赛尼哌说明书.docx
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赛尼哌说明书.docx
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赛尼哌说明书
ZENAPAX®
(daclizumab)
STERILECONCENTRATEFORINJECTION
WARNING
OnlyphysiciansexperiencedinimmunosuppressivetherapyandmanagementoforgantransplantpatientsshouldprescribeZENAPAX®(daclizumab).ThephysicianresponsibleforZENAPAXadministrationshouldhavecompleteinformationrequisiteforthefollow-upofthepatient.ZENAPAXshouldonlybeadministeredbyhealthcarepersonneltrainedintheadministrationofthedrugwhohaveavailableadequatelaboratoryandsupportivemedicalresources.
DESCRIPTION
ZENAPAX® (daclizumab)isanimmunosuppressive,humanizedIgG1monoclonalantibodyproducedbyrecombinantDNAtechnologythatbindsspecificallytothealphasubunit(p55alpha,CD25,orTacsubunit)ofthehumanhigh-affinityinterleukin-2(IL-2)receptorthatisexpressedonthesurfaceofactivatedlymphocytes.
Daclizumabisacompositeofhuman(90%)andmurine(10%)antibodysequences.ThehumansequenceswerederivedfromtheconstantdomainsofhumanIgG1andthevariableframeworkregionsoftheEumyelomaantibody.Themurinesequenceswerederivedfromthecomplementarity-determiningregionsofamurineanti-Tacantibody.ThemolecularweightpredictedfromtheDNAsequenceis144kilodaltons.
ZENAPAX25mg/5mLissuppliedasaclear,sterile,colorlessconcentrateforfurtherdilutionandintravenousadministration.EachmilliliterofZENAPAXcontains5mgofdaclizumaband3.6mgsodiumphosphatemonobasicmonohydrate,11mgsodiumphosphatedibasicheptahydrate,4.6mgsodiumchloride,0.2mgpolysorbate80,andmaycontainhydrochloricacidorsodiumhydroxidetoadjustthepHto6.9.Nopreservativesareadded.
CLINICALPHARMACOLOGY
General
MechanismofAction
DaclizumabfunctionsasanIL-2receptorantagonistthatbindswithhigh-affinitytotheTacsubunitofthehigh-affinityIL-2receptorcomplexandinhibitsIL-2binding.DaclizumabbindingishighlyspecificforTac,whichisexpressedonactivatedbutnotrestinglymphocytes.AdministrationofZENAPAXinhibitsIL-2-mediatedactivationoflymphocytes,acriticalpathwayinthecellularimmuneresponseinvolvedinallograftrejection.
Whileinthecirculation,ZENAPAXimpairstheresponseoftheimmunesystemtoantigenicchallenges.WhethertheabilitytorespondtorepeatedorongoingchallengeswiththoseantigensreturnstonormalafterZENAPAXisclearedisunknown(see PRECAUTIONS).
Pharmacokinetics
Adults
Inclinicaltrialsinvolvingrenalallograftpatientstreatedwitha1mg/kgIVdoseofZENAPAXevery14daysforatotaloffivedoses,peakserumconcentration(mean±SD)rosebetweenthefirstdose(21±14µg/mL)andfifthdose(32±22µg/mL).Themeantroughserumconcentrationbeforethefifthdosewas7.6±4.0µg/mL.Populationpharmacokineticanalysisofthedatausingatwo-compartmentopenmodelgavethefollowingvaluesforareferencepatient(45-year-oldmaleCaucasianpatientwithabodyweightof80kgandnoproteinuria):
systemicclearance=15mL/hour,volumeofcentralcompartment=2.5liter,volumeofperipheralcompartment=3.4liter.Theestimatedterminaleliminationhalf-lifeforthereferencepatientwas20days(480hours),whichissimilartotheterminaleliminationhalf-lifeforhumanIgG(18to23days).Bayesianestimatesofterminaleliminationhalf-liferangedfrom11to38daysforthe123patientsincludedinthepopulationanalysis.TheinfluenceofbodyweightonsystemicclearancesupportsthedosingofZENAPAXonamilligramperkilogram(mg/kg)basis.Forpatientsstudied,thisdosingmaintaineddrugexposurewithin30%ofthereferenceexposure.Covariateanalysesshowedthatnodosageadjustmentsbasedonage,race,genderordegreeofproteinuria,arerequiredforrenalallograftpatients.Theestimatedinterpatientvariability(percentcoefficientofvariation)insystemicclearanceandcentralvolumeofdistributionwere15%and27%,respectively.
Pediatrics
Pharmacokineticparameterswereevaluatedin61pediatricpatientstreatedwitha1mg/kgIVdoseofZENAPAXevery14daysforatotaloffivedoses.Peakserumconcentration(mean±SD)rosebetweenthefirstdose(16±12µg/mL)andfifthdose(21±14µg/mL).Themeantroughserumconcentrationbeforethefifthdosewas5.0±2.7µg/mL.Populationpharmacokineticanalysisofthedatausingatwo-compartmentopenmodelgavethefollowingvaluesforareferencepatient(Caucasianpatientwithabodyweightof29.7kg):
systemicclearance=10mL/hour,volumeofcentralcompartment=2.0liter,volumeofperipheralcompartment=1.4liter.Theestimatedterminaleliminationhalf-lifeforthereferencepatientwas13days(317hours).Forthepatientsstudied,thisdosingmaintaineddrugexposurewithin50%ofthereferenceexposure.Covariateanalysessuggestedthatdispositionparameterswerenotinfluencedtoaclinicallyrelevantextentbyrace,genderordegreeofproteinuria.Theestimatedinterpatientvariability(percentcoefficientofvariation)insystemicclearanceandcentralvolumeofdistributionwere30%and40%,respectively.
Pharmacodynamics
Invitroandinvivodatasuggestthatserumlevelsof5to10µg/mLarenecessaryforsaturationoftheTacsubunitoftheIL-2receptorstoblocktheresponsesofactivatedTlymphocytes.Attherecommendeddosageregimen,daclizumabsaturatestheTacsubunitoftheIL-2receptorforapproximately90and120daysposttransplant,respectivelyinpediatricandadultpatients.ThedurationofclinicallysignificantIL-2receptorblockadeaftertherecommendedcourseofZENAPAXisnotknown.Nosignificantchangestocirculatinglymphocytenumbersorcellphenotypeswereobservedbyflowcytometry.CytokinereleasesyndromehasnotbeenobservedafterZENAPAXadministration.
CLINICALSTUDIES
ThesafetyandefficacyofZENAPAXfortheprophylaxisofacuteorganrejectioninadultpatientsreceivingtheirfirstcadaverickidneytransplantwereassessedintworandomized,double-blind,placebo-controlled,multicentertrials.Thesetrialscomparedadoseof1.0mg/kgofZENAPAXwithplacebowheneachwasadministeredaspartofstandardimmunosuppressiveregimenscontainingeithercyclosporineandcorticosteroids(double-therapytrial,noUSsites)orcyclosporine,corticosteroids,andazathioprine(triple-therapytrial,predominantlyUSsites)topreventacuterenalallograftrejection.ZENAPAXdosingwasinitiatedwithin24hourspretransplant,withsubsequentdosesgivenevery14daysforatotaloffivedoses.
Theprimaryefficacyendpointofbothtrialswastheproportionofpatientswhodevelopedabiopsy-provenacuterejectionepisodewithinthefirst6monthsfollowingtransplantation.Asshownin Table1,thisincidencewassignificantlylowerinthegrouptreatedwithZENAPAXinboththedouble-therapyandtriple-therapytrials.
Table1EfficacyParameters
Triple-therapyRegimen
(cyclosporine,corticosteroids,and
azathioprine)
Double-therapyRegimen
(cyclosporineand
corticosteroids)
Placebo
ZENAPAX
Placebo
ZENAPAX
(N=134)
(N=126)
p-value
(N=134)
(N=141)
p-value
n.s.=notsignificant
Incidenceofbiopsy-provenacuterejectionat6months
No.ofpatients
47(35%)
28(22%)
0.03
63(47%)
39(28%)
0.001
Incidenceofbiopsy-provenacuterejectionat1year
No.ofpatients
51(38%)
35(28%)
n.s.
65(49%)
39(28%)
<0.001
Graftsurvivalat3yearsposttransplant
No.ofpatientswithfunctioninggraft
111(83%)
106(84%)
n.s.
105(78%)
116(82%)
n.s.
Patientsurvivalat3yearsposttransplant
No.ofpatients
126(94%)
116(92%)
n.s.
118(88%)
135(96%)
0.02
TreatmentwithZENAPAXwasassociatedwithbetterpatientsurvivalupto3yearsposttransplantinthedouble-therapystudy.Nodifferenceinpatientsurvivalwasobservedinthetriple-therapystudybetweenpatientstreatedwithZENAPAXorplaceboupto3yearsposttransplant.Nodifferencewasobservedforgraftsurvivalbetweentreatmentgroupsinbothstudiesat3yearsposttransplant.
TheincidenceofdelayedgraftfunctionwasnotdifferentbetweenpatientstreatedwithplaceboorZENAPAXineitherstudy.Nodifferenceingraftfunctionwasobserved1yearand3yearsposttransplantineitherstudybetweenpatientstreatedwithplaceboorZENAPAX.
Inarandomized,double-blindstudytoassesstolerability,pharmacokinetics,anddruginteractionsinrenalallograftrecipients,ZENAPAX(50patients)orplacebo(25patients)wasaddedtoanimmunosuppressiveregimenofcyclosporine,mycophenolatemofetil,andcorticosteroids.Inthisstudy,theadditionofZENAPAXdidnotresultinanincreasedincidenceofadverseeventsorachangeinthetypesofadverseeventsreported.Theincidenceofthecombinedendpointofbiopsy-provenorclinicallypresumptiveacuterejectionwas20%(5of25patients)intheplacebogroupand12%(6of50patients)intheZENAPAXgroup.Althoughnumericallylower,thedifferenceinacuterejectionwasnotsignificant.However,inarandomized,double-blind,placebo-controlledtrialofZENAPAXincardiactransplantrecipients(n=434)receivingconcomitantcyclosporine,mycophenolatemofetil,andcorticosteroids,mortalitywasincreasedinpatientsrandomizedtoreceiveZENAPAXcomparedwiththoserandomizedtoreceiveplacebo(see WARNINGS and ADVERSEREACTIONS).
INDICATIONSANDUSAGE
ZENAPAXisindicatedfortheprophylaxisofacuteorganrejectioninpatientsreceivingrenaltransplants.Itisusedaspartofanimmunosuppressiveregimenthatincludescyclosporineandcorticosteroids.
TheefficacyofZENAPAXfortheprophylaxisofacuterejectioninrecipientsofothersolidorganallograftshasnotbeendemonstrated.
CONTRAINDICATION
ZENAPAXiscontraindicatedinpatientswithknownhypersensitivitytodaclizumabortoanyc
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