PDR®
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`20 11
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`EDITION
`
`PERKINS COIE
`
`MAR 16 2011
`LAW LIBRARY
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`REFERENCE®
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`
`ISBN: 978-1-56363-780-3
`
`MPI EXHIBIT 1039 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1039-0001
`
`

`

`For the latest PDR product information "I
`2668/NOVO NORDISK • NOVOSEVEN RT
`- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - , - - - - - - - - - - - - - • •Sij
`WARNINGS AND PRi,;CAll'l'l() -
`Study 4: Dosing by Treatment Group
`• Thyioiil C..c;eU twno~s in nnimnl,i:
`f:!UJna •
`known; ColII1$cl patumfs regnrcl.fllg t.he ~ r(il
`thyr,iid carcinomu nnd tba symptoms of ti of
`5'J ),
`l,'l'!lid I
`• PIU\'cruaf::i~s: Tn olinicnl trfols, th.en, we
`pan.cr!!atil.l!! among Victozn-t.ronled pat;: mo
`comparntor-ll'Cll.ted pntionts. If p,mcrentiulo·r.\;.;"
`llf
`Vio!:o1.~ and othc:r pot11n~nlly 8ltllpoct dru / ' '
`~~nla I.
`cantf.n11ed. Victozn ~hould noL bu re&tu:rt,.~
`ill,Conllrmed, Use with rautiol:I in purJont.s .;;Jl~llttt
`·«ilh ll l1111
`uf pnnor ntitis 5.2).
`• crioll!' .bv,oglycemiJc
`on ocour whe.n Vi
`-,
`w(t,b an Ull!ulin aecrehgogue (e.g, 0 ~'Ulfo '0l\Ju I,
`sidar lowering the. dosi, of the illl!u1in secr: ~llit, I
`duce the rL'ik ofl,ypoglycomfo (6.3),
`flO!lu.,
`• Macm,=culnr outcomes,
`'l'here have boo
`O lfu. .
`establishing conclusive oviclemc of macroVUll
`ducLion w.itb Vic,ozn OJ' ruiy other nntidinbo(k 'cl nil,
`ADVERSE REACTION~
`• Th~ mD_At' oumruon_ a d~
`• reactions, repor~ ln
`p11tiants ~nted w,th V,ctow and.more commonly th
`patienl,8 l rooted. wilh .plncebo, ore: bendnche lUI ' ao 11,
`a:rclwa and llllt\-liraglutidc antibody formati~n (OJ
`ill
`• lmmucogqnicity-J:o!ated evonts, including urti1:.1rhi
`mol'll comnion nmo.og V!otmm-trcab:>d patientB (0,8 '
`among cq_mpntalor-t.I=tcd pntfonu (0-4~ ) in tljnf ll
`fill! (6},
`C lh
`To report SUSPECTED ADVERSE REACTIONS, contact
`No\/o Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FOA
`1088 or'WWw.fda.gov/medwatch.
`•
`•
`DRUG INTERACTIONS-----
`• Vitto:za dblays gastric emptying. Mny impact.•allio :;;
`of ,weomitnntly administered oral m,:,diontiona. u 111 v,
`tum 17).
`---USE IN SPECIFIC POPOL/\TIONS------.-_
`• Tbi,ro nre no dutn in piitlanl.a below 18 yeru,; or ir~
`~1
`• Use with cn\Jtion in pntient,qyitb rt1nnl or'bepali'li lll)P,tit•
`mcnt. Limited dal'll (8,6, 8.7)i
`See 17 for PATIENT COUNSELING INFORMATION
`and Medication Guide
`
`Outcome*
`
`Effective N (%)
`
`Partial N 1%1
`
`Ineffective N (%)
`
`Unknown N (%1
`
`Unknown
`
`<61
`
`1 (33)
`
`11:13)
`
`0(0)
`
`1 (33)
`
`3 (7,5)
`
`0 (OJ
`
`1 125)
`
`0 (0)
`
`4
`
`• Outcome ::issesscd at end of treatment. la!--t ob~crvation carrjed forward .
`I N (C,;) do not add up to 100 due to roundini(
`+ One patienl in the HTRS registry was excluded
`bernostnsis after bleeding had been controlled
`
`from efficacy nnalysis since Nm·oScvcn was used to maintain
`
`The diluent for rceonsW.utinn of NovoSoven RT is a 10
`mmol solution llf L-hill'\idinc in water for lajection nnd is
`supplied as a t leiu- colorlcss l!l)[otion, ;tnd referred t-0 aJl tho
`h.is(idine diluent. The v!lllil nre mlldc of glass closed wlth a
`lnt~,-free, chlorobutyi rubber <llic, and covered with an nlu(cid:173)
`mimun cop. Tho elriaed vialJ. n:re cqmpped. with a trunpor(cid:173)
`evidem snap•offcop ,vhich is made of polypropylene.
`Prior 10 ruconstitutioil, koc,p rcfriger.llted or ,tore betwei,n
`2-26'C/36-'17'1'~ Do 01,t frecw. Store protected from light. Do
`not use past tho e.'qlin>tiQn di1te.
`Afte.r,·oconsillubon. No\'oSovun RT may be stored eifbcr at
`roam temperature or rel'rigerateil for up to !l hours. Do not
`freeze recoru;tituied NovoSc"cn RT or st1;1re It in syringes.
`17
`--PATIENT COUNSEIJ.NG INFORMATION
`P atients rece,v ng NovoSovon R'l"sbould be informed of tho
`benofi.ts and r~ks a.m;o intod with l.rea.tment. Patients
`should be warned nbout the cnrly •il!]lll of hypc:raensitirity
`rcuction•, including bivca, urticaria, tighmol!l! nf the ohest,
`wheezing, bypotansion, nnd ruuiphyh.,:i~. Pat!Cll.1;$ should
`a.1.Bo be warned oboot the signs of thrombo~i•, Including new
`Ulll!llL w~lling and pnin in I.he limbs or abdomen, no, oneet
`cliest p11Illj sborl-r1css of brenth, lcr,;s of 61!11&1tlon ur ml)tor
`powm-, or ,1llcred consciousne;,,; or opecch. Pntfontll tlbould
`be told to Juuru>diately seek medical help if nny of tho tibove
`si{l'.rul or s.ymptom, occu r.
`Dn!e af iS51la: August G, 2010
`Vcn;lo~4
`License Number: 1261
`Not•o Nordish® i:-; a registered tradi•marl: of Novo Nordh;k
`A/S.
`Nm•oS~u 11® i~ c1
`Hca It Ii Cor )1G.
`ID 1998·2010 No,·o Nordisk A/S
`For inform~tion contact:
`No,·o Nordisk Inc.
`100 College Road w,,,t
`Princeton, N,J 085-W, USA
`l-877•NOVQ.777
`www.NowiScYenRT.com
`Mnnlifact11red by:
`NOi o Nordisk A/S
`2880 Bng,\'aerd, Denmark
`
`,.('f..[i.-:t, ·rf.'(/ tradema rl: of Nor•o Nordish
`
`VICTOZA®
`JVIC-1011,.za l
`(liraglultide (rDNA origin) injection)
`Solution for Subcutaneous Use
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not Include all 1he Information needed
`to use Vlctozirsafely a.nd effectively. See full p1escriblng In-
`formation for Victoza.
`•
`Victoza" (liraglutide (rDNA origin) injection)
`
`solution for subcutaneous use
`Initial U.S. Approval: 2010
`
`WARNING: RISK OF TtlYROID. C-CELL TUMORS
`Sea full p,escribing information for compll!fe boxed
`warning.
`• Liraglutide causes thyroid C-cell tumors at cllnically
`relevant exposures In roden~. It is unknown
`whether Victoza causes thyroid. C-call·1umors, includ(cid:173)
`ing medullary thyroid carcinoma (MTC), in humans,
`as human relevance could not be determined-by clin(cid:173)
`lcol or nonclini1ml studies (5, 1 I.
`• Vlctoza is contraindicated In patients with a personal
`or family history al MTC or in patienUwlth Multiple
`Endocrine Neoplasla syndrome1ype 2 (MEN 2) (5.1).
`
`-----INDICATIONS AND lJSAGE~-- - -
`v'ictoza is II gluco.gon-liko pflpfid()-1 CGLP-1 ) TCraptor n_go-
`ni&t-irulicated ns nn adjunci lo dfo.t arul exorcise to improve
`glyct?mic control in udultR ~ ~ype 2 diobat"" mellitus (1).
`Important Llmitntians of Use (1 .1):
`• Not r~~endciu lirst.-line thei:npy for pa:µentli !nad-
`cqualcly controlled on \Li\!~ nn.d e.xorci.~o /5,l).
`• Ha, not been studied suffiofenllly in patients with 4 his-
`tory of panc,,eoLit/,,. 'U)ll1 r;autlon (5.2).
`• Not for trc,,tmant of type 1 dinbctos mellitrnl or diabctio
`keroncldo.,µs;
`• Has not been studi,ed. ln c9mbinatioo with.insulin,
`----DPSAGE'.t\NDADMINISTRATI.ON
`• Adn\lnultcr once doily at nnytime ofdny, indepondnntl~of
`meals 2).
`• Inject subcutaneously in the abdomen, thigh or upper
`arm (2).
`• The injection site and timing can be changed without dose
`• fuitinte at .0.6 mg pe.11 day for one week, Th.is "°"" i,dn-
`adjustment (2).
`a . . .. I
`!
`t'-" '
`•
`ded. to ed
`:~ uco gru,trotntes uuu-Bymp 'l}nIB unng m1tin
`ten
`titration, und is not effective firr gl)'cenlk_ L'Olltrol. After.
`on0 wee.k:, increase the dose t.oJ..2 mg. JUh L2 mg d050.
`docs not rosul~ in o.ceepto.hlll g]yc~ c11ntrol, bbe dm;e
`can be lncreWled to 1.8 mg (2).
`• When initi'lting Victozn consider r during thi, dose of
`conoomita.ntJy•adminbt~red fosulin .sccretngogwa to re-
`duce the ris k of bypoglycemfo (2).
`---DOSAGE FOR.MS AND STRENGTHS--
`• Solution tbr s ubeutnnoous Injection, Qre-_filled, mulfi-doso
`pen that deli,'tlrl! doses oro:s mg, 1.2 mg , or L8 m1;f6 mg/
`ml., 3 m'Ll (3),
`.
`- --
`---,,;ONTRAINDJCATIONi:;------
`Do not uae in patients 'Wilb n personal rn" fiunily history of
`medul!ary thyroid carctnoma:-or 1n pat:icntll w:itb. .Multiple
`E ndocrine Neoplasin l!ylldr~c Lype 2 (4),
`
`Revised: 04/2010
`
`2
`3
`4
`5
`
`13
`
`FULL PRESCRIBING INFORMATION: CONTENTS•
`WARNING: RISK OF THYROID C-CELL TUMORS
`1
`INDICATIONS AND USAGE
`1 l
`Important Limitations of Use
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Risk of Thyroid C-cell Tumors
`5.2
`Pancrcatitis
`Use with Medications Kno\\'n to Cou>t' Hypogly·
`5.:J
`cemia
`5.4 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Oral Medications
`8 USE IN SPECIFIC POPULATIONS
`8 1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8 ii Geriatric Use
`8.6 Renal Impairment
`8. 7 Hepatic Impairment
`8.8 Gastroparesis
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12,l Mechanism of Action
`12.2 Pharmacodynamies
`12.3 Pharmacokinctics
`CO GY
`AL
`. nirntuffer·
`TOXI • iW
`.
`NONCLINI, C
`13.1 Cm:tanugimesi~, 1\(11Ull!l'l'es1s, Impair
`'b1ify
`14 CLINICAL STUDIES
`14,1 Monother:ipy
`14•2 Comhinatlan. Therapy
`16 HOW SUPPLIED/STORAGE AND
`16,1 How Supplied
`JON
`16.2 Recommended Storage
`17 PATIENT COUNSELING INFORMAT
`17 1 Risk of Thyroid C-cell Tumors
`pat1,-nt'
`17 .2 Pancrentitis
`17.3 Never Share a Victozu Pen Bctll'l•cn
`17.4 Instructions
`.
`17,5 Laboratory Tests
`17 .6 FDA-Approved Medic:ition Guide
`
`fIANDLJNG
`
`IMPORTANT NOTICE: Updated drug information is sent bi-monthly via the PDR ' Update Insert. For monthly email updates, register at
`
`pDfl,11et,
`
`11,
`
`1~
`
`Days of dosing, mC'dian (range J
`
`No bolus injection s. median (range)
`
`No. of additional bolus injections. median (rang-e)
`
`Mean tobl dose. mg
`
`Bolus Injection
`90 micrograms/kg
`(n = 12)
`
`Continuous Infusion
`50 micrograms/kg/h
`(n = 12)
`
`10 (4-15)'
`
`38 (36-42)
`
`0 10-3)
`
`237.5
`
`10 (2-116)
`
`15 (0-7)
`
`0 (0-4)
`
`292,2
`
`• Includes dosing during the folluw•up period :.ifier the JO.day study period ,
`
`Efficacy by Dose Group, for Patients Receiving Doses Ranging from <61 to ,-90 micrograms/kg NovoSeven,
`Compassionate Use Programs and HTRS Registry
`
`61 -69
`
`5 (63)
`
`NovoSeven Dose (micrograms/kg)
`
`70-80
`
`81-89
`
`90
`
`,.90
`
`Total
`
`10 (63)
`
`12 (57)
`
`10 (67)
`
`26 (58)
`
`0 (0)
`
`3 (19)
`
`3 (38)
`
`2 (13)
`
`0 (0)
`
`8
`
`1 (6)
`
`16
`
`3 (14)
`
`2 (10)
`
`·1 (19)
`
`21
`
`2 (13)
`
`11 (24)
`
`2 (131
`
`7 (16)
`
`1 (7)
`
`15
`
`1 (2)
`
`45
`
`67
`
`20
`
`17
`
`8
`
`112'
`
`No. of Bleeding Episodes'
`
`3
`
`MPI EXHIBIT 1039 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1039-0002
`
`

`

`lrNrl.ml!llt 0£.dlilb(,tfQ_ kctoncidbsia~ as il wowd n01 be of(cid:173)
`fictivo in llhea\! 1<ettmgll.
`• Th• COilCW;ten~ Ul!e. of Victoza L1Ild in.sul,n hru! no~ brum
`11JJdied,
`! DOSAGE AND ADMINJSTRA'11;10N
`\'i!nwt cnn he '1dministored .bnee daily at 1'11)' lainn of doy,
`1ndependentjy oE.mcnls, w d cun be ini!lct<id spb:cul=,8Jlusly
`~ me abd~, llhigh or ,u:ppor nnn. the injcctipn.aite and
`liming l'.l1D bu ahangcd withou dose adju~tmen,!.
`Tor oil plltients .. Victoza sbould,b;, in1tiatll(l wiffi a doae of
`15 mg per day for one week. 'l'he l0,6.Jlll:'dOBe is ll $Lnrlil'lg
`dni< intcndc.d to 11l!ducc gost;rqint!elltinal aympLolllli duclng:
`mrtlol titrntaon: nnd is oot effective for glytemic o:onti'oL M(cid:173)
`kr an~ wook11t016 i;oll,po:rd/,y, tht! i\oQi.should h'o lncro11~ed
`~ L2 mg. If: th,,_ 1.2 .ng,·dllsu ,doo TIOt \'IISlllt in li~plable
`,~,,mic control, the dqae em, be, i m:roru,Qd lx>•UI mg.
`Iii.en !nitiotlng Victo,;a, conQirlor r-Oducing the dC!Ss of con-
`it,an.tly admiru~l,,rcd lmmlin,sectctn1:ogue.11 (suah na sul(cid:173)
`lloyluraas) to rn1ue(l tlic risk ~f bypoglj•oornia [11ec Wam (cid:173)
`~.a and l'm;au/jo11• (fi.3J mul Atlliuac Reactionll (6)],
`\i~ti,is ~olufjon Hborild ~ insp~r.re\l prior Lo eatlh mji;ction.
`irul I.ho salu(ion houldl,o, 1,U!ed Qn!yiR ie clear, colorlCS!ll
`IJ!!l tnnt:ainj ni,-puticl~a.
`I DOSAGE FORMS AND STRENG.ms
`!t,'ution ror 6\lb~u,mrieo,116 injootion, pre-fille-a, llllilei-i!ose
`"" thnt deliver,;aoaes of 0.6 mg, Umg, or UI mg,(6 mg/
`.~ a mL).
`-
`I C~1OM'I0NS
`lirtoln is- contramdfc t.ed -in. J>fll;le.1it!! witl-i n p<!tsmfal ~
`!,mil,v history .of _me~iillbry tbyroiil cnrolnolllll (l\'l!fC) ·or in
`p!i,ntP. with Multiple Endocrin•• Ncoplnsia~arome type
`!ll,IEN 2).
`I WARNJN'ftSAlSD PRECAO'l'lONS
`~I Risk of Tlwroid C-cell Tumors
`lli,Jlutido ~~dosiJ-d~endco~ and t,;catment.duri\l:lont
`!,pendant tliyroid O•cufl lmmor,; ladenomns nnd/or Clttcinn•
`11:111 01 cl.i:blcnlfy rclovrur~po•UW1 in wt:b 81'1l'.d(1rz1.ofrb\:ll
`ond tni!!l! [,,L~ No11Ninfoul Tmclcoluip_ ol11J1 Maligna11t thy•
`rld C-c~ll. cru:dnomn&"WDue detecfud irt rills and'1muie.A illa•
`t!rtlt1,ffy !ig:rtilluaot inart!ase in cancer ww; o~eerveii: in l'\lla
`rail'ing lirngh1Lk!o aL 8!nmes cftmllul l!XJ)osllhl coni4lllrl!d
`w conP'oll!. rt is unkru>wn f huO.ot J'ictdui will ,,rn~e tJhy.
`llitl. 0-toll tumors, irn:Judiii~ mednIIA'ry"Uj,'V!'Otd t-ro-lflm>lllD
`ll!TCli, in liumnna1 a& tifiu bnrrul:n l"tilc\•IUlc,, of llraglutlde-
`
`-~ebo nnd o~~iv~· .,;,~t~i,--;.e";;p~ti~cly.
`,Otherwise, Vict.o,w did not· pl'.oduce consistanb do,so(cid:173)
`depandcnt or \irui,.daJlfilidcnt i!ll!rCalllS in serum calcitonin,
`'i>atinnts wii;h MT0 usoruly have. ooldtonin \laluoi, >50 og{L.
`ln Victo•
`clini~al f;riiili;, umong r,atinnts with pre(cid:173)
`,trMtmC!l)t sorum caloltmun <(iO IJJl'/L. ooc Vfotuza-trant,cd
`patient 141d no oompnrato.r-±rt!ilted pa.tieot!! developed
`~erumcalti!mrino,>tiOllg/L. Tho Victo1.a-treated patient whQ
`devolopi,i'! scrum. caloitonin >50 ng/L hnd an elovnted prc(cid:173)
`troottnmt llemm t-alcitonin of 10.7 nglL t ho.t mcrcnscd to
`30/1 ag/L nv Week 12 and 58.5 ng/L ol the ona_ o.f fl\e
`6°molith trial E'ollow-up .se1'tlll1 caloitottin 1"{1Jl 22.:l 11g/L
`l)lOre thn11, 2,6 yclll's nfwr tha last dose ofVictoza. The llll'g•
`l!l!I. increase in a.ei:um cnMtonin in a compnrn_tor-tree,ted pa(cid:173)
`tionl was seen wil:h gllinepiride in a pati~L whose ~ rum
`cnlcitonin inc.ro11Sed from 19.S:og/L ni ~llll!lliru! Ix> 44.8,ng/L
`at -Week 65 nnd 38.1 ng/L nt Weck H>4-. Among pnflonts wh9
`bog1111 with scrum calait,)nin <20 ng/L, _oolcjtonin efoVlltions
`to >20 og/t. oC-Ourroo in 0.7% of Vlc.toY.11-trootod patient!!,
`0.3~ of placebo-treated patienla, nnd 0.5~ of nctivo(cid:173)
`comps.rator,treated J)l1tients, wil.h M
`inuidl'nce or 1 .1~
`among patienta,tn,;tted wi.th l.&mg/d11y ofV'wto'U\. Th!! clin,
`iwl significance or l:hl,se lindiug11 i.s uala:mwn.
`Counsel pa Irion~ regardingi;he risk foe M'llC <lnil the a}'lllp•
`toma of thyril(d tumo~ (o.g, 11. nulss lrr the 11eck, dy")lbagia,
`dy")lnWl or pers:iatcnt bOlll'BWlCss). It i.s unknown whether
`momtori:µg with •erum clll¢1onin br tlzyroid ultrn.Bouna will
`'!Ditigste true pot;entiel ci!lk 11f MTC, and ~ch mouitarit1g
`tnoy more11ill! l!he risk o[ unnecessarJ procedures due to lnw
`l;e,!l apeciflclty'for stirurii clllcitoni.n ·llnd n rugh bruikgromuL
`illl!idenl-o of thyroid disease, PS:til!llts ,viih i.ltyroid ruidulcs
`nowa on1p1:iy&ical examination urmecl. rmoging obl.nfuod Cot
`other reason.II 'should be rnfenmd to ·an endocclnologiBL for
`li.lrlher cvaluation: IA!thougb routine mo11ilotinir of wrulll
`~o!lcitonin' is of il:n'cortai:n Ynluu lu_ 1Jetienli; treated i\lith.
`Vi«tow_, ihlll'lllll l!lllllitonin ,is measured end found tn be !iJ.
`ovated, the.p'ntienl.should be refem;d to a:n:eni;locr.inorog!Bl
`far further evliluntion,
`Pancreatlti1
`5.2
`1ti clinlcaJ trials ,otVlttO"!I, the:,:e ww:I! 'l CIIA or~cr-e.nti•
`till among 'liclnz.a•trM~ed: p11hle11va ruu3 l co • umOnl!
`eomp!tl:8to,..u-eata11' p!imd'ot.11 {2,2- 'ViL 0,6 . '
`• irnr 1 Ooo
`ptnient-ycru,a), Ff\11! case wi~b Victoltlt wor repor1,t,d ru,
`neute pwrnl'llstitis and i;wo C!llSCII w\tb Victo\UI were reporu'<l
`8il chronic pID!llr~t(tiJ,, J)l OllG C)ll;O-i:n II Vktdllll,tri!alcd (lll•
`'liaot, JllUlctnatltts, with 11001:0,ei:s, .\vtlS ob~rved ' a nd li:,d to
`
`1.um1. wcrlJ w-eawa. wu.n v1cwl.;,l1 .L.o cug, prnc;coo, or uu;.wm
`gllirgln~. In I.he odd-on to '11\etformin + ~ •igllLo.-.oAe tdnl
`patients were fre ted with Victo,m L2 mg, VictQ~ h8 rug or
`l'lnrebo lsev Clinical Studi.,. (Ui),
`Wf)hdmwul"
`The incidence ofwilhdrnwnl due Lo ad•ersc ~v"I)µ WW! 7 .811i
`for ViJ:l:ll'l:tl-"tJ-oated pntientii arul' S..11 for compariJtor0
`lxeat.l!d pnttcnts in' he Jive, control!~ miilao.r26 l\'l!el,s du(cid:173)
`rati6o. or longer. Thia dilforence wa.. drlven. oy withdi:awa!J;
`due-to gruitrolntl!Jltinul. advCJ;I! rooetions, whkb ·occurred in
`5,01{ of Victo1.n-trunted pntieni.s and •0,5\t. Qf" comparilidr•
`treaood )?Btienbi. The mo_$t coom{on nilyetife re:ictioos lead(cid:173)
`ing t-0 withdrawal (qr VMoza-tr'e ~a p11ticnts wJrl! ll1lU6')1l
`t2.81i, \'!lnWI b'll, for tompara'.tor)' iind vrimitin~ (L5'Jb Vffi'SUB
`O.J 1 !or campnra1or); Wjilidruwal dP!! ti.) g11strpintolltinal
`ndvol":j~ eveni:s mainly gceurred during tM ll:nit l►.:.S · months
`oHha trial~.
`Thnllll! l "IIIld 2- summamo tlU! adv= events ro.porred,in
`
`~* of Vic!oza-ireatetl--i,ulients in'tru:dive ~on11rollcd trwls
`
`of,26 weuka dum)inn or longor:
`
`Table 1 Advers&- events reported in ;,:5;~ of
`Vlttoza,treated 'patients or :a:s<r., of11fimepl~lda-tre)it11d
`l!otients: ~2•week monotherupy trial
`
`All Victuzn
`N = 497
`
`Gllmepiride
`N=248
`
`Adver!NI_ Everrl Torm
`
`Nnusea
`
`D1111Then
`
`Vomt1ing
`
`Cunsti~otiion.
`
`UJ1P9r RC<!pimtoey Tract
`Inu,cµ,011,
`
`1-1:eadnchc.
`
`lo.ll~enza
`
`UtlnAry ?'.)-net In'tecti!!Jl
`
`( J
`
`28.4
`
`17.1
`
`10.9
`
`9.9
`
`9.a
`
`9 1
`
`7,4
`
`60
`
`(%}
`
`8.6
`
`8.9
`
`8.6
`
`4.8
`
`M
`
`9.ll
`
`3,6
`
`4 .0·
`
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`
`MPI EXHIBIT 1039 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1039-0003
`
`

`

`2670/NOVO NORDISK • VICTOZA
`
`Dizziness
`
`Sinusitis
`
`Nasopharyngitis
`
`Back Pain
`
`Hypertension
`
`5,8
`
`5.6
`
`5.2
`
`5.0
`
`3.0
`
`5.2
`
`6.0
`
`5.2
`
`4.4
`
`6.0
`
`Table 2 Adverse events reported in 2:5% of Victoza-treated patients and occurring more frequently with Victoza
`compared to placebo: 26-week combination therapy trials
`
`For the latest PDR product information, visit PDR.net
`
`Adverse Event Term
`
`Nausea
`
`Diarrhea
`
`Headache
`
`Vomiting
`
`Adverse Event Term
`
`Nausea
`
`Diarrhea
`
`Constipation
`
`Dyspepsia
`
`--•-
`
`.
`
`•·
`
`,-.,
`k
`
`• J.__,_
`
`~
`
`·-
`
`Add-on to Metformin Trial
`
`All Victoz a -;-
`Metformin
`N = 724
`
`Placebo+
`Metformin
`N = 121
`
`Glimepiridc ;
`Mctformin
`N = 2-f2
`
`(" I
`
`15.2
`
`10.9
`
`9,0
`
`6.5
`
`((/(_I
`
`4 1
`
`.. . 1
`
`6,6
`
`0.8
`
`(~)
`
`33
`
`37
`
`9,S
`
`0.4
`
`Add-on to Glimepiride Trial
`
`All Victoza +
`Glimepiride
`N = 695
`
`Placebo+
`Glimepiridc
`N = 114
`
`Rosig!it~zor,(· ':'
`Glimcoinck
`N = -~:ll
`
`(~cl
`
`7.5
`
`7.2
`
`5.3
`
`5.2
`
`(',)
`
`1.8
`
`1.8
`
`0.9
`
`0.9
`
`('t)
`
`2.6
`
`22
`
`1.7
`
`2.6
`
`.
`
`Add-on to Metformin + Glimepiride
`
`Placebo+
`Metfo1111in
`+ Glimepiridc
`N = 114
`
`GlarQne +
`Mctformin
`+ Glimepiridc
`N = 2:12
`
`Victoca 18 +
`Mctformin +
`Glimepiride
`N = 230
`
`1
`
`-
`
`( '.,)
`
`13.9
`
`10.0
`
`9.6
`
`6,5
`
`6,5
`
`Add-on to Metformin + Rosiglitazone
`
`[See table 2 at right]
`Gastrointl!stinal adverse erents
`In the five clinical trials of 26 weeks duration or longer, gas(cid:173)
`trointestinal adverse events were reported in 41 '1, of
`Victoza-treated patients and were dose-related. Gastroin(cid:173)
`testinal adverse events occurred in 17r:"r; of comparator•
`treated patients. Events thaL occurred more commonly
`among 'llctoia-trented patients inaluded nausea, vomiting,
`diarrhea, 0dytpepllia and constipation. In cllnical trials of 26
`weeks duration or longer. the percentage of patients who re(cid:173)
`ported nausea declined over time. Approximately 13~i: of
`Victoza-treated potients and 2'); of comparator-treated pa(cid:173)
`tients reported nausea during the first 2 weeks of treat(cid:173)
`ment.
`Immunoglmciiy
`Oonsisten.t with the potentially immunogenic properties of
`protcln and pe_ptido phonnaccucicals, patien14 treated with
`Victoza may develop a.nti-liroglutide antibodies. Approxi•
`mately 50-70$ ofVictozn-trcnted patients in the five clinical
`trial.a of 26 weekil duration or longer we~e tel!ted fur the
`presence of anti-liraglutide amibodies :it the end of treat(cid:173)
`ment. Low titers /concentrations not requiring dilution of
`scrum) of anti-liraglutide antibodies were detected in 8.6",
`of these Victoza-treated patients . Sampling was not per(cid:173)
`formed uniformly across all patients in the clinical trials,
`and this may have resulted in an underestimate of the ac(cid:173)
`tual percentage of patients who developed nntibodies.
`to native
`Cross-reacting ant-1-llraglutide an tibodies
`glucngon-like _peptide-! (GL-P-1) occurred In 6.9" of th.c
`Vieteui-croat.ed .patient! in the 52•wcek monotbcrapy tnal
`and in 4.8% of the Victoza-trcated patients in the 26-weck
`add-on combination therapy trials . These cross-reacting an(cid:173)
`tibodies were not tested for neutralizing effect against na(cid:173)
`tive GLP-1, and thus the potential for clinically significant
`neutralization of native GLP-1 was not asses,cd, Antibodies
`that had a neutralizing effect on liraglutide in an in l"itro
`assay occurred in 2,3'k of the Victoza-treated patients in the
`52-week monotherap,' trial and in l.O?i of the Victoza(cid:173)
`trcated patients in the 26-week add-on combination therapy
`trials
`Among Viet-Oza-treated patienl.s who developed anti(cid:173)
`lirnglutide antibodies, the m05t common category or adverse
`OVl'llts was that of infections, which occnrreil amo.ng 4.1)% of
`these ·patients compared to 36';. 3-10 and 35c, of antibody(cid:173)
`negative Victoza-treated. placebo-treated and actiYe(cid:173)
`control-treated patients, re5pecti\'c1y. The specific infections
`which occurred with greater frequency among Victoz:1-
`treated antibody-po.s.itiYe patients were primarih· nonseri(cid:173)
`ous upper rcapirntery tract infections , which· occurred
`among 11''< of Victoza-treated antibody-positiYC patients;
`and among 7':(, 7Cfr and 5 <( of antibody-ncgatin~ Victoza(cid:173)
`treated, placebo-treated and actiYe-control-treated patients.
`respectively. Among Victoza-treated antibod,<-negative pa(cid:173)
`tients, the most common category of adverse cYcnts ,,,as
`that of gastrointestinal ewnts. whjch occurred in 43', . 18';\'
`and 19'.'i of 11ntibody-negati\'e Victow-treated, placebo(cid:173)
`treated and actiYe-control-treatcd patients. respccti\'ely.
`Antibody formation was not associated with reduced efficac,•
`of Victoza when comparing mean HbA1c of all antibody(cid:173)
`positi,·e :ind all antibody-negati\'e patients. Howe\'cr. the 3
`patients with the highest titers of anti-liroglutidc antibod(cid:173)
`ies had no r eduction in HbA1c "ith Victoza treatment.
`In clinical trials of Victoza. events from a composite
`of adverse events potentially rebtcd to immunogcnicit.\'
`(e~g. urticari::i, angiocdcm~) occurred among O~,S ',;. ot
`Victoza-treated patients and among O ~'/. of comparator(cid:173)
`fonylutea. lloth patients ware r<!c,,lving Vic1ou, one •
`cinomas ·were <1 cm in greatc..;t diameter .:ind were diag(cid:173)
`treated patients , Urticaria accounted for J.pproximately
`monotberapy o.na the otb.!!1' in. combination "iih maformill!
`nosed in surgic.'.11 pathology sprcimens after thyr01dectomy
`one-half of the cvi::nts in this compo;:;itc for Victoza-trc:1tcd
`.Both patien had another likely eirplllD.llcion tor lb! hyp,
`prompted by findings on protocol-specified screening wiLh
`patients. Patients who de\'elopcd anti-lirag-lutidc antibodies
`glyoemia (Mil r~'<!l!ivcd i:luntlin during a frequently-<ruDPW
`~Crum calcitonin or th\Toid ultrasound,
`were not more likely to develop events from the immunogP(cid:173)
`mtni,'l!Dous_glu.cose tolerance tesL. and the othC!T fud imlt(cid:173)
`•
`H_vpo~lycemio
`nicity events composite th:m were patients who did not dr(cid:173)
`cranfr1l hemorrhage and uncertain food intakr }.
`In the clinical trials of ~t least 26 weeks duration. hypogly(cid:173)
`,·clop anti-liraglutide antibodies.
`[Sec table 3 at top of next page I
`cemia requiring the aE.::is.tancc of another pc-r!ion for treat(cid:173)
`Injection sitt n.:action~·
`In a-pooled ann.iysis of olinical trials, tb m111dcna, rJ12(pu
`ment occurred in 7 Victozo.-tre~tcd patient.~ (2 6 cc1!-.es per
`Injection site reactlons ~c g., injection ~ite ra.c:h , erythcm.J l
`'41
`1,000 pationt•yt!!tra) tor malignant neopllll!m•
`1000 patient-years) and in no com-para.lor--treatcd patients.
`were reported in approximately 2,;. of Victoza-trcated pa(cid:173)
`investigator- reported l!'ients, medfoal hi.!itory, patbril!I;!'
`Si, of these 7 patients treatL•d with Viclo?A were also taking
`tients in the fiw clinical trials of at least 26 weeks duration
`Pl)rtll, (U]d surgical reports from both blinded nndopen-lml
`a :;ulfonylurca. One other patient was taking Victoza in
`Less than 0,2'.i, ofVictoza-treated patients discontinued due
`stud.}'. periods wna 10.9 for Victo:r.a, 6.3 for plnCl)bo, and7-
`combinLl.tion with metformin but had another likely expla(cid:173)
`to injection site ri:actions
`ror active oompnretor. After e.xcluding _papillary uryrold a.~
`nation for the hypoglycemia (this e1·ent occurred during hos(cid:173)
`Papilla~• thyroid curcinamu
`•
`cinolll8 c,·ents [-, Mi/en.-Y Recmtion, (6.J)}, no _pllltj
`pitalization and aft.er .insulin infusion) (Table 31. Two addi(cid:173)
`In clinical trials of Victoza, there were 6 reported cases of
`enncer cell type predominated, Seven malignant nit
`tional cases of hypoglycemia requiring the· a,.,istance of
`papillary thyroid carcinoma in patients treated with Victoza
`n,;ents w.ere reported beyond 1 year of exposure to 1bidy
`another person for treatment have subsequently been re(cid:173)
`and 1 case in a comparator-treated patient (1 9 \"S , 0,6 case s
`medicnl;ion, six ven~ mnoog Vicloz :\-tr~ntcd p., tle!ll
`ported in patifnts who \vcrc not taking a concomitant sul-
`per 1000 patient-yearsJ. Most ofth0se papillary thyroid car-
`IMPORTANT NOTICE: Updated drug information is sent bi-monthly via the PDR" Update Insert. For monthly email updates, register at PDR.net.
`
`All Victoza + Metforrnin
`+ Rosiglitazonc
`N = 355
`
`Adverse Event Term
`
`Nausea
`
`Diarrhea
`
`Headache
`
`Dy.:-pcp~ia
`
`Vomiting
`
`.
`
`Adverse Event Term
`
`Nausea
`
`Diarrhea
`
`Vomiting
`
`Decreased Appetite
`
`Anorexia
`
`Headache
`
`Constipation
`
`Fatigue
`
`I
`
`'
`
`-
`
`t 'x
`
`3.5
`
`~-3
`
`7.9
`
`0.9
`8 .s
`
`I
`
`"•
`
`L
`
`('.f)
`
`1.3
`
`1.3
`
`5 6
`
`1.7
`
`0 ,;
`
`Placebo + r.ldor..:ic,
`Ro.':iglibzor.c
`N = 175
`
`,.~; )
`
`8 G
`
`6,3
`
`2.9
`
`1.1
`o.o
`
`-1.fi
`
`II
`
`1 7
`
`I
`
`T
`
`I
`
`,,
`
`(~n
`
`34.6
`
`14.1
`
`12A
`
`9,3
`
`9,0
`
`8,2
`
`,5 .1
`
`5.1
`
`••
`
`'t' I
`
`MPI EXHIBIT 1039 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1039-0004
`
`

`

`ocidence of fetal malformations in liraglutide-treated
`,roups exceeding concurrent and historical controls were
`r,i;;hapen oropharynx and/or narrowed opening into larynx
`,10.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/
`~•dav.
`p;,gi;ant rabbits given subcutaneous doses of 0,01, 0.025
`ind 0.05 mg/kg/day liraglutide from gestation day 6
`:brough day 18 inclusive, had estimated systemic exposures
`I;;, than the human exposure at the MRHD of 1.8 mg/day
`,tall doses, based on plasma AUC, Liraglutide decreased
`f;!al weight and dose-dependently increased the incidence
`,i total major fetal abnormalities at all doses. The incidence
`,i mslformations exceeded concurrent and historical con(cid:173)
`::,!; al 0.01 mg/kg/day (kidneys, scapula), ;e: 0.01 mg/kg/
`iiy (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral
`mtebrae, major blood vessels and heart, umbilicus),
`a 0.025 mg/kg/day (sternum) and at 0,05 mg/kg/day (pari(cid:173)
`,:,1 bones, major blood vessels). Irregular ossification
`d'or skeletal abnormalities occurred in the skull and jaw,
`,,rtebrae and ribs, sternum, pelvis, tail, and scapula; and
`i'.i,-dependent minor skeletal variations were observed.
`L,mal abnormalities occurred in blood vessels, lung, liver,
`md esophagus. Bilobed or bifurcated gallbladder was seen
`i:J all treatment groups, but not in the control group.
`In pregnant female rats given subcutaneous doses of 0.1,
`025 and 1.0 mg/kg/day liraglutide from gestation day 6
`ii,ougb weaning or termination of nursing on lactation day
`·t (stimated systemic exposures were 0.8-, 3-, and 11-times
`!::man exposure at the MRHD of L8 mg/day, based on
`cl.l!ma AUC. A slight delay in parturition was observed in
`~, majority of treated rats. Group mean body weight of
`ce<catal rats from liraglutide-trcated dams was lower than
`,;inatal rats from control group dams. Bloody scabs and
`unated behavior occurred in male rats descended from
`b:l,; treated with 1 mg/kg/day liraglutide, Group mean
`t,;iyweight from birth to postpartum day 14 trended lower
`~ F1 generation rats descended from liraglutide-treated
`n·J compared to F 2 generation rats descended from con(cid:173)
`~ ;. but differences did not reach statistical significance
`::: any group,
`13 Nursing Mothers
`i:i;not known whether Victoza is excreted in human milk.
`S<au;e many drugs are excreted in human milk and be(cid:173)
`nu;e of the potential for tumorigenicity shown for
`criglutide in animal studies, a decisioo should be made
`1:bt-ther to discontinue nursing or to discontinue Victoza,
`tilir.g into account the importance of the drug to the
`
`Patient not able to self-treat
`
`Patient able to self-treat
`
`Not classified
`
`2.2 (0.06)
`
`27,-l (1.16)
`
`0
`
`28.9 (1.29)
`
`1,7 (0.04)
`
`16.7 (0.95)
`
`0
`
`mother. In lactating rats, liraglutide was excreted un(cid:173)
`changed in milk at concentrations approximately 50<:"c of
`maternal plasma concentrations.
`8.4
`Pediatric Use
`Safety and effectiveness of Victoza have not been estab(cid:173)
`lished in pediatric patients. Victoza is not recommended for
`use in pediatric patients,
`8.5
`Geriatric Use
`In the Victoza clinical trials, a total of 797 (20'/', ) of the pa(cid:173)
`tients were 65 years of age and over and 113 (2.8~f) were 75
`years of age and over. No overall differences in safety or ef(cid:173)
`fectiveness were observed between these patients and
`younger patients, but greater sensitivity of some older indi(cid:173)
`viduals cannot be ruled out.
`8.6
`Renal Impairment
`There is limited experience in patients with mild , moderate.
`and severe renal impairment, including end-stage renal dis(cid:173)
`ease. Therefore, Victoza should be used with caution in this
`patient population. No dose adjustment ofVictoza is recom(cid:173)
`mended