NEW DRUG UPDATE 2016 - cdn.ymaws.com · • New Drug Update 2016 is accredited for 1.5 contact...

NEWDRUGUPDATE2016LaurajoRyan,PharmD,MSc,BCPS

ClinicalAssociateProfessorRyanL@uthscsa.edu

BrysonDuhon,PharmD,BCPSClinicalAssistantProfessor

Duhon@uthscsa.edu

AccreditaIon•  NewDrugUpdate2016isaccreditedfor1.5contacthours– Pharmacists ACPE0154-0000-16-010-L01-P– Technicians ACPE0154-0000-16-010-L01-T– BrysonDuhon&LaurajoRyanhavenotdisclosedanyfinancialorconflictsofinterestinrelaIontothisprogram

PresentaIonObjecIves1.  Discussthebasicpharmacologyofthenew

drugspresentedandhowthepharmacologicacIonsrelatetoboththerapeuIcandadverseeffects.

2.  DiscussclinicallysignificantadverseeffectsanddruginteracIons,andtheappropriatedosingandmonitoringofthenewdrugspresented.

3.  DiscussthetherapeuIcroleofthenewdrugspresentedascomparedtoagentsalreadymarketed.

NotableDrugPatentExpiraIonsin2016•  Crestor–$6.4billionannualrevenue•  Benicar–$2.6billionannualrevenue•  ZeIa–$2.6billionannualrevenue•  Cubicin–$1.5billionannualrevenue•  SeroquelXR–$1.2billionannualrevenue•  AciphexSprinkle–$1.1billionannualrevenue•  Norvir–$1.0billionannualrevenue•  Kaletra–$1.0billionannualrevenue•  Epzicom–$1.0billionrevenue

hap://medcitynews.com/2016/01/drugs-off-patent/

FDADrugApprovalsin2015/2016•  2015– 45newdrugapprovals(mostsince1950)

– 16withnovelMOA(36%)– Almost½usedforrarediseases

– Expeditedreviewgrantedto60%ofnewdrugs

•  2016– 29drugsapprovedsofar

hap://www.forbes.com/sites/bernardmunos/2016/01/04/2015-new-drug-approvals-hit-66-year-high/#7b1b86721044hap://cen.acs.org/arIcles/94/i5/Year-New-Drugs.html

IDARUCIZUMAB(PRAXIBIND®-BOEHRINGER-INGELHEIM)

Idarucizumab•  Dabigatranreversalagent– Life-threateningoruncontrolledbleeding– Emergent/urgentprocedure

Idarucizumab•  HumanizedmonoclonalanIbodyfragment(Fab)–  Bindsspecificallytodabigatran&dabigatranmetabolites•  350Xaffinityfordabigatranvs.thrombin

–  ReversesanIcoagulanteffects•  Onsetinminutes•  HemostasIs~11½hours

– Doesnotinterferewithclorngproteinsdirectly

JACC2016;67:1654

Idarucizumab•  Dosing– 5gIV•  Pushorinfusion•  2X2.5g(50mL)

–  ≤15minutesapart

– ConInuedorrepeatbleeding•  Dataon2nddoselimited

Anesthes2015;123:A21

Idarucizumab•  Adverseeffects– Headache– Hypokalemia– Delirium– PotenIalimmunereacIon

– ThromboIcrisk•  Noincreaseoverbaseline

Anesthes2015;123:A21

Idarucizumab•  SomesubjectsinRE-VERSEAD™trial– Re-elevaIonofbleedrisk

– RedistribuIonofdabigatranfromIssuestoplasma

IdarucizumabprescribinginformaIon

CEFTAZIDIME/AVIBACTAM(AVYCAZ®-ALLERGAN/ASTRAZENECA)

Cexazidime/Avibactam•  50,000FootView– AnIbioIcwithnovelbetalactamaseinhibitorusedfor“Armageddon”gram–negaIvepathogens

•  DrugClass– CephalosporinclassanIbioIc

•  FDAIndicaIons– Complicatedintra–abdominalinfecIons

•  IncombinaIonw/metronidazole

– ComplicatedurinarytractinfecIons•  IncombinaIonw/metronidazole

Cexazidime/Avibactam•  MOA– Cexazidime

•  3rdgeneraIoncephalosporinonmarketsince1980s•  Cellwallinhibitor(bindsPBPs)•  AcIvityvs.Pseudomonasspp.

– Avibactam•  Betalactamaseinhibitor•  AcIvevs.AmpC,ESBL,KPC•  NotacIvevs.metallo–betalactamases

Cexazidime/Avibactam•  Dosing(IVonly)–  2.5gevery8hoursincombinaIonwithmetronidazole–  For5–14daysincIAI–  For7–14daysincUTI

•  Contains2gofcexazidimeand0.5gofavibactam•  Dosingbasedonthesumofingredients(e.g.2.5g)•  Requiresrenaldoseadjustmentw/CrCl<50mL/min

•  Administeraxerdialysis•  Administerovertwohours

Cexazidime/Avibactam•  ClinicalEvidence– cIAI(LucasIJAC2013;MazuskiCID2016)

•  Cexaz/avi+metrononinferiortomeropenem

– cUTI(VazquezCurrMedResOpin2012)•  Cexaz/avi+metrononinferiortoimipenem/cilastaIn

•  SafetyData– NonspecificGIsymptoms/headache– OnecaseofincreasedLFTs– Welltolerated

JAC2013;68:1183-92CID2016;62(11):1380-9

CurrMedResOpin2012;28(12):1921-31

Cexazidime/Avibactam•  DrugInteracIons– MayincreaseeffectofVKAs– Levelsdecreasedbyprobenecid

•  WarningsandPrecauIons– Neurotoxicityw/highdose(βlactam,duh)

•  PregnancyCategoryB/excretedinbreastmilk•  ContraindicaIons– HypersensiIvitytocephalosporins

Cexazidime/Avibactam•  MarketNiche– SeriousgramnegaIveinfecIons– ContainingKPCbetalactamases– SparingtoxicalternaIves(i.e.colisIn)–  IndicatedincIAIandcUTI,butlikelytobeusedofflabelindiresituaIons

•  Pricing:$1,000/dayAWP

SUGAMMADEX(BRIDION®-MERCK)

Sugammadex•  AnIdote– SelecIvereversalofaminosteroidalnon-depolarizingneuromuscularblockers•  Rocuronium>vecuronium>>pancuronium

•  MechanismofacIon– Bindsrocuronium1:1

•  Decreasesfreerocuronium–  Formsplasmagradient

•  BoundrocuroniumdiffusesfromneuromuscularjuncIon–  Newlyfreerocuroniumbindstosugammadex

• Water-solublecomplex–  Excretedunchangedintheurine

Sugammadex•  Dosing– RouInereversalofneuromuscularblockade

•  IVassingledosebasedonactualbodyweight–  Deepblockade=4mg/kg– Moderateblockade=2mg/kg

–  Immediatereversalofneuromuscularblockade•  IV16mg/kg

– Within3minutesof1.2mg/kgofrocuroniumdose

– WaitImesforre-administraIonvary•  Ifimmediateneuromuscularblockaderequiredaxersugammadex–  Canusenon-steroidalagent

Sugammadex•  DruginteracIons– Displacementbysteroid-likestructures– Toremifene– Fusidicacid– Progesterones?

•  Monitorforrecurrenceofneuromuscularblockade

PATIROMER(VELTASSA®-RELYPSA)

PaIromer•  AnIdoteforhyperkalemia– ForchronicadministraIonispaIentswhorequireRAASinhibitors

– Notforemergentuse

•  Mechanism– Non-absorbablecaIon-exchangepolymer•  Calcium/sorbitol

PaIromer•  Dosing–  8.4goraldaily

•  Mixpowderwithwater;drinkimmediately•  Takewithfood•  Adjust≥weekly;maxdose25.2gperday

•  DruginteracIons–  Boxedwarning

•  Bindsoraldrugs—separatedosesby6hoursbefore/axer•  Adverseeffects– Hypomagnesemia– GI

•  MaycauseconsIpaIonordiarrhea•  IneffecIveinsevereconsIpaIon

ROLAPITANT(VARUBI®-TESARO)

Rolapitant•  AnI-emeIc–  IndicatedforprevenIonofdelayedchemotherapy-inducednausea&vomiIng(CINV)

•  MechanismofacIon– SubstanceP/neurokinin1(NK1)receptorblocker•  SubstancePsImulateschemoreceptortriggerzonecausingnausea/vomiIng

Rolapitant•  Highlyemetogenictherapy

–  180mg1-2hourspriortotherapyonday1only•  Givewithdexamethasone&5-HT3regimen

•  DonotgivemorefrequentlythanQ2weeks

•  Moderatelyemetogenictherapy–  180mg1-2hourspriortotherapyonday1only•  DonotgivemorefrequentlythanQ2weeks

•  t½~7days•  MetabolizedviaCYP3A4to

acIvemetabolites

ISAVUCONAZOLECRESEMBA®-ASTELLAS

Isavuconazole•  50,000FootView– AnIfungalw/acIvityagainstAspergillusandMucormycosesspp.

•  DrugClass– AzoleanIfungal

•  FDAIndicaIons–  InvasiveAspergillosis–  InvasiveMucormycosis

Isavuconazole•  MOA–  InhibitsCYP450–dependent14α–lanosterol– EssenIalforfungalcellmembraneformaIon– AcIveagainstyeasts,molds

•  Administeredasprodrug– 186mgisavuconazoniumsulfate=100mgisavuconazole

•  Dosing– LoadingDose:372mgq8hoursx6doses– MaintenanceDose:200mgoncedaily

Isavuconazole•  AvailableIVandPO;98%bioavailability•  Verylonghalf–life=>4days•  MetabolizedviaCYP3A4– Notrecommendedinadvancedliverdisease

•  Eliminatedviafeces– Noneedforrenaldoseadjustment– NotgoodforUTItreatment

Isavuconazole•  ClinicalEvidence–  SECURE:non–inferiortovoriconazoleforaspergillus–  Preliminarydatavs.Mucormycosesindicatesimilarmortalitytohistoricaldata(35%)

–  LimiteddataagainstFusarium/Endemicmolds•  SafetyData– NonspecificGIsymptoms– Novisualdisturbanceslikevoriconazole–  LiverenzymeelevaIons(it’sanazole)–  ShortensQTc–  InfusionreacIonsinafewpaIentsàusefilter

Isavuconazole•  DrugInteracIons–  CYP3A4àrifampin,CBZ,immunosuppressants

•  WarningsandPrecauIons– HepaIceffects(10xLFTsin1.2%)–  InfusionrelatedreacIons

•  PregnancyCategoryC/excretedinbreastmilk– Higherperinatalmortalityinratsw/halfmaintenancedose

•  ContraindicaIons– Useofstrong3A4inhibitors/inducers–  FamilialshortQTcsyndrome

Isavuconazole•  MarketNiche– AlternaIvetovoriconazoleforAspergillosis

•  Beaerbioavailability•  Beaersideeffectprofile

– AlternaIvetoposaconazole/anotheropIonagainstMucormycoses•  Beaerbioavailability

•  Pricing–  IV:Onedose=$285– POOnedose=$168

INSULINDEGLUDECTRESIBA®–NOVONORDISK

InsulinDegludec•  50,000FootView– Ultra–longacIngbasalinsulinwithpromisestoreducehypoglycemia

•  FDAIndicaIons–  ImprovedglucosecontrolinType1andType2diabetesmellitus

InsulinDegludec•  Dosing– T1DM

•  Insulin–naïve:1/3to1/2oftotaldailyinsulindose(usually0.2–0.4units/kg)givenoncedaily•  Insulin–experienced:Samedoseattotaldailybasaldose

– T2DM•  Insulin–naïve:10unitsoncedaily•  Insulin–experienced:Samedoseattotaldailybasaldose

– Ensure8hoursbetweenconsecuIvedoses

InsulinDegludec•  Pharmacology– UsesphenolinformulaIontoformsolubledihexamers– Onceinjectedsubcutaneously,phenoldisperses,andself–associatesintolargermulIhexamers

–  Individualinsulinmoleculesgraduallydissociateasmonomers

•  KineIcs–  SteadyabsorpIon–  Zero–orderkineIcs– Onset=30–90minutes– Half–life=25hours– DuraIonofacIon>42hours

InsulinDegludec•  Differencesfromdetemirandglargine– LessvariabilityinbloodglucoseloweringfrominjecIontoinjecIon

– Abilitytoco-formulatewithbolusinsulins•  Glargineformsprecipitate•  Detemirlowerseffectofbolusinsulin•  Degludecincombow/aspartindevelopment

–  Increasedflexibilityindosing•  ChangesininjecIonImew/degludecdonotadverselyeffectglucosecontrol

– StabilityinhepaIc/renaldisease

InsulinDegludec

BEGINBasal–BolusType1Degludec Glargine

A1cReducIon 0.4% 0.39%Nocturnal

Hypoglycemia 3.9% 5.2%

Lancet2012;379(9825):1489-97Lancet2012;379(9825):1498-1507

BEGINBasal–BolusType2Degludec Glargine

A1cReducIon 1.1% 1.18%Overall

Hypoglycemia 11% 13.6%

InsulinDegludec•  WarningsandPrecauIons– Hypoglycemia/hypokalemia– NotforuseinDKA

•  PregnancyCategoryC– Notstudiedinpregnantwoman/animalstudiesrevealedadverseeventsduetomaternalhypoglycemia

•  Excretedinbreastmilk•  OpImaltransiIondosingfromotherlong–acInginsulinsyettobeelucidated

•  Storage:Stablefor8weeksatroomtemperature

InsulinDegludec•  MarketNiche– Alreadyco–formulatedwithinsulinaspart

•  IDegAspàRyzodeg70/30®

– TheFuture•  IDegLiraàliragluIde/degludecco–formulaIon

•  Pricing– 100units/mL(3mL)=$100– 200units/mL(3mL)=$213

SELEXIPAG(UPTRAVI®–ACTELION)

Selexipag•  50,000FootView– NewPAHdrugforearlystagedisease(WHOII/III)

•  MOA–  ProstacyclinIPreceptoragonistàrelaxedsmoothmuscle

–  LessGIeffectsthanotherPAHdrugs•  Dosing–  Startedat200mcgtwicedaily–  Titratedweeklyupto1600mcgtwicedaily–  Ifdosemissedfor>3days,restartatlowerdose

•  AvoidgemfibrozilincombinaIon•  Onetablet=$155

PIMAVANSERIN(NUPLAZID®–ACADIA)

Pimavanserin•  50,000FootView– NondopamineatypicalanI-psychoIcforParkinson’spsychosis

•  MOA–  Inverseagonistofserotonin5-HT2A– ExciIngtargetforpsychosisofdifferentdiseases

•  Dosing– 34mgQDay(1/2dosew/Strong3A4inhibitors)

•  CanprolongQTcinterval

AnIpsychoIcReceptorAcIvity

NeurochemRes2014;39:2008-17

SECUKINUMAB(COSENTYX®–NOVARTIS)

NeurochemRes2014

Secukinumab•  50,000FootView– AnIbodyinjectableformoderate–severeplaquepsoriasis,ankylosingspondyliIs,andpsoriaIcarthriIs

•  MOA–  IL-17AmonocolonalanIbody

•  Dosing– Psoriasis:300mgSCQWkx5doses,thenQmonth– AS/PA:150mgSCQWkx5doses,thenQmonth

•  IncreasesriskofinfecIon/RequiresTBtestNeurochemRes2014

CANGRELOR(KENGREAL®-THEMEDICINECO.)

Cangrelor•  Plateletinhibitor– Decreasesriskofperi-proceduralmyocardialinfarcIonduringpercutaneouscoronaryintervenIon(PCI)

•  Mechanism– Direct-acIngP2Y12inhibitor•  IrreversiblyinhibitsADPreceptor

NatRevCardol2011;8:547

Cangrelor•  IVadministraIon– 30mcg/kgbolus30minutepriortoPCI

– 4mcg/kg/minuteinfusionduringprocudure•  ConInueatleast2hours

NatRevCardol2011;8:547

Cangrelor•  TransiIontooralagent–  600mgclopidogrelor60mgprasugrel•  Immediatelyatendofinfusion;doNOTgivepriortodisconInuaIonofinfusion

–  180mgIcagrelor•  Immediatelyatendof,orduringinfusion

•  Rapidonset/offset– DonotusewithgpIIB/IIIaP2Y12inhibitor

NatRevCardol2011;8:547

SACUBATRIL/VALSARTAN(ENTRESTO®-NOVARTIS)

•  DegradesvasoacIvepepIdes–  NatriureIcpepIdes–  Bradykinin–  Others

Neprilysin

•  IncreasesnaIureIcpepIdes&opposesneurohormonalacIvity

NeprilysinInhibiIon

PARADIGM-HF•  HFrEF– LCZ696(valsartan&neprilysininhibitor)vs.enalapril

•  Methods– Double-blindRCT•  N=8442classII-IVHF•  EF≤40%

– Primaryoutcome•  CompositeofCVdeathorhospitalizaIonforHF

NEnglJMed2014;371;11

PARADIGM-HF•  Results

–  Trialstopped@meanf/u27months

–  Primaryoutcome•  LCZ696=914(21.8%)vs.enalapril=1117(26.5%)–  HazardraIo0.80;95%CI0.73

to0.87;P<0.001

–  LCZ696group•  >hypotension,non-seriousangioedema

•  <renalimpairment,hyperkalemia,cough

•  Conclusions–  LCZ696superiortoenalaprilinreducingriskofdeath&hospitalizaIonforHF

NEnglJMed2014;371;11

Sacubatril&Valsartan(Entresto®)•  PotenIaltoreplaceACEinhibitor– ContraindicatedwithACEI,pregnancy– HFrEFNYHAclassII-IV

•  LVEF≤40%•  Stable

–  SymptomaIcdespiteopImaltherapy

•  Dosing– Sacubatril/valsartan

•  24mg/26mg=50mg(~40mgvalsartan)•  49mg/51mg=100mg(~80mgvalsartan)•  97mg/103mg=200mg(~160mgvalsartan)

IVABRADINE(CORLANOR®-AMGEN)

HeartRateControl•  HFrEFpaIents–  ElevatedHR

•  Increaseinmorbidity&mortality

•  PlacebogroupinSHIFTtrial–  RiskofCVdeathorHFhospitalizaIon•  2.9%per1BPMincrease•  15.6%per5BPMincrease

•  HR<60bpmvs.>75bpm–  32.4%decreasemortality&HFhospitalizaIon

HRRegulaIon•  SAnodeproduces“pacemaker”impulses– SpreadstoAVnodetriggeringventricularcontracIon

•  Ifcurrent–  IniIatesdiastolicdepolarizaIonofSAnode

Ivabradine•  Ifinhibitor–  BindstoHCNchannels

•  “usedependent”

•  SAnode(fchannels)–  CarriesIfcurrent

•  prolongsdiastolicIme•  InhibiIonreducesheartrate

•  ReIna(hchannels)–  CarriesIhcurrent

•  InhibiIoncausesvisualdisturbances

Ivabradine•  ProlongsdiastolicIme–  InhibitsIfcurrent,reducingheartrate

•  Increasesstrokevolume– PreservesmyocardialcontracIlity

– BP

NatRevDrugDisc2006;5:1034

Ivabradine•  HFrEFpaIents

–  ElevatedHR•  Increaseinmorbidity&mortality

•  HR≥87BPM–  >2XriskforCVdeathorhospitalizaIonforHFvs.HR70-72BPM•  HazardraIo2.34,95%CI1.84–2.98,p<0.0001

•  ElderlyHFpEFpaIentshadsymptomaIcimprovement&HRreducIon

EurHeartJ2013;34:suppl1CirculaIon2001;103:1428

Lancet2010;376:886

Ivabradine(Corlanor®)•  ApprovedtoreducehospitalizaIonfromHF–  ConsiderinHFrEF

•  LVEF≤35%•  ResIngheartrate

–  ≥70BPM

•  OnmaxdoseofBB–  Orintolerant

•  TitratetoresIngHR