בנפיקס 2000 יח' בינל

ישראל - עברית - Ministry of Health

קנה את זה

עלון מידע עלון מידע (PIL)

28-11-2020

מרכיב פעיל:
COAGULATION FACTOR IX RECOMBINANT-RFIX
זמין מ:
PFIZER PHARMACEUTICALS ISRAEL LTD
קוד ATC:
B02BD04
טופס פרצבטיות:
אבקה מיובשת בהקפאה להזרקה
הרכב:
COAGULATION FACTOR IX RECOMBINANT-RFIX 2000 IU
מסלול נתינה (של תרופות):
תוך-ורידי
סוג מרשם:
מרשם נדרש
תוצרת:
WYETH FARMA S.A, SPAIN
קבוצה תרפויטית:
COAGULATION FACTOR IX
איזור תרפויטי:
COAGULATION FACTOR IX
סממני תרפויטית:
Benefix is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B (congenital factor IX deficiency or christmas disease), including control and prevention of bleeding in surgical settings, in previously treated patients (PTP) and previously untreated patients (PUP). Benefix is not indicated for the treatment of other factor deficiencies (e.g. factors II,VII, and X)' nor for the treatment of hemophilia A patients with inhibitors to factor VIII, nor for the reversal of coumarin-induced anticoagulation, nor for the treatment of bleeding due to low levels of liver-dependent coagulation factors.
leaflet_short:
1. התרופה האמורה תינתן לטיפול בקטינים בלא היסטוריה משפחתית של התפתחות נוגדן לאחר חשיפות מועטות לתרכיזי קרישה שמקורם בדם אנושי. 2. התרופה האמורה תינתן במרכז ארצי לטיפול בחולי המופיליה שנקבע לכך על ידי המנהל הכללי של משרד הבריאות.
מספר אישור:
142 66 31926 00
תאריך אישור:
2015-01-31

מסמכים בשפות אחרות

עלון מידע עלון מידע - אנגלית

31-05-2018

מאפייני מוצר מאפייני מוצר - אנגלית

31-05-2018

עלון מידע עלון מידע - ערבית

28-11-2020

BeneFIX ®

-

FULLPRESCRIBINGINFORMATION

1 INDICATIONSANDUSAGE

1.1ControlandPreventionBleedingEpisodesinHemophiliaB

BeneFIX ® ,CoagulationFactorIX(Recombinant),isindicatedforthecontrolandprevention

ofbleedingepisodesinadultandpediatricpatientswithhemophiliaB(congenitalfactorIX

deficiencyorChristmasdisease).

1.2Peri –operativeManagementinPatientswithHemophiliaB

BeneFIX,CoagulationFactorIX(Recombinant),isindicatedforperi-operative

managementinadultandpediatricpatientswith

hemophiliaB.

BeneFIX ® ,CoagulationFactorIX(Recombinant),isNOTindicatedfor:

Thetreatmentofotherfactordeficiencies(e.g.,factorsII,VII,VIII,andX)

TreatmentofhemophiliaApatientswithinhibitorstofactorVIII

Reversalofcoumarin-inducedanticoagulation

Treatmentofbleedingduetolowlevelsofliver-dependentcoagulationfactors.

2DOSAGEANDADMINISTRATION

2.1GeneralConsiderations forAdministration

ForIntravenousUseafter Reconstitution

TreatmentwithBeneFIX ® ,CoagulationFactorIX(Recombinant),shouldbeinitiated

underthesupervisionofaphysicianexperiencedinthetreatmentofhemophiliaB .

EachvialofBeneFIXhastherFIXpotencyintheInternationalUnits(IU)statedon

the vial.

Dosage anddurationoftreatmentforallfactorIXproductsdependonthe severity

ofthe factorIXdeficiency,the locationandextentofbleeding,andthepatient's

clinicalcondition,age andrecoveryoffactorIX.

ToensurethatthedesiredfactorIXactivitylevelhasbeenachieved,precise

monitoringusingthefactorIXactivityassayisadvised. Dosesshouldbetitratedusing

thefactorIXactivity,pharmacokineticparameters,suchashalf-lifeandrecovery,aswellas

takingtheclinical

situationintoconsiderationinordertoadjustthedoseasappropriate.

DosingofBeneFIX ® maydifferfromthatofplasma-derivedfactorIXproducts [see

ClinicalPharmacology(12)].Subjectsatthe lowendofthe observedfactorIXrecovery

mayrequireupwarddosage adjustmentofBeneFIXtoasmuchastwotimes(2X)the

initialempiricallycalculateddoseinordertoachievetheintendedriseincirculating

factorIXactivity.

ThesafetyandefficacyofBeneFIX ® administrationbycontinuousinfusionhavenotbeen

established(seeWARNINGSandPrecautions(5)]).

2.2MethodofCalculatingInitialEstimatedDose:

ThemethodofcalculatingthefactorIXdoseisshowninTable1:

Table1

numberof

factorIXIU

required(IU) = body

weight

(kg) x desiredfactor

IXincrease

(%orIU/dL) x reciprocalof

observed

recovery(IU/kg

perIU/dL)

Average RecoveryAdultPatientsinClinicalTrial

InadultPTPs,onaverage,oneInternationalUnit(IU)ofBeneFIXperkilogramofbody

weightincreasedthecirculatingactivityoffactorIXby0.8±0.2IU/dL(range0.4to1.2

IU/dL).ThemethodofdoseestimationisillustratedinTable2.Ifyouuse0.8IU/dLaverage

increaseoffactorIXperIU/kgbodyweightadministered,then:

Table2

numberof

factorIXIU

required(IU) = body

weight

(kg) x desiredfactor

IXincrease

(%orIU/dL) x 1.3(IU/kgper

IU/dL)

Average RecoveryPediatricPatients(<15years)inClinicalTrial

Inpediatricpatients,onaverage,oneinternationalunitofBeneFIXperkilogramofbody

weightincreasedthecirculatingactivityoffactorIXby0.7±0.3IU/dL(range0.2to2.1

IU/dL;medianof0.6IU/dLperIU/kg).ThemethodofdoseestimationisillustratedinTable

3.Ifyouuse

0.7IU/dLaverageincreaseoffactorIXperIU/kgbodyweightadministered,then:

Table3

numberof

factorIXIU

required(IU) = body

Weight

(kg) x desiredfactor

IXincrease

(%orIU/dL) x 1.4(IU/kgper

IU/dL)

Dosesadministeredshouldbetitratedtothepatient’sclinicalresponse.Patientsmayvary

intheirpharmacokinetic(e.g.,half-life,invivorecovery)andclinicalresponsestoBeneFIX.

Althoughthedosecanbeestimatedbythecalculationsabove,itishighlyrecommended

that,wheneverpossible,appropriatelaboratorytests,includingserialfactorIXactivity

assays,beperformed.

2.3DosingGuide forControlandPreventionofBleedingEpisodesandPeri-

operativeManagement

Table4

TypeofHemorrhage CirculatingFactorIX

ActivityRequired

[%or(IU/dL)] DosingInterval

[hours] DurationofTherapy

[days]

Minor

Uncomplicatedhemarthroses,

superficial

muscle,orsofttissue 20-30 12-24 1-2

Moderate

Intramuscleorsofttissuewith

dissection,

mucous membranes,dental

extractions,orhematuria 25-50 12-24 Treatuntilbleeding

stopsandhealing

begins,about2to7

Table4

TypeofHemorrhage CirculatingFactorIX

ActivityRequired

[%or(IU/dL)] DosingInterval

[hours] DurationofTherapy

[days]

Major

Pharynx,retropharynx,

retroperitoneum,CNS,surgery 50-100 12-24 7-10

Adaptedfrom:RobertsandEberst 1

2.4InstructionsforUse

BeneFIXisadministeredbyintravenous(IV)infusionafterreconstitutionofthelyophilized

powderwiththesuppliedpre-filleddiluent(0.234%sodiumchloridesolution)syringe.

Patientsshouldfollowthespecificreconstitutionandadministrationproceduresprovidedby

their physicians.

Reconstitution,productadministration,andhandlingoftheadministrationsetmustbedone

withcaution.Discardallequipment,includinganyreconstitutedBeneFIXproduct,inan

appropriatecontainer.Placeneedlesusedforvenopunctureinasharpscontainerafter

singleuse.Percutaneouspuncturewithaneedlecontaminatedwithbloodfromaninfected

patientcan

transmitinfectiousvirusesincludingHIV(AIDS)andhepatitis.Obtainimmediatemedical

attentionifinjuryoccurs.

2.5PreparationandReconstitution

Theproceduresbelowareprovidedasgeneralguidelinesforthereconstitutionand

administrationofBeneFIX.

Preparation

1. Alwayswashyourhandsbeforeperformingthefollowingprocedures.

2. Aseptictechnique(meaningcleanandgerm-free)shouldbeusedduringthe

reconstitutionprocedure.

3. Useallcomponentsinthereconstitutionandadministrationofthisproductassoonas

possibleafteropeningtheirsterilecontainerstominimizeunnecessaryexposureto

theatmosphere.

Note: IfyouusemorethanonevialofBeneFIX ® perinfusion,eachvialshouldbe

reconstitutedaccordingtothefollowinginstructions.Thediluentsyringeshouldberemoved

leavingthevialadapterinplace,andaseparatelargeluerlocksyringemaybeusedto

drawbackthereconstitutedcontentsofeachvial.Donotdetachthediluentsyringesorthe

largeluerlocksyringeuntilyouarereadytoattachthelargeluerlocksyringetothenext

vialadapter.

Reconstitution

1. AllowthevialoflyophilizedBeneFIX ® andthepre-filleddiluentsyringetoreachroom

temperature.

2. Removetheplasticflip-topcapfromtheBeneFIX ® vialtoexposethecentralportions

oftherubberstopper.

3. Wipethetopofthevialwiththealcoholswabprovided,oruseanotherantiseptic

solution,andallowtodry.Aftercleaning,donottouchtherubberstopperwithyour

handorallowittotouchanysurface.

4. Peelbackthecoverfromtheclearplasticvialadapterpackage.

Donotremovetheadapterfromthe package .

5. Placethevialonaflatsurface.Whileholdingtheadapterinthe

package,placethevialadapteroverthevialandpressdown

firmlyonthepackageuntiltheadapterspikepenetrates

thevialstopper.

6. Grasptheplungerrodasshowninthediagram.Avoidcontactwiththeshaftofthe

plungerrod.Attachthethreadedendoftheplungerrodtothe

diluentsyringeplungerbypushingandturningfirmly.

7. Breakoffthetamper-resistant,plastic-tipcapfromthediluentsyringebysnappingthe

perforationofthecap.Donottouchtheinsideofthecaporthesyringetip.Thediluent

syringemayneedtoberecapped(ifnotadministeringreconstituted

BeneFIX®immediately),soplacethecaponitstoponaclean

surfaceinaspotwhereitwouldbeleastlikelyto

becomeenvironmentallycontaminated.

8. Liftthepackageawayfromtheadapteranddiscardthepackage.

9. Placethevialonaflatsurface.Connectthediluentsyringetothe

vialadapterbyinsertingthetipintotheadapteropening

whilefirmlypushingandturningthesyringe

clockwiseuntilsecured.

10.Slowlydepresstheplungerrodtoinjectallthediluents

intotheBeneFIX ® vial.

11.Withoutremovingthesyringe,gentlyswirlthecontentsofthe

vialuntilthepowderisdissolved.

Note:The finalsolutionshouldbe inspectedvisuallyforparticulatematterbefore

administration.The solutionshouldappearclearandcolorless.Ifitisnot,the

solutionshouldbediscardedandanewkitshouldbeused.

12.Invertthevialandslowlydrawthesolutionintothesyringe.

13.Detachthesyringefromthevialadapterbygentlypullingandturningthesyringe

counter-clockwise.Discardthevialwiththeadapterattached.

Note :Ifthesolutionisnottobeusedimmediately,thesyringecapshouldbecarefully

replaced.Donottouchthesyringetiportheinsideofthecap.

BeneFIX ® ,whenreconstituted,containspolysorbate-80,whichisknowntoincrease

therateofdi-(2-ethylhexyl)phthalate(DEHP)extractionfrompolyvinylchloride

(PVC).Thisshouldbeconsideredduringthepreparationandadministrationof

BeneFIX®,includingstorage timeelapsedinaPVCcontainerfollowing

reconstitution.Itisimportantthattherecommendationsfordosage and

administrationbefollowedclosely [seeDosageandAdministration(2)]

2.6Administration(IntravenousInjection)

ForIntravenousUseonlyafterReconstitution

BeneFIX ® isadministeredbyintravenous(IV)infusionafterreconstitutionwiththepre-filled

diluent(0.234%sodiumchloridesolution)syringe.

BeneFIXshouldbeinspectedforparticulatematteranddiscolorationpriorto

administration,wheneversolutionandcontainerpermit.

Thereconstitutedsolutionmaybestoredatroomtemperaturepriortoadministration,but

BeneFIXshouldbeadministeredwithin3hours.BeneFIXshouldbeadministeredusing

thetubingprovidedinthiskit,andthepre-filleddiluentsyringeprovided,orasingle

steriledisposableplasticsyringe.Inaddition,thesolutionshouldbewithdrawnfromthe

vialusingthevialadapter.

AdoseofBeneFIXmaybeadministeredoveraperiodofseveralminutes.Therateof

administration,however,shouldbeadaptedtothecomfortlevelofeachindividual

patient.

1. Attachthesyringetotheluerendoftheprovidedinfusionsettubing.

2. Applyatourniquetandpreparetheinjectionssitebywipingtheskin

wellwithanalcoholswabprovidedinthekit.

3. Performvenipuncture.Inserttheneedleontheinfusionsettubinginto

thevein,andremovethetourniquet.ThereconstitutedBeneFIX

productshouldbeinjectedintravenouslyoverseveralminutes.The

rateofadministrationshouldbedeterminedbythepatient’scomfort

level.

ReconstitutedBeneFIXshouldnot beadministeredinthesametubingor

containerwithothermedicinalproducts.

Agglutinationofredbloodcellsinthetubing/syringehasbeenreportedwiththe

administrationofBeneFIX .Noadverseeventshavebeenreportedin

associationwiththisobservation.Tominimizethepossibilityofagglutination,itis

importanttolimittheamountofbloodenteringthetubing.Bloodshouldnotenter

thesyringe.Ifredbloodcellagglutinationisobservedinthetubingorsyringe,

discardallmaterial(tubing,syringeandBeneFIX solution)andresume

administrationwithanewpackage.

FollowingcompletionofBeneFIXtreatment,removetheinfusionsetanddiscard.The

amountofdrugproductleftintheinfusionsetwillnotaffectyourtreatment.Disposeofall

unusedsolution,emptyvial(s),andusedneedlesandsyringesinanappropriatecontainer

forthrowingawaywastethatmighthurtothersifnothandledproperly.

The safetyandefficacyofadministrationbycontinuousinfusionhavenot been

established [seeWarningsandPrecautions(5)].

3DOSAGEFORMSANDSTRENGTHS

BeneFIXissuppliedasawhitelyophilizedpowderinthefollowingdosages:

250IU,500IU,1000IU,2000IU.

4CONTRAINDICATIONS

BeneFIXiscontraindicatedinpatientswhohavemanifestedlife-threatening,immediate

hypersensitivityreactions,includinganaphylaxis,totheproductoritscomponents,

includinghamsterprotein.

5WARNINGSANDPRECAUTIONS

5.1General

TheclinicalresponsetoBeneFIXmayvary.Ifbleedingisnotcontrolledwiththe

recommendeddose,theplasmaleveloffactorIXshouldbedetermined,andasufficient

doseofBeneFIXshouldbeadministeredtoachieveasatisfactoryclinicalresponse.Ifthe

patient’splasmafactorIXlevelfailstoincreaseasexpectedorifbleedingisnotcontrolled

aftertheexpecteddose,thepresenceofaninhibitor(neutralizingantibodies)shouldbe

suspected,andappropriatetestingperformed[seeWarningsandPrecautions(5.6)].

5.2AnaphylaxisandSevereHypersensitivityReactions

Allergictypehypersensitivityreactions,includinganaphylaxis,havebeenreportedwith

BeneFIXandhavemanifestedaspruritus,rash,urticaria,hives,facialswelling,dizziness,

hypotension,nausea,chestdiscomfort,cough,dyspnea,wheezing,flushing,discomfort

(generalized)andfatigue.Frequently,theseeventshaveoccurredinclosetemporal

associationwiththedevelopmentoffactorIXinhibitors.Advisepatientstodiscontinueuse

oftheproductandcontacttheir physicianand/orseekimmediateemergencycare.

BeneFIXcontainstraceamountsofhamster(CHO)proteins.Patientstreatedwiththis

productmaydevelophypersensitivitytothesenon-humanmammalianproteins.

5.3ThromboembolicComplications

ThesafetyandefficacyofBeneFIXadministrationbycontinuousinfusionhavenotbeen

established[seeDosageandAdministration(2)].Therehavebeenpost-marketingreports

ofthromboticeventsinpatientsreceivingcontinuous-infusionBeneFIXthroughacentral

venouscatheter,includinglife-threateningsuperiorvenacava(SVC)syndromeincritically

illneonates[seeAdverseReactions(6)].

5.4NephroticSyndrome

NephroticsyndromehasbeenreportedfollowingimmunetoleranceinductionwithfactorIX

productsinhemophiliaBpatientswithfactorIXinhibitorsandahistoryofallergicreactions

tofactorIX.ThesafetyandefficacyofusingBeneFIXforimmunetoleranceinductionhave

notbeenestablished.

5.5NeutralizingAntibodies(Immunogenicity)

PatientsusingBeneFIXshouldbemonitoredforthedevelopmentoffactorIXinhibitorsby

appropriateclinicalobservationsandlaboratorytests.Inhibitorshavebeenreported

followingadministrationofBeneFIX[seeClinicalPharmacology(12)].Ifexpectedplasma

factorIXactivitylevelsarenotattained,orifbleedingisnotcontrolledwithanexpected

dose,anassay

thatmeasuresfactorIXinhibitorconcentrationshouldbeperformed.

PatientswithfactorIXinhibitorsmaybeatanincreasedriskofanaphylaxisupon

subsequentchallengewithfactorIX.2Patientsexperiencingallergicreactionsshouldbe

evaluatedforthepresenceofaninhibitor.Patientsshouldbeobservedcloselyforsigns

andsymptomsofacutehypersensitivityreactions,particularlyduringtheearlyphasesof

initialexposuretoproduct.

Becauseofthe potentialforallergicreactionswithfactorIXconcentrates,the initial

(approximately10-20)administrationsoffactorIXshouldbeperformedunder

medicalsupervisionwherepropermedicalcareforallergicreactionscouldbe

provided.

5.6MonitoringLaboratoryTests

PatientsshouldbemonitoredforfactorIXactivitylevelsbytheone-stageclottingassay

toconfirmthatadequatefactorIXlevelshavebeenachievedandmaintained,when

clinicallyindicated[seeDosageandAdministration(2)].

PatientsshouldbemonitoredforthedevelopmentofinhibitorsifexpectedfactorIX

activityplasmalevelsarenotattained,orifbleedingisnotcontrolledwiththe

recommendeddoseofBeneFIX.AssaysusedtodetermineiffactorIXinhibitorispresent

shouldbetiteredinBethesdaUnits(BUs).

6ADVERSEREACTIONS

Themostseriousadversereactionsaresystemichypersensitivityreactions,including

bronchospasticreactionsand/orhypotensionandanaphylaxisandthedevelopmentof

high-titerinhibitorsnecessitatingalternativetreatmentstofactorIXreplacementtherapy.

Themostcommonadversereactionsobservedinclinicaltrials(frequency>5%ofPTPsor

PUPs)wereheadaches,dizziness,nausea,injectionssitereaction,injectionsitepainand

skin-relatedhypersensitivityreactions(e.g.,rash,hives).

6.1ClinicalTrialsExperience

Becauseclinicaltrialsareconductedunderwidelyvaryingconditions,adversereaction

ratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesinthe

clinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinclinicalpractice.

Duringuncontrolledopen-labelclinicalstudieswithBeneFIX,CoagulationFactorIX

(Recombinant),conductedinpreviouslytreatedpatients(PTPs),113adversereactions

withknownorunknownrelationtoBeneFIXtherapywerereportedamong38.5%(25of65)

ofsubjects(withsomesubjectsreportingmorethanoneevent)whoreceivedatotalof

7,573infusions.theseadversereactionsaresummarizedintable5.

Table5:AdverseReactionsReportedforPTPs*

BodySystem AdverseReaction Numberofpatients

(%)

Bloodandlymphaticsystemdisorders FactorIXinhibition 1 1(1.5%)

Eyedisorders Blurredvision 1(1.5%)

Gastrointestinaldisorders Nausea 4(6.2%)

Vomiting 1(1.5%)

General disorders andadministrationsite

conditions Injectionsitereaction 5(7.7%)

Injectionsitepain 4(6.2%)

Fever 2(3.1%)

Infections andinfestations CellulitisatIVsite 1(1.5%)

Phlebitis atIVsite 1(1.5%)

Nervoussystemdisorders Headache 7(10.8%)

Dizziness 5(7.7%)

Tasteperversion(altered

taste) 3(4.6%)

Shaking 1(1.5%)

Drowsiness 1(1.5%)

Renalandurinarydisorders Renalinfarct 2 1(1.5%)

Respiratory,thoracicandmediastinal disordersDrycough 1(1.5%)

Hypoxia 1(1.5%)

Chesttightness 1(1.5%)

Skinandsubcutaneous disorders Rash 4(6.2%)

Hives 2(3.1%)

Vasculardisorders Flushing 2(3.1%)

*Adversereactionsreportedwithin72hours ofaninfusionofBeneFIX.

Low-titertransientinhibitorformation.

Therenalinfarctdevelopedinahepatitis Cantibody-positivepatient12days afteradoseofBeneFIXforableeding

episode.TherelationshipoftheinfarcttotheprioradministrationofBeneFIXis uncertain.

Inthe63previouslyuntreatedpatients(PUPs),whoreceivedatotalof5,538infusions,10

adversereactionswerereportedamong9.5%ofthepatients(6outof63)havingknownor

unknownrelationshiptoBeneFIX.TheseeventsaresummarizedinTable6.

Datafrom57PUPsubjectswhounderwentrepeat

Recoverytestingforupto60monthsdemonstrated

thattheaverageincrementalFIXrecoverywas

consistentovertime,asshowninFigure1.

Table6:AdverseReactionsReportedforPUPs*

BodySystem AdverseReaction NumberofPatients

(%)

Bloodandlymphaticsystemdisorders FactorIXinhibition 1 2(3.2%)

General disorders andadministrationsite

conditions Injectionsitereaction 1(1.6%)

Chills 1(1.6%)

Respiratory,thoracicandmediastinal disordersDyspnea(respiratory

distress) 2(3.2%)

Skinandsubcutaneous disorders Hives 3(4.8%)

Rash 1(1.6%)

*Adversereactionsreportedwithin72hours ofaninfusionofBeneFIX.

Twosubjectsdevelopedhigh-titerinhibitorformationduringtreatmentwithBeneFIX.

ForadversereactionsthoughttoberelatedtotheadministrationofBeneFIX,therateof

infusionshouldbedecreasedortheinfusionstopped.

Immunogenicity

Inclinicalstudieswith65PTPs(definedashavingmorethan50exposuredays),alow-titer

inhibitorwasobservedinonepatient.Theinhibitorwastransient,thepatientcontinuedon

studyandhadnormalfactorIXrecoverypharmacokineticsatstudycompletion

(approximately15monthsafterinhibitordetection).

InclinicalstudieswithpediatricPUPs,inhibitordevelopmentwasobservedin2outof63

patients(3.2%),bothwerehigh-titer(>5BU)inhibitorsdetectedafter7and15exposure

days,respectively.Bothpatientswerewithdrawnfromthestudy.

6.2Post-marketingExperience

Thefollowingpost-marketingadversereactionshavebeenreportedforBeneFIX

inadequatefactorIXrecovery,inadequatetherapeuticresponse,inhibitordevelopment[see

ClinicalPharmacology(12) ],anaphylaxis[seeWarningsandPrecautions(5.2)],

angioedema,dyspnea,hypotension,andthrombosis.

Becausethesereactionsarereportedvoluntarilyfromapopulationofuncertainsize,itis

notalwayspossibletoreliablyestimatetheirfrequencyorestablishacausalrelationshipto

drugexposure.

ThesafetyandefficacyofBeneFIXadministrationbycontinuousinfusionhavenotbeen

established[seeWarningsandPrecautions(5.3)].Therehavebeenpost-marketingreports

ofthromboticevents,includinglife-threateningSVCsyndromeincriticallyillneonates,while

receivingcontinuous-infusionBeneFIXthroughacentralvenouscatheter.Casesof

peripheralthrombophlebitisandDVThavealsobeenreported.Insome,BeneFIXwas

administeredviacontinuousinfusion,whichisnot anapprovedmethodof

administration [seeDosageandAdministration].

7DRUGINTERACTIONS

Noneknown.

8USEINSPECIFICPOPULATIONS

8.1Pregnancy

PregnancyCategoryC

AnimalreproductionandlactationstudieshavenotbeenconductedwithBeneFIX,

CoagulationFactorIX(Recombinant).ItisnotknownwhetherBeneFIXcanaffect

reproductivecapacityorcausefetalharmwhengiventopregnantwomen.BeneFIXshould

beadministeredtopregnantandlactatingwomenonlyifneeded.

8.2LaborandDelivery

ThereisnoinformationavailableontheeffectoffactorIXreplacementtherapyonlabor

anddelivery.Useonlyifneeded.

8.3NursingMothers

Itisnotknownwhetherthisdrugisexcretedintohumanmilk.Becausemanydrugsare

excretedintohumanmilk,cautionshouldbeexercisedifBeneFIXisadministeredto

nursingmothers.

Useonlyifneeded.

8.4PediatricUse

Safety,efficacy,andpharmacokineticsofBeneFIXhavebeenevaluatedinpreviously

treated(PTP)andpreviouslyuntreatedpediatricpatients(PUP)[seeDosageand

Administration(2), ClinicalPharmacology(12),ClinicalStudies(14)andAdverseReactions

(6) ].Onaverage,lowerrecoveryhasbeenobservedinpediatricpatients(<15years).A

doseadjustmentmaybeneeded[seeDosageandAdministration(2)andClinical

Pharmacology(12) ].

8.5GeriatricUse

ClinicalstudiesofBeneFIXdidnotincludesufficientnumbersofsubjectsaged65andover

todeterminewhethertheyresponddifferentlyfromyoungersubjects.Doseselectionforan

elderlypatientshouldbeindividualized[seeDosageandAdministration(2)].

10OVERDOSAGE

Nosymptomsofoverdosehavebeenreported.

11DESCRIPTION

BeneFIX,CoagulationFactorIX(Recombinant),isapurifiedproteinproducedby

recombinantDNA.IthasaprimaryaminoacidsequencethatisidenticaltotheAla 148 allelic

formofplasma-derivedfactorIX,andhasstructuralandfunctionalcharacteristicssimilarto

thoseofendogenousfactorIX.

BeneFIXisproducedbyageneticallyengineeredChinesehamsterovary(CHO)cellline

thatisextensivelycharacterized.Nohumanoranimalproteinsareaddedduringthe

purificationandformulationprocessesofBeneFIX.

BeneFIXisnotderivedfromhumanbloodandcontainsnopreservatives,andthe

manufactureofBeneFIXincludesnoaddedanimalorhumancomponents.Thestoredcell

banksarefreeofhumanbloodorplasmaproducts.TheCHOcelllinesecretes

recombinantfactorIXintoadefinedcellculturemediumthatdoesnotcontainanyproteins

derivedfromanimalorhumansources,andtherecombinantfactorIXispurifiedbya

processalsoincludesamembranenanofiltrationstepthathastheabilitytoretain

moleculeswithapparentmolecularweights>70,000Da(suchaslargeproteinsandviral

particles).BeneFIXisasinglecomponentbySDS-polyacrylamidegelelectrophoresis

evaluation.Thepotency(inInternationalUnits,IU)isdeterminedusinganinvitroone-

stageclottingassayagainsttheWorldHealthOrganization(WHO)InternationalStandard

forFactorIXconcentrate.OneInternationalUnitistheamountoffactorIXactivitypresent

in1mLofpooled,normalhumanplasma.ThespecificactivityofBeneFIXisgreaterthanor

equalto200IUpermilligramofprotein.

BeneFIXisformulatedasasterile,nonpyrogenic,lyophilizedpowderpreparation.BeneFIX

isintendedforintravenous(IV)injection.Itisavailableinsingle-usevialscontainingthe

labeledamountoffactorIXactivity,expressedinIU.Eachvialcontainsnominally250,500,

1000or2000IUofCoagulationFactorIX(Recombinant).Afterreconstitutionofthe

lyophilizeddrugproduct,theconcentrationsofexcipientsare0.234%sodiumchloride,8

mML-histidine,0.8%sucrose,208mMglycine,0.004%polysorbate80.Alldosage

strengthsyieldaclear,colorlesssolutionuponreconstitution.

12CLINICALPHARMACOLOGY

12.1MechanismofAction

BeneFIXtemporarilyreplacesthemissingclottingfactorIXthatisneededforeffective

hemostasis.

12.2Pharmacodynamics

Theactivatedpartialthromboplastintime(aPTT)isprolongedinpeoplewithhemophiliaB.

TreatmentwithfactorIXconcentratemaynormalizetheaPTTbytemporarilyreplacing

thefactorIX.TheadministrationofBeneFIX,CoagulationFactorIX(Recombinant),

increasesplasmalevelsoffactorIX,andcantemporarilycorrectthecoagulationdefectin

thesepatients.

12.3Pharmacokinetics

Aftersingleintravenous(IV)dosesof50IU/kgofpreviouslymarketedBeneFIX,

CoagulationFactorIX(Recombinant)[reconstitutedwithSterileWaterforInjection],in37

previouslytreatedadultpatients(>15years),eachgivenasa10-minuteinfusion,themean

increasefrompre-infusionlevelincirculatingfactorIXactivitywas0.8±0.2IU/dLperIU/kg

infused(range

0.4to1.4IU/dLperIU/kg)andthemeanbiologichalf-lifewas18.8±5.4hours(range11to

36hours).Intheoriginalrandomized,cross-overpharmacokineticstudyinpreviously

treatedpatients(PTPs),theinvivorecoveryusingpreviouslymarketedBeneFIXwas

statisticallysignificantlyless(28%lower,p<0.05)thantherecoveryusingahighlypurified

plasma-derivedfactorIXproduct(pdFIX).AsummaryofpharmacokineticdataforBeneFIX

andpdFIXarepresentedinTable7.

Table7:PharmacokineticParameterEstimatesforBeneFIXandpdFIXinPreviouslyTreated

PatientswithHemophiliaB

Parameter BeneFIX,n= 11 pdFIX,n=11

Mean±SD Mean±SD

(IU∙hr/dL) 548± 92 928± 191

(hr) 18.1± 5.1 17.7± 5.3

CL(mL/hr/kg) 8.62± 1.7 6.00± 1.4

K-value(IU/dLperIU/kg) 0.84± 0.30 1.17± 0.26

Invivo Recovery(%) 37.8± 14.0 52.6± 12.4

Abbreviations:AUC

=areaundertheplasmaconcentration-timecurvefromtimezerotoinfinity;K-

value= incremental recovery;t

= plasmaeliminationhalf-life;CL= clearance;SD= standard

deviation.

Therewasnosignificantdifferenceinbiologicalhalf-life.Structuraldifferencesofthe

BeneFIXmoleculecomparedwithpdFIXwereshowntocontributetothelowerrecovery.In

subsequentevaluationsforupto24months,thepharmacokineticparametersweresimilar

totheinitialresults.

Inasubsequentrandomized,cross-overpharmacokineticstudy,BeneFIXreconstitutedin

0.234%sodiumchloridediluentwasshowntobepharmacokineticallyequivalenttothe

previouslymarketedBeneFIX(reconstitutedwithSterileWaterforInjection)in24

previouslytreatedpatients(≥12years)atadoseof75IU/kg.Inaddition,pharmacokinetic

parameterswerefollowedupin23previouslytreatedpatientsafterrepeatedadministration

ofBeneFIXforsixmonthsandfoundtobeunchangedcomparedwiththoseobtainedatthe

initialevaluation.AsummaryofpharmacokineticdataarepresentedinTable8:

Table8:PharmacokineticParameterEstimatesforBeneFIXatBaseline(Cross-overphase)and

Month6(Follow-upphase)inPreviouslyTreatedPatientswithHemophiliaB

Parameter ParametersatInitialVisit(Cross-over

phase),n=24 ParametersatMonth6(Follow-up

phase),n=23

Mean±SD Mean±SD

(IU/dL) 54.5± 15.0 57.3± 13.2

(IU∙hr/dL) 940± 237 923± 205

(hr) 22.4± 5.3 23.8± 6.5

CL(mL/hr/kg) 8.47± 2.12 8.54± 2.04

K-value

(IU/dLperIU/kg) 0.73± 0.20 0.76± 0.18

Invivo Recovery

(%) 34.5± 9.3 36.8± 8.7

Abbreviations:AUC

=areaundertheplasmaconcentration-timecurvefromtimezerotoinfinity;AUC

=areaunderthe

plasmaconcentration-timecurvefromzerotothelastmeasurableconcentration;C

=peak concentration;K-value=

incrementalrecovery;t

=plasmaeliminationhalf-life;CL=clearance;SD =standarddeviation.

Nineteen(19)previouslytreatedpediatricpatients(range4to≤15years)underwent

pharmacokineticevaluationsforupto24months.

Fifty-eightpreviouslyuntreatedpatients[PUPs]lessthan15yearsofageatbaseline

underwentatleastonerecoveryassessmentwithin30minutespost-infusioninthe

presenceorabsenceofhemorrhageduringthestudy.Atotalof202recoveryassessments

collectedduringthe60-monthperiodfromthese58PUPsarecombinedwith19recovery

assessmentsfromPTPsandweresummarizedbyagegroupinTable9.Therewasone

recoveryassessmentinaneonate,whichhadavalueof0.46IU/dLperIU/kg.Theoverall

meanrecoveryandFIXeliminationhalf-lifevalueswere0.7±0.3IU/DlperIU/kgand20.2

Table9:SummaryofBeneFIXPharmacokineticParametersinPediatricPatients

AgeGroup n K-value(IU/dLperIU/kg) t

1/2 (h)

Infants(≥1monthto<2years) 330.7±0.4(0.2,2.1) ND

Children(≥2yearsto<12years) 610.7±0.2(0.2,1.5) 19.8± 4.0(14,27) a

Adolescents(≥12yearsto≤15years) 90.8±0.3(0.4,1.4) 21.1±4.5(15,28) b

n= 13

n= 6

Datapresentedaremean±standarddeviation(min,max).

Abbreviations:ND= notdetermined;K-value=incrementalrecovery;t

=terminalphaseeliminationhalf-life.

Note:Thecolumns arenotmutually exclusive;individualpatientsmay belistedundermorethan1agecategory.

Figure1.AverageIncrementalrFIXRecoveryoverTime

Carcinogenesis,Mutagenesis,ImpairmentofFertility

BeneFIX ,CoagulationFactorIX(Recombinant),hasbeenshowntobenonmutagenicin

theAmesassayandnon-clastogenicinachromosomalaberrationsassay.No

investigationsoncarcinogenesisorimpairmentoffertilityhavebeenconducted.

14CLINICALSTUDIES

EfficacyofBeneFIXhasbeenevaluatedinclinicalstudiesinwhichatotalof128subjects

receivedBeneFIXeitherforthetreatmentofbleedingepisodesonanon-demandbasis,for

thepreventionofbleeds(prophylaxis)orformanagementofhemostasisinthesurgical

setting(surgicalprophylaxis).

Fifty-sixPTPsandsixty-threePUPsweretreatedforbleedingepisodesonanon-demand

basisorforthepreventionofbleeds(seeTables9and10).ThePTPswerefollowedovera

medianintervalof24months(mean23.4±5.3months)andforamedianof83.5.The

PUPswerefollowedoveramedianintervalof37months(mean38.1±16.4months)and

foramedianof89exposuredays.

Fifty-fivePTPsandfifty-fourPUPsreceivedBeneFIXforthetreatmentofbleedingepisodes

(seeTable10).

Bleedingepisodesthatweremanagedsuccessfullyincludedhemarthrosisandbleedingin

softtissueandmuscle.Dataconcerningtheseverityofbleedingepisodeswerenot

reported.InthePTPs,88%oftotalinfusionsadministratedforon-demandtreatmentwere

ratedasan“excellent”or“good”response.

Table10:EfficacyofBeneFIXforon-demandtreatmentofPTPsandPUPs

Mediandose:IU/kg

(range) Rateofbleedsresolved

with1infusion Responseto1 st

InfusionRating c

Excellent/Good Moderate No

Response

PTPs

N=55 a 42.8

(6.5-224.6) 81% 90.9% 7.1% 0.7%

PUPs

N=54 b 62.7

(8.2-292) 75% 94.1% 2.9% 1.0%

Onesubjectdiscontinuedthestudyafteronemonthoftreatmentduetobleedingepisodesthatweredifficulttocontrol;

hedidnothaveadetectableinhibitor.

b Threesubjectswerenotsuccessfully treatedincludingoneepisodeinasubjectduetodelayedtimetoinfusionand

insufficientdosingandin2subjectsduetoinhibitorformation.

Responseratingsnotprovidedfor1.3%and2%of1 st infusions forPTPs andPUPs,respectively.

Table11:EfficacyofProphylaxisofBeneFIXinPTPsandPUPs

Total

exposure

(infusions) Durationof

prophylaxis

(months)(mean±

SD) Dose

IU/kg

(mean±

SD) Spontaneousbleeds

within48hrsof

infusion Responserating a

Excellent EffectiveInadequate

PTPs

20 2985 18.2± 8.4 b 40.3±

15.2 b 28 56.0% 37.1% 4.3%

PUPs

32 3158 14.4± 8.1 73.3±

33.1 6 91.3% 6.4% 1.7%

Responseratingsprovidedatapproximately3-monthintervals.Intotal,116and172assessmentsreportedforPTPs

andPUPs,respectively.Responseratings notprovidedfor2.6%and0.6%ofintervalsforPTPs andPUPs,respectively.

N =19

Atotalof20PTPsweretreatedwithBeneFIXforsecondaryprophylaxis(theregular

administrationofFIXreplacementtherapytopreventbleedinginpatientswhomayhave

alreadydemonstratedclinicalevidenceofhemophilicarthropathyorjointdisease)atsome

regularintervalduringthestudywithameanof2.0infusionsperweek(seeTable11).

Thirty-twoPUPswereadministeredBeneFIXforroutine(primaryandsecondary)

prophylaxis(seeTable11).Twenty-fourPUPswereadministeredBeneFIXatleasttwice

weekly,andeightPUPswereadministeredBeneFIXonceweekly.SevenPTPs

experiencedatotalof26spontaneousbleedingepisodeswithin48hoursafteraninfusion.

Sixspontaneousbleedswithin48hoursafteraninfusionwerereportedin5PUPs.

Prophylaxistherapywasratedas“excellent”or“effective”in93%ofPTPsreceiving

prophylaxisonetotwotimesperweek.

ManagementofhemostasiswasevaluatedinthesurgicalsettinginbothPTPsandPUPs

(seeTable12).Thirty-sixsurgicalprocedureshavebeenperformedin28PTPswith23

majorsurgicalproceduresperformed(including6complicateddentalextractions).Thirty

surgicalprocedureshavebeenperformedin23PUPs.Twenty-eightoftheseprocedures

wereconsideredminor.Hemostasiswasmaintainedthroughoutthesurgicalperiod;

however,onePTPsubjectrequiredevacuationofasurgicalwound-sitehematoma,and

anotherPTPsubjectwhoreceivedBeneFIXafteratoothextractionrequiredfurthersurgical

interventionduetooozingattheextractionsite.Therewasnoclinicalevidenceof

thromboticcomplicationsinany

AmongthePTPsurgerysubjects,themedianincreaseincirculatingfactorIXactivitywas

0.7IU/dLperIU/kginfused(range0.3–1.2IU/dL;mean0.8±0.2IU/dLperIU/kg).The

medianeliminationhalf-lifeforthePTPsurgerysubjectswas19.4hours(range10–37

hours;mean21.3±8.1hours).

Table12:EfficacyofBeneFIXforSurgicalProceduresinPTPsandPUPs

SurgeryType NumberofProcedures(Number

ofSubjects) Response

Excellent/

Good Moderate No

Response

PreviouslyTreatedPatients

Anklesurgery 2(2) 2(100%) - -

Hipprosthesis implant(right) 1(1) 1(100%) - -

Kneearthroplasty(2bilateral,

1right) 3(3) 3(100%) - -

Kneearthroscopic

synovectomy 2(2) a 1(50%) - -

Livertransplantation

(orthotopic) 1(1) 1(100%) - -

Splenectomy 1(1) 1(100%) - -

External fixationdevice

removal (wrist) 1(1) 1(100%) - -

Herniarepair 3(2) 3(100%) - -

Subacromialdecompression

(left) 1(1) 1(100%) - -

Calfdebridement,dental

extraction b 1(1) 1(100%) - -

Lymphnoderemoval,dental

extraction b 1(1) 1(100%) - -

Leftheel cordlengthening 1(1) 1(100%) - -

Dental procedures c 12(11) 11(92%) 1(8%) -

Minorprocedures 6(6) 6(100%) - -

PreviouslyUntreatedPatients

Herniarepair 2(2) 2(100%) - -

Minorprocedures 28(21) a 27(96%) - -

Responseassessmentnotprovidedfor1procedure.

b Includes pulseandcontinuous-infusionregimens;CI countedas 1procedureinthis summary.

Includes complicatedextractions (6),clearance,andfillings.

Nineofthemajorsurgicalprocedureswereperformedin8PUPsusingacontinuous-

infusionregimen.FiveofthesurgicalprocedureswereperformedinPUPsusinga

continuous-infusionregimenover3to5days.AlthoughcirculatingfactorIXlevelstargeted

torestoreandmaintainhemostasiswereachievedwithbothpulsereplacementand

continuousinfusionregimens,clinicaltrialexperiencewithcontinuousinfusionofBeneFIX

forsurgicalprophylaxisinhemophiliaBhasbeentoolimitedtoestablishthesafetyand

clinicalefficacyofadministrationoftheproductbycontinuousinfusion.

AllsubjectsparticipatinginthePTP,PUPandsurgerystudiesweremonitoredforclinical

evidenceofthrombosis[seeWarningsandPrecautions(5)].Nothromboticcomplications

were21reportedinPUPsorsurgerysubjects.OnePTPsubjectexperiencedarenalinfarct

12daysafteradoseofBeneFIXforableedingepisode;therelationshipoftheinfarcttothe

prioradministrationofBeneFIXisuncertain.Laboratorystudiesofthrombogenecity

(fibrinopeptideAandprothrombinfragment1+2)wereobtainedin41PTPsand7surgery

subjectspriortoinfusionandupto24hoursfollowinginfusion.Theresultsofthesestudies

wereinconclusive.Outof29PTPsubjectsnotedtohaveelevatedfibrinopeptideAlevels

post-infusionofBeneFIX,22alsohadelevatedlevelsatbaseline.Surgerysubjectsshowed

noevidenceofsignificantincreaseincoagulationactivation.

16HOWSUPPLIED/STORAGEANDHANDLING

16.1HowSupplied

BeneFIX,CoagulationFactorIX(Recombinant),issuppliedinsingle-usevialswhich

containnominally250,500,1000or2000IUpervialwithsterilepre-filleddiluentsyringe,

vialadapterreconstitutiondevice,sterileinfusionset,andtwo(2)alcoholswabs,one

bandageandonegauzepad.ActualfactorIXactivityinIUisstatedonthelabelofeach

vial.

16.2Storage andHandling

Productaspackagedforsale:BeneFIX,CoagulationFactorIX(Recombinant),Storeunder

refrigerationatatemperatureof2to8°C.Priortotheexpirationdate,BeneFIXmayalsobe

storedatroomtemperaturenottoexceed30°Cforupto6months.

Advicepatienttomakenoteofthedatetheproductwasplacedatroomtemperatureinthe

spaceprovidedontheoutercarton.

Donotputtheproductbackintotherefrigeratorattheendofthe6-monthperiod.Useit

immediatelyordiscard.

Donotfreezetopreventdamagetothediluentsyringe.DonotuseBeneFIXafterthe

expirationdateonthelabel.

Productafterreconstitution:Theproductdoesnotcontainapreservativeandshouldbe

usedwithin3hours.

17PATIENTCOUNSELINGINFORMATION

17.1Allergic-type HypersensitivityReactions

Allergic-typehypersensitivityreactionsarepossible.Informpatientsoftheearlysignsof

hypersensitivityreactions[includinghives(rashwithitching),generalizedurticaria,

tightnessofthechest,wheezing,hypotension]andanaphylaxis.Advisepatientsto

discontinueuseoftheproductandcontacttheirphysiciansifthesesymptomsoccur.

17.2NeutralizingAntibodies(Inhibitors)

Advisepatientstocontacttheir physicianortreatmentfacilityforfurthertreatmentand/or

assessmentiftheyexperiencealackofaclinicalresponsetofactorIXreplacement

therapy,asinsomecasesthismaybeamanifestationofaninhibitor.

18MANUFACTURER WyethFarmaS.A,Spain

19REGISTRATIONHOLDER NeopharmLTD.P.O.Box7063,Petach-Tiqva49170

TheformatofthisleaflethasbeendefinedbytheMinistryofHealth;itscontenthasbeen

checkedandapproved -December2010

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