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OrangeBookPreface
FoodandDrugAdministration
CenterforDrugEvaluationandResearch
ApprovedDrugProductswithTherapeuticEquivalenceEvaluations
36thEdition
Thepublication,ApprovedDrugProductswithTherapeuticEquivalenceEvaluations(theList,commonlyknownas
theOrangeBook),identifiesdrugproductsapprovedonthebasisofsafetyandeffectivenessbytheFoodand
DrugAdministration(FDA)undertheFederalFood,Drug,andCosmeticAct(theFD&CAct).Drugsonthe
marketapprovedonlyonthebasisofsafety(coveredbytheongoingDrugEfficacyStudyImplementation[DESI]
review[e.g.,DonnatalTabletsandLibraxCapsules]orpre1938drugs[e.g.,PhenobarbitalTablets])arenot
includedinthispublication.Themaincriterionfortheinclusionofanyproductisthattheproductisthesubjectof
anapplicationwithaneffectiveapprovalthathasnotbeenwithdrawnforsafetyorefficacyreasons.Inclusionof
productsontheListisindependentofanycurrentregulatoryactionthroughadministrativeorjudicialmeans
againstadrugproduct.Inaddition,theListcontainstherapeuticequivalenceevaluationsforapprovedmultisource
prescriptiondrugproducts.Theseevaluationshavebeenpreparedtoserveaspublicinformationandadviceto
statehealthagencies,prescribers,andpharmaciststopromotepubliceducationintheareaofdrugproduct
selectionandtofostercontainmentofhealthcarecosts.Therapeuticequivalenceevaluationsinthispublication
arenotofficialFDAactionsaffectingthelegalstatusofproductsundertheFD&CAct.
BackgroundofthePublication.Tocontaindrugcosts,virtuallyeverystatehasadoptedlawsand/orregulations
thatencouragethesubstitutionofdrugproducts.Thesestatelawsgenerallyrequireeitherthatsubstitutionbe
limitedtodrugsonaspecificlist(thepositiveformularyapproach)orthatitbepermittedforalldrugsexceptthose
prohibitedbyaparticularlist(thenegativeformularyapproach).Becauseofthenumberofrequestsinthelate
1970sforFDAassistanceinpreparingbothpositiveandnegativeformularies,itbecameapparentthatFDAcould
notservetheneedsofeachstateonanindividualbasis.TheAgencyalsorecognizedthatprovidingasinglelist
basedoncommoncriteriawouldbepreferabletoevaluatingdrugproductsonthebasisofdifferingdefinitionsand
criteriainvariousstatelaws.Asaresult,onMay31,1978,theCommissioneroftheFoodandDrug
AdministrationsentalettertoofficialsofeachstatestatingFDA'sintenttoprovidealistofallprescriptiondrug
productsthatareapprovedbyFDAforsafetyandeffectiveness,alongwiththerapeuticequivalence
determinationsformultisourceprescriptionproducts.
TheListwasdistributedasaproposalinJanuaryl979.Itincludedonlycurrentlymarketedprescriptiondrug
productsapprovedbyFDAthroughnewdrugapplications(NDAs)andabbreviatednewdrugapplications
(ANDAs)undertheprovisionsofSection505oftheFD&CAct.
ThetherapeuticequivalenceevaluationsintheListreflectFDA'sapplicationofspecificcriteriatothemultisource
prescriptiondrugproductsontheListapprovedunderSection505oftheFD&CAct.Theseevaluationsare
presentedintheformofcodelettersthatindicatethebasisfortheevaluationmade.Anexplanationofthecode
appearsintheIntroduction.
AcompletediscussionofthebackgroundandbasisofFDA'stherapeuticequivalenceevaluationpolicywas
publishedintheFederalRegisteronJanuary12,1979(44FR2932).Thefinalrule,whichincludesFDA's
responsestothepubliccommentsontheproposal,waspublishedintheFederalRegisteronOctober31,1980
(45FR72582).Thefirstpublication,October1980,ofthefinalversionoftheListincorporatedappropriate
correctionsandadditions.Eachsubsequenteditionhasincludedthenewapprovalsandmadeappropriate
changesindata.

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OnSeptember24,1984,thePresidentsignedintolawtheDrugPriceCompetitionandPatentTermRestoration
Actof1984(1984Amendments).The1984AmendmentsrequirethatFDA,amongotherthings,makepublicly
availablealistofapproveddrugproductswithmonthlysupplements.TheApprovedDrugProductswith
TherapeuticEquivalenceEvaluationspublicationanditsmonthlyCumulativeSupplementssatisfythis
requirement.TheAddendumtothispublicationidentifiesdrugsthatqualifyunderthe1984Amendmentsfor
periodsofexclusivity(duringwhichANDAsorapplicationsdescribedinSection505(b)(2)oftheFD&CActfor
thosedrugsmaynotbesubmittedforaspecifiedperiodoftimeand,ifallowedtobesubmitted,wouldbe
tentativelyapproved)andprovidespatentinformationconcerningthelisteddrugswhichalsomaydelaythe
approvalofANDAsorSection505(b)(2)applications.TheAddendumalsoprovidesadditionalinformationthat
maybehelpfultothosesubmittinganewdrugapplicationtotheAgency.
TheAgencyintendstousethispublicationtofurtheritsobjectiveofobtaininginputandcommentonthe
publicationitselfandrelatedAgencyprocedures.Therefore,ifyouhavecommentsonhowthepublicationcanbe
improved,pleasesendthemtotheDirector,DivisionofLegal&RegulatorySupport,OfficeofGenericDrugs,
CenterforDrugandEvaluationandResearch,7620StandishPlace,Rockville,MD208552773.Comments
receivedarepubliclyavailabletotheextentallowableundertheFreedomofInformationregulations.
1.INTRODUCTION
1.1ContentandExclusion
TheListiscomposedoffourparts:(1)approvedprescriptiondrugproductswiththerapeuticequivalence
evaluations(2)approvedoverthecounter(OTC)drugproductsforthosedrugsthatmaynotbemarketedwithout
NDAsorANDAsbecausetheyarenotcoveredunderexistingOTCmonographs(3)drugproductswithapproval
underSection505oftheFD&CActadministeredbytheCenterforBiologicsEvaluationandResearchand(4)a
cumulativelistofapprovedproductsthathaveneverbeenmarketed,areforexportation,areformilitaryuse,have
beendiscontinuedfrommarketingandwehavenotdeterminedthattheywerewithdrawnforsafetyor
effectivenessreasons,orhavehadtheirapprovalswithdrawnforotherthansafetyorefficacyreasonssubsequent
tobeingdiscontinuedfrommarketing.ThispublicationalsoincludesindicesofprescriptionandOTCdrug
productsbytradeorestablishedname(ifnotradenameexists)andbyapplicantname(holderoftheapproved
application).AllestablishednamesforactiveingredientsgenerallyconformtoofficialcompendialnamesorUnited
StatesAdoptedNames(USAN)asdescribedin(21CFR299.4(e)).Thelatterlistincludesapplicants'namesas
abbreviatedinthispublicationinaddition,alistofuniformtermsisprovidedinAppendixC.
AnAddendumcontainsdrugpatentandexclusivityinformationforthePrescription,OTC,DiscontinuedDrug
ProductLists,andfortheDrugProductswithApprovalunderSection505oftheFD&CActAdministeredbythe
CenterforBiologicsEvaluationandResearch.ThepublicationmayincludeadditionalinformationthattheAgency
deemsappropriatetodisseminate.
Priortothe6thEdition,thepublicationhadexcludedOTCdrugproductsanddrugproductswithapprovalunder
Section505oftheFD&CActadministeredbytheCenterforBiologicsEvaluationandResearch.The1984
AmendmentsrequiredtheAgencytobeginpublishinganuptodatelistofallmarketeddrugproducts,OTCas
wellasprescription,thathavebeenapprovedforsafetyandefficacyandforwhichnewdrugapplicationsare
required.
UndertheFD&CAct,somedrugproductsaregivententativeapprovals.TheAgencywillnotincludedrug
productswithtentativeapprovalsintheList.TentativeapprovallistsareavailableonFDA'swebsiteatDrug
ApprovalReports(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?
fuseaction=Reports.ReportsMenu).Whenthetentativeapprovalbecomesafullapprovalthrougha
subsequentactionlettertotheapplicant,theAgencywilllistthedrugproductandthefinalapprovaldateinthe
appropriateapproveddrugproductlist.
DistributorsorrepackagersofproductsontheListarenotidentified.Becausedistributorsorrepackagersarenot
requiredtonotifyFDAwhentheyshifttheirsourcesofsupplyfromoneapprovedmanufacturertoanother,itisnot
possibletomaintaincompleteinformationlinkingproductapprovalwiththedistributororrepackagerhandlingthe

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products.
1.2TherapeuticEquivalenceRelatedTerms
PharmaceuticalEquivalents.Drugproductsareconsideredpharmaceuticalequivalentsiftheycontainthe
sameactiveingredient(s),areofthesamedosageform,routeofadministrationandareidenticalinstrengthor
concentration(e.g.,chlordiazepoxidehydrochloride,5mgcapsules).Pharmaceuticallyequivalentdrugproducts
areformulatedtocontainthesameamountofactiveingredientinthesamedosageformandtomeetthesameor
compendialorotherapplicablestandards(i.e.,strength,quality,purity,andidentity),buttheymaydifferin
characteristicssuchasshape,scoringconfiguration,releasemechanisms,packaging,excipients(includingcolors,
flavors,preservatives),expirationtime,and,withincertainlimits,labeling.
PharmaceuticalAlternatives.Drugproductsareconsideredpharmaceuticalalternativesiftheycontainthe
sametherapeuticmoiety,butaredifferentsalts,esters,orcomplexesofthatmoiety,oraredifferentdosageforms
orstrengths(e.g.,tetracyclinehydrochloride,250mgcapsulesvs.tetracyclinephosphatecomplex,250mg
capsulesquinidinesulfate,200mgtabletsvs.quinidinesulfate,200mgcapsules).Differentdosageformsand
strengthswithinaproductlinebyasinglemanufacturerarethuspharmaceuticalalternatives,asareextended
releaseproductswhencomparedwithimmediatereleaseorstandardreleaseformulationsofthesameactive
ingredient.
TherapeuticEquivalents.Drugproductsareconsideredtobetherapeuticequivalentsonlyiftheyare
pharmaceuticalequivalentsandiftheycanbeexpectedtohavethesameclinicaleffectandsafetyprofilewhen
administeredtopatientsundertheconditionsspecifiedinthelabeling.
FDAclassifiesastherapeuticallyequivalentthoseproductsthatmeetthefollowinggeneralcriteria:(1)theyare
approvedassafeandeffective(2)theyarepharmaceuticalequivalentsinthatthey(a)containidenticalamounts
ofthesameactivedrugingredientinthesamedosageformandrouteofadministration,and(b)meetcompendial
orotherapplicablestandardsofstrength,quality,purity,andidentity(3)theyarebioequivalentinthat(a)theydo
notpresentaknownorpotentialbioequivalenceproblem,andtheymeetanacceptableinvitrostandard,or(b)if
theydopresentsuchaknownorpotentialproblem,theyareshowntomeetanappropriatebioequivalence
standard(4)theyareadequatelylabeled(5)theyaremanufacturedincompliancewithCurrentGood
ManufacturingPracticeregulations.Theconceptoftherapeuticequivalence,asusedtodeveloptheList,applies
onlytodrugproductscontainingthesameactiveingredient(s)anddoesnotencompassacomparisonofdifferent
therapeuticagentsusedforthesamecondition(e.g.,meperidinehydrochloridevs.morphinesulfateforthe
treatmentofpain).AnydrugproductintheListrepackagedand/ordistributedbyotherthantheapplicantis
consideredtobetherapeuticallyequivalenttotheapplicant'sdrugproducteveniftheapplicant'sdrugproductis
singlesourceorcodedasnonequivalent(e.g.,BN).Also,distributorsorrepackagersofanapplicant'sdrug
productareconsideredtohavethesamecodeastheapplicant.Therapeuticequivalencedeterminationsarenot
madeforunapproved,offlabeluses.
FDAconsidersdrugproductstobetherapeuticallyequivalentiftheymeetthecriteriaoutlinedabove,eventhough
theymaydifferincertainothercharacteristicssuchasshape,scoringconfiguration,releasemechanisms,
packaging,excipients(includingcolors,flavors,preservatives),expirationdate/timeandminoraspectsoflabeling
(e.g.,thepresenceofspecificpharmacokineticinformation)andstorageconditions.Whensuchdifferencesare
importantinthecareofaparticularpatient,itmaybeappropriatefortheprescribingphysiciantorequirethata
specificproductbedispensedasamedicalnecessity.Withthislimitation,however,FDAbelievesthatproducts
classifiedastherapeuticallyequivalentcanbesubstitutedwiththefullexpectationthatthesubstitutedproductwill
producethesameclinicaleffectandsafetyprofileastheprescribedproduct.
Strength.Strengthreferstotheamountofdrugsubstance(activeingredient)containedin,delivered,or
deliverablefromadrugproduct.NotethatifthecriteriatheAgencyestablishesfordeterminingandexpressingthe
amountofdrugsubstanceinaproductevolvesovertime,theAgencygenerallydoesnotintendtorevisethe
expressionsofstrengthfordrugproductsalreadyincludedintheList,butratherintendstoapplythecriteria
prospectivelytodrugproductsaddedtotheList.

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ThestrengthofdrugproductsintheListisgenerallyexpressedintermsoftheamountofdrugsubstance(active
ingredient)inthedrugproduct,butissometimesexpressedintermsoftheamountoftheactivemoiety.For
example,certaindrugproductsincludedintheListincludeadesignationof"EQ"nexttotheirexpressionof
strength.This"EQ"designationgenerallyisusedinconnectionwithsaltdrugproductstoindicatethatthestrength
ofsuchdrugproductisbeingexpressedintermsoftheequivalentstrengthoftheactivemoiety(e.g.,"EQ200MG
BASE"),ratherthanintermsofthestrengthoftheactiveingredient.
Bioavailability.Thistermmeanstherateandextenttowhichtheactiveingredientoractivemoietyisabsorbed
fromadrugproductandbecomesavailableatthesiteofaction.Fordrugproductsthatarenotintendedtobe
absorbedintothebloodstream,bioavailabilitymaybeassessedbymeasurementsintendedtoreflecttherateand
extenttowhichtheactiveingredientoractivemoietybecomesavailableatthesiteofaction.
BioequivalentDrugProducts.Thistermdescribespharmaceuticalequivalentorpharmaceuticalalternative
productsthatdisplaycomparablebioavailabilitywhenstudiedundersimilarexperimentalconditions.Section505
(j)(8)(B)oftheFD&CActdescribesonesetofconditionsunderwhichatestandreferencelisteddrug(see
Section1.4)shallbeconsideredbioequivalent:
therateandextentofabsorptionofthe[test]drugdonotshowasignificantdifferencefromtherateandextentof
absorptionofthe[reference]drugwhenadministeredatthesamemolardoseofthetherapeuticingredientunder
similarexperimentalconditionsineitherasingledoseormultipledosesor
theextentofabsorptionofthe[test]drugdoesnotshowasignificantdifferencefromtheextentofabsorptionof
the[reference]drugwhenadministeredatthesamemolardoseofthetherapeuticingredientundersimilar
experimentalconditionsineitherasingledoseormultipledosesandthedifferencefromthe[reference]druginthe
rateofabsorptionofthedrugisintentional,isreflectedinitsproposedlabeling,isnotessentialtotheattainmentof
effectivebodydrugconcentrationsonchronicuse,andisconsideredmedicallyinsignificantforthedrug.
Wheretheseabovemethodsarenotapplicable(e.g.,fordrugproductsthatarenotintendedtobeabsorbedinto
thebloodstream),otherinvivoorinvitrotestmethodstodemonstratebioequivalencemaybeappropriate.
Forexample,bioequivalencemaysometimesbedemonstratedusinganinvitrobioequivalencestandard,
especiallywhensuchaninvitrotesthasbeencorrelatedwithhumaninvivobioavailabilitydata.Inother
situations,bioequivalencemaysometimesbedemonstratedthroughcomparativeclinicaltrialsor
pharmacodynamicstudies.
1.3FurtherGuidanceonBioequivalence
FDA'sregulationsandguidancedocumentsprovideadditionalinformationregardingbioequivalenceand
bioavailability,includingmethodologiesandstatisticalcriteriausedtoestablishthebioequivalenceofdrugproducts.
1.4ReferenceListedDrug
Areferencelisteddrug(21CFR314.94(a)(3))meansthelisteddrugidentifiedbyFDAasthedrugproductupon
whichanapplicantreliesinseekingapprovalofitsANDA.
FDAhasidentifiedinthePrescriptionDrugProductandOTCDrugProductListsthosereferencelisteddrugsto
whichtheinvivobioequivalence(referencestandard)and,insomeinstances,theinvitrobioequivalenceofthe
applicant'sproductiscompared.Bydesignatingasinglereferencelisteddrugasthestandardtowhichallgeneric
versionsmustbeshowntobebioequivalent,FDAhopestoavoidpossiblesignificantvariationsamonggeneric
drugsandtheirbrandnamecounterpart.Suchvariationscouldresultifgenericdrugswerecomparedtodifferent
drugs.
However,insomeinstanceswhenalisteddrugisnotdesignatedasthereferencelisteddrugand/ornotshownto
bebioequivalenttothereferencelisteddrug,suchlisteddrugmaybeshieldedfromgenericcompetition.An
applicantwishingtomarketagenericversionofalisteddrugthatisnotdesignatedasthereferencelisteddrug
maypetitiontheAgencythroughthecitizenpetitionprocedure(see21CFR10.25(a)andCFR10.30).Ifthe

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citizenpetitionisapproved,thelisteddrugwillbedesignatedasanadditionalreferencelisteddrug,inwhichcase
anANDAcitingthedesignatedreferencelisteddrugmaybesubmitted.Section1.7,TherapeuticEquivalence
EvaluationsCodes(productsmeetingnecessarybioequivalencerequirements)explainsthecharactercoding
system(e.g.,AB,AB1,AB2,AB3...)formultisourcedrugproductslistedunderthesameheadingwithtwo
referencelisteddrugs.
Inaddition,therearetwosituationsinwhichtwolisteddrugsthathavebeenshowntobebioequivalenttoeach
otherhavebothbeendesignatedasreferencelisteddrugs.Thefirstsituationiswhentheinvivodeterminationof
bioequivalenceisselfevidentandawaiverofanyinvivobioequivalencemaybegranted.Thesecondsituationis
whenthebioequivalenceoftwolistedproductsmaybedeterminedthroughinvitromethodology.
Referencelisteddrugsareidentifiedbythesymbol"+"inthePrescriptionandOvertheCounter(OTC)Drug
ProductLists.TheseidentifiedreferencelisteddrugsrepresentthebestjudgmentoftheOfficeofBioequivalence
atthistime.ThePrescriptionandOTCDrugProductListsidentifyreferencedrugsforapproveddrugproducts.It
isrecommendedthatanapplicantplanningtoconductaninvivobioequivalencestudy,orplanningtomanufacture
abatchofadrugproductforwhichaninvivowaiverofbioequivalencewillberequested,submitacontrolled
correspondencetotheOfficeofGenericDrugstoconfirmtheappropriatereferencelisteddrug.
1.5GeneralPoliciesandLegalStatus
TheListcontainspublicinformationandadvice.Itdoesnotmandatethedrugproductsthatarepurchased,
prescribed,dispensed,orsubstitutedforoneanother,nordoesit,conversely,mandatetheproductsthatshouldbe
avoided.TotheextentthattheListsetsforthFDA'sevaluationsofthetherapeuticequivalenceofdrugproducts
thathavebeenapproved,itcontainsFDA'sadvicetothepublic,topractitioners,andtothestatesregardingdrug
productselection.TheseevaluationsdonotconstitutedeterminationsthatanyproductisinviolationoftheFD&C
Actorthatanyproductispreferabletoanyother.Therapeuticequivalenceevaluationsareascientificjudgment
baseduponevidence,whilegenericsubstitutionmayinvolvesocialandeconomicpolicyadministeredbythe
states,intendedtoreducethecostofdrugstoconsumers.TotheextentthattheListidentifiesdrugproducts
approvedunderSection505oftheFD&CAct,itsetsforthinformationthattheAgencyisrequiredtopublishand
thatthepublicisentitledtoundertheFreedomofInformationAct.ExclusionofadrugproductfromtheListdoes
notnecessarilymeanthatthedrugproductiseitherinviolationofSection505oftheFD&CAct,orthatsucha
productisnotsafeoreffective,orthatsuchaproductisnottherapeuticallyequivalenttootherdrugproducts.
Rather,theexclusionisbasedonthefactthatFDAhasnotevaluatedthesafety,effectiveness,andqualityofthe
drugproduct.
1.6Practitioner/UserResponsibilities
ProfessionalcareandjudgmentshouldbeexercisedinusingtheList.Evaluationsoftherapeutic
equivalenceforprescriptiondrugsarebasedonscientificandmedicalevaluationsbyFDA.Productsevaluatedas
therapeuticallyequivalentcanbeexpected,inthejudgmentofFDA,tohaveequivalentclinicaleffectandno
differenceintheirpotentialforadverseeffectswhenusedundertheconditionsoftheirlabeling.However,these
productsmaydifferinothercharacteristicssuchasshape,scoringconfiguration,releasemechanisms,packaging,
excipients(includingcolors,flavors,preservatives),expirationdate/time,and,insomeinstances,labeling.If
productswithsuchdifferencesaresubstitutedforeachother,thereisapotentialforpatientconfusiondueto
differencesincolororshapeoftablets,inabilitytoprovideagivendoseusingapartialtabletiftheproperscoring
configurationisnotavailable,ordecreasedpatientacceptanceofcertainproductsbecauseofflavor.Forexample,
theremayalsobeallergicreactionsinrarecasesduetoacoloringorapreservativeingredient,aswellas
differencesincosttothepatient.
FDAevaluationoftherapeuticequivalenceinnowayrelievespractitionersoftheirprofessionalresponsibilitiesin
prescribinganddispensingsuchproductswithduecareandwithappropriateinformationtoindividualpatients.In
thosecircumstanceswherethecharacteristicsofaspecificproduct,otherthanitsactiveingredient,areimportant
inthetherapyofaparticularpatient,thephysician'sspecificationofthatproductisappropriate.Pharmacistsmust

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alsobefamiliarwiththeexpirationdates/timesandlabelingdirectionsforstorageofthedifferentproducts,
particularlyforreconstitutedproducts,toassurethatpatientsareproperlyadvisedwhenoneproductissubstituted
foranother.
Multisourceandsinglesourcedrugproducts.FDAhasevaluatedfortherapeuticequivalenceonly
multisourceprescriptiondrugproductsapprovedunderSection505oftheFD&CAct,whichinmostinstances
meansthosepharmaceuticalequivalentsavailablefrommorethanonemanufacturer.Forsuchproducts,a
therapeuticequivalencecodeisincludedand,inaddition,productinformationishighlightedinboldfaceand
underlined.Thoseproductswithapprovedapplicationsthataresinglesource(i.e.,thereisonlyoneapproved
productavailableforthatactiveingredient,dosageform,routeofadministration,andstrength)arealsoincluded
ontheList,butnotherapeuticequivalencecodeisincludedwithsuchproducts.AnydrugproductintheList
repackagedand/ordistributedbyotherthantheapplicant(e.g.,anauthorizedgeneric)isconsideredtobe
therapeuticallyequivalenttotheapplicant'sdrugproducteveniftheapplicant'sdrugproductissinglesourceor
codedasnonequivalent(e.g.,BN).Also,althoughnotidentifiedintheList,distributorsorrepackagersofan
applicant'sdrugproductareconsideredtohavethesamecodeastheapplicant.Thedetailsofthesecodesand
thepoliciesunderlyingthemarediscussedinSection1.7,TherapeuticEquivalenceEvaluationsCodes.
ProductsontheListareidentifiedbythenamesoftheholdersofapprovedapplications(applicants)
whomaynotnecessarilybethemanufactureroftheproduct.Therearenumerousentitiesotherthanthe
applicantthatmaybeinvolvedinthedevelopment,manufacturing,and/ormarketingofaproduct.Theapplicant
mayhavehaditsproductmanufacturedbyacontractmanufacturerandmaysimplybedistributingtheproductfor
whichithasobtainedapproval.Inmanyinstances,however,themanufactureroftheproductisalsothe
applicant.Thenameofthemanufacturerispermittedbyregulationtoappearonthelabel,evenwhenthe
manufacturerisnotthemarketer.
AlthoughtheproductsontheListareidentifiedbythenamesoftheapplicants,circumstances,suchaschanging
corporateownership,havesometimesmadeidentificationoftheapplicantdifficult.TheAgencybelieves,basedon
continuingdocumentreviewandcommunicationwithfirms,thattheapplicantdesignationsontheListare,inmost
cases,correct.
TorelatefirmnameinformationonaproductlabeltothatontheList,thefollowingshouldbenoted:the
applicant'snamealwaysappearsontheList.Thisapplieswhethertheapplicant(firmnameonthe
FormFDA356hintheapplication)isthemarketer(firmnameinlargestlettersonthelabel)ornot.However,the
applicant'snamemaynotalwaysappearonthelabeloftheproduct.
Iftheapplicantisthemarketer,itsnameappearsontheListandonthelabeliftheapplicantisnotthemarketer,
andtheAgencyisawareofacorporaterelationship(e.g.,parentandsubsidiary)betweentheapplicantandthe
marketer,thenameoftheapplicantappearsontheListandbothfirmnamesmayappearonthelabel.Firmswith
knowncorporaterelationshipsaredisplayedinAppendixB.Ifthereisnoknowncorporaterelationshipbetween
theapplicantandthemarketer,theapplicant'snameappearsontheListhowever,unlesstheapplicantisthe
manufacturer,packager,ordistributor,theapplicant'snamemaynotappearonthelabel.Inthiscase,the
practitioner,fromlabelingalone,willnotbeabletorelatethemarketedproducttoanapplicantcitedintheList,and
hencetoaspecificapproveddrugproduct.Insuchcases,toassurethattheproductinquestionisthesubjectof
anapprovedapplication,thefirmnamedonthelabelshouldbecontacted.
Torelatetradename(proprietaryname)informationonaproductlabeltothatontheList,thefollowingshouldbe
noted:iftheapplicantisthemarketer,itsnameappearsontheListandonthelabeliftheAgencyisawareofa
corporaterelationshipbetweentheapplicantandthemarketer,thetradename(proprietaryname)ofthedrug
product(establishednameoftheactiveingredient,ifnotradenameexists)appearsontheList.Ifacorporate
relationshipexistsbetweenanapplicantandamarketerandbothfirmsaredistributingthedrugproduct,theFDA
reservestherighttoselectthetradenameofeitherthemarketerortheapplicanttoappearontheList.Ifthereis
noknowncorporaterelationshipbetweentheapplicantandthemarketer,theestablisheddrugname(i.e.,non
proprietaryname)appearsontheList.

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EveryproductontheListissubjectatalltimestoregulatoryaction.Fromtimetotime,approvedproducts
maybefoundinviolationofoneormoreprovisionsoftheFD&CAct.Insuchcircumstances,theAgencymay
commenceappropriateenforcementactiontocorrecttheviolation,ifnecessary,bysecuringremovalofthe
productfromthemarketbyvoluntaryrecall,seizure,orotherenforcementactions.Suchregulatoryactionsare,
however,independentoftheinclusionofaproductontheList.Themaincriterionforinclusionofaproductisthat
ithasanapplicationwithaneffectiveapprovalthathasnotbeenwithdrawnforsafetyorefficacyreasons.FDA
believesthatretentionofaviolativeproductontheListwillnothaveanysignificantadversehealthconsequences,
becauseotherlegalmechanismsareavailabletotheAgencytopreventtheproduct'sactualmarketing.FDAmay
however,changeaproduct'stherapeuticequivalenceratingifthecircumstancesgivingrisetotheviolationchange
orotherwisecallintoquestionthedatauponwhichtheAgency'sassessmentofwhetheraproductmeetsthe
criteriafortherapeuticequivalencewasmade.
1.7TherapeuticEquivalenceEvaluationsCodes
Thecodingsystemfortherapeuticequivalenceevaluationsisconstructedtoallowuserstodeterminequickly
whethertheAgencyhasevaluatedaparticularapprovedproductastherapeuticallyequivalenttoother
pharmaceuticallyequivalentproducts(firstletter)andtoprovideadditionalinformationonthebasisofFDA's
evaluations(secondletter).Withsomeexceptions(e.g.,therapeuticequivalenceevaluationsforcertain505(b)(2)
applications),thetherapeuticequivalenceevaluationdateisthesameastheapprovaldate.
Thetwobasiccategoriesintowhichmultisourcedrugshavebeenplacedareindicatedbythefirstletterofthe
relevanttherapeuticequivalencecodeasfollows:
ADrugproductsthatFDAconsiderstobetherapeuticallyequivalenttootherpharmaceutically
equivalentproducts,i.e.,drugproductsforwhich:
(1)therearenoknownorsuspectedbioequivalenceproblems.ThesearedesignatedAA,AN,AO,AP,orAT,
dependingonthedosageformor
(2)actualorpotentialbioequivalenceproblemshavebeenresolvedwithadequateinvivoand/orinvitroevidence
supportingbioequivalence.ThesearedesignatedAB.
BDrugproductsthatFDAatthistime,considersnottobetherapeuticallyequivalenttoother
pharmaceuticallyequivalentproducts,i.e.,
drugproductsforwhichactualorpotentialbioequivalenceproblemshavenotbeenresolvedbyadequateevidence
ofbioequivalence.Oftentheproblemiswithspecificdosageformsratherthanwiththeactiveingredients.These
aredesignatedBC,BD,BE,BN,BP,BR,BS,BT,BX,orB*.
Individualdrugproductshavebeenevaluatedastherapeuticallyequivalenttothereferenceproductinaccordance
withthedefinitionsandpoliciesoutlinedbelow:
"A"CODES
Drugproductsthatareconsideredtobetherapeuticallyequivalenttootherpharmaceuticallyequivalent
products.
"A"productsarethoseforwhichactualorpotentialbioequivalenceproblemshavebeenresolvedwithadequatein
vivoand/orinvitroevidencesupportingbioequivalence.Drugproductsdesignatedwithan"A"codefallunderone
oftwomainpolicies:
1.forthoseactiveingredientsordosageformsforwhichnoinvivobioequivalenceissueisknownorsuspected,
theinformationnecessarytoshowbioequivalencebetweenpharmaceuticallyequivalentproductsispresumed
andconsideredselfevidentbasedonotherdataintheapplicationforsomedosageforms(e.g.,solutions)or
satisfiedbyashowingthatanacceptableinvitrodissolutionstandardismet.Atherapeuticallyequivalent
ratingisassignedsuchproductssolongastheyaremanufacturedinaccordancewithCurrentGood

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ManufacturingPracticeregulationsandmeettheotherrequirementsoftheirapprovedapplications(theseare
designatedAA,AN,AO,AP,orAT,dependingonthedosageform,asdescribedbelow)or
(2)forthoseDESIdrugproductscontainingactiveingredientsordosageformsthathavebeenidentifiedbyFDA
ashavingactualorpotentialbioequivalenceproblems,andforpost1962drugproductsinadosageform
presentingapotentialbioequivalenceproblem,anevaluationoftherapeuticequivalenceisassignedto
pharmaceuticalequivalentsonlyiftheapprovedapplicationcontainsadequatescientificevidenceestablishing
throughinvivoand/orinvitrostudiesthebioequivalenceoftheproducttoaselectedreferenceproduct(these
productsaredesignatedasAB).
Therearesomegeneralprinciplesthatmayaffectthesubstitutionofpharmaceuticallyequivalentproductsin
specificcases.Prescribersanddispensersofdrugsshouldbealerttotheseprinciplessoastodealappropriately
withsituationsthatrequireprofessionaljudgmentanddiscretion.
Theremaybelabelingdifferencesamongpharmaceuticallyequivalentproductsthatrequireattentiononthepart
ofthehealthprofessional.Forexample,pharmaceuticallyequivalentpowderstobereconstitutedfor
administrationasoralorinjectableliquidsmayvarywithrespecttotheirexpirationtimeorstorageconditionsafter
reconstitution.AnFDAevaluationthatsuchproductsaretherapeuticallyequivalentisapplicableonlywheneach
productisreconstituted,stored,andusedundertheconditionsspecifiedinthelabelingofthatproduct.
TheAgencymayusenotesinthispublicationtopointoutspecialsituationssuchaspotentialdifferencesbetween
twodrugproductsthathavebeenevaluatedasbioequivalentandotherwisetherapeuticallyequivalent,whenthey
shouldbebroughttotheattentionofhealthprofessionals.ThesenotesarecontainedinSection1.8,Description
ofCertainSpecialSituations.
Forexample,inrareinstances,theremaybevariationsamongtherapeuticallyequivalentproductsintheiruseor
inconditionsofadministration.Suchdifferencesmaybeduetopatentorexclusivityrightsassociatedwithsuch
use.Whensuchvariationsmay,intheAgency'sopinion,affectprescribingorsubstitutiondecisionsbyhealth
professionals,anotemaybeaddedtoSection1.8.
Also,occasionallyasituationmayariseinwhichchangesinalisteddrugproductafteritsapproval(forexample,a
changeindosinginterval)mayhaveanimpactonthesubstitutabilityofalreadyapprovedgenericversionsofthat
productthatwereratedbytheAgencyastherapeuticallyequivalenttothelistedproduct.Whensuchchangesin
thelisteddrugproductareconsideredbytheAgencytohaveasignificantimpactontherapeuticequivalence,the
Agencywillchangethetherapeuticequivalenceratingsforotherversionsofthedrugproductunlessthe
manufacturersofthoseotherversionsoftheproductprovideadditionalinformationtoassureequivalenceunder
thechangedconditions.Pendingreceiptoftheadditionaldata,theAgencymayaddanotetoSection1.8,or,in
rarecases,mayevenchangethetherapeuticequivalencerating.
Insomecases(e.g.,IsolyteSw/Dextrose5%inPlasticContainerandPlasmaLyte148andDextrose5%in
PlasticContainer),closelyrelatedproductsarelistedascontainingthesameactiveingredients,butinsomewhat
differentamounts.Indeterminingwhichoftheseproductsarepharmaceuticallyequivalent,theAgencyhas
consideredproductstobepharmaceuticallyequivalentwithlabeledstrengthsofaningredientthatdonotvaryby
morethan1%.
Differentsalts,estersorothernoncovalentderivatives(suchasacomplex,chelate,orclathrate)ofthesame
activemoietyareregardedasdifferentactiveingredients.Forthepurposeofthispublication,productscontaining
suchdifferentactiveingredientsareconsideredpharmaceuticalalternativesandthusnottherapeutically
equivalent.Anhydrousandhydratedentities,aswellasdifferentpolymorphs,areconsideredtobethesame
activeingredientandareexpectedtomeetthesamestandardsforidentitytobeconsideredpharmaceutical
equivalentsandtherapeuticequivalents.
Thecodesinthisbookarenotintendedtoprecludehealthcareprofessionalsfromconvertingpharmaceutically
differentconcentrationsintopharmaceuticalequivalentsusingacceptedprofessionalpractice.

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Wherepackagesizevariationshavetherapeuticimplications,productssopackagedhavenotbeenconsidered
pharmaceuticallyequivalent.Forexample,someoralcontraceptivesaresuppliedin21tabletand28tablet
packetsthe28tabletpacketscontain7placeboorirontablets.Thesetwopackagingconfigurationsarenot
regardedaspharmaceuticallyequivalentthus,theyarenotdesignatedastherapeuticallyequivalent.
Preservativesmaydifferamongsometherapeuticallyequivalentdrugproducts.Differencesinpreservativesand
otherinactiveingredientsdonotaffectFDA'sevaluationoftherapeuticequivalenceexceptincaseswherethese
componentsmayinfluencebioequivalenceorroutesofadministration.
Thespecificsubcodesforthosedrugsevaluatedastherapeuticallyequivalentandthepoliciesunderlyingthese
subcodesfollow:
AAProductsinconventionaldosageformsnotpresentingbioequivalenceproblems
ProductscodedasAAcontainactiveingredientsanddosageformsthatarenotregardedaspresentingeither
actualorpotentialbioequivalenceproblemsordrugqualityorstandardsissues.However,alloraldosageforms
must,nonetheless,meetanappropriateinvitrobioequivalencestandardthatisacceptabletotheAgencyinorder
tobeapproved.
AB,AB1,AB2,AB3...Productsmeetingnecessarybioequivalencerequirements
Multisourcedrugproductslistedunderthesameheading(i.e.,identicalactiveingredients(s),dosageform,and
route(s)ofadministration)andhavingthesamestrength(seeSection1.2,TherapeuticEquivalenceRelated
Terms,Strength)generallywillbecodedABifdataandinformationaresubmitteddemonstratingbioequivalence.
Incertaininstances,anumberisaddedtotheendoftheABcodetomakeathreecharactercode(i.e.,AB1,
AB2,AB3,etc.).Threecharactercodesareassignedonlyinsituationswhenmorethanonereferencelisteddrug
ofthesamestrengthhasbeendesignatedunderthesameheading.Twoormorereferencelisteddrugsare
generallyselectedonlywhenthereareatleasttwopotentialreferencedrugproductsthatarenotidentifiedas
bioequivalenttoeachother.Ifastudyissubmittedthatdemonstratesbioequivalencetoaspecificlisteddrug
product,thegenericproductwillbegiventhesamethreecharactercodeasthereferencelisteddrugitwas
comparedagainst.Forexample,AdalatCCandProcardiaXL,extendedreleasetablets,arelistedunderthe
activeingredientnifedipine.Thesedrugproducts,listedunderthesameheading,arenotbioequivalenttoeach
other.AdalatCCandProcardiaXLhavebeenassignedratingsofAB1andAB2,respectively.Genericdrug
productsdeemedbyFDAtobebioequivalenttoAdalatCCandProcardiaXLhavebeenapproved.Asa
result,thegenericdrugproductsbioequivalenttoAdalatCChavebeenassignedaratingofAB1andthose
bioequivalenttoProcardiaXLhavebeenassignedaratingofAB2.(TheassignmentofanAB1orAB2rating
toaspecificproductdoesnotimplyproductpreference.)Eventhoughdrugproductsofdistributorsand/or
repackagersarenotincludedintheList,theyareconsideredtherapeuticallyequivalenttotheapplicant'sdrug
productiftheapplicant'sdrugproductisratedeitherwithanABorthreecharactercodeorissinglesourceinthe
List.DrugscodedasABunderaheadingareconsideredtherapeuticallyequivalentonlytootherdrugscodedas
ABunderthatheading.Drugscodedwithathreecharactercodeunderaheadingareconsideredtherapeutically
equivalentonlytootherdrugscodedwiththesamethreecharactercodeunderthatheading.
ANSolutionsandpowdersforaerosolization
Uncertaintyregardingthetherapeuticequivalenceofaerosolizedproductsarisesprimarilybecauseofdifferences
inthedrugdeliverysystem.Solutionsandpowdersintendedforaerosolizationthataremarketedforuseinanyof
severaldeliverysystemsareconsideredtobepharmaceuticallyandtherapeuticallyequivalentandarecodedAN.
Thoseproductsthatarecompatibleonlywithaspecificdeliverysystemorthoseproductsthatarepackagedinand
withaspecificdeliverysystemarecodedBN,unlesstheyhavemetanappropriatebioequivalencestandardand
areotherwisedeterminedtobetherapeuticallyequivalent.Solutionsorsuspensionsinaspecificdeliverysystem
willbecodedANifthebioequivalencestandardisbaseduponinvitromethodology,ifbioequivalenceneedstobe
demonstratedbyinvivomethodologythenthedrugproductswillbecodedAB.

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AOInjectableoilsolutions
Theabsorptionofdrugsininjectable(parenteral)oilsolutionsmayvarysubstantiallywiththetypeofoilemployed
asavehicleandtheconcentrationoftheactiveingredient.Injectableoilsolutionsarethereforeconsideredtobe
pharmaceuticallyandtherapeuticallyequivalentonlywhentheactiveingredient,itsconcentration,andthetypeof
oilusedasavehicleareallidentical.
APInjectableaqueoussolutionsand,incertaininstances,intravenousnonaqueous
solutions

Itshouldbenotedthateventhoughinjectable(parenteral)productsunderaspecificlistingmaybeevaluatedas
therapeuticallyequivalent,theremaybeimportantdifferencesamongtheproductsinthegeneralcategory,
InjectableInjection.Forexample,someinjectableproductsthatareratedtherapeuticallyequivalentarelabeled
fordifferentroutesofadministration.Inaddition,someproductsevaluatedastherapeuticallyequivalentmayhave
differentpreservativesornopreservativesatall.Injectableproductsavailableasdrypowdersforreconstitution,
concentratedsterilesolutionsfordilution,orsterilesolutionsreadyforinjectionarepharmaceuticalalternativedrug
products.Theyarenotratedastherapeuticallyequivalent(AP)toeachotherevenifthesepharmaceutical
alternativedrugproductsaredesignedtoproducethesameconcentrationpriortoinjectionandaresimilarly
labeled.Consistentwithacceptedprofessionalpractice,itistheresponsibilityoftheprescriber,dispenser,or
individualadministeringtheproducttobefamiliarwithaproduct'slabelingtoassurethatitisgivenonlybythe
route(s)ofadministrationstatedinthelabeling.
CertaincommonlyusedlargevolumeintravenousproductsinglasscontainersarenotincludedontheList(e.g.,
dextroseinjection5%,dextroseinjection10%,sodiumchlorideinjection0.9%)sincetheseproductsareonthe
marketwithoutFDAapprovalandtheFDAhasnotpublishedconditionsformarketingsuchparenteralproducts
underapprovedNDAs.Whenpackagedinplasticcontainers,however,FDAregulationsrequireapproved
applicationspriortomarketing.Approvalthendependson,amongotherthings,theextentoftheavailablesafety
datainvolvingthespecificplasticcomponentoftheproduct.Alllargevolumeparenteralproductsare
manufacturedundersimilarstandards,regardlessofwhethertheyarepackagedinglassorplastic.Thus,FDA
hasnoreasontobelievethatthepackagingcontaineroflargevolumeparenteraldrugproductsthatare
pharmaceuticallyequivalentwouldhaveanyeffectontheirtherapeuticequivalence.
Thestrengthofparenteraldrugproductsgenerallyisidentifiedbyboththetotaldrugcontentandtheconcentration
ofdrugsubstanceinacontainerapprovedbyFDA.Inthepast,thestrengthofliquidparenteraldrugproductsin
theOrangeBookhasnotbeenfullydisplayed.Rather,thestrengthofliquidparenteraldrugproductsinthe
OrangeBookhasbeendisplayedintermsofconcentration,expressedasxmg/mL.Theamountofdrypowderor
freezedriedpowderinacontainerhasalwaysbeenidentifiedasthestrength,expressedasxmg/vial.
Withthefinalizationofthe1984Amendmentsthatcharacterizedeachstrengthofadrugproductasalisteddrug,it
becameevidentthattheformatoftheOrangeBookshouldbechangedtoreflecteachstrengthofaparenteral
solution.Tothisend,theOrangeBooknowdisplaysthestrengthofallnewapprovalsofparenteralsolutions.
Previously,wewouldhavedisplayedonlytheconcentrationofanapprovedparenteralsolution,e.g.50mg/mL.If
thisdrugproducthada20mLand60mLcontainerapproved,wewouldnowdisplaytwoproductstrengthsforthis
product,listingbothtotaldrugcontentandconcentrationofdrugsubstanceintherelevantapprovedcontainer,
e.g.1Gm/20mL(50mg/mL)and3Gm/60mL(50mg/mL).
ATTopicalproducts
Thereareavarietyoftopicaldosageformsavailablefordermatologic,ophthalmic,otic,rectal,andvaginal
administration,includingcreams,gels,lotions,oils,ointments,pastes,solutions,spraysandsuppositories.Even
thoughdifferenttopicaldosageformsmaycontainthesameactiveingredientandpotency,thesedosageforms
arenotconsideredpharmaceuticallyequivalent.Therefore,theyarenotconsideredtherapeuticallyequivalent.All
solutionsandDESIdrugproductscontainingthesameactiveingredientinthesametopicaldosageformforwhich
awaiverofinvivobioequivalencehasbeengrantedandforwhichchemistryandmanufacturingprocessesare
adequatetodemonstratebioequivalence,areconsideredtherapeuticallyequivalentandcodedAT.

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Pharmaceuticallyequivalenttopicalproductsthatraisequestionsofbioequivalence,includingallpost1962non
solutiontopicaldrugproducts,arecodedABwhensupportedbyadequatebioequivalencedata,andBTinthe
absenceofsuchdata.
"B"CODES
DrugproductsthatFDA,atthistime,considersnottobetherapeuticallyequivalenttoother
pharmaceuticallyequivalentproducts.
"B"products,forwhichactualorpotentialbioequivalenceproblemshavenotbeenresolvedbyadequateevidence
ofbioequivalence,oftenhaveaproblemwithspecificdosageformsratherthanwiththeactiveingredients.Drug
productsdesignatedwitha"B"codefallunderoneofthreemainpolicies:
(1)thedrugproductscontainactiveingredientsoraremanufacturedindosageformsthathavebeenidentifiedby
theAgencyashavingdocumentedbioequivalenceproblemsorasignificantpotentialforsuchproblemsandfor
whichnoadequatestudiesdemonstratingbioequivalencehavebeensubmittedtoFDAor
(2)thequalitystandardsareinadequateorFDAhasaninsufficientbasistodeterminetherapeuticequivalenceor
(3)thedrugproductsareunderregulatoryreview.
Thespecificcodingdefinitionsandpoliciesforthe"B"subcodesareasfollows:
B*DrugproductsrequiringfurtherFDAinvestigationandreviewtodeterminetherapeuticequivalence
ThecodeB*isassignedtoproductspreviouslyassignedanAorBcodewhenFDAreceivesnewinformationthat
raisesasignificantquestionregardingtherapeuticequivalencethatcanberesolvedonlythroughfurtherAgency
investigationand/orreviewofdataandinformationsubmittedbytheapplicant.TheB*codesignifiesthatthe
AgencywilltakenopositionregardingthetherapeuticequivalenceoftheproductuntiltheAgencycompletesits
investigationandreview.
BCExtendedreleasedosageforms(capsules,injectablesandtablets)
Extendedreleasetabletsareformulatedinsuchamannerastomakethecontainedmedicamentavailableover
anextendedperiodoftimefollowingingestion.
Althoughbioavailabilitystudieshavebeenconductedonthesedosageforms,theymaybesubjecttobioavailability
differences,primarilybecauseapplicantsdevelopingextendedreleaseproductsforthesameactiveingredient
rarelyemploythesameformulationapproach.FDA,therefore,doesnotconsiderdifferentextendedrelease
dosageformscontainingthesameactiveingredientinequalstrengthtobetherapeuticallyequivalentunless
equivalencebetweenindividualproductsinbothrateandextenthasbeenspecificallydemonstratedthrough
appropriatebioequivalencestudies.Extendedreleaseproductsforwhichsuchbioequivalencedatahavenotbeen
submittedarecodedBC,whilethoseforwhichsuchdataareavailablehavebeencodedAB.
BDActiveingredientsanddosageformswithdocumentedbioequivalenceproblems
TheBDcodedenotesproductscontainingactiveingredientswithknownbioequivalenceproblemsandforwhich
adequatestudieshavenotbeensubmittedtoFDAdemonstratingbioequivalence.Wherestudiesshowing
bioequivalencehavebeensubmitted,theproducthasbeencodedAB.
BEDelayedreleaseoraldosageforms
Wherethedrugmaybedestroyedorinactivatedbythegastricjuiceorwhereitmayirritatethegastricmucosa,
theuseof"enteric"coatingsisindicated.Suchcoatingsareintendedtodelaythereleaseofthemedicationuntil
thetablethaspassedthroughthestomach.Drugproductsindelayedreleasedosageformscontainingthesame
activeingredientsaresubjecttosignificantdifferencesinabsorption.Unlessotherwisespecificallynoted,the

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Agencyconsidersdifferentdelayedreleaseproductscontainingthesameactiveingredientsaspresentinga
potentialbioequivalenceproblemandcodestheseproductsBEintheabsenceofinvivostudiesshowing
bioequivalence.Ifadequateinvivostudieshavedemonstratedthebioequivalenceofspecificdelayedrelease
products,suchproductsarecodedAB.
BNProductsinaerosolnebulizerdrugdeliverysystems
Thiscodeappliestodrugsolutionsorpowdersthataremarketedonlyasacomponentof,orascompatiblewith,a
specificdrugdeliverysystem.Theremay,forexample,besignificantdifferencesinthedoseofdrugandparticle
sizedeliveredbydifferentproductsofthistype.Therefore,theAgencydoesnotconsiderdifferentmetered
aerosoldosageformscontainingthesameactiveingredient(s)inequalstrengthstobetherapeuticallyequivalent
unlessthedrugproductsmeetanappropriatebioequivalencestandardsuchproductsarecodedAB.
BPActiveingredientsanddosageformswithpotentialbioequivalenceproblems
FDA'sbioequivalenceregulations(21CFR320.33)containcriteriaandproceduresfordeterminingwhethera
specificactiveingredientinaspecificdosageformhasapotentialforcausingabioequivalenceproblem.Itis
FDA'spolicytoconsideraningredientmeetingthesecriteriaashavingapotentialbioequivalenceproblemevenin
theabsenceofpositivedatademonstratinginequivalence.Pharmaceuticallyequivalentproductscontainingthese
ingredientsinoraldosageformsarecodedBPuntiladequatebioequivalencedataaresubmitted,afterwhichsuch
productsarecodedAB.Injectablesuspensionscontaininganactiveingredientsuspendedinanaqueousor
oleaginousvehiclehavealsobeencodedBP.Injectablesuspensionsaresubjecttobioequivalenceproblems
becausedifferencesinparticlesize,polymorphicstructureofthesuspendedactiveingredient,orthesuspension
formulationcansignificantlyaffecttherateofreleaseandabsorption.FDAdoesnotconsiderpharmaceutical
equivalentsoftheseproductsbioequivalentwithoutadequateevidenceofbioequivalencesuchproductswouldbe
codedAB.
BRSuppositoriesorenemasthatdeliverdrugsforsystemicabsorption
Theabsorptionofactiveingredientsfromsuppositoriesorenemasthatareintendedtohaveasystemiceffect(as
distinctfromsuppositoriesadministeredforlocaleffect)canvarysignificantlyfromproducttoproduct.Therefore,
FDAconsiderspharmaceuticallyequivalentsystemicsuppositoriesorenemasbioequivalentonlyifinvivo
evidenceofbioequivalenceisavailable.Inthosecaseswhereinvivoevidenceisavailable,theproductiscoded
AB.Ifsuchevidenceisnotavailable,theproductsarecodedBR.
BSProductshavingdrugstandarddeficiencies
IfthedrugstandardsforanactiveingredientinaparticulardosageformarefoundbyFDAtobedeficientsoasto
preventanFDAevaluationofeitherpharmaceuticalortherapeuticequivalence,alldrugproductscontainingthat
activeingredientinthatdosageformarecodedBS.Forexample,ifthestandardspermitawidevariationin
pharmacologicallyactivecomponentsoftheactiveingredientsuchthatpharmaceuticalequivalenceisinquestion,
allproductscontainingthatactiveingredientinthatdosageformarecodedBS.
BTTopicalproductswithbioequivalenceissues
Thiscodeappliesmainlytopost1962dermatologic,ophthalmic,otic,rectal,andvaginalproductsfortopical
administration,includingcreams,ointments,gels,lotions,pastes,andsprays,aswellassuppositoriesnotintended
forsystemicdrugabsorption.Topicalproductsevaluatedashavingacceptableclinicalperformance,butthatare
notbioequivalenttootherpharmaceuticallyequivalentproductsorthatlacksufficientevidenceofbioequivalence,
willbecodedBT.
BXDrugproductsforwhichthedataareinsufficienttodeterminetherapeuticequivalence
ThecodeBXisassignedtospecificdrugproductsforwhichthedatathathavebeenreviewedbytheAgencyare
insufficienttodeterminetherapeuticequivalenceunderthepoliciesstatedinthisdocument.Inthesesituations,
thedrugproductsarepresumedtobetherapeuticallyinequivalentuntiltheAgencyhasdeterminedthatthereis

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adequateinformationtomakeafullevaluationoftherapeuticequivalence.
1.8DescriptionofCertainSpecialSituations
CertaindrugslistedintheOrangeBookpresentspecialsituationsthatmeritfurtherdiscussion.Thefollowingare
descriptionsofcertainexamplesofthosespecialsituations:
AminoAcidandProteinHydrolysateInjections.Theseproductsdifferintheamountandkindsofaminoacids
theycontainand,therefore,arenotconsideredpharmaceuticalequivalents.Forthisreason,theseproductsare
notconsideredtherapeuticallyequivalent.Atthesametime,theAgencybelievesthatitisappropriatetopointout
thatwherenitrogenbalanceisthesoletherapeuticobjectiveandindividualaminoacidcontentisnota
consideration,pharmaceuticalalternativeswiththesametotalamountofnitrogencontentmaybeconsidered
therapeuticallyequivalent.
Gaviscon.GavisconisanOTCproductthathasbeenmarketedsinceSeptember1970.Theactive
ingredientsinthisproduct,aluminumhydroxideandmagnesiumtrisilicate,werereviewedbytheAgency'sOTC
AntacidPanelandwereconsideredtobesafeandeffectiveingredients(CategoryI)bythatPanel.However,the
tabletfailedtopasstheantacidtestthatisrequiredofallantacidproducts.TheAgency,therefore,placedthe
tabletinCategoryIIIforlackofeffectiveness.AfullNDAwithclinicalstudieswassubmittedbyMarion
Laboratories,Inc.,andapprovedbyFDAonDecember9,1983.Gaviscon'sactivityintreatingrefluxacidityis
madepossiblebythephysicalchemicalpropertiesoftheinactiveingredients,sodiumbicarbonateandalginic
acid.Therefore,allANDAsthatciteGaviscontabletsasthereferencelisteddrugmustcontaintheinactive
ingredientssodiumbicarbonateandalginicacid.AfullNDAwillberequiredtosupporttheeffectivenessofthe
drugproductifdifferentinactiveingredientsaretobesubstitutedforsodiumbicarbonateoralginicacidorif
differentproportionsoftheseingredientsaretobeused.
LevothyroxineSodium.Becausetherearemultiplereferencelisteddrugsoflevothyroxinesodiumtabletsand
somereferencelisteddrugs'sponsorshaveconductedstudiestoestablishtheirdrugs'therapeuticequivalenceto
otherreferencelisteddrugs,FDAhasdeterminedthatitsusualpracticeofassigningtwoorthreecharacterTE
codesmaybepotentiallyconfusingandinadequateforthesedrugproducts.Accordingly,FDAprovidesthe
followingexplanationandchartoftherapeuticequivalenceevaluationsforlevothyroxinesodiumdrugproducts.
LevothyroxineSodium(MylanANDA76187),Levoxyl(KingPharmsNDA021301),Synthroid(AbbvieNDA
021402),andLevoT(AlaraNDA021342)tabletshavebeendeterminedtobetherapeuticallyequivalentto
correspondingstrengthsofUnithroid(JeromeStevensNDA021210)tablets.
LevoT(AlaraNDA021342),LevothyroxineSodium(MylanANDA76187),andUnithroid(JeromeStevensNDA
021210),tabletshavebeendeterminedtobetherapeuticallyequivalenttocorrespondingstrengthsofSynthroid
(AbbvieNDA021402)tablets.
LevoT(AlaraNDA021342),Unithroid(JeromeStevensNDA021210),andLevothyroxineSodium(MylanANDA
076187),tabletshavebeendeterminedtobetherapeuticallyequivalenttocorrespondingstrengthsofLevoxyl
(KingPharmsNDA021301)tablets.
LevothyroxineSodium(MylanANDA76187)tabletshavebeendeterminedtobetherapeuticallyequivalentto
correspondingstrengthsofLevothroid(LloydNDA021116)tablets.
ThechartoutlinesTEcodesforall0.025mgproductsintheactivesectionoftheOrangeBook.Otherproduct
strengthsmaybesimilar.Therapeuticequivalencehasbeenestablishedbetweenproductsthathavethesame
AB+numberTEcode.MorethanoneTEcodemayapplytosomeproducts.OnecommonTEcodeindicates
therapeuticequivalencebetweenproducts.
TradeName

Applicant

Potency

TECode

ApplNo

ProductNo

UNITHROID

STEVENSJ

0.025MG

AB1

21210

001

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TradeName

Applicant

Potency

TECode

ApplNo

ProductNo

LEVOTHYROXINESODIUM

MYLAN

0.025MG

AB1

76187

001

LEVOXYL

KINGPHARMS

0.025MG

AB1

21301

001

SYNTHROID

ABBOTT

0.025MG

AB1

21402

001

LEVOT

ALARAPHARM

0.025MG

AB1

21342

001

SYNTHROID

ABBOTT

0.025MG

AB2

21402

001

LEVOTHYROXINESODIUM

MYLAN

0.025MG

AB2

76187

001

LEVOT

ALARAPHARM

0.025MG

AB2

21342

001

UNITHROID

STEVENSJ

0.025MG

AB2

21210

001

LEVOXYL

KINGPHARMS

0.025MG

AB3

21301

001

LEVOT

ALARAPHARM

0.025MG

AB3

21342

001

UNITHROID

STEVENSJ

0.025MG

AB3

21210

001

LEVOTHYROXINESODIUM

MYLAN

0.025MG

AB3

76187

001

LEVOTHROID

LLOYD

0.025MG

AB4

21116

001

LEVOTHYROXINESODIUM

MYLAN

0.025MG

AB4

76187

001

PatentCertification(s)andReferenceListedDrugbaseduponasuitabilitypetition.AnANDAthatrefers
toareferencelisteddrugapprovedpursuanttoasuitabilitypetitionmustdemonstratethattheproposedproduct
canbeexpectedtohavethesametherapeuticeffectasthereferencelisteddrug,anditmustincludeappropriate
patentcertification(s)andanexclusivitystatementwithrespecttothereferencelisteddrugthatservedasthebasis
fortheapprovedsuitabilitypetition.ThisconceptalsoappliestoanANDAapplicantthatcitesareferencelisted
drugthatwasbaseduponanNDAthatisstillcoveredbypatent(s)and/orexclusivity,e.g.asecondRLDselected
foruseinconductingbioequivalencestudies.
Waivedexclusivity.IfanNDAsubmittedundersection505(b)oftheFD&CActqualifiesforexclusivityunderthe
FD&CAct,theexclusivityislistedinthePatentandExclusivitySectionoftheOrangeBook.Ifadrugproducthas
receivedthisexclusivity,theFDAwillnotacceptforreviewand/orwilldelaytheapprovalofa505(b)(2)application
oranANDAundersection505(j)oftheFD&CAct,asapplicable,inaccordancewiththerelevantexclusivity.If
thelisteddrugisalsoprotectedbyoneormorepatents,theapprovaldateforthe505(b)(2)applicationorANDA
willbedeterminedbasedonananalysisoftheapplicant'spatentcertification(s)orstatement(s)foreachrelevant
patentandtheeffectofrelevantexclusivitylistedintheOrangeBook.However,theholderoftheNDAmaywaive
itsexclusivityastoanyorall505(b)(2)andANDAapplicationsthatmightotherwisebeblockedbysuchNDA.If
anNDAsponsorwaivesitsrighttotheexclusivityprotection,qualified505(b)(2)orANDAapplicationsmaybe
acceptedforreviewand/orapproved,asapplicable,pursuanttotheNDAholder'sexclusivitybeingwaived.An
NDAforwhichtheholderhaswaiveditsexclusivityastoall505(b)(2)andANDAapplicationswillbecodedwitha
"W"inthePatentandExclusivitySectionoftheOrangeBook.Theapplicantwhoseproductmightotherwisebe
blockedbythislisteddrugshouldindicateintheexclusivitystatementthattheholderofthelisteddrughaswaived
itsexclusivity.

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1.9TherapeuticEquivalenceCodeChangeforaDrugEntity
TheAgencywillusethefollowingprocedureswhen,inresponsetoapetitionoronitsowninitiative,itis
consideringachangeinthetherapeuticequivalencecodeforapprovedmultisourcedrugproducts.Suchchanges
willgenerallyoccurwhentheAgencybecomesawareofnewscientificinformationaffectingthetherapeutic
equivalenceofanentirecategoryofdrugproductsintheList(e.g.,informationconcerningtheactiveingredientor
thedosageform),ratherthaninformationconcerningasingledrugproductwithinthecategory.Theseprocedures
willbeusedwhenachangeintherapeuticequivalencecodeisunderconsiderationforalldrugproductsfoundin
thePrescriptionDrugProductListunderaspecificdrugentityanddosageform.Thechangemaybefromthe
codesignifyingthatthedrugdoesnotpresentabioequivalenceproblem(e.g.,AA)toacodesignifyinga
bioequivalenceproblem(e.g.,BP),orviceversa.Thisproceduredoesnotapplytoachangeofaparticular
productcode(e.g.,achangefromBPtoABorfromABtoBX).
Beforemakingachangeinatherapeuticequivalencecodeforanentirecategoryofdrugs,theAgencywill
announceintheIntroductiontotheCumulativeSupplementthatitisconsideringthechangeandwillinvite
comment.Comments,alongwithscientificdata,maybesenttotheDirector,OfficeofBioequivalence,Officeof
GenericDrugs,CenterforDrugEvaluationandResearch,HFD650,7620StandishPlace,Rockville,MD20855.
Thecommentperiodwillgenerallybe60daysinlength,andtheclosingdateforcommentswillbelistedinthe
descriptionoftheproposedchangeforeachdrugentity.
Themostusefultypeofscientificdatasubmittedtosupportcommentsisaninvivobioavailability/bioequivalence
studyconductedonbatchesofthesubjectdrugproducts.Thesesubmissionsshouldpresentafulldescriptionof
theanalyticalproceduresandequipmentused,avalidationoftheanalyticalmethodology,includingthestandard
curve,adescriptionofthemethodofcalculatingresults,andadescriptionofthepharmacokineticandstatistical
modelsusedinanalyzingthedata.AnecdotalortestimonialinformationistheleastusefultotheAgency,andsuch
submissionsarediscouraged.Copiesofsupportingreportspublishedinthescientificliteratureorunpublished
material,however,arewelcome.
1.10ChangeoftheTherapeuticEquivalenceEvaluationforaSingleProduct
TheaforementionedproceduredescribedinSection1.9doesnotapplytoachangeinasingledrugproductcode.
Forexample,achangeinasingledrugproduct'scodefromBPtoABasaresultofthesubmissionofan
acceptablebioequivalencestudyordinarilywillnotbethesubjectofnoticeandcommentintheCumulative
Supplement.Likewise,achangeinasingledrugproduct'scodefromABtoBX(e.g.,asaresultofnew
informationraisingasignificantquestionastobioequivalence)doesnotrequirenoticeandcomment.The
Agency'sresponsibilitytoprovidethepublicwiththeAgency'smostcurrentinformationrelatedtotherapeutic
equivalencemayrequireachangeinadrugproduct'scodepriortoanyformalnoticeandopportunityforthe
applicanttobeheard.ThepublicationintheFederalRegisterofaproposaltowithdrawapprovalofadrug
productwillordinarilyresultinachangeinaproduct'scodefromABtoBXifthisactionhasnotalreadybeen
taken.
Werecognizethatcertaindrugproductsapprovedin505(b)(2)applicationsmaynothavetherapeuticequivalence
codes,andthatFDAmayundertaketherapeuticequivalenceevaluationswithrespecttosuchdrugproducts.A
personseekingtohaveatherapeuticequivalenceratingforadrugproductapprovedina505(b)(2)application
maypetitiontheAgencythroughthecitizenpetitionprocedure(see21CFR10.25(a)andCFR10.30).
1.11DiscontinuedSection
ThosedrugproductsinthediscontinuedsectionoftheOrangeBook(DiscontinuedDrugProductList)forwhicha
determinationhasalreadybeenmadethattheproductswerenotwithdrawnforsafetyoreffectivenessreasons
have"**FederalRegisterdeterminationthatproductwasnotdiscontinuedorwithdrawnforsafetyorefficacy
reasons**"followingtheproductstrength.Thosedrugproductsareonlyreflectiveofdeterminationsmadesince
1995.TheidentificationofthesedrugproductsintheDiscontinuedDrugProductListshouldavoidthesubmission
ofmultiplecitizenpetitionsforthesamedrugproduct.FRnoticesnolongerapplicableareremovedfromthe

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