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`titlDi-WIS
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`CIPLA EXHIBIT 1008
`
`Page 1 of 9
`
`CIPLA EXHIBIT 1008
`Page 1 of 9
`
`

`

`
`
`PRODUCT IDENTIFICATION GUIDEISOB
`
`)__——’ —
`marobums will“ "W'
`
`on} P. "I III
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`Bllll‘nl-Nvlnl soul-n autumn P. am a:
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`amnmbmuu qumn onaatoar I. B”
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`all
`i: [1:
`
`I”
`I
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`I
`20 mg
`n10 mg
`NDIII'IIIIIC.
`50 m5
`1° mg
`[phenylpmpanelamlne HCI. phanlnuamlna
`Him.”
`“in...”
`mm":
`tnrlratu. chlowhnnlmmine malaflm
`
`(megsslml acetate lableta. USP}
`:etoposlds] Capsules
`[memmmgemmnu acatale tablets. USP:
`50 mg ,r 24 mg ,I 4 mg
`BIIIITDL-M'llfl nulaa wool-0M P. on m:
`anmawrm_nnulnamnumou r. m a-m
`clflllllfll
`n. no In:
`trauma!
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`a:
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`-
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`I.
`
`annulment
`
`In an
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`61-3:
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`“1
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`“Hm“
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`’
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`f
`('
`A-
`35 ”'5
`i'ImInIllno
`Bull'l‘lrlla PIM
`[humans]. LISP. melemlnophen. USP:
`
`lphandlmelrazlne taru'ato taulals, USP:
`50 mg I 325 ms
`flvlll
`cumucv.
`n. Inn n:
`ellilfllflfi
`
`9. m
`
`p. m
`
`.
`Illll
`~-
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`'
`‘
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`WINE.
`
`‘rli‘.
`.-
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`mm
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`
`-
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`mi
`:3?“
`200 ml
`
`E
`.fif-
`. 6-5553]
`'
`'
`500 mg
`
`a:
`
`
`
`l
`'
`1
`;
`
`[L
`
`you lnpucuun
`
`1m.
`mM‘
`Wm...
`
`1.5m Mulwom vlal
`
`Ly mlllzod c nun“
`[ dig?”Imam [mff’acflom USP:
`.7 _ch‘wL‘mE—“W Rx
`
`Munoz”
`(mssnal Inlacunn
`aamnmrznunum onumnv I. an ax
`
`'
`
`_
`100
`”ES.
`ermwablegolaperglmBuffered Tablet:
`BRIIIOLMVIIIIDUIIIIMHIIIOIMIYF an N
`
`
`Phrlnllln' Forte
`Iwmlbilal. LISP. semamlnonhan. usp:
`50 ms f 5‘50 fl
`9.90:. or:
`unusual:
`new.
`
`105 “3
`nontrll' Slow-Run"
`lnl'landlmelrazine wtratol
`flillllla)‘
`
`.- - ca Itnl" and coaoln-
`15 “1E
`III Illlllol‘ldal'l
`lacemrnlnophen. meme phosphate)
`120 rnyfi mL. 12 WE mL
`OMINIIIOII
`
`-“‘“ "'5‘
`..
`..,
`w» ."t
`‘5‘“;
`“0mg
`
`“I.
`.
`_
`‘00m5
`
`Droxla“
`__ “um-meal capsules. USP]
`K' mm. --.m IQIIIII oucomv r. so:
`
`“
`
`do mg
`also mallabls In 5 mg and 20 mg
`Mutam ill"
`[mimmycln [or In actlon. USP]
`”lawman-awn uncanny p.914
`' ‘ -
`.
`'—.'
`30ml
`40 mg
`E
`
`
`
`:50 mg
`
`9
`
`hill.
`(stavudlna) Capsules
`m: mum-mmnulummmouv p. m can
`
`
`E
`It“ LA
`
`I». an:
`
`(phsruyIpmnann amlne H01. gualfannaln]
`75 mg g 400 mg
`CIRMRIEI
`
`F -
`
`8657
`
`rm
`
`ax
`
`p.001 mt
`
`
`
`pug-cl”
`[phanlrlprupenulumlns HCI. USP)
`unnuuu
`Q
`.
`
`.
`
`g'
`f
`500mg
`
`:2. I01
`
`5
`
`/]-' 1r
`
`_
`
`\-750 ms
`
`i»
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`-,
`u...
`_ flaw“:
`12“." ___.
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`10”.:-
`4-» _ av
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`g
`
`450 mg
`-
`Paraplailn"
`[cerbnplatin lot lljljecuonl
`um mlllllltllllll one av I an
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`nx
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`
`
`100 mg
`.n
`1'30 m8
`I "ma vlal
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`’- mlaou'
`EPIIHI'IOP'A
`quanta] fut InJacllon
`Iciaplatln Injection
`
`I
`I... v u as mum ammo“ 9. an I:
`umnomnna nuln ouwlonv P. m.
`‘
`I
`
`"
`
`,
`"’
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`
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`‘1
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`l
`
`I.
`
`out.
`llwdroc
`one hllertrate. USP.
`acmminonhan. USP}
`5 mg I 600 mg
`animal
`
`Ill
`
`a In: ow
`
`“"10!“
`Isalsalate lahleta, USP:
`Mammal:
`~
`
`P. we
`
`a-w
`
`P. m In:
`
`I. one
`
`- ---
`zanrr-
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`.-
`_,",'_°"‘“fl§
`:h' :5
`fi'
`-
`L"
`mL
`1
`ml.
`2
`nuns
`[stflULlfllnHI for Olal Solutlon
`BIG P" H R MM: Ell“
`m punmuurluu
`
`mt
`
`
`
`-
`
`MuItI-dosu vial
`Alan mum» in 30 ms.
`100 ms Mum-dose vlala
`TAXOIP
`:pacllml} lnlwion
`WWII.
`autumn“ sauna oncomv n ass n:
`
`C
`I
`; % mt
`|
`-...w-"‘
`_ Q-
`"
`'\ w
`-
`‘
`15 mg tablets
`
`Omdrln"
`{axandrolone taunts. USP}
`In wuanmnlunms
`
`p. on
`
`Illdfln'
`lawmmopmn, USP. Walk-alum
`dluhlora nhanazona. USP.
`IIIIIIIIII‘
`[laumalheftena mucate. USP.
`maleats.USP. WMWIEI‘III-e Hcl. USP!
`awtaminnphan. usp}
`
`650
`j n mg f 25 m5
`65 mg ,l‘ 100 mg f 325 mg
`0""!!!le
`DAIIIIIIIK
`[F3
`.55
`K”2
`W
`alumna
`“°° ’"5
`(dlfunoxln as tha Hal. atmplna sulfatn}
`SI‘OIIIII‘Ila
`
`1 mg 3 0.025 mg
`(metaxalune)
`ennumeu
`nnunm
`
`n. in:
`
`nu
`
`r. m
`
`.
`
`I
`
`I.
`,
`
`_
`3.5
`
`”5
`
`500 ms
`
`100 In!
`
`200 ma
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`.
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`m.
`
`. ..
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`nruslmm '3',Inna
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`”mm'fllnnwmamuiu "‘—
`New“ P. m Int
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`{JEN-.9-
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`2m
`200 mm
`40 WmL
`1 mL un mafia
`5 mL mulllpla
`1
`10° W 600
`_
`me. or.
`I:
`50 m5
`25 mg
`2
`mg.
`was close syringe
`any, vial
`Also avalluble In 150 mg.
`Ithalldumlda) Capsules
`{pnenlndamlno Inmate}
`Imeaealmll $39.;”'"°“
`““5"”
`Dem-lair I-
`Nollhlst‘
`TIIALDMII)’
`{310905135} for Injemlnn
`llestustarone enanume ”news“. USP:
`
`Nlmlnn'
`(naprlnan sodium
`Wifolledxralww IIIDIBISI
`unnmu
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`P. col
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`
`300
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`CELGENE
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`“gunman
`
`r m
`
`CIPLA EXHIBIT 1008
`
`Page 2 of 9
`
`CIPLA EXHIBIT 1008
`Page 2 of 9
`
`

`

`BRISTOL-MYE PIS SOUIBB 0NCJ|MMJ331
`PRODUCT INFORMATION
` Skin reactions associated with
`Handling and Dlspoeel:
`Table 1: Summary of Pharmaenllnnle Par-nature - Mean Value:
`dommhilrin have been repel-bed. Shin aneidentlg exposed to
`om-
`melon
`a
`c...
`AUG III-ear
`T-I-Iau-
`ct.
`dexorubicin should be rinsed copiously with soap and warm
`(Irwin-’1
`Detention no
`tons-nu}
`[-19:le
`Ina-Main
`lbl
`ILmi-n'r
`water. and iftho eyes are involved, standard irrigation tech-
`niques should be used immediately. The use of goggles.
`135
`24
`2
`195
`6300
`52.7
`21.7
`gloves. and protective gowns is recommended during prep
`175
`24
`4
`365
`7993
`15.7
`23.s
`oration and adminisnafion'or’ the drug.
`135
`3
`7
`2170
`7952
`13.1
`17.7
`Procedures for proper handling and dispose] of anticancer
`
`3 5 8650 15007 20.2175 12.2
`
`
`
`
`
`drugs should he considered. Sayers] guidelines on this sub-
`ject have been published.M There is no general agreem—t
`= Maximum plasma concentration
`that all of the procedures recommended in the guidelines
`are necessary or appropriate.
`aiié (ll-W] - Area under the plasma concentration-time cur-vs from time I] to infinity
`(1...: Total body clearance
`HOW SUPPLIED
`DESCRIPTION
`BUBEXCD (docwruhicin hydrochloride for injection, USP) is
`activity recovered in the feces. while metabolites, primarily
`available as follows:
`Gel-hydromaclitaxel. accounted for the balance. in Intro
`TAXOLD (psalitasell Injection is a clear colorless to slightly
`studies with human liver microsernsa and tissue slices
`Ming—Escheingle-dosovialoontains 50mg ofdoaorulri'
`yellow viscous solution. It is supplied as a nopsqueous solu-
`cin HCI. USP as a sterile red-crsnge lyophililed
`showed that paclitmel was metabolized primarily to 8n-
`tion intended for dilution with a suitable parenteral fluid
`powder, MOI: 0016-3352-22Availahls as one indi-
`hydroxypaclitanel by the cytochrome P450 isusyina .
`prior to intravenous infusion TAXOL is available in 30 mg
`vidually cartcned vial.
`CYPZCS: and to two minor metabolites. 8'-P~h!dl'0macli-.
`(5 le. 100 mg (16.7 mL]. and 300 mg (50 mL) midfidose
`100 mg —Eech singiealoee vial contains 100 mg of doctora-
`tamel and Go. 3’-p-dihydroxypulitanel. by CYP3A4. In ultra.
`vials. Each InL of sterile ocnpyinganic solution contains 6
`bicln HCI. USP as a sterile red-orange lyophil'md
`the metabolism ofpanbtaasl to dis:
`clitaxel was in-
`mg paclitexel. 527 mg of purified GremopbcI-Q EL' (poly-
`powder. NBC 00154335322. Available as one indi-
`hibited by a number of agents (Roommate. vorapamj],
`oayethylsted caster oil) and 49.7% (We) dehydrated alcohol.
`USP.
`vidually Iarhnned vial.
`dissepam, quinsdine. daaamethaaone. cyclospon'n tenipo-
`Storage: Store dry powder at controlled room temperature
`Paclitaxel is a natural product with antitumor activity.
`side. etapoaide, and vincxistine]. but the concentrations
`15'40'0 (59'45’Fl.
`used emeded those found is vice following normal thera-
`TAXOL is obtainedvia a asmi-syoflrsfic process From Thurs
`The reconstituted solution is stable for 7 days at room tern-
`peutic doses. Thetaaterooe, 17a~etbinyl eata'adiol. refinoic
`boot-arc. The chemical name tier paclitexel is SBmEposy-
`acid. and quercctin. a specific inhibitorafCYPBCS. also ill-
`paraturo or 15 days under refrigeration T—S'C (”'46'17).
`1.2c1.4,79,103.13o-hexshydrmqrtax-11-en-9-one 4,10—dr'ace—
`hihited the formation of Ga-
`aclitaloel I'J'r vim. The
`Protectfromeaposucetoaunlight.fletainincamnuntil
`tate Zsbenccate Iii-eater with (QRfisl-N-beazoyl-li-pbenyli-
`time of ".39.
`eoserine.
`pl'lsrmsonldnofim ofpanlitaxal may also be altered in ciao
`as a result of interactions with compounds that are sub
`Paclitsxel has the following structural formula:
`REFERENCES
`ah'ates, inducers. cur inhibitors of CYPZCS andfcr CYP3A4.
`1. Rudolph R, Larson BL: Etiology and Treatment. qube-
`(See PRECAUTIONS: Drug Interactions section.) The ef-
`motherspeutic Agent Eatmvsaation Injuries: A Review. J
`fect ofrenal orhspatic dysfunction on the disposition of pa-
`Olin Onto! 1987:5:11.16—1126.
`clitml has not been investigated.
`2. Recommendations for the Safe Handling of Parenteral
`Possible interactions of paclitsrnsl with concomitantly ad-
`Aufineoplas‘hic Drugs. NH-IPuhlication No 83-2621. For
`ministered medicaticns have not been formally investi-
`sale by the Superintendent of Documents US Govern-
`gated.
`ment Printing Oilice. Washington. DC m2.
`3_. AMA Council Report. Guidelines for Handling Parenteral
`‘CremopharOELiethemgiatemdh'ademarkofBASFAk-
`Anfineeplsstics. JAM! 1986; 253 (11]:1590-1592.
`tieogeleflehafit GramophortllELiafiu-firerpurifiedbya
`Bristol-Myers Squibb Company proprietary process before
`4. National Study Commission on Cytotoxic Exposure—
`1188.
`Recommendations fcr Handling Cytotoxic Agents. Avail-
`able from Louis P. Jefl'rsy. ScD. Chairman, National
`CLINICAL STUDIES
`Study Commission on Cytotoxic Exposure, Massachu-
`Ovarian Carcinoma:
`setts College of Pharmacy and Allied Health Sciences.
`179 Lengwood Menus. Boston. Massachusetts 02115.
`_5. Clinical Oncological Society of Australia. Guidelines and
`Recommendafim lbr Batu Handling of Antineoplaafic
`Agents. Med J Australia 1988; 13126-423.
`6.Jonll RB, et a1: Sal’s Handling of Chemotherapeutic
`Agents: A Report from the Mount Sinai Medical Center.
`CA—fi Concer‘Jom-nor' for Clinicians 1933: (SeptI'Octl
`253-383.
`7. American Society ofHospita] Pharmacists Tbchnical Ase
`eistanee Bulletin on Handling Cytotoxic and Hazardous
`Drugs AmJHusp Flier-m 1990; 47:1033—1049
`8. Controlling Occupational
`he Hazardous Drugs.
`(031% WORK:PRACTICE summer. Am J Health-
`Sysr Plum 1.996963 1669-1685.
`Ila-cl Johnson
`ONDDIDGY PRODUCTS
`A Bristol--l\1yera Staribb Company
`Princeton. NJ 03543
`USA.
`Ell-13001499
`51-004726-02
`
`
`
`
`
`CIPLA EXHIBIT 1008
`
`Page 3 of 9
`
`Paclitaxel is a white to eff-white crystalline powder with the
`empiriral fierula CanNOH and a molecular weight. of
`853.9. It is highly lipopbilic. insoluble in water. and melts at
`around 216-217'0.
`.
`_
`CLINICAL mower
`Peelituel is a novel anemia-ems agent that promotes
`the assembly of microt'ubules from tubulin dimers and sta-
`bilizes mimtuhules by preventing depolymerisation. This
`stability results in the inhibition ofthe normal dynamic re-
`organization ofthe mimtu'bule network that is essential for
`vital interpbase. end mitotic cellular firndiona. In addition.
`paclitasel induces abnormal am or 'bundlea' ofmierotu-
`bulee througlmut the cell cycle and multiple asters ofmiero-
`tubules during mitosis.
`Following intravenous administration of I131111011, paelitaxel
`plasma concentrations declined in a hiphaeic manner. The
`initial rapid decline represents distribution to the periph-
`eral compartment and elimination of the drug. The later
`phaeeie due, anart. to a relatively slow sfluxofperli‘tsxal
`from the peripheral compartment.
`Phsmamfinetic parameters ofpoclitaxel fbllowing S- and
`21-hour infusions ofTAXOL at dose levels ef135 and 115
`rr'rgfrn2 weredcherminedinel’haaearandomiaedstudyin
`wadsncancerpsfientsonoameummerissdin thefollm
`irrg table:
`[See table 1 above]
`It appeared that with the 24-hour infusion ofTAXOL. a 30%
`increase in dose (135 mgr‘m" versus 175 Ingfm’} increased
`the C... lay 8796. whereas lhe'A‘UC {0-H} remained propor-
`ticnal. However. with a 3-hour infusion. for a 30% increase
`indoseJhechuandAUClO-euweminmsaedbyfis‘bsnd
`59%, respectively. The mean apparent volume of distribu-
`tion at steady state, with the 24-hour infirsiorn of TAXOL.
`mmwmmw‘.iudinengmmsm-
`cular distribution andJ'cr tissue binding of paclitasel.
`The pharmmlcinefim of psclitaxel were also evaluated in
`adult center patients who received single doses of 15—135
`given by Liner infusions (n:15).80—2?5 ngm'
`
`given byEl6-hour infirsiona (11:36}. and 200-215 mgz‘m‘grven’
`by2+hourinfusionsln=6tlinPheee1k2ehrdiquss
`For CL; andvolume ofdistx'ihnfisn were consistent with the
`findings in the Phase 3 study. The pherrnacokinetics of
`TAXOL in patients with AXES-related Kaposi's sarcoma
`have not. been studied.
`In eilm studies ofbinding to human serum proteins, using
`podium] mneenh-afionsrengingfi-om 0.1t050ugfnrl... in-
`dicate that between Elia-98% ofdrug is bound; the presence
`of cimofidine. rarlitidine. demetbaeone. cr- diphenhydrs—
`mine did ootatfectprotein bindingcfpecb'taxal.
`Ailm- intravenous administration of 15-275 mafia: doses at
`TAXOL as 1‘. 6-. or 24—hour infusions. mean values for cu-
`mulative urinary mover-y of unchanged drug ranged from
`1.3% to 12.5% of the dose. indicating extensive nun-Ten
`clearance. In five patientaadminister'ed a 225 01250le
`dnseefradiolahelsdmflLasasmom-infusion. umeaan
`11% oftbe radioactivity was excreted in the feces in 120
`hem, and 14% was wavered in the urine. Total recovery or
`radioactivity ranged from 55% to 101% of the dose. Pachw
`towel representedameanofase oftheadmjnietarodradio—
`
`first-line Dela—The asset; and cficocy of TAXOL (peeli-
`taxell Injection (136 Inga: ever 24 hours)In combination
`with exisplatin (1'5 mglm )in patients with advanced ovarian
`cancer and. no prior chemotherapy were evaluatedIn a
`Phase 3 multimeter; randomised. controlled (vs. cydophos.
`phomida 750 Inglm fueplafin 75 mom”) 1:311:qu ai-l con-
`ducted by the Gynecologic Oncology Group (606}. Atocal of
`410 patients with Stage III or N disease (>1 no residual
`disease after slam Isparotomy or distant metastases)
`were randomised. Patients heated with TAXOL to combina—
`tion with eiaplatrin had significantly longer time to progres-
`sion (median 16.6 vs. 13.0 months. pecans) and nearly a
`year lengarmedisn survival time 920.0002) compared with
`standard therapy:
`(Seeteble a attopofnextpene]
`The adverse event: profile for patients receiving TAXDL'in
`combination with ciaphtin in this study was generally urn-
`eistentwitb that eeeofirrthepooled analysis olden from
`81.2 patients treated with aingleagsnt 128101. in 1.0 clinical
`atudies.’lhaaesdveraoemtaandadversoavnntsfmmthe
`Phase 8 first-line ovarian cerdnoma study are described in
`them REACTIONS sed‘ionintehularfl‘ableafl
`and 9) and narrative form.
`Second-line Data—Data from live Phase 1 Us 2 clinical
`studies (189 patients). a molticencsr randomised Phase 3
`atnl‘lyldlll’pafienlsl. aswellasauintarimanalyaiaofdata
`from more than 300 patients enrolled in a treatment refer-
`ral center program were used in support of the use of
`IIEMCEJL in patients who have failed initial or subsequent
`chemothsrsoyfpr metastsuccsmnmmoftheovmv. Mot
`tbePhaseZatudieaflfl patientsluliliaedaninitialdoaaod
`135 to 110 argon"In most patients 690%) administered
`ever 21 hours by continuous infusion. Response rates in
`these two studies were 22% (95% Cl: 11% to B'Hd and m
`{55%01: lflhmlwitbsmfleffimplefimd leper
`tial responses in 92 patients. The median duration el'cverall
`reapenseintheestwostndiesmeosuredfiomtheflrstdayod’
`treatment was “1.2 months (range: 3.5—15.5 months] and 1.6
`months (range: 53—116 months). res
`'
`. The median
`survival was 8.1 months (range: 03-30.? months) and 15.9
`months (range: 1.8-8454- months].
`TheP'b'aeessmdyhadabifectminldeaignandcompamd
`the eficecy and safety ofTAXOL. administered at two dif-
`threat. doses (135 or 175 mgl'm') and mines (a. or 24.
`hour infusion]. The overall reapimae rate-for the 11-0? pa-
`tients was 16.2% (95% Cl: 12.8% to 20.2%) with 6 complete
`andfiOpsrtisIrespuoses.Durationofrespouse.mssured
`fromthefiretday oftrealrmentwas 8.3 montbelrange‘. 8.2—
`21.6 months). Median time to progression was 3.1 months
`(range 0.1+ - 251+ months). Median survival was 11.5
`months image: 0&231“ months].
`Reepmsemhamediansurrivalandmedienfimetopm—
`Mofortbesannemgiveninthetcllowingtahle.
`[Seetsbleaattepofnextpagel
`Analyses were performed as planned by the hifectoria]
`study design described in the protocol. by comparing the
`two doses (135 or 175 mgfmel irrespective ol'tbe schedule (3
`Wmmnlfl
`wzooommmmmmm
`
`33513311436
`Revised: September 1998
`
`TAXDLO
`Eton-all
`(petites-ll lnlecllon
`
`I} may
`
`WARNING
`mom (parlitaxell Injection should be administered
`under the supervision ol's physician experienced in the
`use of cancer chemotherapeutic agents. Appropriate
`management: nfcomplicetinne is possible only when Ill-
`equate diagnostic and treatment facilities are readily
`available.
`Amphylaxr's and severe hypersensitivity reactions char-
`acterised by dyapnea and hypetension requiring treat
`ment. angioerlenra, and
`'
`In‘ticsris have oc-
`curred in ”04% ofpatients receivingTAXOL in clinical
`trials. Fats] reactionahm occurred in patients despite
`pmmedieatiuu. All patients should be pretreated with
`corticosteroids. dipbenhydramine. and H, antagonists.
`(See MANDADWION section.) Pa-
`tients who experienm severe hypersensitivity relations
`te‘EAXOLehoaldmt herachallengedwith thedrug.
`TAXOL therapy should not be given to patients with
`solid hunters who have baseline neutropbil counts cfless
`than 1,500 cellsi’mlzu3 and should not be given to pa-
`tients with AIDS-related Kaposi's sarcoma if the base-
`lioeneuh‘cphilcoantisleesthan 1000wllahmn'.1nor~
`dsr to monitor the occurrence of bone marrow suppres—
`sion, primarily neotropenia, which may he more and
`result in infection. it is recommended that frequent pe-
`ripheral blood cell counts be performed on all patients
`
`receiving TAXOL.
`
`CIPLA EXHIBIT 1008
`Page 3 of 9
`
`

`

`PHYSICIANS' DESK REFERENCE®
`BBZIBHISTOLuMYERS SOUIBB ONCJIMM.
`
`Teach—Cont.
`‘Ihhh 2: Eifiucy in th- an... 3 FlrcI-Lln- oe-un Goldman Study
`
`3“
`
`0.04
`
`'
`0301
`
`30
`
`_
`
`'
`
`I
`JW
`Witch!“
`
`rufifil’]
`[W14]
`l1
`. Gilded flecpoms‘
`(11:113]
`(n=127]
`- rate (percent)
`62
`43 -
`- p—mlue
`' FWWIHI
`‘ ““75 (percent)
`. Maine
`' Pathological
`Complete Response
`16
`21
`020
`A utgllperoeut)
`‘
`”on
`.fimtz‘h
`130
`166
`i
`_ made.“ (months)
`'
`‘
`0 m
`_ p-vslue
`,
`. gm
`243
`355
`_ median (months!
`
`- pvalue
`0-0002
`' Among evalushie patients only.
`*Includos patients with pathological complete response plus patients with mimseopie residual disease.
`
`Table 3: Efficacy In the Phase 3 Second-Um Ovarian Carcinoma Study
`
`use
`Mail
`e
`145 -
`(3.5.23.6)
`4.4
`(3.0-5.6)
`
`- 1'8 m
`“Hug-E"
`m
`- 95% Confidence Interval
`'Emuprlmuucin
`. 95c Gonfidenns Idem:
`- sin-mu
`-
`10.7
`13.1
`1.1.8
`11.5
`_
`.mfijfin (months)
`
`- 95c chasm Interval
`[SA—HA)
`lac—24s}
`(9.14145)
`redirect
`that measured mlijacfive sasem'ment of treahnent. Ofthe
`TsflecEficscyinBrslclcenwaFsflunoflMdsl
`seven. the Lung Cancer Specific Symptoms subscale favored
`ChemothsrspynrwlthinBMonfluofAdjuvsntTlWy
`the MOL 135 mglm‘m hour plus cisplstin arm tampered
`to the cisciatinfetopcaide am. For all other factors. than
`was no disarm; in the moat-seizures:
`The adverse event profile for patients who. received TAXOL
`in combination with, cisphtin in H113 may was generally
`coexistent with that men hr ting pooled analysis nf_data
`frgmj 813 whats heated mth music-wt WDI- :21 10
`clinical studies. M 9‘1"” events “d adverse events
`3-0 m B" Pin" 3 hum" "SOLO. mid? are Mb“! in
`the EVE?“ REACgIONB m In tabular mm“ 5'
`ma“ “mm“, m-
`‘D m.
`1.32?“W ‘ 5'3”" {Emil “'9 P23”; 2
`rapy In patients with AIDS-related Kaposi's sarcoma.
`E - “1“ 3” “1’1”?" m“
`”m ‘ “e
`previously received systemic therapy: including interferon
`Iplpha (32%l.DaunoXomeOl31%i.D0mi2%l and dose-
`ruhicin containing chemotherapy (42%), with 64% having
`received prim- anflxracycllnes. Eighty-five percent ofthe pre-
`treated patients had progressed on, or cmald not tolerate,
`prior systemic therapy.
`In Study GA139-174 patients received TAXOLa‘t 135 main}:
`aaa3-ho1rrinfimonevery3weelrstintendeddeseinbansity
`«maim‘fweekl If no dues-limits? toxicity was chewed,
`patients were to receive 155 raglan and 175 made“ in sub
`sequent courses. Hemaoopcietic growth factors were not to
`he used initially. In Study 01:139-281. patients received
`m0]. (paclitexell Injection at 100 mom“ Is a 3-hour
`infusion every 2 weeks (intended dose intensity 50 mgl'm’J
`week) in this study patients could be receiving hematcpui-
`etic Wth fschnrs before theatartol’TAXOL therapy; or
`this support was to be initiated as indicated; the dues of
`TAXDL was not increased. The dose intensity of T8101;
`used in this patient population was lower than the dose in-
`tensity recommended for other solid tumors.
`
`.
`.
`oerhours] and the twoccheduleeu'reqsechvenfdnse. Ps-
`tients receiving the 175 mglnr’ dose had a response rate-
`sirsilsr to thatfor those receiving the 135 mgfm’ dose: 18%
`vs. 14% ($0.28). No difi’erenee in response rate was de-
`tested when comparing the Lhour with the 24-hour infu-
`aion: 15% vs. ”it (pm-0.50). Patients receiving the 175
`mgfnr' of TAXOL had a longer time to progression than
`those receiving the 135 mm“ dose: median 4.2 vs. 3.1
`months (gr-0.03). The median time to progression For pe-
`tients renewingthe 3-hour vs. the 24-hour infusion was 40
`months vs. 37 months. respectively. Median survival was
`11.6mmtheinpatienereeeiviugthemmc'm‘dmef
`TAXDL and 11.0 months in patients receiving the 135
`mgfm‘ dose [pr-0.92). Median survival was 11.7 months for
`patients receiving the 3-hour infusion OTTAXOL and 11.2
`months for patiepterecoiving the 24-hour infusion [H.911
`These mtisfical anaiysssshould beviewed with motion bfi-
`cause of the multiple comparisons made.
`TAXOL remained active in patients who had developed rev
`distance to plafinumeonteining therapy (defined as humor
`progessicu while an. or tumor relapse within 6 months
`Emu completion of. s plafinum-wutsifiugrngenlwilh re-
`sponssratesof14%inihePhaseSstudycnd 81%inthe
`Phase 1 s; 2 finial m
`The adverse event profile in this Phase 3 study was consis-
`sentwith emu; seenforthepoolad analysis graham 312
`mpafimwuwugmimdmzim.simme‘dm‘mzzlfi
`110me ' “abnormal-(1%.“ She d 10 and BEA-G
`on m
`.
`an
`an
`)
`mauve
`““1
`The results ofthe randomised study support the use 3f
`TAXOL tracheal} mm at doses at 135 to 175 mom .
`administered by a 3-hour intravenous infusion The same
`doses administered by some: inflision were more tmo'c.
`However, the study had insulficient power to determine
`whether a pertioslar dose and. schedule produced superior
`silicscy
`emu card-mm: Data from as psfisnta seemed in three
`Phase 2 open label studies and from 171 patients enrolled in
`- m3 -
`a Phase 3 rmdemiced study were available to support the
`. rite (percent)
`mars-axon in patients with met-satin: breast urcinumn.
`- p—valua
`Matron-n Warm—hostudieaware conductediu
`' W110 '0 HOMO“
`53 patients previously heated with smacimum ofone prior
`' "Nd-i“ [months]
`chemotherapeutic regimen. TAXOL was administered in
`' P‘V‘l‘“
`these two trials as a 24-hour infusion at initial doses (£250
`men‘twuhocsrmppumorzoodlp‘m‘.mm 'M'F'
`19-5
`11-7
`m. were amuse 01: 3mm wound 52c (951ml: 32%
`‘ ”9"“ (““9“)
`
`.
`to ms.) respectively. "The third rum 2 study was con-
`“Wam-
`0'3“
`ducted in extensively pron-sated patients who had failed so-
`thrscydine therapy and who had received a minimum of
`The adverse event profile ofthe psfients who received gin-
`two chemotherapy regimens forthsltreetment ofmataststic
`gle-egent TAXDL'in the Phase 3 study was mneistent with
`disease. The dose armor. was 200 m“ as a 24-hour
`that seen for the pooled analysis of data from 312 patisnita
`trestedinmclinicslatudiee.'i'hesesdverseeventsand ad-
`infusion with G-CSF support. Nine of the 30 patients
`vereeeventsfromthePhasthrsastcarsinmnaatndym
`achieved. a partial responae,‘l'or a response rate (£305: [355:
`CI: “Ha-50%).
`described in the ADVERSE REACHONS’sectienin tabu-
`lar (Tables 3 and 11) and narrative firm
`Phase 3 random caddy—This multioenter trial was con-
`Non-Small M Long carcinoma {nectar—In a Phase 3
`ducted in patients previously treated with one or two regi-
`open label randomized study conducted by the Eastern 00‘
`mensofchemotherapy. Patients were randomised in receive
`TAXOL at adoseofeither l’l'fi raglanx or 135m9‘rn' given as
`operative Oncology Group (EC-06). 599:pstients were ran-
`despised to sifller‘EAXOLlT) lSlintgfm’ as u‘M—hourint'u-
`a 8-hour infusion. In the d'l'l patents enrolled. 90% had
`aim in combination with cisplstm In) 75 mgt‘ma, MOI; [Tl
`symptomatic disease with impaired performance stands at
`260 m3 as a 24-hourinfusins'In combination with cisple
`study may. and 78% had visceral metastases. These pa-
`shin (c) 1'5 ramp” with G-CSF supwrt. or cisplsfin (El 15
`tients had failed prior chemotherapy either in the adiuvant
`mg'm’ on day 1 followed by etcposide WP) 100 night:3 on
`setting (30%), the metastatic setting (35%). or hot-ll (315).
`days 1. 2. and3 (control)
`Sixtyseren percent oft-he patients had been previously ex-
`Response rates. median time to progression. median cur:
`viva1.and one-year survival rates are given in the following
`poeedooanthracyclinessndfi‘hm‘thamhnddisessemn—
`sidsred resistant to this class of agents
`table. The reported [2--values have not been adjusted for
`mulfipie comparisons There were statistically significant
`The overall response rate fortho 454 evaluable patients was
`difi‘erenms favor-ingest]: ofths TAXOL plus cicplntin arms
`26% (95% CI: W013}. with 17 complete and 9!) partial
`ferrecponse mteandfimetetumorprcgression Thur-ewes
`responses. The medlsnduretionorl‘response. measuredfi'om
`no statistically significant Maroone'in survival between ei-
`thewfiratdsy oftreatment, was B. 1. months (ranger3.4—13.1+
`months). Overall for the 411 patients,_the median time to
`ther IIEMEOL plus eisplatin arm and the cisplatin plus eta-
`wes3.5 menthslnsng‘e:003—17.lmonthsl.ide-
`poside am
`[See table El below]
`dian survival was 11.7 months (range: 0-189 months)
`In the ECDG studs; the Functional Assessment of'Canoer
`Responserates. median survival and median time to pro-
`Therapy—Lung (FACIAL) questionnaire had seven subsonic:
`gression forthszn-msaregiveninthefollowisgtshle
`Tabl-§:EfiuscyPsmmsinmsPhus3Hm-Lhem9hpdy
`
`.1131,
`
`IE...
`
`.
`
`'
`
`22
`
`23
`
`4-2
`
`11.135
`
`0927
`
`c
`“3:“
`‘53:”
`“32°.
`
`{mm
`mm"
`mI
`
`'
`
`_
`
`_'
`
`_
`
`. gm
`23
`25
`- rate (Wt)
`- <om1
`0,001
`— p-Vflluei
`'
`' 11'". W W“
`4.9
`4.3
`. median {months}
`0.0M
`0.05
`- p-vslae"
`. Survival
`1.10
`s_3
`- median (months)
`p-Vhluoh
`012
`(L08
`43¢»st surVMI
`‘
`-
`
`. percent ofpatients
`'
`'
`36
`4,0
`.
`52
`‘Etoposide (VP) roomful was cdmmistered IV. on days 1 2 and s.
`I’Couppared to eisplafinlelspceide.
`Mnmhwww.mwflHm
`
`1:2
`
`-
`
`2::
`
`14
`
`use:
`ln=1flfil
`.
`21 7
`(14.5—31.0)
`4.2
`(3.5—5.1)
`
`13513
`{RIBS}
`.
`152
`(so-ecu
`3.4.
`{2.3—4.3}
`
`135m
`(M131
`.
`132
`11.7—21.5)
`' as
`(1.9-4.0)
`
` Fifiy—nincafthe 85 patients enrolledinthese studies had
`
`DuanoanneO is a registered iradsmsrk queKs‘lar Phnrv
`maeeuficals, Inc. DOXILD'1e a'rey'stered trademark olSe-
`quus Pharmaceuticals. Inc
`Allpatientshad widespread and pom-risk.dicesse Applying
`the A011} staging miter-is to patients wi‘lh prior systemic
`therapy. 93% were poor risk for extent ufiiisense”11.38%
`had s cm count <soo eelLy'mm‘ (1.), and one hadpoor risk
`considering their systemic illness 65;).
`All petisnts in Study cumin had a Ksrnoi'slq pursue
`msnee ststus orl'Bil or 90 at baseline:in Study CA1“281,
`status of 70
`there were 26 (-16%) patients wim a Kamofsky perform-anal
`w m ”i W'
`Tshlo a: Ext-m at III-nus at Study Em
`P-wfl_.__ of I'm
`. Prior Symplc
`
`Mr
`"“591
`42
`Visceral 1 edema : oral .t
`cutaneous
`41
`Edemsorlymphnodesm-al:
`10
`.
`03mm
`
`Cum-nun only
`' 7
`
`CIPLA EXHIBIT 1008
`
`Page 4 of 9
`
`CIPLA EXHIBIT 1008
`Page 4 of 9
`
`

`

`
`
`BRISTOL-MYERS SOUIBB ONCflMMJm
`PRODUCT INFORMATION
`
`Hmoughmeplannsddoaaintensityinthstwoehulieswea
`MOI. infusion. is recommded. Continuous cud-in: monv
`mm a Java} moo callefmmablm m3 for pc-
`tielriewitb KSlendplslsleteml-oalevelflflflflm
`itofingisnotrequiradexcaptforpnfiantswifli seriouscnn-
`slightly difierent (is mgfmliweek'In Study cares-11¢ and
`ducfion abnormalities {Sea WARNINGS section.)
`cellsI'mIn’.
`50 main.(week'in Study 05139-281). delivered does intsn
`Severe condudion abnormalities have been decimated in
`aity mammimkumm. withasimilar
`Menu System: Although. the oecnrrenee'oi' peripheral
`<1firnl’pationts dufingTAXOLfiienpyandinsmeceses
`range (20-24 to 51-61).
`nsmpsfilyisfi'eqoant. thedsvslnpmant efasvsre syrup-
`EMcscr—Tbs eficas'y ol' TAXOL was evaluated by assess-
`waiting pacemaker placement pratisnts develop signifi-
`hematologyisnnususlandrequiresedoscrcducfianofm
`ingcutsneoustumorrespoacesccoodingtnthesmended
`cant conduction abnormalities during TAXOL interim. ep-
`for all subsequent com-ass of'I‘itXOL.
`ACPG criteria and by seekiogev'idsucsofclininsl hensfitin
`proprisla therapy should be administered and continuous
`TAXOL contains dehydreted alcohol USP, 396nigh-1L;eon
`cardiac monitoring should he performed during subsequent
`patients in six domains ofsymptoms andl'cr conditions that
`airlaratinn should be giventn poan‘hle C'NSand nthersll'ects
`are commonly related toms-related Kaposi’s sarcoma.
`therapy with TAXOL.
`ofaloohoi. [Sea PRECAUTIONS: Pam Us. section.)
`Cutaneous Tumor Reasons. Marauder! am ml—
`Pregnancy: TAXOL can cause fetal harm whaoadminis-
`Hepatic: There isevidence that the toxicity oiTAXOL is en-
`Tbsclfiartivsreaponsoratammwrs‘km: 46% to 72%]
`bored to a pregnant woman. Administration oi psclitaxsl
`hanced in patients with elevated liver
`. Caution
`duringtheperiodcforgauogsaesistnrabbite atdoeesofan
`(35 offi? patients) in patients with prior systemic therapy.
`should beamercised when administering moms patients
`Cutaneous responses were p '
`'
`defined as fiatteningqf
`sty (about i).2 the daily maximum recommended hu-
`with moderate to severe hepatic impairment and dose ad-
`more than 50% of previously raised lednns.
`man does on aroglma basis) mused embryo- and fetotozcicity,
`justments should be considered.
`lniaetlcm 8h- flas