PDR®
`55
`2001
`
`EDI TION
`
`PHYSCIANS'
`DESK
`REFERENCE
`
`111M ~ IIOIM IIIIMI MllltoettftC: Oikran H. BatSarnian
`lllltbt., S.... llillolftapf, ~ s.lea: Anthony Sorce
`~ ~ ~-tf"'n~ KN1<.,..,..1<y
`
`Aecoolnt M.......,
`
`Serllor Aaeoelalte EMtor. Lo<i Mu<ray
`~ Edlter. Gwynnect L Ke~
`o -.. l>onet 1111__,., Ill ICI1ael """"""
`OINct M.U M ......., I.OrTaine M. L0«1.ng
`Serllor M..utlnC Analyet: Dina A. Maeder
`DINctor of PlodiiCtlon: Came Williams
`Data M., ... r: Joffmy D. Schooler
`Productloft M......-: IVTry 8¥o0ka
`P!Odvctlon Coord'"-: Glanno Coradonna, Do. Ann OeRuvo,
`Melissa Katz
`Index kpenlleor. Johanna M. Mazur
`Index £Aitot: Shannon Rekly
`Art Aaeool-: Joan K. Akor11nd
`Dtcttall.,..,nl SupeNiaon Shawn W. Cohill
`DIIJt.oll,.....nc COO«<I!Wite>r. Fronk J. McElroy, Ill
`~IMI CooniiNrlor: Mery Keodon
`Electronic PubllahlftC 0..~ LMo Udtna
`FUlfil - ~ Loula J, Bolctk, Stephanie OoHardl
`
`MariOn G!l!y. Rl'tl
`Lawrence C. Keary
`Suzanne E. Yerrow, RN
`N.UOIMII Sa ... ~~. Neclc.l Economtc. Tr .... S. ... :
`Bin Gaffnoy
`Senior .,...,_ ~ Mark S. Rltehin
`n.t.nd81 Analyllt WAyne M . Soltis
`Vlee PrMident. Clinical c-ncattor. end
`H-
`Bu.lneu O.wlo!MIM"t Mu~esh Menta. Rl'tl
`New llwllneu ~nt M..,...r. Jeffrey D. Duoln
`lnfOrmatkHI S.mcee: Thomas Aemlng, RPI1
`flll~~nacar. Drul
`DIUC lnlom lltlon Specla••t.: Marla Deutsch. MS. PharmD. CDE;
`Cl\ri:;Une W)ble, PharmD
`t llltof, Dl..ctoq S.rvlcee: David w. Sitton
`""''eo1 ~ Edward P. Connor
`M IIDICAJ.. ECONOM ICS ~02001 lOKI p.Jblbliacl by u...--~. Ire. at Menlllllt. NJ ~17<12. M IIQIU- I'IOne of
`- - --"""'1111-- --- - !h e -.. .,....-,mayiM>ropoduood, -.din a..-., cys...,,- , --...ct. Ot-ln-lonnow
`by..,- (olearonlc.. ..-...-. pl-tfoog. rooonlng. Of~ ........... p<tor- .,.,._ ..... pWIIIw.
`PtlR'. The PDR' Famiv Ouclt 10 PJNCripllon llr\.ol". The POR' l'am1y
`PHYSICIANS' OESX REFEFIEIICE". POll". -
`a.MM 10 w-·• -
`olld ~ Ofuvo', ard The P1JR' F.mty Gu.do 10 Nulridon olld Hee'tH"..., reg.stt<ld t~ used ho,.., ordlt -
`· POR lot
`~lie -...a"", PDR lot~ OfuQI anciCie!aly~"'. POR Colnoenion a.-"'. PDR Pnal1l\eCOI)C)Iie'• P<lctet Ed11on. POll" lor H«tleJ
`£,..,.,.,._.. .,,_ Cele"', The POll" Fanl/lf Guklo 1 0 - - an d Hel.-.g Thenlples-, The PDR" Fonrlly Guklo 10 Cornnon ......._,.., The PDR" Family
`.... POR f0<~ ~"'. PDR" ~ Dlellonary"'. P1JR' Nuu't ONg _
`.... POll" - • l>aolwy"'. The POR"FIIInlyGuklo
`_
`G.-10 o-~ ONoa"' tnd PDR" BeciiOftic linrl"., tralio!na>ks used-. ............
`
`_ . , . __ ~ --0Wt£xllal:we~Ccns8.-.;VIc:e ___ l. Solllma~ ---~-
`~ .......... M -Otif!IRtwlciltl()j!lofr:QinaoohefCafd: Vi<e-lll!d~8arryGf8¥; \.b-_ ""'"""'llDMII ~; SIAiorVi<e­
`o...tC<Y- ...... w ...... ----~JohnR..Waoe
`
`Dr.
`
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1016
`
`Exh. 1016
`
`

`
`3104/SMITIIIWNE BEECHAM
`
`lnfanrix-cont.
`IJU~loblo ~mlkide. After tnsertlon or the needle, a.sp.rltte l.o
`enAuNI that. lht:i needle ba6 not Eonten!C:I 31 blood ve&.!el
`Do not Q:dlnmister th1s prodod sobcu.taru"ously.
`Pnmnry ltrtmlmhtt.tion
`11uJ prlmnry i.mmunu.otion eourBc for children 1Ct48 \hon 7
`yeAl"' llfllge i& throo do!ieS or0.5 mL~ glv(l_n intrnmu.tteulort.r,
`nt. 4~ t.o S.Wcek intervals (prefernbly 8 wt.'fjks). 'rhlt cul'it.lJm·
`ary age for th_, O.r.;t doese is 2 montht or ngt~:, but iL mny bo
`giveo 8btrtmg at. 6 wK.ks of age and up Lo the gc;venth hinh·
`tl~y. lL 1!' n.'CC>rnmonded that ln(anri.% be riven for t'H lhretl
`~saan~ no lti.terchangeability d.a.u on a.cellu.lur IYM' vrtc--
`nncs eJtlSl for the pnmary seri~. ln{o.nn% mny be uHd t.o
`Mmpltot4! the pnmAry se~ in infnnhl wbo ha\'• tl"fttVtd
`one or two clo8eJt of whoJe.a.U DTP vacrinlf Howevtr. lhe
`safety and efficacy of l n{anrix. m 5UC:h tn!a.nte han not. bern
`ev•lualA!d.
`~~~r lmmu,.ualiiJII
`When ln{tlnru 1• gwen for- the pnJ'IUU')' .!tMlel. a fourth doM
`i5 rt'«<mmet~dc>d nl 15 to 20 months of ago. on,., U>U.rvol be-
`twcon th•llurd ond fourth dose • hould bo otleMt 6 nwnlha.
`~( ~v~~:l~,~~~~ futl~~:~e:Jhto d=:~~~~~~t~~u:~f.
`drtlf'l WhO hrtve previDU6ly teeei~ four dDSfl Of /tr(fl11fU.
`Jf ft. child h!ta received whole-cell DTP VJ).r.dne for one or
`more d~. /nfararix mey be given to complete the tlv&odAAe
`aerie&. A fourth d~ i~ ret:omme.nd!!d &t 15 to 20 nuu\th.8 of
`6gO. The int.orvnl botween. the third and fourth dOBe ~Jhould
`00 llt. lorUtt 6 month&. Children 4 to 6 yean uf nge (11p to the
`~vcnth birthday) wbo received aU four dotte.oe by the fourth
`birthday, intludln.g one or more doses ofwhol&<lt-11 OTT" tJllC·
`cine. 1thould roreive a gingJe dose of lnfonn% before t11tcring
`k.indftr"gert.en or elen::utot.ltry school Thi.t dose is not ocedad
`if the fOurth dOM W M given OD 0!' aJler the fouJ1h btrtbd•y.
`AdduU>ft.Q/ Do.lll/l /nfomu>li<m
`If an.y recommended dOI!e of ~rlu.sa:is va«intt t:nnoot be
`gwtm, JYr t f"or POOi:aO"'C Use) should be given as n~ed to
`comp~t.e Lbe toenes.
`ln10rrupuoo of the .....,nunended odlod~l• with a d•l.t.Y b.
`lween d01ta 1hould not interfere Wlth the finll tmmunity
`achieved waUl lnfomU. There is no need to ~~otnrt lhe ~rict
`over 8pJn. regardl~.ee of tbt! tim~ ela.~ betwten dOM!tl
`The Uf.!@ of n>duet..-.d volume {froc.t'iona.l d08es) i1 not retolD·
`m<lndcd. 'M\o tlfl't"a of a;~ueh prac.tices on t.he frequency or ...
`riou11 {advcnm evenllf and (In protection ognin!Jt. dftWniJ.O hu1
`not boon dat.urmined. 11
`Prcterm Infanta !hoold be vaccinated Het:orditiiJ t.a t.b(Hr
`ch.ronologicoJ age from bi.nh.11
`For pt!r&OM 7 yeara of ag6 or oJder. Tetanua and f>iphth.erill
`Tox.old_• iTd) for adoh use Mould be gi?en for routine
`boolst.er ammunization agamst tetaoWI and diphtheria.
`SimlllltJ.n«<u• Vacc:ine AdminisJroJion
`In ttinicat Lriab. ln{atull v.-u routinely adm,ni.Jtercd. en
`,...~nllil Sitos. oonromitanUy ""th one or 100«! of the follow·
`inl •attu~""' poliovuus vocci"" live tm~l !OI'Vl. bepouU. 8
`vcam.ne. and HOLmopfuhu influ•nzLJAt type b •a.cc:tne ( U1M
`t ... CUNICAL PHARMACOLOGY).
`No d,>'.a an .. ai!obn on the ti=rl""'- odm!n;odnlttD01
`of meMit!IJ, ruwnpi' and rubeUa 'i'IK'cine tMMRI, Yttnt:~ilo
`vaccine or Inactivated polio virus (]PV) with l1ifonru.
`When conc:omhant administration of other vnocinea t. ,._
`quire<!, they .should be given witb different syringtt~ pnd at
`ditTerent inj~tion ait.l!s.
`The ACif-' encoumges routine simtdtaneous administrtldon
`or accllul<tr DTP, OPV (or IPV!, !lib, MM tl und hep~~till• B
`vaccine for children who are at the- recommended n~c to ro·
`~ive tho&Q vaccines and for whom no specific contnlndica·
`ticaru erJtt nt \he time of the vil$it. u.nles~:, i_n the judgmaru: of
`the prov1der. complete vaccination of the cbJld w11l not be
`comprom•.sed by a.d.ministering vaa:inea at ditre.rant vit1t&.
`Simult-a.neou• ad.m.in.istntion i_fil particuta:rl, impGrtant if
`Lhe ctuld m.ght oot retum for subsequent vncdnations.. _.,
`STORAGE
`Store /nfa.nriz betwNn 2"and a•c (36•and 4fi:'P). Oo not
`ITHu. DiocaJ<I if ~ vaccine has been fr<nen. Do n<>t """
`Q;lteJ' e..-pirotion date shown on the label.
`JlOW SUPPUED
`tnra.nrix tDiphtheria and Tetanus Toxoid& 11nd AcellulAr
`Portu~ai.8 Vactioe Ads.orbed) is sup-plied !\ll a turbid wtul8
`6U.!Sp60lUOn in vials containing a 0.5 mL singled~. 1n Pft¢k·
`ngea of 10 vial&.
`NDC r.aJG0-840·11 tpackage of 101
`Reflf'enc.ee
`1. Cent,e,. for Disease Cont rol. Diphtheria, ~hmu• tmd
`pcrt.UAI!is; Recommendations (Qr vaccine use and other
`preventh·c measures. ~nu:n~ndationa of the lmmuni·
`zalion l'nu:ticeo Advisory Committee (ACIPl. MMWR.
`1991;Vol. 40 (No. RR·lOl:l-28.
`2. C•nters for Dioeooe Control and Provention. Summary
`of Noufiable Disea..,., United Statu, 1993. MMWR
`1994:\lol. 42 (No. 53tl-28.
`3. C.,nte.n for !Me""" Control and Proventooo. Diph~ria
`t!p1df!mlc·Ne-w independent statH of~ (ormt"r Sov~t
`Union. 1990-1994. MMWR. 1995;44 tNo.J0~177-18 1.
`4. Biolupeol produetll; bacterial ''nccme!1 and uucoidr. 1m·
`pletuentat.io:n of effic-ACy review. FtduaJ Rtgiatltr. fo~riday.
`O..:.mbor 13, 1985: Vol. 50 !No. 240):51002-111117.
`15. CeoWr!t ror Disease Control. 'n!tnnus-Urutcct Stnte!\,
`1987 nnd 1988. MMWR. 1990;Vol. 39 (No. 3):37-44.
`l<llndrick PL. Secondary famiJjal ott~ck rote• from ~or·
`turt~is in vaecint'lt.ed and un+~accinotcd ch1ldren. Am J
`1/ygitn<. 1940;32:89-91.
`
`6.
`
`8_
`
`7. Centers for !Me ... Control l'•rtUJ<I&- Unoled Sta ....
`J3Jlutt.ty 1992-June 1995 MMWR 1995; Vol. •14 •No.
`281-525--529.
`~·ari:ro KM, et ttl. Epid~nuol~e r&aturfl:l o r pertu.W.s ~
`the United Stotcs. 1981H989. Clin ln(«l Oi•. 1992;14:
`70S--719.
`9. Nennlg MF., et 111. f>TP.vahmce and incidt~nce of 11dult per·
`t\18Si! in an urban (Xlpulntion, tiAMA W96; Vo\. 275
`(No. 21):1672-1674.
`10. Cowell J-L, et a.1 PrOBpCclivu llnltod.ivo antigens anti Rn·
`ir_lll)l model~ for pcrtusMiff, ln.: l.A:i\'O L and SchJessin~er
`D. edll. Microbwi"'IY· 1984. Wo•IUngton. DC: Ameriwn
`Sodety for Microbiology. 19&1. pp. 172-175.
`1 J Shahin RD. et al Chi\J'a.cti'rlWtiOO or the prolective ca~
`pacity 4nd •mmurlogenicllJ' of U\C'l 69 k.D outt.r mcm·
`hrane protein of Bord~ttllo pt'rtUitSIJ. J f;~~r M~d.
`1990;171(1):63-73.
`12. Gw."lafsaon t.... et at A tontroUed tnal of • two.rompo.
`ne.nt <Kellular, a five--component aeeUular. and a whole·
`cell pertUs&is vattJne. N F!"'tl J M.d. I!I!J6;334(6~.349-
`:l65.
`13. Greco D. et.al AcontroUed tnol of two o..ceUu.l.3r vacc::i.Des
`and one who1e--cell vaoorHt against pertU3fll8- N Y.ngl J
`M<d. 1996;33416~341-348.
`14. Schmitt H..J. et at Efficacy of aCQllular pcrtu~sis vacctne
`in early childhood o!Wr hous•hold ••t><>ov11!. -lAMA.
`1996;2751 1):37-41.
`15. Oatll on file, SmithKline UN!-Chum Pharttl~Ceutir.als,
`Philadelphia, PA.
`16. Blntter M, ~tat lnur,unogenlcity of diphthcna-tetanua-
`accUullll' pertussis (OT·tricnmponent Pa), hepatitis B
`<HB) and Hut!mtJphilu.& influuuot type b (}fib) vaccine$
`administ@red conoomit.o.ntJy •t tepar~te 11tH along with
`oral potiovirm vaa:ine <01'\1) in infanta. Abotrnct G 102.
`fn(.@.rsciet'W"e f'..onferenOf: on Antimicrobia.1 Agenu and
`CheO>Otherapy, 1996.
`17. Centen for Disease CootTOI 11nd Prevmtion. GeoeraJ
`rec:ommeodatioM on immuntzalion. ~omme:ndatiaru~
`or the Advisory CommJltH oo lmmuruwtioo Practiees
`!ACIPl. MMWR. 199<1; Vol ~3 <No. RR·I l<l-38.
`Ul CenterS ror Oi!'!oea!le Cont:tol end Pre.vention. Update~
`Vaccine &ide effects, adtJtrtU;! noctions, contTaindica~
`tions, and preco.ution8--re<:ommendoLionld of tbe Advi-
`!'!Ury Cc.mimittee on ltnmunlution Pra.ct.ices {AClP).
`MMWR. 1996;Vol. 45 INo. RR-12~1...;)5.
`LD. Wi1BOn GS. The haw._rde o( immunitotioo. Pmvocnt.ion
`polio"'))elitis. 1967, pp. 270..274.
`20. American Academy of J>edlotric:a. Ptrtus&il!-. R~port of
`the Committee· on. ln{Pctioull DiB«OU.~. 23rd ed. Elk
`Grovt! Village, rL: American Aeademy of Pediatrics,
`199(.
`21. Ho,....,n CP, • t al. Advo,... eiTocto of pertuam and ,.
`bella vaccines. Institute of Medicine ( IOM I. WL<Iungton,
`DC; Nalioool ~my 1~. 19111.
`22.. St.n:rton KR. et al OPT V&cel.Ge and chronic aervotd
`ay;Jtem dysfunction.: a new aoalytU. lnatitute or Medi-
`cine fiOM). Waohi..,..,n, DC: Ne&nal A<adeJily Press.
`lll94 'S<lpplomeAI.\
`Z3. Livengood JR. et aL !'omily hiiiDry Of <O<IYUfoiO.."lO 4:>d
`... of porto.soiB voccino. J Podiatr. 1989;1JII(4):627-<i31.
`24. Centers for Disease Control. Pert:uui• immunization~
`family b.i.story of convulsion• a,nd u.sa of antipyretic&·
`snpplementary ACIP s·tatement. Recommendations of
`the Immunization Practice~ J\dvie,ot y GommittP.~
`(ACIP). MMWR. 19A7;Vol. 36 !No. 18):281- 282.
`25. Centers for Disease Control und Prow:ot.lon. Uge ofvac.-
`t il'les and immune globulin& for penon& with altered im-
`rnunocompet enee. Recommendt~tiont of t.he Ad .. ·isoey
`Committee on lmmunizetion PrBt.1.icea CACIP). MMWR.
`1993;Vol. 42 (No. RR-4t1-3.
`26_ Ccnt@rs for Disease Control Vt~ecine. Advcne Event Re-
`porting Sy•wm·United S'""''· MJfWR. 1990;Vol. 39
`!No. 41):730-733.
`27. Bernstein HH, et aJ. ~icily and immunogenic·
`ity of • ~ponenl oc.!llular ptttU&&is vll<cine ad-
`minislered as ~ pnmtt.ty 10rieo lo 2. ~ o..nd 6 month-old
`infants in ~ Uniled Statet. ll>«in,_ 1995:Vol. 13(17):
`163)-1635.
`28. Decker MD. et al. Comparison of 13 acellular pertussis
`"·accines: adverSe reatliOnA, Pt.diotrir.s. 1995:96:657-
`566.
`29_ Noble GR, et al. Acellular cmd whole.-cell pertu88is vac·
`ei.nes in Japan. Report or & vi Bit by lJS ~eientista. JAMA
`1987;257(10):1351- 1356.
`30. Blennow M, et aJ. Advcrve reactions t\O.d serologic re--
`sponse to a booster dose of aoellulnr pertutsi-S vaccine in
`ehildre:n immu.n.,ited with aoeUular or whole-eeH vaocine
`as infants. Ptdial.ric•. 1.989;8~()):62-67.
`31. Pim C. eta!. Loco! n:aeti..,.IA> kinderga.wn OPT boost-
`eni-Cranbrook. Di• SIU'Vti/1. 1988; 9:230..239.
`32. Gold R. et aL Safety and ilnmunogenicity of HO<mophi-
`/Q in~ vaecine (tel4!nu. toxoid conJugate) adJnin.
`lHteted roncurrendy or combined with diphtheria and
`tetanus to-xoids, pertussis "accine and inactiv•t.ed pOli-
`om)·elitis .. -aecine to heah.hy infanta at. two, four and six
`months of age. Pw1orr ln{«l D,. J. 1994;13:3>1(1..355.
`3J. Bernstein HH. et al ComparUon o! tt three-co.mponent
`acellular pertuH;slll: vaetine with a whole--«11 pertu$8i!J
`vatrine m 15- through 20·month-old infnnts. Pedlacncs.
`199<1;93!4):65&-<i59 ..
`34. Annunziato PW, tlt nl. Comparison of a throe·compone.nt
`acellular pen.ussis vaccinu with ft whQie•cell pertus!tis
`vaccine in 4- thnmgh 6-ycar-old children. Arch PN.iatr
`Moles< Med. 1!!94;148:503-.';()7.
`
`PHYSICIANS' DESK REFERENCE®
`
`35. Willingu M, et al. lnf.oJlL lloep pothtioo ond risk for Sud·
`dM lnfooL O.nth Syndromo; lls:porL of meeung hold
`JanuAry IS and 14, 1994. Notional lnsl.ttuteo of He~lth,
`Beth.,.da, MO. Pw•atnu. 1994;93:814-819.
`36. Strotton KR, 01 ol. l\dvono ev•nto IIJII!ociat.ed ·Nilh clUJd-
`hood vuccsnee. t;vldan(:(' benring on QJwtaUty. lnstitut.l!
`o( Medicin6 (10 M). Wtt.s.h.ingt.on, DC~ Nat.io·nal Acndemy
`PteBB, l904.
`37. MilleT D. et f.\1. l'ert\1.8!1ht v:~ecine and whooping cou;gb AA
`risk fnewn~ for acute ncurologietll 11loeJU3 and dP.Il rh In
`young chlldron. Dou /Jiol Stafl(/. 1985:61:389-394.
`38. Miller DL. et ~I. Pen.us&il immunization and seriou&
`acut~ ntlurologlul lllne•• in c.h1ldren. Br- Med J.
`1981;282:159[>..1599
`39. 11<>811 E. ot al. RaiL ond pert.u.ssio v3ccioe !letUrl. Al<h
`Oi. Ch1ld. 1986:61:9&-99.
`40_ MiUer D, e:tal ~rn nruroklgica1 illn~ fu.rtMr anal·
`ysoo of the Bntlob Nouon&l Childhood Eo.:ephaWpothy
`Study To.t01 J Exp Clm M.d. 1988;13(suppl~l45-155.
`4 t . i\tillu DL. et at ~rtutNJi.t. unmuruzation nnd senou.a
`acute nf'uroiOClcal 1llneues in children. Br M.-td J.
`1993;307:1171- 1176.
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`utiM! to Vlltci.notaon ln Non.h WCtSt Thames region. Lon~
`""'· 1983;1:753-757.
`43. WalkP.r AM, ct nl. NI'Urol!lgiC f.lveou following cliphthe--
`ria.tetanus·pert.ul'll!lill
`immunization.
`Pf!dia:trit;S.
`1988;81(3):3415--149.
`44. Gritlin MR. et. ol. lti11k of ~zurf!ll and eneephnlopat.hy
`after immunitotion walh the d ipbtheria·tetanus-pertus·
`•is vaccine. J,1MA. 1990;2631 1.2}.1641-1645.
`45. Shield$ wn. f't ~tl. RehalioMhip of pertussis immUn12.ll·
`tion W the ouet of neurologic disorders: a retrospective
`epidemiologk oLudy, J l'o<liotr. 1986;113:801-<105.
`46. Bellman Mil. et al !Jofanula spruoms and pertusslJI om·
`muniuo.tion. Lonort. 1983:11t.l031- 1034.
`47. Melchior JC. lnfonule • .,...,, and early immvnilt3tic>n
`againat whoopin~ c:ough: OanW. •urvey from 19'10 ID
`1975. Al<h 1M Child. 1977;52:134-13'1.
`48. Griffin MR. ~' a1, Risk of Sudden lnf1u1t. De•th Syn·
`drome a.fter tmmunlutioo with the diphtheria·totaoua-
`porlu85io vaccine. N Eng/ J Med. 1988; Vol. 319 001:
`618-623.
`49. Hoffman HJ, ct ol. Diphtheria-tetanus-pertussis i.mmu~
`niz~tion und sudden in rant death; ResuJts of the N,..
`tiona\ ln!!tilu~ of ChHd Health and Human D~'Yelop.
`ment Cooperutive Epidoru.iolog:ic.lll Study of Sudden In~
`fanl Death Syndrum• lllok f'ntl<>l11. Pediotri,., 1987;
`79(4~598-611.
`50. Jacob J, et al. Incrc!-Bsed intracranial pressnre af\.er
`diphtheria, totanu.s and pertuqi.a immtmir.ation. Am J
`Oi. Child. 1979;133(2~.217-218.
`51. Moth~r R, eL ol. 8ulgin1 footal>Ol following trip!~ VO<-
`cu'1!./n4ion Pw1otr. 1961;18(6t,417-418.
`52. Sheodumikar N. et aJ Bulgjnc fontanel following OPT
`vaeeine..lndion ~urlr. 1986: 2J( U ):960.
`53. Cen<En for Di .. ..., Coollol. Nat>onal Childhood Voc·
`cine tztiW7 Au· Requin: mc:nb f"T permanent YOCCJntl~
`d.;jtJ; tecOldl and rnr ~porting n! JC!Kt.ed e-v-enta after
`vaa:inaoon. ,\1,\fK'R. 1988;Vol 37 (No. 13):197-200.
`54. National Voc:cine Injury CompeMation Program: Revl~
`sion of Lhe VRtcine injury table. Fe!hral Reguzer.
`Wednesday, Februnry 8, 1995; Vol. 60 fNo. 261:76!14.
`MB.nufnctured. by Smh.hkJin• BHcham Biological•
`Rixensart, &lgium, U.S. License 1090, and
`Chlron Behring GmbH & Co
`Marburg, O.nnnny. U.S. Llcenoe 0097
`Distributed by Smh.hK1in• S..Ch•m Pharm.c:eutieala
`PIUiadelphia, PA 19101
`Rx onl~
`lnfannx iJ a rcg'U,tered tnd.em11rk of SmithKline Beecham..
`V•t..-.n• AdmJnl-.tration/MilitatY/PHS-0.5 mL Single·
`Dose VIAl, 10'•, 8505-01-442-6262.
`IN:L3
`Shown. m Produ~t ldttnttficataon Guuk, pog~ 331
`
`KYTRILe
`lkr '·trill
`graniMtron
`hydrochloride
`Injection
`
`I~
`
`DESCRIPTION
`Kyt.ril (graniletron hydrochloride) Injection is an anti·
`nauseant 3.nd a.nti~matic agenL Chem.ically it is ~ndo-N-(9-
`m•thyl-9-azabicyelo 13 3.11 noo-3-~1~1-melhyi-IH-indazole·
`3<arbox:amide hJ'drochtoride with 3 molecular weight or
`Ito empirical formula ••
`348.9 !312.4
`free bBi<H.
`c .. H,,N,O·HCI whue Ito chemical stru<tun! is:
`
`03""~•-rn,
`
`· HCI
`
`I
`CH3
`itfanisetron hydrochloride
`
`Exh. 1016
`
`

`
`PRODUCT INFORMATION
`
`SMITHKLINE BEECHAM/3105
`
`To~Mo t . Ph ltfmMOJdn.-tic Pa_f'am•t M'II In A~ C.ncer P•fitflh Uftdwgoing Ch.erno•hM-vt •Ad tn \fok.lltt""- FoUowing
`• Singkt h'ttravonou• «» nl(t/kg Oos• o' Kyt.rll {tJ!aniMtf'on hydtochh>fl.d.J f" Jtction
`T..-min.t Ph•N
`Toul
`PM~ Pl••ma
`a. •• ,..
`Concetrt.-• llon
`PJ.nme H.tf.Ue
`I hi
`(ng/mll
`!lfhll<ol
`oas•
`C.l< to I :;4
`
`638"
`18.~"' 176
`
`8.96"
`0.00"' 31.1
`
`VoJutne of
`Ois-trlbttt:ion
`{ljkgl
`
`3.07"
`OJS5 oo 10.<
`
`64.3 '
`II.~ to 182
`
`S?.O'
`14.610 I~
`
`4 91 '
`0 88tol52
`
`7.oor
`2.66 "' 17.7
`
`0.79 '
`O.l!ll to 2.56
`o-w'
`0.17 to l.06
`
`3.1)4'
`163ooSIJ
`a .971
`1 .7~oo70l
`
`~ ... P•d 41ftte
`M..,.,.
`RanKe
`Volun1etn
`21 to 42 .)'f,at'8
`Mtom
`Range
`6-.~ t () 81 y••(lrfj
`M..,o
`Rang.~
`• f..minut4! mfu!iion.
`1 3 m.iaut.e in(wnon.
`
`Gro.oilkrtro» hydnxh.lc>ndo 11'1 a. whu . .t to ofJ~wb.it.e 10hd t.hua.
`is rtadily •uhlbll, In watt'l' g_nd tlu.tallll &&lbu.: n' 20'C. l(vtraJ.,
`J.Uecuoo t.a a clur. colorleu. »t.enlt.. D01lPlT'Otftuc. equcous
`~ludo• 5:w intm'-'l!'no0'\J3 -.dmipi.t:n.bon~
`Nyrnl it nvailtable in t ml.. JJi.ugk--tkJI!IU tsnd • ntL mult.i-do8e
`vials.
`Si:ngtH)O<M Vieh; e.d:t I m_L ol pntM'rTAU""~ OQUOC.U$
`8<1lutilJII con\.ain11 l.l2 m&: ( nniMe'Cnlfl hydroc:hlcridt: t!ltWY•
`alent tD ~rrruuaetrou. 1.0 "'" aod sodium chloride. 11.0 mr.
`'I'M MJutioo'• pH roogf!l' fioom .f.7 W 1.3.
`Mutt.J.OoM Vi.t~ Et.tc.h I mL C~R~Lnn~ l. Jt me (!1Lllll11Cttul
`hydrochluncm ilctUJvalenL to gr.amst tron, l 0 mg\ aodmm
`cblandl,, 9 mg: titric acid, 2 nllf. ben1.yl altdhol, I 0 JJIJt, 105 A
`~tive.'lhe oolution't pH tao~ from <1 0 t4 G.O
`CUNICAL l'llAitMAOOI,OGY
`Onnl.sotron. &sa ~lt:oetivt 6-.hyd:roJytrn)(amine,(li-11'1', ) ••
`¢pt.or 511~ wstb l1t.1Je, or o.o Aftinit}' for other MrOt..-
`ru.n nocepLOrS, mduding !HIT1; 5-tlT1"; 6-lf11M:; S.-irf2; !or
`a1phA1·, ~alphn,.· l\r OOta·ndrentm~ptors: for dopamin&O):
`or for hi.5tamin6-l\ 1; boru~odiflU\pw~: picrot.o-d.111., or ~ptold
`"""""'"'·
`Semtflnln reooptM\l o(tilo 6-liT1 lype a.relcJCOt.d periph.,.•
`a.Hy on vt'gul 1-u,.-ve- tci'Ti\lnol.ll .lll\d t.entrolly ~n t'tto chonu~-
`1"91.'\!pWr trigg:tr r..coe 1Jf llte a.re.a poRtren\3, 'During cheo»-
`lhfnPY·IIld~«d YlliDitiJit ........... entemduomallin cells
`I'C!I~Allfl _.rotoni-n, wh it:h Jo:ti.mol:tte. S~JM'~ f"(li!l!ptONI .. "nUs
`evolut\ vago.J otferent. d.iiChura;o, induc.u\g vomitit13'. A!Un-..l
`•M"'' d<mo,.tntc tlu~ In blndlnc to 5·11T, """'P"'"'·
`(rtJ)lMtl'tJt'l blockJ S(>ro{t)nin sbnulltt.ioo and ~tJt;w,quent
`Y<fM.it.iog n&t- urn.,t,og~mlc fltim\IJi &utb M ti3pl.atio. 1-n tho
`tent\. a.niru~l model. a 11i.ngle gm.al.setnm injection pre·
`ore11ud vomitina: du• to Juch-dose eHplatill or anest.od ''Om·
`ttiag within 5 I.e) 30 s«ouda.
`to n)()llt. bu.rnan ~1.\ldit.:~. grtu:Wsci.run bou had HILle ttT~ ou
`bi<JOd pmsure, heart rate or ECO. No evidence or sn d'«t
`~tn plaama prola.ttin or akbrternrv tOnc::r.tltratiOM has ~
`Tobie 4. PrevMtion of C!Mmothonopy•l""'ced N.., ... •nd Vomltln!>-SinoiHJoy Hloh-Do•o """' lDw-OoM C lopl•tin
`n-.py'
`bund ill otJ)eY •tudie~J.
`Kytrll I rti1..''4::UoD e.JdJ.ibited rw eO'ect (lf\ oro~>Col tra.mo)\ ume-
`m norma) volunteen ci\'t!a • sin.gl" inba\'~MU.! in{u.lioo ol
`50 mctc/kg or- 200 m<:s/k« Single ancl muJii pie t~nJ d-..
`111awed oolanic trumsit. i.n normal ''u1unteers.
`Pharmacokinetlca
`In adult ca.ootr pdienta uod\":-rco'ng c:h~mc.c..he-mp)' eod in
`•oluntcen~ infuJJOD of a amgle 'lO roqlkg m. o( l(ytnJ lo-
`je(titHl pNJ<iuced th•~ following mc11n J)harrna(nk:inetic data:
`[See !Able 1 .....,...,
`There was bi&h tottr aad mtraub.Ject- vanabibq llOC4.lCI in
`th~lile kt.udjes. N:o difference in m.l)0n AUC was found be-
`twoon ma.lee (j.lld f01-mol~t. a lthougb rn&lo$ bad a h iglu;r C111n
`gen•rally.
`Gmni&etron melabolit:m tovoh·es N-demet.hylaboQ a.nd oJo-
`Rll)t~ ring mtidabon fnll(IWt:d by eonju.;:.tian, An.im:tl ~rtud~
`iM !Ug_geaL thuL JOt:ne o( the tOtllabolit.d fllay al:iJ.o hUV(!
`> H1"3 rta-IXOr antaeonlll activit-y
`C'lcn.r-a.nce U pedotninARtly by he-psli.e: metAbohsm. In nor·
`nl.al "'"lnll~tm:J, 11pproxi ru.ateJs 12';1f, of "he 6d.ro:ioiat.ere.d
`d:Off' 11 e-llroutattd u~ett 1.1'1 t~ u.nt1t •H 4-3 to-.-n. Thi'!
`~t~tndttr ol lb. no- i• excNted lll.t matahoh~ 49'1. tn the
`urine 61\d 3t~ to lhe rcc:6t.
`In uiuo tlve-r mjtr<JS(IIM.) rtud:iea 11how lh.!n granistt.roo's
`~ I"CCUteol met.llbolism U: inhihll/.!d by kctDconamle, l\lft-
`&cttllvo of ruetaboll~ medit~Ud by the cyt.Oehttt'me P-41)0 3A
`~vb(tunily.
`Pll.ltitTU• pi"C)tein hinding it appro'dmateJy 65~ and 2J'IU\iS·
`ctroD di.atril>uta f'n.~oGJy betw C!!C!n plftltna and rod bJoocl «ill.&.
`fkHifY: Tbe ranges of t.he pb.armecokinellc perarnetera in
`elderly voluntet-n (meal\ ttae 11 yenr!U. givtn n smrla 4-0
`~ intnve:nou doae of .Kytril J.ajc.dion, were ge_rl(!rally
`~iwilor to t.bol4t io JU"'J'I« b<t:n.khy V'Cihtn~Hn; ~an values
`wert ln .. -er for cletlrance e11d. Ionatr fer h.aJf~life in the e-1·
`derly c ... Thble ll.
`Pedl•tr*; P•t~ttt•-: t\ phtfm4'!COki~etic etudy i.n pedi~atri~:
`cancer pattenta i Z. to US ye-an of ate), Cf'ltn a single 40
`mc!Vkg intniVOROlli dnse nr l(ytril Injection. l hOWed that
`volu.n"~a o£ diatribuEion ond total clP..t.ra.llOe increased with
`age. No relatiollllhi.p wllh "!:• w .. obseNed r ... peeJc pi08DJ3
`coooootratlon or lermuul phase p1osma half .. llfe. When 1I01·
`\1Jn4! of di~fr--ibutior~ ~and t.obl elo•riU~fl an 111djttatcd !oT
`body weight. the pbormawk.ioctiee of gro.oi1tttron a.-e aimi·
`lar 111 pediatr!c Mel adult""""" pauen ...
`R•IUJ F•iur• P•d•,ts: 'Thtal c:iearuw::e cl grani-.etron was
`not ,-,rrected in patieJJt.t ..-ith ~""ltr~ Tenlll fail\1.re who 'N)·
`ct:ived a single 40 &;'K'g/k( intnvero-us dt~Be •f' Kytn't lnjE<;·
`tion.
`H•p.atbllylm,.w.J P41M~ A pbumAc:okinctic:atvdy ill
`p•tiC<l!• with hepatieimpoirment dut to nooplustlc liver In•
`,-.olveiN:nt showod that total cletr.tnoe waa AJlproxim•U!l_y
`hdv-od cornpcaJ"fd to pAd•nte -'thout ~de inapalmu:n.t.
`Given the wida v(lriabiHty i.tl pha.nu~:h."'kin~c.ic peuo•ttttrt
`noted on parienlJI OJtd rlle (tOOd wleronce ofdo.es well <above
`the ........,.nded 10 tnqll1cg d-. o-.p oc!Ju..,.ont i• pa.
`l.i.~nta wHb poaeibl~ hcpet;ie funttioaa.l impa.lnne:ftl ._ 1101
`OtCtSSIIfY.
`CUNICAL TIIIALB
`Kytrillnj("dion hu been. Jhown to prevent I)AW'ea. and vom·
`iting 'usochHtJd wit h 11i n~h:~day and re·J*ut. cycht CIJ.OC~r
`themotherapy.
`Sint t ... o.., Ch.-no1henpy
`Clsplllin-&JUd ~t•eropy: In a doublet-blind, plucebo-
`controlled study m 28 d1n.cer pAti(!ntJ;, KytnJ Injection. ad·
`minl«orcxl M a aingl.e Uttmvonou. i.J\1\uion of JO n.:gh.g.
`
`Pte ... •ntiOn ot ChemotMr-.pyo4nd"ctd NauM• tnd vomlting--$11\gi• •Oey H1ih.OOS. ClepNt1n Therepy '
`Kytrif tnJKtion
`PNelu..
`( VS. z m<g/•gl
`(mcg/19)
`w
`w
`62
`
`2
`62
`
`~
`53
`
`~
`
`• 0.002
`< 0.001
`NS
`
`< 0.001
`..-o.oot
`0.007
`
`N\1.11.100, of 11utie.nbt
`1\dpo""' O.er :14 Hc>IUO
`C<>mpl•u ResllO ... '
`No Vomiting
`No Mor. 'ntAI) Mild Nau~
`
`1. Cisphltln ad.miraiatration bt:lolaO withio t O nlinuc.e of l<ytril 11'\)ection infi.Js:io.i' 11nd oontinued fot 2.6 hounJ (incan} Moo n
`cuplatin doMe *"" 96 to 90 mglmt.
`2. No vurmtmg a..nd nG n:n.derate or u .ver-e anuatL
`
`~:!~:r~;fi%:::
`~Ovor MIIoun
`Comploi.o Res110"-""'
`No '\hl\littng
`No NauJea
`l..ot6·1Joa,e C~~lm
`NUmber (If be.nU
`kcEifXll\11.0 Over 2.4 l-lou re
`Comptcte Rttipon*''
`N(l VotutJD.R
`No N~u~•
`
`Kytrfllnjeetlofl
`(oncg/kgl
`20
`
`10
`
`{9
`
`<18
`
`40
`
`47
`
`U 'i> ~ 4 7~
`.U'llo
`53'
`4 7~
`S&<JI.
`3~
`43~
`
`41
`
`riG%
`63\1.
`&6')1.
`
`40
`
`~8'1>
`65%
`38'J.
`
`46
`
`4 1'.b
`43%
`33'1.
`
`10
`
`0.018
`NS
`o.oaa
`
`0.012
`0.012
`0.012
`
`5
`
`<10
`
`1811>
`2Rit
`1511.
`
`42
`
`29%
`36 ..
`;!9'1-
`
`P·V•h••
`lvs. 5 meg /kg}
`20
`
`0.0'15
`NS
`0.019
`
`0.009
`0.008
`NS
`
`40
`
`U.004
`1),0 16
`0.()()6
`
`NS
`NS
`NS
`
`1. Cispbtin actmintJtration bega.D Wlt.hin 10 munues cr K:ttlil lnjf(Qoo inrusaon and eonlinued f(lr 2 hours •Jntan) Mtan
`<:i~!plttin dOHfH were. 64 ond 98 rt1W'rt12 for low 1t..nd. high str9ta.
`2.. No voom11-.tng ati.U ntt 11ee tt( ~ a •.•l,o:'l6ot<ttC..
`... ,r rm .. ogon~c a-.. ... -.,., "'"'J 1~.
`_
`wu eign.Jflcaatly n'ICltt' effedlv .. than placebo in pre.,-ot.lnc
`40 1ncWkt, wu c.·ornp:nc<l with the eombinau.icta or chlorproo
`n!lUstP and vl)mittng in1IUOt:d by cit~ platin chemotherapy.
`Soo'l'ablt 2.
`mruinet50w200 m!V'24. hourol and "'""'""thasone (12 mal
`in patient. l::n!at«i with ~nodentely •metogerllc chemother~
`To~ 2. Prevomion of Clltm-.n-lnducN NaUHe
`apy, intludtn& frimari1y urbopl•tin >300 rtJI!Jm', a.,pl#tin
`and Vomlti"g-Slngt•Otv Chphrtin ih•r11f)V 1
`20 to 50 mtllm and tJclophosphamllle >60Q m~m' Kyrrll
`Kytrll
`trUectitm \t9t sol)4;rior to the chlo-rprom:u:ine regime-n in
`ln!e<tio" Pla<obo P·llaluo
`preveofulg oaua<eA 4114 vo-mit:ltl., See 1\\ble 5.
`u
`14
`T•bf• 5. Pnvention of Chemoth.,•py4 1nduced Nllu .. • .,.d
`93,.
`Vomiti09-Singlo-Doy ModO<ttety £motovemc CIIH!o·
`n-.,.,.
`9~
`
`<0.001
`<0.001
`
`Number or Pa.tiefl.l•
`llcP.poMO (}ter 24 f-f l)\Jl"S
`Complete Rospon..,•
`No Vomitinr
`N'o lthr~ Than
`tv1ild Nuu~i
`
`9 3~
`
`<0 .001
`
`l. Cispladn admini•tntion b.,gan wlthia tO minutu of
`K~:ril lnjeetion 'nfueiol) o.nd cxmtin ucd fo'f 1..5- to 3.0
`hours. Mean cifpl~tin d ... was 1!6 Olg/m1 in t he /f.V!riJ
`Wo<lion group and llO mldm' in i.lwJ ploo:<'b6 i"JUP·
`~. No YBntiti"g and: oo modem too,. 8C..~TO tUlUMm.
`
`K)1ni 11'\.k!('boo wu also fVIIh.t.atEd in a randomized dO!e re-
`tt~\1111 ttudy n( cu•ctr patie.nta rtle»i.U., O.pbtin ~75 f'fl.ft
`C¥~2. J\dditiona( ch()motheropeuti(. fllgenta included : anthra·
`cyclin~ll. eart»plntin.. C}'WSI.atic antibiotics, (olic acid derivn.
`tivfs. ntelhylhydruint. J\itrog!'n n'IUS"mrd a.aalop.
`pldophyJiotoxic clprivati•ot , pyrimidine a.nalop nnd vin-ea
`ullro.loillo. K.Wil lqjec\.ioQ, ~ .... or 10 and 40 mc~'l<g were
`supericr to 2 meg/kg in preventing: dlipllltin-indu~d namea
`and "'0-miti:ng. but 40 mcgl'kg w:u not tigni6t:antly euperi«
`to 10 meg/kg. See Table 3.
`!See table 3 abovel
`li7tril 'p..U..o:n1n bydn>chloridcl lnj«1io.. ,. .. aJ.o e•cd ...
`at.ed ttl p doub!~·bliml, ranc.lt~m.i.K'Cl d~ T{l!SfM!Nt! !)1udy a(
`353 1>3WFnts strotifiod for high (>:SCI ID 120 111111\n' l or low
`(50 to 79 ntWm2) a.plutin cloM. Re•-pomc ralo(!l of p<'li0111..ta
`r ... r bolh deplatin " uta a-nt (iven in Table 4.
`l~oe oabl• • above!
`Fnr both the low tt'.d high Ot'Platin arrau, the I 0, 20 and 40
`~ doMtt were- more ~fft:cti~ tt:t.n &be & ~ daae iJt
`prcvtndng nl!usea and qomitU!g wiltun 24 boun of c.bt.m&--
`therapynrlmlniflitrJJtion. -roo tO mrglks: dose w!\sa.~ le.aAtu
`eff«:1ive a_, t.he higher doa«4.
`
`Nwnber of Patients
`Re•ponse Over 24 Hour"
`Co1aplete ~~~~at
`No Vom.itina
`NoMoreTI\o.a
`Mild N'tus.w.
`
`Ch.lo'l)r~
`
`Kytrll
`tnj~ mum. '
`133
`133
`
`6$'l
`73~
`
`7"l~\
`
`47%
`:13\t.
`
`59'.t
`
`I'·Votve
`
`<O.OOL
`..:o.oot
`c O.OOt
`
`I. Palients also rea<oved dexomethasooe. 12 mg
`2. No vomiting 11nd no mod~rste o r se\'om n•usea.
`
`lo 0\ber <tlldleo ofiJIOderotely tme<otreOJC <htmoU"'rat>Y. no
`sipi&cant diffen:nce in tfficaey .,qs faund h«YHn l(y.nJ
`dooos of •o meg/kg ond 160 m<wkg do•••·
`R_.-cyclo Chemothtropy
`In •• UO<OGtroiW tnal, 512 eoncer pa....,l.l ....,.;,eel ~
`fnj~c:t:ion, 40 rncg/ka. prophylaetic:ally, ft.r two C)'daa of
`eydtt and 108 paueno.. ....,.,vel! il for at lea.•t six ,,ytlet.
`chtmothentpy. 22• poOent. n:.'1.lcived h for •t. leu.st four
`
`loformdion on lhe SmitltiOint IIM<hlm Phorm~uticals
`ptoducts •P9••int h..,. ;. b•Md on th• t.bdng fn effect on
`Jun• 15. 2000. Further lnfo.-mttion on these enct oth.r
`PfodiJdS moy bt o~ned from 1M Modieal Dooartment.
`SmithkJiae a..dum Ph.a.rmac1tl\it._ Ont Ftal'llditl Pbu.
`PtiJodelplll•. PA 19101.
`
`Exh. 1016
`
`

`
`3106/SMITHKUNE BEECHAM
`
`PHYSICIANS' DESK REFERENCEe
`
`(l r-llt\•Mlroc• at s..:.bc:uta.nec~w <I~ up to(} mJ;/kc/dby 100
`I>M«<
`111jm'A!oy. 97 t.imts t.llc ...,.mraendf!d human -
`an btwtr Attf&nt- a.n:aJ wat bund tah3ve anP'Sf'(t on Wruhty
`.,.. ~i'r$ pe:tf.onaaAc. of caal. aad C.U..Ica nt6.
`
`!"umber .r r.~o'-­
`Modwl !lumbtr of
`VGmlbniJ EpaJOdM
`Complete A.e.tiOtiM
`Over 14 Ho~.ara1
`
`lytnllnjK11oo DoN lm<Q/klll
`:!0
`10
`40
`Z9
`2.$
`A]
`
`2
`
`'l l""
`
`Jl·~
`
`Kytrll Injection-cont.
`,_.....,
`l(pnJ ln._JOd.JIOo •tnt.ey r-'•&a....! ,.YtJ•t-11 ~taAt 0".,.
`1tw G.rtt ._. npt-M r~~ .-,m COO'pltt• ,.....ponM n.l.ft me l
`r.,.,.,._ Effa<ts. ......,.._ t«0190"' 1. Rl>!lnldurt""'
`.,.,....
`I
`uur.a.ttnt tnd 00 .,..Jfntt H ~~"' nAtb«'a 1n 'll hrurtl d
`t,;.I)C\. &o (;9l1. \lo pllt~aU N.,.. 41odJ«< f~r n'.OI. tlU~tO 1$
`lilud ... he-.• b:ootn Pfrfon.ed ~n. ~· ra\1. at 10tt1W ..
`nov.~ up l:h 9l'l'lCik&/dny 16-4: aw'rtt.:,d~, t.a6 h etu t.he
`rt'(l)mrnrndod humaa dose- on bc<l1 •urf•oe oti'II IOO
`Ptdlatrlc: Stu<IIH
`j\ nrdon'"A-1J*d .mhl.-..bhr.d -.ttWy f'!tahuuf'd tho-- '!-~·MUT ~
`• pooae: o(30 pedulnf Cit leU pabHU t_,. 2 Lt 16 ytc.rs ~
`(lt"f'fr:litWlt rnbbts: at- 1t~:lfaYfai)Ut dMeJ up to 3 m~••
`f J6 4 mw'm1.td•y. 96 tmW!f lb.- rt.'('OID.11Mnded twna.n dow
`J<,cnJ In~ to. m or 40 COCWkc P•t"--"11• ,.,,., th1itM
`t.aJft .,. body£~ ~aJ ud ba\-e roo·~ no .,.tdcouo
`..,u. orp1.a1ut -oo ...... <>unotv"' ~3 111oa' ~
`<llll'lpl11n'<l lrrtilitv or hanD 14 llw r.tu d.., 10 croruwt""'-
`pUm.dp > l r/•1 01 .u,....n nat..Utd • 4; tn.efM1 ~ ,...._ ..
`~,.. u.. ~. aoMtqc:awaad •el-f'C'JGVniM-d~
`lA ptqMal W'I)Dtft lka~ .....,.a n-~~ •~
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`.-r. aOL itJWIJ!. predktrrt tf bo.mtn rupoOJe . llw dnJi:
`T.tft a. r..-.. .mlon Gf tt..mo·u....,.tndructld ,... .... .nc~
`.!would bo u..-.:1 durir-t J>N'(M"'T only il ~any .....dtd
`Vomiting In P_,.11rie Pat•enta
`t<lw.int Moihen
`h ,. nut. known wbt.i.lkr lf'I.O.i.M.tl'OD iS ea.cret<.od m human
`tulk lk.'<aoae!Dallydtupareowetedoo buman m~k. .,. • •
`11011 •'-It bo ""'....u..d '"""" ~tnJ lnj<dioo 11 :odmwo·
`tt"f't'd so 11 qu.naas woman
`Ptdlolric UM
`S.. OOSAGI! AND ADMINISTRATION for""' •• th>lc!,.n
`2 to 16 yeon of"~· S...fny ..wl c::B'mn·eoeee u1 etuldnn ,.,. ..
`dt~r 2 re.an of a.ge ba\""e ncx. t;te,en H"tabhsbed.
`Gorlotrlc Uu
`Oul"ln.: d il))etil trio Ia, 713 Pl•\lMte G6 )'(ltlr't of ago tJr oltltr
`r..c:('Jved Kyt.ril (grllllt~Mtron HCil lnjedJcu1. f~ediver•et&
`llJ\d anf~)! were similar in patients of vano111 ftUM.
`ADVJ!RSE REAcnON5
`.,., following hav• """" ,.port«! d..,.;,g ""'"'>~ltd c!WW
`\:n~~l" or in the RJUtule maJWgfll)eDt of patimw.. '1'bt pe:r-
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`~•U1n und1lut.MI uv.:r 3() ~ontltt. or d.al~ted with 0 94 ~
`dlUJI Chklnde or l'l llelc'1nlfie and 1n1ln<ld ovm- 5 mrouu.o
`f«<iolri< Uw Tt• ,.,..,.<M..Jod dc!olo oo duldr<n 2 •• 16
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`,...no •I ·~• ,. 10 ~ •- tl.INlCAI. TRlALSJ O.d
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`d..., """"r : ~.,. o( age two. IIOl- llud"".
`V• In'"" £ldoffy. fWMI Filion l'oHnlt ., '*"-tluiV Into
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`'~• doNa- -.cl,utuntnl • ~~.d
`,.;.- ,.,..,.,,.
`oS.,. ('UNICAL PIIARMACOIJ)(iY M""""""k>tttoot
`r.tutton ,.,.,.,etlon
`~Jnl l~•!)n. "4dmu•ittuHI u
`t\ 6-m null' ln(•i·M.
`t.ho\o.ld ~ d1l\ll~ t t'l 0()1( s.d•~ (. hlonde O.r £~ llexlm+e
`10 a uaal fOIIt.UJW ef20 co~ mt.
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`lntnw..._. •• , ..... • r K"'"' •~ u.ouw M ~
`•lt~ttllW tl~ru.._