REGULATORY INFORMATION

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1 REGULATORY*INFORMATION/*CANCER*MEDICINES* Summary'of'regulatory'status'of'the'medicines' As#recommended#in#the#EML#Secretariat s#instructions#regarding#applications#for#the#addition#of#new# medicines# on# the# WHO# Model# List# of# Essential# Medicines,# the# following# document# gathers# information#about#the#regulatory#status#of#selected#medicines#in#the#usa,#from#the#us#food#and#drug# Administration# (FDA),# and# in# Europe,# including# from# the# European# Medicines# Agency# (EMA).# This# summary# also# specifies# the# indications# that# the# medicine# is# licensed# for# by# the# FDA# or# the# EMA.# Finally,#information#about#the#patent#status#of#the#medicines#is#also#provided#for#indicative#purposes# based# on# the# FDA# Orange# Book# and# other# publicly# available# information.# All# information# concerns# adults#unless#specified#otherwise.## CONTENT' AFATINIB'...'2 AFLIBERCEPT'B'(zivBaflibercept)'...'2 AROMATASE'INHIBITORS'...'2 BENDAMUSTINE'...'4 BEVACIZUMAB'...'4 BICALUTAMIDE'...'4 CAPECITABINE'...'5 CETUXIMAB'...'5 CISPLATIN'...'6 CRIZOTINIB'...'6 DOXORUBICIN'HYDROCHLORIDE'LIPOSOME'INJECTION'...'7 ERLOTINIB'...'7 FILGRASTIM'...'8 FLUDARABINE'...'8 GEFITINIB'...'8 GEMCITABINE'...'9 IDARUBICIN'...'9 IMATINIB'...'10 IRINOTECAN'...'11 LEUPROLIDE'ACETATE'...'11 MELPHALAN'...'11 MURAMYL'TRIPEPTIDE' 'MTP'B'MIFAMURTIDE'...'12 PANITUMUMAB'...'12 PEMETREXED'...'12 REGORAFENIB'...'13 RITUXIMAB'...'13 SUNITINIB'...'14 THIOTEPA'...'14 TRASTUZUMAB'...'15 TRETINOIN' 'allbtrans'retinoic'acid'(atra)'...'16

2 VINORELBINE'...'16 AFATINIB'' AfatinibhasbeengrantedregulatoryapprovalintheUSAbytheFDAonJuly12,2013(Gilotrif )(1). IntheEuropeanUnion,afatinibhasbeengrantedamarketingauthorizationthroughthecentralized procedure(ema)onseptember25,2013(giotrif )(2). Indications' 'USA'(FDA):'' GILOTRIF isakinaseinhibitorindicatedforthefirstplinetreatmentofpatientswithmetastaticnonp smallcelllungcancer(nsclc)whosetumorshaveepidermalgrowthfactorreceptor(egfr)exon19 deletionsorexon21(l858r)substitutionmutationsasdetectedbyanfdapapprovedtest Limitation of Use: Safety and efficacy of GILOTRIF have not been established in patients whose tumorshaveotheregfrmutations Patent'status:'IntheUSA,patentsonafatinibwillexpirein2018and2029(FDAOrangeBook). AFLIBERCEPT'B'(zivBaflibercept)' Aflibercept(zivPaflibercept,InjectionforIntravenousInfusion)hasbeengrantedregulatoryapproval intheusabythefdaonaugust3,2012(zaltrap )(1).IntheEuropeanUnion,aflibercepthasbeen grantedamarketingauthorizationthroughthecentralisedprocedure (EMA)onFebruary1 st,2013 (Zaltrap )(2). Indications'B'USA'(FDA):'' ZALTRAP, in combination with 5Pfluorouracil, leucovorin, irinotecanp(folfiri), is indicated for patientswithmetastaticcolorectalcancer(mcrc)thatisresistanttoorhasprogressedfollowingan oxaliplatinpcontainingregimen. Patent' status:' IntheUSA,thecompoundpatentisestimatedtoexpirein2020(information#to#be# confirmed). AROMATASE'INHIBITORS'' Anastrozole* Anastrozole has been granted regulatory approval by the FDA in 1995 (Arimidex ) (1). It is also approvedineuropeancountries(vianationalprocedures),aswellasinaustraliaandcanada. Indications'B'USA'(FDA):'' Anastrozole(Arimidex )isanaromataseinhibitorindicatedfor: AdjuvanttreatmentofpostmenopausalwomenwithhormonereceptorPpositiveearlybreast cancer(1.1) FirstPlinetreatmentofpostmenopausalwomenwithhormonereceptorPpositiveorhormone receptorunknownlocallyadvancedormetastaticbreastcancer(1.2) Treatmentofadvancedbreastcancerinpostmenopausalwomenwithdiseaseprogression following tamoxifen therapy. Patients with ERPnegative disease and patients who did not respondtoprevioustamoxifentherapyrarelyrespondedtoarimidex(1.3) ' Patent' status:' Anastrozole is off patent in the USA and in Europe. Generic versions have been grantedregulatoryapprovalsbothintheusaandeuropeancountries.'

3 Anastrozole (branded and generic) is reported to be currently registered for sale in the following countries(source:martindale:thecompletedrugreference.38thed.,2014):argentina,#australia,# Austria,#Belgium,#Brazil,#Canada,#Chile,#China,#Czech#Republic,#Denmark,#Finland,#France,#Germany,# Greece,#Hong#Kong,#Hungary,#India,#Indonesia,#Ireland,#Israel,#Italy,#Malaysia,#Mexico,#Netherlands,# New#Zealand,#Norway,#Philippines,#Poland,#Portugal,#Russia,#Singapore,#South#Africa,#Spain,#Sweden,# Switzerland,#Thailand,#Turkey,#Ukraine,#USA,#Venezuela.## Letrozole* * LetrozolehasbeengrantedinitialregulatoryapprovalbytheFDAin1997(Femara )(1).Itisalso authorizedineuropevianationalprocedures,aswellasinaustraliaandcanada. ' USA'(FDA):'' Letrozole(Femara )isanaromataseinhibitorindicatedfor: Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlybreast cancer; Extendedadjuvanttreatmentofpostmenopausalwomenwithearlybreastcancerwhohave receivedpriorstandardadjuvanttamoxifentherapy; FirstandsecondPlinetreatmentofpostmenopausalwomenwithhormonereceptorpositive orunknownadvancedbreastcancer. Patent'status:LetrozoleisoffpatentintheUSAandinEuropeancountrieswheregenericversions havebeengrantedregulatoryapprovalsbasedonbioequivalence. Letrozole (branded and generic) is reported to be currently registered for sale in the following countries(source:martindale:thecompletedrugreference.38thed.,2014):argentina,#australia,# Austria,#Belgium,#Brazil,#Canada,#Chile,#China,#Czech#Republic,#Denmark,#Finland,#France,#Germany,# Greece,# Hong# Kong,# Hungary,# India,# Indonesia,# Ireland,# Israel,# Italy,# Japan,# Malaysia,# Mexico,# Netherlands,# New# Zealand,# Norway,# Philippines,# Poland,# Portugal,# Russia,# Singapore,# South# Africa,# Spain,#Sweden,#Switzerland,#Thailand,#Turkey,#UK,#Ukraine#USA,#Venezuela Exemestane** Exemestane has been granted regulatory approval in the USA by the FDA on October 21, 1999 (Aromasine ) (1). Exemestane is also approved in Europe via national procedures as well as in AustraliaandCanada. Indications'B'USA'(FDA):'' Exemestane(Aromasin )isanaromataseinhibitorindicatedfor: adjuvanttreatmentofpostmenopausalwomenwithestrogenpreceptorpositiveearlybreast cancerwhohavereceivedtwotothreeyearsoftamoxifenandareswitchedtoaromasin forcompletionofatotaloffiveconsecutiveyearsofadjuvanthormonaltherapy treatment of advanced breast cancer in postmenopausal women whose disease has progressedfollowingtamoxifentherapy. Patent' status: ExemestaneisoffpatentintheUSA(FDAorangebook)andinEuropeancountries wheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence. Exemestane (branded and generic) is reported to be currently registered for sale in the following countries(source:martindale:thecompletedrugreference.38thed.,2014): Argentina#Australia# Austria#Belgium#Brazil#Canada#Chile#China#Czech#Republic#Denmark#Finland#France#Germany#Greece# Hong# Kong# Hungary# Indonesia# Israel# Italy# Malaysia# Mexico# Netherlands# New# Zealand# Norway#

4 Philippines#Poland#Portugal#Russia#Singapore#South#Africa#Spain#Sweden#Switzerland#Thailand#Turkey# UK#Ukraine#Venezuela. BENDAMUSTINE'' BendamustinehydrochloridehasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyon March 20, 2008 (Treanda ) (1). It has also been approved in Europe via national procedures (Levact ). Indications' 'USA'(FDA):'' TREANDAisanalkylatingdrugindicatedfortreatmentofpatientswith: Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucilhasnotbeenestablished.(1.1) Indolent BPcell nonphodgkin lymphoma (NHL) that has progressed during or within six monthsoftreatmentwithrituximaborarituximabpcontainingregimen.(1.2). Patent status: IntheUSA,accordingtotheFDAOrangebook,patentsonbendamustinearedueto expirein2026,2029and2030. BEVACIZUMAB' BevacizumabhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonFebruary26, 2004(Avastin )(1).IthasalsobeenapprovedinEuropethroughthecentralisedprocedure(EMA)on January12,2005(Avastin )(2). Indications'B'USA'(FDA):'' Bevacizumab (Avastin ) is a vascular endothelial growth factorpspecific angiogenesis inhibitor indicatedforthetreatmentof: Metastatic colorectal cancer, with intravenous 5Pfluorouracil based chemotherapy for firstporsecondplinetreatment.(1.1) Metastatic colorectal cancer, with fluoropyrimidinep irinotecanp or fluoropyrimidinep oxaliplatinpbasedchemotherapyforsecondplinetreatmentinpatientswhohaveprogressed onafirstplineavastincontainingregimen.(1.1) NonPsquamous nonpsmall cell lung cancer, with carboplatin and paclitaxel for first line treatmentofunresectable,locallyadvanced,recurrentormetastaticdisease.(1.2) Glioblastoma,asasingleagentforadultpatientswithprogressivediseasefollowingprior therapy.(1.3) PEffectiveness based on improvement in objective response rate. No data available demonstratingimprovementindiseaseprelatedsymptomsorsurvivalwithavastin. Cervicalcancer,incombinationwithpaclitaxelandcisplatinorpaclitaxelandtopotecanin persistent,recurrent,ormetastaticdisease.(1.5) Metastaticrenalcellcarcinomawithinterferonalfa(1.4) LimitationofUse:Avastinisnotindicatedforadjuvanttreatmentofcoloncancer.(1.1) Patent'status:'IntheUSA,thepatentonbevacizumabisexpectedtoexpirein2019. BICALUTAMIDE'

5 BicalutamidehasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonOctober5,1995 (Casodex )(1).ItisalsoapprovedinEuropeancountriesthroughnationalprocedures. Indications'B'USA'(FDA):'' Bicalutamide(Casodex )50mgisanandrogenreceptorinhibitorindicatedforuseincombination therapywithaluteinizinghormonepreleasinghormone(lhrh)analogforthetreatmentofstaged2 metastaticcarcinomaoftheprostate. ' Patent'status:'BicalutamideisoffpatentintheUSA(FDAorangebook)andinEuropeancountries wheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence. CAPECITABINE' Capecitabine has been granted regulatory approval in the USA by the FDA on April 30, 1998 (Xeloda ) (1). Capecitabine is also approved in Europe through the centralized procedure (EMA) since2001,aswellasincanadasince1998andinaustraliasince2000. Indications'B'USA'(FDA):'' Capecitabine(Xeloda )isanucleosidemetabolicinhibitorwithantineoplasticactivityindicatedfor: AdjuvantColonCancer(1.1) PatientswithDukes Ccoloncancer MetastaticColorectalCancer(1.1) FirstPlineasmonotherapywhentreatmentwithfluoropyrimidinetherapyaloneispreferred MetastaticBreastCancer(1.2) Incombinationwithdocetaxelafterfailureofprioranthracyclinecontainingtherapy AsmonotherapyinpatientsresistanttobothpaclitaxelandananthracyclinePcontainingregimen Patent'status:'IntheUSA,thekeypatentoncapecitabine(Xeloda )expiredondec14,2013(and June14,2014forpediatricindicationswithdataexclusivityuntilJune10,2017)(FDAOrangeBook). CapecitabineisoffpatentinEuropeancountriessince2013.Regulatoryapprovalshavebeengranted togenericmanufacturersintheusa(fda)andineurope(ema)basedonbioequivalence. Capecitabine(brandedandgeneric)isreportedtobecurrentlyregisteredforsaleinthefollowing countries(source:martindale:thecompletedrugreference.38thed.,2014):argentina#australia# Austria#Belgium#Brazil#Canada#Chile#China#Czech#Republic#Denmark#Finland#France#Germany#Greece# Hong# Kong# Hungary# India# Indonesia# Ireland# Israel# Italy# Japan# Mexico# Netherlands# New# Zealand# Norway# Philippines# Poland# Portugal# Russia# Singapore# South# Africa# Spain# Sweden# Switzerland# Thailand#Turkey#UK#Ukraine#USA#Venezuela.# CETUXIMAB' CetuximabhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonFebruary12,2004 (Erbitux )(1).InEurope,Ithasbeengrantedamarketingauthorizationthroughthecentralized procedure(ema)onjune29,2004(erbitux )(2). Indications'and'usage'B'USA'(FDA): Erbitux isanepidermalgrowthfactorreceptor(egfr)antagonistindicatedfortreatmentof: Head'and'Neck'Cancer''

6 Locallyorregionallyadvancedsquamouscellcarcinomaoftheheadandneckincombinationwith radiationtherapy.(1.1,14.1) Recurrentlocoregionaldiseaseormetastaticsquamouscellcarcinomaoftheheadandneckin combinationwithplatinumpbasedtherapywith5pfu.(1.1,14.1) RecurrentormetastaticsquamouscellcarcinomaoftheheadandneckprogressingafterplatinumP basedtherapy.(1.1,14.1) Colorectal'Cancer KPRasmutationPnegative(wildPtype),EGFRPexpressing,metastaticcolorectalcancerasdetermined byfdapapprovedtests incombinationwithfolfiriforfirstplinetreatment, incombinationwithirinotecaninpatientswhoarerefractorytoirinotecanpbasedchemotherapy, asasingleagentinpatientswhohavefailedoxaliplatinpandirinotecanpbasedchemotherapyor whoareintoleranttoirinotecan.(1.2,5.7,12.1,14.2) LimitationofUse:ErbituxisnotindicatedfortreatmentofKPRasmutationPpositivecolorectalcancer. (5.7,14.2). Patent' status:' In the USA, data exclusivity is due to expire in In Europe, the protection on cetuximabexpiredin2014. CISPLATIN' CisplatinhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyin1978(Platinol )(1). ItisalsoapprovedinEuropethroughnationalprocedures. Indications'B'USA'(FDA):'' PLATINOL(cisplatinforinjection,USP)isindicatedastherapytobeemployedasfollows: MetastaticTesticularTumors Inestablishedcombinationtherapywithotherapprovedchemotherapeuticagentsinpatientswith metastatictesticulartumorswhohavealreadyreceivedappropriatesurgicaland/orradiotherapeutic procedures. MetastaticOvarianTumors Inestablishedcombinationtherapywithotherapprovedchemotherapeuticagentsinpatientswith metastaticovariantumorswhohavealreadyreceivedappropriatesurgicaland/orradiotherapeutic procedures.anestablishedcombinationconsistsofplatinolandcyclophosphamide.platinol,asa singleagent,isindicatedassecondarytherapyinpatientswithmetastaticovariantumorsrefractory tostandardchemotherapywhohavenotpreviouslyreceivedplatinoltherapy. AdvancedBladderCancer PLATINOLisindicatedasasingleagentforpatientswithtransitionalcellbladdercancerwhichisno longeramenabletolocaltreatments,suchassurgeryand/orradiotherapy." Patent'status:CisplatinisoffpatentintheUSA(FDAOrangeBook)aswellasinEuropeancountries wheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence. CRIZOTINIB'' CrizotinibhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonAugust26,2011 (Xalkori )(1).IthasalsobeengrantedamarketingauthorizationinEuropethroughthecentralized procedure(ema)onoctober23,2012(xalkori )(2). Indications' 'USA'(FDA):''

7 XALKORI isakinaseinhibitorindicatedforthetreatmentofpatientswithmetastaticnonpsmallcell lungcancer(nsclc)whosetumorsareanaplasticlymphomakinase(alk)ppositiveasdetectedbyan FDAPapprovedtest. ' Patent'status:'' In the US, patents on crizotinib are due to expire from 2025 (FDA Orange Book). In Europe, the patentisduetoexpirein2025. DOXORUBICIN'HYDROCHLORIDE'LIPOSOME'INJECTION'' DoxorubicinHydrochlorideLiposomeInjectionforintravenousinfusionhasbeenapprovedinthe USAbytheFDAinNovember17,1995(Doxilliposomal )(1).Thepegylatedliposomeformulationof doxorubicinalsoobtainedamarketingauthorizationineuropein1996(caelyx ). Indications'B'USA'(FDA): DOXIL isananthracyclinetopoisomeraseinhibitorindicatedfor: Ovarian'cancer'(1.1) AfterfailureofplatinumPbasedchemotherapy. AIDSBrelated'Kaposi s'sarcoma'(1.2) Afterfailureofpriorsystemicchemotherapyorintolerancetosuchtherapy. Multiple'Myeloma'(1.3) Incombinationwithbortezomibinpatientswhohavenotpreviouslyreceivedbortezomibandhave receivedatleastonepriortherapy. Patent'status:AccordingtotheFDAOrangeBook,therearenounexpiredpatentsforDoxorubicin HydrochlorideLiposomeInjectionintheUSA. ERLOTINIB'' ErlotinibhydrochloridehasbeengrantedregulatoryapprovalintheUSAbytheFDAonNovember 18, 2004 (Tarceva ) (1). It has also been approved in Europe through the centralised procedure (EMA)onSeptember19,2005(Tarceva )(2). Indications'and'usage'B'US'(FDA): Erlotinibhydrochloride(Tarceva )isakinaseinhibitorindicatedfor: FirstPlinetreatmentofpatientswithmetastaticnonPsmallcelllungcancer(NSCLC)whosetumors haveepidermalgrowthfactorreceptor(egfr)exon19deletionsorexon21(l858r)substitution mutationsasdetectedbyanfdapapprovedtest.(1.1) MaintenancetreatmentofpatientswithlocallyadvancedormetastaticNSCLCwhosediseasehas notprogressedafterfourcyclesofplatinumpbasedfirstplinechemotherapy.(1.1) TreatmentoflocallyadvancedormetastaticNSCLCafterfailureofatleastonepriorchemotherapy regimen.(1.1) FirstPline treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer,incombinationwithgemcitabine.(1.2) LimitationsofUse: TARCEVAisnotrecommendedforuseincombinationwithplatinumPbasedchemotherapy. SafetyandefficacyofTARCEVAhavenotbeenevaluatedasfirstPline treatment in patients with metastatic NSCLC whose tumors have EGFR mutations other than exon 19 deletions or exon 21(L858R)substitution.

8 Patent'status:'' IntheUS,patentsonerlotinibareduetoexpirein2018and2020(FDAOrangeBook).Inanumberof Europeancountries,erlonitibisprotectedbysupplementaryprotectioncertificatesuntilMarch2020. FILGRASTIM'' FilgrastimhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonFebruary20,1991 (Neupogen )(1).ItisalsoapprovedinEuropeancountriesthroughnationalprocedures. Indications'and'usage'B'US'(FDA): CancerPatientsReceivingMyelosuppressiveChemotherapy PatientsWithAcuteMyeloidLeukemiaReceivingInductionorConsolidation Chemotherapy CancerPatientsReceivingBoneMarrowTransplant PatientsUndergoingPeripheralBloodProgenitorCellCollectionandTherapy PatientsWithSevereChronicNeutropenia Patent' status: In the US, the compound patent on filgrastim (Neupogen ) expired in December In Europe, filgrastim (Neupogen ) is off patent since Biosimilar versions of filgrastim havebeenapprovedbytheema. FLUDARABINE' FludarabinephosphatehasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonApril 18,1991(1).ItisalsoapprovedinEuropeancountriesthroughnationalprocedures. Indications'and'usage'B'US'(FDA): FludarabinePhosphateInjectionisanucleotidemetabolicinhibitorindicatedfor: The treatment of adult patients with BPcell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylatingpagentcontainingregimen.benefitintreatmentpnaïveornonprefractorycllpatientsisnot established. Patent' status: Fludarabine phosphate is off patent in the USA (FDA Orange Book) as well as in European countries where generic versions have been granted regulatory approvals based on bioequivalence. Fludarabinephosphate(brandedandgeneric)isreportedtobecurrentlyregisteredforsaleinthe followingcountries(source:martindale:thecompletedrugreference.38thed.,2014): Argentina Australia Austria Belgium Brazil Canada Chile China Denmark France Germany Greece Hong Kong Hungary India Italy Malaysia Mexico Netherlands New Zealand Philippines Poland Portugal Russia Singapore South Africa Spain Sweden Switzerland Thailand Turkey UK USA Venezuela. GEFITINIB'' * GefitinibwasapprovedintheUSAbytheFDAonMay5,2003(Iressa )butwaslaterdiscontinued (1, 2). In Europe, Gefitinib has been granted a marketing authorisation through the centralised procedure(ema)onjune24,2009(iressa )(3).

9 Indications'B'EU'(EMA):'' IRESSAisindicatedforthetreatmentofadultpatientswithlocallyadvancedormetastaticnonPsmall celllungcancer(nsclc)withactivatingmutationsofegfrptk. Patent'status:'IntheUSA,thepatentonGefitinibisduetoexpireinMay2017(FDAOrangeBook Discontinued drug product). In Europe, the patent on Gefitinib is due to expire in 2016 and supplementaryprotectioncertificateshavebeengrantedinanumberofcountriesuntil2019. GEMCITABINE'' GemcitabineHydrochloridehasbeengrantedregulatoryapprovalintheUSAbytheFDAonMay15, 1996(Gemzar )(1).ItisalsoapprovedinEuropeancountriesthroughnationalprocedures. Indications'B'USA'(FDA):'' Gemcitabine(Gemzar )isanucleosidemetabolicinhibitorindicated: incombinationwithcarboplatin,forthetreatmentofadvancedovariancancerthathas relapsedatleast6monthsaftercompletionofplatinumpbasedtherapy(1.1) incombinationwithpaclitaxel,forfirstplinetreatmentofmetastaticbreastcancerafter failure of prior anthracyclinepcontaining adjuvant chemotherapy, unless anthracyclines wereclinicallycontraindicated(1.2) incombinationwithcisplatinforthetreatmentofnonpsmallcelllungcancer(1.3) asasingleagentforthetreatmentofpancreaticcancer(1.4) Patent' status:gemcitabineisoffpatentintheusa(fdaorangebook)andineuropeancountries wheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence. Gemcitabine(brandedandgeneric)isreportedtobecurrentlyregisteredforsaleinthefollowing countries(source:martindale:thecompletedrugreference.38thed.,2014): Argentina#Australia# Austria#Belgium#Brazil#Canada#Chile#China#Czech#Republic#Denmark#Finland#France#Germany#Greece# Hong# Kong# Hungary# India# Indonesia# Ireland# Israel# Italy# Malaysia# Mexico# Netherlands# Norway# Philippines#Poland#Portugal#Russia#Singapore#South#Africa#Spain#Sweden#Switzerland#Thailand#Turkey# UK#Ukraine#USA#Venezuela# IDARUBICIN' IdarubicinHydrochloridehasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyin1990 andinitscurrentformonfebruary 17,1997 (Idamycin PFS )(1). It is also approved in European countriesthroughnationalprocedures. Indications'B'USA'(FDA):'' IdarubicinHydrochloride(IdamycinPFS )Injectionincombinationwithotherapprovedantileukemic drugsisindicatedforthetreatmentofacutemyeloidleukemia(aml)inadults. Patent'status:'IdarubicinHydrochlorideisoffpatentintheUSA(FDAorangebook)andinEuropean countrieswheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence.' IdarubicinHydrochloride(brandedandgeneric)isreportedtobecurrentlyregisteredforsaleinthe followingcountries(source:martindale:thecompletedrugreference.38thed.,2014): Argentina# Australia#Austria#Belgium#Brazil#Canada#Chile#China#Czech#Republic#Denmark#Finland#France#Greece# Hong# Kong# Hungary# Ireland# Israel# Italy# Malaysia# Mexico# Netherlands# New# Zealand# Norway#

10 Philippines#Poland#Portugal#Russia#Singapore#South#Africa#Spain#Sweden#Switzerland#Thailand#Turkey# UK#Ukraine#USA#Venezuela IMATINIB'' Imatinib(imatinibmesylate)hasbeengrantedregulatoryapprovalbytheFDAin2001(Gleevec ) (1). Imatinib has also been granted a marketing authorization in Europe through the centralized procedure (EMA) (Glivec ) in Imatinib is currently approved in over 110 countries for the treatmentofbothhaematologicalmalignanciesandsolidtumours. Indications'B'USA'(FDA):'' Gleevecisakinaseinhibitorindicatedforthetreatmentof: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloidleukemia(ph+cml)inchronicphase(1.1) PatientswithPhiladelphiachromosomepositivechronicmyeloidleukemia(Ph+CML)inblastcrisis (BC),acceleratedphase(AP),orinchronicphase(CP)afterfailureofinterferonPalphatherapy(1.2) AdultpatientswithrelapsedorrefractoryPhiladelphiachromosomepositiveacutelymphoblastic leukemia(ph+all)(1.3) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia(ph+all)incombinationwithchemotherapy(1.4) Adult patients with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with PDGFR(plateletPderivedgrowthfactorreceptor)genereParrangements(1.5) Adultpatientswithaggressivesystemicmastocytosis(ASM)withouttheD816VcPKitmutationor withcpkitmutationalstatusunknown(1.6) Adultpatientswithhypereosinophilicsyndrome(HES)and/orchroniceosinophilicleukemia(CEL) who have the FIP1L1PPDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 alleledeletion)andforpatientswithhesand/orcelwhoarefip1l1pdgfrαfusionkinasenegativeor unknown(1.7) Adultpatientswithunresectable,recurrentand/ormetastaticdermatofibrosarcomaprotuberans (DFSP)(1.8) Patients with Kit (CD117) positive un resectable and/or metastatic malignant gastrointestinal stromaltumors(gist)(1.9) AdjuvanttreatmentofadultpatientsfollowingresectionofKit(CD117)positiveGIST(1.10) Patent' status: In the USA, according to the FDA Orange book, the original compound patent will expire on January 4, In Europe, the patent expired in March However, in certain European countries, supplementary protection certificates (SPC) have been granted, protecting imatinibfromgenericcompetitionuntil20june2016(e.g.uk). Since 2013, marketingauthorisations for generic versions of imatinib (100 mg and 400 mg forms) have been granted in Canada (Teva, Apotex, Actavis) as well as in Europe (accord, Teva, Actavis, Medac). Imatinib (branded and generic) is reported to be currently registered for sale in the following countries (Source: Martindale: The Complete Drug Reference. 38th ed., 2014): Argentina,# India,# Canada,# South# Africa,# USA,# Netherlands,# Australia,# Austria,# Belgium,# Brazil,# Chile,# China,# Czech# Republic,#Denmark,#Finland,#France,#Germany,#Greece,#Hong#Kong,#Hungary,#India,#Indonesia,#Ireland,# Israel,# Italy,# Japan,# Malaysia,# Mexico,# New# Zealand,# Netherlands,# Norway,# Philippines,# Poland,# Portugal,#Russia,#Singapore,#Spain,#Sweden,#Switzerland,#Thailand,#Turkey,#UK,#Ukraine,#Venezuela.#

11 IRINOTECAN'' Irinotecan has been granted regulatory approval in the USA by the FDA initially in 1996 (Camptosar )(1).ItisalsoapprovedinEuropethroughnationalprocedures. Indications' 'USA'(FDA): Irinotecan(Camptosar )isatopoisomeraseinhibitorindicatedfor: FirstPlinetherapyincombinationwith5Pfluorouracilandleucovorinforpatientswithmetastatic carcinomaofthecolonorrectum. Patientswithmetastaticcarcinomaofthecolonorrectumwhosediseasehasrecurredor progressedfollowinginitialfluorouracilpbasedtherapy. Patent'status:'' IntheUSA,thecompoundpatentforirinotecan(camptosar )expiredin2008.accordingtothefda orangebook,combinationpatentsofirinotecanwith5pfluorouracilandleucovorinareduetoexpire in2020.ineurope,thecompoundpatentexpiredin2009andgenericversionshavebeengranted regulatoryapprovalsinvariouseuropeancountriesbasedonbioequivalence. LEUPROLIDE'ACETATE' Leuprolide acetate (suspension depot for injection) is approved in the USA by the FDA (Lupron depot ) since 1989 (1). Leuprolide acetate (suspension for subcutaneous injection) (Eligard) is approved by the FDA since 2002 (2). It has also been approved in European countries through nationalprocedures(eligard ). Indications' 'USA'(FDA): LUPRONDEPOT isagonadotropinreleasinghormone(gnrh)agonistindicatedfor: palliativetreatmentofadvancedprostaticcancer. ELIGARD is a gonadatropin releasing hormone (GnRH) agonist indicated for the palliative treatmentofadvancedprostatecancer Patent'status:IntheUSA,accordingtotheFDAOrangeBook,thekeypatentsonleuprolideacetate (LupronDepot )expired.apatenton releasemicrospheresandpreparationofthereof willexpire in2016.accordingtothefdaorangebook,thefirstpatentoneligard expiredbutotherpatents mightimpedegenericcompetitionuntilmarch2020. MELPHALAN'' MelphalanhasbeenapprovedintheUSAbytheFDA(Alkeran )(1)aswellasinEuropeancountries throughvianationalprocedures. Indications' 'USA'(FDA): ALKERAN Tablets are indicated for the palliative treatment of multiple myeloma and for the palliationofnonpresectableepithelialcarcinomaoftheovary. Patent'status:MelphalanisoffpatentintheUSA(FDAOrangeBook).

12 MURAMYL'TRIPEPTIDE' 'MTP'B'MIFAMURTIDE' Mifamurtide has been granted a marketing authorization in the European Union (centralized procedure EMA)onMarch6,2009(Mepact )(1).ItisnotapprovedintheUSAbytheFDA. Indications' 'EU'(EMA):'' MEPACT is indicated in children, adolescents and young adults for the treatment of highpgrade resectablenonpmetastaticosteosarcomaaftermacroscopicallycompletesurgicalresection.itisused in combination with postpoperative multipagent chemotherapy. Safety and efficacy have been assessedinstudiesofpatients2to30yearsofageatinitialdiagnosis. Patent'status:Accordingtoavailableinformation,itseemsthatthepatentonmifamurtidewasdue toexpirein2010intheusa(information#to#be#completed). PANITUMUMAB' PanitumumabhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonSeptember27, 2006(Vectibix )(1).InEurope,ithasbeengrantedamarketingauthorizationthroughcentralized procedure(ema)ondecember3,2007(vectibix )(2). Indications' 'USA'(FDA): Panitumumab(Vectibix )isanepidermalgrowthfactorreceptor(egfr)antagonistindicatedfor thetreatmentofwildptypekras(exon2)metastaticcolorectalcancer(mcrc)asdeterminedbyan FDAPapprovedtestforthisuse: IncombinationwithFOLFOXforfirstPlinetreatment.(1.1,14.2) Asmonotherapyfollowingdiseaseprogressionafterpriortreatmentwithfluoropyrimidine, oxaliplatin,andirinotecanpcontainingchemotherapy.(1.1,14.1) LimitationofUse:VectibixisnotindicatedforthetreatmentofpatientswithKRASPmutantmCRCor forwhomkrasmutationstatusisunknown.(1.2,2.1,5.2,12.1) Patent'status:'Accordingtoavailableinformation,intheUSA,thekeypatentonpanitunumabisdue toexpirein2017(extensionuntil2020).ineurope,thepatentisduetoexpirein2018,withspcs havingbeengrantedinanumberofeuropeancountriesuntil2022(information#to#be#completed). PEMETREXED' PremetexedhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyin2004(Alimta ) (1). In the European Union, premetrexed has also been granted a marketing approval (EMA centralisedprocedure)onseptember20,2004(alimta )(2). Indications' 'USA'(FDA): ALIMTA isafolateanalogmetabolicinhibitorindicatedfor: LocallyAdvancedorMetastaticNonsquamousNonPSmallCellLungCancer: Initialtreatmentincombinationwithcisplatin.(1.1) Maintenancetreatmentofpatientswhosediseasehasnotprogressedafterfourcyclesof platinumpbasedfirstplinechemotherapy.(1.2) AfterpriorchemotherapyasasinglePagent.(1.3) Mesothelioma:incombinationwithcisplatin(1.4)

13 LimitationsofUse: ALIMTAisnotindicatedforthetreatmentofpatientswithsquamouscellnonPsmallcelllungcancer. (1.5) Patent'status:'IntheUSA,patentprotectiononpremetexedisduetoexpirein2016.InEurope,the basiccompoundpatentexpired,withspcshavingbeengrantedinvariouseuropeancountriesuntil December2015. REGORAFENIB'' # RegorafenibhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyin2012(stivarga, tabletsfororaluse)(1).ineurope,amarketingauthorizationhasbeengrantedbytheemain2013 (stivarga )(2). # Indications' 'USA'(FDA): Regorafenib(Stivarga )isakinaseinhibitorindicatedforthetreatmentofpatientswith: Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidinep, oxaliplatinp and irinotecanpbased chemotherapy, an antipvegf therapy, and, if KRAS wild type, an antipegfrtherapy.(1.1) Locallyadvanced,unresectableormetastaticgastrointestinalstromaltumor(GIST)whohavebeen previouslytreatedwithimatinibmesylateandsunitinibmalate.(1.2) Patent'status:IntheUSA(FDAOrangeBook),patentsonregorafenibareduetoexpirefrom2020. RITUXIMAB'' RituximabhasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyin1997(Rituxan ) (1).IthasalsobeengrantedapprovalinEurope(EMA)(2)andinAustralia(TGA)(Mabthera )(3)in 1998,aswellasinCanada(Rituxan )in2000(4).rituximabisapprovedinmorethan102countries worldwide. USA'(FDA) Rituximabisindicatedforthetreatmentofpatientsforthefollowingtherapeuticindications: 1.1.NonPHodgkin slymphoma(nhl): Relapsedorrefractory,lowPgradeorfollicular,CD20Ppositive,BPcellNHLasasingleagent Previouslyuntreatedfollicular,CD20Ppositive,BPcellNHLincombinationwithfirstline chemotherapyand,inpatientsachievingacompleteorpartialresponsetorituxanin combinationwithchemotherapy,assinglepagentmaintenancetherapy. NonPprogressing(includingstabledisease),lowPgrade,CD20Ppositive,BPcellNHLasasingle agentafterfirstplinecvpchemotherapy PreviouslyuntreateddiffuselargeBPcell,CD20PpositiveNHLincombinationwithCHOPor otheranthracyclinepbasedchemotherapyregimens 1.2.ChronicLymphocyticLeukemia(CLL) Rituxan (rituximab)isindicated,incombinationwithfludarabineandcyclophosphamide (FC),forthetreatmentofpatientswithpreviouslyuntreatedandpreviouslytreatedCD20P positivecll.

14 Other'indications:RituximabisalsoindicatedforthetreatmentofRheumatoidArthritis(RA)aswell asforgranulomatosiswithpolyangiitis(gpa). Patent' status:' IntheUSA,thekeypatentonrituximab(Rituxan )willexpireonapril7,2015.in Europe,thekeypatentonrituximab(Mabthera )expiredonnovember21,2013.' Biosimilarsofrituximabhavebeenapprovedinotherjurisdictions,includingIndiain2007(Reditux manufacturedbydrreddy'slaboratories). Rituximab is reported to be currently registered for sale in the following countries (Source: Martindale:TheCompleteDrugReference.38thed.,2014):Argentina,#Australia,#Austria,#Belgium,# Brazil,#Chile,#Czech#Republic,#Denmark,#Finland,#France,#Germany,#Greece,#Hong#Kong,#Hungary,#India,# Indonesia,# Ireland,# Israel,# Italy,# Malaysia,# Mexico,# New# Zealand,# Netherlands,# Norway,# Philippines,# Poland,#Portugal,#Russia,#South#Africa,#Singapore,#Spain,#Sweden,#Switzerland,#Thailand,#Turkey,#UK,# Ukraine,#Venezuela,#Japan,#USA,#Canada.# SUNITINIB'' # Sunitinib malate has been granted regulatory approval in the USA by the FDA in 2006 (Sutent, capsules,oral)(1).ineurope,amarketingauthorizationhasbeengranted throughthecentralized procedure(ema)in2006(sutent )(2). Indications' 'USA'(FDA): Sunitinib(Sutent )isakinaseinhibitorindicatedforthetreatmentof: Gastrointestinalstromaltumor(GIST)afterdiseaseprogressiononorintolerancetoimatinib mesylate. Advancedrenalcellcarcinoma(RCC). Progressive,wellPdifferentiatedpancreaticneuroendocrinetumors(pNET)inpatientswith unresectablelocallyadvancedormetastaticdisease. Patent'status:'IntheUSA(FDAOrangeBook),patentsonsunitinibwillexpireinFebruary2021and December2020. THIOTEPA'' ThiotepaisapprovedintheUSAbytheFDA(initiallyin1994thenrePregisteredin2001underthe namethiotepa) (1). InEurope,Thiotepahasalsobeengrantedamarketingauthorizationthrough thecentralisedprocedure(ema)onmay6,2010(tepadina )(2). Indications' 'USA'(FDA): Thiotepahasbeentriedwithvaryingresultsinthepalliationofawidevarietyofneoplasticdiseases. However,themostconsistentresultshavebeenseeninthefollowingtumors: P adenocarcinomaofthebreast P adenocarcinomaoftheovery P forcontrollingintracavitaryeffusionssecondarytodiffuseorlocalizedneoplasticdiseasesof variousserosalcavities P forthetreatmentofsuperficialpapillarycarcinomaoftheurinarybladder Whilenowlargelysupersededbyothertreatments,thiotepahasbeeneffectiveagainstother lymphomas,suchaslymphosarcomaandhodgkin sdisease.

15 ' Indications'B'EU'(EMA):'' Incombinationwithotherchemotherapymedicinalproducts: 1) with or without total body irradiation (TBI), as conditioning treatment prior to allogeneic or autologoushaematopoieticprogenitorcelltransplantation(hpct)inhaematologicaldiseasesinadult andpaediatricpatients; 2) when high dose chemotherapy with HPCT support is appropriate for the treatment of solid tumours in adult and paediatric patients.". It is proposed that Tepadina must be prescribed by physicians experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation. Patent'status:AccordingtotheFDAOrangeBook,therearenounexpiredpatentsonthiotepa. TRASTUZUMAB'' # ThefirstmarketingauthorizationfortrastuzumabwasgrantedintheUnitedStatesofAmerica(FDA) in1998(1)(herceptin ).ItisalsoapprovedintheEU(EMA)in2000(2).Trastuzumabiscurrently approvedinover120countriesglobally. US'(FDA): 1.1.AdjuvantBreastCancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative(er/prnegativeorwithonehighriskfeaturebreastcancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxelordocetaxel withdocetaxelandcarboplatin asasingleagentfollowingmultipmodalityanthracyclinebasedtherapy. 1.2.MetastaticBreastCancer Herceptinisindicated: In combination with paclitaxel for firstpline treatment of HER2Poverexpressing metastatic breastcancer AsasingleagentfortreatmentofHER2Poverexpressingbreastcancerinpatientswhohave receivedoneormorechemotherapyregimensformetastaticdisease. 1.3MetastaticGastricCancer Herceptin is indicated, in combination with cisplatin and capecitabine or 5Pfluorouracil, for the treatmentofpatientswithher2overexpressingmetastaticgastricorgastroesophagealjunction adenocarcinoma,whohavenotreceivedpriortreatmentformetastaticdisease. Patent'status:'IntheUSA,thekeypatentontrastuzumab(herceptin )willexpireonjune18,2019. InEurope,thekeypatentexpiredin2012andsupplementaryprotectioncertificates(SPC)grantedby countries(e.g.uk)expiredonjune28,2014. Trastuzumab (Herceptin) is reported to be currently registered for sale in the following countries (Source: Martindale: The Complete Drug Reference. 38th ed., 2014): Japan,# USA,# Argentina,# Australia,#Austria,#Belgium,#Brazil,#Canada,#Chile,#China,#Czech#Republic,#Denmark,#Finland,#France,# Germany,#Greece,#Hong#Kong,#Hungary,#India,#Indonesia,#Ireland,#Israel,#Italy,#Malaysia,#Mexico,#New# Zealand,#Netherlands,#Norway,#Philippines,#Poland,#Portugal,#Russia,#South#Africa,#Singapore,#Spain,# Sweden,#Switzerland,#Thailand,#Turkey,#UK,#Ukraine,#Venezuela.

16 TRETINOIN' 'allbtrans'retinoic'acid'(atra)'' Tretinoin(allPtransretinoicacid ATRA)wasapprovedbytheFDAonNov22,1995(Vesanoid marketingdiscontinued nowavailableunderthenametretinoin ANDA77P684).Tretinoinisalso approvedineuropeancountriesthroughnationalprocedures(vesanoid ). Indications' 'USA'(FDA): VESANOID(tretinoin)capsulesareindicatedfortheinductionofremissioninpatientswithacute promyelocytic leukemia (APL), FrenchPAmericanPBritish (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARαgenewhoarerefractoryto,orwhohaverelapsedfrom,anthracyclinechemotherapy,or for whom anthracyclinepbased chemotherapy is contraindicated. VESANOID is for the induction of remissiononly.theoptimalconsolidationormaintenanceregimenshavenotbeendefined,butall patientsshouldreceiveanacceptedformofremissionconsolidationand/ormaintenancetherapyfor APLaftercompletionofinductiontherapywithVESANOID. # Patents' status:' According to the FDA Orange Book, there are no unexpired patents on tretinoin, capsules10mg.' VINORELBINE' VinorelbineTartratehasbeengrantedregulatoryapprovalintheUSAbytheFDAinitiallyonDec23, 1994(Navelbine )(1).ItisalsoapprovedinEuropeancountriesthroughnationalprocedures. Indications' 'USA'(FDA): VinorelbineTartrate(Navelbine )isavincaalkaloidindicated: IncombinationwithcisplatinforfirstPlinetreatmentofpatientswithlocallyadvancedormetastatic nonpsmallcelllungcancer(nsclc) AsasingleagentforfirstPlinetreatmentofpatientswithmetastaticNSCLC. Patent' status:' Vinorelbine is off patent in the USA (FDA Orange Book) and in European countries wheregenericversionshavebeengrantedregulatoryapprovalsbasedonbioequivalence.

17 Medicine) *not*on*the*who*model*eml*2013 Afatinib* Gilotrif- ON Aflibercept* Zaltrap ON Allopurinol* Zyloprim FDA-Orange-Book:- US =-July)29,)2018 US (process)-=--Oct-10,-2029 US (form)-=-Dec-19,-2029 USRE43431-=-Jan-22,-2022 Not-in-FDA-Orange-Book Estimation:*2020*(2022*if*PTE*is*granted) Anastrozole* Arimidex Letrozole* Femara 2011 Exemestane* Aromasine 2011 Asparaginase Elspar Bendamustine* Treanda,-Levact ON Bevacizumab* Avastin- ON Bicalutamide* Casodex- Bleomycin Blenoxane Calcium*folinate*(leucovorin) Wellcovorin Capecitabine* Xeloda- Carboplatin*(platinum*class*representative) Paraplat Cetuximab* Erbitux- ON Cisplatin* US)brandnames) (NCI)Drug) Dictionary)) Platinol Chlorambucil Ambochlorin*(multiple) Crizotinib* Xalkori ON Cyclophosphamide *Cytoxan,*Neosar,*Revim Cytarabine CytosarNU,*Tarabine*PFS Dacarbazine DTICNDome PATENT)STATUS)IN)THE)UNITED)STATES) Sources:)FDA)Orange)book)/)internet)search,)patent)USPTO Patent)status) (compound)patent) ON/) Expiry)date decentralised-=-generics-available-incountries decentralised-=-generics-available-incountries decentralised-=-generics-available-incountries FDA-Orange-Book:- US =-Oct-26,-2030 US and =--Jan-12, US =-March-27, data-exclusivity:-2015-and-2016 Not-in-FDA-orange-book. US US Expiry-date: FDA-Orange-Book:-"no-unexpired-patentsfor-this-product" -US Expired- decentralised-=-generics-available-incountries US =-Expired)Dec)14,) *PED-=--Jun-14,-2014-(dataexclusivity-PED)Jun)10,)2017) Not-in-FDA-Orange-Book Indicative*information: Data*exclusivity*until*2016* A*combination*patent*with*with*5N FluorouracilN*is*due*to*expire*in*2018 decentralised-=-generics-available-incountries FDA-Orange-Book:- US =-March)1,)2025 US =-May-12,-2027 US =-Oct-8,-2029 US =-Nov-6,-2029 ON ON ON ON Estimation:*2020* EP * 2008 ON PATENT)STATUS)IN)EUROPEAN)COUNTRIES) Sources:)EPO,)UK)and)IE)IPO)for)SCP Patent)status) ON/) Expiry)date) (including)information)on)supplementary) Protection)Certificates).)SPCs)) 5-generics-approved-by-the-EMAfrom-2012-=generics-available-in-countries EP Expired-June SPCs-in-various-European-countries-expiredin-september-2014 EP Expiry-date)2025 SPCs-in-some-countries-(e.g.-Ireland-until- 2027) European)countries).)regulatory) approvals)of)generic)versions) EMA)status).)Generics)/)Biosimilars) marketing)authorization)(or,) decentralised) procedure=availability)of)generics) in)france) EP A-and-EP A Expired-November FDA-Orange-Book No-unexpired-patents-for-this-product-

18 Medicine) *not*on*the*who*model*eml*2013 US)brandnames) (NCI)Drug) Dictionary)) PATENT)STATUS)IN)THE)UNITED)STATES) Sources:)FDA)Orange)book)/)internet)search,)patent)USPTO Patent)status) (compound)patent) ON/) Dactinomycin Cosmegen Daunorubicin Cerubidine*Rubidomycin Dexamethasone AerosebNDex*(multiple) Docetaxel *Taxotere Doxorubicin Doxorubicin-Hydrochloride-Liposome-Injection* Doxil/Caelys Erlotinib* Tarceva ON Etoposide Toposar*VePesid Filgrastim*- Neupogen- Fludarabine* Fludara Fluorouracil* drucil*efudex*fluorople Gefitinib*- Iressa ON Expiry)date SPCs-granted-until-March Not-in-FDA-Orange-Book Estimation:-Expired-december FDA-Orange-Book:- "No-unexpired-patents-for-this-product"nounexpired-patents-for-this-product Basic-compound-patent:-US decentralisedgenerics-available-in-countries FDA-Orange-Book-(discontinued-drug- product):- US =-May)5,)2017 PATENT)STATUS)IN)EUROPEAN)COUNTRIES) Sources:)EPO,)UK)and)IE)IPO)for)SCP Patent)status) ON/) ON Expiry)date) (including)information)on)supplementary) Protection)Certificates).)SPCs)) FDA-Orange-Book:- "No-unexpired-patents-for-this-product" -(data-exclusivity-for-indication-multiplemyeloma-until-may-2014) FDA-Orange-Book:- US =-Nov)8,)2018) US (crystalline-polymorph)-and- other-patents--=-nov-9, European)countries).)regulatory) approvals)of)generic)versions) EMA)status).)Generics)/)Biosimilars) marketing)authorization)(or,) decentralised) procedure=availability)of)generics) in)france) biosimilars-approved-by-the-EMA ON) EP-(UK) =-)22)April)2016) (SPCs-in-various-countries-until-2019) Gemcitabine* Gemzar Hydroxycarbamide/hydroxyurea Droxia*Hydrea Decentralised-=-generics-available-incountries Ifosfamide Cyfos*Ifex*Ifosfamidum Imatinib* Gleevec- ON Irinotecan* Camptosar Idarubicin* -Idamycin 2007 Decentralised- FDA-Orange-Book:- Compound-patent-US =-Jan)4,)2015 US PED-=-Jul)4,)2015 However,-the-patent-protecting-the-betacrystal-form-of-the-active-ingredient-willexpire-on-23-May-2019,-while-the-patentfor-the-treatment-of-gastrointestinalstromal-tumours-extends-until-December Data-exclusivity)Jan)25,)2016 Key-patent:-expired-Feb-2008 FDA-Orange-Book:- Combination-patents-US and- US (with-5=Fluorouracil-andleucovorin-for-the-treatment-of-metastaticcolorectal-cancer)--=--Apr-28,-2020-and-May- 1, (but-spc) EP =-Expired)March)2013- The-basic-patent-EP expired-in- March By-virtue-of-SPCs,-imatinib-isprotected-in-certain-EU-countries-againstcompetition-from-generics-until-20)June) 2016)(e.g.-UK) generics-approved-by-the-EMA- from decentralised-=-generics-available-incountries

19 Medicine) *not*on*the*who*model*eml*2013 Leuprolide*- US)brandnames) (NCI)Drug) Dictionary)) Lupron*depot,*eligard* PATENT)STATUS)IN)THE)UNITED)STATES) Sources:)FDA)Orange)book)/)internet)search,)patent)USPTO Patent)status) (compound)patent) ON/) Melphalan* Alkeran Mercaptopurine Purinethol*Purixan Mesna Mesnex Methotrexate Abitrexate*Folex*Mexate Mifamurtide* Oxaliplatin*(platinum)* Eloxatin Paclitaxel *Taxol Panitumumab* Vectibix- ON Pemetrexed* Alimta- ON Prednisone*(under*class*representative*prednisolotef*Hydeltra*Hydeltraso Procarbazine Matulane Regorafenib*- Stivarga- ON Rituximab* Rituxan ON Expiry)date FDA-Orange-Book-(Lupron-depot):- US and =-Sept-2013 US =-May US (release-microspheres-andpreparation-of-thereof)-=-Dec-2016 FDA-Orange-Book-(Eligard):- US =-sept US =-Feb-2014 US and =-Oct US =-March-2020 FDA-Orange-Book:- "No-unexpired-patent-for-this-product" Not-in-FDA-Orange-Book.- US *N*expired*(2007*with*an* extension*until*2010) Not-in-FDA-Orange-Book US *N*May*5,*2017*(extension*April* 8,*2020)* Not-in-FDA-Orange-Book US *N*July*24,*2016*(Ped*exclusivity* 2017)* FDA-Orange-Book: Basic*compound*patent:*US Due-to-expire-on)Jan)12,)2020 US (Treatment-of-cancers-withacquired-resistance-to-kit-inhibitors)-=-2028 US = Not-in-FDA-Orange-Book Key*patent:*US *N*April7,2015 PATENT)STATUS)IN)EUROPEAN)COUNTRIES) Sources:)EPO,)UK)and)IE)IPO)for)SCP Patent)status) ON/) ON -(but-spc) Expiry)date) (including)information)on)supplementary) Protection)Certificates).)SPCs)) EP Patent*expiry*date:*2018.* (SPCs*until*2022) Basic-compound-patent:- EP =-expired-- SPCs-in-various-European-countries-(e.g.- UK,-Germany)-until-December) ON - -(but-spc) Key-Patent:-EP Nov)21,)2013 SPCs-until-November-2018-(e.g.-UK)- European)countries).)regulatory) approvals)of)generic)versions) EMA)status).)Generics)/)Biosimilars) marketing)authorization)(or,) decentralised) procedure=availability)of)generics) in)france) No-submission-(expected-2014= 2015) Sunitinib* Sutent- ON) US and-US =-due-to-expireon-Feb)15,)2021 US =-due-to-expire)on-Dec-22,-2020 ON Key-patent:-EP Estimation-of-SPC-maximum-expiry-date= (e.g.-UK-SPC/GB08/007)- Tamoxifen Nolvadex Thioguanine loid*brand*thioguanine Thiotepa*- Thiotepa-(US),- Tepadina-(EU) FDA-Orange-Book:- "no-unexpired-patents-for-this-product"*

20 Medicine) *not*on*the*who*model*eml*2013 US)brandnames) (NCI)Drug) Dictionary)) PATENT)STATUS)IN)THE)UNITED)STATES) Sources:)FDA)Orange)book)/)internet)search,)patent)USPTO Patent)status) (compound)patent) ON/) Trastuzumab* Herceptin- ON Tretinoin*- Tretinoin,-Vesanoid Expiry)date Not-in-FDA-Orange-Book Key-patent:-US June)18,)2019- FDA-Orange-Book: "No-unexpired-patents-for-this-product"- PATENT)STATUS)IN)EUROPEAN)COUNTRIES) Sources:)EPO,)UK)and)IE)IPO)for)SCP Patent)status) ON/) Expiry)date) (including)information)on)supplementary) Protection)Certificates).)SPCs)) Key-patent:-EP SPC-expired-in)July)28)2014)(e.g.-UK) the-key-patent-expired-since European)countries).)regulatory) approvals)of)generic)versions) EMA)status).)Generics)/)Biosimilars) marketing)authorization)(or,) decentralised) procedure=availability)of)generics) in)france) Vinblastine Velban*Velsar Vincristine Vincasar* Vinorelbine* Navelbine