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`NOVARTIS EXHIBIT 2019
`Par v. Novartis, IPR 2016-01479
`Page 1 of 7
`
`

`
`1844/ELI LILLY
`
`F_orteo-Cont.
`
`PA 9241 FSAMP
`Copyright © 2002, Eli Lilly and Company. All rights
`reserved.
`Shown in Product Identification Guide, page 320
`
`GEMZAR~
`[iem-zar]
`(GEMCITABINE HCI)
`FOR INJECTION
`
`DESCRIPTION
`Gemza'® (gemcitabine HCl) is a nucleoside analogue that
`exhibits antitumor activity. Gemcitabine HCl is 2' -deoxy-
`2' ,2' -difiuorocytidine monohydrochloride ({3-isomer ). The
`structural formula is as follows:
`
`The empirical formula for gemcitabi;,e HCl is Cgll11F2N30 4
`• HCI. It has a molecular weight of 299.66.
`Gemcitabine HCl is a whita t o off-white solid. It is soluble in
`water, slightly soluble in methanol, and practically insolu(cid:173)
`ble. in ethanol and polar organic solvents.
`The clinical formulation is supplied in a sterile form for in(cid:173)
`travenous use only. Vials of Gemzar contaip either .200 mg
`or 1 g of gemcitabine HCl (expressed as free base) formu(cid:173)
`lated with mannitol (200 mg or 1 g, respectively) and so(cid:173)
`dium acetate (12.5 mg or 62.5 mg, respectively) as a sterile
`lyophilized powder. Hydrochloric acid, and/or sodium hy,
`droxide may have been added for pH acljustment.
`CLINICAL PHARMACOLOGY
`Gemcitabine exhibits cell phase speciftclty, primarily kiUing
`cells undergoing DNA synthesis (S-phase) and also blocking
`the progression of cells through the G 1/S-phase boundary.
`Gemcitabine is.metabolized intracellularly by nucleoside ki(cid:173)
`nases to the active diphosphate (dFdCDP) and .triphosphate
`(dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is
`attributed to a combination of two actions of the diphos(cid:173)
`phate and the triphosphate nucleo_sides, which leads to in(cid:173)
`hlbition of DNA synthesis. First, gemcitabine diphosphat e
`inhibits ribonucleotide reductase, which is responsible for
`catalyzing the reactions that generate the deoxynucleoside
`triphosphates for DNA synthesis. Inhibition of this enzyme
`by the diphosphate nucleoside _causes a reduction in th~ con(cid:173)
`centrations of deoxynucleotides, including dCTP. Second,
`gemcitabine triphpsphate competes with dCTP for incorpo(cid:173)
`ration into DNA. The reduction in the intraceJlular concen(cid:173)
`tration of dCTP (by the action of the di phosphate) enhances
`the incorporation of gemcitabine triphosphate into DNA
`(self-potentiation). After the gemcitabine nucleotide is incor(cid:173)
`porated.into DNA, only one additional nucleQtide is added to
`the growing DNA strands. After _this addition , there is inhi(cid:173)
`bition of further DNA synthesis. DNA polymerase epsilol\ .is
`unable to remove the gemcitabine nucleotide 8l_l<;l repair th e
`growing DNA strands .(m_asked chain termination). b,.
`
`CEM T lymphoblastoid cells, gemcitabine induces internu(cid:173)
`cleosomal DNA fragmentation; one of the characteristics of
`programmed cell death.
`Gemcitabine demonstrated dose-dependent synergistic ac(cid:173)
`tivity with cisplatin in vitro. No effect of cisplatin on gem(cid:173)
`citabine triphosphate accumulat.ion or DNA double-strand
`breaks was observed. In uiuo, gemcitabine showed activity
`in combination with cisplatin against the LX-1 and CALU-6
`human lung xenografts, but minimal activity was seen with
`the NCI-H460. or NCI-H52.0 xenografts. Gemcitabine was
`synergistic with cisplatin in the Lewis lung murine xeno(cid:173)
`graft. Sequential exposure to gemcitabine 4 hours before
`cisplatin produced the greatestinteraction.
`Human Pharmacokinetics - Gemcitabine disposition was
`studied in 5 patients who received a single 1000 mg/m2/30
`minute infusion of radiolabeled drug. Within one (1) ,yeek,
`92% to 98% of the dose was recovered, almost entirely in the
`urµ,.e. Gemcitabil)e ( < 10%) and the inactive uracil metabo(cid:173)
`lite, 2' ,deoxy-2' ,2' -difiuorouridine (dFd],T), accounted for
`99% of the excreted dose. The metabolite dFdU is also found
`in plasma. Gemcitabine plasma protein binding is negligi-
`ble.
`'
`The phannacoki;,etics of gemcitabine were examined in 353
`patients, about 2/3 men, with various soliq.tumors. f!harma(cid:173)
`cokinetic parameters were derived using.'a'ata from patients
`treated for varying dur.ations of therapy given weekly with
`periodic rest weeks and using_ both ,short . infusions ( < 70
`minutes) and long infusions (70 to. 285 minutes). The total
`Gemzar dose varied from 500 to 3600 mg/m2
`•
`Gemcitabine pharmacokinetics are -linear and are described
`by a 2-compartment ·model. Population pharm~cqkinetic
`analyses of combined single and multiple dose studies
`showed that the volume of distribution of gemcitabine was
`significantly influenced by duration of infusion "1ld. gender.
`_Clearance was affected by age and gender. Differences in ei(cid:173)
`tber clearance or volume of distribution based on patient
`characteristics or the duration of infu~ion result in changes
`in half-life and plasma concentrations. Table l shows
`plasma clearance and half-life of gemcitabine .following
`short infusions for typical patients by age and gen.der.
`
`Table 1: Gemcitabine Clearance and
`Half-Life for the "Typical" Patient
`
`Age '
`
`Clearance Clear8.nce Half-Life•
`Men
`Women
`Men
`(I/hr/m2)
`(Uhr/m2)
`"(min)
`
`Half-Life'
`Women
`(min)
`
`29
`45
`65
`·79
`
`92.2
`· 75_7
`55.1
`40:7
`
`69.4
`57.0
`41.·5
`30.7
`
`42
`48
`·61
`79
`
`·49
`57
`73
`94
`
`.•
`• Half-life for patients receiving a short infusion ( < 70 min).
`
`Gemcitabine half-life for short infusions ra;,_ged from ' 32 to
`94 minutes, and the value for long infusions varied fr6m 245
`to 638 minutes1 depending on age anti gender, reflecting a
`greatly increased volume of distribution with longer infu(cid:173)
`sions. The lower clearance in women and the elderly results
`in higher concentrations of gemcitabine for any given dose.
`The volume of distribution ,;,as increased with infusion
`length. Volume of distribution of gemci_tabine was 50 Um2
`following infusions lasting < 70 minutes, indicating that
`gemcitabine, after short infusions, is not extensively distrib(cid:173)
`uted into tissues. For long infusions, the volume of distribu(cid:173)
`tion rose to 370 l/m2, 'reflecting slow. equilibration of'gem(cid:173)
`citabine within the tissue compartment.
`
`Table 2: Gemzar Plus Paclit~lC81 Versus Paclitaxel in-Breast Cancer
`
`Gemzar/Paclitaxel
`
`Paclitaxel
`
`Number of patients
`
`Median age, years
`Range
`
`Metastatic disease
`
`Baseline KPS· 2 90
`
`Number of tumor sites :
`1-2
`23
`
`Visceral disease
`
`Prior anthracycline
`
`Time to Documented Disease
`Progressionb
`Median (95%, C.I.), months
`
`Hazard Ratio (95% C.I.)
`
`Overall Response Rate•
`(95%, C.1.)
`
`.267
`
`53
`26 to 83
`
`97.051,
`
`70:4%
`
`56.6%
`43.4%
`
`73.4%
`
`96.6%
`
`262
`
`52 ·
`26 to 75
`
`96.9%
`
`74.4%
`
`58.8%
`41.2%
`
`·12:9%
`
`95.8%
`
`5.2 (4.2, 5.6)
`
`2.9 (2.6, 3. 7)
`
`0.650 (0.524, 0.805)
`
`_40.8% (34.9, 46. 7)
`
`22.1% (17.1, 27.2)
`
`p < 0.0001
`
`p<0.0001
`
`p< 0.0001
`
`• Kamofsky Performance Status.
`.
`.
`• These represent reconciliation ofinvestigator and Independent Review Commi.ttee assessme.nts according to a predefined
`algorithm.
`
`'Information will ba superseded by supplements and subsequent editions
`
`The maximum plasma concentrations of dF'd
`tabolite) were achieved up to ~O minutes a~ Un
`O r di
`tion of the infusions and the metabolite is
`without undergoing further l>iotransformatXc"'t.d
`olite did not accumulate with weekly dosin•on. ~
`nation is .dependent on renal excretion, anl' hut i
`
`00uld
`lat e with decreased renal function.
`The effects of significant renal or hepatic .
`the disposition of gemcitabine have not bee •nsullici
`The active metabolite, gemcitabine triphosph a,
`tracted from peripheral blood _mononuclear ate, '-II
`life of the terminal phase for gemcitabine tri chlls.
`mononuclear cells ranges from 1. 7 to 19.4 h~/8Pht
`'8;
`Drug In.teractio11s - When Gemzar 11250 n,
`and 8) and cisplatin (75 mg/m2 on Day 1) we,Wrn Oil
`in NSCLC patients, the clearance of gemcii,;'b~
`·
`was 128 I/hr/m2 and on Day 8 was 107 I.Jbri ~e on
`ance of cisplatin in the same study was , rn · 'i'he
`3.94 mUmin/m2 with a corresponding half-li£'P~rte,(
`(see Drug Interactions under PRECAUTION;~ 184
`,CLINICAL STUDIBS
`Breast Cancer - Data from a multi-national
`Phase 3 study (529 patients) support the use 'f~
`combination with paclitaxel for treatment of~
`patients who have received pri9r adjuvant/ne<J:~~•t
`thracycline chemotherapy unless clinically COnlr i~vd
`Gemzar 1250·mg/m2 was administered on Days tn
`21:day cycl~ with paclitaxel 175 mg/m2 adminis aDd
`to Gemzar on Day l of each .cycle. Single-agent~
`175 mg/m2 was administered on Day 1 of each 2/d
`87
`as the control arm.
`The addition of Gemzar to paclitaxel resulted in sta .
`significant improvement in time to documented dise
`gression and overall response rate compared to
`therapy with paditaxel as shown in Table 2 and F'
`Further, there was. a strong trend toward improved
`for the group given Gemzar based. on an interim
`analysis.
`[See table 2 below]
`
`Median Jlme to Documented DINaH eroe....,
`Gemzar!Paclltaxel
`S.2 month,
`Paclltexef
`2.9 months
`Log rank pdJ.0001
`
`a .
`20
`16
`12
`· 4
`Time to Documented Disease Progression (MonlhsJ
`
`Figure I: Kaplan-Meier Curve of Time to
`Documented Disease Progression in Gem;IIII'
`plus Paditaxel versus Paclitaxel
`Breast Cancer Study (N=529).
`
`Non-S',,,all Cell L ung Cancer (NSCLC)- Data fi~ma
`domized clinical studies (657 patients) support ~
`Gemzar in -combination with cisplatin for the "
`treatment of patients with locally advanced or me
`NSCI,.C.
`·
`Gemzar plus cisplatin versus cisplatin: This study
`ducted in Europe, the US, and Canada in 522 pa tied
`inoperable Stage IIIA, IIIB, or JV NSCLC wh~ ha
`ceived prior chemotherapy. Gemzar 1000 mg/m .:i',9'·
`isteJed .Qn Days 1, 8, and 15 of a .28-day cycle WI
`100 mg/m2 administered on Day 1 of eacP cycle.
`agent cisplatin 100 mg/m2 was. ad.tµinis tered on
`
`each 28-day cycle .. The primary endpoint was su:
`
`tient demographi_cs are shown in Table 3. An ~
`with .regard to histology was observed with 48~}1e
`on t he cisplatin arm and 37% of patients on
`plus cisplatin arm having·adenocarcinoma._·. f"gtl
`The Kaplan-Meier survival curve is show~ in ;.
`0
`dian survival time on the . Gemzar plus c1spla / ..
`9.0 months compared to 7.6months on the sin~ia•
`platin. arm (Logrank p=0.008, two-sided). Me 1)1t
`disease progression was 5,2 months on the Go~ p
`platin arm compared to 3. 7 months ?n the c~~
`(Logrank p=0.009, two-sided). The obJective r
`on the Qemz.ar plus cis~latin arm was 26% cofll_dedJ.
`with dspfatin (Fisher's Exact p< 0.0001, twod-s~ du
`ference between treatment arms with regar
`, It
`response was observed.
`Gemzar lus cis la tin versus eto side Ius cis N
`ond, multi-center, study in Stage IIIB or 2 n p
`dornized 135 patients to Gemzar 1250 mg/rn ;.,
`8, and cisplatin 100 mg/m2 on Day 1 of a 213 ;.i,d
`etoposide 100 mg/m2 I.V. on Days 1, 2, and S),
`-100· mg/ro.2 on Day 1 on-a 21-day cycle (Table 1
`There was no significant difference in surviY~ded~
`two treatment arms (Logrank p=0.18, two·51 pl
`dian survival was 8. 7 months for the Gem••\iS
`arm versus 7.0 months-for the etoposide pl~
`Median time to disease progression for the
`platin _arm was ?·O m?nths compared to 4.l ~.
`etopos1de plus c,splatm arm (Logrank p~o.O
`
`NOVARTIS EXHIBIT 2019
`Par v. Novartis, IPR 2016-01479
`Page 2 of 7
`
`

`
`Table 3· Randomized Trials of Combination Therapy with Gemzar plus Cisplatin in NSCLC
`
`ELI LILLY/1845
`
`Trial
`
`Treatment Arm
`
`Number of patients
`Male
`Female
`
`Median age, years
`Range
`
`Stage IIIA
`Stage IIIB
`Stage N
`
`Median Survival
`9.0 months
`7 .6 months
`
`1-Year Survival
`39 %
`28 %
`
`Baseline KPS' 70 to 80
`Baseline KPS' 90 to 100
`
`TostStatistic. p.,alu.e
`Log rank
`0.008
`Wilcoxon
`0,018
`
`Survival
`Median, months
`(95%, C.I.) months
`
`~
`
`Gemcitabine/
`Cisplatin
`(N=260)
`
`Time to Disease Progression
`Median, months
`(95%, C.I.) months
`
`'
`
`28-day Schedule'
`
`21-day Schedule"
`
`Gemzarl
`Cisplatin
`
`Cisplatin
`
`260
`182
`78
`
`262
`186
`76
`
`62
`36 to 88
`
`63
`35 to 79
`
`7%
`26%
`67%
`
`41%
`57%
`
`7%
`23%
`70%
`
`44%
`55%
`
`Gemzarl -
`Cisplatin
`
`,. Cisplatin/
`Etoposide
`
`69
`64
`5
`
`66
`61
`5
`
`58
`33 to 76
`
`60
`35 to 75
`
`NIA
`48%
`52%
`
`45%
`55%
`
`NIA
`52%
`49%
`
`52%
`49%
`
`9.0
`8.2, 11.0
`
`7.6
`6.6;8.8
`
`5.2
`4 .. 2, 5.7
`
`26%
`
`3.7
`3.0, 4.3
`
`p=0.008
`
`p=0.009
`
`p< 0.0001•
`
`8.7
`7.8, 10.1
`
`7.0
`6.0, 9.7
`
`5;0
`4.2, 6.4
`
`4.1
`2.4, 4.5
`
`p=0.18
`
`p70,0.15
`
`10
`
`15
`
`survival time (months)
`
`Figure 2: Kaplan-Meier Survival Curve in
`Gemzar plus Cisplatin versus Cisplatin
`NSCLC Study (N=522).
`
`table 3 at right]
`tic Cancer - Data from 2 clirucal trials evaluated
`me of Gemzar in patients with locally advanced or
`tic pancreatic cancer. The :first trial compared
`r to 5-Fluoro\Jracil (5-FU) in patients who had re(cid:173)
`no prior chemotherapy. A second trial studied the use
`r in pancreatic cancer patients previotisly treated
`5,FlJ or a 5-FU-containing regimen. In both studies,
`int cycle of Gemzar was administered intravenously at
`of 1000 mg/m2 over 30 minutes once weekly for up to
`.-ks (or until toxicity_necessitated holding a dose) fol(cid:173)
`by a week of rest from treatment with Gemzar. Sub(cid:173)
`t cycles consisted of injections .once weekly for 3 con-
`Uve weeks out of every 4 weeks.
`primary efficacy parameter in these studies was "clini-
`nefit response," which is a measure of clinical im(cid:173)
`nt based on analgesic consumption, pain intensity,
`ance status, and weight change. Definitions for im(cid:173)
`nt m these variables were formulated prospectively
`the design of the 2 trials. A patient was considered a
`benefit responder if either:
`J>ati.ent showed a 250% reduction in pain intensity
`lio onal Pain Assessment Card) or analgesic consump(cid:173)
`~ r a 20-point or greater improvement in perfor-
`1111 1 status (Karnofsky Performance Scale) for a period
`lliJied'ast 4 consecutive weeks, without showing any sus·
`ed worseni.ng in any of the other parameters. Sus(cid:173)
`. Worsemng was defined as 4 consecutive weeks
`eith~r any increase in pain inteiisity or analgesic
`~Phon or a 20-point decrease in performance status
`ng during the first 12 weeks of therapy.
`
`J>alient W;s stable on all of the aforementioned pa(cid:173)
`showed a marked, sustained weight gain
`maintain~d for 24 weeks) not due to fluid
`
`p~:tudy .~as a. multi-center (17 sites in US and Can(cid:173)
`i..,:·~~ve, single-blinded, two-arm, randomized,
`or n, 0
`em~ar and 5-FU in patients with locally ad-
`lreatn,etast~tic pancreatic cancer who had received no
`entw1th chemotherapy. 5-FUwas administered
`a weekly dose of 600 mg/m2 for 30 minutes.
`this randomized trial are shown in Table 4.
`
`in a/. With Gemzar had statistically signi~cant
`
`c 1n1c 1 benefit response, smyival, and time to
`compared to 5-FU. The Kaplan-Meier
`wn in Figure 3. No confirmed objec(cid:173)
`were observed with either treatment.
`
`Tu!llor Response
`
`10%
`
`33%
`
`14%
`
`p=0.01•
`
`• 28-day schedule-Gemzar plus cisplatin: Gernzar 1000 mg/~2 on Da;s 1, 8, and 15 and cisplatin 100 mg/m2 on Day [ every
`28 days;,Single-agent cisplatin: cisp)atin 100 mglm on Day 1 every 28 days.
`h 21-day schedule-Gemzar plµs cisplatin: Gernzar 1250 mg/m2 on Days 1 and 8 and cisplatin 100 mg/m2 on Day 1 every 21
`days; Etoposide plus Cisplatin: cisplatin 100 mg/m2 on Day 1 and LV: etoposide 100 mg/m2 on Days 1, 2,
`and 3 every 21 days.
`C Karnofsky Performance Status.
`d p 4value for tumor response was calculated using the two-sided Fisher's exact test for difference in binomial proportions. All
`other p-values were calculated using the Logrank test for differenc~ in overall time to an event.
`NIA Not applicable.
`
`-
`
`,,
`
`Number of patients
`Male
`Female
`
`Median age
`Range
`
`Stage N disease
`
`Baseline KPS' s70
`
`Clinical benefit response
`
`Survival
`Median
`6-rnonth probabiliti
`9-month probability"
`1-year probability•
`Range
`95% C.I. of the median
`
`Time to Disease Progression
`Median
`Range
`95% C.I. of the median
`
`Table 4: Gemzar Versus 5-FU in Pancreatic Cancer
`
`Gemzar
`
`63
`34
`29
`
`62 years
`37 to79
`
`71.4%
`
`69.8%
`
`22.2%
`(N"=14)
`
`5-FU
`
`63
`34
`29
`
`61 years
`36 to 77
`
`76.2%
`
`68.3%
`
`4.8%
`(N=3)
`
`5.7 months
`(N=30) 46%
`(N = 14) 24%
`(N = 9) 18%
`0.2 to 18.6 months
`4.7 to 6.9 months
`
`4.2 months
`(N=19J 29%
`(N =4)5%
`(N =2)2%
`0.4 ,to 15.1+ montl;,.s
`3.1 to 5.1 months
`
`2.1 months
`0.1+ to 9.4 months
`1.9 to 3.4 months
`
`0.9 months
`0.1 to 12.0+ months
`0.9 to 1.1 months
`
`p=0.004
`
`p=0.0009
`
`Ir
`
`p = 0.0013
`
`' Karnofsky Performance Status.
`b Kaplan-Meier estimates.
`'N=riumber of patients.
`+ No-progression at last visit; remains a1ive.
`The p-value for clinical benefit response was calculated using the two-sided test for difference in binomial proportions. All
`other p-values were calculated using the Logrank test for difference in overall time to an event.
`
`sity and analgesic consumption with improvement in
`performance status. No patient on either arm achieved a
`clinical benefit response based on weight gain.
`[See figure at top of next page]
`The second trial was a multi-center (17 US and Canadian
`centers), open-label study of Gemzar in 63 patients with ad(cid:173)
`vanced pancreatic cancer previously treated with 5-FU or a
`5-FU-containing regimen. The study showed a clinical b.en(cid:173)
`efit response rate of 27% and median survival of 3.9 months.
`Other Clinical Studies - When Gemzar was administered
`more frequently than once weekly or with infusions longer
`than 60 minutes, increased toxicity was observed. Results of
`a Phase 1 study of Gemzar to assess the maximum tolerated
`dose (MTD) on a daily x 5 schedule showed that patients
`developed significant hypotension and severe flu-like symp(cid:173)
`toms that were intolerable at doses above 10 mg/m2
`• The
`incidence and severity of these events were dose-related.
`Other Phase 1 studies using a twice-Weekly schedule
`reached MTDs of only 65 mg/m2 (30-minute infusion) and
`150 mglm2 (5-minute bolus). The dose-limiting toxicities
`were thrombocytopenia and flu-like symptoms, particularly
`asthenia. In a Phase 1 study to assess the maximum toler-
`
`ated infusion time, clinically significant toxicity, defined as
`'with week1y doses of
`myelosuprression, was seeil
`300 mg/m at or above a 270-minute infusion time. The half(cid:173)
`life of gemcitabine is influenced by the length of the infusion
`(see CLINICAL PHARMACOLOGY) and the toxicity ap(cid:173)
`pears to be increased if Gemzar is admini.stered more fre(cid:173)
`quently than once weekly or with infusions longer than 60
`minµtes (see WARNINGS).
`
`INDICATIONS AND USAGE
`Therapeutic Indications
`Breast Cancer - Gemzar in combination with paclitaxel is
`indicated for the first,line treatment of patients with mets-
`
`Continued on next page
`
`* ldenti-Code® symbol. This product information was
`prepared in June 2004. Current information on these and other
`products of Eli Lilly and Company may be obtained by direct
`inquiry to Lilly Research Laboratories, Lilly Corporate Center,
`Indianapolis, Indiana 46285,.(8001 545-5979.
`
`Consult 2 O O 5 PDR3 supplements and future editions for revisions
`
`NOVARTIS EXHIBIT 2019
`Par v. Novartis, IPR 2016-01479
`Page 3 of 7
`
`

`
`1846/ELI ,LILLY
`
`Gemzar-Cont.
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`g, 0.6
`'>
`·~
`0.5
`(/)
`C: 0.4
`
`0 i 0.3
`
`lJ..
`
`0.2
`
`0.1
`
`0.0
`
`0
`
`4
`
`12
`8
`Survival Time (months)
`
`16
`
`20
`
`Figuj 3: Kaplan-Meier Sµrvival Curve.
`
`static breast cancer after failure of prior antliracycline(cid:173)
`containing adjuvant chemotherapy, unless anthracyc1ines
`were clinically contraindicated.
`Non-Small Cell Lung Cancer - Gemzaris indicated in com(cid:173)
`bination with cisplatin for the first-line treatment of pa(cid:173)
`tients with inoperable, locally advanced (Stage IIIA or IIIB),
`or metastatic (Stage IV) non-small cell lung cancer.
`Pancreatic Cancer - Gemzar is indicated as first-line treat(cid:173)
`ment for patients with locally advanced (nonresectable
`Stage II or Stage HI) or metastatic (Stage IV) adenocarci(cid:173)
`noma of the pancreas. Gomzar is indicated for patients pre(cid:173)
`viously treated with 5-FU.
`CONTRAINDICATION
`Gemzar is contraindicated in those patients with a known
`hypersensitivity to the drug (see Allergic under ADVERSE
`REACTIONS).
`WARNINGS
`Caution - Prolongation of the infusion time beyond 60 min(cid:173)
`utes and more frequent than weekly dosing have been
`shown to increase toxicity (see CLINICAL STUDIES).
`Heniatology - Gemzar can suppress bone marrow function
`as manifested by leukopenia, thrombocytopenia, and ane(cid:173)
`mia (see ADVERSEREACTIONS), and myelosuppression
`is usually the dose-limiting toxicity. Patients should be
`monitored for myelosupp1·ession during therapy. See
`DOSAGE AND ADMINISTRATION for recommended
`dose adjustments.
`Pulmonary - Pulmonary toxicity has been reported with
`the use of Gemzar. In cases of severe lung toxicity, Gemzar
`therapy should be discontinued immediately and appropri(cid:173)
`at e suppmtive care measures instituted (see Pulmonary un(cid:173)
`der Single-Agent Use and under Post-marketing exper(cid:173)
`ience in ADVERSE REACTIONS section).
`Renal - Hemolytic Uremic Syndrome (HUS) and/or renal
`failure have been reported following one or more doses of
`Gemzar. Renal failure leading to death or requiring dialysis,
`despite discontinuation of therapy, has been rarely re(cid:173)
`ported. The majority of the cases of renal failure leading to
`death were due to HUS (see Renal under Single-Agent Use
`and under Post-marketing experience in ADVERSE RE·
`ACTIONS section).
`Hepatic - Serious hepatotoxicity, in.eluding liver failure
`~nd death, has been r~ported ."e~ rarely i_n patients re:eiv(cid:173)
`mg Gemzar alone or m eombmahon with other potentially
`hepatotoxic drugs (see Hepatic under Single-Agent Use and
`under Post-marketing experience in ADVERSE REAC·
`TIONS section).
`Pregnancy - Prngnancy Category D. Gemzar can cause fe(cid:173)
`tal harm when administered to a pregnant woman. Gemcit-
`3.bine is embryotoxic causing fetal malformations (cleft pal(cid:173)
`ate, incomplete ossification) at doses of 1.5 mg/kg/day in
`mice (about 1/200 the recommended human . dose on a
`mg/m2 basis). Gemcitabine is fetotoxic causing fetal malfor(cid:173)
`mations (fused pulmonary artery, absence of gall bladder) at
`doses of 0.1 mg/kg/day in rabbits (about 1/600 tho recom(cid:173)
`mended human dose on a mg/m2 basis). Embryotoxicity was
`characterized by decreased fetal viability, reduced live)itter
`sizes, and developmental delays. The,_·e are no studies Qf
`Gemzar in pregnant women. IfGemzar is used during preg(cid:173)
`nancy, or if the patient becomes pregnant while taking
`Gemzar, the patient should be apprised of the potential ha(cid:173)
`zard to the fetus.
`PRECAUTIONS
`General - Patients receiving th",,rapy with Gemzar sliould
`be monitored closely by a physician experienced in the use
`of cancer chemotherapeutic agents. Most adverse events are
`reversible and do not need to result in discontinuation, al(cid:173)
`though doses may need to be withheld or reduced. There
`was a greater tendency in women, especially older women,
`not to proceed to the next cycle.
`Laboratory Tests - Patients receiving Gemzar should be
`monitored prior to each dose with a complete blood count
`(CBC), including differential and platelet count. Suspension
`
`Table 5: Selected WHO-Graded Adverse Events in Patients Receiving Single-Agent Geni,a
`WHO Grades'(% incidence)
`'
`
`All Patients'
`
`Pancreatic Can~er Patientsh
`
`I~
`
`All
`All
`Grades Grade 3 Grade 4 Gn1des Grade 3 Grade 4
`
`Laboratoryd
`Hematologic
`Anemia
`Leukopenia
`N eutropeilia
`Thrombocytopenia
`
`Hepatic
`ALT
`AST
`Alkaline Phosphatase
`Bilirubin
`
`Renal
`Protein uria
`Hematuria
`BUN
`Creatinine
`
`Non•laboratorye
`Nausea and Vomiting
`Pain
`FeVer
`Rash
`Dyspnea
`Constipation
`Diarrhea
`Hemorrhage
`Infection
`Alopecia
`Stomatitis
`Somnolence
`Paresthesias
`
`'
`
`68
`62
`63
`24
`
`68
`67
`55
`13
`
`45
`35
`16
`8
`
`69
`48
`41
`30
`23
`23
`19
`17
`16
`15
`11
`11
`10
`
`7
`9
`19
`4
`
`< l
`< l
`0
`< 1
`
`13
`9
`2
`< l
`3
`1
`1
`<l
`1
`' < 1 '
`< l
`< l
`< l
`
`1
`<l
`6
`1
`
`2
`2
`2
`< l
`
`0
`0
`0
`0
`
`< l
`0
`0
`< l
`< 1
`0
`< l
`< l
`0
`0
`<l
`0
`
`73
`64
`61
`36
`
`72
`78
`77
`26
`
`32
`23
`15
`6
`
`71
`42
`38
`28
`10
`31
`30
`4
`10
`16
`10
`11
`10
`
`8
`8
`17
`7
`
`10
`12
`16
`6
`
`< l
`0
`0
`0
`
`10
`6
`2
`< 1
`0
`3
`3
`2
`2
`0
`<l
`2
`<l
`
`<l
`
`1
`5
`4
`2
`
`0
`0
`0
`0
`
`2
`< 1
`0
`0
`< l
`< l
`0
`< l
`< l
`0
`0
`< l
`0
`
`,q
`• )
`< l
`<l
`0
`0
`<l
`<l
`0
`1
`C)
`0
`
`Grade based .on criteria from the World Health Organization (WHO).
`a N=699-974; all patients with laboratory or non-laboratory data.
`"N=l61-241; all pancreatic cancer patients with laboratory or non-laboratory data.
`'N=979.
`d Regardless of causality.
`'Table includes non-laboratory data with incidence for all patients e:10%. For approximately 60% of the' pationi.,
`laboratory events were graded only if assessed to be possibly drug-related.
`
`Table 6: Selected WHO-Graded Adverse Events from Comparative Trial of Gemzar and 5-FU
`in Pancreatic I ca'nce·r
`WHO Grades (% incidence)
`
`Laboratoryc
`Hematologic
`Anemia
`Leukopenia
`Neutropenia
`Thrombo~~openia
`
`Hepatic
`ALT
`AST
`Alkaline Phosphatase
`Bilirubin
`
`Renal ·
`PrOteinuria
`Hematuria
`BUN
`Creatinine
`
`Non-laboratoryd
`Nausea and Vomiting
`Pain
`Fever
`Rash
`Dyspnea
`Constipation
`Diarrhea
`
`~l~~~r;~age
`Alopecia
`Stoma ti tis
`Somnolence
`Paresthesias
`
`2,
`2
`
`0
`2
`10
`6
`
`Gemzar8
`
`All
`Grades
`
`Grade 3
`
`Grade 4
`
`All
`Grades
`
`65
`71
`62
`47
`
`72
`72
`71
`16
`
`10
`13
`8
`2
`
`64
`10
`30
`24
`6
`10
`24
`0
`8
`18
`14
`5
`2
`
`7
`10
`19
`10
`
`8
`10
`16
`2
`
`10
`2
`0
`0
`0
`3
`2
`0
`0
`0
`0
`2
`0
`
`0
`0
`0
`0
`
`, o
`0
`
`45
`15
`18
`15
`
`38
`52
`64
`25
`
`2
`0
`10
`0
`
`58
`7
`16
`13
`3
`11
`31
`2
`3
`16
`15
`7
`2
`
`Grade based on criteria from the World Health Organization (WHO).
`• N =58-63; all Gemzar patients with laboratory or non-laboratory data.
`h N=61-63; all 5-FU patients with laboratory or non-laboratory data.
`' f{egar(jless of causality.
`' Nori-laboratory events were graded only if assessed to be possibly drug-related:
`
`or modification of therapy should be .considered when
`marrow suppression , is detected (see DOSAGE AND
`ADMINISTRATION).
`
`Laboratory evaluation of renal and hepatic functi
`be performed prior to initiation of therapy • nd
`thereafter (see WARNINGS).
`
`Information will ba superseded by supplements and subsequent editions
`
`NOVARTIS EXHIBIT 2019
`Par v. Novartis, IPR 2016-01479
`Page 4 of 7
`
`

`
`Table 7: Selected CTC-Graded Adverse Events from Comparative Trial of Gemzar plus Cisplatin versus
`Single-Agent Cisplatln in NSCLC
`CTC Grades (o/o incidence)
`
`Gemzar plus Cisplatin'
`
`C!~plat1n•
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`ELI LILL Y/1847
`
`Laboratory'
`Hematologic
`Anemia
`RBC Transfusiond
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Platelet Transfusionsd
`Lymphocytos
`
`Hepatic
`Transaminase '
`Alkaline Phosphatase
`
`-
`
`Renal
`Proteirturia
`Hematuria
`·CreatiDine
`- - -
`Other Laboratory
`Hyperglycemia
`Hypomagnesernia
`Hypocalcemia
`
`Non-laboratory•
`Nausea
`Vomiting
`Alopecia
`Neuro Motor
`Constipation
`Neuro Hearing
`Diarrhea
`Neuro Sensory
`Infection
`Fever
`Neuro Cortical
`Neuro Mood
`Local
`Neuro Headache
`Stomatitis
`Hemorrhage
`Dyspnea ·,
`Hypotension
`Rash
`
`89
`39
`82
`79
`85
`21
`75
`
`22
`19
`
`23
`15
`38
`
`30
`30
`18
`
`93
`78
`53
`35
`28
`25
`24
`23
`18
`16
`16
`16
`15
`14
`14
`14
`12
`12
`11
`
`22
`
`35
`22
`25
`
`25
`
`2
`1
`
`0
`0
`4
`
`4
`4
`2
`
`25
`11
`1
`12
`3
`6
`2
`1
`3
`0
`3
`1
`0
`0
`1
`1
`4
`1
`0
`
`I
`
`3
`
`11
`35
`25
`
`18
`
`1
`0
`
`0
`0
`< 1
`
`0
`3
`0
`
`2
`12
`0
`,o
`0
`0
`2
`0
`2
`0
`1
`0
`0
`0
`0
`0
`3
`0
`0
`
`67
`13
`25
`20
`13
`< 1
`51
`
`10
`13
`
`18
`13
`31
`
`23
`17
`7
`
`87
`71
`33
`15
`21
`21
`13
`18
`12
`5
`9
`10
`6
`7
`5
`4
`11
`7
`3
`
`6
`
`2
`3
`:{
`
`12
`
`1
`0
`
`0
`0
`2
`
`3
`2
`0
`
`20
`10
`0
`3
`0
`6
`0
`1
`1
`0
`l
`1
`0
`0
`0
`0
`3
`1
`0
`
`1
`
`1
`1
`1
`
`5
`
`0
`0
`
`0
`0
`< 1
`
`0
`0
`< l
`
`< 1
`9
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`2
`0
`0
`
`Grade based on Common Toxicity Criteria (CTC). Table includes data for adverse events with incidence ;;, to% in either ann.
`• N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data. Gernzar at 1000 mglm2 on Days 1,
`8, and 15 and cisplatin at 100 mg/m2 on Day 1 every 28 days.
`• N=213-248; all cisplatin patients with laboratory or non-laboratory data, Cisplatin at 100 mglm2 on Day 1 every 28 days.
`' Regardless of causality.
`d Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.
`• Non-laboratory events were graded only if assessed to be possibly drug-relat