NOVARTIS EXHIBIT 2049
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 10
`
`

`

`-
`
`61
`2007
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
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`NOVARTIS EXHIBIT 2049
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 10
`
`

`

`. TABLE 3: Relationship Between INRand PT Ratios
`~or Thromboplastins lIIo'it!1 Different lSI Values (Sensitivities)
`
`100's
`
`1000's
`
`NDC 0056-0169-70
`NDC 0056-0170-70
`NDC 0056~0176-70
`NDC 0056-0188-70
`'NDC 0056-0168-70
`NDC 0056-0172-70
`NDC 0056-0189-70
`NDC 0056-0173-70
`,NDC0056-0174-70
`
`NDC 0056'0169-90
`NDe 0056-0170-90
`NDC 0056-0176-90
`NDC 0056'018Sc90'
`NDC 0056-0168-90
`NDC 0056-0172-90
`NDC 00~6,OiS9-90 '.
`
`Hospital
`. Blister P.ckag~of 100
`NDC 0056-0169-75'
`NDC 0056'0170-75'
`NDC 0056-0176-75
`,NDC 0056-0188-75
`
`NDC 0056-0172-75
`;f "NDC 0056-0189'75'
`
`1.5 to 2.5 times control mean norn'>al PT,u.ed
`. thrombOplastin. When using' 'the
`-",:,,:..,,-~,- thromboplastins common:ly ern(cid:173)
`today,adjustments must be made to
`';,,.1Ilietarl~et.ed I~I range that r.~flect this ge<?rease iI). s~ns_itiv-
`
`of the INR to P1' .rat~os JOT t!le less:intense
`J'!!l~",",u,o.UJ and more intense .(INR 2.5-3.5) therapeutic
`l!JDge.recommended by the ACCP for thromboplastins over
`,aqSI values is shown·inTable3.5
`.
`'.'
`leSabove]
`. . . . .
`.
`'.. .. f'IVT DURING DENTISTRY AND§URGERY The
`,.:,~?gement of. patients w40 ~dergQ de!ltal and surgi~3:1
`',.·a?~q\l.re$:requir~s close liai~on bet\Veen a~tel1diiig physi(cid:173)
`'c.~t surge0I?:s ,a,Il.d d.enti~ts. PTJ.INR d~ten:nination is r~c­
`>~~nqe4.just pria:r. to .any dep~§lJ or surgical Pfa:cedure.
`.".J.1J.l·p.~tieQ~,.undergoing miniplal invasive .px:ocedures wh~
`; ~.,Jm!¥.l.tP~ anticoagulated prior to, d,uring, or immediatelyfol(cid:173)
`;;:.':~p.'I(ing,: these procedures, adjusting ,the dosage of
`:':.&OUMADIN (Warfarin Sodium) to maintain the PTIINR
`·
`ow end ofthe tl;1er~peutic range may safely allow for
`. ed anticoagulation .. The operative site should be
`y limited and ac~essible to permit the effective
`'procedures for hemostasis. Under these
`, dental .and minor surgical prpc'edures may be
`,without up.due risk of hemorrhage. Some dental
`,
`i\:"
`i0~~~f.:¥ procedures may necessitate the interruption of
`;:,,aQuNiALlIN therapy. When discontinuing COUMADIN
`·
`r a short period of, time, ,the benefits and ~sks
`e st~ongly ~~msidered.
`'. RSION FROM HEPARIN THERAPY Since the anti(cid:173)
`.'.
`-.~ant.effect of COUMADIN is delayed, heparin is pre(cid:173)
`':,hrr~d'·i.nitially ,(or rapid anticoagulation. Conversion to
`,j;HWIlADIN may begin concomitantly with _ heparin
`~~~py or may be'delayed 3 to f? days. ':fo ensure,continu-
`0- ,~Q:S,~ticoagulation, it is ,advisable to continu.e. full dose
`-l~~pann. therapy and that COUMADIN therapy be· over(cid:173)
`A~pped with heparin for 4. to 5 days, until COUMADIN has
`,~~uced the desired therapeutic response as deterrW.ned t
`· .7Q,J!T/INR. When COUMADIN has produced the. desired ;
`',~.f.INR or prothroIl?-b~n activity, hepaFin may be,discon~- i
`.
`,,-~,
`i9QPMAoIN' may increase,the aPTT t.est, even in theab(cid:173)
`'~i'~ of heparin. During initial therapy with COUMADIN,
`,'~~~:~~::;,~~ hepari!) anticO~gulation is. of minimal
`'.~e¥,~rin maY,aife,t the PTIINR;p",tients ~~ceiving both
`";i'P~and COUMADIN should have blood for l':rIlNR.de(cid:173)
`::'-~'.\r,<*on dra:wn at least:
`'. ;~<,",,!tojl!s after the last IV bolus dose of heparin, or
`after cessation of a ,co.ntinuoll.s 'Iv ,~sion of
`.'
`.or
`'
`"a~r th~ l~a~~~subcllt~n~~?-~,~eparin ,~pj:ectio?
`PLIED
`,~or oral use~' 'sing.Ie scored' ~th o'ne' face:' i"m(cid:173)
`umericruly With 1, 2;2'112, 3~ 4, 5, 6, 7-112 or 10 .
`osed and inscribed with "COUMADIN (Wanarin
`and with the opposit.e face plain. COUMADINis
`in bottles and Hospital Unit'Dose Blister< Pack-
`. ' :
`. potencies and colors as follows:
`d table abOve]
`om ,light. Store at controlled room temperature
`, 15"-30"C). Dispense in a tight, light-resistant
`er as defined in the USP.
`
`,
`
`Hospital Unit-Dose Blister Packages are to be stored inc;:ar(cid:173)
`ton uptil:contents haye been used ..
`Injection: ", 4vaUable;.for intravenous use only. N:ot recom(cid:173)
`.wended fo);',' in~ramuscular adJ,Dinistr.ation. Reconstitute
`with 2.7 mL.o( st.eril~'Wat.er for Injection to yield 2 mWmL.
`N.et. .cpnt.ents 5.4<mg lyophilized powder. Maximum yield
`. . . .
`. , ........
`2.5:m):, .. ;.
`5. mg vi~ (box of 6) . NDC 0590-Q324-35
`Prot.ect fro", light. Keep yial in b01{ until used. Store at
`controlled room t.empe~lltu~e. (!i9"-86"F, 15"-30"C).
`.
`After reconStitution. store at controlled ·rQ9m ,temperature
`(59~.s()'F, 15"-30"C) and use within 4 hours. Do nOhefrig(cid:173)
`e.ra.te,' Discard,any unused solution.
`REFE~NCES
`1.P~ller,J,.: Laboratory Control of An~ic.oagulant Th~~~py.
`Semin,ars. if:! Thrombosis and He~qsUisis, Vol. 12, No.1,
`.' pp. 13:19, 1986.
`. , .' ,
`'
`2., Hirsh; J.: Is the Do.se ofWatfarin ~rescribed by AIDeri(cid:173)
`.. can Physicians Unnece.ssllrily· High? Arch Int Med, Vol.
`,:J47"pp. 769-771, 1987:
`. . . .
`.
`'"
`3.:.Cook,. D.J., Guyatt.H.G., La)lpacis, A.,. ~ackett, D_J.,.:
`Rules of Evidence a~d Clinical Recomniend.ations QI1 the
`U~e ofAxitithrombotic Agents. Ghest ACCP C';:nse;:'s;'s
`Gonferedce .01.1 Antithrombotic. Therapy. CJ!.e.~t, Vol.
`102(Suppl), pp. 305S-311S, 1992,
`. . . . "
`4. Hirsh, ,J" Dalen, J., D~ykin, D., Poller, L,: Oral.Antico(cid:173)
`a~~ts ~e~hanism of ,Action, Clinic~il ~ffectivenes~,
`al\d Optimal Therapeuti~ Range._Chesi ACCP Consen(cid:173)
`sus Conference on AI.ltjthrombo.tic 'l:'herapl." Chest, Vol.
`102(Suppl), pp. 312S-326S, 1992.
`.
`5. Hirsh;,J" M.D., F.C.C.P.:· Hamilt<on. Civic-Hospitals Re(cid:173)
`,1:: search Center, Hamil,ton, Onta~o, Person~l Co~mu~­
`: 'cation:
`. " ' , ", .
`DistriQutad. by:
`Bristol-Myers Sqnipb C0I!lpany
`PrincetQn, NJ 08543 U.S.A.'
`COUMADIN® and
`the color and configuration of
`CQUMAnIN tl!blets· are ·tradel'lar~S 0(. Bristol-Myers
`'Squibb Company. Any unlicensed use of theSe trademarks
`is expressly prohibit.ed U1lder the U.S. Trademark Act.
`©2005 Bristol,Myers' Squibb Company, Princeton;NJ
`08543
`T'lcB0001-04-05
`Print.ed in U.S.A. 1170696A1
`Shown in Product Identification'Guide, page 309 .
`
`:RevisedApril2005
`
`EMSAM®
`[em-sam]
`jSELEGILlNE TRANSDERMAL SYSTEM)
`CONTINUOUS DELIVERY FOR ONCE-DAILY
`APPLICATION
`Rx only
`, ,
`
`Suicidality in Children and Adolescents
`Antidepressants increased the risk of suicidal thinking
`and behavior' (suicidality} in short-term studies 'in.:
`., children and adolescents with major depressive disor(cid:173)
`der, (MOD) and other psychiatric disorders. Anyone con(cid:173)
`sidering,the use of 'EMSAM 'Or any other antidepressant
`in. a child or a~olescent'must balance this'risk with the
`. ,clinical need.· Patients who are started on therapy
`:should be obse"lVed closely for clinical ,worsening, suici-'"
`-dality, or unusual cha ... ges, in. behavior.' Families and·
`caregivers should be advised for die need for close ob(cid:173)
`servation . and communication: with' the prescriber.'
`" .EMSAM··js' not approved'for use in pediatric patients: "
`'(See WARNINGS and PRECAUTIONS, Pediatric Use.)
`Pooled.anafyses,.of .short-term:.(4 to 16 .weeks) placebo(cid:173)
`controUedtrials of nine antidepressant drugs (SSRlsand
`others) in children and .adolescents with major'deines;,.'
`sive disorder (MDDJ~ obsessive compulsive disorder
`.' (OeD), or'"other psychiatric disorders (a total of 24 trials
`involving over 4400 patients) have revealed i{g'reater:
`risk of, adverse events',.t!presenting suicidal thirili:ing .or-·
`behavior (suicidality)' during' the first'· few, months of
`
`BRISTOl-'MYERS SQUIBB/903
`
`treatment in those receiving antidep;r~ants. Th~ayer-,;
`age risk of such events in patients r~i';ing antidepres- '
`sants was 4%, twice the placebo risk of 2%. No suicides
`O?Curred i.n thesf:!:,tr~~ls.
`
`DESCRIPTION
`EMSAM® (selegiline transdermal. syst.em)is .a transder(cid:173)
`mally admiuist.ered antidepressant. When applied to intact
`skin, EMSAM is designed to continuously deliver selegiline
`over a 24-hour period.
`Selegilin~ base is a colorless to yellow liquid. chemically
`as
`(-)-(N)-Methyl-N-[(lR)-1-methyl-2-
`described
`phenylethylJprop-2-yn-1-amine. It has an empirical
`formula OfC,3H n N and a molecular weight of 187.30. The
`structuralformula is:
`
`Sclcgiljnc Base
`
`EMSAM syst.ems are transdermal patches that contain
`1 mg of selegillne per em and·deliverapproxiinately.0.3 mg
`of selegiline per cm2 0ver 24' hours. EMSAM syst.ems are
`available in. three sizes: 20 mw20 cm2, 30 mw30 cm2, and
`40 mg/40 cm2 that deliver, on average, doses of 6 mg, 9 mg
`or 12 mg, respectively, of selegiline ov~r: ~4 ~~)Urs.
`EMSAM is a matrix-type tran~dermal.syst.em composed:Of
`three layers as iIIustrat.ed in Figure 1 below. Layer 1 is the
`Backing Film that provides the matrix: system with occlu(cid:173)
`sivity and physical int.egrity and prot.ects the adhesive!
`drug layer..!,.ayer.·2;is the Adhesive/Drug Layer. Layer 3
`consists of side-by-side release, liners that are peeled off
`and discarded by the patient prior to applying EM~AM, The
`inactive i.J;l,gr,edie:Q~. are acrylic adhesive, ~thyIEfn~' vinyl
`acetaWp\iryethyle.ne,' polyester, polyu:,..thane, and silicon
`coated poly~ster! ' . ;;
`.'
`, '
`.
`
`Figure 1: Side view of EMSAM system. (Not to scale.)
`
`. P~~rn:;acody.namics, '
`."
`"
`.
`Seleg\line (the drug s.ubstance ofEM~AM) ;san i;.r~~er"i\!je
`~nhibitqr,prmono~il:l~ o~~~~ '<MA.Q), an in!X&~lellul,ar
`e~zyme,associ8:ted with· thel pute:r D:J.eriibrane ofmitoGhon(cid:173)
`dna. MAO exists a~ fWo,isoe~ym~s~' refe~d to'~~.MAQ,.A
`and MAO-B. Selegiline has a gieai.!r affinity forMAO-B,
`compared ~;MAO-A, .. ;Howe.ver" ~~ B:D;ti.~~ep:ress~t doses,
`selegiline inhibits bgth isoeniYmes (see below).
`~~:lJl~chllnismo,(aqtiolio~~M~""M '\S an .ant!depressant
`IS .not fully .unders~d, but 15 p~esumed to b~ hilked to po(cid:173)
`tentiation of monoairiine neurotransmitter actiVity in tlie
`ceptra).nervous.5YSt.em.(C~S) resuItitlg from its inhibitiop.
`o(~U activity. In anjn.. vivo a.i;llni:"al model ,used to test for
`a'nti!lepress.ant actlYity (Forceq Swi1n Test), selegiljne ad(cid:173)
`minist.ered by transdermal patC.h exhibit.ed antid~pr"ssali.t
`properties only at doses that 'inhibited both MAo-A and
`MAO-Bactivity in thEi brain. In th~ CNS, MAO-A aii'd
`. MAO-B' play iniport9.\lt rei)es in the. catabolism of neuro(cid:173)
`transmitter amines such 'as _ norepinephrine, dopapline,
`.~f.ld'ser~~ni~, a's .yv~ll. as ~eu.romo~!J1ators such,as p!H~ny­
`l~tp.Y~?:rn~ne. Oth~i mol~cUlar sites or-action ~ave also been
`explor;'~d a,nd in this r~gard, a direct.p'hannaco,logicaJ iiIter(cid:173)
`action n1ay ,also' occur' between selegiline' an,d brain neu(cid:173)
`ronal 'a28 receptors. In ~n Vitroreceptor' 'binding assays,
`selegiline 'has demonstrat.ed affinity' fot the h"mail
`recombinant adl'energic ix2B receptor fK; ='284 JlM). N68f(cid:173)
`finity [K; > lO'JlM] was noted at dopaniine receptors, adre(cid:173)
`nergic 133,' glutamate, muscariirlc'MI-M5'~ nicotinic, or roli:"
`ptam receptor/sites.
`. , .
`Phiumacokinetics '
`.',,;
`Absorption
`.Following dermal application of EMSAM to hUmans; 25%-
`30% of the selegili~e conterit on average 'is 'n~livered 8yS(cid:173)
`t.eiiricallyover:24 hours (range:'" 10%-40%): Consequently,
`the degree of'drug absorPtion maybe 1I3,higher'than'the
`average amounts of6'td 12'nig per 24> hours,Transdermal
`dosing results in' substantially higher' exposUre to
`selegiline and lower exposUre' to metabolites"compared'w
`oral dosing, where extensive first-pass 'metabolism occurs
`(Figure 2):ln a10-day studywith EMSAM administ.ered to
`horma:l volunteers, steady-state selegiline plasma concen(cid:173)
`trationswete achieved Within'5 days' of daily dosing' Ab(cid:173)
`sorption of selegiline .js similar when EMSAM ·is applied to
`the upper torso or upper thigh. Me$-(95.% 'CI) stt>lidjr.-stat.e
`plasma concentrations 41 healthy. men ana WOInEm follow(cid:173)
`ingappliClition of EMS AM tothe nppelCtorso'O" npper thigh
`are sbdwnin Figure 3.
`
`Continued on next page
`
`Consult 2007 PDR~ supplements: and futua:e editions for revisions
`
`NOVARTIS EXHIBIT 2049
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 10
`
`

`

`,
`
`The risk of suicidality was most consistently observed in ;~
`the MDD trials, but there were signals ofri'sk a~singfro~!!J.
`trials in other psychiatric indications (obsessive compU1<'~
`sive disorder and social anxiety disorder) as well.' No' su~·'
`cides 'occurred in these trials. It is unknown whether tli~~
`suicidality risk in pediatric patients extends to longer-te~
`use, 'ie., beyond several months. It is also unknoWn
`"'j
`whether the suicidality risk exte;nds to adults:
`All pedi~dric patients being treated ~ith antidepressants,'9:T
`any'indicBlio'n should be observed closely for clinical wors-:,
`ening, suicidalitv •. and unusual changes in behavior,
`'cially during the initial 'few' months of a course' of dr'u~
`therapy, or at times of dose changes, either increases or, ~\::
`creases. Such observation would generally include at le~~
`weekly face-to~face contact with patients or' their fa~IJY
`members'~or caregi,vers' during' the first 4 weeks of~r~a~~
`ment, then every' other 'week visits for the next 4 wee~
`then at 12 weeks, and as clinically indicated beyon~: 12-
`weeks. Additional contact by telephone may be approp~ia!e
`between face-to-face visits. ' , '
`.
`,
`Adults ~ith IVIDD or ~o-m~rbid depression in the settirig'~~
`other psychiatric iilness being treated with anti
`'
`should be observed similarly for clinical worsening'
`ci~ality, esp~,cially during t~,e. initial few months of
`0; ~rug therapy, or a,t!mes of dose Change's, eitheri
`or decreases.
`,
`.
`.
`The following symptpms, all?'iety, agitati<?n, panic a
`insomni~, irritability, hostility, aggressiveness,imp
`akathisia (psychomotor restlessness), hypomania,
`nia, have been reported in adult and pediatric pa
`ing treated with antidepressants for major depressi
`order as well as for other indications, both psychiat .
`nonpsychiatric, Although a causal link between the
`
`"'I ".!
`~ I
`~'~j
`I ~oo .
`~I
`
`-
`
`Information wiltb'e,superseded.by supplements and subsequent,editions~,
`
`"']
`
`• SefegIIine TranSdermal Sy$tem 8 mgI24 hours
`
`o $alegIlineJiCtp.o. 10mg
`
`904/BRISTOL-MYERS SQUIBB
`PHYSICIANS' DESK REFERENCE®·~l
`:..:..==.:....::..:=----~=-----------,----------------,--------------- •• ~
`CONTRAINDICATIONS
`Gender- No gender differences have been' observed -in
`the pharmacokinetics or metaboliSm of selegiline during
`EMSAM'is contiaindicated in patients with known hyPer_
`administration of EMSAM. No adjustment of EMSAM dos(cid:173)
`sensitivity to selegiline or to any component of the
`age based on gender is n,eeded.
`'
`triinsdermal system.
`Reduced Hepatic Function
`is contraindicated with selective serotonin
`EM$AM
`After a'single administration of EMS AM 6 mgl24 hours in 8
`reuptake inhibitors (S8RIs, e.g., fiuoxetine, sertraline, and
`patients with mild or moderate liver impairment (Child(cid:173)
`pa'roxetine); dual serotonin and norepinephrine reuptake
`Pugh classifications of A or B), no differences in either the
`inhibitors (SNRIs, e_g., veulafaxine and duloxetine);tricy_
`metabolism or pharmacokirietic behavior ofselegiline or its
`imipramine and
`clic antidepressants· (TCAs, e.g."
`metabolites were observed as compared with data of nor(cid:173)
`ainitriptyliri.e); bupropion hydrochloride; meperidine and
`mal subjects. No adjustment of EMS AM dosage is required
`analgesic agents Sl;lch as tramadol, methadone' '~d
`in patientS with moderate liver impairment.
`' .
`propoxyphene; ,the antitussive agent dextromethorphan;
`Reduced Renal Function
`St. John's wort; mirtazapine;and cyclobemaprine. EMSAM
`Data from a single dose study examining the pharmacoki(cid:173)
`should not be used with oral selegiline or other MAO inhib_
`netics of EMSI\M 6 mgl24 hours in 12 patients with renal
`itors
`(MAOIs e.g.,
`isocarboxazid, phenelzine, and
`impairment suggest that mild, moderate, or severe ,renal
`tranylcyprOInine) (see WARNINGS).
`impairment does not affect the pharmacokinet~cs of
`Carbamazepine and oxcarbazepine are contraindicated in
`selegiline after transdermal applicatiop.. Therefore, no ad(cid:173)
`patients taking selegiline (see PRECAUTIONS, Drug Inter(cid:173)
`justment of EMS AM dosage is required.in.patients with re(cid:173)
`actions).
`nal impairment.
`. As ·with other·MAOIs, EMSAM is contraindicated for use
`Dermal Adhesion
`with sympathomimetic amines, including 'amphetamines
`Dermal adhesion· of EMSAM was examined after applica(cid:173)
`as well as cold products and weight~reducing preparations
`tion of 6 mgl24 hours selegiline patches for 10 days to the
`that contain vasoconstrictors (e.g.; pseudoephedrine,
`upper torso. Approximately 880/0--89% of 6 mgl24 hours
`phenylephrine, phenylpropanolamine, and ephedrine).
`selegiline patches applied to the upper torso eXhibited
`As with other MAOIs, patients taking EMSAM should. not
`<10% lift with approximately 60/0--7% of patches becoming
`undergo 'elective' surgery requiring general anesthesia,
`detached.
`Also, th,ey should not be given cocaine or local anesthesia
`External Heat
`containing sympathomimetic vasoconstrictors. EMSAM
`The effect of direct heat applied to the EMSAM patch on the
`should be discontinued at least 10 days prior to electiv!,!
`bioavailability of selegiline has not been studied. However,
`surgery: If surgery is necessary ~ooner, benzodia'zepines,
`iIi theory, heat may result in an increase in the amount of
`mivacurium, rapacuroruum, fentanyl, morphine, a~d
`selegiline absorbed from the EMSAM patch and produce el(cid:173)
`codeine may be used cautiously:
`'
`evated serum levels of selegiline. Patients should be ad(cid:173)
`As with other MAOIs, EMSAM is contraindicated for usem
`vised to avoid exposing the EMSAM application' site to
`patie~ts with pheochromocytOma.
`external sources of direct heat, such as heating pads or
`EMSAM is an irreversible MAO inhibitor. As a class, these
`'electric blankets, heat lamps, s'aunas, hot tubs, heated wa(cid:173)
`'compound,S have be:e~ associated with 'hypertensi~e ci.is~
`ter beds, and prolonged direct sunlight.
`caused by the ingestion of foo,ds containing high amounts
`Clinical Efficacy Trials
`~
`of tyramine. In lis entirety,"the data for EMSAM 6 mgl24
`The efficacy of EMS AM as a treatment for major depressive
`ho,~s SUPP?rt the recommendati,on ~~_t a modif).ed diet i~
`disorder was established'in two placebo..:controlled studies
`not required at this dose. Du~ ~ the more Fmited da~ ,
`of 6 and 8 weeks duration in adult outpatients (ages 18 to
`available for EMSAM 9 mgl24 hours and 12 mgl24 hours, ::
`70 years) meeting D8M-IV criteria for major depressive
`patie'nts r~ceiving these doses should follo~ Dietary Modi~
`disorder. 10. both', studies~ patients were ran~omized to
`ficat_ons' 'Required for Patients Taking EMSAM 9 mg/24 "
`'double-blind treatment with EMSAM or placebo. The 6-
`bour's and 12 m9/24 hours. (See WARNINGS and PRE(cid:173)
`week trial (N = 176) showed that EMSAM 6 ingl24 hours
`CAUTIONS, Drug Interactions, Tyramine.)
`was sigllificantly Ip.ore 'effective than placebo' on the 17-
`item Hainilton DepressiOll Rating Scale (HAM-D). In an 8-
`WARNINGS
`week dose titration trial, depressed patients (N = 265), ,...ho
`Clinical Worsening and'Suicide Risk
`receIved EMSAM or placebo at a starting dose' of 6 mgl24
`Patients With major depressive disorder(MDD), both adult
`'hours, With:possible increases to 9mgl24 hours or 12 mg/24
`and pediatric, may expe:rience worsening of ~heir depres~
`hours bas'erl on clinical response, showed sigiIificant im(cid:173)
`sion and/or t~e emergence of suicidal ideation 'and,behavior
`provemeilt compared with placebo on the prim-Bry o:utc:ome
`(suicidality) o~ unusual ~4a~ges in beha~or, \Yhether or
`meas'Q,re, the 28-item HAM-D total score.
`'
`not they'are taking"antidepressant medications, and this
`In another trial, 322 patieJ?U? meeting D8M~IV criteria for
`risk may persist until significant remission occurs. There
`major depressive disorder who had responded ~uri~g an
`has been"a ;long'':stapd,ing' concern that antidepressants
`initial I'D-week op~n-:label treatment phase for a,bout ·25
`may have a; 'role in inducing worsening of depression and
`days, on average, to EMSAM 6 mg/24 hours were random(cid:173)
`the emergence of suici<:lality in 'certain patients. Antide(cid:173)
`.
`ized either to continuation of EMSAM at the same dose
`'pressantS increased,the risk 'of suicidal thinking and be-
`(N = 159) or to placebo (N = 163) under double-blind
`havior (suicidality) ih short-term studies in children ana ~'
`adolescents with Major Depressive Disorder (MDD) .and
`conditions for observation of relapse. About 52% of the
`/
`EMSAM-treated patients, as well as about 52% of the
`i)ther psychiatric disorders.
`" ':
`placebo-treated patients, had discontinued treatment by
`Pooled analyses 6f short-term placebo~controlled trials 'of,
`week 12 of the double-blind phase. Response 'during the
`nine antidepressant drugs (88RIs and others) in children :
`and adolescents with MDD, OCD, or other psychiatric dis- .\
`open-label phase was defined as 17-item HAM-D score <10
`orders (a total of 24· trials involving over 4400 patients) ':'1
`at either week 8 or 9 and at week 10 of the open:label
`phase. Relapse during the double-blind phase was defined
`have revea,led a greater risk of adverse e,vents representing .:~
`as follows: (1) a 17-item HAM-D score "'14, (2) a CGI-S
`suicidal behavior or thinking (suicidality} during the first ']j
`few mOilths of treatment in' those receiving, antid,epre~- ~.~
`score of ~3 (with at least a 2-point increase from double(cid:173)
`sa~ts: The average risk of such events in patients receivin~ /b
`blind baseline), and (3) meeting DSM-IV criteria for major
`antidepressants· was 4%, twice the placebo risk o:f 2%. 3il
`depressive disorder on two consecutive visits 2::11 days
`a tendency toward an increase for almost all'drugs studi~d: :l
`apart. In the double-blind phase, patients receivingcontin(cid:173)
`There was considerable variation in'risk among dru'gs, bl!t ~
`ued EMSAM (selegiline transdennal system) experienced a
`significantly longer time to relapse.
`An examim,1.tion of population subgroups did not reveal any
`'clear evidence of differential responsiveness on the basis of
`age, gender, or race.
`INDICATIONS AND USAGE
`EMSAM is indicated for the treatment of major depressive
`disorder.
`'
`'
`'
`The efficacy of EMSAM in the treatment of major depres:(cid:173)
`sive disorder was established in 6- and 8~week placebo(cid:173)
`controlled trials of outpatients with diagnoses of DSM-IV
`category of major depressive disorder (see Clinical Effi'"
`cacy Trials).
`A major depressive episode (D8M,.lV) implies a'prominent
`and relatively persistent (nearly every day for. at least 2
`weeks) depressed or dysphoric mood that usually interferes
`·with daily functioning, and includes at least five.of the fol(cid:173)
`lowing nine symptoms: depressed mood, loss of i,nterest in
`,usual activities, significant change:in weight and/or, appe(cid:173)
`tite, insomnia· or hypersomnia, psychomotor- agitation or
`retardation, increased fatigue, feelings of guilt or worth(cid:173)
`le'ssness; slowed thinking·or impa,ired concentration; and
`suicide attempt or suicidal ideation ..
`The benefit of maintaining. patients with major depressive ,
`disorder on therapy with EMSAM after achieving a re(cid:173)
`'sponder status for an ,average duration of about 25 days
`'was demonstrated' in a controlled trial (see·Clinical Efficacy
`Trials under CLINICAL· PHARMACOLOGY). The physician
`who elects -to use EMSAM for·.extended periods showd pe(cid:173)
`riodically re-evaluate the long-term usefulness of the drug
`for the individual patient (see DOSAGE AND ADMINIS(cid:173)
`TRATION).
`:The 'antidepressant action of EMSAM' in .hospitalized de:(cid:173)
`pressed patients has notbe~n'stud~ed.
`
`. . . . .
`Distribution
`Following dermal application of radiolabeled · ... eleg;line to
`laboratory animals, selegiline is rapidly distrihutei:\ to· all
`body tissues. Selegiline rapidly penetrates the bloodclirain
`barrier.
`In humans, selegiline is approximately 90%. bound to
`plasma pr'?tein over a 2--500. nglmL concentration range.
`SeleiiliDe does not accumula~ in the skin.
`- .
`In vivo Metabolism
`Transderinally-absorbed seleg;line (via EMSAMl is not me(cid:173)
`tab{m~zedjil. hlJinan skin and- does not "unde1150 extensive
`firs~~-ass "lhetll'Bdlism. Selegiline is "extensively metabo(cid:173)
`lized by several CYP 450-depen4ent enzyme systems (see !!!.
`vitro Metabolism). Selegiline is metabolized initially via
`N-dealkylation
`or N-depropargylation
`to
`form
`N-desmethylselegiline or R(-)-methamphetamine, respec(cid:173)
`tively. Both of these metabolites can be firrther metaboli~ed
`to R(-)-amphetamine. These metabolites' are
`'all
`: no
`and
`(1-)en~ntiomers
`l~vorotatory
`r~cemic
`'biotrinsform'ation to the dextrorotatory fomi (i.e., S( ... l-am(cid:173)
`'phetamine or S(+)-methamphetamine) occurs. R(+
`methab:rp.hetamine··and.·~(~~:.al'll:~hetamlne are' mai~ly ex-
`creted unchanged in unne:""
`'
`In vitro'Mf!tabolism
`'
`,
`"
`In vitro' "studies utilizing hUIl'l:an live~ microsom~s demon(cid:173)
`strated that several CYP4.60-dependent enzymes a~e in(cid:173)
`volved in the m~ta~olisrri 'of selegiiine and'its metabolites.
`CYP2B6, CYP2C9, and CYP3A4I5 appeared to bethe major
`formatiori
`en~~es in
`~ntributing
`t~e
`,~~
`R(-)-methamphetamine from selegiline, with CYP2A6 hav(cid:173)
`ing a minor role: CYP2A6, CYP2B6, and CYP3A4I5. ap(cid:173)
`peared to ~ontribute to the formation of R( -)-amphetamine
`from N-desmethylselegiline.·
`.'
`...
`The potential for selegiline or N-desmethylselegiline to in(cid:173)
`hibit individual CYP,so-dependent enzyme pathways waS
`also examitied in vitrowith human liver microsomes. Each
`substraie was exa~ed ov~r a concentra,tion r~nge of 2:.9 ,
`to 250 flM. Consistent with competitive inhibi~ion., both' .
`selegnin'e',~d N-desI;I1etl1ylselegiline c~used a .~o~c,eri.t~a­
`tion dependent inhiDition of C:YP2D6 at 10-250 flM and
`CYP3A4I5 at. 25C-250 flM. CYP2C19 andCYP2B6 were also
`i!\hibited at cOIlcentrations "'100. JiM. All in!i.ibitory effects
`'of seIegiliDe and N-desmethylsel~giline occnITed at cOncen(cid:173)
`trations that are. several orders: of magnitude higher than
`concentrations seen clinically (highest predose concentra(cid:173)
`tion observed' at 'a' dose of 12 mgl24 hours at steady-state
`was 0.046 flM) (see PRECAUTIONS, Drug Interactions),
`, "
`Excretion'
`Approximately 10% and 2% of a radiolabeled dose,,,pplied
`dermally, ~s:a lIM80 solution, was re~ove.re~~n,urine and
`fe~es r,espectively, ,with at least ,?3% of the dose rema~ning
`unabsQrbed. The remaining 2p% of the dose was unac(cid:173)
`coun~,ed fo~. 'Ur;inary excretion of unchanged selegiline a~­
`.counted for 0.1% of the applied dose with the remainder of
`the dose re~overe~ in urine being metabolites.,
`1;he systemic clearance of selegiline afte.r intravenous ad(cid:173)
`ministration ,was 1.4 ,:Umi~ and ,the mea.:p. h.alf-liv~s
`of • selegiline
`and
`its
`three
`"metabolites,
`R(-)-N-desmethylselegiline,
`R(-)-amphetamine,
`and
`R( -)-methamphetamine, ranged from 18--25 ho.urs,
`Population Subgroups
`Age- The effect ,of age on the phannacokinetics,or me(cid:173)
`tabolism of selegiline.during administration of EMS AM has
`not been systematically evaluated. The r.ecommended dose
`for elderly patients is EMSAM 6 mgl24 hours. (See DOS(cid:173)
`AGE AND ADMINISTRATION.)
`
`NOVARTIS EXHIBIT 2049
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 10
`
`

`

`INFORMATION
`
`BRISTOL-MYERS SQUIBB/905
`
`such .symptoms and either the worsening. of de-
`'':'':~~''iionand/or the emergence of suicidal impulses has not
`established, there"is concern that such symptoms may
`,represent precursors to emerging suicidality.
`GQ!!Sideration should be given to changing the therapeutic
`regimen, including possibly discontinuing the medication,
`iri patients whose depression is persistently worse, 'or who
`are experiencing emergent suicidality or symptoms that
`itrigbt be precursors to worsening depression or suicidality,
`especially if these syinptoms are severe, abrupt in onset, or
`"''Were'not part of the patient's presenting symptoms.
`· Jf:the" "decision has been made to discontinue treatment,
`· iUedication should be tapered, as rapidly as is feasible, but
`'~:"'With recognition that abrupt discontinuation can: be
`associated with certain symptoms.
`.
`, Families and caregivers of pediatric patient