`
`fl
`
`If Ewrug News
`2!! 33A @ppmwm i?
`14 mbmfl Updmficws and CM“?
`
`
`
`\
`Advcme J.’ MK; 1% Var»? i:.?)«::1j;»t»c-:¢rrffirm,
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`
`Page 1 of 10
`
`SLAYBACK EXHIBIT 1037
`
`Page 1 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`ED I TION
`
`2012
`
`PHVSCANS'
`DESK
`REFERENCE®
`
`CEO: Edward Fetsch, MD
`President: Richard C. Altus
`Chief Medical Officer: Steven Merahn, MD
`Chief Technology Officer: David Cheng
`Chief Financial Officer: Dawn Carfora
`
`Senior Vice President, Publishing 8c Operations: Valerie E. Berger
`Vice President, Emerging Products: Debra Del Guidice
`Senior Vice President, Product Sales, Corporate Development 8c
`General Counsel: Andrew Gelman
`Senior Vice President, Sales: John Loucks
`Senior VIce President, Product Management: Lucian Taylor
`VIce President, Business Development: Tom Dieker
`
`Director of Sales: Eileen Bruno
`Senior Business Manager: Karen Fass
`Senior Account Executive: Marjorie Jaxel
`Account Executives: Nick Clark, Carlos Cornejo, Michael Loechel,
`Hitesh Mistry, Gary Naccarato
`Director, Regulatory Solutions: Chris Thornton
`
`Senior Director, Operations 8c Client Services: Stephanie Struble
`Director, Clinical Services: Sylvia Nashed, PharmD
`Director, Marketing: Kim Marich
`
`Client Services Manager: Kathleen O'Brien
`Manager, Clinical Services: Nermin Shenouda, PharmD
`Senior Drug Information Specialist,
`Database Management: Christine Sunwoo, PharmD
`Senior Drug Information Specialist,
`Product Development: Anila Patel, PharmD
`Drug Information Specialists: Pauline Lee, PharmD;
`Peter Leighton, PharmD; Kristine Mecca, PharmD
`Clinical Editor: Julia Tonelli, MD
`Managing Editor: J. Harris Fleming, Jr.
`Manager, Art Department: Livio Udina
`
`Senior Director, Content Operations: Jeffrey D. Schaefer
`Associate Director, Manufacturing 8c Distribution: Thomas Westburgh
`Senior Production Manager, PDR: Steven Maher
`Senior Manager, Content Operations: Noel Deloughery
`Senior Index Editor: Allison O'Hare
`Index Editor: Julie L. Cross
`Senior Production Coordinator: Yasmin Hernandez
`Production Coordinators: Eric Udina, Christopher Whalen
`Associate Manager, Fulfillment: Gary Lew
`Web Operations and Customer Service Manager: Lee Reynolds
`
`Copyright© 2011 PDR Network, LLC. Published by PDR Network, LLC at Montvale, NJ 07645-1725. All rights reserved. None of the content of this publication may be
`reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise)
`without the prior written permission of the publisher. Physicians' Desk Reference"' and PDR"' are registered trademarks of PDR Network, LLC. PDR" for Ophthalmic Medicines;
`PDR"' for Nonprescription Drugs; PDR"' Pharmacopoeia; and PDR"'3D are trademarks of PDR Network, LLC.
`
`ISBN: 978-1-56363-800-8
`
`Page 2 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`.Atilb~ ..
`IJ\frl!~id!ll\e I:ICIJ
`,
`.
`ti!!Jl!I1S fpr&ral, a.d\Tiini!ltrli.tiqn
`
`• If your COPD ~:>:tnptoms worse'ri over tjme'donotincrea~e
`·your dose of BROVANA; 'instead cllll your Jiealthcare 'pfo-
`yider ... ·
`, ..... · ;
`.·
`·
`·
`· '
`· ··
`'
`• Increased blood pressur9
`•.·Fast orirreJNlar .heartbel!~ .,
`. ;u.
`. ··••
`. .
`•.serious .allergic re11ctions ·iocluding .rash,. hivas, s\1\!elling
`·of the face, mouth; and·tongue, anil breathing problems.
`Call your hea:lthcare provider 'or 'get •emergency; medical
`care if you get any symptoms of a slllious allergic reaction.
`Common sicle.effe~~ of B~OV~NA inclu'c!e: .. ·.
`' .
`• chest.or.backpain ·
`,; diarrhea
`··: •
`• sinus congejltion
`• headache
`• tremor
`, n~~~u~n~ss
`~'ill~ ~rlui\P's ·
`• high blpo'! I?!'J,S,Si!J~,
`~ sl!or:tness of· ~re11th;.
`· •' :•· · ·
`~·rash · ··
`
`• vOmiting'·· t\\/>~0
`• tiredness · ,.; •: , ·
`oleg .• Wellihg<:
`• chest. congl\stjon or b~onchitis :
`Tell your Ii'eaithcarHrovider'if}ou get any side ~ffect·.t~.a~
`bothers you or that does not go away.
`· · · ' ' '
`
`These are not<all the side effects with ~ROVANA;Ask yotit
`healthcare prd\'ider or pharma'cist>for'Alore 'iilfiwma:tion.
`Call your doct6r 'for medical advice about side.•efi'ects; You
`may report side eft;~cts to,FDAat' f•BO,O•FDA~1088."L •
`. . · · · :· .. tH,. · ·
`·
`How $holiltf'I'Store BROV~NA?• ,.,,.
`• Store BROV.(\NA m•a refrigeratoi. between:· 36" to'46'F (2'
`to 8'C)>iii tile: protective fbi!• pouch; .Protect from light and
`· excessi~e·hliltk oo·notbpen·a sealed•pouch untikvou'llre
`ready to use a dose of BROVANA. After operting the
`pouch,< unused ready-to•use vials should 'be•returned tCi,
`and'stored•lhi-lh~"pbuch.:An•opened''ready'td'use vilil
`should be used right away. -BROVANA may' be• used ·di'
`'· ·'•·
`' ·;::,.,..,,
`.
`rectly from the refrigerator.'
`•13ROVA:NX;may also be· itorea·at room"t~mperattirl3 he'
`tween 68'F to 77'F (2o•eio'25'CNornp·to6 'weeks C42
`days). If stored at room temperatiire;discatd ~ROVANA if
`'•it IS'llOt used .after 6 wee~ or if past the eJl:piration date,
`• whiche~er is sooner. Space is provided ou the packaging'to
`record•room•te'mpera"turestorag~tinies."''~' "''' · •r. :,.
`••Do ftbt 'USe 'BROVANN after•. the' expir~tion date' provided
`on the <foil j)ouch !tiM' read:y'2to'use via.Jtw " '
`• BROVANA should be coibi-less! Discard 'BROVANA ifit is
`. . . ·,;,
`. . · . . ~;~ ', l\ J
`P:o~ 'C~lo'H~~J.
`~\
`. · ( ·
`• Ke~p'BROVANA'arid a.ll medicirtes'out of tlle·relich of chil-
`··citeil/'":
`''.
`· ·"' ...... ,,
`GenerallnJor"!ation ~bout BROVANA '• • '' > . . ..
`MediCines are 'scinietfro'es prescribed for illni>oses ·not m~n::
`tioned in a Medication Guide. Do not use BROVANA:for a
`
`Tablets: 40 mg and 80 mg (3)
`
`Page 3 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`··~» ·}.'[',~ ,,
`
`n~~ 'i~~<~~._=·IJ>
`Jj.c:.·",.·t,- :·'!~.'/",.
`,,hvAi:iNiNG:l!,JNORE;\SEiliM:oni.vAiirJ,iY,iJN!::E~;c
`OiDERL1liPATIENTSiWITHDEMENTM·REliATED;>;
`ci~SY,,CHOSIS,I:l'i"i",i!,",r~o:;1c;,;{,flil !,;;lJz,,,;.i\nc;
`. 0r;§;;':
`"' elili!r19Vp'atiei\t~· ,with'''tli!'t'~rit'ili<relilt«a'' psychosis'' 1
`·· ~r.e~\eil V.ith' ~ntiJ)s~c@jic :arLiiJs ~rl' ~t. an, in~rdilsEilt1l'
`'"tisk'otraeatht'Aniilyll'li'Siof'17'"PIIlcel;lb"ai:\lllrolled'trials·
`fl±(i'rio"at~~rlitiOifoiiifiiWijtiksli lar\Jii!Y, rlf'''ftierit!i' tak''' • ·
`i'rll~g"litYpica'ii iiiltipsfl:Wotlc''lirti!Js;c rl'iViiiilitd••a''tisli cW'
`'death in dl'ilii'trilatadp\itients'bf b'illw'elin'1i6'tci1'1.7',
`ti~es; :the rlski of£\,feoth . in' pF6:ceb'o.!t~eilflld'piltients.'' ·
`f{yQ\.ter1th'e!liil:urlle71>f.,dJfY'P)cali10•weilk'cbrltrolled'trial;,
`·r'thetrateof:'tliiath·in'dfiili'treated'p:litiilntliWas;,~bbl!t·''
`~'24;5%(.i:oii\pai'eil {b 'ii'riitd'bf a})'QUt 2iilo/o ltfthe pJilcilbo "
`llr.oilp1'>iltli'o!lobi:tM' .ca!is'es•·ot. deatli''Wetli varteil/'.
`" 1moit1oHiie•tl"iitiJIIiapp'!1ahia til lil!'either caralovils'''
`·""'11111\i·r:'lili9;p1Jeart'f"i.llli'i1F'iluaa~l'l:aeatht,sor:•.li:ite~toilsln
`·,•r
`(e,g., pneumonia) in·naturl!.
`
`(e.g., e
`ti~~~E-)}~~1J(~lM~~ . ..... . . . ldLJ, "''" ·"
`5~··0; •:\V~.GS1Affi>,•ll~G:4l!!f~ON$JI;.•c
`5;t:;.',s.li)~rf!~•elli•MiirtlilitY,:,iiv·~l!lderly •• PatieM~·'''with.
`D&I)JIIOtia•flel!lted Psychosis'"''
`'.,.;,.,, ·
`:c~,, dr,
`Eld!lfiY Pati~tnts l/lfltiJ lillmantia·related,•psychcists' tr
`lll(it1H!nt!psy~!Joti9 .lirugs:!lre.l!t a.ifillctlla(•a;rj~k;of de
`t~l;llPN•iil !l'l.cifl1'1).flPrb9;1lli'~" thetrllatrlient•of<'demeh
`rll!lltild1J)sych~~~s:'!:lllle'~ox'~ld(arning!: ,;, ';i: ;•;,,L;i·Y•m;
`
`Page 4 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`Sel'jlm G)ucose
`(;;, 126 mg!dL)
`
`'lbtal,chol~sterol
`Triglyc~rldes
`
`'lbtai cholesterol
`(:i' 240 ill.g/dL)
`
`Triglycerides
`(;;, 200 mg/dL)
`
`All Patients
`
`·.:7.3%,
`(21/287) c.
`
`14.0%
`(37/264)
`
`8.7%.
`(17'1196)' .•
`
`LATUDA
`40 mg/day
`(n=358}
`
`0.67
`
`LATUDA
`LATUD'A
`120 mg/day
`80 mg/c:fay
`In~~~~~:.'
`. '.L. (n:):~~1l
`"1:14' ·.j.·
`
`.:Cer,l!brov(lscular, Ad.ver!le. )lel!cti.ops, . lnclu,dil!9
`~.2,.,
`Stro.ke
`..
`..
`.. .
`.
`.
`~n place)Jo-controlled trials wit,h risperiqone, aripip,razol~,
`ll,lld olanzapipe in e!l!erly subj~cts, ~t!lllemPntia, ~jlere was
`aJligher.incidence c:>f cerebrovascular a!iverse reactions. (ce(cid:173)
`r~bro.vascular lj.CCide~ts . .;uid tr{illsjent i~chemic 11ttaykS), in(cid:173)
`cluding fatalities, compar~d to pla,cebq,trell,ted subjects;
`l4,Tl/PMs not approved for the. t~~a~w,ept of p~tiePt~ w,ith
`dementia-related ,psyc!lOsi~ [see .. al~q .Boxed .Warnt;:~,g an.d
`}Vq,/:nings and Precautions (!j.'W,. · ·
`. · .' · · ·
`·
`.Neuroleptic Malionant Sy11drome . , .
`.
`5.3 .. ,
`A potentially fatal symptom complex 'l'loinetiines re(erre~ to
`as Neuroleptic Malignant Syndrome (NMS) has' been re:
`ported in association with administration of antipsychotic
`.,
`•.
`drugs, including LATUDA.
`Clinical manifestations o£NMS are,hypel'))yrexia; muscle ri,
`gidity, altered mental status; and evidence •of autonomie:in'
`stability (irregular pulse or blood pressure, tachycardia;.di(cid:173)
`aphoresis, .and cardiac dysrhythmia), Additional signs may
`include elevated creatinine' phOsphokinase, myoglobinuria
`,
`,
`(:~:hl'lb40myolysis), and a~u,te repl'll failure.. . , . ,
`The dillgnostic evaluation of pati~nts with' this syudroine is
`complicate!~. It js important to exclucle cases wl:J.ere the clip(cid:173)
`ical presentation includ.es ~9,thserio,us medical illpess (e.g.,
`pneumonia, systemic inrec#on) and untreated or inade(cid:173)
`quately treated extrapyramidal signs and symptoms (EPS).
`Other important considerations in.the differential diagnosis
`include central anticholinergic toxicity, heat stroke, drugfe(cid:173)
`ver, and primary central nervous system pathology.
`The management of NMS sl:J.ol;!ld inchc~de;;l);@.,medi~te di~­
`continuation of antipsychotic drugs and other drugs not es;
`s~ntial to concurrent th~rapy; .~) iptepsfy'l ~ympto~a~ic
`treatment and medical monitoring; and 3) treatment of a11y
`concomitant serious. medical,pro)J1~ms,for whic~ ~~ried.fic
`treatments are. ;J.vailable. T,here is rio ~:eneral aiireelllent
`about 's:p'ecific. pharmacological treatm~nt regimens fot
`•'' ··'I
`'
`'
`. '
`'
`NMS.
`.
`..• .
`If a patient requires antipsycho\iC druk treabiiimt after re(cid:173)
`covery from NMS, the'jlote.ntiaLreintroducti6ri'.of'drug ther(cid:173)
`apy should be' carefully consideted.lf.reintroduced, the pa(cid:173)
`tient should be carefully monitoredr stnce ·recurrences of
`NMS1 have been reported.· ·· ·
`, <. ,,.
`,,, ·
`· ,, .. ,.
`·ra{dive Dysldnesia '"
`5!4•
`Tardive dyskinesia< is. a. syndrome,consi~ting,of potentially
`irreversible; involuppary,,dyskinetic .. movements that• can
`
`develop in patients treilted· with· antij:uiy¢hotic drugs. Al(cid:173)
`though the prevalence of th~· syudro}lle ~ppe~r.s }9, b~ high;
`est among the elderly, espec1ally elderly women;·1tr IS Impos(cid:173)
`sible to rely upon prevalence estimates it'o t>tedict'; at the
`inception of antipsychotiC'treatment; which patients are
`likely to develop the syndrome. Whether antipsychotic drug
`products differ in their potential to,cause tardive .dYskinesia
`. :~; r
`is unknown.
`, .
`, ,
`. . .
`, ,
`, ... _ ..
`..· . · . ·:/. .
`The risk of developing tardive .dYsl,tine~ja a~:~!i·~e.lilj:elihop<).
`that it will become irreversible. (U'e ,bl,l)jeved to inc)·ease· as
`tl}e, c;lp~atio!l, qf tre\)-tme\1~ ,~d. tl:J.e, tRtal ,C~Ip.U.l~#'f~, dose ,.9(
`antlpsyc,hot!C dr.l;!g$ adnll!llster.e<,l to Abe p\l,tlent mcrease.
`Howev~r, tf?,e 's;Yilaroine ciili d~velop~ although much le~s
`comni6nly, ·after r,~latively,b'tief tre*t~~11t periods at low
`doses.
`·
`· ' ' · '
`·
`·
`·
`There is rio'knbWii'treiltmerit ·fof·established cases of tar(cid:173)
`dive dyskinesia, i altlibugh the s:yildrome' may remit, par(cid:173)
`tially or completely, if antipsycliotic treatment is with(cid:173)
`drawn. Antipsychotic. treatment, ·itself, however, may
`suppr~ssi(ot,partially suppress) the signs, and s:Ymptomsof
`the syndrome and thereby may possibly. mask the underly(cid:173)
`ing process. The ef!'ec.t,tl:J.at :sYffiPt9mlltic suppression has
`upon the long-term cQ\lrSe gf'the,syndrome is unk;l)own.
`Given these cmwid~ratiqns, J,.ATUJ:)A ~hqll,ld be prescribed
`in.a.m~er.tha,.~is ~o~t!Yffi!Y,.to, mjpi~jZj!,~l)e gcmwr.w,:t.ce
`of tard1ve dyskmesia. Chron\C . jln.tiP#y~ho~ic , tre~t~m~nt
`should generally be. reserved for patients who suffer from a
`chronic illness that(1) isj<:no\¥r to r~spond to j\P,tipsychotic
`drugs, and (2) for whom alternative; equallY effective; but
`potentially less. ~a~mf~l t~eatmen~s l'l'e. ;10~ a':aihtble ?r ap-,
`proprlate.•·In patients who dcr reqmre.chromc treatment;·the
`smiiJlest dose ilnd 'thiH\hortest duratioJ:l bf:treatnient pro•
`duCing a satisfactory clinical response should'b'e •sought.:
`~he.!keecl hr contiquecl treat~pt ollhoulcl.be.reE)S~~ssed pe-,
`,
`•. ,.,;; r,:·u.o,·-.:
`no\1\c~lly ....• :.
`h··i•.
`Jf signs I!Pd• sYmptoms of t.ar.ffiv,e, dyJl'"!lesia ,appear in .a pa•
`tieqt qn :M.TV;DA, clrl:'g,.d(sce!ltill\latipJl,sl:J.eul!i b.e,cPilsid-,
`~red, :@:Qw!lver,:som.e. patients.m.aY·.wquire treatmellt.:witll
`LA'I'UI!A!lesnit.~tl:J.e Pr!'sepce,pf tl:!<;>. sYI\c:lr,!Jme. , , ; ,
`5.~·•f··, . .,Mlllll.i;!.PI.!p Chii!!Yilll·: ,,' ·;,,,;, ;,
`:·•'·
`·'"'·
`AtypjcJll®Hj),sychqtic drugs .l:J.I!ve; )Jeen. aj!S9C.il\te,d. :with
`met . .WoJjc,~h!ll)ges ... t!mt. m11yJncrease canliovascJI!!lr(cere(cid:173)
`brqvascular. rjslj: . .:rhese. m~ta)JQ\ic' CPI'!llgejl ;il;\c!nde . hyper'
`~I:Ycemia, dyslipidemill, .an<!l>ocly :w~igh,t,gain., Wl:J.jll\ all of
`the.clrugs ,Jn ti).e;cJI'!sS h;J.ve, keeli\:§h9wll .tP·Pro!luceclll>me,
`metabo)!c. chapges, .ll!lch ,dr).lg, hlls:its,qw!l, specijig. ri~]l;,pro~
`file.
`
`tieilts1 .versns 4.lJ%.ror· pJacE~!loetrc;R~eapa,ctellts.
`[See table.ll.abovel-' . ,,.,;,wP.i>Jil;;.
`In the uncontrolled, lon,iC~r;tprm studies (primarily
`label 'extension studiM1m'IJNI.lU.DA•was associated
`mean change in weight.of;'0.38·kg. at..week .24
`·0.47.l<g. at week 36 (n=303)nand.,0,71.kg ·
`(Il:;244),.
`~~th~rC!JIZY!;~3rtTr.~ta/ioni~~·a~parlitne1
`. LATUDAelevates prolactin leyels:
`·
`Hyperptolactinemia may suppress 1\ypothalamic
`suiting in r~duced pituitary gonadotrophin
`in ,turn: may inhibit 'reproductive furicti.on'bv·iilipai
`nadal steroidogenesis in·both female and
`lactorrhea, amenorrhea; gynecomastia;
`been reported with prolactin-elevating corlipc>un.ds.
`standing•hyperprolactinemia;wheri'as.sociated,wi,~h
`nadism may lead to decreased bone 'density in both
`and:malepatients{see.A.dverse Riiactio,ns (6}].,
`In short-term, placebo-coritrolled studies, the·
`change ifronHbil.lielincMo endpoint iJ:l, prollictin
`LATUDActre&ted patients was 1.1
`.. in the p!~ccetJo-t;reEttgg
`
`Page 5 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`·sqai,,&J;:AlUDA,,,
`.:All .. 1'!19lday
`YK·t;,,:\~~~~'.~ _
`
`(n=351)
`,,.o.9
`b1=llll)
`
`-0.5
`-1.2
`0.5 .· .
`. ,{ll,"f!;l2ll)lii:o ·l 'f'"• 1f!•.•iJ.i;{~?5J);ulv:n~·;·,"l '/1
`1 .(m;gp2)iD•.('' ri
`
`1
`.,
`i •
`
`·~:~n¥,'M1R1r,~ilf~lfli'{2t1t7cl~~~;~~~~m':;
`Wg~niltits'!ilia'PrJcafltiBiis (9!1JJ]'1
`etes 'Mellihi!Nsei!'Wai'li!ngU liftd"
`':Jvi:te.>n :HU Jirii.'ltt<t.:rJcm ':c'; ;,jx_gd
`··warnings u:IIH.1Jrecautibns,(/Ji6)l·
`opel!, a,. eutropenia, and Agranuloeytbsis-£see.1%nw·
`ings and PteC(!Utjof!S (5:c7J),)tJIGij'A':t ?nibuiil l!'l8ii•1!11
`,:!;,(!
`•.. Otthost!)tiellJypP.teilsioii;..and,S:Yn~.oPe;[~J!sW(IrliitiiJa'a7Jilr
`PJJJI'!JautioJISi,(/i;8ji,dt'J v:: ;,•;;i,,n•. ~;;cil,;;i·,.uri·ln,q )f;lfinJm•o
`•'Slliozure~ls~W,WCli!ntngs.antJ, l;'r¢i;Clutiol!JjJ{/UJJlr·!i /,Ucfl\b,J
`• Potentiai for Cognitive lmd Motor Imp~HsgeGWamo 1
`ings andrPneebutiomJi{/iJJ))J,,.,."'"ht; b!i'"''";o '''"""'"'"'";
`~,;apdy .~.m'peMtllre,.RlignlaJ;ioJl.;[Be/!.r Wan»ings,a,ndr&cau:rr
`c;t·iQ'(tslfitll)]t;J /;'f,fk?r? f:rd;J ,'·::yiJ -~'j (H:>t12q , ~ f' < odts:tHf~i '1-·,
`, ~ Sui~id~~[pe~,,War.»ill/?P;{Jil!d[lJ:e.cautions,(6i1:2JJ, r'.f :: k;dNu,
`; ~t0ysphagiaf£$eeriW£U'ni!lt's· a/UkrRr~aJJtion81(6il8l1 'm"''b'
`•.l./Jjeri!lr.Pati'lli~'With 0oncol))itant!Illllesss[see :WanntngsT
`anrJ)/lJ'f!.CaUtWI1JI)(i)_;J,4)},{,r !0:;Jj; i lfr · ( 3i'fr·\t£ ). #!'(£,;]! cHXKrC?.ri' ;i'
`The i!JionnationibelQWrisl'derivedd'romr a .. cllllical ,study:;da-i'
`: ·tabru:;e,forsLA'llJlQa ·,consistibgco~: ovex !209(); pattents• 1withr
`; · sciJj!l;ophw,llilirel!PPsedM:.one,,or!mor.e <loses. with: ato:tal:e1h ·
`; ,pel'ience ,of:62.!i patient:years. Of these patients;;Jl00.4Jparr11
`, tidpl\tadnilt'cahoxt~tllrm,t placeboico.ntl;qlledtschizwhrrllnia<.;
`;.stlldifisf)wjthr,do~.esrofr2.0,mgrr40.mgf>'801rogol'Jl:20,rog101J.ceri
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`Page 6 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`Adverse Event Term
`
`Akathisia
`Somnolence*
`
`Placebo
`IN:455)
`(o/o)
`
`3
`10
`
`Percentage of Subjects Reporting Reaction
`LATUDA
`LATUDA
`LATUDA
`20 mg/day
`40 mg/day
`80 mg/day
`IN: 71 )
`(N: 360)
`IN::282)
`(%)
`(%)
`(o/o)
`
`6
`15
`
`11
`19
`
`15
`23
`
`LATUDA
`120 mg/day
`IN:291 )
`(%)
`
`22
`26
`
`Note: Figures rounded to the nearest integer
`• Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
`
`Table 8: Percentage of EPS Compared to Placebo
`
`Placebo
`(N: 455l
`(o/o)
`
`LATUDA
`20 mg/day
`!N=71 )
`(o/o)
`
`LATUDA
`40 mg/day
`!N: 360)
`(o/ol
`
`LATUDA
`80 mg/day
`(N:282)
`(o/o)
`
`LATUDA
`120 mg/day
`(N:291)
`(o/o )
`
`Adverse Event Term
`
`All EPS events
`
`All EPS events, excluding
`Akathlsia/Restlessness
`
`Akathisia
`Dystonia*
`Parkinsonism ••
`Restlessness
`
`9
`
`5
`
`3
`l
`5
`2
`
`10
`
`6
`
`6
`0
`6
`1
`
`24
`
`13
`
`11
`4
`10
`4
`
`26
`
`11
`
`15
`5
`7
`1
`
`39
`
`22
`
`22
`7
`17
`3
`
`FIND PATIENT SUPPORT RESOURCES at PDR 11
`2802/ SUNOVION • LATUDA
`--------------------------------------------------------------------·----T-----------~-------------------· et
`high occurred in 3.1% (30/977) ofLATUDA-treated Pati
`Table 7: Dose-Related Adverse Events
`and 1.4% (61439) on placebo. The threshold for high cr:~~
`nine value varied from ~ 1.1 to ~ 1.3 mgldL based on ~ 1•
`centralized laboratory definition· for each study [see Dos he
`in Special Populations (2.3); Use in Specific Populatiorr .. ('t{lf.e
`Transaminases: The mean changes in AST and Al,T 1·
`LATUDA- and placebo-treated patients were similar. ~r
`proportion -of patients with transaminases (AST and AJ.:re
`elevations ~ 3 times ULN was similar for all LATUn )
`treated patients ( 0.8% and 0.8%, respectively) to placet!:
`treated patients (0.9% and 1.1%, respectively).
`ECG Changes
`Electrocardiogram (ECG) mebsurements were taken at va
`ious time points during the LATUDA clinical trial progr~·
`No post-baseline QT prolongations exceeding 500 msec we ·
`r~ported in patients treated with LATUDA. Within a subs'~
`of patients defined as having an increased cardiac risk ~
`potentially important changes in ECG parameters were' 0~
`served._ No cases of torsade de pointes or other severe car(cid:173)
`diac arrhythmias were observed in the premarketing clini(cid:173)
`cal program.
`The effects of LATUDA on the QT/QTc interval were evalu.
`ated in a dedicated QT study involving 87 clinically stable
`patients with schizophrenia or schizoaffective disorder who
`· were treated with LATUDA doses of 120 mg daily, 600 mg
`daily, or ziprasidone 160 mg daily. Holter monitor-derived
`electrocardiographic assessments were obtained over an
`eight hour period at baseline and steady state. No patients
`treated with LATUDA experienced QTc increases > 60 msec
`from baseline, nor did any patient experience. a QTc of
`. > 500 msec.
`Other Adverse Reactions Observed During the Pre-
`6.6.
`marketing Evaluation of LATUDA
`Following is a list of MedDRA terms that reflect adverse re(cid:173)
`actions reported by patients treated with LATUDA at mul(cid:173)
`tiple doses of ~ 20 mg once daily during any phase of a study
`within the database of 2096 patients. The reactions listed
`are those that could be of clinical importance, as well as re(cid:173)
`actions that are plausibly drug-related on pharmacologic or
`other grounds. Reactions listed in Table 6 are not included.
`Although the reactions reported occurred during treatment
`with LATUDA, they were not necessarily caused by it.
`Reactions are further eategorized by MedDRA system organ
`class and listed in order of decreasing frequency· according
`to the following definitions: those occurring in at least 11100
`patients (frequent) (only those not already listed in the tab(cid:173)
`ulated results from placebo-controlled studies appear in this
`listing); those occurring in 11100 to 111000 patients (infre(cid:173)
`quent); and those occurring in fewer than 111000 patients
`(rare).
`Blood and l{ymphatic System Disorders: Infrequent: a·m!(cid:173)
`mia; Rare: leukopenia, neutropenia
`Cardiac Disorders: Frequent: tachycardia; Infrequent: AV
`·
`block 1st degree, angina pectoris, bradycardia
`Infrequent: vertigo
`Ear and Labyrinth Disorders:
`Eye Disorders: Frequent: blurred vision
`Gastrointestinal Disorders: Frequent: abdominal pain, di(cid:173)
`arrhea; Infrequent: gastritis, dysphagia
`General Disorders and Administrative Site Conditions:
`Rare: sudden death
`Investigations: Frequent: CPK increased
`Metabqlic and Nutritional System Disorders: Frequent:
`decreased appetite
`Musculoskeletal and Connective Tissue Disorders: Rare:
`.
`. . .
`.
`rhabdOmyolysjs
`Nervous System Disorders:
`Infrequent: tardive dyskiMsW,
`cerebr()vascular accident, dysarthria, syncope; Rare: m!Uro·
`leptic malignant syndrome, seizure
`Psychiatric Disorders: Infrequent: abnormal dreams,
`panic attack, sleep disorder; R• re: suicidal behavior
`Renal and Urinary Disorders: Infrequent: dysuria; Rare:
`renal failure
`Rewoductive System and Breast Disorders: Infrequent:
`amenorrhea, dysmenorrhea; Rare: breast enlargement,
`breast pain, galactorrhea, erectile dysfunction
`Skin and Subcutaneous Tissue Disorders: Frequent: rash.
`,
`pruritus; Rare:-angioedema
`Vascular Disorders:
`Infrequent: hypertension, orthostatiC
`hypotension
`7. DRUG INTERACTIONS
`Given the primary CNS effects of LATUDA, caution should
`be used when it is taken in combination with other centrallY
`acting drugs and alcohol.
`;.G
`7.1.
`Potential for Other Drugs to Affect LATUDA
`LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2
`DG
`2
`CYP4All, CYP2B6, CYP2C8, CYP2C9, CYP2C19, C'f!' of
`or CYP2E1 enzymes. This suggests that an interactto: se
`LATUDA with drugs that are inhibitors-or inducers oft e
`enzymes is unlikely.
`LATUDA is predominantly metabolized by CYP3A~; inte:;
`action of LATUDA with strong and moderate inhibitors g).
`inducers of this enzyme has been observed (Table
`
`incidence of akathisia for LATUDA-treated patients was
`15.0% versus 3.3% for placebo-treated patients. Akathisia
`appeared to be dose-related and the greatest frequency of
`parkin-sonism and dystonia occurred with the highest dose
`of LATUDA, 120 mgtday (Table 8).
`[See table 8 above]
`In the short-term, placebo-controlled schizophrenia studies,
`data was objectively collected on the Simpson Angus Reting
`Scale for extrapyramidal symptoms (EPS), the Barnes Aka(cid:173)
`thisia Scale (for akathisia) and the Abnormal Involuntary
`Movement Scale (for dyskinesias). The mean change from
`baseline for LATUDA-treated patients was comparable to
`placebo-treated patients, with the exception of the Barnes
`Akathisia Scale global score (LATUDA, 0.2; placebo, 0.0).
`The percentage of patients who shifted from normal to ab(cid:173)
`normal was greljttir i:n LATUDA-treated patients versus
`placebo for the BAS (LATUDA, 16.0%; placebo, 7.6%) and
`the SAS (LATUDA, 5.3%; placebo, 2.5%).
`.
`Dystonia
`Class Effect: Symptoms of dystonia, prolonged abnormal
`contractions of mJlscle groups, may occur in susceptible in(cid:173)
`dividuals. during the first few days of treatment. · Dystonic
`symptoms include: spasiD of the neck muscles, sometimes
`progressing to tightness of the throat, swallowing difficulty,
`difficulty breathing, and/or protrusion of the tongue. While
`these symptOms can occur at low doses, they' occur more fre(cid:173)
`quently and with greater severity with high potency and at
`higher doses of first generation antipsychotic drugs. An el(cid:173)
`evated risk of acute dystonia is observE)d in males and
`younger age groups.
`In the short-term, placebo-cQntrolled clinicaJ trials, dystonia
`' occur red in 4,7% of LATUDA-treated subjects (0.0%
`LATUDA 20'mg, 4.2% LATUDA 40 mg, 4.6% LATUDA
`80 mg and 6.5% LATUDA 120 mg) compared to 0.,7% of sub(cid:173)
`jects receiving placebo. Seven subjects (0.7%, 7/1004) dis(cid:173)
`continued clinical trials due to dyston,ic events - 4 were re(cid:173)
`ceiving LATUDA 80 mg/day and 3 were receiving LATUDA
`120 mg/day.
`.
`6.6.
`Laboratory Test Abnormalities and ECG Changes in
`Clinical Studies
`Laboratory Test Abnormalities
`In a· between-group comparison of the pooled data from
`short-term, placebo-controlled studies, there were no clini(cid:173)
`cally important changes· in total cholesterol measurements;
`triglycerides or glucose from Baseline to Endpoil\t [see
`Warnings and Precautions (5.5)]. There were also no clilli(cid:173)
`cally important differences between LATUDA and placebo
`in mean change from baseline to endpointin routine hema(cid:173)
`tology, urinalysis, or serum chemistry. LATUDA was associ(cid:173)
`ated with a dose-related increase in prolactin concentration
`[see Warnings and Precautions (5.6)].
`CreatiniiU!: In short-term, placebo-controlled trials, the
`mean change from Baseline in creatinine was 0.06 mg/dL
`for LATUDA-treated patients compared to 0.03 mg/dL for
`placebo-treated patients. A creatinine shift fi-om normal to
`
`Note:. Figures rounded to the nearest integer
`• Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis,
`and trismus
`** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder,
`hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor
`
`cation discontinuation. There was no attempt to use inves(cid:173)
`tigator causality assessments; i.e. , all events meeting the
`defined criteria, regardless of investigator causality are in(cid:173)
`cluded. It is important to emphasize that, although the ·re(cid:173)
`actions occurred during treatment with LATUDA, they
`were not necessarily caused by it. The label ·should be read·
`in its entirety to gain an understanding of the safety profile
`ofLATUDA.
`The figures in the tables and tabUlations cannot be used to
`predict the incidence of side effects in the course of usual
`medical' practice where patient characteristics and other
`factors differ from those that prevailed in the clinical stud(cid:173)
`ies. Similarly, the cited frequencies c11-nnot be compared
`with figures obtained from other clinical investigations in(cid:173)
`volvi'lg different treatment, uses and investigators. The
`cited figures, however, do provide the prescriber with some
`basis for estimating the relative contribution of drug and
`nondrug factors to the adverse reaction .incidence in the
`population studied.
`Clinical Studies Experience
`6.2.
`The following findings are based on the short-term, placebo(cid:173)
`controlled premarketing studies for schizophrenia in which
`LATUDA was administered at daily doses ranging from 20 ·
`to 120 mg (n=1004);
`Commonly Observed Adverse Reactions:. The most coni(cid:173)
`man adverse· reactions (incidence ~ 5% and at least twice
`the rate of placebo) in patients treated with LATUDA were
`somnolence, akathisia, nausea, parkinsonism imd agitation.
`Adverse Reactions Associated with Discontinuation of
`Treatment: A total of 9.4%.(94/1004) LATUDA-treated pa(cid:173)
`tients and 5.9% (27/455) of placebo-treated patients discon(cid:173)
`tinued due to adverse reactions. There were no adverse re(cid:173)
`actions associated with discontinuation in subjects treated
`with LATUDA that were at least 2% and at least twice the
`placebo· rate.
`Adversa.Reactions Occurring at an Incidence of 2o/o or More
`in LATUDA-Treated Patients: Adverse reactions associated
`with the use of LATUDA (incidence of 2% or greater,
`rounded to the nearest percent and LATUDA incidence
`greater than placebo) that occurred during· acute therapy
`(up to 6 weeks in patients with schizophrenia) are shown in
`Table 6.
`[See table 6 at top of previous page]
`Dose-Related Adverse Reactions
`6.3.
`Based on the · pooled data from the short-term, placebo(cid:173)
`controlled, fixed-dose studies, among the adverse reactions(cid:173)
`that occurred with a greater than 5% incidence in the pa(cid:173)
`tients treated with LATUDA, the apparent dose-related ad(cid:173)
`verse reactions were akathisia and somnolence (Table 7).
`[See table 7 above]
`Extrapyramidal Symptoms
`6.4.
`In the short-term, placebo-controlled schizophrenia studies,
`for LATUDA-treated patients, the incidence of reported
`EPS-related events, excluding akathisia and restlessness,
`was 14.7% versus 5.1% for. placebo-treated patients; and the
`
`FREE CME AND LIABILITY REDUCTION SERVICES at PDR.net
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`Page 7 of 10
`
`SLAYBACK EXHIBIT 1037
`
`

`

`Should not.oe
`· 9-tin\:es·'
`JATUDA.alone coadministered
`wit~ LA.TUD,A.
`
`~.2'tiines
`Lf\TUDA alone
`
`LA.TUDA dose·
`shpuld 'not· ex~eed' ·
`4~ mg/d~y if ·
`. icoadtfiin:isJkted•·' Y<£,
`---~ lt5th':~f,":.:,, :;: ~ Sh~~ICFnbt"be'~;. ~,.f.,.:\.,~-:.
`LA.TU:OA alone' coadm\nis~ered
`with LA.TUDA
`
`).::''}'
`
`"'"i>''
`
`, '1/7th,of- i;,J-
`
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`
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`w~ · 't{/A·
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`' iui!L m,igh~h~Lailc).iti~l'iFJI.dl}ose ,ofLATUDA,res:Ult,Y'!g Jifti
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