PROBUPHINE®(BUPRENORPHINE)IMPLANT

PROBUPHINEREMSPROGRAMLIVETRAINING:LECTURESLIDES

Agenda

• Introduction• Probuphine(buprenorphine)implant

– Indication

• ProbuphineREMSProgram– GoalofREMSProgram– MitigatingPotentialRisks– Roles/ResponsibilitiesofHealthcareProviders(HCPs)– CertificationProcessforHCPs– PatientCounseling

• ProbuphineInsertion/RemovalProcedures– StepbyStepInsertion/RemovalProcedures– ComplicationsandRisksofInsertion/RemovalProcedures

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Probuphine®(Buprenorphine)Implant

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Probuphine(Buprenorphine)Implant

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EVA polymer Buprenorphine

Blended&

Extruded

Probuphine®

• Probuphineisanimplantableformulationofbuprenorphine• Eachimplantcontains74.2mgofbuprenorphine,uniformlydistributedthroughouttheethylenevinylacetateco-polymer(EVA)matrix

• 4Probuphineimplantsareinsertedsubdermallyintheupperarminanofficeprocedureanddelivercontinuous,stablebloodlevelsofbuprenorphinefor6months

• ProbuphinesurgicalprocedurescanonlybeperformedbyHCPswhohavesuccessfullycompletedthelivetrainingprogram

• Dosagewillbe4Probuphineimplants• Suppliedinakitcontaining4individuallypackagedimplantsandsteriledisposableapplicator

26 mm long,2.5mm diameter

ProbuphineIndicationProbuphineisindicatedforthemaintenancetreatmentofopioiddependenceinpatientswhohaveachievedandsustainedprolongedclinicalstabilityonlow-tomoderatedosesofatransmucosalbuprenorphine-containingproduct(i.e.,dosesofnomorethan8mgperdayofSubutexorSuboxonesublingualtabletorgenericequivalent).

Probuphineshouldbeusedaspartofacompletetreatmentprogramtoincludecounselingandpsychosocialsupport.

Probuphineisnotappropriatefornewentrantstotreatmentandpatientswhohavenotachievedandsustainedprolongedclinicalstability,whilebeingmaintainedonbuprenorphine8mgperdayorlessofSubutexorSuboxonesublingualtabletorgenericequivalent.

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ProbuphineREMSProgram

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REMS

• ARiskEvaluationandMitigationStrategy(REMS)isastrategytomanageknownorpotentialseriousrisksassociatedwithadrugproductandisrequiredbytheFoodandDrugAdministration(FDA)toensurethebenefitsofadrugoutweighitsrisks.

• BraeburnPharmaceuticalshasworkedwiththeFDAtodeveloptheProbuphineREMSProgramtomitigatetheriskofcomplicationsofmigration,protrusion,expulsion,andnervedamageassociatedwiththeinsertionandremovalofProbuphineandtherisksofaccidentaloverdose,misuseandabuseifanimplantcomesoutorprotrudesfromtheskin.

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GoalofProbuphineREMSThegoaloftheProbuphineREMSistomitigatetheriskofcomplicationsofmigration,protrusion,expulsionandnervedamageassociatedwiththeinsertionandremovalofProbuphineandtherisksofaccidentaloverdose,misuseandabuseby:

• Ensuringthathealthcareprovidersareeducatedonthefollowing:– ProperinsertionandremovalofProbuphine– Riskofcomplicationsofmigration,protrusion,expulsionandnervedamage

associatedwiththeinsertionandremovalofProbuphine– Risksofaccidentaloverdose,misuseandabuseifanimplantcomesoutor

protrudesfromtheskin• Informingpatientsabouttherisksofcomplicationsofmigration,

protrusion,expulsionandnervedamageassociatedwithinsertionandremoval,aswellas,therisksofaccidentaloverdose,misuseandabuseifanimplantcomesoutorprotrudesfromtheskin

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WhatistheProbuphineREMSProgram?

• ProbuphineisonlyavailablethroughthisREMSProgram– HealthcareProviders(HCPs)WhoPrescribemustbecertifiedto

placeanorderforProbuphine– HCPswhoinsertProbuphinemustbecertifiedtoperformthe

procedure– OnlyHCPwhoarecertifiedtoinsertProbuphinecanperform

removalprocedures– ProbuphinewillbedistributedthroughaClosedDistribution

SystemONLYtoHCPsWhoPrescribeProbuphineandeither(i)arecertifiedtoinsertor(ii)makearrangementsforacertifiedHCPWhoInsertstoperformtheprocedures

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ProbuphineREMS:MitigatingPotentialRisks1. Mitigatingcomplicationsassociatedwiththeinsertion/removal

– InformHCPsonrisksassociatedwiththeinsertion/removal• Migration• Protrusion• Expulsion• Nervedamage

– HCPsWhoPrescribewillbeeducated/trainedon:• Properandasepticinsertion/removalprocedures• Appropriatecareoftheincision/removalsite• Managingcomplicationsassociatedwithinsertion/removal• Referringpatientswhenthereareconcernsregardingtheincision/insertion

site

– HCPswhoperformProbuphinesurgicalprocedureswillbeeducated,trainedanddemonstrateproficiencyon:

• Properandasepticinsertion/removalprocedures• Appropriatecareoftheincision/removalsite• Managingcomplicationsassociatedwithinsertion/removal

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Probuphine REMS:MitigatingPotentialRisks,continued2. Mitigatingtherisksofaccidentaloverdose,misuse,andabuseassociated

withProbuphine ifanimplantcomesoutorprotrudesfromtheskin– MedicationinProbuphine canbeextractedandthenabusedinamanner

similartootheropioids– HCPsmustbeproperlyeducated,trained,passtheknowledgeassessment,

andbecertifiedintheProbuphine REMSProgramtoprescribeanddispenseProbuphine

– Probuphine shouldnotbedispensedtopatientsforself-administration– PrescribersmustgivepatientsWhatYouNeedtoKnowAboutProbuphine:

APatient’sGuide counselingtooltoinformpatientsabout:– Therisksofinsertion/removalofProbuphine– Therisksofaccidentaloverdose,misuse,andabuse,ifanimplantcomesoutor

protrudesfromtheskin– Theimportanceofappropriatewoundcare

– HCPswhoperformProbuphine surgicalproceduremustgivepatientstheProbuphineMedicationGuideateachinsertionprocedureandcounselpatientsabout:

– Therisksofinsertion/removalofProbuphine– Therisksofaccidentaloverdose,misuse,andabuse,ifanimplantcomesoutor

protrudesfromtheskin– Theimportanceofappropriatewoundcare

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HCPswhoPrescribeProbuphine:RolesandResponsibility

• TobecomecertifiedtoprescribeProbuphineintheREMSProgram,HCPmust:1. ReviewthePrescribingInformationforProbuphine.2. CompletetheProbuphineREMSProgramLiveTraining:LectureandPracticum,

andsuccessfullycompletetheProbuphineREMSProgramKnowledgeAssessment.

3. EnrollintheProbuphineREMSProgrambycompletingtheProbuphineREMSProgramPrescriberEnrollmentForm.

• Afterenrollment,prescribermust:o CounselpatientsusingWhatYouNeedtoKnowaboutProbuphine:APatient’s

Guide.o EnsureProbuphinesurgicalproceduresareperformedinyourhealthcaresettingbya

HCPwhoiscertifiedtoinsertProbuphine.PatientsmustbemonitoredtoensureProbuphineisremovedbyaHCPwhoiscertifiedtoinsert.

o Maintaindocumentationofinsertion/removalofProbuphineineachpatient’smedicalrecord.UsetheProbuphineREMSProgramInsertion/RemovalLogoranothermethod/system(e.g.,electronichealthrecord)specifictoHCP’spractice

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HCPswhoPerformProbuphine SurgicalProcedures:RolesandResponsibility

• TobecomecertifiedtoperformProbuphine surgicalproceduresintheProbuphineREMSProgram,HCPsmust:1. ReviewthePrescribingInformationforProbuphine.

2. Attesttoperformingasurgicalprocedureinthe3monthsimmediatelyprecedingenrollmentintheProbuphine REMSProgram.

3. CompletetheProbuphineREMSProgramLiveTraining:LectureandPracticum,andsuccessfullycompletetheProbuphineREMSProgramKnowledgeAssessment,aswellasmeettheProbuphineREMSProgramCriteriaforProceduralCompetency.

4. EnrollintheProbuphineREMSProgrambycompletingtheProbuphineREMSProgramHCPWhoPerformsProbuphineSurgicalProceduresEnrollmentForm orProbuphineREMSProgramHCPDualEnrollmentForm.

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HCPswhoPerformProbuphine SurgicalProcedures:RolesandResponsibility(cont.)• Afterenrollment,HCPswhoperformProbuphine surgical

proceduresmust:o Ensurethatthefacilitywheretheprocedureisbeingconductedhas

appropriateequipmenttoperforminsertions/removalsofProbuphine.PatientsmustbemonitoredtoensureProbuphineisremovedbyaHCPwhoiscertifiedtoinsert.

o CounseleachpatientonrisksassociatedwithProbuphineandprovideeachpatientacopyoftheProbuphineMedicationGuide.

o Documenttheinsertion/removalofProbuphine,usingtheProbuphineREMSProgramInsertion/RemovalLogorbyothermethod/system(e.g.,electronichealthrecord)specifictoHCP’spractice

o RecertifyintheProbuphine REMSProgramannually.

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Probuphine REMSProgramRecertificationRequirements1

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I have current operating privileges at hospitals or out-patient surgical centers:(Select the “yes” or “no” Column below that Applies)

If YESâ

If NOâ

I must review the Probuphine REMS Program Surgical Procedures Recertification Videofound on the Probuphine REMS website every year.

Number of Probuphine procedures in the past 12 months

(Select the Row that applies)

≥10

Performed 10 or more successful2

procedures (comprised of at least five insertions and five removals) à

I must review the Probuphine REMS Program Surgical Procedures Recertification Video found on the Probuphine REMS website every year.

I understand that I should keep documentation of all successfully completed procedures on the Probuphine REMS Program Procedure Record for Recertification or another record of my choosing - which must be provided to the Probuphine REMS Program if I am audited.

<10

Performed less than 10 successful2

procedures (comprised of at least five implantations and five removals) à

I must (annually):• attend a Probuphine REMS Program Live Training:

Lecture and Practicum session• successfully complete the Probuphine REMS Program

Knowledge Assessment test• meet the Probuphine REMS Program Criteria for

Procedural Competency

1 Denotes the minimal requirements. Healthcare Providers should utilize the tools provided for recertification as needed to ensureproper insertion/ removal of Probuphine is conducted in accordance with the Probuphine REMS Program.2 “Successful” implantation and removal procedures exclude attempted procedures that require assistance of other surgical specialties for completion. Removal procedures assisted by imaging studies prior to completion can be included, provided thatthe healthcare provider successfully removes all implants identified by imaging without involving additional surgical consultants.

ProbuphineREMSRecertificationRequirements• OnlyHCPswhoperformProbuphine surgicalprocedures needtoberecertified

every12months,byobtainingtheProbuphineREMSProgramHealthcareProviderWhoPerformsProbuphineSurgicalProceduresRecertificationFormfromtheProbuphineREMSProgramwebsiteandsubmittingviaFaxprovidedintheform.

• HCPswhoperformProbuphine surgicalprocedureswillbenotified60dayspriortorecertificationdeadline.

• HCPswhoperformProbuphine surgicalprocedureswillbesubjecttoauditiftheydonothaveoperatingprivilegesandchoosetorecertifybyattestingtocompletingtensuccessful proceduresinthepastyear.

– Successfulinsertionandremovalproceduresexcludeattemptedproceduresthatrequireassistanceofothersurgicalspecialtiesforcompletion.

– Removalproceduresassistedbyimagingpriortocompletioncanbeincluded,providedtheHCPsuccessfullyremovalallimplantsidentifiedbyimagingwithoutinvolvingadditionalsurgicalconsultations.

• HCPswhoperformProbuphine surgicalproceduresmayusetheProbuphineREMSProgramProcedureRecordforRecertification (foundintheProbuphine REMSProgramwebsite)todocumenteachInsertion/Removalprocedureshouldtheybeaudited 16

REMSMaterials

• ListofMaterialsforHCPs:– ProbuphineREMSProgramHealthcareProviderWhoPrescribesEnrollmentForm– ProbuphineREMSProgramHealthcareProviderWhoPerformsProbuphineSurgicalProceduresEnrollment

Form– ProbuphineREMSProgramHealthcareProviderDualEnrollmentForm– ProbuphineREMSProgramHealthcareProviderWhoPerformsProbuphineSurgicalProcedures

RecertificationForm– WhatYouNeedtoKnowAboutProbuphine:APatient’sGuide– ProbuphineREMSProgramInsertion/RemovalLog– ProbuphineREMSProgramProcedureRecordforRecertification– ProbuphineREMSProgramLiveTraining:LectureandPracticum– ProbuphineREMSProgramSurgicalProceduresRecertificationVideo(availableinlate2016)– ProbuphineREMSProgramKnowledgeAssessment– ProbuphineREMSProgramCriteriaforProceduralCompetency– ProbuphineMedicationGuide– ProbuphineInstructionsforUse– ProbuphineREMSWebsite

• ListofMaterialsforPatients– WhatYouNeedtoKnowaboutProbuphine:APatient’sGuide– ProbuphineMedicationGuide– ProbuphineREMSWebsite

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PatientCounseling,MedicationGuide,&CareoftheIncision

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PatientCounseling

• AllHCPswillprovidepatientcounseling

• Tworesourceswillbeutilizedforpatientcounseling:– WhatYouNeedtoKnowaboutProbuphine :APatient’sGuide– ProbuphineMedicationGuide

• HCPswhoPrescribeProbuphinewillcounselpatientsusingWhatYouNeedtoKnowaboutProbuphine:APatient’sGuide priortoprescribingitforpatients

• HCPswhoperformProbuphine surgicalprocedureswillcounselpatientsusingtheProbuphineMedicationGuidepriortoeachinsertionprocedure(TheMedicationGuideispartofeachProbuphineInsertionKit)

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PatientEducationonPotentialRisks:InsertionandRemovalofProbuphine

• TherearerisksassociatedwithProbuphineimplants,including:– Animplantmaycomeoutbyitself,oranendofanimplantmaybegin

stickingoutoftheskin.– Animplantmaymove(migrate).Probuphineorpiecesofitcanmove

intothebloodvesselsandtoyourlung,andcouldleadtodeath.– Injuryordamagetonervesorbloodvesselscouldoccur.– Implantsmaybedifficulttofindif:

• Theyaretoodeepforadoctortofeel• Apatienttriestomovethemaroundundertheskin• Apatienthasgainedalotofweightsincetheywereinserted

– Specialprocedures,tests,orareferraltoaspecialistmaybeneededtoremovetheimplantsiftheyaredifficulttolocate.

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PatientEducationonPotentialRisks:InsertionandRemovalofProbuphine

• Followingaresomecommonrisksassociatedwithanyminorsurgicalprocedure– Itching,pain,irritationorredness,swelling,bleeding,orbruisingattheinsertion

site– Scarringaroundtheinsertionsite

• AppropriatecareoftheincisionisimportanttoreducetheriskofcomplicationsassociatedwiththeinsertionandremovalofPROBUPHINE

• WhentocallaHCPrightaway:– Iftheimplantscomeoutortheendoftheimplantstartsstickingoutoftheskin– Iftherearesymptomsofinfectionatthesiteafterinsertionorremoval,including

excessiveorworseningitching,pain,irritation,redness,orswelling– Anynumbnessoranyweaknessinthearmaftertheinsertionorremoval

procedure– Iftherearesymptomssuggestingtheimplanthasmigrated,suchasweaknessor

numbnessinthearm,orshortnessofbreath

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PatientEducationonPotentialRisks:CareoftheIncisionInstructions

Explainpropercareoftheincisiontothepatient:• Keeptheincisionsitecleanasdirectedbyyourphysician.• Keeptheincisionsitecleananddry foratleast24hoursaftertheinsertionor

removalofimplants.Thisincludesavoidingshowers/bathsforthefirst24hourstokeepthepressuredressingandinsidebandagedry.Avoidanyactivitiessuchasswimmingorstrenuousactivitiesforthefirstweekaftertheimplantsareinsertedorremoved.

• Applyanicepackoracoldcompresstoyourarmfor40minuteseverytwohoursforthefirst24hoursandasneededafteryourproceduretoreducebruisingandswelling.

• Removethepressuredressing,butnottheinsidebandage24hoursaftertheprocedure.

• Removetheinsidebandage3-5daysaftertheprocedure.• Afterremovaloftheinsidebandage,youshouldgentlywashthewoundarea

(insertionandremovalsitearea)withsoapandwaterandpatdry.• Donotscratch,rub,orpickattheincisionsite,orputanyliquids,ointment

medicationsoranyotherproductontheincisionsite. 22

PatientEducationonPotentialRisks:CareoftheIncisionInstructions,continued• Protecttheincisionsitefromprolongedexposuretosunlightortanninglamps

whiletheincisionishealing.• Checkforanysignsandsymptomsofinfection,suchas:increasedpain,swelling,

redness,fever,drainageofpusorpus-likematerialfromtheinsertionandremovalsite.Ifanyofthesesignsorsymptomsappears,oriftheincisionsiteseemstobeopeningup,immediatelycontactthedoctorwhoperformedtheinsertionorremovalprocedure,thedoctorwhoprescribedProbuphine foryou,oranotherhealthcareprovider.

• AftertheInsertionProcedure:Keepsteri-strips(thethinbandagesstickingtoyourskin)onfor7daysaftertheprocedure.

• AftertheRemovalProcedure:Returntothephysician’soffice7daysaftertheproceduretohaveyourstichesremoved.Ifyouhaveabsorbablestiches,returntohaveyourincisioncheckedtomakesureitishealingwell.

Patientsmayreturnthenextdaytocheckthewound.Whenthepatientcomesback:

– Checkforsignsofinfection:heat,redness,pain,pus– Checkforsuturecomplications:knotfailure,wounddehiscence 23

PatientEducation:RiskofAccidentalOverdose,Abuse,Misuse

Thereisariskofaccidentaloverdose,abuseandmisuseforothersiftheimplantscomeoutandothersareexposedtothem• DonottrytoremoveProbuphineimplantsyourself

– Improperremovalcarriestheriskofimplantsiteinfection– Ifyouremovetheimplants,thismaycauseopioidwithdrawalsyndrome

• IftheProbuphineimplantscomeout:– WashyourhandsifyouhavetouchedtheProbuphineimplants– Covertheareawheretheywereinsertedwithacleanbandage– DonotallowotherstotouchorusetheProbuphineimplants,sincethis

couldbeverydangerous– Puttheminaplasticbagandbringthemtoyourdoctorrightaway– Keeptheimplantsinasafeandsecureplace,awayfromothers,

especiallychildren– Protecttheimplantsfromtheftuntilyoucanreturnthemtoyourdoctor

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ProbuphineInsertionandRemovalProcedure

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InsertionandRemoval

• Itmaybeofbenefitduringtheinsertion/removalprocesstohaveanassistantatalltimes.

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ProbuphineKit

• Only a certified prescriber is allowed to order the Probuphine Kit.• The only equipment from the kit that are needed for the insertion procedure are the

Probuphine implants and the Probuphine Applicator.

Probuphine Kits contain:– Four Probuphine Implants– Probuphine Applicator– Patient ID Card – Patient Chart Sticker – Instruction for Use Booklet– Probuphine Prescribing Information– Probuphine Medication Guide

NOTE: The Serial Number for the kit is located on the back of the kit, in the bottom left hand corner. The Serial Number should be recorded in the Probuphine REMS Program Insertion/Removal Log for tracking and accountability (including, for example, to track adverse events).

Insertion/RemovalProcedureTrainingObjectives

• Reviewanatomyofthebrachium• InsertionProcedure• ImplantLocalization• RemovalProcedure• CareoftheIncision• AvoidingComplications&ImportantPotentialRisksof:

– Migration,protrusion,expulsion,andnervedamage– Insertion/Removalprocedures– Accidentaloverdose,misuse,abuseassociatedifimplantexpulsionandprotrusionoccurs

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Brachium

Medial Bicipital Groove

Triceps

Biceps

Medial epicondyle

BrachiumCrossSection

It is important to avoid the neurovascular bundle that underlies the subcutaneous plane.

BrachiumCutaneousNerves

The medial cutaneous nerve lies within the subcutaneous tissue.

CorrectSubdermalInsertion

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Carefulandcorrectsubdermalinsertionisoneofthekeystosuccessfulplacementandwillfacilitateremoval.

InsertionofProbuphine

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ProbuphineInsertionProcedureEquipment• Anexaminationtableforthepatient

tolieon• Instrumentstand,steriletray• Adequatelighting(e.g.,headlamp)• Sterilefenestrateddrape• Latexandtalc-freesterilegloves• EtOHprep• Surgicalmarker• Antisepticsolution(e.g.,

chlorhexidine)• Localanesthetic(1%lidocainewith

epinephrine1:100,000)• 5mLsyringewith1.5inch25gneedle

• Adsonsingletoothtissueforceps• #15bladescalpel• ¼inchthinadhesivestrip(butterfly

strip)(e.g.Steri-stripskinclosures)• 4X4sterilegauze• Adhesivebandages• 3inchpressurebandages• Liquidadhesive(e.g.,Matisol)• 4Probuphineimplants(includedin

theProbuphineKit)• 1Probuphinedisposableapplicator

(includedintheProbuphineKit)

NOTE: Insertion kits contain all of the equipment, except for exam table, instrument stand, a headlamp, 4 Probuphine implants and 1 Probuphine applicator. Insertion kits are available from Braeburn upon request

ProbuphineApplicator

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Applicator

Bevel-up stop marking

InsertionProcedure

Step1.Havethepatientlieonhis/herback,withtheintendedarmflexedattheelbowandexternallyrotated,sothatthehandispositionednexttothehead.

Step2.Identifytheinsertionsite,whichisattheinnersideoftheupperarmabout8-10cm(3-4inches)abovethemedialepicondyleofthehumerusinthesulcusbetweenthebicepsandtricepsmuscle.Havingthepatientflexthebicepsmusclemayfacilitateidentificationofthesite.

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InsertionProcedure

Theclosertheimplantslietoeachotherattimeofinsertion,themoreeasilytheycanberemoved.Thereshouldbeatleast5mmbetweentheincisionandtheimplantwhentheimplantisproperlypositioned.

Step3.Cleantheinsertionsitewithalcoholpreppadpriortomarkingtheskin.

Step4.Marktheinsertionsitewiththesurgicalmarker.Theimplantswillbeinsertedthroughasmall2.5mm- 3mmsubdermal incision.

Step5.Usingthesurgicalmarker,markthechanneltrackswhereeachimplantwillbeinsertedbydrawing4lineswitheachline4cminlength.Theimplantswillbepositionedinaclosefanshapedistribution4-6mmapartwiththefanopeningtowardstheshoulder.

InsertionProcedureStep6.Putonsterilegloves.

Step7.Usingaseptictechnique,placethesterileequipment,PROBUPHINEimplants,andtheapplicatoronthesterilefieldoftheinstrumentstand.Oneapplicatorisusedtoinsertallfourimplants.

Step8.Checkapplicatorfunctionbyremovingtheobturatorfromthecannulaandrelockingit.

Step9.Cleantheinsertionsitewithanantisepticsolution(e.g.,chlorhexidine)usinggentlerepeatedback-and-forthstrokesfor30seconds.Whenusingthetripleswabstickapplicators,useeachswabsticksequentiallywithinthe30seconds.Allowtheareatoairdryforapproximately30secondsanddonotblotorwipeaway.

Step10.Applythesteriledrapetothearmofthepatient.

InsertionProcedureStep11.Anesthetizetheinsertionareaattheincisionsiteandjustundertheskinalongtheplannedinsertionchannelsusinglocalanesthetic(forexample,byinjecting5mLlidocaine1%withepinephrine1:100,000).

Step12.Afterdeterminingthatanesthesiaisadequateandeffective,makeashallowincisionthatis2.5-3mminlength.

InsertionProcedureStep13.Lifttheedgeoftheincisionopeningwithatoothedforceps.Whileapplyingcounter-tractiontotheskin,insertonlythetipoftheapplicatorataslightangle(nogreaterthan20degrees)intothesubdermalspace(depthof3-4mmbelowtheskin),withthebevel-upstopmarkingonthecannulafacingupwardsandvisiblewiththeobturatorlockedfullyintothecannula. (Figure1)

Step14.Lowertheapplicatortoahorizontalposition,lifttheskinupwiththetipoftheapplicatorbutkeepthecannulainthesubdermalconnectivetissue (Figure2).Whiletenting(lifting)gentlyadvancetheapplicatorsubdermally alongthechannelmarkingontheskinuntiltheproximalmarkingonthecannulajustdisappearsintotheincision(Figure3).

Figure 1

Figure 2

Figure 3

InsertionProcedureStep15.Whileholdingthecannulainplace,unlocktheobturatorandremovetheobturator.

Step16.Insertoneimplantintothecannula,re-inserttheobturator,andgentlypushtheobturatorforward(mildresistanceshouldbefelt)untiltheobturatorstoplineislevelwiththebevel-upstopmarking,whichindicatestheimplantispositionedatthetipofthecannula.Donotforcetheimplantbeyondtheendofthecannulawiththeobturator.Thereshouldbeatleast5mmbetweentheincisionandtheimplantwhentheimplantisproperlypositioned.

InsertionProcedureStep17.Whileholdingtheobturatorfixedinplaceonthearm,retractthecannulaalongtheobturator,leavingtheimplantinplace.Note:donotpushtheobturator.Byholdingtheobturatorfixedinplaceonthearmandbyretractingthecannula,theimplantwillbeleftinitscorrectsubdermalposition.

Step18.Withdrawthecannulauntilthehubisflushwiththeobturator,andthentwisttheobturatorclockwisetolockontothecannula.Retracttheapplicator,bevel-up,untilthedistalmarkingofthecannulaisvisualizedattheincisionopening(thesharptipremaininginthesubcutaneousspace).

InsertionProcedureStep19.Redirecttheapplicatortothenextchannelmarkingwhilestabilizingthepreviouslyinsertedimplant,withyourindexfinger,awayfromthesharptip.Followsteps13through16fortheinsertionofthethreeremainingimplantsthroughthesameincision,placingimplantsinaclosefan-shapeddistribution4-6mmapartatthetopoftheimplant.Theapplicatorcannowberemoved.

InsertionProcedureStep20.Alwaysverifythepresenceofeachimplantinthepatient’sarmbypalpationofthearmimmediatelyaftertheinsertion.Bypalpatingbothendsoftheimplant,youshouldbeabletoconfirmthepresenceofthe26mmimplant.Ifyoucannotfeeleachofthefourimplants,orareindoubtofeachoftheirpresence,useothermethodstoconfirmthepresenceoftheimplant.

Suitablemethodstolocateare:Ultrasoundwithahighfrequencylineararraytransducer(10MHzorgreater),orMagneticResonanceImaging(MRI).PleasenotethatPROBUPHINEimplantsarenotradiopaqueandcannotbeseenbyX-rayorCTscan.IfultrasoundandMRIfail,pleasecall1-844-859-6341.

InsertionProcedureStep21.Applypressuretotheincisionsiteforapproximatelyfiveminutesifnecessary.

Step22.Cleantheincisionsite.Applyliquidadhesivetotheskinmarginsandallowtodrybeforeclosingtheincisionwiththe1⁄4inchthinadhesivestrip(butterflystrip)(forexampleSteri-stripskinclosures).

Step23.Placeasmalladhesivebandageovertheinsertionsite.

Step24.Applyapressurebandagewithsterilegauzetominimizebruising.Thepressurebandagecanberemovedin24hoursandtheadhesivebandagecanberemovedinthreetofivedays.

Step25.CompletethePATIENTIDENTIFICATIONCARDandgiveittothepatienttokeep.Also,completethePATIENTCHARTSTICKERandaffixittothepatientmedicalrecordorscanorinputintoelectronicmedicalrecord.ProvidethepatientwiththeMedicationGuideandexplainpropercareoftheinsertionsite.

InsertionProcedureStep26.Theapplicatorisforsingleuseonly.DisposeoftheapplicatorinaccordancewiththeCentersforDiseaseControlandPreventionguidelinesforhazardouswaste.

Step27.Instructthepatienttoapplyanicepackonhis/herarmfor40minuteseverytwohoursforfirst24hoursandasneeded.

Step28.CompletethePROBUPHINEREMSProgramInsertion/RemovalLogForm.

– TheSerialNumberfromtheProbuphineKitshouldbeincluded fortrackingandaccountabilitypurposes (forexample,totrackAEs)intheProbuphineREMSProgramInsertion/RemovalLogFormandincludetheloginthepatient’schart– orbyusinganothermethodorsystem(e.g.electronichealthrecord)

– RecordtheprocedureintheProbuphineREMSProgramProcedureRecordforRecertification todocumenteachinsertion/removalprocedureshouldtheybeaudited

PatientEducationonPotentialRisks:CareoftheIncisionInstructionsExplainpropercareoftheincisiontothepatient:• Keeptheincisionsitecleanasdirectedbyyourphysician.• Keeptheincisionsitecleananddry foratleast24hoursaftertheinsertionor

removalofimplants.Thisincludesavoidingshowers/bathsforthefirst24hourstokeepthepressuredressingandinsidebandagedry.Avoidanyactivitiessuchasswimmingorstrenuousactivitiesforthefirstweekaftertheimplantsareinsertedorremoved.

• Applyanicepackoracoldcompresstoyourarmfor40minuteseverytwohoursforthefirst24hoursandasneededafteryourproceduretoreducebruisingandswelling.

• Removethepressuredressing,butnottheinsidebandage24hoursaftertheprocedure.

• Removetheinsidebandage 3-5days aftertheprocedure.• Afterremovaloftheinsidebandage,youshouldgentlywashthewoundarea

(insertionandremovalsitearea)withsoapandwaterandpatdry.• Donotscratch,rub,orpickattheincisionsite,orputanyliquids,ointment

medicationsoranyotherproductontheincisionsite.

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PatientEducationonPotentialRisks:CareoftheIncisionInstructions,continued• Protecttheincisionsitefromprolongedexposuretosunlightortanninglamps

whiletheincisionishealing.• Checkforanysignsandsymptomsofinfection,suchas:increasedpain,swelling,

redness,fever,drainageofpusorpus-likematerialfromtheinsertionandremovalsite.Ifanyofthesesignsorsymptomsappears,oriftheincisionsiteseemstobeopeningup,immediatelycontactthedoctorwhoperformedtheinsertionorremovalprocedure,thedoctorwhoprescribedProbuphineforyou,oranotherhealthcareprovider.

• AftertheInsertionProcedure:Keepsteri-strips(thethinbandagesstickingtoyourskin)onfor7daysaftertheprocedure.

Patientsmayreturnthenextdaytocheckthewound.Whenthepatientcomesback:• Checkforsignsofinfection:heat,redness,pain,pus• Checkforsuturecomplications:knotfailure,wounddehiscence

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LocalizationofProbuphineImplants

49

Probuphine Localization

• IdentifythelocationoftheimplantsbyconsultingthePATIENTIDENTIFICATIONCARDand/orTHEPATIENTCHARTSTICKER.– TheProbuphine REMSProgramInsertion/RemovalLoginthepatient’schartorelectronichealthrecordcanalsobeusedtoidentifythelocationoftheimplants.

• Theexactlocationofallimplantsinthearm(patientswillhavefourimplants)shouldbeverifiedbypalpation.

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InabilitytoPalpateProbuphine• Ifalloftheimplantsarenotpalpable,useothermethodstoconfirmthe

presenceoftheimplant(s).Non-palpableimplantsshouldalwaysbelocatedpriortoattemptedremoval.

• Suitablemethodstolocateimplantsare:– Ultrasoundwithahighfrequencylineararraytransducer(10MHzorgreater);or– MagneticResonanceImagine(MRI)

• NotethatProbuphineimplantsarenotradiopaqueandcannotbeseenbyX-rayorCTscan.Call1-844-267-8675ifyouareunabletolocatenon-palpableimplantsusingMRIorultrasound.

• Afterlocalizationofanon-palpableimplant,removalshouldbeperformedunderultrasoundguidance.

– Ifimplant(s)orimplantfragment(s)arenotremovedduringremovalattempt,thepatientshouldundergoimagingforlocalizationassoonasfeasible.

– Subsequentremovalattemptshouldbeperformedonthesamedayoflocalization.– Iflocalizationandasecondremovalattemptarenotperformedonthesamedayasthe

initialremovalattemptthatnecessitatedimagingforlocalization,thewouldshouldbeclosedwithsuturesintheinterim.

• Exploratorysurgerywithoutknowledgeoftheexactlocationofallimplantsisstronglydiscouraged

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Probuphine FourImplants:UltrasoundTransverseImage

RemovalofProbuphine

53

ProbuphineRemoval• Indicationsforremoval

– Attheendof6monthsoftreatment– Patientrequest– Medicalindication

• Beforeinitiatingtheremovalprocedure,readtheinstructionsforremoval.

• Counselpatientsaboutremovalprocedure• Donotattemptremovaluntilthelocationoftheimplants

havebeenverifiedbypalpationorimaging• Confirmnoallergiestoantisepticandanesthetic• Prepareasepticconditions• Allow45minutesforremovals

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ProbuphineRemovalProcedureEquipment• Anexaminationtableforthepatientto

lieon• InstrumentstandandSteriletray• Adequatelighting(e.g.,headlamp)• Sterilefenestrateddrape• Latexandtalc-freesterilegloves• EtOHprep• Antisepticsolution(e.g.,chlorhexidine)• Surgicalmarker• Localanesthetic(1%lidocainewith

epinephrine1:100,000)• 5mLsyringewith1.5inch25g• Adsonsingletoothtissueforceps

• Mosquitoforceps• TwoX-plantclamps(vasectomy

fixationclampswith2.5mmringdiameter)

• IrisScissors• Needledriver• #15bladescalpel• Sterileruler• 4x4sterilegauze• Adhesivebandages• 3-inchpressurebandages• Sutures(e.g.,4-0ProleneTM with

anFS-2cuttingneedle)– Maybeabsorbable

NOTE: Removal kits contain all of the equipment, except for exam table, instrument stand, and a headlamp Removal kits are available from Braeburn upon request

RemovalProcedureStep1.Havethepatientlieonhis/herback,withtheimplantarmflexedattheelbowandexternallyrotated,sothatthehandispositionednexttothehead.

Step2.Reconfirmthelocationoftheimplantsbypalpation.

Step3.Cleanremovalsitewithalcoholpreppadpriortomarkingtheskin.

Step4.Markthelocationoftheimplantswithasurgicalmarker.Inaddition,markthelocationoftheincision,paralleltotheaxisofthearm,betweenthesecondandthirdimplants.

RemovalProcedureStep5.Putonsterilegloves.

Step6.Usingaseptictechnique,placethesterileequipmentonthesterilefieldoftheinstrumentstand.

Step7.Cleantheremovalsitewithanantisepticsolution(e.g.,chlorhexidine)usinggentlerepeatedback-and-forthstrokesfor30seconds.Whenusingtripleswabstickapplicators,useeachswabsticksequentiallywithinthe30seconds.Allowtheareatoairdryforapproximately30secondsanddonotblotorwipeaway.

Step8.Applythesteriledrapetothearmofthepatient.

Step9.Anesthetizetheincisionsiteandthesubcutaneousspacecontainingtheimplants(forexample,byinjecting5-7mLlidocaine1%withepinephrine1:100,000).Separateneedles maybeusedfortheincisionsiteandthesubcutaneousinjections.NOTE:Besuretoinjectthelocalanestheticjustbeneaththeimplants;thiswilleffectivelylifttheimplantstowardtheskin,facilitatingremovaloftheimplants.

Step10.Afterdeterminingthatanesthesiaisadequateandeffective,makea7-10mmincisionwithascalpel,paralleltotheaxisarm,betweenthesecondandthethirdimplants.

RemovalProcedureStep11.PickuptheskinedgewithAdsonsingle-toothedtissueforcepsandseparatethetissuesaboveandbelowthefirstvisualizedimplantusinganirisscissorsoracurvedmosquitoforceps.GraspthecenteroftheimplantwiththeX-plantclampandapplygentletraction.Usethetechniqueofspreadingandclosingwitheithertheirisscissorsormosquitoforcepstoseparatethefibroustissue.Iftheimplantisencapsulatedusethescalpeltoshavethetissuesheathandcarefullydissectthetissuearoundtheimplant.Theimplantcanthenberemoved.

RemovalProcedureStep12.Retractthenextvisibleimplanttowardtheincisionalopening.Youmayseetentingoftheskinatthispointifthesurroundingtissueisstilladheringtotheimplant.Maintaingentletractionontheimplantwhileyoucontinuetodissectproximallyanddistallyuntiltheimplantisfreeofalladheringtissue.Atthispoint,youmayrequiretheuseofyoursecondX-plantclamptoremovetheimplant.Iftheimplantisencapsulatedusethescalpeltoshavethetissuesheathandcarefullydissectthetissuearoundtheimplant.Theimplantcanthenberemoved.

Step13.Afterremovalofeachimplant,confirmthattheentireimplant,whichis26mmlong,hasbeenremovedbymeasuringitslength.Ifapartialimplant(lessthan26mm)isremoved,theremainingpieceshouldberemovedbyfollowingthesameremovalinstructions.Followsteps11through13fortheremovaloftheremainingimplantsthroughthesameincision.Visualidentificationofwhetheranentireimplanthasbeenremovedisunreliable.Therefore,itisimportanttomeasuretheimplanttoensuretheentireimplanthasbeenremoved.

NOTE:arulershouldbeutilizedtomeasuretheremovedimplant

RemovalProcedureStep14.Afterremovalofallfourimplants,cleantheincisionsite.

Step15.Closetheincisionwithsutures.

Step16.Placeanadhesivebandageovertheincision.

Step17.Usethesterilegauzeandapplygentlepressureforfiveminutestotheincisionsitetoensurehemostasis.

Step18.Applyapressurebandagewithsterilegauzetominimizebruising.Thepressurebandagecanberemovedin24hoursandtheadhesivebandageinthreetofivedays.

Step19.Counselthepatientonproperasepticwoundcare.Instructthepatienttoapplyanicepacktohis/herarmfor40minuteseverytwohoursforfirst24hoursandasneeded.

RemovalProcedureStep20.Scheduleanappointmentforthesuturestoberemoved

Step21.Theremovedimplant,containsasignificantamountofresidualbuprenorphine,andmustbehandledwithadequatesecurity,accountability,andproperdisposal,perfacilityprocedureforaScheduleIIIdrugproduct,andperapplicablefederal,state,andlocalregulations.DisposalofPROBUPHINEimplantsshouldalsobeinkeepingwithlocalstateandfederalregulationsgoverningthedisposalofpharmaceuticalbiohazardouswaste.

Step22.CompletethePROBUPHINEREMSProgramInsertion/RemovalLogForm.

PatientEducationonPotentialRisks:CareoftheIncisionInstructionsExplainpropercareoftheincisiontothepatient:• Keeptheincisionsitecleanasdirectedbyyourphysician.• Keeptheincisionsitecleananddry foratleast24hoursaftertheinsertionor

removalofimplants.Thisincludesavoidingshowers/bathsforthefirst24hourstokeepthepressuredressingandinsidebandagedry.Avoidanyactivitiessuchasswimmingorstrenuousactivitiesforthefirstweekaftertheimplantsareinsertedorremoved.

• Applyanicepackoracoldcompresstoyourarmfor40minuteseverytwohoursforthefirst24hoursandasneededafteryourproceduretoreducebruisingandswelling.

• Removethepressuredressing,butnottheinsidebandage24hoursaftertheprocedure.

• Removetheinsidebandage3-5days aftertheprocedure.• Afterremovaloftheinsidebandage,youshouldgentlywashthewoundarea

(insertionandremovalsitearea)withsoapandwaterandpatdry.• Donotscratch,rub,orpickattheincisionsite,orputanyliquids,ointment

medicationsoranyotherproductontheincisionsite.

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PatientEducationonPotentialRisks:CareoftheIncisionInstructions,continued

• Protecttheincisionsitefromprolongedexposuretosunlightortanninglampswhiletheincisionishealing.

• Checkforanysignsandsymptomsofinfection,suchas:increasedpain,swelling,redness,fever,drainageofpusorpus-likematerialfromtheinsertionandremovalsite.Ifanyofthesesignsorsymptomsappears,oriftheincisionsiteseemstobeopeningup,immediatelycontactthedoctorwhoperformedtheinsertionorremovalprocedure,thedoctorwhoprescribedProbuphineforyou,oranotherhealthcareprovider.

• AftertheRemovalProcedure:Returntothephysician’soffice7daysaftertheproceduretohaveyourstichesremoved.Ifyouhaveabsorbablestiches,returntohaveyourincisioncheckedtomakesureitishealingwell.

Patientsmayreturnthenextdaytocheckthewound.Whenthepatientcomesback:• Checkforsignsofinfection:heat,redness,pain,pus• Checkforsuturecomplications:knotfailure,wounddehiscence

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Continuation of Therapy: Subsequent Insertion in the Contralateral Arm• ThereisnoclinicalexperiencewithinsertionofProbuphine beyonda

singleinsertionineacharm.

• Ifcontinuedtreatmentisdesiredattheendofthefirstsix-monthtreatmentcycle,Probuphineimplantsmaybereplacedbynewimplantsatthetimeofremovalinthecontralateralarm,followingtheinsertionstepsintheinstructionsforusetolocatetheappropriateinsertionsite.

• Ifnewimplantsarenotinsertedonthesamedayastheremoval,patientsshouldbemaintainedontheirpreviousdoseoftransmucosalbuprenorphine(i.e.,thedosefromwhichtheyweretransferredtoProbuphine treatment)priortoadditionalProbuphine treatment.

• Thereisnoexperiencewithinsertingadditionalimplantsintoothersitesinthearmtorecommendanapproachtoasecondinsertionintoapreviously-usedarm.

• Neitherre-insertionintopreviously-usedadministrationsites,norintositesotherthantheupperarm,havebeenstudied.

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ContinuationofTherapy:SubsequentInsertionintheContralateralArm

• Itisimportanttoavoidpreviously-implantedsitesbecausetheeffectofscarringandfibrosisinpreviously-usedinsertionsitesoneithertheeffectivenessofProbuphine orthesafetyofinsertionhavenotbeenevaluated.

• Afteroneinsertionineacharm,additionalcyclesoftreatmentshouldonlybeconsideredifthepotentialbenefitsofcontinuingProbuphine outweighthepotentialriskofadditionalinsertionandremovalprocedures,takingintoaccounttheexperienceofthehealthcareproviderwithProbuphine proceduresandrelatedprocedures,andtheclinicalneedofthepatientforongoingtreatmentwithsubdermal medication.

• Inmostcases,patientsshouldbetransitionedbacktoatransmucosal buprenorphine-containingproductforcontinuedtreatment.

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MitigatingComplicationsandRisksofInsertion/RemovalProcedures

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MitigationofComplicationsAssociatedwithInsertion/RemovalProcedure

• Therearerisksassociatedwithinsertion/removalofProbuphinesuchas:– Migration– Protrusion– Expulsion– Nervedamage

• Propertrainingandeducationisneededtoavoidcomplicationsassociatedwithinsertion/removal– Ensuringproperasepticinsertion/removalprocedures

• NOTE:HCPsWhoperformProbuphine surgicalprocedure mustdemonstrateproficiencyonpropertechniqueforcertification

– Providingappropriatecareoftheinsertion/removalsiteandinstructionstopatients

– Appropriatemanagementofcomplications

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PreventionofDeepInsertion

• InsertonlytheTIPoftheapplicator,slightlyanglednogreaterthan(~20°)topreventneurovascularinjury,atadepthof3-4mmbelowtheskin

• Lowertheapplicatortoahorizontalposition

• Gentlyinsert,whileliftingtheskin(tenting),theapplicatoruntiltheproximalmarking justdisappearsintotheincision,withoutusingforce

• Keeptheapplicatorparalleltothesurfaceoftheskin

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PreventionofaFractured/BentImplant• Duringinsertion:

– Avoidpushingthe beyondthebevel-upmarkingonthecannula

– Withdrawcannulauntilhubisflushwithobturator,twist theobturatorclockwisetolockintothecannula

• Duringremoval:– ApplygentletractionwithX-plantclamp,useanassistantifneeded.– Donotgrasptheimplantwithhemostat

• Ifimplant(s)orimplantfragment(s)arenotremovedduringaremovalattempt,thefollowingstepsshouldbetaken:– Thepatientshouldundergoimagingforlocalization.Thesubsequent

removalattemptshouldbeperformedonthesamedayoflocalization– Iflocalizationandasecondremovalattemptarenotperformedonthe

samedayastheinitialremovalattempt(thatnecessitatedimagingforlocalization),thewoundshouldbeclosedwithsuturesintheinterim

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PreventionofWoundInfection

• Adheretoaseptictechnique• Prepskinwithantisepticsolution(e.g.,chlorhexidine)perproductguidelines.

• Instructpatientonpropercareoftheincision

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HowtoAddressSpontaneousExpulsionofImplant1. Scheduletwoappointmentsforthepatienttoreturntotheofficeofthe

insertingHCPassoonaspossibleandtotheofficeoftheprescribingHCP.2. Instructthepatienttoplacetheimplantinaplasticbag,storeitsafelyoutof

reachofchildren,andtobringittotheHCPofficetodeterminewhetherthefullimplanthasbeenexpelled.

3. Ifthepatientreturnstheexpelledimplant,measureittoensurethattheentireimplantwasexpelled(26mm).

4. Disposeoftheremovedimplantinkeepingwithlocal,state,andfederalregulationsgoverningthedisposalofpharmaceuticalbiohazardwaste,aftermeasuring.

5. Examinetheincisionsiteforinfection.Ifinfected,treatappropriatelyanddetermineifremainingimplantsneedtoberemoved.

6. Iftheexpelledimplantisnotintact,palpatetheinsertionlocationtoidentifythelocationofanyremainingpartialimplant.Removetheremainingpartialimplantusingthetechniquesdescribedintheinstructionsforuseforremovalprocedure.

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HowtoAddressSpontaneousExpulsionofImplant

7. Call1-844-859-6341 toobtainanewkitthatwillincludefourimplantsandreturninstructionsforanyunusedimplants.

8. TheprescribingHCPmustcarefullymonitorpatientuntiltheimplantisreplacedtoevaluateforwithdrawalorotherclinicalindicatorsthatsupplementaltransmucosal buprenorphinemaybeneeded.

9. Scheduleanappointmenttoinsertreplacementimplant(s).10. Insertthereplacementimplant(s)inthesamearmeithermediallyor

laterallytoin-situimplants.Alternatively,replacementimplantmaybeinsertedinthecontralateralarm.

11. RecordtheserialnumberontheProbuphineREMSProgramInsertion/RemovalLog.

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AvoidingComplications:InsertionandRemoval

InSummary:Properattentiontotechniqueandfollowingtheinstructionswillminimizepotentialproblemsandcomplications

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ProbuphineREMSResources

• ForanyadditionalinformationaboutthePROBUPHINEREMSProgram,please call1-866-397-8939;OR

• Visitwww.PROBUPHINEREMS.com• ToReportanysuspectedadversereactions,pleasecall1-844-859-6341(pleaseremembertoprovidetheserialnumberofthekitwhenreportinganadverseevent)

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LiveDemonstrationbyTrainer:InsertionandRemovalProcedures

76

StepbyStepInsertion andRemoval Procedures Training

77