay

methodology,samplehandling,timingofsamplecollection,

concomitantmedications,andunderlyingdisease.Forthesereasons,

comparisonoftheincidenceofantibodiestoKALBITORwiththe

incidenceofantibodiestootherproductsmaybemisleading.

7 DRUGINTERACTIONS

Noformaldruginteractionsstudieswereperformed.Noinvitro

metabolismstudieswereperformed.

8 USEINSPECIFICPOPULATIONS

8.1 Pregnancy

PregnancyCategoryC

Therearenoadequateandwell-controlledtrialsofKALBITORin

pregnantwomen.KALBITORhasbeenshowntocause

developmentaltoxicityinrats,butnotrabbits.Becauseanimal

reproductivestudiesarenotalwayspredictiveofhumanresponse,

KALBITORshouldbeusedduringpregnancyonlyifclearlyneeded.

Inrats,intravenousKALBITORatanintravenousdoseapproximately

13timesthemaximumrecommendedhumandose(MRHD)ona

mg/kgbasiscausedincreasednumbersofearlyresorptionsand

percentagesofresorbedconceptusesperlitterinthepresenceofmild

maternaltoxicity.Nodevelopmenttoxicitywasobservedinratsthat

receivedanintravenousdoseapproximately8timestheMRHDona

mg/kgbasis.TherewerenoadverseeffectsofKALBITORon

embryofetaldevelopmentinratsthatreceivedsubcutaneousdosesup

toapproximately2.4timestheMRHDonanAUCbasis,andinrabbits

thatreceivedintravenousdosesuptoapproximately6timesthe

MRHDonanAUCbasis.

8.2 LaborandDelivery

NoinformationisavailableontheeffectsofKALBITORduringlabor

anddelivery.

8.3 NursingMothers

Itisnotknownwhetherecallantideisexcretedinhumanmilk.Caution

shouldbeexercisedwhenecallantideisadministeredtoanursing

Table1: AdverseReactionsOccurringat≥3%andHigher

thanPlaceboin2PlaceboControlledClinicalTrials

inPatientswithHAETreatedwithKALBITOR

KALBITOR

N=100 Placebo

N=81

AdverseReactions n(%) a n(%) a

Headache 8(8%) 6(7%)

Nausea 5(5%) 1(1%)

Diarrhea 4(4%) 3(4%)

Pyrexia 4(4%) 0

Injectionsitereactions 3(3%) 1(1%)

Nasopharyngitis 3(3%) 0

a Patientsexperiencingmorethan1eventwiththesamepreferred

Kalbitor(ecallantide)

Injection,forsubcutaneoususe

HIGHLIGHTSOFPRESCRIBINGINFORMATION

Thesehighlightsdonotincludealltheinformationneededtouse

KALBITOR ® safelyandeffectively.

SeefullprescribinginformationforKALBITOR.

WARNING:ANAPHYLAXIS

Seefullprescribinginformationforcompleteboxedwarning

AnaphylaxishasbeenreportedafteradministrationofKALBITOR ® .

Becauseoftheriskofanaphylaxis,KALBITORshouldonlybe

administeredbyahealthcareprofessionalwithappropriatemedical

supporttomanageanaphylaxisandhereditaryangioedema.Healthcare

professionalsshouldbeawareofthesimilarityofsymptomsbetween

hypersensitivityreactionsandhereditaryangioedemaandpatients

shouldbemonitoredclosely.DonotadministerKALBITORtopatients

withknownclinicalhypersensitivitytoKALBITOR [see

Contraindications(4),WarningsandPrecautions(5.1),andAdverse

Reactions(6)].

----------------------------INDICATIONSAND USAGE---------------------------

KALBITOR isaplasmakallikreininhibitorindicatedfortreatmentof

acuteattacks ofhereditaryangioedema(HAE)inpatients16yearsof

ageandolder.(1)

----------------------DOSAGEANDADMINISTRATION-----------------------

30mg(3mL),administeredsubcutaneouslyinthree10mg(1mL)

injections.Ifanattackpersists,anadditional doseof30mgmaybe

administeredwithina24hourperiod.(2.1)

KALBITOR shouldonlybeadministeredbyahealthcare

professionalwithappropriatemedical supporttomanage

anaphylaxisandhereditaryangioedema.(2.2).

---------------------DOSAGEFORMSAND STRENGTHS----------------------

Singleuseglass vial containing10mg/mLofecallantideasasolution

forinjection.(3)

-------------------------------CONTRAINDICATIONS------------------------------

DonotadministerKALBITOR toapatientwhohas knownclinical

hypersensitivitytoKALBITOR.(4)

-----------------------WARNINGSANDPRECAUTIONS------------------------

HypersensitivityReactionsIncludingAnaphylaxis:Anaphylaxishas

occurredin3.9%oftreatedpatients.AdministerKALBITORinasetting

equippedtomanageanaphylaxisandhereditaryangioedema.Given

thesimilarityinhypersensitivitysymptoms andacuteHAEsymptoms,

monitorpatientscloselyforhypersensitivityreactions(5).

------------------------------ADVERSEREACTIONS-------------------------------

Themostcommonadversereactions occurringin≥3%ofKALBITOR-

treatedpatientsandgreaterthanplaceboareheadache,nausea,

diarrhea,pyrexia,injectionsitereactions,andnasopharyngitis.(6)

See17forPATIENTCOUNSELINGINFORMATION

FULLPRESCRIBINGINFORMATION:CONTENTS*

WARNING:ANAPHYLAXIS

1 INDICATIONSAND USAGE

2 DOSAGEANDADMINISTRATION

2.1 RecommendedDosing

2.2 AdministrationInstructions

3 DOSAGEFORMSANDSTRENGTHS

4 CONTRAINDICATIONS

5 WARNINGSAND PRECAUTIONS

5.1 HypersensitivityReactions,IncludingAnaphylaxis

6 ADVERSEREACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

7 DRUG INTERACTIONS

8 USEIN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 LaborandDelivery

8.3 NursingMothers

8.4 Pediatric Use

8.5 GeriatricUse

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICALPHARMACOLOGY

12.1 MechanismofAction

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICALTOXICOLOGY

13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility

13.2 Animal Toxicology

14 CLINICALSTUDIES

16 HOWSUPPLIED/STORAGEAND HANDLING

17 PATIENTCOUNSELINGINFORMATION

*Sectionsorsubsections omittedfromthefullprescribinginformationarenot

listed.

8.4 PediatricUse

SafetyandeffectivenessofKALBITORinpatientsbelow16yearsof

agehavenotbeenestablished.

8.5 GeriatricUse

ClinicaltrialsofKALBITORdidnotincludesufficientnumbersof

subjectsaged65andovertodeterminewhethertheyrespond

differentlyfromyoungersubjects.Ingeneral,doseselectionforan

elderlypatientshouldbecautious,usuallystartingatthelowendof

thedosingrange,reflectingthegreaterfrequencyofdecreased

hepatic,renal,orcardiacfunction,andofconcomitantdiseaseorother

drugtherapy.

10 OVERDOSAGE

TherehavebeennoreportsofoverdosewithKALBITOR.HAE

patientshavereceivedsingledosesupto90mgintravenouslywithout

evidenceofdose-relatedtoxicity.Nodeathsoccurredinmonkeysthat

receivedintravenousorsubcutaneousdosesupto25mg/kg

(approximately22timestheMRHDonanAUCbasis).

11 DESCRIPTION

KALBITOR(ecallantide)isahumanplasmakallikreininhibitorfor

injectionforsubcutaneoususe.

KALBITORisaclearandcolorless,sterile,andnonpyrogenicsolution.

Eachvialcontains10mgecallantideastheactiveingredient,andthe

followinginactiveingredients:0.76mgdisodiumhydrogen

orthophosphate(dihydrate),0.2mgmonopotassiumphosphate,0.2mg

potassiumchloride,and8mgsodiumchlorideinwaterforinjection,

USP.KALBITORispreservativefree,withapHofapproximately7.0.

A30mgdoseissuppliedas3vialseachcontaining1mLof10mg/mL

KALBITOR.Eachvialcontainsaslightoverfill.Vialsareintendedfor

singleuse.Ecallantideisa60-amino-acidproteinproducedinPichia

pastorisyeastcellsbyrecombinantDNAtechnology.

12 CLINICALPHARMACOLOGY

12.1 MechanismofAction

Hereditaryangioedema(HAE)isararegeneticdisordercausedby

mutationstoC1-esterase-inhibitor(C1-INH)locatedonChromosome

11qandinheritedasanautosomaldominanttrait.HAEis

characterizedbylowlevelsofC1-INHactivityandlowlevelsofC4.

C1-INHfunctionstoregulatetheactivationofthecomplementand

intrinsiccoagulation(contactsystempathway)andisamajor

endogenousinhibitorofplasmakallikrein.Thekallikrein-kininsystem

isacomplexproteolyticcascadeinvolvedintheinitiationofboth

inflammatoryandcoagulationpathways.Onecriticalaspectofthis

pathwayistheconversionofHighMolecularWeight(HMW)kininogen

tobradykininbytheproteaseplasmakallikrein.InHAE,normal

regulationofplasmakallikreinactivityandtheclassicalcomplement

cascadeisthereforenotpresent.Duringattacks,unregulatedactivity

ofplasmakallikreinresultsinexcessivebradykiningeneration.

Bradykininisavasodilatorwhichisthoughtbysometoberesponsible

forthecharacteristicHAEsymptomsoflocalizedswelling,

inflammation,andpain.

KALBITORisapotent(Ki=25pM),selective,reversibleinhibitorof

plasmakallikrein.KALBITORbindstoplasmakallikreinandblocksits

bindingsite,inhibitingtheconversionofHMWkininogentobradykinin.

Bydirectlyinhibitingplasmakallikrein,KALBITORreducesthe

conversionofHMWkininogentobradykininandtherebytreats

symptomsofthediseaseduringacuteepisodicattacksofHAE.

12.2 Pharmacodynamics

Noexposure-responserelationshipsforKALBITORtocomponentsof

thecomplementorkallikrein-kininpathwayshavebeenestablished.

TheeffectofKALBITORonactivatedpartialthromboplastintime

(aPTT)wasmeasuredbecauseofpotentialeffectontheintrinsic

coagulationpathway.ProlongationofaPTThasbeenobserved

At80mgadministeredintravenouslyinhealthysubjects,aPTTvalues

wereprolongedapproximatelytwo-foldoverbaselinevaluesand

returnedtonormalby4hourspost-dose.

ForpatientstakingKALBITOR,nosignificantQTprolongationhas

beenseen.Inarandomized,placebo-controlledtrial(EDEMA4)

studyingthe30mgsubcutaneousdoseversusplacebo,12-lead

ECGswereobtainedatbaseline,2hoursand4hourspost-dose

(coveringthetimeofexpectedC

),andatfollow-up(day7).ECGs

wereevaluatedforPRinterval,QRScomplex,andQTcinterval.

KALBITORhadnosignificanteffectontheQTcinterval,heartrate,or

anyothercomponentsoftheECG.

12.3 Pharmacokinetics

Followingtheadministrationofasingle30mgsubcutaneousdoseof

KALBITORtohealthysubjects,amean(±standarddeviation)

maximumplasmaconcentrationof586±106ng/mLwasobserved

approximately2to3hourspost-dose.Themeanareaunderthe

concentration-timecurvewas3017±402ng*hr/mL.Following

administration,plasmaconcentrationdeclinedwithameanelimination

half-lifeof2.0±0.5hours.Plasmaclearancewas153±20mL/min

andthevolumeofdistributionwas26.4±7.8L.Basedona

populationpharmacokineticanalysis,bodyweight,age,andgender

werenotfoundtoaffectKALBITORexposuresignificantly.

Ecallantideisasmallprotein(7054Da)andrenaleliminationinthe

urineoftreatedsubjectshasbeendemonstrated.

Nopharmacokineticdataareavailableinpatientsorsubjectswith

hepaticorrenalimpairment.

13 NONCLINICALTOXICOLOGY

13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility

Therearenoanimalorhumanstudiestoassessthecarcinogenicor

mutagenicpotentialofKALBITOR(ecallantide).

KALBITORhadnoeffectsonfertilityandreproductiveperformancein

ratsatsubcutaneousdosesupto25mg/kg/day(approximately21

timestheMRHDonamg/kgbasis).

13.2 AnimalToxicology

ReproductiveToxicologyStudies

KALBITORhasbeenshowntocausedevelopmentaltoxicityinrats,

butnotrabbits.Treatmentofratswithanintravenousdoseof15

mg/kg/day(approximately13timestheMRHDonamg/kgbasis)

causedincreasednumbersofearlyresorptionsandpercentagesof

resorbedconceptusesperlitterinthepresenceofmildmaternal

toxicity.However,nodevelopmenttoxicitywasobservedinratsthat

receivedanintravenousdoseof10mg/kg/day(approximately8times

theMRHDonamg/kgbasis).KALBITORwasnotteratogenicinrats

atsubcutaneousdosesupto20mg/kg/day(approximately2.4times

theMRHDonanAUCbasis)andrabbitsthatreceivedintravenous

dosesupto5mg/kg/day(approximately6timestheMRHDonan

AUCbasis).

14 CLINICALSTUDIES

ThesafetyandefficacyofKALBITORwasevaluatedin2randomized,

double-blind,placebo-controlledtrials(EDEMA4andEDEMA3)in168

patientswithHAE.Patientshavinganattackofhereditary

angioedema,atanyanatomiclocation,withatleast1moderateor

severesymptom,weretreatedwith30mgsubcutaneousKALBITOR

orplacebo.Becausepatientscouldparticipateinbothtrials,atotalof

143uniquepatientsparticipated.Ofthe143patients,94werefemale,

123wereCaucasian,andthemeanagewas36years.Therewere64

patientswithabdominalattacks,55withperipheralattacks,and24

withlaryngealattacks.

Inbothtrials,theeffectsofKALBITORwereevaluatedusingtheMean

SymptomComplexSeverity(MSCS)scoreandtheTreatment

OutcomeScore(TOS).Thesemeasuresevaluatedtheseverityof

attacksymptomsatallanatomicallocations(MSCSscore)and

MSCSscoreisapoint-in-timemeasureofsymptomseverity.At

baseline,4hours,and24hours,patientsratedtheseverityona

categoricalscale(0=normal,1=mild,2=moderate,3=severe)for

symptomsateachaffectedanatomicallocation.Ratingswere

averagedtoobtaintheMSCSscore.AdecreaseinMSCSscore

reflectedanimprovementinsymptoms.

TOSisameasureofsymptomresponsetotreatment.At4hoursand

24hours,patientassessmentofresponsecharacterizedbytheir

changefrombaselineinsymptomseverityandcollectedbyanatomic

siteofattackinvolvement,wasrecordedonacategoricalscale

(significantimprovement[100],improvement[50],same[0],worsening

[-50],significantworsening[-100]).Theresponseateachanatomic

sitewasweightedbybaselineseverityandthentheweightedscores

acrossallinvolvedsiteswereaveragedtocalculatetheTOS.ATOS

value>0reflectedanimprovementinsymptomsfrombaseline.

EDEMA4

EDEMA4wasarandomized,double-blind,placebo-controlledtrialin

which96patientswererandomized1:1toreceiveKALBITOR30mg

subcutaneousorplaceboforacuteattacksofHAE.Theprimary

endpointwasthechangefrombaselineinMSCSscoreat4hours,

andtheTOSat4hourswasakeysecondaryendpoint.Patients

treatedwithKALBITORdemonstratedagreaterdecreasefrom

baselineintheMSCSthanplaceboandagreaterTOSthanpatients

withplaceboandtheresultswerestatisticallysignificant(Table2).At

24hours,patientstreatedwithKALBITORalsodemonstrateda

greaterdecreasefrombaselineintheMSCSthanplacebo(-1.5vs.-

1.1;p=0.04)andagreaterTOS(89vs.55,p=0.03).

Table2:ChangeinMSCSScoreandTOSat4Hours

EDEMA4 EDEMA3

KALBITOR

(N=48) Placebo

(N=48) KALBITOR

(N=36) Placebo

(N=36)

ChangeinMSCSScoreat4Hours

n 47 42 34 35

Mean -0.8 -0.4 -1.1 -0.6

95%

CI -1.0,-0.6 -0.6,-0.1 -1.4,-0.8, -0.8,-0.4

value 0.010 0.041

TOSat4Hours

n 47 42 34 35

Mean 53 8 63 36

95%

CI 39,68 -12,28 49,76 17,54

value 0.003 0.045

MSCS:MeanSymptomComplexSeverity

TOS:TreatmentOutcomeScore

CI:confidenceinterval

Morepatientsintheplacebogroup(24/48,50%)requiredmedical

interventiontotreatunresolvedsymptomswithin24hourscompared

totheKALBITOR-treatedgroup(16/48,33%).

Somepatientsreportedimprovementfollowingasecond30mg

subcutaneousdoseofKALBITOR,administeredwithin24hours

followingtheinitialdoseforsymptompersistenceorrelapse,but

efficacywasnotsystematicallyassessedfortheseconddose.

EDEMA3

EDEMA3wasarandomized,double-blind,placebo-controlledtrialin

which72patientswererandomized1:1toreceiveKALBITORor

placeboforacuteattacksofHAE.EDEMA3wassimilarindesignto

EDEMA4withtheexceptionoftheorderoftheprespecifiedefficacy

endpoints.InEDEMA3,theprimaryendpointwastheTOSat4hours,

andthekeysecondaryefficacyendpointwasthechangefrom

baselineinMSCSat4hours.AsinEDEMA4,patientstreatedwith

KALBITORdemonstratedagreaterdecreasefrombaselineinthe

MSCSthanplaceboandagreaterTOSthanpatientstreatedwith

Inaddition,morepatientsintheplacebogroup(13/36,36%)required

medicalinterventiontotreatunresolvedsymptomswithin24hours

comparedtotheKALBITOR-treatedgroup(5/36,14%).

16 HOWSUPPLIED/STORAGEANDHANDLING

KALBITOR(ecallantide)issuppliedasthree10mg/mLsingle-use

vialspackagedinacarton.Eachvialcontains10mgofecallantide.

Eachvialcontainsaslightoverfill.

NDC(47783-101-01):3single-usevialsin1carton

KALBITORshouldbekeptrefrigerated(2ºCto8ºC/36ºFto46ºF).

Vialsremovedfromrefrigerationshouldbestoredbelow86ºF/30ºC

andusedwithin14daysorreturnedtorefrigerationuntiluse.

Protectvialsfromlightuntiluse.

Donotusebeyondtheexpirationdate.

17 PATIENTCOUNSELINGINFORMATION

SeeMedicationGuide

PatientsshouldbeadvisedthatKALBITORmaycauseanaphylaxis

andotherhypersensitivityreactions.Patientsshouldbeadvisedthat

KALBITORshouldbeadministeredbyahealthcareprofessionalwith

appropriatemedicalsupporttomanageanaphylaxisandhereditary

angioedema.Patientswhohaveknownclinicalhypersensitivityto

KALBITORshouldbeinstructednottoreceiveadditionaldosesof

KALBITOR.[seeBoxedWarning,Contraindications(4),andWarnings

andPrecautions(5.1)]

18 REGISTRATIONHOLDER

NeopharmSientificLtd.8Hashiloachstreet,P.O.Box7063,Petach

Tiqva49170.

19 MARKETINGAUTHORISATIONNUMBER(S)

146223325200

20

MANUFACTUREFOR

DyaxCorp.,WA99207,USA.

TheformatofthisleaflethasbeendefinedbytheMOHanditscontent

hasbeencheckedandapproved-June2011

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