For the Treatment of Acute Bacterial Skin and Skin Structure ......pharmacodynamic interactions. –...

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


*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.


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


*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


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


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.


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

For the Treatment of Acute Bacterial Skin and Skin Structure ......pharmacodynamic interactions. –...

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