Revised: 09/2013 FULL PRESCRIBING INFORMATION: CONTENTS*

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not inlude ll the informtion needed to use ALIMTA sfely nd effetively. See full presriing informtion for ALIMTA. ALIMTA (pemetrexed for injetion), for Intrvenous Use Initil U.S. Approvl: RECENT MAJOR CHANGES Dosge nd Administrtion, Premedition Regimen nd Conurrent Meditions (.) / Wrnings nd Preutions, Requirement for Premedition nd Conomitnt Medition to Redue Toxiity (.) / Wrnings nd Preutions, Required Lortory Monitoring (.) / INDICATIONS AND USAGE ALIMTA is folte nlog metoli inhiitor indited for: Lolly Advned or Metstti Nonsqumous Non-Smll Cell Lung Cner: Initil tretment in omintion with ispltin. (.) Mintenne tretment of ptients whose disese hs not progressed fter four yles of pltinum-sed first-line hemotherpy. (.) After prior hemotherpy s single-gent. (.) Mesotheliom: in omintion with ispltin. (.) Limittions of Use: ALIMTA is not indited for the tretment of ptients with squmous ell non-smll ell lung ner. (.) DOSAGE AND ADMINISTRATION Comintion use in Non-Smll Cell Lung Cner nd Mesotheliom: Reommended dose of ALIMTA is mg/m i.v. on Dy of eh -dy yle in omintion with ispltin 7 mg/m i.v. eginning minutes fter ALIMTA dministrtion. (.) Single-Agent use in Non-Smll Cell Lung Cner: Reommended dose of ALIMTA is mg/m i.v. on Dy of eh -dy yle. (.) Prior to inititing ALIMTA, initite supplementtion with orl foli id nd intrmusulr vitmin B. Continue foli id nd vitmin B supplementtion throughout tretment. Administer ortiosteroids the dy efore, the dy of, nd the dy fter ALIMTA dministrtion. (.) Dose Redutions: Dose redutions or disontinution my e needed sed on toxiities from the preeding yle of therpy. (.) DOSAGE FORMS AND STRENGTHS mg vil for injetion () mg vil for injetion () CONTRAINDICATIONS History of severe hypersensitivity retion to pemetrexed. () WARNINGS AND PRECAUTIONS Premedition regimen: Prior to tretment with ALIMTA, initite supplementtion with orl foli id nd intrmusulr vitmin B to redue the severity of hemtologi nd gstrointestinl toxiity of ALIMTA. (.) Bone mrrow suppression: Redue doses for susequent yles sed on hemtologi nd nonhemtologi toxiities. (.) Renl funtion: Do not dminister when CrCl < ml/min. (.,.) NSAIDs with renl insuffiieny: Use ution in ptients with mild to moderte renl insuffiieny (CrCl -79 ml/min). (.) L monitoring: Do not initite yle unless ANC ells/mm, pltelets, ells/mm, nd CrCl ml/min. (.) Pregnny: Fetl hrm n our when dministered to pregnnt womn. Women should e dvised to use effetive ontreption mesures to prevent pregnny during tretment with ALIMTA. (.) ADVERSE REACTIONS The most ommon dverse retions (inidene %) with singlegent use re ftigue, nuse, nd norexi. Additionl ommon dverse retions when used in omintion with ispltin inlude vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromoytopeni, nd onstiption. (.) To report SUSPECTED ADVERSE REACTIONS, ontt Eli Lilly nd Compny t -8-LillyRx ( ) or FDA t -8- FDA-88 or DRUG INTERACTIONS NSAIDs: Use ution with NSAIDs. (7.) Nephrotoxi drugs: Conomitnt use of these drugs nd/or sustnes whih re tuulrly sereted my result in delyed lerne. (7.) See 7 for PATIENT COUNSELING INFORMATION nd FDApproved ptient leling. Revised: 9/ FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE. Nonsqumous Non-Smll Cell Lung Cner Comintion with Cispltin. Nonsqumous Non-Smll Cell Lung Cner Mintenne. Nonsqumous Non-Smll Cell Lung Cner After Prior Chemotherpy. Mesotheliom. Limittions of Use DOSAGE AND ADMINISTRATION. Comintion Use with Cispltin for Nonsqumous Non- Smll Cell Lung Cner or Mlignnt Pleurl Mesotheliom. Single-Agent Use s Mintenne Following First-Line Therpy, or s Seond-Line Therpy. Premedition Regimen nd Conurrent Meditions. Lortory Monitoring nd Dose Redution/Disontinution Reommendtions. Preprtion nd Administrtion Preutions. Preprtion for Intrvenous Infusion Administrtion DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Requirement for Premedition nd Conomitnt Medition to Redue Toxiity. Bone Mrrow Suppression. Deresed Renl Funtion. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insuffiieny. Required Lortory Monitoring. Pregnny Ctegory D ADVERSE REACTIONS. Clinil Trils Experiene. Postmrketing Experiene 7 DRUG INTERACTIONS 7. Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) 7. Nephrotoxi Drugs 8 USE IN SPECIFIC POPULATIONS 8. Pregnny 8. Nursing Mothers 8. Peditri Use 8. Geritri Use 8. Ptients with Hepti Impirment 8.7 Ptients with Renl Impirment

2 Gender Re OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mehnism of Ation. Phrmodynmis. Phrmokinetis NONCLINICAL TOXICOLOGY. Crinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES.... Non-Smll Cell Lung Cner (NSCLC) Comintion with Cispltin Non-Smll Cell Lung Cner Mintenne Non-Smll Cell Lung Cner After Prior Chemotherpy Mlignnt Pleurl Mesotheliom REFERENCES HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. Storge nd Hndling 7 PATIENT COUNSELING INFORMATION *Setions or susetions omitted from the full presriing informtion re not listed. FULL PRESCRIBING INFORMATION. INDICATIONS AND USAGE Nonsqumous Non-Smll Cell Lung Cner Comintion with Cispltin ALIMTA is indited in omintion with ispltin therpy for the initil tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner.. Nonsqumous Non-Smll Cell Lung Cner Mintenne ALIMTA is indited for the mintenne tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner whose disese hs not progressed fter four yles of pltinum-sed first-line hemotherpy.. Nonsqumous Non-Smll Cell Lung Cner After Prior Chemotherpy ALIMTA is indited s single-gent for the tretment of ptients with lolly dvned or metstti nonsqumous non-smll ell lung ner fter prior hemotherpy.. Mesotheliom ALIMTA in omintion with ispltin is indited for the tretment of ptients with mlignnt pleurl mesotheliom whose disese is unresetle or who re otherwise not ndidtes for urtive surgery.. Limittions of Use ALIMTA is not indited for the tretment of ptients with squmous ell non-smll ell lung ner. [see Clinil Studies (.,.,.)] DOSAGE AND ADMINISTRATION. Comintion Use with Cispltin for Nonsqumous Non-Smll Cell Lung Cner or Mlignnt Pleurl Mesotheliom The reommended dose of ALIMTA is mg/m dministered s n intrvenous infusion over minutes on Dy of eh -dy yle. The reommended dose of ispltin is 7 mg/m infused over hours eginning pproximtely minutes fter the end of ALIMTA dministrtion. See ispltin pkge insert for more informtion.. Single-Agent Use s Mintenne Following First-Line Therpy, or s Seond-Line Therpy The reommended dose of ALIMTA is mg/m dministered s n intrvenous infusion over minutes on Dy of eh -dy yle.. Premedition Regimen nd Conurrent Meditions Vitmin Supplementtion Instrut ptients to initite foli id mg to mg orlly one dily eginning 7 dys efore the first dose of ALIMTA. Continue foli id during the full ourse of therpy nd for dys fter the lst dose of ALIMTA [see Wrnings nd Preutions (.)]. Administer vitmin B mg intrmusulrly week prior to the first dose of ALIMTA nd every yles therefter. Susequent vitmin B injetions my e given the sme dy s tretment with ALIMTA [see Wrnings nd Preutions (.)]. Cortiosteroids Administer dexmethsone mg y mouth twie dily the dy efore, the dy of, nd the dy fter ALIMTA dministrtion [see Wrnings nd Preutions (.)].. Lortory Monitoring nd Dose Redution/Disontinution Reommendtions Monitoring Complete lood ell ounts, inluding pltelet ounts, should e performed on ll ptients reeiving ALIMTA. Ptients should e monitored for ndir nd reovery, whih were tested in the linil study efore eh dose nd on dys 8 nd of eh yle. Ptients should not egin new yle of tretment unless the ANC is ells/mm, the pltelet ount is, ells/mm, nd retinine lerne is ml/min. Periodi hemistry tests should e performed to evlute renl nd hepti funtion [see Wrnings nd Preutions (.)]. Dose Redution Reommendtions

3 Dose djustments t the strt of susequent yle should e sed on ndir hemtologi ounts or mximum nonhemtologi toxiity from the preeding yle of therpy. Tretment my e delyed to llow suffiient time for reovery. Upon reovery, ptients should e retreted using the guidelines in Tles -, whih re suitle for using ALIMTA s single-gent or in omintion with ispltin. Tle : Dose Redution for ALIMTA (single-gent or in omintion) nd Cispltin Hemtologi Toxiities Ndir ANC </mm nd ndir pltelets,/mm. 7% of previous dose (pemetrexed nd ispltin). Ndir pltelets <,/mm without leeding regrdless of ndir 7% of previous dose (pemetrexed nd ispltin). ANC. Ndir pltelets <,/mm with leeding, regrdless of ndir ANC. % of previous dose (pemetrexed nd ispltin). These riteri meet the CTC version. (NCI 998) definition of CTC Grde leeding. If ptients develop nonhemtologi toxiities (exluding neurotoxiity) Grde, tretment should e withheld until resolution to less thn or equl to the ptient s pre-therpy vlue. Tretment should e resumed ording to guidelines in Tle. Tle : Dose Redution for ALIMTA (single-gent or in omintion) nd Cispltin Nonhemtologi, Toxiities Dose of ALIMTA Dose of Cispltin (mg/m) (mg/m) Any Grde or toxiities exept muositis 7% of previous dose 7% of previous dose Any dirrhe requiring hospitliztion (irrespetive of Grde) or 7% of previous dose 7% of previous dose Grde or dirrhe Grde or muositis % of previous dose % of previous dose NCI Common Toxiity Criteri (CTC). Exluding neurotoxiity (see Tle ). In the event of neurotoxiity, the reommended dose djustments for ALIMTA nd ispltin re desried in Tle. Ptients should disontinue therpy if Grde or neurotoxiity is experiened. Tle : Dose Redution for ALIMTA (single-gent or in omintion) nd Cispltin Neurotoxiity Dose of ALIMTA Dose of Cispltin (mg/m) (mg/m) CTC Grde - % of previous dose % of previous dose % of previous dose % of previous dose Disontinution Reommendtion ALIMTA therpy should e disontinued if ptient experienes ny hemtologi or nonhemtologi Grde or toxiity fter dose redutions or immeditely if Grde or neurotoxiity is oserved. Renlly Impired Ptients In linil studies, ptients with retinine lerne ml/min required no dose djustments other thn those reommended for ll ptients. Insuffiient numers of ptients with retinine lerne elow ml/min hve een treted to mke dosge reommendtions for this group of ptients [see Clinil Phrmology (.)]. Therefore, ALIMTA should not e dministered to ptients whose retinine lerne is < ml/min using the stndrd Cokroft nd Gult formul (elow) or GFR mesured y T99m-DTPA serum lerne method: Mles: Femles: [ - Age in yers] Atul Body Weight (kg) 7 Serum Cretinine (mg/dl) Estimted retinine lerne for mles.8 = ml/min Cution should e exerised when dministering ALIMTA onurrently with NSAIDs to ptients whose retinine lerne is <8 ml/min [see Drug Intertions (7.)].. Preprtion nd Administrtion Preutions As with other potentilly toxi ntiner gents, re should e exerised in the hndling nd preprtion of infusion solutions of ALIMTA. The use of gloves is reommended. If solution of ALIMTA ontts the skin, wsh the skin immeditely nd thoroughly with sop nd wter. If ALIMTA ontts the muous memrnes, flush thoroughly with wter. Severl pulished guidelines for hndling nd disposl of ntiner gents re ville [see Referenes ()].

4 ALIMTA is not vesint. There is no speifi ntidote for extrvstion of ALIMTA. To dte, there hve een few reported ses of ALIMTA extrvstion, whih were not ssessed s serious y the investigtor. ALIMTA extrvstion should e mnged with lol stndrd prtie for extrvstion s with other non-vesints.. Preprtion for Intrvenous Infusion Administrtion. Use septi tehnique during the reonstitution nd further dilution of ALIMTA for intrvenous infusion dministrtion.. Clulte the dose of ALIMTA nd determine the numer of vils needed. Vils ontin either mg or mg of ALIMTA. The vils ontin n exess of ALIMTA to filitte delivery of lel mount.. Reonstitute eh -mg vil with. ml of.9% Sodium Chloride Injetion (preservtive free). Reonstitute eh -mg vil with ml of.9% Sodium Chloride Injetion (preservtive free). Reonstitution of either size vil gives solution ontining mg/ml ALIMTA. Gently swirl eh vil until the powder is ompletely dissolved. The resulting solution is ler nd rnges in olor from olorless to yellow or green-yellow without dversely ffeting produt qulity. The ph of the reonstituted ALIMTA solution is etween. nd 7.8. FURTHER DILUTION IS REQUIRED.. Prenterl drug produts should e inspeted visully for prtiulte mtter nd disolortion prior to dministrtion, whenever solution nd ontiner permit. If prtiulte mtter is oserved, do not dminister.. An pproprite quntity of the reonstituted ALIMTA solution must e further diluted into solution of.9% Sodium Chloride Injetion (preservtive free), so tht the totl volume of solution is ml. ALIMTA is dministered s n intrvenous infusion over minutes.. Chemil nd physil stility of reonstituted nd infusion solutions of ALIMTA were demonstrted for up to hours following initil reonstitution, when stored refrigerted. When prepred s direted, reonstitution nd infusion solutions of ALIMTA ontin no ntimiroil preservtives. Disrd ny unused portion. Reonstitution nd further dilution prior to intrvenous infusion is only reommended with.9% Sodium Chloride Injetion (preservtive free). ALIMTA is physilly inomptile with diluents ontining lium, inluding Ltted Ringer s Injetion, USP nd Ringer s Injetion, USP nd therefore these should not e used. Codministrtion of ALIMTA with other drugs nd diluents hs not een studied, nd therefore is not reommended. ALIMTA is omptile with stndrd polyvinyl hloride (PVC) dministrtion sets nd intrvenous solution gs. DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injetion, is white to either light-yellow or green-yellow lyophilized powder ville in sterile single-use vils ontining mg or mg pemetrexed. CONTRAINDICATIONS ALIMTA is ontrindited in ptients who hve history of severe hypersensitivity retion to pemetrexed. WARNINGS AND PRECAUTIONS. Requirement for Premedition nd Conomitnt Medition to Redue Toxiity Vitmin Supplementtion Prior to tretment with ALIMTA, initite supplementtion with orl foli id nd intrmusulr vitmin B to redue the severity of hemtologi nd gstrointestinl toxiity of ALIMTA [see Dosge nd Administrtion (.)]. Do not sustitute orl vitmin B for intrmusulr vitmin B. In linil studies, the inidene of the following Grde - toxiities were higher in ptients with mesotheliom who were never supplemented s ompred to ptients who were fully supplemented with foli id nd vitmin B prior to nd throughout ALIMTA tretment: neutropeni [8% versus %], thromoytopeni [9% versus %], ferile neutropeni [9% versus.%], nd infetion with neutropeni [% versus. ]. Cortiosteroids Administer dexmethsone the dy efore, the dy of, nd the dy fter ALIMTA dministrtion [see Dosge nd Administrtion (.)].. Bone Mrrow Suppression ALIMTA n suppress one mrrow funtion, s mnifested y neutropeni, thromoytopeni, nd nemi (or pnytopeni) [see Adverse Retions (.)]; myelosuppression is usully the dose-limiting toxiity. Dose redutions for susequent yles re sed on ndir ANC, pltelet ount, nd mximum nonhemtologi toxiity seen in the previous yle [see Dosge nd Administrtion (.)].. Deresed Renl Funtion ALIMTA is primrily eliminted unhnged y renl exretion. No dosge djustment is needed in ptients with retinine lerne ml/min. Insuffiient numers of ptients hve een studied with retinine lerne < ml/min to give dose reommendtion. Therefore, ALIMTA should not e dministered to ptients whose retinine lerne is < ml/min [see Dosge nd Administrtion (.)]. One ptient with severe renl impirment (retinine lerne 9 ml/min) who did not reeive foli id nd vitmin B died of drug-relted toxiity following dministrtion of ALIMTA lone.. Use with Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) with Mild to Moderte Renl Insuffiieny

5 Cution should e used when dministering NSAIDs onurrently with ALIMTA to ptients with mild to moderte renl insuffiieny (retinine lerne from to 79 ml/min) [see Drug Intertions (7.)].. Required Lortory Monitoring Otin omplete lood ount nd renl funtion tests t the eginning of eh yle nd s needed. Do not initite yle of tretment unless the ANC is ells/mm, the pltelet ount is, ells/mm, nd retinine lerne is ml/min [see Dosge nd Administrtion (.)].. Pregnny Ctegory D Bsed on its mehnism of tion, ALIMTA n use fetl hrm when dministered to pregnnt womn. Pemetrexed dministered intrperitonelly to mie during orgnogenesis ws emryotoxi, fetotoxi nd tertogeni in mie t greter thn /8rd the reommended humn dose. If ALIMTA is used during pregnny, or if the ptient eomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of hildering potentil should e dvised to void eoming pregnnt. Women should e dvised to use effetive ontreptive mesures to prevent pregnny during tretment with ALIMTA [see Use in Speifi Popultions (8.)].. ADVERSE REACTIONS Clinil Trils Experiene Beuse linil trils re onduted under widely vrying onditions, dverse retions rtes nnot e diretly ompred to rtes in other linil trils nd my not reflet the rtes oserved in linil prtie. In linil trils, the most ommon dverse retions (inidene %) during therpy with ALIMTA s singlegent were ftigue, nuse, nd norexi. Additionl ommon dverse retions (inidene %) during therpy with ALIMTA when used in omintion with ispltin inluded vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thromoytopeni, nd onstiption. Non-Smll Cell Lung Cner (NSCLC) ALIMTA in Comintion with Cispltin Tle provides the frequeny nd severity of dverse retions tht hve een reported in >% of 89 ptients with NSCLC who were rndomized to study nd reeived ALIMTA plus ispltin nd 8 ptients with NSCLC who were rndomized to study nd reeived gemitine plus ispltin. All ptients reeived study therpy s initil tretment for lolly dvned or metstti NSCLC nd ptients in oth tretment groups were fully supplemented with foli id nd vitmin B. Tle : Adverse Retions in Fully Supplemented Ptients Reeiving ALIMTA plus Cispltin in NSCLC ALIMTA/ispltin Gemitine/ispltin (N=89) (N=8) Retion All Grdes Grde - All Grdes Grde - All Adverse Retions Lortory Hemtologi Anemi Neutropeni Leukopeni 8 8 Thromoytopeni 7 Renl Cretinine elevtion 7 Clinil Constitutionl Symptoms Ftigue 7 Gstrointestinl Nuse 7 Vomiting Anorexi 7 Constiption Stomtitis/Phryngitis Dirrhe Dyspepsi/Herturn Neurology Neuropthy-sensory 9 Tste disturne 8 9 Dermtology/Skin Alopei

6 Rsh/Desqumtion 7 8 For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to ALIMTA. Refer to NCI CTC Criteri version. for eh Grde of toxiity. Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No linilly relevnt differenes in dverse retions were seen in ptients sed on histology. In ddition to the lower inidene of hemtologi toxiity on the ALIMTA nd ispltin rm, use of trnsfusions (RBC nd pltelet) nd hemtopoieti growth ftors ws lower in the ALIMTA nd ispltin rm ompred to the gemitine nd ispltin rm. The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner rndomly ssigned to reeive ALIMTA plus ispltin. Inidene % to % Body s Whole ferile neutropeni, infetion, pyrexi Generl Disorders dehydrtion Metolism nd Nutrition inresed AST, inresed ALT Renl retinine lerne derese, renl filure Speil Senses onjuntivitis Inidene Less thn % Crdiovsulr rrhythmi Generl Disorders hest pin Metolism nd Nutrition inresed GGT Neurology motor neuropthy Non-Smll Cell Lung Cner (NSCLC) Mintenne ALIMTA Mintenne Following Non-ALIMTA Contining, Pltinum-Bsed Indution Therpy Tle provides the frequeny nd severity of dverse retions reported in >% of the 8 ptients with NSCLC who reeived ALIMTA mintenne nd the 8 ptients with NSCLC who reeived pleo following pltinum-sed indution therpy. All ptients reeived study therpy immeditely following yles of pltinum-sed tretment for lolly dvned or metstti NSCLC. Ptients in oth study rms were fully supplemented with foli id nd vitmin B. Tle : Adverse Retions in Ptients Reeiving ALIMTA versus Pleo in NSCLC Following Pltinum-Bsed Indution Therpy ALIMTA Pleo (N=8) (N=8) Retion All Grdes Grde - All Grdes Grde - All Adverse Retions 7 Lortory Hemtologi Anemi Neutropeni Leukopeni Hepti Inresed ALT Inresed AST 8 Clinil Constitutionl Symptoms Ftigue Gstrointestinl Nuse 9 Anorexi 9 Vomiting 9 Muositis/stomtitis 7 Dirrhe Infetion Neurology Neuropthy-sensory 9 Dermtology/Skin

7 7 Rsh/Desqumtion For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to ALIMTA. Refer to NCI CTCAE Criteri version. for eh Grde of toxiity. No linilly relevnt differenes in Grde / dverse retions were seen in ptients sed on ge, gender, ethni origin, or histology exept higher inidene of Grde / ftigue for Cusin ptients ompred to noncusin ptients (.% versus.%). Sfety ws ssessed y exposure for ptients who reeived t lest one dose of ALIMTA (N=8). The inidene of dverse retions ws evluted for ptients who reeived yles of ALIMTA, nd ompred to ptients who reeived > yles of ALIMTA. Inreses in dverse retions (ll grdes) were oserved with longer exposure; however no linilly relevnt differenes in Grde / dverse retions were seen. Consistent with the higher inidene 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 ompred to the pleo rm (trnsfusions 9.% versus.%, ESAs.9% versus.8%). The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner who reeived ALIMTA. Inidene % to % Dermtology/Skin lopei, pruritis/ithing Gstrointestinl onstiption Generl Disorders edem, fever (in the sene of neutropeni) Hemtologi thromoytopeni Renl deresed retinine lerne, inresed retinine, deresed glomerulr filtrtion rte Speil Senses oulr surfe disese (inluding onjuntivitis), inresed lrimtion Inidene Less thn % Crdiovsulr suprventriulr rrhythmi Dermtology/Skin erythem multiforme Generl Disorders ferile neutropeni, llergi retion/hypersensitivity Neurology motor neuropthy Renl renl filure Continution of ALIMTA s Mintenne Following ALIMTA Plus Pltinum Indution Therpy Tle provides the frequeny nd severity of dverse retions reported in >% of the ptients with nonsqumous NSCLC who reeived t lest one yle of ALIMTA mintenne (n=) or pleo (n=7) on the ontinution mintenne tril. The medin of mintenne yles dministered to ptients reeiving one or more doses of mintenne therpy ws on oth the pemetrexed nd pleo rms. Dose redutions for dverse events ourred in.% of ptients in the ALIMTA rm nd.% in the pleo rm. Dose delys for dverse events ourred in % of ptients in the ALIMTA rm nd % in the pleo rm. Ptients in oth study rms were supplemented with foli id nd vitmin B. Tle : Seleted Adverse Retions Ourring in % of Ptients Reeiving ALIMTA in Nonsqumous NSCLC Following ALIMTA Plus Cispltin Indution Therpy ALIMTA Pleo (N=) (N=7) Adverse Retion Orgn System nd Term All Grdes Grde - All Grdes Grdes - All Adverse Retions 7.8 Lortory Hemtologi Anemi.8.8. Neutropeni 9.9. Clinil Constitutionl Symptoms Ftigue 8.. Gstrointestinl Nuse.. Vomiting.8 Muositis/stomtitis.. Generl Disorders Edem.

8 8 Adverse retions of ny severity (ll grdes) ourring more frequently ( %) or Grde - dverse retions ourring more frequently ( %) in ALIMTA-treted ptients ompred to those reeiving pleo. NCI CTCAE Criteri version. Administrtion of RBC (% versus.8%) nd pltelet (.% versus.%) trnsfusions, erythropoiesis stimulting gents (% versus 7%), nd grnuloyte olony stimulting ftors (% versus ) were higher in the ALIMTA rm ompred to the pleo rm. The following dditionl Grde or dverse retions were oserved more frequently in the ALIMTA rm. Inidene % to % Blood/Bone Mrrow thromoytopeni Generl Disorders ferile neutropeni Inidene Less thn % Crdiovsulr ventriulr thyrdi, synope Generl Disorders pin Gstrointestinl gstrointestinl ostrution Neurologi depression Renl renl filure Vsulr pulmonry emolism Non-Smll Cell Lung Cner (NSCLC) After Prior Chemotherpy Tle 7 provides the frequeny nd severity of dverse retions tht hve een reported in >% of ptients rndomly ssigned to reeive single-gent ALIMTA with foli id nd vitmin B supplementtion nd 7 ptients rndomly ssigned to reeive single-gent doetxel. All ptients were dignosed with lolly dvned or metstti NSCLC nd reeived prior hemotherpy. Tle 7: Adverse Retions in Fully Supplemented Ptients Reeiving ALIMTA versus Doetxel in NSCLC ALIMTA Doetxel (N=) (N=7) Retion All Grdes Grdes - All Grdes Grdes - Lortory Hemtologi Anemi 9 Leukopeni 7 Neutropeni Thromoytopeni 8 Hepti Inresed ALT 8 Inresed AST 7 Clinil Gstrointestinl Nuse 7 Anorexi Vomiting Stomtitis/Phryngitis 7 Dirrhe Constiption Constitutionl Symptoms Ftigue Fever 8 8 Dermtology/Skin Rsh/Desqumtion Pruritis 7 Alopei 8 For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to ALIMTA. Refer to NCI CTC Criteri for l vlues for eh Grde of toxiity (version.). Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or. No linilly relevnt differenes in dverse retions were seen in ptients sed on histology.

9 9 Clinilly relevnt dverse retions ourring in <% of ptients tht reeived ALIMTA tretment ut >% of ptients tht reeived doetxel inlude CTC Grde / ferile neutropeni (.9% ALIMTA,.7% doetxel). The following dditionl dverse retions were oserved in ptients with non-smll ell lung ner rndomly ssigned to reeive ALIMTA. Inidene % to % Body s Whole dominl pin, llergi retion/hypersensitivity, ferile neutropeni, infetion Dermtology/Skin erythem multiforme Neurology motor neuropthy, sensory neuropthy Renl inresed retinine Inidene Less thn % Crdiovsulr suprventriulr rrhythmis Mlignnt Pleurl Mesotheliom (MPM) Tle 8 provides the frequeny nd severity of dverse retions tht hve een reported in >% of 8 ptients with mesotheliom who were rndomly ssigned to reeive ispltin nd ALIMTA nd ptients with mesotheliom rndomly ssigned to reeive single-gent ispltin. In oth tretment rms, these hemonive ptients were fully supplemented with foli id nd vitmin B. Tle 8: Adverse Retions in Fully Supplemented Ptients Reeiving ALIMTA plus Cispltin in MPM ALIMTA/ispltin Cispltin (N=8) (N=) Retion All Grdes Grde - All Grdes Grde - Lortory Hemtologi Neutropeni Leukopeni 7 Anemi Thromoytopeni 9 Renl Cretinine elevtion Cretinine lerne deresed 8 Clinil Eye Disorder Conjuntivitis Gstrointestinl Nuse 8 77 Vomiting 7 Stomtitis/Phryngitis Anorexi Dirrhe 7 8 Constiption 7 Dyspepsi Constitutionl Symptoms Ftigue 8 9 Metolism nd Nutrition Dehydrtion 7 Neurology Neuropthy-sensory Tste Disturne 8 Dermtology/Skin Rsh Alopei For the purpose of this tle ut off of % ws used for inlusion of ll events where the reporter onsidered possile reltionship to ALIMTA. Refer to NCI CTC Criteri version. for eh Grde of toxiity exept the term retinine lerne deresed whih is derived from the CTC term renl/genitourinry-other. Aording to NCI CTC Criteri version., this dverse event term should only e reported s Grde or.

10 The following dditionl dverse retions were oserved in ptients with mlignnt pleurl mesotheliom rndomly ssigned to reeive ALIMTA plus ispltin. Inidene % to % Body s Whole ferile neutropeni, infetion, pyrexi Dermtology/Skin urtiri Generl Disorders hest pin Metolism nd Nutrition inresed AST, inresed ALT, inresed GGT Renl renl filure Inidene Less thn % Crdiovsulr rrhythmi Neurology motor neuropthy Effets of Vitmin Supplementtions on Toxiity Tle 9 ompres the inidene (perentge of ptients) of CTC Grde / toxiities in ptients who reeived vitmin supplementtion with dily foli id nd vitmin B from the time of enrollment in the study (fully supplemented) with the inidene in ptients who never reeived vitmin supplementtion (never supplemented) during the study in the ALIMTA plus ispltin rm. Tle 9: Seleted Grde / Adverse Events Compring Fully Supplemented versus Never Supplemented Ptients in the ALIMTA plus Cispltin rm (% inidene) Fully Supplemented Never Supplemented Ptients Ptients Adverse Event (%) (N=8) (N=) Neutropeni/grnuloytopeni 8 Thromoytopeni 9 Vomiting Ferile neutropeni 9 Infetion with Grde / neutropeni Dirrhe 9 Refer to NCI CTC riteri for l nd non-lortory vlues for eh grde of toxiity (Version.). The following dverse events were greter in the fully supplemented group ompred to the never supplemented group: hypertension (%, %), hest pin (8%, %), nd thromosis/emolism (%, %). No relevnt effet for ALIMTA sfety due to gender or re ws identified, exept n inresed inidene of rsh in men (%) ompred to women (%). Additionl Experiene Aross Clinil Trils Sepsis, whih in some ses ws ftl, ourred in pproximtely % of ptients. Esophgitis ourred in less thn % of ptients.. Postmrketing Experiene The following dverse retions hve een identified during post-pprovl use of ALIMTA. Beuse these retions re reported voluntrily from popultion of unertin size, it is not lwys possile to relily estimte their frequeny or estlish usl reltionship to drug exposure. These retions ourred with ALIMTA when used s single-gent nd in omintion therpies. Blood nd Lymphti System immune-medited hemolyti nemi Gstrointestinl olitis, pnretitis Generl Disorders nd Administrtion Site Conditions edem Injury, poisoning, nd proedurl omplitions Rdition rell hs een reported in ptients who hve previously reeived rdiotherpy. Respirtory interstitil pneumonitis Skin Bullous onditions, inluding Stevens-Johnson syndrome nd toxi epiderml nerolysis. Some ses were ftl DRUG INTERACTIONS Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) Although iuprofen ( mg four times dy) n derese the lerne of pemetrexed, it n e dministered with ALIMTA in ptients with norml renl funtion (retinine lerne 8 ml/min). No dose djustment of ALIMTA is needed with onomitnt NSAIDs in ptients with norml renl funtion [see Clinil Phrmology (.)]. Cution should e used when dministering NSAIDs onurrently with ALIMTA to ptients with mild to moderte renl insuffiieny (retinine lerne from to 79 ml/min). NSAIDs with short elimintion hlf-lives (e.g., dilofen, indomethin) should e voided for period of dys efore, the dy of, nd dys following dministrtion of ALIMTA.

11 In the sene of dt regrding potentil intertion etween ALIMTA nd NSAIDs with longer hlf-lives (e.g., meloxim, numetone), ptients tking these NSAIDs should interrupt dosing for t lest dys efore, the dy of, nd dys following ALIMTA dministrtion. If onomitnt dministrtion of NSAIDs is neessry, ptients should e monitored losely for toxiity, espeilly myelosuppression, renl, nd gstrointestinl toxiity. 7. Nephrotoxi Drugs ALIMTA is primrily eliminted unhnged renlly s result of glomerulr filtrtion nd tuulr seretion. Conomitnt dministrtion of nephrotoxi drugs ould result in delyed lerne of ALIMTA. Conomitnt dministrtion of sustnes tht re lso tuulrly sereted (e.g., proeneid) ould potentilly result in delyed lerne of ALIMTA USE IN SPECIFIC POPULATIONS Pregnny Tertogeni Effets Pregnny Ctegory D [see Wrnings nd Preutions (.)] Bsed on its mehnism of tion, ALIMTA n use fetl hrm when dministered to pregnnt womn. There re no dequte nd well ontrolled studies of ALIMTA in pregnnt women. Pemetrexed ws emryotoxi, fetotoxi, nd tertogeni in mie. In mie, repeted intrperitonel doses of pemetrexed when given during orgnogenesis used fetl mlformtions (inomplete ossifition of tlus nd skull one; out /8rd the reommended intrvenous humn dose on mg/m sis), nd left plte (/rd the reommended intrvenous humn dose on mg/m sis). Emryotoxiity ws hrterized y inresed emryo-fetl deths nd redued litter sizes. If ALIMTA is used during pregnny, or if the ptient eomes pregnnt while tking this drug, the ptient should e pprised of the potentil hzrd to the fetus. Women of hildering potentil should e dvised to use effetive ontreptive mesures to prevent pregnny during the tretment with ALIMTA. 8. Nursing Mothers It is not known whether ALIMTA or its metolites re exreted in humn milk. Beuse mny drugs re exreted in humn milk, nd euse of the potentil for serious dverse retions in nursing infnts from ALIMTA, deision should e mde to disontinue nursing or disontinue the drug, tking into ount the importne of the drug for the mother. 8. Peditri Use Effiy of ALIMTA in peditri ptients hs not een demonstrted. ALIMTA ws dministered s n intrvenous infusion over minutes on Dy of dy yle to peditri ptients with reurrent solid tumors in Phse study ( ptients) nd Phse study (7 ptients). All ptients reeived pretretment with vitmin B nd foli id supplementtion nd dexmethsone. The dose esltion 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 refrtory osteosrom, Ewing srom/peripherl PNET, rhdomyosrom, neurolstom, ependymom, medullolstom/suprtentoril PNET, or non-rinstem high grde gliom. No responses were oserved mong the 7 ptients in this Phse tril. The most ommon toxiities reported were hemtologil (leukopeni, neutropeni/grnuloytopeni, nemi, thromoytopeni, nd lymphopeni), liver funtion normlities (inresed ALT/AST), ftigue, nd nuse. The single dose phrmokinetis of ALIMTA dministered in doses rnging from to 8 mg/m were evluted in the Phse tril in ptients ( mles nd 9 femles) ged to 8 yers (verge ge yers). Pemetrexed exposure (AUC nd Cmx) ppered to inrese proportionlly with dose. The verge pemetrexed lerne (. L/h/m) nd hlf-life (. hours) in peditri ptients were omprle to vlues reported in dults. 8. Geritri Use ALIMTA is known to e sustntilly exreted y the kidney, nd the risk of dverse retions to this drug my e greter in ptients with impired renl funtion. Renl funtion monitoring is reommended with dministrtion of ALIMTA. No dose redutions other thn those reommended for ll ptients re neessry for ptients yers of ge or older [see Dosge nd Administrtion (.)]. Of,9 ptients (.% ) studied ross the five linil trils [see Clinil Studies (.,.,., nd.)], the effet of ALIMTA on survivl ws similr in ptients < ompred to yers of ge. There were no differenes in sfety with the exeption of the following Grde - dverse retions, whih were noted in t lest one of the five trils to e greter in ptients yers of ge nd older s ompred to younger ptients: nemi, ftigue, thromoytopeni, hypertension, nd neutropeni. 8. Ptients with Hepti Impirment There ws no effet of elevted AST, ALT, or totl iliruin on the phrmokinetis of pemetrexed. However, no forml studies hve een onduted to exmine the phrmokinetis of pemetrexed in ptients with hepti impirment [see Clinil Phrmology (.)]. 8.7 Ptients with Renl Impirment ALIMTA is known to e primrily exreted y the kidneys. Deresed renl funtion will result in redued lerne nd greter exposure (AUC) to ALIMTA ompred with ptients with norml renl funtion [see Dosge nd

12 Administrtion (.) nd Clinil Phrmology (.)]. Cispltin odministrtion with ALIMTA hs not een studied in ptients with moderte renl impirment. 8.8 Gender Of,9 ptients (Mle 7.%) studied ross the five registrtion studies for ALIMTA inditions [see Clinil Studies (.,.,., nd.)], the effet of ALIMTA on survivl ws similr in femle nd mle ptients. 8.9 Re Of,9 ptients (Cusin 78.%) studied ross the five registrtion studies for ALIMTA inditions [see Clinil Studies (.,.,., nd.)], the effet of ALIMTA on survivl ws similr in the Cusin nd noncusin ptients. OVERDOSAGE There hve een few ses of ALIMTA overdose. Reported toxiities inluded neutropeni, nemi, thromoytopeni, muositis, nd rsh. Antiipted omplitions of overdose inlude one mrrow suppression s mnifested y neutropeni, thromoytopeni, nd nemi. In ddition, infetion with or without fever, dirrhe, nd muositis my e seen. If n overdose ours, generl supportive mesures should e instituted s deemed neessry y the treting physiin. In linil trils, leuovorin ws permitted for CTC Grde leukopeni lsting dys, CTC Grde neutropeni lsting dys, nd immeditely for CTC Grde thromoytopeni, leeding ssoited with Grde thromoytopeni, or Grde or muositis. The following intrvenous doses nd shedules of leuovorin were reommended for intrvenous use: mg/m, intrvenously one, followed y leuovorin, mg/m, intrvenously every hours for 8 dys. The ility of ALIMTA to e dilyzed is unknown. DESCRIPTION Pemetrexed disodium hepthydrte hs the hemil nme L-Glutmi id, N-[-[-(-mino-,7-dihydro--oxoH-pyrrolo[,-d]pyrimidin--yl)ethyl]enzoyl]-, disodium slt, hepthydrte. It is white to lmost-white solid with moleulr formul of CH9NNO 7HO nd moleulr weight of The struturl formul is s follows: ALIMTA is supplied s sterile lyophilized powder for intrvenous infusion ville in single-dose vils. The produt is white to either light yellow or green-yellow lyophilized solid. Eh -mg or -mg vil of ALIMTA ontins pemetrexed disodium equivlent to mg pemetrexed nd mg mnnitol or mg pemetrexed nd mg mnnitol, respetively. Hydrohlori id nd/or sodium hydroxide my hve een dded to djust ph.. CLINICAL PHARMACOLOGY Mehnism of Ation ALIMTA, pemetrexed for injetion, is folte nlog metoli inhiitor tht exerts its tion y disrupting foltedependent metoli proesses essentil for ell replition. In vitro studies hve shown tht pemetrexed inhiits thymidylte synthse (TS), dihydrofolte redutse (DHFR), nd glyinmide rionuleotide formyltrnsferse (GARFT), whih re folte-dependent enzymes involved in the de novo iosynthesis of thymidine nd purine nuleotides. Pemetrexed is tken into ells y memrne rriers suh s the redued folte rrier nd memrne folte inding protein trnsport systems. One in the ell, pemetrexed is onverted to polyglutmte forms y the enzyme folylpolyglutmte synthetse. The polyglutmte forms re retined in ells nd re inhiitors of TS nd GARFT. Polyglutmtion is time- nd onentrtion-dependent proess tht ours in tumor ells nd, is thought to our to lesser extent, in norml tissues. Polyglutmted metolites re thought to hve n inresed intrellulr hlf-life resulting in prolonged drug tion in mlignnt ells.. Phrmodynmis Prelinil studies hve shown tht pemetrexed inhiits the in vitro growth of mesotheliom ell lines (MSTOH, NCI-H). Studies with the MSTO-H mesotheliom ell line showed synergisti effets when pemetrexed ws omined onurrently with ispltin. Asolute neutrophil ounts (ANC) following single-gent dministrtion of ALIMTA to ptients not reeiving foli id nd vitmin B supplementtion were hrterized using popultion phrmodynmi nlyses. Severity of hemtologi toxiity, s mesured y the depth of the ANC ndir, orreltes with the systemi exposure, or re under the

13 urve (AUC) of pemetrexed. It ws lso oserved tht lower ANC ndirs ourred in ptients with elevted seline ystthionine or homoysteine onentrtions. The levels of these sustnes n e redued y foli id nd vitmin B supplementtion. There is no umultive effet of pemetrexed exposure on ANC ndir over multiple tretment yles. Time to ANC ndir with pemetrexed systemi exposure (AUC), vried etween 8 to 9. dys over rnge of exposures from 8. to.8 mg hr/ml. Return to seline ANC ourred. to 7. dys fter the ndir over the sme rnge of exposures.. Phrmokinetis Asorption The phrmokinetis of ALIMTA dministered s single-gent in doses rnging from. to 88 mg/m infused over -minute period hve een evluted in ner ptients with vriety of solid tumors. Pemetrexed totl systemi exposure (AUC) nd mximum plsm onentrtion (Cmx) inrese proportionlly with dose. The phrmokinetis of pemetrexed do not hnge over multiple tretment yles. Distriution Pemetrexed hs stedy-stte volume of distriution of. liters. In vitro studies indite tht pemetrexed is pproximtely 8% ound to plsm proteins. Binding is not ffeted y degree of renl impirment. Metolism nd Exretion Pemetrexed is not metolized to n ppreile extent nd is primrily eliminted in the urine, with 7% to 9% of the dose reovered unhnged within the first hours following dministrtion. The lerne dereses, nd exposure (AUC) inreses, s renl funtion dereses. The totl systemi lerne of pemetrexed is 9.8 ml/min nd the elimintion hlf-life of pemetrexed is. hours in ptients with norml renl funtion (retinine lerne of 9 ml/min). The phrmokinetis of pemetrexed in speil popultions were exmined in out ptients in ontrolled nd single rm studies. In vitro studies indite tht pemetrexed is sustrte of OAT (orgni nion trnsporter ), trnsporter tht my ply role in tive seretion of pemetrexed. Effet of Age, Gender or Re No effet of ge on the phrmokinetis of pemetrexed ws oserved over rnge of to 8 yers. The phrmokinetis of pemetrexed were not different in mle nd femle ptients. The phrmokinetis of pemetrexed were similr in Cusins nd ptients of Afrin desent. Insuffiient dt re ville to ompre phrmokinetis for other ethni groups. Effet of Hepti Insuffiieny There ws no effet of elevted AST, ALT, or totl iliruin on the phrmokinetis of pemetrexed. However, studies of heptilly impired ptients hve not een onduted [see Dosge nd Administrtion (.) nd Use in Speifi Popultions (8.)]. Effet of Renl Insuffiieny Phrmokineti nlyses of pemetrexed inluded 7 ptients with redued renl funtion. Plsm lerne of pemetrexed dereses s renl funtion dereses, with resultnt inrese in systemi exposure. Ptients with retinine lernes of,, nd 8 ml/min hd %, %, nd % inreses, respetively in pemetrexed totl systemi exposure (AUC) ompred to ptients with retinine lerne of ml/min [see Wrnings nd Preutions (.) nd Dosge nd Administrtion (.)]. Effet of Third Spe Fluid The effet of third spe fluid, suh s pleurl effusion nd sites, on ALIMTA is not fully defined. A study of ALIMTA mg/m ws performed in solid tumor ptients with stle third spe fluid (All ut of the ptients inluded in study hd mild or moderte mounts of third spe fluid). Moderte pleurl effusion ws defined in the study s less thn / the wy up on one side with osuring of the entire hemidiphrgm. Moderte sites ws defined s tht detetle on physil exm. The pemetrexed plsm onentrtions in these ptients were omprle to those oserved in previous linil trils in ptients without third spe fluid olletions. Thus, dringe of mild or moderte third spe fluid olletion prior to ALIMTA tretment should e onsidered, ut is proly not neessry. The effet of severe third spe fluid on phrmokinetis is not known. Effet of Iuprofen Iuprofen doses of mg four times dy redue pemetrexed s lerne y out % (nd inrese AUC y %) in ptients with norml renl funtion. The effet of greter doses of iuprofen on pemetrexed phrmokinetis is unknown [see Drug Intertions (7.)]. Effet of Aspirin Aspirin, dministered in low to moderte doses ( mg every hours), does not ffet the phrmokinetis of pemetrexed. The effet of greter doses of spirin on pemetrexed phrmokinetis is unknown. Effet of Cispltin Cispltin does not ffet the phrmokinetis of pemetrexed nd the phrmokinetis of totl pltinum re unltered y pemetrexed. Effet of Vitmins

14 Codministrtion of orl foli id or intrmusulr vitmin B does not ffet the phrmokinetis of pemetrexed. Drugs Metolized y Cytohrome P Enzymes Results from in vitro studies with humn liver mirosomes predit tht pemetrexed would not use linilly signifint inhiition of metoli lerne of drugs metolized y CYPA, CYPD, CYPC9, nd CYPA.. NONCLINICAL TOXICOLOGY Crinogenesis, Mutgenesis, Impirment of Fertility No rinogeniity studies hve een onduted with pemetrexed. Pemetrexed ws lstogeni in the in vivo mironuleus ssy in mouse one mrrow ut ws not mutgeni in multiple in vitro tests (Ames ssy, CHO ell ssy). Pemetrexed dministered t i.v. doses of. mg/kg/dy or greter to mle mie (out / the reommended humn dose on mg/m sis) resulted in redued fertility, hypospermi, nd testiulr trophy.. CLINICAL STUDIES Non-Smll Cell Lung Cner (NSCLC) Comintion with Cispltin A multi-enter, rndomized, open-lel study in 7 hemonive ptients with Stge III/IV NSCLC ws onduted to ompre the overll survivl following tretment with ALIMTA in omintion with ispltin (AC) versus gemitine in omintion with ispltin (GC). ALIMTA ws dministered intrvenously over minutes t dose of mg/m with ispltin dministered intrvenously t dose of 7 mg/m fter ALIMTA dministrtion, on Dy of eh -dy yle. Gemitine ws dministered t dose of mg/m on Dy nd Dy 8, nd ispltin ws dministered intrvenously t dose of 7 mg/m fter dministrtion of gemitine, on Dy of eh -dy yle. Tretment ws dministered up to totl of yles, nd ptients in oth tretment rms reeived foli id, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.)]. Ptient demogrphis of the intent to tret (ITT) popultion re shown in Tle. The demogrphis nd disese hrteristis were well lned. Tle : First-Line Therpy: Summry of Ptient Chrteristis in Study of NSCLC Gemitine plus Cispltin ALIMTA plus Cispltin (AC) (GC) Ptient hrteristi (N=8) (N=8) Age (yrs) Medin (rnge). (8.8-8.). (.-79.) Gender Mle/Femle 7.%/9.8% 7.%/9.9% Origin Cusin 9 (77.%) 8 (78.8%) Hispni 7 (.%) (.7%) Asin (.9%) (.%) Afrin desent 8 (.%) 8 (.%) Stge t Entry III/IV.8%/7.%.%/7.7% Histology Nonsqumous NSCLC 8 (7.7%) (7.%) Adenorinom (.%) (7.%) Lrge ell 7 (8.8%) 77 (8.9%) Other (.%) (.9%) Squmous (8.%) 9 (.%),d ECOG PS /.%/.%.%/.% e Smoking History Ever/never smoker 8.%/.9% 8.9%/.% Inludes denorinom, lrge ell, nd other histologies exept those with squmous ell type. The sugroup of other represents ptients with primry dignosis of NSCLC whose disese did not lerly qulify s denorinom, squmous ell rinom, or lrge ell rinom. Estern Coopertive Onology Group Performne Sttus. d ECOG PS ws not reported for ll rndomized ptients. Perentges re representtive of N=8 for the ALIMTA plus ispltin rm, nd N=8 for the gemitine plus ispltin rm. e Smoking history ws olleted for 88% of rndomized ptients (N=77 for the ALIMTA plus ispltin rm nd N=79 for the gemitine plus ispltin rm).

15 Ptients reeived medin of yles of tretment in oth study rms. Ptients treted with ALIMTA plus ispltin reeived reltive dose intensity of 9.8% of the protool-speified ALIMTA dose intensity nd 9.% of the protoolspeified ispltin dose intensity. Ptients treted with gemitine plus ispltin reeived reltive dose intensity of 8.8% of the protool-speified gemitine dose intensity nd 9.% of the protool-speified ispltin dose intensity. The primry endpoint in this study ws overll survivl. The medin survivl time ws. months in the ALIMTA plus ispltin tretment rm nd. months in the gemitine plus ispltin rm, with n djusted hzrd rtio of.9. Tle : First-Line Therpy: Effiy in NSCLC ITT Popultion Gemitine plus Cispltin (N=8) Medin overll survivl (9% CI). mos (9.8-.). mos (9.-.9), Adjusted hzrd rtio (HR) (9% CI).9 (.8-.) Medin progression-free survivl (9% CI).8 mos (.-.). mos (.-.), Adjusted hzrd rtio (HR) (9% CI). (.9-.) Overll response rte (9% CI) 7.% (.-.).7% (.8-7.) Adjusted for gender, stge, sis of dignosis, nd performne sttus. A HR tht is less thn. indites tht survivl is etter in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn. indites survivl is etter in the GC rm thn in the AC rm. ALIMTA plus Cispltin (N=8) Figure : Kpln-Meier Curves for Overll Survivl ALIMTA plus Cispltin (AC) versus Gemitine plus Cispltin (GC) in NSCLC ITT Popultion. A pre-speified nlysis of the impt of NSCLC histology on overll survivl ws exmined. Clinilly relevnt differenes in survivl ording to histology were oserved nd re shown in Tle. This differene in tretment effet for ALIMTA sed on histology demonstrting lk of effiy in squmous ell histology ws lso oserved in the single-gent, seond-line study nd the mintenne study [see Clinil Studies (.,.)]. Tle : First-Line Therpy: Overll Survivl in NSCLC Histologi Sugroups Medin Overll Survivl in Months Adjusted Undjusted (9% CI) Hzrd Rtio Hzrd Rtio Histology Sugroup,,, (HR) (HR) ALIMTA plus Cispltin Gemitine plus (9% CI) (9% CI) Cispltin d Nonsqumous NSCLC. N=8. N=.8.8 (N=) (.-.) (9.-.9) (.7-.9) (.7-.9) Adenorinom. N=.9 N=.8.8 (N=87) (.7-.) (.-.9) (.7-.98) (.7-.99)

16 Lrge Cell. N=7.7 N= (N=) (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.. (N=7) (8.-.) (9.-.) (.99-.) (.-.) A HR tht is less thn. indites tht survivl is etter in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn. indites survivl is etter in the GC rm thn in the AC rm. Undjusted for multiple omprisons. HRs djusted for ECOG PS, gender, disese stge, nd sis for pthologil dignosis (histopthologil/ytopthologil). d Inludes denorinom, lrge ell, nd other histologies exept those with squmous ell type. e The sugroup of other represents ptients with primry dignosis of NSCLC whose disese did not lerly qulify s denorinom, squmous ell rinom, or lrge ell rinom. Figure : Kpln-Meier Curves for Overll Survivl ALIMTA plus Cispltin (AC) versus Gemitine plus Cispltin (GC) in NSCLC Nonsqumous NSCLC nd Squmous Cell NSCLC.. Non-Smll Cell Lung Cner Mintenne ALIMTA Mintenne Following Non-ALIMTA Contining Pltinum-Bsed, Indution Therpy A multi-enter, rndomized, doule-lind, pleo-ontrolled study ws onduted in ptients with Stge III/IV NSCLC who did not progress fter four yles of pltinum-sed hemotherpy. Ptients who did not progress were rndomized : to reeive ALIMTA or pleo immeditely following pltinum-sed hemotherpy. Of the rndomized ptients, 7.% versus.7% hieved omplete or prtil response to indution therpy nd.9% versus 7.% hd stle disese fter indution therpy in the ALIMTA nd pleo rms, respetively. ALIMTA ws dministered intrvenously over minutes t dose of mg/m on Dy of eh -dy yle, until disese progression. Ptients in oth study rms reeived foli id, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.)]. The study ws designed to demonstrte superior progression-free survivl nd overll survivl of ALIMTA over pleo. Progression-free survivl (PFS) ws ssessed y independent review. Ptient hrteristis of the intent to tret (ITT) popultion re shown in Tle. The demogrphis nd seline disese hrteristis were well lned etween study rms. Tle : Mintenne Therpy Following Pltinum-Bsed Indution Therpy: Summry of Ptient Chrteristis in Study of NSCLC ALIMTA Pleo Ptient hrteristi (N=) (N=) Age (yrs) Medin (rnge). (.-8.). (.-78.) Gender Mle/Femle 7.%/7.% 7.%/7.% Ethni Origin Cusin 79 (.%) 9 (7.%)

17 7 Est Asin (.%) (.%) Other 8 (.%) (.%) Stge t Entry III/IV 8.%/8.%.%/78.8% Histology (%) Nonsqumous NSCLC (7.7%) (7.%) Adenorinom (.%) (7.7%) Lrge ell (.%) (.%) Other 9 (.%) (8.%) Squmous (.%) (9.7%) ECOG PSd /.%/9.9% 8.%/.7% Smoking Historye Ever/never smoker 7.%/.9% 7.%/8.% Time from strt of indution therpy to study rndomiztion (months) Medin (rnge). (.-.8).9 (.7-.) Stge t Entry ws not reported for ll rndomized ptients. Perentges re representtive of N= for the ALIMTA rm nd N= for the pleo rm. Inludes ptients with denorinom, lrge ell, nd other histologi dignoses. The sugroup of Other represents ptients with primry dignosis of NSCLC whose disese did not lerly qulify s denorinom, lrge ell rinom, or squmous ell rinom. d Estern Coopertive Onology Group Performne Sttus (ECOG PS) ws not reported for ll rndomized ptients. Perentges re representtive of N=9 for the ALIMTA rm, nd N= for the pleo rm. e Smoking history ws not reported for ll rndomized ptients. Perentges re representtive of N=7 for the ALIMTA rm nd N= for the pleo rm. Ptients reeived medin of yles of ALIMTA nd. yles of pleo. Ptients rndomized to ALIMTA reeived reltive dose intensity of 9.7%. A totl of ptients (8.%) ompleted yles nd totl of 98 ptients (.%) ompleted yles of tretment with ALIMTA. In the overll study popultion, ALIMTA ws sttistilly superior to pleo in terms of overll survivl (OS) (medin. months versus. months, HR=.79 (9% CI:.-.9), p-vlue=.) nd PFS (medin. months versus. months, HR=. (9% CI:.9-.7), p-vlue<.). A differene in tretment outomes ws oserved ording to histologi lssifition. For the popultion of ptients with nonsqumous NSCLC, ALIMTA ws superior to pleo for OS (medin. months versus. months, HR=.7 (9% CI:.-.88)) nd PFS (medin. months versus.8 months, HR=.7 (9% CI:.7-.)). For the popultion of ptients with squmous NSCLC, ALIMTA did not improve OS ompred to pleo (medin 9.9 months versus.8 months, HR=.7 (9% CI:.77-.)) or PFS (medin. months versus. months, HR=. (9% CI:.7-.9)). This differene in tretment effet for ALIMTA sed on histology demonstrting lk of enefit in squmous ell histology ws lso oserved in the first-line nd seond-line studies. [see Clinil Studies (.,.)] Effiy results for the overll ptient popultion re presented in Tle nd Figure, nd effiy results y pre-speified histologi sugroups re presented in Tle nd Figure, elow. Tle : Mintenne Therpy Following Pltinum-Bsed Indution Therpy: Effiy of ALIMTA versus Pleo in NSCLC ITT Popultion ALIMTA Pleo, Effiy Prmeter (N=) (N=) Medin overll survivl (9% CI). mos (.9-.9). mos (8.7-.) Hzrd rtio (HR) (9% CI).79 (.-.9) p-vlue p=. Medin progression-free survivl (9% CI). mos (.-.). mos (.-.8) Hzrd rtio (HR) (9% CI). (.9-.7) p-vlue p<. PFS nd OS were lulted from time of rndomiztion, fter ompletion of yles of indution pltinum-sed hemotherpy. Vlues for PFS given sed on independent review (ALIMTA N=87, Pleo N=9). Undjusted hzrd rtios re provided. A HR <. indites tht the result is etter in the ALIMTA rm thn in the pleo rm.

18 8 Tle : Mintenne Therpy Following Pltinum-Bsed Indution Therpy: Effiy in NSCLC y Histologi Sugroups Overll Survivl Progression-Free Survivl ALIMTA Pleo ALIMTA Pleo Medin (months) Medin (months) Medin (months) Medin (months) HR (9% CI) HR (9% CI) Nonsqumous NSCLC d....8 N=8.7 (.-.88).7 (.7-.) Adenorinom N=8.7 (.-.9). (.8-.8) Lrge ell rinom N=.98 (.-.). (.-.9) Other e N=. (.-.9). (.8-.8) Squmous ell N=8.7 (.77-.). (.7-.9) PFS nd OS were lulted from time of rndomiztion, fter ompletion of yles of indution pltinum-sed hemotherpy. All results undjusted for multiple omprisons. d e Vlues for PFS re given sed on independent review (ALIMTA N=87, Pleo N=9). Undjusted hzrd rtios re provided. A HR <. indites tht the result is etter in the ALIMTA rm thn in the pleo rm. A HR >. indites tht the result is etter in the pleo rm thn in the ALIMTA rm. Inludes ptients with denorinom, lrge ell rinom, nd other histology. The sugroup of Other represents ptients with primry dignosis of NSCLC whose disese did not lerly qulify s denorinom, lrge ell rinom, or squmous ell rinom. Figure : Kpln-Meier Curve for Overll Survivl ALIMTA (A) versus Pleo (P) in NSCLC ITT Popultion.

19 9 Figure : Kpln-Meier Curves for Overll Survivl ALIMTA versus Pleo in NSCLC Nonsqumous NSCLC nd Squmous Cell NSCLC. Continution of ALIMTA s Mintenne Following ALIMTA Plus Pltinum Indution Therpy A multi-enter, rndomized, doule-lind, pleo-ontrolled study ws onduted to evlute ontinution of ALIMTA in ptients with Stge III/IV nonsqumous NSCLC. Ptients ompleting indution tretment of four yles of ALIMTA plus ispltin with stle disese or etter nd PS / were rndomized (:) to mintenne tretment with ALIMTA or pleo. Rndomiztion ws strtified y response to indution (omplete response (CR)/prtil response (PR) versus stle disese (SD)), disese stge (III versus IV), nd ECOG performne sttus ( versus ). ALIMTA ws dministered intrvenously over minutes t dose of mg/m on Dy of eh -dy yle nd ontinued until disese progression. Ptients in oth study rms reeived foli id, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.)]. The min effiy outome ws investigtor-ssessed progression-free survivl. A totl of 9 ptients were rndomized; ll ompleted four yles of ALIMTA nd ispltin indution prior to rndomiztion. Of the rndomized ptients, % versus % hieved omplete or prtil response to indution therpy nd % versus % hd stle disese fter indution tretment in the ALIMTA or the pleo rms respetively. Ptient demogrphis of the intent to tret (ITT) popultion re shown in Tle. Tle : ALIMTA s Mintenne Therpy Following ALIMTA Plus Cispltin Indution Therpy: Summry of Ptient Chrteristis in Study of Nonsqumous NSCLC ALIMTA Pleo Ptient hrteristi (N=9) (N=8) Age (yrs) Medin.. Rnge Gender (%) Mle (%) (%) Femle 8 (%) 8 (8%) Ethni Origin (%) Cusin 9 (9%) 7 (9%) Asin (.%) 8 (.%) Afrin (.%) (.%) Stge t Entry III (9%) 8 (%) IV 8 (9%) (9%) Histology (%) Nonsqumous NSCLC Adenorinom (8%) (89%) Lrge ell (7%) (7%) Other (7%) 7 (.9%) ECOG PS (%) (%) (%) (8%) 8 (%) Smoking History Ever 7 (7%) (8%) Never smoker 8 (%) (9%)

20 Histologil or ytologil dignosis of NSCLC defined s other thn predominntly squmous ell histology (squmous ell nd/or mixed smll ell, non-smll ell histology were not permitted on this study). The sutegory of Other represents ptients with primry dignosis of NSCLC whose disese did not lerly qulify s denorinom or lrge-ell rinom. Smoking history ws not reported for ll rndomized ptients. Ptients reeived medin of four yles of ALIMTA mintenne or pleo. The perentges of ptients tht reeived post-study tretment were similr (% in the ALIMTA rm nd 7% in the pleo rm). The tril showed sttistilly signifint improvement in progression-free survivl nd in overll survivl for ptients rndomized to ALIMTA mintenne. Effiy results re presented in Tle 7 nd Figure. Tle 7: ALIMTA Mintenne Therpy Following ALIMTA Plus Cispltin Indution Therpy: Effiy of ALIMTA versus Pleo in Nonsqumous NSCLC Effiy Prmeter, ALIMTA Pleo (N=9) (N=8) Medin overll survivl (9% CI).9 mos (.8-.). mos (.-.) Hzrd rtio (HR) (9% CI).78 (.-.9) p-vlue p=. Medin progression-free survivl (9% CI). mos (.-.).8 mos (.-.) Hzrd rtio (HR) (9% CI). (.9-.79) p-vlue p<. PFS nd OS were lulted from time of rndomiztion, fter ompletion of yles of ALIMTA plus ispltin indution therpy. Vlues for PFS given sed on investigtor ssessment. A hzrd rtio of less thn indites tht the mintenne tretment with pemetrexed is ssoited with lower risk of progression or deth ompred to tretment with pleo. Figure : Kpln-Meier Curves for Overll Survivl ALIMTA versus Pleo in Nonsqumous NSCLC Following ALIMTA Plus Cispltin Indution Therpy.