Consultant Pharmacist Approach to Major Depressive...

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ConsultantPharmacistApproachtoMajorDepressiveDisorder

AlanObringerrph,cph,cgpPresident/owner

GuardianpharmacyofOrlando

Objectives•WhatisDepression?•Discusstheepidemiologyofdepression•Discusstheetiologyofdepression•Discussthepathophysiologyofdepression•Discussthesignsandsymptomsofdepression

•Discusstreatmentsofdepression•Howtode-prescribedepression

SpectrumofPsychiatricDisorders

ANXIETY

AFFECTIVE

PSYCHOSES

Panic disorderGADOCDAgoraphobia

Major DepressionBipolar DisorderDysthymia Schizophrenia

Schizoaffective

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WhatisDepression?• Describedasfeeling

• Blue• Unhappy• Miserable

• Everyonefeelsthiswayatonetimeintheirlife• Goesaway

• Clinicaldepression• Feelingsinterferewitheverydaylife• Lastweeksorpotentiallylonger

Epidemiology• ThetrueprevalenceintheUSisunknown• Womenhavehigherrisk

• Lifetimerisk1.7-2.7xhigherthanmen• Incidencecanhappenatanyage

• Highestinadultsaged18-29y.o.• Higherincidenceinpatientswithfirstdegreerelative• 8-18%comparedto5.6%ofthosewithout• 1.5-3xgreaterchanceofdevelopingdepression

Epidemiology• Depressionisthemostcommonmentalhealthproblemintheelderlyandisassociatedwithasignificantburdenofillnessthataffectspatients,theirfamilies,andcommunitiesandtakesaneconomictollaswell.

• Prevalencestudiessuggestthat14%to20%oftheelderlylivinginthecommunityexperiencedepressivesymptoms,withhigherratesamongtheelderlyinhospital(12%to45%)andevenhigherratesinlong-termcarefacilities(anestimated40%).

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ComorbidityandDepression

• 72.1%ofthosewithlifetimeMDDand64%ofthosewith12-monthMDDhaveatleastoneadditionalmooddisorder

• Primarilyanxietydisorder,substanceabusedisorder,orimpulsecontroldisorder

KesslerRCetal.Theepidemiologyofmajordepressivedisorder:resultsfromtheNationalComorbiditySurveyReplication(NCS-R).JAMA.2003;289(23):3095-3105.

Etiology

•Toocomplextobeexplainedbyasinglesocial,development,orbiologicaltheory

• Severalfactorsworktogether•Reflectschangesinbraintransmitters

•NE,5-HT,DA

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Anxiolytics

Norepinephrine

Anti-Psychotics

Dopamine

Anti-Depressants

Serotonin

NeurotransmittersandPsychiatricPharmacotherapy

GABA, others

Mood,Emotion,Cognitivefunction

Motivation

SexAppetiteAggression

AnxietyIrritabilityEnergy

Interest Impulsivity

Drive

Norepinephrine Serotonin

Dopamine

MajorNeurotransmitters

PathophysiologyofDepression• Exactcauseunknown

• Believedtobechemicalimbalanceinthebrain• Genetic• Triggeredbystressfulevents

• Breakups• Failingaclass• Deathorillnesstosomeoneclosetoyou• Divorce• Childabuseorneglect• Jobloss• Socialisolation

• Playarole• Alcoholordrugabuse• Medicalconditions:Hypothyroid,cancer,chronicpain• Medications• Sleepingproblems

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•Certainmedicationsusedaloneorincombinationcancausesideeffectsmuchlikethesymptomsofdepression.

•UseofAlcoholorotherDrugscanleadtoorworsendepression.

•Depressioncanalsooccurfornoapparentreasonatall!

DSMVClassificationofMajorDepressiveEpisode

• Five(ormore)ofthefollowingsymptomshavebeenpresentduringthesame2-weekperiodandrepresentachangefrompreviousfunctioning;atleastoneofthesymptomsiseither(1)depressedmoodor(2)lossofinterestorpleasure.

• Note: Donotincludesymptomsthatareclearlyduetoageneralmedicalconditionormood-incongruentdelusionsorhallucinations.

• Depressedmoodmostofthedaynearlyeveryday• Markedlydiminishedinterestorpleasureinall,oralmostall,activitiesmostofthedaynearlyeveryday• Significantweightlosswhennotdietingorweightgain(e.g.,achangeofmorethan5%ofbodyweightinamonth),ordecreaseorincreaseinappetitenearlyeveryday

• Insomniaorhypersomnianearlyeveryday• Psychomotoragitationorretardationnearlyeveryday(observablebyothers,notmerelysubjectivefeelingsofrestlessnessorbeingsloweddown)

• Fatigueorlossofenergynearlyeveryday• Feelingsofworthlessnessorexcessiveorinappropriateguiltnearlyeveryday• Diminishedabilitytothinkorconcentrate,orindecisiveness,nearlyeveryday• Recurrentthoughtsofdeath(notjustfearofdying),recurrentsuicidalideationwithoutaspecificplan,orasuicideattemptoraspecificplanforcommittingsuicide

SignsandSymptomsofDepression

• Thesymptomscauseclinicallysignificantdistressorimpairmentinsocial,occupational,orotherimportantareasoffunctioning.

• Thesymptomsarenotduetothedirectphysiologicaleffectsofasubstance(e.g.,adrugofabuse,amedication)orageneralmedicalcondition(e.g.,hypothyroidism).

• Thesymptomsarenotbetteraccountedforbybereavement(i.e.,afterthelossofalovedone),thesymptomspersistforlongerthan2monthsorarecharacterizedbymarkedfunctionalimpairment,morbidpreoccupationwithworthlessness,suicidalideation,psychoticsymptoms,orpsychomotorretardation.

ReprintedwithpermissionfromtheDiagnosticandStatisticalManualofMentalDisorders,FifthEdition(Copyright©2013).AmericanPsychiatricAssociation.AllRightsReserved..

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SignsandSymptomsofDepression

• Completephysical,mental,andlabexaminationmustbecompleted• Canbecausedbycurrentmedicalconditionordruginduced• Seelistofproposedmedicalconditions,substanceuse,andmedications

PhysicalComplaints

•Thesemayinclude:• Sleepdisturbancessuchasinsomnia,earlymorningwaking,orsleepingtoomuch

• Lackofenergy• Lossofappetite•Weightlossorgain•Unexplainedheadachesorbackaches• Stomachaches,indigestionorchangesinbowlhabits

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SymptomsofDepression

•Varyfrompersontoperson

•2keysignsarelossofinterestinthingsyouliketodo,andpervasivesadnessorirritability

SIGECAPS

- Changesinsleeppattern

- Changesininterestsoractivity

- Feelingsofguiltorincreasedworry

- Changesinenergy

- Changesinconcentration

- Changesinappetite

- Psychomotordisturbances

- Suicidalideation

SIGECAPS

Treatment• 3phasestotreatment

• Acutephase:6-10weekstoobtainremission• Continuationphase:4-9monthsafterremission

• Preventrelapse• Maintenancephase:12-36months

• Preventrecurrence• Durationoftreatment

• Dependsonriskofrecurrence• Somerecommendlifetimemaintenancetherapyforpersonsatgreatestriskofrecurrence

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Treatment• Non-pharmacologic

• Psychotherapy• Notrecommendedassoletherapyforacuteepisodesofsevereorpsychoticdepression

• Ifmildtomoderate,firstlinetherapy

• Canbeaddedtopharmacologictreatmentforpatientswithpartialresponses

Treatment• Non-pharmacologic

• Electroconvulsivetherapy(ECT)• Usedwhenrapidresponseisrequired• Risksofothertreatmentsoutweighbenefits• HistoryofpoorresponsetoantidepressantsandgoodresponsetoECT

• Patientpreference• Unilateralorbilateraladministered2-3timesweeklyfor6-12treatments

• Adverseeffectsincludecognitivedysfunction,cardiovasculardysfunction,prolongedapnea,treatment-emergentmania,headache,nausea,andmuscleaches

• Relapseratesarehighinpatientsnottakingmaintenanceantidepressants

Treatment• Pharmacologic

• Cantake4-6weeksoftherapytoseeresponse• Manydifferentcategories

• TCAs• SSRI• SNRI• Triazolopyridines• Aminoketones• Tetracyclics• MAOIs

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StepsforChoosinganEffectiveAntidepressant

1. Recognizethatsomeantidepressantsmaybemoreeffectiveincertainpopulationseventhoughmostaregenerallyofequaleffectiveness.

2. Askaboutpersonalorfamilyhistoryoftreatmentwithantidepressants,particularlyaboutsideeffects.

3. Considertheburdenofsideeffects,particularlyweightgainandsexualsideeffectsinmidlifewomen.

4. Considerdrug-druginteractionswithothermedicationsthepatientistakingormaytake.

5. Considerthepotentiallethalityoftheantidepressantinthecaseofanoverdose.

6. Useantidepressantsideeffectsforefficacy.

MooreDP,JeffersonJW.MoodDisorders.In:Moore&Jefferson:HandbookofMedicalPsychiatry,2nded.Philadelphia:Mosby;2004.

AlgorithmforTreatmentofUncomplicatedMajorDepression

• 1st line: Favorite SSRI or TCA • Failed trial: switch to alternative• Partial response - increase dose, switch or augment• Fully remits (maintain at least 4 to 6 months or longer)

• 2nd line: Switch or Augment• Switch to other favorite - TCA or SSRI• Augment with Li or TCA plus the SSRI (consult with

psychiatrist)• 3rd line: Failed or Partial response to 2nd line

• Consult with psychiatrist• Switch (nefazodone, mirtazapine, bupropion, venlafaxine)• Add newer agent (vortioxetine, aripiprazole)• Augment with Li or TCA plus the SSRI

Adapted from Wells B et al: in Pharmacotherapy, 10th ed, Dipiro, eds., 2016

MechanismofAction• SSRIs

• Inhibitsreuptakeof5-HTintothepre-synapticneuron

• SNRIs(Venlafaxine,Desvenlafaxine,Duloxetine)• Inhibitsre-uptakeof5-HTandNEintothepre-synapticneuron

• Aminoketones(Bupropion)• Inhibitsre-uptakeofNEandDAintothepre-synapticneuron

• Triazolopyridines(Trazodone)• Notfullyunderstood• Thoughttoinhibitre-uptakeof5-HTandantagonistof5-HT2A/2Creceptors

• Tetracyclics(Mirtazapine)• Exactmechanismunknown• Thoughttoworkthrough5-HTreceptorantagonism

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MechanismofAction

•TricyclicAntidepressants• Inhibitsboth5-HTandNEreuptake•Antagonistatbothreceptors

•MonoamineOxidaseInhibitors•Workonmonoamineoxidasebyinhibitingthemfrombreakingdownneurotransmitters

MechanismofAction

•Aripiprazole,Brexpiprazole(Abilify,Rexulti)•ActsasaD2 partialagonist•Partialagonistatthe5-HT1A receptor,andliketheotheratypicalantipsychoticsdisplaysanantagonistprofileatthe5-HT2Areceptor

•Vortioxetine(Trintellix)•Atypicalantidepressant(aserotoninmodulatorandstimulator)

Treatments

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AdverseEvents• Celexa

• Gidistress,N/V,headache,sedation,dizziness,agitation,Stevens-JohnsonSyndrome(SJS)

• Sertraline• Gidistress,N/V,headache,insomnia,dizziness,agitation,SJS

• Cymbalta• Constipation,nausea,headache,dizziness,insomnia,decreasedappetite,SJS

• Buproprion• Tachyarrhythmia,nausea,constipation,dizziness,headache,insomnia,agitation,anxiety

• Trazodone• Diarrhea,nausea,dizziness,headache,insomnia,nervousness

• Mirtazapine• Increasedappetite,constipation,dizziness

• Amitriptyline• Weightgain,constipation,blurredvision

Follow-UpConsiderationsInTheFirstThreeMonths

Week TreatmentActions

2Checkpatientcompliancetomedicationusage.Assessforadherence,sideeffects,suicidalideation,andpatientresponse.Adjust,asappropriate,medicationanddosage.

4 Re-checkpatientcompliancetomedicationusage.Assessforadherence,sideeffects,suicidalideation,andpatientresponse.

6 Adjust,asappropriate,medicationanddosage.

7- 12Monthlycommunicationwithpatient;PatientsAppointmentsevery3rdor4thweek;FurtherMedicationorMedicationDosageAdjustments;Goal:Remission

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APAPracticeGuidelinesfortheTreatmentofPsychiatricDisorders.

TreatmentGoal

Thegoaloftreatmentwithantidepressantmedicationintheacutephaseisthe

remissionofmajordepressivedisordersymptoms

IfInitialTreatmentIneffective

• Medicationtrialshouldlast8-12weeks• Ifnosideeffectsortolerabilityissues,increasedosageevery2-3weeksuntil

• Remissionachieved• Maxdoseachieved• Sideeffectslimittitration

• Combineantidepressantsandpsychotherapy• Combineantidepressantsorconsideraugmentationtrial• Consideringtailoringyourtreatmentforspecificsub-populations(e.g.,elderly,midlifewomenetc).

TexasMedicationAlgorithmProject(TMAP)TreatmentofMajorDepressiveDisorderClinician’sManual-http://www.dshs.state.tx.us/mhprograms/tmapover.shtmKaiserPermanenteCareManagementInstitute.Depressionclinicalpracticeguidelines.http://www.guideline.gov/summary/summary.aspx?doc_id=9632&nbr=5152&ss=6&xl=999.

De-prescribingAntidepressants

Oldthinking:• 50%ofpatientswithMajorDepressionwillexperiencerecurrence

• Admissionintoanursinghomeorotherlong-termcarefacilitycanbeatriggerfordepression

Newthinking:• 50%ofpatientswithMajorDepressionwillNOT experiencerecurrence

• Likethelossofalovedoneorothertraumaticevent,admissionintoalong-termcarefacilitycanbeovercome

• Patientsofallageswhoarestartedonantidepressanttherapyshouldbemonitoredcloselyforemergenceandworseningofsuicidalthoughtsandbehaviors

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Questionstoask:• Istheresidentbenefitingfromtheantidepressanttherapy?• Whatarethebenefitstostoppingtherapyandwhataretherisksofstoppingtherapy?

• IsthisthebestcourseofactionforMYpatient?


Ifusedforlongerthansixweeks,allantidepressantshavethepotentialtocausewithdrawalsyndromesiftheyarestoppedorrapidlyreduced.

Howtoreducethedose:• Theusualrecommendedperiodforantidepressantdosereductionisaminimumoffourweeks.

• Monitorforwithdrawalsymptoms.• Usehalf-lifeofthemedicationtodeterminetaperplan.• Ifswitchingtoanotherantidepressantconsiderawash-outperiodequivalenttoaminimumof5half-livesofthedrugbeingstopped.

Conclusion

•Depressiononeofthemostcommonmentalhealthdisordersinadults

•Pharmacologicinterventionisthecornerstonefortreatment

•Antidepressantsfocusoninhibitingtheuptakeof5-HT,NE,andDAneurotransmitters

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QUESTIONS

References• TeterC.J.,KandoJ.C.,WellsB.G.(2011).Chapter77.MajorDepressiveDisorder.InJ.T.DiPiro,R.L.Talbert,G.C.Yee,G.R.Matzke,B.G.Wells,L.M.Posey(Eds),Pharmacotherapy:APathophysiologicApproach,8e.RetrievedFebruary23,2012fromhttp://www.accesspharmacy.com.lp.hscl.ufl.edu/content.aspx?aID=7988626.

• AlldruginfofromMicromedexandLexicomphandheldinformation• Table77-2DSM-IV-TRCriteriaforMajorDepressiveEpisode• WagnerAK,ChanKA,DashevskyI,etal.FDAdrugprescribingwarnings:istheblackboxhalfemptyorhalffull?PharmacoepidemiolDrugSaf.2006Jun;15(6):369-86.

• Keks,Hope,Keoghetal.Switchingandstoppingantidepressants. AustPrescr.2016Jun;39(3):76–83.

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COPDinTransitionsofCare– anopportunityforPharmacists

Chad Worz, Pharm.D.President, Medication Managers, LLCAdjunct Professor, University of Cincinnati, College of Pharmacy

ObjectivesandAgenda

• Recognizetheburdenofdiseaseinolderadults• AcknowledgeBurdenonourHealthCareSystem• Describethepharmacologyoftreatmentsandtheirimpactonthediseaseprocess

• Demonstratethevariedadministrationmethodsfortreatmentsandtheimportanceinpostacutecare

• RecognizethenewTreatmentGuidelinesforCOPD• Definetheroleofthepharmacist

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COPDHasBeenShowntoBeaCommonandCostlyCondition

•COPDisthe3rd leadingcauseofdeathintheUnitedStates1,2•COPDisthe2nd leadingcauseofdisability3•By2010,therewere14.8milliondiagnosedCOPDpatientsintheUS4•COPDaccountsforanestimated$29.5billionindirecthealthcareexpenses5

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1. Kochanek KD, et al. Deaths: Preliminary data for 2009. National vital statistics reports. 2011;59:1-51. 2. Miniño AM, et al. Deaths: Preliminary data for 2008. National vital statistics reports. 2010;59:1-52. 3. Wise RA. Chronic Obstructive Pulmonary Disease (COPD): Merck Manual Home Edition. 2007. 4. National Heart, Lung, and Blood Institute. Unpublished Tabulations of the National Health Interview Survey, 2010. http://www.cdc.gov/nchs/nhis/nhis_2010_data_release.html. Accessed June 2014. 5. American Lung Association. Chronic obstructive pulmonary disease (COPD) fact sheet. http://www.lung.org/lung-disease/copd/resources/facts-figures/COPD-Fact-Sheet.html. Accessed May 23, 2014.

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MortalityofCOPDIsIncreasing

COPD is the only leading cause of death that is increasing.

COPDinLongTermCare

•OneofeverysixadmissionstonursinghomeswasforpatientswithahistoryofemphysemaorCOPD1

• Inthelast12monthsofCOPDpatients’ lives,onerecentstudyreportedtherewasa40%likelihoodofbeingadmittedtoaLTCfacility2

• Approximately22%oftherespiratory-relatedhealthcarecostsarenursinghomecosts;agreateramountwasspentonhospitalizations(approximately50%)

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COPDinLongTermCare

• ThemajorityofpersonswithCOPDhavecardiovasculardiseaseincludingcoronaryarterydisease,heartfailure,andhypertension.

• StrokeoccursinasignificantportionofpersonswithCOPD.• About25%ofpersonswithCOPDhaveconcurrentasthma.• Age-relatedandsteroid-inducedosteoporosisoccurfrequentlyinpersonswiththedisease,andCOPDisariskfactorfornursinghome–associatedpneumonia.

• AsignificantnumberofpersonswithCOPDhaveobstructivesleepapnea.

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COPDinLongTermCare

•DepressionandanxietyarealsocommoninCOPD;onestudyfoundthat40%ofpersonswithCOPDhavedepressivesymptoms.•Diabetesmellitusoccursinabout25%ofpersonswithCOPD.•MalnutritionisasignificantissueinsomeindividualswithCOPD.•Substantialchronicairwayobstructionleadstogreaterenergyrequirementsduetotheincreasedworkofbreathing,aswellasinactivityfromdeconditioning

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1. American Lung Association. COPD Fact Sheet. http://www.lungusa.org/diseases/copd_factsheet.html. 2. Grasso ME et al. Am J Respir Crit Care Med. 1998;158:133-138. 3. Fishman P et al. Health Aff. 1997;16:239-247.

EconomicBurdenofCOPD

• AnnualcostintheUS:$30.4billion1• Directcost:$14.7billion• Indirectcost:$15.7billion• Emergencyservices,hospitalization

• PercapitaMedicareexpenditurenearly2.5timeshigherwithaCOPDdiagnosisthanwithout2

• $8,482vs.$3,511withoutCOPD• Diagnosisofchronicrespiratorydiseaseisassociatedwitha172%increaseinmeanhealthcarecosts3

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CorrelationBetweenDiseaseSeverityandTotalTreatmentCost1

• Retrospectivepharmacoeconomicanalysis• 413patients,5years

• Stage1(Mild)COPD: $1,681/patient/year• Stage2(Moderate)COPD: $5,037/patient/year• Stage3(Severe)COPD: $10,812/patient/year

1. Hilleman DE et al. Chest. 2000;118:1278-1285.

StepwiseApproachtoTreament

•Earlyandaccuratediagnosis•Preventionofdiseaseprogression(deteriorationofpulmonaryfunction)•Reliefofsymptoms• Improvementinexercisetoleranceandhealthstatus• Preventionandtreatmentofexacerbationsandcomplications• Improvementinqualityoflife• Reductioninmortality.Includesdrugtherapy,smokingcessation,oxygen,pulmonaryrehabilitation,andnutritionalintervention.

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GOLDGUIDELINES

Spirometry,symptoms,andexacerbationhistoryprovideamorecompleteassessmentandpictureofdiseasestatus

12From the Global Strategy for Diagnosis, Management and Prevention of COPD 2014, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.orghttp://www.goldcopd.org. Accessed May 14, 2014.

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MaintenanceTherapyforLong-termCOPDCare–Considerations

• FocusofCOPDcareisshiftingfromacutetreatmenttolong-termmaintenance1-3

•ManypatientsdidnotreceiveanymaintenanceCOPDtherapy4

• GOLDcanbeusedtoinformtheprescribingofmaintenancetherapy3,5

•WhenselectinganinhaledCOPDtherapy,drugdeliveryandtrainingshouldbeconsidered5

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1. Centers for Medicare & Medicaid Services. Accountable Care Organization 2012 program analysis. Quality performance standards narrative measure specifications. Final report. http://www.cms.gov/medicare/medicare-fee-for-service-payment/sharedsavingsprogram/downloads/aco_qualitymeasures.pdf. Accessed May 23, 2014. 2. National Committee for Quality Assurance. Insights for quality improvement: advancing COPD care through quality improvement. 2009. Available at http://www.ncqa.org/portals/0/publications/NCQA_Insights_improvement_FINAL.pdf. Accessed May 23, 2014. 3. Fromer L. Int J Chron Obstruct Pulmon Dis. 2011;6:605-614. 4. Make B, et al. Int J Chron Obstruct Pulmon Dis. 2010;5:341-349 5. Global Initiative for Chronic Obstructive Lung Disease (GOLD). http://www.goldcopd.org. Accessed May 14, 2014.

MaintenanceTherapyforLong-termCOPDCare–Considerations

• Inthehospitalpriortodischarge,patientsshouldstartlong-actingbronchodilators,eitherbeta2-agonistsand/oranticholinergicswithorwithoutinhaledcorticosteroids5

• Add1ormoreclassesoflong-actingbronchodilatorswhenneeded5

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1. Centers for Medicare & Medicaid Services. Accountable Care Organization 2012 program analysis. Quality performance standards narrative measure specifications. Final report. http://www.cms.gov/medicare/medicare-fee-for-service-payment/sharedsavingsprogram/downloads/aco_qualitymeasures.pdf. Accessed May 23, 2014. 2. National Committee for Quality Assurance. Insights for quality improvement: advancing COPD care through quality improvement. 2009. Available at http://www.ncqa.org/portals/0/publications/NCQA_Insights_improvement_FINAL.pdf. Accessed May 23, 2014. 3. Fromer L. Int J Chron Obstruct Pulmon Dis. 2011;6:605-614. 4. Make B, et al. Int J Chron Obstruct Pulmon Dis. 2010;5:341-349 5. Global Initiative for Chronic Obstructive Lung Disease (GOLD). http://www.goldcopd.org. Accessed May 14, 2014.

RiskFactorsforCOPD

S Smokingisthepredominantriskfactor1,2SImplicatedin>90%ofUSpatientswithCOPD

S Othersinclude1:SAirpollutionSPoornutritionSChildhoodrespiratoryinfectionsSPreexistingbronchialhyperreactivitySa1-Antitrypsindeficiency(genetic,rare)SOccupationalandenvironmentalexposure(eg,coaldust,silica)

1. NCAP. J Respir Dis. 2000;21(Suppl):S5-S21. 2. Buist AS, Vollmer WM. In: Textbook of Respiratory Medicine. 1994:1259-1287.

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RiskFactorsforCOPD

1. NCAP. J Respir Dis. 2000;21(Suppl):S5-S21. 2. Buist AS, Vollmer WM. In: Textbook of Respiratory Medicine. 1994:1259-1287.

Age-RelatedDeclineinFEV1 IsAcceleratedinSmokers

Adapted with permission from Fletcher C, Peto R. BMJ. 1977;1:1645-1648.

Never smoked or not susceptible to smokeStopped at 45 yStopped at 65 y

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Pharmacotherapy:AnticholinergicAgents

SBlockbronchoconstrictionSIncreaseFEV1SHavebeenshowntoreduceexacerbationrateSMaybeassociatedwithlowertreatmentcosts1,2

SAnti-cholinergics areconsideredfirstline3-5SMinimalsideeffectsSDonotcrossblood-brainbarrierSMinimalgastrointestinalabsorption

SExtendedtherapyassociatedwithimprovedbaselinepulmonaryfunction6

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Friedman et al. Chest. 1999;115:635-641. 3. NLHEP. 1998:113(suppl):123S-163S.4. PDR.net. Atrovent Inhalation Aerosol. 5. ATS Am J Respir Crit Care Med. 1995;152:S77-S121. 6. Rennard SI et al. Chest. 1996;110:62-70.

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Long-Actingb2-AdrenergicAgonists1

SEffectiveinimprovingFEV1 andFVC,andmayreduceCOPDexacerbationsSMayproviderelieffromnocturnalsymptomsSCanbeusedwithipratropiumifshort-actingb2-agonistusedfrequentlyforrescueSUnlikeshort-actingb2-agonists,NOT forrescue

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21.

InhaledCorticosteroids

• Ifresponsetoanticholinergicandotherbronchodilatortherapyissuboptimal,inhaledcorticosteroidtherapymayprovidebenefitinsomepatients1• Indicatedonlyinpatients

• whoarealreadyreceivingchroniclow-dosecorticosteroidtherapy,or

• whohaveadocumentedobjectiveresponsetocorticosteroidtherapy

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Vestbo J et al. Lancet. 1999;353:1819-1823. 3. Pauwels RA et al. N Engl J Med. 1999;340:1948-1953. 4. The Lung Health Study Research Group. N Engl J Med. 2000;343:1902-1909. 5. Burge PS et al. BMJ. 2000;320:1297-1303.

•4majorstudieshavebeenconducted2–5• Noeffectonmortality,rateofdeclineofFEV1• NosignificantincreaseinFEV1 shortterm

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Vestbo J et al. Lancet. 1999;353:1819-1823. 3. Pauwels RA et al. N Engl J Med. 1999;340:1948-1953. 4. The Lung Health Study Research Group. N Engl J Med. 2000;343:1902-1909. 5. Burge PS et al. BMJ. 2000;320:1297-1303.

Inhaled Corticosteroids

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1. Combivent Inhalation Aerosol Study Group. Chest. 1994;105:1411-1419. 2. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 3. Campbell S. Arch Intern Med. 1999;159:156-160. 4. Friedman M et al. Chest. 1999;115:635-641.

Short-Actingb2-AdrenergicAgonists

SIfresponsetoinitialanticholinergictherapysuboptimal, addb2-adrenergicagonist1,2SCombinationMDI(ipratropiumandalbuterol)1,3,4:

SGreaterefficacy,equivalentsafetySLowerrateofexacerbationsSLowertotaltreatmentcostsS Improvedcost-effectiveness

MDI,metered-doseinhaler

Theophylline1

SIfresponsetoinitialanticholinergic/b2-agonisttherapysuboptimal,consideraddingtheophylline

SLong-actingformulationsgenerallypreferredSModestbronchodilation,mildanti-inflammatoryeffects

SUsefulfornoncompliantpatientsandthosewhohavetroublewithinhalationaerosolsandthosepreferringoraldrugs

STitratedosetoserumleveluptoamaximumof12µg/mLSSomepatientsexperiencesideeffectsatlowerserumlevels

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21.

Anti-InflammatoryAgents

• Ifbronchodilatorresponseissuboptimal,consideraddingananti-inflammatorydrug1

• Corticosteroids(oral/inhaled)

•Usefulinfewpatients1• Consider2-weektrialoforalcorticosteroid(40mgprednisoneQD)• Discontinueifnoresponse• Ifpatientresponds,tapertominimaleffectivedoselevelandswitchtoinhaledcorticosteroid

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Callahan CM et al. Ann Intern Med. 1991;114:216-223. 3. Chanez P et al. Am J Respir Crit Care Med. 1997:155:1529-1534. 4. Pizzichini E et al. Am J Respir Crit Care Med. 1998;158(5 pt 1):1511-1517.

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Anti-InflammatoryAgents

• LimitedroleinchronicCOPD• 10%improveFEV1 20%2

• Mayactuallydetect“hidden” asthma3,4

• Cromolyn,nedocromil,andleukotrienemodifiershavenotbeenproveneffectiveinCOPD1

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Callahan CM et al. Ann Intern Med. 1991;114:216-223. 3. Chanez P et al. Am J Respir Crit Care Med. 1997:155:1529-1534. 4. Pizzichini E et al. Am J Respir Crit Care Med. 1998;158(5 pt 1):1511-1517.

Long-TermOxygenTherapy

SIndicatedforPaO2<55mmHgorSaO2 <88%1

SImproves1-4:SSurvivalinhypoxemicpatientsSCognitivefunction,affectSExerciseperformanceSSleepqualitySActivitiesofdailyliving

1. NCAP. J Respir Dis. 2000;21(suppl):S5-S21. 2. Report of the Medical Research Council Working Party. Lancet. 1981;681-686.3. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980;93:391-398. 4. Bye et al. Am Rev Respir Dis. 1985;132:236-240.

Administration

SMDI(MeteredDoseInhaler)vs.HHN(HandHeldNebulizer)SAHHNisnotsuperiortoanMDI

STheproblemistechnique(consideraspacer)SWithoptimaltechniqueaMDIdeliverscloseto12%ofthedrugtothelung.

SIngeneral,theHHNdoseneedstobe6to10timeshigherthantheMDItodeliverthesamedegreeofbronchodilation.

SConsidernursingadministrationtimeSConsiderthepatient

11

PostAcuteandLongTermCare

SWhatdoesallofthismeantous?SANewFocusonmanagementandanefforttoreducehospitalizationsS ImpacttoSNFS Impactontherapeuticdecisions

SAssessingdevicesandmatchingthemtopatientsSCOSTEFFECTIVENESS


SFormularydevelopmentSAssessmentsurveysorworkupsSCostmanagement

SWorkingwithindustryS EducationS DiscountstoNursingHomes?S Productplacement


• Today:• Hospitalsworktodischarge

• Mayormaynotreconcilethemedicationlistwhensenttothenursinghome• Goalistomaximizepulseoxandlimitresources

• (relatedtopaymentmechanisms)• Noteffectiveatmedicationcounseling

• LTC– day1– cleanuptheprofileonadmission,limitcost

12


• Tomorrow:• Hospitalsworktodischarge

• Betterdataandreconciliation• Recognitionofpenaltiesforre-hospitalizations• Mayaddresourcesformedicationcounseling

• LTC:• Day1– cleanuptheprofileonadmission• PlanofCarefordischarge• ReconciliationandCounselingcritical• Onthehookforre-hospitalizations

Questions

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1

HIV TREATMENT OVERVIEW ANDCONSIDERATIONS FORANTIRETROVIRAL USE IN PATIENTSWITH HCV COINFECTIONJacqueline Byrd, Pharm.D., BCPS, AAHIVPClinical Pharmacy Specialist, Infectious DiseasesOrlando VA Medical CenterJune 24, 2017

DISCLOSURES

¢ I have no financial or other conflicts of interest to report.

2

OBJECTIVES¢ Review the epidemiology and screening

recommendations for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections

¢ Identify treatment goals for HIV-infected patients and for HCV-infected patients

¢ Describe the current HIV treatment guidelines and the appropriate selection of antiretrovirals when initiating therapy in antiretroviral-naïve HIV-infected patients

¢ Describe the current HCV treatment guidelines and the appropriate selection of treatment when initiating therapy in treatment-naïve HCV-infected patients

¢ Discuss how drug interactions between HIV and HCV treatments affect the care of HICV/HCV coinfectedpatients

3

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2

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

¢ Virus that causes Acquired Immunodeficiency Syndrome (AIDS)

¢ Single-stranded RNA retrovirus¢ Two types of HIV:

� HIV -1¢ First identified in 1983¢ Majority of cases seen in U.S. (Group M, Subtype B)¢ Most common and most pathogenic strain ¢ Related to viruses found in chimpanzees and gorillas

� HIV-2¢ First identified in 1989¢ Mostly seen in Western Africa¢ Related to viruses found in sooty mangabeys¢ Less prevalent, less transmissible, less virulent

4

Sharp, P. M.; Hahn, B. H. (2011). "Origins of HIV and the AIDS Pandemic" . Cold Spring Harbor Perspectives in Medicine.

EPIDEMIOLOGY - WORLDWIDE

¢ 36.7 million individuals living with HIV/AIDS in 2015� Up from 33.3 million in 2010� 1.8 million are children (<15 years old)

¢ 2.1 million new infections in 2015¢ In 2015, about 1.1 million people died of AIDS¢ Highest concentration of HIV/AIDS cases is sub-Saharan

Africa� ~70% of people living with HIV� Eastern Africa has declining prevalence rates secondary to

successful prevention strategies¢ Worldwide, heterosexual sex is the most common mode of

transmission 5

19, 2017 Jan. "The Global HIV/AIDS Epidemic." The Henry J. Kaiser Family Foundation.

EPIDEMIOLOGY – U.S. ¢ ~1.25 million people living with HIV in the U.S.

� >700,000 people with AIDS have died since the epidemic¢ In 2015, CDC estimated 40,000 new cases of HIV were

diagnosed� 13% of people with HIV are unaware

61. 02, 2017 Feb. "The HIV/AIDS Epidemic in the United States: The Basics." The Henry J. Kaiser Family

Foundation.2. "HIV/AIDS." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 02 Dec.

2016.

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HIV & RACIAL DISPARITY

7

02, 2017 Feb. "The HIV/AIDS Epidemic in the United States: The Basics." The Henry J. Kaiser Family Foundation.

¢ Minorities represent the majority of new HIV diagnoses, people living with HIV, and deaths among people with HIV

RISK OF HIV TRANSMISSIONExposure Route Risk per 10,000 Exposures

Blood Transfusion 9,250Needle-sharing injection-druguse

63

Receptive anal intercourse 138

Percutaneous needle stick 23

Receptive penile-vaginal intercourse

8

Insertive anal intercourse 11

Insertive penile-vaginal intercourse

4

Receptive oral intercourse Low

Insertive oral intercourse Low8

"HIV/AIDS." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 04 Dec. 2015.

ROUTES AND RATES OF TRANSMISSION

Estimated New HIV Infections By Route, 2010

9

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ASSESSMENT QUESTION #1True or False:

The most common mode of HIV transmission in the United States is heterosexual intercourse.

¢ True¢ False

10

DETECTION & DIAGNOSIS

11

"Steps in the HIV Diagnostic Testing Algorithm." HIV Clinical Resource. Johns Hopkins University HIV Clinical Guidelines Program, July 2016. Web.

LABORATORY MARKERS

¢ Viral RNA (“Viral Load”)� Quantifies the degree of viremia� Best predictor of rate of progression of disease and efficacy of tx� Clinically undetectable: <20-50 copies/mL

¢ CD4+ T Lymphocytes� Normal range: 500-1600 cells/mm3 (40-70% of total lymphocyte count)� Measures the amount of immune system damage� Predictive of risk for opportunistic infections� Leading indicator of need for antiretroviral therapy

¢ AIDS Diagnosis:� CD4 < 200 cells/mm3

� CD4 < 14% (of total lymphocyte count)� AIDS-Defining Illness or malignancy

12"Plasma HIV-1 RNA (Viral Load) and CD4 Count Monitoring." National Institutes of Health. U.S. Department of Health and Human Services, 01 May 2014.

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STAGES OF HIV

13

"The Stages of HIV Infection." National Institutes of Health. U.S. Department of Health and Human Services, 09 Sept. 2016.

CLINICAL PRESENTATION¢ 40-90% of patients experience acute retroviral syndrome

(ARS)¢ Symptoms can last 2-4 weeks and often diagnosis is

missed

14

"Acute and Recent (Early) HIV Infection." National Institutes of Health. U.S. Department of Health and Human Services, 28 Jan. 2016.

ASSESSMENT QUESTION #2¢ When does a person with HIV infection have

AIDS?� A. CD4 count <200

� B. CD4 % <14

� C. Presence of AIDS-defining illness

� D. Has had HIV > 20 years

� E. All except D15

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TREATMENT: WHY WE TREAT

Prior to 1996:1} Treatment of OIs2} Palliative Care

Post-1996:1} Reduce HIV-associated morbidity and prolong the

duration and quality of survival2} Restore and preserve immunologic function3} Maximally and durably suppress plasma HIV viral load4} Prevent HIV transmission

16

“Treatment Goals." National Institutes of Health. U.S. Department of Health and Human Services, 28 Jan. 2016.

TREATMENT: WHO TO TREAT

¢ Treatment is recommended for all HIV-infected individuals, regardless of CD4 count, to reduce the morbidity and mortality associated with HIV infection and to prevent HIV transmission

¢ Increased urgency in following patient populations:� Pregnancy� AIDS-defining conditions� Acute opportunistic infections � Lower CD4 counts (<200 cells/mm3)� HIV-associated nephropathy (HIVAN)� Hep C or Hep B co-infection

17

“Initiation of Antiretroviral Therapy." National Institutes of Health. U.S. Department of Health and Human Services, 28 Jan. 2016.

HIV LIFE CYCLE

18"HIV/AIDS Background Information." HIV POC Project. BioMEMS South Africa, n.d. Web.

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DRUG CLASSES: FUSION/ENTRY INHIBITORS

¢ Fusion inhibitor: Enfuvirtide (T20)� Brand Name: Fuzeon� MOA: synthetic 36-amino acid

peptide that binds gp41 to inhibit fusion of HIV with target cell

� SC administration� ADRs: injection site reactions,

hypersensitivity reactions� Metabolized via protein

catabolism and amino acid recycling

� Has low genetic barrier to resistance

� Dose: 90 mg SC BID

¢ Entry Inhibitor: Maraviroc� Brand Name: Selzentry� MOA: blocks CCR5 receptor� Tropism Assay REQUIRED� ADRs: Abdominal pain, cough,

dizziness, rash, hepatotoxicity� CYP3A & P-gp substrate� Dosing:

¢ 150 mg BID if given concomitantly with strong CYP3A inhibitors including PIs

¢ 300 mg BID if given concomitantly with drugs that are NOT strong CYP3A inhibitors or inducers

¢ 600 mg BID if given concomitantly with strong CYP3A inducers including EFV & ETV

19

“Drugs." National Institutes of Health. U.S. Department of Health and Human Services.

HIV LIFE CYCLE

20

"HIV/AIDS Background Information." HIV POC Project. BioMEMS South Africa, n.d. Web.

DRUG CLASSES: NUCLEOSIDE/NUCLEOTIDEREVERSE TRANSCRIPTASE INHIBITORS (NRTIS)¢ Stavudine (d4T) Zidovudine (AZT or ZDV)¢ Emtricitabine (FTC) Lamivudine (3TC)¢ Abacavir (ABC) Didanosine (ddI)¢ Tenofovir (TDF/TAF)

MOA:1} Competes with endogenous deoxyribonucleotides for catalytic site of

reverse transcriptase2} Prematurely terminates DNA elongation due to lack of 3’-hydroxyl

group

Combos:ABC + ZDV + 3TC – Trizivir ABC + 3TC – EpzicomFTC + EVG + COBI + TDF – Stribild FTC + TDF – Truvada3TC + ZDV – Combivir FTC + TAF – Descovy

21


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DRUG CLASSES: NRTIS

¢ Adverse Effects� Peripheral neuropathy� Pancreatitis� Lipoatrophy� Myopathy� Anemia� Lactic acidosis

¢ Mostly eliminated by the kidney so dose adjustments are needed for renal insufficiency (except abacavir)

¢ Resistance has been reported for all NRTIs

http://eyewiki.aao.org/images/1/c/ce/HIV-associated_facial_lipoatrophy.png

22


DRUG CLASSES: NRTISDrug Dose Renal

Adjustments

Comments

Abacavir (Ziagen)*generic available*

300 mg BID or 600 mg daily

No HLA-B*5701 testing REQUIRED for HSR

Avoid in pts with VL >100k

Didanosine (Videx EC)*generic available*

BW <60 kg: 250 mg daily (with TDF 200 mg daily)

BW ≥60 kg: 400 mg daily (with TDF 250 mg daily)

*take ½ hour before or 2 hours after a meal*

Yes ADRs: peripheral neuropathy, pancreatitis, lactic acidosis, N/V

Emtricitabine (Emtriva) 200 mg daily Yes Hyperpigmentation/skin discoloration of palms and soles

*Indicated for Hep B*

Lamivudine (Epivir)*generic available*

150 mg BID or300 mg daily

Yes *Indicated for Hep B*

Stavudine (Zerit)*generic available*

BW <60 kg: 30 mg BIDBW ≥60 kg: 40 mg BID

Yes ADRs: peripheral neuropathy,pancreatitis, lipoatrophy, lactic acidosis

Tenofovir disoproxil fumarate (Viread)

Tenofovir alafenamide (not available as singleagent)

300 mg daily

10mg (when given with PK booster) or 25mg

Yes ADRs: Fanconi syndrome, renal insufficiency, proximal tubular necrosis, osteomalacia

*Indicated for Hep B*

Zidovudine (Retrovir)*generic available*

300 mg BID or200 mg TID

Yes Bone marrow suppression, lactic acidosis, myopathy, lipoatrophy

23

DRUG CLASSES: NON-NUCLEOSIDE REVERSETRANSCRIPTASE INHIBITORS (NNRTIS)

¢ Efavirenz (EFV) Delavirdine (DLV)¢ Nevirapine (NVP) Etravirine (ETR)¢ Rilpivirine (RPV)

¢ MOA: bind noncompetitively to reverse transcriptase adjacent to the catalytic site *Don’t require intracellular activation like NRTIs*No activity against HIV-2

¢ Combos:� EFV + FTC + TDV – Atripla RPV + FTC + TDF – Complera

RPV + FTC + TAF – Odefsey24


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DRUG CLASSES: NNRTIS¢ Adverse Effects:

� RASH!!! (NVP >> rest)� Elevated liver function tests (particularly NVP)

¢ Mainly cleared by the liver and/or gut through CYP450 metabolism

¢ Have low genetic barrier to resistance

25


DRUG CLASSES: NNRTISDrug Dose Elimination CommentsEfavirenz (Sustiva) 600 mg daily at

bedtime

*take on an empty stomach*

-CYP2B6 and 3A4

-CYP3A4 inducer/inhibitor

(inducer > inhibitor)

ADRs: Rash, neuropsychiatricsymptoms (depression, hallucinations, etc. )

Pregnancy Cat. D

Etravirine (Intelence) 200 mg BID

*take following a meal*

-CYP3A4, 2c9, 2C19

-CYP3A4 inducer-CYP2c9 and 2c19

inhibitor

Nevirapine (Viramune; Viramune XR) *generic available*

200 mg daily x 14 days (lead-in period)

Then, 200 mg BID or 400 mg daily

*Repeat lead-in period if therapy D/C’d for >7 days

-80% excreted in urine

-CYP3A4 and 2B6 inducer

CD4 cut-offs:Women: >250Men: >400

Increased risk of rash, SJS, and hepatitis

Rilpivirine (Edurant) 25 mg daily

*take with a meal*

CYP3A4 substrate Not to be used in pts with VL >100,000

26

HIV LIFE CYCLE

27


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DRUG CLASSES: INTEGRASE INHIBITORS (INSTIS)

¢ Raltegravir (RTG) Elvitegravir (EVG)¢ Dolutegravir (DTG)

¢ MOA: binds to HIV integrase and inhibits the integration of viral DNA into the host cell genome preventing the formation of the HIV provirus halting replication

¢ RTG is metabolized through UGT1A1 and is generally not susceptible to CYP interactions

¢ EVG is metabolized first through CYP3A4, then glucuronidated so drug-drug interactions with CYP substrates are expected

¢ Combos:� DTG + ABC + 3TC - Triumeq EVG/c + FTC + TDF – Stribild

EVG/c + FTC + TAF – Genvoya28


DRUG CLASSES: INSTIS

Drug Dose Elimination CommentsRaltegravir (Isentress) 400 mg BID UGT1A1-mediated

glucuronidationRash including SJS, CPK elevation, rhabdomyolysis, N/D, headache

Elvitegravir(only available co-formulated with FTC + COBI + TDF as Stribild )

1 tab PO daily

*take with food*

*not rec’d for pts with CrCl <70 ml/min or with use of other ART

CYP3A, UGT1A1/3 N/D, new or worsening renal impairment

Dolutegravir (Tivicay) Tx-naïve or treatment-experienced INI-naïve: 50 mg daily

Tx-naïve or treatment-experienced INI-naïve + potent UGT1A/CYP3A inducers or suspected INI resistance: 50 mg BID

Primarily via UGT1A1, some contribution from CYP3A

Insomnia, headache

29

HIV LIFE CYCLE

30


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DRUG CLASSES: PROTEASE INHIBITORS (PIS)

¢ Atazanavir (ATV) Fosamprenavir (FPV)¢ Darunavir (DRV) Indinavir (IDV)¢ Lopinavir (LPV) Nelfinavir (NFV)¢ Ritonavir (RTV) Saquinavir (SQV)¢ Tipranavir (TPV)

¢ MOA: Selectively bind to protease enzyme and block cleavage of protein precursors resulting in production of immature, noninfectious virions

¢ Combos:� DRV/c – Prezcobix ATV/c – Evotaz� LPV/RTV – Kaletra

31


DRUG CLASSES: PIS

¢ Adverse Effects:� GI distress� Increased lipids� Insulin insensitivity� Changes in body fat distribution

¢ Metabolized by liver and gut enzymes (mainly CYP3A4)

¢ Numerous drug-drug interactions

¢ Have high-genetic barrier to resistance 32


DRUG CLASSES: PISDrug Dose Elimination Comments

Atazanavir (Reyataz) 300-400 mg daily + RTV 100 mg daily

*Interaction with PPIs – no more than omeprazole 20 mg daily*

*take with food*

CYP3A4 inhibitor and substrate

*dose adjust in pts with hepatic insufficiency*

ADRs: hyperbilirubinemia,PR interval prolongation, cholelithiasis

Darunavir (Prezista) Tx-naïve or no mutations:800 mg daily + RTV 100

mg daily

Tx-experienced with ≥1 mutation: 600 mg BID + RTV 100 mg BID

*take with food*


*has a sulfonamide moiety*ADRs: rash, SJS, TEN, hepatotoxicity

Fosamprenavir (Lexiva) Tx-naïve: 1400 mg BID or 1400 daily + RTV 100-200 mg daily or 700 mg BID + RTV 100 mg BID

Tx-experienced: 700 mg BID + RTV 100 mg BID

CYP3A4 substrate, inhibitor, and inducer


*has a sulfonamide moiety*Skin rash

Indinavir (Crixivan) 800 mg TID or 800 mg BID + RTV 100-200 mg BID

*if not taken with RTV, take 1 hour before or 2 hours after meals*



ADRs: nephrolithiasis, hyperbilirubinemia, hepatitis, “Crix belly”

33

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DRUG CLASSES: PISDrug Dose Elimination CommentsLopinavir + ritonavir(Kaletra)

400 mg/100 mg BID or 800 mg/200 mg daily


ADRs: N/V/D, pancreatitis, PR and QT interval prolongation

Nelfinavir (Viracept) 1250 mg BID or 750 mg TID

-Metabolized to active M8 metabolite-CYP3A4 and 2C19 substrate-CYP3A4 inhibitor

Diarrhea!!!

Ritonavir (Norvir) 100-400 mg daily in divided doses as PK booster

*take with food*

-CYP3A4, 2D6 substrate

-Potent CYP3A4, 2D6 inhibitor

ADRs: N/V/D, parasthesias, hepatitis, taste perversion

Saquinavir (Invirase) 1000 mg BID + RTV 100 mg BID

*take with food or within 2 hours of a meal*


QT prolongation: pts with AT >450ms shouldn’t receive SQV

Tipranavir (Aptivus) 500 mg BID + RTV 200 mg BID

CYP3A4 inducer and substrate

*has a sulfonamidemoiety*Hepatoxicity, skin rash, ICH (rare)

34

ASSESSMENT QUESTION #3¢ Which of the following NRTIs does not require

renal dose adjustments?� A. Tenofovir

� B. Abacavir

� C. Zidovudine

� D. Emtricitabine

� E. B and D35

HIV TREATMENT OPTIONS

http://crine.org/files/2013/07/CRI_Pill_Chart_Nov_2015-1024x632.jpg

36

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WHAT TO START: RECOMMENDED REGIMENSTenofovir/Emtricitabine∆

ORAbacavir/Lamivudine#

+

PI-basedDarunavir∆(+ritonavir)

INSTI-based

Raltegravir∆Dolutegravir∆#

Elvitegravir∆ (+ COBI)1

1Only for patients with pre-ART CrCl >70 mL/min if TDF component is used 37

"What to Start." National Institutes of Health. U.S. Department of Health and Human Services, 14 July 2016.

WHAT TO START: ALTERNATIVE REGIMENS

Tenofovir/Emtricitabine ∆

OR Abacavir/Lamivudine #

+

NNRTI-based

EFV∆

RPV∆1

PI-based

Boosted ATV∆

Boosted DRV#DRV/c ∆

1Only for patients with HIV RNA >100,000 copies/mL and CD4 count>200 cells/mm338

"What to Start." National Institutes of Health. U.S. Department of Health and Human Services, 14 July 2016.

WHAT NOT TO USE

¢ Single-drug therapy¢ Dual or triple NRTI therapy

� Exception: ABC/ZDV/3TC and possible TDF + ZDV/3TC¢ Atazanavir + Indinavir: increased risk of hyperbilirubinemia;

jaundice¢ Didanosine + stavudine: increased pancreatitis, lactic acidosis,

peripheral neuropathy¢ Didanosine + tenofovir: pancreatitis, lactic acidosis,

immunologic nonresponse¢ Dual NNRTIs¢ FTC + 3TC: no additional benefit; same resistance profiles¢ ETV + unboosted PI or RTV-boosted ATV, FPV, or TPV¢ Unboosted DRV, SQV, or TPV¢ Stavudine + zidovudine: antagonistic effects

39

“What Not To Use." National Institutes of Health. U.S. Department of Health and Human Services, 27 March 2012.

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HIV MEDICATIONS

¢ Current regimens are highly effective with good tolerability

¢ Challenges:� Multi-drug Resistance� Kidney/liver dysfunction� Pill burden� Adherence� Side effects

40

41

WHAT’S THE BIG DEAL??

¢ Hep C is the #1 cause of chronic liver disease.¢ Hep C is the most frequent indication for liver

transplantation.¢ Hep C accounts for 1/3 of all Hepatocellular

Carcinoma (HCC) cases in the U.S.¢ Costs related to HCV is about $5.46 billion dollars

Mortality Rates from HBV, HCV, and HIV in United States, 1999-2007.

Source:http://www.hepatitisc.uw.edu/pdf/screening-diagnosis/epidemiology-us/core-concept/all

42

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PREVALENCE OF HCV IN THE U.S.

¢ Estimated 3.6 million people with chronic HCV infection per NHANES, 2003-2010� Measured by presence of HCV antibodies

¢ 2.7 million people living with chronic HCV infection� Measured by positive HCV RNA

¢ NHANES data has limited capture� Homeless (~500,000)� Institutionalized� Incarcerated (12-35% of all inmates; est. 2.2 million)

1. Armstrong, GL et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705.2. Wasley A, et al. Surveillance for acute viral hepatitis--United States, 2006. MMWR Surveill Summ. 2008;57(2):1.3. Denniston MM, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293.4. Weinbaum C, et al. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention.MMWR Recomm Rep. 2003;52(RR-1):1.

43

ACUTE HEPATITIS C INCIDENCE

Center for Disease Control and PreventionDivision of Viral HepatitisNational Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

44

HCV AND ‘BABY BOOMERS’

¢ 1945 to 1965 “Birth Cohort”� 80% of patients with chronic HCV in the U.S. � Prevalence = 2.6% (6-fold increase compared to all

other adults)The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002

Armstrong, GL et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705.

45

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RECENT “SURGE” OF HEP C

¢ HCV infection rates among young adults is INCREASING

¢ “New” IVDU:� Typically aged ≤24 years� Nonminority� Nonurban� Likely to have used oral prescription opioids before using

heroin¢ 2015 – 170 reported cases of HIV/HCV infection in

those injecting oxymorphone¢ 2016 – 16 reported cases of HCV infection linked to

an RN1. Klevins, R, eta al. “Evolving Epidemiology of Hepatitis C Virus in the United States” Clinical infectious Disease Vol 55; ppS3-9. 2. Hepatitis C virus infection among adolescents and young adults:Massachusetts, 2002-2009. Centers for Disease Control and Prevention (CDC) MMWR Morb Mortal Wkly Rep. 2011;60(17):537.3. Use of enhanced surveillance for hepatitis C virus infection to detect a cluster among young injection-drug users--new York, November 2004-April 2007. Centers for Disease Control and Prevention (CDC) MWR Morb Mortal Wkly Rep. 2008;57(19):517.4. Suryaprasad AG, et al. Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012. Clin Infect Dis. 2014 Nov;59(10):1411-9. Epub 2014 Aug 11.

46

ACUTE HCV IN YOUNG ADULTS

FIGURE 1. Incidence of acute hepatitis C among persons aged ≤30 years, by urbanicity and year — Kentucky, Tennessee, Virginia, and West Virginia, 2006–2012

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6417a2.htm?s_cid=mm6417a2_w

47

HCV TRANSMISSION¢ BLOOD to BLOOD CONTACT¢ Lives ~30 days in vitro¢ Prior to 1990, blood transfusions was an important

source of transmission � Now virtually eliminated due to improved screening of

HCV Ab ¢ “Hidden” Risk Factors

� Illicit intranasal drug use � Tattoo ink� Sharing of personal items (razors, toothbrushes)

48Daw, Mohamed A. "Transmission of Hepatitis C Virus." EScience Central. OMICS Publishing Group, 2014.

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SEXUAL TRANSMISSION OF HCV

¢ Blood must be shared for transmission of HCV to occur¢ Risks of transmission are higher if other STIs (e.g.,

HIV, herpes, etc.) are present¢ Three prospective cohort studies of such discordant

partner-pairs have failed to detect a single transmission in >9000 person-years of observation and an estimated 750 000 sexual encounters

¢ In recent years, acute HCV infection among HIV-infected men who have sex with men have been increasingly detected in Europe and the United States

49Daw, Mohamed A. "Transmission of Hepatitis C Virus." EScienceCentral. OMICS Publishing Group, 2014.

HCV – A GLOBAL HEALTH PROBLEM

http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/hepatitis-c

Over 170 million people living with Hep C worldwide

50

HCV-ASSOCIATED LIVER DISEASE PROGRESSION

Time Course of Chronic HCV Progression

Natural History of Chronic HCV Infection

Source: Thornton, Karla. Natural History of Hepatitis C Infection. Hepatitis C Online

51

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HCV LIFE CYCLE Lifecycle Animation Videohttps://www.youtube.com/watch?v=ZJ0wQ4sTAwQ

1. Attachment

2. Entry

3. Fusion

4. Translation

5. Replication

6. Assembly

7. Release

Dubuisson J, Cosset FL. Virology and cell biology of the hepatitis C virus life cycle: an update. J Hepatol. 2014 Nov;61(1 Suppl):S3-S13. doi: 10.1016/j.jhep.2014.06.031. Epub2014 Nov 3. Review.

52

TREATMENT BENEFITS BEYOND THE LIVER¢ Majority of patients with chronic hepatitis C infections are asymptomatic or have

chronic fatigue/malaise. � Extrahepatic manifestations are common, in the ~30-40% range.

¢ Treatment can improve some extrahepatic manifestations:� Diabetes Mellitus� Hematologic Disease

¢ Cryoglobulinemia¢ Lymphoma

� Renal Disease¢ Membranoproliferative glomerulonephritis

� Autoimmune Disorders¢ Thyroiditis¢ CRST Syndrome (Calcinosis, Raynauds, Sclerodactyly, Telangectasis)¢ Polyarthritis

� Dermatologic Conditions:¢ Porphyria cutanea tarda¢ Lichen planus

� Neuromuscular Disorders¢ Arthritis/Arthralgia¢ Myalgia/Weakness¢ Peripheral Neuropathy

1. Cacoub et al, Medicine (Baltimore), 2000; 79(1):47

2. Soriano et al, Antiviral Therapy, 2016; 21(1):1-8 3. Vanni et al, Digestive and Liver Disease, 2016;

48:105-1111

53

REDUCING DISEASE PROGRESSION RISK¢ Limit acetaminophen

� <4g/ day in general HCV population � <2g/ day if cirrhosis

¢ Quit smoking (tobacco and/or marijuana) ¢ Quit Alcohol

� > 50 grams alcohol per day clearly increases HCV-fibrosis progression

(1 standard drink is 13 grams) ¢ Limit herbals/supplements (e.g.,iron)¢ Lose weight if obese to reduce fatty liver/NASH risk¢ If patient has cirrhosis, avoid NSAIDs ¢ Avoid commonly used hepatotoxic agents

� e.g., statins (contraindicated in HCV and/or CTP Class A Cirrhosis)

54

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DIAGNOSING CHRONIC HCV INFECTION

55

METHODS OF STAGING LIVER FIBROSIS

56

¢ Liver Biopsy� Invasive� Direct visualization of liver tissue� Sample assigned a grade (0-4) to assess

inflammation and a stage (0-4) to assess fibrosis� No longer the “gold standard”

¢ Various Indirect Markers� FIB-4� APRI� Fibrosure/Fibrotest� Hepascore

Various Indirect MarkersFIB-4APRIFibrosure/FibrotestHepascore

All use various lab markers (e.g., ALT, AST, platelets, bilirubin, etc.)

The following lab markers are possibly indicative of cirrhosis:• PLT <150k• T.Bili >1.0• Albumin <3.5• INR >1.2

HCV CLINICAL PRESENTATION

57

¢ Usually ASYMPTOMATIC¢ If sx present, most common is fatigue

� Less common sx include nausea, arthralgia/myalgia, and asthenia¢ Physical Findings of Cirrhosis:

• Jaundice

• Spider angioma

• Palmar erythema

• Splenomegaly

• Ascites

• Peripheral edema

• Muscle wasting

• Vasculitis

• Hepatic encephalopathy

• Asterixis• Nystagmus• Excessive bruising• Esophageal Varices

Ge, Phillip S., and Bruce A. Runyon. "Treatment of Patients with Cirrhosis." New England Journal of Medicine 375.21 (2016): 2102-105.

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DECOMPENSATED CIRRHOSIS

58

� Can be classified using Child-Turcotte-Pugh (CTP) classification system

� Class B (7-9 points); Class C (10+ points)� Ascites, hepatic encephalopathy (HE), esophageal varices,

hepatorenal syndrome

Source: D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-31.

ASSESSMENT QUESTION #4¢ True or False:Hep C is considered a sexually transmitted infection.

¢ True¢ False

59

GOAL OF HCV TREATMENT

¢ To achieve sustained virologicresponse (SVR12)� Measured 12 weeks after completion of Hep

C treatment¢ Improve clinical outcomes

� Reduces progression of liver disease� Reduced risk of hepatocellular carcinoma� Reduced risk of liver failure� Reduced death related to liver disease� Reduced all-cause mortality

Morgan et al, Hepatology, 2010; 52(3):833-844

60

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WHEN TO TREAT?

Issues to Consider

Urgency•Cirrhosis?•Extrahepatic manifestations•HIV or HBV coinfection•Candidate for transplant

Patient Motivation

Treatment Considerations•Uncontrolled comorbidities•Intolerance to Ribavirin•Problems with adherence•Organ failure (liver, kidney)

Appropriateness of Therapy•Cirrhosis?•Viral resistance

McGowan CE, Fried MW. Liver Int. 2012;32(Suppl 1):S151-S156.

61

WHO NOT TO TREAT

¢ Short Life Expectancy� “The panel continues to recommend treatment for all patients with

chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy.”

¢ Transplant Candidates� Case-by-case basis� Consult with Transplant Team� Hope Act

¢ Signed by President Barack Obama in November 2013¢ HIV + organs for HIV patients and HCV+ organs for HCV + patients¢ First transplants were on March 30, 2016; one liver and one kidney¢ Shortens wait for organs from years to weeks

62

"WHEN AND IN WHOM TO INITIATE HCV THERAPY." HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, 6 July 2016.

OUT WITH THE OLD…¢ Pre-2011: Interferon is Standard of Care

� Extended treatment duration� Must be given with ribavirin� Numerous adverse effects� Low SVR rates

INTERFERONHematologic complications (neutropenia, thrombocytopenia)Neuropsychiatric complications (depression,irritability, headaches, memory/concentration disturbances)Flu-like symptomsMetabolic complications(hypo/hyperthyroidism, fever)GI complications (N/V, weight loss)Dermatologic complications (alopecia)Pulmonary complications (interstitial fibrosis)

63

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HISTORICAL INTERFERON SVR RATES

64

…IN WITH THE NEW

http://www.nature.com/nrd/journal/v12/n8/full/nrd4050.html

65

1ST GENERATION DIRECT-ACTING ANTIVIRALSFOR HCV

¢ Approved in June 2011� NS3/4A Inhibitors� GT 1 � Telaprevir (Incivek) and Boceprevir

(Victrelis)¢ Added to weekly pegylated interferon +

Ribavirin� Increased cure from ~30% to ~50-60%

¢ Up to 18 pills daily + weekly IFN injection

¢ Significant side effects¢ NO LONGER RECOMMENDED

66

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SIMEPREVIR

¢ 2nd generation NS3/4A inhibitor¢ Approved in Nov. 2013

� COSMOS trial – small study of 167 patients� In combo with PEG/RBV

¢ November 2014 – approved in combo with Sofosbuvir� 150mg simeprevir + 400mg sofosbuvir daily x

12-24 weeks¢ Q80k polymorphism

� Confers inherent resistance to simeprevir¢ Rarely used anymore due to development of

more effective and less expensive agents¢ Not indicated in decompensated cirrhosis or

in combination with transplant medications

PEG – Pegylated InterferonRBV – Ribavirin

Source: Olysio Prescribing Information. Janssen

67

SOFOSBUVIR¢ Nucleoside analog NS5B inhbitor¢ Prodrug à metabolized to GS-331007 (circulating

compound) and then taken up into hepatocytes where it is converted to GS-461203

¢ Approved in Dec. 2013¢ Pan-genotypic agent (GT 1-6)¢ 400mg daily in combo with other agents

� Ledipasvir (GT 1, 4, 5, 6)� Ribavirin (GT 1, 2, 3)� Daclatasvir (GT 1, 3)� Velpatasvir (GT 1-6)***

¢ Cost - $1000/pill¢ No CYP450 involvement¢ Substrate of P-gp¢ Avoid use in patients with CrCl <30 mL/min due to

accumulation of metabolites¢ Contraindicated with AMIODARONE

� Case reports of symptomatic bradycardia and cardiac arrest� If no other alternative, cardiac monitoring is required

Source: Sovaldi Prescribing Information. Gilead Sciences

68

RIBAVIRIN (RBV)

¢ Purine nucleoside analog¢ Unknown mechanism of action against HCV¢ Approved in 1998 for use with IFN and in 2001

for use with PEG¢ Never used as monotherapy¢ Significantly increases pill burden!!¢ Contraindications:

� Pregnant women and male partners of females who are pregnant¢ Teratogenicity potential¢ 2 forms of contraception in patients of childbearing

potential� Patients with hemoglobinopathies

¢ RBV induces hemolysis à hemolytic anemia69


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RIBAVIRIN ADMINISTRATION¢ Must be dose adjusted if CrCl <50 mL/min

� Once CrCl <60 mL/min, AUC of ribavirin increases at least 2-fold

� RBV is not significantly removed by dialysis� Significantly extended half-life of ~3 weeks

¢ Weight-based dosing for most DAA agents:� <75 kg: 1000mg/day� ≥75 kg: 1200mg/day� When given with Zepatier:

¢ <66 kg: 800mg/day¢ 66 to 88 kg: 1000mg/day¢ 81 to 105 kg: 1200mg/day¢ >105 kg: 1400mg/day

� Low-dose RBV is 600mg/day¢ Transplant, CTP B/C, Anemia

70


RBV SIDE EFFECTS

¢ Caffeine-like side effects� Insomnia (Avoid taking right before bedtime)� Diurectic effects

¢ Dehydration¢ Dry mouth/cough¢ Dry, itchy skin

� Anxiety/irritability¢ Anemia (Fatigue)

� 7% patients’ Hgb drops to less than 10 g/dL in trials� Secondary to hemolysis

¢ Birth Defects� Pregnancy Cat. X� Avoid pregnancy for entire treatment duration and for 6

months later

71


LEDIPASVIR/SOFOSBUVIR (HARVONI)¢ Fixed dose combination tablet of ledipasvir 90mg

(LDV) and sofosbuvir 400mg (SOF)¢ Ledipasvir – NS5A inhibitor¢ FDA Approval:

� 10/2014 – GT 1� 12/2015 – GT 4,5,6 and HIV/HCV co-infection� 02/2016 – GT 1,4 in liver transplant (+/- compensated

cirrhosis) and GT 1 (CTP B or C)

¢ Metabolism/Elimination:� No CYP450 involvement� Ledipasvir: slow oxidative metabolism, 1% renally

cleared¢ Inhibitor and substrate of P-gp

¢ Cost = $1125/pill

Source: Harvoni Prescribing Information, Gilead Sciences, Inc.

72

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LDF/SOF CONTRAINDICATIONS

� Patients with eGFR <30 mL/min¢ CONTRAINDICATED DRUGS:

� Antiarrhythmic: co-administration with amiodaroneresulting in symptomatic bradycardia and fatal cardiac arrest; if no other alternative, cardiac monitoring is required

� Anticonvulsants: carbamazepine, phenytoin, phenobarbital, oxcarbazepine

� Antimycobacterials: rifampin, rifabutin, rifapentine� Antiretroviral therapy: tipranavir/ritonavir� Herbal: St. John’s Wort� HMG CoA reductase inhibitor: rosuvastatin� Simeprevir: increases ledipasvir and sofosbuvir

concentrations


73

LEF/SOF DRUG INTERACTIONS

¢ Selected Drug-Drug Interactions� Proton pump inhibitors

¢ Not to exceed the equivalent of omeprazole 20mg/day¢ Must be given concomitantly on an empty stomach

� H2-receptor antagonists¢ Not to exceed the equivalent of famotidine 40mg BID¢ Take at the same time as Harvoni on an empty stomach (if

BID dosing, take 2nd dose 12 hours later)� Antacids: administer 4 hours apart from Harvoni� Digoxin: increased digoxin effect, monitor digoxin levels� Tenofovir: increased tenofovir effect, monitor for

tenofovir toxicity


74

LDV/SOF TREATMENT REGIMENSGenotype/Patient Populations Treatment

DurationGenotype 1

Treatment-naïve without cirrhosis or with cirrhosis (CTP A)

12 weeks*

Treatment-experienced** without cirrhosis 12 weeksTreatment-experienced** with cirrhosis (CTP A) 24 weeks***Treatment-naïve or treatment-experienced** with cirrhosis (CTP B or C)

Harvoni + RBV12 weeks

Genotype 1 or 4Treatment-naïve and treatment-experienced** liver transplant recipients without cirrhosis or with

cirrhosis (CTP A)

Harvoni + RBV12 weeks

Genotype 4, 5, 6Treatment-naïve or treatment-experienced without

cirrhosis or with cirrhosis (CTP A)12 weeks

*Consider 8 weeks in patients with baseline HCV RNA less than 6 million IU/mL**Treatment experienced = PEG/RBV +/- 1st generation PI***Consider Harvoni + RBV for 12 weeks in RBV-eligible patients

75


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LDF/SOV ADVERSE EFFECTS¢ Reported in ≥5% of subjects


8 weeks 12 weeks 24 weeks

N = 215 N = 539 N = 326

Fatigue 16% 13% 18%

Headache 11% 14% 17%

Nausea 6% 7% 9%

Diarrhea 4% 3% 7%

Insomnia 3% 5% 6%

76

PROD REGIMEN (VIEKIRA PAK)

¢ Approved in Dec. 2014¢ 3-drug (3D) regimen

� Paritaprevir (NS3/4A inhibitor) 75mg¢ Ritonavir (PK booster) 50mg

� Ombitasvir (NS5A inhibitor) 12.5mg� Dasabuvir (nonnucleoside NS5B inhibitor) 250mg

¢ Only approved for GT 1� Technivie for GT 4 (PrO regimen)� Also commonly used for patients on HD

¢ AE: Fatigue, pruritus, insomnia¢ Used with RBV except in GT 1b ONLY¢ Cost: $~80,000 for 12 weeks¢ DO NOT USE:

� Co-administration with drugs that are highly dependent on CYP3A for clearance, strong inducers of CYP3A and CYP2C8, strong inhibitors of CYP2C8

� CTP B or C

Source: Viekira Pak Prescribing Information, Abbvie, Inc.

77

PROD CONTRAINDICATIONS

Additions 04/2016:

Ranolazine (Antianginal)Dronedarone (Antiarrhythmic)Lurasidone (Antipsychotic)Cisapride (GI motility agent)

78


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PROD DRUG INTERACTIONS

79


PROD DRUG INTERACTIONS (CONT.)

80


PROD TREATMENT REGIMENS

*12 weeks for treatment naïve patients and prior relapsers or partial responders; 24 weeks for prior null responders

Follow GT 1a recommendations in patients mixed GT 1 subtypes or unknown GT 1 subtype

Patient Populations Treatment Duration

GT 1a with NO cirrhosis PrOD + RBV12 weeks

GT 1a with cirrhosis PrOD + RBV12-24 weeks*

GT 1b with or without cirrhosis 12 weeks

81


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PROD ADMINISTRATION

¢ GT 1a: 9-10 pills/day¢ GT 1b: 4 pills/day¢ Increased pill burden compared to other DAA

regimens82

DACLATASVIR (DAKLINZA)¢ NS5A inhibitor¢ In vitro activity for GT 1-6¢ Approved in July 2015

� In combo with sofosbuvir for GT 3 ¢ Add’l Indications in Feb. 2016

� GT 1 and 3 in combo with sofosbuvir +/- RBV� HIV coinfection� CTP Class B or C� Post-liver transplantation

¢ Cost: $63,000 for DCV only� Cost significantly increased for complete regimen due to

concomitant SOF use (~147,000 x 12 weeks)

DCV = Daclatasvir

83

Source: Daklinza Prescribing Information, Bristol Myers Squibb, Inc.

DCV ADMINISTRATION

¢ 60mg is standard dose (+/- food)� 30 mg when given when given with strong CYP3A inhibitors/some

HIV meds� 90mg when given with moderate CYP3A inducers and nevirapine

¢ Contraindicated with strong CYP3A inducers� Phenytoin, Carbamazepine, Rifampin, St. John’s Wort

¢ No dose adjustments for any degree of hepatic/renal impairment

¢ AE: Fatigue (14%), Headache (14%), Nausea (85), Diarrhea (5%)

¢ 1st DAA with required resistance testing� NS5A mutations (M28, Q30, L31, Y93) conferred markedly reduced

SVR rates¢ SVR of 33% in GT 1a, cirrhotic patients with at least 1 baseline NS5A

mutation in ALLY-1 and 2¢ SVR of 20-25% in GT 3, cirrhotic patients with NS5A mutation in

84


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DCV TREATMENT REGIMENS

Genotype Patient Population

Treatment and Duration

Genotype 1

Without cirrhosisDCV/SOF x 12 weeksCTP A cirrhosis

CTP B/C cirrhosisDCV/SOF/RBV x 12 weeksPost-transplant

Genotype 3Without cirrhosis DCV/SOF x 12

weeksCirrhosis (CTP A,B,C) DCV/SOF/RBV x 12

weeksPost-transplant

85


ELBASVIR/GRAZOPREVIR (ZEPATIER)

¢ Fixed dose combination tablet� Elbasvir 50mg – NS5A inhibitor � Grazoprevir 100mg – NS3/4A protease inhibitor, active against a

broader array of HCV genotypes than 1st generation protease inhibitors

¢ Approved in January 2016� GT 1,4� HIV coinfection

¢ 2nd DAA that requires baseline resistance testing for some genotypes� 70% SVR rates in GT 1a in patients with at least one major NS5A

mutation¢ DO NOT USE in CTP B/C cirrhotics¢ Approved for use in ESRD, including patients on HD¢ AE: Fatigue, Headache, Nausea, ALT>5x normal at Week 8

of treatment in 1% of patients¢ Cost: $54,600 x12 weeks; $72,800 x 16 weeks

Source: Zepatier Prescribing Information, Merck & Co, Inc.

86

EBV/GRZ CONTRAINDICATIONS

•OATP1B1/3 inhibitors, strong CYP3A inducers, and efavirenz

87


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EBV/GRZ TREATMENT REGIMENS

¢ *Polymorphisms at NS5A positions 28, 30, 31, or 93

Patient Population Treatment DurationGT 1a: Treatment-Naïve or PEG/RBV-experienced(without baseline NS5A polymorphisms*)

EBV/GRZ 12 weeks

GT 1a: Treatment-naïve or PEG/RBV-experienced (with baseline NS5A polymorphisms*)

EBV/GRZ + RBV 16 weeks

GT 1b: Treatment-naïve or PEG/RBV-experienced

EBV/GRZ 12 weeks

GT 1a or 1b: PEG/RBV/PI-experienced


GT 4: Treatment-naïve EBV/GRZ 12 weeks

GT 4: PEG/RBV-experienced


88


SOFOSBUVIR/VELPATASVIR (EPCLUSA)

¢ 1st Pangenotypic NS5A inhibitor ¢ Pangenotypic NS5B inhibitor ¢ GT 1-6¢ Approved June 28, 2016¢ Cost: $74,000 for 12 weeks¢ Very similar to LDF/SOF in terms of

administration, side effects, contraindications, etc.

89

Source: Epclusa Prescribing Information, Gilead Inc.

SUMMARY OF HCV TREATMENT OPTIONS

¢ Add your first bullet point here¢ Add your second bullet point here¢ Add your third bullet point here

Genotype Treatment Options Cure Rates

Genotype 1a/b • Harvoni +/- RBV x 8-24 weeks• Zepatier* +/- RBV x 12-16 weeks• Viekira* +/- RBV x 12-24 weeks

• 92-100% non-cirrhotic• 86-87% cirrhotic

Genotype 2 • Sofosbuvir + RBV x12-16 weeks• Daklinza + SOF x 12 weeks

• 88%-100% non-cirrhotic

• 78-94 % cirrhoticGenotype 3 • Harvoni + RBV x 12 weeks

• Daklinza + SOF + RBV x12-24 weeks• 83%-100% non-

cirrhotic• 70%-100% cirrhotic

Genotype 4 • Harvoni x12 weeks• Zepatier +/- RBV for 12-16 weeks• Viekira (– dasabuvir ) + RBV for 12

weeks

• 90%-100% non-cirrhotic

• 84%-92% cirrhotic

Genotype 5 or 6 • Harvoni for 12 weeks • 75%-100%

*Epclusa can be used for any GT!*Viekira and Zepatier are not to be used in decompensated cirrhosis.

Legend:Harvoni: ledipasvir (NS5A)/sofosbuvir (NS5B)Zepatier: elbasvir (NS5A)/grazoprevir (PI)Viekira: paritaprevir (NS3-4A)/ritonavir(PI)/ombitasvir(NS5A)/dasabuvir (NS5B)Daklinza: daclatasvir (NS5A) hcvguidelines.org/full-report-view.

hepatitis.va.gov/pdf/treatment-considerations-2016-03-28.pdf

90

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ASSESSMENT QUESTION #5¢ 3) Which one of the following groups is

considered unlikely to derive benefit with treatment for hepatitis C infection?

A. Patients with an estimated lifespan of less than 12 months.

B. Patients with genotype 3 HCV infection.C. Patients with porphyria cutanea tarda.D. Patients with chronic kidney disease (CKD).

91

PATIENT CASE LM

92

¢ LM is a 57 yo BM with HIV/HCV coinfection here in clinic for routine f/u. His HIV infection is well-controlled on HAART and he is now interested in being started on Hep C treatment.

¢ PMH:� HIV/AIDS� HCV� HTN� T2DM� GERD

¢ Medication regimen� Darunavir 800mg daily� Ritonavir 100mg daily� TAF/FTC 1 tablet daily� Lisinopril 20mg daily� HCTZ 25mg daily� Metformin 1000mg BID� Glipizide 10mg daily� Simvastatin 20mg daily� Omeprazole 20mg daily� Fluticasone 1 spray IEN daily

PATIENT CASE LM

93

¢Labs:� CD4: 427 cells/mm3 (26%)� HIV-RNA: <20 copies/mL� HCV RNA: 8.9 million IU/mL� HCV Genotype 1a� Treatment naïve

� Alb: 3.7 g/dL� Tbili: 0.8 mg/dL� AST: 215 U/L� ALT: 179 U/L� Alk Phos: 87 mg/dL� INR: 1.03

5.2

17.3

169

52.8

140

4.1 103

24 12

1.189

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DRUG INTERACTIONS BETWEEN HIV ANDHCV TREATMENT

¢ All HIV-infected patients should be screened for hepatitis C virus (HCV) infection. Patients at high risk of HCV infection should be screened annually and whenever HCV infection is suspected.

¢ Antiretroviral therapy (ART) may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation.

¢ ART should be initiated in all HCV/HIV-coinfected patients, regardless of CD4 T lymphocyte (CD4) cell count!

¢ Initial ART regimens recommended for most HCV/HIV-coinfected patients are the same as those recommended for individuals without HCV infection.

¢ In patients with lower CD4 counts (eg, <200 cells/mm3), ART should be initiated promptly and HCV therapy may be delayed until the patient is stable on HIV treatment. 94

“Considerations for Antiretroviral Use in Patients with Coinfections." National Institutes of Health. U.S. Department of Health and Human Services, 14 July 2016.

HCV/HIV DRUG INTERACTIONS¢ University of Liverpool Website:

� http://hiv-druginteractions.org/checker� http://hep-druginteractions.org/checker

95

PATIENT CASE LM

96

Drug Mechanism of Drug Interaction

Action

Fluticasone CYP3A4-mediatedincrease in fluticasone concentrations

D/C and switch to beclomethasone (or flunisolide)

Simvastatin CYP3A4-mediatedincrease in simvastatin concentrations

D/C and switch to pravastatin

Glipizide CYP2C9-mediateddecrease in glipizide concentrations

Monitor BG; increase glipizide dosage, if needed

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97

"UNIQUE PATIENT POPULATIONS: PATIENTS WITH HIV/HCV COINFECTION." HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, 12 Apr. 2017.

PATIENT CASE LM¢ Next step: HCV Treatment¢ Plan: LDF/SOF x 12 weeks

� GT 1a, TN, non-cirrhotic

98

TAF ≠ TDF

99

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1

Marsha K. Millonig, MBA, BSPharmCatalyst Enterprises, LLC

FL-ASCP Senior CareJune 24, 2017

Disclosures

• Marsha K. Millonig discloses that she consults with Strategic Pharma Solutions for their TEVA Respiratory client

Learning Objectives

3

• Determine when a patient with atrial fibrillation is at risk for stroke using evidence-based risk scoring assessments.

• Discuss the risk of stroke versus the risk of intracranial bleeding from anticoagulant therapy in patients with atrial fibrillation.

• Compare the benefits and risks of warfarin and direct-acting oral anticoagulant medications.

• Discuss reversal agents for non-warfarin anticoagulant medications that are currently under late-stage investigation.

• Describe a patient who should remain on warfarin therapy and a patient who should be considered for direct-acting oral anticoagulant therapy.

• Outline current evidence for prescribing aspirin for the prevention of stroke in patients with atrial fibrillation.

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Epidemiology of AF

3. Lloyd-Jones DM, et al. Circulation. 2004;110(9):1042-1046.

• Most common sustained cardiac arrhythmia1

• Currently affects 5.1 million Americans2

• Prevalence expected to increase to 12.1 million by 2050 (15.9 million if increase in incidence continues)2

• Preferentially affects men and the elderly1,2

• Lifetime risk of developing AF: ~1 in 4 for adults � 40 years of age3

1. Lloyd-Jones D, et al. [published online ahead of print December 17, 2009].Circulation. doi:10.1161/CIRCULATIONAHA.109.192667.

2. Miyasaka Y, et al. Circulation. 2006;114(2):119-125.

AF Is Associated With Increased Thromboembolic Risk

55. Page RL, et al. Circulation. 2003;107(8):1141-1145.

• Major cause of stroke in elderly1

• 5-fold in risk of ischemic stroke1,2

• 15% of strokes in US are attributable to AF3

• Stroke severity (and mortality) is worse with AF than withoutAF4

• Incidence of all-cause stroke in patients with AF: 5%1

• Stroke risk persists even in asymptomatic AF5

• Yet, frequently not risk-stratified so often undiagnosed and untreated

1. Fuster V, et al. J Am Coll Cardiol. 2001;38(4):1231-1266.2. Benjamin EJ, et al. Circulation. 1998;98(10):946-952.3. Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457.4. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.

AF Is the Leading Cause of Hospitalizations for Arrhythmia

0 200 400 600Hospital Days (thousands)

N=517,699 (representing 10% of CV admissions). VF,

ventricular fibrillation; VT, ventricular tachycardia.

6Adapted from Waktare JE, et al. J Am Coll Cardiol. 1998;81(suppl 5A):3C-15C.

Hospital Admissions in USAF

AFLCardiac arrest

Conduction diseaseJunctional

Premature beatsSick sinus

UnspecifiedVF VT

800 1000

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Conditions Frequently Associated With Nonvalvular AF1-4

104. Mozaffarian D, et al. Circulation. 2008;118(8):800-807.

1. Wattigney WA, et al. Circulation. 2003;108(6):711-716.2. Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.3. Fuster V, et al. J Am Coll Cardiol. 2006;48(4):854-906.

• Hypertension• Aging• Male sex• Obesity/metabolic syndrome/diabetes• Ischemic heart disease• Heart failure/diastolic dysfunction• Obstructive sleep apnea• Physical inactivity• Thyroid disease• Inflammation?

Classification of AF

8

Recurrent AF*

Paroxysmal Persistent

Permanent• Arrhythmiaterminates spontaneously

• AF is sustained<7 days

• Arrhythmia doesnot terminate spontaneously

• AF is sustained>7 days

• Both paroxysmal and persistent AF can become permanent

*Termination with pharmacologic therapy or direct-current cardioversion does not change the designation.

January C., et al. Circulation. 2014;129 Online March 28, 2014.

9

Understanding the Risk/Benefit Balanceof Anticoagulation Is Critical for NVAF

Amouyel P, et al. Eur J Intern Med. 2009;20(1):63-69.

Ischemic stroke Hemorrhagic stroke

INR below 2 is associated with an increased risk

of ischemic stroke

INR above 3 is associated with an increased risk

of hemorrhagic stroke

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Treatment

• 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation

• January CT, Wann LS, Alpert JS, Calkins H, Cleveland Jr JC, Cigarroa JE, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW, 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation,

• Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.03.022.

10

Treatment Goals and Strategies

11

Maintenance of SR

Pharmacologic Nonpharmacologic

Class IA Class ICClass IIIj3-blocker

Catheter ablationPacing SurgeryImplantable devices

Prevent Remodeling CCB ACE-I, ARB

StatinsFish oil

Stroke prevention

Pharmacologic• Warfarin• Aspirin• Thrombin InhibitorNonpharmacologic• Removal/isolation

LA appendage

Rate control

Pharmacologic• Ca2+ blockers• j3-blockers

(nondihydropyridineCa)

• Digitalis• Amiodarone

Nonpharmacologic• Ablate and pace

CHADS2 Risk Criteria for Stroke in Nonvalvular AF

Risk Factors Score

Recent congestive heart failure 1

Hypertension 1

Age ';≥75 y 1

Diabetes mellitus 1

12Gage BF, et al. JAMA. 2001;285(22):2864-2870.

C

H

AD

S2History of stroke or transient ischemic attack 2

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CHADS2 versus CHA2DS2VASc

Stroke Risk Stratification

Stroke Risk in AF Rises With CHADS2 Score

Fuster V, et al. Circulation 2006;114(7):e257-e354.

20

5

15

10

0

1.92.8

4.0

5.9

8.5

12.5

18.2

0n = 120

1n = 463

2n = 523

3n = 337

4n = 220

5n = 65

6n = 5

CHADS2 score

Str

oke

rate

(%

per

yea

r)

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6

Nonvalvular AF = AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic valve, or mitral valve repair.

CHA2DS2-VAScScore 0 no anticoagulation

Score 1 consider anticoagulationScore >/= 2 anticoagulation

ACC/AHA/HRS 2014 Atrial Fibrillation Guidelines: Summary of Recommendations to Prevent Thromboembolism in AF Patients

ACC/AHA/HRS 2014 Atrial Fibrillation Guidelines: Summary of Recommendations to Prevent Thromboembolism in AF Patients

AF indicates atrial fibrillation; BMS, bare-metal stent; CKD, chronic kidney disease; COR, Class of Recommendation;CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; INR, international normalized ratio; LOE, Level of Evidence;LMWH, low-molecular-weight heparin; N/A, not applicable; PCI, percutaneous coronary intervention; TIA, transient

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Aspirin

• IIB, C• Evidence does not support use as monotherapy

for stroke prevention in AF• 2007 meta analysis found 20% risk reduction

compared to no therapy but was not statistically significant

• Consistently and substantially less effective than warfarin in stroke reduction in all AF patients with CHADS2>1.

Hart RG, Pearce LA, Aguilar MI Ann Intern Med. 2007;146(12):857.

Bleeding Risk Assessment Prior to Therapy

Using CHA2DS2VASc & HAS-BLED

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ACCP Updated 2012 Guidelines

Patient Scenario

• Mr. Wilson, 70-year old with recent AF diagnosis. He drinks heavily due to issues related to his wife’s admission to a local LTC facility with dementia. He is also suffering from high blood pressure.

• Weight: 150 lbs.

• BP: 163/85 mmHg

• Heart Rate: 78, irregular • Normal glucose, liver and CBC values

• INR 1.8

• Meds: Metoprolol 50 mg twice daily, Zolpidem 5 mg qhs

What is Mr. Wilson’s CHA2DS2VASc Score?

A. 1B. 2C. 3D. 4E. 5F. 6G. 7H. 8I. 9

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What is Mr. Wilson’s HAS-BLED Score?

A. 1B. 2C. 3D. 4E. 5F. 6G. 7H. 8I. 9

What treatment would you recommend?

What treatment would you recommend?

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The “Ideal” Anticoagulant

• Oral, fixed dosage, preferably once a day• Rapid onset• Rapid offset of action• No need for renal or liver adjustment• Predictable kinetics• No need to switch therapies• Wide therapeutic window• No need for routine anticoagulant effect

monitoring• Low property for food/drug interactions• Available antidotes

Landscape has Changed with New Agents

Warfarin for Stroke Prophylaxis

• Standard of treatment for 60 years• Lowers stroke risk by 68% versus

22% with antiplatelet agents (aspirin; clopidigrel)

• Often underused in those >75 years with the highest stroke risk

The Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546-554.

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.

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Limitations of Warfarin

31

Limitations

Slow onset of action

Genetic variation in metabolism

Multiple food and drug interactions

Narrow therapeutic window

Hirsh J. N Engl J Med. 1991;324(26):1865-1875.Bates SM, Weitz JI. Br J Haematol. 2006;134(1):3-19.

Courtesy of PR Kowey, MD.

Consequences

Overlap with parenteral anticoagulant

Variable dose requirements

Frequent coagulation monitoring

Frequent coagulation monitoring

Warfarin Limitations

• Clinician may be reluctant to use, especially in older patients

• Advanced age, hemorrhage and bleed risk from falling

• Comorbidities contribute: arthritis, orthopedic problems, Parkinson’s disease, cognitive impairment

• Stroke rates are 5-8 times greater than bleed risk

• Would need to fall 295 times to offset the benefits of the antithrombotic therapy

Targets of New Anticoagulant Agents

Becattini Throm Res 2012

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Available Direct Acting Oral Anticoagulants (DOACs)

• Dabigatran

• Rivaroxaban

• Apixaban

• Edoxaban

DOACs

• Four novel agents• First on market since warfarin• Clinical studies show stroke protective effect ≥

warfarin• Less risk of intracranial bleeding• No food restrictions• Few drug-interactions• Simplified regimen • No INR monitoring• Kinetic differences need to be taken into account

in their use

Main Features of New Anticoagulant Agents


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DOAC Mechanism of Action

Direct Thrombin InhibitorDabigatran

Inhibits Factor XaRivaroxabanApixabanEdoxaban

From Amin AN and Marrs JC.

DOAC Pharmacokinetics

From Amin AN and Marrs JC., Product inserts

Drug Dabigatran Rivaroxaban Apixaban Edoxaban Class Direct

Thrombin Inhibitor

Factor Xa Inhibitor

Factor Xa Inhibitor

Factor Xa Inhibitor

Indications *Reduction of risk of stroke and systemic embolism in nonvalvular AF (NVAF) *Treatment of DVT & PE *Prophylaxis of DVT following hip replacement

*Reduction of risk of stroke and systemic embolism in nonvalvular AF (NVAF) *Treatment of DVT & PE *Reduction of recurrence of DVT & PE *Prophylaxis of DVT following hip/knee replacement

*Reduction of risk of stroke and systemic embolism in nonvalvular AF (NVAF) *Treatment of DVT & PE *Reduction of recurrence of DVT & PE *Prophylaxis of DVT following hip/knee replacement

*Reduction of risk of stroke and systemic embolism in nonvalvular AF (NVAF) *Treatment of DVT & PE

Dosing AF 150 mg BID 20 mg QD 5 mg BID 60 mg QD Renal Dosing Adjustments

CrCL 15-30 mL/min: 75 mg BID

CrCL 15-50 mL/min: 15 mg QD

≥2 present: ≥80 years, body weight ≤60kg, serum cr 1.5mg/dL: 2.5mg BID

CrCL 15-50 mL/min: 30 mg QD CrCl >90 mL/min: do not use

Hepatic Dosing Child-Pugh Class

A No adjustment No adjustment No adjustment No adjustment

B No adjustment Use warfarin Use with caution

Use warfarin

C Use warfarin Use warfarin Use warfarin Use warfarin Cost 30-day $334 $334 $360 $292

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Considerations

Missed Doses• Dabigatran

• – If dose not taken at scheduled time, take as soon as possible on same day

• – Missed dose should be taken at least 6 hours before next scheduled dose

• – Dose should not be doubled to make up for the missed dose

• Rivaroxaban• – For once daily doses: If dose not taken at scheduled time, administer as

soon as possible on same day as follows:

• – For patients receiving 20, 15 or 10 mg once daily, take missed dose immediately

• – For twice daily doses of 15 mg bid: take missed dose the same day; may take

• both doses at same time; resume bid schedule the next day.

• Apixaban

• – If dose not taken at scheduled time, take as soon as possible on same day

• – Missed dose should be taken at least 6 hours before the next scheduled dose

Drug Interactions Drug Interactions Drugs

Dabigatran P-gp inhibitors/inducers Ketoconazole, drondedarone,

rifampin Apixaban CYP3A4 and P-gp

inhibitors/inducersKetoconazole, itraconazole, ritonavir, clarithromycine,

rifampin, phenytoin Rivaroxaban CYP3A4 and P-gp

inhibitors/inducersKetoconazole, itraconazole, ritonavir, clarithromycine,

rifampin, phenytoinEdoxaban CYP3A4 and P-gp

inhibitors/inducers Ketoconazole, itraconazole, ritonavir, clarithromycine, rifampin

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Clinical Trials and new Anticoagulant Agents


TTR=Time in Therapeutic Range

Connoly SJ. JEJM 2009:351:1139.Granger CB. NEJM 2011;36:981. Patel MR. NEJM 2011:35:883.Giugliano RP. NEJM 2013;369:2093.

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Non-Inferiority Trials

• Equivalence: Not unacceptably different

• Non inferior: new intervention is not unacceptably worse

• Used if new txt offers advantage such as fewer side effects, convenience

Meta-Analysis of Stroke Prevention in AF


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• DOAC patients 7876• Warfarin patients 6651• All stroke or TIA history

• DOACs:15% ↓ composite of stroke/systemic embolism14% ↓ major bleeding56% ↓hemorrhagic stroke

The Balance of Ischemic and Hemorrhagic Strokes for NOACs Represents a Favorable Risk/Benefit Profile

Lawrence J, Hung J. Statistical considerations, ENGAGE AF trial. US FDA website. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm421612.pdf. Accessed November 20, 2015.

Ischemic Stroke (%/year)

Hemorrhagic Stroke (%/year)

Placebo ~5 ~0.1

Warfarin ~1.0 0.4-0.5

Aspirin ~4 ~0.2

Approved NOACs 0.8-1.0 0.1-0.3

When DOAC Preferred

• Elderly• High stroke risk• Not at high bleed risk• No significant drug interactions• Adherent to medications• Safety established in secondary

stroke prevention

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When Warfarin Preferred

• Patients stable on warfarin who are comfortable with INR and INR’s have been easy to control in TTR of 65%

• Patients with heart valves, rheumatic mitral valve disease, stenosis or lesions in moderate to severe heart failure

• Patients likely unable to comply with BID dosing

• Patients for whom DOACs are too costly• Patients with CKD and GRF < 30mL/min• Patients on enzyme inducing epilepsy meds or

HIV with protease inhibitor therapy

Which agent do you recommend?

• A 69 year old female patient (5’5”, 140 lbs) with hypertension, diabetes, and liver disease newly diagnosed with AF. Child Pugh C, CHADS2 2.

A. Warfarin to INR 2-3B. Dabigatran 150 mg BIDC. Apixaban 2.5 mg BIDD. Rivaroxaban 15mg dailyE. Dabigatran 75 mg BIDF. Edoxaban 60 mg QD

AF and Chronic Kidney Disease

• Increased risk of stroke: 1.5• Abnormalities in the coagulation

system• Defect in platelet adhesion and

aggregation• Secondary to uremic toxins• Increased risk of bleedingHart RG et al. Can J Cardiol 2013;29:s71.

Capodanno D. Circ 2012; 125: 2649.

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CKD

• http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm GFR = glomerular filtration rate

Warfarin in CKD

Olesen JB et al. N Engl J Med 2012; 367: 625. Hart RG et al. Clin J Am Soc Nephrol 2011; 6: 2599. Hart RG et al, Can J Cardiol 2013;29:s71.

Warfarin in CKD

• No randomized controlled trials• Data conflicting• Some harm suggested• Little evidence to support efficacy• Significant variability in study design and

endpointsShah M et al. Circ 2014; 129:1196.Shen JI et al. Am J Kidney Dis 2015; 66(4): 677. Olesen JB et al. N Engl J Med 2012; 367: 625. Can J Cardiol 2012; 28: 125.

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DOAC Trial CKD Sub-Analysis

Hijazi Z et al. Circ 2014;129:961-70 Fox KA et al. Eur Heart J 2011;32:2387. Hohnloser SH et al. Eur Heart J 2012; 33: 2821.Connolly SJ et al. New Engl J Med 2011; 364: 806.

DOAC Trial Sub-Analysis CrCl

• Using CKD-EPI apixaban decreases stroke and systemic embolism with eGFR < 50ml/min/1.73m2 in ARISTOTLE

Hijazi Z et al. Circ 2014;129:961-70Fox KA et al. Eur Heart J 2011;32:2387. Hohnloser SH et al. Eur Heart J 2012; 33: 2821.Connolly SJ et al. New Engl J Med 2011; 364: 806.

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AHA/ACC/HRS 2014 Guidelines

What would you recommend?

• 75 year old male with diabetes and moderate CKD with CHADs2=2. On insulin. Clcr 42 ml/mn

A. Warfarin adjusted to INR 2-3B. Apixaban 5.0 mg BIDC. Dabigatran 150 mg BIDD. Apixaban 2.5 mg BIDE. Rivaroxaban 15 mg QD

Summary

• All are as effective as warfarin• All have favorable bleeding

profiles• No testing is needed• Once or twice daily fixed dosing• Rapid onset and termination of

action• Reduced intracranial bleeds• Fewer drug interactions

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DOACs Continued: Questions?

• Reversibility?• No head to head studies• Dose adjustments with renal impairment• Possible they cannot be dialyzed with 95%

protein binding• Long-term safety? Especially in the elderly

(>80 years)• Higher costs• Dabigatran storage

65

How important is reversibility?

• Major bleeding not higher than warfarin• Lower all cause mortality by about 10%• Major bleed mortality lower than with warfarin

without a reversal agent• Trials of patients with major bleed suggest

favorable resource utilization with DOACs• Registry data showing real world results• Idarucizumab is now here and agents in studyMajeed A. Circ 2013; 128: 2325.

Graham DJ. Circ 2015; 131(2): 157.Beyer-Westendorf J. ThrombHaemost 2015; 113:1247.

DOACs: Bleeding

• Discontinue use of DOAC• Resuscitate with fluids & packed red blood

cells• Identify source of bleeding• Implement appropriate interventions to

provide control• Antidotes in study• Oral activated charcoal may be used 1-2

hours after accidental ingestion• Prothrombin complex concentrates may be

helpful

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Dosing of Concentrated Clotting Factors

Nutescu EA, et al. Am J Health Syst Pharm. 2013;70:1914. Babilonia K, et al. Thromb J. 2014;12:8.Zahir H, et al. Circulation. 2015;131:82.

Reversal Agents for DOACs

Weitz JI et al. Thromb Haemost. 2015 Jul 9;114(5). Pollack CV Jr et al. N Engl J Med. 2015;373(6):511.Siegal DM et al. N Engl J Med. 2015 Nov 11; doi: 10.1056/NEJMoa1510991.

Idarucizumab (Praxbind)

• Specific for dabigatran• Humanized Fab fragment• Binding affinity is 350 times higher than

dabigatran to thrombin• IV • Immediate onset of action• Short half-life• No pro or anti coagulant effects expected• The recommended dose of PRAXBIND

is 5 g, provided as two separate vials each containing 2.5 g/50 mL

Schiele F et al. Blood. 2013;121(18):3554. Stangier J et al. ISTH 2015; OR320.

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Andexanet alfa: Factor Xa Inhibitors

• Engineered version of human FXa, lacking direct catalytic activity of native protein

• Binds with high-affinity, blocking inhibition of Fxa

• ANNEXA trial• Met primary endpoint: mean percent

change in anti-fXa from baseline to post-infusion nadir was 92% (apixaban) and 97% (rivaroxaban)

Siegal DM, et al. N Engl J Med. 2015;373:2413.

Ciraparantag

• A synthetic small molecule (approximately 500 daltons)

• IV• Reverses anticoagulant effect of NOACs,

fondaparinux, and LMWH• Phase 2 study with edoxaban showed

complete and sustained reversal of steady-state edoxaban on day 3

Ansell JE, et al. N Engl J Med. 2014;371:2141.

Dabigatran

• Pharmacists should only dispense Pradaxa in the original manufacturer bottle with the original dessicantcap. Do not repackage Pradaxa capsules in standard amber pharmacy vials. Patients should not store or place Pradaxa capsules in any other container, such as pill boxes or pill organizers. Open only one bottle of Pradaxa at a time. The approved Pradaxa label states that once opened, the product must be used within 30 days. FDA is currently reviewing data that indicate no significant loss of potency up to 60 days after the bottle is opened as long as Pradaxa is stored in the original bottle and the handling requirements are met. Read the Medication Guide for Pradaxa for more information about these special storage and handling requirements.

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NOACs and Surgery

NOACs and Surgery

NOACs and Post-Surgery

• Depends solely on the postoperative risk for bleeding1,2

• Risk for major bleeding complications postsurgery clearly outweighs risk for thromboembolism1– – For major abdominal or urologic surgery:– • Delay TSOAs until no drainage or signs of active bleeding– – For procedures with good hemostasis shortly afterwards:– • Resume TSOAs a minimum of 4-6 h postsurgery– – In the case of bowel paralysis, bridging with a parenteral

anticoagulant may be required

• Dabigatran, rivaroxaban, apixaban and edoxaban should be resumed 24-48 h after a minor procedure, or 48-72 h after major surgery, assuming that hemostasis has been achieved2

• Dabigatran: resume with half-dose (75 mg) for first dose, then resume

• usual maintenance dose1

• Rivaroxaban: resume with 10 mg, then resume usual maintenance dose1

1. Schulman S et al. Blood. 2012;119:3016-3023. 2. 2. Nutescu EA. Am J Health-Syst Pharm. 2013;70(Suppl 1)S2-S11.

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Which New Agent Should We Recommend ?

• Variables to consider:• - coumadin experience

- approach to new drugs- cost considerations- h/o GI symptoms- compliance issues

Considerations

• Maureen Smyth John Hopkins Anticoagulation Clinic

Switching Anticoagulants

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Switching from one DOAC to another

• If the dose of the first DOAC was correct for• estimated renal function and other patient• parameters, initiate the alternative DOAC at

the time of the next scheduled dose of the prior DOAC

Conclusions

• Atrial fibrillation is common• AF is an important risk factor for stroke.• Stroke risk can be determined using CHADS

and CHADSvasc• Patients at increased risk of stroke should be

anticoagulated• Aspirin does little• The era of new anticoagulants is here and

now

Self-Assessment Question 1

• Which statement about AF is false?A. It is the most common cardiac arrhythimiaB. It affects men and the elderly preferentiallyC. The prevalence of AF is expected to more

than double by 2050D. 30% of all strokes in the US are attributed

to AF

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• Which statement is false?A. 80% of dabigatran is excreted renallyB. Apixaban has drug interactions with potent

P-glycoprotein (P-gp) inducersC. The half-life of rivaroxaban is 11 to 13

hours in older patientsD. None of the above


• When transitioning from warfarin to a new oral anticoagulant (NOAC), apixaban or dabigatran can be administered when INR is <2?

A. TrueB. False

It’s easy to make a buck. It’s a lot harder to make a difference.

–Tom Brokaw

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At the end of the day, we’re all in this together. And, it’s all about the patient.

Thanks for Having Me!

•[email protected]

•651-905-9002

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