NOVARTIS EXHIBIT 2052
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 5
`
`

`

`EDITION
`
`2004
`PHYSCANS'
`DESK
`REFERENCE®
`
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`
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`Suzanne E. Yarrow; RN
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`Copyright © 2004 and published by Thomson PDR at Montvale, NJ 07645-1742. All rights reserved. None of the content of this publication
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`.ISBN: 1-56363-471-6
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`NOVARTIS EXHIBIT 2052
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 5
`
`

`

`33GS/WATSON
`
`Oges~rel-Cont.
`
`contraceptives and will examine you. The physical examma(cid:173)
`tion may be delayed to another time if you request it'and the
`health' care provider believes that it is a good medicalprac(cid:173)
`tice to postpone it. You should be reexamined at'1east once a
`year while taking oral contraceptives, The detailed patient
`mfbrmation leaflet gives you further information which you
`should read and discuss with your health care provider,
`HOW TO TAKE THE PILL,
`See full text of HOW TO TANETHE PILL which is printed
`in full m the DETAILEDPATlEN1' LABELING"
`Keep this and all medication out'of the reach of ·children .. ·
`Rx:only
`
`, Revised: Feb. 7, 2000
`
`Address medical inquiries to:
`WATSON PHARMA,'INC.
`Medical Information
`POBox 1900
`Corona, CA 92878-1149 '
`Mfi, by: Searle.:&' Co.
`. San Judn, PR00936
`,
`'.
`for: WATSON PllARMA, INC.,
`a sU~lii~iary of Watson lAbdrqtorieii, Inc,..' ,
`Corona, CA 928$0
`'
`..
`:
`.. '
`.
`':
`, Shown [n Product IdentificdtibnGttide, paiJe 339
`
`OXVTROLl'M
`[oks~~-trol]
`Oxy~utynin TransdermafSystem"
`Rxoi\ly .
`, ..
`
`the R-isomer. The active metabolite, N-desethyloxybutynin,
`has pharmacological activity on the human detrusor muscle
`that is similar to that of oxybutynfum in,6itro studies,'
`. . .
`Pharmacokinetics
`. .
`Absorption
`Oxybutynfu is transported across mtactskin and mto the
`systemic circulation by passiYe diffusion across the stratum
`corneum: The average daily dose of oitybutynfu· absorbed
`from the 39 cm2 OXYTROLsystem is 3.9 mg. The average
`(SOl nommal dose, 0.10 (0.02) mg oxybutynin'per,cm2 sur"
`face area, was' obtained from analysis of ;residual
`oxybutynfu content of systems worn over a contmuous 4-day
`period during 303 separate occasions:;in 76 healthyvolun(cid:173)
`teers. FoIIowmg application of the first 'oJC:YTROL 3,9 mg!
`d!lysystem, oxyb'utyirin plasma concentration incxeasesfor
`approximately 24 to 48.hours"reaching average maximum
`concentrations of 3 to 4 ng!DiL. Thereafter, stea4y concen(cid:173)
`trations are maintained for up to 96 hours. Absorption of
`o.ybutynin lS bioeqnivalent when OXYTROi. is aPI?lied .to
`the abdomen, buttocks, or !lip. Average,plasma, concentra(cid:173)
`tions measured durIng a randomized, crOSSOVElr stpdy of the
`three recommended application sites m 24 he81thy men and
`women are shown In FlgUre it .
`,
`'
`
`Figure 2: Average plasma oxybutynin concentrations:(Cp),in 24 ,
`healthy male,and,female,volunteers during singJe-dose,applica(cid:173)
`tion of OXYTRQL 3,9 mg/day-!0 the abdomen;)buttock, and ,hip'
`(System removal at 96 hours).
`
`PHYSICIANS' DESK REFERENCE®
`
`After oraladmfuistration of oxybutynffi, pre-systemic.fust(cid:173)
`pass metabOlism results iri lin 6ra:!bio!ivailability' ofappro<,:
`imately 6% .and higher. plasma concentrationof.the.N·des,
`ethylmetabolifu compared to oxyblitynffi(see Figur,i:4):The
`plasma concentration AUC ratio of N-desethyl' inetabiJlite
`to.parerit compound folIowing · .. 'single'5 Dig 'oral· dose 6f
`oxybutynin chloride was 11.9:1. "
`. ' ,
`.' ':
`Trlinsdermal, ,administration oUlxybutynin bypasses' the
`first-pass. gastromtestinal'and hepatic'metabolismi,teduc'
`ing the formation of the N·desethyl metabolite,(see'Ffgilr~
`4). Only smalI amounts ofCYP3A4 are found m'skin;:limit:
`ing pre-systemic' Inetabolism·. during"transdeimal, absorp(cid:173)
`tioniThe resulting' !plasma: concentration. lAUC . ratio; of N(cid:173)
`desethyl metabolite to parent compound folIowing multiple'
`OXYTROL applications was 1.3:1.
`.
`
`FIgure 4: Average plasma concllitratfons (Cp)measli[ea afte.r,
`a single, 96"hour ap'plication!of the OXYTROL 3,9i11g/ilay sys-'
`tem (AUCin,/96) and a single, 5 mg, oral immediaWrelease, r'
`dose of oxybutynill chloride (AUCirii/8)in'16 healthy male arid;
`female volunteers.
`!
`"
`"
`
`.OI<Yl>\rtyt)I~
`mH..d-,~..,bulynln~->'"
`
`DF;SClfJl'TIOi-f.
`OXYTROL;. oxybutyirintransdermat sYStem, is designed to
`deliver oxybutynfu continuously and consistently over a 3-
`to 4-day mterval after application to mtact skin. OXYTROL
`is available , as,!i ,.39, cm2 system. containing,., 36 ·.mg. of
`oxybutyirin. o)<YTROL has a'nommal in 'vivo·delivery rate of
`3.9 mgoxybutyirin per day through skin of average perme(cid:173)
`ability (mterindividual vari!ition m skin permeability is ap(cid:173)
`proximately 20%).-'
`Oxybutynin is an antispasmodic, anticholinergic agent.
`Oxybutynfu is .admfuistered as a racemate of R- ana S.(cid:173)
`iso~ers. Chemically, oxyb~tyirin is d, I (,acemic) .4-diethyF
`amin~-2,butynyi phenylcYcloh~XYlgly~olate,. The empipcal
`fOJFlula of,oxyllutypjn,is C22H31NOg• Its swuct)ITal formpla
`
`. CH3
`is:- W
`cr~:~C~
`
`•
`
`Oxyb~iyrun is a white powder with a mol~"uiar weight of
`357. It is soluble m alcohol, but relatively msoluble in water.
`Transdermal System Components.
`.
`OXYTROL is a matrix:typi. .. tr~sdeJFlal. system cqmposed
`of three :layers as, illustrated m Wgpre • Lbelow. I,ayer ~
`(Backing Film) is,a thin fI~xible polyester/ethyle~e-vinyl
`acetatejilm,th;it pro;Vjdes the matrix system with.oceIusiv(cid:173)
`ity andphysicaI integrity" and ,llro~eFl's th~, adhe~jve/drug
`layer. Laye,'" ~ (AdhesivelDrug Laye;r)is a cast film.ofacrylic
`aQhesive contaffiinKoxyl?':'.tYPM> and triacetin, USP. Layer 3
`(Release: ,Liner) is !wqoverIapped siliconized polyester
`strips that are peeled off, and <,li~carded by the patient prior
`to applyfug the matrix system,
`
`Figure 1: Si~e and top views of the OXYTROL system.
`(Not to scale)
`Side View
`. w;\m!t~ 2.Adhes;ve/Oru~Layer ,
`
`,
`
`,.
`
`1.·PET/EVA Backing Rrm
`
`" ,
`
`, ~,
`
`..
`
`;,
`
`3, OVerlapped Release Liner
`
`.-
`
`,.,1
`
`::;,
`
`Top View " ' , '
`~7.6cm~,·
`
`·c·····,······-r·,
`
`.
`
`.
`
`S.7em
`
`.,."
`',.'
`,':.
`. . . 1
`. . "'.-' ,-~
`
`GLINICALPBARMACQLOGY
`The ,free base'·form ,of oxybutynin is'pharmilcologically
`eqniv-alent. to oxyoutyirin hydrochloride:.OxYbutynin acts as
`a competitive antagonist of !icetylcholine at postganglionic
`muscarinic receptors;"resulting in·relaxatfon ·of bladder
`smooth muscle. In patients with conditions characterized by
`mvoluntary detrusor contractions, cystoDietric studies have
`demonstrated that oxybutyirinmcreases maximwIl'urmary
`bladder capacity and mcreases the volume to first detrusor
`contraction. Oxybutyllin. thus decreases urinarY'urgeney
`and the 'frequency of both mcontinence,episodes lind: volun(cid:173)
`tary urination.
`Oxybutynin is a racemic (50:50) mixture of R· and S(cid:173)
`isomers: Antimuscarinic, aCtivity resides predommantIy m
`
`i 6
`
`I at
`4S' W'
`72
`TIme (Hollrs Post Sy6lem Application)
`
`96" ""1bi!
`
`'120
`
`Steady"state conditions are reached during the second
`OXYTROL application. AVerage steady-state plasma concen:
`trations were 3.1 ng!mL for oxybutynm and 3.8 ng!IIiL :for
`N-desethyloxybutynfu (Figure 3): ,Table' 1, pro'videsiasi:m:l(cid:173)
`Diary of pharinacokinetic parameters of oxybutynin iri
`healthY'volunteers after:smgle and multiple applications of
`OXYTROL.
`
`"Figure 3': 'J\ve(a8e , (SEM)'itiiady-Sfaieoxyb~nin and .,"',
`N·desethyloxybutynin plasma,conc~nt[ations, (Gp) measured in.
`13 healthy volunteers foll6wihg the second transdermal sysfem
`. application in a multiple-dose, r~ndomized, crossover study,
`
`.
`
`&0
`48
`24
`3&
`Tlmo(t1oul'll Pos12ndS~AppIlCil1lon) \
`
`.. '
`
`Tablel: Mean(SD) oxybutyninpharma,cokm~tic"~',
`, '
`parameters from smgleand multiple dose' st)1die's' m
`healthy men and women volunteers after application of
`OXVTROL on the abdomen.
`
`!losing
`
`.Oxybu~,Ynin.
`
`Cmax(SOl
`(ng!mL)
`
`Tmax 1
`(hr)
`
`.. :
`C~vg (SOl AUC (SD)
`(ng!DiL)
`(ng!mLxh)
`
`Single
`
`3.0 (0.8)
`
`3.4 (l.1)"
`
`48
`
`36
`
`-
`
`245 (59)~
`
`___ ~f
`
`279 (99)2
`
`Multiple
`
`6.6,(2.4)
`
`10. '. 4.2 (1.1)
`
`408(108)3
`
`4.2 (l.O)
`
`28
`
`3.1(0.7)
`
`259 (57)4
`
`1 Tm""glven as median
`2 AUCinf
`.3 AUC0-96
`4 AUC0-84
`
`Distribution
`OxYbutynffi iswidely,distributed.-iJl body tissues :folIbwmg
`syst~mic absorption. The volume of distribution was esti(cid:173)
`mated to be 193 L after;mtravenousadministratiQllof 5 mg
`oxyl,>utyirin, chloride.
`..H
`.. ". i '."
`Met"bolism
`.
`'"
`Oxybutynin is metabolized p;rimarily..by the cytochrome
`P450 enzynie systeMs; particularly CYP3A:4, fo'und mostly
`in the'liver and gut wall. Metabolites inc1utle 'phenylCYcr.,:.
`hexylglycblic acid, which is pharmacologically mactive;"ilhd
`N-desethyloxybutynin, which is pharmacologically active.'
`
`FolIowmg ·mtravenous administration, the elimmation·ha:If(cid:173)
`lif~ of 6xybtii)irun!1sapp'rojtifue:telY'2f,h~urs:' FqlloWiflgli'E!"
`moval· of'OXVTROI:!, plas'ma'eoncerifi'atioil!i'of tixy])\it~
`ah(f'N'desethyloXybutynfu'declihe'witil' an' apparilil.t- ha:If'
`life of approximately 7 to 8 hours.
`"or'fww(C,T
`Excretion
`'
`; y,l. '.
`OxybUtyIiin is exten~ively metabolizedbythelivetii~tJi
`less than 0,1% of the adnlinistered'dose'eltcretedimcltaffged
`in th~,Urine! Also, lessithan 0'.1% 6t'the adiriimstered dose is
`llxcretedi as the metab6lite' N'desethyloxYbtitynili: i·, ,i,V(,
`Special Populations
`"", ':i"
`'"
`,,:
`Geriatric: The pharmacokinetics of oxybiitYhln!and'N(cid:173)
`desethyloltybutyniri werii similar iIi all patieiills'studied~ , .
`PediiltriciJ' 'The pharrilacokinetics of oxybutyniii' and' N(cid:173)
`desethylcixybutyuin were 'not evaluated' -in iiidiViduals
`younger than 18 years of age. See PRECAUTIONS:'Pedi~
`atric Use:' ' , .. ' " " ' . .
`_'
`Gender: .. There \Vere nO'sigliificant differences in th,rphar(cid:173)
`macokinetics of oxybutynfu in healthy male a:nd'feDiale vol(cid:173)
`unteers folloWing application of O*YTROL.... '
`Race: Available data-spgge.st that there are no significant
`differences iii: the pharmacokiitiiticsof oxybiitYmn based on
`race in ·healthy volunteers foIIowing administration···of
`OXVTROL: Japanese v-olunteers demonstrateci'asomewha:t
`lower metabolism of oxybutynin to N-desethyloXybut)'ilin
`' , ..,;;>
`.
`compared to Caucasian volunteers,
`Renal Insufficiency: There is no experience with the use of
`OXYTROL in patients with renal msuffi.ciency,
`Hepatic'Insufficiency:' There is no experience 'with the use
`of OXVTROL mpatientswith hepatiemsiifficiencyi
`"
`Drug·Drug Interactions: See PRECAUTIONSiDrugJln-
`' "I
`. ',f
`teractions:
`'",
`Adhesion
`Adhesion. was periodically .evaluated during. the Phase 3
`studies. Of the 4,.746'OXVTROL evaluations' iii the Phase 3
`trials, 20 (0.4%) were obsel'l7ed at clinic visits to have be.:
`come completely detached and 35 (0.7%) became partially
`detached dnri!lg ro~tine .clinic use. Similar to tj1e phanna(cid:173)
`co.kine,tic studies.,> 98% ,.of the systems evf!luatedip"the
`Phase 3 studies were assessed as bemg ;" 75% attached l)Ild
`thus. would be eXjlected to perform as anticipated"
`.
`. . .
`Clinical Studies
`The efficacy and safEltyof OXYTROL were evalpated in pa(cid:173)
`tients with urge urinary mcontinence .in two .Phase 3· con,
`trolled st~dies and one open-label ~*n,sion,Study\,?as'~
`Phase 3, placebo contioIIed study, comparing the'safetya,na
`efficacy of OXYTROL at dose level~. ~f 1.3, 2.6,and3.9';ng!
`day toplac~bom 5'20pa:tieri.~:;Open'JaAel t,,-e~tlherit',~~
`!ivailablefor patients completi1ili'the"studY. Study '2 'was a
`Phase 3stndy, comparing tHesafety'andejlicii'cy: of
`OxYTROL'3,9 mg/day versus active .and I?lacebo c?nfrols in
`361patient~....
`" ' . . :', • . ";::e',
`Study 1 '-Ivas' a randomized, double-blind, placebo,coi'itrolfed;
`paraIIel group study of three dose'Ievelsi of'OXTIFI()Ii.,)lorl(cid:173)
`ducted in' 520' pati\mfs.''Phe 12-weekdouble-blindheatnl,mt
`included OXYTROL doses of 1.3, 2.6,'and'3.9' mg/day"With
`matching placebo. An ppen-liibeI/ddse' titratidn'tteatI!i~nt
`extension allowed"continued ·trllatrilenff9r.up to'!\Ii:'a:ddi."
`tioria:! 40 weeks for patients completingih'e Cloubltl"bIIDd'pe·
`riod .. The majority of patients were Caucasian (91%) aMf",
`male (92%) With"a mean age of 61years'(range,'20tO 88
`years). Entry criteria required that patients have 'urge or
`'mixedincontinimee (with!i pred6mmance of ttrge);ur'geJ,in:
`continence episOdes of;? '10 per'Week;!aJid ;;, 8 miCttiritibm,i'
`per da:y,}The patient's medical history. and a urinary'aiat,Y
`dutihg'tJiiHteatment.free 'baseline. penod confurt1e<fthe'di'.·
`agnosisof urge iMontmence: Approximately 80%:ofpatientS,
`had no prior pharmacological treatment fO't"incontlneilce:
`
`NOVARTIS EXHIBIT 2052
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 5
`
`

`

`I?R91il1J~T:l.ftJFORMATIQN. "
`
`Rediictionsin weeklymcontinence.episodes, urinary fre-.
`quency,. :andurinary void volume ·betWeen placebo andae(cid:173)
`tive treatment groups are summarized in Table 2.
`Table' 2: Meaii and median change from baseline to end of .
`treatment (WeekH:2 or last observation camed fomard)·in.
`incontinence episodes, urinary frequency, and urinary void
`volume in patients treated' with OXYTROL 3.9 mg/day.or
`placebo fOl:.,,~2 weeks (Study 1).
`1
`•
`
`Parameter' .
`"._
`
`Placebo
`(N=127)
`
`~-.. I· Me.an I Median
`
`.
`
`(SD)
`
`OXYTROl~,9 mg/day
`(N=120)
`
`Mean I Median
`
`(SD)
`
`Weekly Incontinence Episodes.
`
`30
`
`15
`
`Baseline
`
`Reduction
`
`p value vs.
`placebo,
`
`37.7
`(24.0)
`
`19.2
`(21.4)
`
`-
`
`34.3
`(18.2)
`
`. 21.0
`(17.1)
`,
`
`0.0265*
`
`Daily Urinary Frequency
`
`Baseline, \.
`
`12.3
`(3.5)
`
`11
`
`11.8 (3.1)
`
`Reduction
`
`1.6 (3.0)
`
`1
`
`2.2 (2.5)
`
`P value VB:
`placebo ..
`..
`Urmary VOId Volume (mL)
`
`-
`
`'.
`
`0.0313*
`
`31
`
`19
`
`11
`
`2
`
`Baselin~" .
`
`Increase
`
`175.9
`(69.5)
`
`16.5
`(56.9)
`
`166.5 ,
`
`5.5"
`
`: 171.6
`(65.1)
`
`31.6
`(65.6)
`
`168
`
`'26
`
`,
`
`,",
`
`p value vs.
`placebo"
`.
`
`-
`
`6.0009**
`
`'Comparison significant if p < 0.05
`*f,Qomparison significant if p ,;0.0167 '
`
`, Increase
`
`9.3
`(6:3:1)
`
`5:5
`
`32.0
`(55.2)
`
`24
`
`.• p·v,uue vs.
`placebo
`
`0.0010*
`
`'INDICATIONS AND USAGE
`OXYTROL is indicated for the t~ea:tment of overactive blad,
`,der with symptoms of urge urinary incontinence, urgency,
`and frequency.
`• "..
`• '
`
`CONT:aAINDICATIONS
`OXYTROL is contraindicated in patientJ'with urinary'r"ten(cid:173)
`tion, gastric retention, or uncontrolled nilITow'aiigl~ glau(cid:173)
`,coma and in patients who are at risk for these conditions.
`'OXYTROL is also contraindicated in patients who have dem,
`onstrated hypersensitivity to oxybutynin or other c~mpo-
`'nents of the product.
`, ' ,
`
`iWAT$ON/3S()9
`
`, .. .', ,.:
`.
`Pediatric Use
`The safety and efficacy of OXVTROL in pediatric patients
`have not been established.
`Geriatric Use
`pf the tot,al nJ.\lllber.of patients .in tl,lecljriic,a) ,studies of
`OXVTI'lOL, ,49.% were 65,aJf4 over. N.o9verall diff;erences in
`safety or effectiveness were observed. betweeJ;l these subjects
`andy~\'Uger subjects, and.o~her reportedc1injl',al e"p~Pen,ce
`h,as not id.entified differ.ences,.in response ,b~tweeli elderly
`3.Il~YouD.gerpati~nts; bUfgreater sen,#tivity of some. old~r
`individuals cannot be ruled out (~ee G~CA,L P~­
`COLOGY, Pha<macokinetics, Special, Populations.:, Geriat-
`ric).
`' . "
`'.,
`'
`.
`. .
`ADVERSE ,REACTIONS'"
`The safety of OXYTROIJ wasevaluatediit a total 'of 417 pa(cid:173)
`tients who "participated in' two' Phase 3 clinical efficacy and
`safety studies and an open-label! extension: Additional
`safety information was,C!'1l~c1;l'd in"Phase 1 aJfd Phase 2 tri~
`aIs" In the. two pi"otal stj1dies, ,a total oq-46 pa,1ii:~ntsre­
`ceiv'ed O~YTROL during the 12:week treatment JI'eriods. A
`total of411,patieIitsent~redthe'9peh-lab~1 exteJ1sion and of
`tliose, 65 patients and 52 patients re,,,,,,iv'~d OX~.OL f(jr at
`least 24 vvee,ks and at least 36, weeks!i'egpectively. ' .' .. ""
`No deatl{~ \Vere rep6rte,fd~g tre~tD:i~n,t,No~e,#9,tis ad(cid:173)
`" ....
`verse events related to treatment were reported.
`Adverse events reported in the pivotal'triaIl{areislllnfua'
`ri~edin ... Tables.4,aJfd5 bel?}V.:
`'\"
`.
`W"
`~ble.4' NJ.\lllPer,\%tor.ady~rse. e1':ent~;?9~umngin",,'2%.,
`6f ()~YTROL-treated patients and greater, cin OXYTR()L
`grq'lP,than.in Placebo gro,np\S~udy 1).
`
`Dry mouth
`
`Application
`site erythema
`
`Applic~t;on
`site vesicles
`
`Diarrhea
`
`11.
`
`.3
`
`0
`
`3
`
`.16.8%,
`-,;/".:. "
`,9.6%
`
`5.6%
`
`3.2%
`
`3.2%
`
`Dysuria
`0
`2.4%
`J!:< .
`* inc1u,des adverse events judged by the investigator as pos-
`sibly, probably or defiriitely tteatment-r~la:ted..
`"
`
`Table 5: Number (%) of adverse events oc.cuITing in. '" 2%
`of OXYTROL-treated patients and greater in OXYTROL
`group than in placebo group (Study 2).
`
`Adv.ers~"· '; (
`"Ev~nt*
`
`Placebo.
`(N,"117,l
`N ' ,%
`
`PRECAUTIONS
`General
`. OXVTROL should be used with caution in patients withlle(cid:173)
`'patic or renal impairment.
`Urinary Retention: OXVTROL should be administered
`'With caution to patients with clinically signifiduit' bladder
`outflow obstruction because of the risk of urinary retention
`(see CONTRAINDICATIONS).
`. ,
`Gastrointestinal Disorders: OXYTROL should be admiriis(cid:173)
`tered with caution to patients with gastrointestinal obst'llc;
`,tive disorders because of the risk' of gastric retention ~~ee
`'CONTRAINDICATIONS).
`'v,
`: OXYTROL, like other anticholinergic drugs, rnay'dec'rease
`gastrointestinal motility and should be used with caution in
`patients with conditions such as ul,cerative c'llitls, intestinal
`~tony, and myasthenia gravis. OxvTRdl 'Should/be us~4
`'with caution in patients who have gastroesophageal relliiX
`andlor who are concurrently taking drugs (such asbisplios(cid:173)
`phonates), that can cause .or exacerbate esophagitis.
`Inforinaticl'n for Patients, . ' "
`Patient~ should b~ inforIll~d that heafprostration(fe~~r
`and lieat stroke due to decreased sweating) can occUr wliim
`antichoI1n,;rgics suchasoloybutYllin are used jn a hot
`enyirpnP.l~nt. Because anticholinergic agents, such as
`oxybutynin, Ilfay produce drowsiness (sonmolence) ot
`blu,rred/vision, Patients shoulIfPe.,!ldvised to exercise cau(cid:173)
`}ion., PatieI).ts Sh9uld be. inforIl),ed that alcohol may enhance
`the dro:wsinessij~ansed!.l>y aI).ticholinel'gic. agents such. as
`oxybutyriin.
`"
`OXYTI'\QL should be applied to dry; intact skin, on the abdo(cid:173)
`men, hip, or buttock;. Anew application site should be se(cid:173)
`.lected with each new system to avoid re-application to the
`same site within 7 days. Details on use of the system are
`explained in the patient information lea1let that should be
`dispensed with the product.
`. Drug Interactions
`The' concomitant use ofoxybutynin with other anticholin:
`ergic drugs or with other agents that produce dry mouth,
`constipation, sonmolence,andlor. other anticholinergic-like
`effects may increase the frequency andlor severity of such
`. effects. Anticholii1ergic agents may potentially alter theab(cid:173)
`sorption of ,some'concOmitantly administered drugs due to
`anticholinergic effects on gastrointestinal motility. 'Phaima(cid:173)
`cokInetic studies have' not. been performed with patients
`concomitantly' i receiving{' cytochrome' P450 enzyme
`inhibitors; ';;llch"as .antimycotic agents (e.g. 'ketoconazole,
`itraconazole, and miconazole) or macrolide antibiotics (e.g.
`erythromycin arid cl9.rithromycin). No specific drug:drug in(cid:173)
`teraction studies have been performed with OXVTROL.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`A 24-month study in rats at dosages &f oxybUtYriiD. chloride
`of'20;80'and 160 mg/kg' showed no evidence of carcinoge(cid:173)
`niCity. These'dosesare approximately 6, 25 and 50 times the
`maximum exposure in humans taking an oral dose ,based on
`body surface area.
`Oxybutyriin chloride showed Iioincrease of mutagenic activ(cid:173)
`ity when tested in Schizosaccharomyces pompholiCiforrMs,
`Saccharomyces cerevisiae, arid Salmonella typhimurium
`test systems .. Reproduction studies with oxybutynin chlo(cid:173)
`ride in the mouse, rat, hamster, and rabbit showed no defi(cid:173)
`niteevidence of impaired fertility.
`Pregnancy: Teratogenic Effects
`"Pregnancy Category B
`.Reproduction studies with oxybutyriin chloride in' the
`mouse, rat, hamster, and rabbit showed no definite evidence
`of impaired fertility or harm to the animal fetus. Subcuta(cid:173)
`neous administration to rats at dosesup to 25 mg/kg(ap:
`proXimately 50 times the hiIman exposure based on sulface
`area) and to rabbits at doses up to 0.4 mglkg (approximately
`1 times the htitnaD eXlJOsure)' revealedno evidence of harm
`to th'e'fetus' due to oxybutynin chloride. The safety of
`OXYTR,OL administration to women who are or whOinay be(cid:173)
`come pregitluit' has' not been· established. Therefore,
`OXYTROL should not be given to pregnant women unless, in
`the judgment of the physician, the probable clinical benefits
`outweigh the possible hazards" ..
`Nursing Mothers
`It is not known whether oxybutyriinis excreted· in human
`milk. Because many drugs are excreted in human milk, cau(cid:173)
`tion should be exercised whenOXVTROL is administered to
`anursing woman.
`
`OXVTROL (3.9mg/day)
`(N~121)
`to
`
`ill
`
`4.3%
`
`17
`
`14.0%'
`
`1.7%
`
`1.7%
`
`0.0%
`
`0.9%
`
`0.0%
`
`~Q
`' , 5
`
`4
`
`4
`
`3
`
`8.3%
`
`4.1%
`
`3.3%
`
`3.3%
`
`2.5%
`
`Application
`site pruritUs
`
`Application
`site ~rythema
`
`Dry mouth
`
`Constipation
`
`Application
`site rash
`
`Application
`site macules
`
`5
`
`2
`
`2
`
`0
`
`1
`
`0
`
`0
`
`0.0%
`
`Abnormal
`vision
`* includes adverse events judged by the investigator as pos-
`sibly, probably or defiriitely treatment-related.
`
`3
`
`2.5%
`
`Other adverse events reported by > 1% of OXVTROL-treated
`patients, and judged by the investigator to be possibly, prob(cid:173)
`ably or defiriitely related to treatment include: abdominal
`pain, nausea, flatulence, fatigue, somnolence, headache,
`flushing, rash, application site burriing ,and back, pain.
`Most treatment-related adverse. events w.ere described, as
`mild or moderate, \II intensity. Severe application site reac(cid:173)
`tions were reported by ,6.4% ofOXYTROL-tteated patients in
`Study 1 and by 5.0% of OXVTROL-treated patients in Study
`.
`~
`Treatment-related adverse events that resulted in discon(cid:173)
`tinuation were reported by 11.2% Of OXVTRbpreated pa(cid:173)
`tients in St'ldy land.l0.7% of ()XVTR()L-treate(l patients in
`Study 2. Most of. these were secondary to application.site
`reaction. In the two pivotal studies, no patient· discontinued
`OXYTROLtreatmentdue to dry mouth.
`'\
`In the open-label extension, the' most common. treatment(cid:173)
`related, adverse eveniswere:applicatiol)t site. pruritus, ,ap(cid:173)
`plication I!ite erythema and dry mouth. '
`
`.Confinued,Qh;nexf.page
`
`Consulf20 04PDR® supplementsand-.futur~'editions for ,rev,isions
`
`Study 2 was a randomized, double-blind, double-dummy,
`study of OXYTROL 3.9 'fig/day, versus active and placebo
`controls conducted in 361 patients. ·The 12-week double(cid:173)
`blind treatment included an OXYTROL dose of 3,9 mg/day,
`an active comparator, and placebo. The majority of patients
`wer" Caucasian (95%) and female (93%) with 'a mean age of
`64 years (range, 18 to 89 years). Entry criteria required that
`aU patients have urge or mized incontinence (witha pre(cid:173)
`dorinance of urge) and had ~chieved a beneficial r~Jponse'
`from the anticholinergic treatment they were using at the
`time of study entry. The average duration of prior pharma(cid:173)
`cological treatment was greater than 2.):,ears. The pati~nt's,
`medic,al history ,¥,d a 'urip.py, p;ary d1l!ing the treatme",t(cid:173)
`free b!lseline period confirmed the diagnosis of urge incon(cid:173)
`tinence. Reductions in daily.incontipenc~ episodes; urinary'
`freql'ency, ap,d ur;inllfY void volume, Petween placebo .and a~- .
`tire tre!'<tment gio.upsare~lll?"!lID.z,e,d in Ta,ble 3.
`
`Table 3: Mean and median change from baseline, to end of
`treatment (Week 12 or last observation carried forward) in
`incontinence episodes, urinary frequency, and urinary void
`volume in patients treated with OXYTROL 3.9, mg/day Jl.r':' (
`placebo for 12 weeks (Study 2).
`
`Parameter,
`
`.;.
`
`placebo
`(N=H7)
`
`OXYTROI,.;3.9mg/day
`(N=121) i.· ..
`
`'.
`
`Mean. I Median
`
`(SD)
`
`.:
`
`Daily Incontinence Episodes
`
`. ,Baseline
`
`5.0(3.~)
`
`.{
`
`4.7J2.9)
`
`4; ,
`
`Reducti()n
`
`2.1 (3.0)
`
`2
`
`2.9(3.0).
`
`3
`
`p'value vs.
`placebo
`
`Daily Urinary Frequency
`
`Baseline
`
`.
`
`12 .. 3
`(3:3) ,
`
`0.0137*
`
`12
`
`12.4 (2.9)
`
`, I;teduction
`
`1.4 (2.7) .
`
`"
`
`1
`
`1.9 (2.7)
`
`P valuevs.
`placebO'
`
`.c..
`
`f
`
`0.1010*
`
`Urinary VoidVolume'(mL)
`
`12
`
`2
`
`160
`
`NOVARTIS EXHIBIT 2052
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 4 of 5
`
`

`

`3370/WATSON
`
`Oxytrol~ont.
`
`OVERDOSAGE
`Plashla' cql1cen~a:tioiJ. of oXybutYriID; dec1iiHis withlll.·l to i 2
`. hours after removal of transdllrmal system(s). Patfimts
`shouid be monitored i:ultil ~ymp~oms resolve. Overdosage
`with .oxybutyilin has beeri a'ssociated with (illticholinergic
`effects inclllding CNSexcitation; fiushing, fever, dehydra(cid:173)
`tiol1? cardiac'llrihytI4Wa, vomiting, and' urinarYre~ntion.
`Ingestion of lOO~ior81'OifYbul;yuin chloride in associatiOn
`with alcohol has:Been'reported ina 13 year old boy whO ex(cid:173)
`perienced memory loss, and in.a 34 year old woman whi>
`developed stupor, followed by disorientation 'and' agitation
`on, a:wl!keuing"dilated .pupils, dry.skiIl'icar,diac arrhythmia,
`Nld retention of urine. Both,pati,wtfuecovered ·£ullywith,
`symptomatic ~e!ltment.
`DOSAGE AND ADMINISTRATION
`OXVTROl.: shohldbeapplied to dry, intact skin onthe ~bao'
`men, hip, ot buttock. A riew application site should be se(cid:173)
`lected witheach,nevJ'sy'gtem to a:"oid re-;"pplicati~ri to the
`samesi~~tl).in'7.,4;'Ys ....... ',.'
`......... '" . ' " . , ......
`.
`The, dose 'Of,OXYTROl is one' 3:9 mg/daysystemapplied
`'. i'; . " j '
`tiCicf!~eek!f(~~ery'~:kb4 days): .' ,"
`.
`HOWSUPPlJED i,
`OXYTROL 3.9 mg/day (oxybuty'riii:rtransdermal'system).
`Each 39cm2gystemii:oprinted with OXYTROL 3.9 mglday
`contalhS.'36irig'm<y]jutyoin for nominal' delivery 0(3.9rog
`oxybuty,un 'pet 'daY whel): dosed in il'1;wjce weekly reg;meh.
`NDC 52544-920-08
`Patient' Calendar Box of 8 Systems
`Storage
`Stor~'at.25;q.(77°F); excursions"permitted £0 15'-'30°C
`(59-86°l?):Pi-6~~ctfrom moisture arid humidity. Do not store
`outside the sealed" lJOuch. Apply ii:omedlately after removal
`fronithe protemvejiouch: Discard used OXYTROL in house(cid:173)
`hold tr"sh in a maJ¥ler that.prevents accidental'"p~lic"j;ion
`or ingestion by children, pets, orothers.
`. .
`WAT!!()N Pharm'a; Ire.
`; . ' ; ;
`A Subsidiary of Watson Phairnaceu.ticals, mc.
`Corona, CA 92880 USA
`DATE OF ISSUANCE: FEBRUARY 2003
`U.S. Pat~nt Nos. 5;QOl,839and5,834>010
`Shown in Product Identification Guide, page ':139.
`
`.rr ' .
`
`TRI-NORINYL®-28
`(norethindrone and ethinyl estradiol)
`~orlly
`Patients should be c()unseled that this product does not
`protect against HIV"iritecitlon (AIDS) and otlier sei<iJally
`transmitted diseases.
`ORAL-CONTRACEPTIVE AGENTS
`DESCRIPTION
`Tri-NoiinY/:28 provi!les.a continuolls oral contraceptive reg(cid:173)
`imen of 7 blue t~blets; 9 yellow-green tablets, 5 .more blue
`tablets, and then '\ orange tablets. Eae!), blue tablet contains
`norethindrone 0.5'mg and ethinyl estradiol 0.035 mg, each
`yellow-green tablet 'contains 'norethindrone i. mg and
`ethinyl estradiol 0.035 mg, and each orange tablet contains
`inert ingredients.
`' .
`Norethindrone is a potent progestational agent with the
`chemical name 17-Hydroxy-19-nor-17a-pregn-4-eI)-20-yu,3-
`O)1e. Ethinyl estradiol is an estrogen with the chemical
`name 19-Nor,17 a-pregna-1,3,5(1O)-trien-20-yue-S,17 -diol.
`Their structwal formulse follow:
`.
`
`C O~"'CH
`
`.HH3
`
`H H
`
`.
`o· ~
`. norethindrone
`
`o£P' . H.
`. -'1rP":"
`
`HO~~
`
`ethinyl estradiol
`
`The yellow'green TRI-NORINYL tablets contain the follow,
`ing inactive ingredients: D&C Green No.5, D&CYellow No.
`10, lactose, magnesium,stearate, povidone, and starch.'
`The blue TRI-NORINYVtablets contam the following inac(cid:173)
`tive ingredients:FD&C Blue No.; i; lactose; magnesium
`stearate, povidone, and st~ch. ' , . . .
`..
`The inactive orange tablets in tbe' 28-day regimen contain
`the following lnactiv.e ingredients: FD&C Yellow No.6, lac(cid:173)
`tose, magnesiUIIl stearate, povidone, 'arid starch.
`CLINICALP:HARMACOLOGY:
`Combination oral contraceptives act by' suppression of gona(cid:173)
`dotrophins. Although the primary mechanism· of this action
`is inhibition of ovulation;·other·altetations includllchanges
`in the cervical mucus (which increase.the difficulty ofsperm
`entry into the uterus) ahd the endometrium (which may re(cid:173)
`ducethe'likelihood of implantation).
`
`PHYSICIANSf,DESK REFERENCE®
`
`Table 1-
`
`Percelltage' of women /axperiencing an WJintended pregnancy'during tbe first ,yeru:of tYPical· use ,and·:theAitst
`ye8l" of perfect use of contracepti6n and tb~ percentage continuing use,at the end· of tbe first year. :United
`'States.
`
`'0/" ofWo'1'en Experiencing an.Unintended
`Pregnancy:Withinthe First Year of Use :,
`
`Method
`(1)
`
`85
`26
`25
`
`.19
`
`40