HIGHLIGHTS OF PRESCRIBING INFORMATION

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ALIMTA sfely nd effectively. See full prescriing informtion for ALIMTA. ALIMTA (pemetrexed for injection) Lyophilized Powder, for Solution for Intrvenous Use Initil U.S. Approvl: RECENT MAJOR CHANGES Dosge nd Administrtion, Premediction Regimen nd Concurrent Medictions (.3) / Wrnings nd Precutions, Requirement for Premediction nd Concomitnt Mediction to Reduce Toxicity (.) / Wrnings nd Precutions, Required Lortory Monitoring (.) / Wrnings nd Precutions, Third Spce Fluid (.7) --- removl / INDICATIONS AND USAGE ALIMTA is folte nlog metolic inhiitor indicted for: Loclly Advnced or Metsttic Nonsqumous Non-Smll Cell Lung Cncer: Initil tretment in comintion with cispltin. (.) Mintennce tretment of ptients whose disese hs not progressed fter four cycles of pltinum-sed first-line chemotherpy. (.) After prior chemotherpy s single-gent. (.3) Mesotheliom: in comintion with cispltin. (.) Limittions of Use: ALIMTA is not indicted for the tretment of ptients with squmous cell non-smll cell lung cncer. (.) DOSAGE AND ADMINISTRATION Comintion use in Non-Smll Cell Lung Cncer nd Mesotheliom: Recommended dose of ALIMTA is mg/m i.v. on Dy of ech -dy cycle in comintion with cispltin 7 mg/m i.v. eginning 3 minutes fter ALIMTA dministrtion. (.) Single-Agent use in Non-Smll Cell Lung Cncer: Recommended dose of ALIMTA is mg/m i.v. on Dy of ech -dy cycle. (.) Prior to inititing ALIMTA, initite supplementtion with orl folic cid nd intrmusculr vitmin B. Continue folic cid nd vitmin B supplementtion throughout tretment. Administer corticosteroids the dy efore, the dy of, nd the dy fter ALIMTA dministrtion. (.3) Dose Reductions: Dose reductions or discontinution my e needed sed on toxicities from the preceding cycle of therpy. (.) DOSAGE FORMS AND STRENGTHS mg vil for injection (3) mg vil for injection (3) CONTRAINDICATIONS History of severe hypersensitivity rection to pemetrexed. () WARNINGS AND PRECAUTIONS Premediction regimen: Prior to tretment with ALIMTA, initite supplementtion with orl folic cid nd intrmusculr vitmin B to reduce the severity of hemtologic nd gstrointestinl toxicity of ALIMTA. (.) Bone mrrow suppression: Reduce doses for susequent cycles sed on hemtologic nd nonhemtologic toxicities. (.) Renl function: Do not dminister when CrCl < ml/min. (.,.3) NSAIDs with renl insufficiency: Use cution in ptients with mild to moderte renl insufficiency (CrCl -79 ml/min). (.) L monitoring: Do not initite cycle unless ANC cells/mm 3, pltelets, cells/mm 3, nd CrCl ml/min. (.) Pregnncy: Fetl hrm cn occur when dministered to pregnnt womn. Women should e dvised to use effective contrception mesures to prevent pregnncy during tretment with ALIMTA. (.) ADVERSE REACTIONS The most common dverse rections (incidence %) with single-gent use re ftigue, nuse, nd norexi. Additionl common dverse rections when used in comintion with cispltin include vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromocytopeni, nd constiption. (.) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t -8-LillyRx ( ) or FDA t -8-FDA-88 or DRUG INTERACTIONS NSAIDs: Use cution with NSAIDs. (7.) Nephrotoxic drugs: Concomitnt use of these drugs nd/or sustnces which re tuulrly secreted my result in delyed clernce. (7.) See 7 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient leling Revised: / FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE. Nonsqumous Non-Smll Cell Lung Cncer Comintion with Cispltin. Nonsqumous Non-Smll Cell Lung Cncer Mintennce.3 Nonsqumous Non-Smll Cell Lung Cncer After Prior Chemotherpy. Mesotheliom. Limittions of Use DOSAGE AND ADMINISTRATION. Comintion Use with Cispltin for Nonsqumous Non-Smll Cell Lung Cncer or Mlignnt Pleurl Mesotheliom. Single-Agent Use s Mintennce Following First-Line Therpy, or s Second-Line Therpy.3 Premediction Regimen nd Concurrent Medictions. Lortory Monitoring nd Dose Reduction/Discontinution Recommendtions. Preprtion nd Administrtion Precutions. Preprtion for Intrvenous Infusion Administrtion 3 DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Requirement for Premediction nd Concomitnt Mediction to Reduce Toxicity. Bone Mrrow Suppression.3 Decresed Renl Function. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insufficiency. Required Lortory Monitoring. Pregnncy Ctegory D ADVERSE REACTIONS. Clinicl Trils Experience. Postmrketing Experience 7 DRUG INTERACTIONS 7. Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) 7. Nephrotoxic Drugs 8 USE IN SPECIFIC POPULATIONS 8. Pregnncy 8.3 Nursing Mothers 8. Peditric Use 8. Geritric Use 8. Ptients with Heptic Impirment 8.7 Ptients with Renl Impirment 8.8 Gender 8.9 Rce OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechnism of Action. Phrmcodynmics.3 Phrmcokinetics 3 NONCLINICAL TOXICOLOGY 3. Crcinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES

2 ...3. Non-Smll Cell Lung Cncer (NSCLC) Comintion with Cispltin Non-Smll Cell Lung Cncer Mintennce Non-Smll Cell Lung Cncer After Prior Chemotherpy Mlignnt Pleurl Mesotheliom HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. Storge nd Hndling 7 PATIENT COUNSELING INFORMATION REFERENCES *Sections or susections omitted from the full prescriing informtion re not listed FULL PRESCRIBING INFORMATION. INDICATIONS AND USAGE Nonsqumous Non-Smll Cell Lung Cncer - Comintion with Cispltin ALIMTA is indicted in comintion with cispltin therpy for the initil tretment of ptients with loclly dvnced or metsttic nonsqumous non-smll cell lung cncer.. Nonsqumous Non-Smll Cell Lung Cncer - Mintennce ALIMTA is indicted for the mintennce tretment of ptients with loclly dvnced or metsttic nonsqumous non-smll cell lung cncer whose disese hs not progressed fter four cycles of pltinum-sed first-line chemotherpy..3 Nonsqumous Non-Smll Cell Lung Cncer - After Prior Chemotherpy ALIMTA is indicted s single-gent for the tretment of ptients with loclly dvnced or metsttic nonsqumous nonsmll cell lung cncer fter prior chemotherpy.. Mesotheliom ALIMTA in comintion with cispltin is indicted for the tretment of ptients with mlignnt pleurl mesotheliom whose disese is unresectle or who re otherwise not cndidtes for curtive surgery.. Limittions of Use ALIMTA is not indicted for the tretment of ptients with squmous cell non-smll cell lung cncer. [see Clinicl Studies (.,.,.3)]. DOSAGE AND ADMINISTRATION Comintion Use with Cispltin for Nonsqumous Non-Smll Cell Lung Cncer or Mlignnt Pleurl Mesotheliom The recommended dose of ALIMTA is mg/m dministered s n intrvenous infusion over minutes on Dy of ech -dy cycle. The recommended dose of cispltin is 7 mg/m infused over hours eginning pproximtely 3 minutes fter the end of ALIMTA dministrtion. See cispltin pckge insert for more informtion.. Single-Agent Use s Mintennce Following First-Line Therpy, or s Second-Line Therpy The recommended dose of ALIMTA is mg/m dministered s n intrvenous infusion over minutes on Dy of ech -dy cycle..3 Premediction Regimen nd Concurrent Medictions Vitmin Supplementtion Instruct ptients to initite folic cid mcg to mcg orlly once dily eginning 7 dys efore the first dose of ALIMTA. Continue folic cid during the full course of therpy nd for dys fter the lst dose of ALIMTA [see Wrnings nd Precutions (.)]. Administer vitmin B mg intrmusculrly week prior to the first dose of ALIMTA nd every 3 cycles therefter. Susequent vitmin B injections my e given the sme dy s tretment with ALIMTA [see Wrnings nd Precutions (.)]. Corticosteroids Administer dexmethsone mg y mouth twice dily the dy efore, the dy of, nd the dy fter ALIMTA dministrtion [see Wrnings nd Precutions (.)].. Lortory Monitoring nd Dose Reduction/Discontinution Recommendtions Monitoring Complete lood cell counts, including pltelet counts, should e performed on ll ptients receiving ALIMTA. Ptients should e monitored for ndir nd recovery, which were tested in the clinicl study efore ech dose nd on dys 8 nd of ech cycle. Ptients should not egin new cycle of tretment unless the ANC is cells/mm3, the pltelet count is, cells/mm3, nd cretinine clernce is ml/min. Periodic chemistry tests should e performed to evlute renl nd heptic function [see Wrnings nd Precutions (.)]. Dose Reduction Recommendtions Dose djustments t the strt of susequent cycle should e sed on ndir hemtologic counts or mximum nonhemtologic toxicity from the preceding cycle of therpy. Tretment my e delyed to llow sufficient time for recovery. Upon recovery, ptients should e retreted using the guidelines in Tles -3, which re suitle for using ALIMTA s single-gent or in comintion with cispltin. Tle : Dose Reduction for ALIMTA (single-gent or in comintion) nd Cispltin - Hemtologic Toxicities 7% of previous dose (pemetrexed nd cispltin). Ndir ANC </mm3 nd ndir pltelets,/mm3.

3 Ndir pltelets <,/mm3 without leeding regrdless of ndir ANC. 7% of previous dose (pemetrexed nd cispltin). Ndir pltelets <,/mm3 with leeding, regrdless of ndir ANC. % of previous dose (pemetrexed nd cispltin). These criteri meet the CTC version. (NCI 998) definition of CTC Grde leeding. 3 If ptients develop nonhemtologic toxicities (excluding neurotoxicity) Grde 3, tretment should e withheld until resolution to less thn or equl to the ptient s pre-therpy vlue. Tretment should e resumed ccording to guidelines in Tle. Tle : Dose Reduction for ALIMTA (single-gent or in comintion) nd Cispltin - Nonhemtologic Toxicities, Dose of ALIMTA Dose of Cispltin (mg/m) (mg/m) Any Grde 3 or toxicities except mucositis 7% of previous dose 7% of previous dose Any dirrhe requiring hospitliztion (irrespective of Grde) or Grde 3 or 7% of previous dose 7% of previous dose dirrhe Grde 3 or mucositis % of previous dose % of previous dose NCI Common Toxicity Criteri (CTC). Excluding neurotoxicity (see Tle 3). In the event of neurotoxicity, the recommended dose djustments for ALIMTA nd cispltin re descried in Tle 3. Ptients should discontinue therpy if Grde 3 or neurotoxicity is experienced. Tle 3: Dose Reduction for ALIMTA (single-gent or in comintion) nd Cispltin - Neurotoxicity Dose of ALIMTA Dose of Cispltin (mg/m) (mg/m) CTC Grde - % of previous dose % of previous dose % of previous dose % of previous dose Discontinution Recommendtion ALIMTA therpy should e discontinued if ptient experiences ny hemtologic or nonhemtologic Grde 3 or toxicity fter dose reductions or immeditely if Grde 3 or neurotoxicity is oserved. Renlly Impired Ptients In clinicl studies, ptients with cretinine clernce ml/min required no dose djustments other thn those recommended for ll ptients. Insufficient numers of ptients with cretinine clernce elow ml/min hve een treted to mke dosge recommendtions for this group of ptients [see Clinicl Phrmcology (.3)]. Therefore, ALIMTA should not e dministered to ptients whose cretinine clernce is < ml/min using the stndrd Cockcroft nd Gult formul (elow) or GFR mesured y Tc99m-DPTA serum clernce method: Mles: Femles: [ - Age in yers] Actul Body Weight (kg) 7 Serum Cretinine (mg/dl) Estimted cretinine clernce for mles.8 = ml/min Cution should e exercised when dministering ALIMTA concurrently with NSAIDs to ptients whose cretinine clernce is <8 ml/min [see Drug Interctions (7.)].. Preprtion nd Administrtion Precutions As with other potentilly toxic nticncer gents, cre should e exercised in the hndling nd preprtion of infusion solutions of ALIMTA. The use of gloves is recommended. If solution of ALIMTA contcts the skin, wsh the skin immeditely nd thoroughly with sop nd wter. If ALIMTA contcts the mucous memrnes, flush thoroughly with wter. Severl pulished guidelines for hndling nd disposl of nticncer gents re ville [see References ()]. ALIMTA is not vesicnt. There is no specific ntidote for extrvstion of ALIMTA. To dte, there hve een few reported cses of ALIMTA extrvstion, which were not ssessed s serious y the investigtor. ALIMTA extrvstion should e mnged with locl stndrd prctice for extrvstion s with other non-vesicnts.. Preprtion for Intrvenous Infusion Administrtion. Use septic technique during the reconstitution nd further dilution of ALIMTA for intrvenous infusion dministrtion.. Clculte the dose of ALIMTA nd determine the numer of vils needed. Vils contin either mg or mg of ALIMTA. The vils contin n excess of ALIMTA to fcilitte delivery of lel mount. 3. Reconstitute ech -mg vil with. ml of.9% Sodium Chloride Injection (preservtive free). Reconstitute ech -mg vil with ml of.9% Sodium Chloride Injection (preservtive free). Reconstitution of either size vil gives solution contining mg/ml ALIMTA. Gently swirl ech vil until the powder is completely dissolved. The resulting solution is cler nd rnges in color from colorless to yellow or green-yellow without dversely ffecting product qulity. The ph of the reconstituted ALIMTA solution is etween. nd 7.8. FURTHER DILUTION IS REQUIRED.

4 . Prenterl drug products should e inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. If prticulte mtter is oserved, do not dminister.. An pproprite quntity of the reconstituted ALIMTA solution must e further diluted into solution of.9% Sodium Chloride Injection (preservtive free), so tht the totl volume of solution is ml. ALIMTA is dministered s n intrvenous infusion over minutes.. Chemicl nd physicl stility of reconstituted nd infusion solutions of ALIMTA were demonstrted for up to hours following initil reconstitution, when stored t refrigerted or mient room temperture [see USP Controlled Room Temperture] nd lighting. When prepred s directed, reconstitution nd infusion solutions of ALIMTA contin no ntimicroil preservtives. Discrd ny unused portion. Reconstitution nd further dilution prior to intrvenous infusion is only recommended with.9% Sodium Chloride Injection (preservtive free). ALIMTA is physiclly incomptile with diluents contining clcium, including Lctted Ringer s Injection, USP nd Ringer s Injection, USP nd therefore these should not e used. Codministrtion of ALIMTA with other drugs nd diluents hs not een studied, nd therefore is not recommended. ALIMTA is comptile with stndrd polyvinyl chloride (PVC) dministrtion sets nd intrvenous solution gs. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is white to either light-yellow or green-yellow lyophilized powder ville in sterile single-use vils contining mg or mg pemetrexed. CONTRAINDICATIONS ALIMTA is contrindicted in ptients who hve history of severe hypersensitivity rection to pemetrexed. WARNINGS AND PRECAUTIONS. Requirement for Premediction nd Concomitnt Mediction to Reduce Toxicity Vitmin Supplementtion Prior to tretment with ALIMTA, initite supplementtion with orl folic cid nd intrmusculr vitmin B to reduce the severity of hemtologic nd gstrointestinl toxicity of ALIMTA [see Dosge nd Administrtion (.3)]. Do not sustitute orl vitmin B for intrmusculr vitmin B. In clinicl studies, the incidence of the following Grde 3- toxicities were higher in ptients with mesotheliom who were never supplemented s compred to ptients who were fully supplemented with folic cid nd vitmin B prior to nd throughout ALIMTA tretment: neutropeni [38% versus 3%], thromocytopeni [9% versus %], ferile neutropeni [9% versus.%], nd infection with neutropeni [% versus. ]. Corticosteroids Administer dexmethsone the dy efore, the dy of, nd the dy fter ALIMTA dministrtion [see Dosge nd Administrtion (.3)].. Bone Mrrow Suppression ALIMTA cn suppress one mrrow function, s mnifested y neutropeni, thromocytopeni, nd nemi (or pncytopeni) [see Adverse Rections (.)]; myelosuppression is usully the dose-limiting toxicity. Dose reductions for susequent cycles re sed on ndir ANC, pltelet count, nd mximum nonhemtologic toxicity seen in the previous cycle [see Dosge nd Administrtion (.)]..3 Decresed Renl Function ALIMTA is primrily eliminted unchnged y renl excretion. No dosge djustment is needed in ptients with cretinine clernce ml/min. Insufficient numers of ptients hve een studied with cretinine clernce < ml/min to give dose recommendtion. Therefore, ALIMTA should not e dministered to ptients whose cretinine clernce is < ml/min [see Dosge nd Administrtion (.)]. One ptient with severe renl impirment (cretinine clernce 9 ml/min) who did not receive folic cid nd vitmin B died of drug-relted toxicity following dministrtion of ALIMTA lone.. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insufficiency Cution should e used when dministering NSAIDs concurrently with ALIMTA to ptients with mild to moderte renl insufficiency (cretinine clernce from to 79 ml/min) [see Drug Interctions (7.)].. Required Lortory Monitoring Otin complete lood count nd renl function tests t the eginning of ech cycle nd s needed. Do not initite cycle of tretment unless the ANC is cells/mm3, the pltelet count is, cells/mm3, nd cretinine clernce is ml/min [see Dosge nd Administrtion (.)].. Pregnncy Ctegory D Bsed on its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn. Pemetrexed dministered intrperitonelly to mice during orgnogenesis ws emryotoxic, fetotoxic nd tertogenic in mice t greter thn /833rd the recommended humn dose. If ALIMTA is used during pregnncy, or if the ptient ecomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of childering potentil should e dvised to void ecoming pregnnt. Women should e dvised to use effective contrceptive mesures to prevent pregnncy during tretment with ALIMTA [see Use in Specific Popultions (8.)].

5 . ADVERSE REACTIONS Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rections rtes cnnot e directly compred to rtes in other clinicl trils nd my not reflect the rtes oserved in clinicl prctice. In clinicl trils, the most common dverse rections (incidence %) during therpy with ALIMTA s single-gent were ftigue, nuse, nd norexi. Additionl common dverse rections (incidence %) during therpy with ALIMTA when used in comintion with cispltin included vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromocytopeni, nd constiption. Non-Smll Cell Lung Cncer (NSCLC) ALIMTA in Comintion with Cispltin Tle provides the frequency nd severity of dverse rections tht hve een reported in >% of 839 ptients with NSCLC who were rndomized to study nd received ALIMTA plus cispltin nd 83 ptients with NSCLC who were rndomized to study nd received gemcitine plus cispltin. All ptients received study therpy s initil tretment for loclly dvnced or metsttic NSCLC nd ptients in oth tretment groups were fully supplemented with folic cid nd vitmin B. Tle : Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA plus Cispltin in NSCLC ALIMTA/cispltin Gemcitine/cispltin (N=839) (N=83) Rection All Grdes Grde 3- All Grdes Grde All Adverse Rections Lortory Hemtologic Anemi 33 Neutropeni Leukopeni 8 8 Thromocytopeni 7 3 Renl Cretinine elevtion 7 Clinicl Constitutionl Symptoms Ftigue 3 7 Gstrointestinl Nuse 7 3 Vomiting 3 Anorexi 7 Constiption Stomtitis/Phryngitis Dirrhe 3 Dyspepsi/Herturn Neurology Neuropthy-sensory 9 Tste disturnce 8 c 9 c Dermtology/Skin Alopeci c c Rsh/Desqumtion 7 8 For the purpose of this tle cut off of % ws used for inclusion of ll events where the reporter considered possile reltionship to ALIMTA. Refer to NCI CTC Criteri version. for ech Grde of toxicity. c According to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No cliniclly relevnt differences in dverse rections were seen in ptients sed on histology. In ddition to the lower incidence of hemtologic toxicity on the ALIMTA nd cispltin rm, use of trnsfusions (RBC nd pltelet) nd hemtopoietic growth fctors ws lower in the ALIMTA nd cispltin rm compred to the gemcitine nd cispltin rm. The following dditionl dverse rections were oserved in ptients with non-smll cell lung cncer rndomly ssigned to receive ALIMTA plus cispltin. Incidence % to % Body s Whole ferile neutropeni, infection, pyrexi Generl Disorders dehydrtion

6 Metolism nd Nutrition incresed AST, incresed ALT Renl cretinine clernce decrese, renl filure Specil Senses conjunctivitis Incidence Less thn % Crdiovsculr rrhythmi Generl Disorders chest pin Metolism nd Nutrition incresed GGT Neurology motor neuropthy Non-Smll Cell Lung Cncer (NSCLC) Mintennce ALIMTA Mintennce Following Non-ALIMTA Contining, Pltinum-Bsed Induction Therpy Tle provides the frequency nd severity of dverse rections reported in >% of the 38 ptients with NSCLC who received ALIMTA mintennce nd the 8 ptients with NSCLC who received plceo following pltinum-sed induction therpy. All ptients received study therpy immeditely following cycles of pltinum-sed tretment for loclly dvnced or metsttic NSCLC. Ptients in oth study rms were fully supplemented with folic cid nd vitmin B. Tle : Adverse Rections in Ptients Receiving ALIMTA versus Plceo in NSCLC Following Pltinum-Bsed Induction Therpy ALIMTA Plceo (N=38) (N=8) Rection All Grdes Grde 3- All Grdes Grde 3-37 All Adverse Rections Lortory Hemtologic Anemi 3 Neutropeni 3 Leukopeni Heptic Incresed ALT Incresed AST 8 Clinicl Constitutionl Symptoms Ftigue Gstrointestinl Nuse 9 Anorexi 9 Vomiting 9 Mucositis/stomtitis 7 Dirrhe 3 Infection Neurology Neuropthy-sensory 9 Dermtology/Skin Rsh/Desqumtion 3 For the purpose of this tle cut off of % ws used for inclusion of ll events where the reporter considered possile reltionship to ALIMTA. Refer to NCI CTCAE Criteri version 3. for ech Grde of toxicity. No cliniclly relevnt differences in Grde 3/ dverse rections were seen in ptients sed on ge, gender, ethnic origin, or histology except higher incidence of Grde 3/ ftigue for Cucsin ptients compred to non-cucsin ptients (.% versus.%). Sfety ws ssessed y exposure for ptients who received t lest one dose of ALIMTA (N=38). The incidence of dverse rections ws evluted for ptients who received cycles of ALIMTA, nd compred to ptients who received > cycles of ALIMTA. Increses in dverse rections (ll grdes) were oserved with longer exposure; however no cliniclly relevnt differences in Grde 3/ dverse rections were seen. Consistent with the higher incidence of nemi (ll grdes) on the ALIMTA rm, use of trnsfusions (minly RBC) nd erythropoiesis stimulting gents (ESAs; erythropoietin nd drepoetin) were higher in the ALIMTA rm compred to the plceo rm (trnsfusions 9.% versus 3.%, ESAs.9% versus.8%).

7 7 The following dditionl dverse rections were oserved in ptients with non-smll cell lung cncer who received ALIMTA. Incidence % to % Dermtology/Skin lopeci, pruritis/itching Gstrointestinl constiption Generl Disorders edem, fever (in the sence of neutropeni) Hemtologic thromocytopeni Renl decresed cretinine clernce, incresed cretinine, decresed glomerulr filtrtion rte Specil Senses oculr surfce disese (including conjunctivitis), incresed lcrimtion Incidence Less thn % Crdiovsculr suprventriculr rrhythmi Dermtology/Skin erythem multiforme Generl Disorders ferile neutropeni, llergic rection/hypersensitivity Neurology motor neuropthy Renl renl filure Continution of ALIMTA s Mintennce Following ALIMTA Plus Pltinum Induction Therpy Tle provides the frequency nd severity of dverse rections reported in >% of the ptients with non-squmous NSCLC who received t lest one cycle of ALIMTA mintennce (n=333) or plceo (n=7) on the continution mintennce tril. The medin of mintennce cycles dministered to ptients receiving one or more doses of mintennce therpy ws on oth the pemetrexed nd plceo rms. Dose reductions for dverse events occurred in 3.3% of ptients in the ALIMTA rm nd.% in the plceo rm. Dose delys for dverse events occurred in % of ptients in the ALIMTA rm nd % in the plceo rm. Ptients in oth study rms were supplemented with folic cid nd vitmin B. Tle : Selected Adverse Rections Occurring in % of Ptients Receiving ALIMTA in Nonsqumous NSCLC Following ALIMTA Plus Cispltin Induction Therpy ALIMTA Plceo (N=333) (N=7) Adverse Rection Orgn System nd Term All Grdes Grde 3- All Grdes Grdes All Adverse Rections Lortory Hemtologic Anemi.8.8. Neutropeni Clinicl Constitutionl Symptoms Ftigue 8.. Gstrointestinl Nuse.3. Vomiting.8 Mucositis/stomtitis.3. Generl Disorders Edem 3. Adverse rections of ny severity (ll grdes) occurring more frequently ( %) or Grde 3- dverse rections occurring more frequently ( %) in ALIMTA-treted ptients compred to those receiving plceo. NCI CTCAE Criteri version 3. Administrtion of RBC (3% versus.8%) nd pltelet (.% versus.%) trnsfusions, erythropoiesis stimulting gents (% versus 7%), nd grnulocyte colony stimulting fctors (% versus ) were higher in the ALIMTA rm compred to the plceo rm. The following dditionl Grde 3 or dverse rections were oserved more frequently in the ALIMTA rm. Incidence % to % Blood/Bone Mrrow thromocytopeni Generl Disorders ferile neutropeni Incidence Less thn % Crdiovsculr ventriculr tchycrdi, syncope Generl Disorders pin Gstrointestinl gstrointestinl ostruction Neurologic depression Renl renl filure

8 8 Vsculr pulmonry emolism Non-Smll Cell Lung Cncer (NSCLC) After Prior Chemotherpy Tle 7 provides the frequency nd severity of dverse rections tht hve een reported in >% of ptients rndomly ssigned to receive single-gent ALIMTA with folic cid nd vitmin B supplementtion nd 7 ptients rndomly ssigned to receive single-gent docetxel. All ptients were dignosed with loclly dvnced or metsttic NSCLC nd received prior chemotherpy. Tle 7: Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA versus Docetxel in NSCLC ALIMTA Docetxel (N=) (N=7) Rection All Grdes Grdes 3- All Grdes Grdes 3- Lortory Hemtologic Anemi 9 Leukopeni 3 7 Neutropeni Thromocytopeni 8 Heptic Incresed ALT 8 Incresed AST 7 Clinicl Gstrointestinl Nuse Anorexi 3 Vomiting Stomtitis/Phryngitis 7 Dirrhe 3 3 Constiption Constitutionl Symptoms Ftigue 3 3 Fever 8 8 Dermtology/Skin Rsh/Desqumtion Pruritis 7 Alopeci c 38 c For the purpose of this tle cut off of % ws used for inclusion of ll events where the reporter considered possile reltionship to ALIMTA. Refer to NCI CTC Criteri for l vlues for ech Grde of toxicity (version.). c According to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No cliniclly relevnt differences in dverse rections were seen in ptients sed on histology. Cliniclly relevnt dverse rections occurring in <% of ptients tht received ALIMTA tretment ut >% of ptients tht received docetxel include CTC Grde 3/ ferile neutropeni (.9% ALIMTA,.7% docetxel). The following dditionl dverse rections were oserved in ptients with non-smll cell lung cncer rndomly ssigned to receive ALIMTA. Incidence % to % Body s Whole dominl pin, llergic rection/hypersensitivity, ferile neutropeni, infection Dermtology/Skin erythem multiforme Neurology motor neuropthy, sensory neuropthy Renl incresed cretinine Incidence Less thn % Crdiovsculr suprventriculr rrhythmis Mlignnt Pleurl Mesotheliom (MPM) Tle 8 provides the frequency nd severity of dverse rections tht hve een reported in >% of 8 ptients with mesotheliom who were rndomly ssigned to receive cispltin nd ALIMTA nd 3 ptients with mesotheliom rndomly ssigned to receive single-gent cispltin. In oth tretment rms, these chemonive ptients were fully supplemented with folic cid nd vitmin B.

9 9 Tle 8: Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA plus Cispltin in MPM ALIMTA/cispltin Cispltin (N=8) (N=3) Rection All Grdes Grde 3- All Grdes Grde 3- Lortory Hemtologic Neutropeni Leukopeni 3 7 Anemi Thromocytopeni 3 9 Renl Cretinine elevtion Cretinine clernce decresed 8 Clinicl Eye Disorder Conjunctivitis Gstrointestinl Nuse 8 77 Vomiting 7 Stomtitis/Phryngitis 3 3 Anorexi Dirrhe 7 8 Constiption 7 Dyspepsi Constitutionl Symptoms Ftigue 8 9 Metolism nd Nutrition Dehydrtion 7 Neurology Neuropthy-sensory Tste Disturnce 8 c c Dermtology/Skin Rsh Alopeci c c For the purpose of this tle cut off of % ws used for inclusion of ll events where the reporter considered possile reltionship to ALIMTA. Refer to NCI CTC Criteri version. for ech Grde of toxicity except the term cretinine clernce decresed which is derived from the CTC term renl/genitourinry-other. c According to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. The following dditionl dverse rections were oserved in ptients with mlignnt pleurl mesotheliom rndomly ssigned to receive ALIMTA plus cispltin. Incidence % to % Body s Whole ferile neutropeni, infection, pyrexi Dermtology/Skin urticri Generl Disorders chest pin Metolism nd Nutrition incresed AST, incresed ALT, incresed GGT Renl renl filure Incidence Less thn % Crdiovsculr rrhythmi Neurology motor neuropthy Effects of Vitmin Supplementtions on Toxicity Tle 9 compres the incidence (percentge of ptients) of CTC Grde 3/ toxicities in ptients who received vitmin supplementtion with dily folic cid nd vitmin B from the time of enrollment in the study (fully supplemented) with the incidence in ptients who never received vitmin supplementtion (never supplemented) during the study in the ALIMTA plus cispltin rm. Tle 9: Selected Grde 3/ Adverse Events Compring Fully Supplemented versus Never Supplemented Ptients in the ALIMTA plus Cispltin rm (% incidence)

10 Fully Supplemented Ptients Never Supplemented Ptients Adverse Event (%) (N=8) (N=3) Neutropeni/grnulocytopeni 3 38 Thromocytopeni 9 Vomiting 3 Ferile neutropeni 9 Infection with Grde 3/ neutropeni Dirrhe 9 Refer to NCI CTC criteri for l nd non-lortory vlues for ech grde of toxicity (Version.). The following dverse events were greter in the fully supplemented group compred to the never supplemented group: hypertension (%, 3%), chest pin (8%, %), nd thromosis/emolism (%, 3%). No relevnt effect for ALIMTA sfety due to gender or rce ws identified, except n incresed incidence of rsh in men (%) compred to women (%). Additionl Experience Across Clinicl Trils Sepsis, which in some cses ws ftl, occurred in pproximtely % of ptients. Esophgitis occurred in less thn % of ptients.. Postmrketing Experience The following dverse rections hve een identified during post-pprovl use of ALIMTA. 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. These rections occurred with ALIMTA when used s single-gent nd in comintion therpies. Gstrointestinl colitis, pncretitis Generl Disorders nd Administrtion Site Conditions edem Injury, poisoning, nd procedurl complictions Rdition recll hs een reported in ptients who hve previously received rdiotherpy. Respirtory interstitil pneumonitis Skin Bullous conditions, including Stevens-Johnson syndrome nd toxic epiderml necrolysis. Some cses were ftl DRUG INTERACTIONS Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) Although iuprofen ( mg four times dy) cn decrese the clernce of pemetrexed, it cn e dministered with ALIMTA in ptients with norml renl function (cretinine clernce 8 ml/min). No dose djustment of ALIMTA is needed with concomitnt NSAIDs in ptients with norml renl function [see Clinicl Phrmcology (.3)]. Cution should e used when dministering NSAIDs concurrently with ALIMTA to ptients with mild to moderte renl insufficiency (cretinine clernce from to 79 ml/min). NSAIDs with short elimintion hlf-lives (e.g., diclofenc, indomethcin) should e voided for period of dys efore, the dy of, nd dys following dministrtion of ALIMTA. In the sence of dt regrding potentil interction etween ALIMTA nd NSAIDs with longer hlf-lives (e.g., meloxicm, numetone), ptients tking these NSAIDs should interrupt dosing for t lest dys efore, the dy of, nd dys following ALIMTA dministrtion. If concomitnt dministrtion of NSAIDs is necessry, ptients should e monitored closely for toxicity, especilly myelosuppression, renl, nd gstrointestinl toxicity. 7. Nephrotoxic Drugs ALIMTA is primrily eliminted unchnged renlly s result of glomerulr filtrtion nd tuulr secretion. Concomitnt dministrtion of nephrotoxic drugs could result in delyed clernce of ALIMTA. Concomitnt dministrtion of sustnces tht re lso tuulrly secreted (e.g., proenecid) could potentilly result in delyed clernce of ALIMTA USE IN SPECIFIC POPULATIONS Pregnncy Tertogenic Effects - Pregnncy Ctegory D [see Wrnings nd Precutions (.)] Bsed on its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn. There re no dequte nd well controlled studies of ALIMTA in pregnnt women. Pemetrexed ws emryotoxic, fetotoxic, nd tertogenic in mice. In mice, repeted intrperitonel doses of pemetrexed when given during orgnogenesis cused fetl mlformtions (incomplete ossifiction of tlus nd skull one; out /833rd the recommended intrvenous humn dose on mg/m sis), nd cleft plte (/33rd the recommended intrvenous humn dose on mg/m sis). Emryotoxicity ws chrcterized y incresed emryo-fetl deths nd reduced litter sizes. If ALIMTA is used during pregnncy, or if the ptient ecomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of childering potentil should e dvised to use effective contrceptive mesures to prevent pregnncy during the tretment with ALIMTA. 8.3 Nursing Mothers

11 It is not known whether ALIMTA or its metolites re 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 ALIMTA, decision should e mde to discontinue nursing or discontinue the drug, tking into ccount the importnce of the drug for the mother. 8. Peditric Use Efficcy of ALIMTA in peditric ptients hs not een demonstrted. ALIMTA ws dministered s n intrvenous infusion over minutes on Dy of dy cycle to peditric ptients with recurrent solid tumors in Phse study (3 ptients) nd Phse study (7 ptients). All ptients received pretretment with vitmin B nd folic cid supplementtion nd dexmethsone. The dose escltion in the Phse study determined the mximum tolerted dose ws 9 mg/m nd this dose (or mg/kg for ptients < months old) ws evluted in the Phse study of ptients with relpsed or refrctory osteosrcom, Ewing srcom/peripherl PNET, rhdomyosrcom, neurolstom, ependymom, medullolstom/suprtentoril PNET, or nonrinstem high grde gliom. No responses were oserved mong the 7 ptients in this Phse tril. The most common toxicities reported were hemtologicl (leukopeni, neutropeni/grnulocytopeni, nemi, thromocytopeni, nd lymphopeni), liver function normlities (incresed ALT/AST), ftigue, nd nuse. The single dose phrmcokinetics of ALIMTA dministered in doses rnging from to 8 mg/m were evluted in the Phse tril in ptients (3 mles nd 9 femles) ged to 8 yers (verge ge yers). Pemetrexed exposure (AUC nd Cmx) ppered to increse proportionlly with dose. The verge pemetrexed clernce (.3 L/h/m) nd hlf-life (.3 hours) in peditric ptients were comprle to vlues reported in dults. 8. Geritric Use ALIMTA is known to e sustntilly excreted y the kidney, nd the risk of dverse rections to this drug my e greter in ptients with impired renl function. Renl function monitoring is recommended with dministrtion of ALIMTA. No dose reductions other thn those recommended for ll ptients re necessry for ptients yers of ge or older [see Dosge nd Administrtion (.)]. Of 3,9 ptients (3.% ) studied cross the five clinicl trils [see Clinicl Studies (.,.,.3, nd.)], the effect of ALIMTA on survivl ws similr in ptients < compred to yers of ge. There were no differences in sfety with the exception of the following Grde 3- dverse rections, which were noted in t lest one of the five trils to e greter in ptients yers of ge nd older s compred to younger ptients: nemi, ftigue, thromocytopeni, hypertension, nd neutropeni. 8. Ptients with Heptic Impirment There ws no effect of elevted AST, ALT, or totl iliruin on the phrmcokinetics of pemetrexed. However, no forml studies hve een conducted to exmine the phrmcokinetics of pemetrexed in ptients with heptic impirment [see Clinicl Phrmcology (.3)]. 8.7 Ptients with Renl Impirment ALIMTA is known to e primrily excreted y the kidneys. Decresed renl function will result in reduced clernce nd greter exposure (AUC) to ALIMTA compred with ptients with norml renl function [see Dosge nd Administrtion (.) nd Clinicl Phrmcology (.3)]. Cispltin codministrtion with ALIMTA hs not een studied in ptients with moderte renl impirment. 8.8 Gender Of 3,9 ptients (Mle 7.%) studied cross the five registrtion studies for ALIMTA indictions [see Clinicl Studies (.,.,.3, nd.)], the effect of ALIMTA on survivl ws similr in femle nd mle ptients. 8.9 Rce Of 3,9 ptients (Cucsin 78.%) studied cross the five registrtion studies for ALIMTA indictions [see Clinicl Studies (.,.,.3, nd.)], the effect of ALIMTA on survivl ws similr in the Cucsin nd non-cucsin ptients. OVERDOSAGE There hve een few cses of ALIMTA overdose. Reported toxicities included neutropeni, nemi, thromocytopeni, mucositis, nd rsh. Anticipted complictions of overdose include one mrrow suppression s mnifested y neutropeni, thromocytopeni, nd nemi. In ddition, infection with or without fever, dirrhe, nd mucositis my e seen. If n overdose occurs, generl supportive mesures should e instituted s deemed necessry y the treting physicin. In clinicl trils, leucovorin ws permitted for CTC Grde leukopeni lsting 3 dys, CTC Grde neutropeni lsting 3 dys, nd immeditely for CTC Grde thromocytopeni, leeding ssocited with Grde 3 thromocytopeni, or Grde 3 or mucositis. The following intrvenous doses nd schedules of leucovorin were recommended for intrvenous use: mg/m, intrvenously once, followed y leucovorin, mg/m, intrvenously every hours for 8 dys. The ility of ALIMTA to e dilyzed is unknown. DESCRIPTION Pemetrexed disodium hepthydrte hs the chemicl nme L-Glutmic cid, N-[-[-(-mino-,7-dihydro--oxo-Hpyrrolo[,3-d]pyrimidin--yl)ethyl]enzoyl]-, disodium slt, hepthydrte. It is white to lmost-white solid with moleculr formul of CH9NNO 7HO nd moleculr weight of The structurl formul is s follows:

12 ALIMTA is supplied s sterile lyophilized powder for intrvenous infusion ville in single-dose vils. The product is white to either light yellow or green-yellow lyophilized solid. Ech -mg or -mg vil of ALIMTA contins pemetrexed disodium equivlent to mg pemetrexed nd mg mnnitol or mg pemetrexed nd mg mnnitol, respectively. Hydrochloric cid nd/or sodium hydroxide my hve een dded to djust ph.. CLINICAL PHARMACOLOGY Mechnism of Action ALIMTA, pemetrexed for injection, is folte nlog metolic inhiitor tht exerts its ction y disrupting folte-dependent metolic processes essentil for cell repliction. In vitro studies hve shown tht pemetrexed inhiits thymidylte synthse (TS), dihydrofolte reductse (DHFR), nd glycinmide rionucleotide formyltrnsferse (GARFT), which re folte-dependent enzymes involved in the de novo iosynthesis of thymidine nd purine nucleotides. Pemetrexed is tken into cells y memrne crriers such s the reduced folte crrier nd memrne folte inding protein trnsport systems. Once in the cell, pemetrexed is converted to polyglutmte forms y the enzyme folylpolyglutmte synthetse. The polyglutmte forms re retined in cells nd re inhiitors of TS nd GARFT. Polyglutmtion is time- nd concentrtion-dependent process tht occurs in tumor cells nd, is thought to occur to lesser extent, in norml tissues. Polyglutmted metolites re thought to hve n incresed intrcellulr hlf-life resulting in prolonged drug ction in mlignnt cells.. Phrmcodynmics Preclinicl studies hve shown tht pemetrexed inhiits the in vitro growth of mesotheliom cell lines (MSTO-H, NCI-H). Studies with the MSTO-H mesotheliom cell line showed synergistic effects when pemetrexed ws comined concurrently with cispltin. Asolute neutrophil counts (ANC) following single-gent dministrtion of ALIMTA to ptients not receiving folic cid nd vitmin B supplementtion were chrcterized using popultion phrmcodynmic nlyses. Severity of hemtologic toxicity, s mesured y the depth of the ANC ndir, correltes with the systemic exposure, or re under the curve (AUC) of pemetrexed. It ws lso oserved tht lower ANC ndirs occurred in ptients with elevted seline cystthionine or homocysteine concentrtions. The levels of these sustnces cn e reduced y folic cid nd vitmin B supplementtion. There is no cumultive effect of pemetrexed exposure on ANC ndir over multiple tretment cycles. Time to ANC ndir with pemetrexed systemic exposure (AUC), vried etween 8 to 9. dys over rnge of exposures from 38.3 to 3.8 mcg hr/ml. Return to seline ANC occurred. to 7. dys fter the ndir over the sme rnge of exposures..3 Phrmcokinetics Asorption The phrmcokinetics of ALIMTA dministered s single-gent in doses rnging from. to 838 mg/m infused over -minute period hve een evluted in cncer ptients with vriety of solid tumors. Pemetrexed totl systemic exposure (AUC) nd mximum plsm concentrtion (Cmx) increse proportionlly with dose. The phrmcokinetics of pemetrexed do not chnge over multiple tretment cycles. Distriution Pemetrexed hs stedy-stte volume of distriution of. liters. In vitro studies indicte tht pemetrexed is pproximtely 8% ound to plsm proteins. Binding is not ffected y degree of renl impirment. Metolism nd Excretion Pemetrexed is not metolized to n pprecile extent nd is primrily eliminted in the urine, with 7% to 9% of the dose recovered unchnged within the first hours following dministrtion. The clernce decreses, nd exposure (AUC) increses, s renl function decreses. The totl systemic clernce of pemetrexed is 9.8 ml/min nd the elimintion hlf-life of pemetrexed is 3. hours in ptients with norml renl function (cretinine clernce of 9 ml/min). The phrmcokinetics of pemetrexed in specil popultions were exmined in out ptients in controlled nd single rm studies. In vitro studies indicte tht pemetrexed is sustrte of OAT3 (orgnic nion trnsporter 3), trnsporter tht my ply role in ctive secretion of pemetrexed. Effect of Age, Gender or Rce No effect of ge on the phrmcokinetics of pemetrexed ws oserved over rnge of to 8 yers. The phrmcokinetics of pemetrexed were not different in mle nd femle ptients. The phrmcokinetics of pemetrexed were similr in Cucsins nd ptients of Africn descent. Insufficient dt re ville to compre phrmcokinetics for other ethnic groups.

13 3 Effect of Heptic Insufficiency There ws no effect of elevted AST, ALT, or totl iliruin on the phrmcokinetics of pemetrexed. However, studies of hepticlly impired ptients hve not een conducted [see Dosge nd Administrtion (.) nd Use in Specific Popultions (8.)]. Effect of Renl Insufficiency Phrmcokinetic nlyses of pemetrexed included 7 ptients with reduced renl function. Plsm clernce of pemetrexed decreses s renl function decreses, with resultnt increse in systemic exposure. Ptients with cretinine clernces of,, nd 8 ml/min hd %, %, nd 3% increses, respectively in pemetrexed totl systemic exposure (AUC) compred to ptients with cretinine clernce of ml/min [see Wrnings nd Precutions (.) nd Dosge nd Administrtion (.)]. Effect of Third Spce Fluid The effect of third spce fluid, such s pleurl effusion nd scites, on ALIMTA is not fully defined. A study of ALIMTA mg/m ws performed in 3 solid tumor ptients with stle third spce fluid (All ut of the 3 ptients included in study hd mild or moderte mounts of third spce fluid). Moderte pleurl effusion ws defined in the study s less thn /3 the wy up on one side with oscuring of the entire hemidiphrgm. Moderte scites ws defined s tht detectle on physicl exm. The pemetrexed plsm concentrtions in these ptients were comprle to those oserved in previous clinicl trils in ptients without third spce fluid collections. Thus, dringe of mild or moderte third spce fluid collection prior to ALIMTA tretment should e considered, ut is proly not necessry. The effect of severe third spce fluid on phrmcokinetics is not known. Effect of Iuprofen Iuprofen doses of mg four times dy reduce pemetrexed s clernce y out % (nd increse AUC y %) in ptients with norml renl function. The effect of greter doses of iuprofen on pemetrexed phrmcokinetics is unknown [see Drug Interctions (7.)]. Effect of Aspirin Aspirin, dministered in low to moderte doses (3 mg every hours), does not ffect the phrmcokinetics of pemetrexed. The effect of greter doses of spirin on pemetrexed phrmcokinetics is unknown. Effect of Cispltin Cispltin does not ffect the phrmcokinetics of pemetrexed nd the phrmcokinetics of totl pltinum re unltered y pemetrexed. Effect of Vitmins Codministrtion of orl folic cid or intrmusculr vitmin B does not ffect the phrmcokinetics of pemetrexed. Drugs Metolized y Cytochrome P Enzymes Results from in vitro studies with humn liver microsomes predict tht pemetrexed would not cuse cliniclly significnt inhiition of metolic clernce of drugs metolized y CYP3A, CYPD, CYPC9, nd CYPA NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility No crcinogenicity studies hve een conducted with pemetrexed. Pemetrexed ws clstogenic in the in vivo micronucleus ssy in mouse one mrrow ut ws not mutgenic in multiple in vitro tests (Ames ssy, CHO cell ssy). Pemetrexed dministered t i.v. doses of. mg/kg/dy or greter to mle mice (out / the recommended humn dose on mg/m sis) resulted in reduced fertility, hypospermi, nd testiculr trophy.. CLINICAL STUDIES Non-Smll Cell Lung Cncer (NSCLC) - Comintion with Cispltin A multi-center, rndomized, open-lel study in 7 chemonive ptients with Stge III/IV NSCLC ws conducted to compre the overll survivl following tretment with ALIMTA in comintion with cispltin (AC) versus gemcitine in comintion with cispltin (GC). ALIMTA ws dministered intrvenously over minutes t dose of mg/m with cispltin dministered intrvenously t dose of 7 mg/m fter ALIMTA dministrtion, on Dy of ech -dy cycle. Gemcitine ws dministered t dose of mg/m on Dy nd Dy 8, nd cispltin ws dministered intrvenously t dose of 7 mg/m fter dministrtion of gemcitine, on Dy of ech -dy cycle. Tretment ws dministered up to totl of cycles, nd ptients in oth tretment rms received folic cid, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.3)]. Ptient demogrphics of the intent to tret (ITT) popultion re shown in Tle. The demogrphics nd disese chrcteristics were well lnced. Tle : First-Line Therpy: Summry of Ptient Chrcteristics in Study of NSCLC ALIMTA plus Cispltin (AC) Gemcitine plus Cispltin (GC) Ptient chrcteristic (N=8) (N=83) Age (yrs) Medin (rnge). ( ). (.-79.) Gender Mle/Femle 7.%/9.8% 7.%/9.9% Origin Cucsin 9 (77.%) 8 (78.8%)

14 Hispnic 7 (3.%) 3 (.7%) Asin (.9%) (.3%) Africn descent 8 (.%) 8 (.%) Stge t Entry III/IV 3.8%/7.%.3%/7.7% Histology Nonsqumous NSCLC 8 (7.7%) 3 (73.%) Adenocrcinom 3 (.%) (7.%) Lrge cell 7 (8.8%) 77 (8.9%) Other (.3%) (.9%) Squmous (8.3%) 9 (.%) ECOG PS c,d / 3.%/.% 3.%/.3% Smoking History e Ever/never smoker 83.%/.9% 83.9%/.% Includes denocrcinom, lrge cell, nd other histologies except those with squmous cell type. The sugroup of other represents ptients with primry dignosis of NSCLC whose disese did not clerly qulify s denocrcinom, squmous cell crcinom, or lrge cell crcinom. c Estern Coopertive Oncology Group Performnce Sttus. d ECOG PS ws not reported for ll rndomized ptients. Percentges re representtive of N=8 for the ALIMTA plus cispltin rm, nd N=8 for the gemcitine plus cispltin rm. e Smoking history ws collected for 88% of rndomized ptients (N=77 for the ALIMTA plus cispltin rm nd N=79 for the gemcitine plus cispltin rm). Ptients received medin of cycles of tretment in oth study rms. Ptients treted with ALIMTA plus cispltin received reltive dose intensity of 9.8% of the protocol-specified ALIMTA dose intensity nd 9.% of the protocol-specified cispltin dose intensity. Ptients treted with gemcitine plus cispltin received reltive dose intensity of 8.8% of the protocol-specified gemcitine dose intensity nd 93.% of the protocol-specified cispltin dose intensity. The primry endpoint in this study ws overll survivl. The medin survivl time ws.3 months in the ALIMTA plus cispltin tretment rm nd.3 months in the gemcitine plus cispltin rm, with n djusted hzrd rtio of.9. Tle : First-Line Therpy: Efficcy in NSCLC - ITT Popultion ALIMTA plus Cispltin (N=8) Gemcitine plus Cispltin (N=83) Medin overll survivl (9% CI).3 mos (9.8-.).3 mos (9.-.9) Adjusted hzrd rtio (HR), (9% CI).9 (.8-.) Medin progression-free survivl (9% CI).8 mos (.-.3). mos (.-.) Adjusted hzrd rtio (HR), (9% CI). (.9-.) Overll response rte (9% CI) 7.% (.-3.).7% (.8-7.) Adjusted for gender, stge, sis of dignosis, nd performnce sttus. A HR tht is less thn. indictes tht survivl is etter in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn. indictes survivl is etter in the GC rm thn in the AC rm.

15 Figure : Kpln-Meier Curves for Overll Survivl ALIMTA plus Cispltin (AC) versus Gemcitine plus Cispltin (GC) in NSCLC - ITT Popultion. A pre-specified nlysis of the impct of NSCLC histology on overll survivl ws exmined. Cliniclly relevnt differences in survivl ccording to histology were oserved nd re shown in Tle. This difference in tretment effect for ALIMTA sed on histology demonstrting lck of efficcy in squmous cell histology ws lso oserved in the single-gent, second-line study nd the mintennce study [see Clinicl Studies (.,.3)]. Tle : First-Line Therpy: Overll Survivl in NSCLC Histologic Sugroups Medin Overll Survivl in Months Undjusted Adjusted Hzrd (9% CI) Hzrd Rtio (HR),,c Histology Sugroup, Rtio (HR) (9% CI) ALIMTA plus Cispltin Gemcitine plus Cispltin (9% CI) Nonsqumous NSCLCd. N=8. N=3.8.8 (N=) (.-.) (9.3-.9) (.7-.9) (.7-.9) Adenocrcinom. N=3.9 N=.8.8 (N=87) (.7-3.) (.-.9) (.7-.98) (.7-.99) Lrge Cell. N=7.7 N= (N=3) (8.-.) (.-9.) (.8-.97) (.8-.9) Othere 8. N= 9. N=..8 (N=) (.8-.) (8.-.) (.8-.9) (.8-.) Squmous Cell 9. N=.8 N=9..3 (N=73) (8.-.) (9.-.) (.99-.) (.-.) A HR tht is less thn. indictes tht survivl is etter in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn. indictes survivl is etter in the GC rm thn in the AC rm. Undjusted for multiple comprisons. c HRs djusted for ECOG PS, gender, disese stge, nd sis for pthologicl dignosis (histopthologicl/cytopthologicl). d Includes denocrcinom, lrge cell, nd other histologies except those with squmous cell type. e The sugroup of other represents ptients with primry dignosis of NSCLC whose disese did not clerly qulify s denocrcinom, squmous cell crcinom, or lrge cell crcinom.