for the treatment of acute bacterial skin and skin...
TRANSCRIPT
Dalbavancin(Xydalba™)
FortheTreatmentofAcuteBacterialSkinandSkinStructureInfections(ABSSSI)
inadults
Thismedicinalproductissubjecttoadditionalmonitoring.Thiswillallowquickidentificationofnewsafetyinformation.Healthcareprofessionalsareaskedtoreportanysuspectedadversereactions.
Prescription Only Medication. Marketing Authorization Number(s): EU/1/14/986/001. Marketing Authorization Holder: Allergan Pharmaceuticals International Ltd., Clonshaugh Industrial Estate, Coolock, Dublin 17, Ireland.
■ Dalbavancin is a second generation lipoglycopeptide bactericidal antibiotic against susceptible Gram-positive pathogens
■ Has a pharmacokinetic profile allowing either single or two dose (once-weekly) intravenous regimen
Dalbavancinisalong-actingbactericidallipoglycopeptide
XYDALBAEUSmPCMarch17,2017;Juuletal.TherClinRiskManag.2016;12:225-32
StructureofDalbavancin
3,3-dimethylaminopropylamide
Fattya c i dchain
FDABriefingDocument.Anti-infectiveDrugsAdvisoryCommitteeMeeting.March31,2014.
Correlateswithextendedhalflife(t1/2)in
vivo
Enhancesantibacterial
activity
Definesfamilyofhomologues,
allwithantibacterial
activity
MechanismofActionInterfereswithcellwallsynthesisandcausesbacterialdeath
Dalbavancin,likeotherglycopeptides,interfereswiththecellwallformationbybindingtotheD-alanyl-D-alanin(D-ala-D-ala)terminusofthepeptidoglycan
preventingcrosslinking,therebyinterruptingcellwallsynthesisandresultinginbacterialcelldeath
Gram-negativeGram-positive
PeptidoglycanOutermembrane
Peptidoglycan
Membrane
Gly Gly Gly Gly Gly Lys
D-Glu
Ala
D-Ala Lys
D-Glu D-Ala
Ala
Gly Gly Gly Gly Gly Lys
D-GluD-Ala
D-Ala
D-Ala
Ala
XYDALBAAssessmentreportEMA/39820/2015
Approveddosingoptions
Single-doseregimen:§ 1500mgIVover30minutesDay1Two-doseregimen:§ 1000mgIVover30minutesDay1500mgIVover30minutesDay8
XYDALBAEUSmPCMarch17,2017
DosinginSpecialPopulations
Norecommendeddosageadjustmentfor:ü Elderlyü Genderü MildHepaticImpairment*ü Mildormoderaterenalimpairment(CrCl≥30ml/min).ü SevereRenalImpairmentwithregularhaemodialysis(3x/week),
administrationwithoutregardtotimingofhaemodialysisDosereductionfor:§ ChronicRenalImpairmentwithCrCl<30ml/minandwithoutregular
scheduledhaemodialysisØ 1000mgassingleinfusionor750mgonDay1and375mgonDay8
XYDALBAEUSmPCMarch17,2017
*CautionshouldbeexercisedwhenprescribingXYDALBAtopatientswithmoderateorseverehepaticimpairment(Child-PughClassBorC)asnodataareavailabletodeterminetheappropriatedosinginthesepatients.
LowpotentialforDrugInteraction
� Dalbavancinhasalowpotentialfordrug-druginteractions*– DalbavancinisnotmetabolisedbycytochromeP450isoenzymesinvitro– Resultsfromaninvitroreceptorscreeningstudydonotindicatealikely
interactionwithothertherapeutictargetsorapotentialforclinicallyrelevantpharmacodynamicinteractions.
– Noantagonismbetweendalbavancinandothercommonlyusedantibioticswhentestedagainst12speciesofGram-negativepathogensininvitrostudiesØ cefepime,ceftazidime,ceftriaxone,imipenem,meropenem,amikacin,
aztreonam,ciprofloxacin,piperacillin/tazobactamandtrimethoprim/sulfamethoxazole
*Clinicaldrug-druginteractionstudieswithXYDALBAhavenotbeenconducted.ItisnotknownifXYDALBAisasubstrateforhepaticuptakeandeffluxtransporters.Co-administrationwithinhibitorsofthesetransportersmayincreasetheexposuretoXYDALBA.Examplesofsuchtransporterinhibitorsareboostedproteaseinhibitors,verapamil,quinidine,itraconazole,clarithromycinandcyclosporine.Itisnotknownifdalbavancinisaninhibitoroftransporters.Increasedexposuretotransportersubstratessensitiveforinhibitedtransporteractivity,suchasstatinsanddigoxin,cannotbeexcludedifcombinedwithdalbavancin.
XYDALBAEUSmPCMarch17,2017;XYDALBAAssessmentreportEMA/39820/2015
EfficacyagainstspecificpathogensGram-positivePathogens
DemonstratedClinicalEfficacyagainstthepathogenslistedforABSSSIthatweresusceptibletodalbavancininvitro:•Staphylococcusaureus,•Streptococcuspyogenes,•Streptococcusagalactiae,•Streptococcusdysgalactiae,•Streptococcusanginosusgroup(includesS.anginosus,S.intermedius,andS.constellatus).InvitroSusceptibility(inabsenceofacquiredmechanismsofresistance)•GroupGstreptococci•Clostridiumperfringens•Peptostreptococcusspp.
XYDALBAEUSmPCMarch17,2017
PotentdalbavancininvitroactivityagainstGram-positiveclinicalisolatesfrom39Europeanhospitals(2011–13)
Organism(No.tested)
MIC(mg/L) %inhibitedatdalbavancinMIC(mg/L)
50% 90% ≤0.03 0.06 0.12 0.25
S.aureus(2861) 0.06 0.06 29.4 91.0 >99.9 100
MSSA(2203) 0.06 0.06 27.1 90.3 100
MRSA(658) 0.06 0.06 37.1 93.3 99.8 100
VancomycinMIC<1mg/L(642) 0.06 0.06 38.0 94.2 100
VancomycinMIC2mg/L(16) 0.06 0.12 0.0 56.3 93.8 100
VGSa(69) ≤0.03 ≤0.03 97.1 98.6 100
S.anginosusgroup(48) ≤0.03 ≤0.03 100
BHSb(466) ≤0.03 ≤0.03 91.0 98.5 100
S.pyogenes(223) ≤0.03 ≤0.03 92.8 98.2 100
S.agalactiae(135) ≤0.03 0.06 88.9 98.5 100
S.dysgalactiae(47) ≤0.03 ≤0.03 91.5 100
BHS,β-haemolyticstreptococci.aIncludes:S.anginosus(28isolates),S.anginosusgroup(5),Streptococcusbovisgroup(2),Streptococcusconstellatus(14),Streptococcusintermedius(1),Streptococcusmitis/oralis(4),S.mitisgroup(5),S.oralis(5),Streptococcusparasanguinis(1),Streptococcussalivarius(1),Streptococcussanguinis(1)andunspeciatedVGS(2).bIncludes:S.agalactiae(135isolates),S.dysgalactiae(47),Streptococcusequisimilis(5),S.pyogenes(223),groupCstreptococci(13),groupFstreptococci(1)andgroupGstreptococci(42).
R.EMendesetalJAntimicrobChemother2016doi:10.1093/jac/dkv303JMILaboratories,NorthLiberty,IA,USA
Dalbavancinhasin-vitroActivityagainstEnterococcusssp.withVanB,butnotthosewithVanA
VSE,VancomycinsensitiveEnterococcus;VRE,VancomycinresistantEnterococcus
Smithetal.;InfectDisTher(2015)4:245–258
Organism(Numbertested) MIC(µg/ml)
MIC90(µg/ml)
Range
%susceptible
Enterococcusspp.(116) 0.06 >4 ≤0.03to>4 56
VSE(63) ≤0.03 0.12 ≤0.03to0.25 96.8
VRE(53) >4 >4 ≤0.03to>4 7.5
VREVanA(49) >4 >4 0.25to>4 0
VREVanB(4) ≤0.03 0.12 ≤0.03to0.12 100
E.faecalis(25) 0.06 >4 ≤0.03to>4 76
VSEfaecalis(19) ≤0.03 0.06 ≤0.03to0.06 100
VREfaecalis(6) >4 >4 >4 0
E.faecium(31) 1 >4 ≤0.03to>4 41.9
VSEfaecium(11) 0.06 0.12 ≤0.03to0.12 100
VREfaecium(20) >4 >4 ≤0.03to>4 10
DalbavancinexhibitsinvitroactivityagainstCoNSresistanttolinezolid,vancomycin,teicoplaninordaptomycin
Rodríguez-LozanoJetal.ECCMID,ViennaApril2017,P1501
0
10
20
30
40
50
60
70
80
90
Isolates(n
)
MICvalue
MICdistributions(µg/mL)Coagulase-negativeStaphylococci
EUCASTBreakpoint
Source:Bloodculture(n=110),skin&softtissues(n=44),abdominalspecimen(n=26),Osteoarticularspecimens(n=20),cerebrospinalfluid(n=17),urine(n=13),andrespiratorytract(n=6)
CoNS,N=236• 190S.epidermidis• 26S.hominis• 16S.haemolyticus• 3S.warneri• 1S.capitis
CoNS=Coagulase-negativeStyphylococci
Resistance
LowpotentialforResistanceDevelopment
• Resistancedevelopmentstudiesbybothdirectselection(resistancefrequency,<10-10)andserialpassagefailedtoproducestablemutantswithdecreasedsusceptibilitytodalbavancin1
• SENTRYAntimicrobialSurveillanceProgram(2011):DalbavancinMICresultsagainst1555USGram-positivepathogensconsistentwithearliersurveillance;NoindicationofMICchangeoremergingresistances2
• InternationalDalbavancinEvaluationofActivity(IDEA)SurveillanceProgram2015:potentinvitroactivityofdalbavancinagainstcontemporaryEuropeandUSisolatesofSA(N=5,724),BHS(N=1125),andVSE(N=949).Allisolateswere100%susceptiblewheninterpretedusingEUCASTandFDAbreakpoints3
1. Goldstein BP et al. Antimicr Agents Chemother 2007; 51(4):1150-54; 2. Jones RN et al. Diagn Microbiol Infect Dis 2013; 75:304–307; 3. Critchley I et al. ECCMID 2017, Vienna, Austria, April 22–25, 2017
SA=Staphylococcusaureus;BHS=β-hemolyticstreptococci;VSE=vancomycin-susceptibleEnterococcusfaecalis
Pharmacology
§ PK/PDcharacteristics§ DrugInteractions§ Tissuepenetration
DalbavancinmeanPlasmaConcentrationsversustimeinatypicalABSSSIpatient(simulationusingpopulationpharmacokineticmodel)forboththesingleandthetwo-doseregimens
Single-dose regimen
Two-dose regimen
Pharmacokinetics:Oneandtwo-doseregimenofDalbavancin
MinimumInhibitoryConcentrationofdalbavancin1(Susceptible*≤0.125mg/l;
Resistant>0.125mg/l)
FigureadaptedfromXYDALBAEUSmPCMarch17,2017
1DeterminedbyEUCAST;*Staphylococcusspp.*Beta-haemolyticstreptococciofGroupsA,B,C,G*Viridansgroupstreptococci(Streptococcusanginosusgrouponly)
BactericidalPKlevelswithTwoDoseRegimenofDalbavancin
1
10
100
1000
0 7 21 28
Dalbavan
cinplasmaconcen
tration,m
g/L
14Time,days
TotaldrugCalculatedfreedrug
Dalbavancindosedas1000mgIVonDay1and500mgIVonDay8over30minutes
1stdosedalbavancin1000mg
2nddosedalbavancin500mg
MinimumBactericidalConcentrationofdalbavancinforS.aureus(1.0µg/mL)
0.1
AdaptedfromFDABriefingPresentation.Anti-infectiveDrugsAdvisoryCommitteeMeeting.March31,2014.NDA21-883.
MICbreakpointforS.aureus(EUCAST:0.125µg/mL)
EfficacyinABSSSI
DISCOVER1andDISCOVER2(n=1312)Phase3,double-blind,double-dummy,international,multicenter,randomizedtrialsaimingtodemonstratenon-inferiorefficacyandtocomparethesafetyofdalbavancintovancomycin/linezolid
BoucherHW,etal.NEnglJMed.2014;370:2169-79
StudyDesign-keyfeaturesDISCOVER1andDISCOVER2
Dalbavancin Vancomycin Vancomycin/Linezolid
3 8 14Day 1
48-72hours
EOT*
Randomization
DalbavancinArm**
Vancomycin/Linezolidarm***
treatmentduration
Post-treatmentfollow-up
Short-termFUvisitatDay28
Long-termFUvisitatDay70
10
BoucherHW,etal.NEnglJMed.2014;370:2169-79
*EndofTherapy
Placebotreatment:**Dalbavancingroup:placeboinfusionevery12hours,plusanoralplaceboiftherewasaswitchtooraltherapy.***Vancomycin/linezolidgroup:placeboinfusiononDay1and8
■ Key Inclusion Criteria
● Diagnosis of ABSSSI required the presence of cellulitis, a major abscess, or a wound infection, each associated with at least 75 cm2 of erythema with at least one of the following systemic signs of infection: ■ Fever (≥38°C within 24 hours of baseline) ■ Leukocytosis (WBC count >12,000 cells/
mm3) ■ Left shift (peripheral smear with ≥10% band
forms) ● At least two additional local signs of
ABSSSI: ■ Purulent drainage/discharge, fluctuance,
heat/localized warmth, tenderness on palpation, swelling/induration
● Infection severity including systemic signs requiring a minimum of 3 days of IV therapy
■ Key Exclusion Criteria ● Prior antibiotic, systemically or
topically administered, within 14 days prior to randomization
● Gram-negative bacteremia ● Burns ● Diabetic foot infection ● Decubitus ulcer ● Perirectal abcess ● Infected device ● Venous catheter entry-site
infection ● Immunocompromised patients ● Necrotizing fasciitis ● Osteomyelitis ● Endovascular infection ● Septic arthritis ● Meningitis
DISCOVER1andDISCOVER2
BoucherHW,etal.NEnglJMed.2014;370:2169-79
DISCOVER 1 Absolute Difference (95% CI) Percentage Points [1.5 (–4.6 to 7.9)]. DISCOVER 2 Absolute Difference (95% CI) Percentage Points [-1.5 (–7.4, 4.6)] Pooled Analysis Absolute Difference
(95% CI) Percentage Points [-0.1 (–4.5 to 4.2)].
83.3 76.8 79.7 81.8
78.3 79.8
0
10
20
30
40
50
60
70
80
90
DISCOVER 1 DISCOVER 2 Pooled Analysis
Patie
nts,
%
PrimaryEndpoint:Early(48-72hours)ClinicalResponse
Dalbavancin Vancomycin/Linezolid
BoucherHW,etal.NEnglJMed.2014;370:2169-79
TimetoAbsenceofFeverorCessationofSpread-Responsewithin48to72hours
Dalbavancin Vancomycin/linezolid++Censored
Fever
Spread
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 120 135 150 165 180
Prop
ortio
nwith
oute
vent
15 30 45 60 75 90 105Time,hours
DalbavancinVancomycin/linezolid
72hours
FDABriefingPresentation.Anti-infectiveDrugsAdvisoryCommitteeMeeting.March31,2014.NDA21-883.
Spread
Fever
Most common adverse reactions in Phase 2/3 Studies in >1% of Patients
Treated With Dalbavancin n=2,473
Nausea 2.4% Diarrhoea 1.9% Headache 1.3%
§ In Phase 2/3 clinical studies, 2,473 patients received Dalbavancin administered as either a single infusion of 1500 mg or as 1000 mg followed one week later by 500 mg.
§ The most common adverse reactions were generally of mild or moderate severity.
XYDALBAEUSmPCMarch17,2017
AdverseReactionshavingoccurredin>1%ofPatients*-AllPhase2/3trials
*CompleteTabulatedlistofadversereactionsavailableinSmPC
SimilarDistributionofDayofOnsetofAdverseEventsbetweenDalbavancinandComparatorPhase2/3trials
Lateonsetadverseeventswereseenatsimilarratesinpatientstreatedwithdalbavancinrelativetothosereceivingcomparatoragents;vancomycin,linezolid,cefazolin,nafcillin,oroxacillin.
TimetoonsetoffirstTEAE Dalbavancinn=1778
Comparatorn=1224
PatientswithAE(%) 799(44,9%) 573(46,8%)*Mediandays,n 3.0 3.0Meandays,n 6.4 7.2Min-max 1-71 1-64
TotaldalbavancinTotalcomparator
15
20
1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031-60Timetoonset,days
0
5
10
25
Treatm
ent-em
ergentAdverseEvents,%
DunneMWetal.DrugSaf(2016)39:147–157
*p=0.012
AE,adverseevent;TEAE,Treatment-emergentadverseevent
SimilarDistributionofDurationofAdverseEventswithDalbavancinandComparatorPhase2/3trials
Adverseeventduration
DalbavancinEvents=799
ComparatorEvents=573
Mediandays,n 3.0 4.0Meandays,n 7.7 8.0
1 2 3 4 5 6 7 860Duration,days
30
Adverseeven
ts,%
25 20 15 10 5
0
9 10111213141516171819202122232425262728293031->60
TotaldalbavancinTotalcomparator
DunneMWetal.DrugSaf(2016)39:147–157
RealWorldExperience
29.4
70.6
20.2
29.4
64.7
23.5
11.4
00
10
20
30
40
50
60
70
80
Clinicalcure LosttoFU LoS(days) 30d-Readmission
%Patients
Outcomesinhomelessand/orIDUPatients
Pre-Dalbavancin
Dalbavancin
4.3
8.0
5.0
0
2
4
6
8
10
Hospita
lStay[Days]
Dalbavancin N=44
Comparator N=945
Length of hospitalisation for ABSSSI
2989
7863
0
2000
4000
6000
8000
10000
TotalCostp
erCase[USD
]Total Cost/case
P<0.001 P<0.001
Dalbavancin N=44
Comparator N=945
Dalbavancin N=44
Comparator N=945
P=0.34
Readmission Within 30 day
National Average (2011)
National Average (2011)
11.4
8.6
13.2
0
2
4
6
8
10
12
14
Readmissionswith
in30
days[%
Patients]
Jones,IDweek,SanDiego,Poster1107;Falconer,ECCMID2018,P0282
DalbavancinandOPAT
Summary:� ConsistentlyeffectiveinpatientswithABSSSIregardlessofclinical
variablesandendpointsassessed– Onlyoneortwodosesrequired– 100%compliancewithsingle1500mgdose– BactericidallevelsthroughoutthetreatmentperiodagainstMRSAand
otherABSSSI-relatedgram-positivepathogens– lowpotentialforresistancedevelopment
� Well-characterizedsafetyprofile
� Easytouse– NoneedforindwellingIVcatheters,includingPICClines– Noweightbaseddosing/doseadjustmentformajorgroups– Lowpotentialfordruginteractions– Noneedfortherapeuticdrugmonitoring