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`Actavis - an2017-o11o1
`Actavis - IPR2017-01101
`Ex. 1008, p. 1 of 9
`Ex. 1008, p.1 or 9
`
`
`
`

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`Actavis - IPR2017-01101, Ex. 1008, p. of 2 of 9
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`-OTTO‘I, X.
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`
`

`

`Cm = Maximum plasma concentration
`curve from time I] to infinity
`AUG (0-00] — Area under the plasma
`QLT= I'l'otal body clearance
`DECRIPTION
`activity recovered in the feces. while metabolites, primarily
`(is-hydromnclitaxel. accounted for the balance. In oitro
`TAKOLD (peelitazell [Junction is a clear colorless to slightly
`studies with human liver microsomes and tissue slices
`yellow viscous solution. It is supplied as a nonaqueous solu-
`showed that paclitssel was metslmlinad primarily to 6n-
`tion intended for dilution with a suitable parenteral fluid
`hyqu'psclitaxel by the cytochrome P450 isosyina _
`prior to intravenous
`TAXOL is available in 30 mg
`m; and to-two minor metabolites, 8'—p-hydm:qrpacli—.
`(5 mL}. 100 mg (16.7 le. and 300 mg (50 le multidose
`taml and 6a. 31-p-dihydroxypsditaxsl. by CYP3A4. In ultra.
`vials. Each ml. of sterile nsnpyroganic solution contains 6
`the metabolism of psclitaxel to tin-hydroxypaclitexel was in-
`mg paclitaxel. 52'? mg of purified CremophorQ EL’ (poly-
`hibited by a number of agents (ketoeonazols. verapamj],
`methylated caster oil) and 49.7% (vhf) dehydrated alcohol.
`USP.
`diasepam, quinidine. deramethasone. cyclospotin. telupo-
`side, eteposide, and vincristinel. but the concentrations
`Psclitsxsl is a natural product with .antitumor' activity.
`used exceeded those found in viva following normal thera-
`TAXOL is obtained via a asmi-synflretic process from Thurs
`peutic doses. Tbstosterene, I'lu-ethiayl estradiol, retinoic
`boecoro. The chmica] name for paclitaxel is 53.20-qu-
`acid. and quercetio. a specific
`of CYP2I38. also in-
`1.2n.4,79,103.13n-haxahydroxytsx-11-en-9-one 4,10-diace—
`hihited the formation of 6a.—
`aclitanel in uitro. The
`tate 2-banaoate lit-eater with (2R,SSl-N-benzoyl-3-phenylj-
`soserme.
`pharmacolrinotica ofpaclitaxel may also be altered in vivo
`as a result of interactions with compounds that are sub
`Paclitsxel has the following structural formula:
`stratus, inducers, or inhibitors of CYPZCS andl'or CYP3A4.
`(See PRECAUTIONS: Drug Interactions section.) The ef—
`fect ofrenal or hepatic dysfimction on the
`of pa-
`clitsme] has not been investigated.
`Possible interactions of paclitamsl with concomitantly ad-
`ministered medications have not been formally investi-
`gated.
`
`
`
`
`
`BRISTOL-MYERS SOUIBB ONCJIMMJSB‘t
`PRODUCT INFORMATION
`
`Skin reactions associated with
`Handling and Dlspoosl:
`Table ‘l: SummaryI of Phsnnnooltlnltlo Plum - Mean Value
`dombicin have been reported. Skin auridently exposed to
`om
`Infusion
`s
`cm
`auc Io-ut
`T-HALF
`CL.
`doxorubioin should be rinsed copiously with soap and warm
`tmoirn’l
`Damion lhl
`(Mental
`[nulle
`(nu-Mrs”
`III}
`(Uln‘in’l
`water. and ifthe eyes are involved, standard irrigation tech-
`niques should be used immediately. The use of goggles.
`135
`24
`2
`195
`6300
`52.?
`21.?
`glovesI and protective gowns is mmmended during prep
`175
`24
`4
`865
`T993
`15.?
`23.8
`oration and administration'of the drug.
`135
`3
`7
`2170
`7952
`13.1
`17.7
`Procedures for proper handling and disposal of anticancer
`175
`3
`5
`8650
`15ml?I
`20.2
`12.2
`drugs should be considered. Several guidelines on this sub-
`ject have been published.M There is no general agreemt
`that: all of the procedures recommended in the guidelines
`are necessary or appropriate.
`HOW SUPPLIED
`RUBEKCD (dooooruhicin hydrochloride for injection, US?) is
`availahle as follows:
`50 mg —Each single-dose vial contains 5|] mg or'domruhi-
`cin HCI. USP as s sterile red-orange lyophilired
`powder, NDc 0015-3352-22. Available as one
`vidually car-toned vial.
`100 mg —Each single-dose vial contains 100 mg of deutero-
`bicin HCI, USP as a sterile red-orange lyophilirsd
`powder, NDC 0015-3353-22. Available as one indi-
`viduslly mrtonerl vial.
`Storage: Store dry powder at controlled room temperature
`15°—30°C (SW—36?).
`The reconstituted solution is stable for '3 days at room tem-
`perature or 16 days under refrigeration 2‘—8'C (33“46'17}.
`Protect from exposure to sunlight. Retain in car-ton until
`time of use.
`BEFEBEN
`1. Rudolph R, Larson DL' Etiology and Treatment ofChe-
`matherapeutic Agent Extravasation Injuries: A Review. J
`Clio Once! 1987: 54116—1323.
`2. Recommendations for the Safe Handling of Parenteral
`Antinaoplastic Drugs. NIH Publication No. 83-2621. For
`sale by the Superintendent of Documents, US Govern-
`ment Printing Otfice. Washington. DC m2.
`3. AMA Council Report. Guidelines for Handling Parenteral
`Antineoplastics. JAM 1935; 253 (11]:1590—1592.
`4. National Study Commission on Cytotoxic Exposure—
`Recontmendations for Handling Cytotocric Agents. Avail-
`able from Louis P. Jefirey. ScD. Chairman, National
`Study Commission on Cytotoxic Exposure, Massachu-
`setts College of Pharmacy and Allied Health Sciences,
`179 Longwood Avenue. Boston. Massachusetts 92115.
`5. Clinical Oncologicsl Society of Australia. Guidelines and
`Recommendaficna for Safe Handling of Antineoplastic
`Agents. Med J Australia 1983; 1326—423.
`6.Jonee RB, at al: Safe Handling of Chemotherapeutic
`Agents: A Report from the Mount Sinai Medical Center.
`(DA—A Concer_ Journal for Clinicians 1938: (Sspn'Octl
`255-863.
`7. American Society ofHosmta] Pharmacists 'Ibchnical As-
`ststsncehulletin on Handling Cytotoxic and Hazardous
`Drugs. Am J Hosp Flier-m 1990; 47:1033—1049. .
`8. Controlling Occupational Exposure to Hazardous Drugs.
`(OSHA WOW-PRACTICE GUDJEIm'EfilJm J Health-
`Sysl Pilot-m 1996;53:1639—1635.
`Mend Johnson
`ONCOLOGY PRODUCTS
`A Bristol-Myers Squibb Company
`Princeton, NJ 03643
`USA.
`Kit-13001399
`51-004‘i‘26-02
`
`Paclitsxel is a white to {ii—white crystalline powderwith the
`empirical formnla CnHflNOH and a molecular weight of
`353.9. It is highly lipophilic, insoluble in water. and melts at
`around 216-2le.
`CLINICAL PHARMACOLOGY
`Paclituel is a novel sntimicromhnls agent that promotes
`the assembly of microtubules from tubulin dimers and sta-
`bilizes microtuhules by preventing depolymsriaah'on. This
`stability results in the inhibition ofthe normal dynamic re-
`organisation oft'he microtu'bule network that is essential for
`vital inter-phase.st mitotic cellular fundions. In addition.
`paclitaxel induces abnormal arrays or Irbundles" ofmicrotu-
`bules throughout. the cell cycle and multiple asters ofmic-m-
`tubules during
`Following intravenous administration of'IEAXOL paclitsrel
`plasma concentrations declined in a biphasic manner. The
`initial rapid decline represents distribution to the periph-
`eral compartment and elimination of the drug. The later
`phase is due, in part. to a relatively slow emu ofpaclitaml
`from the peripheral compartment.
`Pharmacnlcine‘tic parameters ofpaclitaxel following 3- and
`24-hour infusions of TAXOL at dose levels of 135 and 115
`mglmsweredeterminedbiaPhaseSrandomisedatudyin
`ovarisncancerpstientssndaresummarisadinthefollmv-
`ing table:
`.
`'
`[See table 1 above]
`It appeared that with the 24-hour infusion of TAXOL. a 30%
`inm'ease in dose (185 mgt‘m" versus 1'15 mgfmsl increased
`the cm by 87%. whereas die AUG (M) remained propor-
`tional. However. with a 3-hour infilsion. for a 30% increase
`indose, thecu sndAUC (leere inmaaedby Sfiwa'nd
`329%, respectively. The mean apparent volume of distribu-
`tion at steady state, with the 24-hour infusion of TAXOL.
`ranged from 227 to 688 Um“, indicating extensive ext-avas-
`cular distribution andl'or tissue binding of pselitaxel.
`The pharmacolcinetim of paclitaxsl were also evaluated in
`adult cancer patients who received single doses of 15—135
`mm? given by l-hour infusions (n=15). 30—21% mgi'm’
`given by 6-hour infusions (11:36), and coo-215 mg‘m’ given
`by 24-hour infusions (n=54l in Phase 1 & 2 studies. .Vhlues
`for CL; and volume oi'distrihution were consistent with the
`findings in the Phase 3 study. The pharmacokinetics of
`TAXOL in patients with AIDS-related Kaposi's sarcoma
`have not been studied.
`In uitm studies ol’binding to human serumproteina, using
`pacljtsnl concentrations ranging from Ill to 50 pg‘mL. in-
`dicate that between 3995-9596 ofdrug is bound; the presence
`of cimetidine. raniticlins. dexsmothasone, or diphenhydre—
`mine did not all'ect protein binding of paclitaxel.
`-
`nan- inn-vawn
`of 15-275 pig‘s]: doses of
`TAXOL as 1-, 6-. or 24-hour infusions, mean values for cu-
`mulative urinary recovery of unchanged drug ranged from
`1.3% to 13.3% of the dose. indicating extensive non-renal
`c1earanoe.1n five patients administered a 225 or 250 mghna
`dose ofrsdinlahaled 'IEAXCIL aa a 3-hour infusion. 21 mean of
`11% of the radioactivity was excreted in the faces in 120
`hours. and 14% was recovered in the urine. 'Ih‘tal recovery of
`radioactivity ranged from 56% to 101% of the dose. Pooli-
`tenelrepresentednmeanoffifior’theadminiateradradio-
`Actavis - IPR2017-01101
`Actavis - IPR2017-01101
`Ex. 1008, p. 3 of 9
`Ex. 1008, p. 3 of 9
`
`33511313146
`Revised: September 1993
`
`TAXOLO
`[tax-all
`habitual} injection
`
`It omv
`
`WWO
`should be administered
`TAXOLO (paclitsxell
`under the supervision of a physician experienced in the
`use of cancer chemotherapeutic agents. Appropriate
`managemantof‘complicstions is possible only when ed-
`equata diagnostic and treatment facilities are readily
`available.
`_
`Anaphylaxie and severe hypersensitivity reactions char-
`acterised by dyapnea and hypotenaion requiring treat—
`ment. sngioedema, and generalized tn‘ticaria have oc-
`curred in 2H“: of patients receivingTAXOL in clinical
`trials. Fatal reactions have occurred in patients despite
`premedicatiou. All patients should be pretreated with
`corticosteroids. diphenhydmmine. and H, antagonists.
`(See DOSAGEANDADWI‘S‘I‘RATION section.) Pa-
`tients who experience severe hypersensitivity reactions
`to'EAXOLshooldnotberechallengedwiththedrug.
`TAXOL therapy should not be given to patits with
`solid tumors who have baseline neutrophil counts ofless
`than 1,500 rallsi’mma and should not be given to pa-
`tients with AIDS-related Kaposi's sarcoma if the base-
`lineneuh'ophilconntislesstlianlflooceflshmn’JnW
`der to monitor the occurrence of bone marrow suppres—
`sion, primarily neutropenia. which may he severe and
`result in infection. it is recommended that fiequent pe-
`ripheral blood cell counts be periormed on all patients
`
`receiving TAXOL.
`
`
`
`‘Cremophoro EL is the registered mm of BASF Alt-
`tiengssellalmfi. CremephorO EL is firrther purified by s
`Bristol-Myers Squibb Company proprietary proccsahefare
`use.
`CLINICAL STUDIES
`Ovarian Carcinoma:
`
`Her-Um Dots—The safiatz and eficscy of mm (parli-
`taxel} Injection (135 Inga: over 24 hours) in combination
`with cisplatin (1'5 mgfm l in patients with advanced ovarian
`cancer and no prior chemotherapy were evaluated in a
`Phase 3 multicultural;f randomised. controlled (vs. cyclophos-
`phamide 750 mglm icisplatin 75 my’m’) clinical trial con-
`ducted by the Gynecologic Oncology Group (GOG).Atotal of
`em patients with Stage III or N disease (:1 no residual
`disease afiar staging laparotomy or distant metastases)
`were randomised. Patient-shamed with TAXDL in combina-
`tion with cisplstin had significantly longer time to progres-
`sion (median 16.6 vs. 13.0 months. p=0.0008l and nearly a
`year longermedian survival time (p:0.0002) compared with
`standard therapy.
`[Seetshlefiattopofnaxtpamel
`The adverse event profile for patients receiving TAXOL in
`combination with cisplatin in this study was generally con-
`sistent with that seenforthepooled analysis ofdats from
`31.2 patienw heated with single-agent TAXOL in 10 clinical
`stodies.’lhesesdversosventsandadverseevents&omthe
`PhaseSfirst-linsovariancardnnmastudyaredesaibedin
`mmmons sectionintabularfl‘ahiess
`and 91 and narrative form.
`Second-Um Data—Data from live Phase 1 3; 2 clinical
`studies (139 patients). a multicenter randomized Phase 3
`study (407 pafieutsl. as well as an interim analysis ofIiata
`from more than 300 patients enrolled in a treatment refer-
`ral center program were used in support of the use of
`TAIDL in patients who have failed
`or subsequent
`chemothmpyfprmataataticcarfinomsoftheovaryMnf
`tbePhsse2studies(92 patients) utilisedaninitialdoseof
`135 to 110 mghn” in most patients (>913) administered
`over 24 hours by continuous infusion. Response rates in
`these two studies were 22%(95'11 Cl: 11% to 37%) and m
`(95% Cl: 13% “46%) with a total offi complete and 13 par
`tial responses in 92 patients. The median duration ol'oversll
`responsein these two studies measured fromtheflrstdayor’
`treatment was 1.2 months (range: 35—153 months} and 1'5
`months (range: 5.3—1'16 months). respectively. The median
`survival was 8.1 months (range: (13-36.? months) and 15.9
`months (range: 1.844.54- months).
`ThePbaeeSshrdyhadsbifactorialdesignsndcompared
`the elicacy and safety ofTAXOL. administered at two dif-
`ferent doses (135 or 175 mgtm‘) and mines {3- or 24-
`' hour infusion]. The overall response rate-for the 407 pa-
`tianta was 16.2% (95% CI: 12.8% to 20.2%) with 6 complete
`and 30 partial responses. Duration of response. measured
`from the first day oftreatment was 8.3 months (range: 8.2—
`213 months). Median time to progression was 3.1 months
`(range 0.1+ —- 25.1+ months). Median survival was 11.5
`months (range: 02,233+ montbsl.
`Response rates, median survival and median time to pro-
`greasionfortheearmsaregiveninthefollowingtahls.
`[Seetable3attopofnextpage]
`Analyses were performed as planned by the bifactoris]
`study design described in the protocol. by comparing the
`two doses (135 or 175 mglmel irrespective oftbe schedule (8
`
`Wmmmgs
`WZDMF‘DMWNWMWM
`
`
`
`

`

`PHYSICIANS' DESK REFERENCEO
`BBZIBRISTOL~MYERS SQUIBB ONCJIMM.
`
`Tonal—Cont.
`‘l'shls 2: Efficacy in ths Him 3 Flrst-Llns Ovarian Carcinoma away
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`DuanoXomeO is a registered trademark of Nexstar Phar-
`maceuticals, Inc. DOXIDD is a'regjstiered trademark ofSe-
`quus Fhamaceuticals.
`__
`All patients had widespread and poor risk disease. Applying
`the ACTG staging miter-in to patients with prior systemic
`therapy, 93% were poor risk for extent of disease {T1}. 88%
`had a CD4 count “(200 collisional:8 (II), and 97% had
`risk
`considering their systemic iIlnsss (51).
`All potionte in Study CA139-1?4 had a Karnol'sky perfor-
`mance status ofstl or 90 at baseline: in Study CAMS-281.
`there were as (46%) patients with a Karnofsky performance
`status of 7D or worse at baseline.
`'
`
`or 24 hours] and the two schedules irrespective of dose. Pa-
`tients receiving the 115 Ingi‘ma dose had a response rate
`o thnicd Respons'
`similar to that for those receiving the 135 nigilni2 dose: 18%
`- rate (percent)
`vs. 14% [p=fl.28). No di'fi’erenoe in response rate was de-
`— p—value
`tested when comparing the 3-hour with the 24-hour infu-
`' Flflioloolcll Response”
`sion: 15% vs. me (p-O.50}. Patients receiving the 175
`‘ “We (Ema
`Inglisll of TAXOL had a longer time to progression than
`' PM“?
`those receiving the 135 mgfni' dose: median 4.2 vs. 3.1
`' MM;
`months (yr-0.03). The median time to progression for pa-
`tients
`8-hour vs. the 24-hour infusion was 4.0 W Wm
`15
`2“
`months vs. 3.7 months. respectively. Median survival was
`‘ “alum”
`I”
`11.6 months in patients receiving our :75 mm! dose or
`_ IRE: ‘29P.
`130
`166
`TAXDLend 11.0 months in patients receiving the 135
`_ mam“ (months)
`'
`‘
`mgrm” dose [pr-0‘92). Median sin-rival was 113.1I months for
`_ Full“
`patients receiving the 3-hour infusion of'EAXOL and 1.1.2
`. m“.
`2412
`355
`months for patients receiving the 24-hour infusion (H.911.
`. mgdjm (months)
`
`These statistics] analysesshould bev‘iewsd with motion be.
`. 1H,“;
`mom
`muse of the multiple comparisons made.
`' Among evaluable patients only.
`TAXOL remained active in patients who had developed re-
`" Includes patients with pathological complete response plus patients with mimeoopie residual disease.
`sistance co platinum-containing therapy (defined as tumor
`
`progression while on. or tumor relapse within 6 months
`Table 3: Efficacy in 1110' Film 3 Second-Lina Ovarian Carcinoma Study
`from completion of. a platinum-containingreginienlwith re-
`
`spomerstesoifld‘kinthePheseSstudyand 31%inthe
`
`
`phase 1 & 2 Grimm mm
`17513
`175124
`135324
`R
`The adverse event profile in this Phase 3 study was consis-
`In“
`“=10”
`("film
`'
`° “pm
`tent with that seen for the pooled analysis ofdata from 812
`- rate {percent}
`. um .
`.
`.
`v
`I
`-
`'
`14.8
`21.7
`13.2
`A use Confidence Interval
`mdwm “"1 m “imam”5*“
`03"?”
`(3.5.23.6)
`(14.5mm
`(17—215)
`more??? E” ii??? “‘9 Immanprimnueln
`4.4
`4.2
`" 2:8
`on m
`-
`as
`an
`)
`mauve
`- 95% Confidence Interval
`(3.0-5.5)
`(3.5—5.1l
`{1.9-4.0}
`-
`- Smut
`Rum-
`-
`10.7
`13.1
`1.1.8
`11.5
`_
`The results of the randomised study support the use if
`- median (months)
`
`TAXOL (pachtaxel) Madam! at doses of 135 to 1'35 myth .
`- 95% Confidence Interval
`(SA—14.4}
`{33-143}
`(9.14145)
`{SJ—13.6]-
`administered by a 3-hour intravenous infusion. The same
`doses administered by 24~hour inl'usion were more toxic.
`that measured subjective assessment of treahnent. Oftho
`seven, the Lung Cancer Specific Symptoms subscale favored
`However, the study had insufl‘icient power to determine
`the TAXOL 135 mgim‘m hour plus cisptatzin arm compared
`whether a pertiorlar dose and'schedale produced superior
`to the deplefinletcposide am. For all other factors. than
`ellicecy
`Breast Cardnoma: Data from 33 patients accrued in three
`“'33 '10 inference in the WW? W955
`Phase 2 open label studies and from 471 patients enrolled in
`The adverse event profile for Dalian“ “€110.19”le TAXOL
`. W1
`a Phase 3 random may were available to support the
`in combination with cisplafin in this study was-generally
`v we (percent)
`use ofTAXOL in patients with metastatic breast osmium
`22 mm “Eh that "an is? “39 Pooled “313m “fists
`- p—velue
`m 2 open label mam—nun shidies were conducted in
`frills] 313 when” heated mfli meleth MOI: In 10
`' “I110 ‘0 "W00
`53 patients previously treated with a maximum ofene prior
`filmed mid”; The” have!“ em“ and “hem
`3-0
`4-2
`- median (months)
`chemotherapeutic regimen. TAXOL was administered in
`in” “‘3 PW” 3 MM” "saw. “‘5‘? a” 4M“ 1“
`' P‘Vd‘le
`these two trials as a 24-hour infiision at
`doses of 250
`m m tabular “an” a
`1n 5
`11 7
`adj I
`ma (With GOSF support) or 209 mi N mm -
`AIDS-1:th mm. Snsn‘uomr Data from two Phase 2
`a“
`rates were are. (95-15 CI: 37% m 159nm see (95-30-61: 32's
`fin]: ("10"
`-
`- w label mm, mm the m; “Tam a. Maw“
`3
`0,321
`
`to 12%), respectiver "The third Phase 2 study was con-
`therapy in patients with AIDS-related Kaposi's sarcoma.
`ducted in extensively pretreated patients who had failed an-
`fifiy—m‘ne afthe 85 patients enrolled in these studies had
`thracycline therapy and who had received a minimum of
`previously received systemic therapy, including interferon
`II‘he adverse event profile of the patients who received ain—
`two chemotherapy regimens far thetreatmcnt ofmatastatic
`gle-egent TAXOL- in the Phase 3 study was consistent with
`alpha (32%}. DaunoXomeO (31%}, Home {2%) and doom-
`rubicin containing chemotherapy (42%), with 64% having
`disease. The dose of TAXOL was 200 mga‘nla as a 24-hour
`that seen for the pooled analysis of data from 312 patients
`treated in 10 clinical studies. These adverse ovens and ad-
`received prior anflmcythnes. Eighty-five percent of the pre-
`infusion with G-CSF support. Nine of the 3|] patients
`verseeventafiomthe Phasedhresetcarcinomaatudysre
`treated patients had progressed on, or could not tolerate,
`achieved a partial responseLEor a response rate of 30% (95%
`prior systemic therapy.
`CI: m).
`described in the ADVERSE menflNS section in tabu-
`lar (Tables 8 and 11} and narrative'liirm.
`'
`In Study CA139-17-1 patients received TAXOLat 136 night”
`Phase 3 madam study—This multioenter trial was con-
`as a 3-hour infiiaion every 3 weeks (intended close intensity
`Non-Smell our Lung (broil-rams reactor—1n a Phase 3
`ducted in patients previously treated with one or two regi-
`open label randomized study wnduclcd by the Eastern Co-
`mcnaofcbemotherepy. Patients were randomised to receive
`«is mgfm‘fweek]. Ii‘ no dose-limiting toxicity was observed,
`operative Oncology Group CEGOG). 599 patients wore ran-
`patients were to receive 155 ingiln and 175 mgim‘ in sub
`TAXOL at a close ofeither 1’15 mgi'm2 or l.":'»’rmg;‘m2 given as
`sequent courses. Hematopoietic growth factors were not to
`domized to either‘EAXDL 1T) :35 mgi’m’as aZd-hour infu-
`a 8-hour infirsion. In the 471 patients enrolled. 60% had
`be used initially. In Study CA139-281 patients received
`sion in combination with cisplatin lo) 75 mgi‘mz, MOL [Tl
`symptomatic disease with impaired performance atoms at
`mini. (mum!) Inieotion at 100 inglni” as a 3-hour
`250 night, as a
`in combination with cispl-
`study entry. and 73% had visceral metastases. These pa-
`atin (c) 'e'fi mgi‘mI with G-CSF support. or ciaplafin {cl 15
`infusion every 2 weeks (intended dose intensity 50 night"!
`tients had failed prior chemotherapy either in the adiuvant
`week). In this study patients could be receiving hemetopci-
`D1951]: on day 1, followed by eteposide WP} 100 irigl‘i'o2 on
`setting {30%}, the metastatic setting (33%}. or both [31%).
`stic growth factors before thestartofTAXOL therapy or
`daysl.2.and3[oontrol)r
`_
`Sixty-seven percent ofthe patients had been previously-ex-
`this support was to be
`as indicated; the dose of
`Response rates, median time to progression. median sur-
`TAXOL was not increased. The dose intensity of.TA'XOL
`posedtoanthracyclinesandZS‘ltofthemhsddiseaaecon-
`vival. and one-year survival rates are given in the following
`used in this patient population was lower than the dose in—
`aidered rosistent'to this class of agents.
`_
`table. The reported p-values have not been adjusted for
`tensity remnamended for other solid tumors.
`multiple comparisons. There were statistically significant
`The overall response rate fmthe 454 evaluable patients was
`difi’erenoes favoring each of the TAXOL plus cisplatin arms
`36% (95% CI: WM}. with 1? mplete
`99
`responses. The median duration ofresponse. measured from
`formsponse rateand tints totumo'r
`Thai-ewes
`no statistically significant difli'erence in survival between ei-
`the first day'oftreaunent, was 8.1 months (range: Bet-48.11-
`monthali Overall for the 411 patients,_the median time to
`ther IIlitll'IIIIL plus cisplatinarm andthe cisplatin plus eto-
`poside arm.
`'
`progression was 3.5 months (songs: one—17.1 months]. He
`I
`[See table 5 below]
`disn survival was 11.1r months (range: III-18.9 months).
`In tl'le'ECOG study, the Functional Assessment of'Csnoer
`Response _rates. median survival and‘mcdian time to pro-
`gression for the 2 arm are given in the following table.
`ITherapy-Lung fi‘ACT-Ll questionnaire had seven subscalies
`stleE:EffictoyPaminrhePtmi3Hut—Lhafl9¢t¢9m
`"35m
`“5””
`“‘1”
`as
`“5
`‘75
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`ln=1sflt
`imzim
`imamI
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`u
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`- ra
`poms
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`0.001
`— p—velue" '
`- Time to Won
`is
`4.3
`- median {months}
`0.0:}:
`0.05
`- p-vaiua"
`- Survival
`Visceral c edema : oral :
`I“
`93
`. mag“ [mu-hm].
`mm and +
`. pvvalue"
`0.12
`0.05
`maorlymphnndes
`_
`-OurYoou-Sorvtnl
`-'
`'
`
`. percent ofpatierics
`_
`as
`w I
`32 o
`‘Etopsside (VP) 100ng was administered LV. on days 1, 2 and 8.‘
`Cutaneous only
`I'Coiinpered to cisplatinr‘etopoaide.
`mimuwemmmw-iwm Actavis - lPR2017-01101
`Actavis - IPR2017-01101
`Ex. 1008, p. 4 of 9
`Ex. 1008, p. 4 of 9
`
`Tmemnmnsnmem
`I'm—0'Plum
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`Mr
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`

`Complete response
`Partial response
`Stable disease
`Progression
`Early deathftooicity
`
`3
`56
`29
`8
`3
`
`
`
`BRiSTOL-MYERS SQUIBB ONCJIMM.”
`PRODUCT [NFORMATION
`
`TAXOL infusion. is recommended. Continuous caldia: mon—
`Althoughtheplenneddoseintenaityinthetwostmiieswas
`recover to a level $1500 calls’mmsblm caller'nnn’3 for pa—
`tientswith Kslendplateletsreccvertoalevelsvlmfiw
`itoringisnotrequiredexoeptforpatientswith serious con-
`slightly difierant (45 mgimliweek in Study 03139-111 and
`duction
`{Sea WARNINGS section.)
`palladium“.
`50 mfiwssk in Study 05139-281). delivered dose intenv
`Severe conduction almwmalities have been documented in
`sitywaaSB—SngI‘mziweekinbothstudies.withasimilsr
`Nes'wue System: Although. the occurrence !of peripheral
`range (20-24 to 51-61).
`«(1% ofpatianta during TAXOL therapy and in some cases
`neuropathy is frequent. the development of severe symp—
`Maser—The sficacy oi' TAXOL was evaluated by assess-
`requiring pacemaker placement If patients develop
`tomatologyisnnusual and requiresa dosereducflon em
`cant conduction abnormalities during TAXOL infusion. ap-
`ing cutaneous tumor response semi-ding to the amended
`for all subsequent corneas of TAXOL.
`ACI‘G uiteriaaridhyseeldngev‘idance nfclinicalbensfitin
`propriate therapy should be administered and continuous
`TAXDL contains dehydratod alcohol USP, 396 mgi‘silg'con-
`cardiac monitoring should he parlhrmed during Want
`padsnts in six domains ofsymptoms andior ccnditiomi that
`aidaration should be givento possible CNSand ctherail'ects
`are commonly related to AIDS-related Kaposi’s sarcoma
`cm” with TAXOL.
`of alcohol. (See PRECAUTIONS: Pedetrle Use section.)
`Cutaneous firmer Response {Amended acre Wel—
`Pregnancy: TAXOL can