See 17 for PATIENT COUNSELING INFORMATION. Revised: 09/2017 FULL PRESCRIBING INFORMATION: CONTENTS*

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use Gemzr sfely nd effectively. See full prescriing informtion for Gemzr. GEMZAR (gemcitine for injection), for intrvenous use Initil U.S. Approvl: INDICATIONS AND USAGE Gemzr is nucleoside metolic inhiitor indicted: in comintion with cropltin, for the tretment of dvnced ovrin cncer tht hs relpsed t lest months fter completion of pltinum- sed therpy. (.) in comintion with pclitxel, for first-line tretment of metsttic rest cncer fter filure of prior nthrcycline-contining djuvnt chemotherpy, unless nthrcyclines were cliniclly contrindicted. (.) in comintion with cispltin for the tretment of non-smll cell lung cncer. (.) s single gent for the tretment of pncretic cncer. (.) DOSAGE AND ADMINISTRATION Gemzr is for intrvenous use only. Ovrin Cncer: mg/m over minutes on Dys nd 8 of ech -dy cycle. (.) Brest Cncer: mg/m over minutes on Dys nd 8 of ech -dy cycle. (.) Non-Smll Cell Lung Cncer: mg/m over minutes on Dys, 8, nd of ech 8-dy cycle or mg/m over minutes on Dys nd 8 of ech -dy cycle. (.) Pncretic Cncer: mg/m over minutes once weekly for the first weeks, then one week rest, then once weekly for weeks of ech 8-dy cycle. (.) DOSAGE FORMS AND STRENGTHS mg/single-use vil () g/single-use vil () CONTRAINDICATIONS Ptients with known hypersensitivity to gemcitine. () WARNINGS AND PRECAUTIONS Schedule-dependent toxicity: Incresed toxicity with infusion time greter thn minutes or dosing more frequently thn once weekly. (.) Myelosuppression: Monitor for myelosuppression prior to ech cycle nd reduce or withhold dose for severe myelosuppression. (.,.) Pulmonry Toxicity nd Respirtory Filure: Discontinue Gemzr immeditely for unexplined new or worsening dyspne or evidence of severe pulmonry toxicity. (.) Hemolytic-Uremic Syndrome (HUS): Monitor renl function prior to initition nd during therpy. Discontinue Gemzr for HUS or severe renl impirment. (.) Heptic Toxicity: Monitor heptic function prior to initition nd during therpy. Discontinue Gemzr for severe heptic toxicity. (.) Emryofetl Toxicity: Cn cuse fetl hrm. Advise women of potentil risk to the fetus. (., 8.) Excertion of Rdition Therpy Toxicity: My cuse severe nd life-thretening toxicity when dministered during or within dys of rdition therpy. (.) Cpillry Lek Syndrome: Discontinue Gemzr. (.8) Posterior reversile encephlopthy syndrome (PRES): Discontinue Gemzr. (.9) ADVERSE REACTIONS The most common dverse rections for the single gent ( %) re nuse/vomiting, nemi, heptic trnsminitis, neutropeni, incresed lkline phosphtse, proteinuri, fever, hemturi, rsh, thromocytopeni, dyspne, nd peripherl edem. (.) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t -8-LillyRx (-8--99) or FDA t -8- FDA-88 or See for PATIENT COUNSELING INFORMATION. Revised: 9/ FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE. Ovrin Cncer. Brest Cncer. Non-Smll Cell Lung Cncer. Pncretic Cncer DOSAGE AND ADMINISTRATION. Ovrin Cncer. Brest Cncer. Non-Smll Cell Lung Cncer. Pncretic Cncer. Dose Modifictions for Non-Hemtologic Adverse Rections. Preprtion nd Administrtion Precutions. Preprtion for Intrvenous Infusion Administrtion DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Schedule-dependent Toxicity. Myelosuppression. Pulmonry Toxicity nd Respirtory Filure. Hemolytic Uremic Syndrome. Heptic Toxicity. Emryofetl Toxicity. Excertion of Rdition Therpy Toxicity.8 Cpillry Lek Syndrome.9 Posterior Reversile Encephlopthy Syndrome ADVERSE REACTIONS. Clinicl Trils Experience. Post-Mrketing Experience DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8. Pregnncy 8. Nursing Mothers 8. Peditric Use 8. Geritric Use 8. Renl Impirment 8. Heptic Impirment 8.8 Gender OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechnism of Action. Phrmcokinetics NONCLINICAL TOXICOLOGY. Crcinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES. Ovrin Cncer. Brest Cncer. Non-Smll Cell Lung Cncer (NSCLC). Pncretic Cncer HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. Storge nd Hndling PATIENT COUNSELING INFORMATION * Sections or susections omitted from the full prescriing informtion re not listed

2 FULL PRESCRIBING INFORMATION. INDICATIONS AND USAGE Ovrin Cncer Gemzr in comintion with cropltin is indicted for the tretment of ptients with dvnced ovrin cncer tht hs relpsed t lest months fter completion of pltinum-sed therpy.. Brest Cncer Gemzr in comintion with pclitxel is indicted for the first-line tretment of ptients with metsttic rest cncer fter filure of prior nthrcycline-contining djuvnt chemotherpy, unless nthrcyclines were cliniclly contrindicted.. Non-Smll Cell Lung Cncer Gemzr is indicted in comintion with cispltin for the first-line tretment of ptients with inoperle, loclly dvnced (Stge IIIA or IIIB), or metsttic (Stge IV) non-smll cell lung cncer.. Pncretic Cncer Gemzr is indicted s first-line tretment for ptients with loclly dvnced (nonresectle Stge II or Stge III) or metsttic (Stge IV) denocrcinom of the pncres. Gemzr is indicted for ptients previously treted with -FU. DOSAGE AND ADMINISTRATION. Ovrin Cncer Recommended Dose nd Schedule The recommended dose of Gemzr is mg/m s n intrvenous infusion over minutes on Dys nd 8 of ech -dy cycle, in comintion with cropltin AUC intrvenously fter Gemzr dministrtion on Dy of ech dy cycle. Refer to cropltin prescriing informtion for dditionl informtion. Dose Modifictions Recommended Gemzr dose modifictions for myelosuppression re descried in Tle nd Tle [see Wrnings nd Precutions (.)]. Refer to Dosge nd Administrtion (.) for recommendtions for non-hemtologic dverse rections. Tle : Dosge Reduction Guidelines for Gemzr for Myelosuppression on Dy of Tretment in Ovrin Cncer Tretment Dy Asolute grnulocyte count Pltelet count % of full dose (x /L) (x /L) Dy nd, % or, Dely Tretment Cycle Dy 8 nd, % -99 or,-99,999 % or <, Hold Tle : Gemzr Dose Modifiction for Myelosuppression in Previous Cycle In Ovrin Cncer Occurrence Myelosuppression During Tretment Cycle Dose Modifiction Initil Asolute grnulocyte count less thn x /L for Permnently reduce Gemzr to 8 mg/m on Occurrence more thn dys Dys nd 8 Asolute grnulocyte count less thn x /L for more thn dys Ferile neutropeni Pltelets less thn,x /L Cycle dely of more thn one week due to toxicity Susequent If ny of the ove toxicities occur fter the initil dose Permnently reduce Gemzr dose to Occurrence reduction 8 mg/m on Dy only. Brest Cncer Recommended Dose nd Schedule The recommended dose of Gemzr is mg/m intrvenously over minutes on Dys nd 8 of ech -dy cycle tht includes pclitxel. Pclitxel should e dministered t mg/m on Dy s hour intrvenous infusion efore Gemzr dministrtion. Dose Modifictions Recommended dose modifictions for Gemzr for myelosuppression re descried in Tle [see Wrnings nd Precutions (.)]. Refer to Dosge nd Administrtion (.) for recommendtions for non-hemtologic dverse rections.

3 Tle : Recommended Dose Reductions for Gemzr for Myelosuppression on Dy of Tretment in Brest Cncer Tretment Dy Asolute grnulocyte count Pltelet count % of full dose (x /L) (x /L) Dy nd, % less thn or less thn, Hold Dy 8 nd >, % -99 or,-, % -999 nd, % < or <, Hold. Non-Smll Cell Lung Cncer Recommended Dose nd Schedule Every -week schedule The recommended dose of Gemzr is mg/m intrvenously over minutes on Dys, 8, nd in comintion with cispltin therpy. Administer cispltin intrvenously t mg/m on Dy fter the infusion of Gemzr. Every -week schedule The recommended dose of Gemzr is mg/m intrvenously over minutes on Dys nd 8 in comintion with cispltin therpy. Administer cispltin intrvenously t mg/m on Dy fter the infusion of Gemzr. Dose Modifictions Recommended dose modifictions for Gemzr myelosuppression re descried in Tle [see Wrnings nd Precutions (.)]. Refer to Dosge nd Administrtion (.) for Gemzr recommendtions for non-hemtologic dverse rections.. Pncretic Cncer Recommended Dose nd Schedule The recommended dose of Gemzr is mg/m over minutes intrvenously. The recommended tretment schedule is s follows: Weeks -8: weekly dosing for the first weeks followed y one week rest. After week 8: weekly dosing on Dys, 8, nd of 8-dy cycles. Dose Modifictions Recommended dose modifictions for Gemzr for myelosuppression re descried in Tle [see Wrnings nd Precutions (.)]. Refer to Dosge nd Administrtion (.) for recommendtions for non-hemtologic dverse rections. Ptients receiving Gemzr should e monitored prior to ech dose with complete lood count (CBC), including differentil nd pltelet count. If mrrow suppression is detected, therpy should e modified or suspended ccording to the guidelines in Tle. Tle : Recommended Dose Reductions for Gemzr for Myelosuppression in Pncretic Cncer nd Non-Smll Cell Lung Cncer Asolute grnulocyte count Pltelet count % of full dose (x /L) (x /L) And, % -999 Or,-99,999 % < Or <, Hold. Dose Modifictions for Non-Hemtologic Adverse Rections Permnently discontinue Gemzr for ny of the following: Unexplined dyspne or other evidence of severe pulmonry toxicity Severe heptic toxicity Hemolytic-uremic syndrome Cpillry lek syndrome Posterior reversile encephlopthy syndrome Withhold Gemzr or reduce dose y % for other severe (Grde or ) non-hemtologicl toxicity until resolved. No dose modifictions re recommended for lopeci, nuse, or vomiting.. Preprtion nd Administrtion Precutions Exercise cution nd wer gloves when prepring Gemzr solutions. Immeditely wsh the skin thoroughly or rinse the mucos with copious mounts of wter if Gemzr contcts the skin or mucus memrnes. Deth hs occurred in niml studies due to derml sorption. For further guidnce on hndling Gemzr go to OSHA Hzrdous Drugs

4 (refer to ntineoplstic welinks including OSHA Technicl Mnul) t OSHA. Preprtion for Intrvenous Infusion Administrtion Reconstitute the vils with.9% Sodium Chloride Injection without preservtives. Add ml to the -mg vil or ml to the -g vil. These dilutions ech yield Gemzr concentrtion of 8 mg/ml. Complete withdrwl of the vil contents will provide mg or g of Gemzr. Prior to dministrtion the pproprite mount of drug must e diluted with.9% Sodium Chloride Injection. Finl concentrtions my e s low s. mg/ml. Reconstituted Gemzr is cler, colorless to light strw-colored solution. Inspect visully prior to dministrtion nd discrd for prticulte mtter or discolortion. Gemzr solutions re stle for hours t controlled room temperture of to C (8 to F). Do not refrigerte s crystlliztion cn occur. No incomptiilities hve een oserved with infusion ottles or polyvinyl chloride gs nd dministrtion sets. DOSAGE FORMS AND STRENGTHS Gemzr (gemcitine for injection USP) is white to off-white lyophilized powder ville in sterile single-use vils contining mg or g gemcitine.. CONTRAINDICATIONS Gemzr is contrindicted in ptients with known hypersensitivity to gemcitine. WARNINGS AND PRECAUTIONS Schedule-dependent Toxicity In clinicl trils evluting the mximum tolerted dose of Gemzr, prolongtion of the infusion time eyond minutes or more frequent thn weekly dosing resulted in n incresed incidence of cliniclly significnt hypotension, severe flu-like symptoms, myelosuppression, nd stheni. The hlf-life of Gemzr is influenced y the length of the infusion [see Clinicl Phrmcology (.)].. Myelosuppression Myelosuppression mnifested y neutropeni, thromocytopeni, nd nemi occurs with Gemzr s single gent nd the risks re incresed when Gemzr is comined with other cytotoxic drugs. In clinicl trils, Grde - neutropeni, nemi, nd thromocytopeni occurred in %, 8%, nd %, respectively of ptients receiving single-gent Gemzr. The frequencies of Grde - neutropeni, nemi, nd thromocytopeni vried from 8% to %, 8 to 8%, nd to %, respectively, in ptients receiving Gemzr in comintion with nother drug.. Pulmonry Toxicity nd Respirtory Filure Pulmonry toxicity, including interstitil pneumonitis, pulmonry firosis, pulmonry edem, nd dult respirtory distress syndrome (ARDS), hs een reported. In some cses, these pulmonry events cn led to ftl respirtory filure despite discontinution of therpy. The onset of pulmonry symptoms my occur up to weeks fter the lst dose of Gemzr. Discontinue Gemzr in ptients who develop unexplined dyspne, with or without ronchospsm, or hve ny evidence of pulmonry toxicity [see Adverse Rections (. nd.)].. Hemolytic Uremic Syndrome Hemolytic uremic syndrome, including ftlities from renl filure or the requirement for dilysis, cn occur in ptients treted with Gemzr. In clinicl trils, HUS ws reported in of 9 ptients (.%). Most ftl cses of renl filure were due to HUS [see Adverse Rections (. nd.)]. Assess renl function prior to initition of Gemzr nd periodiclly during tretment. Consider the dignosis of HUS in ptients who develops nemi with evidence of microngiopthic hemolysis, elevtion of iliruin or LDH, or reticulocytosis; severe thromocytopeni; or evidence of renl filure (elevtion of serum cretinine or BUN) [see Dosge nd Administrtion (.) nd Use in Specific Popultions (8.)]. Permnently discontinue Gemzr in ptients with HUS or severe renl impirment. Renl filure my not e reversile even with discontinution of therpy.. Heptic Toxicity Drug-induced liver injury, including liver filure nd deth, hs een reported in ptients receiving Gemzr lone or in comintion with other potentilly heptotoxic drugs [see Adverse Rections (. nd.)]. Administrtion of Gemzr in ptients with concurrent liver metstses or pre-existing medicl history or heptitis, lcoholism, or liver cirrhosis cn led to excertion of the underlying heptic insufficiency [see Use in Specific Popultions (8.)]. Assess heptic function prior to initition of Gemzr nd periodiclly during tretment. Discontinue Gemzr in ptients tht develop severe liver injury.. Emryofetl Toxicity Gemzr cn cuse fetl hrm when dministered to pregnnt womn, sed on its mechnism of ction. Gemcitine ws tertogenic, emryotoxic, nd fetotoxic in mice nd rits. If this drug is used during pregnncy, or if womn ecomes pregnnt while tking Gemzr, the ptient should e pprised of the potentil hzrd to fetus [see Use in Specific Popultions (8.)].. Excertion of Rdition Therpy Toxicity

5 Gemzr is not indicted for use in comintion with rdition therpy. Concurrent (given together or dys prt) Life-thretening mucositis, especilly esophgitis nd pneumonitis occurred in tril in which Gemzr ws dministered t dose of mg/m to ptients with non-smll cell lung cncer for up to consecutive weeks concurrently with thorcic rdition. Non-concurrent (given > dys prt) Excessive toxicity hs not een oserved when Gemzr is dministered more thn dys efore or fter rdition. Rdition recll hs een reported in ptients who receive Gemzr fter prior rdition..8 Cpillry Lek Syndrome Cpillry lek syndrome (CLS) with severe consequences hs een reported in ptients receiving Gemzr s single gent or in comintion with other chemotherpeutic gents. Discontinue Gemzr if CLS develops during therpy..9 Posterior Reversile Encephlopthy Syndrome Posterior reversile encephlopthy syndrome (PRES) hs een reported in ptients receiving Gemzr s single gent or in comintion with other chemotherpeutic gents. PRES cn present with hedche, seizure, lethrgy, hypertension, confusion, lindness, nd other visul nd neurologic disturnces. Confirm the dignosis of PRES with mgnetic resonnce imging (MRI) nd discontinue Gemzr if PRES develops during therpy. ADVERSE REACTIONS The following serious dverse rections re discussed in greter detil in nother section of the lel Schedule-dependent Toxicity [see Wrnings nd Precutions (.)] Myelosuppression [see Wrnings nd Precutions (.)] Pulmonry Toxicity nd Respirtory Filure [see Wrnings nd Precutions (.)] Hemolytic Uremic Syndrome [see Wrnings nd Precutions (.)] Heptic Toxicity [see Wrnings nd Precutions (.)] Emryofetl Toxicity [see Wrnings nd Precutions (.), Use in Specific Popultions (8.), nd Nonclinicl Toxicology (.)] Excertion of Rdition Toxicity [see Wrnings nd Precutions (.)] Cpillry Lek Syndrome [see Wrnings nd Precutions (.8)] Posterior Reversile Encephlopthy Syndrome [see Wrnings nd Precutions (.9)]. Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in clinicl prctice. Single-Agent Use: The dt descried elow reflect exposure to Gemzr s single gent dministered t doses etween 8 mg/m to mg/m over minutes intrvenously, once weekly, in 99 ptients with vriety of mlignncies. The most common ( %) dverse rections of single-gent Gemzr re nuse/vomiting, nemi, incresed ALT, incresed AST, neutropeni, incresed lkline phosphtse, proteinuri, fever, hemturi, rsh, thromocytopeni, dyspne, nd edem. The most common ( %) Grde or dverse rections were neutropeni, nuse/vomiting; incresed ALT, increse lkline phosphtse, nemi, incresed AST, nd thromocytopeni. Approximtely % of the 99 ptients discontinued Gemzr due to dverse rections. Adverse rections resulting in discontinution of Gemzr in % of 99 ptients were crdiovsculr dverse events (myocrdil infrction, cererovsculr ccident, rrhythmi, nd hypertension) nd dverse rections resulting in discontinution of Gemzr in less thn % of the 99 ptients were nemi, thromocytopeni, heptic dysfunction, renl dysfunction, nuse/vomiting, fever, rsh, dyspne, hemorrhge, infection, stomtitis, somnolence, flu-like syndrome, nd edem. Tle presents the incidence of dverse rections reported in 99 ptients with vrious mlignncies receiving single-gent Gemzr cross clinicl trils. Tle includes ll clinicl dverse rections, reported in t lest % of ptients. A listing of cliniclly significnt dverse rections is provided following the tle. Tle : Selected Per-Ptient Incidence of Adverse Events in Ptients Receiving Single-Agent Gemzr All Ptients All Grdes Grde Grde c Lortory Hemtologic Anemi 8 Neutropeni 9 Thromocytopeni Heptic Incresed ALT 8 8 Incresed AST Incresed Alkline Phosphtse

6 Hyperiliruinemi Renl Proteinuri Hemturi Incresed BUN Incresed Cretinine 8 d Non-lortory Nuse nd Vomiting 9 Fever Rsh Dyspne Dirrhe 9 Hemorrhge Infection Alopeci Stomtitis Somnolence Presthesis Grde sed on criteri from the World Helth Orgniztion (WHO). N=99-9; ll ptients with lortory or non-lortory dt. c Regrdless of cuslity. d For pproximtely % of ptients, non-lortory dverse events were grded only if ssessed to e possily drugrelted. Trnsfusion requirements Red lood cell trnsfusions (9%); pltelet trnsfusions (%) Fever Fever occurred in the sence of clinicl infection nd frequently in comintion with other flu-like symptoms. Pulmonry Dyspne unrelted to underlying disese nd sometimes ccompnied y ronchospsm. Edem Edem (%), peripherl edem (%), nd generlized edem (%); % of ptients. discontinued Gemzr due to edem. Flu-like Symptoms Chrcterized y fever, stheni, norexi, hedche, cough, chills, mylgi, stheni insomni, rhinitis, sweting, nd/or mlise (9%); % of ptients discontinued Gemzr due to flu-like symptoms Infection Sepsis (%) Extrvstion Injection-site rections (%) Allergic Bronchospsm (<%); nphylctoid rections [see Contrindictions ()]. Non-Smll Cell Lung Cncer: Tle presents the incidence of selected dverse rections, occurring in % of Gemzr-treted ptients nd t higher incidence in the Gemzr plus cispltin rm, reported in rndomized tril of Gemzr plus cispltin (n=) dministered in 8-dy cycles s compred to cispltin lone (n=) in ptients receiving first-line tretment for loclly dvnced or metsttic non-smll cell lung cncer (NSCLC) [see Clinicl Studies (.)]. Ptients rndomized to Gemzr plus cispltin received medin of cycles of tretment nd those rndomized to cispltin received medin of cycles of tretment. In this tril, the requirement for dose djustments (>9% versus %), discontinution of tretment for dverse rections (% versus 8%), nd the proportion of ptients hospitlized (% versus %) were ll higher for ptients receiving Gemzr plus cispltin rm compred to those receiving cispltin lone. The incidence of ferile neutropeni (9/ versus /), sepsis (% versus %), Grde crdic dysrhythmis (% versus %) were ll higher in the Gemzr plus cispltin rm compred to the cispltin lone rm. The two-drug comintion ws more myelosuppressive with (.%) possily tretment-relted deths, including resulting from myelosuppression with infection nd one cse of renl filure ssocited with pncytopeni nd infection. No deths due to tretment were reported on the cispltin rm. Tle : Per-Ptient Incidence of Selected Adverse Rections from Rndomized Tril of Gemzr plus Cispltin versus Single-Agent Cispltin in Ptients with NSCLC Occurring t Higher Incidence in Gemzr-Treted Ptients [Between Arm Difference of % (All Grdes) or % (Grdes -)] Gemzr plus Cispltin Cispltinc All Grdes Grde Grde All Grdes Grde Grde Lortoryd Hemtologic Anemi 89 RBC Trnsfusione 9

7 Neutropeni 9 Thromocytopeni 8 e Pltelet Trnsfusions Lymphopeni 8 Heptic Incresed Trnsminses Incresed Alkline 9 Phosphtse Renl Proteinuri 8 Hemturi Elevted cretinine 8 Other Lortory Hyperglycemi Hypomgnesemi Hypoclcemi 8 Non-lortoryf Nuse 9 8 Vomiting 8 9 Alopeci Neuro Motor Dirrhe Neuro Sensory 8 Infection 8 Fever Neuro Corticl 9 Neuro Mood Locl Neuro Hedche Stomtitis Hemorrhge Hypotension Rsh Ntionl Cncer Institute Common Toxicity Criteri (CTC) for severity grding. N=-; ll Gemzr plus cispltin ptients with lortory or non-lortory dt Gemzr t mg/m on Dys, 8, nd nd cispltin t mg/m on Dy every 8 dys. c N=-8; ll cispltin ptients with lortory or non-lortory dt. Cispltin t mg/m on Dy every 8 dys. d Regrdless of cuslity. e Percent of ptients receiving trnsfusions. Percent trnsfusions re not CTC-grded events. f Non-lortory events were grded only if ssessed to e possily drug-relted. Tle presents the incidence of selected dverse rections, occurring in % of Gemzr-treted ptients nd t higher incidence in the Gemzr plus cispltin rm, reported in rndomized tril of Gemzr plus cispltin (n=9) dministered in -dy cycles s compred to etoposide plus cispltin lone (n=) in ptients receiving first-line tretment for loclly dvnced or metsttic non-smll cell lung cncer (NSCLC) [see Clinicl Studies (.)]. A listing of cliniclly significnt dverse rections is provided following the tle. Ptients in the Gemzr cispltin (GC) rm received medin of cycles nd those in the etoposide/cispltin (EC) rm received medin of cycles. The mjority of ptients receiving more thn one cycle of tretment required dose djustments; 8% in the (GC) rm nd 8% in the (EC) rm. The incidence of hospitliztions for tretment-relted dverse events ws % (GC) nd % in the (EC) rm. The proportion of discontinution of tretment for tretmentrelted dverse rections ws higher for ptients in the (GC) rm (% versus 8%). The proportion of ptients hospitlized for ferile neutropeni ws lower in the (GC) rm (% versus %). There ws one deth ttriuted to tretment, ptient with ferile neutropeni nd renl filure, which occurred in the Gemzr/cispltin rm. Tle : Per-Ptient Incidence of Selected Adverse Rections in Rndomized Tril of Gemzr plus Cispltin versus Etoposide plus Cispltin in Ptients with NSCLC Gemzr plus Cispltin Etoposide plus Cispltinc All Grdes Grde Grde All Grdes Grde Grde Lortoryd

8 8 Hemtologic Anemi 88 e RBC Trnsfusions 9 Neutropeni Thromocytopeni Pltelet Trnsfusionse 8 Heptic Incresed ALT Incresed AST Incresed Alkline Phosphtse Biliruin Renl Proteinuri Hemturi BUN Cretinine Non-lortoryf Nuse nd Vomiting Fever Rsh Dyspne Dirrhe Hemorrhge 9 Infection 8 8 Alopeci 9 Stomtitis 8 Somnolence Presthesis 8 Flu-like syndromeg Edemg Grde sed on criteri from the World Helth Orgniztion (WHO). N=-9; ll Gemzr plus cispltin ptients with lortory or non-lortory dt. Gemzr t mg/m on Dys nd 8 nd cispltin t mg/m on Dy every dys. c N=-; ll cispltin plus etoposide ptients with lortory or non-lortory dt. Cispltin t mg/m on Dy nd intrvenous etoposide t mg/m on Dys,, nd every dys. d Regrdless of cuslity. e WHO grding scle not pplicle to proportion of ptients with trnsfusions. f Non-lortory events were grded only if ssessed to e possily drug-relted. Pin dt were not collected. g Flu-like syndrome nd edem were not grded. Brest Cncer Tle 8 presents the incidence of selected dverse rections, occurring in % of Gemzr-treted ptients nd t higher incidence in the Gemzr plus pclitxel rm, reported in rndomized tril of Gemzr plus pclitxel (n=) compred to pclitxel lone (n=9) for the first-line tretment of metsttic rest cncer (MBC) in women who received nthrcycline-contining chemotherpy in the djuvnt/neo-djuvnt setting or for whom nthrcyclines were contrindicted [see Clinicl Studies (.)]. The requirement for dose reduction of pclitxel were higher for ptients in the Gemzr/pclitxel rm (% versus %). The numer of pclitxel doses omitted (%), the proportion of ptients discontinuing tretment for tretmentrelted dverse rections (% versus %), nd the numer of tretment-relted deths ( ptient in ech rm) were similr etween the two rms. Tle 8: Per-Ptient Incidence of Selected Adverse Rections from Comprtive Tril of Gemzr plus Pclitxel versus Single-Agent Pclitxel in Brest Cncer Occurring t Higher Incidence in Gemzr-Treted Ptients [Between Arm Difference of % (All Grdes) or % (Grdes -)] Gemzr plus Pclitxel Pclitxel (N=) (N=9) All Grdes Grde Grde All Grdes Grde Grde Lortory

9 9 Hemtologic Anemi 9 Neutropeni 9 Thromocytopeni Heptoiliry Incresed ALT 8 Incresed AST c Non-lortory Alopeci Neuropthy-sensory 8 Nuse Ftigue 8 Vomiting 9 Dirrhe Anorexi Neuropthy-motor Stomtitis/phryngitis 8 Fever Rsh/desqumtion Ferile neutropeni Severity grde sed on Ntionl Cncer Institute Common Toxicity Criteri (CTC) Version.. Regrdless of cuslity. c Non-lortory events were grded only if ssessed to e possily drug-relted. Cliniclly relevnt Grde or dyspne occurred with higher incidence in the Gemzr plus pclitxel rm compred with the pclitxel rm (.9% versus ). Ovrin Cncer Tle 9 presents the incidence of selected dverse rections, occurring in % of gemcitine-treted ptients nd t higher incidence in the Gemzr plus cropltin rm, reported in rndomized tril of Gemzr plus cropltin (n=) compred to cropltin lone (n=) for the second-line tretment of ovrin cncer in women with disese tht hd relpsed more thn months following first-line pltinum-sed chemotherpy [see Clinicl Studies (.)]. Additionl cliniclly significnt dverse rections, occurring in less thn % of ptients, re provided following Tle 9. The proportion of ptients with dose djustments for cropltin (.8% versus.8%), doses of cropltin omitted (.% versus ), nd discontinuing tretment for tretment-relted dverse rections (.9% versus 9.8%), were similr etween rms. Dose djustment for Gemzr occurred in.% of ptients nd Gemzr dose ws omitted in.% of ptients in the Gemzr /cropltin rm. Tle 9: Per-Ptient Incidence of Adverse Rections in Rndomized Tril of Gemzr plus Cropltin versus Cropltin in Ovrin Cncer Occurring t Higher Incidence in Gemzr-Treted Ptients [Between Arm Difference of % (All Grdes) or % (Grdes -)] Gemzr plus Cropltin Cropltin (N=) (N=) All Grdes Grde Grde All Grdes Grde Grde Lortory Hemtologic Neutropeni Anemi 8 9 Thromocytopeni 8 RBC Trnsfusionsc 8 Pltelet Trnsfusionsc 9 Non-lortory Nuse 9 Alopeci 9 Vomiting Constiption Ftigue Dirrhe Stomtitis/phryngitis Grde sed on Common Toxicity Criteri (CTC) Version.. Regrdless of cuslity.

10 c Percent of ptients receiving trnsfusions. Trnsfusions re not CTC-grded events. Blood trnsfusions included oth pcked red lood cells nd whole lood. Hemtopoietic growth fctors were dministered more frequently in the Gemzr-contining rm: grnulocyte growth fctors (.% nd.%) nd erythropoietic gents (.% nd.9%). The following cliniclly relevnt, Grde nd dverse rections occurred more frequently in the Gemzr plus cropltin rm: dyspne (.% versus.9%), ferile neutropeni (.% versus ), hemorrhgic event (.% versus. %), motor neuropthy (.% versus.%), nd rsh/desqumtion (.% versus ).. Post-Mrketing Experience The following dverse rections hve een identified during post-pprovl use of Gemzr. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Crdiovsculr Congestive hert filure, myocrdil infrction, rrhythmis, suprventriculr rrhythmis Vsculr Disorders Peripherl vsculitis, gngrene, nd cpillry lek syndrome [see Wrnings nd Precutions (.8)] Skin Cellulitis, severe skin rections, including desqumtion nd ullous skin eruptions Heptic Heptic filure, heptic veno-occlusive disese Pulmonry Interstitil pneumonitis, pulmonry firosis, pulmonry edem, nd dult respirtory distress syndrome (ARDS) Nervous System Posterior reversile encephlopthy syndrome (PRES) [see Wrnings nd Precutions (.9)] 8 8. DRUG INTERACTIONS No drug interction studies hve een conducted. USE IN SPECIFIC POPULATIONS Pregnncy Pregnncy Ctegory D. [See Wrnings nd Precutions (.)]. Risk Summry Gemzr cn cuse fetl hrm when dministered to pregnnt womn. Bsed on its mechnism of ction, Gemzr is expected to result in dverse reproductive effects. Gemcitine ws tertogenic, emryotoxic, nd fetotoxic in mice nd rits. If Gemzr is used during pregnncy, or if the ptient ecomes pregnnt while tking Gemzr, the ptient should e pprised of the potentil hzrd to fetus. Animl Dt Gemcitine is emryotoxic cusing fetl mlformtions (cleft plte, incomplete ossifiction) t doses of. mg/kg/dy in mice (pproximtely. times the recommended humn dose on mg/m sis). Gemcitine is fetotoxic cusing fetl mlformtions (fused pulmonry rtery, sence of gll ldder) t doses of. mg/kg/dy in rits (out. times the recommended humn dose on mg/m sis). Emryotoxicity ws chrcterized y decresed fetl viility, reduced live litter sizes, nd developmentl delys. [See Wrnings nd Precutions (.)]. 8. Nursing Mothers It is not known whether this drug is excreted in humn milk. Becuse mny drugs re excreted in humn milk nd ecuse of the potentil for serious dverse rections in nursing infnts from Gemzr, decision should e mde whether to discontinue nursing or to discontinue the drug, tking into ccount the importnce of the drug to the mother. 8. Peditric Use The sfety nd effectiveness of Gemzr hve not een estlished in peditric ptients. The sfety nd phrmcokinetics of gemcitine were evluted in tril in peditric ptients with refrctory leukemi. The mximum tolerted dose ws mg/m/min for minutes weekly for three weeks followed y one-week rest period. The sfety nd ctivity of Gemzr were evluted in tril of peditric ptients with relpsed cute lympholstic leukemi ( ptients) nd cute myelogenous leukemi ( ptients) t dose of mg/m/min dministered over minutes weekly for three weeks followed y one-week rest period. Ptients with M or M one mrrow on Dy 8 who did not experience uncceptle toxicity were eligile to receive mximum of one dditionl four-week course. Toxicities oserved included one mrrow suppression, ferile neutropeni, elevtion of serum trnsminses, nuse, nd rsh/desqumtion. No meningful clinicl ctivity ws oserved in this tril. 8. Geritric Use In clinicl studies of GEMZAR, enrolling 99 ptients with vrious cncers who received GEMZAR s single gent, no overll differences in sfety were oserved etween ptients ged nd older nd younger ptients, with the exception of higher rte of Grde - thromocytopeni in older ptients s compred to younger ptients. In rndomized tril in women with ovrin cncer, women received GEMZAR plus cropltin, of which 9% were ge yers or older. Similr effectiveness ws oserved etween older nd younger women. There ws significntly higher Grde / neutropeni in women yers of ge or older.

11 GEMZAR clernce is ffected y ge, however there re no recommended dose djustments sed on ptients ge [see Clinicl Phrmcology (.)]. 8. Renl Impirment No clinicl studies hve een conducted with gemcitine in ptients with decresed renl function. 8. Heptic Impirment No clinicl studies hve een conducted with gemcitine in ptients with decresed heptic function. 8.8 Gender Gemzr clernce is ffected y gender [see Clinicl Phrmcology (.)]. In single-gent studies of Gemzr, women, especilly older women, were more likely not to proceed to susequent cycle nd to experience Grde / neutropeni nd thromocytopeni. OVERDOSAGE Myelosuppression, presthesis, nd severe rsh were the principl toxicities seen when single dose s high s mg/m ws dministered y intrvenous infusion over minutes every weeks to severl ptients in doseescltion study. DESCRIPTION Gemzr (gemcitine for injection, USP) is nucleoside metolic inhiitor tht exhiits ntitumor ctivity. Gemcitine HCl is -deoxy-, -difluorocytidine monohydrochloride ( -isomer). The structurl formul is s follows: The empiricl formul for gemcitine HCl is C9HFNO HCl. It hs moleculr weight of 99.. Gemcitine HCl is solule in wter, slightly solule in methnol, nd prcticlly insolule in ethnol nd polr orgnic solvents. Gemzr is supplied in sterile form for intrvenous use only. Vils of Gemzr contin either mg or g of gemcitine HCl (expressed s free se) formulted with mnnitol ( mg or g, respectively) nd sodium cette (. mg or. mg, respectively) s sterile lyophilized powder. Hydrochloric cid nd/or sodium hydroxide my hve een dded for ph djustment.. CLINICAL PHARMACOLOGY Mechnism of Action Gemcitine kills cells undergoing DNA synthesis nd locks the progression of cells through the G/S-phse oundry. Gemcitine is metolized y nucleoside kinses to diphosphte (dfdcdp) nd triphosphte (dfdctp) nucleosides. Gemcitine diphosphte inhiits rionucleotide reductse, n enzyme responsile for ctlyzing the rections tht generte deoxynucleoside triphosphtes for DNA synthesis, resulting in reductions in deoxynucleotide concentrtions, including dctp. Gemcitine triphosphte competes with dctp for incorportion into DNA. The reduction in the intrcellulr concentrtion of dctp y the ction of the diphosphte enhnces the incorportion of gemcitine triphosphte into DNA (self-potentition). After the gemcitine nucleotide is incorported into DNA, only one dditionl nucleotide is dded to the growing DNA strnds, which eventully results in the initition of poptotic cell deth.. Phrmcokinetics Asorption nd Distriution The phrmcokinetics of gemcitine were exmined in ptients, with vrious solid tumors. Phrmcokinetic prmeters were derived using dt from ptients treted for vrying durtions of therpy given weekly with periodic rest weeks nd using oth short infusions (< minutes) nd long infusions ( to 8 minutes). The totl Gemzr dose vried from to mg/m.

12 The volume of distriution ws incresed with infusion length. Volume of distriution of gemcitine ws L/m following infusions lsting < minutes. For long infusions, the volume of distriution rose to L/m. Gemcitine phrmcokinetics re liner nd re descried y -comprtment model. Popultion phrmcokinetic nlyses of comined single nd multiple dose studies showed tht the volume of distriution of gemcitine ws significntly influenced y durtion of infusion nd gender. Gemcitine plsm protein inding is negligile. Metolism Gemcitine disposition ws studied in ptients who received single mg/m / minute infusion of rdioleled drug. Within one () week, 9% to 98% of the dose ws recovered, lmost entirely in the urine. Gemcitine (%) nd the inctive urcil metolite, -deoxy-, -difluorouridine (dfdu), ccounted for 99% of the excreted dose. The metolite dfdu is lso found in plsm. The ctive metolite, gemcitine triphosphte, cn e extrcted from peripherl lood mononucler cells. The hlf-life of the terminl phse for gemcitine triphosphte from mononucler cells rnges from. to 9. hours. Elimintion Clernce of gemcitine ws ffected y ge nd gender. The lower clernce in women nd the elderly results in higher concentrtions of gemcitine for ny given dose. Differences in either clernce or volume of distriution sed on ptient chrcteristics or the durtion of infusion result in chnges in hlf-life nd plsm concentrtions. Tle shows plsm clernce nd hlf-life of gemcitine following short infusions for typicl ptients y ge nd gender. Tle : Gemcitine Clernce nd Hlf-Life for the Typicl Ptient Clernce Men Clernce Women Hlf-Life Men Hlf-Life Women (L/hr/m ) (L/hr/m ) (min) (min) Hlf-life for ptients receiving < minute infusion. Age Gemcitine hlf-life for short infusions rnged from to 9 minutes, nd the vlue for long infusions vried from to 8 minutes, depending on ge nd gender, reflecting gretly incresed volume of distriution with longer infusions. Drug Interctions When Gemzr ( mg/m on Dys nd 8) nd cispltin ( mg/m on Dy ) were dministered in NSCLC ptients, the clernce of gemcitine on Dy ws 8 L/hr/m nd on Dy 8 ws L/hr/m. Anlysis of dt from metsttic rest cncer ptients shows tht, on verge, Gemzr hs little or no effect on the phrmcokinetics (clernce nd hlf-life) of pclitxel nd pclitxel hs little or no effect on the phrmcokinetics of gemcitine. Dt from NSCLC ptients demonstrte tht Gemzr nd cropltin given in comintion does not lter the phrmcokinetics of gemcitine or cropltin compred to dministrtion of either single gent. However, due to wide confidence intervls nd smll smple size, interptient vriility my e oserved.. NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility Long-term niml studies to evlute the crcinogenic potentil of Gemzr hve not een conducted. Gemcitine ws mutgenic in n in vitro mouse lymphom (L8Y) ssy nd ws clstogenic in n in vivo mouse micronucleus ssy. Gemcitine IP doses of. mg/kg/dy (out / the humn dose on mg/m sis) in mle mice hd n effect on fertility with moderte to severe hypospermtogenesis, decresed fertility, nd decresed implnttions. In femle mice, fertility ws not ffected ut mternl toxicities were oserved t. mg/kg/dy dministered intrvenously (out / the humn dose on mg/m sis) nd fetotoxicity or emryolethlity ws oserved t. mg/kg/dy dministered intrvenously (out / the humn dose on mg/m sis).. CLINICAL STUDIES Ovrin Cncer The sfety nd efficcy of Gemzr ws studied in rndomized tril of women with dvnced ovrin cncer tht hd relpsed t lest months fter first-line pltinum-sed therpy. Ptients were rndomized to receive either Gemzr mg/m on Dys nd 8 of -dy cycle nd cropltin AUC dministered fter Gemzr infusion on Dy of ech cycle (n=8) or to cropltin AUC dministered on Dy of ech -dy cycle (n=8). The primry efficcy outcome mesure ws progression free survivl (PFS). Ptient chrcteristics re shown in Tle. The ddition of Gemzr to cropltin resulted in sttisticlly significnt improvements in PFS nd overll response rte s shown in Tle nd Figure. Approximtely % of ptients in ech rm received dditionl chemotherpy for disese progression; of ptients in the cropltin

13 lone rm received Gemzr for tretment of disese progression. There ws no significnt difference in overll survivl etween the tretment rms. Tle : Rndomized Tril of Gemzr plus Cropltin versus Cropltin in Ovrin Cncer - Bseline Demogrphics nd Clinicl Chrcteristics Gemzr/Cropltin Cropltin Numer of rndomized ptients 8 8 Medin ge, yers 9 8 Rnge to 8 to 8 Bseline ECOG performnce sttus - 9% 9% Disese Sttus Evlule 8% % Bidimensionlly mesurle 9% 9% Pltinum-free intervl - months % % > months 9% % First-line therpy Pltinum-txne comintion % % Pltinum-non-txne comintion 9% 8% Pltinum monotherpy % % ptients on Gemzr plus cropltin rm nd ptients on cropltin rm with no seline Estern Coopertive Oncology Group (ECOG) performnce sttus. on Gemzr plus cropltin rm nd on cropltin rm hd pltinum-free intervl < months. Tle : Rndomized Tril of Gemzr plus Cropltin versus Cropltin in Ovrin Cncer - Efficcy Outcomes Gemzr/Cropltin (N=8) Cropltin (N=8) Progression-free Survivl Medin (9% CI ) months 8. (8., 9.).8 (.,.) Hzrd Rtio (9% CI). (.,.9) p-vlue p=.8 Overll Survivl Medin (9% CI) months 8. (.,.). (., 9.) Hzrd Rtio (9% CI).98 (.8,.) p-vlue p=.89 Investigtor Reviewed Overll Response Rte.%.9% p-vlue c p=. CR d.%.% PR plus PRNM e.%.% Independently Reviewed Overll Response Rte f.%.% p-vlue c p=. CR d 9.%.% PR plus PRNM e.%.% CI=confidence intervl. Log rnk, undjusted. c Chi squre. d CR=Complete response. e PR plus PRNM=Prtil response plus prtil response, non-mesurle disese. f Independently reviewed cohort - Gemzr/cropltin (n=), cropltin (n=); independent reviewers unle to mesure disese detected y sonogrphy or physicl exm.

14 Figure : Kpln-Meier Curve of Progression Free Survivl in Gemzr plus Cropltin versus Cropltin in Ovrin Cncer (N=).. Brest Cncer The sfety nd efficcy of Gemzr were evluted in multi-ntionl, rndomized, open-lel tril conducted in women receiving initil tretment for metsttic rest cncer in women who hve received prior djuvnt/neodjuvnt nthrcycline chemotherpy unless cliniclly contrindicted. Ptients were rndomized to receive Gemzr mg/m on Dys nd 8 of -dy cycle nd pclitxel mg/m dministered prior to Gemzr on Dy of ech cycle (n=) or to receive pclitxel mg/m ws dministered on Dy of ech -dy cycle (n=). The primry efficcy outcome mesure ws time to documented disese progression. A totl of 9 ptients were enrolled; were rndomized to Gemzr nd pclitxel nd to pclitxel lone. Demogrphic nd seline chrcteristics were similr etween tretment rms (see Tle ). Efficcy results re presented in Tle nd Figure. The ddition of Gemzr to pclitxel resulted in sttisticlly significnt improvement in time to documented disese progression nd overll response rte compred to pclitxel lone. There ws no significnt difference in overll survivl. Tle : Rndomized Tril of Gemzr plus Pclitxel versus Pclitxel in Brest Cncer Gemzr/Pclitxel Pclitxel Numer of ptients Demogrphic/Entry Chrcteristics Medin ge (yers) Rnge to 8 to Metsttic disese 9% 9% Bseline KPS 9 % % Numer of tumor sites - % 9% % % Viscerl disese % % Prior nthrcycline 9% 9% Efficcy Outcomes Time to Documented Disese Progression Medin in months..9 (9% CI) (.,.) (.,.) Hzrd Rtio (9% CI). (.,.8) p-vlue p<. Overll Survivlc Medin Survivl in months 8..8 (9% CI) (.,.) (.,.)

15 c Hzrd Rtio (9% CI).8 (.,.) p-vlue Not Significnt Overll Response Rte.8%.% (9% CI) (.9,.) (.,.) p-vlue p<. Krnofsky Performnce Sttus. These represent reconcilition of investigtor nd Independent Review Committee ssessments ccording to predefined lgorithm. Bsed on the ITT popultion. Figure : Kpln-Meier Curve of Time to Documented Disese Progression in Gemzr plus Pclitxel versus Pclitxel Brest Cncer Study (N=9).. Non-Smll Cell Lung Cncer (NSCLC) The sfety nd efficcy of Gemzr ws evluted in two rndomized, multicenter trils. 8-Dy Schedule A multintionl, rndomized tril compred Gemzr plus cispltin to cispltin lone in the tretment of ptients with inoperle Stge IIIA, IIIB, or IV NSCLC who hd not received prior chemotherpy. Ptients were rndomized to receive Gemzr mg/m on Dys, 8, nd of 8-dy cycle with cispltin mg/m dministered on Dy of ech cycle or to receive cispltin mg/m on Dy of ech 8-dy cycle. The primry efficcy outcome mesure ws overll survivl. A totl of ptients were enrolled t clinicl centers in Europe, the US, nd Cnd. Ptient demogrphics nd seline chrcteristics (shown in Tle ) were similr etween rms with the exception of histologic sutype of NSCLC, with 8% of ptients on the cispltin rm nd % of ptients on the Gemzr plus cispltin rm hving denocrcinom. Efficcy results re presented in Tle nd Figure for overll survivl. -Dy Schedule A rndomized (:), multicenter tril ws conducted in ptients with Stge IIIB or IV NSCLC. Ptients were rndomized to receive Gemzr mg/m on Dys nd 8, nd cispltin mg/m on Dy of -dy cycle or to receive etoposide mg/m intrvenously on Dys,, nd nd cispltin mg/m on Dy of -dy cycle. There ws no significnt difference in survivl etween the two tretment rms (Log rnk p=.8, two- sided, see Tle ). The medin survivl ws 8. months for the Gemzr plus cispltin rm versus. months for the etoposide plus cispltin rm. Medin time to disese progression for the Gemzr plus cispltin rm ws. months compred to. months on the etoposide plus cispltin rm (Log rnk p=., two-sided). The ojective response rte for the Gemzr plus cispltin rm ws % compred to % on the etoposide plus cispltin rm (Fisher s Exct p=., two-sided).

16 Figure : Kpln-Meier Survivl Curve in Gemzr plus Cispltin versus Cispltin in Ptients with NSCLC Study (N=). Tle : Rndomized Trils of Gemzr plus Cispltin in Ptients with NSCLC 8-dy Schedule -dy Schedule Gemzr plus Cispltin Gemzr plus Etoposide plus Cispltin Cispltin Cispltin Numer of ptients 9 Demogrphic/Entry Chrcteristics Mle % % 9% 9% Medin ge, yers 8 Rnge to 88 to 9 to to Stge IIIA % % N/Ac N/Ac Stge IIIB % % 8% % Stge IV % % % 9% Bseline KPSd to 8 % % % % Bseline KPSd 9 to % % % 9% Efficcy Outcomes Survivl Medin in months (9% CIe) months 8.,.., 8.8.8,.., 9. p-vluef p=.8 p=.8 Time to Disese Progression Medin in months.... (9% CIe) months.,..,..,..,. p-vluef p=.9 p=. Tumor Response % % % % p-vluef p<. p=. 8-dy schedule Gemzr plus cispltin: Gemzr mg/m on Dys, 8, nd nd cispltin mg/m on Dy every 8 dys; Single-gent cispltin: cispltin mg/m on Dy every 8 dys. -dy schedule Gemzr plus cispltin: Gemzr mg/m on Dys nd 8 nd cispltin mg/m on Dy every dys; Etoposide plus Cispltin: cispltin mg/m on Dy nd intrvenous etoposide mg/m on Dys,, nd every dys. c N/A Not pplicle. Tril Tretment Arm

17 d e f Krnofsky Performnce Sttus. CI=confidence intervls. p-vlue two-sided Fisher s Exct test for difference in inomil proportions; log rnk test for time-to-event nlyses.. Pncretic Cncer The sfety nd efficcy of Gemzr ws evluted in two trils, rndomized, single-lind, two-rm, ctivecontrolled tril conducted in ptients with loclly dvnced or metsttic pncretic cncer who hd received no prior chemotherpy nd in single-rm, open-lel, multicenter tril conducted in ptients with loclly dvnced or metsttic pncretic cncer previously treted with -FU or -FU-contining regimen. The first tril rndomized ptients to receive Gemzr mg/m intrvenously over minutes once weekly for weeks followed y one-week rest, then once weekly dosing for consecutive weeks every 8-dys in susequent cycles (n=) or to -fluorourcil (-FU) mg/m intrvenously over minutes once weekly (n=). In the second tril, ll ptients received Gemzr mg/m intrvenously over minutes once weekly for weeks followed y one-week rest, then once weekly dosing for consecutive weeks every 8-dys in susequent cycles. The primry efficcy outcome mesure in oth trils ws clinicl enefit response. A ptient ws considered to hve hd clinicl enefit response if either of the following occurred: The ptient chieved % reduction in pin intensity (Memoril Pin Assessment Crd) or nlgesic consumption, or -point or greter improvement in performnce sttus (Krnofsky Performnce Sttus) for period of t lest consecutive weeks, without showing ny sustined worsening in ny of the other prmeters. Sustined worsening ws defined s consecutive weeks with either ny increse in pin intensity or nlgesic consumption or -point decrese in performnce sttus occurring during the first weeks of therpy. OR The ptient ws stle on ll of the forementioned prmeters, nd showed mrked, sustined weight gin ( % increse mintined for weeks) not due to fluid ccumultion. The rndomized tril enrolled ptients cross sites in the US nd Cnd. The demogrphic nd entry chrcteristics were similr etween the rms (Tle ). The efficcy outcome results re shown in Tle nd for overll survivl in Figure. Ptients treted with Gemzr hd sttisticlly significnt increses in clinicl enefit response, survivl, nd time to disese progression compred to those rndomized to receive -FU. No confirmed ojective tumor responses were oserved in either tretment rm. Tle : Rndomized Tril of Gemzr versus -Fluorourcil in Pncretic Cncer Gemzr -FU Numer of ptients Demogrphic/Entry Chrcteristics Mle % % Medin ge yers yers Rnge to 9 to Stge IV disese % % Bseline KPS % 8% Efficcy Outcomes Clinicl enefit response.%.8% p-vlue p=. Survivl Medin. months. months (9% CI) (.,.9) (.,.) p-vlue p=.9 Time to Disese Progression Medin. months.9 months (9% CI) (.9,.) (.9,.) p-vlue p=. Krnofsky Performnce Sttus. p-vlue for clinicl enefit response clculted using the two-sided test for difference in inomil proportions. All other p-vlues re clculted using log rnk test.

18 8 Figure : Kpln-Meier Survivl Curve.. HOW SUPPLIED/STORAGE AND HANDLING How Supplied Gemzr (gemcitine for injection, USP), is ville in sterile single-use vils individully pckged in crton contining: mg white to off-white, lyophilized powder in -ml size sterile single-use vil NDC -- (No. ) g white to off-white, lyophilized powder in -ml size sterile single-use vil NDC -- (No. ). Storge nd Hndling Unopened vils of Gemzr re stle until the expirtion dte indicted on the pckge when stored t controlled room temperture to C (8 to F) nd tht llows for excursions etween nd C (9 nd 8 F) [see USP Controlled Room Temperture] [see Dosge nd Administrtion (. nd.)]. PATIENT COUNSELING INFORMATION Advise ptients of the risks of low lood cell counts nd the potentil need for lood trnsfusions nd incresed susceptiility to infections. Instruct ptients to immeditely contct their helthcre provided for development of signs or symptoms of infection, fever, prolonged or unexpected leeding, ruising, or shortness of reth [see Wrnings nd Precutions (.)]. Advise ptients of the risks of pulmonry toxicity including respirtory filure nd deth. Instruct ptients to immeditely contct their helthcre provider for development of shortness of reth, wheezing, or cough [see Wrnings nd Precutions (.)]. Advise ptients of the risks of hemolytic-uremic syndrome nd ssocited renl filure. Instruct ptients to immeditely contct their helthcre provider for chnges in the color or volume of urine output or for incresed ruising or leeding [see Wrnings nd Precutions (.)]. Advise ptients of the risks of heptic toxicity including liver filure nd deth. Instruct ptients to immeditely contct their helthcre provider for signs of jundice or for pin/tenderness in the right upper dominl qudrnt [see Wrnings nd Precutions (.)]. Mrketed y: Lilly USA, LLC Indinpolis, IN 8, USA Copyright 99,, Eli Lilly nd Compny. All rights reserved. GEM--USPI-9

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